Breast cancer is a common manifestation of an underlying genetic susceptibility to cancer, and 5% to 10% of all breast cancers are associated with a germline mutation in a known risk allele. Detection of mutations has implications for targeted screening and prevention strategies for probands, and for genetic counseling and testing of their family members. This report presents a case involving a 35-year-old woman with no family history of breast or ovarian cancer who presented with a palpable right breast lump. Imaging revealed multiple bilateral breast masses and right axillary adenopathy, and core needle biopsies showed invasive ductal carcinoma in both the right and left breast. This report discusses the appropriate genetics evaluation for a patient with bilateral breast cancer at a young age, including testing for mutations in BRCA1 and BRCA2, followed, if negative, by consideration of testing for mutations in TP53 (Li-Fraumeni syndrome). Given the specialized counseling and testing needs of patients with Li-Fraumeni syndrome, and the implications for targeted screening strategies if a mutation is found, referral to a cancer genetics expert is strongly recommended.
Monique A. de Bruin, James M. Ford, and Allison W. Kurian
Megan C. Roberts, Allison W. Kurian, and Valentina I. Petkov
Background: This study assessed uptake of the Oncotype DX 21-gene assay over time and characterized which sociodemographic and clinical factors are associated with test uptake among women with lymph node−positive (LN+), hormone receptor−positive, HER2-negative breast cancer. Methods: Invasive breast cancer cases diagnosed in 2010 through 2013 were included from a SEER database linked to 21-gene assay results performed at Genomic Health’s Clinical Laboratory. Factors associated with 21-gene assay uptake were identified using a multivariable logistic regression model. Results: Uptake of the 21-gene assay increased over time and differed by race, socioeconomic status (SES), and age. In the multivariable model, when clinical and SES variables were controlled for, racial differences in test uptake were no longer observed. Private insurance status was associated with higher odds of 21-gene assay uptake (Medicaid vs private insurance: adjusted odds ratio, 0.86; P=.02), and high area-level SES was associated with an increased odds of uptake (quintile 5 vs 1: adjusted odds ratio, 1.6; P<.001). Demographic factors such as age and marital status influenced test uptake, and use varied greatly by geographic region. Uptake of the 21-gene assay increased over time and preceded the assay’s inclusion in the NCCN Guidelines for LN+ breast cancer. Differences in uptake by race, SES, and age have persisted over time. However, when clinical and SES variables were controlled for, racial differences in assay uptake were no longer observed. Socioeconomic variables, such as health insurance type and area-level SES, were associated with assay uptake. Conclusions: Future research should continue to document practice patterns related to the 21-gene assay. Given variation in testing associated with area-level SES, insurance coverage, and geographic region, interventions to understand and reduce differential uptake are needed to ensure equitable access to this genomic test.
Julia R. Trosman, Christine B. Weldon, Michael P. Douglas, Allison W. Kurian, R. Kate Kelley, Patricia A. Deverka, and Kathryn A. Phillips
Background: Hereditary cancer panels (HCPs), testing for multiple genes and syndromes, are rapidly transforming cancer risk assessment but are controversial and lack formal insurance coverage. We aimed to identify payers' perspectives on barriers to HCP coverage and opportunities to address them. Comprehensive cancer risk assessment is highly relevant to the Precision Medicine Initiative (PMI), and payers' considerations could inform PMI's efforts. We describe our findings and discuss them in the context of PMI priorities. Methods: We conducted semi-structured interviews with 11 major US payers, covering >160 million lives. We used the framework approach of qualitative research to design, conduct, and analyze interviews, and used simple frequencies to further describe findings. Results: Barriers to HCP coverage included poor fit with coverage frameworks (100%); insufficient evidence (100%); departure from pedigree/family history–based testing toward genetic screening (91%); lacking rigor in the HCP hybrid research/clinical setting (82%); and patient transparency and involvement concerns (82%). Addressing barriers requires refining HCP-indicated populations (82%); developing evidence of actionability (82%) and pathogenicity/penetrance (64%); creating infrastructure and standards for informing and recontacting patients (45%); separating research from clinical use in the hybrid clinical-research setting (44%); and adjusting coverage frameworks (18%). Conclusions: Leveraging opportunities suggested by payers to address HCP coverage barriers is essential to ensure patients' access to evolving HCPs. Our findings inform 3 areas of the PMI: addressing insurance coverage to secure access to future PMI discoveries; incorporating payers' evidentiary requirements into PMI's research agenda; and leveraging payers' recommendations and experience to keep patients informed and involved.
Mary B. Daly, Tuya Pal, Michael P. Berry, Saundra S. Buys, Patricia Dickson, Susan M. Domchek, Ahmed Elkhanany, Susan Friedman, Michael Goggins, Mollie L. Hutton, CGC, Beth Y. Karlan, Seema Khan, Catherine Klein, Wendy Kohlmann, CGC, Allison W. Kurian, Christine Laronga, Jennifer K. Litton, Julie S. Mak, LCGC, Carolyn S. Menendez, Sofia D. Merajver, Barbara S. Norquist, Kenneth Offit, Holly J. Pederson, Gwen Reiser, CGC, Leigha Senter-Jamieson, CGC, Kristen Mahoney Shannon, Rebecca Shatsky, Kala Visvanathan, Jeffrey N. Weitzel, Myra J. Wick, Kari B. Wisinski, Matthew B. Yurgelun, Susan D. Darlow, and Mary A. Dwyer
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020
Featured Updates to the NCCN Guidelines
Mary B. Daly, Robert Pilarski, Matthew B. Yurgelun, Michael P. Berry, Saundra S. Buys, Patricia Dickson, Susan M. Domchek, Ahmed Elkhanany, Susan Friedman, Judy E. Garber, Michael Goggins, Mollie L. Hutton, Seema Khan, Catherine Klein, Wendy Kohlmann, Allison W. Kurian, Christine Laronga, Jennifer K. Litton, Julie S. Mak, Carolyn S. Menendez, Sofia D. Merajver, Barbara S. Norquist, Kenneth Offit, Tuya Pal, Holly J. Pederson, Gwen Reiser, Kristen Mahoney Shannon, Kala Visvanathan, Jeffrey N. Weitzel, Myra J. Wick, Kari B. Wisinski, Mary A. Dwyer, and Susan D. Darlow
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.