[PPT] - The Long-Term Ovarian Cancer Survivor Project A Department of PowerPoint Presentation

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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 Finding the Key To Long-Term Survival

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Two-Phase Award

2

Phase I
2 years grant

– 3 teams awarded

Build consortium

– Establish function

network

– Demonstrate effective

communication

– Engage advocates

Obtain initial data
Phase II
2 + 2 years grant

– 2 teams awarded

Use consortium to
btain definitive data
Mid-project oral

presentation after 2 years for additional 2 years funding

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Consortium Structure Phase I Phase II

Coordinating Center

PI: Michael J. Birrer Co-Pi: Lari Wenzel

Advocate Advisory Board Chair: Mary Scroggins International Advisory Board Chair: Eric Pujade- Lauraine Scientific Advisory Board Chair: Phil DiSaia (GOG)

Scientific Committee Research Sites

GOG Tissue Bank

International Tissue Bank Virtual Tissue Bank GOG clinical Trials (391 institutions) Genomic /Biologic / Psychosocial Data Clinical Correlations Clinically Relevant Tools and Targets

International Adovcate Advisory Board Chair: Rose Anorlu

Coordinating Center

PI: Michael J. Birrer Co-Pi: Lari Wenzel

Advocate Advisory Board Chair: Mary Scroggins Scientific Advisory Board Chair: Phil DiSaia

Scientific Committee Research Sites GOG Tissue Bank GOG clinical Trials (391 institutions) Genomic /Biologic /QOL Data Clinical Correlations

Clinically Relevant Tools and Targets

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Specific Aims

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Aim 1: To determine the genomic (RNAseq miRNAseq, methylation patterns) and proteomic characteristics of 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 2: To characterize and quantitate immune infiltrates and angiogenesis in LT versus ST survivors. 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

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Phase I Workflow

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30 bi-monthly phone calls

Selected Key Participants
Advocates Chair

Beginning Year 1 Whole Consortium In Person Meeting End of Year 1 and 2 Whole Consortium In Person Meeting 20 monthly phone calls

Advocates Board
PI and Co-PI
Program Manager

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Phase I Timeline

Jan Nov July Jan July

Technology assessment: RNAseq, miRNAseq, methylCap, IHC Analysis of 52 tumors (individual platforms) Integrated analysis Grant submission Identification of potential biological model(s) News Letter 30 more patients Nancy Yeary partnership 30 more patients Grant submission Paper submission Total 130 patients identified Revised paper Definition of LT survival Defining sub-groups of LT survivors IRB protocol 1 GOG protocol 1 List of GOG Tumors List of events Marketing material IRB protocol 2 GOG protocol 2 List of trial sites IRB protocol 2:

Consent form Phone script invitation letter

SOPs tumor cuts Tumor path review QOL database Tumor distribution QOL distribution MGH web site Partners web Facebook insert First 30 patients identified

Facebook
Events
Web sites

Scientists Advocates

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Phase I Proof of Concept Studies

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Project 1 Collect additional clinically annotated primary ovarian cancers
Group 1 FFPE from patients on GOG 172,182,218
Group 2 Clinical data from GOG136 cases
Group 3 FFPE and clinical data for LT survivors NOT on GOG trial
Project 2 Genomic, epigenomic and biologic analysis of LT survivors
Demonstration study on 30 LT cases
Project 3 Database development for QOL, PROs and Survivorship
Initiate database mergers and identify the LT survivor population
Recruit, consent and pilot a survey on LT survivorship

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Project 1 Use of Consortium to collect

– clinically-annotated primary ovarian tumors

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GOG-Enrolled Patients

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Primary Ovarian Cancer FFPE from Phase III GOG Trials with Long Term Follow-Up QOL FFPE GOG Trial Received Not Received Pending Total 172 1, 3, 4 429 429 175

328

179 507 182

571

3741 4312 213

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657 9 710* 218 2, 4 1701 159 13 1873 TOTAL 3482 5196 54 8732

1FACT-O, 2FACT-O TOI, 3FACT/GOG-Ntx subscale, 4FACT/GOG-Ad subscale

*FFPE only required from surgery arm (n=71); total study accrual n=710

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Identification of NON-GOG LTS

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Advocate Advisory Board Consortium Program Manager Survivor Patient calls MGH Eligibility check Consent, QOL

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Phase I Results

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Group 1: Identification of patients, clinical sites and contact

information for tumors from patients on trial that were not collected at time of trial:

64 LTS identified
46 tumors in pathology
33 tumors obtained
Group 2: Identification of tumors obtained from GOG136 for which

we do not have clinical data:

18 LTS identified
10 patients consented and tumors are available for analysis
Group 3: Identification of patients not on GOG trials:
130 contacted us to be enrolled and 65 enrolled
50 tumors in pathology
21 tumors collected

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Phase II Additional Cases

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Name Resources Affiliation Nicoletta Colombo, MD 2,500 annotated FFPE ~ 400 LTS MANGO Paula Colvert, MD, and Kathleen Scott, PhD 50 + annotated LTS FFPE Can collect QOL ICORG Jalid Sehouli, MD. 150 annotated LTS FFPE: Collecting QOL on LTS CHARITÉ

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Project 2

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Genomic, epigenomic and biologic analysis
f LT survivors
Analysis of 52 samples

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Molecular and Immune Analysis

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RNA-Seq RNA extraction Library prep Sequencing Map to genome Count reads MiRNA-Seq Enrichment Library prep Sequencing Map to mir db Count reads MethyCap-Seq Methyl capture Library prep Sequencing Map to promoters Count reads Normalization Associate with LTS Pathway analysis Normalization Associate with LTS Integrate with RNA Normalization Associate with LTS Pathway analysis Immune System CD8, FOXP3, CD20 plasma cells, and tertiary lymphoid structures Normalization Associate with LTS

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LTS Versus STS Heatmaps

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RNA-seq microRNA-seq MethylCap-seq

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Multiplexed Immunofluorescence

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inForm software tissue segmentation tumor [red] versus stroma [green] multiplexed immunofluorescence CD3=green, CD4=red, CD8=pink, CD45RO=magenta, Cytokeratins=brown, DAPI=blue

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Integrated Analysis

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Gene Expression miRNA Methylation QOL Immune System Survival

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Methylation and RNAseq

2 4 6 8 −2 2 4 6 8

RNF212

Methylation Expression

correlation = −0.69 2 4 6 8 10 1 2 3 4 5

LYPLAL1

Methylation Expression

correlation = −0.68 −1 1 2 3 4 5 3.5 4.0 4.5 5.0 5.5 6.0

PNKP

Methylation Expression

correlation = −0.65 2 3 4 5 6 −4 −2 2 4

MTRNR2L10

Methylation Expression

correlation = −0.55 4 5 6 7 8 9 2 4 6

THNSL2

Methylation Expression

correlation = −0.55 2 4 6 8 10 −1 1 2 3 4

CIDEB

Methylation Expression

correlation = −0.54

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miRNA and mRNA-seq

Negative correlation between miR-634 and HOXA1 in LTS cohort Negative correlation between miR-521 and ERCC8 in LTS cohort

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PC Low PC High −6 −4 −2 2

IFNG

PC Low PC High 2 3 4 5 6

ISG20

PC Low PC High 3 4 5 6 7 8

OAS2

PC Low PC High −4 −2 2 4

SLC28A1

PC Low PC High −6 −4 −2 2

SLC9A3

PC Low PC High 4 5 6 7 8

TRIB2

PC Low PC High 4 5 6 7 8

DDX58

PC Low PC High 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0

NF1

RNA Pathways and Immune Infiltrates

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Phase II Additional Analyses

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Proteomics Angiogenesis SNP profiles and stress factors

(FFPE and plasma from GOG 218)

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Project 3

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Database development and analysis for QOL, PROs and Survivorship
Recruit, consent and pilot a survey on LT survivorship

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GOG 172 Database

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QOL data available for 355 patients
QOL assessments at 4 time points
Pre-treatment, pre-cycle 4, post cycle 6, 12 mo. post cycle 6
Data include:
FACT-O (Physical, Emotional, Social, and Functional Well-Being

plus Ovarian Cancer-specific Concerns)

Abdominal Discomfort
Neurotoxicity

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65 70 75 80 85 90

Pre Treatment Pre cycle 4 3-6 wk post cycle 6 12 mo post cycle 6

Mean Score

FACT-TOI

0-5 yrs 5-10 yrs >10 yrs p<0.001

FACT Trial Outcome Index over Time

GOG 172

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).

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Neurotoxicity does not differ between long-term and short- term survivors (p=0.82)

30 32 34 36 38 40 42 Pre Treatment Pre cycle 4 3-6 wk post cycle 6 12 mo post cycle 6

Mean Score

Neurotoxicity

0-5 yrs 5-10 yrs >10 yrs

p=0.82

Neurotoxicity over Time GOG 172

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Long-term survivors have similar abdominal discomfort at all time points compared to short-term survivors (p=0.079)

11 12 13 14 15

Pre Treatment Pre cycle 4 3-6 wk post cycle 6 12 mo post cycle 6

Mean Score

Abdominal Discomfort

0-5 yrs 5-10 yrs >10 yrs

p=0.079

Abdominal Discomfort over Time GOG 172

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LT Survivors Survey

Non-GOG LTS N=38

38 non GOG patients surveyed
19 qualitative interviews
QOL similar to immediately post

treatment

Approximately 1/3 of the survivors

reported significant fear of recurrence

Associated with poor emotional well-

being (p<0.001)

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LT Survivors Qualitative Interviews

Non-GOG LTS N=19

What is important for LT survivors?
Social support
Power of “giving back”
Positive spirit in the face of adversity
Understanding how cancer treatment

has affected other areas of my health

Identify the health care needs of survivors

specific to non-oncology specialties

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Phase 2 Additional Analyses

GOG 218 database

including integration with plasma stress factors and with gene expression

Additional non-GOG LTS surveys

including LT survivors from CHARITE and ICORG

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