Breast cancer in young women: do BRCA1 or BRCA2 mutations matter?
Authors: Peter A Fasching
Journal: The Lancet Oncology (2018)

Young women with breast cancer have always caught the attention of both clinicians and researchers, despite this group being a rarity. Several factors distinguish the biology of both breast cancer in young patients and the patients themselves from that of tumours and patients who are diagnosed later in life. Additionally, the cancers might be associated with a previous pregnancy or have a pathogenesis that is based on a genetic predisposition; some data even imply that both cancers associated with a previous pregnancy and a genetic predisposition to cancer might be directly connected.1Sigl V Jones LP Penninger JM RANKL/RANK: from bone loss to the prevention of breast cancer.Open Biol. 2016; 6 (pii: 160230)Crossref PubMed Scopus (43) Google Scholar The POSH prospective cohort study by Ellen R Copson and colleagues, published in The Lancet Oncology,2Copson ER Maishman TC Tapper WJ et al.Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.Lancet Oncol. 2018; (published online Jan 11)http://dx.doi.org/10.1016/S1470-2045(17)30891-4Summary Full Text Full Text PDF PubMed Scopus (214) Google Scholar has contributed to the understanding of this patient population after recruiting nearly 3000 patients diagnosed with breast cancer when younger than 40 years, and capturing comprehensive data about patient, tumour, and treatment characteristics, along with extensive follow-up data. Copson and colleagues reported that patients with a BRCA1 or BRCA2 mutation had a similar prognosis as patients without these mutations: in 2733 women included in the analysis, overall survival at 2 years was 97·0% (95% CI 94·5–98·4) for BRCA mutation carriers versus 96·6% (95·8–97·3) for non-carriers (hazard ratio [HR] 0·96 [95% CI 0·76–1·22]; p=0·76). Similar results were seen at 5 years and 10 years. Additionally, in 558 patients with triple-negative breast cancer, those who had a BRCA mutation had better overall survival than did non-carriers at 2 years (95% [95% CI 89–98] vs 91% [88–94]; HR 0·59 [95% CI 0·35–0·99]; p=0·047), although there were no between-group differences at 5 years or 10 years.2Copson ER Maishman TC Tapper WJ et al.Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.Lancet Oncol. 2018; (published online Jan 11)http://dx.doi.org/10.1016/S1470-2045(17)30891-4Summary Full Text Full Text PDF PubMed Scopus (214) Google Scholar Importantly, prognosis in the POSH study meant survival after routine treatment for breast cancer. Among other factors, young age is regarded as an indication for treatment with chemotherapy, because prognosis is generally considered less favourable in younger and untreated patients than in patients diagnosed at an older age.3Coates AS Winer EP Goldhirsch A et al.Tailoring therapies—improving the management of early breast cancer: St Gallen international expert consensus on the primary therapy of early breast cancer.Ann Oncol. 2015; 26: 1533-1546Crossref PubMed Scopus (1289) Google Scholar In the POSH study, only a few patients did not receive chemotherapy.2Copson ER Maishman TC Tapper WJ et al.Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.Lancet Oncol. 2018; (published online Jan 11)http://dx.doi.org/10.1016/S1470-2045(17)30891-4Summary Full Text Full Text PDF PubMed Scopus (214) Google Scholar Studies have suggested that BRCA1 and BRCA2 mutations have an effect on the efficacy of chemotherapy. The neoadjuvant GeparSixto Study,4Hahnen E Lederer B Hauke J et al.Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto randomized clinical trial.JAMA Oncol. 2017; 3: 1378-1385Crossref PubMed Scopus (229) Google Scholar which randomly assigned patients to either standard chemotherapy containing anthracycline and taxane alone or with the addition of carboplatin, showed that in patients with triple-negative breast cancer, a BRCA1 or BRCA2 mutation was associated with a higher proportion of patients achieving a pathological complete response and better survival compared with no mutation, regardless of the kind of chemotherapy used. In patients without a mutation, standard chemotherapy without carboplatin resulted in lower disease-free survival rates than with chemotherapy plus carboplatin.4Hahnen E Lederer B Hauke J et al.Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto randomized clinical trial.JAMA Oncol. 2017; 3: 1378-1385Crossref PubMed Scopus (229) Google Scholar Therefore, patients with triple-negative breast cancer and a BRCA1 or BRCA2 mutation might have a survival advantage because of the higher efficacy of systemic chemotherapy. Although the GeparSixto study was not restricted to younger patients, the population was relatively young (mean age 48 years). Understanding prognosis in young patients is important because patients with BRCA mutations are at increased risk of developing specific conditions, such as secondary cancers, including ovarian cancer, contralateral breast cancer, and de novo breast cancer in the same breast. These risks determine treatment, and knowing that BRCA1 or BRCA2 mutations do not result in a different prognosis might change the therapeutic approach for these risks. With regard to contralateral breast cancers and de novo breast cancers in the same breast, Copson and colleagues2Copson ER Maishman TC Tapper WJ et al.Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.Lancet Oncol. 2018; (published online Jan 11)http://dx.doi.org/10.1016/S1470-2045(17)30891-4Summary Full Text Full Text PDF PubMed Scopus (214) Google Scholar generated data that the survival benefit in the patients with triple-negative breast cancer might not have been caused by bilateral mastectomies. However, the evidence for this hypothesis is merely suggestive, and no formal comparison was done.2Copson ER Maishman TC Tapper WJ et al.Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.Lancet Oncol. 2018; (published online Jan 11)http://dx.doi.org/10.1016/S1470-2045(17)30891-4Summary Full Text Full Text PDF PubMed Scopus (214) Google Scholar Results from retrospective analyses indicate that a bilateral mastectomy confers a benefit regarding overall survival for BRCA1 or BRCA2 mutation carriers.5Metcalfe K Gershman S Ghadirian P et al.Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis.BMJ. 2014; 348: g226Crossref PubMed Scopus (201) Google Scholar This important topic needs more prospective research as preventive surgical measures might have an effect on what might be a very long life after a diagnosis of breast cancer at a young age. The data from POSH deliver a rationale for prospective studies to address these questions. With genotyping becoming cheaper and more accessible, studies that report on mutation frequencies always raise the question about which individuals and patients should get tested. Copson and colleagues showed that 338 (12%) of 2733 patients had a BRCA1 or BRCA2 mutation. However, only 182 (54%) of 337 mutation carriers had been identified in routine health care.2Copson ER Maishman TC Tapper WJ et al.Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.Lancet Oncol. 2018; (published online Jan 11)http://dx.doi.org/10.1016/S1470-2045(17)30891-4Summary Full Text Full Text PDF PubMed Scopus (214) Google Scholar In most national and international guidelines, testing criteria include patients with breast cancer aged less than 35 or 40 years. The fact that in the POSH study there were 155 young women diagnosed with breast cancer who did not know their mutation status raises the question of whether and when testing criteria for certain groups of patients can be allowed for lower mutation probabilities. The report of this study2Copson ER Maishman TC Tapper WJ et al.Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.Lancet Oncol. 2018; (published online Jan 11)http://dx.doi.org/10.1016/S1470-2045(17)30891-4Summary Full Text Full Text PDF PubMed Scopus (214) Google Scholar is surely only the beginning of a better understanding of young patients with breast cancer. The interaction between pregnancies at a young age, other genetic causes such as predisposition genes,6Couch FJ Shimelis H Hu C et al.Associations between cancer predisposition testing panel genes and breast cancer.JAMA Oncol. 2017; 3: 1190-1196Crossref PubMed Scopus (385) Google Scholar and associated pathways such as RANK/RANKL1Sigl V Jones LP Penninger JM RANKL/RANK: from bone loss to the prevention of breast cancer.Open Biol. 2016; 6 (pii: 160230)Crossref PubMed Scopus (43) Google Scholar are just some topics which could be addressed after the POSH study. I declare grants from Novartis, and personal fees from Novartis, Pfizer, Roche, Amgen, and Teva. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort studyPatients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. Full-Text PDF Open Access