Finding the Key To Long-Term Survival The Long-Term Ovarian Cancer Survivor Project A Department of Defense Initiative PI: Michael Birrer Co-PI: Lari Wenzel Scientific Advisory Board Chair: Philip DiSaia International Scientific Advisory Board Chair: Eric Pujade-Lauraine Advocate Advisory Board Chair: Mary Scroggins
Two-Phase Award • • Phase I Phase II 2 years grant 2 + 2 years grant • • – 3 teams awarded – 2 teams awarded Build consortium Use consortium to • • obtain definitive data – Establish function network Mid-project oral • presentation after 2 – Demonstrate effective communication years for additional 2 years funding – Engage advocates Obtain initial data • 2
Consortium Structure Phase I Phase II International Scientific Advisory Advocate Advisory International Scientific Advisory Advocate Advisory Advisory Board Board Board Adovcate Advisory Board Board Chair: Mary Board Chair: Eric Pujade- Chair: Phil DiSaia Chair: Mary Scroggins Chair: Phil DiSaia Lauraine (GOG) Scroggins Chair: Rose Anorlu Coordinating Center Coordinating Center PI: Michael J. Birrer PI: Michael J. Birrer Co-Pi: Lari Wenzel Co-Pi: Lari Wenzel GOG Tissue Bank Scientific Scientific GOG clinical GOG clinical Committee GOG Tissue Committee Trials (391 Trials (391 Research Bank Research institutions) institutions) Sites Sites International Tissue Bank Virtual Tissue Bank Genomic /Biologic /QOL Data Genomic /Biologic / Psychosocial Data Clinical Correlations Clinical Correlations Clinically Relevant Tools and Targets Clinically Relevant Tools and Targets
Specific Aims Aim 1: To determine the genomic (RNAseq miRNAseq, methylation patterns) and proteomic characteristics of LT versus ST survivors. Aim 2: To characterize and quantitate immune infiltrates and angiogenesis in LT versus ST survivors. Aim 3: To validate a genetic signature that predicts for recurrence of early- stage, high-grade EOC Aim 4: To determine the impact of host factors including genomic SNP profiles and key measures of patient stress on long term survival Aim 5: To understand the extent to which health-related QOL measures, additional PROs, and key CTCAE criteria predict LT OC survival Aim 6: To examine, as an exploratory aim, the potential relationship between health-related QOL, PROs, and key CTCAE criteria and genomic features predicting disease recurrence 4
Phase I Workflow Beginning Year 1 End of Year 1 and 2 Whole Consortium Whole Consortium 30 bi-monthly phone calls • Selected Key Participants In Person Meeting In Person Meeting • Advocates Chair 20 monthly phone calls • Advocates Board • PI and Co-PI • Program Manager 5
Phase I Timeline Identification of potential biological Scientists SOPs tumor cuts model(s) Technology assessment: Tumor path review RNAseq, miRNAseq, QOL database IRB protocol 1 methylCap, IHC GOG protocol 1 Integrated analysis IRB protocol 2 List of GOG Tumors Analysis of Grant submission GOG protocol 2 52 tumors Tumor distribution List of trial sites (individual platforms) QOL distribution July July Nov Jan Jan Advocates Grant MGH web site News Letter submission List of events Partners web 30 more patients Paper submission Marketing material Facebook insert Nancy Yeary Total 130 patients partnership First 30 patients identified 30 more patients IRB protocol 2: Revised paper identified Consent form • Facebook Phone script • Events invitation letter • Web sites Defining sub-groups of LT survivors Definition of LT survival
Phase I Proof of Concept Studies • Project 1 Collect additional clinically annotated primary ovarian cancers o Group 1 FFPE from patients on GOG 172,182,218 o Group 2 Clinical data from GOG136 cases o Group 3 FFPE and clinical data for LT survivors NOT on GOG trial • Project 2 Genomic, epigenomic and biologic analysis of LT survivors o Demonstration study on 30 LT cases • Project 3 Database development for QOL, PROs and Survivorship o Initiate database mergers and identify the LT survivor population o Recruit, consent and pilot a survey on LT survivorship 7
Project 1 Use of Consortium to collect – clinically-annotated primary ovarian tumors 8
GOG-Enrolled Patients Primary Ovarian Cancer FFPE from Phase III GOG Trials with Long Term Follow-Up QOL FFPE Received Not Received Pending Total GOG Trial 1, 3, 4 0 429 0 429 172 - 328 179 0 507 175 - 571 3741 0 4312 182 - 44 657 9 710* 213 2, 4 1701 159 13 1873 218 3482 5196 54 8732 TOTAL 1 FACT-O, 2 FACT-O TOI, 3 FACT/GOG-Ntx subscale, 4 FACT/GOG-Ad subscale *FFPE only required from surgery arm (n=71); total study accrual n=710 9
Identification of NON-GOG LTS Advocate Advisory Board Survivor Patient calls MGH Eligibility check Consent, QOL Consortium Program Manager 10
Phase I Results Group 1: Identification of patients, clinical sites and contact • information for tumors from patients on trial that were not collected at time of trial: o 64 LTS identified o 46 tumors in pathology o 33 tumors obtained Group 2: Identification of tumors obtained from GOG136 for which • we do not have clinical data: o 18 LTS identified o 10 patients consented and tumors are available for analysis Group 3: Identification of patients not on GOG trials: • o 130 contacted us to be enrolled and 65 enrolled o 50 tumors in pathology o 21 tumors collected 11
Phase II Additional Cases Name Resources Affiliation Nicoletta Colombo, MD 2,500 annotated FFPE MANGO ~ 400 LTS Paula Colvert, MD, and 50 + annotated LTS FFPE ICORG Kathleen Scott, PhD Can collect QOL Jalid Sehouli, MD. 150 annotated LTS FFPE: CHARITÉ Collecting QOL on LTS 12
Project 2 Genomic, epigenomic and biologic analysis of LT survivors Analysis of 52 samples 13
Molecular and Immune Analysis RNA-Seq MiRNA-Seq MethyCap-Seq Immune System RNA extraction Enrichment Methyl capture CD8, FOXP3, Library prep Library prep Library prep CD20 Sequencing Sequencing Sequencing plasma cells, and Map to genome Map to mir db Map to promoters tertiary lymphoid Count reads Count reads Count reads structures Normalization Normalization Normalization Normalization Associate with LTS Associate with LTS Associate with LTS Associate with LTS Pathway analysis Integrate with RNA Pathway analysis 14
LTS Versus STS Heatmaps RNA-seq microRNA-seq MethylCap-seq 15
Multiplexed Immunofluorescence multiplexed immunofluorescence CD3=green, CD4=red, CD8=pink, inForm software tissue segmentation CD45RO=magenta, tumor [red] versus stroma [green] Cytokeratins=brown, DAPI=blue 16
Integrated Analysis Immune QOL System Survival Gene miRNA Expression Methylation 17
Methylation and RNAseq RNF212 LYPLAL1 PNKP 6.0 8 5 5.5 Expression Expression Expression 6 4 5.0 4 3 4.5 2 2 4.0 0 1 3.5 correlation = −0.69 correlation = −0.68 correlation = −0.65 − 2 0 2 4 6 8 2 4 6 8 10 −1 0 1 2 3 4 5 Methylation Methylation Methylation MTRNR2L10 THNSL2 CIDEB 4 4 6 3 2 Expression Expression Expression 2 4 0 1 − 2 2 0 − 4 − 1 0 correlation = −0.55 correlation = −0.55 correlation = −0.54 2 3 4 5 6 4 5 6 7 8 9 2 4 6 8 10 Methylation Methylation Methylation
miRNA and mRNA-seq Negative correlation between Negative correlation between miR-634 and HOXA1 in LTS miR-521 and ERCC8 in LTS cohort cohort
RNA Pathways and Immune Infiltrates − 6 − 4 − 2 0 2 − 6 − 4 − 2 0 2 PC Low PC Low SLC9A3 IFNG PC High PC High 4 5 6 7 8 2 3 4 5 6 PC Low PC Low TRIB2 ISG20 PC High PC High 4 5 6 7 8 3 4 5 6 7 8 PC Low PC Low DDX58 OAS2 PC High PC High 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 − 4 − 2 0 2 4 SLC28A1 PC Low PC Low NF1 PC High PC High
Phase II Additional Analyses Proteomics Angiogenesis SNP profiles and stress factors (FFPE and plasma from GOG 218) 21
Project 3 Database development and analysis for QOL, PROs and Survivorship • Recruit, consent and pilot a survey on LT survivorship • 22
GOG 172 Database QOL data available for 355 patients • QOL assessments at 4 time points • o Pre-treatment, pre-cycle 4, post cycle 6, 12 mo. post cycle 6 Data include: • o FACT-O (Physical, Emotional, Social, and Functional Well-Being plus Ovarian Cancer-specific Concerns) o Abdominal Discomfort o Neurotoxicity 23
FACT Trial Outcome Index over Time GOG 172 FACT-TOI 90 85 p<0.001 80 Mean Score 75 70 65 Pre Treatment Pre cycle 4 3-6 wk post cycle 6 12 mo post cycle 6 0-5 yrs 5-10 yrs >10 yrs Both FACT-TOI and FACT-O are significantly higher across treatment and follow-up in long-term survivors compared to short-term survivors (p<0.001 and p=0.016 respectively).
Neurotoxicity over Time GOG 172 Neurotoxicity 42 40 38 Mean Score 36 34 32 p=0.82 30 Pre Treatment Pre cycle 4 3-6 wk post cycle 6 12 mo post cycle 6 0-5 yrs 5-10 yrs >10 yrs Neurotoxicity does not differ between long-term and short- term survivors (p=0.82)
Abdominal Discomfort over Time GOG 172 Abdominal Discomfort 15 14 p=0.079 Mean Score 13 12 11 Pre Treatment Pre cycle 4 3-6 wk post cycle 6 12 mo post cycle 6 0-5 yrs 5-10 yrs >10 yrs Long-term survivors have similar abdominal discomfort at all time points compared to short-term survivors (p=0.079)
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