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Page 1: Pancreatic Cancer

Pancreatic Cancer

Malcolm J. Moore MD

Princess Margaret Hospital

Page 2: Pancreatic Cancer

Pancreatic Cancer

US incidence: 32,180 new cases estimated for 20051

– 2% of all new cancer cases

Screening, early detection not on the horizon

Most patients are diagnosed with advanced disease

1 CA Cancer J Clin 2005;55:10-30

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Pancreatic Cancer – Outcome is Poor

US mortality: 31,800 deaths estimated for 20051

– 4th and 5th leading cause of cancer-related death in males and females, respectively

– 5% to 6% of all cancer deaths

5 year survival less than 5%2.

Median survival 3-4

– metastatic disease 3-6 months

– locally advanced disease 9 months

– Resected disease 14 months1 CA Cancer J Clin 2005;55:10-302 SEER Cancer Statistics Review. http://seer.cancer.gov3 Am J Surg 1993;165:68 4 JCO 2005; 23:4538

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Pancreatic Cancer

Epidemiology

– Increases with age

– No major geographical differences

Genetics

– P16, DPC, p53, k-ras

Familial

– Poorly understood

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Pancreatic Tumors

Most are ductal adenocarcinomas.

– Most common site is head of pancreas

– Dense fibrous reaction.

– Precursor lesions – PanIN

Other subtypes

– Adenosquamous

– Acinar cell, medullary, undifferentiated

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Pancreatic Cancer – Ductal Adenocarcinoma most common

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Pancreatic Tumors

Serous cystadenoma/adenocarcinoma.

Mucinous neoplasms

Endocrine tumors

– Range of differentiation-not all malignant

– Functioning vs non

– Well circumscribed

– VascularTumors of the pancreas, Armed Forces Institute of Pathology, Washington 1997. p.145.

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Well differentiated endocrine tumor - + chromogranin

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Pathology

Most are ductal adenocarcinoma– But not all, so …

– Biopsy essential

– Although usually can predict non-adenocarcinoma by imaging or clinical course.

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Making the diagnosisCommon symptoms

Pain

Gastric obstruction

Biliary obstruction

Diabetes

Hypercoaguability

Malabsorption

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CA 19-9

Tumor associated antigen

Elevated in most cases of pancreatic cancer.

Also elevated in other GI cancers, pancreatitis.

Slightly better specificity and sensitivity than CEA.

Unknown value in clinical studies.

Am J Gastroenterol 1999;94:1941-6.

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Pain Pancreatic Cancer

Pain often due to local invasion of tumor.

Improved by XRT +/- chemo in 35-65% of cases

Improved by palliative chemo

Celiac axis blocks

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Pancreatic Cancer Gastric/duodenal obstruction

Occurs in cancers of pancreatic head.

Consider in patients with refractory nausea/vomiting

Remedies are

– Gastrojejunostomy- open or laparoscopic

– Duodenal stenting

? Role of prophylactic gastrojejunostomy

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Pancreatic CancerBiliary obstruction

Cancers of pancreatic head.

Often presenting problem.

? Surgical vs Endoscopic stenting.

– Both effective.

– Surgery a better long term solution.

– Stent occlusion/replacement

Percutaneous drainage not recommended

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Pancreatic CancerDiabetes

? A risk factor for disease.

Can be a presenting problem.

More than just loss of pancreatic function.

Treat symptomatically.

Not a contraindication to steroids

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HypercoaguabilityWell recognized association -Trousseau’s

syndrome.

Can be both central and peripheral.

Generally resistant to oral agents.

Long term therapy required.

Association with early deaths

? Role of prophylactic anti-coagulation

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Malabsorption

Pancreatic insufficiency

One reason for weight loss

Use of narcotics may mask usual symptoms

Trial of pancreatic enzymes

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Surgery

Only 15-20% are resectable.

Whipples resection (pancreaticoduodenectomy) for tumors of the head

– 3 anastamoses

– Should be done in high volume centres

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Is there a role for adjuvant therapy?

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Original Adjuvant TrialGITSG [N=43]1

Median survival 20 versus 11 months

5 year survival 18 vs 8%

But… - 43 patients in 8 years.

A larger EORTC trial (n=114 pancreatic cancer) failed to confirm the benefit of adjuvant CRT 2

5-FU + XRT with systemic 5-FU X 1 yr

vs

No additional treatment

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ESPAC-1 Trial DesignNeoptolemos NEJM 2004 350(12):1200-10

2x2 Factorial Design (Target 280)

Observation CT

CRT CRT CT Chemotherapy – 5-FU/LV [Mayo] X 6

Chemoradiation – 4000/20 [split] + bolus 5-FU.

Adenocarcinoma pancreatic cancer Adenocarcinoma pancreatic cancer undergoing ‘curative’ resectionundergoing ‘curative’ resection

RandomiseRandomise(stratified by centre, tumour type, resection margins)(stratified by centre, tumour type, resection margins)

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Survival by Adjuvant Chemoradiotherapy

Median survivalNo chemoRT 17.9 moChemoRT 15.9 moHR 1.28 [0.99-1.66], p=0.05

N Engl J Med 2004 Mar 18;350(12):1200-10

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Survival by Adjuvant Chemotherapy

Median survivalNo Chemo 15.5 moChemo 20.1 moHR 0.71 [0.55-0.92], p=0.009

N Engl J Med 2004 Mar 18;350(12):1200-10

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CONKO-001Neuhaus ASCO 2005 Resected pancreatic cancer

368 patients

Stratification: R; T; N

Follow up every 8 weeks

Gemcitabinefor 6 months

Observationfor 6 months

J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

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Tumor CharacteristicsCharacteristic Chemotherapy

(N=179)Observation

(N=177)

<T3 25 (14%) 25 (14%)T

3 + 4 154 (86%) 152 (86%)

negative 52 (29%) 48 (27%)N

positive 127 (71%) 129 (73%)

1 10 (5%) 9 (5%)

2 103 (58%) 95 (54%)

3 62 (35%) 69 (39%)G

unknown 4 (2%) 4 (2%)

R0 145 (81%) 149 (84%)R

R1 34 (19%) 28 (16%)

J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

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months

847260483624120

cu

mu

lative

dis

ea

se

fre

e s

urv

iva

l100%

75%

50%

25%

0%

CONKO-001 Kaplan Meier Disease Free Survival

Obs Median DFS 7.46 mo Gem Median DFS 14.21 moLog rank p < 0.001

J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

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CONKO-001 Kaplan Meier Overall Survival

months

847260483624120

cu

mu

lative

su

rviv

al

100%

75%

50%

25%

0%

Gemcitabine53 % patients censored (+)

Observation45 % patients censored (+)

J Clin Oncol (Meeting Abstracts) 2005; 23: Abstract 1092

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ESPAC –3/ NCIC PA.2ESPAC –3/ NCIC PA.2

Pancreatic Adenocarcinoma cancer Pancreatic Adenocarcinoma cancer undergoing ‘curative’ resectionundergoing ‘curative’ resection

RandomiseRandomise(stratified by centre, tumour type, resection margins)(stratified by centre, tumour type, resection margins)

Gemcitabine Gemcitabine N=500N=500

5FU/FA5FU/FAN=500N=500

5-FU/FA:5-FU/FA: FA 20 mg/mFA 20 mg/m2 2 iv, 5-FU 425 mg/miv, 5-FU 425 mg/m2 2 iv X5 every 28 days, x6 cyclesiv X5 every 28 days, x6 cycles

GEMCITABINE:GEMCITABINE: 1000 mg/m1000 mg/m22 iv once weekly x3 wks, 1 wk rest, x6 cycles iv once weekly x3 wks, 1 wk rest, x6 cycles

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Adjuvant Therapy of Pancreatic Cancer

Adjuvant 5FU improves survival compared to observation

Preliminary results show improved PFS (and now survival) with adjuvant gemcitabine vs. observation

The optimal chemotherapy regimen (5FU/gemcitabine) not known

Role of XRT still controversial.

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Locally Advanced Pancreatic Cancer

Page 33: Pancreatic Cancer

Pancreatic Cancer: Unresectable

Moertel1

Radiation Alone 6.3 monthsRadiation and 5-FU 10.4 months

GITSG (randomized) 2

60 Gy Alone 5.3 months40 Gy + 5-FU 8.4 months60 Gy + 5-FU 11.4 months

1 Lancet 2:865-867, 19692 Cancer 48:1705-1710, 1981

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Gemcitabine + RadiationPMH Phase I/II study

Patients with locally advanced (31), resected (32) disease-March 1999 to July 2001.

35 patients received initial gemcitabine. 8 [23%] of these did not get XRT

GEMCITABINE 1000 mg/m 2 IV x7

Followed by

GEMCITABINE 40 mg/m 2 IV 2X/week

with

XRT 3500-5250cGy over 4-6 weeks

GEMCITABINE 1000 mg/m 2 IV x7

Followed by

GEMCITABINE 40 mg/m 2 IV 2X/week

with

XRT 3500-5250cGy over 4-6 weeks

Unpublished Data

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Gemcitabine + RadiationPMH Phase I/II study

32 adjuvant patients Median time to progression 14.3 months Median survival 17.9 months 5 year survival 19%

31 locally advanced 1 complete response, 2 partial responses 10 stable disease Median survival 15.1 months 2 year survival 19%

Unpublished Data

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Locally Advanced Pancreatic Cancer

Chemoradiation in locally advanced pancreatic cancer improves:

– survival 1-2

– and pain in 35-65% of patients 3-6

Outcomes are still poor and better radiation sensitizers are needed

Most use up front chemo for 2 months and then chemo XRT

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Tumor in the body and tail of pancreas with liver metastasis

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Gemcitabine

Registration Study in Pancreatic Cancer

† Composite of measurements of pain (analgesic consumption and pain intensity), KPS and weight

Burris HA, Moore MJ, Andersen J, et al. J Clin Oncol. 1997;15:2403-2413

GemcitabineN = 63

5-FUN = 63 p-value

Clinical benefit response† 24% 5% 0.002

Survival

Median survival, months

5.7

4.4

0.002

1-year survival 18% 2% —

Partial response 5.4% 0 —

Stable disease 39% 19% —

Time to progression, months 2.3 0.9 0.0002

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Gemcitabine vs MMPI: NCIC.PA1PA.1 - FINAL ANALYSIS

Overall Survival By Arm

Bay 12-9566 Gemcitabine

Pe

rce

nta

ge

0

20

40

60

80

100

Time (Months) # At Risk(Bay 12-9566) # At Risk(Gemcitabine)

0.0138139

3.077110

6.04076

9.02246

12.09

25

15.0511

18.036

GEM = 6.67m (5.75-8.02)BAY = 3.74m (2.79-4.57)HR = 0.565 (0.44-0.73)P= 0.0001BAY

GEM

• Survival of untreated metastatic disease is short.

• Salvage of patients with crossover is not possible.

• Gemcitabine needs to be included in all treatments.

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Negative Combination Chemotherapy Trials 2004-2006

Gemcitabine vs gemcitabine FDR + oxaliplatin [N=313]– Louvet C et al. ASCO 2004;22:14S (Abs. 4008)

Gemcitabine vs gem FDR + gem FDR + oxaliplatin [N= 835]– Poplin et al. ASCO 2006;24:14S (Abs. 4003)

Gemcitabine vs gemcitabine + pemetrexed [N=565]– Richards DA et al. ASCO 2004;22:14S (Abs. 4007)

Gemcitabine vs gemcitabine + irinotecan [N=360]– Roche Lima, J Clin Oncol 2004

Gemcitabine vs gemcitabine + exatecan [N=349]– O’Reilly EM et al. ASCO 2004;22:14S (Abs. 4006)

Gemcitabine vs gemcitabine + capecitabine [N=319]– Hermann et al. ASCO 2005;23:14S (Abs. 4508)

Gemcitabine vs gemcitabine + 5FU/LV [N= 473]– Reiss et al. ASCO 2005;23:14S (Abs. 4509)

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Gemcitabine and Fluoropyrimidines Phase III trials

Trial Treatment arms n Overall survival pMedian 1-year

Berlin et al Gemcitabine 162 5.4 months 18 % 0.09(2002) Gem/bolus 5-FU 160 6.7 months 19 %

Riess et al Gemcitabine 236 6.2 months ~18% 0.683(2005) Gem/FU/LV 230 5.85 months ~18%

Herrmann et al Gemcitabine 159 7.3 months 31% 0.314(2005) Gem/capecitabine1 160 8.4 months 31%

Cunningham Gemcitabine 266 6.0 months 19% 0.026(2005) Gem/capecitabine2 267 7.4 months 26%

1 Gemcitabine 1000mg/m2 wkly ×2 q3 weeksCapecitabine 1300mg/m2/day X 14 q3 weeks

2 Gemcitabine 1000mg/m2 weekly ×3 q4 weeksCapecitabine 1660mg/m2/day for 21days q4 weeks

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5FU/LV +/- Oxaliplatin Second Line therapy

168 patients randomized

Mostly good PS status

PFS also better by 4 wks

Effect most pronounced in non- responders to gem in first line

Kubica et al ASCO 2008

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Gemcitabine + Drug Vs Gemcitabine?Heinemann, et al. ASCO 2007

HRSurvival

P-Value N

Gem + platinum

0.85 0.01 623, 5 trials

Gem + 5-FU 0.90 0.03 901, 6 trials

Good PS 90%+Poor PS 60- 80%

0.761.08

<0.0001

0.04

1,108, 5 trials574

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Combination Chemotherapy in Pancreatic Cancer

One positive study in first line ?

– Gemcitabine + Capecitabine.

One positive study in second line.

– 5FU + oxaliplatin.

Many negative studies

Incremental benefit of combination chemotherapy.

– Restricted to patients with (very) good PS

Is it worth doing any more studies?

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Oncogene Relevance

K-ras Noted in 75% to 90% of cases‘Signature’ defect of pancreatic cancer

Sonic Hedgehog

Crucial role in embryological signaling Evolving role in pancreas cancer

AURKA Encodes Aurora-A kinaseOveramplification - chromosomal

instability

Suppressor Relevance

CDKN2A/p16 Normal function induces cell cycle arrestEarly event –enhances effect of K-ras

SMAD4 Encodes transcription factor; lost in 50% casesMay also potentiate K-ras phenotype

p53 Role in cell cycle arrest and apoptosis Loss contributes to chromosomal instability

Some key molecular abnormalities in Pancreatic Cancer

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Y

Y

Y

Y

Y

Y

ras FAK

Srcraf

ERK

MEK

ECM

Integrin Homodimer

PI3K

Akt

Nucleus

Regulation of Gene Transcription

Pro-MMP

Growth Factor Ligand (EGF, VEGF)

EGF Receptor

Pancreatic Cancer: Other Molecular Targets

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The Epidermal Growth Factor Signaling Pathway

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SWOG: Gemcitabine +/- CetuximabSWOG: Gemcitabine +/- CetuximabOverall SurvivalOverall Survival

HR = 1.09 (95% CI: 0.93, 1.27)

Progression-Free Survival by Treatment Arm

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30Months After Registration

GemcitabineGemcitabine and Cetuximab

N369366

Events360351

Medianin Months

34

P = 0.058

PFS

Page 49: Pancreatic Cancer

Patient Population Adenocarcinoma of

pancreas No prior

chemotherapy Measurable or non-

measurable disease

EGFR status not an eligibility criterion

Stratification Center PS (0/1 vs 2) Stage of disease

(Loc Adv / Metastatic)

RANDOM I ZE

Gemcitabine +

Erlotinib 100/150 mg

Gemcitabine +

Placebo

NCIC. PA.3 Study Schema

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Overall Survival for All PatientsP

erc

enta

ge

0

20

40

60

80

100

Time (Months)0 6 12 18 24

HR = 0.81*95% CI (0.67, 0.97)P = 0.025

Gemcitabine + ErlotinibMedian = 6.4 months1 Year Survival = 24%

Gemcitabine + PlaceboMedian = 5.9 months1 Year Survival = 17%

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Progression-Free Survival

* Adjusted for PS, pain and disease extent at randomization

Pe

rcen

tage

0

20

40

60

80

100

Time (Months)0 5 10 15

HR = 0.76*95% CI (0.63, 0.91)P = 0.003

Gemcitabine + ErlotinibMedian = 3.75 months

Gemcitabine + PlaceboMedian = 3.55 months

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PA.3 Rash vs SurvivalPerc

enta

ge

0

20

40

60

80

100

Time (Months)0 5 10 15 20

Grade 2

Grade 0

Hazard Ratio =0.71

p<0.0001

Grade 1

Grade 0

N= 79

Grade 1

N= 108

Grade >2

N= 103

Median Survival 5.29 5.75 10.51

1 year Survival 16% 11% 43%

Page 53: Pancreatic Cancer

NCIC PA.3: K-ras, EGFR & Survival

N= 569; 146 adequate specimens (26%)

Gem + Erlotinib

Gem + Placebo

HR P

K-ras WT (21%)

6.1 mths 4.5 mths 0.66 0.34

K-ras Mut (79%)

6.0 mths 7.4 mths 1.07 0.78

EGFR Pos (47%)

5.2 mths 5.2 mths 0.90 0.32

EGFR Neg (53%)

8.4 mths 6.7 mths 0.60 0.08

Page 54: Pancreatic Cancer

PA3 : Impact of venous thromboembolism on survival

Gemcitabine alone

Gemcitabine + erlotinib

Incidence 14% in both arms

Associated with poor outcome HR 2.1

Page 55: Pancreatic Cancer

VEGF and Angiogenesis

Page 56: Pancreatic Cancer

CALGB 80303Gemcitabine +/- Bevacizumab

GEM + BEVACIZUMAB

(n=302)

GEM

ALONE

(n=300)

HR p

Median survival (mos)

5.8 6.1 1.03 0.78

PFS (months) 4.9 4.7 1.0 0.99

Response (%)

CR + PR 11 10

SD 36 31

Kindler HL et al. J Clin Oncol

Phase II : 8.7 mos median survival; 5.8 mos PFS 67% tumor control rate (PR+SD)

0 5 10 15 20 25

Months from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n S

urv

ivin

g BevacizumabPlacebo

Page 57: Pancreatic Cancer

Why were phase II and III data different?

Phase III

Gem + B

Phase III

Gem

Phase II

Gem + B

Median age 64 65 63

PS 0 36% 39% 60%

PS 1

PS 2

53%

11%

52%

9%

38%

2%

Thrombosis -----------Permitted----------- Excluded

Kindler HL et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):420s (Abstract 4508)

Page 58: Pancreatic Cancer

Primary endpoint: overall survival (6.9 - 9.0 months)

Trial closed October 2006. Presented at ASCO 2008.

Previously untreated metastatic pancreatic

cancer (n=600)

Gemcitabine + Erlotinib 100 mg

+ placebo

Gemcitabine + Erlotinib 100 mg + Bevacizumab

5mg/kg q 2 weeks

Phase III trial of first-line Gemcitabine + Erlotinib +/- Bevacizumab in (AVITA)

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Results

Tumor Control (CR + PR + SD): G + E = 54% G + B + E = 63%

Page 60: Pancreatic Cancer

Treating the individual patient

One size (gemcitabine) fits all?

Probably not…

(with an admitted lack of level 1 evidence)

Good performance status - KPS 90 +

– Consider combination chemotherapy – I would use gemcitabine + cisplatin.

K-ras wild type

– Gemcitabine + erlotinib.

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Treating the individual patient

Locally advanced disease should be approached differently than metastatic disease.

Prophylactic anticoagulation

– No phase III studies

– VTE is common - associated with bad outcome

– I do it (low molecular wt heparin) routinely.

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The way forward inClinical Research

Test novel targets and combinations in the phase II setting.

No phase III studies without a clear signal from phase II.

Separate studies for locally advanced and metastatic disease.

Translational research is critical!!

– Routine tissue collection in trials

– We need to understand a lot more about biology


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