Mucinous Ovarian Carcinoma

Transcription

1 Mucinous Ovarian Carcinoma Professor Timothy Perren Leeds Institute of Cancer Medicine & Pathology St James s Institute of Oncology University of Leeds and St James s University Hospital Leeds UK

2 Mucinous ovarian tumours 15% of all ovarian neoplasms Continuum from benign borderline malignant benign mucinous cystadenoma 10-15% mucinous tumours of low malignant potential (mucinous borderline tumours) 67% invasive mucinous adenocarcinoma tumours metastatic to the ovary 4%

3 Mucinous Tumour - Ovary

4 Pseudomyxoma peritonei

5 Pseudomyxoma peritonei

6 Appendix

7 Mucinous Carcinoma Primary Unilateral >10cm Metastatic Bilateral If Unilateral <10 cm Seidman J.D. et al Am J Surg Pathol 2003; 27: 985 The Leeds Teaching Hospitals NHS Trust

8 Mucinous carcinoma MC rarely bilateral present as Stage Ia Grade 1 or 2 treated by surgical resection and no adjuvant chemotherapy Recurrent or metastatic MC associated with poor prognosis Unusual sites for mets (lung/bone) Mucinous carcinoma (show reduced mucin cf borderline mucinous tumours) Most of intestinal type endocervical (Mullarian type) rare

9 Distinction between primary ovarian carcinoma and metastases to the ovary (1) Feature Primary Metastatic Laterality Unilateral Bilateral Size Max diameter > 12 cm Max diameter < 10 cm Extensive intraabdominal spread Multinodular growth pattern with intervening normal parenchyma Surface involvement Unlikely Not usual Not usual (other than background endometriosis) More likely Characteristic Characteristic Hilar involvement Absent/not typical Typical Extensive vascular invasion Not usual Favours metastasis Singh, N; 2014

10 Distinction between primary ovarian carcinoma and metastases to the ovary (2) Feature Primary Metastatic Patterns specifically favouring primary or metastatic carcinoma Associated benign, borderline and malignant appearing areas Complex papillary architecture Association with background changes such as endometriosis, Brenner tumour, mature cystic teratoma, Sertoli- Leydig cell tumour, adenofibroma Beware phenomenon of maturation of ovarian metastases may result in similar gradation of features Signet ring carcinoma Pseudomyxoma peritoneii or ovarii; Colloid carcinoma; Infiltrative pattern of small glands with desmoplastic reaction; Single cell infiltrate Singh, N; 2014

11 Decision tree for differential diagnosis of primary ovarian versus metastatic carcinoma Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11):

12 Decision tree for differential diagnosis of primary ovarian versus metastatic carcinoma Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11):

13 Decision tree for differential diagnosis of primary ovarian versus metastatic carcinoma Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11):

14 Decision tree for differential diagnosis of primary ovarian versus metastatic carcinoma Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11):

15 Marker CK7 CK20 CEA Immunohistochemistry profile Ovary intestinal diffuse Focal or diffuse Ovary Mullarian Diffuse CA19.9 Diffuse Negative or Colorectal Appendix Pancreas & biliary Negative (except rectal) negative Negative Diffuse negative diffuse negative Negative Diffuse Diffuse Diffuse or Stomach diffuse negative Diffuse or Cervix Diffuse negative Diffuse or Diffuse Diffuse Diffuse Diffuse Diffuse CDX2 Focal Negative Diffuse Diffuse Focal Focal Negative or CA125 Negative Diffuse Negative Negative Negative Negative Diffuse ER Negative Diffuse Negative Negative Negative Negative Negative or DPC4/ SMAD4 P16 PAX8 Betacatenin Singh, N; 2014 Diffuse Diffuse Diffuse Diffuse Negative in 50% Negative or negative Sometimes pos Negative or Negative or Negative or Negative or Diffuse Negative or Diffuse Diffuse Positive Negative Negative Negative Negative Positive Sometimes pos Positive positive Variable Positive Variable

16 Marker CK7 CK20 CEA Immunohistochemistry profile Ovary intestinal diffuse Focal or diffuse Ovary Mullarian Diffuse CA19.9 Diffuse Negative or Colorectal Appendix Pancreas & biliary Negative (except rectal) negative Negative Diffuse negative diffuse negative Negative Diffuse Diffuse Diffuse or Stomach diffuse negative Diffuse or Cervix Diffuse negative Diffuse or Diffuse Diffuse Diffuse Diffuse Diffuse CDX2 Focal Negative Diffuse Diffuse Focal Focal Negative or CA125 Negative Diffuse Negative Negative Negative Negative Diffuse ER Negative Diffuse Negative Negative Negative Negative Negative or DPC4/ SMAD4 P16 PAX8 Betacatenin Singh, N; 2014 Diffuse Diffuse Diffuse Diffuse Negative in 50% Negative or negative Sometimes pos Negative or Negative or Negative or Negative or Diffuse Negative or Diffuse Diffuse Positive Negative Negative Negative Negative Positive Sometimes pos Positive positive Variable Positive Variable

17 Marker CK7 CK20 CEA Immunohistochemistry profile Ovary intestinal diffuse Focal or diffuse Ovary Mullarian Diffuse CA19.9 Diffuse Negative or Colorectal Appendix Pancreas & biliary Negative (except rectal) negative Negative Diffuse negative diffuse negative Negative Diffuse Diffuse Diffuse or Stomach diffuse negative Diffuse or Cervix Diffuse negative Diffuse or Diffuse Diffuse Diffuse Diffuse Diffuse CDX2 Focal Negative Diffuse Diffuse Focal Focal Negative or CA125 Negative Diffuse Negative Negative Negative Negative Diffuse ER Negative Diffuse Negative Negative Negative Negative Negative or DPC4/ SMAD4 P16 PAX8 Betacatenin Singh, N; 2014 Diffuse Diffuse Diffuse Diffuse Negative in 50% Negative or negative Sometimes pos Negative or Negative or Negative or Negative or Diffuse Negative or Diffuse Diffuse Positive Negative Negative Negative Negative Positive Sometimes pos Positive positive Variable Positive Variable

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20 Falling incidence of primary mucinous ovarian carcinoma diagnosis better recognition of the clinical importance of making the distinction stage I mucinous ovarian carcinoma has an excellent prognosis metastasis from upper GI / pancreatic primary very poor prognosis treatment quite different better histological distinction between metastases to the ovary and primary mucinous ovarian carcinoma pattern recognition cytokeratin and other immunohistochemical staining better preoperative work-up with imaging, and tumour markers coupled with MDT discussion

21 Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment Patients & methods Cases: 27 of 50 evaluable pts with stage III/IV meoc from RMH Controls: 54 pts stage III/IV non-meoc matched for date of Dx and stage First line treatment: 1/3 rd all pts single agent platinum; 2/3 rd platinum containing combinations Results meoc (n=27) Prog on Rx 63% CR+PR (measurable disease) Median PFS (26%) Control (n=54) (65%) 5.7 mos 14.1 mos Median OS 12.0 mos 36.7 mos Hess et al: J Clin Oncol 2004; 22(6):

22 Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment PFS OS Hess et al: J Clin Oncol 2004; 22(6):

23 P Retrospective analysis of GOG182 [ICON5] 54 of 3435 (1.5%) pts entered by GOG classified as mucinous carcinoma 10 had insufficient material for review or not mucinous 44 reviewed independently by 3 pathologists according to 2 classification systems (no IHC) 16 to 18% judged primary meoc 57 to 63% judged metastatic No difference in OS between primary and metastatic mucinous Survival of primary meoc substantially worse than serous Median OS 14 mos vs 42 mos P < Cancer 2011;117:554 62

24 Mucinous ovarian carcinoma responds poorly to platinum based chemotherapy Harrison et al; Int J Gynecol Cancer 2008:

25 Mucinous ovarian carcinoma may respond preferentially to oxaliplatin & 5FU meoc cell lines MN-1, OMC-1, RMUG-L, RMUG-S, TU-OM-1 All resistant to platinum & Paclitaxel All sensitive to oxaliplatin & FU with additive or synergistic effect In a xenograft model treatment with oxaliplatin & FU increased survival over PBS or either drug alone Sato et al; Cancer Science 2009 March, 100 (3)

26 A GCIG Intergroup multicentre trial of open label carboplatin and paclitaxel +/- bevacizumab compared with oxaliplatin and capecitabine +/- bevacizumab as first line chemotherapy in patients with mucinous Epithelial Ovarian Cancer (meoc) [GOG241] Cancer Research UK & UCL Cancer Trials Centre

27 meoc [GOG 0241] Trial Design 2x2 Factorial Randomise (332 patients 83 patients in each arm) Carboplatin & Paclitaxel 6 x 21-day cycles Oxaliplatin & Capecitabine 6 x 21-day cycles Carboplatin & Paclitaxel 6 x 21-day cycles Oxaliplatin & Capecitabine 6 x 21-day cycles Bevacizumab given every 3 weeks for 5 or 6* cycles Bevacizumab given every 3 weeks for 5 or 6* cycles Clinical assessment every 6 weeks for 36 weeks Telephone call between visits Bevacizumab given every 3 weeks for 12 cycles Clinical assessment every 6 weeks for 36 weeks Follow-up

28 meoc Trial Timelines and Recruitment MHRA approval September 2008 MREC approval October 2008 Launch meeting 6 th Feb 2009 Start date December 2009 Trial stopped early (2013) due to poor accrual 50 pts recruited Median follow up 23 months 31 progressions/deaths

29 meoc (GOG 0241) Recruitment Aim to randomise (332 patients 83 patients in each arm) Recruitment 50 pts [End 09 to Early 2013] [A] Carboplatin & Paclitaxel 6 x 21-day cycles N=13 [B] Oxaliplatin & Capecitabine 6 x 21-day cycles N=13 [C] Carboplatin & Paclitaxel 6 x 21-day cycles Bevacizumab given every 3 weeks for 5 or 6* cycles [D] Oxaliplatin & Capecitabine 6 x 21-day cycles Bevacizumab given every 3 weeks for 5 or 6* cycles N=11 N=13 Target Statistics 332 pts required to detect 5 month increase in median PFS: oxaliplatin/capecitabine [B+D] adding bevacizumab [C+D] Abstract submitted to ASCO 2015 Gore et al [A&C] vs [B&D] n=24 n=26 Carbo/Paclitaxel vs Oxaliplatin/Capecitabine [A&B] vs [C&D] n=26 n=24 No Bevacizumab vs addition of Bevacizumab

30 meoc Data submitted to ASCO 2015 Specialist pathology review n = were considered to not have primary meoc (many metastatic disease) Setting up & conducting this international trial was challenging in this rare group Correctly assigning histological diagnosis was difficult. Primary meoc is rare so different approaches are needed to evaluate new therapies.

31 A dualistic approach to the classification of ovarian carcinoma Kurman RJ, Shih IM: Hum Pathol 2011, 42:

32 Ovarian Cancer Genotyping EORTC GCG and EORTC GCG Translational Research Group 262 high risk stage I and stage II-IV from University Hospitals Leuven and EORTC Genotyped for hotspot mutations in KRAS, BRAF, NRAS, PIK3CA, PTEN, AKT2, AKT3, and FOXL2, using Sequenom MassARRAY Type 1 tumours (13%): 49% were KRAS or PIK3CA mutant Type 2 tumours (87%): 2.9% were KRAS or PIK3CA mutant Mucinous subtypes significantly more KRAS mutations than all nonmucinous tumours (50% vs 4%, P < 0.001) PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis Low-grade serous tumours were more frequently KRAS or BRAF mutated (44%) than highgrade serous tumours (0.6%) Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%) KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival Despierre et al (2014). Int J Gynecol Cancer 24(3):

33 Ovarian Cancer Genotyping EORTC GCG and EORTC GCG Translational Research Group 262 high risk stage I and stage II-IV from University Hospitals Leuven and EORTC Genotyped for hotspot mutations in KRAS, BRAF, NRAS, PIK3CA, PTEN, AKT2, AKT3, and FOXL2, using Sequenom MassARRAY Type 1 tumours (13%): 49% were KRAS or PIK3CA mutant Type 2 tumours (87%): 2.9% were KRAS or PIK3CA mutant Mucinous subtypes significantly more KRAS mutations than all nonmucinous tumours (50% vs 4%, P < 0.001) PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis Low-grade serous tumours were more frequently KRAS or BRAF mutated (44%) than highgrade serous tumours (0.6%) Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%) KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival Despierre et al (2014). Int J Gynecol Cancer 24(3):

34 Ovarian Cancer Genotyping EORTC GCG and EORTC GCG Translational Research Group 262 high risk stage I and stage II-IV from University Hospitals Leuven and EORTC Genotyped for hotspot mutations in KRAS, BRAF, NRAS, PIK3CA, PTEN, AKT2, AKT3, and FOXL2, using Sequenom MassARRAY Type 1 tumours (13%): 49% were KRAS or PIK3CA mutant Type 2 tumours (87%): 2.9% were KRAS or PIK3CA mutant Mucinous subtypes significantly more KRAS mutations than all nonmucinous tumours (50% vs 4%, P < 0.001) PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis Low-grade serous tumours were more frequently KRAS or BRAF mutated (44%) than highgrade serous tumours (0.6%) Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%) KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival Despierre et al (2014). Int J Gynecol Cancer 24(3):

35 Ovarian Cancer Genotyping EORTC GCG and EORTC GCG Translational Research Group 262 high risk stage I and stage II-IV from University Hospitals Leuven and EORTC Genotyped for hotspot mutations in KRAS, BRAF, NRAS, PIK3CA, PTEN, AKT2, AKT3, and FOXL2, using Sequenom MassARRAY Type 1 tumours (13%): 49% were KRAS or PIK3CA mutant Type 2 tumours (87%): 2.9% were KRAS or PIK3CA mutant Mucinous subtypes significantly more KRAS mutations than all nonmucinous tumours (50% vs 4%, P < 0.001) PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis Low-grade serous tumours were more frequently KRAS or BRAF mutated (44%) than highgrade serous tumours (0.6%) Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%) KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival Despierre et al (2014). Int J Gynecol Cancer 24(3):

36 Molecular alterations in ovarian and colorectal mucinous carcinomas Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11):

37 Molecular alterations in ovarian and colorectal mucinous carcinomas Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11):

38 Molecular alterations in ovarian and colorectal mucinous carcinomas Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11):

39 Molecular alterations in ovarian and colorectal mucinous carcinomas Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11):

40 Molecular alterations in ovarian and colorectal mucinous carcinomas Alterations in KRAS, BRAF or HER2 tend to be mutually exclusive So Alterations in MAPK 60% 40% 38% (Ras/Raf/MEK/ERK) Kelemen, L. E. and M. Köbel (2011) Lancet Oncology 12(11):

41 Molecular characterisation of meoc supports stratified approach with HER2 targeting Cases from Mayo Clinic, Australian Ovarian Cancer Study Group, Toronto PMH & General, Alberta Cancer Research biorepository HER2 amplification & KRAS mutation status investigated in189 meoc & 199 mucinous BOT HER2 investigated by IHC, with FISH & CISH as appropriate KRAS mutation investigated by Sanger Sequencing KRAS mutation: 26/33 (79%) MBOT 31/71 (44%) meoc HER2 amplification 11/176 (6%) MBOT 29/154 (19%) meoc HER2 and KRAS mutation status both known in 74 mucinous carcinomas Anglesio et al, J Pathol 2013; 229:

42 Prognostic significance of HER2 and HER2/KRAS expression HER2 PFS ---- KRAS + HER KRAS + HER KRAS wt HER KRAS wt HER2 - HER2 OS Anglesio et al, J Pathol 2013; 229:

43 Potential treatment algorithm for primary mucinous ovarian carcinoma Anglesio et al, J Pathol 2013; 229:

44 Cetuximab in mucinous ovarian cancer cell lines EGFR & KRAS mutation status investigated in 5 ovarian cell lines MN-1, OMC-1, RMUG-L, RMUG-S, MCAS EGFR expressed in all but MN-1 KRAS at codon 12 only in MCAS Evaluated in vivo & in vitro effects of cetuximab inhibited RMUG-L & OMC-1 growth in vitro completely blocked RMUG-L tumour in vivo no effect on MCAS in vitro & only partial growth reduction in vitro Sato et al 2012, Oncology Reports; 27:

45 HER2 targeting in mucinous ovarian carcinoma HER2 status investigated in 33 meoc & 16 mbots 5 cases of documented recurrence with tissue avail 3 prospectively documented HER2 pos recurrent meoc HER2 amplification observed in 6/33 (18%) meoc 3/16 (19%) mbot 1/3 HER2 amplified recurent meoc had dramatic response to trastuzumab McAlpine J et al. BMC Cancer 2009; 9(1): 433

46 Possible approaches to management of metastatic or recurrent mucinous ovarian carcinoma Molecular phenotype First line Second line HER2+, KRAS wt Anti HER2 therapy Add anti EGFR thrapy HER2+, KRAS mut (very rare) KRAS mut, HER2- Anti HER2 therapy Gi chemotherapy or trial GI chemotherapy option or trial Gi chemotherapy or trial HER2-, KRAS wt Anti EGFR therapy Gi chemotherapy or trial P53 gene mutation? Platinum based chemotherapy Adapted from Anglesio et al J Patho, 2013; 229:

47 Potential new approaches for mucinous ovarian carcinoma Anti HER2 therapy: Trastuzumab, MGAH22, lapatinib, TDM-1, Anti EGFR therapy for KRAS wt cetuximab, panitumumab KRAS mut Targeting Src and Tubulin in Mucinous Ovarian Carcinoma: Liu T et al; Clin Cancer Res 2013; 19(23): Phase 1 selumetanib + MK-2206: Durable response in 1 of 2 low grade ovarian with RAS mutation. Tolcher 2014 Chemotherapy phase II Japanese study of women with advanced or recurrent are undergoing treatment with oxaliplatin and S1, an orally active drug combining tegafur, gimeracil, oteracil

48 Mucinous ovarian carcinoma conclusions Probably the most challenging subtype of ovarian cancer due to its rarity and diagnostic difficulty Large phase disease orientated 3 trials seem unlikely to succeed (meoc) Would a broader study enroling patients with advanced stage mucinous tumours involving the ovary whether primary or secondary be more likely to succeed??adaptive trial design platform study with a series of single arms or randomised phase 2 trials defined by molecular phenotype. Clinical & translational endpoints Monitoring & reporting strategy: SMART [Shared Access Medicine an Approach to Rare Tumours] Broad international cooperation

49 Thank you Acknowledgments: Dr Nafisa Wilkinson for histology slides and guidance