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FDA approves diazepam nasal spray for seizure clusters
The drug may be administered by a care partner outside of a medical setting for the treatment of intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient’s usual seizure pattern. The formulation is the first nasal spray approved by the FDA as a rescue treatment for people with epilepsy aged 6 years and older, according to Neurelis, the developer of the drug. Midazolam nasal spray, approved in May 2019, is indicated for patients with epilepsy aged 12 years and older.
Investigators evaluated the safety of diazepam nasal spray in a long-term, open-label, repeat-dose, clinical trial. The study enrolled 130 patients aged 6 years and older; more than 2,000 seizures were treated. The drug generally was safe and well tolerated, and the most common adverse reactions were somnolence, headache, and nasal discomfort.
The FDA has granted Valtoco 7 years of orphan drug exclusivity. In the United States, about 170,000 patients with epilepsy are at risk of cluster or acute repetitive seizures, the company said. Until recently, approved rescue medications had been rectally administered.
Patients may receive a second dose of diazepam nasal spray at least 4 hours after an initial dose if needed, but caregivers should not use more than two doses to treat a single episode, according to the prescribing information. In addition, the prescribing information recommends that diazepam nasal spray be used for no more than one episode every 5 days and no more than five episodes per month.
The drug may be administered by a care partner outside of a medical setting for the treatment of intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient’s usual seizure pattern. The formulation is the first nasal spray approved by the FDA as a rescue treatment for people with epilepsy aged 6 years and older, according to Neurelis, the developer of the drug. Midazolam nasal spray, approved in May 2019, is indicated for patients with epilepsy aged 12 years and older.
Investigators evaluated the safety of diazepam nasal spray in a long-term, open-label, repeat-dose, clinical trial. The study enrolled 130 patients aged 6 years and older; more than 2,000 seizures were treated. The drug generally was safe and well tolerated, and the most common adverse reactions were somnolence, headache, and nasal discomfort.
The FDA has granted Valtoco 7 years of orphan drug exclusivity. In the United States, about 170,000 patients with epilepsy are at risk of cluster or acute repetitive seizures, the company said. Until recently, approved rescue medications had been rectally administered.
Patients may receive a second dose of diazepam nasal spray at least 4 hours after an initial dose if needed, but caregivers should not use more than two doses to treat a single episode, according to the prescribing information. In addition, the prescribing information recommends that diazepam nasal spray be used for no more than one episode every 5 days and no more than five episodes per month.
The drug may be administered by a care partner outside of a medical setting for the treatment of intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient’s usual seizure pattern. The formulation is the first nasal spray approved by the FDA as a rescue treatment for people with epilepsy aged 6 years and older, according to Neurelis, the developer of the drug. Midazolam nasal spray, approved in May 2019, is indicated for patients with epilepsy aged 12 years and older.
Investigators evaluated the safety of diazepam nasal spray in a long-term, open-label, repeat-dose, clinical trial. The study enrolled 130 patients aged 6 years and older; more than 2,000 seizures were treated. The drug generally was safe and well tolerated, and the most common adverse reactions were somnolence, headache, and nasal discomfort.
The FDA has granted Valtoco 7 years of orphan drug exclusivity. In the United States, about 170,000 patients with epilepsy are at risk of cluster or acute repetitive seizures, the company said. Until recently, approved rescue medications had been rectally administered.
Patients may receive a second dose of diazepam nasal spray at least 4 hours after an initial dose if needed, but caregivers should not use more than two doses to treat a single episode, according to the prescribing information. In addition, the prescribing information recommends that diazepam nasal spray be used for no more than one episode every 5 days and no more than five episodes per month.
Researchers win funding for breast cancer studies
Five breast cancer researchers have won 3 years of funding from the National Comprehensive Cancer Network’s Oncology Research Program and Pfizer Global Medical Grants. The researchers will receive up to $1.4 million.
Allison Lipitz-Snyderman, PhD, and Erin Gillespie, MD, of Memorial Sloan Kettering Cancer Center in New York, have won funding for a project entitled, “Leveraging an academic-community partnership model to improve the quality of radiation treatment for metastatic breast cancer patients.”
Dr. Gillespie and Dr. Lipitz-Snyderman plan to use an existing partnership between Memorial Sloan Kettering and three community-based institutions to test a system for implementing best practices in radiation treatment. The system includes a web-based platform that disseminates expert recommendations as well as weekly conferences during which community radiation oncologists can consult with specialists on complex cases.
Aki Morikawa, MD, PhD, of the University of Michigan Rogel Cancer Center in Ann Arbor, won funding for a project entitled, “Personalized multi-care: A tailored approach to multidisciplinary care coordination delivery for metastatic breast cancer patients with central nervous system metastases.”
The goals of Dr. Morikawa’s project are to educate patients and providers on managing central nervous system metastases in the breast cancer setting, tailor care coordination and planning to patient and provider needs, and increase patient participation in studies.
Karen Lisa Smith, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, won funding for a project entitled, “The Johns Hopkins Metastatic Breast Cancer Partners Program: Collaborating to improve metastatic breast cancer care.”
The goal of the Metastatic Breast Cancer Partners Program is for Johns Hopkins and mid-Atlantic regional practices to fight metastatic breast cancer together. To that end, Dr. Smith plans to create a multidisciplinary clinic that offers supportive care and treatment recommendations, a database for patient tracking and trial screening, educational resources, and new opportunities for provider collaboration.
Laura Spring, MD, of Massachusetts General Hospital Cancer Center in Boston, won funding for a project entitled, “Expanding precision medicine for patients with metastatic breast cancer in the community: Leveraging academic strength and community partnership.”
The goal of Dr. Spring’s project is to extend academic resources to affiliated network sites. This will involve increasing access to tissue-based and blood-based tumor genotyping for patients with metastatic breast cancer, creating a virtual molecular and precision medicine clinic that provides interpretation of genomic data and treatment recommendations, and offering clinical trial matching to metastatic breast cancer patients treated at network sites.
Five breast cancer researchers have won 3 years of funding from the National Comprehensive Cancer Network’s Oncology Research Program and Pfizer Global Medical Grants. The researchers will receive up to $1.4 million.
Allison Lipitz-Snyderman, PhD, and Erin Gillespie, MD, of Memorial Sloan Kettering Cancer Center in New York, have won funding for a project entitled, “Leveraging an academic-community partnership model to improve the quality of radiation treatment for metastatic breast cancer patients.”
Dr. Gillespie and Dr. Lipitz-Snyderman plan to use an existing partnership between Memorial Sloan Kettering and three community-based institutions to test a system for implementing best practices in radiation treatment. The system includes a web-based platform that disseminates expert recommendations as well as weekly conferences during which community radiation oncologists can consult with specialists on complex cases.
Aki Morikawa, MD, PhD, of the University of Michigan Rogel Cancer Center in Ann Arbor, won funding for a project entitled, “Personalized multi-care: A tailored approach to multidisciplinary care coordination delivery for metastatic breast cancer patients with central nervous system metastases.”
The goals of Dr. Morikawa’s project are to educate patients and providers on managing central nervous system metastases in the breast cancer setting, tailor care coordination and planning to patient and provider needs, and increase patient participation in studies.
Karen Lisa Smith, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, won funding for a project entitled, “The Johns Hopkins Metastatic Breast Cancer Partners Program: Collaborating to improve metastatic breast cancer care.”
The goal of the Metastatic Breast Cancer Partners Program is for Johns Hopkins and mid-Atlantic regional practices to fight metastatic breast cancer together. To that end, Dr. Smith plans to create a multidisciplinary clinic that offers supportive care and treatment recommendations, a database for patient tracking and trial screening, educational resources, and new opportunities for provider collaboration.
Laura Spring, MD, of Massachusetts General Hospital Cancer Center in Boston, won funding for a project entitled, “Expanding precision medicine for patients with metastatic breast cancer in the community: Leveraging academic strength and community partnership.”
The goal of Dr. Spring’s project is to extend academic resources to affiliated network sites. This will involve increasing access to tissue-based and blood-based tumor genotyping for patients with metastatic breast cancer, creating a virtual molecular and precision medicine clinic that provides interpretation of genomic data and treatment recommendations, and offering clinical trial matching to metastatic breast cancer patients treated at network sites.
Five breast cancer researchers have won 3 years of funding from the National Comprehensive Cancer Network’s Oncology Research Program and Pfizer Global Medical Grants. The researchers will receive up to $1.4 million.
Allison Lipitz-Snyderman, PhD, and Erin Gillespie, MD, of Memorial Sloan Kettering Cancer Center in New York, have won funding for a project entitled, “Leveraging an academic-community partnership model to improve the quality of radiation treatment for metastatic breast cancer patients.”
Dr. Gillespie and Dr. Lipitz-Snyderman plan to use an existing partnership between Memorial Sloan Kettering and three community-based institutions to test a system for implementing best practices in radiation treatment. The system includes a web-based platform that disseminates expert recommendations as well as weekly conferences during which community radiation oncologists can consult with specialists on complex cases.
Aki Morikawa, MD, PhD, of the University of Michigan Rogel Cancer Center in Ann Arbor, won funding for a project entitled, “Personalized multi-care: A tailored approach to multidisciplinary care coordination delivery for metastatic breast cancer patients with central nervous system metastases.”
The goals of Dr. Morikawa’s project are to educate patients and providers on managing central nervous system metastases in the breast cancer setting, tailor care coordination and planning to patient and provider needs, and increase patient participation in studies.
Karen Lisa Smith, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, won funding for a project entitled, “The Johns Hopkins Metastatic Breast Cancer Partners Program: Collaborating to improve metastatic breast cancer care.”
The goal of the Metastatic Breast Cancer Partners Program is for Johns Hopkins and mid-Atlantic regional practices to fight metastatic breast cancer together. To that end, Dr. Smith plans to create a multidisciplinary clinic that offers supportive care and treatment recommendations, a database for patient tracking and trial screening, educational resources, and new opportunities for provider collaboration.
Laura Spring, MD, of Massachusetts General Hospital Cancer Center in Boston, won funding for a project entitled, “Expanding precision medicine for patients with metastatic breast cancer in the community: Leveraging academic strength and community partnership.”
The goal of Dr. Spring’s project is to extend academic resources to affiliated network sites. This will involve increasing access to tissue-based and blood-based tumor genotyping for patients with metastatic breast cancer, creating a virtual molecular and precision medicine clinic that provides interpretation of genomic data and treatment recommendations, and offering clinical trial matching to metastatic breast cancer patients treated at network sites.
Score predicts locoregional recurrence of breast cancer
The 21-gene assay recurrence score can aid decisions about radiotherapy for postmenopausal patients with node-positive breast cancer, according to researchers.
The researchers analyzed patients who underwent mastectomy or breast-conserving surgery (excision and radiation) and received chemotherapy plus tamoxifen or tamoxifen alone. Results showed that patients with an intermediate or high recurrence score, according to the 21-gene assay OncotypeDX, were more likely to have locoregional recurrence (LRR).
“We believe that the recurrence score adds independent prognostic information that could be used with standard clinical factors for identifying LRR risk and making radiotherapy decisions,” Wendy A. Woodward, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and coauthors wrote in JAMA Oncology.
Dr. Woodward and colleagues analyzed data from a phase 3 trial (NCT00929591) of postmenopausal women with estrogen or progesterone receptor–positive, node-positive breast cancer. There were 367 patients who received tamoxifen alone (n = 148) or cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen (n = 219).
Of the 367 patients, 316 were included in the primary analysis. This includes 252 patients who underwent mastectomy without radiotherapy and 64 patients who underwent breast-conserving surgery with radiotherapy.
The researchers defined LRR as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes.
The LRR incidence was 5.8% (7/121) among patients with a low recurrence score and 13.8% (27/195) among patients with an intermediate or high recurrence score. The estimated 10-year cumulative LRR incidence rates were 9.7% and 16.5%, respectively (P = .02).
The researchers conducted a multivariable analysis for LRR, which included the recurrence score, randomized treatment (combination regimen vs. tamoxifen alone), number of positive nodes (three or fewer vs. four or more), and type of surgery (mastectomy vs. excision and radiation).
Having intermediate or high recurrence scores was a significant predictor of LRR, with a hazard ratio of 2.36 (P = .04). Having four or more involved nodes was a significant predictor of LRR as well (hazard ratio, 3.37; P = .001). Randomized treatment and surgery were not significantly associated with LRR.
The researchers also conducted an exploratory analysis and found that a recurrence score of 18 was the optimal cutoff for the association of recurrence score and LRR.
“This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes,” Dr. Woodward and colleagues wrote. “This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision making. We recommend considering the recurrence score, when available, as one of the factors in selecting patients for postmastectomy radiotherapy.”
This research was funded by the National Cancer Institute of Canada, Canadian Cancer Society, and Genomic Health, which markets the 21-gene assay OncotypeDX. Dr. Woodward disclosed receiving personal fees from Genomic Health outside this research as well as an advisory fee from Merck.
SOURCE: Woodward WA et al. JAMA Oncol. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5559.
The 21-gene assay recurrence score can aid decisions about radiotherapy for postmenopausal patients with node-positive breast cancer, according to researchers.
The researchers analyzed patients who underwent mastectomy or breast-conserving surgery (excision and radiation) and received chemotherapy plus tamoxifen or tamoxifen alone. Results showed that patients with an intermediate or high recurrence score, according to the 21-gene assay OncotypeDX, were more likely to have locoregional recurrence (LRR).
“We believe that the recurrence score adds independent prognostic information that could be used with standard clinical factors for identifying LRR risk and making radiotherapy decisions,” Wendy A. Woodward, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and coauthors wrote in JAMA Oncology.
Dr. Woodward and colleagues analyzed data from a phase 3 trial (NCT00929591) of postmenopausal women with estrogen or progesterone receptor–positive, node-positive breast cancer. There were 367 patients who received tamoxifen alone (n = 148) or cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen (n = 219).
Of the 367 patients, 316 were included in the primary analysis. This includes 252 patients who underwent mastectomy without radiotherapy and 64 patients who underwent breast-conserving surgery with radiotherapy.
The researchers defined LRR as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes.
The LRR incidence was 5.8% (7/121) among patients with a low recurrence score and 13.8% (27/195) among patients with an intermediate or high recurrence score. The estimated 10-year cumulative LRR incidence rates were 9.7% and 16.5%, respectively (P = .02).
The researchers conducted a multivariable analysis for LRR, which included the recurrence score, randomized treatment (combination regimen vs. tamoxifen alone), number of positive nodes (three or fewer vs. four or more), and type of surgery (mastectomy vs. excision and radiation).
Having intermediate or high recurrence scores was a significant predictor of LRR, with a hazard ratio of 2.36 (P = .04). Having four or more involved nodes was a significant predictor of LRR as well (hazard ratio, 3.37; P = .001). Randomized treatment and surgery were not significantly associated with LRR.
The researchers also conducted an exploratory analysis and found that a recurrence score of 18 was the optimal cutoff for the association of recurrence score and LRR.
“This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes,” Dr. Woodward and colleagues wrote. “This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision making. We recommend considering the recurrence score, when available, as one of the factors in selecting patients for postmastectomy radiotherapy.”
This research was funded by the National Cancer Institute of Canada, Canadian Cancer Society, and Genomic Health, which markets the 21-gene assay OncotypeDX. Dr. Woodward disclosed receiving personal fees from Genomic Health outside this research as well as an advisory fee from Merck.
SOURCE: Woodward WA et al. JAMA Oncol. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5559.
The 21-gene assay recurrence score can aid decisions about radiotherapy for postmenopausal patients with node-positive breast cancer, according to researchers.
The researchers analyzed patients who underwent mastectomy or breast-conserving surgery (excision and radiation) and received chemotherapy plus tamoxifen or tamoxifen alone. Results showed that patients with an intermediate or high recurrence score, according to the 21-gene assay OncotypeDX, were more likely to have locoregional recurrence (LRR).
“We believe that the recurrence score adds independent prognostic information that could be used with standard clinical factors for identifying LRR risk and making radiotherapy decisions,” Wendy A. Woodward, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and coauthors wrote in JAMA Oncology.
Dr. Woodward and colleagues analyzed data from a phase 3 trial (NCT00929591) of postmenopausal women with estrogen or progesterone receptor–positive, node-positive breast cancer. There were 367 patients who received tamoxifen alone (n = 148) or cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen (n = 219).
Of the 367 patients, 316 were included in the primary analysis. This includes 252 patients who underwent mastectomy without radiotherapy and 64 patients who underwent breast-conserving surgery with radiotherapy.
The researchers defined LRR as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes.
The LRR incidence was 5.8% (7/121) among patients with a low recurrence score and 13.8% (27/195) among patients with an intermediate or high recurrence score. The estimated 10-year cumulative LRR incidence rates were 9.7% and 16.5%, respectively (P = .02).
The researchers conducted a multivariable analysis for LRR, which included the recurrence score, randomized treatment (combination regimen vs. tamoxifen alone), number of positive nodes (three or fewer vs. four or more), and type of surgery (mastectomy vs. excision and radiation).
Having intermediate or high recurrence scores was a significant predictor of LRR, with a hazard ratio of 2.36 (P = .04). Having four or more involved nodes was a significant predictor of LRR as well (hazard ratio, 3.37; P = .001). Randomized treatment and surgery were not significantly associated with LRR.
The researchers also conducted an exploratory analysis and found that a recurrence score of 18 was the optimal cutoff for the association of recurrence score and LRR.
“This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes,” Dr. Woodward and colleagues wrote. “This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision making. We recommend considering the recurrence score, when available, as one of the factors in selecting patients for postmastectomy radiotherapy.”
This research was funded by the National Cancer Institute of Canada, Canadian Cancer Society, and Genomic Health, which markets the 21-gene assay OncotypeDX. Dr. Woodward disclosed receiving personal fees from Genomic Health outside this research as well as an advisory fee from Merck.
SOURCE: Woodward WA et al. JAMA Oncol. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5559.
FROM JAMA ONCOLOGY
Insurance coverage mediates racial disparities in breast cancer
according to new study.
Insurance coverage “mediates nearly half of the increased risk for later-stage breast cancer diagnosis seen among racial/ethnic minorities,” Naomi Ko, MD, of Boston University and colleagues wrote in a research report published in JAMA Oncology.
With Surveillance, Epidemiology, and End Results Program data, the researchers looked at patient records on 177,075 women (148,124 insured and 28,951 uninsured or on Medicaid) aged 40-64 years who received a breast cancer diagnosis between Jan. 1, 2010, and Dec. 31, 2016. They found that a higher proportion of women (20%) uninsured or on Medicaid received a diagnosis of a higher-stage breast cancer (stage III), compared with women who had health insurance (11%).
More non-Hispanic black women (17%), American Indian or Alaskan native (15%), and Hispanic women (16%) received a stage III breast cancer diagnosis, compared with non-Hispanic white women (12%). Non-Hispanic white women were more likely to have insurance coverage at the time of diagnosis (89%), compared with non-Hispanic black women (75%), American Indian or Alaskan native (58%), and Hispanic women (67%).
“Without insurance coverage, the lack of prevention, screening, and access to care, as well as delays in diagnosis, lead to later stage of disease at diagnosis and thus worse survival,” Dr. Ko and colleagues wrote, adding that patients with a diagnosis of later-stage cancer require more intensive treatment and are at higher risk for treatment-associated morbidity and poorer overall quality of life.
Another consequence of the later-stage diagnosis is increased financial costs related to treatment for these patients, according to the investigator. They cite research that shows stage III cancer was 58% more costly to treat than was stage I or II breast cancer.
“Overall, earlier stage at diagnosis of breast cancer is not only beneficial for individual patients and families but also on society as a whole to decrease costs and equity among all populations,” Dr. Ko and colleagues added.
The researchers noted some of the limitations of the study, which include the source of data (the Surveillance, Epidemiology, and End Results Program, which covers 18 regions and might not be generalizable to all populations), as well as the age range of the studied population.
That being said, the authors also acknowledged that the findings “do not suggest that insurance alone will eliminate racial/ethnic disparities in breast cancer,” but “the ability to quantify the association that insurance has with breast cancer stage is relevant to potential policy changes regarding insurance and a prioritization of solutions for the increased burden of cancer mortality and morbidity disproportionately placed on racial/ethnic minority populations.”
Funding sources include the National Institutes of Health, National Center for Advancing Translational Sciences, National Cancer Institute, and National Institute on Minority Health and Health Disparities. The authors reported no conflicts of interest related to this study.
SOURCE: Ko N et al. JAMA Onc. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5672.
according to new study.
Insurance coverage “mediates nearly half of the increased risk for later-stage breast cancer diagnosis seen among racial/ethnic minorities,” Naomi Ko, MD, of Boston University and colleagues wrote in a research report published in JAMA Oncology.
With Surveillance, Epidemiology, and End Results Program data, the researchers looked at patient records on 177,075 women (148,124 insured and 28,951 uninsured or on Medicaid) aged 40-64 years who received a breast cancer diagnosis between Jan. 1, 2010, and Dec. 31, 2016. They found that a higher proportion of women (20%) uninsured or on Medicaid received a diagnosis of a higher-stage breast cancer (stage III), compared with women who had health insurance (11%).
More non-Hispanic black women (17%), American Indian or Alaskan native (15%), and Hispanic women (16%) received a stage III breast cancer diagnosis, compared with non-Hispanic white women (12%). Non-Hispanic white women were more likely to have insurance coverage at the time of diagnosis (89%), compared with non-Hispanic black women (75%), American Indian or Alaskan native (58%), and Hispanic women (67%).
“Without insurance coverage, the lack of prevention, screening, and access to care, as well as delays in diagnosis, lead to later stage of disease at diagnosis and thus worse survival,” Dr. Ko and colleagues wrote, adding that patients with a diagnosis of later-stage cancer require more intensive treatment and are at higher risk for treatment-associated morbidity and poorer overall quality of life.
Another consequence of the later-stage diagnosis is increased financial costs related to treatment for these patients, according to the investigator. They cite research that shows stage III cancer was 58% more costly to treat than was stage I or II breast cancer.
“Overall, earlier stage at diagnosis of breast cancer is not only beneficial for individual patients and families but also on society as a whole to decrease costs and equity among all populations,” Dr. Ko and colleagues added.
The researchers noted some of the limitations of the study, which include the source of data (the Surveillance, Epidemiology, and End Results Program, which covers 18 regions and might not be generalizable to all populations), as well as the age range of the studied population.
That being said, the authors also acknowledged that the findings “do not suggest that insurance alone will eliminate racial/ethnic disparities in breast cancer,” but “the ability to quantify the association that insurance has with breast cancer stage is relevant to potential policy changes regarding insurance and a prioritization of solutions for the increased burden of cancer mortality and morbidity disproportionately placed on racial/ethnic minority populations.”
Funding sources include the National Institutes of Health, National Center for Advancing Translational Sciences, National Cancer Institute, and National Institute on Minority Health and Health Disparities. The authors reported no conflicts of interest related to this study.
SOURCE: Ko N et al. JAMA Onc. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5672.
according to new study.
Insurance coverage “mediates nearly half of the increased risk for later-stage breast cancer diagnosis seen among racial/ethnic minorities,” Naomi Ko, MD, of Boston University and colleagues wrote in a research report published in JAMA Oncology.
With Surveillance, Epidemiology, and End Results Program data, the researchers looked at patient records on 177,075 women (148,124 insured and 28,951 uninsured or on Medicaid) aged 40-64 years who received a breast cancer diagnosis between Jan. 1, 2010, and Dec. 31, 2016. They found that a higher proportion of women (20%) uninsured or on Medicaid received a diagnosis of a higher-stage breast cancer (stage III), compared with women who had health insurance (11%).
More non-Hispanic black women (17%), American Indian or Alaskan native (15%), and Hispanic women (16%) received a stage III breast cancer diagnosis, compared with non-Hispanic white women (12%). Non-Hispanic white women were more likely to have insurance coverage at the time of diagnosis (89%), compared with non-Hispanic black women (75%), American Indian or Alaskan native (58%), and Hispanic women (67%).
“Without insurance coverage, the lack of prevention, screening, and access to care, as well as delays in diagnosis, lead to later stage of disease at diagnosis and thus worse survival,” Dr. Ko and colleagues wrote, adding that patients with a diagnosis of later-stage cancer require more intensive treatment and are at higher risk for treatment-associated morbidity and poorer overall quality of life.
Another consequence of the later-stage diagnosis is increased financial costs related to treatment for these patients, according to the investigator. They cite research that shows stage III cancer was 58% more costly to treat than was stage I or II breast cancer.
“Overall, earlier stage at diagnosis of breast cancer is not only beneficial for individual patients and families but also on society as a whole to decrease costs and equity among all populations,” Dr. Ko and colleagues added.
The researchers noted some of the limitations of the study, which include the source of data (the Surveillance, Epidemiology, and End Results Program, which covers 18 regions and might not be generalizable to all populations), as well as the age range of the studied population.
That being said, the authors also acknowledged that the findings “do not suggest that insurance alone will eliminate racial/ethnic disparities in breast cancer,” but “the ability to quantify the association that insurance has with breast cancer stage is relevant to potential policy changes regarding insurance and a prioritization of solutions for the increased burden of cancer mortality and morbidity disproportionately placed on racial/ethnic minority populations.”
Funding sources include the National Institutes of Health, National Center for Advancing Translational Sciences, National Cancer Institute, and National Institute on Minority Health and Health Disparities. The authors reported no conflicts of interest related to this study.
SOURCE: Ko N et al. JAMA Onc. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5672.
FROM JAMA ONCOLOGY
AED exposure from breastfeeding appears to be low
, according to a study published online ahead of print Dec. 30, 2019, in JAMA Neurology. The results may explain why previous research failed to find adverse neurodevelopmental effects of breastfeeding in infants whose mothers are undergoing AED treatment, said the authors.
“The results of this study add support to the general safety of breastfeeding by mothers with epilepsy who take AEDs,” wrote Angela K. Birnbaum, PhD, professor of experimental and clinical pharmacology at the University of Minnesota in Minneapolis, and colleagues.
Investigators measured infants’ blood AED concentrations
To date, medical consensus about the safety of breastfeeding while the mother is taking AEDs has been elusive. Researchers have investigated breast milk concentrations of AEDs as surrogate markers of AED concentrations in children. Breast milk concentrations, however, do not account for differences in infant pharmacokinetic processes and thus could misrepresent AED exposure in children through breastfeeding.
Dr. Birnbaum and colleagues sought to measure blood concentrations of AEDs in mothers with epilepsy and the infants that they breastfed to achieve an objective measure of AED exposure through breastfeeding. They examined data collected from December 2012 to October 2016 in the prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study. Eligible participants were pregnant women with epilepsy between the ages of 14 and 45 years whose pregnancies had progressed to fewer than 20 weeks’ gestational age and who had IQ scores greater than 70 points. Participants were followed up throughout pregnancy and for 9 months post partum. Children were enrolled at birth.
The investigators collected blood samples from mothers and infants who were breastfed at the same visit, which occurred at between 5 and 20 weeks after birth. The volume of ingested breast milk delivered through graduated feeding bottles each day and the total duration of all daily breastfeeding sessions were recorded. For infants, blood samples were collected from the plantar surface of the heel and stored as dried blood spots on filter paper. The study’s primary endpoint was the percentage of infant-to-mother concentration of AEDs. Concentrations of AEDs in infants at less than the lower limit of quantification were assessed as half of the lower limit.
Exposure in utero may be greater than exposure through breast milk
In all, the researchers enrolled 351 pregnant women with epilepsy into the study and collected data on 345 infants. Two hundred twenty-two (64.3%) of the infants were breastfed, and 146 (42.3%) had AED concentrations available. After excluding outliers and mothers with missing concentration data, Dr. Birnbaum and colleagues included 164 matching infant-mother concentration pairs in their analysis (i.e., of 135 mothers and 138 infants). Approximately 52% of the infants were female, and their median age at blood collection was 13 weeks. The mothers’ median age was 32 years. About 82% of mothers were receiving monotherapy. The investigators found no demographic differences between groups of mothers taking various AEDs.
Sixty-eight infants (49.3%) had AED concentrations that were less than the lower limit of quantification. AED concentration was not greater than the lower limit of quantification for any infants breastfed by mothers taking carbamazepine, oxcarbazepine, valproic acid, or topiramate. Most levetiracetam (71.4%) and zonisamide (60.0%) concentrations in infants were less than the lower limit of quantification. Most lamotrigine concentrations in infants (88.6%) were greater than the lower limit of quantification.
The median percentage of infant-to-mother concentration was 28.9% for lamotrigine, 5.3% for levetiracetam, 44.2% for zonisamide, 5.7% for carbamazepine, 5.4% for carbamazepine epoxide, 0.3% for oxcarbazepine, 17.2% for topiramate, and 21.4% for valproic acid. Multiple linear regression models indicated that maternal concentration was significantly associated with lamotrigine concentration in infants, but not levetiracetam concentration in infants.
“Prior studies at delivery demonstrated that umbilical-cord concentrations were nearly equal to maternal concentrations, suggesting extensive placental passage to the fetus,” wrote Dr. Birnbaum and colleagues. “Therefore, the amount of AED exposure via breast milk is likely substantially lower than fetal exposure during pregnancy and appears unlikely to confer any additional risks beyond those that might be associated with exposure in pregnancy, especially given prior studies showing no adverse neurodevelopmental effects of breastfeeding while taking AEDs.”
The investigators acknowledged several limitations of their research, including the observational design of the MONEAD study. The amount of AED in participants’ breast milk is unknown, and the investigators could not calculate relative infant dosages. Only one blood sample was taken per infant, thus the results may not reflect infants’ total exposure over time.
The National Institute of Neurological Disorders and Stroke and the National Institute of Child Health and Development funded the research. The authors reported receiving research support from various pharmaceutical companies.
SOURCE: Birnbaum AK et al. JAMA Neurol. 2019 Dec 30. doi: 10.1001/jamaneurol.2019.4443.
, according to a study published online ahead of print Dec. 30, 2019, in JAMA Neurology. The results may explain why previous research failed to find adverse neurodevelopmental effects of breastfeeding in infants whose mothers are undergoing AED treatment, said the authors.
“The results of this study add support to the general safety of breastfeeding by mothers with epilepsy who take AEDs,” wrote Angela K. Birnbaum, PhD, professor of experimental and clinical pharmacology at the University of Minnesota in Minneapolis, and colleagues.
Investigators measured infants’ blood AED concentrations
To date, medical consensus about the safety of breastfeeding while the mother is taking AEDs has been elusive. Researchers have investigated breast milk concentrations of AEDs as surrogate markers of AED concentrations in children. Breast milk concentrations, however, do not account for differences in infant pharmacokinetic processes and thus could misrepresent AED exposure in children through breastfeeding.
Dr. Birnbaum and colleagues sought to measure blood concentrations of AEDs in mothers with epilepsy and the infants that they breastfed to achieve an objective measure of AED exposure through breastfeeding. They examined data collected from December 2012 to October 2016 in the prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study. Eligible participants were pregnant women with epilepsy between the ages of 14 and 45 years whose pregnancies had progressed to fewer than 20 weeks’ gestational age and who had IQ scores greater than 70 points. Participants were followed up throughout pregnancy and for 9 months post partum. Children were enrolled at birth.
The investigators collected blood samples from mothers and infants who were breastfed at the same visit, which occurred at between 5 and 20 weeks after birth. The volume of ingested breast milk delivered through graduated feeding bottles each day and the total duration of all daily breastfeeding sessions were recorded. For infants, blood samples were collected from the plantar surface of the heel and stored as dried blood spots on filter paper. The study’s primary endpoint was the percentage of infant-to-mother concentration of AEDs. Concentrations of AEDs in infants at less than the lower limit of quantification were assessed as half of the lower limit.
Exposure in utero may be greater than exposure through breast milk
In all, the researchers enrolled 351 pregnant women with epilepsy into the study and collected data on 345 infants. Two hundred twenty-two (64.3%) of the infants were breastfed, and 146 (42.3%) had AED concentrations available. After excluding outliers and mothers with missing concentration data, Dr. Birnbaum and colleagues included 164 matching infant-mother concentration pairs in their analysis (i.e., of 135 mothers and 138 infants). Approximately 52% of the infants were female, and their median age at blood collection was 13 weeks. The mothers’ median age was 32 years. About 82% of mothers were receiving monotherapy. The investigators found no demographic differences between groups of mothers taking various AEDs.
Sixty-eight infants (49.3%) had AED concentrations that were less than the lower limit of quantification. AED concentration was not greater than the lower limit of quantification for any infants breastfed by mothers taking carbamazepine, oxcarbazepine, valproic acid, or topiramate. Most levetiracetam (71.4%) and zonisamide (60.0%) concentrations in infants were less than the lower limit of quantification. Most lamotrigine concentrations in infants (88.6%) were greater than the lower limit of quantification.
The median percentage of infant-to-mother concentration was 28.9% for lamotrigine, 5.3% for levetiracetam, 44.2% for zonisamide, 5.7% for carbamazepine, 5.4% for carbamazepine epoxide, 0.3% for oxcarbazepine, 17.2% for topiramate, and 21.4% for valproic acid. Multiple linear regression models indicated that maternal concentration was significantly associated with lamotrigine concentration in infants, but not levetiracetam concentration in infants.
“Prior studies at delivery demonstrated that umbilical-cord concentrations were nearly equal to maternal concentrations, suggesting extensive placental passage to the fetus,” wrote Dr. Birnbaum and colleagues. “Therefore, the amount of AED exposure via breast milk is likely substantially lower than fetal exposure during pregnancy and appears unlikely to confer any additional risks beyond those that might be associated with exposure in pregnancy, especially given prior studies showing no adverse neurodevelopmental effects of breastfeeding while taking AEDs.”
The investigators acknowledged several limitations of their research, including the observational design of the MONEAD study. The amount of AED in participants’ breast milk is unknown, and the investigators could not calculate relative infant dosages. Only one blood sample was taken per infant, thus the results may not reflect infants’ total exposure over time.
The National Institute of Neurological Disorders and Stroke and the National Institute of Child Health and Development funded the research. The authors reported receiving research support from various pharmaceutical companies.
SOURCE: Birnbaum AK et al. JAMA Neurol. 2019 Dec 30. doi: 10.1001/jamaneurol.2019.4443.
, according to a study published online ahead of print Dec. 30, 2019, in JAMA Neurology. The results may explain why previous research failed to find adverse neurodevelopmental effects of breastfeeding in infants whose mothers are undergoing AED treatment, said the authors.
“The results of this study add support to the general safety of breastfeeding by mothers with epilepsy who take AEDs,” wrote Angela K. Birnbaum, PhD, professor of experimental and clinical pharmacology at the University of Minnesota in Minneapolis, and colleagues.
Investigators measured infants’ blood AED concentrations
To date, medical consensus about the safety of breastfeeding while the mother is taking AEDs has been elusive. Researchers have investigated breast milk concentrations of AEDs as surrogate markers of AED concentrations in children. Breast milk concentrations, however, do not account for differences in infant pharmacokinetic processes and thus could misrepresent AED exposure in children through breastfeeding.
Dr. Birnbaum and colleagues sought to measure blood concentrations of AEDs in mothers with epilepsy and the infants that they breastfed to achieve an objective measure of AED exposure through breastfeeding. They examined data collected from December 2012 to October 2016 in the prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study. Eligible participants were pregnant women with epilepsy between the ages of 14 and 45 years whose pregnancies had progressed to fewer than 20 weeks’ gestational age and who had IQ scores greater than 70 points. Participants were followed up throughout pregnancy and for 9 months post partum. Children were enrolled at birth.
The investigators collected blood samples from mothers and infants who were breastfed at the same visit, which occurred at between 5 and 20 weeks after birth. The volume of ingested breast milk delivered through graduated feeding bottles each day and the total duration of all daily breastfeeding sessions were recorded. For infants, blood samples were collected from the plantar surface of the heel and stored as dried blood spots on filter paper. The study’s primary endpoint was the percentage of infant-to-mother concentration of AEDs. Concentrations of AEDs in infants at less than the lower limit of quantification were assessed as half of the lower limit.
Exposure in utero may be greater than exposure through breast milk
In all, the researchers enrolled 351 pregnant women with epilepsy into the study and collected data on 345 infants. Two hundred twenty-two (64.3%) of the infants were breastfed, and 146 (42.3%) had AED concentrations available. After excluding outliers and mothers with missing concentration data, Dr. Birnbaum and colleagues included 164 matching infant-mother concentration pairs in their analysis (i.e., of 135 mothers and 138 infants). Approximately 52% of the infants were female, and their median age at blood collection was 13 weeks. The mothers’ median age was 32 years. About 82% of mothers were receiving monotherapy. The investigators found no demographic differences between groups of mothers taking various AEDs.
Sixty-eight infants (49.3%) had AED concentrations that were less than the lower limit of quantification. AED concentration was not greater than the lower limit of quantification for any infants breastfed by mothers taking carbamazepine, oxcarbazepine, valproic acid, or topiramate. Most levetiracetam (71.4%) and zonisamide (60.0%) concentrations in infants were less than the lower limit of quantification. Most lamotrigine concentrations in infants (88.6%) were greater than the lower limit of quantification.
The median percentage of infant-to-mother concentration was 28.9% for lamotrigine, 5.3% for levetiracetam, 44.2% for zonisamide, 5.7% for carbamazepine, 5.4% for carbamazepine epoxide, 0.3% for oxcarbazepine, 17.2% for topiramate, and 21.4% for valproic acid. Multiple linear regression models indicated that maternal concentration was significantly associated with lamotrigine concentration in infants, but not levetiracetam concentration in infants.
“Prior studies at delivery demonstrated that umbilical-cord concentrations were nearly equal to maternal concentrations, suggesting extensive placental passage to the fetus,” wrote Dr. Birnbaum and colleagues. “Therefore, the amount of AED exposure via breast milk is likely substantially lower than fetal exposure during pregnancy and appears unlikely to confer any additional risks beyond those that might be associated with exposure in pregnancy, especially given prior studies showing no adverse neurodevelopmental effects of breastfeeding while taking AEDs.”
The investigators acknowledged several limitations of their research, including the observational design of the MONEAD study. The amount of AED in participants’ breast milk is unknown, and the investigators could not calculate relative infant dosages. Only one blood sample was taken per infant, thus the results may not reflect infants’ total exposure over time.
The National Institute of Neurological Disorders and Stroke and the National Institute of Child Health and Development funded the research. The authors reported receiving research support from various pharmaceutical companies.
SOURCE: Birnbaum AK et al. JAMA Neurol. 2019 Dec 30. doi: 10.1001/jamaneurol.2019.4443.
FROM JAMA NEUROLOGY
Delayed clinical care after concussion may prolong recovery
, according to a study published Jan. 6 in JAMA Neurology.
In addition, more severe visual motion sensitivity symptoms are associated with longer recovery times, said lead author Anthony P. Kontos, PhD, and colleagues. Dr. Kontos is associate professor of orthopedic surgery at the University of Pittsburgh and the research director of the University of Pittsburgh Medical Center Sports Medicine Concussion Program.
“Without clinical guidance and behavioral management recommendations post injury, athletes may have been engaging in counterproductive recovery strategies, such as a strict rest or excessive physical activity,” the authors said. “This explanation is supported by the fact that athletes recovered in a similar amount of time after that first evaluation.”
Various factors may influence recovery after a concussion, including age, sex, and comorbidities. To examine the relationship between time since injury at the start of clinical care and recovery time, the investigators conducted a retrospective, cross-sectional study. They analyzed data from patients seen in a sports medicine clinic between August 2016 and March 2018. Eligible patients were aged 12-22 years and had a diagnosed, symptomatic, sport-related concussion. The researchers excluded patients with incomplete recovery data.
The investigators included 162 patients in their analyses; 98 of these patients were seen within 7 days of the injury, and 64 were seen 8-20 days after a concussion. Both groups had a mean age of 15 years and similar proportions of female patients (52% in the early-care group vs. 62.5% in the late-care group). At the first clinical visit, symptom severity and cognitive, ocular, and vestibular test results were similar in both groups.
The researchers defined recovery time as the number of days from injury until the date of clearance for a full return to play. Physicians cleared patients to return to play when they returned to preinjury levels of symptoms and preinjury performance on cognitive, ocular, and vestibular tests with no increase in symptoms after exertion.
Patients’ recovery times ranged from 9 to 299 days; the average recovery time was 57 days. Fifty-two percent of patients in the early-care group recovered in 30 days or fewer, compared with 19% of patients in late-care group. Patients in the early-care group had a mean recovery of 51.1 days, whereas patients in the late-care group had a mean recovery of 66 days.
In a logistic regression model, late care “was associated with a 5.8-times increased likelihood of a recovery longer than 30 days,” the researchers reported. Visual motion sensitivity symptoms also were associated with increased odds of protracted recovery (adjusted odds ratio, 4.5).
“Once care was established, time to recovery did not differ for athletes evaluated within the first week of injury compared with those evaluated 2-3 weeks post injury,” Dr. Kontos and colleagues concluded. “Education on injury and behavioral recommendations to optimize concussion recovery and earlier initiation of active rehabilitation strategies, including exertion and vestibular therapy, are plausible explanations for the association of a shorter recovery time with earlier care. However, future research should focus on the specific mechanisms by which earlier health care postconcussion promotes faster recovery and determine if these findings apply to other subpopulations, including military personnel.”
The researchers noted that they excluded from their analysis 254 patients who had incomplete recovery data but otherwise met inclusion criteria, which may have led to selection bias.
Dr. Kontos disclosed grants from the National Football League and personal fees from APA Books and University of Pittsburgh projects outside the scope of this study.
SOURCE: Kontos AP et al. JAMA Neurol. 2020 Jan 6. doi: 10.1001/jamaneurol.2019.4552.
, according to a study published Jan. 6 in JAMA Neurology.
In addition, more severe visual motion sensitivity symptoms are associated with longer recovery times, said lead author Anthony P. Kontos, PhD, and colleagues. Dr. Kontos is associate professor of orthopedic surgery at the University of Pittsburgh and the research director of the University of Pittsburgh Medical Center Sports Medicine Concussion Program.
“Without clinical guidance and behavioral management recommendations post injury, athletes may have been engaging in counterproductive recovery strategies, such as a strict rest or excessive physical activity,” the authors said. “This explanation is supported by the fact that athletes recovered in a similar amount of time after that first evaluation.”
Various factors may influence recovery after a concussion, including age, sex, and comorbidities. To examine the relationship between time since injury at the start of clinical care and recovery time, the investigators conducted a retrospective, cross-sectional study. They analyzed data from patients seen in a sports medicine clinic between August 2016 and March 2018. Eligible patients were aged 12-22 years and had a diagnosed, symptomatic, sport-related concussion. The researchers excluded patients with incomplete recovery data.
The investigators included 162 patients in their analyses; 98 of these patients were seen within 7 days of the injury, and 64 were seen 8-20 days after a concussion. Both groups had a mean age of 15 years and similar proportions of female patients (52% in the early-care group vs. 62.5% in the late-care group). At the first clinical visit, symptom severity and cognitive, ocular, and vestibular test results were similar in both groups.
The researchers defined recovery time as the number of days from injury until the date of clearance for a full return to play. Physicians cleared patients to return to play when they returned to preinjury levels of symptoms and preinjury performance on cognitive, ocular, and vestibular tests with no increase in symptoms after exertion.
Patients’ recovery times ranged from 9 to 299 days; the average recovery time was 57 days. Fifty-two percent of patients in the early-care group recovered in 30 days or fewer, compared with 19% of patients in late-care group. Patients in the early-care group had a mean recovery of 51.1 days, whereas patients in the late-care group had a mean recovery of 66 days.
In a logistic regression model, late care “was associated with a 5.8-times increased likelihood of a recovery longer than 30 days,” the researchers reported. Visual motion sensitivity symptoms also were associated with increased odds of protracted recovery (adjusted odds ratio, 4.5).
“Once care was established, time to recovery did not differ for athletes evaluated within the first week of injury compared with those evaluated 2-3 weeks post injury,” Dr. Kontos and colleagues concluded. “Education on injury and behavioral recommendations to optimize concussion recovery and earlier initiation of active rehabilitation strategies, including exertion and vestibular therapy, are plausible explanations for the association of a shorter recovery time with earlier care. However, future research should focus on the specific mechanisms by which earlier health care postconcussion promotes faster recovery and determine if these findings apply to other subpopulations, including military personnel.”
The researchers noted that they excluded from their analysis 254 patients who had incomplete recovery data but otherwise met inclusion criteria, which may have led to selection bias.
Dr. Kontos disclosed grants from the National Football League and personal fees from APA Books and University of Pittsburgh projects outside the scope of this study.
SOURCE: Kontos AP et al. JAMA Neurol. 2020 Jan 6. doi: 10.1001/jamaneurol.2019.4552.
, according to a study published Jan. 6 in JAMA Neurology.
In addition, more severe visual motion sensitivity symptoms are associated with longer recovery times, said lead author Anthony P. Kontos, PhD, and colleagues. Dr. Kontos is associate professor of orthopedic surgery at the University of Pittsburgh and the research director of the University of Pittsburgh Medical Center Sports Medicine Concussion Program.
“Without clinical guidance and behavioral management recommendations post injury, athletes may have been engaging in counterproductive recovery strategies, such as a strict rest or excessive physical activity,” the authors said. “This explanation is supported by the fact that athletes recovered in a similar amount of time after that first evaluation.”
Various factors may influence recovery after a concussion, including age, sex, and comorbidities. To examine the relationship between time since injury at the start of clinical care and recovery time, the investigators conducted a retrospective, cross-sectional study. They analyzed data from patients seen in a sports medicine clinic between August 2016 and March 2018. Eligible patients were aged 12-22 years and had a diagnosed, symptomatic, sport-related concussion. The researchers excluded patients with incomplete recovery data.
The investigators included 162 patients in their analyses; 98 of these patients were seen within 7 days of the injury, and 64 were seen 8-20 days after a concussion. Both groups had a mean age of 15 years and similar proportions of female patients (52% in the early-care group vs. 62.5% in the late-care group). At the first clinical visit, symptom severity and cognitive, ocular, and vestibular test results were similar in both groups.
The researchers defined recovery time as the number of days from injury until the date of clearance for a full return to play. Physicians cleared patients to return to play when they returned to preinjury levels of symptoms and preinjury performance on cognitive, ocular, and vestibular tests with no increase in symptoms after exertion.
Patients’ recovery times ranged from 9 to 299 days; the average recovery time was 57 days. Fifty-two percent of patients in the early-care group recovered in 30 days or fewer, compared with 19% of patients in late-care group. Patients in the early-care group had a mean recovery of 51.1 days, whereas patients in the late-care group had a mean recovery of 66 days.
In a logistic regression model, late care “was associated with a 5.8-times increased likelihood of a recovery longer than 30 days,” the researchers reported. Visual motion sensitivity symptoms also were associated with increased odds of protracted recovery (adjusted odds ratio, 4.5).
“Once care was established, time to recovery did not differ for athletes evaluated within the first week of injury compared with those evaluated 2-3 weeks post injury,” Dr. Kontos and colleagues concluded. “Education on injury and behavioral recommendations to optimize concussion recovery and earlier initiation of active rehabilitation strategies, including exertion and vestibular therapy, are plausible explanations for the association of a shorter recovery time with earlier care. However, future research should focus on the specific mechanisms by which earlier health care postconcussion promotes faster recovery and determine if these findings apply to other subpopulations, including military personnel.”
The researchers noted that they excluded from their analysis 254 patients who had incomplete recovery data but otherwise met inclusion criteria, which may have led to selection bias.
Dr. Kontos disclosed grants from the National Football League and personal fees from APA Books and University of Pittsburgh projects outside the scope of this study.
SOURCE: Kontos AP et al. JAMA Neurol. 2020 Jan 6. doi: 10.1001/jamaneurol.2019.4552.
FROM JAMA NEUROLOGY
SABCS research changes practice
In this edition of “How I Will Treat My Next Patient,” I highlight two presentations from the recent San Antonio Breast Cancer Symposium (SABCS) that will likely change practice for some breast cancer patients – even before the ball drops in Times Square on New Year’s Eve.
Residual cancer burden
Researchers reported a multi-institutional analysis of individual patient-level data on 5,160 patients who had received neoadjuvant chemotherapy (NAC) for localized breast cancer at 11 different centers. They found that residual cancer burden (RCB) was significantly associated with event-free (EFS) and distant recurrence-free survival. The value of calculating RCB was seen across all breast cancer tumor phenotypes (SABCS 2019, Abstract GS5-01).
RCB is calculated by analyzing the residual disease after NAC for the primary tumor bed, the number of positive axillary nodes, and the size of largest node metastasis. It is graded from RCB-0 (pCR) to RCB-III (extensive residual disease).
Both EFS and distant recurrence-free survival were strongly associated with RCB for the overall population and for each breast cancer subtype. For hormone receptor–positive/HER2-negative disease there was a slight hiccup in that RCB-0 was associated with a 10-year EFS of 81%, but EFS was 86% for RCB-I. Fortunately, the prognostic reliability of RCB was clear for RCB-II (69%) and RCB-III (52%). The presenter, W. Fraser Symmans, MD, commented that RCB is most prognostic when higher levels of residual disease are present. RCB remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis.
How these results influence practice
After neoadjuvant chemotherapy in patients with localized breast cancer, we struggle when patients ask: “So, doctor, how am I likely to do?” We piece together a complicated – and inconsistent – answer, based on breast cancer subtype, original stage of disease, whether pCR was attained, and other factors.
For patients with triple-negative breast cancer, we have the option of adding capecitabine and/or participation in ongoing clinical trials, for patients with residual disease after NAC. Among the HER2-positive patients, we have data from the KATHERINE, ExtaNET, and APHINITY trials that provide options for additional treatment in those patients, as well. For patients with potentially hormonally responsive, HER2-negative disease, we can emphasize the importance of postoperative adjuvant endocrine therapy, the mandate for continued adherence to oral therapy, and the lower likelihood of (and prognostic value of) pCR in that breast cancer subtype.
Where we previously had a complicated, nuanced discussion, we now have data from a multi-institutional, meticulous analysis to guide further treatment, candidacy for clinical trials, and our expectations of what would be meaningful results from additional therapy. This meets my definition of “practice-changing” research.
APHINITY follow-up
APHINITY was a randomized, multicenter, double-blind, placebo-controlled trial that previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest, but statistically significant, improvement in invasive disease–free survival (IDFS), compared with placebo and chemotherapy plus trastuzumab (hazard ratio, 0.81; P = .04). When the initial results – with a median follow-up of 45.4 months – were published, the authors promised an update at 6 years. Martine Piccart, MD, PhD, provided that update at the 2019 SABCS (Abstract GS1-04).
In the updated analysis, overall survival was 94.8% among patients on the pertuzumab arm and 93.9% among patients taking placebo (HR, 0.85). IDFS rates were 90.6% versus 87.8% in the intent-to-treat population. The investigator commented that this difference was caused mainly by a reduction in distant and loco-regional recurrences.
Central nervous system metastases, contralateral invasive breast cancers, and death without a prior event were no different between the two treatment groups.
Improvement in IDFS (the primary endpoint) from pertuzumab was most impressive in the node-positive cohort, 87.9% versus 83.4% for placebo (HR, 0.72). There was no benefit in the node-negative population (95.0% vs. 94.9%; HR, 1.02).
In contrast to the 3-year analysis, the benefits in IDFS were seen regardless of hormone receptor status. Additionally, no new safety concerns emerged. The rate of severe cardiac events was below 1% in both groups.
How these results influence practice
“Patience is a virtue” appeared for the first time in the English language around 1360, in William Langland’s poem “Piers Plowman.” They are true words, indeed.
When the initial results of APHINITY were published in 2017, they led to the approval of pertuzumab as an addition to chemotherapy plus trastuzumab for high-risk, early, HER2-positive breast cancer patients. Still, the difference in IDFS curves was visually unimpressive (absolute difference 1.7% in the intent-to-treat and 3.2% in the node-positive patients) and pertuzumab was associated with more grade 3 toxicities (primarily diarrhea) and treatment discontinuations.
An optimist would have observed that the IDFS curves in 2017 did not start to diverge until 24 months and would have noted that the divergence increased with time. That virtuously patient person would have expected that the second interim analysis would show larger absolute benefits, and that the hormone receptor–positive patients (64% of the total) would not yet have relapsed by the first interim analysis and that pertuzumab’s benefit in that group would emerge late.
That appears to be what is happening. It provides hope that an overall survival benefit will become more evident with time. If the target P value for an overall survival difference (.0012) is met by the time of the third interim analysis, our patience (and the FDA’s decision to grant approval for pertuzumab for this indication) will have been amply rewarded. For selected HER2-posiitve patients with high RCB, especially those who tolerated neoadjuvant trastuzumab plus pertuzumab regimens, postoperative adjuvant pertuzumab may be an appealing option.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I Will Treat My Next Patient,” I highlight two presentations from the recent San Antonio Breast Cancer Symposium (SABCS) that will likely change practice for some breast cancer patients – even before the ball drops in Times Square on New Year’s Eve.
Residual cancer burden
Researchers reported a multi-institutional analysis of individual patient-level data on 5,160 patients who had received neoadjuvant chemotherapy (NAC) for localized breast cancer at 11 different centers. They found that residual cancer burden (RCB) was significantly associated with event-free (EFS) and distant recurrence-free survival. The value of calculating RCB was seen across all breast cancer tumor phenotypes (SABCS 2019, Abstract GS5-01).
RCB is calculated by analyzing the residual disease after NAC for the primary tumor bed, the number of positive axillary nodes, and the size of largest node metastasis. It is graded from RCB-0 (pCR) to RCB-III (extensive residual disease).
Both EFS and distant recurrence-free survival were strongly associated with RCB for the overall population and for each breast cancer subtype. For hormone receptor–positive/HER2-negative disease there was a slight hiccup in that RCB-0 was associated with a 10-year EFS of 81%, but EFS was 86% for RCB-I. Fortunately, the prognostic reliability of RCB was clear for RCB-II (69%) and RCB-III (52%). The presenter, W. Fraser Symmans, MD, commented that RCB is most prognostic when higher levels of residual disease are present. RCB remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis.
How these results influence practice
After neoadjuvant chemotherapy in patients with localized breast cancer, we struggle when patients ask: “So, doctor, how am I likely to do?” We piece together a complicated – and inconsistent – answer, based on breast cancer subtype, original stage of disease, whether pCR was attained, and other factors.
For patients with triple-negative breast cancer, we have the option of adding capecitabine and/or participation in ongoing clinical trials, for patients with residual disease after NAC. Among the HER2-positive patients, we have data from the KATHERINE, ExtaNET, and APHINITY trials that provide options for additional treatment in those patients, as well. For patients with potentially hormonally responsive, HER2-negative disease, we can emphasize the importance of postoperative adjuvant endocrine therapy, the mandate for continued adherence to oral therapy, and the lower likelihood of (and prognostic value of) pCR in that breast cancer subtype.
Where we previously had a complicated, nuanced discussion, we now have data from a multi-institutional, meticulous analysis to guide further treatment, candidacy for clinical trials, and our expectations of what would be meaningful results from additional therapy. This meets my definition of “practice-changing” research.
APHINITY follow-up
APHINITY was a randomized, multicenter, double-blind, placebo-controlled trial that previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest, but statistically significant, improvement in invasive disease–free survival (IDFS), compared with placebo and chemotherapy plus trastuzumab (hazard ratio, 0.81; P = .04). When the initial results – with a median follow-up of 45.4 months – were published, the authors promised an update at 6 years. Martine Piccart, MD, PhD, provided that update at the 2019 SABCS (Abstract GS1-04).
In the updated analysis, overall survival was 94.8% among patients on the pertuzumab arm and 93.9% among patients taking placebo (HR, 0.85). IDFS rates were 90.6% versus 87.8% in the intent-to-treat population. The investigator commented that this difference was caused mainly by a reduction in distant and loco-regional recurrences.
Central nervous system metastases, contralateral invasive breast cancers, and death without a prior event were no different between the two treatment groups.
Improvement in IDFS (the primary endpoint) from pertuzumab was most impressive in the node-positive cohort, 87.9% versus 83.4% for placebo (HR, 0.72). There was no benefit in the node-negative population (95.0% vs. 94.9%; HR, 1.02).
In contrast to the 3-year analysis, the benefits in IDFS were seen regardless of hormone receptor status. Additionally, no new safety concerns emerged. The rate of severe cardiac events was below 1% in both groups.
How these results influence practice
“Patience is a virtue” appeared for the first time in the English language around 1360, in William Langland’s poem “Piers Plowman.” They are true words, indeed.
When the initial results of APHINITY were published in 2017, they led to the approval of pertuzumab as an addition to chemotherapy plus trastuzumab for high-risk, early, HER2-positive breast cancer patients. Still, the difference in IDFS curves was visually unimpressive (absolute difference 1.7% in the intent-to-treat and 3.2% in the node-positive patients) and pertuzumab was associated with more grade 3 toxicities (primarily diarrhea) and treatment discontinuations.
An optimist would have observed that the IDFS curves in 2017 did not start to diverge until 24 months and would have noted that the divergence increased with time. That virtuously patient person would have expected that the second interim analysis would show larger absolute benefits, and that the hormone receptor–positive patients (64% of the total) would not yet have relapsed by the first interim analysis and that pertuzumab’s benefit in that group would emerge late.
That appears to be what is happening. It provides hope that an overall survival benefit will become more evident with time. If the target P value for an overall survival difference (.0012) is met by the time of the third interim analysis, our patience (and the FDA’s decision to grant approval for pertuzumab for this indication) will have been amply rewarded. For selected HER2-posiitve patients with high RCB, especially those who tolerated neoadjuvant trastuzumab plus pertuzumab regimens, postoperative adjuvant pertuzumab may be an appealing option.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I Will Treat My Next Patient,” I highlight two presentations from the recent San Antonio Breast Cancer Symposium (SABCS) that will likely change practice for some breast cancer patients – even before the ball drops in Times Square on New Year’s Eve.
Residual cancer burden
Researchers reported a multi-institutional analysis of individual patient-level data on 5,160 patients who had received neoadjuvant chemotherapy (NAC) for localized breast cancer at 11 different centers. They found that residual cancer burden (RCB) was significantly associated with event-free (EFS) and distant recurrence-free survival. The value of calculating RCB was seen across all breast cancer tumor phenotypes (SABCS 2019, Abstract GS5-01).
RCB is calculated by analyzing the residual disease after NAC for the primary tumor bed, the number of positive axillary nodes, and the size of largest node metastasis. It is graded from RCB-0 (pCR) to RCB-III (extensive residual disease).
Both EFS and distant recurrence-free survival were strongly associated with RCB for the overall population and for each breast cancer subtype. For hormone receptor–positive/HER2-negative disease there was a slight hiccup in that RCB-0 was associated with a 10-year EFS of 81%, but EFS was 86% for RCB-I. Fortunately, the prognostic reliability of RCB was clear for RCB-II (69%) and RCB-III (52%). The presenter, W. Fraser Symmans, MD, commented that RCB is most prognostic when higher levels of residual disease are present. RCB remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis.
How these results influence practice
After neoadjuvant chemotherapy in patients with localized breast cancer, we struggle when patients ask: “So, doctor, how am I likely to do?” We piece together a complicated – and inconsistent – answer, based on breast cancer subtype, original stage of disease, whether pCR was attained, and other factors.
For patients with triple-negative breast cancer, we have the option of adding capecitabine and/or participation in ongoing clinical trials, for patients with residual disease after NAC. Among the HER2-positive patients, we have data from the KATHERINE, ExtaNET, and APHINITY trials that provide options for additional treatment in those patients, as well. For patients with potentially hormonally responsive, HER2-negative disease, we can emphasize the importance of postoperative adjuvant endocrine therapy, the mandate for continued adherence to oral therapy, and the lower likelihood of (and prognostic value of) pCR in that breast cancer subtype.
Where we previously had a complicated, nuanced discussion, we now have data from a multi-institutional, meticulous analysis to guide further treatment, candidacy for clinical trials, and our expectations of what would be meaningful results from additional therapy. This meets my definition of “practice-changing” research.
APHINITY follow-up
APHINITY was a randomized, multicenter, double-blind, placebo-controlled trial that previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest, but statistically significant, improvement in invasive disease–free survival (IDFS), compared with placebo and chemotherapy plus trastuzumab (hazard ratio, 0.81; P = .04). When the initial results – with a median follow-up of 45.4 months – were published, the authors promised an update at 6 years. Martine Piccart, MD, PhD, provided that update at the 2019 SABCS (Abstract GS1-04).
In the updated analysis, overall survival was 94.8% among patients on the pertuzumab arm and 93.9% among patients taking placebo (HR, 0.85). IDFS rates were 90.6% versus 87.8% in the intent-to-treat population. The investigator commented that this difference was caused mainly by a reduction in distant and loco-regional recurrences.
Central nervous system metastases, contralateral invasive breast cancers, and death without a prior event were no different between the two treatment groups.
Improvement in IDFS (the primary endpoint) from pertuzumab was most impressive in the node-positive cohort, 87.9% versus 83.4% for placebo (HR, 0.72). There was no benefit in the node-negative population (95.0% vs. 94.9%; HR, 1.02).
In contrast to the 3-year analysis, the benefits in IDFS were seen regardless of hormone receptor status. Additionally, no new safety concerns emerged. The rate of severe cardiac events was below 1% in both groups.
How these results influence practice
“Patience is a virtue” appeared for the first time in the English language around 1360, in William Langland’s poem “Piers Plowman.” They are true words, indeed.
When the initial results of APHINITY were published in 2017, they led to the approval of pertuzumab as an addition to chemotherapy plus trastuzumab for high-risk, early, HER2-positive breast cancer patients. Still, the difference in IDFS curves was visually unimpressive (absolute difference 1.7% in the intent-to-treat and 3.2% in the node-positive patients) and pertuzumab was associated with more grade 3 toxicities (primarily diarrhea) and treatment discontinuations.
An optimist would have observed that the IDFS curves in 2017 did not start to diverge until 24 months and would have noted that the divergence increased with time. That virtuously patient person would have expected that the second interim analysis would show larger absolute benefits, and that the hormone receptor–positive patients (64% of the total) would not yet have relapsed by the first interim analysis and that pertuzumab’s benefit in that group would emerge late.
That appears to be what is happening. It provides hope that an overall survival benefit will become more evident with time. If the target P value for an overall survival difference (.0012) is met by the time of the third interim analysis, our patience (and the FDA’s decision to grant approval for pertuzumab for this indication) will have been amply rewarded. For selected HER2-posiitve patients with high RCB, especially those who tolerated neoadjuvant trastuzumab plus pertuzumab regimens, postoperative adjuvant pertuzumab may be an appealing option.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
ctDNA shows clinical value in advanced breast cancer
SAN ANTONIO – The high accuracy and efficiency of circulating tumor DNA (ctDNA) testing allows for routine clinical use in advanced breast cancer, according to investigators.
The plasmaMATCH trial showed that gene level agreement between ctDNA results measured by digital PCR versus sequencing was as high as 99.4%, reported lead author Nicholas Turner, MA, MRCP, PhD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London.
Dr. Turner, who presented findings at the San Antonio Breast Cancer Symposium, said that ctDNA testing can detect rare mutations and link patients with targeted therapies that have clinically relevant response rates.
“Multiple somatic mutations are potentially targetable in the treatment of advanced breast cancer,” Dr. Turner said. “In addition, mutations may be acquired [during treatment].”
The diverse and dynamic landscape of mutations in breast cancer creates a need to genotype tumors without repeating biopsies, Dr. Turner said. He noted that ctDNA is one possible means of fulfilling this need, although more prospective research is required to determine clinical utility.
To this end, the investigators conducted the phase II plasmaMATCH trial, a multiple parallel cohort, multicenter study involving 1,044 patients with advanced breast cancer. All patients had ctDNA testing performed prospectively with digital droplet PCR (ddPCR); in addition, ctDNA testing was performed with error-corrected sequencing using Guardant360, either prospectively or retrospectively. If actionable mutations were identified, and consent was provided, then patients entered the treatment cohort, which was composed of 142 participants.
Patients were divided into four parallel treatment cohorts based on ctDNA mutation results and accompanying treatments, as follows:
- (A) ESR1 mutation; extended-dose fulvestrant.
- (B) HER2 mutation; neratinib with or without fulvestrant.
- (C) AKT1 in estrogen receptor–positive disease; capivasertib plus fulvestrant.
- (D) “AKT basket” – AKT1 in estrogen receptor–negative disease or PTEN inactivating mutation; capivasertib.
The primary objective was response rate. For cohort A, at least 13 out of 78 evaluable patients (17%) needed to have a response to infer sufficient efficacy of the matched therapy. For the remaining cohorts, sufficient efficacy was defined by responses in at least 3 out of 16 evaluable patients (19%).
Secondary objectives included frequency of targetable mutations, accuracy of ctDNA testing (to be reported later), and others.
Results showed that ESR1 mutations were most common within the original population (27.7%), followed by AKT1 mutations (4.2%) and HER2 mutations (2.7%). In the treatment cohort, more than half of the patients had a HER2 mutation (58%) and/or an AKT1 mutation (54%), whereas a smaller proportion had an ESR1 mutation (38%). Approximately two-thirds of patients (64%) had hormone receptor–positive, HER2-negative breast cancer; 17% had triple-negative breast cancer; 6% had hormone receptor–positive, HER2-positive disease; 3% had hormone receptor–negative, HER2-positive disease; and 9% had other/unknown phenotypes. Approximately two-thirds of patients (65%) had received at least two lines of prior therapy for advanced disease.
For patients with an ESR1 mutation treated with extended-dose fulvestrant (cohort A) only 8.1% achieved a response, which was below the threshold for inferred efficacy. For patients with a HER2 mutation treated with neratinib with or without fulvestrant (cohort B), 25.0% had a response, thereby demonstrating inferred efficacy. Efficacy was also inferred in patients with an AKT1 mutation treated with capivasertib plus fulvestrant (cohort C), as 22.2% of these patients had a response. In the AKT basket (cohort D), 10.5% of patients had a response, which fell below the efficacy threshold; however, an exploratory analysis of this cohort showed that patients with an AKT1 mutation had a response rate of 33.3% (two out of six patients), which did meet efficacy criteria.
Adverse events were consistent with previous reports. The investigators noted that extended-dose fulvestrant was well tolerated.
“In conclusion, we show that circulating tumor DNA testing offers a simple, efficient and relatively fast method of tumor genotyping,” Dr. Turner said.
The investigators disclosed relationships with Puma Biotechnology, AstraZeneca, Guardant Health, and Bio-Rad.
SOURCE: Turner et al. SABCS. 2019 Dec 12. Abstract GS3-06.
SAN ANTONIO – The high accuracy and efficiency of circulating tumor DNA (ctDNA) testing allows for routine clinical use in advanced breast cancer, according to investigators.
The plasmaMATCH trial showed that gene level agreement between ctDNA results measured by digital PCR versus sequencing was as high as 99.4%, reported lead author Nicholas Turner, MA, MRCP, PhD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London.
Dr. Turner, who presented findings at the San Antonio Breast Cancer Symposium, said that ctDNA testing can detect rare mutations and link patients with targeted therapies that have clinically relevant response rates.
“Multiple somatic mutations are potentially targetable in the treatment of advanced breast cancer,” Dr. Turner said. “In addition, mutations may be acquired [during treatment].”
The diverse and dynamic landscape of mutations in breast cancer creates a need to genotype tumors without repeating biopsies, Dr. Turner said. He noted that ctDNA is one possible means of fulfilling this need, although more prospective research is required to determine clinical utility.
To this end, the investigators conducted the phase II plasmaMATCH trial, a multiple parallel cohort, multicenter study involving 1,044 patients with advanced breast cancer. All patients had ctDNA testing performed prospectively with digital droplet PCR (ddPCR); in addition, ctDNA testing was performed with error-corrected sequencing using Guardant360, either prospectively or retrospectively. If actionable mutations were identified, and consent was provided, then patients entered the treatment cohort, which was composed of 142 participants.
Patients were divided into four parallel treatment cohorts based on ctDNA mutation results and accompanying treatments, as follows:
- (A) ESR1 mutation; extended-dose fulvestrant.
- (B) HER2 mutation; neratinib with or without fulvestrant.
- (C) AKT1 in estrogen receptor–positive disease; capivasertib plus fulvestrant.
- (D) “AKT basket” – AKT1 in estrogen receptor–negative disease or PTEN inactivating mutation; capivasertib.
The primary objective was response rate. For cohort A, at least 13 out of 78 evaluable patients (17%) needed to have a response to infer sufficient efficacy of the matched therapy. For the remaining cohorts, sufficient efficacy was defined by responses in at least 3 out of 16 evaluable patients (19%).
Secondary objectives included frequency of targetable mutations, accuracy of ctDNA testing (to be reported later), and others.
Results showed that ESR1 mutations were most common within the original population (27.7%), followed by AKT1 mutations (4.2%) and HER2 mutations (2.7%). In the treatment cohort, more than half of the patients had a HER2 mutation (58%) and/or an AKT1 mutation (54%), whereas a smaller proportion had an ESR1 mutation (38%). Approximately two-thirds of patients (64%) had hormone receptor–positive, HER2-negative breast cancer; 17% had triple-negative breast cancer; 6% had hormone receptor–positive, HER2-positive disease; 3% had hormone receptor–negative, HER2-positive disease; and 9% had other/unknown phenotypes. Approximately two-thirds of patients (65%) had received at least two lines of prior therapy for advanced disease.
For patients with an ESR1 mutation treated with extended-dose fulvestrant (cohort A) only 8.1% achieved a response, which was below the threshold for inferred efficacy. For patients with a HER2 mutation treated with neratinib with or without fulvestrant (cohort B), 25.0% had a response, thereby demonstrating inferred efficacy. Efficacy was also inferred in patients with an AKT1 mutation treated with capivasertib plus fulvestrant (cohort C), as 22.2% of these patients had a response. In the AKT basket (cohort D), 10.5% of patients had a response, which fell below the efficacy threshold; however, an exploratory analysis of this cohort showed that patients with an AKT1 mutation had a response rate of 33.3% (two out of six patients), which did meet efficacy criteria.
Adverse events were consistent with previous reports. The investigators noted that extended-dose fulvestrant was well tolerated.
“In conclusion, we show that circulating tumor DNA testing offers a simple, efficient and relatively fast method of tumor genotyping,” Dr. Turner said.
The investigators disclosed relationships with Puma Biotechnology, AstraZeneca, Guardant Health, and Bio-Rad.
SOURCE: Turner et al. SABCS. 2019 Dec 12. Abstract GS3-06.
SAN ANTONIO – The high accuracy and efficiency of circulating tumor DNA (ctDNA) testing allows for routine clinical use in advanced breast cancer, according to investigators.
The plasmaMATCH trial showed that gene level agreement between ctDNA results measured by digital PCR versus sequencing was as high as 99.4%, reported lead author Nicholas Turner, MA, MRCP, PhD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London.
Dr. Turner, who presented findings at the San Antonio Breast Cancer Symposium, said that ctDNA testing can detect rare mutations and link patients with targeted therapies that have clinically relevant response rates.
“Multiple somatic mutations are potentially targetable in the treatment of advanced breast cancer,” Dr. Turner said. “In addition, mutations may be acquired [during treatment].”
The diverse and dynamic landscape of mutations in breast cancer creates a need to genotype tumors without repeating biopsies, Dr. Turner said. He noted that ctDNA is one possible means of fulfilling this need, although more prospective research is required to determine clinical utility.
To this end, the investigators conducted the phase II plasmaMATCH trial, a multiple parallel cohort, multicenter study involving 1,044 patients with advanced breast cancer. All patients had ctDNA testing performed prospectively with digital droplet PCR (ddPCR); in addition, ctDNA testing was performed with error-corrected sequencing using Guardant360, either prospectively or retrospectively. If actionable mutations were identified, and consent was provided, then patients entered the treatment cohort, which was composed of 142 participants.
Patients were divided into four parallel treatment cohorts based on ctDNA mutation results and accompanying treatments, as follows:
- (A) ESR1 mutation; extended-dose fulvestrant.
- (B) HER2 mutation; neratinib with or without fulvestrant.
- (C) AKT1 in estrogen receptor–positive disease; capivasertib plus fulvestrant.
- (D) “AKT basket” – AKT1 in estrogen receptor–negative disease or PTEN inactivating mutation; capivasertib.
The primary objective was response rate. For cohort A, at least 13 out of 78 evaluable patients (17%) needed to have a response to infer sufficient efficacy of the matched therapy. For the remaining cohorts, sufficient efficacy was defined by responses in at least 3 out of 16 evaluable patients (19%).
Secondary objectives included frequency of targetable mutations, accuracy of ctDNA testing (to be reported later), and others.
Results showed that ESR1 mutations were most common within the original population (27.7%), followed by AKT1 mutations (4.2%) and HER2 mutations (2.7%). In the treatment cohort, more than half of the patients had a HER2 mutation (58%) and/or an AKT1 mutation (54%), whereas a smaller proportion had an ESR1 mutation (38%). Approximately two-thirds of patients (64%) had hormone receptor–positive, HER2-negative breast cancer; 17% had triple-negative breast cancer; 6% had hormone receptor–positive, HER2-positive disease; 3% had hormone receptor–negative, HER2-positive disease; and 9% had other/unknown phenotypes. Approximately two-thirds of patients (65%) had received at least two lines of prior therapy for advanced disease.
For patients with an ESR1 mutation treated with extended-dose fulvestrant (cohort A) only 8.1% achieved a response, which was below the threshold for inferred efficacy. For patients with a HER2 mutation treated with neratinib with or without fulvestrant (cohort B), 25.0% had a response, thereby demonstrating inferred efficacy. Efficacy was also inferred in patients with an AKT1 mutation treated with capivasertib plus fulvestrant (cohort C), as 22.2% of these patients had a response. In the AKT basket (cohort D), 10.5% of patients had a response, which fell below the efficacy threshold; however, an exploratory analysis of this cohort showed that patients with an AKT1 mutation had a response rate of 33.3% (two out of six patients), which did meet efficacy criteria.
Adverse events were consistent with previous reports. The investigators noted that extended-dose fulvestrant was well tolerated.
“In conclusion, we show that circulating tumor DNA testing offers a simple, efficient and relatively fast method of tumor genotyping,” Dr. Turner said.
The investigators disclosed relationships with Puma Biotechnology, AstraZeneca, Guardant Health, and Bio-Rad.
SOURCE: Turner et al. SABCS. 2019 Dec 12. Abstract GS3-06.
REPORTING FROM SABCS 2019
Study Supports Vertigo as “Integral Manifestation” of Migraine, Rather Than Symptom
Key Points:
- The “Migraine and Neck Pain Study” analyzed data from nearly 500 adult participants in an effort to uncover an association between migraine-related episodic vertigo and the phases of migraine.
- The study participants included men and women aged 18 to 65, who had episodic migraine with aura and/or without aura.
- Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache.
- 30% of participants reported episodic vertigo at any point during their migraine attack, while 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand.
- The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom.
Alan M. Rapoport, MD:
Vertigo in a migraineur has long created confusion as to diagnosis and treatment. I myself always wondered how much I had to work up vertigo or even dizziness if a patient had migraine. I also did not know what to do when a patient with migraine had attacks of vertigo without headache. Were they manifestations of migraine and should they be treated that way?
This study examined a 500 adult patient population who had migraine with or without aura. Christian Lampl was interested in seeing how many had headache, and the timing of when vertigo occurred. It was carefully measured to determine if it usually occurred during or before the headache phase. Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache, when prodrome occurs.
- The study determined that 30 % of the patients reported vertigo at some point during their migraine attack; 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand., which would have been in the prodromal phase.
- The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom. This was interesting but it left unanswered one of my questions which is, how many had vertigo unrelated to headache and what is that and how do we treat it.
- Although not addressed in this study, there is consensus that if there is enough vertigo in a migraineur, they should be placed on a migraine preventive therapy. It will be interesting to see what the new monoclonal antibodies to CGRP do to vertigo in a treated migraineur. Some headache specialists will even treat an attack of vertigo without headache with a triptan.
Key Points:
- The “Migraine and Neck Pain Study” analyzed data from nearly 500 adult participants in an effort to uncover an association between migraine-related episodic vertigo and the phases of migraine.
- The study participants included men and women aged 18 to 65, who had episodic migraine with aura and/or without aura.
- Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache.
- 30% of participants reported episodic vertigo at any point during their migraine attack, while 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand.
- The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom.
Alan M. Rapoport, MD:
Vertigo in a migraineur has long created confusion as to diagnosis and treatment. I myself always wondered how much I had to work up vertigo or even dizziness if a patient had migraine. I also did not know what to do when a patient with migraine had attacks of vertigo without headache. Were they manifestations of migraine and should they be treated that way?
This study examined a 500 adult patient population who had migraine with or without aura. Christian Lampl was interested in seeing how many had headache, and the timing of when vertigo occurred. It was carefully measured to determine if it usually occurred during or before the headache phase. Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache, when prodrome occurs.
- The study determined that 30 % of the patients reported vertigo at some point during their migraine attack; 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand., which would have been in the prodromal phase.
- The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom. This was interesting but it left unanswered one of my questions which is, how many had vertigo unrelated to headache and what is that and how do we treat it.
- Although not addressed in this study, there is consensus that if there is enough vertigo in a migraineur, they should be placed on a migraine preventive therapy. It will be interesting to see what the new monoclonal antibodies to CGRP do to vertigo in a treated migraineur. Some headache specialists will even treat an attack of vertigo without headache with a triptan.
Key Points:
- The “Migraine and Neck Pain Study” analyzed data from nearly 500 adult participants in an effort to uncover an association between migraine-related episodic vertigo and the phases of migraine.
- The study participants included men and women aged 18 to 65, who had episodic migraine with aura and/or without aura.
- Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache.
- 30% of participants reported episodic vertigo at any point during their migraine attack, while 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand.
- The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom.
Alan M. Rapoport, MD:
Vertigo in a migraineur has long created confusion as to diagnosis and treatment. I myself always wondered how much I had to work up vertigo or even dizziness if a patient had migraine. I also did not know what to do when a patient with migraine had attacks of vertigo without headache. Were they manifestations of migraine and should they be treated that way?
This study examined a 500 adult patient population who had migraine with or without aura. Christian Lampl was interested in seeing how many had headache, and the timing of when vertigo occurred. It was carefully measured to determine if it usually occurred during or before the headache phase. Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache, when prodrome occurs.
- The study determined that 30 % of the patients reported vertigo at some point during their migraine attack; 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand., which would have been in the prodromal phase.
- The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom. This was interesting but it left unanswered one of my questions which is, how many had vertigo unrelated to headache and what is that and how do we treat it.
- Although not addressed in this study, there is consensus that if there is enough vertigo in a migraineur, they should be placed on a migraine preventive therapy. It will be interesting to see what the new monoclonal antibodies to CGRP do to vertigo in a treated migraineur. Some headache specialists will even treat an attack of vertigo without headache with a triptan.
Sensitivity of ctDNA equivalent to that of tumor tissue sequencing
SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.
When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.
In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.
“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.
The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).
Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.
Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.
Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.
For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.
Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).
“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.
Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.
Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.
A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.
Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.
Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.
“You indicated there was overall concordance between ddPCR and the targeted capture assay,” Dr. Arteaga said. “That suggests that you did select the better hotspots; however, you could be missing some genomic space captured by the targeted capture assay that may change over time as a function of tumor evolution, drug resistance, or whatever,” Dr. Arteaga said. “So have you assessed how stable that component is as a function of time and treatment, or do you plan to do that?”
Dr. Kingston said that although these data are not yet available, plans are underway to perform ctDNA during the treatment process, so that concordance between the two techniques may be evaluated over time.
The investigators disclosed ties with Puma Biotechnology, AstraZeneca, Guardant Health, and Bio-Rad.
SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.
SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.
When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.
In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.
“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.
The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).
Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.
Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.
Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.
For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.
Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).
“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.
Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.
Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.
A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.
Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.
Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.
“You indicated there was overall concordance between ddPCR and the targeted capture assay,” Dr. Arteaga said. “That suggests that you did select the better hotspots; however, you could be missing some genomic space captured by the targeted capture assay that may change over time as a function of tumor evolution, drug resistance, or whatever,” Dr. Arteaga said. “So have you assessed how stable that component is as a function of time and treatment, or do you plan to do that?”
Dr. Kingston said that although these data are not yet available, plans are underway to perform ctDNA during the treatment process, so that concordance between the two techniques may be evaluated over time.
The investigators disclosed ties with Puma Biotechnology, AstraZeneca, Guardant Health, and Bio-Rad.
SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.
SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.
When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.
In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.
“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.
The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).
Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.
Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.
Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.
For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.
Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).
“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.
Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.
Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.
A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.
Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.
Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.
“You indicated there was overall concordance between ddPCR and the targeted capture assay,” Dr. Arteaga said. “That suggests that you did select the better hotspots; however, you could be missing some genomic space captured by the targeted capture assay that may change over time as a function of tumor evolution, drug resistance, or whatever,” Dr. Arteaga said. “So have you assessed how stable that component is as a function of time and treatment, or do you plan to do that?”
Dr. Kingston said that although these data are not yet available, plans are underway to perform ctDNA during the treatment process, so that concordance between the two techniques may be evaluated over time.
The investigators disclosed ties with Puma Biotechnology, AstraZeneca, Guardant Health, and Bio-Rad.
SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.
REPORTING FROM SABCS 2019