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Abstract PD07-04: A randomized phase II neoadjuvant trial evaluating anastrozole and fulvestrant efficiency for post-menopausal ER-positive, HER2-negative Breast Cancer patients: first results of the UNICANCER CARMINA 02 French trial
Abstract
Purpose: Neoadjuvant hormone therapy (HT) promotes breast-conserving surgery (BCS) and minimizes treatment-related toxicities for oestrogen receptor (ER)-positive HER2 negative breast cancer (BC). We aimed to evaluate the response rates to an AI (anastrozole) or an antioestrogen (fulvestrant) and to identify specific biomarkers of sensitivity to both treatments.
Patients and Methods: A phase II multicentre, open-label trial was conducted to evaluate the efficacy of anastrozole and fulvestrant. 116 postmenopausal patients (pts) with ER positive, HER2 negative, operable BC were recruited in 6 centers and randomly assigned to receive either neoadjuvant anastrozole (arm A; 1mg/day) or fulvestrant (arm B; 500mg, with a loading dose during first month then q4w) for 4 months (mo). Pts with a good clinical response estimated by the clinician at 4 mo were allowed to pursue treatment for 2 more mo (i.e. up to 6 mo). The primary endpoint was to evaluate the best clinical response (by palpation) by RECIST criteria at 6 mo (or 4 mo). US and MR imaging were performed at baseline, after 1 mo treatment, and before surgery. Pathological response was evaluated using Sataloff classification. Follow-up is planned for 5 yrs.
Results: Between Oct 2007 and Apr 2011, 59 pts were randomized to arm A and 57 to arm B. Main baseline characteristics were well-balanced between the 2 arms: Median age was 68 yrs-old (53–91) in arm A and 74 yrs-old (51–88) in arm B. Histological grades were EE I-II in 53 pts (89 %) and 49 pts (86%) and median clinical size before treatment was 41.5 mm and 42.3 mm in arm A and B respectively.
Neither SAE nor grade 3/4 toxicity was reported. The most common treatment-related AEs were grade1/2 hot flushes (27% and 12% of pts in arm A and B respectively), and musculoskeletal symptoms (20% and 21%).
35 pts in arm A and 29 pts in arm B continued assigned treatment up to 6 mo depending on the clinical response evaluated at 4 mo. Also, the clinical response rate was estimated at 4 mo orat 6 mo. 1 death post-surgery was reported in arm B with no proven relationship with treatment.
Overall clinical response rates (CR + PR) at 4 or 6 mo were 62% (CI 95% [49–75]) in arm A and 46% (CI 95% [32–59]) in arm B. Clinical response rate amelioration at 6 mo was observed among 15% of pts in each arm.
BCS was performed in 59% of pts in arm A and 49% in arm B. (1 pt from arm B refused surgery).
Pathological response according to Sataloff classification: TA and TB tumor responses were observed in 17/59 pts (29%) in arm A vs 12/57 (21%) in arm B respectively.
Conclusions: Both anastrozole and fulvestrant show excellent efficacy and tolerability as neoadjuvant therapy in post-menopausal pts with endocrine-dependent, HER2-negative BC.
Objective response rates and improvement in surgical outcome seem to be more frequent with anastrozole. However disease stabilization and tolerability are in favour of fulvestrant.
Our data suggest that neo-adjuvant HT improves surgical options for HR+ post-menopausal women. Correlation between clinical & pathological responses and outcome as well as the identification of markers of sensitivity to both treatments will be also studied.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-04.
... 8,21-24 However, in a phase II on the neoadjuvant setting, fulvestrant was not superior to standard AI therapy. 25 • What is the optimal duration? Based on earlier experience with NCT, a three to fourmonth duration of NET has been proposed in the majority of the clinical trials, such as the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT), 26 the Pre-Operative "Arimidex" Compared to Tamoxifen (PROACT) 27 and the PO24. ...
Breast cancer is the most common type of cancer and the leading cause of cancer-related death among women worldwide. Hormone receptor-positive (HR+) tumors represent the most common form of this disease, with more than 70% of breast cancers expressing these receptors. Response and benefit to neoadjuvant chemotherapy (NCT) varies according to HR expression, with lower responses in luminal tumors as compared with hormone receptor-negative (HR-) and human epidermal growth factor receptor 2-positive (HER2+) tumors. Neoadjuvant endocrine therapy (NET) is an option for selected patients with HR+ locally advanced breast cancer. Neoadjuvant endocrine therapy has a favorable toxicity profile, and is associated with benefits such as having low cost and being more easily available even for cancer care professionals outside major urban areas or tertiary centers. These factors are particularly relevant, as 70% of breast cancer deaths occur in women from low-income and middle-income countries. Additionally, NET is being increasingly explored, not simply to allow for less extensive surgery, but also as a scientific tool, with the use of biomarkers to predict outcomes in adjuvant trials and for the individual patient. This review details the current and most relevant evidence about NET for breast cancer as well as the future directions of this field.
Endocrine therapy (ET) is the mainstay of treatment of estrogen receptor-positive (ER+) breast cancer both in the early-stage as in the advanced disease settings. ET targets the ER pathway by blocking the body’s ability to produce estrogen or by directly modulating the ER. Since the estrogens are produced by the ovaries in premenopausal women and by some other tissues such as fat and skin in both premenopausal and postmenopausal women, ET for premenopausal women is different from for postmenopausal women. Needless to say, therapeutic options for early breast cancer are different to metastatic setting where more drugs are approved. This chapter will mainly review the clinical use of ET through all stages of breast cancer, with special considerations on recent advances in this field like ovarian function suppression in premenopausal patients with higher-risk early-stage tumors and the incorporation of targeted therapies that aim to circumvent mechanisms of endocrine resistance in metastatic ER+ breast cancer.
Opinion statement:
Neoadjuvant endocrine therapy (NET) with Ki67-based response monitoring is a practical, cost-effective approach to the management of clinical stage II and III estrogen receptor-positive (ER+) breast cancer. In addition to marked improvements in rates of breast conservation, the identification of extreme responders on the basis of the preoperative endocrine prognostic index (PEPI) provides a rationale to avoid chemotherapy on the basis of highly favorable prognosis in some patients. Finally, samples accrued from patients treated with neoadjuvant therapy are providing valuable insights into the molecular basis for intrinsic resistance to endocrine therapy and promise a more rational basis and precise approach to the systemic treatment of ER+ breast cancer.
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