Precision Medicine Approaches to Hormone-Driven Cancer

Abstract

Cancers of the breast and prostate are primarily driven by sex hormone signaling which has been targeted clinically with considerable success. The genomic and transcriptomic landscape of these tumors has been thoroughly elucidated and major advances have been made in non-invasive techniques, however, the full potential of these advances is yet to be realized in the clinic. Two areas of our focus, with such opportunities to improve patient outcomes in hormone-driven cancers are: 1) Non-invasive tracking of metastatic breast cancer (mBC) evolution for precision medicine; 2) Non-invasive early detection of prostate cancer (PCa). mBC is an ultimately treatment-resistant, lethal disease characterized by intra-patient molecular heterogeneity including genomic alterations driving resistance to therapy directed at estrogen receptor (ER; ESR1) signaling (endocrine therapy). Tumor biopsies are not routinely available in this setting. We sought to determine whether circulating tumor cells (CTCs) recapitulate the genomic landscape of bulk tumor tissue. In project 1, we isolated and genomically profiled individual CTCs from 12 patients with mBC who had concurrent whole exome sequencing of their metastatic biopsy bulk tissue. In 76 individual and pooled informative CTCs, we observed 85% concordance in at least one driver somatic mutation/copy number alteration (CNA) between CTCs and matched tissue metastases, with CTC profiling identifying diverse intra- and inter-patient molecular mechanisms. For example, in one patient, we observed CTCs that were either wild type for ESR1 (n = 5/32), harbored the known activating ESR1 p.Y537S mutation (n = 26/32) also present in tissue, or harbored a novel ESR1 p.A569S mutation not observed in tissue (n = 1/32), which was demonstrated to be modestly activating in vitro. Our results demonstrate the feasibility and potential clinical utility of comprehensive profiling of archived CTCs. Despite advances in biomarker development, early detection of aggressive PCa remains challenging. We previously developed a clinical-grade laboratory-developed test—MiProstate Score (MiPS)—for individualized aggressive PCa risk prediction. MiPS combines serum PSA with transcription-mediated amplification (TMA)-quantified expression of the gene-fusion TMPRSS2:ERG and the lncRNA PCA3 from whole urine obtained after a digital rectal exam (DRE). To improve MiPS, in our second project, we describe the pre-clinical development and validation of a post-DRE whole urine targeted RNA NGS assay (NGS-MiPS) assessing ~90 PCa candidate transcriptomic biomarkers, including: TMPRSS2:ERG.T1E4 and PCA3, additional common PCa gene fusion isoforms, mRNAs, lncRNAs, and expressed mutations. NGS-MiPS showed high analytic validity and was able to detect expressed germline risk HOXB13 and somatic driver SPOP mutations. In an extreme design cohort (benign or Grade Group (GG) 1 vs. GG 3-5 cancer on biopsy) NGS-MiPS showed expected differences in the levels of TMPRSS2:ERG.T1E4, PCA3, and additional biomarkers, between benign/GG 1 vs. GG 3-5 PCa. A machine learning approach trained on a subset of the extreme design cohort (n=73) generated a 15-transcript model that outperformed derived MiPS and serum PSA models in predicting biopsy outcome in two validation cohorts: 1. A held-out set from the extreme design cohort (n=36); and 2. A separate PCa active surveillance cohort (n=45). These results support the potential utility and continued development of our novel urine-based targeted RNA NGS assay to improve aggressive PCa early detection. Leveraging recent technological advances—CTC isolation, NGS, liquid biopsy techniques—as well as knowledge of the genomic landscape of hormone-driven cancers, we demonstrate feasibility of non-invasive precision medicine in mBC and PCa with potential clinical utility.