Two‐point‐NGS analysis of cancer genes in cell‐free DNA of metastatic cancer patients

• Published in: Cancer medicine (Malden, MA) MA), 2020-03, Vol.9 (6), p.2052-2061
• Main Authors: Palmieri, Maria, Baldassarri, Margherita, Fava, Francesca, Fabbiani, Alessandra, Gelli, Elisa, Tita, Rossella, Torre, Pamela, Petrioli, Roberto, Hadijstilianou, Theodora, Galimberti, Daniela, Cinotti, Elisa, Bengala, Carmelo, Mandalà, Marco, Piu, Pietro, Miano, Salvatora Tindara, Martellucci, Ignazio, Vannini, Agnese, Pinto, Anna Maria, Mencarelli, Maria Antonietta, Marsili, Stefania, Renieri, Alessandra, Frullanti, Elisa
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; Biopsy; Cancer; cell‐free DNA; Child; Child, Preschool; Circulating Tumor DNA - blood; Circulating Tumor DNA - genetics; Clinical Cancer Research; Clonal Evolution; Cloning; Copy number; Deoxyribonucleic acid; Disease Progression; DNA; DNA Copy Number Variations; DNA Mutational Analysis; ErbB-2 protein; FDA approval; Feasibility Studies; Female; Fibroblast growth factor receptors; Follow-Up Studies; Gene frequency; Genetic counseling; High-Throughput Nucleotide Sequencing; Humans; Infant; liquid biopsy; Lung cancer; Male; Metastases; Metastasis; Middle Aged; Mutation; Neoplasms - blood; Neoplasms - diagnosis; Neoplasms - genetics; Neoplasms - therapy; next‐generation sequencing; Oncology; Original Research; Ovarian cancer; p53 Protein; Patients; Plasma; Point Mutation; Precision medicine; Precision Medicine - methods; Prospective Studies; Solid tumors; Statistical analysis; Studies; Survival analysis; targeted‐therapy; Tumors; Variation; Young Adult
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.2782

Background Although the efficacy of molecularly target agents in vitro, their use in routine setting is limited mainly to the use of anti‐HER2 and antiEGFR agents in vivo. Moreover, core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. Methods We assessed the status of a large panel of cancer driver genes by cell‐free DNA (cfDNA) analysis in a cohort of 68 patients with 13 different solid tumors at disease progression. Whenever possible, a second cfDNA analysis was performed after a mean of 2.5 months, in order to confirm the identified clone(s) and to check the correlation with clinical evolution. Results The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. A mean of 1.4 mutated genes (range 1‐3) for each tumor was found. Point mutations in TP53, PIK3CA, and KRAS and copy number variations in FGFR3 were the gene alterations more commonly observed, with a rate of 48%, 20%, 16%, and 20%, respectively. Two‐points‐Next‐Generation Sequencing (NGS) analysis demonstrated statistically significant correlation between allele frequency variation and clinical outcome (P = .026). Conclusions Irrespective of the primary tumor mutational burden, few mutated genes are present at disease progression. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two‐point‐NGS analysis of cancer driver genes could be an efficacy tool for precision oncology. Core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. In this study, we performed a first and whenever possible, a second NGS liquid biopsy analysis after a mean of 2.5 months in advanced cancer patients. The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two point‐NGS analysis of cancer driver genes could be an efficacy tool for precision oncology.