Systematically Defining Single-Gene Determinants of Response to Neoadjuvant Chemotherapy Reveals Specific Biomarkers

Abstract

Purpose We sought to systematically define determinants of the response to neoadjuvant chemotherapy to elucidate predictive biomarkers for breast cancer. Experimental Design An unbiased systematic analysis was performed in multiple independent datasets to define genes predictive of complete pathologic response (pCR) following treatment with neoadjuvant chemotherapy. These genes were interrogated across estrogen receptor (ER)–positive and ER-negative breast cancer and those in common across three different treatment regimens were analyzed for optimal predictive power. Subsequent validation was performed on independent cohorts by gene expression and IHC analyses. Results Genes that were highly associated with the response to neoadjuvant chemotherapy in breast cancer were readily defined using a computational method ranking individual genes by their respective ROC. Such predictive genes of the response to taxane-associated therapies were strongly enriched for cell-cycle control processes in both ER-positive and ER-negative breast cancer and correlated with pCR. However, other genes that were specifically associated with residual disease were also identified under other treatment conditions. Using the intersection between treatment groups, nine genes were identified that harbored strong predictive power in multiple contexts and validation cohort. In particular, the nuclear oncogene DEK was strongly associated with pCR, whereas the cell surface protein BCAM was strongly associated with residual disease. By IHC staining, these markers exhibited potent predictive power that remained significant in multivariate analysis. Conclusion Systematic computational approaches can define key genes that will be able to predict the response to chemotherapy across multiple treatment modalities yielding a small collection of biomarkers that can be readily deployed by IHC analyses.

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

“…It is well-known that highly proliferative cancers are more likely to respond to cytotoxic chemotherapy [21]. As we found that a high G2M pathway score reflects cell proliferation, we speculated that the G2M score would decrease when tumors respond to chemotherapy.…”

BCAM and LAMA5 Mediate the Recognition between Tumor Cells and the Endothelium in the Metastatic Spreading of KRAS-Mutant Colorectal Cancer

“…Finally, despite its characterization as adhesion protein in the Lutheran blood group system and circulating sickle red cells, BCAM has been shown upregulated in skin (45), brain (46), and endometrial-ovarian (47) tumors, in hepatocellular carcinoma (48), and in breast cancer (49), where it represents an independent marker of response to neoadjuvant chemotherapy (50). These data suggest that BCAM-targeted agents might have broad application in different tumor types besides the specific approach against KRAS-mutant colorectal cancer metastasis described in the present work.…”

Gene signature‐based prediction of triple‐negative breast cancer patient response to Neoadjuvant chemotherapy

“…After excluding publications with no gene expression-based signature, or which were not validated in at least two independent datasets, 19 gene signatures remained. 28,[49][50][51] The methods of calculating those 19 gene signatures were as follows:…”

“…Signature 1: Witkiewicz et al reported that cell-cycle-related genes are important for NCT and used nine genes to quantify the related pathway activity. 49 The average expression of these nine genes were calculated as the metric for prediction. In detail, this signature was composed of the sum of the STAT1 module score (immune function), TOP2A (tumor proliferation), and LAPTM4B (tumor proliferation regulator) gene expression.…”