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Serous Epithelial Ovarian Cancers: A Pathologic and Clinical Perspective

Serous Epithelial Ovarian Cancers: A Pathologic and Clinical Perspective. Amanda Nickles Fader, MD Associate Professor, The Kelly Gynecologic Oncology Service Johns Hopkins Medicine. Disclosures. I have no financial relationships to disclose. My First Patient: Erin. Optimal Debulk to R0

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Serous Epithelial Ovarian Cancers: A Pathologic and Clinical Perspective

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  1. Serous Epithelial Ovarian Cancers: A Pathologic and Clinical Perspective Amanda Nickles Fader, MD Associate Professor, The Kelly Gynecologic Oncology Service Johns Hopkins Medicine

  2. Disclosures • I have no financial relationships to disclose

  3. My First Patient: Erin Optimal Debulk to R0 Stage III low-grade serous carcinoma A crazy chemo regimen that included carbo/doxil/avastin NED x 76 months

  4. Objectives • To review the epidemiology, molecular biology and clinical behavior of low-grade (LGSC) compared with high-grade serous carcinoma of the ovary (HGSC) • To review the clinical trials facilitated from the rare tumor networks • To understand the evidence supporting best surgical, chemotherapeutic and hormonal practices for LGSC vs HGSC

  5. One Size Doesn’t Fit All • Most medical treatments are designed for the “average patient ” as “one-size-fits-all-approach,” that is successful for some patients but not for others • Precision medicine: an innovative approach to disease prevention and treatment that takes into account differences in people’s genes, environments and lifestyles • Pioneering studies in GYN Oncology with an emphasis on rare tumors • United States President Obama’s Precision Medicine Initiative

  6. Background • Epithelial ovarian cancer (EOC) is not one, but several, distinct entities • Yet in last decade, most women with EOC have been treated identically • Advances in the understanding of heterogeneity of ovarian malignancies • Refining pathologic diagnostic criteria • Molecular biology and genetics Jemal, Cancer Stats. 2014

  7. Background • Serous carcinomas: 65% of all epithelial ovarian cancers • Histologic grade an important determinant of survival Malpica et al, Am J Pathol 2007; Vang et al, Am J Surg Path, 2008

  8. Two-tiered Histologic Criteria LGSC HGSC Malpica et al, Am J Path, 2007

  9. High-grade serous carcinoma mimicking serous borderline tumor at low-power

  10. High-grade serous carcinoma with high-grade cytology and mitotic activity

  11. Typical Serous Borderline Tumor

  12. Clear cell CA mimicking Micropapillary Serous Borderline Tumor

  13. Micropapillary Serous Borderline Tumor

  14. Ancillary Analysis: GOG 158 • Retrospectively reviewed data of 290 patients with stage III serous carcinoma of the ovary treated with upfront surgery + T/C chemo • Panel of 6 GYN pathologists performed a blinded review to reclassify these tumors using the binary grading system • With binary system, patients with LGSC had significantly longer PFS than those with HGSC • Multivariate analysis: no difference in outcome in patients with grade 2 or 3 tumors using FIGO system Bodurka et al, Cancer, 2011

  15. Hormonal Receptors • LGSC 3x more likely to robustly express estrogen and progesterone receptors than HGSC

  16. Map Kinase Pathway

  17. Mutations of LGSC • LGSC driven by activating mutations of: • PIK3CA (40%) • Inactivating mutations of PTEN (3-8%) • Expression of insulin-like growth factor (IGF) receptor • PIK3CA mutations, like PTEN loss, lead to constitutive activation of PI3K signaling • Downstream effectors of IGF pathway, including PI3K/AKT/mTOR have well-established roles as mitogens in carcinogenesis

  18. Segregation of LGSC vs. HGSC in Genomic Profiling Studies Bonome et al, Cancer Res. 2005

  19. Epidemiology • LGSC accounts for 10% of all serous ovarian carcinomas • 3-5% of all epithelial ovarian cancers • Serous borderline tumor--a precursor lesion to LGSC, which likely originates in the ovary • Deleterious BRCA1 and 2 mutations infrequently observed with LGSC, but observed in as high as 18-47% of women diagnosed with HGSC Gershenson et al, Gynecol Oncol, 2012 Fader et al, Obstet Gynecol, 2013

  20. Epidemiology • Women w/ LGSC diagnosed at a younger age and have a longer overall survival than those with HGSC • Pooled retrospective data on 5-year survival • 40-56% for advanced LGSC versus 9-34% for HGSC • LGSC have lower response rates to conventional chemotherapy and overall poor survival outcomes

  21. Surgery is the mainstay of therapy.

  22. Survival by Residual Disease After Primary Cytoreductive Surgery: GOG 182 • An ancillary analysis of women with stage III-IV epithelial ovarian cancer • Treated with primary cytoreductive surgery • T/C compared with triplet or sequential doublet regimens • 189 had Grade 1 disease (surrogate for LGSC) • On multivariate analysis, only residual disease status after primary debulking was significantly associated with survival (p=.006) Fader et al, Obstet Gynecol, 2013

  23. Survival by Residual Disease After Primary Cytoreductive Surgery: GOG 182 *Grade 1 serous used as a surrogate For LGSC N=187 patients P<.001 Fader et al, Obstet Gynecol, 2013

  24. Survival by Residual Disease After Primary Cytoreductive Surgery: GOG 182 *Grade 1 serous used as a surrogate For LGSC N=187 patients P<.001 Fader et al, Obstet Gynecol, 2013

  25. Role of 2ndary Cytoreduction 41 pts; Median time between primary tumor debulking and SCRS was 33.2 months 32 (78%) had gross residual disease at the completion of secondary surgery The median PFS w/ NGRD after SCRS was 60.3 months, compared to 10.7 months for patients with gross residual disease (p = 0.008) Median OS w/ NGRD after SCRS was 167.5 months compared to 88.9 months (p = 0.10) Crane et al, Gynecol Oncol, 2015

  26. Neoadjuvant chemotherapy? • Relative chemoresistance also observed in a review of women who received neoadjuvant chemotherapy for advanced stage LGSC • 25 patients, median age 45 years • Only 4% response rate • Half of evaluable patients had a greater than 50% reduction in serum CA 125 levels after chemo--only one patient had an objective response by imaging assessment Schmeler et al, Gynecol Oncol. 2008

  27. CA-125? • Are standard parameters for evaluation of response—serial imaging and CA 125—adequate determinants of outcome? • What is the prognostic significance of serum CA-125 levels in women with LGSC?

  28. CA-125 Response Rates in Grade 1 Serous Carcinoma • Ancillary analysis of GOG 182 • 184 had grade 1 serous disease and CA-125 levels Fader et al, Gynecol Oncol. 2013

  29. CA-125 Normalization During Chemo and Survival Fader et al, Gynecol Oncol. 2013

  30. Chemotherapy After Primary Cytoreductive Surgery? • Evidence to date suggests that LGSC relatively resistant to first-line chemotherapy • MD Anderson: Review of 112 patients with newly diagnosed stage II-IV LGSC treated with primary surgery and platinum-based chemotherapy • Median age 43 • Treatment not as successful as expected given high frequency of persistent disease at completion of therapy and low negative second-look rate • Only 52% of patients were disease-free after PCS and completion of platinum-based chemo Gershenson et al, Gynecol Oncol. 2008

  31. MD Anderson Experience • Stage I –IV LGSC and Stage II-IV LGSPC • 350 eligible patients • Median PFS 28.1 months • Median OS 101.7 months • MV analysis: compared w/ women age ≤35 years, those diagnosed at age >35 years had a 43% reduction in likelihood of dying (hazard ratio, 0.53; 95% CI, 0.37 to 0.74; P < .001) Gershenson et al, JCO, 2015

  32. MD Anderson Experience: The Impact of Residual Disease • Having disease present at completion of primary therapy was associated with a 1.78 increased hazard of dying compared with being clinically disease free (P < .001) Gershenson et al, JCO, 2015

  33. MD Anderson Experience • Similar trends noted in the smaller patient LGSPC cohort • Women with LGSPC had a 41% decreased chance of dying (hazard ratio, 0.59; 95% CI, 0.36 to 0.98; P = .04) compared with those with LGSOC Gershenson et al, JCO, 2015

  34. So… • Is chemotherapy beneficial in the treatment of low grade serous carcinoma of the ovary? • Well…it depends

  35. Chemotherapy for Recurrence: Appraisal Farley et al, Lancet Oncol. 2013; Gershenson et al, Gynecol Oncol. 2012; Gershenson, et al Gynecol Oncol. 2009

  36. Evolution of Clinical Trials in LGSC • Development of the binary grading system for serous carcinomaand establishment of the GOG Rare Tumor Committee in 2005 • Led to recognition of this histologic subtype • Dawn of separate clinical trials for women diagnosed with this rare malignancy • Principle of separate clinical trials for major rare histologic subtypes of ovarian cancer subsequently validated in two consensus confereneces • Clear cell carcinoma, mucinous carcinoma, and LGSC Stuart GCE, In J Gynecol Oncol, 2011

  37. MEK Inhibition: GOG 239 • Primary objectives: • Determine response rate of patients and toxicity of selumetinib • Secondary objectives: • Estimate PFS and OS • Translational research objectives: • BRAF and KRAS mutation analysis and relationship with tumor response Farley et al, Lancet Oncol. 2013

  38. GOG 239 • Selumetinib: potent, selective, orally-available, and non-ATP competitive small molecule inhibitor of mitogen-activated protein (MAP) kinase kinase, MEK-1/2 • Open label Phase II study • Eligibility • Women with recurrent low-grade serous (invasive micropapillary) carcinoma of ovary or peritoneum • Biopsy proven • Prospective pathologic evaluation • Treatment: selumetinib 50 mg BID (4 wks = 1 cycle) Farley et al, Lancet Oncol. 2013

  39. N=52 patients Farley et al, Lancet Oncol. 2013

  40. Survival Outcomes: GOG 239 Farley et al, Lancet Oncol. 2013

  41. Mutational Analysis of LGSC Tumors • 65% of tumors found to have a mutation in one of 114 oncogenes • 62% specimens with mutations in RAS genes • 6% specimens with mutations in BRAF gene • Newly identified mutations in N and H ras genes Farley et al, Lancet Oncol. 2013

  42. Extraordinary Responders:LGSC • Next-gen sequencing was used to analyze a pt >5 yr PFS patient's tumor as well as an additional 28 SB/LGS tumors • Analysis of extraordinary responder's tumor identified a 15-nucleotide deletion in negative regulatory helix of the MAP2K1 gene encoding for MEK1 • Retained sensitivity to selumetinib • Additional mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions Grisham et al, JCO, 2015

  43. The Johns Hopkins Experience • Since 2011, have treated women with advanced LGSC after primary cytoreductive surgery with hormonal therapy alone • Aromatase inhibition • Continue indefinitely until disease progression or toxicity

  44. Patient 1 • 38 year old w/ Stage IV LGSC—extensive parenchymal liver metastases and carcinomatosis • Carbo/Taxol x2—disease progression and SBO • Debulk with total colectomy, diaphragm, spleen, ileostomy—July 1, 2014 • Optimal <1 cm residual but tiny parenchymal liver mets could not be debulked

  45. Patient 1 • Tumor • ER +90% • PR +40% • AI initiated—CT @ 6 months w/ regression of all liver mets • Asymptomatic w/ tiny, stable liver mets x 18 months

  46. Future Directions: LGSC Trials • Whether high rate of stable disease observed in studies of both primary and recurrent LGSC relates more to tumor biology and cytoreductive effort or the influence of chemotherapy remains unclear • Biomarker-driven clinical trials will increase opportunities to refine existing treatments and may optimize survival outcomes for women with LGSC

  47. Future Directions: LGSC Trials • Ancillary analysis of GOG IP trials and impact of IP chemo on low-grade, type I epithelial subtypes • Neoadjuvant MEK +/- AKT study in advanced LGSC—NRG vs. institutional

  48. Trials Under Development: GOG/NRG RTC Randomized Phase II (Fader/Gershenson) Primary ovarian, fallopian tube or PPC LGSC Attempt at maximal surgical cytoreduction Carboplatin/paclitaxel x 6 cycles Trametinib and AKT inhibitor x6 cycles f/b maintenance

  49. Conclusions • Development of binary (two-tiered) grading system for serous carcinoma of the ovary has facilitated the concept of separate clinical trials for this rare subtype • Low-grade serous carcinoma associated with • 20%-40% frequency of KRAS mutations, a 5% frequency of BRAF mutations, and a high rate of ER and PR positivity • PI3K and IGF pathway significant- • Potential for MTOR and AKT inhibition

  50. Thank You! • Dr Vang • Our patients

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