Impact of intertumoral heterogeneity on predicting chemotherapy response of BRCA1-deficient mammary tumors
The lack of markers to predict chemotherapy responses in patients poses a major handicap in cancer treatment. We searched for gene expression patterns that correlate with docetaxel or cisplatin response in a mouse model for breast cancer associated with BRCA1 deficiency. Array-based expression profiling did not identify a single marker gene predicting docetaxel response, despite an increase in Abcb1 (P-glycoprotein) expression that was sufficient to explain resistance in several poor responders. Intertumoral heterogeneity explained the inability to identify a predictive gene expression signature for docetaxel. To address this problem, we used a novel algorithm designed to detect differential gene expression in a subgroup of the poor responders that could identify tumors with increased Abcb1 transcript levels. In contrast, standard analytical tools, such as significance analysis of microarrays, detected a marker only if it correlated with response in a substantial fraction of tumors. For example, low expression of the Xist gene correlated with cisplatin hypersensitivity in most tumors, and it also predicted long recurrence-free survival of HER2-negative, stage III breast cancer patients treated with intensive platinum-based chemotherapy. Our findings may prove useful for selecting patients with high-risk breast cancer who could benefit from platinum-based therapy.
|Persistent URL||dx.doi.org/10.1158/0008-5472.CAN-11-4201, hdl.handle.net/1765/69991|
Rottenberg, S, Vollebergh, M.A, de Hoon, B, de Ronde, J, Schouten, P.C, Kersbergen, A, … Borst, P. (2012). Impact of intertumoral heterogeneity on predicting chemotherapy response of BRCA1-deficient mammary tumors. Cancer Research, 72(9), 2350–2361. doi:10.1158/0008-5472.CAN-11-4201