AVAHO

Amazon is working with the Fred Hutchinson Cancer Research Center to develop cancer vaccines in a new clinical trial.

The trial is aimed at finding “personalized vaccines” to treat breast cancer and melanoma. The phase 1 trial is recruiting 20 people over the age of 18 to study the safety of the vaccines, according to CNBC.

The Fred Hutchinson Cancer Research Center and University of Washington Cancer Consortium are listed as the researchers of the clinical trial, and Amazon is listed as a collaborator, according to a filing on the ClinicalTrials.gov database.

“Amazon is contributing scientific and machine learning expertise to a partnership with Fred Hutch to explore the development of a personalized treatment for certain forms of cancer,” an Amazon spokesperson told CNBC.

“It’s very early, but Fred Hutch recently received permission from the U.S. Food and Drug Administration to proceed with a phase 1 clinical trial, and it’s unclear whether it will be successful,” the spokesperson said. “This will be a long, multiyear process – should it progress, we would be open to working with other organizations in health care and life sciences that might also be interested in similar efforts.”

In recent years, Amazon has grown its presence in the health care industry, CNBC reported. The company launched an online pharmacy in 2020, developed a telehealth service called Amazon Care, and released its own COVID-19 test during the pandemic.

A research and development group inside Amazon, known as Grand Challenge, oversaw the company’s early cancer vaccine effort, according to Business Insider. It’s now under the purview of a cancer research team that reports to Robert Williams, the company’s vice president of devices.

The study was first posted on ClinicalTrials.gov in October 2021 and began recruiting patients on June 9, according to the filing. The phase 1 trial is expected to run through November 2023.

The phase 1 trial will study the safety of personalized vaccines to treat patients with late-stage melanoma or hormone receptor-positive HER2-negative breast cancer which has either spread to other parts of the body or doesn’t respond to treatment.

More information about the study can be found on ClinicalTrials.gov under the identifier NCT05098210.

A version of this article first appeared on WebMD.com.

Amazon is working with the Fred Hutchinson Cancer Research Center to develop cancer vaccines in a new clinical trial.

The trial is aimed at finding “personalized vaccines” to treat breast cancer and melanoma. The phase 1 trial is recruiting 20 people over the age of 18 to study the safety of the vaccines, according to CNBC.

The Fred Hutchinson Cancer Research Center and University of Washington Cancer Consortium are listed as the researchers of the clinical trial, and Amazon is listed as a collaborator, according to a filing on the ClinicalTrials.gov database.

“Amazon is contributing scientific and machine learning expertise to a partnership with Fred Hutch to explore the development of a personalized treatment for certain forms of cancer,” an Amazon spokesperson told CNBC.

“It’s very early, but Fred Hutch recently received permission from the U.S. Food and Drug Administration to proceed with a phase 1 clinical trial, and it’s unclear whether it will be successful,” the spokesperson said. “This will be a long, multiyear process – should it progress, we would be open to working with other organizations in health care and life sciences that might also be interested in similar efforts.”

In recent years, Amazon has grown its presence in the health care industry, CNBC reported. The company launched an online pharmacy in 2020, developed a telehealth service called Amazon Care, and released its own COVID-19 test during the pandemic.

A research and development group inside Amazon, known as Grand Challenge, oversaw the company’s early cancer vaccine effort, according to Business Insider. It’s now under the purview of a cancer research team that reports to Robert Williams, the company’s vice president of devices.

The study was first posted on ClinicalTrials.gov in October 2021 and began recruiting patients on June 9, according to the filing. The phase 1 trial is expected to run through November 2023.

The phase 1 trial will study the safety of personalized vaccines to treat patients with late-stage melanoma or hormone receptor-positive HER2-negative breast cancer which has either spread to other parts of the body or doesn’t respond to treatment.

More information about the study can be found on ClinicalTrials.gov under the identifier NCT05098210.

A version of this article first appeared on WebMD.com.

Amazon is working with the Fred Hutchinson Cancer Research Center to develop cancer vaccines in a new clinical trial.

The trial is aimed at finding “personalized vaccines” to treat breast cancer and melanoma. The phase 1 trial is recruiting 20 people over the age of 18 to study the safety of the vaccines, according to CNBC.

The Fred Hutchinson Cancer Research Center and University of Washington Cancer Consortium are listed as the researchers of the clinical trial, and Amazon is listed as a collaborator, according to a filing on the ClinicalTrials.gov database.

“Amazon is contributing scientific and machine learning expertise to a partnership with Fred Hutch to explore the development of a personalized treatment for certain forms of cancer,” an Amazon spokesperson told CNBC.

“It’s very early, but Fred Hutch recently received permission from the U.S. Food and Drug Administration to proceed with a phase 1 clinical trial, and it’s unclear whether it will be successful,” the spokesperson said. “This will be a long, multiyear process – should it progress, we would be open to working with other organizations in health care and life sciences that might also be interested in similar efforts.”

In recent years, Amazon has grown its presence in the health care industry, CNBC reported. The company launched an online pharmacy in 2020, developed a telehealth service called Amazon Care, and released its own COVID-19 test during the pandemic.

A research and development group inside Amazon, known as Grand Challenge, oversaw the company’s early cancer vaccine effort, according to Business Insider. It’s now under the purview of a cancer research team that reports to Robert Williams, the company’s vice president of devices.

The study was first posted on ClinicalTrials.gov in October 2021 and began recruiting patients on June 9, according to the filing. The phase 1 trial is expected to run through November 2023.

The phase 1 trial will study the safety of personalized vaccines to treat patients with late-stage melanoma or hormone receptor-positive HER2-negative breast cancer which has either spread to other parts of the body or doesn’t respond to treatment.

More information about the study can be found on ClinicalTrials.gov under the identifier NCT05098210.

A version of this article first appeared on WebMD.com.

Skin cancer is the most diagnosed cancer in the United States. Nonmelanoma skin cancers (NMSC), which include basal cell carcinoma and squamous cell carcinoma, are usually cured with removal.¹ The incidence of NMSC increases with age and is commonly found in nursing homes and geriatric units. These cancers are not usually metastatic or fatal but can cause local destruction and disfigurement if neglected.² The current standard of care is to treat diagnosed NMSC; however, the dermatology and geriatric care literature have questioned the logic of treating asymptomatic skin cancers that will not affect a patient’s life expectancy.^2-4

Forty-seven percent of the current living veteran population is aged ≥ 65 years.⁵ Older adult patients are frequently referred to the US Department of Veterans Affairs (VA) surgical service for the treatment of NMSC. The veteran population includes a higher percentage of individuals at an elevated risk of skin cancers (older, White, and male) compared with the general population.⁶ World War II veterans deployed in regions closer to the equator have been found to have an elevated risk of melanoma and nonmelanoma skin carcinomas.⁷ A retrospective study of Vietnam veterans exposed to Agent Orange (2,3,7,8-tetrachlorodibenzodioxin) found a significantly higher risk of invasive NMSC in Fitzpatrick skin types I-IV compared with an age-matched subset of the general population.⁸ Younger veterans who were deployed in Afghanistan and Iraq for Operation Enduring Freedom/Operation Iraqi Freedom worked at more equatorial latitudes than the rest of the US population and may be at increased risk of NMSC. Inadequate sunscreen access, immediate safety concerns, outdoor recreational activities, harsh weather, and insufficient emphasis on sun protection have created a multifactorial challenge for the military population. Riemenschneider and colleagues recommended targeted screening for at-risk veteran patients and prioritizing annual skin cancer screenings during medical mission physical examinations for active military.⁷

The plastic surgery service regularly receives consults from dermatology, general surgery, and primary care to remove skin cancers on the face, scalp, hands, and forearms. Skin cancer treatment can create serious hardships for older adult patients and their families with multiple appointments for the consult, procedure, and follow-up. Patients are often told to hold their anticoagulant medications when the surgery will be performed on a highly vascular region, such as the scalp or face. This can create wide swings in their laboratory test values and result in life-threatening complications from either bleeding or clotting. The appropriateness of offering surgery to patients with serious comorbidities and a limited life expectancy has been questioned.^2-4 The purpose of this study was to measure the morbidity and unrelated 5-year mortality for patients with skin cancer referred to the plastic surgery service to help patients and families make a more informed treatment decision, particularly when the patients are aged > 80 years and have significant life-threatening comorbidities.

Methods

The University of Florida and Malcom Randall VA Medical Center Institutional review board in Gainesville, approved a retrospective review of all consults completed by the plastic surgery service for the treatment of NMSC performed from July 1, 2011 to June 30, 2015. Data collected included age and common life-limiting comorbidities at the time of referral. Morbidities were found on the electronic health record, including coronary artery disease (CAD), congestive heart failure (CHF), cerebral vascular disease (CVD), peripheral vascular disease, dementia, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), tobacco use, diabetes mellitus (DM), liver disease, alcohol use, and obstructive sleep apnea.

Treatment, complications, and 5-year mortality were recorded. A χ² analysis with P value < .05 was used to determine statistical significance between individual risk factors and 5-year mortality. The relative risk of 5-year mortality was calculated by combining advanced age (aged > 80 years) with the individual comorbidities.

Results

Over 4 years, 800 consults for NMSC were completed by the plastic surgery service. Treatment decisions included 210 excisions (with or without reconstruction) in the operating room, 402 excisions (with or without reconstruction) under local anesthesia in clinic, 55 Mohs surgical dermatology referrals, 21 other service or hospital referrals, and 112 patient who were observed, declined intervention, or died prior to intervention. Five-year mortality was 28.6%. No patients died of NMSC. The median age at consult submission for patients deceased 5 years later was 78 years. Complication rate was 5% and included wound infection, dehiscence, bleeding, or graft loss. Two patients, both deceased within 5 years, had unplanned admissions due to bleeding from either a skin graft donor site or recipient bleeding. Aged ≥ 80 years, CAD, CHF, CVD, peripheral vascular disease, dementia, CKD, COPD, and DM were all found individually to be statistically significant predictors of 5-year mortality (Table 1). Combining aged ≥ 80 years plus CAD, CHF, or dementia all increased the 5-year mortality by a relative risk of > 3 (Table 2).

Discussion

The standard of care is to treat NMSC. Most NMSCs are treated surgically without consideration of patient age or life expectancy.^2,4,9,10 A prospective cohort study involving a university-based private practice and a VA medical center in San Francisco found a 22.6% overall 5-year mortality and a 43.3% mortality in the group defined as limited life expectancy (LLE) based on age (≥ 85 years) and medical comorbidities. None died due to the NMSC. Leading cause of death was cardiac, cerebrovascular, and respiratory disease, lung and prostate cancer, and Alzheimer disease. The authors suggested the LLE group may be exposed to wound complications without benefiting from the treatment.⁴

Another study of 440 patients receiving excision for biopsy-proven facial NMSC at the Roudebush VA Medical Center in Indianapolis, Indiana, found no residual carcinoma in 35.3% of excisions, and in patients aged > 90 years, more than half of the excisions had no residual carcinoma. More than half of the patients aged > 90 years died within 1 year, not as a result of the NMSC. The authors argued for watchful waiting in select patients to maximize comfort and outcomes.¹⁰

Strengths and Limitations

A strength of this study is that the data were obtained from a closed system. Patients tend to stay long-term within the VA and their health record is accessible throughout the country as long as they are seen at a VA facility. Complications, therefore, return to the treating service or primary care, who would route the patient back to the surgeon.

One limitation of the study is that this is a retrospective review from 2011. The authors are limited to data that are recorded in the patient record. Multiple health care professionals saw the patients and notes lack consistency in detail. Size of the lesions were not consistently recorded and did not get logged into our database for that reason.

Conclusions

Treatment of NMSC in older adult patients has a low morbidity but needs to be balanced against a patient and family’s goals when the patient presents with life-limiting comorbidities. An elevated 5-year mortality in patients aged > 80 years with serious unrelated medical conditions is intuitive, but this study may help put treatment plans into perspective for families and health care professionals who want to provide an indicated service while maximizing patient quality of life.

Acknowledgments

This manuscript is the result of work supported with resources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.

Skin cancer is the most diagnosed cancer in the United States. Nonmelanoma skin cancers (NMSC), which include basal cell carcinoma and squamous cell carcinoma, are usually cured with removal.¹ The incidence of NMSC increases with age and is commonly found in nursing homes and geriatric units. These cancers are not usually metastatic or fatal but can cause local destruction and disfigurement if neglected.² The current standard of care is to treat diagnosed NMSC; however, the dermatology and geriatric care literature have questioned the logic of treating asymptomatic skin cancers that will not affect a patient’s life expectancy.^2-4

Forty-seven percent of the current living veteran population is aged ≥ 65 years.⁵ Older adult patients are frequently referred to the US Department of Veterans Affairs (VA) surgical service for the treatment of NMSC. The veteran population includes a higher percentage of individuals at an elevated risk of skin cancers (older, White, and male) compared with the general population.⁶ World War II veterans deployed in regions closer to the equator have been found to have an elevated risk of melanoma and nonmelanoma skin carcinomas.⁷ A retrospective study of Vietnam veterans exposed to Agent Orange (2,3,7,8-tetrachlorodibenzodioxin) found a significantly higher risk of invasive NMSC in Fitzpatrick skin types I-IV compared with an age-matched subset of the general population.⁸ Younger veterans who were deployed in Afghanistan and Iraq for Operation Enduring Freedom/Operation Iraqi Freedom worked at more equatorial latitudes than the rest of the US population and may be at increased risk of NMSC. Inadequate sunscreen access, immediate safety concerns, outdoor recreational activities, harsh weather, and insufficient emphasis on sun protection have created a multifactorial challenge for the military population. Riemenschneider and colleagues recommended targeted screening for at-risk veteran patients and prioritizing annual skin cancer screenings during medical mission physical examinations for active military.⁷

The plastic surgery service regularly receives consults from dermatology, general surgery, and primary care to remove skin cancers on the face, scalp, hands, and forearms. Skin cancer treatment can create serious hardships for older adult patients and their families with multiple appointments for the consult, procedure, and follow-up. Patients are often told to hold their anticoagulant medications when the surgery will be performed on a highly vascular region, such as the scalp or face. This can create wide swings in their laboratory test values and result in life-threatening complications from either bleeding or clotting. The appropriateness of offering surgery to patients with serious comorbidities and a limited life expectancy has been questioned.^2-4 The purpose of this study was to measure the morbidity and unrelated 5-year mortality for patients with skin cancer referred to the plastic surgery service to help patients and families make a more informed treatment decision, particularly when the patients are aged > 80 years and have significant life-threatening comorbidities.

Methods

The University of Florida and Malcom Randall VA Medical Center Institutional review board in Gainesville, approved a retrospective review of all consults completed by the plastic surgery service for the treatment of NMSC performed from July 1, 2011 to June 30, 2015. Data collected included age and common life-limiting comorbidities at the time of referral. Morbidities were found on the electronic health record, including coronary artery disease (CAD), congestive heart failure (CHF), cerebral vascular disease (CVD), peripheral vascular disease, dementia, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), tobacco use, diabetes mellitus (DM), liver disease, alcohol use, and obstructive sleep apnea.

Treatment, complications, and 5-year mortality were recorded. A χ² analysis with P value < .05 was used to determine statistical significance between individual risk factors and 5-year mortality. The relative risk of 5-year mortality was calculated by combining advanced age (aged > 80 years) with the individual comorbidities.

Results

Over 4 years, 800 consults for NMSC were completed by the plastic surgery service. Treatment decisions included 210 excisions (with or without reconstruction) in the operating room, 402 excisions (with or without reconstruction) under local anesthesia in clinic, 55 Mohs surgical dermatology referrals, 21 other service or hospital referrals, and 112 patient who were observed, declined intervention, or died prior to intervention. Five-year mortality was 28.6%. No patients died of NMSC. The median age at consult submission for patients deceased 5 years later was 78 years. Complication rate was 5% and included wound infection, dehiscence, bleeding, or graft loss. Two patients, both deceased within 5 years, had unplanned admissions due to bleeding from either a skin graft donor site or recipient bleeding. Aged ≥ 80 years, CAD, CHF, CVD, peripheral vascular disease, dementia, CKD, COPD, and DM were all found individually to be statistically significant predictors of 5-year mortality (Table 1). Combining aged ≥ 80 years plus CAD, CHF, or dementia all increased the 5-year mortality by a relative risk of > 3 (Table 2).

Discussion

The standard of care is to treat NMSC. Most NMSCs are treated surgically without consideration of patient age or life expectancy.^2,4,9,10 A prospective cohort study involving a university-based private practice and a VA medical center in San Francisco found a 22.6% overall 5-year mortality and a 43.3% mortality in the group defined as limited life expectancy (LLE) based on age (≥ 85 years) and medical comorbidities. None died due to the NMSC. Leading cause of death was cardiac, cerebrovascular, and respiratory disease, lung and prostate cancer, and Alzheimer disease. The authors suggested the LLE group may be exposed to wound complications without benefiting from the treatment.⁴

Another study of 440 patients receiving excision for biopsy-proven facial NMSC at the Roudebush VA Medical Center in Indianapolis, Indiana, found no residual carcinoma in 35.3% of excisions, and in patients aged > 90 years, more than half of the excisions had no residual carcinoma. More than half of the patients aged > 90 years died within 1 year, not as a result of the NMSC. The authors argued for watchful waiting in select patients to maximize comfort and outcomes.¹⁰

Strengths and Limitations

A strength of this study is that the data were obtained from a closed system. Patients tend to stay long-term within the VA and their health record is accessible throughout the country as long as they are seen at a VA facility. Complications, therefore, return to the treating service or primary care, who would route the patient back to the surgeon.

One limitation of the study is that this is a retrospective review from 2011. The authors are limited to data that are recorded in the patient record. Multiple health care professionals saw the patients and notes lack consistency in detail. Size of the lesions were not consistently recorded and did not get logged into our database for that reason.

Conclusions

Treatment of NMSC in older adult patients has a low morbidity but needs to be balanced against a patient and family’s goals when the patient presents with life-limiting comorbidities. An elevated 5-year mortality in patients aged > 80 years with serious unrelated medical conditions is intuitive, but this study may help put treatment plans into perspective for families and health care professionals who want to provide an indicated service while maximizing patient quality of life.

Acknowledgments

This manuscript is the result of work supported with resources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.

Skin cancer is the most diagnosed cancer in the United States. Nonmelanoma skin cancers (NMSC), which include basal cell carcinoma and squamous cell carcinoma, are usually cured with removal.¹ The incidence of NMSC increases with age and is commonly found in nursing homes and geriatric units. These cancers are not usually metastatic or fatal but can cause local destruction and disfigurement if neglected.² The current standard of care is to treat diagnosed NMSC; however, the dermatology and geriatric care literature have questioned the logic of treating asymptomatic skin cancers that will not affect a patient’s life expectancy.^2-4

Forty-seven percent of the current living veteran population is aged ≥ 65 years.⁵ Older adult patients are frequently referred to the US Department of Veterans Affairs (VA) surgical service for the treatment of NMSC. The veteran population includes a higher percentage of individuals at an elevated risk of skin cancers (older, White, and male) compared with the general population.⁶ World War II veterans deployed in regions closer to the equator have been found to have an elevated risk of melanoma and nonmelanoma skin carcinomas.⁷ A retrospective study of Vietnam veterans exposed to Agent Orange (2,3,7,8-tetrachlorodibenzodioxin) found a significantly higher risk of invasive NMSC in Fitzpatrick skin types I-IV compared with an age-matched subset of the general population.⁸ Younger veterans who were deployed in Afghanistan and Iraq for Operation Enduring Freedom/Operation Iraqi Freedom worked at more equatorial latitudes than the rest of the US population and may be at increased risk of NMSC. Inadequate sunscreen access, immediate safety concerns, outdoor recreational activities, harsh weather, and insufficient emphasis on sun protection have created a multifactorial challenge for the military population. Riemenschneider and colleagues recommended targeted screening for at-risk veteran patients and prioritizing annual skin cancer screenings during medical mission physical examinations for active military.⁷

The plastic surgery service regularly receives consults from dermatology, general surgery, and primary care to remove skin cancers on the face, scalp, hands, and forearms. Skin cancer treatment can create serious hardships for older adult patients and their families with multiple appointments for the consult, procedure, and follow-up. Patients are often told to hold their anticoagulant medications when the surgery will be performed on a highly vascular region, such as the scalp or face. This can create wide swings in their laboratory test values and result in life-threatening complications from either bleeding or clotting. The appropriateness of offering surgery to patients with serious comorbidities and a limited life expectancy has been questioned.^2-4 The purpose of this study was to measure the morbidity and unrelated 5-year mortality for patients with skin cancer referred to the plastic surgery service to help patients and families make a more informed treatment decision, particularly when the patients are aged > 80 years and have significant life-threatening comorbidities.

Methods

The University of Florida and Malcom Randall VA Medical Center Institutional review board in Gainesville, approved a retrospective review of all consults completed by the plastic surgery service for the treatment of NMSC performed from July 1, 2011 to June 30, 2015. Data collected included age and common life-limiting comorbidities at the time of referral. Morbidities were found on the electronic health record, including coronary artery disease (CAD), congestive heart failure (CHF), cerebral vascular disease (CVD), peripheral vascular disease, dementia, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), tobacco use, diabetes mellitus (DM), liver disease, alcohol use, and obstructive sleep apnea.

Treatment, complications, and 5-year mortality were recorded. A χ² analysis with P value < .05 was used to determine statistical significance between individual risk factors and 5-year mortality. The relative risk of 5-year mortality was calculated by combining advanced age (aged > 80 years) with the individual comorbidities.

Results

Over 4 years, 800 consults for NMSC were completed by the plastic surgery service. Treatment decisions included 210 excisions (with or without reconstruction) in the operating room, 402 excisions (with or without reconstruction) under local anesthesia in clinic, 55 Mohs surgical dermatology referrals, 21 other service or hospital referrals, and 112 patient who were observed, declined intervention, or died prior to intervention. Five-year mortality was 28.6%. No patients died of NMSC. The median age at consult submission for patients deceased 5 years later was 78 years. Complication rate was 5% and included wound infection, dehiscence, bleeding, or graft loss. Two patients, both deceased within 5 years, had unplanned admissions due to bleeding from either a skin graft donor site or recipient bleeding. Aged ≥ 80 years, CAD, CHF, CVD, peripheral vascular disease, dementia, CKD, COPD, and DM were all found individually to be statistically significant predictors of 5-year mortality (Table 1). Combining aged ≥ 80 years plus CAD, CHF, or dementia all increased the 5-year mortality by a relative risk of > 3 (Table 2).

Discussion

The standard of care is to treat NMSC. Most NMSCs are treated surgically without consideration of patient age or life expectancy.^2,4,9,10 A prospective cohort study involving a university-based private practice and a VA medical center in San Francisco found a 22.6% overall 5-year mortality and a 43.3% mortality in the group defined as limited life expectancy (LLE) based on age (≥ 85 years) and medical comorbidities. None died due to the NMSC. Leading cause of death was cardiac, cerebrovascular, and respiratory disease, lung and prostate cancer, and Alzheimer disease. The authors suggested the LLE group may be exposed to wound complications without benefiting from the treatment.⁴

Another study of 440 patients receiving excision for biopsy-proven facial NMSC at the Roudebush VA Medical Center in Indianapolis, Indiana, found no residual carcinoma in 35.3% of excisions, and in patients aged > 90 years, more than half of the excisions had no residual carcinoma. More than half of the patients aged > 90 years died within 1 year, not as a result of the NMSC. The authors argued for watchful waiting in select patients to maximize comfort and outcomes.¹⁰

Strengths and Limitations

A strength of this study is that the data were obtained from a closed system. Patients tend to stay long-term within the VA and their health record is accessible throughout the country as long as they are seen at a VA facility. Complications, therefore, return to the treating service or primary care, who would route the patient back to the surgeon.

One limitation of the study is that this is a retrospective review from 2011. The authors are limited to data that are recorded in the patient record. Multiple health care professionals saw the patients and notes lack consistency in detail. Size of the lesions were not consistently recorded and did not get logged into our database for that reason.

Conclusions

Treatment of NMSC in older adult patients has a low morbidity but needs to be balanced against a patient and family’s goals when the patient presents with life-limiting comorbidities. An elevated 5-year mortality in patients aged > 80 years with serious unrelated medical conditions is intuitive, but this study may help put treatment plans into perspective for families and health care professionals who want to provide an indicated service while maximizing patient quality of life.

Acknowledgments

This manuscript is the result of work supported with resources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.

Paraneoplastic syndrome is a rare disorder involving manifestations of immune dysregulation triggered by malignancy. The immune system develops antibodies to the malignancy, which can cause cross reactivation with various tissues in the body, resulting in an autoimmune response. Paraneoplastic cerebellar degeneration (PCD) is a rare condition caused by immune-mediated damage to the Purkinje cells of the cerebellar tract. Symptoms may include gait instability, double vision, decreased fine motor skills, and ataxia, with progression to brainstem-associated symptoms, such as nystagmus, dysarthria, and dysphagia. Early detection and treatment of the underlying malignancy is critical to halt the progression of autoimmune-mediated destruction. We present a case of a young adult female patient with PCD caused by Purkinje cell cytoplasmic–Tr (PCA-Tr) antibody with Hodgkin lymphoma.

Case Presentation

A 20-year-old previously healthy active-duty female patient presented to the emergency department with acute worsening of chronic intermittent, recurrent episodes of lightheadedness and vertigo. Symptoms persisted for 9 months until acutely worsening over the 2 weeks prior to presentation. She reported left eye double vision but did not report seeing spots, photophobia, tinnitus, or headache. She felt off-balance, leaning on nearby objects to remain standing. Symptoms primarily occurred during ambulation; however, occasionally they happened at rest. Episodes lasted up to several minutes and occurred up to 15 times a day. The patient reported no fever, night sweats, unexplained weight loss, muscle aches, weakness, numbness or tingling, loss of bowel or bladder function, or rash. She had no recent illnesses, changes to medications, or recent travel. Oral intake to include food and water was adequate and unchanged. The patient had a remote history of mild concussions without loss of consciousness while playing sports 4 years previously. She reported no recent trauma. Nine months before, she received treatment for benign paroxysmal positional vertigo (BPPV) with the Epley maneuver with full resolution of symptoms lasting several days. She reported no prescription or over-the-counter medications, herbal remedies, or supplements. She reported no other medical or surgical history and no pertinent social or family history.

Physical examination revealed a nontoxic-appearing female patient with intermittent conversational dysarthria, saccadic pursuits, horizontal nystagmus with lateral gaze, and vertical nystagmus with vertical gaze. The patient exhibited dysdiadochokinesia, or impaired ability to perform rapid alternating hand movements with repetition. Finger-to-nose testing was impaired and heel-to-shin motion remained intact. A Romberg test was positive, and the patient had tandem gait instability. Strength testing, sensation, reflexes, and cranial nerves were otherwise intact. Initial laboratory testing was unremarkable except for mild normocytic anemia. Her infectious workup, including testing for venereal disease, HIV, COVID-19, and Coccidioidies was negative. Heavy metals analysis and urine drug screen were negative. Ophthalmology was consulted and workup revealed small amplitude downbeat nystagmus in primary gaze, sustained gaze evoked lateral beating jerk nystagmus with rebound nystagmus R>L gaze, but there was no evidence of afferent package defect and optic nerve function remained intact. Magnetic resonance imaging of the brain demonstrated cerebellar vermis hypoplasia with prominence of the superior cerebellar folia. Due to concerns for autoimmune encephalitis, a lumbar puncture was performed. Antibody testing revealed PCA-Tr antibodies, which is commonly associated with Hodgkin lymphoma, prompting further evaluation for malignancy.

Computed tomography (CT) of the chest with contrast demonstrated multiple mediastinal masses with a conglomeration of lymph nodes along the right paratracheal region. Further evaluation was performed with a positron emission tomography (PET)–CT, revealing a large conglomeration of hypermetabolic pretracheal, mediastinal, and right supraclavicular lymph that were suggestive of lymphoma. Mediastinoscopy with excisional lymph node biopsy was performed with immunohistochemical staining confirming diagnosis of a nodular sclerosing variant of Hodgkin lymphoma. The patient was treated with IV immunoglobulin at 0.4g/kg daily for 5 days. A central venous catheter was placed into the patient’s right internal jugular vein and a chemotherapy regimen of doxorubicin 46 mg, vinblastine 11 mg, bleomycin 19 units, and dacarbazine 700 mg was initiated. The patient’s symptoms improved with resolution of dysarthria; however, her visual impairment and gait instability persisted. Repeat PET-CT imaging 2 months later revealed interval improvement with decreased intensity and extent of the hypermetabolic lymph nodes and no new hypermetabolic foci.

Discussion

PCA-Tr antibodies affect the delta/notchlike epidermal growth factor–related receptor, expressed on the dendrites of cerebellar Purkinje cells.¹ These fibers are the only output neurons of the cerebellar cortex and are critical to the coordination of motor movements, accounting for the ataxia experienced by patients with this subtype of PCD.² The link between Hodgkin lymphoma and PCA-Tr antibodies has been established; however, most reports involve men with a median age of 61 years with lymphoma-associated symptoms (such as lymphadenopathy) or systemic symptoms (fever, night sweats, or weight loss) preceding neurologic manifestations in 80% of cases.³

Our patient was a young, previously healthy adult female who initially presented with vertigo, a common concern with frequently benign origins. Although there was temporary resolution of symptoms after Epley maneuvers, symptoms recurred and progressed over several months to include brainstem manifestations of nystagmus, diplopia, and dysarthria. Previous reports indicate that after remission of the Hodgkin lymphoma, PCA-Tr antibodies disappear and symptoms can improve or resolve.^4,5 Treatment has just begun for our patient and although there has been initial clinical improvement, given the chronicity of symptoms, it is unclear if complete resolution will be achieved.

Conclusions

PCD can result in debilitating neurologic dysfunction and may be associated with malignancy such as Hodgkin lymphoma. This case offers unique insight due to the patient’s demographics and presentation, which involved brainstem pathology typically associated with late-onset disease and preceded by constitutional symptoms. Clinical suspicion of this rare disorder should be considered in all ages, especially if symptoms are progressive or neurologic manifestations arise, as early detection and treatment of the underlying malignancy are paramount to the prevention of significant disability.

Paraneoplastic syndrome is a rare disorder involving manifestations of immune dysregulation triggered by malignancy. The immune system develops antibodies to the malignancy, which can cause cross reactivation with various tissues in the body, resulting in an autoimmune response. Paraneoplastic cerebellar degeneration (PCD) is a rare condition caused by immune-mediated damage to the Purkinje cells of the cerebellar tract. Symptoms may include gait instability, double vision, decreased fine motor skills, and ataxia, with progression to brainstem-associated symptoms, such as nystagmus, dysarthria, and dysphagia. Early detection and treatment of the underlying malignancy is critical to halt the progression of autoimmune-mediated destruction. We present a case of a young adult female patient with PCD caused by Purkinje cell cytoplasmic–Tr (PCA-Tr) antibody with Hodgkin lymphoma.

Case Presentation

A 20-year-old previously healthy active-duty female patient presented to the emergency department with acute worsening of chronic intermittent, recurrent episodes of lightheadedness and vertigo. Symptoms persisted for 9 months until acutely worsening over the 2 weeks prior to presentation. She reported left eye double vision but did not report seeing spots, photophobia, tinnitus, or headache. She felt off-balance, leaning on nearby objects to remain standing. Symptoms primarily occurred during ambulation; however, occasionally they happened at rest. Episodes lasted up to several minutes and occurred up to 15 times a day. The patient reported no fever, night sweats, unexplained weight loss, muscle aches, weakness, numbness or tingling, loss of bowel or bladder function, or rash. She had no recent illnesses, changes to medications, or recent travel. Oral intake to include food and water was adequate and unchanged. The patient had a remote history of mild concussions without loss of consciousness while playing sports 4 years previously. She reported no recent trauma. Nine months before, she received treatment for benign paroxysmal positional vertigo (BPPV) with the Epley maneuver with full resolution of symptoms lasting several days. She reported no prescription or over-the-counter medications, herbal remedies, or supplements. She reported no other medical or surgical history and no pertinent social or family history.

Physical examination revealed a nontoxic-appearing female patient with intermittent conversational dysarthria, saccadic pursuits, horizontal nystagmus with lateral gaze, and vertical nystagmus with vertical gaze. The patient exhibited dysdiadochokinesia, or impaired ability to perform rapid alternating hand movements with repetition. Finger-to-nose testing was impaired and heel-to-shin motion remained intact. A Romberg test was positive, and the patient had tandem gait instability. Strength testing, sensation, reflexes, and cranial nerves were otherwise intact. Initial laboratory testing was unremarkable except for mild normocytic anemia. Her infectious workup, including testing for venereal disease, HIV, COVID-19, and Coccidioidies was negative. Heavy metals analysis and urine drug screen were negative. Ophthalmology was consulted and workup revealed small amplitude downbeat nystagmus in primary gaze, sustained gaze evoked lateral beating jerk nystagmus with rebound nystagmus R>L gaze, but there was no evidence of afferent package defect and optic nerve function remained intact. Magnetic resonance imaging of the brain demonstrated cerebellar vermis hypoplasia with prominence of the superior cerebellar folia. Due to concerns for autoimmune encephalitis, a lumbar puncture was performed. Antibody testing revealed PCA-Tr antibodies, which is commonly associated with Hodgkin lymphoma, prompting further evaluation for malignancy.

Computed tomography (CT) of the chest with contrast demonstrated multiple mediastinal masses with a conglomeration of lymph nodes along the right paratracheal region. Further evaluation was performed with a positron emission tomography (PET)–CT, revealing a large conglomeration of hypermetabolic pretracheal, mediastinal, and right supraclavicular lymph that were suggestive of lymphoma. Mediastinoscopy with excisional lymph node biopsy was performed with immunohistochemical staining confirming diagnosis of a nodular sclerosing variant of Hodgkin lymphoma. The patient was treated with IV immunoglobulin at 0.4g/kg daily for 5 days. A central venous catheter was placed into the patient’s right internal jugular vein and a chemotherapy regimen of doxorubicin 46 mg, vinblastine 11 mg, bleomycin 19 units, and dacarbazine 700 mg was initiated. The patient’s symptoms improved with resolution of dysarthria; however, her visual impairment and gait instability persisted. Repeat PET-CT imaging 2 months later revealed interval improvement with decreased intensity and extent of the hypermetabolic lymph nodes and no new hypermetabolic foci.

Discussion

PCA-Tr antibodies affect the delta/notchlike epidermal growth factor–related receptor, expressed on the dendrites of cerebellar Purkinje cells.¹ These fibers are the only output neurons of the cerebellar cortex and are critical to the coordination of motor movements, accounting for the ataxia experienced by patients with this subtype of PCD.² The link between Hodgkin lymphoma and PCA-Tr antibodies has been established; however, most reports involve men with a median age of 61 years with lymphoma-associated symptoms (such as lymphadenopathy) or systemic symptoms (fever, night sweats, or weight loss) preceding neurologic manifestations in 80% of cases.³

Our patient was a young, previously healthy adult female who initially presented with vertigo, a common concern with frequently benign origins. Although there was temporary resolution of symptoms after Epley maneuvers, symptoms recurred and progressed over several months to include brainstem manifestations of nystagmus, diplopia, and dysarthria. Previous reports indicate that after remission of the Hodgkin lymphoma, PCA-Tr antibodies disappear and symptoms can improve or resolve.^4,5 Treatment has just begun for our patient and although there has been initial clinical improvement, given the chronicity of symptoms, it is unclear if complete resolution will be achieved.

Conclusions

PCD can result in debilitating neurologic dysfunction and may be associated with malignancy such as Hodgkin lymphoma. This case offers unique insight due to the patient’s demographics and presentation, which involved brainstem pathology typically associated with late-onset disease and preceded by constitutional symptoms. Clinical suspicion of this rare disorder should be considered in all ages, especially if symptoms are progressive or neurologic manifestations arise, as early detection and treatment of the underlying malignancy are paramount to the prevention of significant disability.

Paraneoplastic syndrome is a rare disorder involving manifestations of immune dysregulation triggered by malignancy. The immune system develops antibodies to the malignancy, which can cause cross reactivation with various tissues in the body, resulting in an autoimmune response. Paraneoplastic cerebellar degeneration (PCD) is a rare condition caused by immune-mediated damage to the Purkinje cells of the cerebellar tract. Symptoms may include gait instability, double vision, decreased fine motor skills, and ataxia, with progression to brainstem-associated symptoms, such as nystagmus, dysarthria, and dysphagia. Early detection and treatment of the underlying malignancy is critical to halt the progression of autoimmune-mediated destruction. We present a case of a young adult female patient with PCD caused by Purkinje cell cytoplasmic–Tr (PCA-Tr) antibody with Hodgkin lymphoma.

Case Presentation

A 20-year-old previously healthy active-duty female patient presented to the emergency department with acute worsening of chronic intermittent, recurrent episodes of lightheadedness and vertigo. Symptoms persisted for 9 months until acutely worsening over the 2 weeks prior to presentation. She reported left eye double vision but did not report seeing spots, photophobia, tinnitus, or headache. She felt off-balance, leaning on nearby objects to remain standing. Symptoms primarily occurred during ambulation; however, occasionally they happened at rest. Episodes lasted up to several minutes and occurred up to 15 times a day. The patient reported no fever, night sweats, unexplained weight loss, muscle aches, weakness, numbness or tingling, loss of bowel or bladder function, or rash. She had no recent illnesses, changes to medications, or recent travel. Oral intake to include food and water was adequate and unchanged. The patient had a remote history of mild concussions without loss of consciousness while playing sports 4 years previously. She reported no recent trauma. Nine months before, she received treatment for benign paroxysmal positional vertigo (BPPV) with the Epley maneuver with full resolution of symptoms lasting several days. She reported no prescription or over-the-counter medications, herbal remedies, or supplements. She reported no other medical or surgical history and no pertinent social or family history.

Physical examination revealed a nontoxic-appearing female patient with intermittent conversational dysarthria, saccadic pursuits, horizontal nystagmus with lateral gaze, and vertical nystagmus with vertical gaze. The patient exhibited dysdiadochokinesia, or impaired ability to perform rapid alternating hand movements with repetition. Finger-to-nose testing was impaired and heel-to-shin motion remained intact. A Romberg test was positive, and the patient had tandem gait instability. Strength testing, sensation, reflexes, and cranial nerves were otherwise intact. Initial laboratory testing was unremarkable except for mild normocytic anemia. Her infectious workup, including testing for venereal disease, HIV, COVID-19, and Coccidioidies was negative. Heavy metals analysis and urine drug screen were negative. Ophthalmology was consulted and workup revealed small amplitude downbeat nystagmus in primary gaze, sustained gaze evoked lateral beating jerk nystagmus with rebound nystagmus R>L gaze, but there was no evidence of afferent package defect and optic nerve function remained intact. Magnetic resonance imaging of the brain demonstrated cerebellar vermis hypoplasia with prominence of the superior cerebellar folia. Due to concerns for autoimmune encephalitis, a lumbar puncture was performed. Antibody testing revealed PCA-Tr antibodies, which is commonly associated with Hodgkin lymphoma, prompting further evaluation for malignancy.

Computed tomography (CT) of the chest with contrast demonstrated multiple mediastinal masses with a conglomeration of lymph nodes along the right paratracheal region. Further evaluation was performed with a positron emission tomography (PET)–CT, revealing a large conglomeration of hypermetabolic pretracheal, mediastinal, and right supraclavicular lymph that were suggestive of lymphoma. Mediastinoscopy with excisional lymph node biopsy was performed with immunohistochemical staining confirming diagnosis of a nodular sclerosing variant of Hodgkin lymphoma. The patient was treated with IV immunoglobulin at 0.4g/kg daily for 5 days. A central venous catheter was placed into the patient’s right internal jugular vein and a chemotherapy regimen of doxorubicin 46 mg, vinblastine 11 mg, bleomycin 19 units, and dacarbazine 700 mg was initiated. The patient’s symptoms improved with resolution of dysarthria; however, her visual impairment and gait instability persisted. Repeat PET-CT imaging 2 months later revealed interval improvement with decreased intensity and extent of the hypermetabolic lymph nodes and no new hypermetabolic foci.

Discussion

PCA-Tr antibodies affect the delta/notchlike epidermal growth factor–related receptor, expressed on the dendrites of cerebellar Purkinje cells.¹ These fibers are the only output neurons of the cerebellar cortex and are critical to the coordination of motor movements, accounting for the ataxia experienced by patients with this subtype of PCD.² The link between Hodgkin lymphoma and PCA-Tr antibodies has been established; however, most reports involve men with a median age of 61 years with lymphoma-associated symptoms (such as lymphadenopathy) or systemic symptoms (fever, night sweats, or weight loss) preceding neurologic manifestations in 80% of cases.³

Our patient was a young, previously healthy adult female who initially presented with vertigo, a common concern with frequently benign origins. Although there was temporary resolution of symptoms after Epley maneuvers, symptoms recurred and progressed over several months to include brainstem manifestations of nystagmus, diplopia, and dysarthria. Previous reports indicate that after remission of the Hodgkin lymphoma, PCA-Tr antibodies disappear and symptoms can improve or resolve.^4,5 Treatment has just begun for our patient and although there has been initial clinical improvement, given the chronicity of symptoms, it is unclear if complete resolution will be achieved.

Conclusions

PCD can result in debilitating neurologic dysfunction and may be associated with malignancy such as Hodgkin lymphoma. This case offers unique insight due to the patient’s demographics and presentation, which involved brainstem pathology typically associated with late-onset disease and preceded by constitutional symptoms. Clinical suspicion of this rare disorder should be considered in all ages, especially if symptoms are progressive or neurologic manifestations arise, as early detection and treatment of the underlying malignancy are paramount to the prevention of significant disability.

Treatment with oral sabizabulin (Veru Pharmaceuticals) cut the risk for death by more than 55% in hospitalized patients with COVID-19, an interim analysis of a phase 3 placebo-controlled trial found.

Sabizabulin treatment consistently and significantly reduced deaths across patient subgroups “regardless of standard of care treatment received, baseline World Health Organization scores, age, comorbidities, vaccination status, COVID-19 variant, or geography,” study investigator Mitchell Steiner, MD, chairman, president, and CEO of Veru, said in a news release.

The company has submitted an emergency use authorization request to the U.S. Food and Drug Administration to use sabizabulin to treat COVID-19.

The analysis was published online in NEJM Evidence.

Sabizabulin, originally developed to treat metastatic castration-resistant prostate cancer, is a novel, investigational, oral microtubule disruptor with dual antiviral and anti-inflammatory activities. Given the drug’s mechanism, researchers at Veru thought that sabizabulin could help treat lung inflammation in patients with COVID-19 as well.

Findings of the interim analysis are based on 150 adults hospitalized with moderate to severe COVID-19 at high risk for acute respiratory distress syndrome and death. The patients were randomly allocated to receive 9 mg oral sabizabulin (n = 98) or placebo (n = 52) once daily for up to 21 days.

Overall, the mortality rate was 20.2% in the sabizabulin group vs. 45.1% in the placebo group. Compared with placebo, treatment with sabizabulin led to a 24.9–percentage point absolute reduction and a 55.2% relative reduction in death (odds ratio, 3.23; P = .0042).

The key secondary endpoint of mortality through day 29 also favored sabizabulin over placebo, with a mortality rate of 17% vs. 35.3%. In this scenario, treatment with sabizabulin resulted in an absolute reduction in deaths of 18.3 percentage points and a relative reduction of 51.8%.

Sabizabulin led to a significant 43% relative reduction in ICU days, a 49% relative reduction in days on mechanical ventilation, and a 26% relative reduction in days in the hospital, compared with placebo.

Adverse and serious adverse events were also lower in the sabizabulin group (61.5%) than the placebo group (78.3%).

The data are “pretty impressive and in a group of patients that we really have limited things to offer,” Aaron Glatt, MD, a spokesperson for the Infectious Diseases Society of America and chief of infectious diseases and hospital epidemiologist at Mount Sinai South Nassau in Oceanside, N.Y., said in an interview. “This is an interim analysis and obviously we’d like to see more data, but it certainly is something that is novel and quite interesting.”

David Boulware, MD, MPH, an infectious disease expert at the University of Minnesota, Minneapolis, told the New York Times that the large number of deaths in the placebo group seemed “rather high” and that the final analysis might reveal a more modest benefit for sabizabulin.

“I would be skeptical” that the reduced risk for death remains 55%, he noted.

The study was funded by Veru Pharmaceuticals. Several authors are employed by the company or have financial relationships with the company.

A version of this article first appeared on Medscape.com.

Treatment with oral sabizabulin (Veru Pharmaceuticals) cut the risk for death by more than 55% in hospitalized patients with COVID-19, an interim analysis of a phase 3 placebo-controlled trial found.

Sabizabulin treatment consistently and significantly reduced deaths across patient subgroups “regardless of standard of care treatment received, baseline World Health Organization scores, age, comorbidities, vaccination status, COVID-19 variant, or geography,” study investigator Mitchell Steiner, MD, chairman, president, and CEO of Veru, said in a news release.

The company has submitted an emergency use authorization request to the U.S. Food and Drug Administration to use sabizabulin to treat COVID-19.

The analysis was published online in NEJM Evidence.

Sabizabulin, originally developed to treat metastatic castration-resistant prostate cancer, is a novel, investigational, oral microtubule disruptor with dual antiviral and anti-inflammatory activities. Given the drug’s mechanism, researchers at Veru thought that sabizabulin could help treat lung inflammation in patients with COVID-19 as well.

Findings of the interim analysis are based on 150 adults hospitalized with moderate to severe COVID-19 at high risk for acute respiratory distress syndrome and death. The patients were randomly allocated to receive 9 mg oral sabizabulin (n = 98) or placebo (n = 52) once daily for up to 21 days.

Overall, the mortality rate was 20.2% in the sabizabulin group vs. 45.1% in the placebo group. Compared with placebo, treatment with sabizabulin led to a 24.9–percentage point absolute reduction and a 55.2% relative reduction in death (odds ratio, 3.23; P = .0042).

The key secondary endpoint of mortality through day 29 also favored sabizabulin over placebo, with a mortality rate of 17% vs. 35.3%. In this scenario, treatment with sabizabulin resulted in an absolute reduction in deaths of 18.3 percentage points and a relative reduction of 51.8%.

Sabizabulin led to a significant 43% relative reduction in ICU days, a 49% relative reduction in days on mechanical ventilation, and a 26% relative reduction in days in the hospital, compared with placebo.

Adverse and serious adverse events were also lower in the sabizabulin group (61.5%) than the placebo group (78.3%).

The data are “pretty impressive and in a group of patients that we really have limited things to offer,” Aaron Glatt, MD, a spokesperson for the Infectious Diseases Society of America and chief of infectious diseases and hospital epidemiologist at Mount Sinai South Nassau in Oceanside, N.Y., said in an interview. “This is an interim analysis and obviously we’d like to see more data, but it certainly is something that is novel and quite interesting.”

David Boulware, MD, MPH, an infectious disease expert at the University of Minnesota, Minneapolis, told the New York Times that the large number of deaths in the placebo group seemed “rather high” and that the final analysis might reveal a more modest benefit for sabizabulin.

“I would be skeptical” that the reduced risk for death remains 55%, he noted.

The study was funded by Veru Pharmaceuticals. Several authors are employed by the company or have financial relationships with the company.

A version of this article first appeared on Medscape.com.

Treatment with oral sabizabulin (Veru Pharmaceuticals) cut the risk for death by more than 55% in hospitalized patients with COVID-19, an interim analysis of a phase 3 placebo-controlled trial found.

Sabizabulin treatment consistently and significantly reduced deaths across patient subgroups “regardless of standard of care treatment received, baseline World Health Organization scores, age, comorbidities, vaccination status, COVID-19 variant, or geography,” study investigator Mitchell Steiner, MD, chairman, president, and CEO of Veru, said in a news release.

The company has submitted an emergency use authorization request to the U.S. Food and Drug Administration to use sabizabulin to treat COVID-19.

The analysis was published online in NEJM Evidence.

Sabizabulin, originally developed to treat metastatic castration-resistant prostate cancer, is a novel, investigational, oral microtubule disruptor with dual antiviral and anti-inflammatory activities. Given the drug’s mechanism, researchers at Veru thought that sabizabulin could help treat lung inflammation in patients with COVID-19 as well.

Findings of the interim analysis are based on 150 adults hospitalized with moderate to severe COVID-19 at high risk for acute respiratory distress syndrome and death. The patients were randomly allocated to receive 9 mg oral sabizabulin (n = 98) or placebo (n = 52) once daily for up to 21 days.

Overall, the mortality rate was 20.2% in the sabizabulin group vs. 45.1% in the placebo group. Compared with placebo, treatment with sabizabulin led to a 24.9–percentage point absolute reduction and a 55.2% relative reduction in death (odds ratio, 3.23; P = .0042).

The key secondary endpoint of mortality through day 29 also favored sabizabulin over placebo, with a mortality rate of 17% vs. 35.3%. In this scenario, treatment with sabizabulin resulted in an absolute reduction in deaths of 18.3 percentage points and a relative reduction of 51.8%.

Sabizabulin led to a significant 43% relative reduction in ICU days, a 49% relative reduction in days on mechanical ventilation, and a 26% relative reduction in days in the hospital, compared with placebo.

Adverse and serious adverse events were also lower in the sabizabulin group (61.5%) than the placebo group (78.3%).

The data are “pretty impressive and in a group of patients that we really have limited things to offer,” Aaron Glatt, MD, a spokesperson for the Infectious Diseases Society of America and chief of infectious diseases and hospital epidemiologist at Mount Sinai South Nassau in Oceanside, N.Y., said in an interview. “This is an interim analysis and obviously we’d like to see more data, but it certainly is something that is novel and quite interesting.”

David Boulware, MD, MPH, an infectious disease expert at the University of Minnesota, Minneapolis, told the New York Times that the large number of deaths in the placebo group seemed “rather high” and that the final analysis might reveal a more modest benefit for sabizabulin.

“I would be skeptical” that the reduced risk for death remains 55%, he noted.

The study was funded by Veru Pharmaceuticals. Several authors are employed by the company or have financial relationships with the company.

A version of this article first appeared on Medscape.com.

CHICAGO – Pembrolizumab has shown promise as adjuvant therapy for stage IIB and IIC melanoma, shows the first interim analysis of the phase 3 KEYNOTE-716 study recently published in The Lancet.

The findings meet an unmet need as the recurrence risk in stage IIB and IIC melanoma is “underrecognized,” said author Georgina Long, MD, comedical director of the Melanoma Institute Australia, University of Sydney.

In fact, their risk of recurrence is similar to patients with stage IIIB disease, wrote David Killock, PhD, in a related commentary published in Nature Reviews.

The adjuvant treatment resulted in an 89% recurrence-free survival in patients who received pembrolizumab, compared with 83% of patients in the placebo group (hazard ratio, 0.65; P = .0066). These findings were used as the basis for Food and Drug Administration approval of pembrolizumab (Keytruda, Merck) for this patient population in December 2021.

Despite the positive findings, Dr. Killock called for more research on distant metastasis-free survival, overall survival, and quality of life data to “establish the true clinical benefit of adjuvant pembrolizumab.”

At the annual meeting of the American Society of Clinical Oncology, Dr. Long presented the third interim analysis which showed pembrolizumab reduced recurrence and distant metastases at 24 months, although the clinical benefit was relatively small at an approximately 8% improvement in recurrence-free survival and about a 6% improvement in distant metastasis-free survival. About 83% in the pembrolizumab group had treatment-related toxicities versus 64% in the placebo group. There were no deaths caused by treatment. About 90% of pembrolizumab-related endocrinopathies led to long-term hormone replacement.

In a discussion that followed the presentation at ASCO, Charlotte Eielson Ariyan, MD, PhD, said the results are bittersweet. Higher-risk stage IIC patients have a risk of recurrence of about 40%. “It’s high, but the absolute risk reduction is about 8%. This is a very personalized discussion with the patient and the physician in understanding their risk of toxicity is about 17% and higher than their absolute risk reduction with the treatment. For me, this is a bitter pill to swallow because you’re treating people longer and you’re not sure if you’re really helping them. Until we can further define who the highest-risk patients are, I think it’s hard to give it to everyone,” said Dr. Ariyan, who is a surgeon with Memorial Sloan Kettering Cancer Center, New York.

In addition to weighing short-term benefits and toxicity, there are longer-term concerns. Toxicity experienced from PD-1 inhibitors in the adjuvant setting could impact future treatment decisions. “We’re very lucky here in melanoma to know that systemic therapies are effective and we can cure people who recur. I would argue this is why we probably will never really see a difference in the survival benefit in this group because people who cross over will probably do well,” Dr. Ariyan said.

During the Q&A session, Vernon Sondek, MD, Moffitt Cancer Center, Tampa, encouraged physician colleagues to have an open mind about treatments. “Beware of dogma. We thought that adjuvant immunotherapy works much better in patients with ulcerated primary tumors. That’s a dogma in some parts of the world. Yet the T4a patients in KEYNOTE-716 dramatically outperformed the ulcerated T3b and T4b [patients]. We still don’t know what we don’t know.”
 

The study details

KEYNOTE-716 included 976 patients 12 years or older with newly diagnosed completely resected stage IIB or IIC melanoma with a negative sentinel lymph node. Patients were randomized to placebo or 200 mg pembrolizumab every 3 weeks, or 2 mg/kg in pediatric patients, over 17 cycles. Almost 40% of patients were age 65 or older. T3b and T4b were the most common melanoma subcategories at 41% and 35%, respectively.

The planned third interim analysis occurred after the occurrence of 146 distant metastases. After a median follow-up of 27.4 months, distant metastasis-free survival favored the pembrolizumab group (HR, 0.64; P = .0029). At 24 months, the pembrolizumab group had a higher distant metastasis-free survival at 88.1% versus 82.2% and a lower recurrence rate at 81.2% versus 72.8% (HR, 0.64; 95% confidence interval, 0.50-0.84).

At 24 months, only the T4a patients had a statistically significant reduction in distant metastases at 58% (HR, 0.42; 95% CI, 0.19-0.96), although there were numerical reductions in T3a (HR, 0.71; 95% CI, 0.41-1.22) and T4b (HR, 0.70; 95% CI, 0.44-1.33) patients. Of patients experiencing a distant metastasis, 73% of the placebo group had a first distant metastasis to the lung compared with 49% of the pembrolizumab group.

Dr. Long has held consulting or advisory roles for Merck Sharpe & Dohme, which funded this study.

CHICAGO – Pembrolizumab has shown promise as adjuvant therapy for stage IIB and IIC melanoma, shows the first interim analysis of the phase 3 KEYNOTE-716 study recently published in The Lancet.

The findings meet an unmet need as the recurrence risk in stage IIB and IIC melanoma is “underrecognized,” said author Georgina Long, MD, comedical director of the Melanoma Institute Australia, University of Sydney.

In fact, their risk of recurrence is similar to patients with stage IIIB disease, wrote David Killock, PhD, in a related commentary published in Nature Reviews.

The adjuvant treatment resulted in an 89% recurrence-free survival in patients who received pembrolizumab, compared with 83% of patients in the placebo group (hazard ratio, 0.65; P = .0066). These findings were used as the basis for Food and Drug Administration approval of pembrolizumab (Keytruda, Merck) for this patient population in December 2021.

Despite the positive findings, Dr. Killock called for more research on distant metastasis-free survival, overall survival, and quality of life data to “establish the true clinical benefit of adjuvant pembrolizumab.”

At the annual meeting of the American Society of Clinical Oncology, Dr. Long presented the third interim analysis which showed pembrolizumab reduced recurrence and distant metastases at 24 months, although the clinical benefit was relatively small at an approximately 8% improvement in recurrence-free survival and about a 6% improvement in distant metastasis-free survival. About 83% in the pembrolizumab group had treatment-related toxicities versus 64% in the placebo group. There were no deaths caused by treatment. About 90% of pembrolizumab-related endocrinopathies led to long-term hormone replacement.

In a discussion that followed the presentation at ASCO, Charlotte Eielson Ariyan, MD, PhD, said the results are bittersweet. Higher-risk stage IIC patients have a risk of recurrence of about 40%. “It’s high, but the absolute risk reduction is about 8%. This is a very personalized discussion with the patient and the physician in understanding their risk of toxicity is about 17% and higher than their absolute risk reduction with the treatment. For me, this is a bitter pill to swallow because you’re treating people longer and you’re not sure if you’re really helping them. Until we can further define who the highest-risk patients are, I think it’s hard to give it to everyone,” said Dr. Ariyan, who is a surgeon with Memorial Sloan Kettering Cancer Center, New York.

In addition to weighing short-term benefits and toxicity, there are longer-term concerns. Toxicity experienced from PD-1 inhibitors in the adjuvant setting could impact future treatment decisions. “We’re very lucky here in melanoma to know that systemic therapies are effective and we can cure people who recur. I would argue this is why we probably will never really see a difference in the survival benefit in this group because people who cross over will probably do well,” Dr. Ariyan said.

During the Q&A session, Vernon Sondek, MD, Moffitt Cancer Center, Tampa, encouraged physician colleagues to have an open mind about treatments. “Beware of dogma. We thought that adjuvant immunotherapy works much better in patients with ulcerated primary tumors. That’s a dogma in some parts of the world. Yet the T4a patients in KEYNOTE-716 dramatically outperformed the ulcerated T3b and T4b [patients]. We still don’t know what we don’t know.”
 

The study details

KEYNOTE-716 included 976 patients 12 years or older with newly diagnosed completely resected stage IIB or IIC melanoma with a negative sentinel lymph node. Patients were randomized to placebo or 200 mg pembrolizumab every 3 weeks, or 2 mg/kg in pediatric patients, over 17 cycles. Almost 40% of patients were age 65 or older. T3b and T4b were the most common melanoma subcategories at 41% and 35%, respectively.

The planned third interim analysis occurred after the occurrence of 146 distant metastases. After a median follow-up of 27.4 months, distant metastasis-free survival favored the pembrolizumab group (HR, 0.64; P = .0029). At 24 months, the pembrolizumab group had a higher distant metastasis-free survival at 88.1% versus 82.2% and a lower recurrence rate at 81.2% versus 72.8% (HR, 0.64; 95% confidence interval, 0.50-0.84).

At 24 months, only the T4a patients had a statistically significant reduction in distant metastases at 58% (HR, 0.42; 95% CI, 0.19-0.96), although there were numerical reductions in T3a (HR, 0.71; 95% CI, 0.41-1.22) and T4b (HR, 0.70; 95% CI, 0.44-1.33) patients. Of patients experiencing a distant metastasis, 73% of the placebo group had a first distant metastasis to the lung compared with 49% of the pembrolizumab group.

Dr. Long has held consulting or advisory roles for Merck Sharpe & Dohme, which funded this study.

CHICAGO – Pembrolizumab has shown promise as adjuvant therapy for stage IIB and IIC melanoma, shows the first interim analysis of the phase 3 KEYNOTE-716 study recently published in The Lancet.

The findings meet an unmet need as the recurrence risk in stage IIB and IIC melanoma is “underrecognized,” said author Georgina Long, MD, comedical director of the Melanoma Institute Australia, University of Sydney.

In fact, their risk of recurrence is similar to patients with stage IIIB disease, wrote David Killock, PhD, in a related commentary published in Nature Reviews.

The adjuvant treatment resulted in an 89% recurrence-free survival in patients who received pembrolizumab, compared with 83% of patients in the placebo group (hazard ratio, 0.65; P = .0066). These findings were used as the basis for Food and Drug Administration approval of pembrolizumab (Keytruda, Merck) for this patient population in December 2021.

Despite the positive findings, Dr. Killock called for more research on distant metastasis-free survival, overall survival, and quality of life data to “establish the true clinical benefit of adjuvant pembrolizumab.”

At the annual meeting of the American Society of Clinical Oncology, Dr. Long presented the third interim analysis which showed pembrolizumab reduced recurrence and distant metastases at 24 months, although the clinical benefit was relatively small at an approximately 8% improvement in recurrence-free survival and about a 6% improvement in distant metastasis-free survival. About 83% in the pembrolizumab group had treatment-related toxicities versus 64% in the placebo group. There were no deaths caused by treatment. About 90% of pembrolizumab-related endocrinopathies led to long-term hormone replacement.

In a discussion that followed the presentation at ASCO, Charlotte Eielson Ariyan, MD, PhD, said the results are bittersweet. Higher-risk stage IIC patients have a risk of recurrence of about 40%. “It’s high, but the absolute risk reduction is about 8%. This is a very personalized discussion with the patient and the physician in understanding their risk of toxicity is about 17% and higher than their absolute risk reduction with the treatment. For me, this is a bitter pill to swallow because you’re treating people longer and you’re not sure if you’re really helping them. Until we can further define who the highest-risk patients are, I think it’s hard to give it to everyone,” said Dr. Ariyan, who is a surgeon with Memorial Sloan Kettering Cancer Center, New York.

In addition to weighing short-term benefits and toxicity, there are longer-term concerns. Toxicity experienced from PD-1 inhibitors in the adjuvant setting could impact future treatment decisions. “We’re very lucky here in melanoma to know that systemic therapies are effective and we can cure people who recur. I would argue this is why we probably will never really see a difference in the survival benefit in this group because people who cross over will probably do well,” Dr. Ariyan said.

During the Q&A session, Vernon Sondek, MD, Moffitt Cancer Center, Tampa, encouraged physician colleagues to have an open mind about treatments. “Beware of dogma. We thought that adjuvant immunotherapy works much better in patients with ulcerated primary tumors. That’s a dogma in some parts of the world. Yet the T4a patients in KEYNOTE-716 dramatically outperformed the ulcerated T3b and T4b [patients]. We still don’t know what we don’t know.”
 

The study details

KEYNOTE-716 included 976 patients 12 years or older with newly diagnosed completely resected stage IIB or IIC melanoma with a negative sentinel lymph node. Patients were randomized to placebo or 200 mg pembrolizumab every 3 weeks, or 2 mg/kg in pediatric patients, over 17 cycles. Almost 40% of patients were age 65 or older. T3b and T4b were the most common melanoma subcategories at 41% and 35%, respectively.

The planned third interim analysis occurred after the occurrence of 146 distant metastases. After a median follow-up of 27.4 months, distant metastasis-free survival favored the pembrolizumab group (HR, 0.64; P = .0029). At 24 months, the pembrolizumab group had a higher distant metastasis-free survival at 88.1% versus 82.2% and a lower recurrence rate at 81.2% versus 72.8% (HR, 0.64; 95% confidence interval, 0.50-0.84).

At 24 months, only the T4a patients had a statistically significant reduction in distant metastases at 58% (HR, 0.42; 95% CI, 0.19-0.96), although there were numerical reductions in T3a (HR, 0.71; 95% CI, 0.41-1.22) and T4b (HR, 0.70; 95% CI, 0.44-1.33) patients. Of patients experiencing a distant metastasis, 73% of the placebo group had a first distant metastasis to the lung compared with 49% of the pembrolizumab group.

Dr. Long has held consulting or advisory roles for Merck Sharpe & Dohme, which funded this study.

Estrogen exposure helps protect against colorectal cancer (CRC), and in some instances, the protection is site specific, a new analysis finds.

In a 17-year study involving almost 5,000 women, researchers from Germany found that hormone replacement therapy, oral contraceptive use, pregnancy, breastfeeding, and menopause at age 50 or older were all significantly associated with reductions in CRC risk.

Interestingly, the reduced risk of CRC observed for pregnancy and breastfeeding only applied to proximal colon cancer, while the association with oral contraceptive use was confined to the distal colon and rectum.

The results were published online in JNCI Cancer Spectrum.

CRC is the second most common cause of cancer death. It is responsible for more than one million deaths globally, according to the latest figures from the Global Burden of Disease 2019 Cancer Collaboration.

And sex seems to make a difference. The Global Burden analysis, echoing previous data, found that CRC is less common among women and that fewer women die from the disease.

Little, however, is known about the mechanisms of estrogen signaling in CRC or the impact of reproductive factors on CRC, despite a large amount of literature linking CRC risk to exogenous estrogens, such as hormone replacement therapy and oral contraceptives.

In the current analysis, the team recruited 2,650 patients with CRC from 20 German cancer centers between 2003 and 2020. Researchers used standardized questionnaires to garner the women’s reproductive histories.

A matched control group of 2,175 participants who did not have a history of CRC was randomly selected from population registries. All analyses were adjusted for known CRC risk factors, such as age; body mass index; education level; family history; having previously undergone large-bowel endoscopy; diabetes; and smoking status.

The researchers found that each pregnancy was associated with a small but significant 9% reduction in CRC risk (odds ratio, 0.91), specifically in the proximal colon (OR, 0.86).

Overall, breastfeeding for a year or longer was associated with a significantly lower CRC risk, compared with never breastfeeding (OR, 0.74), but the results were only significant for the proximal colon (OR, 0.58).

Oral contraceptive use for 9 years or longer was associated with a lower CRC risk (OR, 0.75) but was only significant for the distal colon (OR, 0.63). Hormone replacement therapy was associated with a lower risk of CRC irrespective of tumor location (OR, 0.76). And using both was linked to a 42% CRC risk reduction (OR, 0.58).

Although age at menarche was not associated with CRC risk, menopause at age 50 or older was associated with a significant 17% lower risk of CRC.

In an email interview, lead author Tobias Niedermaier, PhD, expressed surprise at two of the findings. The first was the small association between pregnancies and CRC risk, “despite the strong increase in estrogen levels during pregnancy,” he said. He speculated that pregnancy-related increases in insulin levels may have “largely offset the protection effects of estrogen exposure during pregnancy.”

The second surprise was that the age at menarche did not have a bearing on CRC risk, which could be because “exposure to estrogen levels in younger ages [is] less relevant with respect to CRC risk, because CRC typically develops at comparably old age.”

John Marshall, MD, who was not involved in the research, commented that such studies “put a lot of pressure on people to perform in a certain way to modify their personal risk of something.” However, “we would not recommend people alter their life choices for reproduction for this,” said Dr. Marshall, chief of the Division of Hematology/Oncology at Georgetown University, Washington, D.C.

Dr. Niedermaier agreed that “while this knowledge will certainly not change a woman’s decision on family planning,” he noted that the findings “could influence current CRC screening strategies, for example, by risk-adapted screening intervals [and] start and stop ages of screening.”

Dr. Niedermaier and colleagues’ work was funded by the German Research Council, the German Federal Ministry of Education and Research, and the Interdisciplinary Research Program of the National Center for Tumor Diseases. Dr. Niedermaier has disclosed no relevant financial relationships. Dr. Marshall writes a column that appears regularly on Medscape: Marshall on Oncology. He has served as speaker or member of a speakers’ bureau for Genentech, Amgen, Bayer, Celgene Corporation, and Caris Life Sciences.

A version of this article first appeared on Medscape.com.

Estrogen exposure helps protect against colorectal cancer (CRC), and in some instances, the protection is site specific, a new analysis finds.

In a 17-year study involving almost 5,000 women, researchers from Germany found that hormone replacement therapy, oral contraceptive use, pregnancy, breastfeeding, and menopause at age 50 or older were all significantly associated with reductions in CRC risk.

Interestingly, the reduced risk of CRC observed for pregnancy and breastfeeding only applied to proximal colon cancer, while the association with oral contraceptive use was confined to the distal colon and rectum.

The results were published online in JNCI Cancer Spectrum.

CRC is the second most common cause of cancer death. It is responsible for more than one million deaths globally, according to the latest figures from the Global Burden of Disease 2019 Cancer Collaboration.

And sex seems to make a difference. The Global Burden analysis, echoing previous data, found that CRC is less common among women and that fewer women die from the disease.

Little, however, is known about the mechanisms of estrogen signaling in CRC or the impact of reproductive factors on CRC, despite a large amount of literature linking CRC risk to exogenous estrogens, such as hormone replacement therapy and oral contraceptives.

In the current analysis, the team recruited 2,650 patients with CRC from 20 German cancer centers between 2003 and 2020. Researchers used standardized questionnaires to garner the women’s reproductive histories.

A matched control group of 2,175 participants who did not have a history of CRC was randomly selected from population registries. All analyses were adjusted for known CRC risk factors, such as age; body mass index; education level; family history; having previously undergone large-bowel endoscopy; diabetes; and smoking status.

The researchers found that each pregnancy was associated with a small but significant 9% reduction in CRC risk (odds ratio, 0.91), specifically in the proximal colon (OR, 0.86).

Overall, breastfeeding for a year or longer was associated with a significantly lower CRC risk, compared with never breastfeeding (OR, 0.74), but the results were only significant for the proximal colon (OR, 0.58).

Oral contraceptive use for 9 years or longer was associated with a lower CRC risk (OR, 0.75) but was only significant for the distal colon (OR, 0.63). Hormone replacement therapy was associated with a lower risk of CRC irrespective of tumor location (OR, 0.76). And using both was linked to a 42% CRC risk reduction (OR, 0.58).

Although age at menarche was not associated with CRC risk, menopause at age 50 or older was associated with a significant 17% lower risk of CRC.

In an email interview, lead author Tobias Niedermaier, PhD, expressed surprise at two of the findings. The first was the small association between pregnancies and CRC risk, “despite the strong increase in estrogen levels during pregnancy,” he said. He speculated that pregnancy-related increases in insulin levels may have “largely offset the protection effects of estrogen exposure during pregnancy.”

The second surprise was that the age at menarche did not have a bearing on CRC risk, which could be because “exposure to estrogen levels in younger ages [is] less relevant with respect to CRC risk, because CRC typically develops at comparably old age.”

John Marshall, MD, who was not involved in the research, commented that such studies “put a lot of pressure on people to perform in a certain way to modify their personal risk of something.” However, “we would not recommend people alter their life choices for reproduction for this,” said Dr. Marshall, chief of the Division of Hematology/Oncology at Georgetown University, Washington, D.C.

Dr. Niedermaier agreed that “while this knowledge will certainly not change a woman’s decision on family planning,” he noted that the findings “could influence current CRC screening strategies, for example, by risk-adapted screening intervals [and] start and stop ages of screening.”

Dr. Niedermaier and colleagues’ work was funded by the German Research Council, the German Federal Ministry of Education and Research, and the Interdisciplinary Research Program of the National Center for Tumor Diseases. Dr. Niedermaier has disclosed no relevant financial relationships. Dr. Marshall writes a column that appears regularly on Medscape: Marshall on Oncology. He has served as speaker or member of a speakers’ bureau for Genentech, Amgen, Bayer, Celgene Corporation, and Caris Life Sciences.

A version of this article first appeared on Medscape.com.

Estrogen exposure helps protect against colorectal cancer (CRC), and in some instances, the protection is site specific, a new analysis finds.

In a 17-year study involving almost 5,000 women, researchers from Germany found that hormone replacement therapy, oral contraceptive use, pregnancy, breastfeeding, and menopause at age 50 or older were all significantly associated with reductions in CRC risk.

Interestingly, the reduced risk of CRC observed for pregnancy and breastfeeding only applied to proximal colon cancer, while the association with oral contraceptive use was confined to the distal colon and rectum.

The results were published online in JNCI Cancer Spectrum.

CRC is the second most common cause of cancer death. It is responsible for more than one million deaths globally, according to the latest figures from the Global Burden of Disease 2019 Cancer Collaboration.

And sex seems to make a difference. The Global Burden analysis, echoing previous data, found that CRC is less common among women and that fewer women die from the disease.

Little, however, is known about the mechanisms of estrogen signaling in CRC or the impact of reproductive factors on CRC, despite a large amount of literature linking CRC risk to exogenous estrogens, such as hormone replacement therapy and oral contraceptives.

In the current analysis, the team recruited 2,650 patients with CRC from 20 German cancer centers between 2003 and 2020. Researchers used standardized questionnaires to garner the women’s reproductive histories.

A matched control group of 2,175 participants who did not have a history of CRC was randomly selected from population registries. All analyses were adjusted for known CRC risk factors, such as age; body mass index; education level; family history; having previously undergone large-bowel endoscopy; diabetes; and smoking status.

The researchers found that each pregnancy was associated with a small but significant 9% reduction in CRC risk (odds ratio, 0.91), specifically in the proximal colon (OR, 0.86).

Overall, breastfeeding for a year or longer was associated with a significantly lower CRC risk, compared with never breastfeeding (OR, 0.74), but the results were only significant for the proximal colon (OR, 0.58).

Oral contraceptive use for 9 years or longer was associated with a lower CRC risk (OR, 0.75) but was only significant for the distal colon (OR, 0.63). Hormone replacement therapy was associated with a lower risk of CRC irrespective of tumor location (OR, 0.76). And using both was linked to a 42% CRC risk reduction (OR, 0.58).

Although age at menarche was not associated with CRC risk, menopause at age 50 or older was associated with a significant 17% lower risk of CRC.

In an email interview, lead author Tobias Niedermaier, PhD, expressed surprise at two of the findings. The first was the small association between pregnancies and CRC risk, “despite the strong increase in estrogen levels during pregnancy,” he said. He speculated that pregnancy-related increases in insulin levels may have “largely offset the protection effects of estrogen exposure during pregnancy.”

The second surprise was that the age at menarche did not have a bearing on CRC risk, which could be because “exposure to estrogen levels in younger ages [is] less relevant with respect to CRC risk, because CRC typically develops at comparably old age.”

John Marshall, MD, who was not involved in the research, commented that such studies “put a lot of pressure on people to perform in a certain way to modify their personal risk of something.” However, “we would not recommend people alter their life choices for reproduction for this,” said Dr. Marshall, chief of the Division of Hematology/Oncology at Georgetown University, Washington, D.C.

Dr. Niedermaier agreed that “while this knowledge will certainly not change a woman’s decision on family planning,” he noted that the findings “could influence current CRC screening strategies, for example, by risk-adapted screening intervals [and] start and stop ages of screening.”

Dr. Niedermaier and colleagues’ work was funded by the German Research Council, the German Federal Ministry of Education and Research, and the Interdisciplinary Research Program of the National Center for Tumor Diseases. Dr. Niedermaier has disclosed no relevant financial relationships. Dr. Marshall writes a column that appears regularly on Medscape: Marshall on Oncology. He has served as speaker or member of a speakers’ bureau for Genentech, Amgen, Bayer, Celgene Corporation, and Caris Life Sciences.

A version of this article first appeared on Medscape.com.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

A new study confirms the very high risk of hepatocellular carcinoma faced by patients with cirrhosis who have been cured of hepatitis C, a finding the researchers hope will encourage clinicians to communicate risk information to patients and encourage regular HCC screening.

On average, the predicted probability of HCC in cirrhosis patients was 410 times greater than the equivalent probability in the general population, the study team found.

“As the prospect of HCV elimination approaches, a key challenge to the clinical community is the management of those who are cured of HCV but have a residual risk of HCC,” Hamish Innes, PhD, with Public Health Scotland, Glasgow, and colleagues wrote.

“Central to this is ensuring that cured cirrhosis patients understand the risk of HCC and are provided with appropriate surveillance,” they added. 

“Most patients with cirrhosis do not adhere to HCC screening guidelines,” Nina Beri, MD, medical oncologist with New York University Perlmutter Cancer Center, who wasn’t involved in the study, said in an interview.

The “important” finding in this study “should be conveyed to patients, as this may help improve screening adherence rates,” Dr. Beri said.

The study was published online in the American Journal of Gastroenterology.
 

Findings may help promote screening uptake

Dr. Innes and colleagues compared the predicted probability of HCC in 1,803 Scottish adults (mean age, 50 years; 74% male) with cirrhosis and cured hepatitis C to the background risk in the general population of Scotland.

The mean predicted 3-year probability of HCC at the time of sustained viral response (SVR), determined using the aMAP prognostic model, was 3.64% (range, 0.012%-36.12%).

This contrasts with a 3-year HCC probability in the general population ranging from less than 0.0001% to 0.25% depending on demographics.

All patients with cirrhosis – even those at lowest risk – had a higher probability of HCC than the general population, but there was considerable heterogeneity from one patient to the next.

For example, the mean 3-year predicted probability was 18 times higher in the top quintile (9.8%) versus the lowest quintile (0.5%) of risk, the researchers found.

They could not identify a patient subgroup who exhibited a similar HCC risk profile to the general population, as was their hope going into the study.

Dr. Innes and colleagues have developed an online tool that allows clinicians to frame a patient›s 3-year HCC probability against the equivalent probability in the general population.

In the future, they said the scope of the tool could be extended by incorporating general population data from countries beyond Scotland.

“Our hope is that this tool will springboard patient-clinician discussions about HCC risk, and could mitigate low screening uptake,” Dr. Innes and colleagues wrote.
 

Curing HCV doesn’t eliminate risk

Commenting on the study, Nancy Reau, MD, section chief of hepatology at Rush University Medical Center, Chicago, said curing HCV is “very important and significantly reduces risk for complications, but it doesn’t return you to the normal population.”

Dr. Reau’s advice to cirrhosis patients: “Get screened twice a year.”

Dr. Beri said, in addition to conveying this risk to patients, “it is also important to disseminate this information to the community and to primary care practices, particularly as some patients may not currently follow in a specialized liver disease clinic.”

Also weighing in, Amit Singal, MD, chief of hepatology at the University of Texas Southwestern Medical Center, Dallas, said this study highlights that underlying cirrhosis is “the strongest risk factor for the development of HCC.”

In contrast to other cancers, such as breast and colorectal cancer, in which high risk populations can be identified by readily available information such as age and sex, implementation of HCC screening programs requires identification of patients with cirrhosis, Dr. Singal noted.

“Underuse of HCC screening in clinical practice is often related to providers having difficulty at this step in the process and contributes to the high proportion of HCC detected at late stages,” he told this news organization.

“Availability of accurate noninvasive markers of fibrosis will hopefully help with better identification of patients with cirrhosis moving forward,” Dr. Singal said, “although we as hepatologists need to work closely with our primary care colleagues to ensure these tools are used routinely in at-risk patients, such as those with nonalcoholic fatty liver disease, alcohol-associated liver disease, or history of cured (post-SVR) hepatitis C infection.”

The study was supported by the Medical Research Foundation and Public Health Scotland. Dr. Innes, Dr. Beri, Dr. Reau, and Dr. Singal reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study confirms the very high risk of hepatocellular carcinoma faced by patients with cirrhosis who have been cured of hepatitis C, a finding the researchers hope will encourage clinicians to communicate risk information to patients and encourage regular HCC screening.

On average, the predicted probability of HCC in cirrhosis patients was 410 times greater than the equivalent probability in the general population, the study team found.

“As the prospect of HCV elimination approaches, a key challenge to the clinical community is the management of those who are cured of HCV but have a residual risk of HCC,” Hamish Innes, PhD, with Public Health Scotland, Glasgow, and colleagues wrote.

“Central to this is ensuring that cured cirrhosis patients understand the risk of HCC and are provided with appropriate surveillance,” they added. 

“Most patients with cirrhosis do not adhere to HCC screening guidelines,” Nina Beri, MD, medical oncologist with New York University Perlmutter Cancer Center, who wasn’t involved in the study, said in an interview.

The “important” finding in this study “should be conveyed to patients, as this may help improve screening adherence rates,” Dr. Beri said.

The study was published online in the American Journal of Gastroenterology.
 

Findings may help promote screening uptake

Dr. Innes and colleagues compared the predicted probability of HCC in 1,803 Scottish adults (mean age, 50 years; 74% male) with cirrhosis and cured hepatitis C to the background risk in the general population of Scotland.

The mean predicted 3-year probability of HCC at the time of sustained viral response (SVR), determined using the aMAP prognostic model, was 3.64% (range, 0.012%-36.12%).

This contrasts with a 3-year HCC probability in the general population ranging from less than 0.0001% to 0.25% depending on demographics.

All patients with cirrhosis – even those at lowest risk – had a higher probability of HCC than the general population, but there was considerable heterogeneity from one patient to the next.

For example, the mean 3-year predicted probability was 18 times higher in the top quintile (9.8%) versus the lowest quintile (0.5%) of risk, the researchers found.

They could not identify a patient subgroup who exhibited a similar HCC risk profile to the general population, as was their hope going into the study.

Dr. Innes and colleagues have developed an online tool that allows clinicians to frame a patient›s 3-year HCC probability against the equivalent probability in the general population.

In the future, they said the scope of the tool could be extended by incorporating general population data from countries beyond Scotland.

“Our hope is that this tool will springboard patient-clinician discussions about HCC risk, and could mitigate low screening uptake,” Dr. Innes and colleagues wrote.
 

Curing HCV doesn’t eliminate risk

Commenting on the study, Nancy Reau, MD, section chief of hepatology at Rush University Medical Center, Chicago, said curing HCV is “very important and significantly reduces risk for complications, but it doesn’t return you to the normal population.”

Dr. Reau’s advice to cirrhosis patients: “Get screened twice a year.”

Dr. Beri said, in addition to conveying this risk to patients, “it is also important to disseminate this information to the community and to primary care practices, particularly as some patients may not currently follow in a specialized liver disease clinic.”

Also weighing in, Amit Singal, MD, chief of hepatology at the University of Texas Southwestern Medical Center, Dallas, said this study highlights that underlying cirrhosis is “the strongest risk factor for the development of HCC.”

In contrast to other cancers, such as breast and colorectal cancer, in which high risk populations can be identified by readily available information such as age and sex, implementation of HCC screening programs requires identification of patients with cirrhosis, Dr. Singal noted.

“Underuse of HCC screening in clinical practice is often related to providers having difficulty at this step in the process and contributes to the high proportion of HCC detected at late stages,” he told this news organization.

“Availability of accurate noninvasive markers of fibrosis will hopefully help with better identification of patients with cirrhosis moving forward,” Dr. Singal said, “although we as hepatologists need to work closely with our primary care colleagues to ensure these tools are used routinely in at-risk patients, such as those with nonalcoholic fatty liver disease, alcohol-associated liver disease, or history of cured (post-SVR) hepatitis C infection.”

The study was supported by the Medical Research Foundation and Public Health Scotland. Dr. Innes, Dr. Beri, Dr. Reau, and Dr. Singal reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study confirms the very high risk of hepatocellular carcinoma faced by patients with cirrhosis who have been cured of hepatitis C, a finding the researchers hope will encourage clinicians to communicate risk information to patients and encourage regular HCC screening.

On average, the predicted probability of HCC in cirrhosis patients was 410 times greater than the equivalent probability in the general population, the study team found.

“As the prospect of HCV elimination approaches, a key challenge to the clinical community is the management of those who are cured of HCV but have a residual risk of HCC,” Hamish Innes, PhD, with Public Health Scotland, Glasgow, and colleagues wrote.

“Central to this is ensuring that cured cirrhosis patients understand the risk of HCC and are provided with appropriate surveillance,” they added. 

“Most patients with cirrhosis do not adhere to HCC screening guidelines,” Nina Beri, MD, medical oncologist with New York University Perlmutter Cancer Center, who wasn’t involved in the study, said in an interview.

The “important” finding in this study “should be conveyed to patients, as this may help improve screening adherence rates,” Dr. Beri said.

The study was published online in the American Journal of Gastroenterology.
 

Findings may help promote screening uptake

Dr. Innes and colleagues compared the predicted probability of HCC in 1,803 Scottish adults (mean age, 50 years; 74% male) with cirrhosis and cured hepatitis C to the background risk in the general population of Scotland.

The mean predicted 3-year probability of HCC at the time of sustained viral response (SVR), determined using the aMAP prognostic model, was 3.64% (range, 0.012%-36.12%).

This contrasts with a 3-year HCC probability in the general population ranging from less than 0.0001% to 0.25% depending on demographics.

All patients with cirrhosis – even those at lowest risk – had a higher probability of HCC than the general population, but there was considerable heterogeneity from one patient to the next.

For example, the mean 3-year predicted probability was 18 times higher in the top quintile (9.8%) versus the lowest quintile (0.5%) of risk, the researchers found.

They could not identify a patient subgroup who exhibited a similar HCC risk profile to the general population, as was their hope going into the study.

Dr. Innes and colleagues have developed an online tool that allows clinicians to frame a patient›s 3-year HCC probability against the equivalent probability in the general population.

In the future, they said the scope of the tool could be extended by incorporating general population data from countries beyond Scotland.

“Our hope is that this tool will springboard patient-clinician discussions about HCC risk, and could mitigate low screening uptake,” Dr. Innes and colleagues wrote.
 

Curing HCV doesn’t eliminate risk

Commenting on the study, Nancy Reau, MD, section chief of hepatology at Rush University Medical Center, Chicago, said curing HCV is “very important and significantly reduces risk for complications, but it doesn’t return you to the normal population.”

Dr. Reau’s advice to cirrhosis patients: “Get screened twice a year.”

Dr. Beri said, in addition to conveying this risk to patients, “it is also important to disseminate this information to the community and to primary care practices, particularly as some patients may not currently follow in a specialized liver disease clinic.”

Also weighing in, Amit Singal, MD, chief of hepatology at the University of Texas Southwestern Medical Center, Dallas, said this study highlights that underlying cirrhosis is “the strongest risk factor for the development of HCC.”

In contrast to other cancers, such as breast and colorectal cancer, in which high risk populations can be identified by readily available information such as age and sex, implementation of HCC screening programs requires identification of patients with cirrhosis, Dr. Singal noted.

“Underuse of HCC screening in clinical practice is often related to providers having difficulty at this step in the process and contributes to the high proportion of HCC detected at late stages,” he told this news organization.

“Availability of accurate noninvasive markers of fibrosis will hopefully help with better identification of patients with cirrhosis moving forward,” Dr. Singal said, “although we as hepatologists need to work closely with our primary care colleagues to ensure these tools are used routinely in at-risk patients, such as those with nonalcoholic fatty liver disease, alcohol-associated liver disease, or history of cured (post-SVR) hepatitis C infection.”

The study was supported by the Medical Research Foundation and Public Health Scotland. Dr. Innes, Dr. Beri, Dr. Reau, and Dr. Singal reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Based on biomarker findings, some patients may be able to avoid radiation therapy following breast-conserving surgery, suggest results from the LUMINA trial.

The women in this trial who skipped radiotherapy, and were treated with breast-conserving surgery followed by endocrine therapy, had an overall survival rate of 97.2%. The local recurrence rate was 2.3%, which was the study’s primary endpoint.

“Women 55 and over, with low-grade luminal A-type breast cancer, following breast conserving surgery and treated with endocrine therapy alone, had a very low rate of local recurrence at 5 years,” commented lead author Timothy Joseph Whelan, MD.

“The prospective and multicenter nature of this study supports that these patients are candidates for the omission of radiotherapy,” said Dr. Whelan, oncology professor and Canada Research Chair in Breast Cancer Research at McMaster University and a radiation oncologist at the Juravinski Cancer Centre, both in Hamilton, Ont.

“Over 300,000 [people] are diagnosed with invasive breast cancer in North America annually, the majority in the United States,” said Dr. Whelan. “We estimate that these results could apply to 10%-15% of them, so about 30,000-40,000 women per year who could avoid the morbidity, the cost, and inconvenience of radiotherapy.”

The results were presented at the annual meeting of the American Society of Clinical Oncology.

Dr. Whelan explained that adjuvant radiation therapy is generally prescribed following breast conservation therapy to lower the risk of local recurrence, but the treatment is also associated with acute and late toxicity. In addition, it can incur high costs and inconvenience for the patient.

Previous studies have found that among women older than 60 with low-grade, luminal A-type breast cancer who received only breast-conserving surgery, there was a low rate of local recurrence. In women aged older than 70 years, the risk of local recurrence was about 4%-5%.

This latest study focused on patients with breast cancer with a luminal A subtype combined with clinical pathological factors (defined as estrogen receptor ≥ 1%, progesterone receptor > 20%, HER2 negative, and Ki67 ≤ 13.25%).

This was a prospective, multicenter cohort study that included 501 patients aged 55 years and older who had undergone breast-conserving surgery for grade 1-2 T1N0 cancer.

The median patient age was 67, with 442 (88%) older than 75 years. The median tumor size was 1.1 cm.

Median follow-up was 5 years. The cohort was followed every 6 months for the first 2 years and then annually.

The primary outcome was local recurrence defined as time from enrollment to any invasive or noninvasive cancer in the ipsilateral breast, and secondary endpoints included contralateral breast cancer, relapse-free survival based on any recurrence, disease free survival, second cancer or death, and overall survival.

At five years, there were 10 events of local recurrence, for a rate of 2.3%. For secondary outcomes, there were eight events of contralateral breast cancer (1.9%); 12 relapses for a recurrence-free survival rate of 97.3%; 47 disease progression (23 second nonbreast cancers) for a disease-free survival rate of 89.9%; and 13 deaths, including 1 from breast cancer, for an overall survival of 97.2%.
 

Confirms earlier data

Penny R. Anderson, MD, professor in the department of radiation oncology at Fox Chase Cancer Center, Philadelphia, commented that this was an “extremely well-designed and important study.

“It has identified a specific subset of patients to be appropriate candidates for consideration of omission of adjuvant breast radiation therapy after breast-conserving surgery,” she added.

Although previously published trials have helped identify certain patient groups who have a low risk of local recurrence – and therefore, for whom it may be appropriate to omit radiation – they have been based on the traditional clinical and pathologic factors of tumor size, margin status, receptor status, and patient age.

“This LUMINA trial utilizes the molecular-defined intrinsic subtype of luminal A breast cancer to provide additional prognostic information,” she said. “This finding certainly suggests that this group of patients are ideal candidates for the omission of radiation, and that this should be discussed with these patients as a potential option in their treatment management.”

Overall, this trial is a “significant addition and a very relevant contribution to the literature demonstrating that adjuvant breast radiation may safely be omitted in this particular subgroup of breast cancer patients,” she said.
 

Unanswered questions

Commenting on the study, Julie Gralow, MD, chief medical officer and executive vice president of ASCO, told this news organization that she thinks the take-home message is that there is “clearly a population of early-stage breast cancer [patients] who after lumpectomy do not benefit from radiation.”

“I think where there will be discussion will be what is the optimal way of identifying that group,” she said, noting that in this study the patients were screened for Ki67, a marker of proliferation. 

Testing for Ki67 is not the standard of care, Dr. Gralow pointed out, and there is also a problem with reproducibility since “every lab does it somewhat differently, because it is not a standard pathology approach.”

There are now many unanswered questions, she noted. “Do we need that central testing of Ki67? Do we need to develop guidelines for how to do this? Is this better than if you’ve already run an Oncotype or a MammaPrint test to see if the patient needs chemo, then would that suffice? That is where the discussion will be. We can reduce the number of patients who need radiation without an increase in local regional recurrence.”

In terms of clinical practice, Dr. Gralow explained that there are already some  data supporting the omission of radiation therapy in an older population with ER-positive small low-grade tumors, and this has become a standard clinical practice. “It’s not based on solid data, but based on an accumulation of retrospective analyses,” she said. “So we have already been doing it for an older population. This would bring down the age group, and it would better define it, and test it prospectively.”
 

Limitations to note

Also commenting on the study, Deborah Axelrod, MD, director of clinical breast surgery at New York University Langone’s Perlmutter Cancer Center, explained that, in the last decade, knowledge about the behavior of breast cancers based on molecular subtyping has greatly increased. “Results of studies such as this have given us information on which cancers need more treatment and for which cancers we can de-escalate treatment,” she said. “Refining this more, it’s about reducing the morbidity and improving quality of life without compromising the oncological outcome.”

She noted that a big strength of this LUMINA study is that it is prospective and multicenter. “It has been supported by other past studies as well and will define for which patients with newly treated breast cancers can we omit radiation, which has been the standard of care,” said Dr. Axelrod. “It is based on the age and biology of breast cancer in defining which patient can forgo radiation and showed a low risk of recurrence in a specific population of women with a favorable breast cancer profile”

There were limitations to the study. “There is a 5-year follow-up and local recurrence for ER-positive cancers continues to rise after 5 years, so longer-term follow-up will be important,” she said. Also, she pointed out that it is a single-arm study so there is no radiation therapy comparison arm.

Other limitations were that the patients were older with smaller tumors, and all were committed to 5 years of endocrine therapy, although compliance with that has not been reported. There may be some older patients who prefer radiation therapy, especially a week of accelerated partial breast irradiation, rather than commit to 5 years of endocrine therapy as mandated in this study.

“Overall, the takeaway message for patients is that the omission of radiation therapy should be considered an option for older women with localized breast cancer with favorable features who receive endocrine therapies,” said Dr. Axelrod.

LUMINA was sponsored by the Canadian Breast Cancer Foundation and the Canadian Cancer Society. Dr. Whelan has reported research funding from Exact Sciences (Inst). Dr. Axelrod and Dr. Anderson reported no disclosures. Dr. Gralow reported relationships with Genentech, AstraZeneca, Hexal, Puma BioTechnology, Roche, Novartis, Seagen, and Genomic Health.

A version of this article first appeared on Medscape.com.

Based on biomarker findings, some patients may be able to avoid radiation therapy following breast-conserving surgery, suggest results from the LUMINA trial.

The women in this trial who skipped radiotherapy, and were treated with breast-conserving surgery followed by endocrine therapy, had an overall survival rate of 97.2%. The local recurrence rate was 2.3%, which was the study’s primary endpoint.

“Women 55 and over, with low-grade luminal A-type breast cancer, following breast conserving surgery and treated with endocrine therapy alone, had a very low rate of local recurrence at 5 years,” commented lead author Timothy Joseph Whelan, MD.

“The prospective and multicenter nature of this study supports that these patients are candidates for the omission of radiotherapy,” said Dr. Whelan, oncology professor and Canada Research Chair in Breast Cancer Research at McMaster University and a radiation oncologist at the Juravinski Cancer Centre, both in Hamilton, Ont.

“Over 300,000 [people] are diagnosed with invasive breast cancer in North America annually, the majority in the United States,” said Dr. Whelan. “We estimate that these results could apply to 10%-15% of them, so about 30,000-40,000 women per year who could avoid the morbidity, the cost, and inconvenience of radiotherapy.”

The results were presented at the annual meeting of the American Society of Clinical Oncology.

Dr. Whelan explained that adjuvant radiation therapy is generally prescribed following breast conservation therapy to lower the risk of local recurrence, but the treatment is also associated with acute and late toxicity. In addition, it can incur high costs and inconvenience for the patient.

Previous studies have found that among women older than 60 with low-grade, luminal A-type breast cancer who received only breast-conserving surgery, there was a low rate of local recurrence. In women aged older than 70 years, the risk of local recurrence was about 4%-5%.

This latest study focused on patients with breast cancer with a luminal A subtype combined with clinical pathological factors (defined as estrogen receptor ≥ 1%, progesterone receptor > 20%, HER2 negative, and Ki67 ≤ 13.25%).

This was a prospective, multicenter cohort study that included 501 patients aged 55 years and older who had undergone breast-conserving surgery for grade 1-2 T1N0 cancer.

The median patient age was 67, with 442 (88%) older than 75 years. The median tumor size was 1.1 cm.

Median follow-up was 5 years. The cohort was followed every 6 months for the first 2 years and then annually.

The primary outcome was local recurrence defined as time from enrollment to any invasive or noninvasive cancer in the ipsilateral breast, and secondary endpoints included contralateral breast cancer, relapse-free survival based on any recurrence, disease free survival, second cancer or death, and overall survival.

At five years, there were 10 events of local recurrence, for a rate of 2.3%. For secondary outcomes, there were eight events of contralateral breast cancer (1.9%); 12 relapses for a recurrence-free survival rate of 97.3%; 47 disease progression (23 second nonbreast cancers) for a disease-free survival rate of 89.9%; and 13 deaths, including 1 from breast cancer, for an overall survival of 97.2%.
 

Confirms earlier data

Penny R. Anderson, MD, professor in the department of radiation oncology at Fox Chase Cancer Center, Philadelphia, commented that this was an “extremely well-designed and important study.

“It has identified a specific subset of patients to be appropriate candidates for consideration of omission of adjuvant breast radiation therapy after breast-conserving surgery,” she added.

Although previously published trials have helped identify certain patient groups who have a low risk of local recurrence – and therefore, for whom it may be appropriate to omit radiation – they have been based on the traditional clinical and pathologic factors of tumor size, margin status, receptor status, and patient age.

“This LUMINA trial utilizes the molecular-defined intrinsic subtype of luminal A breast cancer to provide additional prognostic information,” she said. “This finding certainly suggests that this group of patients are ideal candidates for the omission of radiation, and that this should be discussed with these patients as a potential option in their treatment management.”

Overall, this trial is a “significant addition and a very relevant contribution to the literature demonstrating that adjuvant breast radiation may safely be omitted in this particular subgroup of breast cancer patients,” she said.
 

Unanswered questions

Commenting on the study, Julie Gralow, MD, chief medical officer and executive vice president of ASCO, told this news organization that she thinks the take-home message is that there is “clearly a population of early-stage breast cancer [patients] who after lumpectomy do not benefit from radiation.”

“I think where there will be discussion will be what is the optimal way of identifying that group,” she said, noting that in this study the patients were screened for Ki67, a marker of proliferation. 

Testing for Ki67 is not the standard of care, Dr. Gralow pointed out, and there is also a problem with reproducibility since “every lab does it somewhat differently, because it is not a standard pathology approach.”

There are now many unanswered questions, she noted. “Do we need that central testing of Ki67? Do we need to develop guidelines for how to do this? Is this better than if you’ve already run an Oncotype or a MammaPrint test to see if the patient needs chemo, then would that suffice? That is where the discussion will be. We can reduce the number of patients who need radiation without an increase in local regional recurrence.”

In terms of clinical practice, Dr. Gralow explained that there are already some  data supporting the omission of radiation therapy in an older population with ER-positive small low-grade tumors, and this has become a standard clinical practice. “It’s not based on solid data, but based on an accumulation of retrospective analyses,” she said. “So we have already been doing it for an older population. This would bring down the age group, and it would better define it, and test it prospectively.”
 

Limitations to note

Also commenting on the study, Deborah Axelrod, MD, director of clinical breast surgery at New York University Langone’s Perlmutter Cancer Center, explained that, in the last decade, knowledge about the behavior of breast cancers based on molecular subtyping has greatly increased. “Results of studies such as this have given us information on which cancers need more treatment and for which cancers we can de-escalate treatment,” she said. “Refining this more, it’s about reducing the morbidity and improving quality of life without compromising the oncological outcome.”

She noted that a big strength of this LUMINA study is that it is prospective and multicenter. “It has been supported by other past studies as well and will define for which patients with newly treated breast cancers can we omit radiation, which has been the standard of care,” said Dr. Axelrod. “It is based on the age and biology of breast cancer in defining which patient can forgo radiation and showed a low risk of recurrence in a specific population of women with a favorable breast cancer profile”

There were limitations to the study. “There is a 5-year follow-up and local recurrence for ER-positive cancers continues to rise after 5 years, so longer-term follow-up will be important,” she said. Also, she pointed out that it is a single-arm study so there is no radiation therapy comparison arm.

Other limitations were that the patients were older with smaller tumors, and all were committed to 5 years of endocrine therapy, although compliance with that has not been reported. There may be some older patients who prefer radiation therapy, especially a week of accelerated partial breast irradiation, rather than commit to 5 years of endocrine therapy as mandated in this study.

“Overall, the takeaway message for patients is that the omission of radiation therapy should be considered an option for older women with localized breast cancer with favorable features who receive endocrine therapies,” said Dr. Axelrod.

LUMINA was sponsored by the Canadian Breast Cancer Foundation and the Canadian Cancer Society. Dr. Whelan has reported research funding from Exact Sciences (Inst). Dr. Axelrod and Dr. Anderson reported no disclosures. Dr. Gralow reported relationships with Genentech, AstraZeneca, Hexal, Puma BioTechnology, Roche, Novartis, Seagen, and Genomic Health.

A version of this article first appeared on Medscape.com.

Based on biomarker findings, some patients may be able to avoid radiation therapy following breast-conserving surgery, suggest results from the LUMINA trial.

The women in this trial who skipped radiotherapy, and were treated with breast-conserving surgery followed by endocrine therapy, had an overall survival rate of 97.2%. The local recurrence rate was 2.3%, which was the study’s primary endpoint.

“Women 55 and over, with low-grade luminal A-type breast cancer, following breast conserving surgery and treated with endocrine therapy alone, had a very low rate of local recurrence at 5 years,” commented lead author Timothy Joseph Whelan, MD.

“The prospective and multicenter nature of this study supports that these patients are candidates for the omission of radiotherapy,” said Dr. Whelan, oncology professor and Canada Research Chair in Breast Cancer Research at McMaster University and a radiation oncologist at the Juravinski Cancer Centre, both in Hamilton, Ont.

“Over 300,000 [people] are diagnosed with invasive breast cancer in North America annually, the majority in the United States,” said Dr. Whelan. “We estimate that these results could apply to 10%-15% of them, so about 30,000-40,000 women per year who could avoid the morbidity, the cost, and inconvenience of radiotherapy.”

The results were presented at the annual meeting of the American Society of Clinical Oncology.

Dr. Whelan explained that adjuvant radiation therapy is generally prescribed following breast conservation therapy to lower the risk of local recurrence, but the treatment is also associated with acute and late toxicity. In addition, it can incur high costs and inconvenience for the patient.

Previous studies have found that among women older than 60 with low-grade, luminal A-type breast cancer who received only breast-conserving surgery, there was a low rate of local recurrence. In women aged older than 70 years, the risk of local recurrence was about 4%-5%.

This latest study focused on patients with breast cancer with a luminal A subtype combined with clinical pathological factors (defined as estrogen receptor ≥ 1%, progesterone receptor > 20%, HER2 negative, and Ki67 ≤ 13.25%).

This was a prospective, multicenter cohort study that included 501 patients aged 55 years and older who had undergone breast-conserving surgery for grade 1-2 T1N0 cancer.

The median patient age was 67, with 442 (88%) older than 75 years. The median tumor size was 1.1 cm.

Median follow-up was 5 years. The cohort was followed every 6 months for the first 2 years and then annually.

The primary outcome was local recurrence defined as time from enrollment to any invasive or noninvasive cancer in the ipsilateral breast, and secondary endpoints included contralateral breast cancer, relapse-free survival based on any recurrence, disease free survival, second cancer or death, and overall survival.

At five years, there were 10 events of local recurrence, for a rate of 2.3%. For secondary outcomes, there were eight events of contralateral breast cancer (1.9%); 12 relapses for a recurrence-free survival rate of 97.3%; 47 disease progression (23 second nonbreast cancers) for a disease-free survival rate of 89.9%; and 13 deaths, including 1 from breast cancer, for an overall survival of 97.2%.
 

Confirms earlier data

Penny R. Anderson, MD, professor in the department of radiation oncology at Fox Chase Cancer Center, Philadelphia, commented that this was an “extremely well-designed and important study.

“It has identified a specific subset of patients to be appropriate candidates for consideration of omission of adjuvant breast radiation therapy after breast-conserving surgery,” she added.

Although previously published trials have helped identify certain patient groups who have a low risk of local recurrence – and therefore, for whom it may be appropriate to omit radiation – they have been based on the traditional clinical and pathologic factors of tumor size, margin status, receptor status, and patient age.

“This LUMINA trial utilizes the molecular-defined intrinsic subtype of luminal A breast cancer to provide additional prognostic information,” she said. “This finding certainly suggests that this group of patients are ideal candidates for the omission of radiation, and that this should be discussed with these patients as a potential option in their treatment management.”

Overall, this trial is a “significant addition and a very relevant contribution to the literature demonstrating that adjuvant breast radiation may safely be omitted in this particular subgroup of breast cancer patients,” she said.
 

Unanswered questions

Commenting on the study, Julie Gralow, MD, chief medical officer and executive vice president of ASCO, told this news organization that she thinks the take-home message is that there is “clearly a population of early-stage breast cancer [patients] who after lumpectomy do not benefit from radiation.”

“I think where there will be discussion will be what is the optimal way of identifying that group,” she said, noting that in this study the patients were screened for Ki67, a marker of proliferation. 

Testing for Ki67 is not the standard of care, Dr. Gralow pointed out, and there is also a problem with reproducibility since “every lab does it somewhat differently, because it is not a standard pathology approach.”

There are now many unanswered questions, she noted. “Do we need that central testing of Ki67? Do we need to develop guidelines for how to do this? Is this better than if you’ve already run an Oncotype or a MammaPrint test to see if the patient needs chemo, then would that suffice? That is where the discussion will be. We can reduce the number of patients who need radiation without an increase in local regional recurrence.”

In terms of clinical practice, Dr. Gralow explained that there are already some  data supporting the omission of radiation therapy in an older population with ER-positive small low-grade tumors, and this has become a standard clinical practice. “It’s not based on solid data, but based on an accumulation of retrospective analyses,” she said. “So we have already been doing it for an older population. This would bring down the age group, and it would better define it, and test it prospectively.”
 

Limitations to note

Also commenting on the study, Deborah Axelrod, MD, director of clinical breast surgery at New York University Langone’s Perlmutter Cancer Center, explained that, in the last decade, knowledge about the behavior of breast cancers based on molecular subtyping has greatly increased. “Results of studies such as this have given us information on which cancers need more treatment and for which cancers we can de-escalate treatment,” she said. “Refining this more, it’s about reducing the morbidity and improving quality of life without compromising the oncological outcome.”

She noted that a big strength of this LUMINA study is that it is prospective and multicenter. “It has been supported by other past studies as well and will define for which patients with newly treated breast cancers can we omit radiation, which has been the standard of care,” said Dr. Axelrod. “It is based on the age and biology of breast cancer in defining which patient can forgo radiation and showed a low risk of recurrence in a specific population of women with a favorable breast cancer profile”

There were limitations to the study. “There is a 5-year follow-up and local recurrence for ER-positive cancers continues to rise after 5 years, so longer-term follow-up will be important,” she said. Also, she pointed out that it is a single-arm study so there is no radiation therapy comparison arm.

Other limitations were that the patients were older with smaller tumors, and all were committed to 5 years of endocrine therapy, although compliance with that has not been reported. There may be some older patients who prefer radiation therapy, especially a week of accelerated partial breast irradiation, rather than commit to 5 years of endocrine therapy as mandated in this study.

“Overall, the takeaway message for patients is that the omission of radiation therapy should be considered an option for older women with localized breast cancer with favorable features who receive endocrine therapies,” said Dr. Axelrod.

LUMINA was sponsored by the Canadian Breast Cancer Foundation and the Canadian Cancer Society. Dr. Whelan has reported research funding from Exact Sciences (Inst). Dr. Axelrod and Dr. Anderson reported no disclosures. Dr. Gralow reported relationships with Genentech, AstraZeneca, Hexal, Puma BioTechnology, Roche, Novartis, Seagen, and Genomic Health.

A version of this article first appeared on Medscape.com.