Abstract LB-87: Analysis of luminal-type breast cancer by massively parallel sequencing

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background : Endocrine-therapy resistant HER2 negative luminal-type breast cancer is the commonest cause of breast cancer death but the molecular basis for aggressive clinical behavior is poorly understood. Endocrine therapy resistant cases can be identified early in the course of the disease though the persistant expression of the cell cycle biomarker Ki67 despite neoadjuvant treatment with a potent aromatase inhibitor (JNCI 2008:100;159–61). Methods : Massively parallel DNA sequencing (Nature 2010; 464:999–1005) was applied to samples from two neoadjuvant endocrine trials (“POL” J Am Coll Surg. 2009; 208: 906–14 and “ACOSOG Z1031” JCO in press ) to define the whole genome sequence of 50 luminal-type breast cancers (PAM50 definition, JCO 2009;27:1160–7) with an average 30 fold coverage. Of these, 24 were defined as resistant (surgical specimen Ki67 > 10%) and 26 sensitive (Ki67 ≤ 10%). Approximately 10 trillion base pairs of sequence were analyzed. Putative somatic mutations were confirmed through targeted sequence analysis and the absence of the variant in matched normal DNA. Results : The mean number of single nucleotide non-silent variants (SNV) and small deletions (indels) was greater in the resistant group (49 per case) than sensitive cases (23) (p=0.02). The significantly mutated gene list included PIK3CA, TP53, ATR, RUNX1, MYST3, PRSS8, ZNHIT2 and MAP3K1. A large number of structural variations have also been identified with greater than 800 events from 28 patients orthogonally validated to date, mostly deletions but also translocations, although no recurrent translocations have been seen. About 25% of these deletions were paired with an SNV suggesting multiple novel double-hit tumor suppressor events. Extension analysis in 121 POL/Z1031 samples produced the following mutation incidence data PIK3CA (43%), TP53 (15.2%) and MAP3K1 (9.3%). The MAP3K1 mutations were most frequently frame-shift or nonsense, disrupting the C terminal kinase domain, a logical finding in a kinase activated by caspase 7 to promote apoptosis. Only 1 MAP3K1 mutation was observed in 60 basal-like breast cancers (luminal versus basal MAP3K1 mutation frequency p=0.04). Conclusions : MAP3K1is a novel breast cancer tumor suppressor gene more frequently lost in luminal-type than basal-like breast cancer. Further data analysis will be presented including pathway analyses that place less common mutations into a variety of cancer pathways, including phosphoinositol-3-kinase signaling, cell cycle regulation, metabolism, mitotic spindle regulation and DNA mismatch repair. These analyses suggest a classification of the disease that is not based on individual gene abnormalities but common cancer pathway activation events that ultimately determine outcome for patients with luminal-type disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-87. doi:10.1158/1538-7445.AM2011-LB-87