Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study

Abstract

Background: Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer.

Methods: We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing.

Findings: Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0-9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5-98·4] vs 96·6% [95·8-97·3]; at 5 years: 83·8% [79·3-87·5] vs 85·0% [83·5-86·4]; at 10 years: 73·4% [67·4-78·5] vs 70·1% [67·7-72·3]; hazard ratio [HR] 0·96 [95% CI 0·76-1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89-97] vs 91% [88-94]; HR 0·59 [95% CI 0·35-0·99]; p=0·047) but not 5 years (81% [73-87] vs 74% [70-78]; HR 1·13 [0·70-1·84]; p=0·62) or 10 years (72% [62-80] vs 69% [63-74]; HR 2·12 [0·82-5·49]; p= 0·12).

Interpretation: Patients 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.

Funding: Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.

Figure 1

Trial profile BRCA-positive=patient with BRCA1 or BRCA2 pathogenic mutation. Patients were categorised as BRCA-negative if no BRCA pathogenic mutation was found or they had a BRCA1 or BRCA2 variant of uncertain significance or very low penetrance.

Figure 2

Overall survival for all patients (analysis population) by BRCA mutation status (A) Kaplan-Meier plot and (B) forest plot of corresponding univariable and multivariable hazard ratios. In (B), multivariable analysis was adjusted for age, body-mass index (BMI; kg/m²), grade, tumour size, HER2 status, oestrogen-receptor status, ethnicity, and use of taxane chemotherapy. Groups without a reference were assessed as a continuous variable. The dashed line separates the univariable analysis (UVA) from the multivariable analysis (MVA). Oestrogen-receptor-positive group assessed at 2, 5, and 10 years because the hazard ratio associated with oestrogen-positive status varies with time. HR=hazard ratio. *Number of events (number of patients) from complete data obtained before multiple imputation.

Figure 3

Overall survival for all patients with triple-negative breast cancer* by BRCA mutation status (A) Kaplan-Meier plot and (B) forest plot of corresponding univariable and multivariable hazard ratios. In (B), multivariable analysis was adjusted for age, body-mass index (BMI; kg/m²), grade, tumour size, HER2 status, oestrogen-receptor status, ethnicity, and use of taxane chemotherapy. Groups without a reference were assessed as a continuous variable. The dashed line separates the univariable analyses (UVA) from the multivariable analyses (MVA). HR=hazard ratio. *Number of events (number of patients) from complete data obtained before multiple imputation.