Randomized Phase II Neoadjuvant Comparison Between Letrozole, Anastrozole, and Exemestane for Postmenopausal Women With Estrogen Receptor–Rich Stage 2 to 3 Breast Cancer: Clinical and Biomarker Outcomes and Predictive Value of the Baseline PAM50-Based Intrinsic Subtype—ACOSOG Z1031

Abstract

A B S T R A C T PurposePreoperative aromatase inhibitor (AI) treatment promotes breast-conserving surgery (BCS) for estrogen receptor (ER) -positive breast cancer. To study this treatment option, responses to three AIs were compared in a randomized phase II neoadjuvant trial designed to select agents for phase III investigations. Patients and MethodsThree hundred seventy-seven postmenopausal women with clinical stage II to III ER-positive (Allred score 6-8) breast cancer were randomly assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary end point was clinical response. Secondary end points included BCS, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis. ResultsOn the basis of clinical response rates, letrozole and anastrozole were selected for further investigation; however, no other differences in surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only patients at presentation was 51%. PAM50 analysis identified AI-unresponsive nonluminal subtypes (human epidermal growth factor receptor 2 enriched or basal-like) in 3.3% of patients. Clinical response and surgical outcomes were similar in luminal A (LumA) versus luminal B tumors; however, a PEPI of 0 (best prognostic group) was highest in the LumA subset (27.1% v 10.7%; P ϭ .004). ConclusionNeoadjuvant AI treatment markedly improved surgical outcomes. Ki67 and PEPI data demonstrated that the three agents tested are biologically equivalent and therefore likely to have similar adjuvant activities. LumA tumors were more likely to have favorable biomarker characteristics after treatment; however, occasional paradoxical increases in Ki67 (12% of tumors with Ͼ 5% increase after therapy) suggest treatment-resistant cells, present in some LumA tumors, can be detected by post-treatment profiling.

Age-Specific Changes in Intrinsic Breast Cancer Subtypes: A Focus on Older Women

“…These findings have broad implications, because many older women have estimated survivals exceeding 5 years, and those with high-risk triple-negative and HER2-positive breast cancers are most likely to relapse within 5 years of diagnosis [4]; optimizing treatment for such patients is a major consideration. PAM50 is a 50-gene expression-based predictor that classifies breast cancers into four intrinsic subtypes of prognostic significance [5]: luminal A, luminal B, HER2-enriched (HER2-E), or basal-like [6].The PAM50 assay has been shown to provide more precise prognostic information than immunohistochemical (IHC)-based subtyping and can be performed using paraffinembedded tissues [6][7][8].…”

The development of resistance to tamoxifen in patients with breast cancer: our experience

“…The literature refers to the similar conclusions by Dubsky, Ellis as well as Bartsch in their studies. [8][9][10] International Breast Cancer Study Group (IBCSG) analyzed 314 patients suffering from breast cancer of the age <35 years, and reported that relapse or death disease occurs earlier and more frequently in premenopausal group of patients.…”

Hormonal therapy in breast cancer: A model disease for the personalization of cancer care

“…The prespecified statistical analysis resulted in selection of anastrazole and letrozole for further study in the neo-adjuvant setting, although it is important to note that complete responses seen with exemestane (21.8%) were as frequent as those with letrozole (21.3%) and numerically higher than those with anastrazole (17.9%). Additionally, all three agents were found to have equivalent biological activity in terms of changes in Ki67 and the PEPI score (Preoperative Endocrine Prognostic Index, a measure of response to neo-adjuvant hormonal therapy) post-treatment and comparable toxicity (Ellis et al, 2011).…”