Pancreatic Cancer Session - Facing our Risk · - Prediction of ! High-throughput extraction of quantitative features (from ... markers to target for prevention, diagnosis, and/or

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Session II: Pancreatic Cancer Screening and Treatment

Friday, June 9, 2017 1:40 PM - 3:05 PM

FORCE 2017: Pancreatic Cancer

Dr. Jennifer Permuth: Risk factors and early detection efforts for pancreatic cancer.

Dr. Mokenge Malafa: Chemoprevention of pancreatic cancer: where are we in 2017?

Dr. Heloisa Soares: New Treatments for Pancreatic Cancer


•  Risk factors and early detection efforts for pancreatic cancer.

Jenny B. Permuth, PhD

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HEADER SLIDE Risk Factors and Early Detection Efforts

for Pancreatic Cancer by

Jennifer B. Permuth, PhD, MS Assistant Member

Departments of Cancer Epidemiology and Gastrointestinal Oncology

Moffitt Cancer Center Tampa, Florida

I HAVE NO DISCLOSURES

Outline § Introduction to pancreatic cancer (PC) § Known risk factors § Environmental/Lifestyle § Genetic § Risk assessment

§ Research on PC screening and early detection biomarkers § Resources

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INTRODUCTION

Leading Causes of Cancer Deaths in the US

American Cancer Society, 2017

Pancreatic Cancer is Projected to Become the 2nd Leading Cancer Killer around 2020

Rahib, Can Res 2014

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PC poses numerous clinical challenges § Usually very aggressive. § Early, operable tumors are difficult to detect. § Need strategies to identify those ‘at increased risk.’ § Most patients do not respond to standard treatment options. § Quality of life (QOL) is sub-optimal.

RISK FACTORS AND ASSESSMENT

Modifiable and non-modifiable risk factors

•  Familial •  Inherited cancer

syndrome

•  Obesity •  Pancreatitis •  Diabetes

•  chronic & new •  Infections

•  Average age: 71 •  Males •  African

American •  Ashkenazi

Jewish Age, gender,

race, and ethnicity

Lifestyle/ Environ-

ment

Family history/ genetics

Medical conditions

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Sporadic vs. Familial vs. Inherited PC

Sporadic

Familial

Inherited Cancer Syndrome

90%

7% 3%

Chari et al (2015) Pancreas

(Average lifetime risk = 1 in 67 (1.5%))

Risk increases with # of affected first degree relatives (FDR): 2-4.6x (1 FDR), 3-6.4x (2 FDR), 32-57x (3 FDR)

Inherited Syndrome Gene(s) Risk by age 70-75

Hereditary Breast and Ovarian Cancer

BRCA2 BRCA1, PALB2

4.5-8% 3.6%

Peutz-Jeghers STK11/LKB1 36%

Familial atypical multiple-mole melanoma (FAMMM)

p16/CDKN2A 13-17%

Hereditary non-polyposis colorectal cancer

MSH2, MLH1, MSH6, PMS1, PMS2

3.7%

Familial adenomatous polyposis APC 1.7%

Ataxia telangiectasia ATM <5%

Li Fraumeni TP53 <5%

Syndromes with chronic inflammation of the pancreas

Hereditary pancreatitis PRSS1, SPINK1 25-54%

Cystic Fibrosis CFTR <5%

Inherited Predisposition to PC

3-6x increased PC risk (vs. non-carriers)

~10% of BRCA2+ families have >1 relative with PC

BRCA2 mutations are identified in 4-17% of families with familial

PC, and are the most common alteration in

this condition

Prevalence of BRCA2 mutations in patients with sporadic PC is 4-7% vs. 0.2% in

general population

BRCA2 mutations (6174delT) are

associated with 10-20% of unselected, sporadic PC in Ashkenazi Jews

Patients with BRCA2+ PC are younger than

counterparts with sporadic PC (63 vs 70

years old)

The survival rate in patients with familial PC tends to be better

than those with sporadic PC

Tidbits about BRCA2 carriers and PC

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Rare and common genetic variants contribute to PC susceptibility

From Stolzenberg-Solomon and Amundadottir Hematol Oncol Clin North Am (2015)

What is my risk to develop PC?

Risk assessment is provided during genetic counseling (www.nsgc.org)

PancPro

§ Provides probability of: § carrying a concerning

mutation in a PC susceptibility gene

§ developing PC § Takes into account:

§ cancer history for counselee and family members, age(s) at diagnosis, and current age/age at last follow-up

Absolute risk model

§ Provides probability of: § developing PC

§ Takes into account: § Established risk factors

(age, sex, ethnicity, smoking history, diabetes, alcohol use, family history, body mass index, common genetic variants)

Wang, JCO, 2007 Klein, PLoS One, 2013

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What can I do about my risk?

Is it possible to prevent PC cancer or detect it really

early?

PRIME OPPORTUNITY FOR EARLY DETECTION AND PREVENTION EFFORTS Precursors to pancreatic cancer

Three pancreatic cancer precursors exist

Distler et al (2014), Biomed Research International

Pre-cancerous pancreatic cysts IPMN=intraductal papillary mucinous neoplasms MCN=mucinous cystic neoplasms

noninvasive

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IPMNs §  Account for up to 40% of the ~150,000 pancreatic cysts detected incidentally each year in the general US population. §  Detected in high-risk cohorts. §  Found more often in familial than sporadic cases.

§  Challenging to manage due to the inability to predict: § which lesions can be safely monitored, § which are likely to progress to invasion, and § which may have an associated invasive component.

Need better strategies to identify ‘concerning’ IPMNs

§ Only accurate way to determine severity § surgery & pathologic evaluation

§  Consensus guidelines exist to predict IPMN severity §  based on standard clinical and radiologic features. §  inaccurate for at least 30-70% of cases!

‘Screening’ for Pancreatic Cancer

Can detect lesions <1 cm;

FNA allows cytological

sampling, but is invasive; operator

dependent

Best visualization of

cyst communication

with main pancreatic duct

Can visualize large lesions; accurate in depicting

vascular invasion and metastases;

radiation exposure

Endoscopic ultrasound (EUS) MRI-MRCP Computed Tomography (CT) +/-Fine needle aspiration (FNA)

MRI-MRCP= Magnetic Resonance Imaging (MRI)-Magnetic resonance cholangiopancreatography (MRCP)

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Comparison of selected screening strategy recommendations

Current Yield of High-risk Screening Programs

Canto (2013) Gut

§  Nearly all studies reported precursor lesions (mostly IPMNs). §  Tests are complementary rather than interchangeable. §  Prevalence of lesions increased with age. §  CT, MRI, and EUS detected abnormalities in 11%, 33.3%, and 42.6% of individuals,

respectively (Canto, 2012) §  Prevalence of pancreatic cysts in the general population approximates 20-23%.

§ Candidates for screening: §  FDR of patient with PC from a familial PC kindred with >2 affected FDRs; patients with

PJS; p16, BRCA2, and HNPCC mutation carriers with >1 affected FDR § No consensus on age to initiate screening or stop surveillance §  Initial screening should include EUS and/or MRI/MRCP §  accessible, low morbidity, good concordance for lesion size, number, & location; EUS

better for detecting small solid lesions; MRI sensitive for small cysts §  Need long-term multicenter studies

Canto (2013) Gut

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EARLY DETECTION BIOMARKERS FOR PC Research in Progress at Moffitt Cancer Center

Goal: Prevent Pancreatic Cancer or Detect it Early

Low-risk/ indolent Surveillance

High-risk/ aggressive Surgery

Epidemiologic risk factors

Standard radiologic features

Molecular data

Quantitative imaging features

Pre-clinical models

Clinical and demographic

data

Develop minimally-invasive

approaches to rapidly, cost-

effectively, and accurately predict

cyst type & severity and discover agents

to halt disease progression

Chemoprevention

MOLECULAR DATA

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MicroRNAs (miRNAs) as attractive candidate biomarkers of early pancreatic malignancy

§ regulate cancer-related pathways §  Each miRNA can regulate 1000’s

of genes. § remarkably stable in tissue and biofluids

§ dysregulated in PC vs. normal pancreas tissue

§ a few candidate miRNAs differentiated between IPMNs and normal pancreas tissue (Habbe et al, 2009)

Ruan et al (2009) Cancer Letters

Total Cancer Care®

Total Cancer Care®

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Developing a ‘liquid biopsy’ for pancreatic cancer: additional biomarkers we are studying at Moffitt

Long non-coding RNAs (lncRNAs) Tumor DNA (ctDNA) mutations

Funding: Departmental Innovation Award (PI: Permuth) Status: Project has been completed. Promising results obtained. Manuscript conditionally accepted at Scientific Reports.

Funding: DeBartolo Personalized Medicine Institute (PI: Permuth) Status: Project is underway.

QUANTITATIVE IMAGING FEATURES

Radiomics

Image

Area=1201.6 mm2 Perimeter=152.4 mm Volume=2615 mm3

Surf. area=1099.33 mm2 Surf. Area/volume=0.42 mm-1

Density, Necrosis Mean = 19.33 HU SD = 76.59 HU Min = -249 HU Max = 118 HU Spiculations Slope at margin =133.5±31.3 HU/mm Low density inclusions Rel. vol.= 0.21 mm3

Number=110 Volume=4.89±8.35 mm3

Segment Feature extraction

Analyze

- Contrast Issues - Slice thickness - Scanner setting

-  Semi-Automatic

-  Texture Features (smooth, coarse, regularity) -  Non-texture

(shape/size/ volume)

-  Prediction of clinical parameters

§  High-throughput extraction of quantitative features (from standard-of-care images) into mineable data.

Slide courtesy of Yoganand Balagurunathan, PhD

Image acquisition and reconstruction

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NCI R21 pending

Central/visceral adiposity as a contributor to IPMN development and/or progression?

• What about radiologic measures of obesity? •  Total abdominal fat area

(TAF) • Visceral fat area (VFA) • Subcutaneous fat area

(SFA) • Visceral to sub-

cutaneous fat ratio (V/A)

Vongsuvanh et al, Cancer Letters 2013

Funding: Moffitt Team Science Award Mechanism (Co-PIs: Permuth and Jeong) Jeong

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Central obesity measured by CT scan helps predict aggressive IPMNs

Permuth et al (2017), Cancer Biology and Medicine

PRE-CLINICAL MODELS

Precision medicine: Organoid model development

DeNicola Funding: Moffitt Team Science Award Mechanism (Co-PIs: Permuth and Jeong)

Applications: FAR-REACHING! Tumor modeling, study of molecular markers to target for prevention, diagnosis, and/or therapeutics.

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Eligibility

Males and females 18+ who present to the GI Clinic ,

surgery, or endoscopy at MCC, UF, or SCCC/UM with

a clinical suspicion for (or diagnosis of) a pancreatic

lesion, mass, or cyst or pancreatitis based on symptoms, imaging, or

blood-work (and no prior treatment)

Healthy individuals 18+ without a self-reported personal history of pancreatic disease or related

symptoms (companions and high-risk cohort).

Approach to recruit

and obtain written

informed consent

Kimberly Quinn Amber Bouton Dr. Suzanne Lechner (MOF) (UF) (SCCC/UM)

45

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Who can participate in the Florida Pancreas Collaborative (and how)

• Asymptomatic first or second degree relatives of a family member affected by pancreatic cancer

• Asymptomatic carriers of known PC predisposition mutations •  Individuals with a suspected or diagnosed condition affecting

the pancreas. •  Feel free to send in the response form. • Any q’s, email Dr. Jenny Permuth [email protected]

Epidemiology &Genetics Surgery Oncology Biostatistics

Permuth Wang Malafa Hodul Merchant Trevino Soares George Chen Kim Li Endoscopy Immunology IT/ Bioinformatics

Klapman Harris Abate-Daga Rivera Carvajal G-Calderon Teer

Outreach Radiology Pathology Molecular Biology

Gwede Jeong Choi Gillies Balagurunathan Coppola Magliocco Centeno Jiang DeNicola Karreth Judge

Thanks to an interdisciplinary team

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..and PC survivors and advocates

‘Know it. Fight it. End it. Wage Hope.’





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Chemoprevention for Pancreatic Cancer: Where are we in 2017?

Mokenge P. Malafa, M.D., FACS Professor and Senior Member

Moffitt Cancer Center, Tampa, FL

Chemoprevention For Pancreatic Cancer: Where are we in 2017?

Agenda

•  Rationale for pancreatic cancer chemoprevention.

•  Tocotrienol and pancreatic cancer. •  Future directions.

Chemoprevention Definition

•  Sporn (1976), use of drugs, biologics, or nutrients to inhibit carcinogenesis.

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Chemoprevention of Pancreatic Cancer Rationale (1)

US: Projected to be the 2nd most common cause of cancer death in 2030 (behind Lung; ahead of liver)1.

2012: 330,000 individuals die of pancreatic cancer every year worldwide2.

v  A 10% decrease in PDAC would prevent > 30,000 deaths/yr.

1.  Rahib,L et al. Cancer Research, 2014. 2.  http://globocan.iarc.fr/

Value of Chemoprevention Lessons from heart disease


•  Pancreatic carcinogenesis is a multi-year process thus providing opportunity to intervene.

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Clinical Pancreatic Oncology

§ Early detection and effective prevention strategies are urgently needed .

from each piece for each of the founder and progressor mutations. InPatient Pa08, there were three progressor mutations present in twoindependent peritoneal metastases (defining one subclone) and 23,25 or 27 additional progressor mutations present in liver and lungmetastases (defining three additional subclones; Fig. 2c). Through theanalysis of distinct regions of the primary tumour, it was clear thatsubclones giving rise to each of these metastases were present in theprimary tumour. Moreover, these subclones were not small; from thesize of the pieces (Fig. 2a) and the amounts of DNA recovered, eachsubclonemust have contained in excess of 100million cells. In addition,more than four different subclones, each containing a similarly largenumber of cells, could be identified through the analysis of other piecesof the same tumour. These subclones could be put into an orderedhierarchy establishing an evolutionary path for tumour progression(Fig. 2c). Analysis of multiple primary tumour pieces and metastaticlesions from patient Pa04 revealed a similar clonal evolution, withdistinct, large subclones within the primary tumours giving rise to thevarious metastases (Supplementary Fig. 8).To clarify further clonal evolution within the primary site, we

attempted to correlate the mutation signatures representing the sub-clones of Pa08 (Fig. 2c) with the geographic location of the pieces of theprimary tumourused todefine them (Fig. 2a, b). Samples representativeof the parental clone were located throughout the primary carcinoma.By contrast, samples representing subclones were non-randomlylocated in proximity to each other, within which the subclones speci-fically giving rise to peritoneal versus distant metastases were seen.Thus, we conclude that the genetic heterogeneity of metastases reflectsheterogeneity already existing within the primary carcinoma, and thatthe primary carcinoma is a mixture of numerous subclones, each ofwhichhas independently expanded to constitute a large number of cells.This data set could also be used to infer the timing of the develop-

ment of the various stages of pancreatic tumour progression8. Weassume that the tumour is initiated by a genetic event that confers aselective growth advantage to the cell that goes on to become the

founder cell of the tumour. To estimate the timing, we first usedKi-67 labelling to determine the proliferation rate of seven samplesof normal duct epithelium from surgically resected pancreata of indi-viduals without pancreatic cancer as well as of each index metastasis.Ki-67-positive nuclei constituted an average of 0.4% of normal ductalcells, whereas an average of 16.3% of cancer cells within the indexmetastasis lesions were Ki-67-positive, consistent with prior esti-mates9,10 (Supplementary Table 4). Based on these data plus that fromsequencing of the index lesions, we derived estimates for three criticaltimes in tumour evolution: T1, the time between tumour initiation andthe birth of the cell giving rise to the parental clone; T2, the subsequenttime required for the birth of the cell that gave rise to the indexmetastasis; and T3, the time between the dissemination of this celland the patients’ death (Fig. 3). In other words, there is a time point,t0, when the tumour was initiated, and a time point t1 when a cell isborn that has all mutations that exist in the parental clone. Similarly,there is a time point in tumour evolution, t2, when a cell is born that hasall themutations that exist in the indexmetastasis.T1 is given by t12 t0and T2 is given by t22 t1. If we denote t3 as the time of patient’s death,then T35 t32 t2.Using the mathematical model described in the Methods, we were

able to conservatively estimate an average of 11.7 years from the ini-tiation of tumorigenesis until the birth of the cell giving rise to theparental clone, an average of 6.8 years from then until the birth of thecell giving rise to the index lesion, and an average of 2.7 years from thenuntil the patients’ death (see Supplementary Discussion and Sup-plementary Table 5).We show, for the first time, that primary pancreatic cancers contain a

mix of geographically distinct subclones, each containing large numbers(hundreds of millions) of cells that are present within the primarytumour years before the metastases become clinically evident. The fea-tures of these metastatic subclones that promote metastasis formationhave yet to be discerned, because no consistent genetic signature ofmetastatic subclones could be identified. We did identify several genes

Subclones withmetastatic capacity

Normal ductepithelial cell

Parental clone

LiverLung Liver

Initiatedtumour cell

= Mutation(s) & clonal expansion

= Dissemination to distant organs

Index lesion

T1(average of 11.7 ± 3.1 years)



t0

t1

t2

t3

Figure 3 | Schema of the genetic evolution of pancreatic cancer.Tumorigenesis beginswith an initiatingmutation in a normal cell that confers aselective growth advantage. Successive waves of clonal expansion occur inassociation with the acquisition of additional mutations, corresponding to theprogressionmodel of pancreatic intraepithelial neoplasia (PanIN) and time T1.One founder cell within a PanIN lesion will seed the parental clone and henceinitiate an infiltrating carcinoma (end of T1 and beginning of T2). Eventually,

the cell that will give rise to the index lesion will appear (end of T2 andbeginning ofT3). Unfortunately,most patients are not diagnosed until well intotime interval T3 when cells of these metastatic subclones have already escapedthe pancreas and started to grow within distant organs. The average time forintervalsT1, T2 andT3 for all seven patients is indicated in the parentheses at left(see also Supplementary Table 6).

RESEARCH LETTER

1 1 1 6 | N A T U R E | V O L 4 6 7 | 2 8 O C T O B E R 2 0 1 0

Macmillan Publishers Limited. All rights reserved©2010

Yachida S et al, Nature 2010

Chemoprevention of Pancreatic Cancer Rationale

MODIFIED FROM: VLW Go et. al. J. Nutr. 131:3121S, 2001

Pancreatic Oncogenesis

Bardeesy and DePinho, Nature Reviews Cancer 2:897, 2002

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Normal duct

Normal duct

PanIN Ia

MCN low grade

IPMN low grade

Cancer

PanIN Ib PanIN II PanIN III

Intermediate grade

High grade

PRECURSOR LESIONS OF PANCREATIC ADENOCARCINOMA

PanIN: Pancreatic Intraductal Neoplasia

MCN: Mucinous Cystic Neoplasm

IPMN: Intraductal Papillary Mucinous Neoplasm


•  There are a significant number of individuals that are at high risk to develop pancreatic cancer.

Chemoprevention of Pancreatic Cancer High risk groups

•  Individuals with IPMN. •  Family history. •  Genetic syndromes. •  Pancreatic cancer survivors.

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FDA-APPROVED CHEMOPREVENTION DRUGS

DRUG Cancer Year MOA Tamoxifen Breast 1998 SERM Raloxifen Breast 2007 SERM HPV Vaccine Cervix/Vulva/Anus 2006 Immune Photofrin Esophageal 2003 Reactive Oxygen Fluorouracil Skin 1970 DNA synthesis Diclofenac Na 3% Skin 2000 Unknown 5-aminolevulinic acid + PDT

Skin 1999 Kills precancerous cells

Imiquimod Skin 2004 Enhances immune response and promotes apoptosis

Clinical trials with pancreatic cancer chemoprevention agents

Phase Agent(s) Population Site Status II Curcumin Advanced MD Anderson Published II Curcumin + Gemcitabine Advanced Ramban, Isreal

Pending

III Curcumin, Gemcitabine, and Celecoxib

Advanced Tel Aviv Sourasky Medical Center, Isreal

Pending

II Curcumin Advanced Kyoto University, Japan Pending II Celecoxib Premalignant Indiana Univ Closed I Vitamin E delta-

tocotrienol Presurgical Moffitt Cancer Center Published

I Genistein Presurgical UCLA Pending

Chemoprevention For Pancreatic Cancer: Where are we in 2017?

Agenda



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Development of a Pancreatic Cancer Chemoprevention Agent

Agent Selection

•  Data from Epidemiology studies. •  Published evidence from preclinical and clinical studies.

Pre-clinical testing

•  In vitro screening. •  In vivo safety and efficacy. •  Detailed mechanistic studies in vitro and in vivo (Biomarker discovery).

Clinical trials

•  Phase I- safety, PK, and dose-finding. •  Phase II- further safety, preliminary efficacy, validation of biomarkers. •  Efficacy evidence leading to NDA and FDA approval.

Nutrition and Pancreatic Cancer Protection

•  Increasing vegetable, fruit, and whole grain cereal consumption may protect against pancreatic cancer

Studies Benefit No Benefit

Prospective 4 2 Case Control 11 Cohort 1

Mo Malafa, MD

Pancreatic Cancer Whole grain decreases risk

•  Risk of pancreatic cancer reduced by nearly 50% with whole grain consumption.

•  How? –  Bioactive food components?

0 0.5 1

2Serving

1Serving

Never

OddsRatio

Chan, JM, Am J Epidemiol 2007;166:1174-1185

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Oats

Rye

Annatto

Rice Bran

Barley

Palm

Vitamin E

Tocopherol (T)

Alpha-T Beta-T

Delta-T

Gamma-T

Alpha-T3 Beta-T3

Delta-T3

Gamma-T3


Agent Selection




Clinical trials


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Tocotrienols in Pancreatic Cancer Preclinical studies

•  Delta-tocotrienol was the most effective vitamin E compound against pancreatic cancer1.

•  Mice receiving delta-tocotrienol showed inhibition of pancreatic tumor growth1 and carcinogenesis2.

•  Adequate levels of delta-tocotrienol in the pancreas of mice was achieved with well tolerated oral dosing3.

1.  Husain et al., Molecular Cancer Therapeutics, 2011. 2.  Husain et al., Carcinogenesis, 2013. 3.  Husain et al., Pharmacology, 2009.


Agent Selection




Clinical trials


Tocotrienol and Pancreatic Cancer Clinical

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Phase I Study of Vitamin E δ-Tocotrienol in Pancreatic Neoplasia

0 2 4 6 8

10 12 14 16 18 20

100 200 300 400 800 1600

Cm

ax (µ

M)

Daily Dose of VEDT (mg/twice/day)

SD Mean

Springett et al., EBIOMEDICINE, 2015.

Tocotrienol and Pancreatic Cancer Summary

•  Delta tocotrienol is the most bioactive compound.

•  More than doubles survival and inhibits metastasis in preclinical models.

•  Targets several oncogenic pathways.

•  Safe and reaches bioactive levels in the pancreas in Presurgical biomarker clinical trial.

ANNATTO

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Tocotrienol and Pancreatic Cancer: Hope for Chemoprevention

Agenda




Agent Selection




Clinical trials


Chemoprevention of Pancreatic Cancer Phase 2 in which high-risk group?

•  Individuals with IPMN. •  Family history. •  Genetic syndromes. •  Pancreatic cancer survivors.

Mo Malafa, MD

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Chemoprevention of Pancreatic Cancer Relapse Rationale

§  High recurrence and metastasis rate of PDAC after resection and adjuvant therapy, with 5 year OS 28.8%1.

§  Metastasis initiating cells (Pancreatic Cancer Stem Cells/ Dormant disseminated tumor cells) and the niche in target organs supporting these cells are critical components of the mechanisms underlying PDAC relapse2.

§  Targeting PCSCs and /or the niche supporting them can prevent relapse.

1.  ESPAC 4 Trial, ASCO 2016. 2.  Hermann et al, Cell stem cell, 2007.

TOCOTRIENOL PANCREATIC CANCER VEDT targets PCSCs

Days after treatments0 5 10 15 20 25 30 35

Tum

or V

olum

e(P

hoto

ns/c

m2/

sec/

Ste

ridi

an x

107

)

0

2

4

6

8

10

12

14

16

18

VehicleGemVEDT

Vehicle

Gemcitabine

VEDT

Husain et al., Oncotarget, 2017

TOCOTRIENOL PANCREATIC CANCER VEDT targets PCSCs

Vehicle Gemcitabine VEDT

Husain et al., Oncotarget, 2017

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TOCOTRIENOL PANCREATIC CANCER RELAPSE PREVENTION STUDY (TOPCARPS): A DOUBLE-BLIND, PLACEBO-CONTROLLED

RANDOMIZED PHASE II TRIAL

Eligibility: §  Stage I /II PDAC. §  R0/R1 resection. §  Completed Adjuvant Rx.

Stratification: §  Resection status: R1/R0. §  Nodal status: N+ or N-. §  Tumor grade: Well or

Moderate vs. Poor. §  Neoadjuvant Rx: Yes or No. §  Adjuvant Rx: Gem vs Gem +

Abraxane vs Gem + Capecitabine

R

VEDT (600mg p.o. BID X 1 year)

N=164

Placebo (600mg p.o. BID X 1 year)

N=164

§  Primary endpoint: PFS. §  Secondary endpoints: OS, and

Safety. §  Correlative studies: VEDT and

metabolites, inflammatory and oxidative stress biomarkers.

§  Statistics: 80% power / PFS 13.4 to 17.4 months.

Tocotrienol and Pancreatic Cancer: Hope for Chemoprevention

Summary •  There is potential for high impact with a

chemoprevention strategy for pancreatic cancer.

•  Tocotrienol is a promising agent in early phase trials.

•  Need a home-run proof-of-concept trial to ignite the field.

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Funding: NIH 1R01CA129227






•  New Treatments for Pancreatic Cancer.

Heloisa Soares, MD, PhD

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2017 Annual Joining FORCEs Against Hereditary

Cancer Conference Treatment of pancreatic cancer in patients with mutations associated

with hereditary cancer

Heloisa P. Soares MD, PhD Assistant member

Department of Gastrointestinal Oncology Moffitt Cancer Center

Tampa, FL

The Scope of the Problem: For Pancreatic Cancer, Incidence = Mortality

Siegel R, et al. CA Cancer J Clin. 2012;62:10-29.

Stage Classification % at Diagnosis

5-Yr Survival, %

Localized 8 22

Locally advanced/ unresectable

27 9

Metastatic 53 2

Pancreatic Cancer by Stage (SEER Database)

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Treatment

Metastatic disease

Treatment

Metastatic disease

The Basis of Gemcitabine as the backbone for treatment regimens

Pivotal study defining role for gemcitabine as first-line treatment for patients with advanced pancreatic cancer

–  Median survival (vs bolus 5-FU): 5.65 vs 4.41 mos. (P = .0025)

–  1-year survival: 18% vs 2%

–  Clinical benefit*: 23.8% vs 4.8% (P = .0022)

–  Response rate: 5.4% vs 0% (P = NS)

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

*A composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (≥ 4 weeks) improvement in at least 1 parameter without worsening in any others.

Gemcitabine 5-FU

100

80

60

40

20

0 0 2 4 6 8 10 12 14 16 18 20

Survival Time (Mos)

Patie

nts

Surv

ivin

g (%

)

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Phase III Studies: No Survival Benefit for Gemcitabine Combination (excluding target therapy) vs Monotherapy

Regimen Patients, n Control Arm, Mos

Study Arm, Mos

Gemcitabine vs (gem + cisplatin) 192 6.0 7.6

Gemcitabine vs (gem + oxaliplatin) 313 7.1 9.0

Gemcitabine vs (gem + 5-FU) 322 5.4 6.7

Gemcitabine vs (gem + capecitabine) 533 6.2 7.1

Gemcitabine vs (gem + pemetrexed) 565 6.2 6.3

Gemcitabine vs (gem + irinotecan) 360 6.6 6.3

Gemcitabine vs (gem + exatecan) 349 6.2 6.7

The role of target therapy in pancreatic cancer is still limited

Drug Mechanism Sample Size, n

Median Survival, Mos Gem Alone Gem + Drug X

Marimastat Matrix metalloproteinase

inhibitor

239 5.4 5.4

Tipifarnib Farnesyl transferase

inhibitor

688 6.3 6.0

Erlotinib Oral TKI, EGFR 569 5.9 6.4 Bevacizumab mAb, VEGF 602 6.0 5.7 Cetuximab mAb, EGFR 735 6.0 6.5

Bayraktar S, et al. Mount Sinai J Med. 2010;77:606-619.

Survival Results of Erlotinib trial

Moore MJ, et al. J Clin Oncol. 2007;25:1960-1966.

100

80

60

40

20

0 0 6 12 18 24

Months

Surv

ival

Pro

babi

lity

(%)

Placebo (n = 284) Median: 5.91 mos 1-yr survival: 17%

Erlotinib (n = 285) Median: 6.24 mos 1-yr survival: 23%

HR: 0.82 (95% CI: 0.69-0.99; P = .038)

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Slide courtesy of Thierry Conroy

Emerging role of FOLFIRINOX

Emerging role of FOLFIRINOX

Med Survival: 11.1 vs 6.8 months

Med PFS: 6.4 vs 3.3 months

1-ys OS: 48.4% vs 20.6% ORR: 31.6% vs 9.4% *FFX reduced QoL impairment compared with gemcitabine in patients with metastatic pancreatic cancer

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Safety: hematological AEs

AE, % per patient

Folfirinox N=167

Gemcitabine N=169

p

All Grade 3/4 All Grade 3/4 Grade 3/4

Neutropenia 79.9 45.7 54.8 18.7 0.0001

Febrile Neutropenia 7.2 2.4 0.6 0.009

Anemia 90.4 7.8 94.6 5.4 NS

Thrombocytopenia 75.2 9.1 54.8 2.4 0.008

5.4

42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G arm One toxic death occurred in each arm

Safety: main non-hematological AEs

AE, % per patient Folfirinox N=167 Gemcitabine N=169

p All Grade 3/4 All Grade 3/4

Infection without neutropenia 6 1.2 7.1 1.8 NS

Peripheral neuropathy 70.5 9 0.6 0 0.0001

Vomiting 61.4 14.5 43.2 4.7 0.002

Fatigue 87.3 23.2 78.7 14.2 0.036

Diarrhea 73.3 12.7 30.8 1.2 0.0001

Alopecia (grade 2) 32.5 (11.4) 3.0 (0.6) 0.0001

ALT 64.8 7.3 83.8 0.0022 18.6

Conroy et al, NEJM, 364:1817-1825, 2011

Considerations

•  Study was unintentionally biased with low number of head of pancreas lesions and thus, fewer patients with biliary ductal obstruction and stents

•  Age < 76

•  PS 0 and 1

But: •  Markedly positive survival results; exceed those seen in any

previous randomized phase III trial in advanced PDAC—close to 1 year

•  Was considered the new gold standard for first-line metastatic pancreatic cancer (for patients with good performance score)

41% of patients are older than 75 ys

What is the real % of PS2 patients in real life

50% patients have stents

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Randomized Phase III Study of Weekly nab-Paclitaxel Plus Gemcitabine vs Gemcitabine Alone in Patients With Metastatic Adenocarcinoma of the Pancreas (MPACT)

DD Von Hoff, T Ervin, FP Arena, EG Chiorean, J Infante, M Moore, T Seay, SA Tjulandin, W Ma, MN Saleh, M Harris, M Reni, RK Ramanathan, J Tabernero, M Hidalgo, E Van Cutsem, D Goldstein, X Wei, J Iglesias, MF Renschler

® nab is a registered trademark of Celgene Corporation. Von Hoff DD, Ervin T, Arena FP, et al. Randomized Phase III Study of Weekly nab-Paclitaxel plus Gemcitabine vs Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas (MPACT) [abstract LBA148]. Oral presentation at: The Gastrointestinal Cancers Symposium 2013; January 24-26; San Francisco, CA.

Published NEJM 2013 by Von Hoff, et al.

Study Design

Planned N = 842 • Stage IV • No prior treatment for metastatic disease • Karnofsky PS ≥70 • Measurable disease • Total bilirubin ≤ULN

nab-Paclitaxel 125 mg/m2 IV qw 3/4 weeks

+ Gemcitabine

1000 mg/m2 IV qw 3/4 weeks

Gemcitabine 1000 mg/m2 IV qw for 7 weeks then qw 3/4

weeks

Von Hoff

Overall Survival

Median OS: 8.5 versus 6.7 months

1ys OS: 35% vs 22%

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Median PFS: 5.5 versus 3.7 months

Progression Free Survival

RR: 23% versus 7% By investigator was 29%

Toxicity

Pancreatic ductal adenocarcinoma (PDAC) remains one of the greatest challenges in oncology

•  Around 95 percent of pancreatic tumors are driven by mutations in a gene called KRAS, which signifies a very aggressive and treatment resistant tumor. Mutated KRAS has been dubbed “undruggable

•  Pancreatic tumors are surrounded by more dense fibrotic tissue, known as the stroma, than are most other solid tumors

•  A 2016 study identified four subtypes of pancreatic cancer based on molecular changes

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•  An estimated 10 to 15 percent of PCs are attributable to genetic causes

•  Approximately 5 to 10 percent of individuals with PC have a family history of the disease

•  There are two broad categories of hereditary risk for PC:

•  Genetic predisposition syndromes associated with PC

•  Familial pancreatic cancer (FPC), which is defined as a family with a pair of affected first-degree relatives (parent-child or sibling pair) who do not meet criteria for a known PC-associated genetic predisposition syndrome

Pancreatic cancer as a hereditary disease

1.7%

9.5%

Mutations in BRCA1 and BRCA2 are the most prevalent germline mutations

BRCA

BRCA 1 and BRCA 2 are DNA damage response (DDR) genes

* PARP: of poly(ADP-ribose) polymerase (PARP) enzymes

How can we use this knowledge to treat pancreatic cancer?

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Pre-clinical data

•  Selectively inhibition of growth of cells with defects in either BRCA1 or BRCA2 genes

•  In vitro models: cells with BRCA mutations > 1000 times more sensitivity to PARP inhibitors than wild-type cells

•  In vivo models using PARP inhibitors also showed promising results

Clinical studies RUCAPANC: An open-label, phase 2 trial of the PARP inhibitor rucaparib in patients (pts) with pancreatic cancer (PC) and a known deleterious germline or somatic BRCA mutation.

(J Clin Oncol 34, 2016 (suppl; abstr 4110))

Summary: •  19 patients who progressed after 1 or 2 chemotherapy

regimens received oral rucaparib daily until disease progression.

•  79% had a BRCA2 mutation by local testing •  ORR was 11% (1 partial response [PR] and 1 complete

response [CR]); •  disease control rate (PR or stable disease [SD] for ≥ 12 weeks)

was 32% (6/19) in all pts –  50% (3/6) in pts with only 1 prior regimen

•  Enrollment was stopped due to lack of responses in the first 15 pts evaluated; the 3 PRs occurred in the last 4 pts enrolled

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Common treatment-emergent AEs (in ≥20% of patients) included nausea (63.2%) and anemia (47.4%) The most common treatment-emergent grade ≥3 AE was anemia (31.6%)

RUCAPANC

RUCAPANC •  Rucaparib provided clinical benefit to several patients

(disease control rate, 31.6%; 95% CI, 12.6%−56.6%) with advanced BRCA mut pancreatic cancer –  Less heavily pretreated patients derived durable

clinical benefit, which warrants investigating rucaparib earlier in the treatment course of patients with BRCA mut pancreatic cancer

•  Rucaparib had an acceptable safety profile

•  These findings will inform future rucaparib study designs in patients with advanced BRCA mut pancreatic cancer

Ongoing PARP inhibitors clinical trials

POLO: A Phase III, Randomised, Double Blind, Placebo Controlled, Multicenter Study of Maintenance Olaparib Monotherapy in Patients With BRCA Mutated Metastatic Pancreatic Cancer Whose Disease Has Not Progressed on First Line Platinum Based Chemotherapy NCI 8993: A Randomized Phase 2 Study of Gemcitabine, Cisplatin +/- Veliparib in patients With Pancreas Adenocarcinoma and a known BRCA/ PALB2 Mutation NCT01489865: A Phase I/II Study of ABT-888 (Veliparib) in Combination With 5-fluorouracil and Oxaliplatin (Modified FOLFOX-6) in Patients With Metastatic Pancreatic Cancer NCT02890355: Randomized Phase II Study of 2nd Line FOLFIRI Versus Modified FOLFIRI With PARP Inhibitor ABT-888 (Veliparib) (NSC-737664) in Metastatic Pancreatic Cancer

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Other ongoing trials

Other novel therapies and targets in pancreatic cancer

Garrido-Laguna, I. & Hidalgo, M. (2015) Pancreatic cancer: from state-of-the-art treatments to promising novel therapies Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.53

Ongoing early clinical trials in metastatic pancreatic cancer

Garrido-Laguna, I. & Hidalgo, M. (2015) Pancreatic cancer: from state-of-the-art treatments to promising novel therapies Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.53

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We all need to keep trying!

•  Slowly we are making progress in pancreatic cancer

•  Understanding the tumor biology is key to advance in the field

•  Clinical trials! Clinical trials! Clinical Trials!

Thank you to all my patients and families!

Documents

Pancreatic Cancer Session - Facing our Risk · - Prediction of ! High-throughput extraction of quantitative features (from ... markers to target for prevention, diagnosis, and/or