Newly Diagnosed: Ovarian Cancer 101, Gordon Mills, MD, PhD
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This document discusses high grade serous ovarian cancer (HGSOC), the most common and aggressive form of ovarian cancer. It provides details on: - HGSOC is driven primarily by DNA copy number changes rather than recurrent mutations. - Opportunities for targeted therapies exist for genomic aberrations impacting p53, homologous recombination repair, and other commonly mutated genes. - Improving rates of complete tumor resection (R0) through a personalized surgical approach can significantly improve patient outcomes. - Several clinical trials are exploring targeted agents and immunotherapy approaches, along with developing patient-derived xenograft models to advance precision medicine for HGSOC.
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Newly Diagnosed: Ovarian Cancer 101, Gordon Mills, MD, PhD
- 1. DREAM TEAM DREAM NO SMALL DREAMS GOETHE TIME MAGAZINE WOMEN’S CANCER MOONSHOT
- 2. Ovarian Cancer Karst and Drapkin et al Faculty 1000 Medicine High Grade Serous Ovarian Cancer Is Probably Fallopian Tube Cancer • 22,000 new cases and 15,500 deaths in the USA • Low grade and high grade tumors have distinct genomic aberrations • Low grade and high grade tumors do not interconvert • HGSEOC is the most common and aggressive form of ovarian cancer
- 3. DIFFERENT HISTOLOGICAL SUBTYPES OF OVARIAN CANCER INDICATE DIFFERENT THERAPEUTIC OPPORTUNITIES Serous Endometrioid Mucinous Clear cell High grade low grade High grade low grade Low grade serous KRAS Clear Cell PIK3CA mutations Endometrioid ARID1A mutation and deletion Mucinous Probably metastatic colon High grade serous p53, BRCA1/2 copy number long tail of actionable mutations Targeted agents Bevaczumib PARP inhibitors have now been FDA approved
- 4. Chris Sander Rab25 Adar1 PIK3CA PIK3CB PKCi Mecom mir 569, 551 Snon Cldn 7 Tert HER2 PTEN Ovarian Cancer Myc High grade serous ovarian cancer is driven by copy number changes with low frequency of recurrent mutations Copy number changes may provide opportunity for immunotherapy
- 5. HGSEOC is primarily driven by DNA copy number abnormalities with p53 and BRCA1/2 pathway mutations Gene % of mutations TP53 96.4 CSMD3 4.8 FAT3 4.8 NF1 3.2 BRCA1 2.7 BRCA2 2.5 CDK12 2.2 RB1 1.5 GABRA6 1.5 Somatic Mutated Genes in HGSEOC TCGA Ovarian Network Joe Gray Rab25 PRKCI, MECOM Snon,PIK3CA, TERT mir551 569 MYC PVT1 Cyclin E BRCA1/2 germline mutations and loss in 20- 25% of of ovarian cancers Improved patient outcomes
- 6. Opportunities associated with genomic aberrations in high grade serous ovarian cancer • P53 – Wee1 inhibitors have increased activity in p53 mutated tumors – P53 is frequently retained but unfolded and non-functional • Can be normalized by a number of compounds – COTI2, ZMC1, Prima1 – P53 loss is common • Can result in loss of nearby genes – POL2RA heterozygous loss can sensitize to alpha amanitin • Homologous Recombination (HR) defects – Almost half of HGSEOC have evidence for defective HR – A number of assays have been developed to identify patients likely to benefit from targeting HRD – Sensitize to platinum based therapy – PARP therapy is demonstrating activity • Rational Combinations with PARP therapy • Almost half of all HGSEOC have a mutation in an actionable gene – Are these drivers or passengers Will targeting these genes benefit patients
- 8. The Impact Of Residual Tumor: What Is Optimal Debulking? Progression-free survival Overall Survival Dubois et al, Cancer, 2009: Mar 15; 115(6): 1234-44 R0 R0 R0 25% 0 < R1 <1 cm 50% R2 > 1cm 25%
- 9. Rates of R0 resection Nick et al., Nature Rev Clin Oncol, 2015
- 10. Opportunity For Quality Improvement: Personalized Surgical Therapy Implementation of evidence-based patient care guidelines Multidisciplinary approach Improvement in the quality of surgical care Standardized care Improvement in rates of complete gross resection (R0) with reciprocal improvement in patient overall survival Developing a personalized surgical approach that translates across different clinical practice settings
- 11. Women w/ suspected ovarian cancer Primary Assessment Laparoscopy: Validated score Intraoperative agreement R0 not feasible Neo-adjuvant chemotherapy R0 feasible Primary tumor reductive surgery Tissue Immune & molecular analyses Opportunity For Quality Improvement: Personalized Surgical Therapy
- 12. Primary cytoreduction 20% 88% (n = 87) NACT → Interval cytoreduction 60% 76% (n = 65) Surgical Outcomes (R0 Rates) since implementation of Flagship 2A Pre- implementation Post- implementation Major effort focused on R0 resection included education, clinical retreats (consensus among all 21 gynecologic oncologists), and engaging other specialties (e.g., thoracic, GI surgery) Compliance is over 98%
- 13. Flagship 2B: Novel Clinical Interventions Develop integrated predictors of response to standard chemotherapy Assess tumor heterogeneity and molecular evolution to determine adaptive responses to standard therapeutics Novel clinical trial designs
- 14. New Moonshot Projects - FP2B HGSOC FlagshipProject2 LSC Score <8 FP2b Phase 0 “Window” trials 1-2 wks Single Agents “POSITION” Trial Debulking Tissue acquisition Novel therapy vs. Std therapy Score >8 FP2b Phase Ib-2 Treatment Trials NACT Pac/Carbo + novel Debulking Adjuvant Pac/Carbo + novel Tissue acquisition Tissue acquisition
- 15. Clinical Trial Standard of Care Matched sites Ovary/Primary Omentum Diaphragm Other peritoneum Ovarian Cancer Window of Opportunity Trial Analysis: • HRD assessment • DNA, RNA, Protein • Immune profile • Generation of PDX and lines
- 16. Flagship 2C: PDX Models - Transition to the clinic Development of breast and ovarian cancer patient-derived xenograft models: • Molecularly characterized (DNA, RNA, protein) • Therapy naïve • TNBC: >10 (6 genomically characterized) • HGSOC: 10 • Post-therapy/resistant • TNBC: 5
- 17. Project 2A/B – Agents • DNA Damage – PARPi: BMN-673, olaparib, – Wee1 AZD-1775 – CHK1/2 – ATR, ATM – BRD4 • PI3K pathway: BKM120, BYL219, AZD2014, AZD5363, Copelesib • Angiogenesis: Dll4 (demcizumab), TAMs (AC708) • Immune: PD-1 (MK-3475) PDL-1 (Medimune) • P53: AZD-1775, COTI-2 • Others: Prolanta (PrL), KPT-330
- 18. Expanding our Program Regional care centers in the greater Houston area • Katy, The Woodlands, Sugarland, Bay Area and Pearland • LBJ Hospital (Houston, TX) • MDACC Cancer Network MD Anderson Cancer Center at Banner and Cooper National and International Sister Institutions Other national and international centers
- 19. Building a Pipeline for Future • Translational biology • P53 based approaches – synthetic lethality • New animal models and imaging to prioritize the massive numbers of potential new targets and drugs • Rational combination therapy: new combinations of kinase inhibitors; identify synergistic combinations with PARP inhibitors • Immune modulation/inflammation as therapy targets • Re-define “druggable” targets – co-extinction strategies • Survivorship • Identify and validate predictors of long-term survival • Predictors of toxicity • Early Detection and prevention • New biomarkers for screening and drugs for prevention
- 20. WOMEN’S CANCER MOONSHOT BRCA1 and BRCA2 10% of TNBC or HGSOC Family history TNBC or HGSOC Predisposition to breast and ovarian cancer BRCA2 Male breast cancer Prevention decreases risk by at least 80% New therapy (PARPi) effective for patients
- 21. Germline BRCA-1 and -2 testing (>10% will be positive) FP1A Active Outreach FP1C Screening Prevention Offer genetic testing to all patients with TNBC or HGSOC NCCN Guidelines No charge to patient or MDACC Making Cancer History for the Family
- 22. SCOPE OF PROBLEM: PREVENTING FUTURE OVARIAN CANCERS IN FIRST DEGREE RELATIVES BY TESTING FOR BRCA MUTATIONS Reference strategy 0 tested 0 test+ SGO criteria 4,005 tested 900 test+ Test serous CA 9,337 tested 1,252 test+ Test all 14,000 tested 1,481 test+ 14,000 women with ovarian cancer in U.S. (index cases) 0 FDR tested 0 test+ 216 Ov Ca 1,800 FDR tested 988 test+ 157 Ov Ca 2,504 FDR tested 1,288 test+ 137 Ov Ca 2,962 FDR tested 1,418 test+ 121 Ov Ca 27% 37% 44%Kwon et al, JCO 2009 Despite this, less than 50% of patients offered testing at MDACC and less than 25% elsewhere
- 23. Breast Ovarian Number of patients 2458 680 Number of pts. tested at MDA 1729 389 Percentage tested 72% 57% BRCA⁺ among TNBC/HGSOC 51 73 Percent positive 14% 19% FAMILY OUTREACH PROTOCOL (REACH) Total number of family members 121 Contacted 47 (50%) Current Reporting Metrics for TNBC/HGSOC Patients (9/1/2012 – 3/31/15) IMPACT: Increased testing rate from 25% to 65%!!
- 24. Making Cancer History for the Family Previvors • Surgical Prevention • Chemoprevention • Screening • Recently Funded-SU2C • CHECMATE Trial - CHance to End hereditary ovarian Cancer by MAking Testing better and Easier • WISDOM Trial - Women choosing Interval Salpingectomy with Delayed Oophorectomy to postpone Menopause
- 25. Best way to improve outcomes is to prevent the disease 5 years 80% decrease in deaths in family members 12% improvement in survival Making Cancer History for the Family
- 26. 20-50% of patients will have a defect BRCA1 or BRCA2 function PARP-inhibitor based therapy 8 fold improvement Offer genetic testing to all patients with TNBC or HGSOC HELPING THE PATIENT
- 27. Academic Industrial Collaboration Other moonshots Identification of patients likely to benefit HELPING THE PATIENT Rational combination therapy with PARPi 7 new trials
- 28. Improving outcomes across Houston, Texas and the world PARADIGM SHIFT Patient Family
- 31. Current state-of-knowledge Front-line Therapy: - Surgery • Comprehensive staging or cytoreduction for metastatic disease • Tumor residuum is the strongest prognostic factor - Adjuvant therapy • Nearly all cases • Platinum-taxane based Recurrence Therapy: – Chemo-sensitive disease • Approach like frontline therapy • Surgery (+/-) • Platinum based – Chemo-resistant disease • Emergence is cause of death • Multiple agents of poor response Roles of biologic and maintenance therapy are evolving Somearecured! Nonearecured!