4MO - Multi-focal genomic dissection of synchronous primary and metastatic tissue from de novo metastatic prostate cancer

Background

De novo metastatic castration-sensitive prostate cancer (mCSPC) is highly aggressive, but the lack of routine tumour tissue in this setting hinders genomic stratification and jeopardizes precision oncology efforts. Accurate molecular profiling at diagnosis is imperative for genomics-informed risk stratification and biomarker-guided treatment. Currently, it is unclear the extent that intrapatient heterogeneity impacts clinical cancer genotyping.

Methods

We performed genomic profiling of 607 synchronous primary foci, metastatic lesions, and cell-free DNA from a rare clinical trial cohort of 43 de novo mCSPC patients who underwent radical prostatectomy at diagnosis. Surgery is not currently standard practice in this disease setting. All samples were subjected to targeted DNA sequencing using a bespoke prostate cancer-specific panel and/or whole-exome sequencing.

Results

Sequencing-derived tissue tumour fraction was heterogeneous and low across same-patient foci in ∼20% of patients. In samples with high tumour fraction, the genomic landscape of mCSPC closely resembled metastatic treatment-resistant prostate cancer. In same-patient samples, intra-prostate heterogeneity in mutation, copy number, and whole-genome duplication status was pervasive. Phylogenetic modelling demonstrated additional complexity in several patients driven by polyclonal metastatic seeding from the reservoir of primary populations. While the metastatic clones were often identified in the primary site, frequent discordance between select primary foci and synchronous metastases in clinically-relevant genes, plus highly variable per-sample tumour fraction, resulted in false genotyping of the dominant disease, when relying on a single tissue focus. However, in silico modelling demonstrated that analysis of multiple prostate diagnostic biopsy cores can rescue misassigned somatic genotypes.

Conclusions

Our work reveals extensive polyclonality that undermines standard precision genotyping in de novo mCSPC, nominates practical strategies for improved biomarker profiling and genomics-informed risk stratification, and offers deep biological insight into the relationship between primary and untreated metastases.

Clinical trial identification

Presenting data collected during the LoMP1/2 clinical trials: NCT02138721 and NCT03655886, respectively.

Legal entity responsible for the study

The authors.

Funding

Canadian Institutes of Health Research.

Disclosure

E. Kwan: Financial Interests, Personal, Other, Advisory board, Sponsor/funding (Travel, Accommodations, Expenses), Honoraria, Research grant (institutional): Astellas Pharma; Financial Interests, Personal, Other, Advisory board, Honoraria: Janssen; Financial Interests, Personal, Other, Advisory board, sponsor/funding (Travel, Accommodations, Expenses), Honoraria: Ipsen; Financial Interests, Personal, Sponsor/Funding, Travel, Accommodations, Expenses: Pfizer, Roche; Financial Interests, Personal, Other, Honoraria: Research Review; Financial Interests, Personal, Research Grant: AstraZeneca. M. Annala: Financial Interests, Personal, Ownership Interest: Fluivia. A.W. Wyatt: Financial Interests, Personal, Advisory Board: AstraZeneca, Astellas, Janssen, Merck; Financial Interests, Institutional, Research Grant: ESSA Pharma. All other authors have declared no conflicts of interest.