Pancreatic CancerZeena Nackerdien

Outline

Description• Epidemiology• Risk factors

• Tumor types• Prognosis of different tumor types

• Mutation frequencies in patients• Potential biomarkers & diagnosis• Guidelines for treatment• Investigational & approved drugs

43,538 pancreatic cancer pts in the USA (1)Anticipated to become the 2nd-leading cause of cancer deaths by 2020

Tumor types (3)

Non-endocrine (Adenocarcinoma):

> 75%

Endocrine (glucagonamas &

insulinomas): 1%

Non-endocrine (Other): ~24%

DescriptionEpidemiology, risk factors (1,2) and tumor types (3)

5-year survival

rate (2004-

2010) (1)

6.7%

4th leading cause of cancer

deaths in the USA

1. Surveillance, Epidemiology and End Results (SEER) program website (A service of the surveillance research program at the National Cancer Institute, USA): SEER Stat Fact Sheets. Pancreas Cancer http://seer.cancer.gov/statfacts/html/pancreas.html.2. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. NEJM 2014;371(11):1039-49.3. Johns Hopkins University School of Medicine (The Sol Goldman Pancreatic Cancer Research Center): Types of Pancreas Tumors 2014 http://pathology.jhu.edu/pc/BasicTypes2.php?area=ba

Pancreatic Adenocarcinoma (85% of all pancreatic cancers); median age = 71

years (2)

Risk factors: smoking, long-standing DM, non-hereditary & chronic pancreatitis,

obesity/inactivity/both, non-O blood group (2)

Prognosis of different tumor types

1. Endocrine tumors 6. Giant cell tumors2. Adenocarcinoma 7. Mucinous Cystic Neoplasms3. Acinar cell carcinoma 8. Pancreatoblastoma4. Adenosquamous carcinoma 9. Signet Ring Cell Carcinoma5. Colloid carcinoma 10. Undifferentiated tumors

• (A) Dire prognosis

1. Intraductal papillary mucinous neoplasm2. Serious cystadenomas3. Solid and pseudopapillary tumors

• (B) Potentially curable

(A) Dire and (B) Potentially curable; Johns Hopkins University(1)

3. Johns Hopkins University School of Medicine (The Sol Goldman Pancreatic Cancer Research Center): Types of Pancreas Tumors 2014 [cited 2014 September]. Available from: http://pathology.jhu.edu/pc/BasicTypes2.php?area=ba.

~Mutation frequencies in patients Commonly mutated oncogenes & tumor suppressors

ARID1A, AT-rich interactive domain 1A; ARID1B, AT-rich interactive domain 1B; ATM ataxia telangiectasia–mutated;CDKN2A cyclin-dependent kinase inhibitor 2A; GNAS guanine nucleotide binding protein, alpha stimulating; GPCR G-protein–coupled receptor; IPMNC, intra-papillary mucinous neoplasms; KDM6A lysine (K)-specific demethylase 6A; KRAS Kirsten rat sarcoma viral oncogene homologue; MLL2 mixed-lineage leukemia 2; MLL3 mixed-lineage leukemia 3; PADC, pancreatic ductal adenocarcinoma; RNF43 ring-finger protein 43; SMAD4 SMAD family member 4; SMARCA1 SWI/SNF-related, matrix-associated,actin-dependent regulator of chromatin, subfamily a, member 1; TGF-β transforming growth factor β; TGF-βR1, TGF-β receptor1; and TGF-βR2 TGF-β receptor 2*Tumors with intact or deleted SMAD4 associated with different disease features2. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. NEJM. 2014;371(11):1039-49.

• KRAS (>90%)• P53 (60-70%)• CDKN2A (>50%)• SMAD4, TGF-βR1, TGF-βR2 (50%)• ARID1A, ARID1B,

SMARCA1 (10-15%)• MLL2, MLL3, KDM6A (5-10%)• ATM, BRCA2 (10%)

PADC

• GNAS (40-80%)• KRAS (40-65%)• RNF43 (>50%)

IPMNC

Oncogenes

Tumor suppressor

s

Tumor present(± metastasis): (-): multi-disciplinary review, possible EUS, liver function

tests & chest imaging(+) biopsy to confirm

Investigational biomarkersin addition to CA19.9

• Aberrantly methylated DNA (5)

• miR-205, miR-210, miR-492, and miR-1427 & serum CA19-9 levels (6)

• Serum peptide signatures (7)

• CA125, CA19.9 and LAMC2 (8)

Potential biomarkers* & diagnosisNCCN-recommended tests (4)

No tumor, but cancer is still suspected (±

metastasis):(-): liver function- and

imaging tests, EUS and/or MRI/MRCP or ERCP as needed; (+): biopsy to

confirm and EUS

Imaging

tests: CT or MRI

CT, computed tomography; EUS, endoscopic ultrasound; ERCP, endoscopic retrograpde cholangiopancreatography; MRI, magnetic resonance imaging; MRCP, magnetic cholangiopancreatography, miR is microRNA4. National Comprehensive Cancer Network Guidelines for Patients v1.2014 (Pancreatic Cancer) http://www.nccn.org/patients/guidelines/pancreatic/#1.5. Zhao Y, Sun J, Zhang H, et al. High-frequency aberrantly methylated targets in pancreatic adenocarcinoma identified via global DNA methylation analysis using methylCap-seq. Clinical Epigenetics. 2014;6(1):18.6. Wang J, Raimondo M, Guha S, et al. Circulating microRNAs in Pancreatic Juice as Candidate Biomarkers of Pancreatic Cancer. Journal of Cancer. 2014;5(8):696-705.7. Velstra B, Vonk MA, Bonsing BA, et al. Serum peptide signatures for pancreatic cancer based on mass spectrometry: a comparison to CA19-9 levels and routine imaging techniques. Journal of Cancer Research and Clinical Oncology. 2014.8. Chan A, Prassas I, Dimitromanolakis A, et al. Validation of biomarkers that complement CA19.9 in detecting early pancreatic cancer. Clinical cancer research. 2014.

Chemotherapies

Guidelines for treatmentNCCN (4)

Neoadjuvant

Primary

Adjuvant

2nd-line

Treatment order

Treatment typeSurgery

• Whipple procedure

• Distal/total pancreatectomy

Targeted drugs e.g., erlotinib

Radiation Therapy• 3D-CRT, IMRT & SABR• Brachytherapy

• Capecitabine• Cisplatin• Docetaxel• 5-fluorouracil

• Oxaliplatin• Nab-paclitaxel

Clinical

trials

3D-CRT, three-dimensional conformal radiation therapy; IMRT, intensity-modulated radiation therapy; SABR, stereotactic ablative radiotherapy4. National Comprehensive Cancer Network Guidelines for Patients v1.2014 (Pancreatic Cancer) http://www.nccn.org/patients/guidelines/pancreatic/#1.

Resectable

Tumors not removable by surgery are unresectable

Reprogramming of tumor stroma with

the VDR-ligand, calcipotriol, may

enhance therapy (pre-clinical)9,

Targeted therapies*

Investigational & approved drugsPancreatic cancer market 2014

VDR, vitamin-D-receptor9. Sherman MH, Yu RT, Engle DD, Ding N, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159(1):80-93.

•Jakafi® (Phase II)•Sutent® •Simtuzumab (Phase II)•PEGPH20 (Phase II)•M402 (Phase I/II)

•Tarextumab (Phase Ib)•CA180-375 (Phase II)•Archexin® (Phase IIa)•Masitinib

•RG7600 (Phase I)•AbGn-7 (Phase I)•GVAX Pancrease + CRS-207 (Phase II)•MORAb-066 (orphan drug)

•Abraxane® (post-approval)•IFEX® + 22P1Ga (Phase I/II)•CamposomesTM (Pre-clinical)

•ThermoDox® (Pre-clinical)•MM-398 (Phase III)•OCZ103-OS (Phase I)

Immunotherapies*

Chemotherapies*