1. Nalley, Catlin

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Actionable alterations in metastatic or recurrent ovarian, fallopian tube, and peritoneal carcinomas across various histologic subtypes were identified using comprehensive genomic profiling via liquid biopsies, according to findings released during the Society of Gynecologic Oncology 2021 Virtual Annual Meeting.

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The abstract, "Comprehensive genomic profiling (CGP) via peripheral blood liquid biopsies identifies therapeutically relevant genomic alterations in tubo-ovarian and peritoneal cancer," was presented by Tiffany Lai, MD, an obstetrician-gynecologist at UCLA Health.


"Analysis of circulating tumor DNA extracted from peripheral blood liquid biopsies is a less-invasive alternative to traditional solid tumor tissue testing," the study authors noted. "In this study, we analyzed a large cohort of liquid biopsies collected from advanced tubo-ovarian and peritoneal cancer patients to determine the clinical utility and landscape of potentially actionable genomic alterations."


Through the analysis of liquid biopsies from advanced tubo-ovarian and peritoneal cancer patients, the researchers sought to identify potential actionable alterations and/or therapy resistance mechanisms.


"A subset of these patients also had matched tissue samples obtained at a different time point, which were compared to determine their concordance and identify differences related to treatment or disease evolution," said Lai.


Researchers performed liquid biopsy comprehensive genomic profiling using a "hybrid-capture based sequencing assay on peripheral blood interrogated short variant alterations, rearrangements, copy number gains, and microsatellite instability (MSI-High)."


A total of 718 patients were included in this study, 574 of whom received liquid biopsy analysis using a 70-gene testing platform (Cohort A) and 144 patients received the testing with the use of an updated 324-gene platform (Cohort B), according to Lai.


"Thirty-seven patients in Cohort B also had solid tissue comprehensive genomic profiling results available for comparison, which were analyzed on a platform that included the same 324 genes as in the expanded liquid biopsy panel," she explained.


The median age of included patients was 68 years. Among the cases of known histologic type, serous histology was the highest represented in this cohort (38%), Lai reported. Only 10 percent of patients did not have a reportable alteration detected by the liquid biopsy assay.


"Identified potentially actionable targets, other than BRCA, included NF1 (7%), PIK3CA (6%), KRAS (5%), ERBB2 (1%), BRAF (1%), and PALB2 (0.5%)," Lai noted. "Additionally, possibly targetable rearrangements were also detected in FGFR2 (n=4), RET (n=1), ROS1 (n=1), and ALK (n=1)."


The most frequent alterations were in TP53 (74%) and genes associated with clonal hematopoiesis including CHEK2 (22%) and ATM (14%), as well as DNMT3A and TET2 (Cohort B only), according to the study authors, who noted that "alterations in more than one of these genes co-occurred often in the same patient liquid biopsy sample."


"Of the 718 patients, 91, 12.7 percent, had at least one BRCA alteration identified in a liquid biopsy," Lai stated. "Thirty-six patients had an allelic fraction which suggested a possible germline mutation and 14 exhibited multiple BRCA alterations consistent with possible reversion events."


Six of the patients with multiple BRCA alterations received a PARP inhibitor prior to liquid biopsy collection. The treatment of the other eight patients was unknown or not provided, the study authors reported.


"Of the 37 paired samples, concordance was highest among short variants and gene rearrangements," noted Lai. "The positive percent agreement for BRCA alterations was 88 percent."


Of note, according to Lai, was that two of these discordant pairs had an additional BRCA alteration detected in the second test, which was consistent with the reversion mechanism.


"In conclusion, liquid biopsies from patients with tubo-ovarian and peritoneal cancers were able to detect BRCA alterations, as well as potential reversion mutations, which may impact clinical decision making," Lai noted. "Liquid comprehensive genomic profiling was also fairly concordant with tissue-based tests, which may identify therapeutic opportunities for FDA-approved or investigational drugs.


"There are limitations to the liquid comprehensive genomic profiling assay, which include the detection of copy number changes and the dependence of ctDNA yield on patient tumor burden," she continued. "Additionally, the impact of clonal hematopoiesis on assay findings remains uncertain. Further studies are indicated to define its utility in the care of women with tubo-ovarian and peritoneal cancers."


Catlin Nalley is a contributing writer.