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Commentary: Chemotherapies and gynecologic surgeries relative to breast cancer, April 2023

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Erin Roesch, MD

The goals of adjuvant chemotherapy for early breast cancer are to eradicate micrometastatic disease, reduce distant recurrence risk, and improve survival. Older patients may potentially be at higher risk for chemotherapy-related complications and are often underrepresented in clinical trials. Considering the risks for cardiotoxicity and secondary hematologic cancers with anthracyclines, previous studies have evaluated the influence of anthracyclines on taxane-containing regimens. For example, joint analysis of the ABC trials showed an invasive disease–free survival benefit with anthracycline/taxane based chemotherapy compared with non–anthracycline/taxane treatment, with more pronounced impact in those patients with triple-negative breast cancer (TNBC) and those with node-positive disease.1

However, a combined analysis of two other trials (PlanB and SUCCESS C) did not show a benefit with the addition of anthracycline for most patients with human epidermal growth factor receptor 2 (HER2)–negative early breast cancer.2 Roy and colleagues performed a retrospective study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, including 1106 women ≥ 66 years of age with node-positive TNBC, of whom 69.3% received adjuvant chemotherapy (N = 767). The use of chemotherapy led to a statistically significant improvement in survival outcomes (3-year cancer-specific survival [CSS] 81.8% vs 71.4%; overall survival 70.7% vs 51.3%). Although the anthracycline/taxane–based therapy did not improve CSS in the overall population vs taxane-based (hazard ratio [HR] 0.94; P = .79), among patients aged ≥ 76 years with four or more positive nodes, there was improvement in CSS with anthracycline/taxane therapy (HR 0.09; P = .02). These data further support the benefits of adjuvant chemotherapy in older patients when indicated; stimulate consideration of nonanthracycline combinations, particularly now with the use of immunotherapy for early TNBC; and highlight the need for inclusion of older individuals in clinical trials.

Treatment strategies to improve efficacy and minimize toxicity are highly desired for patients with early breast cancer (EBC). As an example, for small, node-negative, HER2-positive tumors, adjuvant systemic therapy with 12 weeks of paclitaxel/trastuzumab followed by continuation of trastuzumab to complete 1 full year has demonstrated excellent survival outcomes at over 10 years of follow-up.3 In the WSG-ADAPT-TP phase 2 trial, 375 patients with hormone receptor–positive , HER2-positive EBC were randomized to receive neoadjuvant T-DM1 (trastuzumab emtansine) with or without endocrine therapy or trastuzumab plus endocrine therapy. Similar 5-year invasive disease-free and overall survival rates were seen between the three arms. Patients who achieved a pathologic complete response (pCR) vs non-pCR had improved 5-year invasive disease-free survival (iDFS) rates (92.7% vs 82.7%; unadjusted HR 0.40). Furthermore, among the 117 patients who achieved pCR, the omission of adjuvant chemotherapy did not compromise survival outcomes (5-year iDFS 93% vs 92.1% for those who had vs those who did not have chemotherapy, respectively; unadjusted HR 1.15) (Harbeck et al). De-escalation approaches should ideally focus on the identification of biomarkers of response and resistance, as well as tools that can help predict patient outcomes and allow modification of therapy in real time. An example of this latter concept is the use of 18F-FDG-PET to identify patients with HER2-positive EBC who were likely to benefit from a chemotherapy-free dual HER2 blockade (trastuzumab/pertuzumab) treatment approach.4

Gynecologic surgery has been shown to reduce the risk for breast cancer,5 although the specific type of surgery and the impact of hormone replacement therapy add complexity to understanding the risks and outcomes for women. A prospective cohort, the Sister Study, included 50,701 women without a prior diagnosis of breast cancer but with a biological sister who had breast cancer; of these, 13.8% reported having hysterectomy only and 18.1% reported having bilateral oophorectomy with or without hysterectomy. Bilateral oophorectomy was inversely associated with breast cancer incidence (HR 0.91; 95% CI 0.83-1.00), with comparable results for women receiving estrogen only or combination estrogen plus progestin hormone replacement therapy. Contrary to these findings, having a hysterectomy only showed a positive association with breast cancer incidence (HR 1.12; 95% CI 1.02-1.23), with the strongest association among women who used combination estrogen and progestin therapy (HR 1.25; 95% CI 1.01-1.55) (Lovett et al). The impact of other gynecologic surgeries (such as salpingectomy)6 and the timing of the initiation of hormone replacement therapy, as well as the duration, should be investigated in future research.

Additional References

1. Blum JL, Flynn PJ, Yothers G, et al. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG oncology). J Clin Oncol. 2017;35:2647e55. doi: 10.1200/JCO.2016.71.4147

2. de Gregorio A, Janni W, Friedl TW, et al. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022;126:1715-1724. doi: 10.1038/s41416-021-01690-6

3. Tolaney SM, Tarantino P, Graham N, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: Final 10-year analysis of the open-label, single-arm, phase 2 APT trial. Lancet Oncol. 2023;24:273-285. doi: 10.1016/S1470-2045(23)00051-7

4. Pérez-García JM, Gebhart G, Ruiz Borrego M, et al; on behalf of PHERGain steering committee and trial investigators. Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): A multicentre, randomised, open-label, non-comparative, phase 2 trial. Lancet Oncol. 2021;22:858-871. doi: 10.1016/S1470-2045(21)00122-4

5. Chow S, Raine-Bennett T, Samant ND, Postlethwaite DA, Holzapfel M. Breast cancer risk after hysterectomy with and without salpingo-oophorectomy for benign indications. Am J Obstet Gynecol. 2020;223:900.e1-900.e7. doi: 10.1016/j.ajog.2020.06.040

6. ACOG Committee Opinion No. 774: Opportunistic salpingectomy as a strategy for epithelial ovarian cancer prevention. Obstet Gynecol. 2019;133:e279-e284. doi: 10.1097/AOG.0000000000003164

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