BriTROC personalised biomarkers in relapsed ovarian high grade - PowerPoint PPT Presentation

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

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)

HGSC in two patients V.E. 61 retired school teacher M.W. 63 retired school teacher ( BRCA2 VUS) Gem Cis/etop Carbo w.Taxol Carbo 10000 10000 Carbo Carbo Caelyx CarboTaxol Surgery + Taxol With IDS 1000 1000 Carbo CA125 (units) CA125 (units) 100 100 10 10 1 1 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 Time (months) Time (months) January 1998 January 2013

Why does HGSC stop responding to platinum? Carboplatin-based chemotherapy 1 6 12 18 months Sensitive Refractory Resistant Partially sensitive Probability of responding to platinum at relapse 0% 10% 30% 60% Potential biological drivers BRCA1, BRCA2 CCNE1, MYC Data from stage IIIc/IV HGSOC patients in Scotroc1 trial (Vasey et al JNCI (2004) 96:1682)

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

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

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 2012 - Planned accrual completion December 2016

BriTROC study Carboplatin-based chemotherapy 1 6 12 18 months Sensitive Refractory Resistant Partially sensitive 200 biopsies Sample from 100 biopsies platinum-sensitive diagnosis platinum-resistant Q3 Q2 Q1

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 •

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 •

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

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

Why UMFix? - IHC UMFix Formalin 200 200 NBF Histoscore CK7 150 150 Histoscore 100 100 50 50 r=0.844 0 0 0 50 100 150 200 UMFIX NBF UMFIX histoscore 200 200 NBF Histoscore 150 150 Histoscore p53 100 100 50 50 r = 0.846 0 0 0 50 100 150 200 UMFIX NBF UMFIX histoscore Piskorz et al (2016) Ann. Oncol. 27 :532

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

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

BriTROC Recruitment No. prior lines chemo 1 Platinum-resistant relapse 2 (median 2 prior lines) 5 1 Platinum-sensitive relapse (median 1 prior line) 2 3 7 0 24 48 72 96 120 144 168 192 Months since diagnosis

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

DNA yields Biopsy median = 2.76 µg (range 0.05 – 18.7) Surgical median 6.73 µg (range 0.52 – 65) Number of failures = 17/114 (15%) 14 biopsy, 3 surgical 90/114 (79%) samples yield >200ng DNA

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

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

BriTROC – some quick results Relapse sample Diagnostic sample

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

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

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

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