Abstract 3838: Differential expression of Notch1 in lung, ovarian and breast cancers

Abstract

Abstract Targeting the Notch signaling pathway for cancer treatment is currently the subject of early clinical trials. However, treatment-related toxicities, particularly gastrointestinal adverse events, have limited clinical development of this class of agents. The development of efficacy biomarkers to gamma-secretase inhibitors and antibodies to Notch ligands and receptors could speed clinical testing. Mutations in Notch1, a dominant Notch receptor, are rare in human solid tumors, and clinical activity has not been observed in patients with tumors bearing Notch1 activating mutations, including T-cell acute lymphoblastic leukemia from available clinical data. Identification of tumors with abundant target expression and/or active Notch signaling status characteristic of Notch intracellular domain (NICD) expression by immunohistochemistry may have clinical utility. All levels of tumor Notch1 expression comprised of low, moderate and high detected by immunohistochemistry and quantitated by digital imaging technology were observed in 52% (34/66) of lung cancers, 51% (35/68) of ovarian cancers, and 11% (7/63) of breast cancers (lung or ovary vs. breast, P<0.0001 by 2-sided Fisher Exact Test). Notch1 was expressed at high levels in 20% of lung cancers including sarcoma, neuroendocrine, small cell and undifferentiated carcinomas, as well as adenocarcinoma and squamous cell carcinomas. High expression of Notch1 was observed in 9% of ovarian tumors including undifferentiated carcinoma, serous adenocarcinoma, and endometrioid adenocarcinoma. In breast cancer, it was noted in one case of infiltrating ductal carcinoma with triple-negative phenotype. Expression of high-level Notch1 varies in lung cancer vs. ovarian cancer vs. breast cancer (P=0.002 by Chi-square statistic), and was frequently associated with NICD expression. Notch1 was not significantly associated with estrogen receptor, progesterone receptor or HER2 status in breast cancer. These data suggest that the frequency of all levels of Notch1 expression is significantly higher in lung cancer and ovarian cancer than breast cancer; and high-level Notch1 is more frequent in lung cancer than in ovarian cancer, and, likewise, more frequent in ovarian cancer than in breast cancer. For the first time, expression of Notch1/NICD has been identified in undifferentiated carcinomas. The findings may provide useful information for the rational design of Notch inhibitor clinical trials. Citation Format: Dat Nguyen, Larry Rubinstein, Mark E. Sherman, Joseph E. Tomaszewski, Naoko Takebe, Percy Ivy, James H. Doroshow, Sherry X. Yang. Differential expression of Notch1 in lung, ovarian and breast cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3838. doi:10.1158/1538-7445.AM2014-3838