An international, multicentre, hospital-based, retrospective cohort study that included 4752 patients harbouring germline pathogenic/likely pathogenic variants in BRCA1 or BRCA2, who were diagnosed with stage I-III invasive breast cancer at 40 years or younger between January 2000 and December 2020 in 78 centres worldwide, provides evidence on the different clinical behaviour of breast cancer according to the specific BRCA gene and the association of the timing of genetic testing with prognosis.
BRCA1 and BRCA2 carriers were characterised by distinct patient, tumour, and treatment characteristics and a different pattern and risk of disease-free survival (DFS) events over time. Identification of carrying a BRCA pathogenic variant in healthy individuals was associated with earlier-stage breast cancer diagnosis and lower treatment burden, as well as better unadjusted overall survival (OS) according to Dr. Matteo Lambertini of the Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova and Medical Oncology Department, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, both in Genoa, Italy and colleagues, who published the findings from the BRCA BCY Collaboration on 24 February 2025 in the JCO.
The authors wrote in the background that breast cancer diagnosed in women age 40 years or younger requires special multidisciplinary care given age-related issues and needs. Germline genetic testing plays a critical role considering that more than 10% of young women with breast cancer are expected to carry a germline pathogenic/likely pathogenic variant in the BRCA genes. In young women, germline genetic testing has clear clinical implications in terms of reproductive counselling, surveillance, and prevention strategies, as well as therapeutic value once diagnosed with breast cancer.
Breast cancers arising in BRCA carriers are characterised by unique biologic features and clinical behaviour. Loss of function of BRCA1 and BRCA2 proteins leads to genomic instability that affects tumour biology and may also influence sensitivity to standard systemic therapies, subsequent prognosis, and reproductive outcomes.
Limited evidence exists on whether breast cancers in BRCA1 or BRCA2 carriers may differ in clinical behaviour beyond differences in tumour biology. Dedicated efforts to dissect the potential different contribution of the specific altered BRCA gene in the clinical behaviour of breast cancer are crucial to personalise patients' counselling on surveillance, prevention, treatment, and survivorship strategies.
Since the first International Consensus Conference for Breast Cancer in Young Women (BCY1) in November 2012, young age at breast cancer diagnosis is considered per se a criterion for referring patients to genetic counselling irrespective of family history or tumour biology. No breast cancer screening is recommended below age 40 years for women with average risk of breast cancer. Women at higher-than-average risk including BRCA carriers are candidates for an intensive surveillance starting at age 25-30 years. Limited evidence exists on the association of prediagnostic awareness of germline BRCA status with prognosis, and there are no specific data in young women with breast cancer.
The BRCA BCY Collaboration is the largest global cohort of BRCA carriers with diagnosis of breast cancer at young age, representing a unique real-world cohort to explore the clinical behaviour of breast cancer in young BRCA1 and BRCA2 carriers separately and the association of the timing of genetic testing with prognosis.
Compared with 1683 BRCA2 carriers, 3069 BRCA1 carriers had more frequently hormone receptor–negative (74.4% versus 15.5%) and high-grade (77.5% versus 49.1%) tumours. Similar outcomes were observed in BRCA1 and BRCA2 carriers, but with a different pattern and risk of DFS events over time.
Compared with 1671 patients tested for BRCA at diagnosis (between 2 months before and up to 6 months after diagnosis), 411 patients tested any time up to 2 months before diagnosis had smaller tumours (T1: 61.3% versus 32.4%), less nodal involvement (N0: 65.9% versus 50.8%), less frequently received chemotherapy (84.4% versus 92.9%), and axillary dissection (37.5% versus 47.4%).
Patients tested before diagnosis had better OS (unadjusted hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.40 to 0.92]); however, this result lost statistical significance after adjustment for potential confounders including tumour stage (adjusted HR 0.74, 95% CI 0.47 to 1.15).
The authors concluded that their global study provides evidence on the different clinical behaviour of breast cancer according to the specific BRCA gene and the association of the timing of genetic testing with prognosis. Identification of carrying a BRCA pathogenic variant in healthy individuals was associated with earlier-stage breast cancer diagnosis and lower treatment burden, as well as better unadjusted OS.
Increased awareness on the importance of identifying healthy women at risk of carrying a BRCA1 or BRCA2 pathogenic variant is needed to offer genetic counselling and testing to inform them about early detection options that may lead to better prognosis.
The study findings were presented previously in part at the 2024 ASCO Annual Meeting (Chicago, IL, US; 31 May-4 June 2024).
The study was supported by the Italian Association for Cancer Research. Data collection for most Australian participants was through the kConFab Follow‐Up Study with support from Cancer Australia and the National Breast Cancer Foundation, Cancer Australia, the Australian National Breast Cancer Foundation, the Australian National Health and Medical Research Council, the US National Institutes of Health, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia.
Reference
Lambertini M, Blondeaux E, Tomasello LM, et al. Clinical Behavior of Breast Cancer in Young BRCA Carriers and Prediagnostic Awareness of Germline BRCA Status. JCO; Published online 24 February 2025. DOI: https://doi.org/10.1200/JCO-24-01334