Background: The I-SPY trial is a multi-institutional study of locally advanced breast cancers in which serial biopsies of breast tumors are performed at multiple timepoints, allowing comparison of tumor biomarker status pretreatment, during treatment, and after treatment. The primary objective is to identify markers of response to neoadjuvant chemotherapy. The aim of this study was to identify immunohistochemical biomarkers associated with pathologic complete response (pCR).Methods: Eligible patients had biopsy-confirmed primary breast cancer measuring at least 3 cm. Required initial treatment was an anthracycline based neoadjuvant chemotherapy regimen: AC followed by T (91%), AC without T (6%), and chemotherapy beyond AC +/- T 2%. Immunohistochemistry (IHC) for HER2, EGFR, p53, Bcl2 and Ki-67 was performed centrally on core samples at baseline. Estrogen receptor and progesterone receptor results were obtained from each institution. Proxy IHC tumor subtypes were defined as follows: luminal A (ER or PR+/HER2-), luminal B (ER or PR+/HER2+), basal-like (ER-/PR-/HER2-), and HER2 (ER-/PR-/HER2+). Following completion of chemotherapy, post-surgical excision/mastectomy cases were reviewed centrally to determine residual cancer burden including pCR rate.Results: 221 patients were enrolled and completed therapy. The median age was 49 years, with a range of 27-69. Median tumor size was 6 cm; 58% had clinically positive nodes. The positive rate for each biomarker was as follows: ER+ (57%), PR+ (47%), HER2+ (23%), EGFR+ (14%), p53+ (44%), Bcl2+ (49%), Ki-67 index ≥25% (38%), Ki-67 index ≥10% but <25% (34%), and Ki-67 index <10% (27%). The pCR rates based on biomarkers results are shown in the table below.

Conclusion:For patients with locally advanced breast cancer, pCR to neoadjuvant chemotherapy was associated with tumor HER2 overexpression, hormone receptor-negative status, high Ki-67 index, EGFR expression, and absence of Bcl2 expression. Luminal A tumors, defined by IHC proxy, showed a very low pCR rate following neoadjuvant chemotherapy.Support: CALGB CA31964 and CA33601, ACRIN U01 CA079778 and CA080098, NCI SPORE CA58207.