Abstract P3-08-57: A novel gene expression signature score to predict response to neoadjuvant therapy, distant metastasis, and survival in breast cancer
Authors: Masanori Oshi, Eriko Katsuta, Kazuaki Takabe
Journal: Cancer Research (2020)

Abstract Background: Although breast cancer has a better prognosis compared to other cancers, about 40,000 patients die from this disease in the US annually. Distant metastasis of the cancer to organs such as brain and lung accounts for a half to three quarters of these deaths. However, no effective methods of predicting metastasis for breast cancer have been found. We aimed to develop a gene signature score that associate with response to neoadjuvant therapy, distant metastasis, and survival in breast cancer. Methods: A gene signature score was generated using differentially expressed genes between MDA-MB-231 human breast cancer cell-line and its highly metastatic variant, LM2-4, and The Cancer Genome Atlas (TCGA) breast cancer dataset. METABRIC cohort as well as neoadjuvant chemotherapy cohorts (GSE22093, 23988, 25065, 28844, 33658, 82172) and metastatic cohorts (GSE2034, 2603, 12276, 110590) were used as validation cohort. Results: We identified four genes (DOK4, HCCS, PGF and SHCBP1) that had the strongest association with disease-free survival in TCGA among 297 genes that were up-regulated in LM2-4 (HR &amp;gt; 1.2 with p &amp;lt; 0.02 in Cox regression analysis). The gene signature score generated by the combined expression of these genes correlated with overall survival in TCGA (HR = 2.13, 95% CI = 1.52 - 2.98; logrank p &amp;lt; 0.001). This association was validated with disease-specific survival in the METABRIC breast cancer cohort (HR = 1.46, 95% CI = 1.23 - 1.72, p &amp;lt; 0.001). We found that the score was predictive of response to chemotherapy (p &amp;lt; 0.01) and hormonal therapy (p = 0.045) for ER+ patients, and the score decreased following good response to neoadjuvant chemotherapy (p = 0.022) or hormonal therapy (p = 0.021). Tumors with high scores enriched genes related with cancer aggressiveness such as MYC (v1; p = 0.024, v2; p = 0.013), hypoxia (p = 0.019) and PI3K/AKT pathways (p = 0.023), mTOR (p = 0.004), glycolysis (p = 0.003), ROS (p = 0.008), whereas those with low scores had enriched Estrogen response gene sets (early; p &amp;lt; 0.001, late; p = 0.038). We also found that the score associated with distant metastasis to brain or lung (p &amp;lt; 0.001). Kaplan-Meier analyses of site-specific metastasis-free interval demonstrated that for all three cohorts, patients with high scores had significantly increased risk for development of metastasis to the lung (all log-rank p ≤ 0.02). This association of the score with metastasis risk was also seen for brain for two of the three cohorts, but it was not seen for bone in any cohort. In multivariate analysis of DFS in the TCGA, the score was found to be prognostic independently of the other factors for both DFS (HR = 1.64, 95% CI = 1.05 - 2.58, p &amp;lt; 0.001) and OS (HR = 1.94, 95% CI = 1.31 - 2.86, p &amp;lt; 0.001). And similar observations were made in analyses of DSS with the METABRIC cohort (HR = 1.46, 95% CI = 1.21 - 2.78, p &amp;lt; 0.001). Interestingly, the high-score group was associated with worse survival for not only early stage cancer (stage I/II: p = 0.043) and for smaller tumor size (T1/2: p = 0.030) but also late stage cancer (stage III/IV: p &amp;lt; 0.001) and for larger tumor size (T3/4: p &amp;lt; 0.001). Additionally, the score worked regardless of presence of lymph node metastasis (N0 or N1-3: p = 0.035, 0.004) and cancer subtype (TNBC: p = 0.008). Similar observations were made in analyses of OS with the TCGA cohort and of DSS with the METABRIC cohort. Conclusion: The novel score may be a clinically powerful tool with both prognostic and predictive values for metastasis breast cancer patients. Citation Format: Masanori Oshi, Eriko Katsuta, Kazuaki Takabe. A novel gene expression signature score to predict response to neoadjuvant therapy, distant metastasis, and survival in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-57.