Genomic Clues to Poor Outcomes in Young Breast Cancer Patients

Nancy A. Melville

February 14, 2023

Young premenopausal women with early stage hormone receptor (HR)-positive, HER2-negative breast cancer have notable genomic features that may help explain their historically poor outcomes and offer clues about molecular targets for future trials.

Compared with older women with early stage HR-positive breast cancer, women under 40 years of age had significantly higher frequencies of certain mutations, such as GATA3, as well as genomic features associated with a poor prognosis. Notably, the researchers found that women with such poor prognostic features vs those with none had a significantly worse 8-year distant recurrence-free interval and overall survival.

"We have 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," the authors wrote in the study, published last month in the Annals of Oncology. Importantly, the genomic features highlight "the potential for age-focused treatment strategies."

Charis Eng, MD, PhD, of the Cleveland Clinic Genomic Medicine Institute, Ohio, noted that the findings are promising but need further validation.

"With time and the appropriate clinical trials in place, I envision that these findings will enable the personalised genomics-driven management of these cancers — not only treatment, but also towards prevention," said Eng, who was not involved in the study.

Young premenopausal women, particularly those with HR-positive, luminal breast cancer, are known to have significantly higher recurrence rates and worse survival compared with older women, but the reasons have remained unclear.

Although previous studies have identified key gene expression signatures linked to worse outcomes in younger patients with breast cancer, there are limited data on this younger patient population, especially by breast cancer subtype. Given that breast cancer treatment strategies are often similar across age groups, such evidence gaps could represent missed opportunities for developing more targeted treatment strategies for this high-risk population of young women.

To further investigate the cancer-specific genetic profiles in younger women, Sherene Loi, MD, PhD, of the Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia, and colleagues turned to data from the pivotal, multicenter Suppression of Ovarian Function Trial (SOFT).

Using next-generation sequencing, Loi and colleagues evaluated HR-positive, HER2-negative tumors among a subset of 1276 premenopausal women who were diagnosed with early stage breast cancer. The study employed deep-targeted sequencing for most patients (n = 1258) as well as whole-exome sequencing in a matched case-control subsample of young women with a median age of 38 years (n = 82).

Compared with women aged 40 and older, those under 40 years of age (n = 359) had significantly higher frequencies of mutations in GATA3 (19% vs 16%) and copy number-amplifications (47% vs 26%).

Younger women also had significantly higher features suggestive of homologous recombination deficiency (27% vs 21% in older women), and a higher proportion of PIK3CA mutations with concurrent copy number-amplifications (23% vs 11%, respectively), all considered to be poor prognostic features.

In addition, younger women had significantly lower frequencies of certain mutations, including PIK3CA (32% vs 47%), CDH1 (3% vs 9%), and MAP3K1 (7% vs 12%), compared with older women.

Overall, 46% of women had poor prognostic features. These poor prognostic features were observed in 72% of patients under age 35, compared with 54% aged 35-39, and 40% of those 40 and over.

Compared with women without those features, women with poor prognostic features had a lower 8-year distant recurrence-free interval of 84% vs 94% (hazard ratio [HR], 1.85), and worse 8-year overall survival of 88% vs 96%, respectively (HR, 2.20). Notably, younger women under age 40 had the poorest outcomes, with an 8-year distant recurrence-free interval rate of 74% vs 85% in older women, and an 8-year overall survival of 80% vs 93%, respectively.

How might these results inform potential therapeutics?

Drugs targeting the homologous recombination deficiency pathway are well-established, and up to 36% of very young patients in the study showed genomic features of homologous recombination deficiency, the authors noted.

In addition, Eng explained, there are other Food and Drug Administration-approved treatments that can target the copy number amplified, PIK3CA-mutated tumours, including therapies that target PIK3CA itself, or proteins downstream of it. However, use of such therapies would need "to be tested experimentally, especially since pathway inhibition sometimes may result in rebound signalling to promote tumour growth," Eng said.

An important caveat is that patients with germline BRCA1 or BRCA2 mutations may be underrepresented in the SOFT clinical trial, as the trial excluded patients who already had bilateral oophorectomy or planned to within 5 years, the authors noted.

Nevertheless, Loi said that the study is important because "there are no other datasets as large or with this long follow-up for very young women with breast cancer."

Furthermore, "the SOFT clinical trial was practice-changing, so using the tumor samples associated with this study is more impactful than smaller cohorts with no outcome data or institutional retrospective cohorts," she said.

Eng agreed that the study’s size is an important attribute, allowing the authors to "identify differences that would have been missed in a smaller and more heterogeneous series."

She added that future research should also include ancestry and racial diversity.

"While young women have higher occurrences of aggressive breast cancers, mortality is twice as likely in young Black women compared to young White women," Eng said.

The study received funding from a Susan G. Komen for the Cure Promise Grant, the National Health and Research Council of Australia, the Breast Cancer Research Foundation, National Breast Cancer Foundation of Australia, and support from the family of Judy Eisman in Australia. Loi and Eng report no relevant financial disclosures.

Annals of Oncology. Published January 25, 2022. Abstract.

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