Commentary: Aspirin, Childbirth, and Everolimus in BC, June 2024

Erin Roesch, MD

The postpartum period represents a possibly vulnerable time window for development of new cancers with metastatic potential. Studies in young-onset breast cancer have shown a postpartum diagnosis up to 10 years after childbirth associated with adverse breast cancer survival outcomes.⁴ Women with germline BRCA1/2 pathogenic variants have a higher risk of developing breast cancer at a younger age compared to the general population.⁵ A prospective cohort study that included 903 women with germline BRCA1/2 mutations diagnosed with stage I-III breast cancer at age ≤ 45 years investigated whether time since childbirth and time since breast cancer diagnosis were associated with mortality in this population (). A total of 419 women were diagnosed with breast cancer 0-10 years after childbirth (228 at <5 years and 191 at 5-10 years) and 224 women were nulliparous. Breast cancer diagnosis 5 to <10 years postpartum was associated with higher mortality risk vs nulliparous women (adjusted hazard ratio 1.56, 95% CI 1.05-2.03; P = .03), with a more pronounced effect seen among those with estrogen receptor–negative disease (hazard ratio 3.12; 95% CI 1.22-7.97; P = .02) and BRCA1 carriers (hazard ratio 2.03; 95% CI 1.15-3.58; P = .02). This study highlights the importance of appropriate counseling for BRCA1/2 mutation carriers, with efforts aimed at optimizing prevention and treatment strategies in young-onset breast cancer.

The mechanisms involved in development of endocrine therapy (ET) resistance are complex and may include changes in hormone signaling, alterations in growth factor signaling pathway components, and appearance of resistant clonal populations.⁶ Prior studies have shown efficacy with the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with various ET backbones. However, the sequencing of these combinations in current clinical practice has shifted in light of significant therapeutic advancements in this space.⁷ A retrospective observational study including 161 patients with advanced hormone receptor–positive (HR+)/ human epidermal growth factor receptor–2 negative (HER2-) breast cancer treated with everolimus plus ET (exemestane, fulvestrant, tamoxifen) reported outcomes on the real-world use of these regimens after progression on cyclin-dependent kinase (CDK) 4/6 inhibitor therapy (Sánchez-Bayona et al). At a median follow-up of 15 months, the estimated median progression-free survival (PFS) was 6.0 months (95% CI 5.3-7.8 months); PFS was longer among those with previous CDK4/6 inhibitor use lasting >18 months (8.7 months; 95% CI 6.6-11.3 months), patients without visceral disease (8.0 months; 95% CI 5.8-10.5 months), and those who were chemotherapy-naive in the advanced setting (7.2 months; 95% CI 5.9-8.4 months). These data support a role for everolimus plus ET as a treatment option post–CDK4/6 inhibitor treatment for selected patient populations, including those whose tumors lack targetable somatic mutations (such as PIK3CA and ESR1 mutations), and may provide meaningful clinical benefit in this setting.

Additional References

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5. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317:2402-2416. doi: 10.1001/jama.2017.7112 Source
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7. Kornblum N, Zhao F, Manola J, et al. Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: Results of PrE0102. J Clin Oncol. 2018;36:1556-1563. doi: 10.1200/JCO.2017.76.9331 Source