Breast Cancer

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German 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.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German 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.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German 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.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

Health-related social needs and medical financial hardship are associated with increased risk of mortality in adult cancer survivors, based on data from more than 10,000 individuals.

Little is known about the specific association between health-related social needs (HRSNs) and mortality risk even though HRSNs, defined as challenges in affording food, housing, and other necessities of daily living, are potential challenges for cancer survivors, wrote Zhiyuan Zheng, PhD, of the American Cancer Society, Atlanta, and colleagues.

A 2020 study by Dr. Zheng and colleagues published in the Journal of the National Comprehensive Cancer Network (NCCN) showed that food insecurity and financial worries had a negative impact on cancer survivorship. In the new study, published in Cancer, the researchers identified cancer survivors using the 2013-2018 National Health Interview Survey (NHIS) and the NHIS Mortality File through December 31, 2019. The researchers examined mortality using the data from the Centers for Disease Control and Prevention’s National Death Index (NDI) through December 31, 2019, which links to the National Health Interview Survey Data used in the study.

Individuals’ HRSNs were categorized into three groups: severe, moderate, and minor/none. HRSNs included food insecurity and nonmedical financial concerns, such as housing costs (rent, mortgage). Medical financial hardship included material, psychological, and behavioral domains and was divided into three groups: 2-3 domains, 1 domain, or 0 domains.
 

What Are the Potential Financial Implications of this Research?

The high costs of cancer care often cause medical financial hardships for cancer survivors, and expenses also may cause psychological distress and nonmedical financial hardship as survivors try to make ends meet while facing medical bills, wrote Dr. Zheng and colleagues.

Policy makers are increasingly interested in adding HRSNs to insurance coverage; recent guidance from the Centers for Medicare & Medicaid Services (CMS) allows individual states to apply to provide nutrition and housing supports through state Medicaid programs, according to authors of a 2023 article published in JAMA Health Forum.

The new study adds to the understanding of how HRSNs impact people with cancer by examining the association with mortality risk, Yelak Biru, MSc, president and chief executive officer of the International Myeloma Foundation, said in an interview.

“This is a key area of study for addressing the disparities in treatments and outcomes that result in inequities,” said Mr. Biru, a patient advocate and multiple myeloma survivor who was not involved in the study.
 

What Does the New Study Show?

The new study characterized HRSNs in 5,855 adult cancer survivors aged 18-64 years and 5,918 aged 65-79 years. In the 18- to 64-year-old group, 25.5% reported moderate levels of HRSNs, and 18.3% reported severe HRSNs. In patients aged 65-79 years, 15.6% and 6.6% reported moderate HRSNs and severe HRSNs, respectively.

Severe HRSN was significantly associated with higher mortality risk in an adjusted analysis in patients aged 18-64 years (hazard ratio 2.00, P < .001).

Among adults aged 65-79 years, severe HRSN was not associated with higher mortality risk; however, in this older age group, those with 2-3 domains of medical financial hardship had significantly increased mortality risk compared with adults aged 65-79 years with zero domains of medical financial hardship (HR 1.58, P = .007).

Although the findings that HRSNs were associated with increased mortality risk, especially in the younger group, were not surprising, they serve as a call to action to address how HRSNs are contributing to cancer mortality, Mr. Biru said in an interview. “HRSNs, like food or housing insecurity, can lead to patients being unable to undergo the best treatment approach for their cancer,” he said.
 

What Are the Limitations and Research Gaps?

The study findings were limited by several factors including the use of self-reports to measure medical financial hardship, food insecurity, and nonmedical financial concerns in the NHIS, the researchers wrote in their discussion. More research with longer follow-up time beyond 1-5 years is needed, wrote Dr. Zheng and colleagues.

Studies also are needed to illustrate how patient navigation can help prevent patients from falling through the cracks with regard to social needs and financial hardships, Mr. Biru told this news organization.

Other areas for research include how addressing social needs affects health outcomes and whether programs designed to address social needs are effective, he said.

“Finally, qualitative research is needed to capture the lived experiences of cancer survivors facing these challenges. This knowledge can inform the development of more patient-centered interventions and policies that effectively address the social determinants of health and improve overall outcomes for all cancer survivors,” Mr. Biru said.
 

What Is the Takeaway Message for Clinicians?

HRSNs and financial hardship are significantly associated with increased risk of mortality in adult cancer survivors, Dr. Zheng and colleagues concluded. Looking ahead, comprehensive assessment of HRSNs and financial hardship may help clinicians connect patients with relevant services to mitigate the social and financial impacts of cancer, they wrote.

“The takeaway message for oncologists in practice is that addressing [HRSNs] and financial hardship is crucial for providing comprehensive and equitable cancer care,” Mr. Biru said during his interview.

“The impact of social determinants of health on cancer outcomes cannot be ignored, and oncologists play a vital role in identifying and addressing these needs,” he said. Sensitive, discussion-based screenings are needed to identify core needs such as food and transportation, but clinicians also can consider broader social factors and work with a team to connect patients to appropriate resources, he added.

“By recognizing the importance of HRSN screening and taking proactive steps to address these needs, oncologists can contribute to improving health outcomes, reducing healthcare disparities, and providing more equitable cancer care for their patients,” he said.
 

What Other Guidance Is Available?

“High-quality cancer care requires treating the whole person; measuring and addressing anything in their life that could result in poorer health outcomes is a key component of comprehensive care,” Mr. Biru emphasized.

In September 2023, the National Comprehensive Cancer Network (NCCN) convened a working group cochaired by Mr. Biru that developed recommendations for how oncology practices should routinely measure HRSNs (NCCN.org/social-needs).

“The working group proposed that every cancer patient be assessed for food, transportation access, and financial and housing security at least once a year, and be reassessed at every care transition point as well,” Mr. Biru said. Such screenings should include follow-up to connect patients with services to address any HRSNs they are experiencing, he added.

Lead author Dr. Zheng is employed by the American Cancer Society, which as a nonprofit receives funds from the public through fundraising and contributions, as well as some support from corporations and industry to support its mission programs and services. Mr. Biru had no financial conflicts to disclose.

Health-related social needs and medical financial hardship are associated with increased risk of mortality in adult cancer survivors, based on data from more than 10,000 individuals.

Little is known about the specific association between health-related social needs (HRSNs) and mortality risk even though HRSNs, defined as challenges in affording food, housing, and other necessities of daily living, are potential challenges for cancer survivors, wrote Zhiyuan Zheng, PhD, of the American Cancer Society, Atlanta, and colleagues.

A 2020 study by Dr. Zheng and colleagues published in the Journal of the National Comprehensive Cancer Network (NCCN) showed that food insecurity and financial worries had a negative impact on cancer survivorship. In the new study, published in Cancer, the researchers identified cancer survivors using the 2013-2018 National Health Interview Survey (NHIS) and the NHIS Mortality File through December 31, 2019. The researchers examined mortality using the data from the Centers for Disease Control and Prevention’s National Death Index (NDI) through December 31, 2019, which links to the National Health Interview Survey Data used in the study.

Individuals’ HRSNs were categorized into three groups: severe, moderate, and minor/none. HRSNs included food insecurity and nonmedical financial concerns, such as housing costs (rent, mortgage). Medical financial hardship included material, psychological, and behavioral domains and was divided into three groups: 2-3 domains, 1 domain, or 0 domains.
 

What Are the Potential Financial Implications of this Research?

The high costs of cancer care often cause medical financial hardships for cancer survivors, and expenses also may cause psychological distress and nonmedical financial hardship as survivors try to make ends meet while facing medical bills, wrote Dr. Zheng and colleagues.

Policy makers are increasingly interested in adding HRSNs to insurance coverage; recent guidance from the Centers for Medicare & Medicaid Services (CMS) allows individual states to apply to provide nutrition and housing supports through state Medicaid programs, according to authors of a 2023 article published in JAMA Health Forum.

The new study adds to the understanding of how HRSNs impact people with cancer by examining the association with mortality risk, Yelak Biru, MSc, president and chief executive officer of the International Myeloma Foundation, said in an interview.

“This is a key area of study for addressing the disparities in treatments and outcomes that result in inequities,” said Mr. Biru, a patient advocate and multiple myeloma survivor who was not involved in the study.
 

What Does the New Study Show?

The new study characterized HRSNs in 5,855 adult cancer survivors aged 18-64 years and 5,918 aged 65-79 years. In the 18- to 64-year-old group, 25.5% reported moderate levels of HRSNs, and 18.3% reported severe HRSNs. In patients aged 65-79 years, 15.6% and 6.6% reported moderate HRSNs and severe HRSNs, respectively.

Severe HRSN was significantly associated with higher mortality risk in an adjusted analysis in patients aged 18-64 years (hazard ratio 2.00, P < .001).

Among adults aged 65-79 years, severe HRSN was not associated with higher mortality risk; however, in this older age group, those with 2-3 domains of medical financial hardship had significantly increased mortality risk compared with adults aged 65-79 years with zero domains of medical financial hardship (HR 1.58, P = .007).

Although the findings that HRSNs were associated with increased mortality risk, especially in the younger group, were not surprising, they serve as a call to action to address how HRSNs are contributing to cancer mortality, Mr. Biru said in an interview. “HRSNs, like food or housing insecurity, can lead to patients being unable to undergo the best treatment approach for their cancer,” he said.
 

What Are the Limitations and Research Gaps?

The study findings were limited by several factors including the use of self-reports to measure medical financial hardship, food insecurity, and nonmedical financial concerns in the NHIS, the researchers wrote in their discussion. More research with longer follow-up time beyond 1-5 years is needed, wrote Dr. Zheng and colleagues.

Studies also are needed to illustrate how patient navigation can help prevent patients from falling through the cracks with regard to social needs and financial hardships, Mr. Biru told this news organization.

Other areas for research include how addressing social needs affects health outcomes and whether programs designed to address social needs are effective, he said.

“Finally, qualitative research is needed to capture the lived experiences of cancer survivors facing these challenges. This knowledge can inform the development of more patient-centered interventions and policies that effectively address the social determinants of health and improve overall outcomes for all cancer survivors,” Mr. Biru said.
 

What Is the Takeaway Message for Clinicians?

HRSNs and financial hardship are significantly associated with increased risk of mortality in adult cancer survivors, Dr. Zheng and colleagues concluded. Looking ahead, comprehensive assessment of HRSNs and financial hardship may help clinicians connect patients with relevant services to mitigate the social and financial impacts of cancer, they wrote.

“The takeaway message for oncologists in practice is that addressing [HRSNs] and financial hardship is crucial for providing comprehensive and equitable cancer care,” Mr. Biru said during his interview.

“The impact of social determinants of health on cancer outcomes cannot be ignored, and oncologists play a vital role in identifying and addressing these needs,” he said. Sensitive, discussion-based screenings are needed to identify core needs such as food and transportation, but clinicians also can consider broader social factors and work with a team to connect patients to appropriate resources, he added.

“By recognizing the importance of HRSN screening and taking proactive steps to address these needs, oncologists can contribute to improving health outcomes, reducing healthcare disparities, and providing more equitable cancer care for their patients,” he said.
 

What Other Guidance Is Available?

“High-quality cancer care requires treating the whole person; measuring and addressing anything in their life that could result in poorer health outcomes is a key component of comprehensive care,” Mr. Biru emphasized.

In September 2023, the National Comprehensive Cancer Network (NCCN) convened a working group cochaired by Mr. Biru that developed recommendations for how oncology practices should routinely measure HRSNs (NCCN.org/social-needs).

“The working group proposed that every cancer patient be assessed for food, transportation access, and financial and housing security at least once a year, and be reassessed at every care transition point as well,” Mr. Biru said. Such screenings should include follow-up to connect patients with services to address any HRSNs they are experiencing, he added.

Lead author Dr. Zheng is employed by the American Cancer Society, which as a nonprofit receives funds from the public through fundraising and contributions, as well as some support from corporations and industry to support its mission programs and services. Mr. Biru had no financial conflicts to disclose.

Health-related social needs and medical financial hardship are associated with increased risk of mortality in adult cancer survivors, based on data from more than 10,000 individuals.

Little is known about the specific association between health-related social needs (HRSNs) and mortality risk even though HRSNs, defined as challenges in affording food, housing, and other necessities of daily living, are potential challenges for cancer survivors, wrote Zhiyuan Zheng, PhD, of the American Cancer Society, Atlanta, and colleagues.

A 2020 study by Dr. Zheng and colleagues published in the Journal of the National Comprehensive Cancer Network (NCCN) showed that food insecurity and financial worries had a negative impact on cancer survivorship. In the new study, published in Cancer, the researchers identified cancer survivors using the 2013-2018 National Health Interview Survey (NHIS) and the NHIS Mortality File through December 31, 2019. The researchers examined mortality using the data from the Centers for Disease Control and Prevention’s National Death Index (NDI) through December 31, 2019, which links to the National Health Interview Survey Data used in the study.

Individuals’ HRSNs were categorized into three groups: severe, moderate, and minor/none. HRSNs included food insecurity and nonmedical financial concerns, such as housing costs (rent, mortgage). Medical financial hardship included material, psychological, and behavioral domains and was divided into three groups: 2-3 domains, 1 domain, or 0 domains.
 

What Are the Potential Financial Implications of this Research?

The high costs of cancer care often cause medical financial hardships for cancer survivors, and expenses also may cause psychological distress and nonmedical financial hardship as survivors try to make ends meet while facing medical bills, wrote Dr. Zheng and colleagues.

Policy makers are increasingly interested in adding HRSNs to insurance coverage; recent guidance from the Centers for Medicare & Medicaid Services (CMS) allows individual states to apply to provide nutrition and housing supports through state Medicaid programs, according to authors of a 2023 article published in JAMA Health Forum.

The new study adds to the understanding of how HRSNs impact people with cancer by examining the association with mortality risk, Yelak Biru, MSc, president and chief executive officer of the International Myeloma Foundation, said in an interview.

“This is a key area of study for addressing the disparities in treatments and outcomes that result in inequities,” said Mr. Biru, a patient advocate and multiple myeloma survivor who was not involved in the study.
 

What Does the New Study Show?

The new study characterized HRSNs in 5,855 adult cancer survivors aged 18-64 years and 5,918 aged 65-79 years. In the 18- to 64-year-old group, 25.5% reported moderate levels of HRSNs, and 18.3% reported severe HRSNs. In patients aged 65-79 years, 15.6% and 6.6% reported moderate HRSNs and severe HRSNs, respectively.

Severe HRSN was significantly associated with higher mortality risk in an adjusted analysis in patients aged 18-64 years (hazard ratio 2.00, P < .001).

Among adults aged 65-79 years, severe HRSN was not associated with higher mortality risk; however, in this older age group, those with 2-3 domains of medical financial hardship had significantly increased mortality risk compared with adults aged 65-79 years with zero domains of medical financial hardship (HR 1.58, P = .007).

Although the findings that HRSNs were associated with increased mortality risk, especially in the younger group, were not surprising, they serve as a call to action to address how HRSNs are contributing to cancer mortality, Mr. Biru said in an interview. “HRSNs, like food or housing insecurity, can lead to patients being unable to undergo the best treatment approach for their cancer,” he said.
 

What Are the Limitations and Research Gaps?

The study findings were limited by several factors including the use of self-reports to measure medical financial hardship, food insecurity, and nonmedical financial concerns in the NHIS, the researchers wrote in their discussion. More research with longer follow-up time beyond 1-5 years is needed, wrote Dr. Zheng and colleagues.

Studies also are needed to illustrate how patient navigation can help prevent patients from falling through the cracks with regard to social needs and financial hardships, Mr. Biru told this news organization.

Other areas for research include how addressing social needs affects health outcomes and whether programs designed to address social needs are effective, he said.

“Finally, qualitative research is needed to capture the lived experiences of cancer survivors facing these challenges. This knowledge can inform the development of more patient-centered interventions and policies that effectively address the social determinants of health and improve overall outcomes for all cancer survivors,” Mr. Biru said.
 

What Is the Takeaway Message for Clinicians?

HRSNs and financial hardship are significantly associated with increased risk of mortality in adult cancer survivors, Dr. Zheng and colleagues concluded. Looking ahead, comprehensive assessment of HRSNs and financial hardship may help clinicians connect patients with relevant services to mitigate the social and financial impacts of cancer, they wrote.

“The takeaway message for oncologists in practice is that addressing [HRSNs] and financial hardship is crucial for providing comprehensive and equitable cancer care,” Mr. Biru said during his interview.

“The impact of social determinants of health on cancer outcomes cannot be ignored, and oncologists play a vital role in identifying and addressing these needs,” he said. Sensitive, discussion-based screenings are needed to identify core needs such as food and transportation, but clinicians also can consider broader social factors and work with a team to connect patients to appropriate resources, he added.

“By recognizing the importance of HRSN screening and taking proactive steps to address these needs, oncologists can contribute to improving health outcomes, reducing healthcare disparities, and providing more equitable cancer care for their patients,” he said.
 

What Other Guidance Is Available?

“High-quality cancer care requires treating the whole person; measuring and addressing anything in their life that could result in poorer health outcomes is a key component of comprehensive care,” Mr. Biru emphasized.

In September 2023, the National Comprehensive Cancer Network (NCCN) convened a working group cochaired by Mr. Biru that developed recommendations for how oncology practices should routinely measure HRSNs (NCCN.org/social-needs).

“The working group proposed that every cancer patient be assessed for food, transportation access, and financial and housing security at least once a year, and be reassessed at every care transition point as well,” Mr. Biru said. Such screenings should include follow-up to connect patients with services to address any HRSNs they are experiencing, he added.

Lead author Dr. Zheng is employed by the American Cancer Society, which as a nonprofit receives funds from the public through fundraising and contributions, as well as some support from corporations and industry to support its mission programs and services. Mr. Biru had no financial conflicts to disclose.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

What’s most important to patients with terminal cancer and their caregivers?

New research found that patients and caregivers both tend to prioritize symptom control over life extension but often preferring a balance. Patients and caregivers, however, are less aligned on decisions about cost containment, with patients more likely to prioritize cost containment.

“Our research has revealed that patients and caregivers generally share similar end-of-life goals,” with a “notable exception” when it comes to costs, first author Semra Ozdemir, PhD, with the Lien Centre for Palliative Care, Duke-NUS Medical School, Singapore, told this news organization.

However, when patients and caregivers have a better understanding of the patient’s prognosis, both may be more inclined to avoid costly life-extending treatments and prioritize symptom management.

In other words, the survey suggests that “knowing the prognosis helps patients and their families set realistic expectations for care and adequately prepare for end-of-life decisions,” said Dr. Ozdemir.

This study was published online in JAMA Network Open.

Patients with advanced cancer often face difficult decisions: Do they opt for treatments that may — or may not — extend life or do they focus more on symptom control?

Family caregivers, who also play an important role in this decision-making process, may have different care goals. Some research suggests that caregivers tend to prioritize treatments that could extend life, whereas patients prioritize symptom management, but it’s less clear how these priorities may change over time and how patients and caregivers may influence each other.

In the current study, the researchers examined goals of care among patients with stage IV solid tumors and caregivers during the last 2 years of life, focusing on life extension vs symptom management and cost containment, as well as how these goals changed over time.

The survey included 210 patient-caregiver pairs, recruited from outpatient clinics at two major cancer centers in Singapore. Patients had a mean age of 63 years, and about half were men. The caregivers had a mean age of 49 years, and almost two third (63%) were women.

Overall, 34% patients and 29% caregivers prioritized symptom management over life extension, whereas 24% patients and 19% caregivers prioritized life extension. Most patients and caregivers preferred balancing the two, with 34%-47% patients and 37%-69% caregivers supporting this approach.

When balancing cost and treatment decisions, however, patients were more likely to prioritize containing costs — 28% vs 17% for caregivers — over extending life — 26% of patients vs 35% of caregivers.

Cost containment tended to be more of a priority for older patients, those with a higher symptom burden, and those with less family caregiver support. For caregivers, cost containment was more of a priority for those who reported that caregiving had a big impact on their finances, those with worse self-esteem related to their caregiving abilities, as well as those caring for older patients.

To better align cost containment priorities between patients and caregivers, it’s essential for families to engage in open and thorough discussions about the allocation of resources, Dr. Ozdemir said.

Although “patients, families, and physicians often avoid discussions about prognosis,” such conversations are essential for setting realistic expectations for care and adequately preparing for end-of-life decisions, Dr. Ozdemir told this news organization.

“These conversations should aim to balance competing interests and create care plans that are mutually acceptable to both patients and caregivers,” she said, adding that “this approach will help in minimizing any potential conflicts and ensure that both parties feel respected and understood in their decision-making process.”

Managing Unrealistic Expectations

As patients approached the end of life, neither patients nor caregivers shifted their priorities from life extension to symptom management.

This finding raises concerns because it suggests that many patients hold unrealistic expectations regarding their care and “underscores the need for continuous dialogue and reassessment of care goals throughout the progression of illness,” Dr. Ozdemir said.

“This stability in preferences over time suggests that initial care decisions are deeply ingrained or that there may be a lack of ongoing communication about evolving care needs and possibilities as conditions change,” Ozdemir said.

Yet, it can be hard to define what unrealistic expectations mean, said Olivia Seecof, MD, who wasn’t involved in the study.

“I think people are hopeful that a devastating diagnosis won’t lead to the end of their life and that there will be a treatment or something that will change [their prognosis], and they’ll get better,” said Dr. Seecof, palliative care expert with the Supportive Oncology Program at NYU Langone Health’s Perlmutter Cancer Center in New York City.

Giving patients and caregivers a realistic understanding of the prognosis is important, but “there’s more to it than just telling the patient their diagnosis,” she said.

“We have to plan for end of life, what it can look like,” said Dr. Seecof, adding that “often we don’t do a very good job of talking about that early on in an illness course.”

Overall, though, Dr. Seecof stressed that no two patients or situations are the same, and it’s important to understand what’s important in each scenario. End-of-life care requires “an individual approach because every patient is different, even if they have the same diagnosis as someone else,” she said.

This work was supported by funding from the Singapore Millennium Foundation and the Lien Centre for Palliative Care. Dr. Ozdemir and Dr. Seecof had no relevant disclosures.

A version of this article appeared on Medscape.com.

A contentious scientific debate is clouding prospects for a deeper understanding of the microbiome’s role in cancer, a relatively young field of research that some believe could lead to breakthroughs in the diagnosis and treatment of the second-leading cause of death in the United States. 

Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.

The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.

This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.

But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies? 
 

Cancer Controversy

The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.

The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes. 

“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.” 

For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.

“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.” 

The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?

This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom. 

Dr. Salzberg described two major problems with Dr. Knight’s study. 

“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”

Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.

Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.

Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed. 

The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.

For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.

A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading. 

It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.

Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed. 

Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.” 

Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions. 

“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
 

Underdeveloped Technology 

Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question. 

For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies. 

Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one. 

Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said. 

Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible. 

“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.

Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.

Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.

“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said. 
 

Influence on Cancer Treatment Outcomes

Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.

The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said. 

Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.

“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost. 

“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said. 

In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said. 

Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.

Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”

It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted. 
 

No Consensus Yet

Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans. 

It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges. 

“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.

Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.

“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”

A version of this article appeared on Medscape.com.

A contentious scientific debate is clouding prospects for a deeper understanding of the microbiome’s role in cancer, a relatively young field of research that some believe could lead to breakthroughs in the diagnosis and treatment of the second-leading cause of death in the United States. 

Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.

The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.

This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.

But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies? 
 

Cancer Controversy

The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.

The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes. 

“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.” 

For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.

“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.” 

The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?

This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom. 

Dr. Salzberg described two major problems with Dr. Knight’s study. 

“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”

Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.

Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.

Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed. 

The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.

For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.

A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading. 

It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.

Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed. 

Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.” 

Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions. 

“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
 

Underdeveloped Technology 

Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question. 

For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies. 

Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one. 

Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said. 

Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible. 

“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.

Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.

Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.

“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said. 
 

Influence on Cancer Treatment Outcomes

Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.

The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said. 

Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.

“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost. 

“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said. 

In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said. 

Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.

Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”

It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted. 
 

No Consensus Yet

Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans. 

It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges. 

“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.

Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.

“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”

A version of this article appeared on Medscape.com.

A contentious scientific debate is clouding prospects for a deeper understanding of the microbiome’s role in cancer, a relatively young field of research that some believe could lead to breakthroughs in the diagnosis and treatment of the second-leading cause of death in the United States. 

Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.

The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.

This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.

But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies? 
 

Cancer Controversy

The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.

The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes. 

“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.” 

For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.

“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.” 

The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?

This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom. 

Dr. Salzberg described two major problems with Dr. Knight’s study. 

“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”

Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.

Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.

Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed. 

The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.

For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.

A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading. 

It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.

Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed. 

Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.” 

Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions. 

“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
 

Underdeveloped Technology 

Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question. 

For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies. 

Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one. 

Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said. 

Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible. 

“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.

Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.

Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.

“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said. 
 

Influence on Cancer Treatment Outcomes

Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.

The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said. 

Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.

“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost. 

“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said. 

In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said. 

Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.

Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”

It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted. 
 

No Consensus Yet

Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans. 

It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges. 

“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.

Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.

“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”

A version of this article appeared on Medscape.com.

SAN DIEGO — British investigators have demonstrated a “potentially curative” neoadjuvant regimen for early-stage germline BRCA 1/2–mutated breast cancer.

In a small trial, 39 patients randomized to the regimen — a combination of standard chemotherapy with the poly(ADP-ribose)polymerase (PARP) inhibitor olaparib — were alive at 3 years vs 39 of 45 (87%) randomized to chemotherapy alone.

“A remarkable 100% of patients were still alive at 36 months, which is a significant landmark for these patients,” said chief investigator Jean Abraham, PhD, a breast oncologist at the University of Cambridge, England, who presented the findings at the American Association for Cancer Research annual meeting.

It’s a “small but very powerful signal” of “what could be a potentially curative regimen that definitely does need to be confirmed in a larger study,” Dr. Abraham added.

The study, a part of the PARTNER trial, included 84 patients with T1-2 tumors of any hormone status. Just over 70% in both arms had BRCA 1 mutations, and the rest had BRCA 2 mutations.

Past attempts at combining chemotherapy with PARP inhibitors have been hampered by excess bone marrow toxicity. To counter the problem, patients randomized to the combination therapy received olaparib 48 hours after carboplatin to give their bone marrow a chance to recover.

The median age was 38 years in the control group and 47 years in the olaparib arm. A greater proportion of patients in the control arm (42% vs 23%) had axillary node involvement.

Overall, patients received neoadjuvant carboplatin on day 1 and paclitaxel on days 1, 8, and 15 every 3 weeks for four cycles, followed by anthracycline every 3 weeks for three cycles. In the study arm, olaparib 150 mg was administered twice daily starting on day 3 continuing to day 14 during the first four cycles. Almost 90% of patients received at least 80% of their planned olaparib dose.

Despite the delay in olaparib dosing, 56.4% of patients in the combination arm required a transfusion vs 48.9% with chemotherapy alone.

At a median follow-up of 40.7 months, 96% of patients in the combination arm demonstrated event-free survival, with one patient relapsing, vs 80% in the chemotherapy-alone group, with nine patients relapsing.

In the final analysis, 64% of patients who received olaparib had a pathological complete response compared with almost 70% in the chemotherapy group, though the difference was not statistically significant.

The trial was stopped short at 50% enrollment after the data monitoring safety committee determined that olaparib add-on was unlikely to improve pathological complete response rates, the trial’s primary endpoint.

However, pathological complete response rates did not appear to affect overall survival.

“It didn’t seem to matter whether you had a non-pathological complete response, you still survived 100%” with the combination, Dr. Abraham said, adding that this is not the first study to show a disconnect between response rates and survival.

Perhaps, this disconnect could be due to “doomed cells” that look like residual disease but are, in fact, dying and unable to metastasize, she said.

No patients in the combination arm and two in the control arm received olaparib, immunotherapy, or capecitabine after surgery. Both control participants relapsed, and one died.

Toxicity was more severe for patients in the combination arm. More patients who received olaparib (76.9%) experienced a grade 3 or worse adverse event vs 60% of patients in the control arm.

Study discussant Hope S. Rugo, MD, a breast oncologist at the University of California San Francisco, highlighted a few limitations and remaining questions.

First, “this is a very small population, so small differences in the biology of the tumor, the patients, and even stage that we can’t assess in the neoadjuvant setting could make a difference that would affect event-free and overall survival,” she said.

Second, two patients with pathological complete responses relapsed in the control arm and died, “which is quite unusual,” Dr. Rugo said. “Patients who achieve a pathological complete response generally have an excellent outcome.”

Dr. Rugo noted that “gap sequencing doesn’t appear to avoid the toxicity of PARP inhibitors.”

However, she said, “the efficacy results are intriguing” and would need confirmation in a larger randomized trial, perhaps with newer, more selective PARP inhibitors.

The work was funded by AstraZeneca, maker of olaparib. Researchers included AstraZeneca employees. Dr. Abraham is an adviser to and disclosed grants, travel costs, and honoraria from the company. Dr. Rugo disclosed research funding from AstraZeneca and other companies.

A version of this article appeared on Medscape.com.

SAN DIEGO — British investigators have demonstrated a “potentially curative” neoadjuvant regimen for early-stage germline BRCA 1/2–mutated breast cancer.

In a small trial, 39 patients randomized to the regimen — a combination of standard chemotherapy with the poly(ADP-ribose)polymerase (PARP) inhibitor olaparib — were alive at 3 years vs 39 of 45 (87%) randomized to chemotherapy alone.

“A remarkable 100% of patients were still alive at 36 months, which is a significant landmark for these patients,” said chief investigator Jean Abraham, PhD, a breast oncologist at the University of Cambridge, England, who presented the findings at the American Association for Cancer Research annual meeting.

It’s a “small but very powerful signal” of “what could be a potentially curative regimen that definitely does need to be confirmed in a larger study,” Dr. Abraham added.

The study, a part of the PARTNER trial, included 84 patients with T1-2 tumors of any hormone status. Just over 70% in both arms had BRCA 1 mutations, and the rest had BRCA 2 mutations.

Past attempts at combining chemotherapy with PARP inhibitors have been hampered by excess bone marrow toxicity. To counter the problem, patients randomized to the combination therapy received olaparib 48 hours after carboplatin to give their bone marrow a chance to recover.

The median age was 38 years in the control group and 47 years in the olaparib arm. A greater proportion of patients in the control arm (42% vs 23%) had axillary node involvement.

Overall, patients received neoadjuvant carboplatin on day 1 and paclitaxel on days 1, 8, and 15 every 3 weeks for four cycles, followed by anthracycline every 3 weeks for three cycles. In the study arm, olaparib 150 mg was administered twice daily starting on day 3 continuing to day 14 during the first four cycles. Almost 90% of patients received at least 80% of their planned olaparib dose.

Despite the delay in olaparib dosing, 56.4% of patients in the combination arm required a transfusion vs 48.9% with chemotherapy alone.

At a median follow-up of 40.7 months, 96% of patients in the combination arm demonstrated event-free survival, with one patient relapsing, vs 80% in the chemotherapy-alone group, with nine patients relapsing.

In the final analysis, 64% of patients who received olaparib had a pathological complete response compared with almost 70% in the chemotherapy group, though the difference was not statistically significant.

The trial was stopped short at 50% enrollment after the data monitoring safety committee determined that olaparib add-on was unlikely to improve pathological complete response rates, the trial’s primary endpoint.

However, pathological complete response rates did not appear to affect overall survival.

“It didn’t seem to matter whether you had a non-pathological complete response, you still survived 100%” with the combination, Dr. Abraham said, adding that this is not the first study to show a disconnect between response rates and survival.

Perhaps, this disconnect could be due to “doomed cells” that look like residual disease but are, in fact, dying and unable to metastasize, she said.

No patients in the combination arm and two in the control arm received olaparib, immunotherapy, or capecitabine after surgery. Both control participants relapsed, and one died.

Toxicity was more severe for patients in the combination arm. More patients who received olaparib (76.9%) experienced a grade 3 or worse adverse event vs 60% of patients in the control arm.

Study discussant Hope S. Rugo, MD, a breast oncologist at the University of California San Francisco, highlighted a few limitations and remaining questions.

First, “this is a very small population, so small differences in the biology of the tumor, the patients, and even stage that we can’t assess in the neoadjuvant setting could make a difference that would affect event-free and overall survival,” she said.

Second, two patients with pathological complete responses relapsed in the control arm and died, “which is quite unusual,” Dr. Rugo said. “Patients who achieve a pathological complete response generally have an excellent outcome.”

Dr. Rugo noted that “gap sequencing doesn’t appear to avoid the toxicity of PARP inhibitors.”

However, she said, “the efficacy results are intriguing” and would need confirmation in a larger randomized trial, perhaps with newer, more selective PARP inhibitors.

The work was funded by AstraZeneca, maker of olaparib. Researchers included AstraZeneca employees. Dr. Abraham is an adviser to and disclosed grants, travel costs, and honoraria from the company. Dr. Rugo disclosed research funding from AstraZeneca and other companies.

A version of this article appeared on Medscape.com.

SAN DIEGO — British investigators have demonstrated a “potentially curative” neoadjuvant regimen for early-stage germline BRCA 1/2–mutated breast cancer.

In a small trial, 39 patients randomized to the regimen — a combination of standard chemotherapy with the poly(ADP-ribose)polymerase (PARP) inhibitor olaparib — were alive at 3 years vs 39 of 45 (87%) randomized to chemotherapy alone.

“A remarkable 100% of patients were still alive at 36 months, which is a significant landmark for these patients,” said chief investigator Jean Abraham, PhD, a breast oncologist at the University of Cambridge, England, who presented the findings at the American Association for Cancer Research annual meeting.

It’s a “small but very powerful signal” of “what could be a potentially curative regimen that definitely does need to be confirmed in a larger study,” Dr. Abraham added.

The study, a part of the PARTNER trial, included 84 patients with T1-2 tumors of any hormone status. Just over 70% in both arms had BRCA 1 mutations, and the rest had BRCA 2 mutations.

Past attempts at combining chemotherapy with PARP inhibitors have been hampered by excess bone marrow toxicity. To counter the problem, patients randomized to the combination therapy received olaparib 48 hours after carboplatin to give their bone marrow a chance to recover.

The median age was 38 years in the control group and 47 years in the olaparib arm. A greater proportion of patients in the control arm (42% vs 23%) had axillary node involvement.

Overall, patients received neoadjuvant carboplatin on day 1 and paclitaxel on days 1, 8, and 15 every 3 weeks for four cycles, followed by anthracycline every 3 weeks for three cycles. In the study arm, olaparib 150 mg was administered twice daily starting on day 3 continuing to day 14 during the first four cycles. Almost 90% of patients received at least 80% of their planned olaparib dose.

Despite the delay in olaparib dosing, 56.4% of patients in the combination arm required a transfusion vs 48.9% with chemotherapy alone.

At a median follow-up of 40.7 months, 96% of patients in the combination arm demonstrated event-free survival, with one patient relapsing, vs 80% in the chemotherapy-alone group, with nine patients relapsing.

In the final analysis, 64% of patients who received olaparib had a pathological complete response compared with almost 70% in the chemotherapy group, though the difference was not statistically significant.

The trial was stopped short at 50% enrollment after the data monitoring safety committee determined that olaparib add-on was unlikely to improve pathological complete response rates, the trial’s primary endpoint.

However, pathological complete response rates did not appear to affect overall survival.

“It didn’t seem to matter whether you had a non-pathological complete response, you still survived 100%” with the combination, Dr. Abraham said, adding that this is not the first study to show a disconnect between response rates and survival.

Perhaps, this disconnect could be due to “doomed cells” that look like residual disease but are, in fact, dying and unable to metastasize, she said.

No patients in the combination arm and two in the control arm received olaparib, immunotherapy, or capecitabine after surgery. Both control participants relapsed, and one died.

Toxicity was more severe for patients in the combination arm. More patients who received olaparib (76.9%) experienced a grade 3 or worse adverse event vs 60% of patients in the control arm.

Study discussant Hope S. Rugo, MD, a breast oncologist at the University of California San Francisco, highlighted a few limitations and remaining questions.

First, “this is a very small population, so small differences in the biology of the tumor, the patients, and even stage that we can’t assess in the neoadjuvant setting could make a difference that would affect event-free and overall survival,” she said.

Second, two patients with pathological complete responses relapsed in the control arm and died, “which is quite unusual,” Dr. Rugo said. “Patients who achieve a pathological complete response generally have an excellent outcome.”

Dr. Rugo noted that “gap sequencing doesn’t appear to avoid the toxicity of PARP inhibitors.”

However, she said, “the efficacy results are intriguing” and would need confirmation in a larger randomized trial, perhaps with newer, more selective PARP inhibitors.

The work was funded by AstraZeneca, maker of olaparib. Researchers included AstraZeneca employees. Dr. Abraham is an adviser to and disclosed grants, travel costs, and honoraria from the company. Dr. Rugo disclosed research funding from AstraZeneca and other companies.

A version of this article appeared on Medscape.com.

Women who are considered to be at average risk for breast cancer should have mammograms every other year starting at age 40 years until age 74, according to the latest recommendations from the US Preventive Services Task Force (USPSTF).

In its updated recommendations published April 30 in JAMA, the USPSTF also made an urgent call to address reasons why Black women are more likely to die from breast cancer than are White women and pressed for more research to address persisting questions about how best to screen for cancer in dense breasts, which about 40% of women have. The USPSTF highlighted evidence gaps on the benefits and harms of continuing mammography after age 75 years as well.

The updated USPSTF recommendations were first unveiled last year in a draft version. 

In 2016, the task force recommended biennial mammograms for women starting 10 years later, at age 50 years, while stressing a need for clinicians and patients to weigh the risks and benefits of screening for those in their 40s. 

The shift to a general recommendation to start at age 40 years is based on a broad review of available data on mammography, including modeling from Cancer Intervention and Surveillance Modeling Network (CISNET).

Alongside the USPSTF report, JAMA published three separate editorials — a reflection of the controversy that these breast cancer screening recommendations often generate. 

In one editorial, published in JAMA Network Open, Lydia E. Pace, MD, MPH, and Nancy L. Keating, MD, MPH, highlighted that though screening earlier will prevent more deaths from breast cancer, it will also lead to more false positive findings and increase rates of overdiagnosis. 

Dr. Pace and Dr. Keating explained that the modeling study commissioned by the USPSTF estimated that screening every 2 years starting at age 40 years would avoid an additional 1.3 breast cancer deaths compared with screening at age 50 years. Among Black women, screening every 2 years starting at age 40 years would avert an extra 1.8 breast cancer deaths per 1000 people screened. 

However, the model also found that screening every 2 years starting at age 40 years would lead to more false positive tests — a rate of about 8.5% vs 7.8% for those starting at age 50.

“Given mammography screening’s modest benefits, we feel that all women — and particularly those aged 40 to 49 years —should be counseled about the benefits and harms of mammography and supported in deciding whether the balance of benefits to harms fits with their priorities and values,” wrote Dr. Pace and Dr. Keating, who specialize in internal medicine.

In a second editorial, in JAMA, Joann G. Elmore, MD, MPH, of UCLA, and Christoph I. Lee, MD, MS, of the University of Washington, Seattle, noted that the revised recommendations “shed light on 2 major issues that demand greater attention: addressing health inequities related to breast cancer outcomes and ensuring benefits for all women amid rapid screening technological advancements.” 

The USPSTF’s decision to recommend an earlier start age for routine mammography was partly intended to begin to address the fact that Black women are about 40% more likely to die from breast cancer than are White women.

“Despite greater absolute benefits of screening for Black women, the modeling study and systematic review underscore that mammography’s benefits (ie, breast cancer deaths averted) are modest for both Black women and the general population,” wrote Dr. Elmore and Dr. Lee.

The editorialists also cautioned against adopting artificial intelligence (AI) support tools too rapidly, criticizing the USPSTF for overlooking this “pressing issue.” 

“While AI algorithms show promise for enhancing cancer detection, their impact on patient outcomes and the balance between benefit and harms remain uncertain,” the editorialists wrote.

In a third editorial, in JAMA Oncology, Wendie A. Berg, MD, PhD, a radiologist at the University of Pittsburgh, argued that though the updated recommendations are “an important step forward,” they don’t go far enough.

Dr. Berg, for instance, noted her surprise “ to see the USPSTF recommendation only for biennial, rather than annual, screening among women aged 40 to 74 years.”

Compared with no screening, annual screening would reduce rates of breast cancer mortality (35.2%) more than biennial (28.4%) screening does among women aged 40-74 years, according to the CISNET modeling that informed the USPSTF’s decision.

Plus, Dr. Berg noted, regular risk assessments should begin at age 25 years “to identify women at high risk who should start annual MRI screenings.”

The American College of Radiology (ACR) offered similar views in a statement, saying the recommendations “do not go far enough to save more women’s lives.” It urged a more aggressive screening schedule, which starts at age 40 years but occurs annually vs biennially and continues past age 74 years. Like Dr. Berg, the ACR advocated for breast cancer risk assessments to begin at age 25 years.

The American Cancer Society also recommended annual mammography screening, starting as early as age 40 years in average-risk women, with high-risk women receiving a breast MRI and a mammogram every year starting at age 30 years. 
 

Ongoing Uncertainties 

The USPSTF’s 2024 update highlighted persistent evidence gaps in several key areas. 

The USPSTF, for instance, highlighted insufficient evidence on the benefits and harms of continuing to screen women who are 75 years or older as well as the benefits and harms of supplemental screening with breast ultrasonography or MRI in women with dense breasts who had a negative screening mammogram.

In the update, USPSTF noted that it’s still clear what proportion of ductal carcinoma in situ involves lesions detected by screening would not have ultimately caused harm. 

For women with dense breasts, the USPSTF said that “research is needed to help clinicians and patients understand the best strategy for breast cancer screening in women found to have dense breasts,” which includes supplemental screening.

Women with dense breasts should still get mammograms, but there is not enough evidence for a blanket statement about which benefit they might get from additional screening, Carol Mangione, MD, past chair of USPSTF, told this news organization. 

“We don’t want to send a message that the mammogram doesn’t have value in that group, because it does have high value,” said Dr. Mangione, chief of the division of general internal medicine and health services research at UCLA Health. 

Women with dense breasts should work with primary care clinicians who can take a holistic view of their preferences and needs, allowing them to make an informed choice about additional screening, she said.

“But we can’t make a global population choice because we don’t have the studies to do that,” Dr. Mangione said.
 

A version of this article appeared on Medscape.com.

Women who are considered to be at average risk for breast cancer should have mammograms every other year starting at age 40 years until age 74, according to the latest recommendations from the US Preventive Services Task Force (USPSTF).

In its updated recommendations published April 30 in JAMA, the USPSTF also made an urgent call to address reasons why Black women are more likely to die from breast cancer than are White women and pressed for more research to address persisting questions about how best to screen for cancer in dense breasts, which about 40% of women have. The USPSTF highlighted evidence gaps on the benefits and harms of continuing mammography after age 75 years as well.

The updated USPSTF recommendations were first unveiled last year in a draft version. 

In 2016, the task force recommended biennial mammograms for women starting 10 years later, at age 50 years, while stressing a need for clinicians and patients to weigh the risks and benefits of screening for those in their 40s. 

The shift to a general recommendation to start at age 40 years is based on a broad review of available data on mammography, including modeling from Cancer Intervention and Surveillance Modeling Network (CISNET).

Alongside the USPSTF report, JAMA published three separate editorials — a reflection of the controversy that these breast cancer screening recommendations often generate. 

In one editorial, published in JAMA Network Open, Lydia E. Pace, MD, MPH, and Nancy L. Keating, MD, MPH, highlighted that though screening earlier will prevent more deaths from breast cancer, it will also lead to more false positive findings and increase rates of overdiagnosis. 

Dr. Pace and Dr. Keating explained that the modeling study commissioned by the USPSTF estimated that screening every 2 years starting at age 40 years would avoid an additional 1.3 breast cancer deaths compared with screening at age 50 years. Among Black women, screening every 2 years starting at age 40 years would avert an extra 1.8 breast cancer deaths per 1000 people screened. 

However, the model also found that screening every 2 years starting at age 40 years would lead to more false positive tests — a rate of about 8.5% vs 7.8% for those starting at age 50.

“Given mammography screening’s modest benefits, we feel that all women — and particularly those aged 40 to 49 years —should be counseled about the benefits and harms of mammography and supported in deciding whether the balance of benefits to harms fits with their priorities and values,” wrote Dr. Pace and Dr. Keating, who specialize in internal medicine.

In a second editorial, in JAMA, Joann G. Elmore, MD, MPH, of UCLA, and Christoph I. Lee, MD, MS, of the University of Washington, Seattle, noted that the revised recommendations “shed light on 2 major issues that demand greater attention: addressing health inequities related to breast cancer outcomes and ensuring benefits for all women amid rapid screening technological advancements.” 

The USPSTF’s decision to recommend an earlier start age for routine mammography was partly intended to begin to address the fact that Black women are about 40% more likely to die from breast cancer than are White women.

“Despite greater absolute benefits of screening for Black women, the modeling study and systematic review underscore that mammography’s benefits (ie, breast cancer deaths averted) are modest for both Black women and the general population,” wrote Dr. Elmore and Dr. Lee.

The editorialists also cautioned against adopting artificial intelligence (AI) support tools too rapidly, criticizing the USPSTF for overlooking this “pressing issue.” 

“While AI algorithms show promise for enhancing cancer detection, their impact on patient outcomes and the balance between benefit and harms remain uncertain,” the editorialists wrote.

In a third editorial, in JAMA Oncology, Wendie A. Berg, MD, PhD, a radiologist at the University of Pittsburgh, argued that though the updated recommendations are “an important step forward,” they don’t go far enough.

Dr. Berg, for instance, noted her surprise “ to see the USPSTF recommendation only for biennial, rather than annual, screening among women aged 40 to 74 years.”

Compared with no screening, annual screening would reduce rates of breast cancer mortality (35.2%) more than biennial (28.4%) screening does among women aged 40-74 years, according to the CISNET modeling that informed the USPSTF’s decision.

Plus, Dr. Berg noted, regular risk assessments should begin at age 25 years “to identify women at high risk who should start annual MRI screenings.”

The American College of Radiology (ACR) offered similar views in a statement, saying the recommendations “do not go far enough to save more women’s lives.” It urged a more aggressive screening schedule, which starts at age 40 years but occurs annually vs biennially and continues past age 74 years. Like Dr. Berg, the ACR advocated for breast cancer risk assessments to begin at age 25 years.

The American Cancer Society also recommended annual mammography screening, starting as early as age 40 years in average-risk women, with high-risk women receiving a breast MRI and a mammogram every year starting at age 30 years. 
 

Ongoing Uncertainties 

The USPSTF’s 2024 update highlighted persistent evidence gaps in several key areas. 

The USPSTF, for instance, highlighted insufficient evidence on the benefits and harms of continuing to screen women who are 75 years or older as well as the benefits and harms of supplemental screening with breast ultrasonography or MRI in women with dense breasts who had a negative screening mammogram.

In the update, USPSTF noted that it’s still clear what proportion of ductal carcinoma in situ involves lesions detected by screening would not have ultimately caused harm. 

For women with dense breasts, the USPSTF said that “research is needed to help clinicians and patients understand the best strategy for breast cancer screening in women found to have dense breasts,” which includes supplemental screening.

Women with dense breasts should still get mammograms, but there is not enough evidence for a blanket statement about which benefit they might get from additional screening, Carol Mangione, MD, past chair of USPSTF, told this news organization. 

“We don’t want to send a message that the mammogram doesn’t have value in that group, because it does have high value,” said Dr. Mangione, chief of the division of general internal medicine and health services research at UCLA Health. 

Women with dense breasts should work with primary care clinicians who can take a holistic view of their preferences and needs, allowing them to make an informed choice about additional screening, she said.

“But we can’t make a global population choice because we don’t have the studies to do that,” Dr. Mangione said.
 

A version of this article appeared on Medscape.com.

Women who are considered to be at average risk for breast cancer should have mammograms every other year starting at age 40 years until age 74, according to the latest recommendations from the US Preventive Services Task Force (USPSTF).

In its updated recommendations published April 30 in JAMA, the USPSTF also made an urgent call to address reasons why Black women are more likely to die from breast cancer than are White women and pressed for more research to address persisting questions about how best to screen for cancer in dense breasts, which about 40% of women have. The USPSTF highlighted evidence gaps on the benefits and harms of continuing mammography after age 75 years as well.

The updated USPSTF recommendations were first unveiled last year in a draft version. 

In 2016, the task force recommended biennial mammograms for women starting 10 years later, at age 50 years, while stressing a need for clinicians and patients to weigh the risks and benefits of screening for those in their 40s. 

The shift to a general recommendation to start at age 40 years is based on a broad review of available data on mammography, including modeling from Cancer Intervention and Surveillance Modeling Network (CISNET).

Alongside the USPSTF report, JAMA published three separate editorials — a reflection of the controversy that these breast cancer screening recommendations often generate. 

In one editorial, published in JAMA Network Open, Lydia E. Pace, MD, MPH, and Nancy L. Keating, MD, MPH, highlighted that though screening earlier will prevent more deaths from breast cancer, it will also lead to more false positive findings and increase rates of overdiagnosis. 

Dr. Pace and Dr. Keating explained that the modeling study commissioned by the USPSTF estimated that screening every 2 years starting at age 40 years would avoid an additional 1.3 breast cancer deaths compared with screening at age 50 years. Among Black women, screening every 2 years starting at age 40 years would avert an extra 1.8 breast cancer deaths per 1000 people screened. 

However, the model also found that screening every 2 years starting at age 40 years would lead to more false positive tests — a rate of about 8.5% vs 7.8% for those starting at age 50.

“Given mammography screening’s modest benefits, we feel that all women — and particularly those aged 40 to 49 years —should be counseled about the benefits and harms of mammography and supported in deciding whether the balance of benefits to harms fits with their priorities and values,” wrote Dr. Pace and Dr. Keating, who specialize in internal medicine.

In a second editorial, in JAMA, Joann G. Elmore, MD, MPH, of UCLA, and Christoph I. Lee, MD, MS, of the University of Washington, Seattle, noted that the revised recommendations “shed light on 2 major issues that demand greater attention: addressing health inequities related to breast cancer outcomes and ensuring benefits for all women amid rapid screening technological advancements.” 

The USPSTF’s decision to recommend an earlier start age for routine mammography was partly intended to begin to address the fact that Black women are about 40% more likely to die from breast cancer than are White women.

“Despite greater absolute benefits of screening for Black women, the modeling study and systematic review underscore that mammography’s benefits (ie, breast cancer deaths averted) are modest for both Black women and the general population,” wrote Dr. Elmore and Dr. Lee.

The editorialists also cautioned against adopting artificial intelligence (AI) support tools too rapidly, criticizing the USPSTF for overlooking this “pressing issue.” 

“While AI algorithms show promise for enhancing cancer detection, their impact on patient outcomes and the balance between benefit and harms remain uncertain,” the editorialists wrote.

In a third editorial, in JAMA Oncology, Wendie A. Berg, MD, PhD, a radiologist at the University of Pittsburgh, argued that though the updated recommendations are “an important step forward,” they don’t go far enough.

Dr. Berg, for instance, noted her surprise “ to see the USPSTF recommendation only for biennial, rather than annual, screening among women aged 40 to 74 years.”

Compared with no screening, annual screening would reduce rates of breast cancer mortality (35.2%) more than biennial (28.4%) screening does among women aged 40-74 years, according to the CISNET modeling that informed the USPSTF’s decision.

Plus, Dr. Berg noted, regular risk assessments should begin at age 25 years “to identify women at high risk who should start annual MRI screenings.”

The American College of Radiology (ACR) offered similar views in a statement, saying the recommendations “do not go far enough to save more women’s lives.” It urged a more aggressive screening schedule, which starts at age 40 years but occurs annually vs biennially and continues past age 74 years. Like Dr. Berg, the ACR advocated for breast cancer risk assessments to begin at age 25 years.

The American Cancer Society also recommended annual mammography screening, starting as early as age 40 years in average-risk women, with high-risk women receiving a breast MRI and a mammogram every year starting at age 30 years. 
 

Ongoing Uncertainties 

The USPSTF’s 2024 update highlighted persistent evidence gaps in several key areas. 

The USPSTF, for instance, highlighted insufficient evidence on the benefits and harms of continuing to screen women who are 75 years or older as well as the benefits and harms of supplemental screening with breast ultrasonography or MRI in women with dense breasts who had a negative screening mammogram.

In the update, USPSTF noted that it’s still clear what proportion of ductal carcinoma in situ involves lesions detected by screening would not have ultimately caused harm. 

For women with dense breasts, the USPSTF said that “research is needed to help clinicians and patients understand the best strategy for breast cancer screening in women found to have dense breasts,” which includes supplemental screening.

Women with dense breasts should still get mammograms, but there is not enough evidence for a blanket statement about which benefit they might get from additional screening, Carol Mangione, MD, past chair of USPSTF, told this news organization. 

“We don’t want to send a message that the mammogram doesn’t have value in that group, because it does have high value,” said Dr. Mangione, chief of the division of general internal medicine and health services research at UCLA Health. 

Women with dense breasts should work with primary care clinicians who can take a holistic view of their preferences and needs, allowing them to make an informed choice about additional screening, she said.

“But we can’t make a global population choice because we don’t have the studies to do that,” Dr. Mangione said.
 

A version of this article appeared on Medscape.com.

The class of CDK 4/6 inhibitors represents a significant advance in the treatment of hormone receptor (HR)-positive breast cancer. All three CDK 4/6 inhibitors (palbociclib, abemaciclib, and ribociclib) are approved in combination with endocrine therapy in the metastatic setting. As drugs show promise in later-stage disease, they are then often studied in the curative space. Presently, abemaciclib is the only CDK 4/6 inhibitor that has been approved by the US Food and Drug Administration for the treatment of HR-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, high-risk early breast cancer, based on results from the monarchE trial, which demonstrated invasive disease-free survival benefit with the addition of 2 years of abemaciclib to endocrine therapy. At 4 years, the absolute difference in invasive disease-free survival (IDFS) between the groups was 6.4% (85.8% in the abemaciclib + endocrine therapy group vs 79.4% in the endocrine therapy–alone group).^[3] In contrast, the PENELOPE-B and PALLAS trials did not show benefit with the addition of palbociclib to endocrine therapy in the adjuvant setting.^[4,5] The phase 3 NATALEE trial randomly assigned patients with HR-positive, HER2-negative early breast cancer to ribociclib (400 mg daily for 3 weeks followed by 1 week off for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI) or an NSAI alone. At the time of prespecified interim analysis, among 5101 patients, ribociclib + NSAI led to a significant improvement in IDFS compared with endocrine therapy alone (3-year IDFS was 90.4% vs 87.1%; hazard ratio 0.75; 95% CI 0.62-0.91; P = .003). It is certainly noteworthy that the trial design, endocrine therapies, and patient populations differed between these adjuvant studies; for example, NATALEE included a lower-risk population, and all patients received an NSAI (in monarchE approximately 30% received tamoxifen). The current results of NATALEE are encouraging; an absolute benefit of 3.3% should be considered and weighed against toxicities and cost, and longer follow-up is needed to further elucidate the role of ribociclib in the adjuvant space.

The meaningful impact of achieving a pathologic complete response (pCR) has been demonstrated in various prior studies. Response to neoadjuvant chemotherapy informs prognosis and helps tailor adjuvant therapy, the latter of which is particularly relevant for the HER2-positive subtype. Strategies to identify patients who are more likely to achieve pCR and predictors of early responders may aid in improving efficacy outcomes and limiting toxicities. TRAIN-3 is a single-arm, phase 2 study that included 235 and 232 patients with stage II/III HR-/HER2+ and HR+/HER2+ breast cancer, respectively, undergoing neoadjuvant chemotherapy (weekly paclitaxel D1 and D8/carboplatin AUC 6 D1/trastuzumab D1/pertuzumab D1 every 3 weeks for up to nine cycles), and was designed to evaluate radiologic and pathologic response rates and event-free survival. Response was monitored by breast MRI every 3 cycles and lymph node biopsy. Among patients with HR-/HER2+ tumors, 84 (36%; 95% CI 30-43) achieved a radiologic complete response after one to three cycles, of whom the majority (88%; 95% CI 79-94) had pCR. Patients with HR+/HER2+ tumors did not show the same degree of benefit with an MRI-based monitoring strategy; among the 138 patients (59%; 95% CI 53-66) who had a complete radiologic response after one to nine cycles, 73 (53%; 95% CI 44-61) had pCR. Additional imaging-guided modalities being studied to tailor and optimize treatment include [¹⁸F]fluorodeoxyglucose-PET-CT and volumetric MRI, in the PHERGain and I-SPY trials, respectively.^[6,7]

Additional References:

1. Giuliano AE, Ballman KV, McCall L, et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA. 2017;318:918-926. doi: 10.1001/jama.2017.11470 Source
2. Bartels SAL, Donker M, Poncet C, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS trial. J Clin Oncol. 2023;41:2159-2165. doi: 10.1200/JCO.22.01565 Source
3. Johnston SRD, Toi M, O'Shaughnessy J, et al, on behalf of the monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): Results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24:77-90. doi: 10.1016/S1470-2045(22)00694-5 Source
4. Loibl S, Marmé F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer—The Penelope-B trial. J Clin Oncol. 2021;39:1518-1530. doi: 10.1200/JCO.20.03639 Source
5. Gnant M, Dueck AC, Frantal S, et al, on behalf of the PALLAS groups and investigators. Adjuvant palbociclib for early breast cancer: The PALLAS trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40:282-293. doi: 10.1200/JCO.21.02554 Source
6. Pérez-García JM, Cortés J, Ruiz-Borrego M, et al, on behalf of the PHERGain trial investigators. 3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): A randomised, open-label, phase 2 trial. Lancet. 2024;403:1649-1659. doi: 10.1016/S0140-6736(24)00054-0 Source
7. Hylton NM, Gatsonis CA, Rosen MA, et al, for the ACRIN 6657 trial team and I-SPY 1 trial investigators. Neoadjuvant chemotherapy for breast cancer: Functional tumor volume by MR imaging predicts recurrence-free survival-results from the ACRIN 6657/CALGB 150007 I-SPY 1 trial. Radiology. 2016;279:44-55. doi: 10.1148/radiol.2015150013 Source

The class of CDK 4/6 inhibitors represents a significant advance in the treatment of hormone receptor (HR)-positive breast cancer. All three CDK 4/6 inhibitors (palbociclib, abemaciclib, and ribociclib) are approved in combination with endocrine therapy in the metastatic setting. As drugs show promise in later-stage disease, they are then often studied in the curative space. Presently, abemaciclib is the only CDK 4/6 inhibitor that has been approved by the US Food and Drug Administration for the treatment of HR-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, high-risk early breast cancer, based on results from the monarchE trial, which demonstrated invasive disease-free survival benefit with the addition of 2 years of abemaciclib to endocrine therapy. At 4 years, the absolute difference in invasive disease-free survival (IDFS) between the groups was 6.4% (85.8% in the abemaciclib + endocrine therapy group vs 79.4% in the endocrine therapy–alone group).^[3] In contrast, the PENELOPE-B and PALLAS trials did not show benefit with the addition of palbociclib to endocrine therapy in the adjuvant setting.^[4,5] The phase 3 NATALEE trial randomly assigned patients with HR-positive, HER2-negative early breast cancer to ribociclib (400 mg daily for 3 weeks followed by 1 week off for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI) or an NSAI alone. At the time of prespecified interim analysis, among 5101 patients, ribociclib + NSAI led to a significant improvement in IDFS compared with endocrine therapy alone (3-year IDFS was 90.4% vs 87.1%; hazard ratio 0.75; 95% CI 0.62-0.91; P = .003). It is certainly noteworthy that the trial design, endocrine therapies, and patient populations differed between these adjuvant studies; for example, NATALEE included a lower-risk population, and all patients received an NSAI (in monarchE approximately 30% received tamoxifen). The current results of NATALEE are encouraging; an absolute benefit of 3.3% should be considered and weighed against toxicities and cost, and longer follow-up is needed to further elucidate the role of ribociclib in the adjuvant space.

The meaningful impact of achieving a pathologic complete response (pCR) has been demonstrated in various prior studies. Response to neoadjuvant chemotherapy informs prognosis and helps tailor adjuvant therapy, the latter of which is particularly relevant for the HER2-positive subtype. Strategies to identify patients who are more likely to achieve pCR and predictors of early responders may aid in improving efficacy outcomes and limiting toxicities. TRAIN-3 is a single-arm, phase 2 study that included 235 and 232 patients with stage II/III HR-/HER2+ and HR+/HER2+ breast cancer, respectively, undergoing neoadjuvant chemotherapy (weekly paclitaxel D1 and D8/carboplatin AUC 6 D1/trastuzumab D1/pertuzumab D1 every 3 weeks for up to nine cycles), and was designed to evaluate radiologic and pathologic response rates and event-free survival. Response was monitored by breast MRI every 3 cycles and lymph node biopsy. Among patients with HR-/HER2+ tumors, 84 (36%; 95% CI 30-43) achieved a radiologic complete response after one to three cycles, of whom the majority (88%; 95% CI 79-94) had pCR. Patients with HR+/HER2+ tumors did not show the same degree of benefit with an MRI-based monitoring strategy; among the 138 patients (59%; 95% CI 53-66) who had a complete radiologic response after one to nine cycles, 73 (53%; 95% CI 44-61) had pCR. Additional imaging-guided modalities being studied to tailor and optimize treatment include [¹⁸F]fluorodeoxyglucose-PET-CT and volumetric MRI, in the PHERGain and I-SPY trials, respectively.^[6,7]

Additional References:

1. Giuliano AE, Ballman KV, McCall L, et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA. 2017;318:918-926. doi: 10.1001/jama.2017.11470 Source
2. Bartels SAL, Donker M, Poncet C, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS trial. J Clin Oncol. 2023;41:2159-2165. doi: 10.1200/JCO.22.01565 Source
3. Johnston SRD, Toi M, O'Shaughnessy J, et al, on behalf of the monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): Results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24:77-90. doi: 10.1016/S1470-2045(22)00694-5 Source
4. Loibl S, Marmé F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer—The Penelope-B trial. J Clin Oncol. 2021;39:1518-1530. doi: 10.1200/JCO.20.03639 Source
5. Gnant M, Dueck AC, Frantal S, et al, on behalf of the PALLAS groups and investigators. Adjuvant palbociclib for early breast cancer: The PALLAS trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40:282-293. doi: 10.1200/JCO.21.02554 Source
6. Pérez-García JM, Cortés J, Ruiz-Borrego M, et al, on behalf of the PHERGain trial investigators. 3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): A randomised, open-label, phase 2 trial. Lancet. 2024;403:1649-1659. doi: 10.1016/S0140-6736(24)00054-0 Source
7. Hylton NM, Gatsonis CA, Rosen MA, et al, for the ACRIN 6657 trial team and I-SPY 1 trial investigators. Neoadjuvant chemotherapy for breast cancer: Functional tumor volume by MR imaging predicts recurrence-free survival-results from the ACRIN 6657/CALGB 150007 I-SPY 1 trial. Radiology. 2016;279:44-55. doi: 10.1148/radiol.2015150013 Source

The class of CDK 4/6 inhibitors represents a significant advance in the treatment of hormone receptor (HR)-positive breast cancer. All three CDK 4/6 inhibitors (palbociclib, abemaciclib, and ribociclib) are approved in combination with endocrine therapy in the metastatic setting. As drugs show promise in later-stage disease, they are then often studied in the curative space. Presently, abemaciclib is the only CDK 4/6 inhibitor that has been approved by the US Food and Drug Administration for the treatment of HR-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, high-risk early breast cancer, based on results from the monarchE trial, which demonstrated invasive disease-free survival benefit with the addition of 2 years of abemaciclib to endocrine therapy. At 4 years, the absolute difference in invasive disease-free survival (IDFS) between the groups was 6.4% (85.8% in the abemaciclib + endocrine therapy group vs 79.4% in the endocrine therapy–alone group).^[3] In contrast, the PENELOPE-B and PALLAS trials did not show benefit with the addition of palbociclib to endocrine therapy in the adjuvant setting.^[4,5] The phase 3 NATALEE trial randomly assigned patients with HR-positive, HER2-negative early breast cancer to ribociclib (400 mg daily for 3 weeks followed by 1 week off for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI) or an NSAI alone. At the time of prespecified interim analysis, among 5101 patients, ribociclib + NSAI led to a significant improvement in IDFS compared with endocrine therapy alone (3-year IDFS was 90.4% vs 87.1%; hazard ratio 0.75; 95% CI 0.62-0.91; P = .003). It is certainly noteworthy that the trial design, endocrine therapies, and patient populations differed between these adjuvant studies; for example, NATALEE included a lower-risk population, and all patients received an NSAI (in monarchE approximately 30% received tamoxifen). The current results of NATALEE are encouraging; an absolute benefit of 3.3% should be considered and weighed against toxicities and cost, and longer follow-up is needed to further elucidate the role of ribociclib in the adjuvant space.

The meaningful impact of achieving a pathologic complete response (pCR) has been demonstrated in various prior studies. Response to neoadjuvant chemotherapy informs prognosis and helps tailor adjuvant therapy, the latter of which is particularly relevant for the HER2-positive subtype. Strategies to identify patients who are more likely to achieve pCR and predictors of early responders may aid in improving efficacy outcomes and limiting toxicities. TRAIN-3 is a single-arm, phase 2 study that included 235 and 232 patients with stage II/III HR-/HER2+ and HR+/HER2+ breast cancer, respectively, undergoing neoadjuvant chemotherapy (weekly paclitaxel D1 and D8/carboplatin AUC 6 D1/trastuzumab D1/pertuzumab D1 every 3 weeks for up to nine cycles), and was designed to evaluate radiologic and pathologic response rates and event-free survival. Response was monitored by breast MRI every 3 cycles and lymph node biopsy. Among patients with HR-/HER2+ tumors, 84 (36%; 95% CI 30-43) achieved a radiologic complete response after one to three cycles, of whom the majority (88%; 95% CI 79-94) had pCR. Patients with HR+/HER2+ tumors did not show the same degree of benefit with an MRI-based monitoring strategy; among the 138 patients (59%; 95% CI 53-66) who had a complete radiologic response after one to nine cycles, 73 (53%; 95% CI 44-61) had pCR. Additional imaging-guided modalities being studied to tailor and optimize treatment include [¹⁸F]fluorodeoxyglucose-PET-CT and volumetric MRI, in the PHERGain and I-SPY trials, respectively.^[6,7]

Additional References:

1. Giuliano AE, Ballman KV, McCall L, et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA. 2017;318:918-926. doi: 10.1001/jama.2017.11470 Source
2. Bartels SAL, Donker M, Poncet C, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS trial. J Clin Oncol. 2023;41:2159-2165. doi: 10.1200/JCO.22.01565 Source
3. Johnston SRD, Toi M, O'Shaughnessy J, et al, on behalf of the monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): Results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24:77-90. doi: 10.1016/S1470-2045(22)00694-5 Source
4. Loibl S, Marmé F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer—The Penelope-B trial. J Clin Oncol. 2021;39:1518-1530. doi: 10.1200/JCO.20.03639 Source
5. Gnant M, Dueck AC, Frantal S, et al, on behalf of the PALLAS groups and investigators. Adjuvant palbociclib for early breast cancer: The PALLAS trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40:282-293. doi: 10.1200/JCO.21.02554 Source
6. Pérez-García JM, Cortés J, Ruiz-Borrego M, et al, on behalf of the PHERGain trial investigators. 3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): A randomised, open-label, phase 2 trial. Lancet. 2024;403:1649-1659. doi: 10.1016/S0140-6736(24)00054-0 Source
7. Hylton NM, Gatsonis CA, Rosen MA, et al, for the ACRIN 6657 trial team and I-SPY 1 trial investigators. Neoadjuvant chemotherapy for breast cancer: Functional tumor volume by MR imaging predicts recurrence-free survival-results from the ACRIN 6657/CALGB 150007 I-SPY 1 trial. Radiology. 2016;279:44-55. doi: 10.1148/radiol.2015150013 Source

Adjuvant therapy with aspirin offers no protection against recurrence or survival benefit in patients with high-risk nonmetastatic breast cancer, the results of a new phase 3 randomized controlled trial suggest.

These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.

What Data Support Aspirin for Treating Breast Cancer?

“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”

This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).

Brigham &amp; Women&#039;s Hospital

What Were The Key Findings From The A011502 Trial?

The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.

Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.

After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant  (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.

How Will This Study Change Practice?

In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.

“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.

Georgetown University

How Might the Findings From the A011502 Trial Impact Future Research?

Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.

They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.

This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.

Adjuvant therapy with aspirin offers no protection against recurrence or survival benefit in patients with high-risk nonmetastatic breast cancer, the results of a new phase 3 randomized controlled trial suggest.

These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.

What Data Support Aspirin for Treating Breast Cancer?

“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”

This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).

Brigham &amp; Women&#039;s Hospital

What Were The Key Findings From The A011502 Trial?

The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.

Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.

After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant  (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.

How Will This Study Change Practice?

In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.

“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.

Georgetown University

How Might the Findings From the A011502 Trial Impact Future Research?

Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.

They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.

This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.

Adjuvant therapy with aspirin offers no protection against recurrence or survival benefit in patients with high-risk nonmetastatic breast cancer, the results of a new phase 3 randomized controlled trial suggest.

These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.

What Data Support Aspirin for Treating Breast Cancer?

“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”

This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).

Brigham &amp; Women&#039;s Hospital

What Were The Key Findings From The A011502 Trial?

The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.

Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.

After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant  (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.

How Will This Study Change Practice?

In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.

“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.

Georgetown University

How Might the Findings From the A011502 Trial Impact Future Research?

Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.

They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.

This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.