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 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.

PMID: 36805919
PMCID: PMC9971549
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

Omali Pitiyarachchi et al. Transl Oncol. 2023 May.

. 2023 May:31:101638.

doi: 10.1016/j.tranon.2023.101638. Epub 2023 Feb 18.

Authors

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.

PMID: 36805919
PMCID: PMC9971549
DOI: 10.1016/j.tranon.2023.101638

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.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ADeF has received grant funding from AstraZeneca for unrelated work. All other authors reported no conflicts of interest related to this work.

Figures

Image, graphical abstract — **Graphical abstract**

**Fig. 1**
Process of sample selection from AACR Project GENIE Cohort v11.0-public database .

**Fig. 2**
**Age distribution of *BRCA1/2* somatic-only pathogenic variants in GENIE and INOVATe.** Median age at testing of patient samples is represented by a horizontal line with patient samples represented by coloured dots. Dashed line denotes age 70 years.

See this image and copyright information in PMC

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous