BriTROC personalised biomarkers in relapsed ovarian high grade serous carcinoma

Transcription

1 BriTROC personalised biomarkers in relapsed ovarian high grade serous carcinoma GCIG Translational Committee 4 th June 2016 Iain McNeish Professor of Gynaecological Oncology Wolfson Wohl Cancer Research Centre Institute of Cancer Sciences University of Glasgow, UK

2 Big translational questions in HGSOC Can we develop novel therapies for HGSOC with accurate predictive biomarkers? (Clinical) How does recurrent HGSC evolve into platinum-resistant disease? (Translational) Can we develop decent pre-clinical models of HGSC? (Basic science)

3 CA125 (units) CA125 (units) HGSC in two patients V.E. 61 retired school teacher M.W. 63 retired school teacher (BRCA2 VUS) Surgery + Carbo Carbo Taxol Gem Carbo Cis/etop CarboTaxol With IDS Carbo Caelyx Carbo w.taxol Time (months) Time (months) January 1998 January 2013

4 Why does HGSC stop responding to platinum? Carboplatin-based chemotherapy months Refractory Resistant Partially sensitive Sensitive Probability of responding to platinum at relapse 0% 10% 30% 60% Potential biological drivers CCNE1, MYC BRCA1, BRCA2 Data from stage IIIc/IV HGSOC patients in Scotroc1 trial (Vasey et al JNCI (2004) 96:1682)

5 BriTROC collaborative UK Translational Research in Ovarian Cancer Collaborative 12 major UK ovarian cancer centres (Cambridge, Glasgow, Newcastle, Imperial, Barts, Edinburgh, Leeds, Manchester, Belfast, Birmingham, Bristol, Kings) Ovarian Cancer Action provides infrastructure funding James Brenton

6 BriTROC1 Study Sample Collection Study to Investigate the Role of Homologous Recombination Deficiency in Platinum Sensitivity in Recurrent High Grade Serous Ovarian Cancer

7 BriTROC1 study Multi-centre, study. Study recruitment: 300 biopsies/samples (c.12 sites in the UK) over 4 years. Timelines: - Open to recruitment 14 th December Planned accrual completion December 2016

8 BriTROC study Carboplatin-based chemotherapy months Refractory Resistant Partially sensitive Sensitive Sample from diagnosis Q3 100 biopsies platinum-resistant Q2 200 biopsies platinum-sensitive Q1

9 Study Objectives Safety and feasibility of obtaining recurrent biopsies. To obtain 300 biopsies from women with relapsed HGSC. To assess Homologous Recombination (HR) genes in relapsed HGSC compared with the same genes in tumours at first presentation. To compare HR genes in platinum-sensitive vs platinum-resistant relapsed HGSC. To compared somatic mutations with those identified in ctdna

10 Inclusion Criteria Relapsed HGSC (+ G3 endometrioid) At least one line of platinum-containing chemotherapy FFPE material from time of diagnosis available (NOT ascites cytology). Disease suitable for biopsy Patients also allowed to enter at secondary debulking

11 Exclusion Criteria Non-HGSC pathology Original diagnosis of high grade serous cancer made on cytology only Disease not amenable to biopsy

12 Samples and Sample Collection 2 x 14 16G cores fixed in methanol (UMFix) Access to 1 archival FFPE block. 20ml blood for plasma for ctdna. Extra 20ml for genomic DNA extraction Optional 10ml blood immediately prior to both first and second cycles of chemotherapy following biopsy for ctdna

13 NBF Histoscore Histoscore NBF Histoscore Histoscore Why UMFix? - IHC Formalin UMFix CK7 50 r= UMFIX histoscore 50 0 UMFIX NBF p53 50 r = UMFIX histoscore 50 0 UMFIX NBF Piskorz et al (2016) Ann. Oncol. 27:532

14 Why UMFix? - DNA Greater DNA yields than formalin Better copy number estimation than formalin with less noise Piskorz et al (2016) Ann. Oncol. 27:532

15 BriTROC Recruitment N = 207 (26 th May 2016) 150 = platinum-sensitive 43 = platinum-resistant

16 BriTROC Recruitment No. prior lines chemo Platinum-resistant relapse (median 2 prior lines) Platinum-sensitive relapse (median 1 prior line) Months since diagnosis

17 Screening and toxicity Screening after 150 recruited 322 patients screened 67 declined 26 declined biopsy 20 needed to start chemotherapy urgently 2 too much pain 19 others Toxicity 3 biopsy-related SAE 2 = grade 2 pain 1 = grade 2 haemorrhage (liver) 120 ineligible including 60 due to disease not accessible for biopsy 17 contra-indication to biopsy 20 due to no FFPE material from diagnosis

18 DNA yields Biopsy median = 2.76 µg (range ) Surgical median 6.73 µg (range ) Number of failures = 17/114 (15%) 14 biopsy, 3 surgical 90/114 (79%) samples yield >200ng DNA

19 The science programme Personalised biomarkers of response in ovarian high-grade serous cancer James D. Brenton Iain A. McNeish

20 Aim 1: How does relapsed HGSC differ from time of diagnosis? 1. Sequencing of BriTROC relapse samples TAm-Seq cancer panel at great depth (2000x) Shallow whole genome sequencing - CNA Deep whole genome sequencing - SV Comparison with sample at time of diagnosis Germline DNA sequencing 2. Clonal heterogeneity Detailed re-sequencing of primary tumour

21 BriTROC some quick results Relapse sample Diagnostic sample

22 BriTROC some quick results Patient number 1. Diagnosed 20 months prior to enrolment. Two prior lines of chemo, platinum-resistant relapse TAmSeq: (archival and relapse) TP53 H179Y PIK3CA E542K

23 BriTROC some quick results Patient number 17. Diagnosed 30 months prior to enrolment. One prior line of chemo, platinum-sensitive relapse TAmSeq (archival and relapse): TP53 R282W

24 Conclusions part 2 and future direction Obtaining tissue in relapsed HGSC is feasible and safe p53 mutations are constant Deep WGS on relapsed samples Define utility of ctdna

25 University of Glasgow Darren Ennis Suzanne Dowson Josephine Walton Malcolm Farquharson Elaine Leung Oliver Hofmann University of Cambridge James Brenton Anna Piskorz Teodora Goranova Anna Supernat Geoff McIntyre Acknowledgements CRUK Clinical Trials Unit Glasgow Liz-Anne Lewsley Diann Taggert Jim Paul CRUK Beatson Institute Karen Vousden Julianna Blagih David Stevenson Karen Blyth BriTROC investigators Hani Gabra Charlie Gourley Andrew Clamp Michelle Lockley Geoff Hall Richard Kennedy Sudha Sundar Axel Walther Ana Montes Marcia Hall Beatson West of Scotland Cancer Centre Ros Glasspool David Kay