Potential Predictive Markers of Benefit from Cetuximab in Metastatic Breast Cancer: An Analysis of Two Randomized Phase 2 Trials.
Authors: Carey L. , O'Shaughnessy J. , O'Shaughnessy J. , Hoadley K. , Khambata-Ford S. , Horak C. , Xu L. , Awad M. , Brickman D. , Muller S. , Donato J. , Asmar L. , Stiljeman I. , Ebbert M. , Bernard P. , Perou C. 
Published: December 2010

Abstract
Background: Two randomized phase 2 studies investigated the efficacy of cetuximab (C), a mAb directed against EGFR, in metastatic breast cancer (MBC) patients (pts). Trial 1 (T1) compared the response rates in triple negative breast cancer (TNBC) pts on C vs. C plus carboplatin (Cb), and, in Trial 2 (T2), both TNBC and ER+/HER2- pt subsets were assessed for response to irinotecan (I) plus Cb vs. C plus ICb. In T2, TNBC pts showed an improved objective response rate with C treatment, while ER+/HER2- pts did not. Formalin-fixed paraffin-embedded (FFPE) primary breast cancer tissues were available from pts on both trials for retrospective analyses of potential predictive biomarkers of C treatment.Material and Methods: In T1 and T2, 64 and 68 pts, respectively, had tissue for qRT-PCR analyses of genes important for breast cancer subtyping (PAM50) and EGFR pathway-related genes. PAM50 analysis showed that 76 of the 132 pts on the 2 trials had basal-like breast cancer (BBC). In T1, 43 of the 64 (67%) TNBC pts had BBC, 3 were HER2-enriched, 5 were luminal A and 13 were normal-like breast cancer. In this trial, 10 of 64 pts (16%) had progression-free survival (PFS) duration ≥6 mo (long remitters [LRs]) with 4 pts having PFS ≥12 mo; 6 of the 10 LRs had BBC. In T2, 22 of 68 pts were LRs (32%) (11 of 22 received C) and 9 pts had PFS ≥12 mo (5 received C). 11 of the 37 BBC pts in T2 had PFS ≥6 mo (5 received C) and 4 of 11 had PFS ≥12 mo (2 received C). The following EGFR pathway-related markers were also assessed by qRT-PCR: EGFR, KRAS, PTEN, alpha basic crystallin (CRYAB) gene expression, and K-Ras amplification (average expression by qPCR of 7 genes in KRAS amplicon). Expression of these markers was compared in the pts who had PFS of &lt;6 mo versus ≥6mo, with or without C treatment, and in the BBC vs. non-BBC subtypes.Results: In preliminary analyses, in T1 (all C-treated pts), higher levels of EGFR expression trended with PFS ≥6 mo in both BBC pts (p=.09) and non-BBC pts (p=.06). In T2, a trend towards benefit with C with high EGFR levels was seen in non-BBC but not BBC pts. In both trials, resistance to treatment in general was associated with low PTEN or high CRYAB levels. BBC and non-BBC pts with low PTEN or high CRYAB did not benefit from C. Interestingly, in T2, non-BBC benefit from C was associated with significantly higher PTEN levels (p=.04). Lack of KRAS amplification predicted for benefit from C in BBC (but not in non-BBC) in T1 (p=.09) and in T2 benefit with C was seen in BBC that lacked KRAS amplification. KRAS gene expression alone did not appear to distinguish the MBC pts who were LRs vs. not, regardless of C therapy. Additional analyses correlating benefit from C therapy with EGFR and PTEN expression by IHC, and with KRAS and PIK3CA mutation status on T2 will be available in addition to updated analyses of the above markers.Conclusion: Approximately 15% of the MBC pts with FFPE tissue available for molecular analyses had prolonged benefit with C in 2 randomized phase 2 trials. Preliminary results from our analyses suggest that benefit from C in MBC may be correlated with lower expression of CRYAB, with higher expression of PTEN, and in BBC, with lack of KRAS amplification.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2014.