Candidate predictive biomarkers of cetuximab benefit in triple-negative breast cancer.

Abstract

1056 Background: A randomized phase II trial, USOR 04-070, investigated cetuximab (C) plus irinotecan/carboplatin (ICb) vs. ICb alone in metastatic breast cancer (mBC) patients (pts) without subtype restrictions. C improved overall response rate (ORR) only in triple negative (TN) pts (50.6% of total pts): 49% vs. 38% on ICb alone, without a difference in progression-free survival (PFS). To identify pts more likely to benefit from C, EGFR- related candidate biomarkers, including PTEN, EGFR, K-Ras, and PIK3CA, were retrospectively assessed in available specimens. Methods: Of 154 total pts, 124 had evaluable FFPE primary tumor tissue samples. K-Ras and PIK3CA mutations were analyzed by direct sequencing. EGFR and PTEN status was determined by immunohistochemistry (IHC) using the EGFR PharmDx kit and a monoclonal PTEN antibody. Gene/chromosomal copy number alterations are under evaluation globally by array comparative genomic hybridization (aCGH) with Agilent 4x180k arrays. Associations between BC subtype and biomarker status were assessed by chi-square tests. Relationships between biomarker status and PFS, overall survival (OS), and ORR were assessed by log-rank tests per study arm for treatment-specific effects across the total evaluable and the TN populations. Results: K-Ras (exon 2) mutation rate was 5% (n=119). PIK3CA mutations (exons 9 and 20) were present in 17% of samples overall (n=86), with similar rate in TN (17%) and ER+ pts (18%). Rates of EGFR and PTEN-positivity were 47% (n==08) and 48% (n=110), respectively. EGFR positive status was significantly associated with the TN BC subtype (p<0.0001). None of the candidate biomarkers was significantly associated with C benefit in the overall population including all BC subtypes. In TN pts, PTEN-positivity was associated with improved PFS on the C arm (HR=0.40; p=0.04). Conclusions: PTEN-positivity is associated with improved PFS on C in TN mBC. Our prior report (Carey et al, SABCS 2009) had shown that low gene expression levels of alpha-B crystalline (CRYAB) are associated with C benefit in these pts. These biomarkers may be useful for selecting patients that would benefit from C and should be evaluated further. Additional biomarkers may be identified by ongoing aCGH efforts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb