“…However, the only randomized phase 2 study failed to show a benefit of the MMT strategy, with a median progression-free survival (PFS) of 2.3 months in the experimental group versus 2.0 months in the control group (p = 0.41) [25]. Hypotheses to explain these results could be spatial and temporal intratumor heterogeneity, or molecular differences between primary tumor and metastases that occur under multiple selective pressures (treatments, immune system) [26,27]. Considering this heterogeneity, it appears fundamental to determine a "real-time" comprehensive genomic profile before therapy initiation, ensuring the best therapy choice.…”
Background: Cancer therapies targeting actionable molecular alterations (AMA) have developed, but the clinical routine impact of high-throughput molecular profiling remains unclear. We present a monocentric experience of molecular profiling based on liquid biopsy in patients with cancer. Methods: Patients included had solid cancer and underwent cfDNA genomic profiling with FoudationOne Liquid CDx (F1LCDx) test, analyzing 324 genes. Primary endpoint was to describe patients with an AMA for whom clinical decisions were impacted by F1LCDx test results. Results: 191 patients were included, mostly with lung cancer (46%). An AMA was found in 52%. The most common molecular alterations were: TP53 (52%), KRAS (14%) and DNMT3 (11%). The most common AMA were: CHEK2 (10%), PIK3CA (9%), ATM (7%). There was no difference in progression-free survival (2.66 months vs. 3.81 months, p = 0.17), overall survival (5.3 months vs. 7.1 months, p = 0.64), or PFS2/PFS1 ratio ≥ 1.3 (20% vs. 24%, p = 0.72) between patients receiving a molecularly matched therapy (MMT) or a non-MMT, respectively. Patients with a MMT had an overall response rate of 19% and a disease control of 32%. Conclusions: Routine cfDNA molecular profiling is feasible and can lead to the access of targeted therapies. However, no notable benefit in patient’s outcomes was shown in this unselected pan-cancer study.
“…However, the only randomized phase 2 study failed to show a benefit of the MMT strategy, with a median progression-free survival (PFS) of 2.3 months in the experimental group versus 2.0 months in the control group (p = 0.41) [25]. Hypotheses to explain these results could be spatial and temporal intratumor heterogeneity, or molecular differences between primary tumor and metastases that occur under multiple selective pressures (treatments, immune system) [26,27]. Considering this heterogeneity, it appears fundamental to determine a "real-time" comprehensive genomic profile before therapy initiation, ensuring the best therapy choice.…”
Background: Cancer therapies targeting actionable molecular alterations (AMA) have developed, but the clinical routine impact of high-throughput molecular profiling remains unclear. We present a monocentric experience of molecular profiling based on liquid biopsy in patients with cancer. Methods: Patients included had solid cancer and underwent cfDNA genomic profiling with FoudationOne Liquid CDx (F1LCDx) test, analyzing 324 genes. Primary endpoint was to describe patients with an AMA for whom clinical decisions were impacted by F1LCDx test results. Results: 191 patients were included, mostly with lung cancer (46%). An AMA was found in 52%. The most common molecular alterations were: TP53 (52%), KRAS (14%) and DNMT3 (11%). The most common AMA were: CHEK2 (10%), PIK3CA (9%), ATM (7%). There was no difference in progression-free survival (2.66 months vs. 3.81 months, p = 0.17), overall survival (5.3 months vs. 7.1 months, p = 0.64), or PFS2/PFS1 ratio ≥ 1.3 (20% vs. 24%, p = 0.72) between patients receiving a molecularly matched therapy (MMT) or a non-MMT, respectively. Patients with a MMT had an overall response rate of 19% and a disease control of 32%. Conclusions: Routine cfDNA molecular profiling is feasible and can lead to the access of targeted therapies. However, no notable benefit in patient’s outcomes was shown in this unselected pan-cancer study.
“…1f-h). Recurrent BMassociated ampli cations on chr5p and 8q were also previously identi ed in a small cohort of 7 primary lung cancer and BM pairs pro led by WES 11 .…”
Section: Nsclc-bm Harbor More Copy Number Alterations Compared To Mat...mentioning
Brain metastases (BM) severely impact the prognosis and quality of life of patients with non-small cell lung cancer (NSCLC). To identify targetable drivers of NSCLC-BM, we profiled somatic copy number alterations (SCNAs) in 51 matched pairs of primary NSCLC and BM samples from 33 patients with lung adenocarcinoma (LUAD) and 18 patients with lung squamous cell carcinoma (LUSC). BM consistently had a higher burden of SCNAs compared to the matched primary tumors, and SCNAs were typically homogeneously distributed within BM, as revealed by multi-region SCNA profiling in 15 BM samples, suggesting that BM do not undergo extensive evolution once formed. By comparing focal SCNAs in matched NSCLC-BM pairs, we identified BM driving alterations affecting multiple cancer genes, including several targetable genes such as CDK12, DDR2, ERBB2, and NTRK1, which we validated in an independent cohort of 84 BM samples. We explored the metastatic potential of CDK12 and DDR2 in vitro and in vivo and found that overexpression of either gene alone in murine lung cancer cells causes the induction of key genes involved in epithelial-mesenchymal transition. Finally, we performed whole-exome sequencing of 40 NSCLC-BM pairs and identified BM driver mutations in multiple cancer genes, including several genes involved in epigenome editing and 3D genome organization, such as EP300, CTCF, and STAG2, which we validated by targeted sequencing of an independent cohort of 115 BM samples. Our study represents the most comprehensive genomic characterization of LUAD and LUSC BM available to date, uncovering potentially targetable NSCLC-BM drivers and inspiring the design of novel precision treatment strategies for NSCLC patients.
“…Recurrent BM-associated amplifications on chr5p and 8q were also previously identified in a small cohort of seven primary lung cancer and BM pairs profiled by WES. 25 Figure 1 NSCLC-BM harbor significantly more SCNAs compared to the primary tumor samples. ( A ) Schematic representation of the discovery cohort and of the genomic assays performed on it.…”
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