Oral Presentation 31st Lorne Cancer Conference 2019

The estrogen receptor positive subset is the dominant contributor to global deaths from breast cancer which now exceeds 500,000 deaths annually. The overall objectives of our research is to identify treatment-resistance drivers in ER⁺ breast cancer and to target their therapeutic vulnerabilities.  Our discovery approach is to use DNA, RNA and peptide sequencing techniques to identify resistance drivers that can be subjected to mechanistic studies and therapeutic modeling. As sources of material we have analyzed includes both primary tumors that have been treated with neoadjuvant endocrine therapy, metastatic specimens and patient derived xenografts.  These analysis have generated a number of new mechanistic hypotheses that relate resistance to endocrine agents to 1) specific defects in mismatch repair¹, 2) the generation of in-frame ESR1 gene fusion events², and 3) loss of the NF1 tumor suppressor gene³.  Furthermore, the immunosuppressive microenvironment has a role to play in aggressive luminal B disease and subsets of these tumors will be sensitive to immune checkpoint therapy (submitted).  Finally we are generating new proteogenomic tools that may provide better insights into the integrated effects of somatic mutations on the progression of ER+ disease as well as diagnosing therapeutic vulnerabilities⁴.

1. Haricharan, S., et al. Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer. Cancer Discov 7, 1168-1183 (2017).
2. Lei, J.T., et al. Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer. Cell Rep 24, 1434-1444 e1437 (2018).
3. Griffith, O.L., et al. The prognostic effects of somatic mutations in ER-positive breast cancer. Nat Commun 9, 3476 (2018).
4. Mertins, P., et al. Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534, 55-62 (2016).