Abstract
Background: While critical insights have been gained from evaluating the genomic landscape of metastatic prostate cancer, utilizing this information to inform personalized treatment is in its infancy. We performed a retrospective pilot study to assess the current impact of precision medicine for locally advanced and metastatic prostate adenocarcinoma and evaluate how genomic data could be harnessed to individualize treatment. Methods: Deep whole genome-sequencing was performed on 16 tumour-blood pairs from 13 prostate cancer patients; whole genome optical mapping was performed in a subset of 9 patients to further identify large structural variants. Tumour samples were derived from prostate, lymph nodes, bone and brain. Results: Most samples had acquired genomic alterations in multiple therapeutically relevant pathways, including DNA damage response (11/13 cases), PI3K (7/13), MAPK (10/13) and Wnt (9/13). Five patients had somatic copy number losses in genes that may indicate sensitivity to immunotherapy (LRP1B, CDK12, MLH1) and one patient had germline and somatic BRCA2 alterations. Conclusions: Most cases, whether primary or metastatic, harboured therapeutically relevant alterations, including those associated with PARP inhibitor sensitivity, immunotherapy sensitivity and resistance to androgen pathway targeting agents. The observed intra-patient heterogeneity and presence of genomic alterations in multiple growth pathways in individual cases suggests that a precision medicine model in prostate cancer needs to simultaneously incorporate multiple pathway-targeting agents. Our whole genome approach allowed for structural variant assessment in addition to the ability to rapidly reassess an individual’s molecular landscape as knowledge of relevant biomarkers evolve. This retrospective oncological assessment highlights the genomic complexity of prostate cancer and the potential impact of assessing genomic data for an individual at any stage of the disease.
Highlights
Worldwide, prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in men and a leading cause of cancer-related male deaths [1]
We focused on the study published by Wedge et al in 2018 for 112 patients (92 primary and 20 metastatic) with the metastases evenly distributed between HSPC and CRPC and biased towards lymph node metastasis (15/20) [8]
In addition to identifying annotated pathogenic and likely pathogenic alterations as well as the top genes affected by somatic copy number alterations (SCNA), we reviewed alterations involving potential PCa driver genes and non-coding events associated with prostate cancer
Summary
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in men and a leading cause of cancer-related male deaths [1]. Disease is potentially curable whereas eventual treatment resistance is an intractable problem in metastatic disease. In both early and advanced disease, escalation of treatment including combination therapies, such as androgen deprivation therapy (ADT). While critical insights have been gained from evaluating the genomic landscape of metastatic prostate cancer, utilizing this information to inform personalized treatment is in its infancy. Results: Most samples had acquired genomic alterations in multiple therapeutically relevant pathways, including DNA damage response (11/13 cases), PI3K (7/13), MAPK (10/13) and Wnt (9/13). Conclusions: Most cases, whether primary or metastatic, harboured therapeutically relevant alterations, including those associated with PARP
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