Douglas B. EvansPancreatic Cancer Program

Department of SurgeryMedical College of Wisconsin

devans@mcw.edu

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