Impact of intertumoral heterogeneity on predicting chemotherapy response of BRCA1-deficient mammary tumors

S. Rottenberg, M.A. Vollebergh, B. De Hoon, J. De Ronde, P.C. Schouten, A. Kersbergen, S.A.L. Zander, M. Pajic, J.E. Jaspers, M. Jonkers, M. Lodén, W. Sol, E. Van Der Burg, J. Wesseling, J.-P. Gillet, M.M. Gottesman, J. Gribnau, L. Wessels, S.C. Linn, J. JonkersP. Borst

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Résumé

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.
langue originaleAnglais
Pages (de - à)2350-2361
Nombre de pages12
journalCancer Research
Volume72
Numéro de publication9
Les DOIs
Etat de la publicationPublié - 1 mai 2012

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