Breast Cancer

Adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer, according to a new study of more than 44,000 individuals.

The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
 

What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

 What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
 

What Is the Takeaway Message for Clinical Practice?

The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded. 

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.

More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.

The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.

Adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer, according to a new study of more than 44,000 individuals.

The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
 

What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

 What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
 

What Is the Takeaway Message for Clinical Practice?

The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded. 

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.

More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.

The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.

Adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer, according to a new study of more than 44,000 individuals.

The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
 

What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

 What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
 

What Is the Takeaway Message for Clinical Practice?

The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded. 

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.

More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.

The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.

A new drug-device combo aimed at detecting residual cancer in real time during lumpectomy is one step closer to gaining federal approval, but some physicians aren’t convinced the technology is safe — or effective enough — to start using on patients.

A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.

LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.

Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.

“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.

However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.

In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.

“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”

The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.

On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.

“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”

Is the Technology Safe?

Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.

After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.

If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.

In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.

Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.

Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.

“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”

During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.

Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.

David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.

“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.

Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.

She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.

MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.

Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.

“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”

During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.

“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
 

Committee Expresses Support

During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.

Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.

Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.

“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”

Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.

“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”

Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.

The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.

If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.

Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.

The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.

A new drug-device combo aimed at detecting residual cancer in real time during lumpectomy is one step closer to gaining federal approval, but some physicians aren’t convinced the technology is safe — or effective enough — to start using on patients.

A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.

LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.

Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.

“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.

However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.

In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.

“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”

The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.

On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.

“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”

Is the Technology Safe?

Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.

After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.

If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.

In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.

Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.

Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.

“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”

During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.

Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.

David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.

“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.

Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.

She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.

MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.

Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.

“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”

During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.

“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
 

Committee Expresses Support

During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.

Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.

Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.

“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”

Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.

“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”

Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.

The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.

If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.

Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.

The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.

A new drug-device combo aimed at detecting residual cancer in real time during lumpectomy is one step closer to gaining federal approval, but some physicians aren’t convinced the technology is safe — or effective enough — to start using on patients.

A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.

LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.

Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.

“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.

However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.

In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.

“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”

The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.

On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.

“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”

Is the Technology Safe?

Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.

After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.

If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.

In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.

Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.

Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.

“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”

During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.

Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.

David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.

“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.

Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.

She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.

MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.

Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.

“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”

During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.

“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
 

Committee Expresses Support

During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.

Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.

Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.

“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”

Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.

“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”

Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.

The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.

If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.

Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.

The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.

“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.

Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.

Despite confidently worded recommendations, the relationship between exercise and cancer risk is much less certain than the guidelines would suggest. The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.

What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?

Here’s an overview of the state of the evidence.

Exercise and Cancer Types: A Mixed Bag

When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.

For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.

The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.

The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”

Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations. 

“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.

That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.

“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”

And it’s challenging to put all the evidence together, Dr. Jones added.

The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.

Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.

In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.

The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.

Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).

What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.

Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).

The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.

But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.

How Big Is the Effect?

Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.

But how much of a difference can exercise make?

Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.

These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.

“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.

“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.

The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.

Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.

For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).

But there may be an exercise sweet spot that maximizes the cancer risk benefit.

Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.

The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.

Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.

Why Exercise May Lower Cancer Risk

Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.

Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.

The why remains unclear, though some studies offer clues.

“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.

That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.

A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.

Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.

Defining an Exercise ‘Prescription’

Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.

The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.

But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.

Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.

Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.

But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.

“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.

Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.

There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.

“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.

Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.

“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”

A version of this article appeared on Medscape.com.

“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.

Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.

Despite confidently worded recommendations, the relationship between exercise and cancer risk is much less certain than the guidelines would suggest. The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.

What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?

Here’s an overview of the state of the evidence.

Exercise and Cancer Types: A Mixed Bag

When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.

For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.

The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.

The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”

Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations. 

“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.

That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.

“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”

And it’s challenging to put all the evidence together, Dr. Jones added.

The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.

Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.

In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.

The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.

Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).

What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.

Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).

The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.

But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.

How Big Is the Effect?

Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.

But how much of a difference can exercise make?

Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.

These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.

“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.

“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.

The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.

Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.

For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).

But there may be an exercise sweet spot that maximizes the cancer risk benefit.

Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.

The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.

Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.

Why Exercise May Lower Cancer Risk

Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.

Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.

The why remains unclear, though some studies offer clues.

“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.

That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.

A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.

Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.

Defining an Exercise ‘Prescription’

Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.

The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.

But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.

Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.

Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.

But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.

“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.

Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.

There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.

“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.

Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.

“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”

A version of this article appeared on Medscape.com.

“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.

Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.

Despite confidently worded recommendations, the relationship between exercise and cancer risk is much less certain than the guidelines would suggest. The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.

What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?

Here’s an overview of the state of the evidence.

Exercise and Cancer Types: A Mixed Bag

When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.

For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.

The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.

The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”

Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations. 

“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.

That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.

“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”

And it’s challenging to put all the evidence together, Dr. Jones added.

The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.

Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.

In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.

The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.

Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).

What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.

Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).

The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.

But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.

How Big Is the Effect?

Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.

But how much of a difference can exercise make?

Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.

These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.

“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.

“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.

The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.

Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.

For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).

But there may be an exercise sweet spot that maximizes the cancer risk benefit.

Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.

The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.

Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.

Why Exercise May Lower Cancer Risk

Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.

Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.

The why remains unclear, though some studies offer clues.

“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.

That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.

A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.

Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.

Defining an Exercise ‘Prescription’

Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.

The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.

But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.

Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.

Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.

But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.

“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.

Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.

There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.

“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.

Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.

“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”

A version of this article appeared on Medscape.com.

TOPLINE:

Women with daily exposure to spironolactone for dermatologic conditions showed no higher risk of developing breast or gynecologic cancer than that of unexposed women.

METHODOLOGY:

• Spironolactone, used off-label for several skin conditions in women, carries a warning about an increased tumor risk associated with high doses in rat models, and its antiandrogen properties have prompted hypotheses about a possible increased risk for breast or gynecologic cancers.
• The researchers reviewed data on 420 women with a history of spironolactone use for acne, hair loss, and hirsutism and 3272 women with no spironolactone use at the authors› institution. Their mean age ranged from 42 to 63 years; the majority were White, and 38% were non-White.
• Median spironolactone doses ranged from 25 mg to 225 mg; chart reviews included 5-year follow-up data from the first spironolactone exposure to allow time for tumor development.

TAKEAWAY:

• A total of 37 of the 420 women exposed to spironolactone developed any tumors, as did 546 of the 3272 with no spironolactone exposure.
• After the researchers controlled for age and race, women exposed to spironolactone were no more likely to develop a malignant tumor than a benign tumor, compared with unexposed women (odds ratio [OR], 0.48, P = .2).
• The risk for breast or uterine cancer was not significantly different in the spironolactone and non-spironolactone groups (OR, 0.95, P > .9).

IN PRACTICE:

“Women taking spironolactone for acne, hair loss, and hirsutism and who are at low risk of breast or gynecologic cancers may be counseled to have regular gynecology follow-up, but no more frequently than the general population,” but more studies are needed to evaluate risk over longer periods of time, the researchers wrote.

SOURCE:

The lead author of the study was Rachel C. Hill, BS, a student at Weill Cornell Medical College, New York City, and Shari R. Lipner, MD, PhD, of the department of dermatology at Weill Cornell Medical College, was the corresponding author. The study was published online in The Journal of the American Academy of Dermatology.

LIMITATIONS:

The findings were limited by the retrospective design, as well as the small number of spironolactone patients analyzed, the short follow-up period, the lack of information about spironolactone courses, and the inability to control for family history of malignancy.

DISCLOSURES:

The study was supported by the National Center for Advancing Translational Sciences and a grant from the Clinical and Translational Science Center at Weill Cornell Medical College awarded to Ms. Hill. None of the authors had relevant disclosures; Dr. Lipner disclosed serving as a consultant for Ortho-Dermatologics, Eli Lilly, Moberg Pharmaceuticals, and BelleTorus Corporation.

A version of this article appeared on Medscape.com.

TOPLINE:

Women with daily exposure to spironolactone for dermatologic conditions showed no higher risk of developing breast or gynecologic cancer than that of unexposed women.

METHODOLOGY:

• Spironolactone, used off-label for several skin conditions in women, carries a warning about an increased tumor risk associated with high doses in rat models, and its antiandrogen properties have prompted hypotheses about a possible increased risk for breast or gynecologic cancers.
• The researchers reviewed data on 420 women with a history of spironolactone use for acne, hair loss, and hirsutism and 3272 women with no spironolactone use at the authors› institution. Their mean age ranged from 42 to 63 years; the majority were White, and 38% were non-White.
• Median spironolactone doses ranged from 25 mg to 225 mg; chart reviews included 5-year follow-up data from the first spironolactone exposure to allow time for tumor development.

TAKEAWAY:

• A total of 37 of the 420 women exposed to spironolactone developed any tumors, as did 546 of the 3272 with no spironolactone exposure.
• After the researchers controlled for age and race, women exposed to spironolactone were no more likely to develop a malignant tumor than a benign tumor, compared with unexposed women (odds ratio [OR], 0.48, P = .2).
• The risk for breast or uterine cancer was not significantly different in the spironolactone and non-spironolactone groups (OR, 0.95, P > .9).

IN PRACTICE:

“Women taking spironolactone for acne, hair loss, and hirsutism and who are at low risk of breast or gynecologic cancers may be counseled to have regular gynecology follow-up, but no more frequently than the general population,” but more studies are needed to evaluate risk over longer periods of time, the researchers wrote.

SOURCE:

The lead author of the study was Rachel C. Hill, BS, a student at Weill Cornell Medical College, New York City, and Shari R. Lipner, MD, PhD, of the department of dermatology at Weill Cornell Medical College, was the corresponding author. The study was published online in The Journal of the American Academy of Dermatology.

LIMITATIONS:

The findings were limited by the retrospective design, as well as the small number of spironolactone patients analyzed, the short follow-up period, the lack of information about spironolactone courses, and the inability to control for family history of malignancy.

DISCLOSURES:

The study was supported by the National Center for Advancing Translational Sciences and a grant from the Clinical and Translational Science Center at Weill Cornell Medical College awarded to Ms. Hill. None of the authors had relevant disclosures; Dr. Lipner disclosed serving as a consultant for Ortho-Dermatologics, Eli Lilly, Moberg Pharmaceuticals, and BelleTorus Corporation.

A version of this article appeared on Medscape.com.

TOPLINE:

Women with daily exposure to spironolactone for dermatologic conditions showed no higher risk of developing breast or gynecologic cancer than that of unexposed women.

METHODOLOGY:

• Spironolactone, used off-label for several skin conditions in women, carries a warning about an increased tumor risk associated with high doses in rat models, and its antiandrogen properties have prompted hypotheses about a possible increased risk for breast or gynecologic cancers.
• The researchers reviewed data on 420 women with a history of spironolactone use for acne, hair loss, and hirsutism and 3272 women with no spironolactone use at the authors› institution. Their mean age ranged from 42 to 63 years; the majority were White, and 38% were non-White.
• Median spironolactone doses ranged from 25 mg to 225 mg; chart reviews included 5-year follow-up data from the first spironolactone exposure to allow time for tumor development.

TAKEAWAY:

• A total of 37 of the 420 women exposed to spironolactone developed any tumors, as did 546 of the 3272 with no spironolactone exposure.
• After the researchers controlled for age and race, women exposed to spironolactone were no more likely to develop a malignant tumor than a benign tumor, compared with unexposed women (odds ratio [OR], 0.48, P = .2).
• The risk for breast or uterine cancer was not significantly different in the spironolactone and non-spironolactone groups (OR, 0.95, P > .9).

IN PRACTICE:

“Women taking spironolactone for acne, hair loss, and hirsutism and who are at low risk of breast or gynecologic cancers may be counseled to have regular gynecology follow-up, but no more frequently than the general population,” but more studies are needed to evaluate risk over longer periods of time, the researchers wrote.

SOURCE:

The lead author of the study was Rachel C. Hill, BS, a student at Weill Cornell Medical College, New York City, and Shari R. Lipner, MD, PhD, of the department of dermatology at Weill Cornell Medical College, was the corresponding author. The study was published online in The Journal of the American Academy of Dermatology.

LIMITATIONS:

The findings were limited by the retrospective design, as well as the small number of spironolactone patients analyzed, the short follow-up period, the lack of information about spironolactone courses, and the inability to control for family history of malignancy.

DISCLOSURES:

The study was supported by the National Center for Advancing Translational Sciences and a grant from the Clinical and Translational Science Center at Weill Cornell Medical College awarded to Ms. Hill. None of the authors had relevant disclosures; Dr. Lipner disclosed serving as a consultant for Ortho-Dermatologics, Eli Lilly, Moberg Pharmaceuticals, and BelleTorus Corporation.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the first biosimilar to denosumab, denosumab-bddz (Wyost/Jubbonti).

The biosimilar was also granted interchangeability status, which allows pharmacists to substitute the biosimilar for the reference product without involving the prescribing clinician (according to state law). Sandoz announced the approval on March 5, 2024. The lower dosage of denosumab-bddz, marketed as Jubbonti, was also approved by Health Canada in February. 

The FDA approval “is based on robust clinical studies and accompanied by labeling with safety warnings,” according to the press release. Like the reference products Prolia and Xgeva, denosumab-bddz is approved for two indications at separate doses.

Wyost (120-mg/1.7-mL injection) is approved to:

• Prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors
• Treat adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity
• Treat hypercalcemia of cancer that is refractory to bisphosphonate therapy

Jubbonti (60-mg/1-mL injection) is approved to:

• Treat postmenopausal women with osteoporosis who are at high risk for fracture
• Increase bone mass in men with osteoporosis who are at high risk for fracture
• Treat glucocorticoid-induced osteoporosis in men and women who are at high risk for fracture
• Increase bone mass in men who are at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer
• Increase bone mass in women who are at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer.

Both doses are contraindicated for hypocalcemia and known clinically significant hypersensitivity to denosumab products. Exposure to denosumab products during pregnancy can cause fetal harm, so women of reproductive potential should be advised to use effective contraception during therapy and for at least 5 months after the last dose of denosumab-bddz.

Sandoz did not provide information on US launch details, citing “ongoing patent litigation around these products.”

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the first biosimilar to denosumab, denosumab-bddz (Wyost/Jubbonti).

The biosimilar was also granted interchangeability status, which allows pharmacists to substitute the biosimilar for the reference product without involving the prescribing clinician (according to state law). Sandoz announced the approval on March 5, 2024. The lower dosage of denosumab-bddz, marketed as Jubbonti, was also approved by Health Canada in February. 

The FDA approval “is based on robust clinical studies and accompanied by labeling with safety warnings,” according to the press release. Like the reference products Prolia and Xgeva, denosumab-bddz is approved for two indications at separate doses.

Wyost (120-mg/1.7-mL injection) is approved to:

• Prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors
• Treat adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity
• Treat hypercalcemia of cancer that is refractory to bisphosphonate therapy

Jubbonti (60-mg/1-mL injection) is approved to:

• Treat postmenopausal women with osteoporosis who are at high risk for fracture
• Increase bone mass in men with osteoporosis who are at high risk for fracture
• Treat glucocorticoid-induced osteoporosis in men and women who are at high risk for fracture
• Increase bone mass in men who are at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer
• Increase bone mass in women who are at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer.

Both doses are contraindicated for hypocalcemia and known clinically significant hypersensitivity to denosumab products. Exposure to denosumab products during pregnancy can cause fetal harm, so women of reproductive potential should be advised to use effective contraception during therapy and for at least 5 months after the last dose of denosumab-bddz.

Sandoz did not provide information on US launch details, citing “ongoing patent litigation around these products.”

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the first biosimilar to denosumab, denosumab-bddz (Wyost/Jubbonti).

The biosimilar was also granted interchangeability status, which allows pharmacists to substitute the biosimilar for the reference product without involving the prescribing clinician (according to state law). Sandoz announced the approval on March 5, 2024. The lower dosage of denosumab-bddz, marketed as Jubbonti, was also approved by Health Canada in February. 

The FDA approval “is based on robust clinical studies and accompanied by labeling with safety warnings,” according to the press release. Like the reference products Prolia and Xgeva, denosumab-bddz is approved for two indications at separate doses.

Wyost (120-mg/1.7-mL injection) is approved to:

• Prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors
• Treat adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity
• Treat hypercalcemia of cancer that is refractory to bisphosphonate therapy

Jubbonti (60-mg/1-mL injection) is approved to:

• Treat postmenopausal women with osteoporosis who are at high risk for fracture
• Increase bone mass in men with osteoporosis who are at high risk for fracture
• Treat glucocorticoid-induced osteoporosis in men and women who are at high risk for fracture
• Increase bone mass in men who are at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer
• Increase bone mass in women who are at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer.

Both doses are contraindicated for hypocalcemia and known clinically significant hypersensitivity to denosumab products. Exposure to denosumab products during pregnancy can cause fetal harm, so women of reproductive potential should be advised to use effective contraception during therapy and for at least 5 months after the last dose of denosumab-bddz.

Sandoz did not provide information on US launch details, citing “ongoing patent litigation around these products.”

A version of this article appeared on Medscape.com.

Breast cancer-specific mortality risk in men with hormone receptor–positive breast cancer persists for at least 20 years, but patterns of breast cancer–specific mortality (BCSM) are distinct from those in women, a new study finds.

Previous studies in women with hormone receptor–positive (HR+) breast cancer have shown a risk of distant recurrence and death for at least 20 years after diagnosis, but data for men are limited, wrote Julieta Leone, MD, of the Dana Farber Cancer Institute, Boston, and colleagues.
 

What is Known About Hormone Receptor–Positive Breast Cancer Mortality in Men vs. Women?

Invasive breast cancer in men is rare and consequently understudied, the researchers wrote. Previous studies of BCSM in men with more than 5 years’ follow-up consist mainly of case series at single institutions, the researchers wrote in JAMA Oncology (2024 Feb 29. doi: 10.1001/jamaoncol.2023.7194).

“We believed it would be important to study this issue to help inform the management of men with breast cancer,” corresponding author, José P. Leone, MD, said in an interview.

In 2021, Dr. J.P. Leone and colleagues published a study in Breast Cancer Research and Treatment that examined the 20-year risk of BCSM in women that included more than 36,000 individuals who had survived for 5 years, with a median of 14 years’ follow-up.

In that study of women, the BCSM risk at 20 years was significantly higher for those with HR-negative tumors, but the risk was still elevated for both types. Patients with stage IIIC HR-positive disease had four times the risk of BCSM over 20 years and those with stage IIIC HR-negative disease had seven times the risk of BCSM over 20 years compared with the risk of death not related to breast cancer, the researchers wrote.

Another study of nearly 2,400 men with breast cancer (mainly HR+) by Dr. J.P. Leone and colleagues showed that cancer stage, tumor subtype, and race were associated with overall survival and breast cancer-specific survival.
 

What Does the New Study Add?

The current study included 2,836 men diagnosed with stage I to stage III HR+ breast cancer between 1990 and 2008, using data from the Surveillance, Epidemiology, and End Results (SEER) database.

“We found that in men with breast cancer, the risk of breast cancer mortality persists for at least 20 years and that [the risk] depends on traditional clinicopathologic factors, such as age, tumor size, nodal status and tumor grade,” Dr. J.P. Leone said in an interview.

“The prolonged risk [of breast-cancer specific mortality] over 20 years that we observed in our study is similar to that previously reported in women; however, the kinetics of the risk over the 20-year period appears different in men,” he emphasized.

The men in the study, especially those with a higher stage of disease, appeared to have a bimodal distribution of the BRCA mortality risk, he said.

Two peaks were identified, he explained; an early peak in mortality risk at approximately 4 years from diagnosis and another at approximately 11 years after diagnosis.

Although women with breast cancer had a prolonged risk of breast cancer mortality, “the kinetics of the risk does not include 2 peaks, even in women with higher stage of disease.” In women with higher stage breast cancer, the peak mortality risk occurs approximately 5 years after diagnosis, he said.

The reasons for the later peak in men remain unclear, the researchers wrote in the study, but possible explanations include nonadherence to endocrine therapy, differences in tumor biologic factors, and differences in the tumor microenvironment between men and women, they noted, in the discussion section.
 

What Drives the Risk?

Key factors for breast cancer-specific mortality were age, tumor stage, and tumor grade.

The cumulative 20-year risk of BCSM in the current study was 12.4%, 26.2%, and 46.0% for stage I, II, and III, respectively. The adjusted BCSM risk was increased in patients younger than 50 years, those with grade II or III/IV tumors, and those with stage II or III disease.
 

What Are the Limitations?

The current study by Leone and colleagues was limited by the relatively small subgroup sample of men with stage III and N3 disease, lack of data on the use of systemic therapies, and lack of data on human epidermal growth factor receptor 2 gene (ERBB2), the researchers wrote. However, the long-term follow-up strengthened the results, and the study is the first known to assess 20-year BCSM risk in men with nonmetastatic HR+ breast cancer.

What Do Oncologists Need to Know About the Study?

The study findings indicate that the risk of breast cancer mortality persists for 20 years in men with hormone receptor–positive breast cancer, Dr. J.P. Leone said in an interview. As in women, the risk depends on traditional clinicopathologic factors, he noted.

“However, the kinetics of that risk appears to be different between men and women. In order to reduce the breast cancer mortality risk in men with hormone receptor–positive breast cancer, it will be important for men to consider the benefits of the treatment options that may be indicated for their specific situation,” he said.

“I think early detection is also very important,” he emphasized. To that end, increased awareness of the possibility for breast cancer in men, as well as prompt intervention when breast cancer is suspected, will help to improve early detection when the risk of breast cancer mortality is lower, he added.
 

What Are the Next Steps for Research?

“I think our study underscores the need for additional research to improve our adjuvant therapy options in both men and women with hormone receptor-positive breast cancer, to reduce the risk of long-term mortality,” he said.

The study received no outside funding. Lead author Julieta Leone had no financial conflicts to disclose. Dr. José P. Leone disclosed receiving institutional grants from Kazia Therapeutics and Seagen unrelated to the current study.

Breast cancer-specific mortality risk in men with hormone receptor–positive breast cancer persists for at least 20 years, but patterns of breast cancer–specific mortality (BCSM) are distinct from those in women, a new study finds.

Previous studies in women with hormone receptor–positive (HR+) breast cancer have shown a risk of distant recurrence and death for at least 20 years after diagnosis, but data for men are limited, wrote Julieta Leone, MD, of the Dana Farber Cancer Institute, Boston, and colleagues.
 

What is Known About Hormone Receptor–Positive Breast Cancer Mortality in Men vs. Women?

Invasive breast cancer in men is rare and consequently understudied, the researchers wrote. Previous studies of BCSM in men with more than 5 years’ follow-up consist mainly of case series at single institutions, the researchers wrote in JAMA Oncology (2024 Feb 29. doi: 10.1001/jamaoncol.2023.7194).

“We believed it would be important to study this issue to help inform the management of men with breast cancer,” corresponding author, José P. Leone, MD, said in an interview.

In 2021, Dr. J.P. Leone and colleagues published a study in Breast Cancer Research and Treatment that examined the 20-year risk of BCSM in women that included more than 36,000 individuals who had survived for 5 years, with a median of 14 years’ follow-up.

In that study of women, the BCSM risk at 20 years was significantly higher for those with HR-negative tumors, but the risk was still elevated for both types. Patients with stage IIIC HR-positive disease had four times the risk of BCSM over 20 years and those with stage IIIC HR-negative disease had seven times the risk of BCSM over 20 years compared with the risk of death not related to breast cancer, the researchers wrote.

Another study of nearly 2,400 men with breast cancer (mainly HR+) by Dr. J.P. Leone and colleagues showed that cancer stage, tumor subtype, and race were associated with overall survival and breast cancer-specific survival.
 

What Does the New Study Add?

The current study included 2,836 men diagnosed with stage I to stage III HR+ breast cancer between 1990 and 2008, using data from the Surveillance, Epidemiology, and End Results (SEER) database.

“We found that in men with breast cancer, the risk of breast cancer mortality persists for at least 20 years and that [the risk] depends on traditional clinicopathologic factors, such as age, tumor size, nodal status and tumor grade,” Dr. J.P. Leone said in an interview.

“The prolonged risk [of breast-cancer specific mortality] over 20 years that we observed in our study is similar to that previously reported in women; however, the kinetics of the risk over the 20-year period appears different in men,” he emphasized.

The men in the study, especially those with a higher stage of disease, appeared to have a bimodal distribution of the BRCA mortality risk, he said.

Two peaks were identified, he explained; an early peak in mortality risk at approximately 4 years from diagnosis and another at approximately 11 years after diagnosis.

Although women with breast cancer had a prolonged risk of breast cancer mortality, “the kinetics of the risk does not include 2 peaks, even in women with higher stage of disease.” In women with higher stage breast cancer, the peak mortality risk occurs approximately 5 years after diagnosis, he said.

The reasons for the later peak in men remain unclear, the researchers wrote in the study, but possible explanations include nonadherence to endocrine therapy, differences in tumor biologic factors, and differences in the tumor microenvironment between men and women, they noted, in the discussion section.
 

What Drives the Risk?

Key factors for breast cancer-specific mortality were age, tumor stage, and tumor grade.

The cumulative 20-year risk of BCSM in the current study was 12.4%, 26.2%, and 46.0% for stage I, II, and III, respectively. The adjusted BCSM risk was increased in patients younger than 50 years, those with grade II or III/IV tumors, and those with stage II or III disease.
 

What Are the Limitations?

The current study by Leone and colleagues was limited by the relatively small subgroup sample of men with stage III and N3 disease, lack of data on the use of systemic therapies, and lack of data on human epidermal growth factor receptor 2 gene (ERBB2), the researchers wrote. However, the long-term follow-up strengthened the results, and the study is the first known to assess 20-year BCSM risk in men with nonmetastatic HR+ breast cancer.

What Do Oncologists Need to Know About the Study?

The study findings indicate that the risk of breast cancer mortality persists for 20 years in men with hormone receptor–positive breast cancer, Dr. J.P. Leone said in an interview. As in women, the risk depends on traditional clinicopathologic factors, he noted.

“However, the kinetics of that risk appears to be different between men and women. In order to reduce the breast cancer mortality risk in men with hormone receptor–positive breast cancer, it will be important for men to consider the benefits of the treatment options that may be indicated for their specific situation,” he said.

“I think early detection is also very important,” he emphasized. To that end, increased awareness of the possibility for breast cancer in men, as well as prompt intervention when breast cancer is suspected, will help to improve early detection when the risk of breast cancer mortality is lower, he added.
 

What Are the Next Steps for Research?

“I think our study underscores the need for additional research to improve our adjuvant therapy options in both men and women with hormone receptor-positive breast cancer, to reduce the risk of long-term mortality,” he said.

The study received no outside funding. Lead author Julieta Leone had no financial conflicts to disclose. Dr. José P. Leone disclosed receiving institutional grants from Kazia Therapeutics and Seagen unrelated to the current study.

Breast cancer-specific mortality risk in men with hormone receptor–positive breast cancer persists for at least 20 years, but patterns of breast cancer–specific mortality (BCSM) are distinct from those in women, a new study finds.

Previous studies in women with hormone receptor–positive (HR+) breast cancer have shown a risk of distant recurrence and death for at least 20 years after diagnosis, but data for men are limited, wrote Julieta Leone, MD, of the Dana Farber Cancer Institute, Boston, and colleagues.
 

What is Known About Hormone Receptor–Positive Breast Cancer Mortality in Men vs. Women?

Invasive breast cancer in men is rare and consequently understudied, the researchers wrote. Previous studies of BCSM in men with more than 5 years’ follow-up consist mainly of case series at single institutions, the researchers wrote in JAMA Oncology (2024 Feb 29. doi: 10.1001/jamaoncol.2023.7194).

“We believed it would be important to study this issue to help inform the management of men with breast cancer,” corresponding author, José P. Leone, MD, said in an interview.

In 2021, Dr. J.P. Leone and colleagues published a study in Breast Cancer Research and Treatment that examined the 20-year risk of BCSM in women that included more than 36,000 individuals who had survived for 5 years, with a median of 14 years’ follow-up.

In that study of women, the BCSM risk at 20 years was significantly higher for those with HR-negative tumors, but the risk was still elevated for both types. Patients with stage IIIC HR-positive disease had four times the risk of BCSM over 20 years and those with stage IIIC HR-negative disease had seven times the risk of BCSM over 20 years compared with the risk of death not related to breast cancer, the researchers wrote.

Another study of nearly 2,400 men with breast cancer (mainly HR+) by Dr. J.P. Leone and colleagues showed that cancer stage, tumor subtype, and race were associated with overall survival and breast cancer-specific survival.
 

What Does the New Study Add?

The current study included 2,836 men diagnosed with stage I to stage III HR+ breast cancer between 1990 and 2008, using data from the Surveillance, Epidemiology, and End Results (SEER) database.

“We found that in men with breast cancer, the risk of breast cancer mortality persists for at least 20 years and that [the risk] depends on traditional clinicopathologic factors, such as age, tumor size, nodal status and tumor grade,” Dr. J.P. Leone said in an interview.

“The prolonged risk [of breast-cancer specific mortality] over 20 years that we observed in our study is similar to that previously reported in women; however, the kinetics of the risk over the 20-year period appears different in men,” he emphasized.

The men in the study, especially those with a higher stage of disease, appeared to have a bimodal distribution of the BRCA mortality risk, he said.

Two peaks were identified, he explained; an early peak in mortality risk at approximately 4 years from diagnosis and another at approximately 11 years after diagnosis.

Although women with breast cancer had a prolonged risk of breast cancer mortality, “the kinetics of the risk does not include 2 peaks, even in women with higher stage of disease.” In women with higher stage breast cancer, the peak mortality risk occurs approximately 5 years after diagnosis, he said.

The reasons for the later peak in men remain unclear, the researchers wrote in the study, but possible explanations include nonadherence to endocrine therapy, differences in tumor biologic factors, and differences in the tumor microenvironment between men and women, they noted, in the discussion section.
 

What Drives the Risk?

Key factors for breast cancer-specific mortality were age, tumor stage, and tumor grade.

The cumulative 20-year risk of BCSM in the current study was 12.4%, 26.2%, and 46.0% for stage I, II, and III, respectively. The adjusted BCSM risk was increased in patients younger than 50 years, those with grade II or III/IV tumors, and those with stage II or III disease.
 

What Are the Limitations?

The current study by Leone and colleagues was limited by the relatively small subgroup sample of men with stage III and N3 disease, lack of data on the use of systemic therapies, and lack of data on human epidermal growth factor receptor 2 gene (ERBB2), the researchers wrote. However, the long-term follow-up strengthened the results, and the study is the first known to assess 20-year BCSM risk in men with nonmetastatic HR+ breast cancer.

What Do Oncologists Need to Know About the Study?

The study findings indicate that the risk of breast cancer mortality persists for 20 years in men with hormone receptor–positive breast cancer, Dr. J.P. Leone said in an interview. As in women, the risk depends on traditional clinicopathologic factors, he noted.

“However, the kinetics of that risk appears to be different between men and women. In order to reduce the breast cancer mortality risk in men with hormone receptor–positive breast cancer, it will be important for men to consider the benefits of the treatment options that may be indicated for their specific situation,” he said.

“I think early detection is also very important,” he emphasized. To that end, increased awareness of the possibility for breast cancer in men, as well as prompt intervention when breast cancer is suspected, will help to improve early detection when the risk of breast cancer mortality is lower, he added.
 

What Are the Next Steps for Research?

“I think our study underscores the need for additional research to improve our adjuvant therapy options in both men and women with hormone receptor-positive breast cancer, to reduce the risk of long-term mortality,” he said.

The study received no outside funding. Lead author Julieta Leone had no financial conflicts to disclose. Dr. José P. Leone disclosed receiving institutional grants from Kazia Therapeutics and Seagen unrelated to the current study.

The US Food and Drug Administration (FDA) announced the removal of the endocrine-disrupting chemicals (EDCs) per- and polyfluoroalkyl substances (PFAS) from food packaging.

Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.

In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.

PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
 

Endocrine Society Report Sounds the Alarm About PFAS and Others

The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.

“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.

The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.

At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”

Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”

While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.

Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.

Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.

“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
 

New Data on Four Classes of EDCs

Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.

The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.

Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.

Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.

The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
 

‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’

Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.

The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”

The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) announced the removal of the endocrine-disrupting chemicals (EDCs) per- and polyfluoroalkyl substances (PFAS) from food packaging.

Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.

In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.

PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
 

Endocrine Society Report Sounds the Alarm About PFAS and Others

The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.

“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.

The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.

At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”

Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”

While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.

Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.

Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.

“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
 

New Data on Four Classes of EDCs

Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.

The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.

Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.

Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.

The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
 

‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’

Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.

The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”

The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) announced the removal of the endocrine-disrupting chemicals (EDCs) per- and polyfluoroalkyl substances (PFAS) from food packaging.

Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.

In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.

PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
 

Endocrine Society Report Sounds the Alarm About PFAS and Others

The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.

“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.

The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.

At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”

Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”

While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.

Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.

Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.

“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
 

New Data on Four Classes of EDCs

Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.

The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.

Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.

Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.

The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
 

‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’

Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.

The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”

The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.

A version of this article appeared on Medscape.com.

TOPLINE:

Doxorubicin increases the risk for breast cancer in women with Hodgkin lymphoma, suggesting the need for increased surveillance.

METHODOLOGY:

• Doxorubicin is a mainstay of Hodgkin lymphoma treatment.
• Studies suggest that girls with Hodgkin lymphoma who receive doxorubicin have a higher risk for breast cancer later in life, but it is unclear if women treated as adults face that same risk.
• To find out, investigators reviewed breast cancer incidence in 1964 Dutch women, ages 15-50, who were treated for Hodgkin lymphoma from 1975 to 2008.
• Patients had survived for at least 5 years, and 57% received doxorubicin.

TAKEAWAY:

• Women treated with doxorubicin had a 40% higher risk for breast cancer, and that risk was independent of age of treatment, receipt of chest radiation, and the use of gonadotoxic agents.
• The risk for breast cancer with doxorubicin was dose-dependent, with each 100 mg/m2 dose increment increasing the risk by 18%.
• The findings held whether women were treated years ago or more recently, despite the evolution of treatment strategies for Hodgkin lymphoma.
• After 30 years of follow-up, nearly one in five survivors (20.8%) developed breast cancer. It took 20 years for the elevated risk for breast cancer following treatment with doxorubicin to emerge.

IN PRACTICE:

The study suggests that adolescent and adult women survivors of Hodgkin lymphoma who received doxorubicin have an increased risk for breast cancer, and this risk is independent of age at first Hodgkin lymphoma treatment, receipt of chest radiotherapy, and gonadotoxic treatment, the authors concluded. “Our results have implications for [breast cancer] surveillance guidelines for [Hodgkin lymphoma] survivors and treatment strategies for patients with newly diagnosed” Hodgkin lymphoma.

SOURCE:

The study, led by Suzanne Neppelenbroek of the Netherlands Cancer Institute, Amsterdam, was published February 15 in the Journal of Clinical Oncology. 

LIMITATIONS:

Recruitment ended in 2008 before the advent of newer treatments such as antibody-drug conjugates and immune checkpoint inhibitors.

DISCLOSURES:

The work was funded by the Dutch Cancer Society. Several authors reported ties to Lilly, AbbVie, Amgen, and other companies.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Doxorubicin increases the risk for breast cancer in women with Hodgkin lymphoma, suggesting the need for increased surveillance.

METHODOLOGY:

• Doxorubicin is a mainstay of Hodgkin lymphoma treatment.
• Studies suggest that girls with Hodgkin lymphoma who receive doxorubicin have a higher risk for breast cancer later in life, but it is unclear if women treated as adults face that same risk.
• To find out, investigators reviewed breast cancer incidence in 1964 Dutch women, ages 15-50, who were treated for Hodgkin lymphoma from 1975 to 2008.
• Patients had survived for at least 5 years, and 57% received doxorubicin.

TAKEAWAY:

• Women treated with doxorubicin had a 40% higher risk for breast cancer, and that risk was independent of age of treatment, receipt of chest radiation, and the use of gonadotoxic agents.
• The risk for breast cancer with doxorubicin was dose-dependent, with each 100 mg/m2 dose increment increasing the risk by 18%.
• The findings held whether women were treated years ago or more recently, despite the evolution of treatment strategies for Hodgkin lymphoma.
• After 30 years of follow-up, nearly one in five survivors (20.8%) developed breast cancer. It took 20 years for the elevated risk for breast cancer following treatment with doxorubicin to emerge.

IN PRACTICE:

The study suggests that adolescent and adult women survivors of Hodgkin lymphoma who received doxorubicin have an increased risk for breast cancer, and this risk is independent of age at first Hodgkin lymphoma treatment, receipt of chest radiotherapy, and gonadotoxic treatment, the authors concluded. “Our results have implications for [breast cancer] surveillance guidelines for [Hodgkin lymphoma] survivors and treatment strategies for patients with newly diagnosed” Hodgkin lymphoma.

SOURCE:

The study, led by Suzanne Neppelenbroek of the Netherlands Cancer Institute, Amsterdam, was published February 15 in the Journal of Clinical Oncology. 

LIMITATIONS:

Recruitment ended in 2008 before the advent of newer treatments such as antibody-drug conjugates and immune checkpoint inhibitors.

DISCLOSURES:

The work was funded by the Dutch Cancer Society. Several authors reported ties to Lilly, AbbVie, Amgen, and other companies.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Doxorubicin increases the risk for breast cancer in women with Hodgkin lymphoma, suggesting the need for increased surveillance.

METHODOLOGY:

• Doxorubicin is a mainstay of Hodgkin lymphoma treatment.
• Studies suggest that girls with Hodgkin lymphoma who receive doxorubicin have a higher risk for breast cancer later in life, but it is unclear if women treated as adults face that same risk.
• To find out, investigators reviewed breast cancer incidence in 1964 Dutch women, ages 15-50, who were treated for Hodgkin lymphoma from 1975 to 2008.
• Patients had survived for at least 5 years, and 57% received doxorubicin.

TAKEAWAY:

• Women treated with doxorubicin had a 40% higher risk for breast cancer, and that risk was independent of age of treatment, receipt of chest radiation, and the use of gonadotoxic agents.
• The risk for breast cancer with doxorubicin was dose-dependent, with each 100 mg/m2 dose increment increasing the risk by 18%.
• The findings held whether women were treated years ago or more recently, despite the evolution of treatment strategies for Hodgkin lymphoma.
• After 30 years of follow-up, nearly one in five survivors (20.8%) developed breast cancer. It took 20 years for the elevated risk for breast cancer following treatment with doxorubicin to emerge.

IN PRACTICE:

The study suggests that adolescent and adult women survivors of Hodgkin lymphoma who received doxorubicin have an increased risk for breast cancer, and this risk is independent of age at first Hodgkin lymphoma treatment, receipt of chest radiotherapy, and gonadotoxic treatment, the authors concluded. “Our results have implications for [breast cancer] surveillance guidelines for [Hodgkin lymphoma] survivors and treatment strategies for patients with newly diagnosed” Hodgkin lymphoma.

SOURCE:

The study, led by Suzanne Neppelenbroek of the Netherlands Cancer Institute, Amsterdam, was published February 15 in the Journal of Clinical Oncology. 

LIMITATIONS:

Recruitment ended in 2008 before the advent of newer treatments such as antibody-drug conjugates and immune checkpoint inhibitors.

DISCLOSURES:

The work was funded by the Dutch Cancer Society. Several authors reported ties to Lilly, AbbVie, Amgen, and other companies.
 

A version of this article appeared on Medscape.com.

The phase 3 KEYNOTE-355 trial established the role of chemotherapy in combination with pembrolizumab in the first-line setting for programmed death-ligand 1 (PD-L1)–positive advanced triple-negative breast cancer (TNBC). Patients unselected for PD-L1 status in this trial who received platinum- or taxane-based chemotherapy with placebo had a median progression-free survival of 5.6 months.^[3] Strategies to improve upon efficacy and tolerability are desired in this space, and various trials have evaluated "switch maintenance" that involves receipt of an intensive induction regimen followed by a switch to an alternative/more tolerable regimen after response is achieved.^[4] The phase II DORA trial randomized 45 patients with advanced TNBC and ongoing stable disease or complete or partial response from first- or second-line platinum-based chemotherapy to a maintenance regimen of olaparib (300 mg orally twice daily) with or without durvalumab (1500 mg on day 1 and every 4 weeks) (Tan et al). At a median follow-up of 9.8 months, median progression-free survival was 4.0 months (95% CI 2.6-6.1) with olaparib and 6.1 months (95% CI 3.7-10.1) with the combination; both were significantly longer than the historical control of continued platinum-based therapy (P = .0023 and P < .0001, respectively). Durable disease control appeared more pronounced in patients with complete or partial response to prior platinum therapy, and no new safety signals were observed. Future efforts to study this approach include the phase 2/3 KEYLYNK-009 trial, which is evaluating olaparib plus pembrolizumab maintenance therapy after first-line chemotherapy plus pembrolizumab for TNBC.^[5]

TNBC is a heterogenous subtype, characterized by aggressive biology, and it benefits from chemotherapy and immunotherapy treatment approaches. Presently, the management of early-stage TNBC often involves neoadjuvant systemic therapy; however, a proportion of patients receive treatment in the postoperative setting, highlighting the relevance of time to initiation of adjuvant therapy as well.^[6] Various prior studies have showed that delayed administration of adjuvant chemotherapy for EBC can lead to adverse survival outcomes. Furthermore, this effect is subtype-dependent, with more aggressive tumors (luminal B, triple-negative, human epidermal growth factor receptor 2 [HER2]-positive) exhibiting inferior outcomes with delayed chemotherapy.^[7] A retrospective cohort study that included 245 patients with early TNBC who received adjuvant chemotherapy after surgery evaluated the impact of time to initiation of adjuvant therapy in this population (Hatzipanagiotou et al). Superior survival outcomes were observed for the group receiving systemic therapy 22-28 days after surgery (median overall survival 10.2 years) compared with those receiving adjuvant chemotherapy at later time points (29-35 days, 36-42 days, and >6 weeks after surgery; median overall survival 8.3 years, 7.8 years, and 6.9 years, respectively). Patients receiving chemotherapy 22-28 days after surgery had significantly better survival than those receiving chemotherapy 29-35 days (P = .043) and >6 weeks (P = 0.033) postoperatively. This study emphasizes the importance of timely administration of adjuvant chemotherapy for early TNBC, and efforts aimed to identify potential challenges and propose solutions to optimize outcomes in this space are valuable.

Additional References

1. Gnant M, Frantal S, Pfeiler G, et al, for the Austrian Breast & Colorectal Cancer Study Group. Long-term outcomes of adjuvant denosumab in breast cancer. NEJM Evid. 2022;1:EVIDoa2200162. doi: 10.1056/EVIDoa2200162 Source
2. Fassio A, Idolazzi L, Rossini M, et al. The obesity paradox and osteoporosis. Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity. 2018;23:293-30 doi: 10.1007/s40519-018-0505-2 Source
3. Cortes J, Cescon DW, Rugo HS, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396:1817-1828. doi: 10.1016/S0140-6736(20)32531-9 Source
4. Bachelot T, Filleron T, Bieche I, et al. Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: The randomized phase II SAFIR02-BREAST IMMUNO trial. Nat Med. 2021;27:250-255. doi: 10.1038/s41591-020-01189-2 Source
5. Saji S, Cussac AL, Andre F, et al. 68TiP KEYLYNK-009: a phase II/III, open-label, randomized study of pembrolizumab (pembro) + olaparib (ola) vs pembro + chemotherapy after induction with first-line (1L) pembro + chemo in patients (pts) with locally recurrent inoperable or metastatic TNBC (abstract). Ann Oncol. 2020;31(Suppl 6):S1268. doi: 10.1016/j.annonc.2020.10.088 Source
6. Ortmann O, Blohmer JU, Sibert NT, et al for 55 breast cancer centers certified by the German Cancer Society. Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: Analysis of individual data from 94,638 patients treated in 55 breast cancer centers. J Cancer Res Clin Oncol. 2023;149:1195-1209. doi: 10.1007/s00432-022-03938-x Source
7. Yu KD, Fan L, Qiu LX, et al. Influence of delayed initiation of adjuvant chemotherapy on breast cancer survival is subtype-dependent. Oncotarget. 2017;8:46549-46556. doi: 10.18632/oncotarget.10551 Source

The phase 3 KEYNOTE-355 trial established the role of chemotherapy in combination with pembrolizumab in the first-line setting for programmed death-ligand 1 (PD-L1)–positive advanced triple-negative breast cancer (TNBC). Patients unselected for PD-L1 status in this trial who received platinum- or taxane-based chemotherapy with placebo had a median progression-free survival of 5.6 months.^[3] Strategies to improve upon efficacy and tolerability are desired in this space, and various trials have evaluated "switch maintenance" that involves receipt of an intensive induction regimen followed by a switch to an alternative/more tolerable regimen after response is achieved.^[4] The phase II DORA trial randomized 45 patients with advanced TNBC and ongoing stable disease or complete or partial response from first- or second-line platinum-based chemotherapy to a maintenance regimen of olaparib (300 mg orally twice daily) with or without durvalumab (1500 mg on day 1 and every 4 weeks) (Tan et al). At a median follow-up of 9.8 months, median progression-free survival was 4.0 months (95% CI 2.6-6.1) with olaparib and 6.1 months (95% CI 3.7-10.1) with the combination; both were significantly longer than the historical control of continued platinum-based therapy (P = .0023 and P < .0001, respectively). Durable disease control appeared more pronounced in patients with complete or partial response to prior platinum therapy, and no new safety signals were observed. Future efforts to study this approach include the phase 2/3 KEYLYNK-009 trial, which is evaluating olaparib plus pembrolizumab maintenance therapy after first-line chemotherapy plus pembrolizumab for TNBC.^[5]

TNBC is a heterogenous subtype, characterized by aggressive biology, and it benefits from chemotherapy and immunotherapy treatment approaches. Presently, the management of early-stage TNBC often involves neoadjuvant systemic therapy; however, a proportion of patients receive treatment in the postoperative setting, highlighting the relevance of time to initiation of adjuvant therapy as well.^[6] Various prior studies have showed that delayed administration of adjuvant chemotherapy for EBC can lead to adverse survival outcomes. Furthermore, this effect is subtype-dependent, with more aggressive tumors (luminal B, triple-negative, human epidermal growth factor receptor 2 [HER2]-positive) exhibiting inferior outcomes with delayed chemotherapy.^[7] A retrospective cohort study that included 245 patients with early TNBC who received adjuvant chemotherapy after surgery evaluated the impact of time to initiation of adjuvant therapy in this population (Hatzipanagiotou et al). Superior survival outcomes were observed for the group receiving systemic therapy 22-28 days after surgery (median overall survival 10.2 years) compared with those receiving adjuvant chemotherapy at later time points (29-35 days, 36-42 days, and >6 weeks after surgery; median overall survival 8.3 years, 7.8 years, and 6.9 years, respectively). Patients receiving chemotherapy 22-28 days after surgery had significantly better survival than those receiving chemotherapy 29-35 days (P = .043) and >6 weeks (P = 0.033) postoperatively. This study emphasizes the importance of timely administration of adjuvant chemotherapy for early TNBC, and efforts aimed to identify potential challenges and propose solutions to optimize outcomes in this space are valuable.

Additional References

1. Gnant M, Frantal S, Pfeiler G, et al, for the Austrian Breast & Colorectal Cancer Study Group. Long-term outcomes of adjuvant denosumab in breast cancer. NEJM Evid. 2022;1:EVIDoa2200162. doi: 10.1056/EVIDoa2200162 Source
2. Fassio A, Idolazzi L, Rossini M, et al. The obesity paradox and osteoporosis. Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity. 2018;23:293-30 doi: 10.1007/s40519-018-0505-2 Source
3. Cortes J, Cescon DW, Rugo HS, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396:1817-1828. doi: 10.1016/S0140-6736(20)32531-9 Source
4. Bachelot T, Filleron T, Bieche I, et al. Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: The randomized phase II SAFIR02-BREAST IMMUNO trial. Nat Med. 2021;27:250-255. doi: 10.1038/s41591-020-01189-2 Source
5. Saji S, Cussac AL, Andre F, et al. 68TiP KEYLYNK-009: a phase II/III, open-label, randomized study of pembrolizumab (pembro) + olaparib (ola) vs pembro + chemotherapy after induction with first-line (1L) pembro + chemo in patients (pts) with locally recurrent inoperable or metastatic TNBC (abstract). Ann Oncol. 2020;31(Suppl 6):S1268. doi: 10.1016/j.annonc.2020.10.088 Source
6. Ortmann O, Blohmer JU, Sibert NT, et al for 55 breast cancer centers certified by the German Cancer Society. Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: Analysis of individual data from 94,638 patients treated in 55 breast cancer centers. J Cancer Res Clin Oncol. 2023;149:1195-1209. doi: 10.1007/s00432-022-03938-x Source
7. Yu KD, Fan L, Qiu LX, et al. Influence of delayed initiation of adjuvant chemotherapy on breast cancer survival is subtype-dependent. Oncotarget. 2017;8:46549-46556. doi: 10.18632/oncotarget.10551 Source

The phase 3 KEYNOTE-355 trial established the role of chemotherapy in combination with pembrolizumab in the first-line setting for programmed death-ligand 1 (PD-L1)–positive advanced triple-negative breast cancer (TNBC). Patients unselected for PD-L1 status in this trial who received platinum- or taxane-based chemotherapy with placebo had a median progression-free survival of 5.6 months.^[3] Strategies to improve upon efficacy and tolerability are desired in this space, and various trials have evaluated "switch maintenance" that involves receipt of an intensive induction regimen followed by a switch to an alternative/more tolerable regimen after response is achieved.^[4] The phase II DORA trial randomized 45 patients with advanced TNBC and ongoing stable disease or complete or partial response from first- or second-line platinum-based chemotherapy to a maintenance regimen of olaparib (300 mg orally twice daily) with or without durvalumab (1500 mg on day 1 and every 4 weeks) (Tan et al). At a median follow-up of 9.8 months, median progression-free survival was 4.0 months (95% CI 2.6-6.1) with olaparib and 6.1 months (95% CI 3.7-10.1) with the combination; both were significantly longer than the historical control of continued platinum-based therapy (P = .0023 and P < .0001, respectively). Durable disease control appeared more pronounced in patients with complete or partial response to prior platinum therapy, and no new safety signals were observed. Future efforts to study this approach include the phase 2/3 KEYLYNK-009 trial, which is evaluating olaparib plus pembrolizumab maintenance therapy after first-line chemotherapy plus pembrolizumab for TNBC.^[5]

TNBC is a heterogenous subtype, characterized by aggressive biology, and it benefits from chemotherapy and immunotherapy treatment approaches. Presently, the management of early-stage TNBC often involves neoadjuvant systemic therapy; however, a proportion of patients receive treatment in the postoperative setting, highlighting the relevance of time to initiation of adjuvant therapy as well.^[6] Various prior studies have showed that delayed administration of adjuvant chemotherapy for EBC can lead to adverse survival outcomes. Furthermore, this effect is subtype-dependent, with more aggressive tumors (luminal B, triple-negative, human epidermal growth factor receptor 2 [HER2]-positive) exhibiting inferior outcomes with delayed chemotherapy.^[7] A retrospective cohort study that included 245 patients with early TNBC who received adjuvant chemotherapy after surgery evaluated the impact of time to initiation of adjuvant therapy in this population (Hatzipanagiotou et al). Superior survival outcomes were observed for the group receiving systemic therapy 22-28 days after surgery (median overall survival 10.2 years) compared with those receiving adjuvant chemotherapy at later time points (29-35 days, 36-42 days, and >6 weeks after surgery; median overall survival 8.3 years, 7.8 years, and 6.9 years, respectively). Patients receiving chemotherapy 22-28 days after surgery had significantly better survival than those receiving chemotherapy 29-35 days (P = .043) and >6 weeks (P = 0.033) postoperatively. This study emphasizes the importance of timely administration of adjuvant chemotherapy for early TNBC, and efforts aimed to identify potential challenges and propose solutions to optimize outcomes in this space are valuable.

Additional References

1. Gnant M, Frantal S, Pfeiler G, et al, for the Austrian Breast & Colorectal Cancer Study Group. Long-term outcomes of adjuvant denosumab in breast cancer. NEJM Evid. 2022;1:EVIDoa2200162. doi: 10.1056/EVIDoa2200162 Source
2. Fassio A, Idolazzi L, Rossini M, et al. The obesity paradox and osteoporosis. Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity. 2018;23:293-30 doi: 10.1007/s40519-018-0505-2 Source
3. Cortes J, Cescon DW, Rugo HS, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396:1817-1828. doi: 10.1016/S0140-6736(20)32531-9 Source
4. Bachelot T, Filleron T, Bieche I, et al. Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: The randomized phase II SAFIR02-BREAST IMMUNO trial. Nat Med. 2021;27:250-255. doi: 10.1038/s41591-020-01189-2 Source
5. Saji S, Cussac AL, Andre F, et al. 68TiP KEYLYNK-009: a phase II/III, open-label, randomized study of pembrolizumab (pembro) + olaparib (ola) vs pembro + chemotherapy after induction with first-line (1L) pembro + chemo in patients (pts) with locally recurrent inoperable or metastatic TNBC (abstract). Ann Oncol. 2020;31(Suppl 6):S1268. doi: 10.1016/j.annonc.2020.10.088 Source
6. Ortmann O, Blohmer JU, Sibert NT, et al for 55 breast cancer centers certified by the German Cancer Society. Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: Analysis of individual data from 94,638 patients treated in 55 breast cancer centers. J Cancer Res Clin Oncol. 2023;149:1195-1209. doi: 10.1007/s00432-022-03938-x Source
7. Yu KD, Fan L, Qiu LX, et al. Influence of delayed initiation of adjuvant chemotherapy on breast cancer survival is subtype-dependent. Oncotarget. 2017;8:46549-46556. doi: 10.18632/oncotarget.10551 Source

Food emulsifiers are among the most widespread food additives. A large cohort study highlighted an association between the consumption of certain emulsifiers and an increased risk for certain cancers, particularly breast and prostate cancer.

Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.

Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.

Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.

The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.

In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).

Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.

In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.

The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.

It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Food emulsifiers are among the most widespread food additives. A large cohort study highlighted an association between the consumption of certain emulsifiers and an increased risk for certain cancers, particularly breast and prostate cancer.

Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.

Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.

Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.

The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.

In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).

Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.

In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.

The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.

It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Food emulsifiers are among the most widespread food additives. A large cohort study highlighted an association between the consumption of certain emulsifiers and an increased risk for certain cancers, particularly breast and prostate cancer.

Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.

Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.

Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.

The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.

In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).

Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.

In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.

The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.

It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.