Erin Roesch, MD
Studies have demonstrated inferior survival outcomes associated with delays in time to surgery and adjuvant chemotherapy for early breast cancer. The timing of adjuvant endocrine therapy is also notable because of the favorable effect on recurrence risk and survival with these agents in early HR+ breast cancer. A cohort study from the National Cancer Database including 144,103 women demonstrated a 31% increase in the risk for death (hazard ratio [HR] 1.31; P < .001) with a time to adjuvant hormone therapy (TTH) > 150 days (6.4% of patients) compared with those with TTH ≤ 150 days (93.6% of patients). Factors associated with delay in TTH included Black race, nonprivate insurance, metropolitan residence (vs. urban or rural), community hospital setting (vs. academic), higher comorbidity index, poorly differentiated tumors, higher stage, breast conservation surgery (vs. mastectomy), and radiation therapy. This study highlights the need to avoid unnecessary delays in adjuvant hormone therapy and encourages further exploration of barriers to timely initiation of breast cancer therapies to maximize outcomes for patients.
The role of reproductive hormones in breast cancer risk and carcinogenesis has been extensively studied and hormonal therapies are an essential component of the management of HR+ breast cancer. Lan and colleagues performed a retrospective analysis including 196 premenopausal and 137 postmenopausal women treated with neoadjuvant chemotherapy for breast cancer, investigating the correlation between pretreatment levels of reproductive hormone levels with pathologic and survival outcomes. Higher likelihood of achieving pathologic complete response was seen in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower follicle-stimulating hormone levels (OR 1.045; P = .005). Furthermore, lower progesterone levels in premenopausal patients was associated with inferior overall survival (OS) (3-year OS 72.9% vs. 97.4% for lowest tertile progesterone vs. higher tertiles; P = .007). These data suggest a potential role of reproductive hormones in the preoperative evaluation for breast cancer patients. Also, the complex actions of progesterone and "crosstalk" between estrogen receptors and progesterone receptors continue to be elucidated and ongoing studies are evaluating progestin combined with endocrine therapy.
The CLEOPATRA trial has established the regimen of trastuzumab plus pertuzumab plus docetaxel as first-line therapy for metastatic HER2-positive (HER2+) breast cancer with an absolute survival benefit of 16.3 months vs. trastuzumab plus docetaxel. A retrospective study conducted in Ontario, Canada, explored real-world outcomes of pertuzumab plus trastuzumab plus chemotherapy among 1158 patients and demonstrated a similar magnitude of survival improvement with the addition of pertuzumab (14.9 months) ( Dai et al ). The median OS was higher among patients receiving pertuzumab compared with control (40.2 vs. 25.3 months), and although the median OS was shorter in the real-world setting than in the CLEOPATRA trial, they had similar HRs for mortality reduction (0.66 for real-world and 0.69 for trial). Furthermore, there was no increase in cardiotoxicity and lower cumulative incidence of hospitalization at 1 year with pertuzumab vs. control (11.7% vs. 19.0%; P < .001). This study adds to the existing body of data supporting first-line treatment with pertuzumab plus trastuzumab plus chemotherapy for metastatic HER2+ breast cancer. The treatment landscape for these patients is certainly dynamic with the development of novel therapies and combinations in this space and resultant shifts in the current algorithm.
Recommended Additional Reading:
Hortobagyi GN et al. LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290-S1291. Doi: 10.1016/j.annonc.2021.08.2090
Chavez-MacGregor M et al . Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol. 2016;2:322-329. Doi:10.1001/jamaoncol.2015.3856
Trabert B et al. Progesterone and breast cancer. Endocr Rev. 2020;41:320-344. Doi: 10.1210/endrev/bnz001
Swain SM et al; on behalf of the CLEOPATRA study group . Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol . 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0