Abstract P6-09-47: The development of personalized diagnostic tests and therapeutic strategies in breast cancer

Abstract

Abstract Despite some improvement in the overall survival rates of breast cancer, it remains as a leading cause of cancer-related deaths in women. Currently, we are unable to accurately predict patients' response to therapies and their long-term outcome. We developed and patented a 275-gene signature based on in silico meta-analysis of global transcriptome profiles (approximately 10,000 cases) that can predict which patients suffer from aggressive disease and succumb to their disease within 5 years of diagnosis. This test, the integrated Breast Cancer Recurrence (iBCR) score outperformed every clinicopathological indicator available in three independent, large cohorts of breast cancer. The iBCR can also predict the likelihood of response to standard treatments and which emerging targeted therapies should be added to an individual's treatment regime to improve outcomes. In addition, 21 of the genes in this signature are novel potential drug targets that have not previously been described in aggressive breast tumours. We performed a pilot study using the NanoString nCounter Dx platform to measure the expression of the top 125 genes within the signature in a cohort of 48 patients. We have validated with 100% accuracy the prognostic power of the iBCR in the Queensland Follow Up (QFU) cohort with 25 years of follow up (p<0.0001), irrespective of clinicopathological features. Our pilot study using the Nanostring platform successfully counted mRNA molecules from samples that averaged 26.8 years of age (range 24 – 29 years), with an average RNA Integrity (RIN) score of 2.4. Future work will expand this test to the full 275-gene set across 500 patients from the QFU cohort. In vitro siRNA screening of the 21 novel genes revealed that at least 10 of these genes are required for breast cancer cell survival. We have started validation of the top 4 hits and these studies confirm the requirement of these genes in breast cancer progression. These data will pave the way towards the study of these genes as new drug targets. Collectively, our test addresses the significant issue of heterogeneous responses to breast cancer treatment. The iBCR platform aims to improve both patients' clinical outcome and quality of life by directing more appropriate treatment with greater likelihood of success, and preventing overtreatment for those with a less aggressive tumor type. Citation Format: Kutasovic JR, Rozali E, Miranda M, Lakhani SR, Al-Ejeh F. The development of personalized diagnostic tests and therapeutic strategies in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-47.