Older age should not be a barrier to testing for somatic variants in homologous recombination DNA repair-related genes in patients with high-grade serous ovarian carcinoma

Omali Pitiyarachchi; Yeh Chen Lee; Hao-Wen Sim; Sivatharsny Srirangan; Cristina Mapagu; Judy Kirk; Paul R Harnett; Rosemary L Balleine; David D L Bowtell; Goli Samimi; Alison H Brand; Deborah J Marsh; Philip Beale; Lyndal Anderson; Natalie Bouantoun; Pamela Provan; INOVATe Investigators; Susan J Ramus; Anna DeFazio; Michael Friedlander

doi:10.1016/j.tranon.2023.101638

Older age should not be a barrier to testing for somatic variants in homologous recombination DNA repair-related genes in patients with high-grade serous ovarian carcinoma

Transl Oncol. 2023 May:31:101638. doi: 10.1016/j.tranon.2023.101638. Epub 2023 Feb 18.

Authors

Omali Pitiyarachchi¹, Yeh Chen Lee², Hao-Wen Sim³, Sivatharsny Srirangan⁴, Cristina Mapagu⁵, Judy Kirk⁶, Paul R Harnett⁶, Rosemary L Balleine⁷, David D L Bowtell⁸, Goli Samimi⁹, Alison H Brand¹⁰, Deborah J Marsh¹¹, Philip Beale¹², Lyndal Anderson¹³, Natalie Bouantoun⁴, Pamela Provan⁴; INOVATe Investigators; Susan J Ramus¹⁴, Anna DeFazio¹⁵, Michael Friedlander²

Affiliations

¹ School of Biomedical Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia. Electronic address: Omali.Pitiyarachchi@unsw.edu.au.
² School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Prince of Wales and Royal Hospital for Women, Randwick, NSW, Australia.
³ School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia; NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, NSW, Australia; Department of Medical Oncology, The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁴ Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia; Department of Gynaecological Oncology, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁵ Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Illawarra and Shoalhaven Cancer Care Centres, Wollongong and Nowra, NSW, Australia.
⁶ Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; The Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, NSW, Australia.
⁷ Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁸ Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
⁹ National Cancer Institute, Bethesda, Maryland, United States of America.
¹⁰ Department of Gynaecological Oncology, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
¹¹ Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, Australia; Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
¹² Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
¹³ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; NSW Health Pathology, NSW, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
¹⁴ School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia; Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.
¹⁵ Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, NSW, Australia; Department of Gynaecological Oncology, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia.

Abstract

Background: Somatic pathogenic variants (PVs) in homologous recombination DNA repair (HR)-related genes found in high-grade serous ovarian carcinomas (HGSC) are not well-characterised in older patients (≥70 years). This may reflect low testing rates in older patients.

Methods: Data from 1210 HGSC patients in AACR Project GENIE and 324 patients in an independent dataset INOVATe were analysed. Cases where somatic variants could be distinguished from germline variants were included, and analysis was restricted to those with a somatic TP53 variant, to ensure cases were HGSC.

Results: Of 1210 patients in GENIE, 27% (n = 325) were aged ≥70 years at testing. Patients with somatic-only PVs in BRCA2 were older compared with BRCA1 (median 71 vs 60 years, p = 0.002). Median age for 21 patients with somatic-only PVs in 11 other HR-related genes ranged from 40 to 67 years. In older patients, 7% (n = 22) had somatic BRCA1/2 PVs, and 1% (n = 2) had PVs other HR-related genes; this rate was not significantly different to younger patients (<70 years), 7% (n = 62) BRCA1/2 and 2% (n = 19) other HR-related genes (p = 0.36). The overall frequency of somatic BRCA1/2 PVs was similar in INOVATe (n = 25; 7.7%) and somatic-only BRCA2 PVs were again found in older patients compared with BRCA1 (median age: at testing, 70 vs 63 years; at diagnosis, 68 vs 60 years).

Conclusions: The overall frequency of somatic-only PVs in HR-related genes was similar in older and younger patients with HGSC, highlighting the importance of somatic testing irrespective of age. Limiting somatic testing by age may exclude patients who could benefit from maintenance poly(ADP-ribose) polymerase (PARP) inhibitors.

Keywords: Older patients; Ovarian cancer; Somatic testing.