Abstract
PurposePatients with advanced/relapsed rare cancers have few treatment options. Analysis of circulating tumor DNA in plasma may identify actionable genomic biomarkers using a non-invasive approach.Patients and MethodsRare cancer patients underwent prospective plasma-based NGS testing. Tissue NGS to test concordance was also conducted. Plasma DNA alterations were assessed for incidence, functional impact, therapeutic implications, correlation to survival, and comparison with tissue NGS.ResultsNinety-eight patients were analyzed. Diseases included soft-tissue sarcoma, ovarian carcinoma, and others. Mean turn-around-time for results was 9.5 days. Seventy-six patients had detectable gene alterations in plasma, with a median of 2.8 alterations/patient. Sixty patients had a likely pathogenic alteration. Five received matched-therapy based on plasma NGS results. Two developed known resistance mutations while on targeted therapy. Patients with an alteration having VAF ≥5% had a significantly shorter survival compared to those of lower VAF. Tissue NGS results from eleven of 22 patients showed complete or partial concordance with plasma NGS.ConclusionPlasma NGS testing is less invasive and capable of identifying alterations in advanced rare cancers in a clinically meaningful timeframe. It should be further studied as a prospective enrollment assay in interventional studies for patients with rare advanced stage cancers.Clinical Registration[https://www.umin.ac.jp/ctr/index-j.htm], identifier UMIN000034394.
Highlights
Multiplexed tissue-based genotyping has become standard of care in the diagnostic algorithm of patients with metastatic cancers
Plasma next generation sequencing (NGS) tests were performed on patients 16 years or older with advanced/metastatic rare solid tumors who matched the criteria for the MASTER KEY Project [4] and who provided
The following levels of evidence were assigned to each gene alteration: level 1A, a Pharmaceuticals and Medical Devices Agency (PMDA)-approved biomarker for the tumor type; 1B, a United States FDA-approved biomarker for the tumor type or a biomarker verified by a prospective molecularly driven clinical trial; 2A, a biomarker identified by subgroup analysis in a prospective clinical trial; 2B, an approved biomarker for a different tumor type or a biomarker with evidence supporting its clinical utility; 3A, a biomarker with evidence of proof-of-concept in at least one case report; 3B, a biomarker with evidence obtained from in vitro/in vivo experiments; and 4, other gene mutations in cancer
Summary
Multiplexed tissue-based genotyping has become standard of care in the diagnostic algorithm of patients with metastatic cancers. Repeated tissue biopsies are not feasible in many of these patients, especially for those with rare cancers, because of anatomical difficulties, existing comorbidities and/or clinical deterioration that necessitates rapid initiation of medical treatment. Patients with rare cancers have few treatment options due to a limited understanding of molecular characteristics and lack of clinical trials. Some ctDNA assays have demonstrated clinical validity and utility in certain types of advanced common cancers. The recent advent of ctDNA assays has drastically altered the diagnostic paradigm in non-small cell lung cancer [1, 2]. There is insufficient evidence of clinical validity and utility for ctDNA assays in advanced rare cancers [3]
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