Pancreatic Cancer- 2017 Valeriya Semenisty Department of Oncology

Pancreatic Cancer- 2017 Valeriya Semenisty Department of Oncology, Rambam Medical Center, Haifa, Israel

Topics • Part 1 – – • Epidemiology Pathology Risk factors Genetics Part 2 – Clinical course – Treatment • Metastatic disease • Locally advanced non-resectable tumor • Resectable tumor • Part 3 – Personalized treatment – Imaging

Cancer statistics CA: A Cancer Journal for Clinicians Volume 63, Issue 1, pages 11 -30, 17 JAN 2013 DOI: 10. 3322/caac. 21166 http: //onlinelibrary. wiley. com/doi/10. 3322/caac. 21166/full#fig 1

USA statistics • The American Cancer Society's most recent estimates for pancreatic cancer in the United States are for 2014: – About 43, 930 people will be diagnosed with pancreatic cancer. – About 37, 890 people will die of pancreatic cancer – Overall incidence of pancreatic cancer is approximately 8 -10 cases per 100, 000 persons per year (2 in India → 16 in black males) – The lifetime risk of developing pancreatic cancer is about 1 in 71 (1. 41%).

• Overall incidence of pancreatic cancer is approximately 8 -10 cases per 100, 000 persons per year • Black males • White males 16. 2/100, 000 12. 7/100, 000 • black females • white females 13. 7/100, 000 9. 8/100, 000 • In India – 2/100, 000 Israel – 8/100, 00 • The lifetime risk of developing pancreatic cancer is about 1 in 71 (1. 41%).

Incidence in Israel

EXOCRINE AND ENDOCRINE ORGAN

Pathology • Exocrine tumors – Solid – Cystic • Endocrine tumors

Solid Epithelial Tumors • Adenocarcinomas: 75 -80%, white yellow, poorly defined, often obstruct bile duct or main pancreatic duct. • Often associated with a desmoplastic reaction that causes fibrosis and chronic pancreatitis.

• Infiltrate into vascular, lymphatic, perineural spaces. • At resection, most mets to lymph nodes. • Mets to liver (80%), peritoneum (60%), lungs and pleura (50 -70%), adrenal (25%). Direct invasion of adjacent organs as well. • Others include adenosquamous, acinar cell (1%, better prognosis), giant cell (5%, poorer prognosis), pancreatoblastoma (children 1 -15 years, more favorable).

GENETICS OF PANCREATIC CANCER

• Nature 467, 1114 -1117 (28 October 2010) • Distant metastasis occurs late during the genetic evolution of pancreatic cancer • • Shinichi Yachida 1 et al 7, Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA

A quantitative analysis of the timing of the genetic evolution of pancreatic cancer – At least a decade between the occurrence of the initiating mutation and the birth of the parental, nonmetastatic founder cell. – At least five more years are required for the acquisition of metastatic ability – Patients die an average of two years thereafter. There is a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

Components of Pancreatic Cancer Hidalgo M. N Engl J Med 2010; 362: 1605 -1617

RISK FACTORS • • Advanced age Smoking diet Chronic pancreatitis • Diabetes mellitus • Blood type A, B, AB • Family history

Age • Age is the most significant risk factor for pancreatic cancer. • In the absence of predisposing conditions pancreatic cancer is unusual in persons younger than 45 years. Only 10% of patients are diagnosed when younger than 50 years of age. • After age 50 years, the frequency of pancreatic cancer increases linearly. • The median age at diagnosis is 69 years in whites and 65 years in blacks

The age-specific incidence rates of pancreatic cancer in different racial groups pancreatic cancer is unusual in persons younger than 45 years

RISK FACTORS • • Advanced age Smoking diet Chronic pancreatitis • Diabetes mellitus • Blood type A, B, AB • Family history

Smoking • Associated with 20 -25% of PC cases • People who smoke have 2. 7 -3. 7 -fold increased risk for pancreatic cancer. • Current smokers with over a 40 pack-year history of smoking may have up to a 5 -fold increase risk of the disease. • It takes 5 -10 years of discontinued smoking to reduce the increased risk of smoking to approximately that of nonsmokers.

RISK FACTORS • • Advanced age Smoking diet Chronic pancreatitis • Diabetes mellitus • Blood type A, B, AB • Family history

Obesity & nutrition • High caloric intake & obesity are risk factors for PC • Red meat consumption, especially processed, is associated with a higher risk of pancreatic cancer

Anthropometric Measures, Body Mass Index, and Pancreatic Cancer A Pooled Analysis From the Pancreatic Cancer Cohort Consortium (Pan. Scan) Arch Intern Med. 2010; 170(9): 791 -802. • A positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs lowest BMI quartile, 1. 33; 95% CI, 1. 12 -1. 58; Ptrend <. 001). • Increased waist to hip ratio was associated with increased risk of pancreatic cancer in women (adjusted OR for the highest vs lowest quartile, 1. 87; 95% CI, 1. 31 -2. 69; Ptrend =. 003) but less so in men.

Obesity & nutrition • High caloric intake & obesity are risk factors for PC • Red meat consumption, especially processed, is associated with a higher risk of pancreatic cancer

Alcohol Intake and Pancreatic Cancer Risk: A Pooled Analysis of Fourteen Cohort Studies. Cancer Epidemiol Biomarkers Prev 2009; 18(3): 765– 76 “…a modest increase in risk of pancreatic cancer with consumption of 30 or more grams of alcohol per day. ” Soft Drink and Juice Consumption and Risk of Pancreatic Cancer: The Singapore Chinese Health Study Cancer Epidemiol Biomarkers Prev; 19(2); 447– 55, 2010 “Individuals consuming ≥ 2 soft drinks/wk experienced a statistically significant increased risk of pancreatic cancer (hazard ratio, 1. 87; 95% confidence interval, 1. 10 -3. 15) compared with individuals who did not consume soft drinks after adjustment for potential confounders. There was no statistically significant association between juice consumption and risk of pancreatic cancer”

RISK FACTORS • • Advanced age Smoking diet Chronic pancreatitis • Diabetes mellitus • Blood type A, B, AB • Family history

• 14 -fold increased risk of PC in chronic pancreatitis patients • Hereditary pancreatitiis → 40 -55% lifetime risk of PC

RISK FACTORS • • Advanced age Smoking diet Chronic pancreatitis • Diabetes mellitus • Blood type A, B, AB • Family history

• Increased risk of PC in type II diabetes (RR 2. 1 -2. 6) – Etiologic factor ? – Manifestation of PC ?

RISK FACTORS • • Advanced age Smoking diet Chronic pancreatitis • Diabetes mellitus • Blood type A, B, AB • Family history

ABO Blood Group and the Risk of Pancreatic Cancer J Natl Cancer Inst 2009; 101: 424 -31. Brian M. Wolpin, Andrew T. Chan, Patricia Hartge, Stephen J. Chanock, Peter Kraft, David J. Hunter, Edward L. Giovannucci, Charles S. Fuchs • Compared with participants with blood group O, those with blood groups A, AB, or B were more likely to develop pancreatic cancer • Adjusted hazard ratios for incident pancreatic cancer were 1. 32 [95% confidence interval {CI} = 1. 02 to 1. 72], 1. 51 [95% CI = 1. 02 to 2. 23], and 1. 72 [95% CI = 1. 25 to 2. 38], respectively.

RISK FACTORS • • Advanced age Smoking diet Chronic pancreatitis • Diabetes mellitus • Blood type A, B, AB • Family history

Inherited pancreatic cancer • An inherited tendency to develop this cancer may occur in about 10% of all patients with pancreatic cancer. • Minority (< 20%) of inherited pancreatic cancers are associated with known genetic syndromes

Familial pancreatic cancer • Familial pancreatic cancer (FPC) = >2 first degree family members are diagnosed with PC and known genetic syndromes have been excluded • PC in one 1 st degree relative: RR= 4. 6 (lifetime risk 6%) • PC in 2 1 st degree relatives: RR= 6. 4 -9. 0 (8 -12%) • In ≥ 3 1 st degree relatives RR= 32 (40%)

Genetic syndromes

• Both BRCA 1 (breast cancer gene 1) and BRCA 2 are tumor suppressor genes and are involved in DNA repair of double-strand breaks. • Related mainly to breast and ovarian cancers.

Pancreatic cancer in BRCA 1/2 • Risk of PC in BRCA 1 carriers is low (RR ~2. 3) • BRCA 1: Cumulative age-adjusted lifetime risk of pancreatic cancer – 3. 6% • Risk of PC in BRCA 2 carriers is higher (RR ~ 6) • BRCA 2: cumulative risk – 5 -10% • Estimated population risk of PC: 1 -1. 3%

BRCA 1/2 in pancreatic cancer • BRCA 2 in sporadic PC – 0. 8% • BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma – 5. 5% (Ferrone et al, JCO 2009) • In association of family history – up to 17%

BRCA 1/2 in pancreatic cancer RAMABM HCC • BRCA 1/2 in patients with PC, unselected (Rambam Health Care Campus) – 58 tested – 10 positive for mutation ( BRCA 2 -7, BRCA 1 -2) = 17. 2 % – Age: 58. 7 vs 66 y – Positive family history (breast, ovary, pancreas) : 60% vs 25%

Low risk (less than 5 -fold) • Factors – Race/sex: • male • black • Ashkenazi Jewish descent – Exposures: • • obesity smoking diabetes mellitus Helicobacter pylori infection – Family history: • cancer history in a first-degree relative • history of pancreatic cancer in one first-degree relative – Inherited conditions: • hereditary non-polyposis colorectal cancer • familial adenomatous polyposis • BRCA 1 mutation carrier Brand RE et al, Gut 2007

Moderate risk (5 to 10 -fold) • Factors – Family history: • history of pancreatic cancer in two first-degree relatives – Inherited conditions: • cystic fibrosis • BRCA 2 mutation carrier – Comorbidities: • chronic pancreatitis Brand RE et al, Gut 2007

High risk (greater than 10 -fold) • Factors – Inherited conditions: • familial atypical multiple mole melanoma syndrome (FAMMM) kindreds with p 16 germline mutation and at least one case of pancreatic cancer in first-degree or second-degree relative; • hereditary pancreatitis; • Peutz–Jeghers syndrome; • BRCA 2 or BRCA 1 mutation carrier with at least one case of pancreatic cancer in first-degree or second-degree relative. – Family history: • three or more first-degree, second-degree or third-degree relatives with pancreatic cancer. Brand RE et al, Gut 2007

BRCA 1/2 in pancreatic cancer RAMABM HCC • For the 1 st degree relative - – High prevalence (of BRCA) + high risk (for PC+breast) = Genetic counseling! (early detection? - EUS, markers, fecal DNA methylation analysis, metabolomics… )

How to screen? • • Which strategy should be used for the follow-up program of high-risk individuals? When to begin? – – • Imaging techniques Markers EUS is the preferable initial imaging test – – Canto et al, 2004: 2/38 (5. 3%) pancreatic neoplasia, 4/38 (10. 6%) benign masses – Canto et al, 2006 : EUS+CT- 8/78 (10%) with pancreatic neoplasia ( 6 IPMN + 1 Pan. IN surgery → no cancer, 1 IPMN no surgery → cancer) – Poley et al, 2009: 3/44 (7%) adenocarcinoma, 7/44 (16%) IPMN (premalignant lesions) – Annual EUS examination, beginning 10 years before the earliest diagnosis of pancreatic carcinoma in the patient’s family • Markers: CA 19 -9…. PAM 4 (MAb to MIC-1), sens. 81%, spec. 95%, also for early stage

Clinical course and treatment

Pancreatic Cancer- diagnosis: Symptoms Head % Weight loss Jaundice Pain Anorexia Nausea Vomiting Weakness 92100 82 7 72 87 64 33 45 43 37 37 35 43 Body and tail %

Pancreatic Cancer- Diagnosis: imaging and lab • Computer Tomography (CT) ± FNA/B • Endoscopic Ultrasound ± FNA/B • Endoscopic Retrograde Cholangiopancreatiography (ERCP) • Tumor marker (CA 19 -9, CEA)

Staging Primary Tumor (T) TX cannot be determine T 0 No evidence Tis In situ T 1 Limited to pancreas, 2 cm or less in greatest dimension T 2 Limited to pancreas, more than 2 cm in greatest dimension T 3 Extends beyond pancreas but without involvement of celiac axis or SMA T 4 Involves celiac axis or the SMA Regional Lymph Nodes (N) NX Cannot be assessed N 0 No regional lymph node metastasis N 1 Regional lymph node metastasis Distant Metastasis (M) MX Cannot assess M 0 No distant metastasis M 1 Distant metastasis Tram et al. “Diagnosis, Staging, and Surveillance of Pancreatic Cancer. ” Am. J. Roentgenol. May 2003 180: 1311 -1323

Pancreatic cancer: stage at diagnosis • 10 - 15 % have disease confined to the pancreas and resectable. • 40 % have locally advanced disease = unresectable. • 40 – 50% present with visceral metastasis (usually liver)

Pancreatic cancer Survival Median (m) • Resectable 15 -19 5 -y (%) 5 -20 • Locally advanced 6 -10 0 - ? • Metastatic 3 - 6 0

• Why are the results so poor ? – Symptoms tend to occur rather late – Surgery to remove pancreatic cancer is very complicated – The biology of pancreatic cancer makes it an unusually aggressive cancer (small tumor-big effect; resistance to treatment)

Treatment of metastatic pancreatic cancer

Treatment Schedule i. Gemcitabine i 5 -Fluorouracil (5 FU) Pts = 126 1000 mg/m 2/wk 600 mg/m 2/wk

Metastatic pancreatic cancer Gemcitabine • No confirmed objective responses • Clinical benefit response 23. 8% in Gem arm, 4. 8% in 5 -FU arm (P=. 0022) • Median survival 5. 65 vs. 4. 41 mos (P=. 0025)

Beyond single-agent gemcitabine ? • Gemcitabine-based combination CT – G + cisplatin modest improvement, if at all – G + capecitabine (xeloda) – G + Abraxane • non-gemcitabine based combination CT – FOLFORINOX (5 FU, oxaliplatin, irinotecan) RR X 3 (31. 6 vs 9. 4%), OS 6. 8 ↑to 11. 1 m • Targeted therapy • G + erlotinib (tarceva= Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER 1/EGFR) tyrosine kinase inhibitor)

FOLFIRINOX versus gemcitabine OS Probability 1 HR = 0, 57 ; IC 95 : 0, 45 -0, 73 0, 75 0, 5 p < 0, 0001 FOLFIRINOX OS = 11. 1 m 0, 25 Gemcitabine OS = 6. 8 m 0 0 6 12 18 24 30 36 3 9 2 3 2 2 M Gemcitabine 171 FOLFIRINOX 171 89 116 28 62 7 20 ASCO 2010 - Conroy T et al. , abstr. 4010

Beyond single-agent gemcitabine ? • Gemcitabine-based combination CT – G + cisplatin modest improvement, if at all – G + capecitabine (xeloda) • non-gemcitabine based combination CT – FOLFORINOX (5 FU, oxaliplatin, irinotecan) RR X 3, OS 6. 8 ↑to 11. 1 m • Targeted therapy • G + erlotinib (tarceva= Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER 1/EGFR) tyrosine kinase inhibitor)

GEM plus Erlotinib Gemcitabine (1000 mg/m 2) + Erlotinib (100 or 150 mg/die) vs. Gemcitabine (1000 mg/m 2) + Placebo Pts=569 (naïve advanced pancreatic cancer) OS 6. 24 months (GEM+ERL) vs. 5. 91 months (GEM) P=0. 038

GEM plus Erlotinib Grade 0 (n=79) Grade 1 (n=102) Grade ≥ 2 (n=101) Median survival (months) 5. 3 5. 8 10. 5 1 -year survival (%) 16 9 43

Locally advanced disease (LAD) clinical highlights • Median survival of LAD is 6 -10 months • Most patients are symptomatic ( pain, weight loss, fatigue)

LAD Aims of treatment • Improvement of quality of life = clinical benefit response (CBR) • Local control = prolongation of survival ? • Downstaging = resectability ?

Practical guidelines 2013 Rambam • Gemcitabine-based chemotherapy for up to 4 months (as long as there is no progression), followed by gemcitabine or 5 -FU or capecitabine –based chemoradiation. • Single-agent gemcitabine in patients with poor performance status.

The Whipple Resection Specimen (Pancreaticoduodenal resection)

אלבום תמונות על ידי אר

Resectable pancreatic cancer • Long-term survival after resection (10 -20% 5 -y), probably there is no plateau = no cure (10 & 20 -y ) • Local recurrence (50 -85%), peritoneal spread (40%), liver metastases (60 -90%). • Do we have an effective adjuvant therapy?

overall survival among all 1, 092 resected pancreatic adenocarcinoma patients with (583, yellow line) and without (509, blue line) adjuvant chemoradiation therapy (P <. 001) The Johns Hopkins Hospital—Mayo Clinic Collaborative Study • Median OS – – • S = 15. 5 m S+CRT= ▲ 5. 6 m 21. 1 m 2 y OS – S = 34. 6% ▲ 10. 1% – • S+CRT = 44. 7% 5 y OS – S = 16. 1% ▲ 6. 2% – S+CRT = 22. 3% Charles C. Hsu et al. Ann Surg Oncol. 2010 April; 17(4): 981– 990.

Adjuvant chemoradiotherapy – randomized studies (2) ESPAC-1 (European Study Group for Pancreatic Cancer) , accrual 1994 -2000 Neoptolemos, LANCET 2001 + NEJM 2004 (median FU=47 m) CT/RT (split-course 40 Gy + bolus 5 FU daily for 3 initial days of RT) vs. CT ( 5 FU + folinic acid, Mayo x 6 cycles) vs CT/RT+CT vs. Observation

Resectable pancreatic cancer adjuvant therapy chemotherapy only? • Charité Onkologie [CONKO]-001) German study (Oettle, JAMA 2007) (Neuhaus, ASCO 2008) DFS-m OS-m : Gemcitabine (6 m) 13. 4 (182 pts): observation 6. 9 – (189 pts) 22. 8 – 20. 2 p<0. 001 (cross over !) p=0. 005

Practical guidelines 2014 Rambam Medical Center • Chemoradiation Chemotherapy for most patients • Chemoradiation only is also an acceptable option. (might be 1 st option for patients with R 1 resection) • • An option for no adjuvant therapy for the few “very good” patients = without any risk factor ( size↓, WD, R 0, N 0, perivascular/perineural involvement) or ”very frail” patients. • Chemotherapy: gemcitabine or 5 FU (same results)

Still unclear… • Pancreatology. 2012 Mar; 12(2): 162 -9. Epub 2012 Feb • Adjuvant chemotherapy, with or without postoperative radiotherapy, for resectable advanced pancreatic adenocarcinoma: Continue or stop? • • Ren F, Xu YC, Wang HX, Tang L, Ma Y. Department of Oncology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.

• Conclusions: – A significant benefit with regard to DFS and median OS for adjuvant chemotherapy after PAC resection was demonstrated by this analysis. – These results do not support the use of adjuvant radiotherapy for PAC.

Future directions The future is here, now…? • Genomics • Personalized medicine = רפואה מתאמת אישית

Personalized medicine • patients with the same cancer type respond differently to therapies due to their unique molecular profiles. • Acquired or germeline changes in our DNA that cause a cancer to develop and grow can differ from person to person with the same tumor. • Molecular testing reveals those differences.

Personalized medicine • Gene expression profiling, molecular profiling, of the specific tumor of the specific patient • To find biomarkers with ↑, ↓, mutated genes = potential targets for different drugs • Metabolism • Direct targeting

RRM 1 → Gemcitabine • RRM 1 (Ribonucleotide Reductase subunit M 1) involved in DNA synthesis and inhibited by gemcitabine • Thus, RRM 1 gene-over-expression may be a negative predictive marker for treatment with gemcitabine.

• SPARC (Secreted Protein Acidic and Rich in Cystein) is a matrix-associated protein • Because of a SPARC-albumin interaction, tumoral SPARC facilitates the accumulation of albumin in the tumor and increases the effectiveness of albumin-bound drugs

SPARC

• • Evidence for SPARC as a biomarker for the anti-tumor effectiveness of nab-paclitaxel in breast and head&neck cancers In pancreatic cancer -

BRCA 1/2 m → PARP inhibitors

• immunohistochemistry (IHC) analysis: – level of important proteins in cancer cells • Polymerase Chain Reaction (PCR) • DNA sequencing) NGS=Next Generation Sequencing) to determine gene mutations in the DNA tumor (Specific genes, exome, whole genome sequencing)

Target Now • A comprehensive patient’s tumor analysis + • An exhaustive clinical literature search = • Matching appropriate therapies to patientspecific biomarker information to generate an evidence-based treatment approach (= finding actionable or druggable targets).

Analysis of CTCs Yu et al. (2011) J Cell Biol

Identification of treatment-associated mutational changes from exome sequencing of serial plasma samples (= circulating cell-free tumor DNA) Nineteen samples in 5 pts with breast, lung, ovarian cancers M Murtaza et al. Nature April 7 (2013), Cambridge, UK