Douglas A. Levine Professor Director Gynecologic Oncology Laura and Isaac Perlmutter Cancer Center Head, Gynecology Research Laboratory NYU Langone

Transcription

1 Douglas A. Levine Professor Director Gynecologic Oncology Laura and Isaac Perlmutter Cancer Center Head, Gynecology Research Laboratory NYU Langone Health, New York, USA

2 Precision Medicine for Gynecologic Cancers Opportunities and Obstacles Douglas A. Levine, MD Director, Gynecologic Oncology Head, Gynecology Research Laboratory Professor, Obstetrics and Gynecology Perlmutter Cancer Center, NYU Langone Medical Center

3 Disclaimers and conflicts I will discuss science fiction I will discuss the use of an investigation device for which I am a paid consultant I will discuss a device that is in need of financial support

4 Gyn Res Lab

5 The Gynecology Research Laboratory studies ovarian and endometrial cancers. Rare tumor research Novel biomarkers Precision medicine

6 Welcome to the pelvis

7 Overview About ovarian cancers Obstacles to screening and early detection Clinical trials for salpingectomy Nanobiosensors for proximal fluid monitoring Extending the applications of PARP inhibition for ovarian cancer Precision medicine in clinical practice Immuno-opportunities in endometrial cancer NGS where are we heading

8 Ovarian carcinomas do not originate in the ovary.

9 Ovarian cancer screening is not recommended for the general population (USPSTF recommends against screening Grade D). Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial The Lancet Volume 387, Issue 10022, Pages (March 2016) Rate of change of CA-125 was more promising than ultrasonography, but requires proprietary algorithm. Ovarian cancer screening is recommended for high-risk women, specifically those with mutations in BRCA1, BRCA2, other known high risk genes, and those women with a very strong family history

10 Occult lesions are found in the fallopian tube. Shared mutations between occult tubal lesions and established disease Precursor lesions found in ~50% of women with advanced ovarian cancers

11

12 PTEN DICER DKO mouse develops HGSC Mice without tubes do not get HGSC All others do Fallopian tubes are required to develop HGSC in a DKO mouse model

13 Will it work? Future

14 Testing the hypothesis Women Choosing Surgical Prevention (WISP) Study A Three-Arm Cohort Study of Salpingectomy to Reduce the Risk of High-Grade Serous Carcinoma among Premenopausal BRCA1 Carriers Women 35 and 50 years of age with a BRCA1 mutations Surgical consultation, study consent, and medical decision making TVUS and CA125 within 6 weeks of study enrollment Patient Reported Outcomes (PROs) - Baseline Screening cohort BLS cohort RRSO cohort TVUS and CA125 q six months Bilateral salpingectomy +/- hysterectomy (BS+/- Hyst) Bilateral salpingooophorectomy +/- hysterectomy (BSO+/- Hyst) Tissue for tissue bank PROs 6 and 12 months PROs 6 and 12 months TVUS and CA125 q six months CA125 per clinician discretion Cancer incidence annually for 20 years or until funding is exhausted RRSO risk-reducing salpingo-oophorectomy; BLS bilateral salpingectomy

15 Implantable sensor for high-risk patients BRCA + Familial history After treatment/monitor recurrence Implantation of nanosensor between cervix and ovary will allow for minimally-invasive near-ir detection

16 Carbon Nanotubes: Ab-conjugated near-infrared sensors

17 In vivo CNT reproducible wavelength shift

18 In vivo CNT antigen specificity $$ $$

19 UNTIL THEN

20 Ovarian carcinomas are not one disease. Not HRD HRD Created by Douglas A. Levine, MD from data compiled from the cbio Cancer Genomics Portal, MSKCC and Patch et al., Nature, 2015.

21 Genomic scarring The many mechanisms of impaired DNA repair in tumors leaves a signature (or scar) that can be detected through NGS (WES or WGS) This scar can be used to classify tumors Tumors with HRD have a unique scar of medium size >15Mbps that is consistent with BRCA1 or BRCA2 mutations and other putative HRD mechanisms HRD-LOH scores are high in ovarian cancer Lord and Ashworth, Nature, 2012

22 BRCA events are loosely correlated with HRD scores Score Using the published HRD-LOH scores and classifications of 316 sequenced TCGA pts from cbio Portal 40 HRD-LOH BRCA1 BRCA2 Methylated WT

23 PARP inhibitors are effective treatment for patients with BRCA mutations or homologous recombination deficiency. HRD subgroup Median PFS, mos (95% CI) HRD subgroup Hazard Ratio (95% CI) BRCA mut 12.8 (9.0, 14.7) BRCA WT/HRD pos BRCA WT/HRD neg 5.7 (5.3, 7.6) 5.2 (3.6, 5.5) BRCA mut vs. HRD neg HRD pos vs HRD neg 0.27 (0.16, 0.44) 0.62 (0.42, 0.90)

24 PARP inhibitors are effective maintenance for all ovarian cancer patients. Mirza et al, NEJM, October 2016

25 PARP inhibitors in maintenance after platinum-sensitive recurrence FDA-Approved FDA-Approved Niraparib Rucaparib Olaparib Population Platinum sensitive tbrca mut HRD+ gbrca mut PFS gbrca mut : 21 vs. 5.5mo (15.5mo) HRD+: 12.9 vs. 3.8mo (9.1mo) Non-HRD: 6.9 vs. 3.8mo (3.1mo) tbrca mut : 16.6 vs. 5.4mo (11.2mo) HRD+: 13.6 vs. 5.4mo (8.2mo) gbrca mut : 19.1 vs. 5.5 mo (13.6mo) Diagnostic NA FoundationFocus CDx BRCA BRCAnalysis CDx Clinical Trial NOVA ARIEL3 SOLO2 Courtesy of Dmitriy Zamarin, MD, PhD

26 Advanced ovarian cancer treatment 1. Surgery cytoreduction (debulking) 50-80% optimal cytoreduction 20-75% complete gross resection 2. Chemotherapy Taxane/Platinum x % platinum sensitive 3. Remission/Observation/Cytoreduction & 30-50% 5yr survival,? 10yr survival

27 M-Trap: A Novel Tumor Cell Capture Device M-Trap (Metastatic Trap) is an implantable medical device that captures disseminated tumor cells. It is initially intended for use in advanced ovarian cancer. Device consists of a proprietary, non-resorbable polyurethane scaffold with a collagen coating Preclinical studies have shown that M-Trap focalizes disseminating tumor cells through one-year in-vivo Survival studies have shown >3X survival benefit when the device is removed following tumor cell capture Scaffold SEM, 23X M-Trap Device Control Animal M-Trap Focalization M-Trap Survival Study: Kaplan-Meier Survival Curves Pancreas M-Trap Fat Pad Source: MTrap preclinical studies, ER , ER

28 A Phase I Study Is Underway at 8 Sites in Spain Prospective, multi-center, non-blinded, single-arm study of M-Trap therapy Device Implantation At Time of Debulking Surgery Laparoscopic Device Removal Upon Cancer Recurrence Study is enrolling 22 patients with Stage IIIc or IV high grade serous ovarian cancer at high risk of recurrence Primary outcomes are designed to assess device safety and performance 28

29 Precision medicine in clinical practice

30 The case of uncertain histology 85yo presented with constipation and headaches, history of breast cancer Had CT scan that showed peritoneal disease CA125 = 10, CEA = 3.4, CA27.29 = 66 (ULN-37)

31 The case of uncertain histology Stubborn 85yo who presented with constipation and headaches Had CT scan that showed peritoneal disease CA125 = 10, CEA = 3.4, CA27.29 = 66 (ULN-37) Referring MD ordered IR bx of peritoneal lesion 1. PERITONEAL IMPLANT, LEFT: BIOPSY - METASTATIC ADENOCARCINOMA, CONSISTENT WITH MULLERIAN ORIGIN, SEE NOTE, THESE FINDINGS ARE CONSISTENT WITH LOW GRADE SEROUS CARCINOMA. Went to OR for: Diagnostic laparoscopy, exploratory laparotomy, extensive adhesiolysis, infracolic omentectomy, tumor debulking, left ureterolysis, total abdominal hysterectomy, bilateral salpingooophorectomy and bladder mobilization. RIGHT OVARY (and more) from debulking surgery - OVARIAN SEROSA FOCALLY INVOLVED BY PAPILLARY SEROUS ADENOCARCINOMA, HIGH GRADE -Clinical ADDENDUM: Patient refuses chemotherapy

32 Somatic mutations in some of my favorite cancers

33 Molecular profiling opportunity to clarify differential diagnosis Hormonal treatment prescribed

34 The case of uncertain cancer pathogenicity 26yo with known familial mutation in BRCA2 presents with intestinal mass At surgery, and found to have scattered small volume disease including pelvis and omentum, completely resected Pelvic organs left in situ for fertility preservation Path c/w LGSC Pt question Is my cancer caused by the BRCA2 mutation?

35 Low grade serous carcinoma 26yo with known germline BRCA2 mutation and LGSC Is my cancer caused by the BRCA2 mutation? Should she get a PARP inhibitor? No evidence for LOH at the BRCA2 locus

36 Low grade serous carcinoma 26yo with known germline BRCA2 mutation and LGSC Is my cancer caused by the BRCA2 mutation? Let s look at heterozygosity LOH = pathogenic; increased allele fraction of mutant allele Normal Tumor Normal Tumor Retention of both alleles (wild-type allele) Loss of the wild-type allele in tumor; Loss of heterozygosity (LOH)

37 A case of clinical trial to precision-directed treatment 64yo with recurrent endometrial clear cell carcinoma very rare She had Foundation One sent But while waiting for results enrolled on the Takeda phase 2, open-label trial to evaluate a dual TORC1/2 inhibitor alone, the dual TORC1/2 inhibitor in combination with a PI3Kα inhibitor, weekly paclitaxel, OR the combination of weekly paclitaxel and the dual TORC1/2 inhibitor in women with advanced, recurrent, or persistent endometrial

38 A case of clinical trial to precision-directed treatment 64yo with recurrent endometrial clear cell carcinoma very rare If she fails the clinical trial, she will receive traztuzumab Tumor HER2 FISH in progress

39 FDA-approved disease-agnostic therapy with a twist 60yo with recurrent endometrial endometrioid carcinoma very common Pt suffered from an early recurrence and had foundation one sent IHC showed loss of MLH1 and MSH6 MLH1 promoter was methylated Germline genetic testing was negative Clearly has MSI + tumor, due to either MLH1 methylation, MSH6 somatic mutation, or both Outstanding question of future PARP treatment for somatic BRCA1 mutation

40 FDA-approved disease-agnostic therapy with a twist 60yo with recurrent endometrial endometrioid carcinoma very common Pt suffered from an early recurrence and had foundation one sent IHC showed loss of MLH1 and MSH6 MLH1 promoter was methylated Germline genetic testing was negative MSH6 mutation seems clonal BRCA1 mutation appears subclonal Not clear that PARPi would be useful??

41 Immuno-oncology for endometrial cancers

42 Mutation spectrum/subtypes Very high background mutation rate; ~ / Mb High background mutation rate; ~10-20 / Mb Low background mutation rate; ~2-3 / Mb Hypermutators associated with MSI and MLH1 DNA promoter methylation TCGA, Nature, 2013

43 Integrated features All endometrioid, PTEN mutations, few TP53 mutations All endometrioid, PTEN mutations, no TP53 mutations TP53 mutations, few PTEN mutations, high grade tumors, serous and some endometrioid TCGA, Nature, 2013

44 SMGs Significantly Mutated Genes

45 Clinical application 1. POLE mutated cases: low risk of recurrence 2. CN high cases: Chemotherapy 3. MSI cases ICI 4. Stratified trials analysis of CTNNB1 mutated, 1q amp d and WT copy number low cases

46 Translational potential Many opportunities exist for molecular stratification to provide accurate and precise treatment to endometrial cancer patients 243 POLE hotspot or exonuclease domain mutation POLE sequencing (31 patients without data) 203 IHC (9 patients without PMS2 or MSH6 data) POLE (n=4, 2%) PMS2 or MSH6 loss 199 TP53 sequencing MSI (n=49, 24%) TP53 Wildtype 150 TP53 Mutant Copy-Number Low (n=62, 31%) Copy-Number High (n=88, 43%) NEJM. 2015; 372:

47 GOG 86P: A 3-arm randomized phase II trial Open: 9/14/09 Closed: 1/9/12 Endometrial Cancer No prior chemotherapy -Stage III or IVA (measurable disease) -Stage IVB (measurable disease or not) -Recurrent (measurable disease or not) Paclitaxel 175 mg/m 2 IV 3 hours Carboplatin AUC 6 IV Bevacizumab 15 mg/kg IV* Paclitaxel 175 mg/m 2 IV 3 hours Carboplatin AUC 5 IV Temsirolimus 25 mg IV days 1 & 8* Ixabepilone 30 mg/m 2 IV 1 hour Carboplatin AUC 6 IV Bevacizumab 15 mg/kg IV* Bevacizumab 15 mg/kg IV Temsirolimus 25 mg IV days 1, 8 and 15 Bevacizumab 15 mg/kg IV Matched group from GOG209 PC Arm used as historical control

48 Sequencing results by patient and histology Endometrioid, G1 Endometrioid, G2 Endometrioid, G3 Serous Other Total Gene n (%) n (%) n (%) n (%) n (%) n (%) PTEN 27 (73.0) 49 (71.0) 34 (57.6) 4 (8.9) 7 (21.2) 121 (49.8) TP53 5 (13.5) 14 (20.3) 26 (44.1) 39 (86.7) 24 (72.7) 108 (44.4) PIK3CA 14 (37.8) 37 (53.6) 31 (52.5) 13 (28.9) 11 (33.3) 106 (43.6) ARID1A 14 (37.8) 33 (47.8) 23 (39.0) 1 (2.2) 6 (18.2) 77 (31.7) CTNNB1 21 (56.8) 22 (31.9) 18 (30.5) 1 (2.2) 2 (6.1) 64 (26.3) PIK3R1 10 (27.0) 18 (26.1) 11 (18.6) 3 (6.7) 3 (9.1) 45 (18.5) CTCF 6 (16.2) 16 (23.2) 17 (28.8) 1 (2.2) 2 (6.1) 42 (17.3) KRAS 7 (18.9) 14 (20.3) 14 (23.7) 1 (2.2) 2 (6.1) 38 (17.9) CHD4 10 (27.0) 8 (11.6) 12 (20.3) 5 (11.1) 2 (6.1) 37 (17.5) KMT2B 3 (8.1) 16 (23.2) 13 (22.0) 1 (2.2) 1 (3.0) 34 (16.0) ARHGAP35 1 (2.7) 7 (10.1) 7 (11.9) 8 (17.8) 7 (21.2) 30 (14.2) PPP2R1A 4 (10.8) 3 (4.3) 3 (5.1) 13 (28.9) 4 (12.1) 27 (12.7) FBXW7 0 (0) 4 (5.8) 6 (10.2) 7 (15.6) 4 (12.1) 21 (8.6) ATM 2 (5.4) 8 (11.6) 7 (11.9) 1 (2.2) 1 (3.0) 19 (9.0) MTOR 2 (5.4) 6 (8.7) 8 (13.6) 2 (4.4) 1 (3.0) 19 (7.8) POLE 4 (10.8) 4 (5.8) 5 (8.5) 1 (2.2) 3 (9.1) 17 (8.0) SPOP 1 (2.7) 7 (10.1) 4 (6.8) 2 (4.4) 3 (9.1) 17 (8.0) TSC1 3 (8.1) 2 (2.9) 10 (16.9) 0 (0) 1 (3.0) 16 (7.5) FGFR2 4 (10.8) 5 (7.2) 5 (8.5) 0 (0) 1 (3.0) 15 (7.1) NF1 2 (5.4) 6 (8.7) 5 (8.5) 1 (2.2) 1 (3.0) 15 (7.1) TSC2 1 (2.7) 7 (10.1) 5 (8.5) 0 (0) 1 (3.0) 14 (5.8) ATR 1 (2.7) 4 (5.8) 3 (5.1) 0 (0) 2 (6.1) 10 (4.7) ARID5B 2 (5.4) 4 (5.8) 3 (5.1) 0 (0) 0 (0) 9 (4.8) PIK3R2 0 (0) 5 (7.2) 1 (1.7) 0 (0) 0 (0) 6 (2.8) RICTOR 0 (0) 2 (2.9) 0 (0) 0 (0) 1 (3.0) 3 (1.2) # Patients Sequenced

49 Profile of grade 3 endometrioid cases (n=59)

50 CTNNB1 mutation as a prognostic biomarker All Patients CTNNB1 WT CTNNB1 Mutant Median PFS (m) P value (<) CTNNB1 Wildtype Tumors CTNNB1 Mutant Tumors Histograde N (%) N (%) N Endometrioid G1 16 (43.2) 21 (56.8) 37 Endometrioid G2 47 (68.1) 22 (31.9) 69 Endometrioid G3 41 (69.5) 18 (30.5) 59 Serous 44 (97.8) 1 (2.2) 45 Other 31 (93.9) 2 (6.1) 33 Total Total 179 (73.7) 64 (26.3) % of CTNNB1 mutations are in patients with endometrioid tumors

51 CTNNB1 mutation is predictive of response to bevacizumab in endometrioid tumors All patients Endometrioid patients Arm1,3 Carbo/Tax/Bev Carbo/Ixa/Bev CTNNB1 WT CTNNB1 Mutant Median PFS (m) P value (<) Arm2 Carbo/Tax/Tem CTNNB1 WT CTNNB1 Mutant Arm1,3 Carbo/Tax/Bev Carbo/Ixa/Bev Arm2 Carbo/Tax/Tem CTNNB1 WT CTNNB1 Mutant CTNNB1 WT CTNNB1 Mutant Median PFS (m) P value (<) Treatment Arm Arm 1,3 Arm 2 CTNNB1 Mutation Status Total N N Events N Censored Percent Censored Wildtype Mutant Wildtype Mutant

52 Up next: NRG-GY012 A Four Arm Randomized Phase II Study Comparing Single-Agent Olaparib, Single Agent Cediranib, the Combination of Cediranib/Olaparib and the Combination of Olaparib / Wee1 Inhibitor AZD 1775 in Women with Recurrent, Persistent or Metastatic Endometrial Cancer (EEC)

53 Areas of controversy What type of genetic testing should be performed at diagnosis and/or at the time of recurrence? All patients with ovarian cancer should be tested for germline mutations in BRCA1 and BRCA2 at the time of diagnosis This could occur through initial germline testing or somatic testing with reflex germline testing for identified mutations When is the best time to administer PARP inhibitors? For non-brca carriers, PARP inhibitors are only FDA approved for maintenance For BRCA carriers, PARP inhibitors are approved for treatment of recurrent disease

54 Opportunities and obstacles We can prevent ovarian cancer in most women who have inherited BRCA1 or BRCA2 mutations (opportunity) We can not effectively screen for ovarian cancer today and recommend against ovarian cancer screening for women at average/population risk (obstacle) We are working very hard to develop new approaches for early detection and clinical trials are here (opportunity) Molecular heterogeneity of endometrial cancer leads to therapeutic opportunities that are active in the clinic (opportunity) Few robust targets exist for ovarian cancer pts without germline mutations (obstacle) Precision medicine through broad tumor profiling can identify unexpected opportunities for a minority of gynecologic oncology patients (opportunity) NGS is quickly becoming routine but interpretation is increasingly complex (both)

55 It takes a village Small ell Ovarian Cancer Foundatio n

56 This slide intentionally blank

57 Backup slides

58 Ovarian cancer clinical trials are available across the treatment continuum at Perlmutter Cancer Center. Upfront Ovarian Cancer Clinical Trials Maintenance Pla num sensi ve Pla num resistant S SIV 3/10/2017 GOG 3015 A Phase III, Mul center, Randomized, Placebo Controlled Study Of Atezolizumab Versus Placebo In Combina on With Paclitaxel, Carbopla n, And Bevacizumab For Pa ents With Newly Diagnosed Stage Iii/Iv Ovarian, Fallopian Tube, Or Primary Peritoneal Cancer S Mul -gene panel tes ng at the me of diagnosis for pa ents with epithelial ovarian, primary peritoneal and fallopian tube cancer S S A Phase 3, Randomized, Double- Blind, Placebo- Controlled, Mul center Study of Niraparib Maintenance Treatment in Pa ents with HRD-Posi ve Advanced Ovarian Cancer Following Response on Front-Line Pla num-based Chemotherapy S NRG-GY004: A Phase III Study Comparing Single- Agent Olaparib or the Combina on of Cediranib and Olaparib to Standard Pla num-based Chemotherapy in Women with Recurrent Pla num-sensi ve Ovarian, Fallopian Tube, or Primary Peritoneal Cancer S NRG-GY005: A Randomized Phase II/III study of the combina on of Cediranib and Olaparib compared to Cediranib or Olaparib alone, or Standard of care chemotherapy in women with recurrent pla num-resistant or -refractory ovarian, fallopian tube, or primary peritoneal cancer (COCOS) s FORWARD 1: A Randomized, Open Label Phase 3 Study to Evaluate the Safety and Efficacy of Mirvetuximab soravtansine (IMGN853) Versus Inves gator s choice of Chemotherapy in Woman with Folate Receptor α-posi ve Advance Epithelial Ovarian Cancer, Primary Peritoneal Cancer or Fallopian Tube Cancer FDG-PET / MRI as predictor of response to neoadjuvant chemo in pts with epithelial ovarian, primary peritoneal, or fallopian tube cancer

59 Outcome of POLE-mutated patients: Clinically significant-yes! Clinically useful-maybe? Serous poorest PFS No difference between MSI and MSS groups No events in small POLE group, but interpretation is limited by heterogeneous adjuvant treatment approaches