Comparison of Practice Guidelines, BRCAPRO, and Genetic Counselor Estimates to Identify Germline BRCA1 and BRCA2 Mutations in Pancreatic Cancer
Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic ductal adenocarcinoma (PDAC) may benefit from precision therapies and their relatives should undergo tailored cancer prevention. In this study, we compared strategies to identify BRCA carriers with PDAC. Incident cases of PDAC were prospectively recruited for BRCA sequencing. Probands were evaluated using the National Comprehensive Cancer Network (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines. The probability of each proband carrying a mutation was estimated by surveying genetic counselors and using BRCAPRO. BRCA mutations were detected in 22/484 (4.5%) probands. 152/484 (31.2%) and 16/484 (3.3%) probands met the NCCN and MOHLTC guidelines, respectively. The NCCN guidelines had higher sensitivity than the MOHLTC guidelines (0.864 versus 0.227, P < 0.001) but lower specificity (0.712 versus 0.976, P < 0.001). One hundred and nineteen genetic counselors completed the survey. Discrimination was similar between genetic counselors and BRCAPRO (area-under-the-curve: 0.755 and 0.775, respectively, P = 0.702). Genetic counselors generally overestimated (P = 0.008), whereas BRCAPRO severely underestimated (P < 0.001), the probability that each proband carried a mutation. Our results indicate that the NCCN guidelines and genetic counselors accurately identify BRCA mutations in PDAC, while the MOHLTC guidelines and BRCAPRO should be updated to account for the association between BRCA and PDAC.
KeywordsPancreatic cancer BRCA1 BRCA2 Genetic counseling BRCAPRO Guidelines
We thank the genetic counselors and patients who participated in this study, Harden Huang for generating the website to direct genetic counselors to the surveys, and Kara Semotiuk, Melyssa Aronson, and Laura Winter for assistance with survey development.
Compliance with Ethical Standards
Conflict of Interest
Robert C. Grant, Spring Holter, Ayelet Borgida, Neesha C. Dhani, David W. Hedley, Mohammad R. Akbari, George Zogopoulos, and Steven Gallinger declare that they have no conflict of interest.
Human Studies and Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
No animal studies were carried out by the authors for this article.
- Berry, D. A., Iversen Jr., E. S., Gudbjartsson, D. F., Hiller, E. H., Garber, J. E., Peshkin, B. N., et al. (2002). BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. Journal of Clinical Oncology, 20(11), 2701–2712. https://doi.org/10.1200/JCO.2002.05.121.CrossRefPubMedGoogle Scholar
- Connor, A. A., Denroche, R. E., Jang, G. H., Timms, L., Kalimuthu, S. N., Selander, I., et al. (2016). Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma. JAMA Oncology. https://doi.org/10.1001/jamaoncol.2016.3916.
- Fischer, C., Kuchenbacker, K., Engel, C., Zachariae, S., Rhiem, K., Meindl, A., et al. (2013). Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast And Ovarian Cancer Consortium. Journal of Medical Genetics, 50(6), 360–367. https://doi.org/10.1136/jmedgenet-2012-101415.CrossRefPubMedGoogle Scholar
- Golan, T., Kanji, Z. S., Epelbaum, R., Devaud, N., Dagan, E., Holter, S., et al. (2014). Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. British Journal of Cancer, 111(6), 1132–1138. https://doi.org/10.1038/bjc.2014.418.CrossRefPubMedPubMedCentralGoogle Scholar
- Grant, R. C., Selander, I., Connor, A. A., Selvarajah, S., Borgida, A., Briollais, L., et al. (2015). Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology, 148(3), 556–564. https://doi.org/10.1053/j.gastro.2014.11.042.CrossRefPubMedGoogle Scholar
- Holter, S., Borgida, A., Dodd, A., Grant, R., Semotiuk, K., Hedley, D., et al. (2015). Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. Journal of Clinical Oncology, 33(28), 3124–3129. https://doi.org/10.1200/JCO.2014.59.7401.CrossRefPubMedGoogle Scholar
- Kaufman, B., Shapira-Frommer, R., Schmutzler, R. K., Audeh, M. W., Friedlander, M., Balmana, J., et al. (2015). Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. Journal of Clinical Oncology, 33(3), 244–250. https://doi.org/10.1200/JCO.2014.56.2728.CrossRefPubMedGoogle Scholar
- McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., et al. (2010). The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Research, 20(9), 1297–1303. https://doi.org/10.1101/gr.107524.110.CrossRefPubMedPubMedCentralGoogle Scholar
- National Comprehensive Cancer Network. (2017). Genetic/familial high-risk assessment: breast and ovarian (Version 1.2017).Google Scholar
- Pritchard, C. C., Mateo, J., Walsh, M. F., De Sarkar, N., Abida, W., Beltran, H., et al. (2016). Inherited DNA-repair gene mutations in men with metastatic prostate cancer. The New England Journal of Medicine, 375(5), 443–453. https://doi.org/10.1056/NEJMoa1603144.CrossRefPubMedPubMedCentralGoogle Scholar
- Robson, M. E., Im, S.-A., Senkus, E., Xu, B., Domchek, S. M., Masuda, N., et al. (2017). OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). Journal of Clinical Oncology, 35(18_suppl), LBA4. https://doi.org/10.1200/JCO.2017.35.18_suppl.LBA4.CrossRefGoogle Scholar
- Shindo, K., Yu, J., Suenaga, M., Fesharakizadeh, S., Cho, C., Macgregor-Das, A., et al. (2017). Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. Journal of Clinical Oncology, 35(30), 3382–3390. https://doi.org/10.1200/JCO.2017.72.3502.CrossRefPubMedGoogle Scholar