Abstract 77P
Background
Partner and Localizer of BRCA2 (PALB2) is a nuclear protein that localizes to sites of DNA double-strand breaks and interacts with BRCA1 and BRCA2 to promote DNA repair. PALB2 germline mutations are associated with an increased risk of hereditary cancers. PALB2 somatic variants have been found in various cancers; however, their prevalence, functional impact and therapeutic implications in cancers remains largely unknown.
Methods
Next-generation sequencing (NGS) data from patients (pts) with advanced cancers treated at MD Anderson Cancer Center were reviewed to identify tumors with PALB2 variants and co-occurring genomic alterations. Demographics, histopathology, and treatment response data were collected through retrospective chart review. The intervar in-silico tool was used to classify PALB2 variant pathogenicity.
Results
NGS data from 13,599 pts identified PALB2 variants in 219 (∼1.6%) pts, comparable to 2.1% of PALB2 alterations in the TCGA PanCancer database. Of these 219 pts, PALB2 variants were annotated as follows: 44 (20%) as pathogenic or likely pathogenic, 88 (40%) as benign or likely benign, 78 (36%) as variants of unknown significance (VUS) and 9 (4%) as indeterminate. 501 unique co-occurring mutations were identified, including TP53 (83%), LRP1B (38%), PIK3CA (34%), NF1 (32%) and MLL2 (30%). The most common cancers with PALB2 alterations were cholangiocarcinoma (15%), breast (11%), melanoma (10%), colon (10%) and non-small cell lung cancer (8%). Of 31 pts with advanced cholangiocarcinoma and PALB2 alterations, 2 had germline PALB2 mutations. 22/31 (71%) received platinum-based therapy and had evaluable response data; 9/22 (41%) pts achieved radiological partial response (PR), 1/22 (5%) had stable disease (SD), 12/22 (55%) had progressive disease, for a clinical benefit rate (PR+SD) of 45.5% with mean therapy duration of 137 days (range 42- 476).
Conclusions
PALB2 variants were detected in different cancers, including cholangiocarcinoma. Patients with advanced cholangiocarcinoma and PALB2 alterations may derive greater benefit from platinum-based therapy versus historical controls. PALB2 alterations warrant further investigation as predictive biomarkers of response to platinum-based therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
P.G. Pilie: Licensing/Royalties, Biomarker patent pending: MD Anderson Cancer Center. M. Javle: Advisory/Consultancy, Non-remunerated activity/ies: Incyte; Advisory/Consultancy: Mundi; Advisory/Consultancy: Oncosil; Advisory/Consultancy, Non-remunerated activity/ies: QED Therapeutics; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): BriGene; Research grant/Funding (institution): Serono; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Pieris Pharmaceutical; Research grant/Funding (institution): Rafael Pharmaceuticals; Research grant/Funding (institution): Seattle Genetics. J. Rodon: Advisory/Consultancy: Bayer; Advisory/Consultancy: Certera; Advisory/Consultancy: Ellipses Pharma; Advisory/Consultancy: Ionctura; Advisory/Consultancy: Kelun Pharmaceuticals; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Peptomyc; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche/ Genentech; Advisory/Consultancy: Spectrum Pharmaceuticals; Research grant/Funding (self): Bayer; Research grant/Funding (self): Novartis. K.R. Mills Shaw: Advisory/Consultancy: Guidepoint Global; Research grant/Funding (institution): Guardant Health; Research grant/Funding (institution): Philips Healthcare; Research grant/Funding (institution): Tempus. F. Meric-Bernstam: Advisory/Consultancy: Aduro Biotech; Advisory/Consultancy: DebioPharm; Advisory/Consultancy: eFFECTOR Therapeutics; Advisory/Consultancy: F. Hoffman-LaRoch; Advisory/Consultancy: Genentech; Advisory/Consultancy: IBM Watson Health; Advisory/Consultancy: Jackson Laboratory; Advisory/Consultancy: Kolon Life Science; Advisory/Consultancy: Origimed; Advisory/Consultancy: PACT Pharma; Advisory/Consultancy: Parexel International; Advisory/Consultancy: Pfizer Inc.; Advisory/Consultancy: Samsung Bioepis; Advisory/Consultancy: Seattle Genetics Inc.; Advisory/Consultancy: Tyra Biosciences; Advisory/Consultancy: Xencor; Advisory/Consultancy: Zymeworks; Advisory/Consultancy: Immunomedics; Advisory/Consultancy: Inflection Biosciences; Advisory/Consultancy: Meersana Therapeutics; Advisory/Consultancy: Puma Biotechnology inc.; Advisory/Consultancy: Seattle Genetics Inc.; Advisory/Consultancy: Silverback Therapeutics; Advisory/Consultancy: Spectrum Pharmaceuticals; Honoraria (self): Chugai Biopharmaceuticals; Honoraria (self): Mayo Clinic; Honoraria (self): Rutgers Cancer Institute of New Jersey; Travel/Accommodation/Expenses: Beth Israel Deaconess Medical Center. T.A. Yap: Licensing/Royalties, Intellectual property of IACS-010759: MD Anderson Cancer Center; Advisory/Consultancy: Almac; Advisory/Consultancy: Aduro; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Atrin Pharmaceuticals; Advisory/Consultancy: Axiom; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Calithera; Advisory/Consultancy, Research grant/Funding (institution): Clovis; Advisory/Consultancy: Cybrexa; Advisory/Consultancy, Research grant/Funding (institution): EMD Serono; Advisory/Consultancy, Research grant/Funding (institution): F-star; Advisory/Consultancy: Guidepoint; Advisory/Consultancy: Ignyta; Advisory/Consultancy: I-mab; Advisory/Consultancy: Jansen; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Repare; Advisory/Consultancy: Roche; Advisory/Consultancy: Rubius; Advisory/Consultancy: Schrodinger; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy: Varian; Advisory/Consultancy: Zains Labs; Research grant/Funding (institution): Atrios; Research grant/Funding (institution): Constellation; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Forbius. All other authors have declared no conflicts of interest.