Younger premenopausal women with HR-positive, HER2-negative early breast cancer typically face higher rates of recurrence and death than their older peers.
A new analysis has identified specific genomic alterations enriched in these younger women, which may help explain their worse outcomes. More specifically, researchers identified higher rates of GATA3 mutations and PIK3CA mutations with concurrent copy number amplifications, as well as higher frequencies of features suggestive of homologous recombination deﬁciency (HRD) in patients under age 40 years.
Using a large cohort of breast cancer samples taken from very young women, the findings show “their tumors are enriched with aggressive biological features,” said study author Sherene Loi, MD, PhD, medical oncologist at Peter MacCallum Cancer Centre, in Melbourne, Australia.
These signatures may explain the more frequent instances of recurrence and death in younger patients and “highlight priority molecular targets for future clinical trials,” the authors said.
The study was published online January 25 in Annals of Oncology.
Young premenopausal women with HR-positive, HER2-negative early breast cancer have higher rates of recurrence and mortality, but the reasons “remain largely unexplained,” the authors note.
To better understand why younger women fare so poorly, Loi and colleagues analyzed breast cancer samples from 1276 patients whose tumors had undergone next-generation genetic sequencing. The researchers performed whole-exome sequencing on samples from 82 younger patients to identify features that could help predict breast cancer recurrence. Genomic alteration frequencies between premenopausal women younger than 40 years and age 40 and over were analyzed for associations with distant recurrence-free interval and overall survival. Median patient follow-up was 8 years.
Compared with older patients, the 359 younger patients (< 40 years) exhibited higher frequencies of mutations in 353262 (19% vs 16%), copy number amplifications (47% vs 26%), PIK3CA mutations with concurrent copy number amplifications (23% vs 11%), and features suggestive of HRD (27% vs 21%).
These poor prognostic features were identified in 72% of patients under age 35 years, 54% of those aged 35-39, and 40% of those aged 40 and older.
Collectively, these poor prognostic features were associated with a significantly higher risk of distant recurrence (hazard ratio [HR], 1.85) and worse overall survival (HR, 2.20), with an 8-year overall survival rate of 88% compared with 96% of patients with no such features.
When looking at the outcomes by age, younger women had worse outcomes: an 8-year distant recurrence-free interval of 74% vs 85% and an overall survival of 80% vs 93%, respectively.
Overall, the findings “demonstrated age-related differences in genomic profiles with enrichment of genomic features associated with poor prognosis in these younger premenopausal women compared with older premenopausal and postmenopausal women” and identified several possible therapeutic targets enriched in younger patients, “highlighting the potential for age-focused treatment strategies,” the authors conclude.
Joan Garrett, PhD, of the University of Cincinnati, Ohio, who was not involved in the research, agreed, noting that the information gleaned from this analysis “is important for setting up clinical trials targeting PIK3CA and/or HRD in the patient population to improve outcomes for [these younger] patients.”
The study was supported by a Susan G. Komen for the Cure Promise Grant, the National Health and Research Council, the BCRF, NBCF Australia, and with the support from the family of Judy Eisman in Australia. Loi reported receiving research funding to her institution from Novartis, BMS, Merck, Roche-Genentech, Puma Biotechnology and Pfizer; consulting (not compensated) for Seattle Genetics, Pfizer, Novartis, BMS, Merck, and Roche-Genentech. Garrett has disclosed no relevant financial relationships.
Ann Oncol. Published online January 25, 2023. Abstract
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