Genomic analysis performed in samples obtained from the patients enroled in the SOFT study highlight the genomic alterations in hormone receptor (HR)-positive, HER2-negative early breast cancers arising in premenopausal women, focusing on the women aged less than 40 years. The findings demonstrate key genomic features that are particularly enriched with younger age rather than menopausal status per se. Genomic features suggestive of homologous recombination deficiency (HRD), PIK3CA mutations with copy number amplifications, and copy number amplifications associated with significantly worse distant recurrence-free interval (DRFI) and overall survival (OS) compared with those without these features. The results are published by Prof. Sherene Loi of the Peter MacCallum Cancer Centre, University of Melbourne in Melbourne, Australia, and colleagues on 25 January 2023 in the Annals of Oncology. The investigators propose that prospective studies in young women with HR-positive, HER2-negative early breast cancer addressing these specific molecular pathways will be pivotal to improving their clinical outcomes.
Younger premenopausal women diagnosed with early breast cancer have a significantly higher risk of recurrence and death than older women for reasons that remain largely unexplained. This is particularly true for HR-positive, luminal breast cancers. The pivotal SOFT was a multicentre, open label, phase III study for premenopausal women diagnosed with HR-positive early breast cancer. The study demonstrated a significant improvement in disease-free survival and OS with the addition of ovarian function suppression to tamoxifen. Despite the addition of ovarian function suppression therapy, the prognosis of women aged less than 35 years remained significantly worse than older women.
The biology underlying the poor prognosis observed in very young women with HR-positive, HER2-negative breast cancer remains uncompletely understood. In a large, pooled analysis of 71 studies investigating gene expression assays, young women aged no more than 40 years had higher proportions of intermediate to high-risk tumours by EndoPredict, MammaPrint and Oncotype DX assay compared with older women, however this analysis was not stratified by breast cancer subtype.
This is also consistent with data demonstrating that young women with HR-positive breast cancers have higher proportions of luminal B tumours and lower proportions of luminal A tumours than older women. Analysis of The Cancer Genome Atlas (TCGA) Breast dataset using broader gene expression data showed increases in gene expression signatures indicating proliferation, stem cell features and endocrine resistance in young patients compared with older patients, however this analysis was also not stratified by breast cancer subtype.
There are limited numbers of HR-positive, HER2-negative breast cancer samples from young women represented in publicly available databases. Germline cancer predisposition alterations such as with BRCA1, BRCA2, and PALB2 occur in a higher frequency in young women, but this is observed to a greater degree in patients with triple negative breast cancer rather than HR-positive, HER2-negative breast cancers.
TCGA Breast analysis demonstrated higher frequencies of GATA3 mutations and chromosome 6q27 deletions in younger patients compared with older patients, but this was not stratified by breast cancer subtype. A recently reported study investigating patients aged no more than 35 years at diagnosis identified higher rates of alterations in GATA3 and ARID1A, and lower rates of PIK3CA mutations in young patients compared with older patients, particularly in luminal A tumours.
In the latest analysis published in the Annals of Oncology, genomic sequencing was applied to HR-positive, HER2-negative tumours from patients enroled in the SOFT study to determine genomic drivers that are enriched in young premenopausal women. Current treatment strategies for very young patients are similar to older premenopausal women and postmenopausal women, and the study investigators hypothesised that uniquely designed prospective trials may be required for this at-risk population.
Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients. The study team defined copy number subgroups and assessed for features suggestive of HRD. Genomic alteration frequencies were compared between young premenopausal women (younger than 40 years) and older premenopausal women (at least 40 years old) and assessed for associations with DRFI and OS.
In total, 359 younger women (younger than 40 years) compared with 917 older women (at least 40 years old) had significantly higher frequencies of mutations in GATA3 (19% versus 16%) and copy number amplifications (47% versus 26%), but significantly lower frequencies of mutations in PIK3CA (32% versus 47%), CDH1 (3% versus 9%), and MAP3K1 (7% versus 12%). Furthermore, significantly higher frequencies of features suggestive of HRD (27% versus 21%), and a higher proportion of PIK3CA mutations with concurrent copy number amplifications (23% versus 11%).
Genomic features suggestive of HRD, PIK3CA mutations with copy number amplifications, and copy number amplifications associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients, in particular 72% of patients aged less than 35 years, 54% aged 35-39 years, and 40% aged at least 40 years. Those with poor prognostic features (46%) versus none (54%) had an 8-year DRFI of 84% versus 94% and OS of 88% versus 96%. Younger women (younger than 40 years) had the poorest outcomes: 8-year DRFI 74% versus 85% and OS of 80% versus 93%.
The authors commented that strength of this work is the use of a unique patient dataset, with tumour samples from those enroled in a landmark clinical trial of premenopausal women, which has well-annotated clinical data and long and accurate survival follow-up. This is the largest such cohort of young, premenopausal women with HR-positive, HER2-negative early breast cancer. These findings are in the context of patients who have received contemporary and standard of care treatments including ovarian function suppression. The results provide insights into genomic alterations that are enriched in young women with HR-positive, HER2-negative early breast cancer, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.
Reference
Luen SJ, Viale G, Nik-Zainal S, et al. Genomic characterisation of hormone receptor-positive breast cancer arising in very young women. Annals of Oncology; Published online 25 January 2023. DOI: https://doi.org/10.1016/j.annonc.2023.01.009