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5 Vaccinations Adults Need Beyond COVID and Flu
Many adults are complacent about vaccinations, believing that annual COVID and flu shots aside, they had all the immunizations they need as children and teens. But adults need vaccines as well, especially if they have missed earlier doses. And older and health-compromised adults, in particular, can benefit from newer vaccines that were not part of the childhood schedule.
“The question is whether adults had the vaccinations they need in the first place,” Sandra Adamson Fryhofer, MD, an internist in Atlanta and the American Medical Association’s liaison to the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention, said in an interview. “Many do not even have reliable records of vaccination.”
Primary care physicians are ideally positioned to get adult patients to update their vaccination status on older vaccines and obtain newer ones as needed. “ACIP recommendations for adult vaccines are getting longer and more complicated and the way they’re administered is more complex, too, in that they’re not all given in the primary care office but sometimes in pharmacies,” Dr. Fryhofer said.
Not all adult patients want to update their vaccinations. “Vaccine hesitancy among many adults is accelerated by the several new vaccines that have been recommended in recent years,” Lauren Block, MD, MPH, an internist at Northwell Health and assistant professor in the Institute of Health System Science at the Feinstein Institutes for Medical Research in metropolitan New York City, said in an interview.
Physicians are rightly concerned about the lagging rates of adult vaccination, Dr. Block said. “Given the prevalence of conditions like pneumonia and shingles and the morbidity associated with them, healthcare providers should take every opportunity to discuss vaccination with patients, from well visits to hospital visits,” Dr. Block added. 
She pointed to several obstacles to broader uptake, including product shortages, financial barriers, and, increasingly, the negative vocal messaging from media outlets and social media.
Current Recommendations
The main vaccines recommended for adults, besides flu and COVID shots, are for respiratory syncytial virus (RVS); shingles; pneumococcal disease; measles, mumps, and rubella (MMR); and tetanus, diphtheria, and pertussis (Tdap). Less commonly, booster vaccines for MM, and hepatitis are recommended when titers are proven to be low.
ACIP’s updated 2024 Adult Immunization Schedule can be downloaded from the website of the CDC.
The newest additions to the schedule include RSV vaccines, the mpox vaccine (Jynneos), a new MenACWY-MenB combo vaccine (Penbraya), and the new 2023-2024 formulation of updated COVID vaccines (both mRNA and protein-based adjuvanted versions).
1. Respiratory Syncytial Virus Vaccines
There are two licensed RSV vaccines, Arexvy and Abrysvo. The CDC schedule recommends a single-dose RSV vaccine for adults age 60 years and older, especially those at high risk of contracting the virus — but after shared decision-making based on a discussion of the risk-harm balance since this vaccine carries a small increased chance of developing the neurological symptoms of Guillain-Barré syndrome.
Chronic health conditions associated with a higher risk of severe RVS include cardiopulmonary disease, diabetes, and kidney, liver, and hematologic disorders, as well as compromised immunity, older age, and frailty.
2. Shingles Vaccines
This painful disease carries the potential complication of postherpetic neuralgia (PHN), which leads to long-term nerve pain in 10%-18% of patients, especially those over age 40. ACIP recommends two doses of the recombinant zoster vaccine (Shingrix) for individuals 50 years and older. Those 19 years and older with weakened immune systems due to disease or medical treatments should get two doses of the recombinant vaccine, as they have a higher risk of getting shingles and its complications, including neurological problems and skin and eye infections.
3 Pneumococcal Vaccines
There are three approved pneumococcal vaccines: PCV15 (Vaxneuvance), PCV20 (Prevnar20), and PPSV23 (Pneumovax23).
“The pneumococcal vaccine schedule is the most complicated one as higher-valent products continue to become available,” Dr. Fryhofer said.
The two types are pneumococcal conjugate vaccines (PCVs, specifically PCV15 and PCV20) and the pneumococcal polysaccharide vaccine (PPSV23). “While PPSV23 covers 23 strains, it doesn’t give the long-term immunity of the conjugate vaccine,” said Dr. Fryhofer. “A patient may have completed their vaccination with the polysaccharide vaccine but 5 years out may no longer be protected. So we offer the option of getting a dose of PCV20 to round out the protection and confer greater immune memory.”
The ACIP schedule recommends immunization against the Streptococcus pneumoniae pathogen for all older and all at-risk adults. Routine administration of PCV15 or PCV20 is advised for those 65 years or older who have never received any pneumococcal conjugate vaccine or whose previous vaccination history is unknown. If PCV15 is used, it should be followed by PPSV23. Those 65 years or older should get PPSV23 even if they already had one or more doses of pneumococcal vaccine before turning 65.
Further vaccination is recommended for younger at-risk adults aged 19-64 years who have received both PCV13 and PPSV23 but have incomplete vaccination status. These individuals are advised to complete their pneumococcal series by receiving either a single dose of PCV20 at an interval of at least 5 years after the last pneumococcal vaccine dose or more than one dose of PPSV23.
See Pneumococcal Vaccination: Summary of Who and When to Vaccinate for CDC guidance on vaccination options for adults who have previously received a pneumococcal conjugate vaccine. Or, to sort out quickly who gets what and when based on their age, concurrent conditions, and vaccination history, the CDC offers a type-in app called the PneumoRecs VaxAdvisor.
4. Measles, Mumps, and Rubella, and Varicella Vaccines
The two approved MMR vaccines are M-M-R II and PRIORIX. A third vaccine, ProQuad, adds varicella.
Adults lacking presumptive evidence of immunity should get at least one dose of the MMR combination vaccine.
Those born before 1957 are deemed to be immune, Dr. Fryhofer noted.
Two doses are recommended for adults entering high-risk settings for measles or mumps transmission such as healthcare personnel, students away at college, and international travelers. The two doses should be separated by at least 28 days. It’s no secret that measles, though preventable, is making a comeback, with 146 reported cases (48 in adults) across 21 states as of May 31 — most linked to international travel.
Women who plan to get pregnant should be vaccinated before but not during each pregnancy. (The vaccine is safe during lactation.) And those of childbearing age with no presumptive evidence of immunity are advised to get at least one dose of the MMR vaccine.
5. Tetanus, Diphtheria, and Pertussis Vaccine
Adults with no previous Tdap vaccination should receive a single dose of Adacel or Boostrix followed by a booster every 10 years. Boostrix is recommended for adults over 64 years.
During every pregnancy, women should have a single dose of Tdap, preferably in gestational weeks 27 through 36.
As to the immediate postpartum period, Tdap is recommended only for mothers who did not receive it during their current pregnancy and never received a prior dose. If a woman did not receive Tdap during her current pregnancy but did receive a prior dose of Tdap, she does not need Tdap postpartum.
The Challenges
According to Dr. Fryhofer, widespread disinformation about the risks of immunization against vaccine-preventable diseases has brought us to a flashpoint. “It’s now more important than ever to keep telling patients that vaccination is one of the most effective tools for preventing individual illness and protecting public health.”
She recommends that doctors follow the National Institutes of Health’s AIMS method to broach the subject of adult vaccination and increase participation in an inquiring, reassuring, and low-pressure way. Standing for Announce, Inquire, Mirror, and Secure, AIMS structures a nonjudgmental, patient-friendly conversation around immunization to elicit and acknowledge the reasons for hesitancy while explaining the safety and efficacy of vaccines.
Dr. Fryhofer frequently uses AIMS to bring inoculation-averse patients around. “Keep the conversation open with reluctant patients but leave them where they are. They need to see you as a reliable source and nonjudgmental source of information,” she said.
Dr. Block recommends outlining the diseases that have been eliminated through vaccines, from polio to measles, as well as the dangers of vaccine refusal, as indicated by recent outbreaks of vaccine-preventable diseases in areas with low immunization rates. “This approach highlights the opportunity we all have to get vaccinated to protect ourselves and our communities,” she said.
In Dr. Fryhofer’s view, the situation is urgent and doctors need to be proactive. “We’re now at a public-health tipping point where we may see a sliding back and a reversing of many years of progress.”
Dr. Fryhofer and Dr. Block disclosed no competing interests relevant to their comments.
Many adults are complacent about vaccinations, believing that annual COVID and flu shots aside, they had all the immunizations they need as children and teens. But adults need vaccines as well, especially if they have missed earlier doses. And older and health-compromised adults, in particular, can benefit from newer vaccines that were not part of the childhood schedule.
“The question is whether adults had the vaccinations they need in the first place,” Sandra Adamson Fryhofer, MD, an internist in Atlanta and the American Medical Association’s liaison to the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention, said in an interview. “Many do not even have reliable records of vaccination.”
Primary care physicians are ideally positioned to get adult patients to update their vaccination status on older vaccines and obtain newer ones as needed. “ACIP recommendations for adult vaccines are getting longer and more complicated and the way they’re administered is more complex, too, in that they’re not all given in the primary care office but sometimes in pharmacies,” Dr. Fryhofer said.
Not all adult patients want to update their vaccinations. “Vaccine hesitancy among many adults is accelerated by the several new vaccines that have been recommended in recent years,” Lauren Block, MD, MPH, an internist at Northwell Health and assistant professor in the Institute of Health System Science at the Feinstein Institutes for Medical Research in metropolitan New York City, said in an interview.
Physicians are rightly concerned about the lagging rates of adult vaccination, Dr. Block said. “Given the prevalence of conditions like pneumonia and shingles and the morbidity associated with them, healthcare providers should take every opportunity to discuss vaccination with patients, from well visits to hospital visits,” Dr. Block added.
She pointed to several obstacles to broader uptake, including product shortages, financial barriers, and, increasingly, the negative vocal messaging from media outlets and social media.
Current Recommendations
The main vaccines recommended for adults, besides flu and COVID shots, are for respiratory syncytial virus (RVS); shingles; pneumococcal disease; measles, mumps, and rubella (MMR); and tetanus, diphtheria, and pertussis (Tdap). Less commonly, booster vaccines for MM, and hepatitis are recommended when titers are proven to be low.
ACIP’s updated 2024 Adult Immunization Schedule can be downloaded from the website of the CDC.
The newest additions to the schedule include RSV vaccines, the mpox vaccine (Jynneos), a new MenACWY-MenB combo vaccine (Penbraya), and the new 2023-2024 formulation of updated COVID vaccines (both mRNA and protein-based adjuvanted versions).
1. Respiratory Syncytial Virus Vaccines
There are two licensed RSV vaccines, Arexvy and Abrysvo. The CDC schedule recommends a single-dose RSV vaccine for adults age 60 years and older, especially those at high risk of contracting the virus — but after shared decision-making based on a discussion of the risk-harm balance since this vaccine carries a small increased chance of developing the neurological symptoms of Guillain-Barré syndrome.
Chronic health conditions associated with a higher risk of severe RVS include cardiopulmonary disease, diabetes, and kidney, liver, and hematologic disorders, as well as compromised immunity, older age, and frailty.
2. Shingles Vaccines
This painful disease carries the potential complication of postherpetic neuralgia (PHN), which leads to long-term nerve pain in 10%-18% of patients, especially those over age 40. ACIP recommends two doses of the recombinant zoster vaccine (Shingrix) for individuals 50 years and older. Those 19 years and older with weakened immune systems due to disease or medical treatments should get two doses of the recombinant vaccine, as they have a higher risk of getting shingles and its complications, including neurological problems and skin and eye infections.
3 Pneumococcal Vaccines
There are three approved pneumococcal vaccines: PCV15 (Vaxneuvance), PCV20 (Prevnar20), and PPSV23 (Pneumovax23).
“The pneumococcal vaccine schedule is the most complicated one as higher-valent products continue to become available,” Dr. Fryhofer said.
The two types are pneumococcal conjugate vaccines (PCVs, specifically PCV15 and PCV20) and the pneumococcal polysaccharide vaccine (PPSV23). “While PPSV23 covers 23 strains, it doesn’t give the long-term immunity of the conjugate vaccine,” said Dr. Fryhofer. “A patient may have completed their vaccination with the polysaccharide vaccine but 5 years out may no longer be protected. So we offer the option of getting a dose of PCV20 to round out the protection and confer greater immune memory.”
The ACIP schedule recommends immunization against the Streptococcus pneumoniae pathogen for all older and all at-risk adults. Routine administration of PCV15 or PCV20 is advised for those 65 years or older who have never received any pneumococcal conjugate vaccine or whose previous vaccination history is unknown. If PCV15 is used, it should be followed by PPSV23. Those 65 years or older should get PPSV23 even if they already had one or more doses of pneumococcal vaccine before turning 65.
Further vaccination is recommended for younger at-risk adults aged 19-64 years who have received both PCV13 and PPSV23 but have incomplete vaccination status. These individuals are advised to complete their pneumococcal series by receiving either a single dose of PCV20 at an interval of at least 5 years after the last pneumococcal vaccine dose or more than one dose of PPSV23.
See Pneumococcal Vaccination: Summary of Who and When to Vaccinate for CDC guidance on vaccination options for adults who have previously received a pneumococcal conjugate vaccine. Or, to sort out quickly who gets what and when based on their age, concurrent conditions, and vaccination history, the CDC offers a type-in app called the PneumoRecs VaxAdvisor.
4. Measles, Mumps, and Rubella, and Varicella Vaccines
The two approved MMR vaccines are M-M-R II and PRIORIX. A third vaccine, ProQuad, adds varicella.
Adults lacking presumptive evidence of immunity should get at least one dose of the MMR combination vaccine.
Those born before 1957 are deemed to be immune, Dr. Fryhofer noted.
Two doses are recommended for adults entering high-risk settings for measles or mumps transmission such as healthcare personnel, students away at college, and international travelers. The two doses should be separated by at least 28 days. It’s no secret that measles, though preventable, is making a comeback, with 146 reported cases (48 in adults) across 21 states as of May 31 — most linked to international travel.
Women who plan to get pregnant should be vaccinated before but not during each pregnancy. (The vaccine is safe during lactation.) And those of childbearing age with no presumptive evidence of immunity are advised to get at least one dose of the MMR vaccine.
5. Tetanus, Diphtheria, and Pertussis Vaccine
Adults with no previous Tdap vaccination should receive a single dose of Adacel or Boostrix followed by a booster every 10 years. Boostrix is recommended for adults over 64 years.
During every pregnancy, women should have a single dose of Tdap, preferably in gestational weeks 27 through 36.
As to the immediate postpartum period, Tdap is recommended only for mothers who did not receive it during their current pregnancy and never received a prior dose. If a woman did not receive Tdap during her current pregnancy but did receive a prior dose of Tdap, she does not need Tdap postpartum.
The Challenges
According to Dr. Fryhofer, widespread disinformation about the risks of immunization against vaccine-preventable diseases has brought us to a flashpoint. “It’s now more important than ever to keep telling patients that vaccination is one of the most effective tools for preventing individual illness and protecting public health.”
She recommends that doctors follow the National Institutes of Health’s AIMS method to broach the subject of adult vaccination and increase participation in an inquiring, reassuring, and low-pressure way. Standing for Announce, Inquire, Mirror, and Secure, AIMS structures a nonjudgmental, patient-friendly conversation around immunization to elicit and acknowledge the reasons for hesitancy while explaining the safety and efficacy of vaccines.
Dr. Fryhofer frequently uses AIMS to bring inoculation-averse patients around. “Keep the conversation open with reluctant patients but leave them where they are. They need to see you as a reliable source and nonjudgmental source of information,” she said.
Dr. Block recommends outlining the diseases that have been eliminated through vaccines, from polio to measles, as well as the dangers of vaccine refusal, as indicated by recent outbreaks of vaccine-preventable diseases in areas with low immunization rates. “This approach highlights the opportunity we all have to get vaccinated to protect ourselves and our communities,” she said.
In Dr. Fryhofer’s view, the situation is urgent and doctors need to be proactive. “We’re now at a public-health tipping point where we may see a sliding back and a reversing of many years of progress.”
Dr. Fryhofer and Dr. Block disclosed no competing interests relevant to their comments.
Many adults are complacent about vaccinations, believing that annual COVID and flu shots aside, they had all the immunizations they need as children and teens. But adults need vaccines as well, especially if they have missed earlier doses. And older and health-compromised adults, in particular, can benefit from newer vaccines that were not part of the childhood schedule.
“The question is whether adults had the vaccinations they need in the first place,” Sandra Adamson Fryhofer, MD, an internist in Atlanta and the American Medical Association’s liaison to the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention, said in an interview. “Many do not even have reliable records of vaccination.”
Primary care physicians are ideally positioned to get adult patients to update their vaccination status on older vaccines and obtain newer ones as needed. “ACIP recommendations for adult vaccines are getting longer and more complicated and the way they’re administered is more complex, too, in that they’re not all given in the primary care office but sometimes in pharmacies,” Dr. Fryhofer said.
Not all adult patients want to update their vaccinations. “Vaccine hesitancy among many adults is accelerated by the several new vaccines that have been recommended in recent years,” Lauren Block, MD, MPH, an internist at Northwell Health and assistant professor in the Institute of Health System Science at the Feinstein Institutes for Medical Research in metropolitan New York City, said in an interview.
Physicians are rightly concerned about the lagging rates of adult vaccination, Dr. Block said. “Given the prevalence of conditions like pneumonia and shingles and the morbidity associated with them, healthcare providers should take every opportunity to discuss vaccination with patients, from well visits to hospital visits,” Dr. Block added.
She pointed to several obstacles to broader uptake, including product shortages, financial barriers, and, increasingly, the negative vocal messaging from media outlets and social media.
Current Recommendations
The main vaccines recommended for adults, besides flu and COVID shots, are for respiratory syncytial virus (RVS); shingles; pneumococcal disease; measles, mumps, and rubella (MMR); and tetanus, diphtheria, and pertussis (Tdap). Less commonly, booster vaccines for MM, and hepatitis are recommended when titers are proven to be low.
ACIP’s updated 2024 Adult Immunization Schedule can be downloaded from the website of the CDC.
The newest additions to the schedule include RSV vaccines, the mpox vaccine (Jynneos), a new MenACWY-MenB combo vaccine (Penbraya), and the new 2023-2024 formulation of updated COVID vaccines (both mRNA and protein-based adjuvanted versions).
1. Respiratory Syncytial Virus Vaccines
There are two licensed RSV vaccines, Arexvy and Abrysvo. The CDC schedule recommends a single-dose RSV vaccine for adults age 60 years and older, especially those at high risk of contracting the virus — but after shared decision-making based on a discussion of the risk-harm balance since this vaccine carries a small increased chance of developing the neurological symptoms of Guillain-Barré syndrome.
Chronic health conditions associated with a higher risk of severe RVS include cardiopulmonary disease, diabetes, and kidney, liver, and hematologic disorders, as well as compromised immunity, older age, and frailty.
2. Shingles Vaccines
This painful disease carries the potential complication of postherpetic neuralgia (PHN), which leads to long-term nerve pain in 10%-18% of patients, especially those over age 40. ACIP recommends two doses of the recombinant zoster vaccine (Shingrix) for individuals 50 years and older. Those 19 years and older with weakened immune systems due to disease or medical treatments should get two doses of the recombinant vaccine, as they have a higher risk of getting shingles and its complications, including neurological problems and skin and eye infections.
3 Pneumococcal Vaccines
There are three approved pneumococcal vaccines: PCV15 (Vaxneuvance), PCV20 (Prevnar20), and PPSV23 (Pneumovax23).
“The pneumococcal vaccine schedule is the most complicated one as higher-valent products continue to become available,” Dr. Fryhofer said.
The two types are pneumococcal conjugate vaccines (PCVs, specifically PCV15 and PCV20) and the pneumococcal polysaccharide vaccine (PPSV23). “While PPSV23 covers 23 strains, it doesn’t give the long-term immunity of the conjugate vaccine,” said Dr. Fryhofer. “A patient may have completed their vaccination with the polysaccharide vaccine but 5 years out may no longer be protected. So we offer the option of getting a dose of PCV20 to round out the protection and confer greater immune memory.”
The ACIP schedule recommends immunization against the Streptococcus pneumoniae pathogen for all older and all at-risk adults. Routine administration of PCV15 or PCV20 is advised for those 65 years or older who have never received any pneumococcal conjugate vaccine or whose previous vaccination history is unknown. If PCV15 is used, it should be followed by PPSV23. Those 65 years or older should get PPSV23 even if they already had one or more doses of pneumococcal vaccine before turning 65.
Further vaccination is recommended for younger at-risk adults aged 19-64 years who have received both PCV13 and PPSV23 but have incomplete vaccination status. These individuals are advised to complete their pneumococcal series by receiving either a single dose of PCV20 at an interval of at least 5 years after the last pneumococcal vaccine dose or more than one dose of PPSV23.
See Pneumococcal Vaccination: Summary of Who and When to Vaccinate for CDC guidance on vaccination options for adults who have previously received a pneumococcal conjugate vaccine. Or, to sort out quickly who gets what and when based on their age, concurrent conditions, and vaccination history, the CDC offers a type-in app called the PneumoRecs VaxAdvisor.
4. Measles, Mumps, and Rubella, and Varicella Vaccines
The two approved MMR vaccines are M-M-R II and PRIORIX. A third vaccine, ProQuad, adds varicella.
Adults lacking presumptive evidence of immunity should get at least one dose of the MMR combination vaccine.
Those born before 1957 are deemed to be immune, Dr. Fryhofer noted.
Two doses are recommended for adults entering high-risk settings for measles or mumps transmission such as healthcare personnel, students away at college, and international travelers. The two doses should be separated by at least 28 days. It’s no secret that measles, though preventable, is making a comeback, with 146 reported cases (48 in adults) across 21 states as of May 31 — most linked to international travel.
Women who plan to get pregnant should be vaccinated before but not during each pregnancy. (The vaccine is safe during lactation.) And those of childbearing age with no presumptive evidence of immunity are advised to get at least one dose of the MMR vaccine.
5. Tetanus, Diphtheria, and Pertussis Vaccine
Adults with no previous Tdap vaccination should receive a single dose of Adacel or Boostrix followed by a booster every 10 years. Boostrix is recommended for adults over 64 years.
During every pregnancy, women should have a single dose of Tdap, preferably in gestational weeks 27 through 36.
As to the immediate postpartum period, Tdap is recommended only for mothers who did not receive it during their current pregnancy and never received a prior dose. If a woman did not receive Tdap during her current pregnancy but did receive a prior dose of Tdap, she does not need Tdap postpartum.
The Challenges
According to Dr. Fryhofer, widespread disinformation about the risks of immunization against vaccine-preventable diseases has brought us to a flashpoint. “It’s now more important than ever to keep telling patients that vaccination is one of the most effective tools for preventing individual illness and protecting public health.”
She recommends that doctors follow the National Institutes of Health’s AIMS method to broach the subject of adult vaccination and increase participation in an inquiring, reassuring, and low-pressure way. Standing for Announce, Inquire, Mirror, and Secure, AIMS structures a nonjudgmental, patient-friendly conversation around immunization to elicit and acknowledge the reasons for hesitancy while explaining the safety and efficacy of vaccines.
Dr. Fryhofer frequently uses AIMS to bring inoculation-averse patients around. “Keep the conversation open with reluctant patients but leave them where they are. They need to see you as a reliable source and nonjudgmental source of information,” she said.
Dr. Block recommends outlining the diseases that have been eliminated through vaccines, from polio to measles, as well as the dangers of vaccine refusal, as indicated by recent outbreaks of vaccine-preventable diseases in areas with low immunization rates. “This approach highlights the opportunity we all have to get vaccinated to protect ourselves and our communities,” she said.
In Dr. Fryhofer’s view, the situation is urgent and doctors need to be proactive. “We’re now at a public-health tipping point where we may see a sliding back and a reversing of many years of progress.”
Dr. Fryhofer and Dr. Block disclosed no competing interests relevant to their comments.
Another Reason to Control Lp(a): To Protect the Kidneys Too
LYON, FRANCE — High levels of lipoprotein(a) [Lp(a)] in the blood are associated with a significantly increased risk for chronic kidney disease, report investigators who are studying the link in a two-part study of more than 100,000 people.
There is already genetic evidence showing that Lp(a) can cause cardiovascular conditions, including myocardial infarction, aortic valve stenosis, peripheral artery disease, and ischemic stroke.
Now, researchers presenting at the European Atherosclerosis Society (EAS) 2024 Congress are adding new organs – the kidneys – to the list of those that can be damaged by elevated Lp(a).
“This is very important,” said lead investigator Anne Langsted, MD, PhD, DMSc, from the Department of Clinical Biochemistry at the Rigshospitalet in Denmark. And “hopefully, we’ll have a treatment for Lp(a) on the market very soon. Until then, I think individuals who have kidney disease would benefit a lot from reducing other risk factors, if they also have high levels” of Lp(a).
Using data gathered from the Copenhagen General Population Study, the study involved 108,439 individuals who had a range of tests including estimated glomerular filtration rate (eGFR), plasma Lp(a) levels, and LPA genotyping. The patients were then linked to a series of national registries to study outcomes.
The researchers conducted two separate analyses: an observational study of Lp(a) levels in 70,040 individuals and a Mendelian randomization study of LPA kringle IV–type 2 domain repeats in 106,624 individuals. The number of those repeats is inversely associated with median Lp(a) plasma levels.
The observational study showed that eGFR decreased with increasing median plasma Lp(a) levels; the Mendelian randomization study indicated that eGFR decreased KIV-2 repeat numbers dropped.
Across both parts of the study, it was found that each 50 mg/dL increase in plasma Lp(a) levels was associated with an increased risk of at least 25% for chronic kidney disease.
Lp(a) and Chronic Kidney Disease
When high plasma levels of Lp(a) have been spotted before in patients with kidney disease, “we’ve kind of assumed that it was probably the kidney disease that caused the higher levels,” Dr. Langsted said. But her team hypothesized that the opposite was at play and that Lp(a) levels are genetically determined, and increased plasma Lp(a) levels may be causally associated with rising risk for chronic kidney disease.
Gerald F. Watts, MD, PhD, DSc, Winthrop Professor of cardiometabolic and internal medicine at the University of Western Australia in Perth, and co-chair of the study, said in an interview that “although Mendelian randomization is a technique that allows you to infer causality, it’s probably a little bit more complex than that in reality,” adding that there is likely a bidirectional relationship between Lp(a) and chronic kidney disease.
Having increased Lp(a) levels on their own is not sufficient to trigger chronic kidney disease. “You probably need another event and then you get into a vicious cycle,” Dr. Watts said.
The mechanism linking Lp(a) with chronic kidney disease remains unclear, but Dr. Watts explained that the lipoprotein probably damages the renal tubes when it is reabsorbed after it dissociates from low-density lipoprotein cholesterol.
The next step will be to identify the people who are most susceptible to this and figure out what treatment might help. Dr. Watts suggested that gene silencing, in which Lp(a) is “completely obliterated,” will lead to an improvement in renal function.
A version of this article appeared on Medscape.com.
LYON, FRANCE — High levels of lipoprotein(a) [Lp(a)] in the blood are associated with a significantly increased risk for chronic kidney disease, report investigators who are studying the link in a two-part study of more than 100,000 people.
There is already genetic evidence showing that Lp(a) can cause cardiovascular conditions, including myocardial infarction, aortic valve stenosis, peripheral artery disease, and ischemic stroke.
Now, researchers presenting at the European Atherosclerosis Society (EAS) 2024 Congress are adding new organs – the kidneys – to the list of those that can be damaged by elevated Lp(a).
“This is very important,” said lead investigator Anne Langsted, MD, PhD, DMSc, from the Department of Clinical Biochemistry at the Rigshospitalet in Denmark. And “hopefully, we’ll have a treatment for Lp(a) on the market very soon. Until then, I think individuals who have kidney disease would benefit a lot from reducing other risk factors, if they also have high levels” of Lp(a).
Using data gathered from the Copenhagen General Population Study, the study involved 108,439 individuals who had a range of tests including estimated glomerular filtration rate (eGFR), plasma Lp(a) levels, and LPA genotyping. The patients were then linked to a series of national registries to study outcomes.
The researchers conducted two separate analyses: an observational study of Lp(a) levels in 70,040 individuals and a Mendelian randomization study of LPA kringle IV–type 2 domain repeats in 106,624 individuals. The number of those repeats is inversely associated with median Lp(a) plasma levels.
The observational study showed that eGFR decreased with increasing median plasma Lp(a) levels; the Mendelian randomization study indicated that eGFR decreased KIV-2 repeat numbers dropped.
Across both parts of the study, it was found that each 50 mg/dL increase in plasma Lp(a) levels was associated with an increased risk of at least 25% for chronic kidney disease.
Lp(a) and Chronic Kidney Disease
When high plasma levels of Lp(a) have been spotted before in patients with kidney disease, “we’ve kind of assumed that it was probably the kidney disease that caused the higher levels,” Dr. Langsted said. But her team hypothesized that the opposite was at play and that Lp(a) levels are genetically determined, and increased plasma Lp(a) levels may be causally associated with rising risk for chronic kidney disease.
Gerald F. Watts, MD, PhD, DSc, Winthrop Professor of cardiometabolic and internal medicine at the University of Western Australia in Perth, and co-chair of the study, said in an interview that “although Mendelian randomization is a technique that allows you to infer causality, it’s probably a little bit more complex than that in reality,” adding that there is likely a bidirectional relationship between Lp(a) and chronic kidney disease.
Having increased Lp(a) levels on their own is not sufficient to trigger chronic kidney disease. “You probably need another event and then you get into a vicious cycle,” Dr. Watts said.
The mechanism linking Lp(a) with chronic kidney disease remains unclear, but Dr. Watts explained that the lipoprotein probably damages the renal tubes when it is reabsorbed after it dissociates from low-density lipoprotein cholesterol.
The next step will be to identify the people who are most susceptible to this and figure out what treatment might help. Dr. Watts suggested that gene silencing, in which Lp(a) is “completely obliterated,” will lead to an improvement in renal function.
A version of this article appeared on Medscape.com.
LYON, FRANCE — High levels of lipoprotein(a) [Lp(a)] in the blood are associated with a significantly increased risk for chronic kidney disease, report investigators who are studying the link in a two-part study of more than 100,000 people.
There is already genetic evidence showing that Lp(a) can cause cardiovascular conditions, including myocardial infarction, aortic valve stenosis, peripheral artery disease, and ischemic stroke.
Now, researchers presenting at the European Atherosclerosis Society (EAS) 2024 Congress are adding new organs – the kidneys – to the list of those that can be damaged by elevated Lp(a).
“This is very important,” said lead investigator Anne Langsted, MD, PhD, DMSc, from the Department of Clinical Biochemistry at the Rigshospitalet in Denmark. And “hopefully, we’ll have a treatment for Lp(a) on the market very soon. Until then, I think individuals who have kidney disease would benefit a lot from reducing other risk factors, if they also have high levels” of Lp(a).
Using data gathered from the Copenhagen General Population Study, the study involved 108,439 individuals who had a range of tests including estimated glomerular filtration rate (eGFR), plasma Lp(a) levels, and LPA genotyping. The patients were then linked to a series of national registries to study outcomes.
The researchers conducted two separate analyses: an observational study of Lp(a) levels in 70,040 individuals and a Mendelian randomization study of LPA kringle IV–type 2 domain repeats in 106,624 individuals. The number of those repeats is inversely associated with median Lp(a) plasma levels.
The observational study showed that eGFR decreased with increasing median plasma Lp(a) levels; the Mendelian randomization study indicated that eGFR decreased KIV-2 repeat numbers dropped.
Across both parts of the study, it was found that each 50 mg/dL increase in plasma Lp(a) levels was associated with an increased risk of at least 25% for chronic kidney disease.
Lp(a) and Chronic Kidney Disease
When high plasma levels of Lp(a) have been spotted before in patients with kidney disease, “we’ve kind of assumed that it was probably the kidney disease that caused the higher levels,” Dr. Langsted said. But her team hypothesized that the opposite was at play and that Lp(a) levels are genetically determined, and increased plasma Lp(a) levels may be causally associated with rising risk for chronic kidney disease.
Gerald F. Watts, MD, PhD, DSc, Winthrop Professor of cardiometabolic and internal medicine at the University of Western Australia in Perth, and co-chair of the study, said in an interview that “although Mendelian randomization is a technique that allows you to infer causality, it’s probably a little bit more complex than that in reality,” adding that there is likely a bidirectional relationship between Lp(a) and chronic kidney disease.
Having increased Lp(a) levels on their own is not sufficient to trigger chronic kidney disease. “You probably need another event and then you get into a vicious cycle,” Dr. Watts said.
The mechanism linking Lp(a) with chronic kidney disease remains unclear, but Dr. Watts explained that the lipoprotein probably damages the renal tubes when it is reabsorbed after it dissociates from low-density lipoprotein cholesterol.
The next step will be to identify the people who are most susceptible to this and figure out what treatment might help. Dr. Watts suggested that gene silencing, in which Lp(a) is “completely obliterated,” will lead to an improvement in renal function.
A version of this article appeared on Medscape.com.
Neoadjuvant Checkpoint Inhibition Study Sets New Standard of Care in Melanoma
These results set a new standard of care in this patient population, the study’s lead author, Christian U. Blank, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology in Chicago.
Dr. Blank, a hematologist/oncologist from the Netherlands Cancer Institute in Amsterdam, called the result “very special,” noting that the trial included an active comparator, rather than a placebo control.
“When we treat these patients with surgery only, the outcome … is very bad: The 5-year relapse-free survival is only 30% and the overall survival is only 50%. Adjuvant therapy improves relapse-free survival but not overall survival ...Thus, there is an urgent need for these patients for novel therapy approaches,” he said during a press conference at the meeting.
Study Methods and Results
The study included 423 patients with stage III de novo or recurrent pathologically proven resectable melanoma with at least 1 lymph node metastasis. Patients were randomized to either the experimental neoadjuvant arm (n = 212), or the standard treatment control arm (n = 211), which consisted of therapeutic lymph node dissection (TLND) followed by 12 cycles of adjuvant nivolumab (NIVO 480 mg every 4 weeks).
Patients in the experimental arm received two cycles of neoadjuvant ipilimumab (IPI 80 mg every 3 weeks) plus NIVO 240 mg for 3 weeks followed by TLND. Those with a major pathologic response (MPR), defined as less than 10% vital tumor cells in the post-neoadjuvant resection specimen, went straight to follow-up.
Those without an MPR received adjuvant therapy. For patients with BRAF wild-type, this involved 11 cycles of adjuvant NIVO (480 mg every 4 weeks), while BRAF-mutated patients received dabrafenib plus trametinib (150 mg b.i.d./2 mg once a day; 46 weeks).
The study met its primary endpoint — event-free survival (EFS) — at the first interim analysis. After a median follow-up of 9.9 months, the estimated EFS was 83.7% for neoadjuvant immunotherapy versus 57.2% for standard of care, (P less than .0001, hazard ratio [HR] = 0.32).
“When we look into the subgroups, for example BRAF-mutated status or BRAF-wild-type status ... you see for both groups also a highly statistically significant outcome favoring the neoadjuvant therapy with hazard ratios of 0.29 and 0.35,” said Dr. Blank.
In total, 59% of patients in the experimental arm had an MPR needing no further treatment. “This is important, because the patients that achieve a major pathologic response have excellent outcomes, with an EFS of 95%,” said Dr. Blank.
He added that those with a partial response had an EFS of 76%, and among those who had “nonresponse,” the EFS was 57% — the same as that of patients in the control arm.
Toxicities were considered transient and acceptable, with systemic treatment-related grade 3 or 4 events in 29.7% of the neoadjuvant arm and 14.7% of the adjuvant arm.
NADINA is the first neoadjuvant checkpoint inhibitor phase 3 study in melanoma and the first phase 3 trial in oncology testing a checkpoint inhibitor without chemotherapy, noted Dr. Blank.
“At the moment we see only additions of immunotherapy to the chemotherapy neoadjuvant arms, but here you see that we can also treat patients with pure immunotherapy.”
Neoadjuvant Therapy Defined as Standard of Care
When considered along with evidence from the phase 2 SWOG 1801 study (N Engl J Med. 2023;388:813-8), “NADINA defines neoadjuvant therapy as the new standard of care for macroscopic stage III melanoma “which means that all trials currently ongoing need to be amended from adjuvant comparators to neoadjuvant comparators,” he said.
Dr. Blank called the trial a “new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by a response-driven adjuvant therapy.
“I think we see at the moment only sandwich designs, and this is more sales driven than patient driven, because what we have seen is that if a patient achieves a really deep response, the patient doesn’t need an adjuvant part,” he said.
Commenting during the press conference, Michael Lowe, MD, said the result “confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery.”
Dr. Lowe, associate professor in the Division of Surgical Oncology, at Emory University School of Medicine, Atlanta, added that the study “also confirms that giving two immunotherapy drugs before surgery results in excellent responses.”
However, he cautioned that “we cannot make comparisons to trials in which patients only got one immunotherapy. But this study confirms that consistency that patients who receive ipilimumab and nivolumab have superior responses compared to single-agent immunotherapy.”
He noted that all of the patients in the new study had all of their lymph nodes removed and called for doing that to remain the standard of care in terms of surgical approach.
“With short follow-up, it is too early to tell if some patients may have benefited from that adjuvant therapy. However, NADINA confirms that immunotherapy should be given to all patients with advanced melanoma before surgery, when possible, and establishes dual therapy with nivolumab and ipilimumab, as the standard of care in the appropriate patient,” Dr. Lowe said.
EFS Improvement Exceeds Expectations
In an interview, Rodabe N. Amaria, MD, a medical oncologist and professor at The University of Texas MD Anderson Cancer Center in Houston, agreed with Dr. Lowe’s assessment of the findings.
“For years we have been doing neoadjuvant immunotherapy trials, all with favorable results, but all relatively small, with data that was intriguing, but not necessarily definitive,” she said. “I see the data from the NADINA trial as being definitive and true evidence of the many advantages of neoadjuvant immunotherapy for clinical stage 3 melanoma ... This work builds on the data from the SWOG 1801 trial but also exceeds expectations with the 68% improvement in EFS appreciated with the dual combination immunotherapy regimen compared to adjuvant nivolumab.”
Additionally, the approximately 30% grade 3 or higher immune-mediated toxicity is reasonable and in keeping with known data, and this trial demonstrates clearly that neoadjuvant immunotherapy does not increase the rate of surgical complications, she said.
Dr. Amaria also considered that 59% of patients who achieved a major pathologic response were observed in the neoadjuvant setting to be a key finding.
This indicates thats “over half the patients could be spared additional immunotherapy and risk of further immune-mediated toxicities by having only two doses of neoadjuvant immunotherapy, she said.
The results “demonstrate the superiority of a neoadjuvant combination immunotherapy approach for patients with clinical stage III melanoma,” she added.
The study was funded by Bristol Myers-Squibb and the Australian government.
Dr. Blank disclosed ties with Immagene, Signature Oncology, AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Third Rock Ventures, 4SC, NanoString Technologies, WO 2021/177822 A1, and Freshfields Bruckhaus Deringer. No other experts reported any relevant disclosures.
These results set a new standard of care in this patient population, the study’s lead author, Christian U. Blank, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology in Chicago.
Dr. Blank, a hematologist/oncologist from the Netherlands Cancer Institute in Amsterdam, called the result “very special,” noting that the trial included an active comparator, rather than a placebo control.
“When we treat these patients with surgery only, the outcome … is very bad: The 5-year relapse-free survival is only 30% and the overall survival is only 50%. Adjuvant therapy improves relapse-free survival but not overall survival ...Thus, there is an urgent need for these patients for novel therapy approaches,” he said during a press conference at the meeting.
Study Methods and Results
The study included 423 patients with stage III de novo or recurrent pathologically proven resectable melanoma with at least 1 lymph node metastasis. Patients were randomized to either the experimental neoadjuvant arm (n = 212), or the standard treatment control arm (n = 211), which consisted of therapeutic lymph node dissection (TLND) followed by 12 cycles of adjuvant nivolumab (NIVO 480 mg every 4 weeks).
Patients in the experimental arm received two cycles of neoadjuvant ipilimumab (IPI 80 mg every 3 weeks) plus NIVO 240 mg for 3 weeks followed by TLND. Those with a major pathologic response (MPR), defined as less than 10% vital tumor cells in the post-neoadjuvant resection specimen, went straight to follow-up.
Those without an MPR received adjuvant therapy. For patients with BRAF wild-type, this involved 11 cycles of adjuvant NIVO (480 mg every 4 weeks), while BRAF-mutated patients received dabrafenib plus trametinib (150 mg b.i.d./2 mg once a day; 46 weeks).
The study met its primary endpoint — event-free survival (EFS) — at the first interim analysis. After a median follow-up of 9.9 months, the estimated EFS was 83.7% for neoadjuvant immunotherapy versus 57.2% for standard of care, (P less than .0001, hazard ratio [HR] = 0.32).
“When we look into the subgroups, for example BRAF-mutated status or BRAF-wild-type status ... you see for both groups also a highly statistically significant outcome favoring the neoadjuvant therapy with hazard ratios of 0.29 and 0.35,” said Dr. Blank.
In total, 59% of patients in the experimental arm had an MPR needing no further treatment. “This is important, because the patients that achieve a major pathologic response have excellent outcomes, with an EFS of 95%,” said Dr. Blank.
He added that those with a partial response had an EFS of 76%, and among those who had “nonresponse,” the EFS was 57% — the same as that of patients in the control arm.
Toxicities were considered transient and acceptable, with systemic treatment-related grade 3 or 4 events in 29.7% of the neoadjuvant arm and 14.7% of the adjuvant arm.
NADINA is the first neoadjuvant checkpoint inhibitor phase 3 study in melanoma and the first phase 3 trial in oncology testing a checkpoint inhibitor without chemotherapy, noted Dr. Blank.
“At the moment we see only additions of immunotherapy to the chemotherapy neoadjuvant arms, but here you see that we can also treat patients with pure immunotherapy.”
Neoadjuvant Therapy Defined as Standard of Care
When considered along with evidence from the phase 2 SWOG 1801 study (N Engl J Med. 2023;388:813-8), “NADINA defines neoadjuvant therapy as the new standard of care for macroscopic stage III melanoma “which means that all trials currently ongoing need to be amended from adjuvant comparators to neoadjuvant comparators,” he said.
Dr. Blank called the trial a “new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by a response-driven adjuvant therapy.
“I think we see at the moment only sandwich designs, and this is more sales driven than patient driven, because what we have seen is that if a patient achieves a really deep response, the patient doesn’t need an adjuvant part,” he said.
Commenting during the press conference, Michael Lowe, MD, said the result “confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery.”
Dr. Lowe, associate professor in the Division of Surgical Oncology, at Emory University School of Medicine, Atlanta, added that the study “also confirms that giving two immunotherapy drugs before surgery results in excellent responses.”
However, he cautioned that “we cannot make comparisons to trials in which patients only got one immunotherapy. But this study confirms that consistency that patients who receive ipilimumab and nivolumab have superior responses compared to single-agent immunotherapy.”
He noted that all of the patients in the new study had all of their lymph nodes removed and called for doing that to remain the standard of care in terms of surgical approach.
“With short follow-up, it is too early to tell if some patients may have benefited from that adjuvant therapy. However, NADINA confirms that immunotherapy should be given to all patients with advanced melanoma before surgery, when possible, and establishes dual therapy with nivolumab and ipilimumab, as the standard of care in the appropriate patient,” Dr. Lowe said.
EFS Improvement Exceeds Expectations
In an interview, Rodabe N. Amaria, MD, a medical oncologist and professor at The University of Texas MD Anderson Cancer Center in Houston, agreed with Dr. Lowe’s assessment of the findings.
“For years we have been doing neoadjuvant immunotherapy trials, all with favorable results, but all relatively small, with data that was intriguing, but not necessarily definitive,” she said. “I see the data from the NADINA trial as being definitive and true evidence of the many advantages of neoadjuvant immunotherapy for clinical stage 3 melanoma ... This work builds on the data from the SWOG 1801 trial but also exceeds expectations with the 68% improvement in EFS appreciated with the dual combination immunotherapy regimen compared to adjuvant nivolumab.”
Additionally, the approximately 30% grade 3 or higher immune-mediated toxicity is reasonable and in keeping with known data, and this trial demonstrates clearly that neoadjuvant immunotherapy does not increase the rate of surgical complications, she said.
Dr. Amaria also considered that 59% of patients who achieved a major pathologic response were observed in the neoadjuvant setting to be a key finding.
This indicates thats “over half the patients could be spared additional immunotherapy and risk of further immune-mediated toxicities by having only two doses of neoadjuvant immunotherapy, she said.
The results “demonstrate the superiority of a neoadjuvant combination immunotherapy approach for patients with clinical stage III melanoma,” she added.
The study was funded by Bristol Myers-Squibb and the Australian government.
Dr. Blank disclosed ties with Immagene, Signature Oncology, AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Third Rock Ventures, 4SC, NanoString Technologies, WO 2021/177822 A1, and Freshfields Bruckhaus Deringer. No other experts reported any relevant disclosures.
These results set a new standard of care in this patient population, the study’s lead author, Christian U. Blank, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology in Chicago.
Dr. Blank, a hematologist/oncologist from the Netherlands Cancer Institute in Amsterdam, called the result “very special,” noting that the trial included an active comparator, rather than a placebo control.
“When we treat these patients with surgery only, the outcome … is very bad: The 5-year relapse-free survival is only 30% and the overall survival is only 50%. Adjuvant therapy improves relapse-free survival but not overall survival ...Thus, there is an urgent need for these patients for novel therapy approaches,” he said during a press conference at the meeting.
Study Methods and Results
The study included 423 patients with stage III de novo or recurrent pathologically proven resectable melanoma with at least 1 lymph node metastasis. Patients were randomized to either the experimental neoadjuvant arm (n = 212), or the standard treatment control arm (n = 211), which consisted of therapeutic lymph node dissection (TLND) followed by 12 cycles of adjuvant nivolumab (NIVO 480 mg every 4 weeks).
Patients in the experimental arm received two cycles of neoadjuvant ipilimumab (IPI 80 mg every 3 weeks) plus NIVO 240 mg for 3 weeks followed by TLND. Those with a major pathologic response (MPR), defined as less than 10% vital tumor cells in the post-neoadjuvant resection specimen, went straight to follow-up.
Those without an MPR received adjuvant therapy. For patients with BRAF wild-type, this involved 11 cycles of adjuvant NIVO (480 mg every 4 weeks), while BRAF-mutated patients received dabrafenib plus trametinib (150 mg b.i.d./2 mg once a day; 46 weeks).
The study met its primary endpoint — event-free survival (EFS) — at the first interim analysis. After a median follow-up of 9.9 months, the estimated EFS was 83.7% for neoadjuvant immunotherapy versus 57.2% for standard of care, (P less than .0001, hazard ratio [HR] = 0.32).
“When we look into the subgroups, for example BRAF-mutated status or BRAF-wild-type status ... you see for both groups also a highly statistically significant outcome favoring the neoadjuvant therapy with hazard ratios of 0.29 and 0.35,” said Dr. Blank.
In total, 59% of patients in the experimental arm had an MPR needing no further treatment. “This is important, because the patients that achieve a major pathologic response have excellent outcomes, with an EFS of 95%,” said Dr. Blank.
He added that those with a partial response had an EFS of 76%, and among those who had “nonresponse,” the EFS was 57% — the same as that of patients in the control arm.
Toxicities were considered transient and acceptable, with systemic treatment-related grade 3 or 4 events in 29.7% of the neoadjuvant arm and 14.7% of the adjuvant arm.
NADINA is the first neoadjuvant checkpoint inhibitor phase 3 study in melanoma and the first phase 3 trial in oncology testing a checkpoint inhibitor without chemotherapy, noted Dr. Blank.
“At the moment we see only additions of immunotherapy to the chemotherapy neoadjuvant arms, but here you see that we can also treat patients with pure immunotherapy.”
Neoadjuvant Therapy Defined as Standard of Care
When considered along with evidence from the phase 2 SWOG 1801 study (N Engl J Med. 2023;388:813-8), “NADINA defines neoadjuvant therapy as the new standard of care for macroscopic stage III melanoma “which means that all trials currently ongoing need to be amended from adjuvant comparators to neoadjuvant comparators,” he said.
Dr. Blank called the trial a “new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by a response-driven adjuvant therapy.
“I think we see at the moment only sandwich designs, and this is more sales driven than patient driven, because what we have seen is that if a patient achieves a really deep response, the patient doesn’t need an adjuvant part,” he said.
Commenting during the press conference, Michael Lowe, MD, said the result “confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery.”
Dr. Lowe, associate professor in the Division of Surgical Oncology, at Emory University School of Medicine, Atlanta, added that the study “also confirms that giving two immunotherapy drugs before surgery results in excellent responses.”
However, he cautioned that “we cannot make comparisons to trials in which patients only got one immunotherapy. But this study confirms that consistency that patients who receive ipilimumab and nivolumab have superior responses compared to single-agent immunotherapy.”
He noted that all of the patients in the new study had all of their lymph nodes removed and called for doing that to remain the standard of care in terms of surgical approach.
“With short follow-up, it is too early to tell if some patients may have benefited from that adjuvant therapy. However, NADINA confirms that immunotherapy should be given to all patients with advanced melanoma before surgery, when possible, and establishes dual therapy with nivolumab and ipilimumab, as the standard of care in the appropriate patient,” Dr. Lowe said.
EFS Improvement Exceeds Expectations
In an interview, Rodabe N. Amaria, MD, a medical oncologist and professor at The University of Texas MD Anderson Cancer Center in Houston, agreed with Dr. Lowe’s assessment of the findings.
“For years we have been doing neoadjuvant immunotherapy trials, all with favorable results, but all relatively small, with data that was intriguing, but not necessarily definitive,” she said. “I see the data from the NADINA trial as being definitive and true evidence of the many advantages of neoadjuvant immunotherapy for clinical stage 3 melanoma ... This work builds on the data from the SWOG 1801 trial but also exceeds expectations with the 68% improvement in EFS appreciated with the dual combination immunotherapy regimen compared to adjuvant nivolumab.”
Additionally, the approximately 30% grade 3 or higher immune-mediated toxicity is reasonable and in keeping with known data, and this trial demonstrates clearly that neoadjuvant immunotherapy does not increase the rate of surgical complications, she said.
Dr. Amaria also considered that 59% of patients who achieved a major pathologic response were observed in the neoadjuvant setting to be a key finding.
This indicates thats “over half the patients could be spared additional immunotherapy and risk of further immune-mediated toxicities by having only two doses of neoadjuvant immunotherapy, she said.
The results “demonstrate the superiority of a neoadjuvant combination immunotherapy approach for patients with clinical stage III melanoma,” she added.
The study was funded by Bristol Myers-Squibb and the Australian government.
Dr. Blank disclosed ties with Immagene, Signature Oncology, AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Third Rock Ventures, 4SC, NanoString Technologies, WO 2021/177822 A1, and Freshfields Bruckhaus Deringer. No other experts reported any relevant disclosures.
FROM ASCO 2024
ADCs for Breast Cancer: Clear Benefits, Manageable Risks
These medications, which are designed to selectively deliver potent cytotoxic drugs to cancer cells expressing specific surface antigens such as human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (TROP2), can be highly effective but can also come with significant toxicities.
The latest data on several ADCs — their clinical benefit and safety — were the focus of three presentations here at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
TROPION-Breast01
In her presentation, Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City, reported additional safety analyses from the phase 3 TROPION-Breast01 trial looking at datopotamab deruxtecan (Dato-DXd) in patients with metastatic hormone receptor–positive (HR+)/HER2− breast cancer resistant to endocrine therapy.
Dato-DXd is an investigational ADC composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.
As previously reported by this news organization, median progression-free survival was 6.9 months with Dato-DXd compared with 4.9 months for investigator’s choice of chemotherapy (eribulin mesylate, vinorelbine, gemcitabine, or capecitabine), which translated into a 37% (hazard ratio [HR], 0.63; P < .0001) reduction in risk for disease progression.
In addition, the rate of grade 3 or higher treatment-related adverse events with Dato-DXd was less than half that with standard chemotherapy and led to fewer dose interruptions or reductions, indicating that Dato-DXd is better tolerated.
Dr. Jhaveri focused on three treatment-related adverse events of special interest: Stomatitis/oral mucositis, ocular surface events, and adjudicated drug-related interstitial lung disease.
The rate of any grade oral mucositis with Dato-DXd was 56%, she reported. Most were grade 1 (25%) or grade 2 (23%), with only 7% grade 3. About 13% of patients had a dose reduction for oral mucositis, and only one (0.3%) patient discontinued treatment.
The median time to onset was 22 days, and median time to resolution (for events recovered/resolved at data cutoff) was 36 days.
“The study did provide toxicity management guidelines for patients who experienced stomatitis,” Dr. Jhaveri told attendees. The guidelines highly recommended daily use of a steroid-containing mouthwash as prophylaxis or, if that wasn’t available, an inert, bland mouth rinse.
“Prophylactic cryotherapy — ice chips or ice water held in the mouth throughout the infusion — was also suggested,” she said.
The overall rate of ocular surface events with Dato-DXd was 40%, with most grade 1 (32%) or grade 2 (7%), with only 0.8% grade 3. Rates of dose reduction/interruption (3.3%) and discontinuation (0.3%) were low. Most ocular events were either dry eye (22%) or keratitis (14%).
The incidence of ocular events in the chemotherapy group was 12%, higher than typically seen. The study mandated regular ocular assessments, and Jhaveri noted that it was possible that this contributed to the high rate of low-grade ocular events found in both arms.
Median time to onset of ocular events was 65 days, and median time to resolution was 67 days.
Toxicity management guidelines were also incorporated for ocular events, suggesting daily use of artificial tears and avoidance of contact lenses, Dr. Jhaveri said.
In the Dato-DXd group, there were 12 adjudicated cases (3.3%) of drug-related interstitial lung disease; most were grade 1 (1.4%) and grade 2 (1.1%).
“There was one patient who had a grade 5 event, which was characterized by the investigator as grade 3 pneumonitis, with death attributed to disease progression,” Dr. Jhaveri said. This was subsequently adjudicated to be a grade 5 drug-related death.
The median time to onset of interstitial lung disease was 84.5 days, and median time to resolution was 28 days.
Among other treatment-related adverse events of clinical interest, any grade nausea was the most common event with Dato-DXd, reported by 51% of patients, with only 1.4% grade 3 or higher.
“Prophylactic antiemetic agents are highly recommended prior to infusion of Dato-DXd and on subsequent days as needed,” Dr. Jhaveri said.
Any grade diarrhea was reported in 7.5%, with no grade 3+ diarrhea. Alopecia was reported in 36.4%, of which grade 1 was 21% and grade 2 was 15%.
Summing up, the researcher said the new safety data suggest that Dato-DXd offers “better tolerability” than standard chemotherapy. Coupled with the efficacy data, this further supports “Dato-DXd as a potential new therapeutic option for patients with previously treated, inoperable, or metastatic HR+/HER2− breast cancer.”
DESTINY-Breast02
New data from the phase 3 DESTINY-Breast02 study confirm a long-term survival benefit, as well as a favorable benefit/risk profile of trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1), reported Sung-Bae Kim, MD, PhD, with University of Ulsan College of Medicine, Seoul, Republic of Korea.
In the phase 3 randomized, multicenter, open-label clinical trial, study participants received either trastuzumab deruxtecan or physician’s choice of trastuzumab plus capecitabine or lapatinib or capecitabine. The primary results of the trial were published last year in The Lancet.
As previously reported by this news organization, after median follow-up of 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the treatment of choice group, median progression-free survival was 17.8 months for trastuzumab deruxtecan vs 6.9 months for the physician’s choice group (HR, 0.36; P < .000001).
The latest data show that after a median follow-up of 30.2 months in the trastuzumab deruxtecan group and 20.5 months in the treatment of choice group, median progression-free survival was 16.7 months with trastuzumab deruxtecan vs 5.5 months with the treatment of choice — a 70% reduction in risk for progression (HR, 0.30), Dr. Kim said.
From time of randomization to progression to next line of therapy or death, median progression-free survival was 33.0 months with trastuzumab deruxtecan vs 15.0 with treatment of choice (HR, 0.42).
Median overall survival was 35.7 months with trastuzumab deruxtecan vs 25.0 months with the treatment of choice, with the risk for death reduced by 31% with trastuzumab deruxtecan (HR, 0.69).
The safety profile of trastuzumab deruxtecan continues to be “manageable, with no long-term toxicity observed with longer follow-up,” Dr. Kim told attendees. The most common treatment-emergent adverse events were nausea (73%), fatigue (62%), and vomiting (38%).
There were a total of 46 (11.4%) adjudicated drug-related interstitial lung disease/pneumonitis cases with trastuzumab deruxtecan. Most were grade 1 or 2. This risk did not increase with longer treatment duration; most events occurred within 12 months of starting treatment, Dr. Kim noted.
With longer follow-up, results of DESTINY-Breast02 “reinforce the substantial benefit” of trastuzumab deruxtecan over the treatment of physician’s choice in patients with HER2+ metastatic breast cancer previously treated with T-DM1, he concluded.
Pooled Data from TROPiCS-02 and EVER-132-002
Hope S. Rugo, MD, of the University of California San Francisco, and colleagues reported a meta-analysis of data from the phase 3 TROPiCS-02 and EVER-132-002 trials of the TROP2-directed ADC sacituzumab govitecan vs the treatment of physician’s choice in HR+/HER2− metastatic breast cancer.
In the pooled analysis, median overall survival was significantly longer with sacituzumab govitecan than with the treatment of physician’s choice in the overall population (16.2 vs 12.7 months) and in patients who received prior CDK4/6 inhibitor treatment (15.4 vs 11.5 months). Progression-free survival also favored sacituzumab govitecan.
These results are consistent with trial-level results from TROPICS-02 and EVER-132-002, reinforcing the efficacy benefits of sacituzumab govitecan over the treatment of physician’s choice, the study team said.
Evolving Landscape of ADCs in Breast Cancer
Giuseppe Curigliano, MD, PhD, with the University of Milan, Italy, who served as discussant for the TROPION-Breast01 safety analysis, noted that the clinical landscape of ADCs has “evolved over time.”
He added that despite having a similar target and similar payload, the anti-TROP2 ADCs in development for HR+/HER2− metastatic breast cancer — Dato-DXd, sacituzumab govitecan, and sacituzumab tirumotecan — appear to have different spectrums of toxicity.
Looking ahead, he said it will be important to determine whether toxicity of these agents can be predicted with a pharmacogenomic analysis and whether toxicity is related to the payload or to the linker antibody complex.
“The science and chemistry of ADCs has shown significant promise in terms of clinical activity, but we also need to better understand safety,” Dr. Curigliano told attendees.
“We need to pay attention to signals in the early phase trials of ADCs and be willing to adjust accordingly to maximize therapeutic benefit and minimize toxicity. Team science will be important in the future developmental ADCs,” he added.
TROPION-Breast01 was sponsored by AstraZeneca. DESTINY-Breast-02 was sponsored by Daiichi Sankyo. TROPiCS-02 and EVER-132-002 were supported by Gilead Sciences. Several trial investigators have disclosed various relationships with these and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
These medications, which are designed to selectively deliver potent cytotoxic drugs to cancer cells expressing specific surface antigens such as human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (TROP2), can be highly effective but can also come with significant toxicities.
The latest data on several ADCs — their clinical benefit and safety — were the focus of three presentations here at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
TROPION-Breast01
In her presentation, Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City, reported additional safety analyses from the phase 3 TROPION-Breast01 trial looking at datopotamab deruxtecan (Dato-DXd) in patients with metastatic hormone receptor–positive (HR+)/HER2− breast cancer resistant to endocrine therapy.
Dato-DXd is an investigational ADC composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.
As previously reported by this news organization, median progression-free survival was 6.9 months with Dato-DXd compared with 4.9 months for investigator’s choice of chemotherapy (eribulin mesylate, vinorelbine, gemcitabine, or capecitabine), which translated into a 37% (hazard ratio [HR], 0.63; P < .0001) reduction in risk for disease progression.
In addition, the rate of grade 3 or higher treatment-related adverse events with Dato-DXd was less than half that with standard chemotherapy and led to fewer dose interruptions or reductions, indicating that Dato-DXd is better tolerated.
Dr. Jhaveri focused on three treatment-related adverse events of special interest: Stomatitis/oral mucositis, ocular surface events, and adjudicated drug-related interstitial lung disease.
The rate of any grade oral mucositis with Dato-DXd was 56%, she reported. Most were grade 1 (25%) or grade 2 (23%), with only 7% grade 3. About 13% of patients had a dose reduction for oral mucositis, and only one (0.3%) patient discontinued treatment.
The median time to onset was 22 days, and median time to resolution (for events recovered/resolved at data cutoff) was 36 days.
“The study did provide toxicity management guidelines for patients who experienced stomatitis,” Dr. Jhaveri told attendees. The guidelines highly recommended daily use of a steroid-containing mouthwash as prophylaxis or, if that wasn’t available, an inert, bland mouth rinse.
“Prophylactic cryotherapy — ice chips or ice water held in the mouth throughout the infusion — was also suggested,” she said.
The overall rate of ocular surface events with Dato-DXd was 40%, with most grade 1 (32%) or grade 2 (7%), with only 0.8% grade 3. Rates of dose reduction/interruption (3.3%) and discontinuation (0.3%) were low. Most ocular events were either dry eye (22%) or keratitis (14%).
The incidence of ocular events in the chemotherapy group was 12%, higher than typically seen. The study mandated regular ocular assessments, and Jhaveri noted that it was possible that this contributed to the high rate of low-grade ocular events found in both arms.
Median time to onset of ocular events was 65 days, and median time to resolution was 67 days.
Toxicity management guidelines were also incorporated for ocular events, suggesting daily use of artificial tears and avoidance of contact lenses, Dr. Jhaveri said.
In the Dato-DXd group, there were 12 adjudicated cases (3.3%) of drug-related interstitial lung disease; most were grade 1 (1.4%) and grade 2 (1.1%).
“There was one patient who had a grade 5 event, which was characterized by the investigator as grade 3 pneumonitis, with death attributed to disease progression,” Dr. Jhaveri said. This was subsequently adjudicated to be a grade 5 drug-related death.
The median time to onset of interstitial lung disease was 84.5 days, and median time to resolution was 28 days.
Among other treatment-related adverse events of clinical interest, any grade nausea was the most common event with Dato-DXd, reported by 51% of patients, with only 1.4% grade 3 or higher.
“Prophylactic antiemetic agents are highly recommended prior to infusion of Dato-DXd and on subsequent days as needed,” Dr. Jhaveri said.
Any grade diarrhea was reported in 7.5%, with no grade 3+ diarrhea. Alopecia was reported in 36.4%, of which grade 1 was 21% and grade 2 was 15%.
Summing up, the researcher said the new safety data suggest that Dato-DXd offers “better tolerability” than standard chemotherapy. Coupled with the efficacy data, this further supports “Dato-DXd as a potential new therapeutic option for patients with previously treated, inoperable, or metastatic HR+/HER2− breast cancer.”
DESTINY-Breast02
New data from the phase 3 DESTINY-Breast02 study confirm a long-term survival benefit, as well as a favorable benefit/risk profile of trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1), reported Sung-Bae Kim, MD, PhD, with University of Ulsan College of Medicine, Seoul, Republic of Korea.
In the phase 3 randomized, multicenter, open-label clinical trial, study participants received either trastuzumab deruxtecan or physician’s choice of trastuzumab plus capecitabine or lapatinib or capecitabine. The primary results of the trial were published last year in The Lancet.
As previously reported by this news organization, after median follow-up of 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the treatment of choice group, median progression-free survival was 17.8 months for trastuzumab deruxtecan vs 6.9 months for the physician’s choice group (HR, 0.36; P < .000001).
The latest data show that after a median follow-up of 30.2 months in the trastuzumab deruxtecan group and 20.5 months in the treatment of choice group, median progression-free survival was 16.7 months with trastuzumab deruxtecan vs 5.5 months with the treatment of choice — a 70% reduction in risk for progression (HR, 0.30), Dr. Kim said.
From time of randomization to progression to next line of therapy or death, median progression-free survival was 33.0 months with trastuzumab deruxtecan vs 15.0 with treatment of choice (HR, 0.42).
Median overall survival was 35.7 months with trastuzumab deruxtecan vs 25.0 months with the treatment of choice, with the risk for death reduced by 31% with trastuzumab deruxtecan (HR, 0.69).
The safety profile of trastuzumab deruxtecan continues to be “manageable, with no long-term toxicity observed with longer follow-up,” Dr. Kim told attendees. The most common treatment-emergent adverse events were nausea (73%), fatigue (62%), and vomiting (38%).
There were a total of 46 (11.4%) adjudicated drug-related interstitial lung disease/pneumonitis cases with trastuzumab deruxtecan. Most were grade 1 or 2. This risk did not increase with longer treatment duration; most events occurred within 12 months of starting treatment, Dr. Kim noted.
With longer follow-up, results of DESTINY-Breast02 “reinforce the substantial benefit” of trastuzumab deruxtecan over the treatment of physician’s choice in patients with HER2+ metastatic breast cancer previously treated with T-DM1, he concluded.
Pooled Data from TROPiCS-02 and EVER-132-002
Hope S. Rugo, MD, of the University of California San Francisco, and colleagues reported a meta-analysis of data from the phase 3 TROPiCS-02 and EVER-132-002 trials of the TROP2-directed ADC sacituzumab govitecan vs the treatment of physician’s choice in HR+/HER2− metastatic breast cancer.
In the pooled analysis, median overall survival was significantly longer with sacituzumab govitecan than with the treatment of physician’s choice in the overall population (16.2 vs 12.7 months) and in patients who received prior CDK4/6 inhibitor treatment (15.4 vs 11.5 months). Progression-free survival also favored sacituzumab govitecan.
These results are consistent with trial-level results from TROPICS-02 and EVER-132-002, reinforcing the efficacy benefits of sacituzumab govitecan over the treatment of physician’s choice, the study team said.
Evolving Landscape of ADCs in Breast Cancer
Giuseppe Curigliano, MD, PhD, with the University of Milan, Italy, who served as discussant for the TROPION-Breast01 safety analysis, noted that the clinical landscape of ADCs has “evolved over time.”
He added that despite having a similar target and similar payload, the anti-TROP2 ADCs in development for HR+/HER2− metastatic breast cancer — Dato-DXd, sacituzumab govitecan, and sacituzumab tirumotecan — appear to have different spectrums of toxicity.
Looking ahead, he said it will be important to determine whether toxicity of these agents can be predicted with a pharmacogenomic analysis and whether toxicity is related to the payload or to the linker antibody complex.
“The science and chemistry of ADCs has shown significant promise in terms of clinical activity, but we also need to better understand safety,” Dr. Curigliano told attendees.
“We need to pay attention to signals in the early phase trials of ADCs and be willing to adjust accordingly to maximize therapeutic benefit and minimize toxicity. Team science will be important in the future developmental ADCs,” he added.
TROPION-Breast01 was sponsored by AstraZeneca. DESTINY-Breast-02 was sponsored by Daiichi Sankyo. TROPiCS-02 and EVER-132-002 were supported by Gilead Sciences. Several trial investigators have disclosed various relationships with these and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
These medications, which are designed to selectively deliver potent cytotoxic drugs to cancer cells expressing specific surface antigens such as human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (TROP2), can be highly effective but can also come with significant toxicities.
The latest data on several ADCs — their clinical benefit and safety — were the focus of three presentations here at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
TROPION-Breast01
In her presentation, Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City, reported additional safety analyses from the phase 3 TROPION-Breast01 trial looking at datopotamab deruxtecan (Dato-DXd) in patients with metastatic hormone receptor–positive (HR+)/HER2− breast cancer resistant to endocrine therapy.
Dato-DXd is an investigational ADC composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.
As previously reported by this news organization, median progression-free survival was 6.9 months with Dato-DXd compared with 4.9 months for investigator’s choice of chemotherapy (eribulin mesylate, vinorelbine, gemcitabine, or capecitabine), which translated into a 37% (hazard ratio [HR], 0.63; P < .0001) reduction in risk for disease progression.
In addition, the rate of grade 3 or higher treatment-related adverse events with Dato-DXd was less than half that with standard chemotherapy and led to fewer dose interruptions or reductions, indicating that Dato-DXd is better tolerated.
Dr. Jhaveri focused on three treatment-related adverse events of special interest: Stomatitis/oral mucositis, ocular surface events, and adjudicated drug-related interstitial lung disease.
The rate of any grade oral mucositis with Dato-DXd was 56%, she reported. Most were grade 1 (25%) or grade 2 (23%), with only 7% grade 3. About 13% of patients had a dose reduction for oral mucositis, and only one (0.3%) patient discontinued treatment.
The median time to onset was 22 days, and median time to resolution (for events recovered/resolved at data cutoff) was 36 days.
“The study did provide toxicity management guidelines for patients who experienced stomatitis,” Dr. Jhaveri told attendees. The guidelines highly recommended daily use of a steroid-containing mouthwash as prophylaxis or, if that wasn’t available, an inert, bland mouth rinse.
“Prophylactic cryotherapy — ice chips or ice water held in the mouth throughout the infusion — was also suggested,” she said.
The overall rate of ocular surface events with Dato-DXd was 40%, with most grade 1 (32%) or grade 2 (7%), with only 0.8% grade 3. Rates of dose reduction/interruption (3.3%) and discontinuation (0.3%) were low. Most ocular events were either dry eye (22%) or keratitis (14%).
The incidence of ocular events in the chemotherapy group was 12%, higher than typically seen. The study mandated regular ocular assessments, and Jhaveri noted that it was possible that this contributed to the high rate of low-grade ocular events found in both arms.
Median time to onset of ocular events was 65 days, and median time to resolution was 67 days.
Toxicity management guidelines were also incorporated for ocular events, suggesting daily use of artificial tears and avoidance of contact lenses, Dr. Jhaveri said.
In the Dato-DXd group, there were 12 adjudicated cases (3.3%) of drug-related interstitial lung disease; most were grade 1 (1.4%) and grade 2 (1.1%).
“There was one patient who had a grade 5 event, which was characterized by the investigator as grade 3 pneumonitis, with death attributed to disease progression,” Dr. Jhaveri said. This was subsequently adjudicated to be a grade 5 drug-related death.
The median time to onset of interstitial lung disease was 84.5 days, and median time to resolution was 28 days.
Among other treatment-related adverse events of clinical interest, any grade nausea was the most common event with Dato-DXd, reported by 51% of patients, with only 1.4% grade 3 or higher.
“Prophylactic antiemetic agents are highly recommended prior to infusion of Dato-DXd and on subsequent days as needed,” Dr. Jhaveri said.
Any grade diarrhea was reported in 7.5%, with no grade 3+ diarrhea. Alopecia was reported in 36.4%, of which grade 1 was 21% and grade 2 was 15%.
Summing up, the researcher said the new safety data suggest that Dato-DXd offers “better tolerability” than standard chemotherapy. Coupled with the efficacy data, this further supports “Dato-DXd as a potential new therapeutic option for patients with previously treated, inoperable, or metastatic HR+/HER2− breast cancer.”
DESTINY-Breast02
New data from the phase 3 DESTINY-Breast02 study confirm a long-term survival benefit, as well as a favorable benefit/risk profile of trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1), reported Sung-Bae Kim, MD, PhD, with University of Ulsan College of Medicine, Seoul, Republic of Korea.
In the phase 3 randomized, multicenter, open-label clinical trial, study participants received either trastuzumab deruxtecan or physician’s choice of trastuzumab plus capecitabine or lapatinib or capecitabine. The primary results of the trial were published last year in The Lancet.
As previously reported by this news organization, after median follow-up of 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the treatment of choice group, median progression-free survival was 17.8 months for trastuzumab deruxtecan vs 6.9 months for the physician’s choice group (HR, 0.36; P < .000001).
The latest data show that after a median follow-up of 30.2 months in the trastuzumab deruxtecan group and 20.5 months in the treatment of choice group, median progression-free survival was 16.7 months with trastuzumab deruxtecan vs 5.5 months with the treatment of choice — a 70% reduction in risk for progression (HR, 0.30), Dr. Kim said.
From time of randomization to progression to next line of therapy or death, median progression-free survival was 33.0 months with trastuzumab deruxtecan vs 15.0 with treatment of choice (HR, 0.42).
Median overall survival was 35.7 months with trastuzumab deruxtecan vs 25.0 months with the treatment of choice, with the risk for death reduced by 31% with trastuzumab deruxtecan (HR, 0.69).
The safety profile of trastuzumab deruxtecan continues to be “manageable, with no long-term toxicity observed with longer follow-up,” Dr. Kim told attendees. The most common treatment-emergent adverse events were nausea (73%), fatigue (62%), and vomiting (38%).
There were a total of 46 (11.4%) adjudicated drug-related interstitial lung disease/pneumonitis cases with trastuzumab deruxtecan. Most were grade 1 or 2. This risk did not increase with longer treatment duration; most events occurred within 12 months of starting treatment, Dr. Kim noted.
With longer follow-up, results of DESTINY-Breast02 “reinforce the substantial benefit” of trastuzumab deruxtecan over the treatment of physician’s choice in patients with HER2+ metastatic breast cancer previously treated with T-DM1, he concluded.
Pooled Data from TROPiCS-02 and EVER-132-002
Hope S. Rugo, MD, of the University of California San Francisco, and colleagues reported a meta-analysis of data from the phase 3 TROPiCS-02 and EVER-132-002 trials of the TROP2-directed ADC sacituzumab govitecan vs the treatment of physician’s choice in HR+/HER2− metastatic breast cancer.
In the pooled analysis, median overall survival was significantly longer with sacituzumab govitecan than with the treatment of physician’s choice in the overall population (16.2 vs 12.7 months) and in patients who received prior CDK4/6 inhibitor treatment (15.4 vs 11.5 months). Progression-free survival also favored sacituzumab govitecan.
These results are consistent with trial-level results from TROPICS-02 and EVER-132-002, reinforcing the efficacy benefits of sacituzumab govitecan over the treatment of physician’s choice, the study team said.
Evolving Landscape of ADCs in Breast Cancer
Giuseppe Curigliano, MD, PhD, with the University of Milan, Italy, who served as discussant for the TROPION-Breast01 safety analysis, noted that the clinical landscape of ADCs has “evolved over time.”
He added that despite having a similar target and similar payload, the anti-TROP2 ADCs in development for HR+/HER2− metastatic breast cancer — Dato-DXd, sacituzumab govitecan, and sacituzumab tirumotecan — appear to have different spectrums of toxicity.
Looking ahead, he said it will be important to determine whether toxicity of these agents can be predicted with a pharmacogenomic analysis and whether toxicity is related to the payload or to the linker antibody complex.
“The science and chemistry of ADCs has shown significant promise in terms of clinical activity, but we also need to better understand safety,” Dr. Curigliano told attendees.
“We need to pay attention to signals in the early phase trials of ADCs and be willing to adjust accordingly to maximize therapeutic benefit and minimize toxicity. Team science will be important in the future developmental ADCs,” he added.
TROPION-Breast01 was sponsored by AstraZeneca. DESTINY-Breast-02 was sponsored by Daiichi Sankyo. TROPiCS-02 and EVER-132-002 were supported by Gilead Sciences. Several trial investigators have disclosed various relationships with these and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
FROM ESMO BREAST CANCER 2024
The ASCO Annual Meeting Starts This Week
From its origins in 1964, ASCO’s annual event has grown to become the world’s largest clinical oncology meeting, drawing attendees from across the globe.
More than 7000 abstracts were submitted for this year’s meeting a new record — and over 5000 were selected for presentation.
This year’s chair of the Annual Meeting Education Committee, Thomas William LeBlanc, MD, told us he has been attending the meeting since his training days more than a decade ago.
The event is “just incredibly empowering and energizing,” Dr. LeBlanc said, with opportunities to catch up with old colleagues and meet new ones, learn how far oncology has come and where it’s headed, and hear clinical pearls to take back the clinic.
This year’s theme, selected by ASCO President Lynn M. Schuchter, MD, is “The Art and Science of Cancer Care: From Comfort to Cure.”
Dr. LeBlanc, a blood cancer specialist at Duke University, Durham, North Carolina, said the theme has been woven throughout the abstract and educational sessions. Most sessions will have at least one presentation related to how we support people — not only “when we cure them but also when we can’t cure them,” he said.
Topics will include patient well-being, comfort measures, and survivorship. And for the first time the plenary session will include a palliative care abstract that addresses whether or not palliative care can be delivered effectively through telemedicine. The session is on Sunday, June 2.
Other potentially practice changing plenary abstracts tackle immunotherapy combinations for resectable melanoma, perioperative chemotherapy vs neoadjuvant chemoradiation for esophageal cancer, and osimertinib after definitive chemoradiotherapy for unresectable non–small cell lung cancer.
ASCO is piloting a slightly different format for research presentations this year. Instead of starting with context and background, speakers have been asked to present study results upfront as well as repeat them at the end of the talk. The reason behind the tweak is that engagement and retention tend to be better when results are presented upfront, instead of just at the end of a talk.
A popular session — ASCO Voices — has also been given a more central position in the conference: Friday, May 31. In this session, speakers will give short presentations about their personal experiences as providers, researchers, or patients.
ASCO Voices is a relatively recent addition to the meeting that has grown and gotten better. The talks are usually “very powerful narratives” that remind clinicians about “the importance of what they’re doing each day,” Dr. LeBlanc said.
Snippets of the talks will be played while people wait for sessions to begin at the meeting, so attendees who miss the Friday talks can still hear them.
In terms of educational sessions, Dr. LeBlanc highlighted two that might be of general interest to practicing oncologists: A joint ASCO/American Association for Cancer Research session entitled “Drugging the ‘Undruggable’ Target: Successes, Challenges, and the Road Ahead,” on Sunday morning and “Common Sense Oncology: Equity, Value, and Outcomes That Matter” on Monday morning.
As a blood cancer specialist, he said he is particularly interested in the topline results from the ASC4FIRST trial of asciminib, a newer kinase inhibitor, in newly diagnosed chronic myeloid leukemia, presented on Friday.
As in past years, this news organization will be on hand providing coverage with a dedicated team of reporters, editors, and videographers. Stop by our exhibit hall booth — number 26030 — to learn about the tools we offer to support your practice.
A version of this article appeared on Medscape.com .
From its origins in 1964, ASCO’s annual event has grown to become the world’s largest clinical oncology meeting, drawing attendees from across the globe.
More than 7000 abstracts were submitted for this year’s meeting a new record — and over 5000 were selected for presentation.
This year’s chair of the Annual Meeting Education Committee, Thomas William LeBlanc, MD, told us he has been attending the meeting since his training days more than a decade ago.
The event is “just incredibly empowering and energizing,” Dr. LeBlanc said, with opportunities to catch up with old colleagues and meet new ones, learn how far oncology has come and where it’s headed, and hear clinical pearls to take back the clinic.
This year’s theme, selected by ASCO President Lynn M. Schuchter, MD, is “The Art and Science of Cancer Care: From Comfort to Cure.”
Dr. LeBlanc, a blood cancer specialist at Duke University, Durham, North Carolina, said the theme has been woven throughout the abstract and educational sessions. Most sessions will have at least one presentation related to how we support people — not only “when we cure them but also when we can’t cure them,” he said.
Topics will include patient well-being, comfort measures, and survivorship. And for the first time the plenary session will include a palliative care abstract that addresses whether or not palliative care can be delivered effectively through telemedicine. The session is on Sunday, June 2.
Other potentially practice changing plenary abstracts tackle immunotherapy combinations for resectable melanoma, perioperative chemotherapy vs neoadjuvant chemoradiation for esophageal cancer, and osimertinib after definitive chemoradiotherapy for unresectable non–small cell lung cancer.
ASCO is piloting a slightly different format for research presentations this year. Instead of starting with context and background, speakers have been asked to present study results upfront as well as repeat them at the end of the talk. The reason behind the tweak is that engagement and retention tend to be better when results are presented upfront, instead of just at the end of a talk.
A popular session — ASCO Voices — has also been given a more central position in the conference: Friday, May 31. In this session, speakers will give short presentations about their personal experiences as providers, researchers, or patients.
ASCO Voices is a relatively recent addition to the meeting that has grown and gotten better. The talks are usually “very powerful narratives” that remind clinicians about “the importance of what they’re doing each day,” Dr. LeBlanc said.
Snippets of the talks will be played while people wait for sessions to begin at the meeting, so attendees who miss the Friday talks can still hear them.
In terms of educational sessions, Dr. LeBlanc highlighted two that might be of general interest to practicing oncologists: A joint ASCO/American Association for Cancer Research session entitled “Drugging the ‘Undruggable’ Target: Successes, Challenges, and the Road Ahead,” on Sunday morning and “Common Sense Oncology: Equity, Value, and Outcomes That Matter” on Monday morning.
As a blood cancer specialist, he said he is particularly interested in the topline results from the ASC4FIRST trial of asciminib, a newer kinase inhibitor, in newly diagnosed chronic myeloid leukemia, presented on Friday.
As in past years, this news organization will be on hand providing coverage with a dedicated team of reporters, editors, and videographers. Stop by our exhibit hall booth — number 26030 — to learn about the tools we offer to support your practice.
A version of this article appeared on Medscape.com .
From its origins in 1964, ASCO’s annual event has grown to become the world’s largest clinical oncology meeting, drawing attendees from across the globe.
More than 7000 abstracts were submitted for this year’s meeting a new record — and over 5000 were selected for presentation.
This year’s chair of the Annual Meeting Education Committee, Thomas William LeBlanc, MD, told us he has been attending the meeting since his training days more than a decade ago.
The event is “just incredibly empowering and energizing,” Dr. LeBlanc said, with opportunities to catch up with old colleagues and meet new ones, learn how far oncology has come and where it’s headed, and hear clinical pearls to take back the clinic.
This year’s theme, selected by ASCO President Lynn M. Schuchter, MD, is “The Art and Science of Cancer Care: From Comfort to Cure.”
Dr. LeBlanc, a blood cancer specialist at Duke University, Durham, North Carolina, said the theme has been woven throughout the abstract and educational sessions. Most sessions will have at least one presentation related to how we support people — not only “when we cure them but also when we can’t cure them,” he said.
Topics will include patient well-being, comfort measures, and survivorship. And for the first time the plenary session will include a palliative care abstract that addresses whether or not palliative care can be delivered effectively through telemedicine. The session is on Sunday, June 2.
Other potentially practice changing plenary abstracts tackle immunotherapy combinations for resectable melanoma, perioperative chemotherapy vs neoadjuvant chemoradiation for esophageal cancer, and osimertinib after definitive chemoradiotherapy for unresectable non–small cell lung cancer.
ASCO is piloting a slightly different format for research presentations this year. Instead of starting with context and background, speakers have been asked to present study results upfront as well as repeat them at the end of the talk. The reason behind the tweak is that engagement and retention tend to be better when results are presented upfront, instead of just at the end of a talk.
A popular session — ASCO Voices — has also been given a more central position in the conference: Friday, May 31. In this session, speakers will give short presentations about their personal experiences as providers, researchers, or patients.
ASCO Voices is a relatively recent addition to the meeting that has grown and gotten better. The talks are usually “very powerful narratives” that remind clinicians about “the importance of what they’re doing each day,” Dr. LeBlanc said.
Snippets of the talks will be played while people wait for sessions to begin at the meeting, so attendees who miss the Friday talks can still hear them.
In terms of educational sessions, Dr. LeBlanc highlighted two that might be of general interest to practicing oncologists: A joint ASCO/American Association for Cancer Research session entitled “Drugging the ‘Undruggable’ Target: Successes, Challenges, and the Road Ahead,” on Sunday morning and “Common Sense Oncology: Equity, Value, and Outcomes That Matter” on Monday morning.
As a blood cancer specialist, he said he is particularly interested in the topline results from the ASC4FIRST trial of asciminib, a newer kinase inhibitor, in newly diagnosed chronic myeloid leukemia, presented on Friday.
As in past years, this news organization will be on hand providing coverage with a dedicated team of reporters, editors, and videographers. Stop by our exhibit hall booth — number 26030 — to learn about the tools we offer to support your practice.
A version of this article appeared on Medscape.com .
Could a Fungal Infection Cause a Future Pandemic?
The principle of resilience and survival is crucial for medically significant fungi. These microorganisms are far from creating the postapocalyptic scenario depicted in TV series like The Last of Us, and much work is necessary to learn more about them. Accurate statistics on fungal infections, accompanied by clinical histories, simple laboratory tests, new antifungals, and a necessary One Health approach are lacking.
The entomopathogenic fungus Ophiocordyceps unilateralis was made notorious by the TV series, but for now, it only manages to control the brains of some ants at will. Luckily, there are no signs that fungi affecting humans are inclined to create zombies.
What is clear is that the world belongs to the kingdom of fungi and that fungi are everywhere. There are already close to 150,000 described species, but millions remain to be discovered. They abound in decomposing organic matter, soil, or animal excrement, including that of bats and pigeons. Some fungi have even managed to find a home in hospitals. Lastly, we must not forget those that establish themselves in the human microbiome.
Given such diversity, it is legitimate to ask whether any of them could be capable of generating new pandemics. Could the forgotten Cryptococcus neoformans, Aspergillus fumigatus, or Histoplasma species, among others, trigger new health emergencies on the scale of the one generated by SARS-CoV-2?
We cannot forget that a coronavirus has already confirmed that reality can surpass fiction. However, Edith Sánchez Paredes, a biologist, doctor in biomedical sciences, and specialist in medical mycology, provided a reassuring response to Medscape Spanish Edition on this point.
“That would be very difficult to see because the way fungal infections are acquired is not from person to person, in most cases,” said Dr. Sánchez Paredes, from the Mycology Unit of the Faculty of Medicine at the National Autonomous University of Mexico.
Close to 300 species have already been classified as pathogenic in humans. Although the numbers are not precise and are increasing, it is estimated that around 1,500,000 people worldwide die each year of systemic fungal infections.
“However, it is important to emphasize that establishment of an infection depends not only on the causal agent. A crucial factor is the host, in this case, the human. Generally, these types of infections will develop in individuals with some deficiency in their immune system. The more deficient the immune response, the more likely a fungal infection may occur,” stated Dr. Sánchez Paredes.
The possibility of a pandemic like the one experienced with SARS-CoV-2 in the short term is remote, but the threat posed by fungal infections persists.
In 2022, the World Health Organization (WHO) defined a priority list of pathogenic fungi, with the aim of guiding actions to control them. It is mentioned there that invasive fungal diseases are on the rise worldwide, particularly in immunocompromised populations.
“Despite the growing concern, fungal infections receive very little attention and resources, leading to a paucity of quality data on fungal disease distribution and antifungal resistance patterns. Consequently, it is impossible to estimate their exact burden,” as stated in the document.
In line with this, an article published in Mycoses in 2022 concluded that fungal infections are neglected diseases in Latin America. Among other difficulties, deficiencies in access to tests such as polymerase chain reaction or serum detection of beta-1,3-D-glucan have been reported there.
In terms of treatments, most countries encounter problems with access to liposomal amphotericin B and new azoles, such as posaconazole and isavuconazole.
“Unfortunately, in Latin America, we suffer from a poor infrastructure for diagnosing fungal infections; likewise, we have limited access to antifungals available in the global market. What’s more, we lack reliable data on the epidemiology of fungal infections in the region, so many times governments are unaware of the true extent of the problem,” said Rogelio de Jesús Treviño Rangel, PhD, a medical microbiologist and expert in clinical mycology, professor, and researcher at the Faculty of Medicine of the Autonomous University of Nuevo León in Mexico.
Need for More Medical Mycology Training
Dr. Fernando Messina is a medical mycologist with the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital in Buenos Aires, Argentina. He has noted an increase in the number of cases of cryptococcosis, histoplasmosis, and aspergillosis in his daily practice.
“Particularly, pulmonary aspergillosis is steadily increasing. This is because many patients have structural lung alterations that favor the appearance of this mycosis. This is related to the increase in cases of tuberculosis and the rise in life expectancy of patients with chronic obstructive pulmonary disease or other pulmonary or systemic diseases,” Dr. Messina stated.
For Dr. Messina, the main obstacle in current clinical practice is the low level of awareness among nonspecialist physicians regarding the presence of systemic fungal infections, and because these infections are more common than realized, it is vital to consider fungal etiology before starting empirical antibiotic therapy.
“Health professionals usually do not think about mycoses because mycology occupies a very small space in medical education at universities. As the Venezuelan mycologist Gioconda Cunto de San Blas once said, ‘Mycology is the Cinderella of microbiology.’ To change this, we need to give more space to mycoses in undergraduate and postgraduate studies,” Dr. Messina asserted.
He added, “The main challenge is to train professionals with an emphasis on the clinical interpretation of cases. Current medicine has a strong trend toward molecular biology and the use of rapid diagnostic methods, without considering the clinical symptoms or the patient’s history. Determinations are very useful, but it is necessary to interpret the results.”
Dr. Messina sees it as unlikely in the short term for a pandemic to be caused by fungi, but if it were to occur, he believes it would happen in healthcare systems in regions that are not prepared in terms of infrastructure. However, as seen in the health emergency resulting from SARS-CoV-2, he thinks the impact would be mitigated by the performance of healthcare professionals.
“In general, we have the ability to adapt to any adverse situation or change — although it is clear that we need more doctors, biochemists, and microbiologists trained in mycology,” emphasized Dr. Messina.
More than 40 interns pass through Muñiz Hospital each year. They are doctors and biochemists from Argentina, other countries in the region, or even Europe, seeking to enhance their training in mycology. Regarding fungal infection laboratory work, the interest lies in learning to use traditional techniques and innovative molecular methods.
“Rapid diagnostic methods, especially the detection of circulating antigens, have marked a change in the prognosis of deep mycosis in immunocompromised hosts. The possibility of screening and monitoring in this group of patients is very important and has a great benefit,” said Gabriela Santiso, PhD, a biochemist and head of the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital.
According to Dr. Santiso, the current landscape includes the ability to identify genus and species, which can help in understanding resistance to antifungals. Furthermore, conducting sensitivity tests to these drugs, using standardized commercial methods, also provides timely information for treatment.
But Dr. Santiso warns that Latin America is a vast region with great disparity in human and technological resources. Although most countries in the region have networks facilitating access to timely diagnosis, resources are generally more available in major urban centers.
This often clashes with the epidemiology of most fungal infections. “Let’s not forget that many fungal pathologies affect low-income people who have difficulties accessing health centers, which sometimes turns them into chronic diseases that are hard to treat,” Dr. Santiso pointed out.
In mycology laboratories, the biggest cost is incurred by new diagnostic tests, such as those allowing molecular identification. Conventional methods are not usually expensive, but they require time and effort to train human resources to handle them.
Because new methodologies are not always available or easily accessible throughout the region, Dr. Santiso recommended not neglecting traditional mycological techniques. “Molecular methods, rapid diagnostic methods, and conventional mycology techniques are complementary and not mutually exclusive tests. Continuous training and updating are needed in this area,” she emphasized.
Why Are Resistant Fungal Infections Becoming Increasingly Common?
The first barrier for fungi to cause infection in humans is body temperature; most of them cannot withstand 37 °C. However, they also struggle to evade the immune response that is activated when they try to enter the body.
“We are normally exposed to many of these fungi, almost all the time, but if our immune system is adequate, it may not go beyond a mild infection, in most cases subclinical, which will resolve quickly,” Dr. Sánchez Paredes stated.
However, according to Dr. Sánchez Paredes, if the immune response is weak, “the fungus will have no trouble establishing itself in our organs. Some are even part of our microbiota, such as Candida albicans, which in the face of an imbalance or immunocompromise, can lead to serious infections.”
It is clear that the population at risk for immunosuppression has increased. According to the WHO, this is due to the high prevalence of such diseases as tuberculosis, cancer, and HIV infection, among others.
But the WHO also believes that the increase in fungal infections is related to greater population access to critical care units, invasive procedures, chemotherapy, or immunotherapy treatments.
Furthermore, factors related to the fungus itself and the environment play a role. “These organisms have enzymes, proteins, and other molecules that allow them to survive in the environment in which they normally inhabit. When they face a new and stressful one, they must express other molecules that will allow them to survive. All of this helps them evade elements of the immune system, antifungals, and, of course, body temperature,” according to Dr. Sánchez Paredes.
It is possible that climate change is also behind the noticeable increase in fungal infections and that this crisis may have an even greater impact in the future. The temperature of the environment has increased, and fungi will have to adapt to the planet’s temperature, to the point where body temperature may no longer be a significant barrier for them.
Environmental changes would also be responsible for modifications in the distribution of endemic mycoses, and it is believed that fungi will more frequently find new ecological niches, be able to survive in other environments, and alter distribution zones.
This is what is happening between Mexico and the United States with coccidioidomycosis, or valley fever. “We will begin to see cases of some mycoses where they were not normally seen, so we will have to conduct more studies to confirm that the fungus is inhabiting these new areas or is simply appearing in new sites owing to migration and the great mobility of populations,” Dr. Sánchez Paredes said.
Finally, exposure to environmental factors would partly be responsible for the increasing resistance to first-line antifungals observed in these microorganisms. This seems to be the case with A. fumigatus when exposed to azoles used as fungicides in agriculture.
One Health in Fungal Infections
The increasing resistance to antifungals is a clear testament that human, animal, and environmental health are interconnected. This is why a multidisciplinary approach that adopts the perspective of One Health is necessary for its management.
“The use of fungicides in agriculture, structurally similar to the azoles used in clinics, generates resistance in Aspergillus fumigatus found in the environment. These fungi in humans can be associated with infections that do not respond to first-line treatment,” explained Carlos Arturo Álvarez, an infectious diseases physician and professor at the Faculty of Medicine at the National University of Colombia.
According to Dr. Álvarez, the approach to control them should not only focus on the search for diagnostic methods that allow early detection of antifungal resistance or research on new antifungal treatments. He believes that progress must also be made with strategies that allow for the proper use of antifungals in agriculture.
“Unfortunately, the One Health approach is not yet well implemented in the region, and in my view, there is a lack of articulation in the different sectors. That is, there is a need for true coordination between government offices of agriculture, animal and human health, academia, and international organizations. This is not happening yet, and I believe we are in the initial stage of visibility,” Dr. Álvarez opined.
Veterinary public health is another pillar of the aforementioned approach. For various reasons, animals experience a higher frequency of fungal infections. A few carry and transmit true zoonoses that affect human health, but most often, animals act only as sentinels indicating a potential source of transmission.
Carolina Segundo Zaragoza, PhD, has worked in veterinary mycology for 30 years. She currently heads the veterinary mycology laboratory at the Animal Production Teaching, Research, and Extension Center in Altiplano, under the Faculty of Veterinary Medicine and Animal Husbandry at the National Autonomous University of Mexico. Because she has frequent contact with specialists in human mycology, during her professional career she has received several patient consultations, most of which were for cutaneous mycoses.
“They detect some dermatomycosis and realize that the common factor is owning a companion animal or a production animal with which the patient has contact. Both animals and humans present the same type of lesions, and then comes the question: Who infected whom? I remind them that the main source of infection is the soil and that animals should not be blamed in the first instance,” Dr. Segundo Zaragoza clarified.
She is currently collaborating on a research project analyzing the presence of Coccidioides immitis in the soil. This pathogen is responsible for coccidioidomycosis in dogs and humans, and she sees with satisfaction how these types of initiatives, which include some components of the One Health vision, are becoming more common in Mexico.
“Fortunately, human mycologists are increasingly providing more space for the dissemination of veterinary mycology. So I have had the opportunity to be invited to different forums on medical mycology to present the clinical cases we can have in animals and talk about the research projects we carry out. I have more and more opportunities to conduct joint research with human mycologists and veterinary doctors,” she said.
Dr. Segundo Zaragoza believes that to better implement the One Health vision, standardizing the criteria for detecting, diagnosing, and treating mycoses is necessary. She considers that teamwork will be key to achieving the common goal of safeguarding the well-being and health of humans and animals.
Alarms Sound for Candida auris
The WHO included the yeast Candida auris in its group of pathogens with critical priority, and since 2009, it has raised alarm owing to the ease with which it grows in hospitals. In that setting, C auris is known for its high transmissibility, its ability to cause outbreaks, and the high mortality rate from disseminated infections.
“It has been a concern for the mycological community because it shows resistance to most antifungals used clinically, mainly azoles, but also for causing epidemic outbreaks,” emphasized Dr. Sánchez Paredes.
Its mode of transmission is not very clear, but it has been documented to be present on the skin and persist in hospital materials and furniture. It causes nosocomial infections in critically ill patients, such as those in intensive care, and those with cancer or who have received a transplant.
Risk factors for its development include renal insufficiency, hospital stays of more than 15 days, mechanical ventilation, central lines, use of parenteral nutrition, and presence of sepsis.
As for other mycoses, there are no precise studies reporting global incidence rates, but the trend indicates an increase in the detection of outbreaks in various countries lately — something that began to be visible during the COVID-19 pandemic.
In Mexico, Dr. Treviño Rangel and colleagues from Nuevo León reported the first case of candidemia caused by this agent. It occurred in May 2020 and involved a 58-year-old woman with a history of severe endometriosis and multiple complications in the gastrointestinal tract. The patient’s condition improved favorably thanks to antifungal therapy with caspofungin and liposomal amphotericin B.
However, 3 months after that episode, the group reported an outbreak of C. auris at the same hospital in 12 critically ill patients co-infected with SARS-CoV-2. All were on mechanical ventilation, had peripherally inserted central catheters and urinary catheters, and had a prolonged hospital stay (20-70 days). The mortality in patients with candidemia in this cohort was 83.3%.
Open Ending
As seen in some science fiction series, fungal infections in the region still have an open ending, and Global Action For Fungal Infections (GAFFI) has estimated that with better diagnostics and treatments, deaths caused by fungi could decrease to less than 750,000 per year worldwide.
But if everything continues as is, some aspects of what is to come may resemble the dystopia depicted in The Last of Us. No zombies, but emerging and reemerging fungi in a chaotic distribution, and resistant to all established treatments.
“The risk factors of patients and their immune status, combined with the behavior of mycoses, bring a complicated scenario. But therapeutic failure resulting from multidrug resistance to antifungals could make it catastrophic,” Dr. Sánchez Paredes summarized.
At the moment, there are only four families of drugs capable of counteracting fungal infections — and as mentioned, some are already scarce in Latin America’s hospital pharmacies.
“Historically, fungal infections have been given less importance than those caused by viruses or bacteria. Even in some developed countries, the true extent of morbidity and mortality they present is unknown. This results in less investment in the development of new antifungal molecules because knowledge is lacking about the incidence and prevalence of these diseases,” Dr. Treviño Rangel pointed out.
He added that the main limitation for the development of new drugs is economic. “Unfortunately, not many pharmaceutical companies are willing to invest in the development of new antifungals, and there are no government programs specifically promoting and supporting research into new therapeutic options against these neglected diseases,” he asserted.
Development of vaccines to prevent fungal infections faces the same barriers. Although, according to Dr. Treviño Rangel, the difficulties are compounded by the great similarity between fungal cells and human cells. This makes it possible for harmful cross-reactivity to occur. In addition, because most severe fungal infections occur in individuals with immunosuppression, a vaccine would need to trigger an adequate immune response despite this issue.
Meanwhile, fungi quietly continue to do what they do best: resist and survive. For millions of years, they have mutated and adapted to new environments. Some theories even blame them for the extinction of dinosaurs and the subsequent rise of mammals. They exist on the edge of life and death, decomposing and creating. There is consensus that at the moment, it does not seem feasible for them to generate a pandemic like the one due to SARS-CoV-2, given their transmission mechanism. But who is willing to rule out that this may not happen in the long or medium term?
Dr. Sánchez Paredes, Dr. Treviño Rangel, Dr. Messina, Dr. Santiso, Dr. Álvarez, and Dr. Segundo Zaragoza have declared no relevant financial conflicts of interest.
This story was translated from Medscape Spanish Edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The principle of resilience and survival is crucial for medically significant fungi. These microorganisms are far from creating the postapocalyptic scenario depicted in TV series like The Last of Us, and much work is necessary to learn more about them. Accurate statistics on fungal infections, accompanied by clinical histories, simple laboratory tests, new antifungals, and a necessary One Health approach are lacking.
The entomopathogenic fungus Ophiocordyceps unilateralis was made notorious by the TV series, but for now, it only manages to control the brains of some ants at will. Luckily, there are no signs that fungi affecting humans are inclined to create zombies.
What is clear is that the world belongs to the kingdom of fungi and that fungi are everywhere. There are already close to 150,000 described species, but millions remain to be discovered. They abound in decomposing organic matter, soil, or animal excrement, including that of bats and pigeons. Some fungi have even managed to find a home in hospitals. Lastly, we must not forget those that establish themselves in the human microbiome.
Given such diversity, it is legitimate to ask whether any of them could be capable of generating new pandemics. Could the forgotten Cryptococcus neoformans, Aspergillus fumigatus, or Histoplasma species, among others, trigger new health emergencies on the scale of the one generated by SARS-CoV-2?
We cannot forget that a coronavirus has already confirmed that reality can surpass fiction. However, Edith Sánchez Paredes, a biologist, doctor in biomedical sciences, and specialist in medical mycology, provided a reassuring response to Medscape Spanish Edition on this point.
“That would be very difficult to see because the way fungal infections are acquired is not from person to person, in most cases,” said Dr. Sánchez Paredes, from the Mycology Unit of the Faculty of Medicine at the National Autonomous University of Mexico.
Close to 300 species have already been classified as pathogenic in humans. Although the numbers are not precise and are increasing, it is estimated that around 1,500,000 people worldwide die each year of systemic fungal infections.
“However, it is important to emphasize that establishment of an infection depends not only on the causal agent. A crucial factor is the host, in this case, the human. Generally, these types of infections will develop in individuals with some deficiency in their immune system. The more deficient the immune response, the more likely a fungal infection may occur,” stated Dr. Sánchez Paredes.
The possibility of a pandemic like the one experienced with SARS-CoV-2 in the short term is remote, but the threat posed by fungal infections persists.
In 2022, the World Health Organization (WHO) defined a priority list of pathogenic fungi, with the aim of guiding actions to control them. It is mentioned there that invasive fungal diseases are on the rise worldwide, particularly in immunocompromised populations.
“Despite the growing concern, fungal infections receive very little attention and resources, leading to a paucity of quality data on fungal disease distribution and antifungal resistance patterns. Consequently, it is impossible to estimate their exact burden,” as stated in the document.
In line with this, an article published in Mycoses in 2022 concluded that fungal infections are neglected diseases in Latin America. Among other difficulties, deficiencies in access to tests such as polymerase chain reaction or serum detection of beta-1,3-D-glucan have been reported there.
In terms of treatments, most countries encounter problems with access to liposomal amphotericin B and new azoles, such as posaconazole and isavuconazole.
“Unfortunately, in Latin America, we suffer from a poor infrastructure for diagnosing fungal infections; likewise, we have limited access to antifungals available in the global market. What’s more, we lack reliable data on the epidemiology of fungal infections in the region, so many times governments are unaware of the true extent of the problem,” said Rogelio de Jesús Treviño Rangel, PhD, a medical microbiologist and expert in clinical mycology, professor, and researcher at the Faculty of Medicine of the Autonomous University of Nuevo León in Mexico.
Need for More Medical Mycology Training
Dr. Fernando Messina is a medical mycologist with the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital in Buenos Aires, Argentina. He has noted an increase in the number of cases of cryptococcosis, histoplasmosis, and aspergillosis in his daily practice.
“Particularly, pulmonary aspergillosis is steadily increasing. This is because many patients have structural lung alterations that favor the appearance of this mycosis. This is related to the increase in cases of tuberculosis and the rise in life expectancy of patients with chronic obstructive pulmonary disease or other pulmonary or systemic diseases,” Dr. Messina stated.
For Dr. Messina, the main obstacle in current clinical practice is the low level of awareness among nonspecialist physicians regarding the presence of systemic fungal infections, and because these infections are more common than realized, it is vital to consider fungal etiology before starting empirical antibiotic therapy.
“Health professionals usually do not think about mycoses because mycology occupies a very small space in medical education at universities. As the Venezuelan mycologist Gioconda Cunto de San Blas once said, ‘Mycology is the Cinderella of microbiology.’ To change this, we need to give more space to mycoses in undergraduate and postgraduate studies,” Dr. Messina asserted.
He added, “The main challenge is to train professionals with an emphasis on the clinical interpretation of cases. Current medicine has a strong trend toward molecular biology and the use of rapid diagnostic methods, without considering the clinical symptoms or the patient’s history. Determinations are very useful, but it is necessary to interpret the results.”
Dr. Messina sees it as unlikely in the short term for a pandemic to be caused by fungi, but if it were to occur, he believes it would happen in healthcare systems in regions that are not prepared in terms of infrastructure. However, as seen in the health emergency resulting from SARS-CoV-2, he thinks the impact would be mitigated by the performance of healthcare professionals.
“In general, we have the ability to adapt to any adverse situation or change — although it is clear that we need more doctors, biochemists, and microbiologists trained in mycology,” emphasized Dr. Messina.
More than 40 interns pass through Muñiz Hospital each year. They are doctors and biochemists from Argentina, other countries in the region, or even Europe, seeking to enhance their training in mycology. Regarding fungal infection laboratory work, the interest lies in learning to use traditional techniques and innovative molecular methods.
“Rapid diagnostic methods, especially the detection of circulating antigens, have marked a change in the prognosis of deep mycosis in immunocompromised hosts. The possibility of screening and monitoring in this group of patients is very important and has a great benefit,” said Gabriela Santiso, PhD, a biochemist and head of the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital.
According to Dr. Santiso, the current landscape includes the ability to identify genus and species, which can help in understanding resistance to antifungals. Furthermore, conducting sensitivity tests to these drugs, using standardized commercial methods, also provides timely information for treatment.
But Dr. Santiso warns that Latin America is a vast region with great disparity in human and technological resources. Although most countries in the region have networks facilitating access to timely diagnosis, resources are generally more available in major urban centers.
This often clashes with the epidemiology of most fungal infections. “Let’s not forget that many fungal pathologies affect low-income people who have difficulties accessing health centers, which sometimes turns them into chronic diseases that are hard to treat,” Dr. Santiso pointed out.
In mycology laboratories, the biggest cost is incurred by new diagnostic tests, such as those allowing molecular identification. Conventional methods are not usually expensive, but they require time and effort to train human resources to handle them.
Because new methodologies are not always available or easily accessible throughout the region, Dr. Santiso recommended not neglecting traditional mycological techniques. “Molecular methods, rapid diagnostic methods, and conventional mycology techniques are complementary and not mutually exclusive tests. Continuous training and updating are needed in this area,” she emphasized.
Why Are Resistant Fungal Infections Becoming Increasingly Common?
The first barrier for fungi to cause infection in humans is body temperature; most of them cannot withstand 37 °C. However, they also struggle to evade the immune response that is activated when they try to enter the body.
“We are normally exposed to many of these fungi, almost all the time, but if our immune system is adequate, it may not go beyond a mild infection, in most cases subclinical, which will resolve quickly,” Dr. Sánchez Paredes stated.
However, according to Dr. Sánchez Paredes, if the immune response is weak, “the fungus will have no trouble establishing itself in our organs. Some are even part of our microbiota, such as Candida albicans, which in the face of an imbalance or immunocompromise, can lead to serious infections.”
It is clear that the population at risk for immunosuppression has increased. According to the WHO, this is due to the high prevalence of such diseases as tuberculosis, cancer, and HIV infection, among others.
But the WHO also believes that the increase in fungal infections is related to greater population access to critical care units, invasive procedures, chemotherapy, or immunotherapy treatments.
Furthermore, factors related to the fungus itself and the environment play a role. “These organisms have enzymes, proteins, and other molecules that allow them to survive in the environment in which they normally inhabit. When they face a new and stressful one, they must express other molecules that will allow them to survive. All of this helps them evade elements of the immune system, antifungals, and, of course, body temperature,” according to Dr. Sánchez Paredes.
It is possible that climate change is also behind the noticeable increase in fungal infections and that this crisis may have an even greater impact in the future. The temperature of the environment has increased, and fungi will have to adapt to the planet’s temperature, to the point where body temperature may no longer be a significant barrier for them.
Environmental changes would also be responsible for modifications in the distribution of endemic mycoses, and it is believed that fungi will more frequently find new ecological niches, be able to survive in other environments, and alter distribution zones.
This is what is happening between Mexico and the United States with coccidioidomycosis, or valley fever. “We will begin to see cases of some mycoses where they were not normally seen, so we will have to conduct more studies to confirm that the fungus is inhabiting these new areas or is simply appearing in new sites owing to migration and the great mobility of populations,” Dr. Sánchez Paredes said.
Finally, exposure to environmental factors would partly be responsible for the increasing resistance to first-line antifungals observed in these microorganisms. This seems to be the case with A. fumigatus when exposed to azoles used as fungicides in agriculture.
One Health in Fungal Infections
The increasing resistance to antifungals is a clear testament that human, animal, and environmental health are interconnected. This is why a multidisciplinary approach that adopts the perspective of One Health is necessary for its management.
“The use of fungicides in agriculture, structurally similar to the azoles used in clinics, generates resistance in Aspergillus fumigatus found in the environment. These fungi in humans can be associated with infections that do not respond to first-line treatment,” explained Carlos Arturo Álvarez, an infectious diseases physician and professor at the Faculty of Medicine at the National University of Colombia.
According to Dr. Álvarez, the approach to control them should not only focus on the search for diagnostic methods that allow early detection of antifungal resistance or research on new antifungal treatments. He believes that progress must also be made with strategies that allow for the proper use of antifungals in agriculture.
“Unfortunately, the One Health approach is not yet well implemented in the region, and in my view, there is a lack of articulation in the different sectors. That is, there is a need for true coordination between government offices of agriculture, animal and human health, academia, and international organizations. This is not happening yet, and I believe we are in the initial stage of visibility,” Dr. Álvarez opined.
Veterinary public health is another pillar of the aforementioned approach. For various reasons, animals experience a higher frequency of fungal infections. A few carry and transmit true zoonoses that affect human health, but most often, animals act only as sentinels indicating a potential source of transmission.
Carolina Segundo Zaragoza, PhD, has worked in veterinary mycology for 30 years. She currently heads the veterinary mycology laboratory at the Animal Production Teaching, Research, and Extension Center in Altiplano, under the Faculty of Veterinary Medicine and Animal Husbandry at the National Autonomous University of Mexico. Because she has frequent contact with specialists in human mycology, during her professional career she has received several patient consultations, most of which were for cutaneous mycoses.
“They detect some dermatomycosis and realize that the common factor is owning a companion animal or a production animal with which the patient has contact. Both animals and humans present the same type of lesions, and then comes the question: Who infected whom? I remind them that the main source of infection is the soil and that animals should not be blamed in the first instance,” Dr. Segundo Zaragoza clarified.
She is currently collaborating on a research project analyzing the presence of Coccidioides immitis in the soil. This pathogen is responsible for coccidioidomycosis in dogs and humans, and she sees with satisfaction how these types of initiatives, which include some components of the One Health vision, are becoming more common in Mexico.
“Fortunately, human mycologists are increasingly providing more space for the dissemination of veterinary mycology. So I have had the opportunity to be invited to different forums on medical mycology to present the clinical cases we can have in animals and talk about the research projects we carry out. I have more and more opportunities to conduct joint research with human mycologists and veterinary doctors,” she said.
Dr. Segundo Zaragoza believes that to better implement the One Health vision, standardizing the criteria for detecting, diagnosing, and treating mycoses is necessary. She considers that teamwork will be key to achieving the common goal of safeguarding the well-being and health of humans and animals.
Alarms Sound for Candida auris
The WHO included the yeast Candida auris in its group of pathogens with critical priority, and since 2009, it has raised alarm owing to the ease with which it grows in hospitals. In that setting, C auris is known for its high transmissibility, its ability to cause outbreaks, and the high mortality rate from disseminated infections.
“It has been a concern for the mycological community because it shows resistance to most antifungals used clinically, mainly azoles, but also for causing epidemic outbreaks,” emphasized Dr. Sánchez Paredes.
Its mode of transmission is not very clear, but it has been documented to be present on the skin and persist in hospital materials and furniture. It causes nosocomial infections in critically ill patients, such as those in intensive care, and those with cancer or who have received a transplant.
Risk factors for its development include renal insufficiency, hospital stays of more than 15 days, mechanical ventilation, central lines, use of parenteral nutrition, and presence of sepsis.
As for other mycoses, there are no precise studies reporting global incidence rates, but the trend indicates an increase in the detection of outbreaks in various countries lately — something that began to be visible during the COVID-19 pandemic.
In Mexico, Dr. Treviño Rangel and colleagues from Nuevo León reported the first case of candidemia caused by this agent. It occurred in May 2020 and involved a 58-year-old woman with a history of severe endometriosis and multiple complications in the gastrointestinal tract. The patient’s condition improved favorably thanks to antifungal therapy with caspofungin and liposomal amphotericin B.
However, 3 months after that episode, the group reported an outbreak of C. auris at the same hospital in 12 critically ill patients co-infected with SARS-CoV-2. All were on mechanical ventilation, had peripherally inserted central catheters and urinary catheters, and had a prolonged hospital stay (20-70 days). The mortality in patients with candidemia in this cohort was 83.3%.
Open Ending
As seen in some science fiction series, fungal infections in the region still have an open ending, and Global Action For Fungal Infections (GAFFI) has estimated that with better diagnostics and treatments, deaths caused by fungi could decrease to less than 750,000 per year worldwide.
But if everything continues as is, some aspects of what is to come may resemble the dystopia depicted in The Last of Us. No zombies, but emerging and reemerging fungi in a chaotic distribution, and resistant to all established treatments.
“The risk factors of patients and their immune status, combined with the behavior of mycoses, bring a complicated scenario. But therapeutic failure resulting from multidrug resistance to antifungals could make it catastrophic,” Dr. Sánchez Paredes summarized.
At the moment, there are only four families of drugs capable of counteracting fungal infections — and as mentioned, some are already scarce in Latin America’s hospital pharmacies.
“Historically, fungal infections have been given less importance than those caused by viruses or bacteria. Even in some developed countries, the true extent of morbidity and mortality they present is unknown. This results in less investment in the development of new antifungal molecules because knowledge is lacking about the incidence and prevalence of these diseases,” Dr. Treviño Rangel pointed out.
He added that the main limitation for the development of new drugs is economic. “Unfortunately, not many pharmaceutical companies are willing to invest in the development of new antifungals, and there are no government programs specifically promoting and supporting research into new therapeutic options against these neglected diseases,” he asserted.
Development of vaccines to prevent fungal infections faces the same barriers. Although, according to Dr. Treviño Rangel, the difficulties are compounded by the great similarity between fungal cells and human cells. This makes it possible for harmful cross-reactivity to occur. In addition, because most severe fungal infections occur in individuals with immunosuppression, a vaccine would need to trigger an adequate immune response despite this issue.
Meanwhile, fungi quietly continue to do what they do best: resist and survive. For millions of years, they have mutated and adapted to new environments. Some theories even blame them for the extinction of dinosaurs and the subsequent rise of mammals. They exist on the edge of life and death, decomposing and creating. There is consensus that at the moment, it does not seem feasible for them to generate a pandemic like the one due to SARS-CoV-2, given their transmission mechanism. But who is willing to rule out that this may not happen in the long or medium term?
Dr. Sánchez Paredes, Dr. Treviño Rangel, Dr. Messina, Dr. Santiso, Dr. Álvarez, and Dr. Segundo Zaragoza have declared no relevant financial conflicts of interest.
This story was translated from Medscape Spanish Edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The principle of resilience and survival is crucial for medically significant fungi. These microorganisms are far from creating the postapocalyptic scenario depicted in TV series like The Last of Us, and much work is necessary to learn more about them. Accurate statistics on fungal infections, accompanied by clinical histories, simple laboratory tests, new antifungals, and a necessary One Health approach are lacking.
The entomopathogenic fungus Ophiocordyceps unilateralis was made notorious by the TV series, but for now, it only manages to control the brains of some ants at will. Luckily, there are no signs that fungi affecting humans are inclined to create zombies.
What is clear is that the world belongs to the kingdom of fungi and that fungi are everywhere. There are already close to 150,000 described species, but millions remain to be discovered. They abound in decomposing organic matter, soil, or animal excrement, including that of bats and pigeons. Some fungi have even managed to find a home in hospitals. Lastly, we must not forget those that establish themselves in the human microbiome.
Given such diversity, it is legitimate to ask whether any of them could be capable of generating new pandemics. Could the forgotten Cryptococcus neoformans, Aspergillus fumigatus, or Histoplasma species, among others, trigger new health emergencies on the scale of the one generated by SARS-CoV-2?
We cannot forget that a coronavirus has already confirmed that reality can surpass fiction. However, Edith Sánchez Paredes, a biologist, doctor in biomedical sciences, and specialist in medical mycology, provided a reassuring response to Medscape Spanish Edition on this point.
“That would be very difficult to see because the way fungal infections are acquired is not from person to person, in most cases,” said Dr. Sánchez Paredes, from the Mycology Unit of the Faculty of Medicine at the National Autonomous University of Mexico.
Close to 300 species have already been classified as pathogenic in humans. Although the numbers are not precise and are increasing, it is estimated that around 1,500,000 people worldwide die each year of systemic fungal infections.
“However, it is important to emphasize that establishment of an infection depends not only on the causal agent. A crucial factor is the host, in this case, the human. Generally, these types of infections will develop in individuals with some deficiency in their immune system. The more deficient the immune response, the more likely a fungal infection may occur,” stated Dr. Sánchez Paredes.
The possibility of a pandemic like the one experienced with SARS-CoV-2 in the short term is remote, but the threat posed by fungal infections persists.
In 2022, the World Health Organization (WHO) defined a priority list of pathogenic fungi, with the aim of guiding actions to control them. It is mentioned there that invasive fungal diseases are on the rise worldwide, particularly in immunocompromised populations.
“Despite the growing concern, fungal infections receive very little attention and resources, leading to a paucity of quality data on fungal disease distribution and antifungal resistance patterns. Consequently, it is impossible to estimate their exact burden,” as stated in the document.
In line with this, an article published in Mycoses in 2022 concluded that fungal infections are neglected diseases in Latin America. Among other difficulties, deficiencies in access to tests such as polymerase chain reaction or serum detection of beta-1,3-D-glucan have been reported there.
In terms of treatments, most countries encounter problems with access to liposomal amphotericin B and new azoles, such as posaconazole and isavuconazole.
“Unfortunately, in Latin America, we suffer from a poor infrastructure for diagnosing fungal infections; likewise, we have limited access to antifungals available in the global market. What’s more, we lack reliable data on the epidemiology of fungal infections in the region, so many times governments are unaware of the true extent of the problem,” said Rogelio de Jesús Treviño Rangel, PhD, a medical microbiologist and expert in clinical mycology, professor, and researcher at the Faculty of Medicine of the Autonomous University of Nuevo León in Mexico.
Need for More Medical Mycology Training
Dr. Fernando Messina is a medical mycologist with the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital in Buenos Aires, Argentina. He has noted an increase in the number of cases of cryptococcosis, histoplasmosis, and aspergillosis in his daily practice.
“Particularly, pulmonary aspergillosis is steadily increasing. This is because many patients have structural lung alterations that favor the appearance of this mycosis. This is related to the increase in cases of tuberculosis and the rise in life expectancy of patients with chronic obstructive pulmonary disease or other pulmonary or systemic diseases,” Dr. Messina stated.
For Dr. Messina, the main obstacle in current clinical practice is the low level of awareness among nonspecialist physicians regarding the presence of systemic fungal infections, and because these infections are more common than realized, it is vital to consider fungal etiology before starting empirical antibiotic therapy.
“Health professionals usually do not think about mycoses because mycology occupies a very small space in medical education at universities. As the Venezuelan mycologist Gioconda Cunto de San Blas once said, ‘Mycology is the Cinderella of microbiology.’ To change this, we need to give more space to mycoses in undergraduate and postgraduate studies,” Dr. Messina asserted.
He added, “The main challenge is to train professionals with an emphasis on the clinical interpretation of cases. Current medicine has a strong trend toward molecular biology and the use of rapid diagnostic methods, without considering the clinical symptoms or the patient’s history. Determinations are very useful, but it is necessary to interpret the results.”
Dr. Messina sees it as unlikely in the short term for a pandemic to be caused by fungi, but if it were to occur, he believes it would happen in healthcare systems in regions that are not prepared in terms of infrastructure. However, as seen in the health emergency resulting from SARS-CoV-2, he thinks the impact would be mitigated by the performance of healthcare professionals.
“In general, we have the ability to adapt to any adverse situation or change — although it is clear that we need more doctors, biochemists, and microbiologists trained in mycology,” emphasized Dr. Messina.
More than 40 interns pass through Muñiz Hospital each year. They are doctors and biochemists from Argentina, other countries in the region, or even Europe, seeking to enhance their training in mycology. Regarding fungal infection laboratory work, the interest lies in learning to use traditional techniques and innovative molecular methods.
“Rapid diagnostic methods, especially the detection of circulating antigens, have marked a change in the prognosis of deep mycosis in immunocompromised hosts. The possibility of screening and monitoring in this group of patients is very important and has a great benefit,” said Gabriela Santiso, PhD, a biochemist and head of the Mycology Unit of the Francisco Javier Muñiz Infectious Diseases Hospital.
According to Dr. Santiso, the current landscape includes the ability to identify genus and species, which can help in understanding resistance to antifungals. Furthermore, conducting sensitivity tests to these drugs, using standardized commercial methods, also provides timely information for treatment.
But Dr. Santiso warns that Latin America is a vast region with great disparity in human and technological resources. Although most countries in the region have networks facilitating access to timely diagnosis, resources are generally more available in major urban centers.
This often clashes with the epidemiology of most fungal infections. “Let’s not forget that many fungal pathologies affect low-income people who have difficulties accessing health centers, which sometimes turns them into chronic diseases that are hard to treat,” Dr. Santiso pointed out.
In mycology laboratories, the biggest cost is incurred by new diagnostic tests, such as those allowing molecular identification. Conventional methods are not usually expensive, but they require time and effort to train human resources to handle them.
Because new methodologies are not always available or easily accessible throughout the region, Dr. Santiso recommended not neglecting traditional mycological techniques. “Molecular methods, rapid diagnostic methods, and conventional mycology techniques are complementary and not mutually exclusive tests. Continuous training and updating are needed in this area,” she emphasized.
Why Are Resistant Fungal Infections Becoming Increasingly Common?
The first barrier for fungi to cause infection in humans is body temperature; most of them cannot withstand 37 °C. However, they also struggle to evade the immune response that is activated when they try to enter the body.
“We are normally exposed to many of these fungi, almost all the time, but if our immune system is adequate, it may not go beyond a mild infection, in most cases subclinical, which will resolve quickly,” Dr. Sánchez Paredes stated.
However, according to Dr. Sánchez Paredes, if the immune response is weak, “the fungus will have no trouble establishing itself in our organs. Some are even part of our microbiota, such as Candida albicans, which in the face of an imbalance or immunocompromise, can lead to serious infections.”
It is clear that the population at risk for immunosuppression has increased. According to the WHO, this is due to the high prevalence of such diseases as tuberculosis, cancer, and HIV infection, among others.
But the WHO also believes that the increase in fungal infections is related to greater population access to critical care units, invasive procedures, chemotherapy, or immunotherapy treatments.
Furthermore, factors related to the fungus itself and the environment play a role. “These organisms have enzymes, proteins, and other molecules that allow them to survive in the environment in which they normally inhabit. When they face a new and stressful one, they must express other molecules that will allow them to survive. All of this helps them evade elements of the immune system, antifungals, and, of course, body temperature,” according to Dr. Sánchez Paredes.
It is possible that climate change is also behind the noticeable increase in fungal infections and that this crisis may have an even greater impact in the future. The temperature of the environment has increased, and fungi will have to adapt to the planet’s temperature, to the point where body temperature may no longer be a significant barrier for them.
Environmental changes would also be responsible for modifications in the distribution of endemic mycoses, and it is believed that fungi will more frequently find new ecological niches, be able to survive in other environments, and alter distribution zones.
This is what is happening between Mexico and the United States with coccidioidomycosis, or valley fever. “We will begin to see cases of some mycoses where they were not normally seen, so we will have to conduct more studies to confirm that the fungus is inhabiting these new areas or is simply appearing in new sites owing to migration and the great mobility of populations,” Dr. Sánchez Paredes said.
Finally, exposure to environmental factors would partly be responsible for the increasing resistance to first-line antifungals observed in these microorganisms. This seems to be the case with A. fumigatus when exposed to azoles used as fungicides in agriculture.
One Health in Fungal Infections
The increasing resistance to antifungals is a clear testament that human, animal, and environmental health are interconnected. This is why a multidisciplinary approach that adopts the perspective of One Health is necessary for its management.
“The use of fungicides in agriculture, structurally similar to the azoles used in clinics, generates resistance in Aspergillus fumigatus found in the environment. These fungi in humans can be associated with infections that do not respond to first-line treatment,” explained Carlos Arturo Álvarez, an infectious diseases physician and professor at the Faculty of Medicine at the National University of Colombia.
According to Dr. Álvarez, the approach to control them should not only focus on the search for diagnostic methods that allow early detection of antifungal resistance or research on new antifungal treatments. He believes that progress must also be made with strategies that allow for the proper use of antifungals in agriculture.
“Unfortunately, the One Health approach is not yet well implemented in the region, and in my view, there is a lack of articulation in the different sectors. That is, there is a need for true coordination between government offices of agriculture, animal and human health, academia, and international organizations. This is not happening yet, and I believe we are in the initial stage of visibility,” Dr. Álvarez opined.
Veterinary public health is another pillar of the aforementioned approach. For various reasons, animals experience a higher frequency of fungal infections. A few carry and transmit true zoonoses that affect human health, but most often, animals act only as sentinels indicating a potential source of transmission.
Carolina Segundo Zaragoza, PhD, has worked in veterinary mycology for 30 years. She currently heads the veterinary mycology laboratory at the Animal Production Teaching, Research, and Extension Center in Altiplano, under the Faculty of Veterinary Medicine and Animal Husbandry at the National Autonomous University of Mexico. Because she has frequent contact with specialists in human mycology, during her professional career she has received several patient consultations, most of which were for cutaneous mycoses.
“They detect some dermatomycosis and realize that the common factor is owning a companion animal or a production animal with which the patient has contact. Both animals and humans present the same type of lesions, and then comes the question: Who infected whom? I remind them that the main source of infection is the soil and that animals should not be blamed in the first instance,” Dr. Segundo Zaragoza clarified.
She is currently collaborating on a research project analyzing the presence of Coccidioides immitis in the soil. This pathogen is responsible for coccidioidomycosis in dogs and humans, and she sees with satisfaction how these types of initiatives, which include some components of the One Health vision, are becoming more common in Mexico.
“Fortunately, human mycologists are increasingly providing more space for the dissemination of veterinary mycology. So I have had the opportunity to be invited to different forums on medical mycology to present the clinical cases we can have in animals and talk about the research projects we carry out. I have more and more opportunities to conduct joint research with human mycologists and veterinary doctors,” she said.
Dr. Segundo Zaragoza believes that to better implement the One Health vision, standardizing the criteria for detecting, diagnosing, and treating mycoses is necessary. She considers that teamwork will be key to achieving the common goal of safeguarding the well-being and health of humans and animals.
Alarms Sound for Candida auris
The WHO included the yeast Candida auris in its group of pathogens with critical priority, and since 2009, it has raised alarm owing to the ease with which it grows in hospitals. In that setting, C auris is known for its high transmissibility, its ability to cause outbreaks, and the high mortality rate from disseminated infections.
“It has been a concern for the mycological community because it shows resistance to most antifungals used clinically, mainly azoles, but also for causing epidemic outbreaks,” emphasized Dr. Sánchez Paredes.
Its mode of transmission is not very clear, but it has been documented to be present on the skin and persist in hospital materials and furniture. It causes nosocomial infections in critically ill patients, such as those in intensive care, and those with cancer or who have received a transplant.
Risk factors for its development include renal insufficiency, hospital stays of more than 15 days, mechanical ventilation, central lines, use of parenteral nutrition, and presence of sepsis.
As for other mycoses, there are no precise studies reporting global incidence rates, but the trend indicates an increase in the detection of outbreaks in various countries lately — something that began to be visible during the COVID-19 pandemic.
In Mexico, Dr. Treviño Rangel and colleagues from Nuevo León reported the first case of candidemia caused by this agent. It occurred in May 2020 and involved a 58-year-old woman with a history of severe endometriosis and multiple complications in the gastrointestinal tract. The patient’s condition improved favorably thanks to antifungal therapy with caspofungin and liposomal amphotericin B.
However, 3 months after that episode, the group reported an outbreak of C. auris at the same hospital in 12 critically ill patients co-infected with SARS-CoV-2. All were on mechanical ventilation, had peripherally inserted central catheters and urinary catheters, and had a prolonged hospital stay (20-70 days). The mortality in patients with candidemia in this cohort was 83.3%.
Open Ending
As seen in some science fiction series, fungal infections in the region still have an open ending, and Global Action For Fungal Infections (GAFFI) has estimated that with better diagnostics and treatments, deaths caused by fungi could decrease to less than 750,000 per year worldwide.
But if everything continues as is, some aspects of what is to come may resemble the dystopia depicted in The Last of Us. No zombies, but emerging and reemerging fungi in a chaotic distribution, and resistant to all established treatments.
“The risk factors of patients and their immune status, combined with the behavior of mycoses, bring a complicated scenario. But therapeutic failure resulting from multidrug resistance to antifungals could make it catastrophic,” Dr. Sánchez Paredes summarized.
At the moment, there are only four families of drugs capable of counteracting fungal infections — and as mentioned, some are already scarce in Latin America’s hospital pharmacies.
“Historically, fungal infections have been given less importance than those caused by viruses or bacteria. Even in some developed countries, the true extent of morbidity and mortality they present is unknown. This results in less investment in the development of new antifungal molecules because knowledge is lacking about the incidence and prevalence of these diseases,” Dr. Treviño Rangel pointed out.
He added that the main limitation for the development of new drugs is economic. “Unfortunately, not many pharmaceutical companies are willing to invest in the development of new antifungals, and there are no government programs specifically promoting and supporting research into new therapeutic options against these neglected diseases,” he asserted.
Development of vaccines to prevent fungal infections faces the same barriers. Although, according to Dr. Treviño Rangel, the difficulties are compounded by the great similarity between fungal cells and human cells. This makes it possible for harmful cross-reactivity to occur. In addition, because most severe fungal infections occur in individuals with immunosuppression, a vaccine would need to trigger an adequate immune response despite this issue.
Meanwhile, fungi quietly continue to do what they do best: resist and survive. For millions of years, they have mutated and adapted to new environments. Some theories even blame them for the extinction of dinosaurs and the subsequent rise of mammals. They exist on the edge of life and death, decomposing and creating. There is consensus that at the moment, it does not seem feasible for them to generate a pandemic like the one due to SARS-CoV-2, given their transmission mechanism. But who is willing to rule out that this may not happen in the long or medium term?
Dr. Sánchez Paredes, Dr. Treviño Rangel, Dr. Messina, Dr. Santiso, Dr. Álvarez, and Dr. Segundo Zaragoza have declared no relevant financial conflicts of interest.
This story was translated from Medscape Spanish Edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
ASTRO Releases New EBRT Guideline for Symptomatic Bone Mets
The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.
The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.
In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
Indications for Palliative Radiation
EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.
For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.
Implementation of other Treatments Alongside Palliative Radiation
Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.
Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.
For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.
Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation
For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.
For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.
When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.
Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.
The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.
For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation
For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.
Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.
The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity
For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.
“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.
Limitations
While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.
Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.
The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.
The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.
In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
Indications for Palliative Radiation
EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.
For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.
Implementation of other Treatments Alongside Palliative Radiation
Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.
Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.
For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.
Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation
For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.
For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.
When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.
Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.
The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.
For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation
For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.
Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.
The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity
For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.
“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.
Limitations
While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.
Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.
The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.
The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.
In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
Indications for Palliative Radiation
EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.
For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.
Implementation of other Treatments Alongside Palliative Radiation
Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.
Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.
For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.
Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation
For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.
For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.
When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.
Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.
The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.
For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation
For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.
Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.
The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity
For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.
“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.
Limitations
While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.
Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.
FROM PRACTICAL RADIATION ONCOLOGY
ASCO Provides Guidance on CDK4/6 Inhibitors for Early Breast Cancer
TOPLINE:
METHODOLOGY:
- The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
- The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).
TAKEAWAY:
- Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
- Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
- For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
- Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
- Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.
IN PRACTICE:
This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.
SOURCE:
The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.
LIMITATIONS:
The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.
DISCLOSURES:
Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.
TOPLINE:
METHODOLOGY:
- The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
- The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).
TAKEAWAY:
- Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
- Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
- For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
- Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
- Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.
IN PRACTICE:
This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.
SOURCE:
The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.
LIMITATIONS:
The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.
DISCLOSURES:
Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.
TOPLINE:
METHODOLOGY:
- The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
- The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).
TAKEAWAY:
- Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
- Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
- For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
- Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
- Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.
IN PRACTICE:
This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.
SOURCE:
The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.
LIMITATIONS:
The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.
DISCLOSURES:
Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.
FROM JOURNAL OF CLINICAL ONCOLOGY
Obesity and Cancer: Untangling a Complex Web
According to the Centers for Disease Control and Prevention (CDC), over 684,000 Americans are diagnosed with an “obesity-associated” cancer each year.
The incidence of many of these cancers has been rising in recent years, particularly among younger people — a trend that sits in contrast with the overall decline in cancers with no established relationship to excess weight, such as lung and skin cancers.
Is obesity the new smoking? Not exactly.
While about 42% of cancers — including common ones such as colorectal and postmenopausal breast cancers — are considered obesity-related, only about 8% of incident cancers are attributed to excess body weight. People often develop those diseases regardless of weight.
Although plenty of evidence points to excess body fat as a cancer risk factor, it’s unclear at what point excess weight has an effect. Is gaining weight later in life, for instance, better or worse for cancer risk than being overweight or obese from a young age?
There’s another glaring knowledge gap: Does losing weight at some point in adulthood change the picture? In other words, how many of those 684,000 diagnoses might have been prevented if people shed excess pounds?
When it comes to weight and cancer risk, “there’s a lot we don’t know,” said Jennifer W. Bea, PhD, associate professor, health promotion sciences, University of Arizona, Tucson.
A Consistent but Complicated Relationship
Given the growing incidence of obesity — which currently affects about 42% of US adults and 20% of children and teenagers — it’s no surprise that many studies have delved into the potential effects of excess weight on cancer rates.
Although virtually all the evidence comes from large cohort studies, leaving the cause-effect question open, certain associations keep showing up.
“What we know is that, consistently, a higher body mass index [BMI] — particularly in the obese category — leads to a higher risk of multiple cancers,” said Jeffrey A. Meyerhardt, MD, MPH, codirector, Colon and Rectal Cancer Center, Dana-Farber Cancer Institute, Boston.
In a widely cited report published in The New England Journal of Medicine in 2016, the International Agency for Research on Cancer (IARC) analyzed over 1000 epidemiologic studies on body fat and cancer. The agency pointed to over a dozen cancers, including some of the most common and deadly, linked to excess body weight.
That list includes esophageal adenocarcinoma and endometrial cancer — associated with the highest risk — along with kidney, liver, stomach (gastric cardia), pancreatic, colorectal, postmenopausal breast, gallbladder, ovarian, and thyroid cancers, plus multiple myeloma and meningioma. There’s also “limited” evidence linking excess weight to additional cancer types, including aggressive prostate cancer and certain head and neck cancers.
At the same time, Dr. Meyerhardt said, many of those same cancers are also associated with issues that lead to, or coexist with, overweight and obesity, including poor diet, lack of exercise, and metabolic conditions such as diabetes.
It’s a complicated web, and it’s likely, Dr. Meyerhardt said, that high BMI both directly affects cancer risk and is part of a “causal pathway” of other factors that do.
Regarding direct effects, preclinical research has pointed to multiple ways in which excess body fat could contribute to cancer, said Karen M. Basen-Engquist, PhD, MPH, professor, Division of Cancer Prevention and Population Services, The University of Texas MD Anderson Cancer Center, Houston.
One broad mechanism to help explain the obesity-cancer link is chronic systemic inflammation because excess fat tissue can raise levels of substances in the body, such as tumor necrosis factor alpha and interleukin 6, which fuel inflammation. Excess fat also contributes to hyperinsulinemia — too much insulin in the blood — which can help promote the growth and spread of tumor cells.
But the underlying reasons also appear to vary by cancer type, Dr. Basen-Engquist said. With hormonally driven cancer types, such as breast and endometrial, excess body fat may alter hormone levels in ways that spur tumor growth. Extra fat tissue may, for example, convert androgens into estrogens, which could help feed estrogen-dependent tumors.
That, Dr. Basen-Engquist noted, could be why excess weight is associated with postmenopausal, not premenopausal, breast cancer: Before menopause, body fat is a relatively minor contributor to estrogen levels but becomes more important after menopause.
How Big Is the Effect?
While more than a dozen cancers have been consistently linked to excess weight, the strength of those associations varies considerably.
Endometrial and esophageal cancers are two that stand out. In the 2016 IARC analysis, people with severe obesity had a seven-times greater risk for endometrial cancer and 4.8-times greater risk for esophageal adenocarcinoma vs people with a normal BMI.
With other cancers, the risk increases for those with severe obesity compared with a normal BMI were far more modest: 10% for ovarian cancer, 30% for colorectal cancer, and 80% for kidney and stomach cancers, for example. For postmenopausal breast cancer, every five-unit increase in BMI was associated with a 10% relative risk increase.
A 2018 study from the American Cancer Society, which attempted to estimate the proportion of cancers in the United States attributable to modifiable risk factors — including alcohol consumption, ultraviolet rays exposure, and physical inactivity — found that smoking accounted for the highest proportion of cancer cases by a wide margin (19%), but excess weight came in second (7.8%).
Again, weight appeared to play a bigger role in certain cancers than others: An estimated 60% of endometrial cancers were linked to excess weight, as were roughly one third of esophageal, kidney, and liver cancers. At the other end of the spectrum, just over 11% of breast, 5% of colorectal, and 4% of ovarian cancers were attributable to excess weight.
Even at the lower end, those rates could make a big difference on the population level, especially for groups with higher rates of obesity.
CDC data show that obesity-related cancers are rising among women younger than 50 years, most rapidly among Hispanic women, and some less common obesity-related cancers, such as stomach, thyroid and pancreatic, are also rising among Black individuals and Hispanic Americans.
Obesity may be one reason for growing cancer disparities, said Leah Ferrucci, PhD, MPH, assistant professor, epidemiology, Yale School of Public Health, New Haven, Connecticut. But, she added, the evidence is limited because Black individuals and Hispanic Americans are understudied.
When Do Extra Pounds Matter?
When it comes to cancer risk, at what point in life does excess weight, or weight gain, matter? Is the standard weight gain in middle age, for instance, as hazardous as being overweight or obese from a young age?
Some evidence suggests there’s no “safe” time for putting on excess pounds.
A recent meta-analysis concluded that weight gain at any point after age 18 years is associated with incremental increases in the risk for postmenopausal breast cancer. A 2023 study in JAMA Network Open found a similar pattern with colorectal and other gastrointestinal cancers: People who had sustained overweight or obesity from age 20 years through middle age faced an increased risk of developing those cancers after age 55 years.
The timing of weight gain didn’t seem to matter either. The same elevated risk held among people who were normal weight in their younger years but became overweight after age 55 years.
Those studies focused on later-onset disease. But, in recent years, experts have tracked a troubling rise in early-onset cancers — those diagnosed before age 50 years — particularly gastrointestinal cancers.
An obvious question, Dr. Meyerhardt said, is whether the growing prevalence of obesity among young people is partly to blame.
There’s some data to support that, he said. An analysis from the Nurses’ Health Study II found that women with obesity had double the risk for early-onset colorectal cancer as those with a normal BMI. And every 5-kg increase in weight after age 18 years was associated with a 9% increase in colorectal cancer risk.
But while obesity trends probably partly explain the rise in early-onset cancers, there is likely more to the story, Dr. Meyerhardt said.
“I think all of us who see an increasing number of patients under 50 with colorectal cancer know there’s a fair number who do not fit that [high BMI] profile,” he said. “There’s a fair number over 50 who don’t either.”
Does Weight Loss Help?
With all the evidence pointing to high BMI as a cancer risk factor, a logical conclusion is that weight loss should reduce that excess risk. However, Dr. Bea said, there’s actually little data to support that, and what exists comes from observational studies.
Some research has focused on people who had substantial weight loss after bariatric surgery, with encouraging results. A study published in JAMA found that among 5053 people who underwent bariatric surgery, 2.9% developed an obesity-related cancer over 10 years compared with 4.9% in the nonsurgery group.
Most people, however, aim for less dramatic weight loss, with the help of diet and exercise or sometimes medication. Some evidence shows that a modest degree of weight loss may lower the risks for postmenopausal breast and endometrial cancers.
A 2020 pooled analysis found, for instance, that among women aged ≥ 50 years, those who lost as little as 2.0-4.5 kg, or 4.4-10.0 pounds, and kept it off for 10 years had a lower risk for breast cancer than women whose weight remained stable. And losing more weight — 9 kg, or about 20 pounds, or more — was even better for lowering cancer risk.
But other research suggests the opposite. A recent analysis found that people who lost weight within the past 2 years through diet and exercise had a higher risk for a range of cancers compared with those who did not lose weight. Overall, though, the increased risk was quite low.
Whatever the research does, or doesn’t, show about weight and cancer risk, Dr. Basen-Engquist said, it’s important that risk factors, obesity and otherwise, aren’t “used as blame tools.”
“With obesity, behavior certainly plays into it,” she said. “But there are so many influences on our behavior that are socially determined.”
Both Dr. Basen-Engquist and Dr. Meyerhardt said it’s important for clinicians to consider the individual in front of them and for everyone to set realistic expectations.
People with obesity should not feel they have to become thin to be healthier, and no one has to leap from being sedentary to exercising several hours a week.
“We don’t want patients to feel that if they don’t get to a stated goal in a guideline, it’s all for naught,” Dr. Meyerhardt said.
A version of this article appeared on Medscape.com.
According to the Centers for Disease Control and Prevention (CDC), over 684,000 Americans are diagnosed with an “obesity-associated” cancer each year.
The incidence of many of these cancers has been rising in recent years, particularly among younger people — a trend that sits in contrast with the overall decline in cancers with no established relationship to excess weight, such as lung and skin cancers.
Is obesity the new smoking? Not exactly.
While about 42% of cancers — including common ones such as colorectal and postmenopausal breast cancers — are considered obesity-related, only about 8% of incident cancers are attributed to excess body weight. People often develop those diseases regardless of weight.
Although plenty of evidence points to excess body fat as a cancer risk factor, it’s unclear at what point excess weight has an effect. Is gaining weight later in life, for instance, better or worse for cancer risk than being overweight or obese from a young age?
There’s another glaring knowledge gap: Does losing weight at some point in adulthood change the picture? In other words, how many of those 684,000 diagnoses might have been prevented if people shed excess pounds?
When it comes to weight and cancer risk, “there’s a lot we don’t know,” said Jennifer W. Bea, PhD, associate professor, health promotion sciences, University of Arizona, Tucson.
A Consistent but Complicated Relationship
Given the growing incidence of obesity — which currently affects about 42% of US adults and 20% of children and teenagers — it’s no surprise that many studies have delved into the potential effects of excess weight on cancer rates.
Although virtually all the evidence comes from large cohort studies, leaving the cause-effect question open, certain associations keep showing up.
“What we know is that, consistently, a higher body mass index [BMI] — particularly in the obese category — leads to a higher risk of multiple cancers,” said Jeffrey A. Meyerhardt, MD, MPH, codirector, Colon and Rectal Cancer Center, Dana-Farber Cancer Institute, Boston.
In a widely cited report published in The New England Journal of Medicine in 2016, the International Agency for Research on Cancer (IARC) analyzed over 1000 epidemiologic studies on body fat and cancer. The agency pointed to over a dozen cancers, including some of the most common and deadly, linked to excess body weight.
That list includes esophageal adenocarcinoma and endometrial cancer — associated with the highest risk — along with kidney, liver, stomach (gastric cardia), pancreatic, colorectal, postmenopausal breast, gallbladder, ovarian, and thyroid cancers, plus multiple myeloma and meningioma. There’s also “limited” evidence linking excess weight to additional cancer types, including aggressive prostate cancer and certain head and neck cancers.
At the same time, Dr. Meyerhardt said, many of those same cancers are also associated with issues that lead to, or coexist with, overweight and obesity, including poor diet, lack of exercise, and metabolic conditions such as diabetes.
It’s a complicated web, and it’s likely, Dr. Meyerhardt said, that high BMI both directly affects cancer risk and is part of a “causal pathway” of other factors that do.
Regarding direct effects, preclinical research has pointed to multiple ways in which excess body fat could contribute to cancer, said Karen M. Basen-Engquist, PhD, MPH, professor, Division of Cancer Prevention and Population Services, The University of Texas MD Anderson Cancer Center, Houston.
One broad mechanism to help explain the obesity-cancer link is chronic systemic inflammation because excess fat tissue can raise levels of substances in the body, such as tumor necrosis factor alpha and interleukin 6, which fuel inflammation. Excess fat also contributes to hyperinsulinemia — too much insulin in the blood — which can help promote the growth and spread of tumor cells.
But the underlying reasons also appear to vary by cancer type, Dr. Basen-Engquist said. With hormonally driven cancer types, such as breast and endometrial, excess body fat may alter hormone levels in ways that spur tumor growth. Extra fat tissue may, for example, convert androgens into estrogens, which could help feed estrogen-dependent tumors.
That, Dr. Basen-Engquist noted, could be why excess weight is associated with postmenopausal, not premenopausal, breast cancer: Before menopause, body fat is a relatively minor contributor to estrogen levels but becomes more important after menopause.
How Big Is the Effect?
While more than a dozen cancers have been consistently linked to excess weight, the strength of those associations varies considerably.
Endometrial and esophageal cancers are two that stand out. In the 2016 IARC analysis, people with severe obesity had a seven-times greater risk for endometrial cancer and 4.8-times greater risk for esophageal adenocarcinoma vs people with a normal BMI.
With other cancers, the risk increases for those with severe obesity compared with a normal BMI were far more modest: 10% for ovarian cancer, 30% for colorectal cancer, and 80% for kidney and stomach cancers, for example. For postmenopausal breast cancer, every five-unit increase in BMI was associated with a 10% relative risk increase.
A 2018 study from the American Cancer Society, which attempted to estimate the proportion of cancers in the United States attributable to modifiable risk factors — including alcohol consumption, ultraviolet rays exposure, and physical inactivity — found that smoking accounted for the highest proportion of cancer cases by a wide margin (19%), but excess weight came in second (7.8%).
Again, weight appeared to play a bigger role in certain cancers than others: An estimated 60% of endometrial cancers were linked to excess weight, as were roughly one third of esophageal, kidney, and liver cancers. At the other end of the spectrum, just over 11% of breast, 5% of colorectal, and 4% of ovarian cancers were attributable to excess weight.
Even at the lower end, those rates could make a big difference on the population level, especially for groups with higher rates of obesity.
CDC data show that obesity-related cancers are rising among women younger than 50 years, most rapidly among Hispanic women, and some less common obesity-related cancers, such as stomach, thyroid and pancreatic, are also rising among Black individuals and Hispanic Americans.
Obesity may be one reason for growing cancer disparities, said Leah Ferrucci, PhD, MPH, assistant professor, epidemiology, Yale School of Public Health, New Haven, Connecticut. But, she added, the evidence is limited because Black individuals and Hispanic Americans are understudied.
When Do Extra Pounds Matter?
When it comes to cancer risk, at what point in life does excess weight, or weight gain, matter? Is the standard weight gain in middle age, for instance, as hazardous as being overweight or obese from a young age?
Some evidence suggests there’s no “safe” time for putting on excess pounds.
A recent meta-analysis concluded that weight gain at any point after age 18 years is associated with incremental increases in the risk for postmenopausal breast cancer. A 2023 study in JAMA Network Open found a similar pattern with colorectal and other gastrointestinal cancers: People who had sustained overweight or obesity from age 20 years through middle age faced an increased risk of developing those cancers after age 55 years.
The timing of weight gain didn’t seem to matter either. The same elevated risk held among people who were normal weight in their younger years but became overweight after age 55 years.
Those studies focused on later-onset disease. But, in recent years, experts have tracked a troubling rise in early-onset cancers — those diagnosed before age 50 years — particularly gastrointestinal cancers.
An obvious question, Dr. Meyerhardt said, is whether the growing prevalence of obesity among young people is partly to blame.
There’s some data to support that, he said. An analysis from the Nurses’ Health Study II found that women with obesity had double the risk for early-onset colorectal cancer as those with a normal BMI. And every 5-kg increase in weight after age 18 years was associated with a 9% increase in colorectal cancer risk.
But while obesity trends probably partly explain the rise in early-onset cancers, there is likely more to the story, Dr. Meyerhardt said.
“I think all of us who see an increasing number of patients under 50 with colorectal cancer know there’s a fair number who do not fit that [high BMI] profile,” he said. “There’s a fair number over 50 who don’t either.”
Does Weight Loss Help?
With all the evidence pointing to high BMI as a cancer risk factor, a logical conclusion is that weight loss should reduce that excess risk. However, Dr. Bea said, there’s actually little data to support that, and what exists comes from observational studies.
Some research has focused on people who had substantial weight loss after bariatric surgery, with encouraging results. A study published in JAMA found that among 5053 people who underwent bariatric surgery, 2.9% developed an obesity-related cancer over 10 years compared with 4.9% in the nonsurgery group.
Most people, however, aim for less dramatic weight loss, with the help of diet and exercise or sometimes medication. Some evidence shows that a modest degree of weight loss may lower the risks for postmenopausal breast and endometrial cancers.
A 2020 pooled analysis found, for instance, that among women aged ≥ 50 years, those who lost as little as 2.0-4.5 kg, or 4.4-10.0 pounds, and kept it off for 10 years had a lower risk for breast cancer than women whose weight remained stable. And losing more weight — 9 kg, or about 20 pounds, or more — was even better for lowering cancer risk.
But other research suggests the opposite. A recent analysis found that people who lost weight within the past 2 years through diet and exercise had a higher risk for a range of cancers compared with those who did not lose weight. Overall, though, the increased risk was quite low.
Whatever the research does, or doesn’t, show about weight and cancer risk, Dr. Basen-Engquist said, it’s important that risk factors, obesity and otherwise, aren’t “used as blame tools.”
“With obesity, behavior certainly plays into it,” she said. “But there are so many influences on our behavior that are socially determined.”
Both Dr. Basen-Engquist and Dr. Meyerhardt said it’s important for clinicians to consider the individual in front of them and for everyone to set realistic expectations.
People with obesity should not feel they have to become thin to be healthier, and no one has to leap from being sedentary to exercising several hours a week.
“We don’t want patients to feel that if they don’t get to a stated goal in a guideline, it’s all for naught,” Dr. Meyerhardt said.
A version of this article appeared on Medscape.com.
According to the Centers for Disease Control and Prevention (CDC), over 684,000 Americans are diagnosed with an “obesity-associated” cancer each year.
The incidence of many of these cancers has been rising in recent years, particularly among younger people — a trend that sits in contrast with the overall decline in cancers with no established relationship to excess weight, such as lung and skin cancers.
Is obesity the new smoking? Not exactly.
While about 42% of cancers — including common ones such as colorectal and postmenopausal breast cancers — are considered obesity-related, only about 8% of incident cancers are attributed to excess body weight. People often develop those diseases regardless of weight.
Although plenty of evidence points to excess body fat as a cancer risk factor, it’s unclear at what point excess weight has an effect. Is gaining weight later in life, for instance, better or worse for cancer risk than being overweight or obese from a young age?
There’s another glaring knowledge gap: Does losing weight at some point in adulthood change the picture? In other words, how many of those 684,000 diagnoses might have been prevented if people shed excess pounds?
When it comes to weight and cancer risk, “there’s a lot we don’t know,” said Jennifer W. Bea, PhD, associate professor, health promotion sciences, University of Arizona, Tucson.
A Consistent but Complicated Relationship
Given the growing incidence of obesity — which currently affects about 42% of US adults and 20% of children and teenagers — it’s no surprise that many studies have delved into the potential effects of excess weight on cancer rates.
Although virtually all the evidence comes from large cohort studies, leaving the cause-effect question open, certain associations keep showing up.
“What we know is that, consistently, a higher body mass index [BMI] — particularly in the obese category — leads to a higher risk of multiple cancers,” said Jeffrey A. Meyerhardt, MD, MPH, codirector, Colon and Rectal Cancer Center, Dana-Farber Cancer Institute, Boston.
In a widely cited report published in The New England Journal of Medicine in 2016, the International Agency for Research on Cancer (IARC) analyzed over 1000 epidemiologic studies on body fat and cancer. The agency pointed to over a dozen cancers, including some of the most common and deadly, linked to excess body weight.
That list includes esophageal adenocarcinoma and endometrial cancer — associated with the highest risk — along with kidney, liver, stomach (gastric cardia), pancreatic, colorectal, postmenopausal breast, gallbladder, ovarian, and thyroid cancers, plus multiple myeloma and meningioma. There’s also “limited” evidence linking excess weight to additional cancer types, including aggressive prostate cancer and certain head and neck cancers.
At the same time, Dr. Meyerhardt said, many of those same cancers are also associated with issues that lead to, or coexist with, overweight and obesity, including poor diet, lack of exercise, and metabolic conditions such as diabetes.
It’s a complicated web, and it’s likely, Dr. Meyerhardt said, that high BMI both directly affects cancer risk and is part of a “causal pathway” of other factors that do.
Regarding direct effects, preclinical research has pointed to multiple ways in which excess body fat could contribute to cancer, said Karen M. Basen-Engquist, PhD, MPH, professor, Division of Cancer Prevention and Population Services, The University of Texas MD Anderson Cancer Center, Houston.
One broad mechanism to help explain the obesity-cancer link is chronic systemic inflammation because excess fat tissue can raise levels of substances in the body, such as tumor necrosis factor alpha and interleukin 6, which fuel inflammation. Excess fat also contributes to hyperinsulinemia — too much insulin in the blood — which can help promote the growth and spread of tumor cells.
But the underlying reasons also appear to vary by cancer type, Dr. Basen-Engquist said. With hormonally driven cancer types, such as breast and endometrial, excess body fat may alter hormone levels in ways that spur tumor growth. Extra fat tissue may, for example, convert androgens into estrogens, which could help feed estrogen-dependent tumors.
That, Dr. Basen-Engquist noted, could be why excess weight is associated with postmenopausal, not premenopausal, breast cancer: Before menopause, body fat is a relatively minor contributor to estrogen levels but becomes more important after menopause.
How Big Is the Effect?
While more than a dozen cancers have been consistently linked to excess weight, the strength of those associations varies considerably.
Endometrial and esophageal cancers are two that stand out. In the 2016 IARC analysis, people with severe obesity had a seven-times greater risk for endometrial cancer and 4.8-times greater risk for esophageal adenocarcinoma vs people with a normal BMI.
With other cancers, the risk increases for those with severe obesity compared with a normal BMI were far more modest: 10% for ovarian cancer, 30% for colorectal cancer, and 80% for kidney and stomach cancers, for example. For postmenopausal breast cancer, every five-unit increase in BMI was associated with a 10% relative risk increase.
A 2018 study from the American Cancer Society, which attempted to estimate the proportion of cancers in the United States attributable to modifiable risk factors — including alcohol consumption, ultraviolet rays exposure, and physical inactivity — found that smoking accounted for the highest proportion of cancer cases by a wide margin (19%), but excess weight came in second (7.8%).
Again, weight appeared to play a bigger role in certain cancers than others: An estimated 60% of endometrial cancers were linked to excess weight, as were roughly one third of esophageal, kidney, and liver cancers. At the other end of the spectrum, just over 11% of breast, 5% of colorectal, and 4% of ovarian cancers were attributable to excess weight.
Even at the lower end, those rates could make a big difference on the population level, especially for groups with higher rates of obesity.
CDC data show that obesity-related cancers are rising among women younger than 50 years, most rapidly among Hispanic women, and some less common obesity-related cancers, such as stomach, thyroid and pancreatic, are also rising among Black individuals and Hispanic Americans.
Obesity may be one reason for growing cancer disparities, said Leah Ferrucci, PhD, MPH, assistant professor, epidemiology, Yale School of Public Health, New Haven, Connecticut. But, she added, the evidence is limited because Black individuals and Hispanic Americans are understudied.
When Do Extra Pounds Matter?
When it comes to cancer risk, at what point in life does excess weight, or weight gain, matter? Is the standard weight gain in middle age, for instance, as hazardous as being overweight or obese from a young age?
Some evidence suggests there’s no “safe” time for putting on excess pounds.
A recent meta-analysis concluded that weight gain at any point after age 18 years is associated with incremental increases in the risk for postmenopausal breast cancer. A 2023 study in JAMA Network Open found a similar pattern with colorectal and other gastrointestinal cancers: People who had sustained overweight or obesity from age 20 years through middle age faced an increased risk of developing those cancers after age 55 years.
The timing of weight gain didn’t seem to matter either. The same elevated risk held among people who were normal weight in their younger years but became overweight after age 55 years.
Those studies focused on later-onset disease. But, in recent years, experts have tracked a troubling rise in early-onset cancers — those diagnosed before age 50 years — particularly gastrointestinal cancers.
An obvious question, Dr. Meyerhardt said, is whether the growing prevalence of obesity among young people is partly to blame.
There’s some data to support that, he said. An analysis from the Nurses’ Health Study II found that women with obesity had double the risk for early-onset colorectal cancer as those with a normal BMI. And every 5-kg increase in weight after age 18 years was associated with a 9% increase in colorectal cancer risk.
But while obesity trends probably partly explain the rise in early-onset cancers, there is likely more to the story, Dr. Meyerhardt said.
“I think all of us who see an increasing number of patients under 50 with colorectal cancer know there’s a fair number who do not fit that [high BMI] profile,” he said. “There’s a fair number over 50 who don’t either.”
Does Weight Loss Help?
With all the evidence pointing to high BMI as a cancer risk factor, a logical conclusion is that weight loss should reduce that excess risk. However, Dr. Bea said, there’s actually little data to support that, and what exists comes from observational studies.
Some research has focused on people who had substantial weight loss after bariatric surgery, with encouraging results. A study published in JAMA found that among 5053 people who underwent bariatric surgery, 2.9% developed an obesity-related cancer over 10 years compared with 4.9% in the nonsurgery group.
Most people, however, aim for less dramatic weight loss, with the help of diet and exercise or sometimes medication. Some evidence shows that a modest degree of weight loss may lower the risks for postmenopausal breast and endometrial cancers.
A 2020 pooled analysis found, for instance, that among women aged ≥ 50 years, those who lost as little as 2.0-4.5 kg, or 4.4-10.0 pounds, and kept it off for 10 years had a lower risk for breast cancer than women whose weight remained stable. And losing more weight — 9 kg, or about 20 pounds, or more — was even better for lowering cancer risk.
But other research suggests the opposite. A recent analysis found that people who lost weight within the past 2 years through diet and exercise had a higher risk for a range of cancers compared with those who did not lose weight. Overall, though, the increased risk was quite low.
Whatever the research does, or doesn’t, show about weight and cancer risk, Dr. Basen-Engquist said, it’s important that risk factors, obesity and otherwise, aren’t “used as blame tools.”
“With obesity, behavior certainly plays into it,” she said. “But there are so many influences on our behavior that are socially determined.”
Both Dr. Basen-Engquist and Dr. Meyerhardt said it’s important for clinicians to consider the individual in front of them and for everyone to set realistic expectations.
People with obesity should not feel they have to become thin to be healthier, and no one has to leap from being sedentary to exercising several hours a week.
“We don’t want patients to feel that if they don’t get to a stated goal in a guideline, it’s all for naught,” Dr. Meyerhardt said.
A version of this article appeared on Medscape.com.
Urine Test Could Prevent Unnecessary Prostate Biopsies
To date, men undergoing screening through the measurement of prostate-specific antigen (PSA) levels have had a significant reduction in neoplastic mortality. Because of its low specificity, however, this practice often leads to frequent, unnecessary, invasive biopsies and the diagnosis of low-grade, indolent cancer.
The National Comprehensive Cancer Network proposes a test consisting of six blood and urine biomarkers for all grades of prostate cancer, and it outperforms PSA testing. However, current practice focuses on detecting high-grade cancers. It has been hypothesized that increasing the number of biomarkers by including molecules specifically expressed in aggressive high-grade prostate cancers could improve test accuracy. Based on the identification of new genes that are overexpressed in high-grade cancers, a polymerase chain reaction (PCR) technique targeting 54 candidate markers was used to develop an optimal 18-gene test that could be used before imaging (with MRI) and biopsy and to assess whether the latter procedures are warranted.
Development Cohort
In the development cohort (n = 815; median age, 63 years), quantitative PCR (qPCR) analysis of the 54 candidate genes was performed on urine samples that had been prospectively collected before biopsy following a digital rectal examination. Patients with previously diagnosed prostate cancer, abnormal MRI results, and those who had already undergone a prostate biopsy were excluded. Participants’ PSA levels ranged from 3 to 10 ng/mL (median interquartile range [IQR], 5.6 [4.6-7.2] ng/mL). Valid qPCR results were obtained from 761 participants (93.4%). Subsequently, prostate biopsy revealed grade 2 or higher cancer in 293 participants (38.5%).
Thus, a urine test called MyProstateScore 2.0 (MPSA) was developed, with two formulations: MPSA2 and MPSA2+, depending on whether a prostate volume was considered. The final MPSA2 development model included clinical data and 17 of the most informative markers, including nine specific to cancer, which were associated with the KLK3 reference gene.
Validation and Analyses
The external validation cohort (n = 813) consisted of participants in the NCI EDRN PCA3 Evaluation trial. Valid qPCR results were obtained from 743 participants, of whom 151 (20.3%) were found to have high-grade prostate cancer.
The median MPS2 score was higher in patients with grade 2 or higher prostate cancer (0.44; IQR, 0.23-0.69) than in those with noncontributory biopsies (0.08; IQR, 0.03-0.19; P < .001) or grade 1 cancer (0.25; IQR, 0.09-0.48; P < .01).
Comparative analyses included PSA, the Prostate Cancer Prevention Trial risk calculator, the Prostate Health Index (PHI), and various previous genetic models. Decision curve analyses quantified the benefit of each biomarker studied. The 151 participants with high-grade prostate cancer had operating curve values ranging from 0.60 for PSA alone to 0.77 for PHI and 0.76 for a two-gene multiplex model. The MPSA model had values of 0.81 and 0.82 for MPSA2+. For a required sensitivity of 95%, the MPS2 model could reduce the rate of unnecessary initial biopsies in the population by 35%-42%, with an impact of 15%-30% for other tests. Among the subgroups analyzed, MPS2 models showed negative predictive values of 95%-99% for grade 2 or higher prostate cancers and 99% for grade 3 or higher tumors.
MPS2 and Competitors
Existing biomarkers have reduced selectivity in detecting high-grade prostate tumors. This lower performance has led to the development of a new urine test including, for the first time, markers specifically overexpressed in high-grade prostate cancer. This new MPS2 test has a sensitivity of 95% for high-grade prostate cancer and a specificity ranging from 35% to 51%, depending on the subgroups. For clinicians, widespread use of MPS2 could greatly reduce the number of unnecessary biopsies while maintaining a high detection rate of grade 2 or higher prostate cancer.
Among patients who have had a negative first biopsy, MPS2 would have a sensitivity of 94.4% and a specificity of 51%, which is much higher than other tests like prostate cancer antigen 3 gene, three-gene model, and MPS. In addition, in patients with grade 1 prostate cancer, urinary markers for high-grade cancer could indicate the existence of a more aggressive tumor requiring increased monitoring.
This study has limitations, however. The ethnic diversity of its population was limited. A few Black men were included, for example. Second, a systematic biopsy was used as the reference, which can increase negative predictive value and decrease positive predictive value. Classification errors may have occurred. Therefore, further studies are needed to confirm these initial results and the long-term positive impact of using MPS2.
In conclusion, an 18-gene urine test seems to be more relevant for diagnosing high-grade prostate cancer than existing tests. It could prevent additional imaging or biopsy examinations in 35%-41% of patients. Therefore, the use of such tests in patients with high PSA levels could reduce the potential risks associated with prostate cancer screening while preserving its long-term benefits.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
To date, men undergoing screening through the measurement of prostate-specific antigen (PSA) levels have had a significant reduction in neoplastic mortality. Because of its low specificity, however, this practice often leads to frequent, unnecessary, invasive biopsies and the diagnosis of low-grade, indolent cancer.
The National Comprehensive Cancer Network proposes a test consisting of six blood and urine biomarkers for all grades of prostate cancer, and it outperforms PSA testing. However, current practice focuses on detecting high-grade cancers. It has been hypothesized that increasing the number of biomarkers by including molecules specifically expressed in aggressive high-grade prostate cancers could improve test accuracy. Based on the identification of new genes that are overexpressed in high-grade cancers, a polymerase chain reaction (PCR) technique targeting 54 candidate markers was used to develop an optimal 18-gene test that could be used before imaging (with MRI) and biopsy and to assess whether the latter procedures are warranted.
Development Cohort
In the development cohort (n = 815; median age, 63 years), quantitative PCR (qPCR) analysis of the 54 candidate genes was performed on urine samples that had been prospectively collected before biopsy following a digital rectal examination. Patients with previously diagnosed prostate cancer, abnormal MRI results, and those who had already undergone a prostate biopsy were excluded. Participants’ PSA levels ranged from 3 to 10 ng/mL (median interquartile range [IQR], 5.6 [4.6-7.2] ng/mL). Valid qPCR results were obtained from 761 participants (93.4%). Subsequently, prostate biopsy revealed grade 2 or higher cancer in 293 participants (38.5%).
Thus, a urine test called MyProstateScore 2.0 (MPSA) was developed, with two formulations: MPSA2 and MPSA2+, depending on whether a prostate volume was considered. The final MPSA2 development model included clinical data and 17 of the most informative markers, including nine specific to cancer, which were associated with the KLK3 reference gene.
Validation and Analyses
The external validation cohort (n = 813) consisted of participants in the NCI EDRN PCA3 Evaluation trial. Valid qPCR results were obtained from 743 participants, of whom 151 (20.3%) were found to have high-grade prostate cancer.
The median MPS2 score was higher in patients with grade 2 or higher prostate cancer (0.44; IQR, 0.23-0.69) than in those with noncontributory biopsies (0.08; IQR, 0.03-0.19; P < .001) or grade 1 cancer (0.25; IQR, 0.09-0.48; P < .01).
Comparative analyses included PSA, the Prostate Cancer Prevention Trial risk calculator, the Prostate Health Index (PHI), and various previous genetic models. Decision curve analyses quantified the benefit of each biomarker studied. The 151 participants with high-grade prostate cancer had operating curve values ranging from 0.60 for PSA alone to 0.77 for PHI and 0.76 for a two-gene multiplex model. The MPSA model had values of 0.81 and 0.82 for MPSA2+. For a required sensitivity of 95%, the MPS2 model could reduce the rate of unnecessary initial biopsies in the population by 35%-42%, with an impact of 15%-30% for other tests. Among the subgroups analyzed, MPS2 models showed negative predictive values of 95%-99% for grade 2 or higher prostate cancers and 99% for grade 3 or higher tumors.
MPS2 and Competitors
Existing biomarkers have reduced selectivity in detecting high-grade prostate tumors. This lower performance has led to the development of a new urine test including, for the first time, markers specifically overexpressed in high-grade prostate cancer. This new MPS2 test has a sensitivity of 95% for high-grade prostate cancer and a specificity ranging from 35% to 51%, depending on the subgroups. For clinicians, widespread use of MPS2 could greatly reduce the number of unnecessary biopsies while maintaining a high detection rate of grade 2 or higher prostate cancer.
Among patients who have had a negative first biopsy, MPS2 would have a sensitivity of 94.4% and a specificity of 51%, which is much higher than other tests like prostate cancer antigen 3 gene, three-gene model, and MPS. In addition, in patients with grade 1 prostate cancer, urinary markers for high-grade cancer could indicate the existence of a more aggressive tumor requiring increased monitoring.
This study has limitations, however. The ethnic diversity of its population was limited. A few Black men were included, for example. Second, a systematic biopsy was used as the reference, which can increase negative predictive value and decrease positive predictive value. Classification errors may have occurred. Therefore, further studies are needed to confirm these initial results and the long-term positive impact of using MPS2.
In conclusion, an 18-gene urine test seems to be more relevant for diagnosing high-grade prostate cancer than existing tests. It could prevent additional imaging or biopsy examinations in 35%-41% of patients. Therefore, the use of such tests in patients with high PSA levels could reduce the potential risks associated with prostate cancer screening while preserving its long-term benefits.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
To date, men undergoing screening through the measurement of prostate-specific antigen (PSA) levels have had a significant reduction in neoplastic mortality. Because of its low specificity, however, this practice often leads to frequent, unnecessary, invasive biopsies and the diagnosis of low-grade, indolent cancer.
The National Comprehensive Cancer Network proposes a test consisting of six blood and urine biomarkers for all grades of prostate cancer, and it outperforms PSA testing. However, current practice focuses on detecting high-grade cancers. It has been hypothesized that increasing the number of biomarkers by including molecules specifically expressed in aggressive high-grade prostate cancers could improve test accuracy. Based on the identification of new genes that are overexpressed in high-grade cancers, a polymerase chain reaction (PCR) technique targeting 54 candidate markers was used to develop an optimal 18-gene test that could be used before imaging (with MRI) and biopsy and to assess whether the latter procedures are warranted.
Development Cohort
In the development cohort (n = 815; median age, 63 years), quantitative PCR (qPCR) analysis of the 54 candidate genes was performed on urine samples that had been prospectively collected before biopsy following a digital rectal examination. Patients with previously diagnosed prostate cancer, abnormal MRI results, and those who had already undergone a prostate biopsy were excluded. Participants’ PSA levels ranged from 3 to 10 ng/mL (median interquartile range [IQR], 5.6 [4.6-7.2] ng/mL). Valid qPCR results were obtained from 761 participants (93.4%). Subsequently, prostate biopsy revealed grade 2 or higher cancer in 293 participants (38.5%).
Thus, a urine test called MyProstateScore 2.0 (MPSA) was developed, with two formulations: MPSA2 and MPSA2+, depending on whether a prostate volume was considered. The final MPSA2 development model included clinical data and 17 of the most informative markers, including nine specific to cancer, which were associated with the KLK3 reference gene.
Validation and Analyses
The external validation cohort (n = 813) consisted of participants in the NCI EDRN PCA3 Evaluation trial. Valid qPCR results were obtained from 743 participants, of whom 151 (20.3%) were found to have high-grade prostate cancer.
The median MPS2 score was higher in patients with grade 2 or higher prostate cancer (0.44; IQR, 0.23-0.69) than in those with noncontributory biopsies (0.08; IQR, 0.03-0.19; P < .001) or grade 1 cancer (0.25; IQR, 0.09-0.48; P < .01).
Comparative analyses included PSA, the Prostate Cancer Prevention Trial risk calculator, the Prostate Health Index (PHI), and various previous genetic models. Decision curve analyses quantified the benefit of each biomarker studied. The 151 participants with high-grade prostate cancer had operating curve values ranging from 0.60 for PSA alone to 0.77 for PHI and 0.76 for a two-gene multiplex model. The MPSA model had values of 0.81 and 0.82 for MPSA2+. For a required sensitivity of 95%, the MPS2 model could reduce the rate of unnecessary initial biopsies in the population by 35%-42%, with an impact of 15%-30% for other tests. Among the subgroups analyzed, MPS2 models showed negative predictive values of 95%-99% for grade 2 or higher prostate cancers and 99% for grade 3 or higher tumors.
MPS2 and Competitors
Existing biomarkers have reduced selectivity in detecting high-grade prostate tumors. This lower performance has led to the development of a new urine test including, for the first time, markers specifically overexpressed in high-grade prostate cancer. This new MPS2 test has a sensitivity of 95% for high-grade prostate cancer and a specificity ranging from 35% to 51%, depending on the subgroups. For clinicians, widespread use of MPS2 could greatly reduce the number of unnecessary biopsies while maintaining a high detection rate of grade 2 or higher prostate cancer.
Among patients who have had a negative first biopsy, MPS2 would have a sensitivity of 94.4% and a specificity of 51%, which is much higher than other tests like prostate cancer antigen 3 gene, three-gene model, and MPS. In addition, in patients with grade 1 prostate cancer, urinary markers for high-grade cancer could indicate the existence of a more aggressive tumor requiring increased monitoring.
This study has limitations, however. The ethnic diversity of its population was limited. A few Black men were included, for example. Second, a systematic biopsy was used as the reference, which can increase negative predictive value and decrease positive predictive value. Classification errors may have occurred. Therefore, further studies are needed to confirm these initial results and the long-term positive impact of using MPS2.
In conclusion, an 18-gene urine test seems to be more relevant for diagnosing high-grade prostate cancer than existing tests. It could prevent additional imaging or biopsy examinations in 35%-41% of patients. Therefore, the use of such tests in patients with high PSA levels could reduce the potential risks associated with prostate cancer screening while preserving its long-term benefits.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.