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Potential Predictive Markers of Benefit from Cetuximab in Metastatic Breast Cancer: An Analysis of Two Randomized Phase 2 Trials.

2009; American Association for Cancer Research; Volume: 69; Issue: 24_Supplement Linguagem: Inglês

10.1158/0008-5472.sabcs-09-2014

1538-7445

Lisa A. Carey, Joyce O’Shaughnessy, Joyce O’Shaughnessy, KA Hoadley, Shirin Khambata‐Ford, Christine E. Horak, Li Xu, M. Awad, Daniel Brickman, Simon Müller, Jessica Donato, L. Asmar, I. Stiljeman, Mark Ebbert, Philip S. Bernard, C. Perou,

Colorectal Cancer Treatments and Studies

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 <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.