Grade 3 GEP Neuroendocrine Neoplasms: from pathology to the clinic and back What the oncologist needs to know from the pathologist? Marianne Pavel Friedrich Alexander Universität Erlangen-Nürnberg 30th European Congress of Pathology Joint Symposium ENETS and Endocrine Pathology WG 22.10.2018 Bilbao, Sept 11, 2018
Disclosures Honoraria for Presentations and Advisory Boards - Novartis, IPSEN, Pfizer, Lexicon Research grant to former institution (Charité University Medicine Berlin): Novartis, IPSEN
What the oncologist needs to know from pathologist? Mandatory Morphology/ Differentiation Cell morphology in NEC: large cell or small cell Grade/ Proliferative activity Precise Ki67 and mitotic count Pure NEN or mixed NE and nne neoplasm (MiNEN) or MANEC TNM: Any signs of invasion? R status Optional SSTR expression (if SRI not available or after resection) Transcription factors (CDX-2, TTF-1, Islet-1 in WD NET G3) Others: PD-1/PDL-1, NGS, MGMT,
Prognosis of NEN G3: SEER 1973-2010; Bethesda, MD: National Cancer Institute, Cancer Statistics Branch; 2013 Sorbye et al Cancer 2014
Why is morphology/ differentiation important in NEN G3?
Are G3 ENETS neuroendocrine neoplasms heterogeneous? 28 patients Well differentiated Poorly differentiated: Large cell NEC mos 41 mo vs. 17 mo. (p=0.34) SRS + 88% vs. 50 % Median Ki67 21 30 (range) (21 60) (21 90) Velayoudom-Cephise, Endocr Rel Cancer 2013 Short survival (<2 years) In 25% of G3-WDNET In 62.5% of G3-LCNEC (p<0.049)
NEN G3 are not all the same Distinct prognosis in NETG3 and NEC Heetfeld et al ORR with Platinum-Etoposide NETG3 vs NEC: 17 vs. 35%
Why is it important to know the precise proliferative activity?
Neuroendocrine Tumors Prognosis according to Ki67 Data of the Spanish NET Registry 2813 Patients Morphology and Grading are important Impact on therapy selection NU NEZ-VALDOVINOS et al, The Oncologist 2018
Impact of Ki67 in NEN G3 N= 305 Patients Ki67 cut-off 55% Response to CTx is depending on Ki67 ORR 15% vs 42% in NEN with Ki67 <55% vs > 55% Sorbye et al Cancer 2014 Sorbye et al, Annals of Oncology 24: 152 160, 2013
Why is it important to discriminate NET G3 from NEC G3?
Distinct features of NET G3 and NEC NET G3 Primary site Pancreas >>> GI NEC Upper GI Tract, Colorectal Pancreas SSTR Often +++ ++ but often weak expression Ki67 median range Response to platinumbased chemotherapy 30-47 Impact % on diagnostic & 70-80 therapeutic % 21-70 % 10-100 % decision making Low (<20%) High (30-61 %) Overall survival median More durable 41-99 mo Short 11-16 mo.
ENETS Guidelines 2016 for NEN G3 NEC: Cisplatin or Carboplatin + Etoposide Well differentiated NET G3 Alternative approaches (not validated) e.g. Temozolomide based regimen e.g. PRRT in selected cases e.g. molecular targeted therapies, preferably within clinical trials (NORDIC NET, EVINEC, AVINEC) Rocio Carbonero et al Neuroendocrinology 2016
Treatment options in NET G3? Options o Everolimus o Sunitinib? o PRRT o Temozolomid o FOLFOX o STZ/5-FU* * in Pan-NET only Selection criteria Morphology Ki67 SSTR Status Primary site Primary site dependent therapy selection
51 yr old patient Surgeon, active 02/13 first consultation NET clinic Medical history: increasing abdominal pain for several months, dark stools, no weight loss Ultrasonography: multiple liver lesions Liver biopsy: Well differentiated Neuroendocrine Tumor Immunhistochemistry: Synaptophysin +++, CgA+, Panzytokeratin +, Zytokeratin 8+, Serotonin +, SSTR-2A >90%, ISLET-1+; MiB-1 25-30% (NET G3). Negative: Gastrin, Glucagon, Somatostatin, Pancreatic Polypeptide, Calcitonin Therapy: none
Everolimus Everolimus at 3 mo 51 year old patient with pancreatic NET (Ki67 30%) 02/13 01/14 08/14 TEM/CAP 3 mo PD 12/14 FOLFOX 3mo MR STZ/ 5-FU PR 06/15 Everolimus Minor remission
Patient with Pancreatic NET G3 - Follow-up 07/15 07/16 In summary treatment like a NET G2 with STZ/5-FU, CAPTEM, Everolimus and FOLFOX Everolimus 10 mg/ d ongoing Succeding therapies: sunitinib, pembrolizumab
Clinical features NET G3 - Charité series PATIENTS FEATURES N = 33 Gender [male; n (%)] 13 (39.4) Age [years; median (range)] 50 (29-78) Ki-67 [%; median (range)] * < 50%, n (%) 50%, n (%) Tumor primary site Pancreas, n (%) Others Functionality No, n (%) Yes, n (%) Somatostatin receptors expression Positive, n (%) Negative, n (%) Unknown, n (%) Stage III, n (%) IV, n (%) Metastatic pattern Liver metastases, n (%) Extra-hepatic metastases, n (%) 30 (20-60) 29 (87.9) 4 (12.1) 29 (87.9) 4 (12.1) 29 (87.9) 4 (12.1) 20 (60.6) 10 (30.3) 3 (9.1) 3 (9.1) 30 (90.9) 16 (53.3) 14 (46.7) * evaluated at diagnosis., Assessed by Somatostatin Receptor Scintigraphy or 68Ga-DOTATOC PET. Extra-hepatic metastases (e.g. bone, CNS)
Tumor response to first-line systemic therapy in NET G3 FIRST LINE THERAPY TTP, [mo.; median (range)] DCR (=SD+PR), n (%) PR, n (%) STZ+5FU 10 (3-21) 10/14 (71.4) 8/14 (57.1) TEM+CAP 16 (2-21) 5/6 (83.3) 3/6 (50) CIS/CARBO+ETO 5 (1-10) 2/6 (33.3) 2/6 (33.3) FOLFOX 7 (3-31) 4/5 (80) 3/5 (60) In pancreatic NET G3 a similar approach is followed as in NETG2
Proposal for the Management of NET G3 NET G3 Ki67 55%* *Prospective validation required; no precise cut- off value established Primary site matters GI Pancreas STZ based chemotherapy not considered in GI NET G3 Ki67 matters FOLFOX CAP/TEM STZ/5-FU CAP/TEM In GI NET G3 as compared to Pan- NET G3, Ki67>20% is in general associated with more aggressive behaviour Progression Progression PRRT*** SSTR expression? Everolimus- Trial* PRRT*** FOLFOX Progression For PRRT whole body SRI is required (exclude heterogeneous expression) Pathological assessment may guide the use of functional imaging (costs!) Clinical trial Everolimus- Study*
ENETS Guidelines 2016 for NEN G3 NEC: Cisplatin or Carboplatin + Etoposide Rocio Carbonero et al Neuroendocrinology 2016
ENETS Guidelines NENG3 Management of poorly differentiated NEN 2nd Line- no standard : FOLFOX, FOLFIRI, TEM/CAP ~ 30% (median PFS 4 mo)
51 year old patient Large cell NEC G3 (Ki67 30-40 %), Pan-NEC 08/15-12/15 Cisplatin/ Etoposide standard chemotherapy (6 cycles) 12/2015 Progressive disease Start on Everolimus (EVINEC study) study) Baseline 01/2016 07/2016 stable disease for 9 mo.
Clinical trials with Everolimus in NEN G3 Studie Therapie Referenz NORDIC NEC study Everolimus + temozolomide 1 st line in GEP NEC (Ki67 up to 55%) NCT02248012 EVINEC Pulmonary or Gastroenteropancreatic NEC Everolimus 2 nd line after failure of platinum-based therapies in NETG3/ NEC3; NETG2 NETG3 Everolimus as Maintenance therapy in metastatic NEC; randomized phase 2 study NCT00363051 NCT02687958 www.clinicaltrials.gov
G3 large cell NEC Patient US GEP-NEC study (NCT02595424) Cisplatin/ etoposide vs. TEM/ CAP in large cell NEC (optimal Ki67 will be defined for OR/ OS) Temozolomide + Capecitabin+ Bevacizumab Courtesy Kjell Öberg
Proposal for the Management of NEC G3 Ki67 matters for therapy selection NEC small cell or large cell Cisplatin (Carboplatin) + Etoposide CAPTEM or trageted drugs in large cell NEC preferably if Ki67<50-60% CIS/ETO vs. CAPTEM in large cell NEC (prosp. evaluation of Ki67 cut- off ) PD-1/ PDL-1 Molecular Markers Progression Clinical trial: e.g. Checkpoint- Inhibitor** FOLFIRI CAP/TEM FOLFOX Optionally RTX in obstructive GI NEC Bone/ Brain metastases
MANEC Proportion of neuroendocrine and non-neuroendocrine neoplasm with respective Ki67 In case of PDEC with high ki67 -> CE* regimen In case of low grade NEN G3 e.g. FOLFIRINOX; FOLFOX or other depending on primary site and nonne component Sequential therapies: CE FOLFOX (or other) to treat each component, respectively (consider rebiopsy in the F/Uwhich component is remaining?) *CE, cisplatin or carboplatin/ etoposide
Summary: What the oncologist needs to know from the pathologist? Precise Morphology Ki67 (absolute figure) and/ or mitotic count Cell type in NEC G3 (small cell or large cell) Primary site information (transcription factors), optional MiNEN? (morphology and Ki67 for each component) SSTR-2 expression (weak, strong, homogeneous): optional
Summary: Importance of the pathologist for decision making Impact of morphology and grading information on risk assessment and follow-up (2 or 3 mo) Impact of morphology and grade (and SSTR) on choice of functional imaging Impact of morphology and grade on therapeutic decision making (avoid toxicity!)
What the oncologist needs to know optionally (next to SSTR-2)? PD-1/ PDL-1 staining MMR gene defects Microsatellite instability (MSI high) Preselection of patients for Immune therapy Molecular profiling (NGS, WGS) for target identification
Immunotherapy Studies in NEN Target PD-1: Pembrolizumab, Nivolumab, PDR001 Target PD-L1: Durvalumab, Atezolizumab Avelumab Target CTLA-4: Ipilimumab Tremelimumab 31 Pembrolizumab KEYNOTE-158; NCT02628067 Advanced solid tumors; N=1100 Including lung carcinoids NCT03012620 Rare cancers; N=300 NCT02939651 High-grade NEN; N=21 PDR001 Advanced Solid tumors ELEVATION: Neuroendocrine tumors of lung, GI or Pancreatic origi, NEC VEGF, vascular endothelial growth factor. Nivolumab + Ipilimumab NCT02923934 Rare cancers; N=60 DART; NCT02834013 Rare tumors; N=334 Durvalumab + Tremelimumab DUNE; NCT03095274 Advanced GEP/lung NET; N=126 NCT02938793 Rare solid tumors; N=50 Atezolizumab + Bevacizumab NCT03074513 Rare solid tumors; N=160 Avelumab - G2/ G3 GEP NET or Lung; NEC G3
What I need to provide to the pathologist History of the disease: transition of NETG1/G2 to NET G3 or large cell NEC (exceptional) Disease sites (lung, pancreatic ) Evolution of the disease (e.g. rapid growth) Circulating biomarkers (LDH, NSE.) Hereditary background
Take home messages The pathologist is of utmost importance for clinical decison making NEN G3 need to be well defined (Morphology/ Differentiation, Proliferative activity; Molecular markers optional (e.g. p53, Rb, SSTR) Very few data are available on systemic therapy (all retrospective) Less toxic treatment options than cisplatinum/ etoposide should be used upfront in NET G3 (benefit risk ratio!)
Take home messages Clinical trials will provide more evidence on the efficacy of targeted drugs, temozolomide based chemotherapy and PRRT in NEN G3 Immunoncology studies ongoing Only together we will be able to better understand the disease and identify the best (most useful and least toxic) treatment for different subsets of NEN G3 patients
Thank you!
Grading for GEP-NET (Ki-67) Ki-67 Grade 2% >3 20% >20% G1 G2 G3 Octreoscan/ 68Ga-DOTATOC-PET/CT pos. FDG-PET pos. 36
Everolimus in pancreatic NEC G3 (WHO 2010) Retrospective Analysis 15 Patients with NEN G3 Median Ki67: 30%, ECOG 0-1; Everolimus 1st line: 4 Patients Efficacy of Everolimus in Pan-NET G3 with well/ moderately differentiated NET and Ki67 of <55% Median PFS 6 mo.; median OS 28 mo Panzuto et al, Pancreas 2017
Preclinical / molecular data for the use of mtor Inhibitors in NEN G3 Oncogenic mutation of mtor in LCNEC Yamaguchi et al Cancer Sci 2015 p-mtor is high in 6/9 PD NEC p-mtor high 6/6 large cell NEC Shida et al, Cancer Chemother Pharmacl 2010
Verantwortlicher Studienleiter nach AMG: Prof. Dr. med. M Pavel, Charité Everolimus bei NET/ NEC G3 (AIO Studie) NEC G3 NET G3 NETG2 NETG3 Platin-haltige Chemotherapie PD Everolimus 10mg/d Patienten Zentren 40 Patienten mit histologisch bestätigtem nicht pulmonalen NEC / NET G3 (Zweitlinientherapie) an 10 Zentren in Deutschland Primärer Endpunkt: Tolerabilität/ Sicherheit Sekundäre Endpunkte: PFS, DCR, ORR, Biomarker Zentraler Review der Pathologie: Prof. Dr G. Klöppel, TUM
Comprehensive genomic profiling of 724 gastroenteropancreatic neuroendocrine tumors Background: Genomic analysis is available for low number of patients with NEN Analysis of 639 genes by NextGen sequencing, immunhistochemistry and in-situ Hybridisation Assessment of Tumor mutational burden (TML) and microsatellite instability (MSI) GI (N = 469), Pan-NET (N = 255), High Grade (N = 135), and Low Grade (N = 336). TML TML MSI PD-L1 over- BRAF KRAS PI3KCA high median high expression mutated mutated mutated Alberto Puccini et al., ASCO Annual Meeting 2018