Douglas B. EvansPancreatic Cancer Program
Department of SurgeryMedical College of Wisconsin
Department of Surgery
• Cardiothoracic Surgery• Community Surgery• Colorectal Surgery• General Surgery• Pediatric Surgery• Surgical Oncology• Transplantation• Trauma, CC, Acute Care Surgery• Vascular Surgery
Personalized Medicine for Localized Pancreatic
Cancer:Thomas Seay Lecture
MCW Surgical Oncology – Leading the Way
Thomas E. Seay, M.D., Ph.D. Lectureship
Patient of Today
Patient of Tomorrow
Level of celiac axis
Level of SMA
Level of celiac axis
Jan 2011 Jan 2012
AP 09529635
PortalVein
Hepatic artery
SMA
LRV
Aorta
Celiac
SMV
Pancreatictransection
Tumor and associated pancreas attached by celiac
and hepatic arteries
AP 09529635
AP 09529635
Distal pancreas and spleen, distal pancreatectomy andsplenectomy:- Invasive ductal adenocarcinoma, well-differentiated, confined to the pancreas.- The surgical resection margins are free.- Sixteen lymph nodes, no evidence of tumor (0/16).
- AJCC Stage: T1 N0 MX.
SMV
PV
Celiac axis dividedHepatic artery
Pancreatic transection
LRVSMA
Left gastric artery divided
PortalVein
Aorta
Celiac
Saphenous vein graft
Caudate lobe of liver
SMA LRV
Pancreatic transection(stapled)AP 09529635
L adrenalvein
MCW Surgical Oncology – Leading the Way
64 yr old woman from Whitefish Bay, WI
RS 094173514
PV
SMVSplV
Pancreas
CHA
SMA
RHA
IVC
RS 094173514
LHA
1-2 wks
6-10 wks
Recovery from surgeryDiagnosis, staging and preparation for surgery
OR
Surgery-first approach to localized pancreatic cancer
Adj Therapy
CT
What we know:No progress in decades
What we do not know:The biologic impact of surgery first
Hopkins:Wenchuan, et al. Ann Surg Oncol 2014;21:2873–2881
MCW Surgical Oncology – Leading the Way
Surgery First
Swanson RS, Ann Surg Oncol 2014;21:4059–4067
NCDB pancreatectomy
MCW Surgical Oncology – Leading the Way
492495
SMV
Spl A
CHA
Spl V
saph veinpatch
dividedbile duct PV
Rev saphvein graft
Final path:R0 resectionLymph nodes: 0/24
MCW Surgical Oncology – Leading the Way
Presented at the SSO , Spring 1992
Initial experience with multimodality / neoadjuvant therapy for pancreatic cancer
0.00
0.20
0.40
0.60
0.80
1.00
27 23 14 6 3N246 41 24 15 8N1138 129 91 62 41N0
Number at risk
0 10 20 30 40months from diagnosis
N0
N1
N2
Nodal Status Basturk/ Adsay. MCW
N0, n (%) 52 (23%) 138 (65%)
N1 (1-2+), n (%) 60 (26%) 46 (22%)
N2 (3+), n(%) 115 (51%) 27 (13%)
Median # LN examined 17 (range: 2-43) 25 (IQR:14)
Median # positive LN 3 (range: 1-47) 2 (IQR: 3)
N0 = 43 months
N1 = 33 months
N2 = 26 monthsBasturk et al. ASO 2015
MCW, unpublished data
Surgery First Approach Neoadjuvant Therapy
N0 = 43 months
N1 = 33 months
N2 = 26 months
Tsai, S: unpublishedMCW Surgical Oncology – Leading the Way
Protocol-based preop chemoradiation• 88-004 50.4 Gy/ 5-FU 300mg/m2
• 92-002 wide field liver irradiation• 93-007 30 Gy/ 5-FU 300mg/m2
• 95-224 30 Gy/paclitaxel 60mg/m2/wk• 98-020 30 Gy/Gem 400mg/m2/wk• 01-341 Gem/Cis, 30 Gy/Gem• 05-0784 Gem/Bev, 50.4 Gy• 08-0459 Gem/Erlotinib +/- XRT
Preop Clinical Trialsinvestigator initiated – industry supported
7 wks 3-4 wks
XRT: 30 Gy (3Gy/F; M-F)
Chemo: Gemcitabine (400)
Staging CT
Staging CT OR
3 months
Gem-XRT
JCO 2008;26:3496-3502
Group N Median Survival 5-yr surv
Resected 64 34 mo 21/64
Not Resected 22 7 mo 0
Median survival for all 86 patients = 23 monthsLocal recur = 11% (all neg SMA margin; isolated LR 2/7)
98-020GemXRT
JCO 2008;26:3496-3502
0.00
0.25
0.50
0.75
1.00
189 157 104 56 37 16 eted all therapy70 41 8 2 0 0 = Not Resected99 77 53 33 26 19 eted all therapy
Number at risk
0 10 20 30 40 50months from diagnosis
Surgery FirstNeoadjuvant/ Not ResectedNeoadjuvant/Resected
y q g g
Prop
ortio
n Su
rviv
ing
Medical College of Wisconsin
Surgery FirstNeoadjuvant/Not Resect
Neoadjuvant/Resected
Median overall survival:Surgery First: 24.0 mo
Neoadj + Surg: 34.0 moNeoadj - Surg: 11.4 mo
Susan Tsai, MD
0.00
0.20
0.40
0.60
0.80
1.00
120 70 30 9Neoadjuvant + Surg24 3 0 0Not Resected
Number at risk
0 20 40 60months from diagnosis
Not ResectedCompleted all therapy
Overall Survival of Resectable PC Receiving Neoadjuvant Therapy
83% of pts with resectable PC complete all neoadjuvant therapy and surgery. Median OS: 45 mo
17% of pts with resectable PC fail to complete all neoadjuvant therapy (no surgery). Median OS: 11 mo
Median f/u 17.9 mo (range 6-66)Updated data: Tsai - unpublished
MCW: Christians KK, et al. Survival of patients with resectablepancreatic cancer who received neoadjuvant therapy
Surgery 2016;159(3):893-900.
Signal stronger
MCW Surgical Oncology – Leading the Way
0.00
0.25
0.50
0.75
1.00
27 16 8 4 3 199grp = increased99 78 38 12 7 3199grp = declined67 56 40 27 17 89grp = normalized
Number at risk
0 10 20 30 40 50months from diagnosis
Grp A: Normalized CA19-9Grp B: Decreased CA19-9Grp C: Increased CA19-9
Overall Survival by Preop CA19-9
Prop
ortio
n Su
rviv
ing
Grp AGrp BGrp C
Median overall survival:Grp A: 36.5 moGrp B: 20.3 moGrp C: 13.2 mo
p=0.002
Susan Tsai, MD
Variables
Patient:• host immune response• DNA repair
Tumor:determine the vulnerability of the tumor and match it with the correct treatment
Treatment:Try to match the right treatment with the vulnerabilities of the tumor
Tumor
Host
Rx
Positive for adenocarcinoma
Molecular profile: biomarker analysis
Target identifiedProfile predictive
Extra-hepatic obstruction of the bile duct on CT with a pancreatic mass
EUS
ERCP stent if necessary
Target identifiedProfile NOT predictive
Target NOTidentified
Diagnosis
Treatment
Personalized Neoadjuvant Therapy
• Effective Chemotherapeutic Regimens for PDAC exist• Known prognostic/?predictive biomarkers
• STREET profiling of EUS/FNA samples acquired at the time of diagnosis
STREET Biomarkers Abbrev Related Drug
Secreted Protein Acid Rich in Cysteine SPARC nab-paclitaxel
Thymidylate Synthase TYMS 5-flurouracil
Ribonucleotide reductase M1 RRM1 gemcitabine
Equilibrative nucleoside transpt ENT1 gemcitabine
Excision repair cross-complementing ERCC platinum
Topoisomerase I TOPO irinotecan
Susan Tsai, unpublished
STREET Biomarker Summary
Biomarker Expression Predicted Response
SPARC High SPARC Benefit from nab-Paclitaxel
TOPO1 High TOPO1 Benefit from Irinotecan
RRM1 Low RRM1 Benefit from gemcitabine
ENT1 High ENT1 Benefit from gemcitibine
ERCC1 Low ERCC1 Benefit from platinum analogs
TYMS Low TYMS Benefit from 5-FU
Biomarker Assessment
Gemcitabine Based
5-FUBased
Either Gem or 5-FU
Neither Gem or 5-FU
FNA profiling
TYMS high & RRM1 high or hENT1- or Target not Identified
Gem(-)/5FU(-)
TYMS low & RRM1 high or hENT1 -Gem(-)/5FU(+)
GTYMS high & RRM1 low & hENT1 +
Gem(+)/5FU(-)
Gem/Platin
FOLFIRINOX Gem/nab
FOLFIRI Cap/XRT Gem/Irino Gem/XRT
ERCCexpression -+
TOPOexpressn -+
SPARC expressn -+
ERCC expressn -+
TOPO expressn -+
SPARCexpressn -+
Cap/nab
Profile Not Predictive:
Chemo/XRT
Target not identified (resectable): chemoXRTTarget not identified (BL resect): FOLFIRINOX
TYMS low & RRM1 low & hENT1 +
Gem(+)/5FU(+)
SPARC expressn -+
ERCC expressn -+Gem/nab
FOLFIRINOXTOPO
expressn -+
FOLFIRI vs. Gem /Irino
Gem/Cap
Jeske BLFOLFIRINOX, Then Gem orCap/XRT
BIOMARKER INTENSITY PERCENT STAIN
Drug
SPARC NA NA No NabTYMS 0 NA 5-FURRM1 0 NA GemENT1 0 NA No Gem
ERCC1 1 100 PlatinTOPO1 3 100 Irino
Patient Results FNA
FNA profiling
TYMS high & RRM1 high or hENT1- or Target not Identified
Gem(-)/5FU(-)
TYMS low & RRM1 high or hENT1 -Gem(-)/5FU(+)
GTYMS high & RRM1 low & hENT1 +
Gem(+)/5FU(-)
Gem/Platin
FOLFIRINOX Gem/nab
FOLFIRI Cap/XRT Gem/Irino Gem/XRT
ERCCexpression -+
TOPOexpressn -+
SPARC expressn -+
ERCC expressn -+
TOPO expressn -+
SPARCexpressn -+
Cape/nab
Profile Not Predictive:
Chemo/XRT
Target not identified (resectable): chemoXRTTarget not identified (BL resect): FOLFIRINOX
TYMS low & RRM1 low & hENT1 +
Gem(+)/5FU(+)
SPARC expressn -+
ERCC expressn -+Gem/nab
FOLFIRINOXTOPO
expressn -+
FOLFIRI vs. Gem /Irino
Gem/Cap
Newman ResectableCap/Nab
BIOMARKER INTENSITY PERCENT STAIN
Drug
SPARC 2 trace NabTYMS 0 NA 5-FURRM1 2 50 No GemENT1 0 NA No Gem
ERCC1 2 100 No PlatinTOPO1 3 100 Irino
Patient Results FNA
FNA profiling
TYMS high & RRM1 high or hENT1- or Target not Identified
Gem(-)/5FU(-)
TYMS low & RRM1 high or hENT1 -Gem(-)/5FU(+)
GTYMS high & RRM1 low & hENT1 +
Gem(+)/5FU(-)
Gem/Platin
FOLFIRINOX Gem/nab
FOLFIRI Cap/XRT Gem/Irino Gem/XRT
ERCCexpression -+
TOPOexpressn -+
SPARC expressn -+
ERCC expressn -+
TOPO expressn -+
SPARCexpressn -+
Cap/nab
Profile Not Predictive:
Chemo/XRT
TYMS low & RRM1 low & hENT1 +
Gem(+)/5FU(+)
SPARC expressn -+
ERCC expressn -+Gem/nab
FOLFIRINOXTOPO
expressn -+
FOLFIRI vs. Gem /Irino
Gem/Cap
Quinene BLFOLFIRI, then Cap or Gem/XRT
BIOMARKER INTENSITY PERCENT STAIN
Drug
SPARC NA NA No NabTYMS 0 NA 5-FURRM1 0 NA GemENT1 2 75 Gem
ERCC1 3 75 No PlatinTOPO1 3 100 Irino
Patient Results FNA
Dx: 2/4/15 After FOLFIRI
CA19-9: 346 CA19-9: 79
STREET
FOLFIRI 4 cycles
Molecular Profiling from EUS FNA
• EUS FNA performed with 22 gauge needle• On-site cytopathologist
Adequate FNA cytology for molecular profiling
25 26
74 73
0
10
20
30
40
50
60
70
80
90
100
Resectable BLR
Yes
No
% o
f pat
ient
s
0
2
4
6
8
10
12
14
16
18
0 20 40 60 80 100
Timeframe of STREET Reporting
# Patients
# B
usin
ess D
ays
Results Resection
BIOMARKER INTENSITYPERCENT
STAIN Drug
SPARC 2 25 NabTYMS 1 50 5-FURRM1 3 100 No GemENT1 2 100 Gem
ERCC1 3 100 No PlatinTOPO1 3 100 Irino
Resection Profiling (previous neoadj XRT)
TYMS high & RRM1 high or hENT1- or Target not Identified
Gem(-)/5FU(-)TYMS low & RRM1 high or hENT1 -
Gem(-)/5FU(+)GTYMS high & RRM1 low & hENT1 +
Gem(+)/5FU(-)
Gem/Platin
FOLFIRINOX Gem/nab
T066 Cap/Nab
FOLFIRI 5-FU Gem/Irino Gem
Profile Not Predictive
ERCC expressn -+
TOPO expressn -+
SPARC expressn -+
ERCC expressn -+
TOPO expressn -+
SPARC expressn -+
Cape/nab
SMAD expressn -+
GemNo further Rx
Target not identified: 4 mo Gem
Gem/Cap
FOLFIRINOX
ERCC expressn -+
SPARC expressn -+
Gem/nab
TOPO expressn -+
FOLFIRI vs. Gem/Irino
| Resectability from| Imaging
completerxn | resectabl BL resect | Total----------------------+----------------------+----------
Not Resected | 16 63 | 79 | 20.25 79.75 | 100.00 | 18.82 45.32 | 35.27
----------------------+----------------------+----------Completed all therapy | 69 76 | 145
| 47.59 52.41 | 100.00 | 81.18 54.68 | 64.73
----------------------+----------------------+----------Total | 85 139 | 224
| 37.95 62.05 | 100.00 | 100.00 100.00 | 100.00
Fisher's exact = 0.0001-sided Fisher's exact = 0.000
Primary Endpoint: completion of all therapy (surgery)
| Resectability from| Imaging
completerxn | resectabl BL resect | Total----------------------+----------------------+----------
Not Resected | 3 9 | 12 | 25.00 75.00 | 100.00 | 6.82 22.50 | 14.29
----------------------+----------------------+----------Completed all therapy | 41 31 | 72
| 56.94 43.06 | 100.00 | 93.18 77.50 | 85.71
----------------------+----------------------+----------Total | 44 40 | 84
| 52.38 47.62 | 100.00 | 100.00 100.00 | 100.00
Fisher's exact = 0.0601-sided Fisher's exact = 0.040
Historical Controls Current Trial
surgeryrestaging
Treatment completed
diagnosis and staging
Neoadjuvant Therapy
| Resectability fromFNA Sample | ImagingAdequate | resectabl BL resect | Total
-----------+----------------------+----------No | 12 13 | 25
| 48.00 52.00 | 100.00 | 26.09 27.66 | 26.88
-----------+----------------------+----------Yes | 34 34 | 68
| 50.00 50.00 | 100.00 | 73.91 72.34 | 73.12
-----------+----------------------+----------Total | 46 47 | 93
| 49.46 50.54 | 100.00 | 100.00 100.00 | 100.00
Fisher's exact = 1.0001-sided Fisher's exact = 0.525
.
Profiled therapy
Target identified Target identified vs. completion of all
therapyFNA Sample | completerxnAdequate | Not Resec Completed | Total
-----------+----------------------+----------No | 6 15 | 21
| 28.57 71.43 | 100.00 | 50.00 21.13 | 25.30
-----------+----------------------+----------Yes | 6 56 | 62
| 9.68 90.32 | 100.00 | 50.00 78.87 | 74.70
-----------+----------------------+----------Total | 12 71 | 83
| 14.46 85.54 | 100.00 | 100.00 100.00 | 100.00
Fisher's exact = 0.0661-sided Fisher's exact = 0.044
surgeryrestaging
Treatment completed
diagnosis and staging
Neoadjuvant Therapy
1. Serial Blood and Tissue Acquisition2. Integrated Clinical Data3. In vivo tissue expansion
4. Rapid Autopsy Program• Pt entering hospice may donate their tumors
after death• “Warm” autopsy is performed within 2 hours
of death• Source of metastatic tumors which normally
would not be accessible
XENOGRAFT TUMOR
Pancreas Biorepository
Courtesy of Dr. Susan Tsai
It does take a villageMCW Pancreatic Cancer Program
Pancreatic Cancer Group• Douglas Evans, MD• Susan Tsai, MD, MHS• Kathleen Christians, MD• Fabian Johnston, MD, MHS• Paul Ritch, MD• Jim Thomas, MD, PhD• Ben George, MD• Beth Erickson, MD• A. Craig Mackinnon, MD, PhD• Kiyoko Oshima, MD• Katherine Hagen, MD• Kulwinder Dua, MD• Abdul Khan, MD• Murad Abu Rajab, MD• Jennifer Knight, MD• Jenny Geurts, CGC
Clinical Staff• Beth Krzywda, NP• Shannon Lahiff, NP• Lisa Graber, NP• Sarah Misustin, PA• Dena McDowell, RD• Kara Sonntag, RD
Research Core• Anne Laulederkind, RN• Mohammed Aldakkak, MD, PhD• Jenny Grewal, MS• Karthika Divakaran, PhD• Annie Dwyer
Pancreas Outcomes Research• Ashley Krepline• Sophia Rokkas
Internal Collaborators• Mats Hidestrand Ph.D.• Aoy Mitchell, Ph.D.• Mike Mitchell, M.D.• Guan Chen, M.D., Ph.D.• Jill Gershan, Ph.D.• Bryon Johnson, Ph.D.• Matt Riese, M.D., Ph.D.• Mike Dwinell, Ph.D.• Raman Kalyanaraman, Ph.D.• Carol Williams, Ph.D.
Funding• Advancing Healthier
Wisconsin• Ronald Burklund Eich PC
Research Fund• Research Affair
Committee Grant• Lockton Fund• WeCare Fund• American Cancer Society
Pilot Grant
External Collaborators• Elena Gostjeva, Ph.D.• Bill Thilly, Sc.D.• Wisconsin Donor Network• WI State Hygiene Lab• Dept of Veterans Affairs
SMV
SplV
IJ
PV
Renal V
Gallbladderfossa
Reversed saphenous vein graft from RRA to RHA
Left internal jugular vein interposition graft replacing portal vein. A temporary anastomosis of the IJ graft to the IVC was created to allow complete diversion of all portal flow allowing for a safe portal dissection
Bile Duct
- FOLFIRINOX- Cape-XRT- Gem-nab(DVT, stent obstruction, cholecystostomy tube)
Patients will become increasingly complicated
Thomas E. Seay, M.D., Ph.D.Created a village around him – made the complicated appear understandable
Patient of Today
Patient of Tomorrow
Patrick Swayze
Joseph Cardinal BernardinArchbishop of Chicago
Luciano Pavarotti
Gene Upshaw
Count Basie
Michael Landon
Fred Gwynne
Judge Ruth Bader Ginsburg
Sheikh Zayed
Gail Allen
“Surgery” as a component of “Surgical Oncology” will become even more complex as systemic therapies improve
DATE OF SERVICE: 01/31/2012Mrs. C is 77 years old, received an extensive program of gemcitabine, Taxotere and capecitabine (GTX) beginning in July 2011, followed by capeXRT beginning in early December 2011. She has experienced a nice decline in CA19-9; 173 into the low-normal range. CT scan has shown stable disease with no evidence of disease progression.
WC 09546353
Post Neoadjuvant (Pre-Op) Evaluation- clinical benefit ?- imaging better ?- CA19-9 ?
SMV
CHA
SMA
SplV
IVC
CHA
IVC
SMV
PV
SplV
Divided Splenic Vein (as IMV entered Splenic Vein)
PV
February 2010
SMV Anatomy
PV
Splenic V
SMV
Ileal branch Jejunal branch
IMV may enter spl vein or SMV
SMA
From: ling lam Sent: Tuesday, January 13, 2015 5:00 PMTo: Evans, DouglasSubject: mom
Dear Dr Evans, Happy New Year! My mom is doing well. Her check up three months ago was still looking good. She is maintaining her weight. Our biggest struggle so far is controlling her diabetes. She is on insulin and oral agent but still not well controlled. Otherwise, she is well.
September, 2012
JM 10022862
SMV
PV CHA
SplV
IMV
IVC
SMA
Pancreasremnant
GDA closure
10730319
SMV
PV
SMA57 y.o. man with pancreatic cancerJaundice, CT with resectable tumor, booked for OR, and had an EUS-FNA and stent placement prior to surgery
Panc
CBDGDA
February, 2012
DC 09573585
SMA
SMV
53 woman with borderline resectable pancreas cancer presented with pain and biliary obstruction
September 24, 2012
C 09573585
SMVSMV
SMA
53 woman received 8 cycles of FOLFIRINOX and then Gem-XRT
“Surgery” as a component of “Surgical Oncology” will become even more complex as systemic therapies improve
SMV Anatomy
PV
Splenic V
SMV
Ileal branch Jejunal branch
Spl vein prevents access to proximal SMA
SMA
SMV Anatomy
PV
Splenic V
SMV
Ileal branch Jejunal branch
Spl vein prevents access to proximal SMA
SMATemporary mesocaval shunt using left IJ to connect SMV to IVC
Transectedpancreas
SMV
IJ
duodenum
Umbilical Tape on SMA
SplV
PV
SplV
PV
IVC
IJ
SMV
SMA
Divided SMV
SplV
PV
IVC
IJ
SMV
SMASaphenous vein spiral wrap
Divided SMV
IVC
Site of temporary mesocaval shunt
IJgraft
SMV
PV
SMA
Replaced right hepatic artery
Replaced right hepatic artery
CHAGDA stump
EB 7-21-2010
IVC
SMV
PV
SMA
IMV
PancreasReplaced RHA
LHA
G 07558466
Resectable
Borderline Resectable
Locally Advanced
Chemotherapeutic Agents
• Effective Chemotherapeutic Regimens for PDAC:– FOLFIRINOX (Conroy et al. NEJM 2011)– Gemcitabine /nab-paclitaxel (Von Hoff et al. NEJM 2013)
TS: Thymidylate synthetase generates dTMP which is phosphorylated to dTTP for use in DNA synthesis and repair. Low expression of TS is associated with response to fluoropyrimidines
ERCC1: Excision repair cross-complementation group 1 is important in nucleoside excision and repair. Platinum based drugs induce DNA cross-links that interfere with DNA replication and transcription. Low ERCC1 expression is associated with response to platinum-based therapy
TOPO1: Topoisomerase1 is an enzyme that alters the supercoiling of double stranded DNA. TOPO1 acts by transiently cutting one strand of the DNA to relax the coil and extend the DNA molecule. Higher expression of TOPO1 has been associated with the response to irinotecan, a TOPO inhibitor.
SPARC: Secreted protein acidic and rich in cysteine is a calcium binding matricellular glycoprotein which functions in cell-matrix interactions. Over-expression improves the response to nab-paclitaxelby accumulating albumin and albumin targeted agents within tumor tissue (tumor and stroma).
RRM1: Ribonucleotide reductase subunit M1 is a component of the ribonucleotide reductaseholoenzyme which is a rate-limiting enzyme involved in the production of nucleotides required for DNA synthesis. Gemcitabine is a deoxycitidine analogue with inhibits RRM1 activity. Low RRM1 levels are associated with response to gemcitabine.
hENT1: Human equilibrative nucleoside transporter 1 is responsible for transportation of gemcitabineinto cells. Patients with high levels of hENT1 are more likely to benefit from gemcitabine therapy
Personalized MedicinePancreatic Cancer
May 2011
Median survival 11.1 vs. 6.8
FOLFIRINOX: oxaliplatin 85 mg/m2
irinotecan 180 mg/m2
leucovorin 400 mg/m2
bolus fluorouracil (5-FU) 400 mg/m2
followed by 5-FU 2,400 mg/m2 IV as a 46-hour CIcycled every 2 weeks for a total of 4 cycles