E-Newsletter - December 2017

Growth Biomarker Strategy in Neoadjuvant Setting May Predict Long-term Outcome for Patients with ER+ Breast Cancer

Alliance A011106 - Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment (ALTERNATE) in postmenopausal women

Estrogen receptor positive (ER-positive) breast cancer in postmenopausal women is a major public health problem. In the U.S., one in 8 women will be diagnosed with breast cancer in their life time. More than 252,000 new cancer cases and nearly 40,600 deaths are expected to be attributed to breast cancer each year, according to the American Cancer Society. Among all breast cancer cases, more than 75 percent occur in postmenopausal women, in whom 80 percent of the cases are ER-positive. Since the majority of breast cancer cases are diagnosed at an early stage (I-III), relapse of early-stage disease accounts for the majority of breast cancer deaths. Although ER-positive breast cancer tends to recur later in the course of disease than ER-negative breast cancer, the cumulative rate of recurrence over time is similar for both disease groups. Therefore, recurrence of ER-positive breast cancer in postmenopausal women is a major contributor of breast cancer mortality.

Adjuvant therapy following curative surgery has significantly improved breast cancer outcome. In the case of ER-positive breast cancer, systemic chemotherapy followed by endocrine treatment with tamoxifen has been shown to half the breast cancer mortality rate. The recent introduction of aromatase inhibitors (AIs) in early stage breast cancer has further reduced the recurrence rate, however a significant number of patients recur despite the current standard treatment. At a median follow-up of 120 months in patients enrolled in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, recurrence was observed in 19.7 percent and 24.0 percent of patients treated with five years of adjuvant anastrozole and tamoxifen, respectively, with a persistent risk of relapse over time observed in both treatment arms, indicating a need to improve the current standard therapy. However, the evaluation of new agents in the adjuvant setting has traditionally required large number of patients and years of follow up to demonstrate the effectiveness in reducing cancer relapse and/or mortality. The development of surrogate endpoints for disease free survival (DFS) and overall survival (OS) is needed for efficient drug screening and to expedite the drug development process.

The goal of Alliance A011106 is to develop a Ki67-based (growth) biomarker strategy in the neoadjuvant setting to predict long-term outcome of patients with ER+ breast cancer. Alliance researchers intend to validate the achievement of the Modified Preoperative Endocrine Prognostic Index (PEPI) score of 0, post neoadjuvant endocrine therapy as a surrogate marker of success for DFS.8 Based on promising data in the metastatic setting, researchers will also compare fulvestrant alone, fulvestrant in combination with anastrozole and anastrozole alone in regards to the rate of modified PEPI 0 to provide rationale for future adjuvant studies of fulvestrant in ER+ early stage breast cancer. In this trial, endocrine resistant tumors are identified early by Ki67 assessment on the four-week tumor (required) and then the 12-week (optional) biopsies. Patients with tumor levels of Ki67 greater than 10 percent at these time points will be switched to neoadjuvant weekly paclitaxel, or other standard taxane and/or anthracycline or CMF (cyclophosphamide, methotrexate and fluorouracil) regimens to assess the rate of complete pathologic response (pCR) to chemotherapy as a secondary endpoint.

By providing validated surrogate endpoints for endocrine therapy agents and the response data (pCR rate) to standard chemotherapy for the resistant population, results from this study are expected to provide the foundation for future novel therapeutics development for early stage ER+ breast cancer.

Refer to the study protocol (Alliance A011106), which can be found on the CTSU menu (ctsu.org) for complete information on the trial design, treatment plan and patient eligibility. The Alliance Study Chair is Cynthia Ma, MD, PhD, Washington University School of Medicine, e-mail: cma@dom.wustl.edu.

Learn more about the Alliance A011106 trial here.


For other articles in the December issue of the Alliance E-News newsletter, see below.