ctDNA Genomic Profiling Can Guide Targeted Therapy in Advanced Cancer

Findings from a prospective study suggest that circulating tumor DNA sequencing with a large panel may efficiently identify actionable alterations in patients with advanced solid tumors.

Genomic profiling of circulating tumor DNA (ctDNA) with a large panel appeared feasible in a routine setting and helped to obtain relevant molecular information that could inform strategies with targeted therapies for patients with metastatic solid tumors, according to findings from the prospective PRISM study published in Annals of Oncology.

"ctDNA sequencing with a large panel is an efficient approach to identify actionable alterations in patients with advanced cancer," according to the authors of a study published in Annals of Oncology.

"ctDNA sequencing with a large panel is an efficient approach to identify actionable alterations in patients with advanced cancer," according to the authors of a study published in Annals of Oncology.

Following ctDNA sequencing and subsequent multidisciplinary tumor board recommendations of matched therapies for 107 assessable patients, 4 achieved complete responses (CRs), 35 had partial responses (PRs), 27 had stable disease, and 41 experienced progressive disease as a best overall response. Additionally, 54 patients underwent next-generation sequencing of tumor tissue. ctDNA-identified alterations were present in 3 complete responders, 20 partial responders, 10 of those who had stable disease, and 12 of those who had progressive disease.

The median follow-up was 9 months.

The median progression-free survival (PFS) and overall survival (OS) among evaluable patients, respectively, was 4.7 months (95% CI, 2.7-6.7) and 8.3 months (95% CI, 4.7-11.9). Additionally, 475 patients did not receive their recommended treatmens due to performance status decline or death ( n =123), no disease progression (n = 79), and referral clinician’s choice of another treatment (n = 69).

Investigators detected at least 1 targetable genetic aberration in 1059 patients, which included a total of 1825 actionable alterations. The detected aberrations most commonly included mutations of genes involved in the DNA damage repair response pathway (18%), high tumor mutational burden (TMB-H) of more than 16 mutations/Mb (13%), PIK3CA mutations (8%), and ERBB family gene mutations or amplifications (7%).

“ctDNA sequencing with a large panel is an efficient approach to identify actionable alterations in patients with advanced cancer,” the study authors stated. “Patients who may benefit from such molecular profiling should be carefully selected to improve the proportion of them who may effectively receive a matched therapy.”

Investigators of this study performed genomic analysis on plasma samples taken from patients with solid malignant neoplasms using the FoundationOne Liquid CDx Assay, which evaluated 324 cancer-related genes, TMB, and microsatellite instability (MSI) status.

Calculation of TMB involved counting somatic variants with a variant allele frequency of at least 5% in tissue or at least 0.5% in ctDNA. Investigators determined MSI scores using 95 repetitive loci and principal component analysis with tissue or using more than 1800 repetitive loci in plasma.

A multidisciplinary tumor board convened weekly to review and discuss individual genomic reports; the board included medical oncologists, pathologists, molecular geneticists, bio-informaticians, and study coordinators. The board defined actionable targets according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) tiers and provided matched therapies where possible.

The patient population for this study included those enrolled in the ongoing phase 1 precision medicine Gustave Roussy Cancer Profiling or STING study (NCT04932525). Patients with a locally advanced, unresectable, or metastatic solid tumor were eligible to enroll on the trial.

Of 1772 patients, the median age was 63 years (interquartile range, 54-71). Additionally, 86% of patients had an ECOG performance status of 0 or 1 at the time of ctDNA profiling.

The most common tumor types included non–small cell lung cancer (16%), prostate cancer (11%), colorectal cancer (10%), breast cancer (10%), and pancreatic cancer (7%). Moreover, most patients received 0 (28.2%) or 1 (24.9%) previous lines of systemic therapy at time of ctDNA profiling.

Overall, 93.6% of patients had evaluable results for ctDNA profiling. Following exclusion of genes related to the Clonal Hematopoiesis of Indeterminate Potential, the 5 more common cancer-related variations included TP53 (16.25%), ATM (8.21%), APC (5.90%), KRAS (4.20%), and PIK3CA (3.25%).

Investigators noted that 1.1% of patients had MSI-high tumors and that 8.3% were TMB-H blood with a cut-off of 16 mutations/Mb.

Of the 1825 detected genetic aberrations, 31% were classified as ESCAT tier I or II, 24% were tier IIIA, 6% were tier IIIB, and 39% were tier IV.

The multidisciplinary tumor board recommend matched therapies for 597 patients, carrying out 819 total recommendations. This included enrollment in genotype-matched clinical trials (n = 639), off-label or compassionate use of genotype-matched agents (n = 81), genotype-matched approved drugs for the indication (n = 51), and genotype-matched agents based on performance status (n = 49) or other reasons (n = 50).

The remaining 462 patients did not receive any recommendations for matched therapy because of lack of availability of clinical trials (n = 421), they were already receiving the genotype-matched treatment (n = 169), worsening performance statuses (n = 49), and another reason (n = 50).

Reference

Bayle A, Belcaid L, Aldea M, et al. Clinical utility of circulating tumor DNA sequencing with a large panel: a National Center for Precision Medicine (PRISM) study. Ann Oncol. 2023;34(4):389-396. doi:10.1016/j.annonc.2023.01.008

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