TY - JOUR
T1 - Prospective high-throughput genome profiling of advanced cancers
T2 - results of the PERMED-01 clinical trial
AU - Bertucci, François
AU - Gonçalves, Anthony
AU - Guille, Arnaud
AU - Adelaïde, José
AU - Garnier, Séverine
AU - Carbuccia, Nadine
AU - Billon, Emilien
AU - Finetti, Pascal
AU - Sfumato, Patrick
AU - Monneur, Audrey
AU - Pécheux, Christophe
AU - Khran, Martin
AU - Brunelle, Serge
AU - Mescam, Lenaïg
AU - Thomassin-Piana, Jeanne
AU - Poizat, Flora
AU - Charafe-Jauffret, Emmanuelle
AU - Turrini, Olivier
AU - Lambaudie, Eric
AU - Provansal, Magali
AU - Extra, Jean Marc
AU - Madroszyk, Anne
AU - Gilabert, Marine
AU - Sabatier, Renaud
AU - Vicier, Cécile
AU - Mamessier, Emilie
AU - Chabannon, Christian
AU - Pakradouni, Jihane
AU - Viens, Patrice
AU - André, Fabrice
AU - Gravis, Gwenaelle
AU - Popovici, Cornel
AU - Birnbaum, Daniel
AU - Chaffanet, Max
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
KW - Advanced cancers
KW - Mutation
KW - PERMED-01 trial
KW - Precision medicine
KW - Sequencing
KW - WES
KW - aCGH
KW - t-NGS
UR - http://www.scopus.com/inward/record.url?scp=85106175733&partnerID=8YFLogxK
U2 - 10.1186/s13073-021-00897-9
DO - 10.1186/s13073-021-00897-9
M3 - Article
C2 - 34006291
AN - SCOPUS:85106175733
SN - 1756-994X
VL - 13
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 87
ER -