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Cancer rates on the rise in adolescents and young adults
Rates of cancer increased by 30% from 1973 to 2015 in adolescents and young adults (AYAs) aged 15–39 years in the United States, according to a review of almost a half million cases in the National Institutes of Health’s Surveillance, Epidemiology, and End Results database.
There was an annual increase of 0.537 new cases per 100,000 people, from 57.2 cases per 100,000 in 1973 to 74.2 in 2015.
Kidney carcinoma led with the highest rate increase. There were also marked increases in thyroid and colorectal carcinoma, germ cell and trophoblastic neoplasms, and melanoma, among others.
The report was published online December 1 in JAMA Network Open.
“Clinicians should be on the lookout for these cancers in their adolescent and young adult patients,” said senior investigator Nicholas Zaorsky, MD, an assistant professor of radiation oncology and public health sciences at the Penn State Cancer Institute, Hershey, Pennsylvania.
“Now that there is a better understanding of the types of cancer that are prevalent and rising in this age group, prevention, screening, diagnosis and treatment protocols specifically targeted to this population should be developed,” he said in a press release.
The reasons for the increases are unclear, but environmental and dietary factors, increasing obesity, and changing screening practices are likely in play, the authors comment. In addition, “cancer screening and overdiagnosis are thought to account for much of the increasing rates of thyroid and kidney carcinoma, among others,” they add.
The American Cancer Society (ACS) recently found similar increases in thyroid, kidney, and colorectal cancer among AYAs, as well as an increase in uterine cancer.
It’s important to note, however, that “this phenomenon is largely driven by trends for thyroid cancer, which is thought to be a result of overdiagnosis,” said ACS surveillance researcher Kimberly Miller, MPH, when asked to comment on the new study.
“As such, it is extremely important to also consider trends in cancer mortality rates among this age group, which are declining overall but are increasing for colorectal and uterine cancers. The fact that both incidence and mortality rates are increasing for these two cancers suggests a true increase in disease burden and certainly requires further attention and research,” she said.
Historically, management of cancer in AYAs has fallen somewhere between pediatric and adult oncology, neither of which capture the distinct biological, social, and economic needs of AYAs. Research has also focused on childhood and adult cancers, leaving cancer in AYAs inadequately studied.
The new findings are “valuable to guide more targeted research and interventions specifically to AYAs,” Zaorsky and colleagues say in their report.
Among female patients ― 59.1% of the study population ― incidence increased for 15 cancers, including kidney carcinoma (annual percent change [APC], 3.632), thyroid carcinoma (APC, 3.456), and myeloma, mast cell, and miscellaneous lymphoreticular neoplasms not otherwise specified (APC, 2.805). Rates of five cancers declined, led by astrocytoma not otherwise specified (APC, –3.369) and carcinoma of the gonads (APC, –1.743).
Among male patients, incidence increased for 14 cancers, including kidney carcinoma (APC, 3.572), unspecified soft tissue sarcoma (APC 2.543), and thyroid carcinoma (APC, 2.273). Incidence fell for seven, led by astrocytoma not otherwise specified (APC, –3.759) and carcinoma of the trachea, bronchus, and lung (APC, –2.635).
Increased testicular cancer rates (APC, 1.246) could be related to greater prenatal exposure to estrogen and progesterone or through dairy consumption; increasing survival of premature infants; and greater exposure to cannabis, among other possibilities, the investigators say.
Increases in colorectal cancer might be related to fewer vegetables and more fat and processed meat in the diet; lack of exercise; and increasing obesity. Human papillomavirus infection has also been implicated.
Higher rates of melanoma could be related to tanning bed use.
Declines in some cancers could be related to greater use of oral contraceptives; laws reducing exposure to benzene and other chemicals; and fewer people smoking.
Although kidney carcinoma has increased at the greatest rate, it’s uncommon. Colorectal and thyroid carcinoma, melanoma, non-Hodgkin lymphoma, and germ cell and trophoblastic neoplasms of the gonads contribute more to the overall increase in cancers among AYAs, the investigators note.
Almost 80% of the patients were White; 10.3% were Black.
The study was funded by the National Center for Advancing Translational Sciences. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Rates of cancer increased by 30% from 1973 to 2015 in adolescents and young adults (AYAs) aged 15–39 years in the United States, according to a review of almost a half million cases in the National Institutes of Health’s Surveillance, Epidemiology, and End Results database.
There was an annual increase of 0.537 new cases per 100,000 people, from 57.2 cases per 100,000 in 1973 to 74.2 in 2015.
Kidney carcinoma led with the highest rate increase. There were also marked increases in thyroid and colorectal carcinoma, germ cell and trophoblastic neoplasms, and melanoma, among others.
The report was published online December 1 in JAMA Network Open.
“Clinicians should be on the lookout for these cancers in their adolescent and young adult patients,” said senior investigator Nicholas Zaorsky, MD, an assistant professor of radiation oncology and public health sciences at the Penn State Cancer Institute, Hershey, Pennsylvania.
“Now that there is a better understanding of the types of cancer that are prevalent and rising in this age group, prevention, screening, diagnosis and treatment protocols specifically targeted to this population should be developed,” he said in a press release.
The reasons for the increases are unclear, but environmental and dietary factors, increasing obesity, and changing screening practices are likely in play, the authors comment. In addition, “cancer screening and overdiagnosis are thought to account for much of the increasing rates of thyroid and kidney carcinoma, among others,” they add.
The American Cancer Society (ACS) recently found similar increases in thyroid, kidney, and colorectal cancer among AYAs, as well as an increase in uterine cancer.
It’s important to note, however, that “this phenomenon is largely driven by trends for thyroid cancer, which is thought to be a result of overdiagnosis,” said ACS surveillance researcher Kimberly Miller, MPH, when asked to comment on the new study.
“As such, it is extremely important to also consider trends in cancer mortality rates among this age group, which are declining overall but are increasing for colorectal and uterine cancers. The fact that both incidence and mortality rates are increasing for these two cancers suggests a true increase in disease burden and certainly requires further attention and research,” she said.
Historically, management of cancer in AYAs has fallen somewhere between pediatric and adult oncology, neither of which capture the distinct biological, social, and economic needs of AYAs. Research has also focused on childhood and adult cancers, leaving cancer in AYAs inadequately studied.
The new findings are “valuable to guide more targeted research and interventions specifically to AYAs,” Zaorsky and colleagues say in their report.
Among female patients ― 59.1% of the study population ― incidence increased for 15 cancers, including kidney carcinoma (annual percent change [APC], 3.632), thyroid carcinoma (APC, 3.456), and myeloma, mast cell, and miscellaneous lymphoreticular neoplasms not otherwise specified (APC, 2.805). Rates of five cancers declined, led by astrocytoma not otherwise specified (APC, –3.369) and carcinoma of the gonads (APC, –1.743).
Among male patients, incidence increased for 14 cancers, including kidney carcinoma (APC, 3.572), unspecified soft tissue sarcoma (APC 2.543), and thyroid carcinoma (APC, 2.273). Incidence fell for seven, led by astrocytoma not otherwise specified (APC, –3.759) and carcinoma of the trachea, bronchus, and lung (APC, –2.635).
Increased testicular cancer rates (APC, 1.246) could be related to greater prenatal exposure to estrogen and progesterone or through dairy consumption; increasing survival of premature infants; and greater exposure to cannabis, among other possibilities, the investigators say.
Increases in colorectal cancer might be related to fewer vegetables and more fat and processed meat in the diet; lack of exercise; and increasing obesity. Human papillomavirus infection has also been implicated.
Higher rates of melanoma could be related to tanning bed use.
Declines in some cancers could be related to greater use of oral contraceptives; laws reducing exposure to benzene and other chemicals; and fewer people smoking.
Although kidney carcinoma has increased at the greatest rate, it’s uncommon. Colorectal and thyroid carcinoma, melanoma, non-Hodgkin lymphoma, and germ cell and trophoblastic neoplasms of the gonads contribute more to the overall increase in cancers among AYAs, the investigators note.
Almost 80% of the patients were White; 10.3% were Black.
The study was funded by the National Center for Advancing Translational Sciences. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Rates of cancer increased by 30% from 1973 to 2015 in adolescents and young adults (AYAs) aged 15–39 years in the United States, according to a review of almost a half million cases in the National Institutes of Health’s Surveillance, Epidemiology, and End Results database.
There was an annual increase of 0.537 new cases per 100,000 people, from 57.2 cases per 100,000 in 1973 to 74.2 in 2015.
Kidney carcinoma led with the highest rate increase. There were also marked increases in thyroid and colorectal carcinoma, germ cell and trophoblastic neoplasms, and melanoma, among others.
The report was published online December 1 in JAMA Network Open.
“Clinicians should be on the lookout for these cancers in their adolescent and young adult patients,” said senior investigator Nicholas Zaorsky, MD, an assistant professor of radiation oncology and public health sciences at the Penn State Cancer Institute, Hershey, Pennsylvania.
“Now that there is a better understanding of the types of cancer that are prevalent and rising in this age group, prevention, screening, diagnosis and treatment protocols specifically targeted to this population should be developed,” he said in a press release.
The reasons for the increases are unclear, but environmental and dietary factors, increasing obesity, and changing screening practices are likely in play, the authors comment. In addition, “cancer screening and overdiagnosis are thought to account for much of the increasing rates of thyroid and kidney carcinoma, among others,” they add.
The American Cancer Society (ACS) recently found similar increases in thyroid, kidney, and colorectal cancer among AYAs, as well as an increase in uterine cancer.
It’s important to note, however, that “this phenomenon is largely driven by trends for thyroid cancer, which is thought to be a result of overdiagnosis,” said ACS surveillance researcher Kimberly Miller, MPH, when asked to comment on the new study.
“As such, it is extremely important to also consider trends in cancer mortality rates among this age group, which are declining overall but are increasing for colorectal and uterine cancers. The fact that both incidence and mortality rates are increasing for these two cancers suggests a true increase in disease burden and certainly requires further attention and research,” she said.
Historically, management of cancer in AYAs has fallen somewhere between pediatric and adult oncology, neither of which capture the distinct biological, social, and economic needs of AYAs. Research has also focused on childhood and adult cancers, leaving cancer in AYAs inadequately studied.
The new findings are “valuable to guide more targeted research and interventions specifically to AYAs,” Zaorsky and colleagues say in their report.
Among female patients ― 59.1% of the study population ― incidence increased for 15 cancers, including kidney carcinoma (annual percent change [APC], 3.632), thyroid carcinoma (APC, 3.456), and myeloma, mast cell, and miscellaneous lymphoreticular neoplasms not otherwise specified (APC, 2.805). Rates of five cancers declined, led by astrocytoma not otherwise specified (APC, –3.369) and carcinoma of the gonads (APC, –1.743).
Among male patients, incidence increased for 14 cancers, including kidney carcinoma (APC, 3.572), unspecified soft tissue sarcoma (APC 2.543), and thyroid carcinoma (APC, 2.273). Incidence fell for seven, led by astrocytoma not otherwise specified (APC, –3.759) and carcinoma of the trachea, bronchus, and lung (APC, –2.635).
Increased testicular cancer rates (APC, 1.246) could be related to greater prenatal exposure to estrogen and progesterone or through dairy consumption; increasing survival of premature infants; and greater exposure to cannabis, among other possibilities, the investigators say.
Increases in colorectal cancer might be related to fewer vegetables and more fat and processed meat in the diet; lack of exercise; and increasing obesity. Human papillomavirus infection has also been implicated.
Higher rates of melanoma could be related to tanning bed use.
Declines in some cancers could be related to greater use of oral contraceptives; laws reducing exposure to benzene and other chemicals; and fewer people smoking.
Although kidney carcinoma has increased at the greatest rate, it’s uncommon. Colorectal and thyroid carcinoma, melanoma, non-Hodgkin lymphoma, and germ cell and trophoblastic neoplasms of the gonads contribute more to the overall increase in cancers among AYAs, the investigators note.
Almost 80% of the patients were White; 10.3% were Black.
The study was funded by the National Center for Advancing Translational Sciences. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Should CTCs guide treatment choice in HR+, HER2– breast cancer?
investigators wrote in JAMA Oncology.
However, authors of a related editorial suggested CTC counts are not adequate for guiding treatment choice in this population.
In a phase 3 trial, investigators compared the use of CTC counts and the use of clinical factors to guide the decision between chemotherapy and endocrine therapy. Results showed similar progression-free survival (PFS) and overall survival (OS) with both methods but more chemotherapy use with the CTC method.
“The results of this trial demonstrate the reliability and clinical utility of CTC count to guide the choice between single-agent endocrine therapy and chemotherapy as first-line treatment,” but “at the cost of a higher proportion of patients treated with chemotherapy,” study author François-Clement Bidard, MD, PhD, of Institut Curie in Saint-Cloud, France, and colleagues wrote.
The investigators explained that endocrine therapy is the preferred first-line treatment option in this patient population, but chemotherapy is used when women are in visceral crisis, with rapidly progressive, symptomatic disease. The decision usually rests on clinical factors, such as tumor subtype and performance status, but there’s interphysician variability.
The team hoped to find a “more reliable, standardized, and reproducible” biomarker to help remove some of the uncertainty from the situation. They tested CTC count, a well-established prognostic indicator of PFS and OS, as a candidate.
Study results
The trial included 755 patients with hormone receptor–positive, HER2-negative breast cancer in the per-protocol population. The patients’ median age was 63 years (range, 30-88 years).
Among the 377 patients randomized to the CTC arm, those with counts at or above 5 CTCs per 7.5 mL received chemotherapy, while those with a lower count received endocrine therapy.
The 378 patients in the standard-care group received endocrine therapy or chemotherapy based on provider choice guided by clinical factors.
Chemotherapy was given to 37% of patients in the CTC arm and 27% of those in the standard arm.
The median PFS was 15.5 months in the CTC arm and 13.9 months in the standard arm, which meant the primary endpoint of noninferiority was met (hazard ratio, 0.94; 90% confidence interval, 0.81-1.09).
Age older than 60 years was the only baseline characteristic associated with better PFS with CTC-driven decision-making. This may be because of the greater “use of endocrine therapy as the clinically favored treatment, whatever the other clinicopathologic characteristics,” in older subjects, the investigators wrote.
As with PFS, the median OS was similar between the study arms – 47.3 months in the CTC arm and 42.8 months in the standard arm (HR, 0.91; 95% CI, 0.71-1.16).
‘Not good enough’
The investigators behind this study had “a worthy goal,” according to authors of a related editorial.
Without “predictive biomarkers, we are left with our clinical knowledge, experience, and intuition. Patients are left with uncertainty, doubt, and fear,” Tarah Ballinger, MD,, of Indiana University, Indianapolis, and colleagues wrote in the editorial.
However, the editorialists had concerns about the findings. For one thing, the investigators hypothesized that relying on CTC would lead to a deescalation from chemotherapy to endocrine therapy, but use of chemotherapy was actually 10% higher in the CTC arm.
“Adding to or replacing the parameters we use to make a clinical decision should help us improve the lives of patients. ... We should demand an improvement in outcomes before accepting a strategy that exposes more patients to more toxic therapy. Not worse simply is not good enough,” the editorialists wrote.
In addition, the trial was completed before CDK4/6 inhibitors became a standard add-on with endocrine therapy for hormone receptor–positive, HER2-negative patients.
“The overall response rate to CDK4/6 inhibitor therapy is higher than with traditional chemotherapy, and several randomized trials have failed to show a survival benefit of upfront chemotherapy compared with CDK4/6 inhibitor use. ... Thus, it is even less likely that we can assume that baseline high CTC count corresponds to a need for chemotherapy in a modern treatment landscape that offers more patients more benefit from hormone therapy,” Dr. Ballinger and colleagues wrote.
The editorialists concluded that CTC count “alone at baseline primarily reflects disease bulk, much like anatomic staging, rather than disease biology. As treatments become more rooted in our knowledge of breast cancer biology, decisions based on disease bulk are decidedly out of place.”
Perhaps a better use, they suggested, is for treatment personalization. For instance, patients with persistently elevated CTCs despite standard approaches could consider trials of novel targeted therapies, or CTCs could be sequenced to identify actionable molecular targets, achieving a “clinical utility that merely counting CTCs lacks,” the editorialists wrote.
This study was funded by the Institut Curie, the French National Cancer Institute, and Menarini Silicon Biosystems, the maker of the CTC assay used in the trial. The investigators disclosed relationships with Menarini and many other companies. Dr. Ballinger receives honoraria from Medscape, which is owned by the same company as this news organization.
SOURCE: Bidard FC et al. JAMA Oncol. 2020 Nov 5. doi: 10.1001/jamaoncol.2020.5660.
investigators wrote in JAMA Oncology.
However, authors of a related editorial suggested CTC counts are not adequate for guiding treatment choice in this population.
In a phase 3 trial, investigators compared the use of CTC counts and the use of clinical factors to guide the decision between chemotherapy and endocrine therapy. Results showed similar progression-free survival (PFS) and overall survival (OS) with both methods but more chemotherapy use with the CTC method.
“The results of this trial demonstrate the reliability and clinical utility of CTC count to guide the choice between single-agent endocrine therapy and chemotherapy as first-line treatment,” but “at the cost of a higher proportion of patients treated with chemotherapy,” study author François-Clement Bidard, MD, PhD, of Institut Curie in Saint-Cloud, France, and colleagues wrote.
The investigators explained that endocrine therapy is the preferred first-line treatment option in this patient population, but chemotherapy is used when women are in visceral crisis, with rapidly progressive, symptomatic disease. The decision usually rests on clinical factors, such as tumor subtype and performance status, but there’s interphysician variability.
The team hoped to find a “more reliable, standardized, and reproducible” biomarker to help remove some of the uncertainty from the situation. They tested CTC count, a well-established prognostic indicator of PFS and OS, as a candidate.
Study results
The trial included 755 patients with hormone receptor–positive, HER2-negative breast cancer in the per-protocol population. The patients’ median age was 63 years (range, 30-88 years).
Among the 377 patients randomized to the CTC arm, those with counts at or above 5 CTCs per 7.5 mL received chemotherapy, while those with a lower count received endocrine therapy.
The 378 patients in the standard-care group received endocrine therapy or chemotherapy based on provider choice guided by clinical factors.
Chemotherapy was given to 37% of patients in the CTC arm and 27% of those in the standard arm.
The median PFS was 15.5 months in the CTC arm and 13.9 months in the standard arm, which meant the primary endpoint of noninferiority was met (hazard ratio, 0.94; 90% confidence interval, 0.81-1.09).
Age older than 60 years was the only baseline characteristic associated with better PFS with CTC-driven decision-making. This may be because of the greater “use of endocrine therapy as the clinically favored treatment, whatever the other clinicopathologic characteristics,” in older subjects, the investigators wrote.
As with PFS, the median OS was similar between the study arms – 47.3 months in the CTC arm and 42.8 months in the standard arm (HR, 0.91; 95% CI, 0.71-1.16).
‘Not good enough’
The investigators behind this study had “a worthy goal,” according to authors of a related editorial.
Without “predictive biomarkers, we are left with our clinical knowledge, experience, and intuition. Patients are left with uncertainty, doubt, and fear,” Tarah Ballinger, MD,, of Indiana University, Indianapolis, and colleagues wrote in the editorial.
However, the editorialists had concerns about the findings. For one thing, the investigators hypothesized that relying on CTC would lead to a deescalation from chemotherapy to endocrine therapy, but use of chemotherapy was actually 10% higher in the CTC arm.
“Adding to or replacing the parameters we use to make a clinical decision should help us improve the lives of patients. ... We should demand an improvement in outcomes before accepting a strategy that exposes more patients to more toxic therapy. Not worse simply is not good enough,” the editorialists wrote.
In addition, the trial was completed before CDK4/6 inhibitors became a standard add-on with endocrine therapy for hormone receptor–positive, HER2-negative patients.
“The overall response rate to CDK4/6 inhibitor therapy is higher than with traditional chemotherapy, and several randomized trials have failed to show a survival benefit of upfront chemotherapy compared with CDK4/6 inhibitor use. ... Thus, it is even less likely that we can assume that baseline high CTC count corresponds to a need for chemotherapy in a modern treatment landscape that offers more patients more benefit from hormone therapy,” Dr. Ballinger and colleagues wrote.
The editorialists concluded that CTC count “alone at baseline primarily reflects disease bulk, much like anatomic staging, rather than disease biology. As treatments become more rooted in our knowledge of breast cancer biology, decisions based on disease bulk are decidedly out of place.”
Perhaps a better use, they suggested, is for treatment personalization. For instance, patients with persistently elevated CTCs despite standard approaches could consider trials of novel targeted therapies, or CTCs could be sequenced to identify actionable molecular targets, achieving a “clinical utility that merely counting CTCs lacks,” the editorialists wrote.
This study was funded by the Institut Curie, the French National Cancer Institute, and Menarini Silicon Biosystems, the maker of the CTC assay used in the trial. The investigators disclosed relationships with Menarini and many other companies. Dr. Ballinger receives honoraria from Medscape, which is owned by the same company as this news organization.
SOURCE: Bidard FC et al. JAMA Oncol. 2020 Nov 5. doi: 10.1001/jamaoncol.2020.5660.
investigators wrote in JAMA Oncology.
However, authors of a related editorial suggested CTC counts are not adequate for guiding treatment choice in this population.
In a phase 3 trial, investigators compared the use of CTC counts and the use of clinical factors to guide the decision between chemotherapy and endocrine therapy. Results showed similar progression-free survival (PFS) and overall survival (OS) with both methods but more chemotherapy use with the CTC method.
“The results of this trial demonstrate the reliability and clinical utility of CTC count to guide the choice between single-agent endocrine therapy and chemotherapy as first-line treatment,” but “at the cost of a higher proportion of patients treated with chemotherapy,” study author François-Clement Bidard, MD, PhD, of Institut Curie in Saint-Cloud, France, and colleagues wrote.
The investigators explained that endocrine therapy is the preferred first-line treatment option in this patient population, but chemotherapy is used when women are in visceral crisis, with rapidly progressive, symptomatic disease. The decision usually rests on clinical factors, such as tumor subtype and performance status, but there’s interphysician variability.
The team hoped to find a “more reliable, standardized, and reproducible” biomarker to help remove some of the uncertainty from the situation. They tested CTC count, a well-established prognostic indicator of PFS and OS, as a candidate.
Study results
The trial included 755 patients with hormone receptor–positive, HER2-negative breast cancer in the per-protocol population. The patients’ median age was 63 years (range, 30-88 years).
Among the 377 patients randomized to the CTC arm, those with counts at or above 5 CTCs per 7.5 mL received chemotherapy, while those with a lower count received endocrine therapy.
The 378 patients in the standard-care group received endocrine therapy or chemotherapy based on provider choice guided by clinical factors.
Chemotherapy was given to 37% of patients in the CTC arm and 27% of those in the standard arm.
The median PFS was 15.5 months in the CTC arm and 13.9 months in the standard arm, which meant the primary endpoint of noninferiority was met (hazard ratio, 0.94; 90% confidence interval, 0.81-1.09).
Age older than 60 years was the only baseline characteristic associated with better PFS with CTC-driven decision-making. This may be because of the greater “use of endocrine therapy as the clinically favored treatment, whatever the other clinicopathologic characteristics,” in older subjects, the investigators wrote.
As with PFS, the median OS was similar between the study arms – 47.3 months in the CTC arm and 42.8 months in the standard arm (HR, 0.91; 95% CI, 0.71-1.16).
‘Not good enough’
The investigators behind this study had “a worthy goal,” according to authors of a related editorial.
Without “predictive biomarkers, we are left with our clinical knowledge, experience, and intuition. Patients are left with uncertainty, doubt, and fear,” Tarah Ballinger, MD,, of Indiana University, Indianapolis, and colleagues wrote in the editorial.
However, the editorialists had concerns about the findings. For one thing, the investigators hypothesized that relying on CTC would lead to a deescalation from chemotherapy to endocrine therapy, but use of chemotherapy was actually 10% higher in the CTC arm.
“Adding to or replacing the parameters we use to make a clinical decision should help us improve the lives of patients. ... We should demand an improvement in outcomes before accepting a strategy that exposes more patients to more toxic therapy. Not worse simply is not good enough,” the editorialists wrote.
In addition, the trial was completed before CDK4/6 inhibitors became a standard add-on with endocrine therapy for hormone receptor–positive, HER2-negative patients.
“The overall response rate to CDK4/6 inhibitor therapy is higher than with traditional chemotherapy, and several randomized trials have failed to show a survival benefit of upfront chemotherapy compared with CDK4/6 inhibitor use. ... Thus, it is even less likely that we can assume that baseline high CTC count corresponds to a need for chemotherapy in a modern treatment landscape that offers more patients more benefit from hormone therapy,” Dr. Ballinger and colleagues wrote.
The editorialists concluded that CTC count “alone at baseline primarily reflects disease bulk, much like anatomic staging, rather than disease biology. As treatments become more rooted in our knowledge of breast cancer biology, decisions based on disease bulk are decidedly out of place.”
Perhaps a better use, they suggested, is for treatment personalization. For instance, patients with persistently elevated CTCs despite standard approaches could consider trials of novel targeted therapies, or CTCs could be sequenced to identify actionable molecular targets, achieving a “clinical utility that merely counting CTCs lacks,” the editorialists wrote.
This study was funded by the Institut Curie, the French National Cancer Institute, and Menarini Silicon Biosystems, the maker of the CTC assay used in the trial. The investigators disclosed relationships with Menarini and many other companies. Dr. Ballinger receives honoraria from Medscape, which is owned by the same company as this news organization.
SOURCE: Bidard FC et al. JAMA Oncol. 2020 Nov 5. doi: 10.1001/jamaoncol.2020.5660.
FROM JAMA ONCOLOGY
Reduced cancer mortality with Medicaid expansion
Researchers reviewed data on 523,802 patients in the National Cancer Database who were diagnosed with cancer from 2012 through 2015. Slightly more than half of patients (55.2%) lived in Medicaid expansion states.
After expansion, mortality significantly decreased in expansion states (hazard ratio, 0.98; P = .008) but not in nonexpansion states (HR, 1.01; P = .43). The difference was significant in a difference-in-difference analysis (HR, 1.03; P = .01).
Across 69,000 patients with newly diagnosed cancer in Medicaid expansion states, the 2% decrease in the hazard of death would translate to 1,384 lives saved annually.
The benefit was primarily observed in patients with nonmetastatic cancer. For patients with stage I-III cancer, the risk of death was increased in nonexpansion states (HR, 1.05; P < .001) and unchanged in expansion states (HR, 0.99; P = .64). Mortality significantly improved in expansion states vs. nonexpansion states (HR, 1.05; P = .003).
For patients with stage IV cancer, both expansion and nonexpansion states had improvements in mortality, but the differences were not significant.
“Earlier stage at diagnosis appears to explain the mortality improvement,” wrote study author Miranda Lam, MD, of Harvard Medical School, Boston, and colleagues.
Clinical benefits, ‘no economic downside’
Under the Affordable Care Act, passed in 2010, states have the option of expanding Medicaid eligibility to adults with incomes at or below 138% of the federal poverty level. As of March 2020, 36 states and the District of Columbia had expanded Medicaid, with more than 20 million residents obtaining coverage.
Previous studies have associated Medicaid expansion with fewer patients being uninsured, increased cancer screening, and earlier stage of diagnosis, as well as reduced racial disparities in access to high-volume hospitals for cancer surgery and increased rates of cancer surgery among low-income patients.
“This study adds to an increasingly large body of research finding that Medicaid expansion has improved our ability to fight cancer,” said Coleman Drake, PhD, of the University of Pittsburgh, who was not involved in this study.
“Obtaining health insurance through Medicaid allows patients to receive recommended preventive cancer screenings, which explains the increase in early-stage diagnosis rates. Detecting cancer early is critical for successful cancer treatment,” Dr. Drake noted.
“It is hard to overstate the positive effects of Medicaid expansion on health outcomes. At the same time, concerns that Medicaid expansion would be costly to state governments’ budgets have not been realized. In short, Medicaid expansion yields many benefits and has no economic downside for state policymakers. Clinical and economic evidence make an overwhelming case for states to expand Medicaid,” Dr. Drake said.
Significant difference for lung cancer
Most patients in this study were women (73.6%), and the patients’ mean age was 54.8 years (range, 40-64 years). Patients had newly diagnosed breast cancer (52.2%), colorectal cancer (21.3%), and lung cancer (26.5%).
The benefits of Medicaid expansion persisted after adjustment for education, income, insurance, and race.
The lower mortality in expansion states compared with nonexpansion states was similar across all three cancer types. However, in stratified analyses, the difference was significant only for lung cancer (P = .03).
“Lung cancer has a higher mortality rate than breast and colorectal cancer, and with longer follow-up, it is possible that the lower mortality rates seen for breast and colorectal cancer may also become significant,” the authors wrote.
This research was funded by Harvard Catalyst, the Harvard Clinical and Translational Science Center, and the National Center for Advancing Translational Sciences at the National Institutes of Health. The investigators and Dr. Drake had no relevant disclosures.
SOURCE: Lam MB et al. JAMA Netw Open. 2020 Nov 2;3(11):e2024366.
Researchers reviewed data on 523,802 patients in the National Cancer Database who were diagnosed with cancer from 2012 through 2015. Slightly more than half of patients (55.2%) lived in Medicaid expansion states.
After expansion, mortality significantly decreased in expansion states (hazard ratio, 0.98; P = .008) but not in nonexpansion states (HR, 1.01; P = .43). The difference was significant in a difference-in-difference analysis (HR, 1.03; P = .01).
Across 69,000 patients with newly diagnosed cancer in Medicaid expansion states, the 2% decrease in the hazard of death would translate to 1,384 lives saved annually.
The benefit was primarily observed in patients with nonmetastatic cancer. For patients with stage I-III cancer, the risk of death was increased in nonexpansion states (HR, 1.05; P < .001) and unchanged in expansion states (HR, 0.99; P = .64). Mortality significantly improved in expansion states vs. nonexpansion states (HR, 1.05; P = .003).
For patients with stage IV cancer, both expansion and nonexpansion states had improvements in mortality, but the differences were not significant.
“Earlier stage at diagnosis appears to explain the mortality improvement,” wrote study author Miranda Lam, MD, of Harvard Medical School, Boston, and colleagues.
Clinical benefits, ‘no economic downside’
Under the Affordable Care Act, passed in 2010, states have the option of expanding Medicaid eligibility to adults with incomes at or below 138% of the federal poverty level. As of March 2020, 36 states and the District of Columbia had expanded Medicaid, with more than 20 million residents obtaining coverage.
Previous studies have associated Medicaid expansion with fewer patients being uninsured, increased cancer screening, and earlier stage of diagnosis, as well as reduced racial disparities in access to high-volume hospitals for cancer surgery and increased rates of cancer surgery among low-income patients.
“This study adds to an increasingly large body of research finding that Medicaid expansion has improved our ability to fight cancer,” said Coleman Drake, PhD, of the University of Pittsburgh, who was not involved in this study.
“Obtaining health insurance through Medicaid allows patients to receive recommended preventive cancer screenings, which explains the increase in early-stage diagnosis rates. Detecting cancer early is critical for successful cancer treatment,” Dr. Drake noted.
“It is hard to overstate the positive effects of Medicaid expansion on health outcomes. At the same time, concerns that Medicaid expansion would be costly to state governments’ budgets have not been realized. In short, Medicaid expansion yields many benefits and has no economic downside for state policymakers. Clinical and economic evidence make an overwhelming case for states to expand Medicaid,” Dr. Drake said.
Significant difference for lung cancer
Most patients in this study were women (73.6%), and the patients’ mean age was 54.8 years (range, 40-64 years). Patients had newly diagnosed breast cancer (52.2%), colorectal cancer (21.3%), and lung cancer (26.5%).
The benefits of Medicaid expansion persisted after adjustment for education, income, insurance, and race.
The lower mortality in expansion states compared with nonexpansion states was similar across all three cancer types. However, in stratified analyses, the difference was significant only for lung cancer (P = .03).
“Lung cancer has a higher mortality rate than breast and colorectal cancer, and with longer follow-up, it is possible that the lower mortality rates seen for breast and colorectal cancer may also become significant,” the authors wrote.
This research was funded by Harvard Catalyst, the Harvard Clinical and Translational Science Center, and the National Center for Advancing Translational Sciences at the National Institutes of Health. The investigators and Dr. Drake had no relevant disclosures.
SOURCE: Lam MB et al. JAMA Netw Open. 2020 Nov 2;3(11):e2024366.
Researchers reviewed data on 523,802 patients in the National Cancer Database who were diagnosed with cancer from 2012 through 2015. Slightly more than half of patients (55.2%) lived in Medicaid expansion states.
After expansion, mortality significantly decreased in expansion states (hazard ratio, 0.98; P = .008) but not in nonexpansion states (HR, 1.01; P = .43). The difference was significant in a difference-in-difference analysis (HR, 1.03; P = .01).
Across 69,000 patients with newly diagnosed cancer in Medicaid expansion states, the 2% decrease in the hazard of death would translate to 1,384 lives saved annually.
The benefit was primarily observed in patients with nonmetastatic cancer. For patients with stage I-III cancer, the risk of death was increased in nonexpansion states (HR, 1.05; P < .001) and unchanged in expansion states (HR, 0.99; P = .64). Mortality significantly improved in expansion states vs. nonexpansion states (HR, 1.05; P = .003).
For patients with stage IV cancer, both expansion and nonexpansion states had improvements in mortality, but the differences were not significant.
“Earlier stage at diagnosis appears to explain the mortality improvement,” wrote study author Miranda Lam, MD, of Harvard Medical School, Boston, and colleagues.
Clinical benefits, ‘no economic downside’
Under the Affordable Care Act, passed in 2010, states have the option of expanding Medicaid eligibility to adults with incomes at or below 138% of the federal poverty level. As of March 2020, 36 states and the District of Columbia had expanded Medicaid, with more than 20 million residents obtaining coverage.
Previous studies have associated Medicaid expansion with fewer patients being uninsured, increased cancer screening, and earlier stage of diagnosis, as well as reduced racial disparities in access to high-volume hospitals for cancer surgery and increased rates of cancer surgery among low-income patients.
“This study adds to an increasingly large body of research finding that Medicaid expansion has improved our ability to fight cancer,” said Coleman Drake, PhD, of the University of Pittsburgh, who was not involved in this study.
“Obtaining health insurance through Medicaid allows patients to receive recommended preventive cancer screenings, which explains the increase in early-stage diagnosis rates. Detecting cancer early is critical for successful cancer treatment,” Dr. Drake noted.
“It is hard to overstate the positive effects of Medicaid expansion on health outcomes. At the same time, concerns that Medicaid expansion would be costly to state governments’ budgets have not been realized. In short, Medicaid expansion yields many benefits and has no economic downside for state policymakers. Clinical and economic evidence make an overwhelming case for states to expand Medicaid,” Dr. Drake said.
Significant difference for lung cancer
Most patients in this study were women (73.6%), and the patients’ mean age was 54.8 years (range, 40-64 years). Patients had newly diagnosed breast cancer (52.2%), colorectal cancer (21.3%), and lung cancer (26.5%).
The benefits of Medicaid expansion persisted after adjustment for education, income, insurance, and race.
The lower mortality in expansion states compared with nonexpansion states was similar across all three cancer types. However, in stratified analyses, the difference was significant only for lung cancer (P = .03).
“Lung cancer has a higher mortality rate than breast and colorectal cancer, and with longer follow-up, it is possible that the lower mortality rates seen for breast and colorectal cancer may also become significant,” the authors wrote.
This research was funded by Harvard Catalyst, the Harvard Clinical and Translational Science Center, and the National Center for Advancing Translational Sciences at the National Institutes of Health. The investigators and Dr. Drake had no relevant disclosures.
SOURCE: Lam MB et al. JAMA Netw Open. 2020 Nov 2;3(11):e2024366.
FROM JAMA OPEN NETWORK
New findings on ‘exceptional responders’ to cancer therapies
An ongoing research project is studying why some patients have exceptional responses. The researchers have found particular molecular features in the tumors of about a quarter of these patients. In some cases, there are multiple rare genetic changes in the tumor genome. In other cases, the tumors are infiltrated with certain types of immune cells.
The findings were published online November 19 in Cancer Cell. They come from a genomic analysis of tumor biopsy specimens from 111 patients who were identified by the National Cancer Institute’s (NCI’s) Exceptional Responders Initiative, a national project launched in 2014.
An exceptional responder is defined as an individual who achieves a partial or complete response to a treatment that would be effective in fewer than 10% of similar patients. For exceptional response, the duration of response is at least three times longer than the usual median response time.
In this study of 111 such patients, about one quarter (24%, n = 26 patients) were found to have tumors in which there were molecular features that could potentially explain exceptional responses to treatment.
“We won’t be able to identify, in every patient, which particular drugs will be beneficial,” said Louis Staudt, MD, PhD, director of the NCI’s Center for Cancer Genomics, who co-led the study. “We are nowhere near that. But what it does say is that we have identified particular mutations, some of which we knew about in some types of cancer but can also occur less commonly in other cancer types.”
Staudt noted that these mutations can “illuminate” the path that the cancer will take — and potentially can be used to predict whether the cancer will be aggressive and will require treatment or could be managed with surveillance. This is why this research can be useful in the short term, he said.
“In the longer term, this is the kind of research that inspires future work,” he told Medscape Medical News. “That would encompass clinical trials involving drugs that target some of the pathways we found to be genetically inactivated in some of these responders.”
These results support the use of genetic testing in routine clinical care, he said.
Earlier this year, the NCI team published the results of a pilot study that affirmed the feasibility of this approach. Of the more than 100 cases that were analyzed, six were identified as involving potentially clinically actionable germline mutations.
‘Curiosity drove the research’
“We had these wonderful and gratifying experiences with our patients, so we were immediately curious how that happened, so it was pretty much that curiosity that drove a lot of this work,” said Staudt.
In the current study, Staudt and colleagues used multiple genomic methodologies to detect mutations, copy number changes, aberrant methylation, outlier gene expression, and the cellular makeup of the tumor microenvironment.
The hypothesized mechanisms for exceptional responses were broadly divided into the following four categories: DNA damage response (n = 15), intracellular signaling pathway (n = 9), prognostic genetics (n = 9), and immunologic engagement (n = 16). For many patients, two or more of these mechanisms were involved.
The authors note that the “predominance of plausible DNA damage response mechanisms parallels the frequent use of cytotoxic chemotherapy in routine cancer treatment reflected in this cohort.”
Twenty-six patients were identified as exceptional responders. Among these patients, a variety of cancer types was represented: brain (8); gastrointestinal tract (6); breast (4); cholangiocarcinoma (2); lung (2); pancreas, endometrium, ovarian, and bladder (1 each). Many of these patients (65%, n = 17) were treated with chemotherapy that included DNA-damaging agents. For more than half (54%, n = 14), targeted therapies were used, and some patients received both.
The authors highlight several patients as examples of exceptional responders:
- One patient with glioblastoma multiforme (GBM) was treated sequentially with surgery, localized carmustine, and radiotherapy. When the cancer recurred, temozolomide was administered. This induced a complete response that has lasted for more than a decade.
- A patient with metastatic colon adenocarcinoma has had an ongoing and nearly complete response that has lasted 45 months (last follow-up) after receiving temozolomide in combination with the investigational drug TRC102 (methoxyamine, under development by Tracon) in a phase 1 clinical trial. TRC102 is an inhibitor of the DNA base excision repair pathway, which is a pathway that causes resistance to alkylating and antimetabolite chemotherapeutics.
- A patient with metastatic, estrogen receptor–positive breast cancer received trastuzumab because of a high-level ERBB2 amplification, together with anastrozole. This resulted in an ongoing 2.4-year partial response.
- Although the patient was clinically HER2 positive, her tumor had exceedingly low expression of ERBB2 mRNA. Molecular profiling had classified the tumor as of the basal-like subtype rather than the HER2-enriched subtype. This meant that it was unlikely that trastuzumab contributed to the exceptional response, the authors note. Because the patient was estrogen-receptor positive, she received anastrozole, an inhibitor of aromatase (CYP19A), which converts testosterone into estradiol.
- A patient who had a gastrointestinal stromal tumor with a deletion of KIT exon 11 experienced relapse after an initial response to imatinib, which targets KIT and other tyrosine kinases, but then achieved a complete response with sunitinib. Gene expression profiling revealed high expression not only of KIT but also of genes encoding several tyrosine kinases that are targeted by sunitinib (KDR, FLT1, and FLT3). This may have accounted for the patient’s response.
Favorable genomic characteristics
The authors defined a “prognostic genetics” category of tumors, characterized by genetic lesions that are now known to be associated with a favorable prognosis but that were not addressed through routine care that these patients received when they were first diagnosed. Although the patients experienced relapse after first-line treatment, their exceptional survival after salvage therapy could be linked to favorable genomic characteristics.
For example, several of the patients with high-grade GBMs and astrocytomas had genetic lesions that are generally more common in low-grade glioma and that have been associated with an indolent clinical course following standard therapy.
The authors also assessed immune response. Examining immune cell infiltration in responder tumors in comparison with control cases, the team found that signatures of B cells and activated (CD56dim) natural killer cells were higher in exceptional-responder tumors.
In one patient with metastatic urothelial cancer who experienced disease progression after chemotherapy, radiotherapy, and surgery, treatment with nivolumab produced a complete response that lasted 7 months. Such an outcome occurs in only about 3% of bladder cancer patients. The tumor expressed high mRNA levels of PDCD1, which encodes the nivolumab target PD-1, and CD274, which encodes the PD-1 ligand PD-L1. There was also a high level of amplification of IFNG, which encodes interferon-gamma, a cytokine that has been linked to favorable response to immune checkpoint blockade.
Moving to precision medicine
“It is very valuable to be tested up front and again when the disease progresses, because there may have been some genetic changes, and this may change the treatment,” said co–lead author S. Percy Ivy, MD, of the NCI’s Division of Cancer Treatment and Diagnosis.
“The goal of this study was to understand what was unique about these patients and their genetic makeup that led them to be classified as exceptional responders, and hopefully we will be able to tease that out,” she added.
“As researchers, we have a lot to learn from these patients, and they have a lot to teach us,” she added. “In the future, they will help us as we move closer to the goal of delivering precision oncology to all of our patients. We’re not there yet, but every time we study more deeply and learn more, we are able to provide better care.”
To encourage participation in this effort by investigators around the world, the NCI team and their colleagues have made their molecular profiling results and clinical information publicly available in the NCI Genomic Data Commons.
The study was supported by the NCI’s Intramural Research Program, the National Institutes of Health, the Center for Cancer Research, and the NCI’s Center for Cancer Genomics. Staudt and Ivy have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
An ongoing research project is studying why some patients have exceptional responses. The researchers have found particular molecular features in the tumors of about a quarter of these patients. In some cases, there are multiple rare genetic changes in the tumor genome. In other cases, the tumors are infiltrated with certain types of immune cells.
The findings were published online November 19 in Cancer Cell. They come from a genomic analysis of tumor biopsy specimens from 111 patients who were identified by the National Cancer Institute’s (NCI’s) Exceptional Responders Initiative, a national project launched in 2014.
An exceptional responder is defined as an individual who achieves a partial or complete response to a treatment that would be effective in fewer than 10% of similar patients. For exceptional response, the duration of response is at least three times longer than the usual median response time.
In this study of 111 such patients, about one quarter (24%, n = 26 patients) were found to have tumors in which there were molecular features that could potentially explain exceptional responses to treatment.
“We won’t be able to identify, in every patient, which particular drugs will be beneficial,” said Louis Staudt, MD, PhD, director of the NCI’s Center for Cancer Genomics, who co-led the study. “We are nowhere near that. But what it does say is that we have identified particular mutations, some of which we knew about in some types of cancer but can also occur less commonly in other cancer types.”
Staudt noted that these mutations can “illuminate” the path that the cancer will take — and potentially can be used to predict whether the cancer will be aggressive and will require treatment or could be managed with surveillance. This is why this research can be useful in the short term, he said.
“In the longer term, this is the kind of research that inspires future work,” he told Medscape Medical News. “That would encompass clinical trials involving drugs that target some of the pathways we found to be genetically inactivated in some of these responders.”
These results support the use of genetic testing in routine clinical care, he said.
Earlier this year, the NCI team published the results of a pilot study that affirmed the feasibility of this approach. Of the more than 100 cases that were analyzed, six were identified as involving potentially clinically actionable germline mutations.
‘Curiosity drove the research’
“We had these wonderful and gratifying experiences with our patients, so we were immediately curious how that happened, so it was pretty much that curiosity that drove a lot of this work,” said Staudt.
In the current study, Staudt and colleagues used multiple genomic methodologies to detect mutations, copy number changes, aberrant methylation, outlier gene expression, and the cellular makeup of the tumor microenvironment.
The hypothesized mechanisms for exceptional responses were broadly divided into the following four categories: DNA damage response (n = 15), intracellular signaling pathway (n = 9), prognostic genetics (n = 9), and immunologic engagement (n = 16). For many patients, two or more of these mechanisms were involved.
The authors note that the “predominance of plausible DNA damage response mechanisms parallels the frequent use of cytotoxic chemotherapy in routine cancer treatment reflected in this cohort.”
Twenty-six patients were identified as exceptional responders. Among these patients, a variety of cancer types was represented: brain (8); gastrointestinal tract (6); breast (4); cholangiocarcinoma (2); lung (2); pancreas, endometrium, ovarian, and bladder (1 each). Many of these patients (65%, n = 17) were treated with chemotherapy that included DNA-damaging agents. For more than half (54%, n = 14), targeted therapies were used, and some patients received both.
The authors highlight several patients as examples of exceptional responders:
- One patient with glioblastoma multiforme (GBM) was treated sequentially with surgery, localized carmustine, and radiotherapy. When the cancer recurred, temozolomide was administered. This induced a complete response that has lasted for more than a decade.
- A patient with metastatic colon adenocarcinoma has had an ongoing and nearly complete response that has lasted 45 months (last follow-up) after receiving temozolomide in combination with the investigational drug TRC102 (methoxyamine, under development by Tracon) in a phase 1 clinical trial. TRC102 is an inhibitor of the DNA base excision repair pathway, which is a pathway that causes resistance to alkylating and antimetabolite chemotherapeutics.
- A patient with metastatic, estrogen receptor–positive breast cancer received trastuzumab because of a high-level ERBB2 amplification, together with anastrozole. This resulted in an ongoing 2.4-year partial response.
- Although the patient was clinically HER2 positive, her tumor had exceedingly low expression of ERBB2 mRNA. Molecular profiling had classified the tumor as of the basal-like subtype rather than the HER2-enriched subtype. This meant that it was unlikely that trastuzumab contributed to the exceptional response, the authors note. Because the patient was estrogen-receptor positive, she received anastrozole, an inhibitor of aromatase (CYP19A), which converts testosterone into estradiol.
- A patient who had a gastrointestinal stromal tumor with a deletion of KIT exon 11 experienced relapse after an initial response to imatinib, which targets KIT and other tyrosine kinases, but then achieved a complete response with sunitinib. Gene expression profiling revealed high expression not only of KIT but also of genes encoding several tyrosine kinases that are targeted by sunitinib (KDR, FLT1, and FLT3). This may have accounted for the patient’s response.
Favorable genomic characteristics
The authors defined a “prognostic genetics” category of tumors, characterized by genetic lesions that are now known to be associated with a favorable prognosis but that were not addressed through routine care that these patients received when they were first diagnosed. Although the patients experienced relapse after first-line treatment, their exceptional survival after salvage therapy could be linked to favorable genomic characteristics.
For example, several of the patients with high-grade GBMs and astrocytomas had genetic lesions that are generally more common in low-grade glioma and that have been associated with an indolent clinical course following standard therapy.
The authors also assessed immune response. Examining immune cell infiltration in responder tumors in comparison with control cases, the team found that signatures of B cells and activated (CD56dim) natural killer cells were higher in exceptional-responder tumors.
In one patient with metastatic urothelial cancer who experienced disease progression after chemotherapy, radiotherapy, and surgery, treatment with nivolumab produced a complete response that lasted 7 months. Such an outcome occurs in only about 3% of bladder cancer patients. The tumor expressed high mRNA levels of PDCD1, which encodes the nivolumab target PD-1, and CD274, which encodes the PD-1 ligand PD-L1. There was also a high level of amplification of IFNG, which encodes interferon-gamma, a cytokine that has been linked to favorable response to immune checkpoint blockade.
Moving to precision medicine
“It is very valuable to be tested up front and again when the disease progresses, because there may have been some genetic changes, and this may change the treatment,” said co–lead author S. Percy Ivy, MD, of the NCI’s Division of Cancer Treatment and Diagnosis.
“The goal of this study was to understand what was unique about these patients and their genetic makeup that led them to be classified as exceptional responders, and hopefully we will be able to tease that out,” she added.
“As researchers, we have a lot to learn from these patients, and they have a lot to teach us,” she added. “In the future, they will help us as we move closer to the goal of delivering precision oncology to all of our patients. We’re not there yet, but every time we study more deeply and learn more, we are able to provide better care.”
To encourage participation in this effort by investigators around the world, the NCI team and their colleagues have made their molecular profiling results and clinical information publicly available in the NCI Genomic Data Commons.
The study was supported by the NCI’s Intramural Research Program, the National Institutes of Health, the Center for Cancer Research, and the NCI’s Center for Cancer Genomics. Staudt and Ivy have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
An ongoing research project is studying why some patients have exceptional responses. The researchers have found particular molecular features in the tumors of about a quarter of these patients. In some cases, there are multiple rare genetic changes in the tumor genome. In other cases, the tumors are infiltrated with certain types of immune cells.
The findings were published online November 19 in Cancer Cell. They come from a genomic analysis of tumor biopsy specimens from 111 patients who were identified by the National Cancer Institute’s (NCI’s) Exceptional Responders Initiative, a national project launched in 2014.
An exceptional responder is defined as an individual who achieves a partial or complete response to a treatment that would be effective in fewer than 10% of similar patients. For exceptional response, the duration of response is at least three times longer than the usual median response time.
In this study of 111 such patients, about one quarter (24%, n = 26 patients) were found to have tumors in which there were molecular features that could potentially explain exceptional responses to treatment.
“We won’t be able to identify, in every patient, which particular drugs will be beneficial,” said Louis Staudt, MD, PhD, director of the NCI’s Center for Cancer Genomics, who co-led the study. “We are nowhere near that. But what it does say is that we have identified particular mutations, some of which we knew about in some types of cancer but can also occur less commonly in other cancer types.”
Staudt noted that these mutations can “illuminate” the path that the cancer will take — and potentially can be used to predict whether the cancer will be aggressive and will require treatment or could be managed with surveillance. This is why this research can be useful in the short term, he said.
“In the longer term, this is the kind of research that inspires future work,” he told Medscape Medical News. “That would encompass clinical trials involving drugs that target some of the pathways we found to be genetically inactivated in some of these responders.”
These results support the use of genetic testing in routine clinical care, he said.
Earlier this year, the NCI team published the results of a pilot study that affirmed the feasibility of this approach. Of the more than 100 cases that were analyzed, six were identified as involving potentially clinically actionable germline mutations.
‘Curiosity drove the research’
“We had these wonderful and gratifying experiences with our patients, so we were immediately curious how that happened, so it was pretty much that curiosity that drove a lot of this work,” said Staudt.
In the current study, Staudt and colleagues used multiple genomic methodologies to detect mutations, copy number changes, aberrant methylation, outlier gene expression, and the cellular makeup of the tumor microenvironment.
The hypothesized mechanisms for exceptional responses were broadly divided into the following four categories: DNA damage response (n = 15), intracellular signaling pathway (n = 9), prognostic genetics (n = 9), and immunologic engagement (n = 16). For many patients, two or more of these mechanisms were involved.
The authors note that the “predominance of plausible DNA damage response mechanisms parallels the frequent use of cytotoxic chemotherapy in routine cancer treatment reflected in this cohort.”
Twenty-six patients were identified as exceptional responders. Among these patients, a variety of cancer types was represented: brain (8); gastrointestinal tract (6); breast (4); cholangiocarcinoma (2); lung (2); pancreas, endometrium, ovarian, and bladder (1 each). Many of these patients (65%, n = 17) were treated with chemotherapy that included DNA-damaging agents. For more than half (54%, n = 14), targeted therapies were used, and some patients received both.
The authors highlight several patients as examples of exceptional responders:
- One patient with glioblastoma multiforme (GBM) was treated sequentially with surgery, localized carmustine, and radiotherapy. When the cancer recurred, temozolomide was administered. This induced a complete response that has lasted for more than a decade.
- A patient with metastatic colon adenocarcinoma has had an ongoing and nearly complete response that has lasted 45 months (last follow-up) after receiving temozolomide in combination with the investigational drug TRC102 (methoxyamine, under development by Tracon) in a phase 1 clinical trial. TRC102 is an inhibitor of the DNA base excision repair pathway, which is a pathway that causes resistance to alkylating and antimetabolite chemotherapeutics.
- A patient with metastatic, estrogen receptor–positive breast cancer received trastuzumab because of a high-level ERBB2 amplification, together with anastrozole. This resulted in an ongoing 2.4-year partial response.
- Although the patient was clinically HER2 positive, her tumor had exceedingly low expression of ERBB2 mRNA. Molecular profiling had classified the tumor as of the basal-like subtype rather than the HER2-enriched subtype. This meant that it was unlikely that trastuzumab contributed to the exceptional response, the authors note. Because the patient was estrogen-receptor positive, she received anastrozole, an inhibitor of aromatase (CYP19A), which converts testosterone into estradiol.
- A patient who had a gastrointestinal stromal tumor with a deletion of KIT exon 11 experienced relapse after an initial response to imatinib, which targets KIT and other tyrosine kinases, but then achieved a complete response with sunitinib. Gene expression profiling revealed high expression not only of KIT but also of genes encoding several tyrosine kinases that are targeted by sunitinib (KDR, FLT1, and FLT3). This may have accounted for the patient’s response.
Favorable genomic characteristics
The authors defined a “prognostic genetics” category of tumors, characterized by genetic lesions that are now known to be associated with a favorable prognosis but that were not addressed through routine care that these patients received when they were first diagnosed. Although the patients experienced relapse after first-line treatment, their exceptional survival after salvage therapy could be linked to favorable genomic characteristics.
For example, several of the patients with high-grade GBMs and astrocytomas had genetic lesions that are generally more common in low-grade glioma and that have been associated with an indolent clinical course following standard therapy.
The authors also assessed immune response. Examining immune cell infiltration in responder tumors in comparison with control cases, the team found that signatures of B cells and activated (CD56dim) natural killer cells were higher in exceptional-responder tumors.
In one patient with metastatic urothelial cancer who experienced disease progression after chemotherapy, radiotherapy, and surgery, treatment with nivolumab produced a complete response that lasted 7 months. Such an outcome occurs in only about 3% of bladder cancer patients. The tumor expressed high mRNA levels of PDCD1, which encodes the nivolumab target PD-1, and CD274, which encodes the PD-1 ligand PD-L1. There was also a high level of amplification of IFNG, which encodes interferon-gamma, a cytokine that has been linked to favorable response to immune checkpoint blockade.
Moving to precision medicine
“It is very valuable to be tested up front and again when the disease progresses, because there may have been some genetic changes, and this may change the treatment,” said co–lead author S. Percy Ivy, MD, of the NCI’s Division of Cancer Treatment and Diagnosis.
“The goal of this study was to understand what was unique about these patients and their genetic makeup that led them to be classified as exceptional responders, and hopefully we will be able to tease that out,” she added.
“As researchers, we have a lot to learn from these patients, and they have a lot to teach us,” she added. “In the future, they will help us as we move closer to the goal of delivering precision oncology to all of our patients. We’re not there yet, but every time we study more deeply and learn more, we are able to provide better care.”
To encourage participation in this effort by investigators around the world, the NCI team and their colleagues have made their molecular profiling results and clinical information publicly available in the NCI Genomic Data Commons.
The study was supported by the NCI’s Intramural Research Program, the National Institutes of Health, the Center for Cancer Research, and the NCI’s Center for Cancer Genomics. Staudt and Ivy have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Immunotherapy could fill unmet need in leptomeningeal metastases
Results from the trial were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Unfortunately, when patients present with leptomeningeal disease, they usually have a poor prognosis. Their median survival is measured at 6-24 weeks,” commented lead study author Jarushka Naidoo, MBBCh, an adjunct assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, and a consultant medical oncologist at Beaumont Hospital in Dublin.
“While there may be some standard approaches for how we treat leptomeningeal disease, there are no universal standard therapies that are efficacious across solid tumor types,” Dr. Naidoo added.
With this in mind, Dr. Naidoo and colleagues tested systemic pembrolizumab in a trial of patients with leptomeningeal metastases from solid tumors.
The trial closed early because of poor accrual, after enrolling 13 patients: 5 with breast carcinoma, 3 with high-grade glioma, 3 with non–small cell lung cancer, 1 with squamous cell carcinoma of the skin, and 1 with head and neck squamous carcinoma. Nine patients (69%) had received at least two prior lines of systemic therapy.
Response, safety, and biomarkers
Overall, five patients (38%) had a central nervous system response, as ascertained from radiologic response on MRI, cytologic response in cerebrospinal fluid (CSF), and/or clinical response in neurologic symptoms, Dr. Naidoo reported.
Two patients had a complete CNS response: a patient with squamous cell carcinoma of the skin, who was still alive at 3 years, and a patient with non–small cell lung cancer, who survived 9 months but succumbed to metastases elsewhere.
For the entire cohort, median CNS progression-free survival was 2.9 months, and median overall survival was 4.9 months.
“This is consistent with published prospective studies of systemic agents for leptomeningeal disease,” Dr. Naidoo pointed out. “Notably, even though numbers are small, we do see the tail-on-the-curve phenomenon in both of these survival curves, which is consistent with immune checkpoint blockade prospective studies.”
The rate of grade 3 or higher treatment-related adverse events was 15.4%, and there were no grade 3 or higher immune-related adverse events.
The number of patients was too small for formal correlational testing, but both patients who achieved a complete response developed immune-related adverse events.
The trial’s biomarker analyses showed that an aneuploidy assay using CSF tumor-derived DNA performed well at detecting leptomeningeal metastases, with sensitivity of 84.6%, compared with just 53.8% for CSF cytopathology (the current preferred method).
A multiplex assay of CSF cytokines identified similar baseline profiles for patients who went on to have responses and showed similar changes in profile (notably a reduction in proinflammatory cytokines) for the two patients who had complete responses.
Given the trial’s 38% CNS response rate, pembrolizumab “needs to be studied in larger populations of patients to confirm this result, but it could be used as a potential treatment option for patients with leptomeningeal disease from solid tumors,” Dr. Naidoo concluded. “Reassuringly, pembrolizumab was well tolerated, and this is extremely important in a patient population that is traditionally quite frail and in which other standard therapies that are used, such as high-dose methotrexate or intrathecal chemotherapy, are associated with far higher rates of toxicity.”
An unmet need
“Leptomeningeal metastasis is a strong unmet need, although its occurrence is fortunately quite rare,” commented Kim Margolin, MD, a clinical professor and medical oncologist at City of Hope National Medical Center in Duarte, Calif., who was not involved in this study.
The trial is noteworthy for showing activity of programmed death–1 (PD-1) blockade given only systemically and not with additional intrathecal therapy (as has been done in a concurrent study at MD Anderson Cancer Center) and for providing insight into various biomarkers, Dr. Margolin said in an interview.
“I cannot take a stand on author conclusions other than to agree it warrants further evaluation in carefully selected patients, and it would be great to compare something like peripheral PD-1 blockade alone versus in combination with intrathecal therapy versus a combination such as CTLA4 blockade plus PD-1 blockade such as our group and others have shown to have increased activity in CNS metastases over PD-1 block alone,” Dr. Margolin said.
“The drugs in this class are already approved, so there is no reason not to try them,” she noted.
However, patients with leptomeningeal metastases of melanoma, for example, are likely to have already received anti-PD-1 immunotherapy.
“So the settings in which off-the-shelf PD-1 blockade would be useful are extremely limited,” she concluded.
The current trial was funded by Merck, the National Institutes of Health, the Lung Cancer Foundation of America, the International Association for the Study of Lung Cancer, and Johns Hopkins University Seed Grants. Dr. Naidoo disclosed relationships with AstraZeneca, Merck, Bristol Myers Squibb, and Roche/Genentech. Dr. Margolin disclosed no relevant conflicts of interest.
SOURCE: Naidoo J et al. SITC 2020, Abstract 788.
Results from the trial were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Unfortunately, when patients present with leptomeningeal disease, they usually have a poor prognosis. Their median survival is measured at 6-24 weeks,” commented lead study author Jarushka Naidoo, MBBCh, an adjunct assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, and a consultant medical oncologist at Beaumont Hospital in Dublin.
“While there may be some standard approaches for how we treat leptomeningeal disease, there are no universal standard therapies that are efficacious across solid tumor types,” Dr. Naidoo added.
With this in mind, Dr. Naidoo and colleagues tested systemic pembrolizumab in a trial of patients with leptomeningeal metastases from solid tumors.
The trial closed early because of poor accrual, after enrolling 13 patients: 5 with breast carcinoma, 3 with high-grade glioma, 3 with non–small cell lung cancer, 1 with squamous cell carcinoma of the skin, and 1 with head and neck squamous carcinoma. Nine patients (69%) had received at least two prior lines of systemic therapy.
Response, safety, and biomarkers
Overall, five patients (38%) had a central nervous system response, as ascertained from radiologic response on MRI, cytologic response in cerebrospinal fluid (CSF), and/or clinical response in neurologic symptoms, Dr. Naidoo reported.
Two patients had a complete CNS response: a patient with squamous cell carcinoma of the skin, who was still alive at 3 years, and a patient with non–small cell lung cancer, who survived 9 months but succumbed to metastases elsewhere.
For the entire cohort, median CNS progression-free survival was 2.9 months, and median overall survival was 4.9 months.
“This is consistent with published prospective studies of systemic agents for leptomeningeal disease,” Dr. Naidoo pointed out. “Notably, even though numbers are small, we do see the tail-on-the-curve phenomenon in both of these survival curves, which is consistent with immune checkpoint blockade prospective studies.”
The rate of grade 3 or higher treatment-related adverse events was 15.4%, and there were no grade 3 or higher immune-related adverse events.
The number of patients was too small for formal correlational testing, but both patients who achieved a complete response developed immune-related adverse events.
The trial’s biomarker analyses showed that an aneuploidy assay using CSF tumor-derived DNA performed well at detecting leptomeningeal metastases, with sensitivity of 84.6%, compared with just 53.8% for CSF cytopathology (the current preferred method).
A multiplex assay of CSF cytokines identified similar baseline profiles for patients who went on to have responses and showed similar changes in profile (notably a reduction in proinflammatory cytokines) for the two patients who had complete responses.
Given the trial’s 38% CNS response rate, pembrolizumab “needs to be studied in larger populations of patients to confirm this result, but it could be used as a potential treatment option for patients with leptomeningeal disease from solid tumors,” Dr. Naidoo concluded. “Reassuringly, pembrolizumab was well tolerated, and this is extremely important in a patient population that is traditionally quite frail and in which other standard therapies that are used, such as high-dose methotrexate or intrathecal chemotherapy, are associated with far higher rates of toxicity.”
An unmet need
“Leptomeningeal metastasis is a strong unmet need, although its occurrence is fortunately quite rare,” commented Kim Margolin, MD, a clinical professor and medical oncologist at City of Hope National Medical Center in Duarte, Calif., who was not involved in this study.
The trial is noteworthy for showing activity of programmed death–1 (PD-1) blockade given only systemically and not with additional intrathecal therapy (as has been done in a concurrent study at MD Anderson Cancer Center) and for providing insight into various biomarkers, Dr. Margolin said in an interview.
“I cannot take a stand on author conclusions other than to agree it warrants further evaluation in carefully selected patients, and it would be great to compare something like peripheral PD-1 blockade alone versus in combination with intrathecal therapy versus a combination such as CTLA4 blockade plus PD-1 blockade such as our group and others have shown to have increased activity in CNS metastases over PD-1 block alone,” Dr. Margolin said.
“The drugs in this class are already approved, so there is no reason not to try them,” she noted.
However, patients with leptomeningeal metastases of melanoma, for example, are likely to have already received anti-PD-1 immunotherapy.
“So the settings in which off-the-shelf PD-1 blockade would be useful are extremely limited,” she concluded.
The current trial was funded by Merck, the National Institutes of Health, the Lung Cancer Foundation of America, the International Association for the Study of Lung Cancer, and Johns Hopkins University Seed Grants. Dr. Naidoo disclosed relationships with AstraZeneca, Merck, Bristol Myers Squibb, and Roche/Genentech. Dr. Margolin disclosed no relevant conflicts of interest.
SOURCE: Naidoo J et al. SITC 2020, Abstract 788.
Results from the trial were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Unfortunately, when patients present with leptomeningeal disease, they usually have a poor prognosis. Their median survival is measured at 6-24 weeks,” commented lead study author Jarushka Naidoo, MBBCh, an adjunct assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, and a consultant medical oncologist at Beaumont Hospital in Dublin.
“While there may be some standard approaches for how we treat leptomeningeal disease, there are no universal standard therapies that are efficacious across solid tumor types,” Dr. Naidoo added.
With this in mind, Dr. Naidoo and colleagues tested systemic pembrolizumab in a trial of patients with leptomeningeal metastases from solid tumors.
The trial closed early because of poor accrual, after enrolling 13 patients: 5 with breast carcinoma, 3 with high-grade glioma, 3 with non–small cell lung cancer, 1 with squamous cell carcinoma of the skin, and 1 with head and neck squamous carcinoma. Nine patients (69%) had received at least two prior lines of systemic therapy.
Response, safety, and biomarkers
Overall, five patients (38%) had a central nervous system response, as ascertained from radiologic response on MRI, cytologic response in cerebrospinal fluid (CSF), and/or clinical response in neurologic symptoms, Dr. Naidoo reported.
Two patients had a complete CNS response: a patient with squamous cell carcinoma of the skin, who was still alive at 3 years, and a patient with non–small cell lung cancer, who survived 9 months but succumbed to metastases elsewhere.
For the entire cohort, median CNS progression-free survival was 2.9 months, and median overall survival was 4.9 months.
“This is consistent with published prospective studies of systemic agents for leptomeningeal disease,” Dr. Naidoo pointed out. “Notably, even though numbers are small, we do see the tail-on-the-curve phenomenon in both of these survival curves, which is consistent with immune checkpoint blockade prospective studies.”
The rate of grade 3 or higher treatment-related adverse events was 15.4%, and there were no grade 3 or higher immune-related adverse events.
The number of patients was too small for formal correlational testing, but both patients who achieved a complete response developed immune-related adverse events.
The trial’s biomarker analyses showed that an aneuploidy assay using CSF tumor-derived DNA performed well at detecting leptomeningeal metastases, with sensitivity of 84.6%, compared with just 53.8% for CSF cytopathology (the current preferred method).
A multiplex assay of CSF cytokines identified similar baseline profiles for patients who went on to have responses and showed similar changes in profile (notably a reduction in proinflammatory cytokines) for the two patients who had complete responses.
Given the trial’s 38% CNS response rate, pembrolizumab “needs to be studied in larger populations of patients to confirm this result, but it could be used as a potential treatment option for patients with leptomeningeal disease from solid tumors,” Dr. Naidoo concluded. “Reassuringly, pembrolizumab was well tolerated, and this is extremely important in a patient population that is traditionally quite frail and in which other standard therapies that are used, such as high-dose methotrexate or intrathecal chemotherapy, are associated with far higher rates of toxicity.”
An unmet need
“Leptomeningeal metastasis is a strong unmet need, although its occurrence is fortunately quite rare,” commented Kim Margolin, MD, a clinical professor and medical oncologist at City of Hope National Medical Center in Duarte, Calif., who was not involved in this study.
The trial is noteworthy for showing activity of programmed death–1 (PD-1) blockade given only systemically and not with additional intrathecal therapy (as has been done in a concurrent study at MD Anderson Cancer Center) and for providing insight into various biomarkers, Dr. Margolin said in an interview.
“I cannot take a stand on author conclusions other than to agree it warrants further evaluation in carefully selected patients, and it would be great to compare something like peripheral PD-1 blockade alone versus in combination with intrathecal therapy versus a combination such as CTLA4 blockade plus PD-1 blockade such as our group and others have shown to have increased activity in CNS metastases over PD-1 block alone,” Dr. Margolin said.
“The drugs in this class are already approved, so there is no reason not to try them,” she noted.
However, patients with leptomeningeal metastases of melanoma, for example, are likely to have already received anti-PD-1 immunotherapy.
“So the settings in which off-the-shelf PD-1 blockade would be useful are extremely limited,” she concluded.
The current trial was funded by Merck, the National Institutes of Health, the Lung Cancer Foundation of America, the International Association for the Study of Lung Cancer, and Johns Hopkins University Seed Grants. Dr. Naidoo disclosed relationships with AstraZeneca, Merck, Bristol Myers Squibb, and Roche/Genentech. Dr. Margolin disclosed no relevant conflicts of interest.
SOURCE: Naidoo J et al. SITC 2020, Abstract 788.
FROM SITC 2020
Breast Cancer Journal Scans: November 2020
The utilization of neoadjuvant chemotherapy is increasing, and is considered standard of care for the majority of patients with HER2-positive and triple-negative breast cancer subtypes. A significant benefit of neoadjuvant systemic therapy is assessment of the tumor biology via chemotherapy response, which has prognostic implications and additionally can help tailor therapy in the adjuvant setting. In the era of precision medicine, de-escalation strategies are considered to provide patients with efficacious treatment and spare toxicity. Tasoulis et al assessed the accuracy of image-guided biopsy after neoadjuvant therapy to predict residual disease, and found a false negative rate (FNR) of 3.2% and negative predictive value (NPV) of 97.4% when the residual imaging abnormality was 2cm or smaller with a minimum of 6 vacuum-assisted biopsies performed. They also demonstrated a FNR of 4.2% and NPV of 97.2% in the subgroup of patients with ERBB2-positive and triple-negative subtypes, those most likely to achieve a pathologic complete response. These findings suggest that local therapy de-escalation may be a relevant strategy for those patients who have excellent responses to neoadjuvant chemotherapy.
Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) have historically been, and still are, considered important prognostic and predictive factors. Beyond these, the role of genomic assays in breast cancer is evolving, and the 21-gene recurrence score is a valuable prognostic tool to assess chemotherapy benefit in women with early-stage ER-positive, HER2-negative breast cancer. Precision medicine in oncology strives to identify and apply an individualized approach to cancer care based on strong scientific data. Zhang and colleagues demonstrated the prognostic ability of an 8 DNA repair-related gene signature that was constructed from gene expression profiles from over 1,000 women diagnosed with breast cancer. These genes have roles in ER-mediated transactivation, DNA damage repair and cell adhesion processes. Additionally, Kudela et al showed that microRNAs (mRNAs), which are small RNAs that regulate gene expression, are able to classify intrinsic breast cancer subtype, play a role in endocrine resistance, and may also enhance the function of predictive models such as the 21-gene recurrence score (Kudela). Ongoing research in the field of tumor genomics will help advance the field of personalized treatment for breast cancer.
Erin Roesch, MD
The Cleveland Clinic
References:
Killelea BK, Yang VQ, Wang SY, Hayse B, Mougalian S, Horowitz NR, Chagpar AB, Pusztai L, Lannin DR. Racial differences in the use and outcome of neoadjuvant chemotherapy for breast cancer: results from the National Cancer Data Base. J Clin Oncol. 2015;33:4267-76.
Heil J, Schaefgen B, Sinn P, Harcos A, Gomez C, Stieber A, Hennings A, Schuetz F, Sohn C, Schneeweiss A, Golatta M. Diagnosis of pathological complete response to neoadjuvant chemotherapy in breast cancer by minimal invasive biopsy techniques. Br J Cancer. 2015;113:1565-70.
Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379:111-21.
Emmadi R, Canestrari E, Arbieva ZH, Mu W, Dai Y, Frasor J, Wiley E. Correlative analysis of miRNA expression and Oncotype Dx Recurrence Score in estrogen receptor positive breast carcinomas. PLoS One. 2015;10:e0145346.
The utilization of neoadjuvant chemotherapy is increasing, and is considered standard of care for the majority of patients with HER2-positive and triple-negative breast cancer subtypes. A significant benefit of neoadjuvant systemic therapy is assessment of the tumor biology via chemotherapy response, which has prognostic implications and additionally can help tailor therapy in the adjuvant setting. In the era of precision medicine, de-escalation strategies are considered to provide patients with efficacious treatment and spare toxicity. Tasoulis et al assessed the accuracy of image-guided biopsy after neoadjuvant therapy to predict residual disease, and found a false negative rate (FNR) of 3.2% and negative predictive value (NPV) of 97.4% when the residual imaging abnormality was 2cm or smaller with a minimum of 6 vacuum-assisted biopsies performed. They also demonstrated a FNR of 4.2% and NPV of 97.2% in the subgroup of patients with ERBB2-positive and triple-negative subtypes, those most likely to achieve a pathologic complete response. These findings suggest that local therapy de-escalation may be a relevant strategy for those patients who have excellent responses to neoadjuvant chemotherapy.
Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) have historically been, and still are, considered important prognostic and predictive factors. Beyond these, the role of genomic assays in breast cancer is evolving, and the 21-gene recurrence score is a valuable prognostic tool to assess chemotherapy benefit in women with early-stage ER-positive, HER2-negative breast cancer. Precision medicine in oncology strives to identify and apply an individualized approach to cancer care based on strong scientific data. Zhang and colleagues demonstrated the prognostic ability of an 8 DNA repair-related gene signature that was constructed from gene expression profiles from over 1,000 women diagnosed with breast cancer. These genes have roles in ER-mediated transactivation, DNA damage repair and cell adhesion processes. Additionally, Kudela et al showed that microRNAs (mRNAs), which are small RNAs that regulate gene expression, are able to classify intrinsic breast cancer subtype, play a role in endocrine resistance, and may also enhance the function of predictive models such as the 21-gene recurrence score (Kudela). Ongoing research in the field of tumor genomics will help advance the field of personalized treatment for breast cancer.
Erin Roesch, MD
The Cleveland Clinic
References:
Killelea BK, Yang VQ, Wang SY, Hayse B, Mougalian S, Horowitz NR, Chagpar AB, Pusztai L, Lannin DR. Racial differences in the use and outcome of neoadjuvant chemotherapy for breast cancer: results from the National Cancer Data Base. J Clin Oncol. 2015;33:4267-76.
Heil J, Schaefgen B, Sinn P, Harcos A, Gomez C, Stieber A, Hennings A, Schuetz F, Sohn C, Schneeweiss A, Golatta M. Diagnosis of pathological complete response to neoadjuvant chemotherapy in breast cancer by minimal invasive biopsy techniques. Br J Cancer. 2015;113:1565-70.
Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379:111-21.
Emmadi R, Canestrari E, Arbieva ZH, Mu W, Dai Y, Frasor J, Wiley E. Correlative analysis of miRNA expression and Oncotype Dx Recurrence Score in estrogen receptor positive breast carcinomas. PLoS One. 2015;10:e0145346.
The utilization of neoadjuvant chemotherapy is increasing, and is considered standard of care for the majority of patients with HER2-positive and triple-negative breast cancer subtypes. A significant benefit of neoadjuvant systemic therapy is assessment of the tumor biology via chemotherapy response, which has prognostic implications and additionally can help tailor therapy in the adjuvant setting. In the era of precision medicine, de-escalation strategies are considered to provide patients with efficacious treatment and spare toxicity. Tasoulis et al assessed the accuracy of image-guided biopsy after neoadjuvant therapy to predict residual disease, and found a false negative rate (FNR) of 3.2% and negative predictive value (NPV) of 97.4% when the residual imaging abnormality was 2cm or smaller with a minimum of 6 vacuum-assisted biopsies performed. They also demonstrated a FNR of 4.2% and NPV of 97.2% in the subgroup of patients with ERBB2-positive and triple-negative subtypes, those most likely to achieve a pathologic complete response. These findings suggest that local therapy de-escalation may be a relevant strategy for those patients who have excellent responses to neoadjuvant chemotherapy.
Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) have historically been, and still are, considered important prognostic and predictive factors. Beyond these, the role of genomic assays in breast cancer is evolving, and the 21-gene recurrence score is a valuable prognostic tool to assess chemotherapy benefit in women with early-stage ER-positive, HER2-negative breast cancer. Precision medicine in oncology strives to identify and apply an individualized approach to cancer care based on strong scientific data. Zhang and colleagues demonstrated the prognostic ability of an 8 DNA repair-related gene signature that was constructed from gene expression profiles from over 1,000 women diagnosed with breast cancer. These genes have roles in ER-mediated transactivation, DNA damage repair and cell adhesion processes. Additionally, Kudela et al showed that microRNAs (mRNAs), which are small RNAs that regulate gene expression, are able to classify intrinsic breast cancer subtype, play a role in endocrine resistance, and may also enhance the function of predictive models such as the 21-gene recurrence score (Kudela). Ongoing research in the field of tumor genomics will help advance the field of personalized treatment for breast cancer.
Erin Roesch, MD
The Cleveland Clinic
References:
Killelea BK, Yang VQ, Wang SY, Hayse B, Mougalian S, Horowitz NR, Chagpar AB, Pusztai L, Lannin DR. Racial differences in the use and outcome of neoadjuvant chemotherapy for breast cancer: results from the National Cancer Data Base. J Clin Oncol. 2015;33:4267-76.
Heil J, Schaefgen B, Sinn P, Harcos A, Gomez C, Stieber A, Hennings A, Schuetz F, Sohn C, Schneeweiss A, Golatta M. Diagnosis of pathological complete response to neoadjuvant chemotherapy in breast cancer by minimal invasive biopsy techniques. Br J Cancer. 2015;113:1565-70.
Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379:111-21.
Emmadi R, Canestrari E, Arbieva ZH, Mu W, Dai Y, Frasor J, Wiley E. Correlative analysis of miRNA expression and Oncotype Dx Recurrence Score in estrogen receptor positive breast carcinomas. PLoS One. 2015;10:e0145346.
MicroRNAs show promising predictive value for early breast cancer
Key clinical point: Differences in microRNAs (mRNAs), a group of small RNAs that regulate gene expression, can be used to distinguish among breast cancer subtypes.
Major finding: Altered expression of microRNAs distinguished between cancer and healthy samples, and also identified breast cancer subtypes including HER2, Luminal A, Luminal B, and triple negative breast cancer, according to a retrospective study of 740 breast cancer cases included in the review.
Study details: The data come from a review of the latest research on the prognostic and predictive value of microRNAs in patients with luminal A breast cancer.
Disclosures: The study was supported by the Scientific Grant Agency of the Ministry of Education of the Slovak Republic, the Slovak Research and Development Agency, and the Operational Programme Research and Innovation funded by the ERDF.
Citation: Kudela E et al. Int J Mol Sci. 2020 Oct 17. doi: 10.3390/ijms21207691.
Key clinical point: Differences in microRNAs (mRNAs), a group of small RNAs that regulate gene expression, can be used to distinguish among breast cancer subtypes.
Major finding: Altered expression of microRNAs distinguished between cancer and healthy samples, and also identified breast cancer subtypes including HER2, Luminal A, Luminal B, and triple negative breast cancer, according to a retrospective study of 740 breast cancer cases included in the review.
Study details: The data come from a review of the latest research on the prognostic and predictive value of microRNAs in patients with luminal A breast cancer.
Disclosures: The study was supported by the Scientific Grant Agency of the Ministry of Education of the Slovak Republic, the Slovak Research and Development Agency, and the Operational Programme Research and Innovation funded by the ERDF.
Citation: Kudela E et al. Int J Mol Sci. 2020 Oct 17. doi: 10.3390/ijms21207691.
Key clinical point: Differences in microRNAs (mRNAs), a group of small RNAs that regulate gene expression, can be used to distinguish among breast cancer subtypes.
Major finding: Altered expression of microRNAs distinguished between cancer and healthy samples, and also identified breast cancer subtypes including HER2, Luminal A, Luminal B, and triple negative breast cancer, according to a retrospective study of 740 breast cancer cases included in the review.
Study details: The data come from a review of the latest research on the prognostic and predictive value of microRNAs in patients with luminal A breast cancer.
Disclosures: The study was supported by the Scientific Grant Agency of the Ministry of Education of the Slovak Republic, the Slovak Research and Development Agency, and the Operational Programme Research and Innovation funded by the ERDF.
Citation: Kudela E et al. Int J Mol Sci. 2020 Oct 17. doi: 10.3390/ijms21207691.
Income loss shows no link to stress levels in young women with breast cancer
Key clinical point: Over a 12-month period, 15.4% of women with early breast cancer reported losing income. Although stress, anxiety, and depression were not association with household income changes (risk ratios 2.42, 1.12, and 1.41, respectively), the proportion of women reporting high stress was greatest among those who lost income (13.2%, compared to 3.1% among women maintaining an income of $100,000 or higher).
Major finding: Women with a household income below $50,000 had a higher risk of losing household income compared to those with incomes of $50,000 or higher, suggesting that lower income women may be more vulnerable to income loss after diagnosis with breast cancer.
Study details: The data come from a prospective, longitudinal cohort study including 467 women with early breast cancer enrolled in the Young and Strong cohort trial from 2012 to 2013.
Disclosures: The study was supported by an ASCO Improving Cancer Care grant, the National Institutes of Health, an NIH training grants. The researchers had no financial conflicts to disclose.
Citation: Cook EE et al. BMC Public Health. 2020 Oct 6. doi: 10.1186/s12889-020-09562-z.
Key clinical point: Over a 12-month period, 15.4% of women with early breast cancer reported losing income. Although stress, anxiety, and depression were not association with household income changes (risk ratios 2.42, 1.12, and 1.41, respectively), the proportion of women reporting high stress was greatest among those who lost income (13.2%, compared to 3.1% among women maintaining an income of $100,000 or higher).
Major finding: Women with a household income below $50,000 had a higher risk of losing household income compared to those with incomes of $50,000 or higher, suggesting that lower income women may be more vulnerable to income loss after diagnosis with breast cancer.
Study details: The data come from a prospective, longitudinal cohort study including 467 women with early breast cancer enrolled in the Young and Strong cohort trial from 2012 to 2013.
Disclosures: The study was supported by an ASCO Improving Cancer Care grant, the National Institutes of Health, an NIH training grants. The researchers had no financial conflicts to disclose.
Citation: Cook EE et al. BMC Public Health. 2020 Oct 6. doi: 10.1186/s12889-020-09562-z.
Key clinical point: Over a 12-month period, 15.4% of women with early breast cancer reported losing income. Although stress, anxiety, and depression were not association with household income changes (risk ratios 2.42, 1.12, and 1.41, respectively), the proportion of women reporting high stress was greatest among those who lost income (13.2%, compared to 3.1% among women maintaining an income of $100,000 or higher).
Major finding: Women with a household income below $50,000 had a higher risk of losing household income compared to those with incomes of $50,000 or higher, suggesting that lower income women may be more vulnerable to income loss after diagnosis with breast cancer.
Study details: The data come from a prospective, longitudinal cohort study including 467 women with early breast cancer enrolled in the Young and Strong cohort trial from 2012 to 2013.
Disclosures: The study was supported by an ASCO Improving Cancer Care grant, the National Institutes of Health, an NIH training grants. The researchers had no financial conflicts to disclose.
Citation: Cook EE et al. BMC Public Health. 2020 Oct 6. doi: 10.1186/s12889-020-09562-z.
Exercise and diet intervention fail to improve fatigue in breast cancer patients on chemotherapy
Key clinical point: An exercise and diet intervention had no significant impact on fatigue in women with breast cancer who were undergoing chemotherapy or radiotherapy.
Major finding: Based on the general cancer-related fatigue score using the MFI-20 questionnaire, general fatigue levels were not significantly different between groups of breast cancer patients randomized to an Adapted Physical Activity Diet (APAD) program and controls (P = 0.274).
Study details: The data come from a randomized, controlled trial of 360 adult women with early breast cancer designed to evaluate the impact of an exercise and nutrition intervention on fatigue during 6 months of chemotherapy and radiotherapy.
Disclosures: The study was supported by the INCa-DGOS and by a Montpellier Cancer SIRIC grant. The researchers had no financial conflicts to disclose.
Citation: Jacot W et al. Nutrients. 2020 Oct 9. doi: 10.3390/nu12103081.
Key clinical point: An exercise and diet intervention had no significant impact on fatigue in women with breast cancer who were undergoing chemotherapy or radiotherapy.
Major finding: Based on the general cancer-related fatigue score using the MFI-20 questionnaire, general fatigue levels were not significantly different between groups of breast cancer patients randomized to an Adapted Physical Activity Diet (APAD) program and controls (P = 0.274).
Study details: The data come from a randomized, controlled trial of 360 adult women with early breast cancer designed to evaluate the impact of an exercise and nutrition intervention on fatigue during 6 months of chemotherapy and radiotherapy.
Disclosures: The study was supported by the INCa-DGOS and by a Montpellier Cancer SIRIC grant. The researchers had no financial conflicts to disclose.
Citation: Jacot W et al. Nutrients. 2020 Oct 9. doi: 10.3390/nu12103081.
Key clinical point: An exercise and diet intervention had no significant impact on fatigue in women with breast cancer who were undergoing chemotherapy or radiotherapy.
Major finding: Based on the general cancer-related fatigue score using the MFI-20 questionnaire, general fatigue levels were not significantly different between groups of breast cancer patients randomized to an Adapted Physical Activity Diet (APAD) program and controls (P = 0.274).
Study details: The data come from a randomized, controlled trial of 360 adult women with early breast cancer designed to evaluate the impact of an exercise and nutrition intervention on fatigue during 6 months of chemotherapy and radiotherapy.
Disclosures: The study was supported by the INCa-DGOS and by a Montpellier Cancer SIRIC grant. The researchers had no financial conflicts to disclose.
Citation: Jacot W et al. Nutrients. 2020 Oct 9. doi: 10.3390/nu12103081.
DNA-based model predicts overall survival in breast cancer
Key clinical point: A prognostic signature including 8 DNA repair-related genes (MDC1, RPA3, MED17, DDB2, SFPQ, XRCC4, CYP19A1, and PARP3) predicted overall survival in breast cancer patients
Major finding: The areas under the curve were for 3-year survival and 5-year survival were 0.717 and 0.772, respectively, in the GSE9893 data set, and 0.691 and 0.718, respectively, in the GSE42568 data set.
Study details: The data come from 1,096 women with breast cancer; gene expression profiles and clinical data were collected from a Chinese health database between October 9, 2019, and February 3, 2020.
Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.
Citation: Zhang D et al. JAMA Netw Open. 2020 Oct 5. doi:10.1001/jamanetworkopen.2020.14622.
Key clinical point: A prognostic signature including 8 DNA repair-related genes (MDC1, RPA3, MED17, DDB2, SFPQ, XRCC4, CYP19A1, and PARP3) predicted overall survival in breast cancer patients
Major finding: The areas under the curve were for 3-year survival and 5-year survival were 0.717 and 0.772, respectively, in the GSE9893 data set, and 0.691 and 0.718, respectively, in the GSE42568 data set.
Study details: The data come from 1,096 women with breast cancer; gene expression profiles and clinical data were collected from a Chinese health database between October 9, 2019, and February 3, 2020.
Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.
Citation: Zhang D et al. JAMA Netw Open. 2020 Oct 5. doi:10.1001/jamanetworkopen.2020.14622.
Key clinical point: A prognostic signature including 8 DNA repair-related genes (MDC1, RPA3, MED17, DDB2, SFPQ, XRCC4, CYP19A1, and PARP3) predicted overall survival in breast cancer patients
Major finding: The areas under the curve were for 3-year survival and 5-year survival were 0.717 and 0.772, respectively, in the GSE9893 data set, and 0.691 and 0.718, respectively, in the GSE42568 data set.
Study details: The data come from 1,096 women with breast cancer; gene expression profiles and clinical data were collected from a Chinese health database between October 9, 2019, and February 3, 2020.
Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.
Citation: Zhang D et al. JAMA Netw Open. 2020 Oct 5. doi:10.1001/jamanetworkopen.2020.14622.