APHP, European Georges Pompidou Hospital, Department of Biochemistry, Pharmacogenetics and Molecular Oncology, Paris Cancer Institute CARPEM, Paris, France
Helene Blons , Justine Abdelli , Valerie Taly , Claire Mulot , Pierre Laurent Puig , Benoit You , Philipp Harter , Domenica Lorusso , Yolanda Garcia , Christian Schauer , Sakari Hietanen , Nicoletta Colombo , Ignace Vergote , Hiroaki Kobayashi , Thibault De La Motte Rouge , Paul Buderath , Sabrina Chiara Cecere , Guillaume Bataillon , Eric Pujade-Lauraine , Isabelle Laure Ray-Coquard
Background: The PAOLA-1/ENGOT-ov25 trial showed that adding olaparib (ola) to maintenance bevacizumab (bev) after first-line therapy led to a progression-free and overall survival benefit in advanced ovarian high-grade carcinoma (AOC) patients with homologous recombination deficiency (HRD) (Myriad MyChoiceR Genomic Instability Score) or BRCA1/2 mutations (BRCAmut). Here, we address the impact of BRCA1 and RAD51C epimutations to improve our understanding of GIS beyond BRCAmut.Methods:BRCA1 and RAD51C methylation analysis was assessed and quantified in pre-treatment biopsies (66%), after neoadjuvant chemotherapy (NACT) (20%) or unknown (14%) from bisulfite converted DNAs using fluorescent methylation specific PCR and methylation specific droplet digital PCR (ddPCR). Methylation status was correlated to clinical data, BRCA1/2 mutations, GIS and HRD scores, PFS (PFS1, PFS2) and OS. R (r-project.org) was used for statistical analysis. Results: Among the 537 patients randomized to maintenance ola + bev and 269 to placebo (pbo) + bev, 348 and 171 were available for methylation analysis. Their baseline molecular and clinical characteristics were well balanced with those of the entire cohort. Promoter methylation was identified in 67 (12.9%) samples for BRCA1 and 25 (4.8%) for RAD51C (4 were methylated on both genes). Methylation and BRCAmut were mutually exclusive except for 3 samples. Mean GIS scores were 62.5 [59.6-65.5]; 59.4 [57.2-61.5]; 54.2 [50.5-57.8]; 23.4 [21.6-25.2] for BRCA1 or RAD51C methylated (met-tumors), BRCAmut, non-mut/non-met HRD+ (b-/m-HRD+) and HRP (proficient) tumors respectively. Among met-tumors 92% (66/72) were GIS positive (>42). The mean GIS score of Met-tumors were significantly higher than that of b-/m- HRD+ samples (p=0,009). Benefit of adding ola maintenance to bev was in a similar between patients with met AOC and those with b-/m- HRD+ tumors (table). Conclusions: Methylated BRCA1/RAD51 tumors are HRD+ and provide to ovarian cancer patients a similar clinical benefit of ola+bev as patients with b-/m- HRD+ tumors. Methylation assessment represents a rapid and cost effective tool; which coupled with BRCA1-2 somatic testing allows the identification of the majority (81%) of HRD+ AOC. Clinical trial information: NCT02477644.
BRCAmut | met | b-/m- HRD+ | HRP | |||||
---|---|---|---|---|---|---|---|---|
Olaparib | placebo | Olaparib | placebo | Olaparib | placebo | Olaparib | placebo | |
N | 106 | 50 | 59 | 26 | 31 | 20 | 152 | 75 |
Median PFS1 | 66.3 | 22.0 | 29.8 | 17.4 | 57.1 | 16.6 | 16.7 | 15.1 |
[42.6-75.2] | [16.6-26.3] | [22.0-42.1] | [11.1-27.7] | [18.7-NR] | [11.8-24.9] | [15.3-18.8] | [14.0-18.7] | |
HR | 0.42 [0.27-0.66] | 0.49 [0.29-0.84] | 0.34 [0.17-0.67] | 0.9 [0.73-1.34] | ||||
Median OS | NR | 66.8 | 64.3 | 65.4 | NR | 54.4 | 36.6 | 42.1 |
[55.6-NR] | [53.3-NR] | [32.3-NR] | [38.5-NR] | [39.9-NR] | [30.5-44.9] | [28.7-54.2] | ||
5-years survival | 75% | 54% | 56% | 52% | 54% | 44% | 28% | 35% |
HR | 0.52 [0.30-0.92] | 0.76 [0.42-1.50] | 0.78 [0.35-1.76] | 1.2 [0.86-1.71] |
(NR: Not reached)
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Abstract Disclosures
2020 ASCO Virtual Scientific Program
First Author: Domenica Lorusso
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