Abstract P4-09-07: Validation of 12-gene chemokine signature as a predictor of treatment response in breast cancer
Authors: Prabhakaran S , Cheng C-H , Boulware D , Ma Z , Mulé JJ , Soliman H 
Published: February 2018

Background: We had previously derived a unique 12-chemokine gene expression score (CS) from a metagene grouping with high enrichment for immune-and inflammation-related genes. A review of selected Stage I - III breast cancer patients showed that higher CS were associated with high-grade tumors and aggressive subtypes and in the HER2 positive group, correlated with increased recurrence free survival that trended towards significance. We tested the predictive capability of this CS for pathological complete response (pCR) in an external dataset. We used the Neratinib and Veliparib arms of the I-SPY2 TRIAL dataset with their respective controls for this analysis.

Methods: Gene expression signature probes (CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11 and CXCL13) were extracted from existing Agilent custom 44k microarray from the I-SPY2 TRIAL dataset. The arrays contain 40,793 probe sets representing ˜25,000 unique genes. The expression data for the 246 distinct solid tumors were normalized using IRON and expression data for the 12- chemokine genes were extracted for principal component analysis (PCA). The first principal component (PC1, explaining ˜57%) was calculated using R package. The median CS of 0.79 was used as the cut-off with any score above this defined as high and scores at or below the median were classified as low. The Chi-Square test or Fisher's exact test was used to test pCR vs CS within each treatment arm [table 1]. Cochran-Mantel-Haenszel test was performed to test the pCR for the pooled control and treatment arms between CS high and low groups adjusting for hormone receptors (HR), HER2 and Mammaprint status. Breslow-Day test was performed to test treatment difference in the odds ratios for the CS and response.

Results: There were 56 patients in the paclitaxel arm (A), 115 in the Paclitaxel+Neratinib arm (B), 22 patients on the Paclitaxel + Trastuzumab arm (C) and 72 on the Paclitaxel + Veliparib + Carboplatin arm (D). In all treatment arms, high CS were associated with higher pCR rates with significant association found in treatment arms A and D (38.5% vs 6.7% and 47.5 vs. 25% respectively)[table 1]. Analysis of pooled data for all arms adjusting for HR, HER2 and Mammaprint status showed statistically significant association between CS and pCR (P &lt; 0.05). There were no significant differences in the odds ratios for the CS and pCR.

Conclusion: The 12 gene CS predicted for treatment response even after adjusting for the treatment with no differences noted in the odds ratio for CS and pCR. The 12 gene CS can be readily obtained from I-SPY2 TRIAL microarrays to characterize tumors immunologically and possibly predict response to novel therapies. Continued investigation of the CS in other I-SPY2 TRIAL treatment arms is warranted.

Table: 1 Comparison of treatment arms with gene scores and treatment responseArm (N)12 gene scorepCR N(%)Incomplete Response N(%)P valueA. Paclitaxel (56)High10 (38.5)16 (61.5)0.007 Low2 (6.7)28 (93.3) B. Paclitaxel+Neratinib (115)High23 (41.8)32 (58.2)0.24 Low18 (30.0)42 (70.0) C. Paclitaxel + Trastuzumab (22)High4 (36.4)7 (63.6)0.31 Low1 (9.1)10 (90.9) D. Paclitaxel + Veliparib + Carboplatin (72)High19 (47.5)21 (52.5)0.05 Low8 (25.0)24 (75.0) 

Citation Format: Prabhakaran S, Cheng C-H, Boulware D, Ma Z, Mulé JJ, Soliman H. Validation of 12-gene chemokine signature as a predictor of treatment response in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-09-07.