In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e17596-e17596
Abstract:
e17596 Background: Metastatic castration-sensitive prostate cancer (mCSPC) eventually progresses to metastatic castration-resistant prostate cancer (mCRPC), which has few treatment options and carries a poor prognosis. We hypothesize that there are specific genomic alterations (GAs) associated with the progression from mCSPC to mCRPC. Methods: Patients (Pts) with mCSPC and mCRPC undergoing next-generation sequencing of cell-free DNA by a CLIA certified lab (G360, Guardant Health Inc., Redwood City, CA) as a part of routine care were retrospectively identified. Principal components analysis, an unsupervised ML algorithm, was used for data exploration and visualization. A combination of feature selection and supervised machine learning classification algorithms were used to identify genes associated with mCRPC. Gene Ontology enrichment analysis was used to identify pathways enriched for mCRPC-associated GAs. Patterns of mCRPC-associated GAs at a gene- and pathway-level were identified by Bayesian networks fitted using an exact structure learning algorithm. Results: 154 Pts with mCSPC and 187 Pts with mCRPC were included. A set of 16 GAs that robustly distinguished mCRPC from mCSPC (PPV = 94%, specificity = 91%) using supervised machine learning algorithms. These GAs, primarily amplifications, corresponded to AR, MAPK signaling, PI3K signaling, G1/S cell cycle, and receptor tyrosine kinases (RTKs). Positive statistical dependencies were observed between genes in these pathways. At a pathway-level, the presence of G1/S GAs in mCRPC samples increased the likelihood of harboring GAs in RTK, MAPK, and PI3K signaling. Limitations: The retrospective nature of our study means that unknown exposures could act as confounding variables, however this is representative of real-world clinical settings. Although the strength of this study is inclusion of clinically annotated patient samples, the limitation is that patients with mCSPC and mCRPC were unmatched. Conclusions: These results provide evidence that progression from mCSPC to mCRPC is associated with stereotyped concomitant gain-of-function in the RTK, PI3K, MAPK, and G1/S pathways in addition to AR. Upon external validation, these hypothesis generating data may warrant further investigation into combinatorial therapies that target these pathways.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2020.38.15_suppl.e17596
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2020
detail.hit.zdb_id:
2005181-5
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