By: Jason M. Broderick
Researchers at the Mayo Clinic maintain that all women aged 65 or under with a breast cancer diagnosis should receive germline genetic testing to identify harmful mutations that increase both their risk of developing secondary cancers and their blood relatives’ risk of developing cancer.1
The researchers published a study in the Journal of Clinical Oncology,2 the results of which suggest that the NCCN guidelines for germline genetic testing in breast are too narrow. The NCCN recommends that all women aged ≥46 years receive germline testing regardless of their disease histology or family history. However, the Mayo study determined that these criteria are excluding a significant number of women older than this cutoff who harbor harmful mutations.
“There is considerable confusion regarding the best method for selecting who may benefit from hereditary cancer genetic testing from among all women diagnosed with breast cancer,” lead investigator Fergus Couch, PhD, a breast cancer researcher at Mayo Clinic, said in a press release. “The NCCN has very specific guidelines for who may benefit from genetic testing based on the age of diagnosis and family history of certain cancers while the American Society of Breast Surgeons (ASBrS) recommends testing all women with breast cancer.”
Couch and his colleagues at Mayo evaluated data from 3907 women enrolled in a Mayo Clinic breast cancer registry between 2000 and 2016 who were tested for germline pathogenic variants in 9 genes known to increase the risk of developing breast cancer: ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53.
Overall, 47.9% (n = 1872) of the women met the criteria and 52.1% (n = 2035) did not. Patient characteristics at baseline were well balanced between the 2 groups for the most part. Across all 3907 patients, the median age was 57, 95.2% were white, and 84% had invasive histology. Hormone receptor status showed that 84.5% were ER-positive and 74.9% were PR-positive. Three hundred seventy-eight (11.5%) patients were HER2-positive. Of note, a higher rate of women in the group meeting the NCCN criteria had a family history of breast cancer (56.6% vs 37.5%), ovarian cancer (15.3% vs 0), pancreatic cancer (16.2% vs 0), and prostate cancer (23.1% vs 20.6%), compared with those who did not meet the criteria.
The women who met the NCCN screening criteria were more likely to harbor a pathogenic variant of 1 of the predisposition genes compared with those who did not meet the criteria (9.0% vs 3.5%; P <.001). Among the women who did not meet the NCCN criteria, 14 (0.7%) carried pathogenic variants of BRCA1 and BRCA2.
The Mayo research team calculated that the NCCN criteria had a 70% sensitivity for the 9 predisposition genes, including 87% for BRCA1 and BRCA2. The specificity of the criteria for the 9 genes was 53%. The suggested Mayo criteria of expanding testing to include all women aged ≤65 years led to a greater than 90% sensitivity for the 9 genes, including a >98% sensitivity for BRCA1 and BRCA2.
“We were surprised to find that the NCCN guidelines missed approximately 30% of mutation carriers in breast cancer predisposition genes,” Siddhartha Yadav, MBBS, a medical oncologist at Mayo Clinic and first author of the study, said in the press release. “A few recent studies have demonstrated that NCCN guidelines could miss a substantial number of mutation carriers. However, these studies included several genes that are not typically associated with breast cancer risk. Our study was appropriately restricted to 9 breast cancer predisposition genes with clear management guidelines.”
In the conclusion of their published research, Couch and coinvestigators wrote, “Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.”
- Mayo researchers recommend all women with breast cancer diagnosis under age 66 be offered genetic testing. Mayo Clinic. Published March 2, 2020. https://mayocl.in/2VNCVVW. Accessed March 5, 2020.
- Yadav S, Hu C, Hart SN, et al. Evaluation of germline genetic testing criteria in a hospital-based series of women with breast cancer [published online March 3, 2020]. J Clin Oncol. doi: 10.1200/JCO.19.02190
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.