Prospective high-throughput genome profiling of advanced cancers: results of the PERMED-01 clinical trial

Abstract

Background The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores. Methods Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 “candidate cancer” genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a “matched therapy” and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES). Results Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68–75%). Only 94/550 patients (17%, 95%CI 14–21) received an “AGA-matched therapy” on progression. The most frequent AGAs leading to “matched therapy” included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such “matched therapy” improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of “matched therapy” was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with “matched therapy,” and 6-month overall survival (OS) was 62% (95%CI 52–73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH. Conclusions Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a “matched therapy” in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results. Trial registration ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158.

Targeting Akt in cancer for precision therapy

“…The genetic, epigenetic and proteomic changes in tumors can be identified by local testing of tumor tissues or central testing of plasma cell-free DNA (cfDNA) by high-throughput approaches [ 292 ]. Local testing of DNA from tumor tissues can be achieved by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, whole-genome array-comparative genomic hybridization or next-generation sequencing (NGS), and exon-capture NGS [ 291 , 293 ]. The approach for central testing of plasma cfDNA includes BEAMing, droplet digital polymerase chain reaction and NGS [ 231 , 294 , 295 ].…”

Actionable Molecular Alterations Are Revealed in Majority of Advanced Non-Small Cell Lung Cancer Patients by Genomic Tumor Profiling at Progression after First Line Treatment

“…Presley et al found in their retrospective study including 875 stage IIIB/IV or un-resectable non-squamous NSCLC patients with performance of broad-based genomic sequencing (>30 genes), a similar frequency of 88.9% [ 6 ]. Lower and more varying frequencies of 40–75% have been reported from precision medicine trials [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. The technological advances in molecular profiling over time have contributed to high-throughput analyses, which can explain some of the variance over time.…”

“…The responses to targeted therapy has increased from approximately 3% in 2006 to 7% in 2020 [ 4 ], which gives hope to the field of precision medicine. Precision medicine trials reports of only 8–27% actually receiving targeted treatment [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ] and response rates of 0.8–3% [ 29 ].…”

“…In precision medicine trials, one of the primary reasons of not receiving the intended targeted treatment is patients’ deterioration [ 9 , 10 , 11 , 12 , 13 , 14 , 17 , 18 ]. In our study, more than one third of patients (38%) did not receive any systemic second line treatment, primarily due to a decline in PS, observed in 60% of patients ( Figure 5 A).…”

“…Reports from precision medicine clinical trials have shown that in 40–75% of patients, a potential targeted treatment is available, but only 8–27% of patients actually receive targeted treatment [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ], mainly due to patients’ deterioration. It is currently debated if comprehensive molecular profiling should be performed before exhaustion of treatment options to increase the benefit of targeted treatment.…”