Impact of Intertumoral Heterogeneity on Predicting Chemotherapy Response of BRCA1-Deficient Mammary Tumors

Abstract

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 which could identify tumors with increased Abcb1 transcript levels. In contrast, standard analytical tools, such as Significance Analysis of Microarrays (SAM), 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.

AMG 900, a Small-Molecule Inhibitor of Aurora Kinases, Potentiates the Activity of Microtubule-Targeting Agents in Human Metastatic Breast Cancer Models

“…The negative impact on normal tissue homeostasis could limit the utility of this combination, although prophylactic administration of granulocyte colony-stimulating factor may help decrease the duration of neutropenia (18). One area for further investigation will be to evaluate the activity of AMG 900 alone and in combination with MTAs in either patientderived cancer xenografts or a genetically engineered mouse model of human MBC (37,38). These alternative preclinical models may more closely mirror human disease (e.g., tumor heterogeneity, multifactorial nature of MDR) and allow for a more fateful assessment of drug efficacy.…”

High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer

“…Recently, two biomarkers associated with resistance were identified in BRCA1-deficient model systems (12,13). The first biomarker, X inactive-specific transcript (XIST), was found to be differentially expressed in BRCA1-deficient mouse tumors that had early and late relapses after treatment with cisplatin.…”

“…The first biomarker, X inactive-specific transcript (XIST), was found to be differentially expressed in BRCA1-deficient mouse tumors that had early and late relapses after treatment with cisplatin. Specifically, low gene expression of XIST was associated with late relapse, suggesting that this may be a predictive biomarker (12). Subsequently, XIST expression was investigated in HER2-negative patients from a randomized trial comparing high-dose (HD) alkylating chemotherapy and conventional (CONV) chemotherapy.…”

Cancer stem cells and addicted cancer cells

“…The differences observed between the tumors are the result of different mutations that arise during their development. Consequently, these differences result in distinct sensitivities to docetaxel and cisplatin in individual tumors [16]. Studies on human cancers have highlighted the role of specific genetic aberrations that contribute to tumor behavior [8].…”