Abstract |
METHODS: PC samples spanning one patient's clinical course: diagnostic biopsies, pre- or post- enzalutamide metastatic biopsies, and rapid autopsy samples including a patient-derived xenograft (PDX) were analyzed by targeted exome sequencing followed by phylogenetic analysis. RESULTS: Left- and right-lobe primary PC tumors appeared to diverge, with the right acquiring additional shared mutations and striking differences in copy number alterations that later appeared in metastatic samples during the treatment course and at autopsy, whereas the left base tumor maintained a quiet copy number alteration landscape and partitioned into a dead-end node. RB1 loss, a common finding in advanced castration-resistant disease, was identified throughout mCRPC samples, but not in the primary tumor. Significantly, a truncal EGFR-activating mutation (R108K) was identified in the primary tumor and was also found to be maintained in the mCRPC samples and in a PDX model. Furthermore, the PDX model remained sensitive to the EGFR inhibitor erlotinib, despite the presence of both RB1 and BRCA2 losses. CONCLUSION: These findings indicate that truncal alterations identified in primary PC can drive advanced mCRPC, even in the presence of additional strong oncogenic drivers (ie, RB1 and BRCA2 loss), and suggest that earlier detection and targeting of these truncal alterations may be effective at halting disease progression.
|
Authors | David J Einstein, Seiji Arai, Carla Calagua, Fang Xie, Olga Voznesensky, Brian J Capaldo, Christina Luffman, Jonathan L Hecht, Steven P Balk, Adam G Sowalsky, Joshua W Russo |
Journal | JCO precision oncology
(JCO Precis Oncol)
Vol. 5
( 2021)
ISSN: 2473-4284 [Electronic] United States |
PMID | 34568716
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
|
Copyright | © 2021 by American Society of Clinical Oncology. |
Topics |
- Biopsy
- Carcinogenesis
- Humans
- Male
- Phylogeny
- Prostatic Neoplasms, Castration-Resistant
(genetics)
|