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Commentary: Radiation therapy, endocrine therapy, metformin, and statins in breast cancer, October 2023

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Erin Roesch, MD

Radiation therapy (RT) is typically administered after breast-conserving surgery (BCS) and has demonstrated reduction in local recurrence risk. A recent phase 3 trial evaluating the omission of radiation among patients aged 65 years or older with hormone receptor-positive, node-negative, T1/2 tumors (≤ 3 cm) treated with BCS and adjuvant endocrine therapy, showed an increased incidence of local recurrence in the no-RT group compared with the RT group (9.5% vs 0.9% within 10 years) but no difference in distant recurrence or overall survival. 1 With advancements in the field of precision medicine, it has been postulated that combining molecular biomarkers and clinicopathologic features can more distinctly identify patients with low-risk disease for whom radiation can be omitted. A prospective cohort study including 500 women aged 55 years or older with T1N0, grade 1 or 2, luminal A–subtype breast cancer (estrogen-receptor positivity [ER+] > 1%, progesterone receptor positivity > 20%, human epidermal growth factor receptor 2–negative [HER2-], Ki67 index ≤ 13.25%) after BCS and adjuvant endocrine therapy demonstrated low rates of local recurrence with the omission of RT ( Whelan et al ). At 5 years, the cumulative incidence of local recurrence was 2.3% (90% CI 1.3-3.8; 95% CI 1.2-4.1), contralateral breast recurrence was 1.9% (90% CI 1.1-3.2), and recurrence of any type was 2.7% (90% CI 1.6-4.1). This study supports consideration of a local therapy de-escalation approach, specifically RT omission, for select patients with tumors characterized by favorable molecular and clinical features.

Endocrine therapy (ET) remains the backbone of treatment for hormone receptor–positive breast cancer; however, 15%-20% of tumors are initially resistant to ET and endocrine resistance develops over time in approximately 30%-40%. 2 In an effort to overcome limitations with historical standard-of-care endocrine agents, the class of oral potent selective estrogen receptor degraders (SERD) is evolving. The phase 2, randomized, controlled coopERA Breast Cancer trial evaluated the antiproliferative effect of giredestrant (a highly potent nonsteroidal oral SERD) compared with anastrozole (each combined with palbociclib after 2-week window-of-opportunity phase) among postmenopausal women with early-stage (cT1c-cT4) ER+/HER2- breast cancer with a Ki67 score ≥ 5% ( Hurvitz et al ). Among 221 enrolled patients (giredestrant group n = 112, and anastrozole group n = 109), giredestrant led to a significantly greater relative geometric mean reduction of Ki67 at 2 weeks from baseline compared with anastrozole (-75% vs -67%; P = 0.043). Neutropenia (26% and 27%) and decreased neutrophil count (15% and 15%) were the most common grade 3-4 adverse events in the giredestrant-palbociclib and anastrozole-palbociclib groups, respectively. The value of Ki67 as a biomarker for efficacy and outcome was demonstrated in the phase 3 POETIC trial, which showed that the degree of Ki67 reduction after 2 weeks of ET correlated with 5-year recurrence risk. 3 These data encourage further investigation of oral SERD combinations, predictors of response, and long-term outcomes that may influence agent selection and sequencing.

Anticancer properties have been demonstrated with aspirin, statins, and metformin, although the data on the prognostic impact of these agents in breast cancer have shown mixed results. 4 A nationwide population-based cohort study including 26,190 women aged 50 years or older diagnosed with breast cancer and surviving 12 months or more after diagnosis was performed to evaluate the postdiagnosis use of aspirin, statins, and metformin and association with breast cancer-specific survival (BCSS) ( Löfling et al ). At 6.1 years of follow-up, there were 2169 deaths related to breast cancer and the results supported an association of postdiagnostic use of statins and metformin with survival (hazard ratio for association between use of statins vs no use and BCSS was 0.84 [95% CI 0.75-0.94]; hazard ratio for association between metformin use vs use of nonmetformin antidiabetics and BCSS was 0.70 [95% CI 0.51-0.96]). Furthermore, there appeared to be differences in association by ER status. An important relationship exists between cardiovascular health and breast cancer, and future efforts should continue to study pharmacologic and lifestyle interventions that may optimize metabolic profiles and improve outcomes for patients.

Additional References

  1. Kunkler IH, Williams LJ, Jack WJL, et al. Breast-conserving surgery with or without irradiation in early breast cancer. N Engl J Med. 2023;388:585-594. doi: 10.1056/NEJMoa2207586
  2. Lei JT, Anurag M, Haricharan S, et al. Endocrine therapy resistance: New insights. Breast. 2019;48:S26-S30. doi: 10.1016/S0960-9776(19)31118-X
  3. Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): An open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21:1443-1454. doi: 10.1016/S1470-2045(20)30458-7
  4. Nowakowska MK, Lei X, Thompson MT, et al. Association of statin use with clinical outcomes in patients with triple-negative breast cancer. Cancer. 2021;127:4142-4150. doi: 10.1002/cncr.33797

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