GENOMIC SIGNATURES TO PREDICT TREATMENT RESPONSE

Background: A genomic test was developed to predict pathologic response to sequential taxane-anthracycline chemotherapy as neoadjuvant treatment. This test was evaluated in a validation cohort and the predicted sensitivity to chemotherapy in 28% of patients was associated with pathologic response in 56%, and significantly improved distant relapse-free survival (5-year DRFS 93%). Also, a significantly higher probability of negative pathologic nodal status after neoadjuvant chemotherapy was shown in patients whose breast cancer was predicted to be sensitive to chemotherapy. Overall, in a cohort of 153 patients there were 65 (42%) who were clinically node-negative (cN-) before treatment, and 69% of those had pathologic node-negative (pN-) status after completion of neoadjuvant chemotherapy. In addition, 44% of those who were clinical node-positive (cN+) at initial diagnosis converted to pN- status after completion of neoadjuvant chemotherapy. Employing the genomic test, we observed that 30% of patients with cN+ status at initial diagnosis were predicted to have chemo-sensitive breast cancer with a significantly higher probability of conversion to pN- status after neoadjuvant chemotherapy (70%, 95% CI: 50-86) compared to patients who were predicted not to be sensitive to chemotherapy (33%, 95% CI: 21-46). Also, 21% of patients with cN- status at initial diagnosis were predicted to have chemo-sensitive breast cancer, with pN- status after neoadjuvant chemotherapy in 86% (95% CI: 57-98) compared to patients who were predicted not to be sensitive to chemotherapy (65%, 95% CI: 50- 78). The primary aim of this study is to prospectively evaluate microarray-based, genomic, test of breast cancer chemosensitivity (before treatment) as a predictor of axillary lymph node-negative status after completion of neoadjuvant chemotherapy and to determine whether the probability of achieving pN- status, and of achieving negative non-sentinel lymph nodes, is sufficiently high for patients whose breast cancer is predicted to be chemo- sensitive to support omitting axillary dissection. Design: In a prospective multicentric trial a part of the diagnostic tissue cores of 277 patients with HER2 negative breast cancer are collected and placed into RNAlater vial. Molecular profiling will be performed in the MDACC Molecular Diagnostics Laboratory and the prediction results will be calculated. Before and after completion of an anthracycline- and taxane-based neoadjuvant chemotherapy regimen the surgeon completes a second survey about the surgical plan. In addition to the information collected from surgery and pathology, patients will be followed for 5 years form initial diagnosis to evaluate the frequency of conservative surgery pathologic response rate (complete response and minimal residual disease), disease-free survival and local failure rates.

Standard treatment for locally advanced breast cancer is neoadjuvant chemotherapy consisting of anthracyclines and taxanes followed by breast and axillary surgery. In patients with a good tumor response breast conserving surgery may be offered. However a proportion of patients with positive axillary lymph nodes at diagnosis will achieve an excellent axillary node response to chemotherapy, i.e. conversion to pathologic node-negative status after chemotherapy, but axillary dissection is still the standard of care. Morbidity after axillary dissection, such as arm/shoulder pain, numbness, lymphedema, is significant lacking survival benefit. Sentinel lymph node biopsy is a minimal invasive surgical technique used by patients with negative axillary nodes. Information about the accuracy of this procedure in locally advanced breast cancer is controversial. We show that routine pathological and radiological parameters such as tumor size or mammography do not accurately predict treatment response in the axillary lymph nodes and we test genomic signatures to determine the accuracy of genomic prediction of tumoral chemosensitivity to identify which patients could safely undergo conservative surgical management of their regional lymph nodes. Our project highlights the need for models that predict treatment response to avoid unnecessary axillary surgery and impairment of quality of life and indicates technical aspects that facilitate future translational studies