TY - JOUR
T1 - Effect of HIPEC according to HRD/BRCAwt genomic profile in stage III ovarian cancer
T2 - Results from the phase III OVHIPEC trial
AU - Koole, Simone N.
AU - Schouten, Philip C.
AU - Hauke, Jan
AU - Kluin, Roel J. C.
AU - Nederlof, Petra
AU - Richters, Lisa K.
AU - Krebsbach, Gabriele
AU - Sikorska, Karolina
AU - Alkemade, Maartje
AU - Opdam, Mark
AU - van Leeuwen, Jules H. Schagen
AU - Schreuder, Henk W. R.
AU - Hermans, Ralph H. M.
AU - de Hingh, Ignace H. J. T.
AU - Mom, Constantijne H.
AU - Arts, Henriette J. G.
AU - van Ham, Maaike
AU - van Dam, Peter
AU - Vuylsteke, Peter
AU - Sanders, Joyce
AU - Horlings, Hugo M.
AU - van de Vijver, Koen K.
AU - Hahnen, Eric
AU - van Driel, Willemien J.
AU - Schmutzler, Rita
AU - Sonke, Gabe S.
AU - Linn, Sabine C.
PY - 2022/10
Y1 - 2022/10
N2 - The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence-free (RFS) and overall survival (OS) in patients with stage III ovarian cancer. Homologous recombination deficient (HRD) ovarian tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD tumors respond best to treatment with HIPEC. We analyzed the effect of HIPEC in patients in the OVHIPEC trial, stratified by HRD status and BRCAm status. Clinical data and tissue samples were collected from patients included in the randomized, phase III OVHIPEC-1 trial. DNA copy number variation (CNV) profiles, HRD-related pathogenic mutations and BRCA1 promotor hypermethylation were determined. CNV-profiles were categorized as HRD or non-HRD, based on a previously validated algorithm-based BRCA1-like classifier. Hazard ratios (HR) and corresponding 99% confidence intervals (CI) for the effect of RFS and OS of HIPEC in the BRCAm, the HRD/BRCAwt and the non-HRD group were estimated using Cox proportional hazard models. Tumor DNA was available from 200/245 (82%) patients. Seventeen (9%) tumors carried a pathogenic mutation in BRCA1 and 14 (7%) in BRCA2. Ninety-one (46%) tumors classified as BRCA1-like. The effect of HIPEC on RFS and OS was absent in BRCAm tumors (HR 1.25; 99%CI 0.48-3.29), and most present in HRD/BRCAwt (HR 0.44; 99%CI 0.21-0.91), and non-HRD/BRCAwt tumors (HR 0.82; 99%CI 0.48-1.42), interaction P value: 0.024. Patients with HRD tumors without pathogenic BRCA1/2 mutation appear to benefit most from treatment with HIPEC, while benefit in patients with BRCA1/2 pathogenic mutations and patients without HRD seems less evident.
AB - The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence-free (RFS) and overall survival (OS) in patients with stage III ovarian cancer. Homologous recombination deficient (HRD) ovarian tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD tumors respond best to treatment with HIPEC. We analyzed the effect of HIPEC in patients in the OVHIPEC trial, stratified by HRD status and BRCAm status. Clinical data and tissue samples were collected from patients included in the randomized, phase III OVHIPEC-1 trial. DNA copy number variation (CNV) profiles, HRD-related pathogenic mutations and BRCA1 promotor hypermethylation were determined. CNV-profiles were categorized as HRD or non-HRD, based on a previously validated algorithm-based BRCA1-like classifier. Hazard ratios (HR) and corresponding 99% confidence intervals (CI) for the effect of RFS and OS of HIPEC in the BRCAm, the HRD/BRCAwt and the non-HRD group were estimated using Cox proportional hazard models. Tumor DNA was available from 200/245 (82%) patients. Seventeen (9%) tumors carried a pathogenic mutation in BRCA1 and 14 (7%) in BRCA2. Ninety-one (46%) tumors classified as BRCA1-like. The effect of HIPEC on RFS and OS was absent in BRCAm tumors (HR 1.25; 99%CI 0.48-3.29), and most present in HRD/BRCAwt (HR 0.44; 99%CI 0.21-0.91), and non-HRD/BRCAwt tumors (HR 0.82; 99%CI 0.48-1.42), interaction P value: 0.024. Patients with HRD tumors without pathogenic BRCA1/2 mutation appear to benefit most from treatment with HIPEC, while benefit in patients with BRCA1/2 pathogenic mutations and patients without HRD seems less evident.
KW - HIPEC
KW - homologous recombination deficiency
KW - ovarian cancer
KW - HOMOLOGOUS RECOMBINATION DEFICIENCY
KW - BREAST-CANCER
KW - CHEMOTHERAPY
KW - DIAGNOSIS
KW - SURVIVAL
KW - BENEFIT
KW - HSP90
KW - BRCA1
U2 - 10.1002/ijc.34124
DO - 10.1002/ijc.34124
M3 - Article
SN - 0020-7136
VL - 151
SP - 1394
EP - 1404
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 8
ER -