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P147 Long-term survival in women with high-grade serous ovarian cancer: interplay between RB1 and BRCA1/2
  1. FAM Saner1,
  2. DW Garsed1,2,
  3. JA Beach1,
  4. A Pandey1,
  5. S Fereday1,
  6. K Alsop1,
  7. MCA Wouters3,
  8. N Traficante1,
  9. CL Pearce4,
  10. MC Pike4,
  11. A de Fazio5,6,7,
  12. SJ Ramus8,9,
  13. M Köbel10,
  14. EL Goode11,
  15. BH Nelson3 and
  16. DDL Bowtell1,2
  1. 1Peter MacCallum Cancer Centre
  2. 2Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
  3. 3Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC, Canada
  4. 4Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  5. 5Centre for Cancer Research, The Westmead Institute for Medical Research
  6. 6Department of Gynaecological Oncology, Westmead Hospital, Westmead
  7. 7The Universtiy of Sydney
  8. 8School of Women’s and Children’s Health, University of New South UK
  9. 9Garvan Institute of Medical Research, Sydney, NSW, Australia
  10. 10Department of Pathology and Laboratory Medicine, Foothill Medical Center, University of Calgary, Calgary, AB, Canada
  11. 11Department of Health Science Research, Divison of Epidemiology, Mayo Clinic Hospital, Rochester, MN, USA


Introduction/Background Only ∼15% of patients with high-grade serous ovarian cancer (HGSC) survive >10 years. Those patients with a more typical disease trajectory may benefit from insights gained from long-term survivors (LTS). Here, we investigated genomic and immunologic determinants of exceptional survival in vivo and in vitro with a focus on the tumour suppressor RB1.

Methodology Whole-genome sequencing (WGS) was performed on a unique set of primary tumors and germline samples from a cohort of 55 women with >10-year survival following a diagnosis of advanced stage (Stage IIIC/IV) HGSC. Tumors were also characterised by RNA sequencing and immunohistochemistry (IHC). RB1 was depleted in HGSC cell lines through CRISPR-Cas9 knockout (KO). The impact of RB1 loss was analysed in assays of chemosensitivity, clonogenicity, immunogenicity and transcriptomics.

Results WGS showed that somatic inactivation of RB1 was common in LTS, with 33% of tumours showing loss of RB1 protein by IHC compared to 13% of unselected HGSC controls (n=207; P=0.001). IHC revealed that RB1 loss was associated with increased numbers of PD-1+ tumour-infiltrating lymphocytes (P=0.015) and MHC class I on tumor cells (P=0.002). In an independent HGSC cohort (n=847) from the OTTA consortium, co-occurrence of germline BRCA1/2 mutations and RB1 loss was associated with a significantly longer overall survival than patients with intact BRCA1/2 and RB1 (HR: 0.44, P<0.001). In RB1 negative tumours, top enriched pathways involved E2F targets and interferon response genes. RB1 KO impaired clonogenic survival after cisplatin/paclitaxel combination therapy specifically in the BRCA1 mutant cell line JHOS2 (P <0.01). Expression of immune markers MHC Class II and PD-L1 was increased in RB1 KO cells.

Conclusion In HGSC, concurrent loss of RB1 and BRCA1/2 mutation is associated with significantly longer overall survival. RB1 loss appears to result in impaired self-renewal after standard chemotherapy and enhanced host immune response.

Disclosure F.A.M.S is supported by a Swiss National Foundation Early Postdoc Mobility Fellowship, a Swiss Cancer Research Foundation grant and the Prof. Dr. Max Cloëtta foundation. D.W.G. is supported by U.S. Army Medical Research and Materiel Command grant. AOCS receives funding support from Astra Zeneca and Ovarian Cancer Australia. C.L.P. and M.C.P. acknowledge support from the US Congressionally Directed Ovarian Cancer Research Program administered by the US Army Medical research and Materiel Command, grant number W81XWH-16-2-0010. D.D.L.B. is supported by U.S. Army Medical Research and Materiel Command grant, by the National Health and Medical Research Council of Australia (NHMRC) grants APP1092856 and APP1117044, the US National Cancer Institute U54 program, and receives research funding from Astra Zeneca, Beigene and Genentech-Roche. A.deF. is supported by grants from the U.S. Army Medical Research and Materiel Command, NHMRC, Cancer Institute NSW, Cancer Council New South Wales and AstraZeneca.

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