Mello Abrams Lecture: Ovarian Cancer Update: Beth Karlan, MD
3 likes3,170 views
This document summarizes a presentation on precision cancer medicine and genomics in risk assessment and treatment for ovarian cancer. Some key points: 1) Precision cancer medicine aims to tailor treatments to patients' and tumors' genetic makeup to improve survival and avoid ineffective treatments, though this approach is not yet standard for most cancers. 2) Recent studies increasingly point to the fallopian tube, not the ovary, as the origin for many high-grade serous ovarian cancers. This has implications for screening and prevention strategies. 3) While early detection could significantly improve ovarian cancer survival rates, current screening methods have not proven effective and are sometimes harmful. New biomarkers and screening approaches are still needed.
Mello Abrams Lecture: Ovarian Cancer Update: Beth Karlan, MD
- 1. Beth Y. Karlan, M.D. Director, Women’s Cancer Program and Division of Gynecologic Oncology, Cedars-Sinai Medical Center Ovarian Cancer National Alliance Annual Conference 2015, San Diego, CA Genomics in Risk Assessment and Tailoring Treatment for Women with Ovarian Cancer Ovarian Cancer Update 2015
- 2. Precision Cancer Medicine • Has captured the imagination and hopes of patients, physicians, scientists, and industry • Treatments custom-tailored to patients’ and tumors’ genetic makeup to improve survival • Would avoid “wasted time” on ineffective strategies and also reduce toxicity • Successes to date have been exhilarating but approach still not standard for most
- 3. State of the Union Address 2015
- 4. Precision Medicine Initiative Includes plan to collect genetic data on one million Americans so scientists can develop drugs and treatments tailored to the individual characteristics of individual patients. $215 million Budget Request Includes: $130 million for research consortium $70 million for the NCI $10 million for the FDA $5 million for health information technology
- 5. • Goes beyond single gene test approach • Multiplex sequencing is becoming affordable and available in a clinically relevant timeframe • Can be done on tumor biopsy tissue or even “liquid biopsy” with CTCs or cfDNA • Opening the door to new era of clinical cancer genomics Corless; Science, 2011 Precision Cancer Medicine
- 6. Precision Medicine has Already Transformed the Therapeutic Approach to Lung Cancer Traditionally lung cancer was treated according to histology A growing list of genetic alterations have helped define subgroups Molecular therapeutics to target these mutations have demonstrated improved responses in clinical trials Companion diagnostics have been developed to match molecular target and treatment Lung Cancer outcomes have been improved by this individualized approach to therapy
- 7. Survival of patients with an oncogenic driver mutations who received targeted therapy was >1 yr longer compared to those without a driver mutation or targeted rx 2014
- 8. 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 2 4 6 8 10 ProportionSurviving Years After Diagnosis 1973-79 1980-89 1990-97 Progress Towards Improving Ovarian Cancer Survival Has Been Insufficient
- 9. Progress Towards Improving Ovarian Cancer Survival Has Been Insufficient
- 10. Multiple Strategies are needed to Reduce the Number of Women Dying from Ovarian Cancer • Improved therapeutic approaches: Scientifically-informed clinical trials accounting for tumor subtypes and molecular pathogenesis Targeted agents and immunotherapies Timing and Approach to Optimizing Cytoreductive Surgical Outcomes • Professional and Public Education • Early detection and Prevention
- 11. Multiple Strategies are needed to Reduce the Number of Women Dying from Ovarian Cancer • Improved therapeutic approaches: • Scientifically-informed clinical trials accounting for tumor subtypes and molecular pathogenesis • Targeted agents and immunotherapies • Timing and Approach to Optimizing Cytoreductive Surgical Outcomes • Professional and Public Education • Early detection and Prevention
- 12. Survival Correlates with Adherence to NCCN Guidelines Stage III/IV Women live twice as long when care is in accordance with standard guidelines (20 mos vs. 40 mos) Bristow RE, et al: JNCI 105:825, 2013
- 13. Gynecologic Cancer Education and Awareness Act: Johanna’s Law, signed in 2007
- 14. Testimony Before the United States House of Representatives: Gynecologic Cancer Education and Awareness Act Johanna’s Law
- 15. Multiple Strategies are needed to Reduce the Number of Women Dying from Ovarian Cancer • Professional and Public Education • Improved therapeutic approaches: • Scientifically-informed clinical trials accounting for tumor subtypes and molecular pathogenesis • Targeted agents and immunotherapies • Timing and Approach to Optimizing Cytoreductive Surgical Outcomes • Early detection and Prevention
- 16. Early Detection Would have a Greater Impact on Ovarian Cancer Survival than a New Therapy for Advanced Disease
- 17. Early Detection Would have a Greater Impact on Ovarian Cancer Survival than a New Therapy for Advanced Disease
- 18. Stage at diagnosis 5 Year Survival Early detection alone, with current day therapies, could increase overall survival by over 100% Most ovarian cancers are detected after they have already spread beyond the ovary and the 5 yr survival is < 30% I II III IV 0 25 50 75 100 0 25 50 75 100 I II III IV Thousands of Lives Could be Saved by Early Detection but an Effective Test Remains Elusive
- 19. Ovarian Cancer Screening in Asymptomatic Healthy Women (at average risk) is NOT Effective
- 20. WOMEN > 55 - 74 years STUDY GROUP 34,253 eligible women 212 primary invasive ovarian/tubal/peritoneal cancers 118 deaths CONTROL GROUP 34,304 eligible women 176 ovarian/tubal/peritoneal cancers 100 deaths • Annual screening with TVS and CA125 • Median follow up 12.4 years (10.9 -13) • No reduction in Ovarian Cancer Mortality (odds ratio 1.18; 95%CI 0.91-1.54) • 15% (163/1080) of patients who had ‘false positives’ went to surgery and had major complications The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial Buys, et al. JAMA 2011
- 21. • Ovarian cancer screening cannot be recommended in the general population • Screening using TVU and serum CA125 was harmful to some • This does not mean screening for ovarian cancer is not possible, but this strategy will not save lives. • We need to focus our efforts on understanding the origin and natural history of ovarian cancer and individualize risk groups to maximize the use of screening resources PLCO: Implications for Clinical Practice Buys, et al. JAMA 2011
- 22. UK Collaborative Trial of Ovarian Cancer Screening (UKTOCS) Trial 200,000 >50 years & post- menopause MULTIMODAL SCREEN GROUP CA 125 50,000 CONTROL GROUP 100,000 ULTRASOUND GROUP TV Ultrasound 50,000 OBJECTIVES Primary: Ovarian Cancer Mortality Secondary: Morbidity Health Economics Quality of Life Acceptability Compliance Additional: Serum Bank Ian Jacobs, Usha Menon, et al
- 23. UKCTOCS Multimodal Protocol USS Annual CA 125 ROC Algorithm SURGERY ABNORMAL INTERMED NORMAL Repeat CA 125 Ian Jacobs, Usha Menon, et al
- 24. Multimodality Strategy (MMS) Arm 46,237 women >50 yo (296,911 woman-yrs of annual screens) 640 surgeries, 133 primary invasive EOCs Sensitivity 85.8% (95% CI, 79.3%-90.9%) Specificity 99.8% (95% CI, 99.8%-99.8%) 4.8 surgeries/invasive EOC Detected ROCA alone detected 87.1% invasive EOCs ** Nearly double the performance of fixed cut off CA125s May 2015
- 25. CA125 used as a “Dynamic Biomarker” Finds More Early Cancers No mortality data yet, but disease “downstaging” seen as a result of MMS screening intervention: • 41.4% invasive EOC were Stage 1 or 2 disease • 82% were type II HGSC Menon U, et al JCO 2015
- 26. Perhaps we need to rethink our approach… • Early detection trials have not YET been able to reduce mortality • Many candidate biomarkers have been identified but none have performed well enough to apply to screening • Thus far, imaging has underperformed and remains expensive • Recent evidence points to precursor lesion in fallopian tube for high grade serous cancers • Primary prevention may be a better strategy than early detection for the majority ovarian cancers
- 27. EOC Subtypes and Unique Characteristics Bookman, et al. JNCI, 2014
- 28. Recent Findings Point to the Fallopian Tube as the Origin of Most HGSC • Occult cancers found at prophylactic surgeries on BRCAmut carriers are usually seen in the fimbria of the fallopian tube • In ovarian cancer cases, the fallopian tubes frequently contain serous tubal intraepithelial carcinoma (STIC) precursor lesions • Virtually all STICs contain TP53 mutations identical to those seen in almost all HGSC • Most high grade serous ovarian cancers originate in the fallopian tube
- 29. Ear Secretory Cell Transformation and Tumor Progression in the Fallopian Tube Fimbria Results in HGSC and Peritoneal Metastasis Ronny Drapkin, with permission
- 30. Author Number Tumor (%) Tubal Involvement (%) Colgan (2001) 39 5 (13) 4 (80) Leeper (2002) 30 5 (17) 3 (60) Powell (2005) 67 7 (10) 4 (57) Carcangiu (2006) 50 6 (12) 4 (67) Finch (2006) 159 7 (4) 6 (86) Callahan (2007) 100 7 (7) 7 (100) Hirst (2009) 45 4 (9) 4 (100) TOTAL 490 41 (8) 32 (78) Most Occult Cancers at RRSO in BRCAmut Carriers are in the Fallopian Tubes
- 31. Author Number Tumor (%) Tubal Involvement (%) Colgan (2001) 39 5 (13) 4 (80) Leeper (2002) 30 5 (17) 3 (60) Powell (2005) 67 7 (10) 4 (57) Carcangiu (2006) 50 6 (12) 4 (67) Finch (2006) 159 7 (4) 6 (86) Callahan (2007) 100 7 (7) 7 (100) Hirst (2009) 45 4 (9) 4 (100) TOTAL 490 41 (8) 32 (78) Most Occult Cancers at RRSO in BRCAmut Carriers are in the Fallopian Tubes
- 32. Author Number Tumor (%) Tubal Involvement (%) Colgan (2001) 39 5 (13) 4 (80) Leeper (2002) 30 5 (17) 3 (60) Powell (2005) 67 7 (10) 4 (57) Carcangiu (2006) 50 6 (12) 4 (67) Finch (2006) 159 7 (4) 6 (86) Callahan (2007) 100 7 (7) 7 (100) Hirst (2009) 45 4 (9) 4 (100) TOTAL 490 41 (8) 32 (78) Most Occult Cancers at RRSO in BRCAmut Carriers are in the Fallopian Tubes
- 33. Author Number Tumor (%) Tubal Involvement (%) Colgan (2001) 39 5 (13) 4 (80) Leeper (2002) 30 5 (17) 3 (60) Powell (2005) 67 7 (10) 4 (57) Carcangiu (2006) 50 6 (12) 4 (67) Finch (2006) 159 7 (4) 6 (86) Callahan (2007) 100 7 (7) 7 (100) Hirst (2009) 45 4 (9) 4 (100) TOTAL 490 41 (8) 32 (78) Most Occult Cancers at RRSO in BRCAmut Carriers are in the Fallopian Tubes
- 34. Kim et al. PNAS, 2012 Animal Models Further Highlight the Tubal Origin of Serous “Ovarian Cancer” Animals with conditional Dicer- Pten deletions develop ascites, fallopian tube tumors that spread to ovaries, and have extensive peritoneal metastasis resembling human disease. Kaplan-Meier survival curve of control and DKO animals demonstrate lethality of lesion. Tumor histology with papillary structures and nuclear polymorphism is characteristic of HGSC
- 35. Kim et al. PNAS, 2012 Unilateral oophorectomy Bilateral oophorectomy Unilateral salpingectomy Bilateral salpingectomy Bilateral Salpingectomy Prevents Tumor Development, Metastasis and Death Animal Models Further Highlight the Tubal Origin of Serous “Ovarian Cancer”
- 36. Ovarian Cancer May be a Preventable Disease Serous Tubal in situ Carcinoma (STIC) Removing the ovaries doesn’t prevent ovarian cancer, but removing the fallopian tube does. Seems to be an important lesson there!
- 37. Salpingectomy significantly reduced ovarian cancer risk: HR 0.65 (95% CI=0.52-0.81) “Dose Response”: Bil-Salp twice as effective as Uni-Salp HR 0.35 vs 0.71 >250,000 women who had surgery for benign indications and 5.5 million controls
- 38. Salpingectomy significantly reduced ovarian cancer risk: HR 0.65 (95% CI=0.52-0.81) “Dose Response”: Bil-Salp twice as effective as Uni-Salp HR 0.35 vs 0.71 >250,000 women who had surgery for benign indications and 5.5 million controls CONCLUSION: Removal of fallopian tubes by itself is an effective measure to reduce ovarian cancer risk in the general population
- 39. 158 women undergoing TLH +/- BS-OR: They assessed AMH, FSH, antral follicle count, ovarian size and blood flow (by TVS and Doppler) April 2013
- 40. 158 women undergoing TLH +/- BS-OR: They assessed AMH, FSH, antral follicle count, ovarian size and blood flow (by TVS and Doppler)—and found no difference April 2013
- 41. 158 women undergoing TLH +/- BS-OR: They assessed AMH, FSH, antral follicle count, ovarian size and blood flow (by TVS and Doppler)—and found no difference No difference in OR time, p-op Hgb, hospital stay, or recovery April 2013
- 42. 158 women undergoing TLH +/- BS-OR: They assessed AMH, FSH, antral follicle count, ovarian size and blood flow (by TVS and Doppler)—and found no difference No difference in OR time, p-op Hgb, hospital stay, or recovery CONCLUSION: BS-OR appears safe and should be widely considered to prevent ovarian cancer April 2013
- 43. Pathologic Conditions that Could be Avoided with Routine Salpingectomy
- 44. Routine Salpingectomy Should Be A New Standard of Care
- 45. Routine Salpingectomy Should Be a New Standard of Care • It’s safe and can prevent most ovarian cancers • It can reduce rates of post-hysterectomy adnexal masses • It should be performed: –As a standard part of hysterectomy procedures –In place of tubal ligation for sterilization –At C-sections, if childbearing complete
- 46. Multiple Strategies are needed to Reduce the Number of Women Dying from Ovarian Cancer • Improved therapeutic approaches: Timing and Approach to Optimizing Cytoreductive Surgical Outcomes Targeted agents and immunotherapies Scientifically-informed clinical trials accounting for tumor subtypes and molecular pathogenesis • Professional and Public Education • Early detection and Prevention
- 47. Cytoreductive Surgery to NO visible disease has the greatest impact on Overall Survival Dubois et al, Cancer, 2009
- 48. Is it Surgical Effort or Tumor Biology that determines cytoreduction status? We need a way to reliably predict no visible residual disease preoperatively to better inform our clinical decision making
- 49. Individualize the Surgical Approach to Assess Likelihood of Optimal Cytroreduction Women w/ suspected ovarian cancer Primary Assessment Ovarian Cancer QI Committee Laparoscopy: Validated score R0 not feasible NACT R0 feasible Primary TRS Courtesy of A. Sood Triage Laparoscopy
- 50. Optimal Interval Cytoreduction Molecular Predictor of Residual Disease Could Help Direct Treatment and Improve Survival Remission Remission Chemotherapy Adjuvant RXs Targeted +/- Immuno- RXs + Tumor Signature Or Serum Biomarkers
- 51. Multiple Strategies are needed to Reduce the Number of Women Dying from Ovarian Cancer • Improved therapeutic approaches: Timing and Approach to Optimizing Cytoreductive Surgical Outcomes Targeted agents and immunotherapies Scientifically-informed clinical trials accounting for tumor subtypes and molecular pathogenesis • Professional and Public Education • Early detection and Prevention
- 53. Molecularly Targeted Agent with Companion Diagnostic now available for some Ovarian Cancers
- 54. Cancer Immunotherapies Are Significantly Improving Treatment Responses and Survival
- 55. There are Many Opportunities for Immune Modulation in Ovarian Cancer: Especially in Certain Subtypes Zsiros, E, et al Current Opinon-Oncology
- 56. Multiple Strategies are needed to Reduce the Number of Women Dying from Ovarian Cancer • Improved therapeutic approaches: Timing and Approach to Optimizing Cytoreductive Surgical Outcomes Targeted agents and immunotherapies Scientifically-informed clinical trials accounting for tumor subtypes and molecular pathogenesis • Professional and Public Education • Early detection and Prevention
- 57. Ovarian Cancer is Many Diseases and Molecularly Complex Vaughan S, et al.: Nature Reviews 2011
- 58. EOC Subtypes and Unique Characteristics Bookman, et al. JNCI, 2014
- 59. Jamal-Hanjani, M, et al. CCR, 2015 Selection pressures such as chemotherapy or microenvironment factors such as hypoxia, infiltrating stromal and immune cells can contribute to therapeutic failure and resistance Tumor Heterogeneity and Clonal Evolution
- 60. Identifying Actionable Molecular Drivers at a Specific Point in Time Remains Challenging • Establishing clonal dominance of a driver event from one biopsy is not trivial • Need to determine stability of actionable alterations—both spatially and longitudinally through disease course in order to distinguish clonally dominant events • Use of NGS for patient stratification and data interpretation will help determine drug-target interaction and response to therapy • Need to keep in mind “inconsequential mutations” that accumulate over time, esp in hyper-mutant tumors. (Bioinformatic algorithms can help predict these somatic mutations)
- 61. Cellular and Genomic Context of Mutations to Guide Treatment Decisions Cellular context matters: Melanomas vs Colon cancers with BRAFv600E mutations Clonal diversity: Small cell hypercalcemic ovarian cancer vs high grade serous ovarian cancer Acquired resistance mutations: To drug target or activated downstream or parallel pathway Identification of Driver vs Passenger mutations Horlings, et al, JAMA Oncology, 2015
- 62. Gerlinger M, et al.: NEJM 366:883; 2012 Tumor Heterogeneity Presents Significant Challenge to Precision Cancer Medicine Biopsies obtained from multiple tumor sites demonstrate marked molecular heterogeneity--with no two sites being identical.
- 63. Adapting Clinical Trials to Address Cancer Heterogeneity • Current trials begin to address inter-patient heterogeneity—but not dynamic tumor changes or the intra-tumor clonal heterogeneity • Frequently based on only one biopsy site, despite recognition of clonal and subclonal frequencies • Often uses archival tissue vs freshly procured biopsy • How do we maximize therapeutic benefits of molecular profiling information? • Need to harness realities of cost, access to sufficient tumor tissue DNA quality/quantity
- 64. Tumor Biopsy Sample Prep Pathology Sequencing Analysis Gene ALK BRAF EGFR ERBB2 PIK3CA PTEN Status WT V600E WT WT WT WT CLIA Pending Sequence Results Can this be done in a clinically relevant timeframe? 28 days Tumor Biopsy to Sequencing Results Roychowdhury S, et al.: Sci Transl Med; 2011
- 65. >60% tumor Tumor Biopsy Sequencing & Analysis Buccal swab or Blood (germline) Target X Target Y Target Z Discovery Trial: X Trial: Y Trial: Z Basic Research Treatment Recommendations Based on Molecular Analysis, Targetable Genes, and Available Agents Roychowdhury S, et al.: Sci Transl Med; 2011
- 66. Roychowdhury S, et al.: Sci Transl Med ; 2011 Treatment decisions now require a multidisciplinary discussion between clinicians, pathologists, geneticists, translational scientists and ethicists A New Paradigm in Clinical Decision Making
- 67. Precision Cancer Medicine Clinical Trials • Umbrella Trials: One histology (stem) but evaluates multiple predictive biomarkers (spokes) to offer drug matching under one protocol (e.g. I-SPY2, ALCHEMIST trials) • Basket Trials: Histology agnostic but tumors share a common molecular aberration are in the same basket and matched with a targeted drug (e.g. NCI-MATCH trial)
- 68. NCI MATCH: Molecular Analysis for Therapy CHoice
- 69. NCI MATCH: Molecular Analysis for Therapy CHoice
- 71. Novel Precision Medicine Clinical Trials are Needed in Ovarian Cancer • Trials utilizing “one size fits all” approach have yielded disappointing results—we need to move beyond Plat-S and Plat-R criteria! • Molecular subgroups can be defined but tumor heterogeneity and adaptive changes remain poorly understood and difficult to target • We need better (non-invasive) ways to molecularly profile tumors at recurrence (such as core biopsy(s), CTC, cfDNA, molecular imaging, etc) • Individualized treatments to match tumors trajectory and heterogeneity are needed
- 72. Precision Cancer Medicine is Here to Stay • Number of agents available to target molecular drivers is rapidly increasing • Companion diagnositics enable matching of right agent to an individual patient/tumor • Organ-agnostic clinical trials are in progress • FDA Fast Track Designation Program was designed to get important new drugs to the patient faster • Treatment algorithms based on molecular targets are already improving outcomes for some patients BUT—”personalized medicine” is still a goal and not a reality for most patients. We need to advocate and fast track advances for ovarian cancer
- 73. Call to Action • Ovarian cancer is a disease in urgent need of more effective therapies and improved outcomes • Effective prevention and early detection strategies will offer an avenue to reduced mortality • Molecular signatures may allow us to better triage patients to surgery and point to scientifically- informed therapeutic strategies • “One size fits all” approaches need to be abandoned • New insights into the tumor microenvironment, immune modulation, microbiome influences, lifestyle, etc—will further add to therapeutic success
- 74. Maintaining “Personable-ness” in Personalized Medicine: Doctoring Should Still Play a Role
- 75. Women’s Cancer Program Cedars Sinai Medical Center