Unraveling the genomic underpinnings of advanced prostate cancer

Metastatic hormone-sensitive prostate cancer (mHSPC) is a highly heterogeneous malignancy with varied outcomes observed across patients. Genomic features have been associated with differential clinical characteristics and treatment outcomes, but it is not yet clear to what degree these features should guide clinical decision-making in mHSPC. Precision medicine in mHSPC care is today confounded by the multifocality and molecular heterogeneity often seen in PCa. In this thesis, we aim to resolve the genomic drivers of mHSPC disease and dissect the tumor heterogeneity with an ultimate goal of enhancing the integration of genomics in cancer practice. In a first phase, a thorough review of the literature to summarize the current understanding of genomic alterations in mHSPC in terms of both the prevalence of alterations involving specific pathways and the relationship of these alterations with clinical features was performed. This study showed that genomic alterations may have prognostic and predictive implications. Another key finding of this study was that genomic data from mHSPC patients varied greatly in terms of the clinical states of patients and the source of material, and that the current study designs, in which only one sample from the resected tumor is sequenced, are not optimized for the study of multifocality. In a second phase, we assessed the prognostic and predictive ability of a genomic signature to risk stratify outcomes for patients with oligometastatic PCa recurrences, by pooling the only two prospective randomized trials, STOMP and ORIOLE, of metastasis-directed therapy (MDT) versus observation in oligometastatic HSPC. In this study, we observed a high-risk mutational signature consisting of pathogenic alterations in ATM, BRCA1/2, Rb1 and TP53 that is highly prognostic and predictive in this patient population suggesting that future trials should integrate these biomarkers to better understand their role in patient selection. Next, we investigated whether lung involvement should be considered as a proxy of more indolent disease in patients with presenting with lung recurrences. To address this question, we determined the genomic alterations that characterize lung-recurrent mHSPC (i.e. patients with lung metastases after curative-intent treatment for PCa) through multi-region profiling of both primary and metastatic lung samples. We found that the presence of lung recurrences associates with clinical and genomic indolence, proposing the site of metastatic recurrence as stratification factor for future predictive models in mHPSC. A second aim was to develop a practical strategy to reliably genotype patients with metastases at first diagnosis of prostate cancer, which is known as de novo mHSPC. First, we explored the extent to which a single diagnostic biopsy captures the metastatic genotype in synchronous metastatic tissue/ctDNA. Clinically relevant alterations were often missed in these single-biopsy approaches due to the heterogeneity within the primary and metastases. Exploration of the relationship between primary and metastatic tumors revealed little genomic evolution in lung-recurrent mHSPC patients, whereas we found extensive polyclonal seeding in a significant proportion of the de novo mHSPC patients