Abstract B27: OncoPredictor: High copy number gain of ERBB2 predicts sensitivity to lapatinib.
Authors: Eddy Sean F. , Tomilo Mark , Sadis Seth , Williams Paul , Wyngaard Peter , Rhodes Daniel 
Published: June 2012

Investigational new drugs for cancer must demonstrate convincing preclinical efficacy and a compelling strategy to translate preclinical observations to the clinical setting. The use of predictive biomarkers are gaining wider acceptance (i.e., HercepTest™, Oncotype DX® Breast Cancer Assay), however, there is no systematic approach to identify candidate predictive biomarkers for new therapies and to characterize their distribution and expression in cancer patient subsets. To meet this challenge, we developed an integrated platform to translate preclinical biomarker profiles, derived from screening compounds across large panels of cancer cell lines, to clinical tumor populations. This platform, known as OncoPredictor, consists of two parallel genomic databases that incorporate DNA copy number, mutation status, and gene expression biomarker annotations for hundreds of cell lines and the same biomarkers annotated across thousands of clinical tumor samples. To illustrate this approach, we used published drug response data for lapatinib (Greshock et al., Cancer Res., 70: 3677–86, 2010) and investigated cell line biomarkers representing each of the genomic data types (mutation, DNA amplification and deletion, and gene over-expression) in an unbiased approach to identify biomarkers that associated with drug sensitivity. Of all genomic biomarkers, high copy number gain of ERBB2 was the most significant biomarker that associated with sensitivity to lapatinib. As expected, several breast cell lines showed high level amplification of ERBB2 and were sensitive to lapatinib, consistent with approved indications for ERBB2-based therapies. Interestingly, two lung cancer cell lines (CALU3 and NCIH2170) were also exquisitely sensitive to lapatinib and both contained significant amplification of ERBB2. Using DNA copy data from &gt;1,000 lung cancer tumor specimens, we estimated that approximately 0.5–1% of lung squamous cell carcinoma and lung adenocarcinoma contained high level copy number gain of ERBB2. Similar to observations in breast cancer, ERBB2 gains were typically focal (5 − 20 genes) and ERBB2 was the most commonly amplified gene in this region. Increased copy number was also significantly correlated with ERBB2 mRNA expression. Because KRAS mutations cause resistance to EGFR family targeting drugs, we investigated the clinical frequency of KRAS mutations in lung cancer. In &gt;12,000 patient samples with available mutation data, approximately 17% of patient samples had KRAS mutations, including 20% of lung adenocarcinoma and 5% of squamous cell lung carcinoma samples. Infrequent high level amplification of ERBB2 in lung cancer coupled with the frequency of KRAS mutation, may account for lack of efficacy in lung cancer patient populations. The cell line data support the use of high level ERBB2 amplification as a predictive biomarker for clinical response to lapatinib, which may lead to improved patient survival.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B27.