AVAHO

After a long day in hematology clinic, I skimmed the inpatient list to see if any of my patients had been admitted. Seeing Ms. Short’s name (changed for privacy), a delightful African American woman I met during my early days of fellowship, had me making the trek to the hospital. She was living with multiple myeloma complicated by extramedullary manifestations that had significantly impacted her quality of life.

During our first encounter, she showed me a growing left subscapular mass the size of an orange that was erythematous, hot, painful, and irritated. As an enthusiastic first-year fellow, I wanted to be aggressive in addressing her concerns in response to her obvious distress about this mass. Ultimately, she left clinic with antibiotics and an appointment with radiation oncology to see if they could use radiation to shrink the subscapular mass.

When I went back in to discuss the plan with her, she grabbed my hand, looked me in my eyes and said: “Thank you, I’ve been mentioning this for a while and you’re the first person to get something done about it.” In that moment I knew that she felt seen.

By the time I made it over to the hospital, she was getting settled in her room to start another cycle of cytoreductive chemotherapy.

“I told them I had a Black doctor!” she exclaimed as I walked into her hospital room. “I was looking for you today in clinic ... I kept telling them I had a Black doctor, but the nurses kept telling me no, that there were only Black nurse practitioners.” She had repeatedly told the staff that I, her “Black doctor,” did indeed exist, and she went on to describe me as “you know, the [heavy-chested] and short Black doctor I saw early this fall.” To this day, her description still makes me chuckle.

Though I laughed at her description, it hurt that I had worked in a clinic for 6 months yet was invisible. Initially disappointed, I left Ms. Short’s room with a smile on my face, energized and encouraged.

My time with Ms. Short prompted me to ruminate on my experience as a Black physician. To put it in perspective, 5% of all physicians are Black, 2% are Black women, and 2.3% are oncologists, even though African Americans make up 13% of the general U.S. population. I reside in a space where I am simultaneously scrutinized because I am one of the few (or the only) Black physicians in the building, and yet I am invisible because my colleagues and coworkers routinely ignore my presence.

Black physicians, let alone hematologists, are so rare that nurses often cannot fathom that a Black woman could be more than a nurse practitioner. Sadly, this is the tip of the iceberg of some of the negative experiences I, and other Black doctors, have had.

How I present myself must be carefully curated to make progress in my career. My peers and superiors seem to hear me better when my hair is straight and not in its naturally curly state. My introversion has been interpreted as being standoffish or disinterested. Any tone other than happy is interpreted as “aggressive” or “angry”. Talking “too much” to Black support staff was reported to my program, as it was viewed as suspicious, disruptive, and “appearances matter”.

I am also expected to be nurturing in ways that White physicians are not required to be. In my presence, White physicians have denigrated an entire patient population that is disproportionately Black by calling them “sicklers.” If there is an interpersonal conflict, I must think about the long-term consequences of voicing my perspective. My non-Black colleagues do not have to think about these things.

Imagine dealing with this at work, then on your commute home being worried about the reality that you may be pulled over and become the next name on the ever-growing list of Black women and men murdered at the hands of police. The cognitive and emotional impact of being invisible is immense and cumulative over the years.

My Blackness creates a bias of inferiority that cannot be overcome by respectability, compliance, professionalism, training, and expertise. This is glaringly apparent on both sides of the physician-patient relationship. Black patients’ concerns are routinely overlooked and dismissed, as seen with Ms. Short, and are reflected in the Black maternal death rate, pain control in Black versus White patients, and personal experience as a patient and an advocate for my family members.

Patients have looked me in the face and said, “all lives matter,” displaying their refusal to recognize that systematic racism and inequality exist. These facts and experiences are the antithesis of “primum non nocere.”

Sadly, my and Ms. Short’s experiences are not singular ones, and racial bias in medicine is a diagnosed, but untreated cancer. Like the malignancies I treat, ignoring the problem has not made it go away; therefore, it continues to fester and spread, causing more destruction. It is of great importance and concern that all physicians recognize, reflect, and correct their implicit biases not only toward their patients, but also colleagues and trainees.

It seems that health care professionals can talk the talk, as many statements have been made against racism and implicit bias in medicine, but can we take true and meaningful action to begin the journey to equity and justice?

I would like to thank Adrienne Glover, MD, MaKenzie Hodge, MD, Maranatha McLean, MD, and Darion Showell, MD, for our stimulating conversations that helped me put pen to paper. I’d also like to thank my family for being my editors.

Daphanie D. Taylor, MD, is a hematology/oncology fellow PGY-6 at Levine Cancer Institute, Charlotte, N.C.

References and further reading

Roy L. “‘It’s My Calling To Change The Statistics’: Why We Need More Black Female Physicians.” Forbes Magazine, 27 Feb. 2020.

“Diversity in Medicine: Facts and Figures 2019.” Association of American Medical Colleges, 2019.

“Facts & Figures: Diversity in Oncology.” American Society of Clinical Oncology. 2020 Jan 16.

After a long day in hematology clinic, I skimmed the inpatient list to see if any of my patients had been admitted. Seeing Ms. Short’s name (changed for privacy), a delightful African American woman I met during my early days of fellowship, had me making the trek to the hospital. She was living with multiple myeloma complicated by extramedullary manifestations that had significantly impacted her quality of life.

During our first encounter, she showed me a growing left subscapular mass the size of an orange that was erythematous, hot, painful, and irritated. As an enthusiastic first-year fellow, I wanted to be aggressive in addressing her concerns in response to her obvious distress about this mass. Ultimately, she left clinic with antibiotics and an appointment with radiation oncology to see if they could use radiation to shrink the subscapular mass.

When I went back in to discuss the plan with her, she grabbed my hand, looked me in my eyes and said: “Thank you, I’ve been mentioning this for a while and you’re the first person to get something done about it.” In that moment I knew that she felt seen.

By the time I made it over to the hospital, she was getting settled in her room to start another cycle of cytoreductive chemotherapy.

“I told them I had a Black doctor!” she exclaimed as I walked into her hospital room. “I was looking for you today in clinic ... I kept telling them I had a Black doctor, but the nurses kept telling me no, that there were only Black nurse practitioners.” She had repeatedly told the staff that I, her “Black doctor,” did indeed exist, and she went on to describe me as “you know, the [heavy-chested] and short Black doctor I saw early this fall.” To this day, her description still makes me chuckle.

Though I laughed at her description, it hurt that I had worked in a clinic for 6 months yet was invisible. Initially disappointed, I left Ms. Short’s room with a smile on my face, energized and encouraged.

My time with Ms. Short prompted me to ruminate on my experience as a Black physician. To put it in perspective, 5% of all physicians are Black, 2% are Black women, and 2.3% are oncologists, even though African Americans make up 13% of the general U.S. population. I reside in a space where I am simultaneously scrutinized because I am one of the few (or the only) Black physicians in the building, and yet I am invisible because my colleagues and coworkers routinely ignore my presence.

Black physicians, let alone hematologists, are so rare that nurses often cannot fathom that a Black woman could be more than a nurse practitioner. Sadly, this is the tip of the iceberg of some of the negative experiences I, and other Black doctors, have had.

How I present myself must be carefully curated to make progress in my career. My peers and superiors seem to hear me better when my hair is straight and not in its naturally curly state. My introversion has been interpreted as being standoffish or disinterested. Any tone other than happy is interpreted as “aggressive” or “angry”. Talking “too much” to Black support staff was reported to my program, as it was viewed as suspicious, disruptive, and “appearances matter”.

I am also expected to be nurturing in ways that White physicians are not required to be. In my presence, White physicians have denigrated an entire patient population that is disproportionately Black by calling them “sicklers.” If there is an interpersonal conflict, I must think about the long-term consequences of voicing my perspective. My non-Black colleagues do not have to think about these things.

Imagine dealing with this at work, then on your commute home being worried about the reality that you may be pulled over and become the next name on the ever-growing list of Black women and men murdered at the hands of police. The cognitive and emotional impact of being invisible is immense and cumulative over the years.

My Blackness creates a bias of inferiority that cannot be overcome by respectability, compliance, professionalism, training, and expertise. This is glaringly apparent on both sides of the physician-patient relationship. Black patients’ concerns are routinely overlooked and dismissed, as seen with Ms. Short, and are reflected in the Black maternal death rate, pain control in Black versus White patients, and personal experience as a patient and an advocate for my family members.

Patients have looked me in the face and said, “all lives matter,” displaying their refusal to recognize that systematic racism and inequality exist. These facts and experiences are the antithesis of “primum non nocere.”

Sadly, my and Ms. Short’s experiences are not singular ones, and racial bias in medicine is a diagnosed, but untreated cancer. Like the malignancies I treat, ignoring the problem has not made it go away; therefore, it continues to fester and spread, causing more destruction. It is of great importance and concern that all physicians recognize, reflect, and correct their implicit biases not only toward their patients, but also colleagues and trainees.

It seems that health care professionals can talk the talk, as many statements have been made against racism and implicit bias in medicine, but can we take true and meaningful action to begin the journey to equity and justice?

I would like to thank Adrienne Glover, MD, MaKenzie Hodge, MD, Maranatha McLean, MD, and Darion Showell, MD, for our stimulating conversations that helped me put pen to paper. I’d also like to thank my family for being my editors.

Daphanie D. Taylor, MD, is a hematology/oncology fellow PGY-6 at Levine Cancer Institute, Charlotte, N.C.

References and further reading

Roy L. “‘It’s My Calling To Change The Statistics’: Why We Need More Black Female Physicians.” Forbes Magazine, 27 Feb. 2020.

“Diversity in Medicine: Facts and Figures 2019.” Association of American Medical Colleges, 2019.

“Facts & Figures: Diversity in Oncology.” American Society of Clinical Oncology. 2020 Jan 16.

After a long day in hematology clinic, I skimmed the inpatient list to see if any of my patients had been admitted. Seeing Ms. Short’s name (changed for privacy), a delightful African American woman I met during my early days of fellowship, had me making the trek to the hospital. She was living with multiple myeloma complicated by extramedullary manifestations that had significantly impacted her quality of life.

During our first encounter, she showed me a growing left subscapular mass the size of an orange that was erythematous, hot, painful, and irritated. As an enthusiastic first-year fellow, I wanted to be aggressive in addressing her concerns in response to her obvious distress about this mass. Ultimately, she left clinic with antibiotics and an appointment with radiation oncology to see if they could use radiation to shrink the subscapular mass.

When I went back in to discuss the plan with her, she grabbed my hand, looked me in my eyes and said: “Thank you, I’ve been mentioning this for a while and you’re the first person to get something done about it.” In that moment I knew that she felt seen.

By the time I made it over to the hospital, she was getting settled in her room to start another cycle of cytoreductive chemotherapy.

“I told them I had a Black doctor!” she exclaimed as I walked into her hospital room. “I was looking for you today in clinic ... I kept telling them I had a Black doctor, but the nurses kept telling me no, that there were only Black nurse practitioners.” She had repeatedly told the staff that I, her “Black doctor,” did indeed exist, and she went on to describe me as “you know, the [heavy-chested] and short Black doctor I saw early this fall.” To this day, her description still makes me chuckle.

Though I laughed at her description, it hurt that I had worked in a clinic for 6 months yet was invisible. Initially disappointed, I left Ms. Short’s room with a smile on my face, energized and encouraged.

My time with Ms. Short prompted me to ruminate on my experience as a Black physician. To put it in perspective, 5% of all physicians are Black, 2% are Black women, and 2.3% are oncologists, even though African Americans make up 13% of the general U.S. population. I reside in a space where I am simultaneously scrutinized because I am one of the few (or the only) Black physicians in the building, and yet I am invisible because my colleagues and coworkers routinely ignore my presence.

Black physicians, let alone hematologists, are so rare that nurses often cannot fathom that a Black woman could be more than a nurse practitioner. Sadly, this is the tip of the iceberg of some of the negative experiences I, and other Black doctors, have had.

How I present myself must be carefully curated to make progress in my career. My peers and superiors seem to hear me better when my hair is straight and not in its naturally curly state. My introversion has been interpreted as being standoffish or disinterested. Any tone other than happy is interpreted as “aggressive” or “angry”. Talking “too much” to Black support staff was reported to my program, as it was viewed as suspicious, disruptive, and “appearances matter”.

I am also expected to be nurturing in ways that White physicians are not required to be. In my presence, White physicians have denigrated an entire patient population that is disproportionately Black by calling them “sicklers.” If there is an interpersonal conflict, I must think about the long-term consequences of voicing my perspective. My non-Black colleagues do not have to think about these things.

Imagine dealing with this at work, then on your commute home being worried about the reality that you may be pulled over and become the next name on the ever-growing list of Black women and men murdered at the hands of police. The cognitive and emotional impact of being invisible is immense and cumulative over the years.

My Blackness creates a bias of inferiority that cannot be overcome by respectability, compliance, professionalism, training, and expertise. This is glaringly apparent on both sides of the physician-patient relationship. Black patients’ concerns are routinely overlooked and dismissed, as seen with Ms. Short, and are reflected in the Black maternal death rate, pain control in Black versus White patients, and personal experience as a patient and an advocate for my family members.

Patients have looked me in the face and said, “all lives matter,” displaying their refusal to recognize that systematic racism and inequality exist. These facts and experiences are the antithesis of “primum non nocere.”

Sadly, my and Ms. Short’s experiences are not singular ones, and racial bias in medicine is a diagnosed, but untreated cancer. Like the malignancies I treat, ignoring the problem has not made it go away; therefore, it continues to fester and spread, causing more destruction. It is of great importance and concern that all physicians recognize, reflect, and correct their implicit biases not only toward their patients, but also colleagues and trainees.

It seems that health care professionals can talk the talk, as many statements have been made against racism and implicit bias in medicine, but can we take true and meaningful action to begin the journey to equity and justice?

I would like to thank Adrienne Glover, MD, MaKenzie Hodge, MD, Maranatha McLean, MD, and Darion Showell, MD, for our stimulating conversations that helped me put pen to paper. I’d also like to thank my family for being my editors.

Daphanie D. Taylor, MD, is a hematology/oncology fellow PGY-6 at Levine Cancer Institute, Charlotte, N.C.

References and further reading

Roy L. “‘It’s My Calling To Change The Statistics’: Why We Need More Black Female Physicians.” Forbes Magazine, 27 Feb. 2020.

“Diversity in Medicine: Facts and Figures 2019.” Association of American Medical Colleges, 2019.

“Facts & Figures: Diversity in Oncology.” American Society of Clinical Oncology. 2020 Jan 16.

Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).

“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.

To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.

Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).

The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.

Incidence of immune-related adverse events

The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.

The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.

Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”

Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).

Study largely bypasses the effects of checkpoint inhibitors on RA patients

“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”

Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.

“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”

She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.

That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”

Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”

The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.

Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).

“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.

To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.

Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).

The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.

Incidence of immune-related adverse events

The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.

The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.

Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”

Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).

Study largely bypasses the effects of checkpoint inhibitors on RA patients

“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”

Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.

“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”

She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.

That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”

Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”

The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.

Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).

“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.

To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.

Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).

The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.

Incidence of immune-related adverse events

The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.

The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.

Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”

Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).

Study largely bypasses the effects of checkpoint inhibitors on RA patients

“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”

Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.

“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”

She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.

That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”

Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”

The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.

A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.

The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.

Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.

“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
 

First drug of its type

Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.

Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.

“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.

“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
 

Approval based on randomized, placebo-controlled trials

The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.

These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.

Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.

Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.

The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.

The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.

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

A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.

The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.

Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.

“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
 

First drug of its type

Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.

Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.

“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.

“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
 

Approval based on randomized, placebo-controlled trials

The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.

These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.

Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.

Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.

The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.

The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.

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

A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.

The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.

Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.

“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
 

First drug of its type

Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.

Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.

“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.

“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
 

Approval based on randomized, placebo-controlled trials

The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.

These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.

Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.

Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.

The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.

The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.

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

The combined clinical cell-cycle risk (CCR) score – derived from both clinical and genetic factors – can identify patients with intermediate- and high-risk localized prostate cancer who could potentially forgo androgen deprivation therapy (ADT), a retrospective study suggests.

The score can identify patients in whom the risk of metastasis after dose-escalated radiation is so small that adding ADT no longer makes clinical sense, according to investigator Jonathan Tward, MD, PhD, of the Genitourinary Cancer Center at the University of Utah, Salt Lake City.

His group’s study, which included 741 patients, showed that, below a CCR score of 2.112, the 10-year risk of metastasis was 4.2% with radiation therapy (RT) alone and 3.9% with the addition of ADT.

“Whether you have RT alone, RT plus any duration of ADT, insufficient duration ADT, or sufficient ADT duration by guideline standard, the risk of metastasis never exceeds 5% at 10 years” even in high- and very-high-risk men, Dr. Tward said.

He and his team found that half the men in their study with unfavorable intermediate-risk disease, 20% with high-risk disease, and 5% with very-high-risk disease scored below the CCR threshold.

This implies that, for many men, ADT after radiation “adds unnecessary morbidity for an extremely small absolute risk reduction in metastasis-free survival,” Dr. Tward said at the 2021 Genitourinary Cancers Symposium, where he presented the findings (Abstract 195).
 

Value of CCR

The CCR score tells you if the relative metastasis risk reduction with ADT after radiation – about 50% based on clinical trials – translates to an absolute risk reduction that would matter, Dr. Tward said in an interview.

“Each patient has in their own mind what that risk reduction is that works for them,” he added.

For some patients, a 1%-2% drop in absolute risk is worth it, he said, but most patients wouldn’t be willing to endure the side effects of hormone therapy if the absolute benefit is less than 5%.

The CCR score is a validated prognosticator of metastasis and death in localized prostate cancer. It’s an amalgam of traditional clinical risk factors from the Cancer of the Prostate Risk Assessment (CAPRA) score and the cell-cycle progression (CCP) score, which measures expression of cell-cycle proliferation genes for a sense of how quickly tumor cells are dividing.

The CCP test is available commercially as Prolaris. It is used mostly to make the call between active surveillance and treatment, Dr. Tward explained, “but I had a hunch this off-the-shelf test would be very good at” helping with ADT decisions after radiation.
 

‘Uncomfortable’ findings, barriers to acceptance

“People are going to be very uncomfortable with these findings because it’s been ingrained in our heads for the past 20-30 years that you must use hormone therapy with high-risk prostate cancer, and you should use hormone therapy with intermediate risk,” Dr. Tward said.

“It took me a while to believe my own data, but we have used this test for several years to help men decide if they would like to have hormone therapy after radiation. Patients clearly benefit from this information,” he said.

The 2.112 cut point for CCR was determined from a prior study that was presented at GUCS 2020 (Abstract 346) and recently accepted for publication.

In the validation study Dr. Tward presented at GUCS 2021, 70% of patients had intermediate-risk disease, and 30% had high- or very-high-risk disease according to National Comprehensive Cancer Network criteria.

All 741 patients received RT equivalent to at least 75.6 Gy at 1.8 Gy per fraction, with 84% getting or exceeding 79.2 Gy. About half the men (53%) had ADT after RT.

Genetic testing was done on stored biopsy samples years after the men were treated. Half of them were below the CCR threshold of 2.112. For those above it, the 10-year risk of metastasis was 25.3%.

CCR outperformed CCP alone, CAPRA alone, and NCCN risk groupings for predicting metastasis risk after RT.

Though this validation study was “successful,” additional research is needed, according to study discussant Richard Valicenti, MD, of the University of California, Davis.

“Widespread acceptance for routine use faces challenges since no biomarker has been prospectively tested or shown to improve long-term outcome,” Dr. Valicenti said. “Clearly, the CCR score may provide highly precise, personalized estimates and justifies testing in tiered and appropriately powered noninferiority studies according to NCCN risk groups. We eagerly await the completion and reporting of such trials so that we have a more personalized approach to treating men with prostate cancer.”

The current study was funded by Myriad Genetics, the company that developed the Prolaris test. Dr. Tward disclosed relationships with Myriad Genetics, Bayer, Blue Earth Diagnostics, Janssen Scientific Affairs, and Merck. Dr. Valicenti has no disclosures.

[email protected]

The combined clinical cell-cycle risk (CCR) score – derived from both clinical and genetic factors – can identify patients with intermediate- and high-risk localized prostate cancer who could potentially forgo androgen deprivation therapy (ADT), a retrospective study suggests.

The score can identify patients in whom the risk of metastasis after dose-escalated radiation is so small that adding ADT no longer makes clinical sense, according to investigator Jonathan Tward, MD, PhD, of the Genitourinary Cancer Center at the University of Utah, Salt Lake City.

His group’s study, which included 741 patients, showed that, below a CCR score of 2.112, the 10-year risk of metastasis was 4.2% with radiation therapy (RT) alone and 3.9% with the addition of ADT.

“Whether you have RT alone, RT plus any duration of ADT, insufficient duration ADT, or sufficient ADT duration by guideline standard, the risk of metastasis never exceeds 5% at 10 years” even in high- and very-high-risk men, Dr. Tward said.

He and his team found that half the men in their study with unfavorable intermediate-risk disease, 20% with high-risk disease, and 5% with very-high-risk disease scored below the CCR threshold.

This implies that, for many men, ADT after radiation “adds unnecessary morbidity for an extremely small absolute risk reduction in metastasis-free survival,” Dr. Tward said at the 2021 Genitourinary Cancers Symposium, where he presented the findings (Abstract 195).
 

Value of CCR

The CCR score tells you if the relative metastasis risk reduction with ADT after radiation – about 50% based on clinical trials – translates to an absolute risk reduction that would matter, Dr. Tward said in an interview.

“Each patient has in their own mind what that risk reduction is that works for them,” he added.

For some patients, a 1%-2% drop in absolute risk is worth it, he said, but most patients wouldn’t be willing to endure the side effects of hormone therapy if the absolute benefit is less than 5%.

The CCR score is a validated prognosticator of metastasis and death in localized prostate cancer. It’s an amalgam of traditional clinical risk factors from the Cancer of the Prostate Risk Assessment (CAPRA) score and the cell-cycle progression (CCP) score, which measures expression of cell-cycle proliferation genes for a sense of how quickly tumor cells are dividing.

The CCP test is available commercially as Prolaris. It is used mostly to make the call between active surveillance and treatment, Dr. Tward explained, “but I had a hunch this off-the-shelf test would be very good at” helping with ADT decisions after radiation.
 

‘Uncomfortable’ findings, barriers to acceptance

“People are going to be very uncomfortable with these findings because it’s been ingrained in our heads for the past 20-30 years that you must use hormone therapy with high-risk prostate cancer, and you should use hormone therapy with intermediate risk,” Dr. Tward said.

“It took me a while to believe my own data, but we have used this test for several years to help men decide if they would like to have hormone therapy after radiation. Patients clearly benefit from this information,” he said.

The 2.112 cut point for CCR was determined from a prior study that was presented at GUCS 2020 (Abstract 346) and recently accepted for publication.

In the validation study Dr. Tward presented at GUCS 2021, 70% of patients had intermediate-risk disease, and 30% had high- or very-high-risk disease according to National Comprehensive Cancer Network criteria.

All 741 patients received RT equivalent to at least 75.6 Gy at 1.8 Gy per fraction, with 84% getting or exceeding 79.2 Gy. About half the men (53%) had ADT after RT.

Genetic testing was done on stored biopsy samples years after the men were treated. Half of them were below the CCR threshold of 2.112. For those above it, the 10-year risk of metastasis was 25.3%.

CCR outperformed CCP alone, CAPRA alone, and NCCN risk groupings for predicting metastasis risk after RT.

Though this validation study was “successful,” additional research is needed, according to study discussant Richard Valicenti, MD, of the University of California, Davis.

“Widespread acceptance for routine use faces challenges since no biomarker has been prospectively tested or shown to improve long-term outcome,” Dr. Valicenti said. “Clearly, the CCR score may provide highly precise, personalized estimates and justifies testing in tiered and appropriately powered noninferiority studies according to NCCN risk groups. We eagerly await the completion and reporting of such trials so that we have a more personalized approach to treating men with prostate cancer.”

The current study was funded by Myriad Genetics, the company that developed the Prolaris test. Dr. Tward disclosed relationships with Myriad Genetics, Bayer, Blue Earth Diagnostics, Janssen Scientific Affairs, and Merck. Dr. Valicenti has no disclosures.

[email protected]

The combined clinical cell-cycle risk (CCR) score – derived from both clinical and genetic factors – can identify patients with intermediate- and high-risk localized prostate cancer who could potentially forgo androgen deprivation therapy (ADT), a retrospective study suggests.

The score can identify patients in whom the risk of metastasis after dose-escalated radiation is so small that adding ADT no longer makes clinical sense, according to investigator Jonathan Tward, MD, PhD, of the Genitourinary Cancer Center at the University of Utah, Salt Lake City.

His group’s study, which included 741 patients, showed that, below a CCR score of 2.112, the 10-year risk of metastasis was 4.2% with radiation therapy (RT) alone and 3.9% with the addition of ADT.

“Whether you have RT alone, RT plus any duration of ADT, insufficient duration ADT, or sufficient ADT duration by guideline standard, the risk of metastasis never exceeds 5% at 10 years” even in high- and very-high-risk men, Dr. Tward said.

He and his team found that half the men in their study with unfavorable intermediate-risk disease, 20% with high-risk disease, and 5% with very-high-risk disease scored below the CCR threshold.

This implies that, for many men, ADT after radiation “adds unnecessary morbidity for an extremely small absolute risk reduction in metastasis-free survival,” Dr. Tward said at the 2021 Genitourinary Cancers Symposium, where he presented the findings (Abstract 195).
 

Value of CCR

The CCR score tells you if the relative metastasis risk reduction with ADT after radiation – about 50% based on clinical trials – translates to an absolute risk reduction that would matter, Dr. Tward said in an interview.

“Each patient has in their own mind what that risk reduction is that works for them,” he added.

For some patients, a 1%-2% drop in absolute risk is worth it, he said, but most patients wouldn’t be willing to endure the side effects of hormone therapy if the absolute benefit is less than 5%.

The CCR score is a validated prognosticator of metastasis and death in localized prostate cancer. It’s an amalgam of traditional clinical risk factors from the Cancer of the Prostate Risk Assessment (CAPRA) score and the cell-cycle progression (CCP) score, which measures expression of cell-cycle proliferation genes for a sense of how quickly tumor cells are dividing.

The CCP test is available commercially as Prolaris. It is used mostly to make the call between active surveillance and treatment, Dr. Tward explained, “but I had a hunch this off-the-shelf test would be very good at” helping with ADT decisions after radiation.
 

‘Uncomfortable’ findings, barriers to acceptance

“People are going to be very uncomfortable with these findings because it’s been ingrained in our heads for the past 20-30 years that you must use hormone therapy with high-risk prostate cancer, and you should use hormone therapy with intermediate risk,” Dr. Tward said.

“It took me a while to believe my own data, but we have used this test for several years to help men decide if they would like to have hormone therapy after radiation. Patients clearly benefit from this information,” he said.

The 2.112 cut point for CCR was determined from a prior study that was presented at GUCS 2020 (Abstract 346) and recently accepted for publication.

In the validation study Dr. Tward presented at GUCS 2021, 70% of patients had intermediate-risk disease, and 30% had high- or very-high-risk disease according to National Comprehensive Cancer Network criteria.

All 741 patients received RT equivalent to at least 75.6 Gy at 1.8 Gy per fraction, with 84% getting or exceeding 79.2 Gy. About half the men (53%) had ADT after RT.

Genetic testing was done on stored biopsy samples years after the men were treated. Half of them were below the CCR threshold of 2.112. For those above it, the 10-year risk of metastasis was 25.3%.

CCR outperformed CCP alone, CAPRA alone, and NCCN risk groupings for predicting metastasis risk after RT.

Though this validation study was “successful,” additional research is needed, according to study discussant Richard Valicenti, MD, of the University of California, Davis.

“Widespread acceptance for routine use faces challenges since no biomarker has been prospectively tested or shown to improve long-term outcome,” Dr. Valicenti said. “Clearly, the CCR score may provide highly precise, personalized estimates and justifies testing in tiered and appropriately powered noninferiority studies according to NCCN risk groups. We eagerly await the completion and reporting of such trials so that we have a more personalized approach to treating men with prostate cancer.”

The current study was funded by Myriad Genetics, the company that developed the Prolaris test. Dr. Tward disclosed relationships with Myriad Genetics, Bayer, Blue Earth Diagnostics, Janssen Scientific Affairs, and Merck. Dr. Valicenti has no disclosures.

[email protected]

The genomic landscape of circulating tumor DNA (ctDNA) was comparable to the landscape of tissue biopsies in a large study of patients with metastatic castration-resistant prostate cancer (mCRPC), according to researchers.

The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.

Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.

“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.

“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”

Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.

ctDNA profiling proves feasible, comparable

CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.

The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.

Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.

“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.

“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.

ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).

“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.

When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.

However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.

Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.

Rare and novel AR alterations

“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.

She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.

Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.

“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.

The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.

“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.

BRCA1/2: High concordance

To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.

The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.

There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.

The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.

Implications for practice

This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.

“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.

“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.

“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”

Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).

The genomic landscape of circulating tumor DNA (ctDNA) was comparable to the landscape of tissue biopsies in a large study of patients with metastatic castration-resistant prostate cancer (mCRPC), according to researchers.

The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.

Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.

“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.

“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”

Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.

ctDNA profiling proves feasible, comparable

CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.

The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.

Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.

“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.

“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.

ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).

“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.

When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.

However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.

Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.

Rare and novel AR alterations

“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.

She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.

Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.

“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.

The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.

“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.

BRCA1/2: High concordance

To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.

The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.

There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.

The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.

Implications for practice

This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.

“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.

“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.

“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”

Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).

The genomic landscape of circulating tumor DNA (ctDNA) was comparable to the landscape of tissue biopsies in a large study of patients with metastatic castration-resistant prostate cancer (mCRPC), according to researchers.

The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.

Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.

“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.

“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”

Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.

ctDNA profiling proves feasible, comparable

CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.

The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.

Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.

“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.

“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.

ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).

“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.

When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.

However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.

Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.

Rare and novel AR alterations

“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.

She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.

Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.

“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.

The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.

“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.

BRCA1/2: High concordance

To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.

The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.

There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.

The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.

Implications for practice

This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.

“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.

“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.

“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”

Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).

The incidence of metastatic prostate cancers at diagnosis increased as prostate-specific antigen (PSA) screenings across U.S. states decreased, registry data show.

Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).

A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.

The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”

Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”

Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.

“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.

PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.

Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”

The task force recommended against PSA screening in men older than 70 years.

The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.

Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.

[email protected]

The incidence of metastatic prostate cancers at diagnosis increased as prostate-specific antigen (PSA) screenings across U.S. states decreased, registry data show.

Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).

A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.

The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”

Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”

Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.

“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.

PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.

Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”

The task force recommended against PSA screening in men older than 70 years.

The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.

Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.

[email protected]

The incidence of metastatic prostate cancers at diagnosis increased as prostate-specific antigen (PSA) screenings across U.S. states decreased, registry data show.

Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).

A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.

The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”

Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”

Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.

“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.

PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.

Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”

The task force recommended against PSA screening in men older than 70 years.

The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.

Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.

[email protected]

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

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

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

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

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

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

A new approach to breast screening proposes that all women should have a baseline evaluation of breast density by mammography at the age of 40.

The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.

Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.

Their modeling study was published online in the Annals of Internal Medicine.

However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
 

New approach proposed

Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.

However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.

“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.

For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).

The team used a computer model to compare seven different breast screening strategies:

• No screening.
• Triennial mammography from age 50 to 75 years (T50).
• Biennial mammography from age 50 to 75 years (B50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).

Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.  

Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).

A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.

On the other hand, false-positive results and overdiagnosis would increase, the authors note.

The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).  

Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.

“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.

“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.  
 

Fundamental problem with this approach 

The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.

Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.

“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.

“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.

An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.

“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”  

Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.

“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.

“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.

Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.

“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.

“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.

The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.

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

A new approach to breast screening proposes that all women should have a baseline evaluation of breast density by mammography at the age of 40.

The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.

Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.

Their modeling study was published online in the Annals of Internal Medicine.

However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
 

New approach proposed

Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.

However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.

“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.

For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).

The team used a computer model to compare seven different breast screening strategies:

• No screening.
• Triennial mammography from age 50 to 75 years (T50).
• Biennial mammography from age 50 to 75 years (B50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).

Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.  

Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).

A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.

On the other hand, false-positive results and overdiagnosis would increase, the authors note.

The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).  

Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.

“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.

“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.  
 

Fundamental problem with this approach 

The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.

Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.

“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.

“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.

An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.

“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”  

Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.

“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.

“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.

Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.

“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.

“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.

The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.

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

A new approach to breast screening proposes that all women should have a baseline evaluation of breast density by mammography at the age of 40.

The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.

Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.

Their modeling study was published online in the Annals of Internal Medicine.

However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
 

New approach proposed

Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.

However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.

“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.

For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).

The team used a computer model to compare seven different breast screening strategies:

• No screening.
• Triennial mammography from age 50 to 75 years (T50).
• Biennial mammography from age 50 to 75 years (B50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
• Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
• Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).

Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.  

Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).

A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.

On the other hand, false-positive results and overdiagnosis would increase, the authors note.

The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).  

Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.

“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.

“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.  
 

Fundamental problem with this approach 

The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.

Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.

“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.

“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.

An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.

“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”  

Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.

“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.

“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.

Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.

“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.

“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.

The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.

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

The next dramatic advance in the treatment of melanoma may arise from highly promising clinical trials in which immune checkpoint inhibitors and anti-BRAF/MEK agents are being pushed forward in the treatment paradigm and utilized as neoadjuvant therapy in patients with stage III resectable disease, John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.

These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.

“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”

Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.

Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.

CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.

In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.

“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.

Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.

There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.

Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.

Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.

“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.

Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.

Global Academy for Medical Education and this news organization are owned by the same company.

[email protected]

The next dramatic advance in the treatment of melanoma may arise from highly promising clinical trials in which immune checkpoint inhibitors and anti-BRAF/MEK agents are being pushed forward in the treatment paradigm and utilized as neoadjuvant therapy in patients with stage III resectable disease, John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.

These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.

“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”

Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.

Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.

CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.

In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.

“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.

Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.

There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.

Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.

Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.

“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.

Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.

Global Academy for Medical Education and this news organization are owned by the same company.

[email protected]

The next dramatic advance in the treatment of melanoma may arise from highly promising clinical trials in which immune checkpoint inhibitors and anti-BRAF/MEK agents are being pushed forward in the treatment paradigm and utilized as neoadjuvant therapy in patients with stage III resectable disease, John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.

These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.

“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”

Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.

Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.

CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.

In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.

“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.

Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.

There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.

Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.

Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.

“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.

Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.

Global Academy for Medical Education and this news organization are owned by the same company.

[email protected]

New research suggests that proposed lung cancer screening guidelines could inadvertently increase racial and ethnic disparities, but adding in a risk prediction model could reduce some of these disparities by identifying people with high predicted benefit, regardless of race or ethnicity.

The draft United States Preventive Services Task Force (USPSTF) 2020 guidelines recommend annual lung cancer screening for individuals aged 50-80 who currently smoke or quit in the last 15 years, and who have a smoking history equivalent to at least one pack of cigarettes per day for 20 years or more.

This expands the age range and smoking history requirement compared to the 2013 USPSTF recommendations in an attempt to partially ameliorate racial disparities in screening eligibility. The 2013 guidelines recommend screening ever-smokers aged 55-80 with 30 or more pack-years and 15 or fewer quit-years.

However, neither the 2013 nor the 2020 USPSTF recommendations consider the higher risk of lung cancer and younger ages at diagnosis among African Americans, despite their smoking less than Whites, according to Rebecca Landy, PhD, of the National Cancer Institute in Bethesda, Md.

“For the same age and smoking history as Whites, minorities have substantially different lung cancer risk,” Dr. Landy said. “Incorporating individualized prediction models into USPSTF guidelines may reduce racial/ethnic disparities in lung cancer screening eligibility.”

Dr. Landy and colleagues set out to test that theory, and she presented the results at the 2020 World Congress on Lung Cancer (Abstract 3564), which was rescheduled for January 2021. The results were published in the Journal of the National Cancer Institute.
 

Study details

Dr. Landy and colleagues modeled the performance of National Lung Screening Trial–like screening (three annual CT screens, 5 years of follow-up) among three cohorts of ever-smokers aged 50-80 using the 2015 National Health Interview Survey.

One group was eligible by USPSTF 2013 guidelines, another by draft USPSTF 2020 guidelines, and yet another by augmenting the USPSTF 2020 guidelines using risk prediction to include individuals with 12 or more days of life gained according to the Life-Years From Screening–CT (LYFS-CT) model.

“Among each race/ethnicity, we calculated the number eligible for screening, proportion of preventable lung cancer deaths prevented, proportion of gainable life-years gained, and screening effectiveness, as well as the relative disparities in lung cancer deaths prevented and life-years gained,” Dr. Landy said.
 

Results

Under the 2013 guidelines, 8 million ever-smokers were eligible. The disparities in lung cancer death sensitivity, compared to Whites, were 15% for African Americans, 15% for Asian Americans, and 24% for Hispanic Americans. Disparities for life-year gained sensitivity were 15%, 13%, and 24%, respectively.

Under the 2020 draft guidelines, 14.5 million ever-smokers were eligible, but racial/ethnic disparities persisted. Disparities in lung cancer death sensitivity were 13% for African Americans, 19% for Asian Americans, and 27% for Hispanic Americans. Disparities for life-year gained sensitivity were 16%, 19%, and 27%, respectively.

Using the LYFS-CT predictive-risk model added an additional 3.5 million people and “nearly eliminated” disparities for African Americans, Dr. Landy noted. However, disparities persisted for Asian Americans and Hispanic Americans.

Disparities in lung cancer death sensitivity were 0% for African Americans, 19% for Asian Americans, and 23% for Hispanic Americans. Disparities for life-year gained sensitivity were 1%, 19%, and 24%, respectively.
 

More and widening disparity

The results showed that augmenting USPSTF criteria to include high-benefit people selected significantly more African Americans than Whites and could therefore reduce or even eliminate disparities between Whites and African Americans.

“The 2020 USPSTF draft recommendations would make 6.5 million more people eligible to be screened, in addition to the 8 million from the 2013 criteria,” said Gerard Silvestri, MD, of the Medical University of South Carolina, Charleston, who was not involved in this study.

“But there will be more White people than African American people added, and the disparity between them may widen. Using the risk prediction model outlined in this well-researched study could close the gap in disparity. It’s important to identify individual risk and life expectancy.”

Dr. Silvestri pointed out that, compared to Whites, African Americans develop lung cancer at an earlier age with fewer pack-years history of smoking and have worse outcomes.

“We can’t just focus on one aspect of disparity,” he said. “African Americans are much less likely to be insured or to identify a primary care provider for integrated care. We know that screening works. The 2020 USPSTF draft recommendations will enlarge the pool of eligible African Americans and reduce disparities if the other part of the equation holds; that is, they get access to care and screening.”

This study was funded by the National Institutes of Health/National Cancer Institute. Dr. Landy and Dr. Silvestri have no disclosures.

New research suggests that proposed lung cancer screening guidelines could inadvertently increase racial and ethnic disparities, but adding in a risk prediction model could reduce some of these disparities by identifying people with high predicted benefit, regardless of race or ethnicity.

The draft United States Preventive Services Task Force (USPSTF) 2020 guidelines recommend annual lung cancer screening for individuals aged 50-80 who currently smoke or quit in the last 15 years, and who have a smoking history equivalent to at least one pack of cigarettes per day for 20 years or more.

This expands the age range and smoking history requirement compared to the 2013 USPSTF recommendations in an attempt to partially ameliorate racial disparities in screening eligibility. The 2013 guidelines recommend screening ever-smokers aged 55-80 with 30 or more pack-years and 15 or fewer quit-years.

However, neither the 2013 nor the 2020 USPSTF recommendations consider the higher risk of lung cancer and younger ages at diagnosis among African Americans, despite their smoking less than Whites, according to Rebecca Landy, PhD, of the National Cancer Institute in Bethesda, Md.

“For the same age and smoking history as Whites, minorities have substantially different lung cancer risk,” Dr. Landy said. “Incorporating individualized prediction models into USPSTF guidelines may reduce racial/ethnic disparities in lung cancer screening eligibility.”

Dr. Landy and colleagues set out to test that theory, and she presented the results at the 2020 World Congress on Lung Cancer (Abstract 3564), which was rescheduled for January 2021. The results were published in the Journal of the National Cancer Institute.
 

Study details

Dr. Landy and colleagues modeled the performance of National Lung Screening Trial–like screening (three annual CT screens, 5 years of follow-up) among three cohorts of ever-smokers aged 50-80 using the 2015 National Health Interview Survey.

One group was eligible by USPSTF 2013 guidelines, another by draft USPSTF 2020 guidelines, and yet another by augmenting the USPSTF 2020 guidelines using risk prediction to include individuals with 12 or more days of life gained according to the Life-Years From Screening–CT (LYFS-CT) model.

“Among each race/ethnicity, we calculated the number eligible for screening, proportion of preventable lung cancer deaths prevented, proportion of gainable life-years gained, and screening effectiveness, as well as the relative disparities in lung cancer deaths prevented and life-years gained,” Dr. Landy said.
 

Results

Under the 2013 guidelines, 8 million ever-smokers were eligible. The disparities in lung cancer death sensitivity, compared to Whites, were 15% for African Americans, 15% for Asian Americans, and 24% for Hispanic Americans. Disparities for life-year gained sensitivity were 15%, 13%, and 24%, respectively.

Under the 2020 draft guidelines, 14.5 million ever-smokers were eligible, but racial/ethnic disparities persisted. Disparities in lung cancer death sensitivity were 13% for African Americans, 19% for Asian Americans, and 27% for Hispanic Americans. Disparities for life-year gained sensitivity were 16%, 19%, and 27%, respectively.

Using the LYFS-CT predictive-risk model added an additional 3.5 million people and “nearly eliminated” disparities for African Americans, Dr. Landy noted. However, disparities persisted for Asian Americans and Hispanic Americans.

Disparities in lung cancer death sensitivity were 0% for African Americans, 19% for Asian Americans, and 23% for Hispanic Americans. Disparities for life-year gained sensitivity were 1%, 19%, and 24%, respectively.
 

More and widening disparity

The results showed that augmenting USPSTF criteria to include high-benefit people selected significantly more African Americans than Whites and could therefore reduce or even eliminate disparities between Whites and African Americans.

“The 2020 USPSTF draft recommendations would make 6.5 million more people eligible to be screened, in addition to the 8 million from the 2013 criteria,” said Gerard Silvestri, MD, of the Medical University of South Carolina, Charleston, who was not involved in this study.

“But there will be more White people than African American people added, and the disparity between them may widen. Using the risk prediction model outlined in this well-researched study could close the gap in disparity. It’s important to identify individual risk and life expectancy.”

Dr. Silvestri pointed out that, compared to Whites, African Americans develop lung cancer at an earlier age with fewer pack-years history of smoking and have worse outcomes.

“We can’t just focus on one aspect of disparity,” he said. “African Americans are much less likely to be insured or to identify a primary care provider for integrated care. We know that screening works. The 2020 USPSTF draft recommendations will enlarge the pool of eligible African Americans and reduce disparities if the other part of the equation holds; that is, they get access to care and screening.”

This study was funded by the National Institutes of Health/National Cancer Institute. Dr. Landy and Dr. Silvestri have no disclosures.

New research suggests that proposed lung cancer screening guidelines could inadvertently increase racial and ethnic disparities, but adding in a risk prediction model could reduce some of these disparities by identifying people with high predicted benefit, regardless of race or ethnicity.

The draft United States Preventive Services Task Force (USPSTF) 2020 guidelines recommend annual lung cancer screening for individuals aged 50-80 who currently smoke or quit in the last 15 years, and who have a smoking history equivalent to at least one pack of cigarettes per day for 20 years or more.

This expands the age range and smoking history requirement compared to the 2013 USPSTF recommendations in an attempt to partially ameliorate racial disparities in screening eligibility. The 2013 guidelines recommend screening ever-smokers aged 55-80 with 30 or more pack-years and 15 or fewer quit-years.

However, neither the 2013 nor the 2020 USPSTF recommendations consider the higher risk of lung cancer and younger ages at diagnosis among African Americans, despite their smoking less than Whites, according to Rebecca Landy, PhD, of the National Cancer Institute in Bethesda, Md.

“For the same age and smoking history as Whites, minorities have substantially different lung cancer risk,” Dr. Landy said. “Incorporating individualized prediction models into USPSTF guidelines may reduce racial/ethnic disparities in lung cancer screening eligibility.”

Dr. Landy and colleagues set out to test that theory, and she presented the results at the 2020 World Congress on Lung Cancer (Abstract 3564), which was rescheduled for January 2021. The results were published in the Journal of the National Cancer Institute.
 

Study details

Dr. Landy and colleagues modeled the performance of National Lung Screening Trial–like screening (three annual CT screens, 5 years of follow-up) among three cohorts of ever-smokers aged 50-80 using the 2015 National Health Interview Survey.

One group was eligible by USPSTF 2013 guidelines, another by draft USPSTF 2020 guidelines, and yet another by augmenting the USPSTF 2020 guidelines using risk prediction to include individuals with 12 or more days of life gained according to the Life-Years From Screening–CT (LYFS-CT) model.

“Among each race/ethnicity, we calculated the number eligible for screening, proportion of preventable lung cancer deaths prevented, proportion of gainable life-years gained, and screening effectiveness, as well as the relative disparities in lung cancer deaths prevented and life-years gained,” Dr. Landy said.
 

Results

Under the 2013 guidelines, 8 million ever-smokers were eligible. The disparities in lung cancer death sensitivity, compared to Whites, were 15% for African Americans, 15% for Asian Americans, and 24% for Hispanic Americans. Disparities for life-year gained sensitivity were 15%, 13%, and 24%, respectively.

Under the 2020 draft guidelines, 14.5 million ever-smokers were eligible, but racial/ethnic disparities persisted. Disparities in lung cancer death sensitivity were 13% for African Americans, 19% for Asian Americans, and 27% for Hispanic Americans. Disparities for life-year gained sensitivity were 16%, 19%, and 27%, respectively.

Using the LYFS-CT predictive-risk model added an additional 3.5 million people and “nearly eliminated” disparities for African Americans, Dr. Landy noted. However, disparities persisted for Asian Americans and Hispanic Americans.

Disparities in lung cancer death sensitivity were 0% for African Americans, 19% for Asian Americans, and 23% for Hispanic Americans. Disparities for life-year gained sensitivity were 1%, 19%, and 24%, respectively.
 

More and widening disparity

The results showed that augmenting USPSTF criteria to include high-benefit people selected significantly more African Americans than Whites and could therefore reduce or even eliminate disparities between Whites and African Americans.

“The 2020 USPSTF draft recommendations would make 6.5 million more people eligible to be screened, in addition to the 8 million from the 2013 criteria,” said Gerard Silvestri, MD, of the Medical University of South Carolina, Charleston, who was not involved in this study.

“But there will be more White people than African American people added, and the disparity between them may widen. Using the risk prediction model outlined in this well-researched study could close the gap in disparity. It’s important to identify individual risk and life expectancy.”

Dr. Silvestri pointed out that, compared to Whites, African Americans develop lung cancer at an earlier age with fewer pack-years history of smoking and have worse outcomes.

“We can’t just focus on one aspect of disparity,” he said. “African Americans are much less likely to be insured or to identify a primary care provider for integrated care. We know that screening works. The 2020 USPSTF draft recommendations will enlarge the pool of eligible African Americans and reduce disparities if the other part of the equation holds; that is, they get access to care and screening.”

This study was funded by the National Institutes of Health/National Cancer Institute. Dr. Landy and Dr. Silvestri have no disclosures.