1. Neuroendocrine tumor: an update on classification and targeted treatment
Ming-Huang Chen MD, PhD Department of Oncology, Taipei Veterans General Hospital
2017/5/7 TJCC talk

2. Outlines New classification of pancreas NETs 2017 WHO classification
Ethnic difference in pancreatic NETs
Peptide Receptor Radiotherapy: experience sharing

3. Comparison of the WHO classifications of pancreatic NETs

4. WHO 2010 classification

5. WHO 2017 classification
Ki67 at least 500 cells in higher nuclear labeling area, 50 HPF, show as per 10 HPF.

6. The changes
1. Ki67 cutoff level of grade 1 pancreatic NET

7. WHO 2017 classification
<3 %

8. Grade 1 NET Cut of 3%
Because this was always the intention of WHO That is Ki67 proliferative index were to be rounded up or down to nearest whole number.
Ex: No ki67= 2.5%

9. The changes 1. Ki67 cutoff level of grade 1 pancreatic NET
2. Subdivision of tumors with Ki67>20% into
- Well differentiated G3 NETs
- Poorly differentiate G3 NECs

10. Increasing evidence suggests that G3 NEN are not a homogenous entity and can be further sub-classified into biologically relevant subgroups . A separation based on the proliferative index (Ki-67 >55%) was shown to have clinical implications regarding response to chemotherapy and prognosis.

11. 2016 ENETS guideline for high grade NETs/NECs

12. Nodic NEC study
Sorbye H et al. Cancer 2014;

13. Nordic NEC study
< 55% less responsive to platinum based chemotherapy
>55% more responsive but worse survival
However, pathology in this study is not well evaluated.

14. Well differentiated

15. Stem cells origin of GEP NETs

16. 德國慕尼黑理工大學

17. Pancreatic neuroendocrine neoplasms with Ki67>20%

18. Pancreatic neuroendocrine neoplasms with Ki67>20%

19. Pancreatic neuroendocrine neoplasms with Ki67>20%

20. The distinction of NETs from NECs
MEN1, DAXX, ATRX mutation
P53, Rb1 mutations
SSTR2A (+)
SSTR2A (-)
Recognisable as NETs
Small cell or large cell types
Often evolve from a recognisable low grade component
No lower grade component
No upper limit given, but usually Ki67<40 to 55%
Mitotic count <20/10HPF
Must have Ki67>20% no lower limit but usually> 55%

21. PNETs with Ki67>20%
Strong evidence that not just Ki67/mitotic rate but also morphological differentiation is important
Large cell, small cell NECs should be considered completely different entities to PNETS.

22. Pancreatic NET and Ki67 3%

23. WHO 2017 classification
<3 %

24. The changes 1. Ki67 cutoff level of grade 1 pancreatic NET
2. Subdivision of tumors with Ki67>20% into
- Well differentiated G3 NETs
- Poorly differentiate G3 NECs
3. MANEC (mixed adenoneuroendocrine carcinoma) becomes MENEN/MINEN

25. WHO 2017 classification
<3 %

26. Mixed endocrine non-endocrine neoplasms (MINEN)
To qualify as MINEN each component must have at least 30%. (No change)
Recognises that MINENs may occasional be well differentiated. (Not always poorly differentiated NECs)
MINENs may have a non-endocrine component other than adenocarcinoma (SCC, acinar cell carcinoma)

27. Unsolved Problems How to treat well differentiated NET grade 3 ?
- chemotherapy ? Which regimens?
- Targeted therapy?
- PRRT?
- Hormone therapy?
How to treat MINENS, especially well differentiated NET + SCC or adenocarcinoma or acinar cell carcinoma?

28. Outlines New classification of pancreas NETs 2017 WHO classification
New 8th AJCC TNM staging of pancreatic NETs  
Ethnic difference in pancreatic NETs
Peptide Receptor Radiotherapy: experience sharing

29. AJCC 8th version of pancreatic NETs
Primary tumor (T)
TX Tumor cannot be assessed
T1 Tumor limited to the pancreas, < 2 cm
T2 Tumor limited to the pancreas, 2-4 cm
T3 Tumor limited to the pancreas, > 4 cm or tumor invading the duodenum or bile duct
T4 Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis or the superior mesenteric artery)
AJCC 7th version of pancreatic cancer
AJCC 8th version of pancreatic neuroendocrine tumor

30. AJCC 8th version of pancreatic NETs
Distance Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined to liver
M1b Metastsis in at least one extrahepatic site (e.g., lung, ovary, nonregional LN, peritoneum, bone)
M1c Both hepatic and extrahepatic metastases
AJCC 7th version of pancreatic cancer
AJCC 8th version of pancreatic neuroendocrine tumor

31. AJCC 8th version of pancreatic NETs
Stage T N M I T1 N0 M0 II T2 T3
III T4
Any T N1 IV
Any N M1
AJCC 7th version of pancreatic cancer
AJCC 8th version of pancreatic neuroendocrine tumor

32. Summary of Changes in AJCC8th version in PNETs
New Chapter
PNETS are staged using a TNM staging predominantly based on size
The criteria of peripancreatic soft tissue invasion was eliminated.
The Tis distinction was eliminated.
M is subdivided to M1a, M1b and M1c

34. Outlines New classification of pancreas NETs 2017 WHO classification
New 8th AJCC TNM staging of pancreatic NETs  
Racial difference in NETs
Ethnic difference in pancreatic NETs
Peptide Receptor Radiotherapy: experience sharing

35. RADIANT3- Japan subgroup
Jpn J Clin Oncol 2012;42:903–911

36. RADIANT3- Japan subgroup
Overall population
Japanese subgroup
Overall population
Japanese subgroup
Everolimus
Placebo
RATIANT3 (Advanced progressive PNETs)
Median PFS, mon
11.0
4.6
19.45
2.83 HR
0.35
0.19
Overall population
Japanese subgroup
Jpn J Clin Oncol 2012;42:903–911

37. RADIANT-4 Study Design Everolimus 10 mg/day N = 205 Placebo N = 97
Patients with well-differentiated (G1/G2), advanced, progressive, nonfunctional NET of lung or GI origin (N = 302)
Absence of active or any history of carcinoid syndrome
Pathologically confirmed advanced disease
Enrolled within 6 months from radiologic progression
Everolimus 10 mg/day
N = 205
Treated until PD, intolerable AE, or consent withdrawal
2:1
RANDOMI ZE
Placebo
N = 97
Endpoints:
Primary: PFS (central)
Key Secondary: OS
Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK
Stratified by:
Prior SSA treatment (yes vs. no)
Tumor origin (stratum A vs. B)*
WHO PS (0 vs. 1)
Abbreviations: AE, adverse event; CgA, chromogranin A; DCR, disease control rate; FACT-G, functional assessment of cancer therapy-general; GI, gastrointestinal; HR, hazard ration; HRQOL, Health Related Quality of Life; NET, Neuroendocrine tumors; NSE, neuron-specific enolase; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, Pharmacokinetics; SSA, somatostatin analogues; WHO PS, World Health Organization performance status.
*Based on prognostic level, grouped as: Stratum A (better prognosis)  appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary. Stratum B (worse prognosis)  lung, stomach, rectum, and colon except caecum.
Crossover to open label everolimus after progression in the placebo arm was not allowed prior to the primary analysis.

38. Primary Endpoint: PFS by Central Review
52% reduction in the relative risk of progression or death with everolimus vs placebo
HR = 0.48 (95% CI, ); P <
205
168
145
124
101 81 65 52 26 1 3 97 39 30 24 21 17 15 11 6 5
Placebo
Everolimus
No.of patients still at risk 2 4 8 10 12 18 27
Months 20 40 50 60 70 80 90
100
Probability of Progression-free Survival (%)
Kaplan-Meier medians
Everolimus: 11.0 months (95% CI, )
Placebo: 3.9 months (95% CI, )
Censoring Times
Everolimus (n/N = 113/205)
Placebo (n/N = 65/97)
P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.

39. PFS HR by Pre-defined Subgroups
All
Age
<65
≥65
Sex
Male
Female
Race
Caucasian
Asian
Other
Tumor grading
Grade 1
Grade 2
302
159
143
142
160
230 50 22
194
107
Hazard Ratio (95% CI)
No.
Subgroups
0.56 ( )
0.55 ( )
0.59 ( )
0.78 ( )
0.39 ( )
0.83 ( )
0.19 ( )
0.26 ( )
0.57 ( )
0.49 ( )
0.1
0.4 1 10
Treatment naive* Y es No 17
185
0.65 ( )
0.51 ( )
Prior chemotherapy
Baseline CgA
>2xULN
≤2xULN
Baseline NSE
>ULN
≤ULN 77
225
139
138 87
188
0.35 ( )
0.60 ( )
0.40 ( )
0.70 (
0.77 ( )
0.44 ( )
Everolimus Better
Placebo Better
*Defined as no prior chemotherapy or no SSA therapy continuously for ≥12 weeks any time before study.
Hazard ratio is obtained from unstratified Cox model.
CgA, chromogranin A; NSE, neuron-specific enolase; ULN, upper limit of normal.

50. Summary and conclusions
In this East Asian subgroup analysis of the RADIANT -3 and -4 studies
Everolimus demonstrated a clinically meaningful 8.1-month prolongation of PFS and an 82% reduction in risk of progression or death compared placebo in patients with advanced, progressive, nonfunctional NET of lung/GI origin consistent with the overall RADIANT-4 study population
In patients with advanced PNET from the RADIANT-3 study, everolimus demonstrated a 7.7-month increase in PFS and a 66% reduction in risk of progression or death compared to placebo
Safety profile was consistent for the East Asian subgroup with the known safety profile of everolimus and no new safety signals were observed
Everolimus is the first targeted agent to show robust antitumor activity with acceptable tolerability across a broad spectrum of NET including those arising from the pancreas, lung, and GI tract
NET, neuroendocrine tumors; GI, gastrointestinal; PNET, pancreatic NET

51. Ethnic and racial difference in pancreatic NETs
RADIANT 3
East Asia
Japan
Taiwan
Median PFS
11.0 months
14.1 months
19.5 months
18.9months
Asia-Pacific Journal of Clinical Oncology 2016; 12: 396–402

52. Customized sequencing panel for 43 genes association with pNETs.
N=40 pNETs.
Customized sequencing panel for 43 genes association with pNETs.
NGS of

54. Take Home Message New WHO 2017 classification of pancreatic NETs.
New AJCC 8th classification of pancreatic NETs.
Everolimus is effective in pancreatic NETs, lung NETs and GI NETs in Asia patients.

55. Thanks for Your Attention