Pancreatic Cancer презентация

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#fig1

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 16.2/100,000
White males 12.7/100,000
black females 13.7/100,000
white females 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 Yachida1Shinichi Yachida1et al7,
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, non-metastatic 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.

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

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 (PanScan)
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 1st degree relative: RR= 4.6 (lifetime risk 6%)
PC in 2 1st degree relatives: RR= 6.4-9.0 (8-12%)
In ≥ 3 1st degree relatives RR= 32 (40%)

Genetic syndromes

Both BRCA1 (breast cancer gene1) and BRCA2 are tumor suppressor genes and are involved in DNA repair of double-strand breaks.
Related mainly to breast and ovarian cancers.

Pancreatic cancer in BRCA1/2
Risk of PC in BRCA1 carriers is low (RR ~2.3)
BRCA1: Cumulative age-adjusted lifetime risk of pancreatic cancer – 3.6%
Risk of PC in BRCA2 carriers is higher (RR ~ 6)
BRCA2: cumulative risk – 5-10%
Estimated population risk of PC: 1-1.3%

BRCA1/2 in pancreatic cancer
BRCA2 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%

BRCA1/2 in pancreatic cancer
RAMABM HCC
BRCA1/2 in patients with PC, unselected (Rambam Health Care Campus)
58 tested
10 positive for mutation ( BRCA2-7, BRCA1-2)
= 17.2 %
Age: 58.7 vs 66y
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
BRCA1 mutation carrier
Brand RE et al, Gut 2007

Moderate risk
(5 to10-fold)
Factors
Family history:
history of pancreatic cancer in two first-degree relatives
Inherited conditions: cystic fibrosis
BRCA2 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 p16 germline mutation and at least one case of pancreatic cancer in first-degree or second-degree relative;
hereditary pancreatitis;
Peutz–Jeghers syndrome;
BRCA2 or BRCA1 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

BRCA1/2 in pancreatic cancer
RAMABM HCC
For the 1st 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 PanIN 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….PAM4 (MAb to MIC-1), sens. 81%, spec. 95%, also for early stage

Clinical course and treatment

Pancreatic Cancer- diagnosis: Symptoms
Symptoms Head % Body and tail %
Weight loss 92 100
Jaundice 82 7
Pain 72 87
Anorexia 64 33
Nausea 45 43
Vomiting 37 37
Weakness 35 43

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
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) 5-y (%)
Resectable 15-19 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

Pts = 126
Treatment Schedule
Gemcitabine 1000mg/m2/wk
5-Fluorouracil (5FU) 600mg/m2/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 (5FU, oxaliplatin, irinotecan) RR X3 (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 (HER1/EGFR) tyrosine kinase inhibitor)

0
0,25
0,5
0,75
1
0
6
12
18
24
30
36
HR = 0,57 ; IC95 : 0,45-0,73
p < 0,0001
M
171
171
89
116
28
62
7
20
3
9
2
3
2
2
Gemcitabine
OS = 6.8m
FOLFIRINOX
OS = 11.1m
Probability
Gemcitabine
FOLFIRINOX
ASCO 2010 - Conroy T et al., abstr. 4010
FOLFIRINOX versus gemcitabine
OS

Beyond single-agent gemcitabine ?
Gemcitabine-based combination CT
G + cisplatin modest improvement, if at all
G + capecitabine (xeloda)
non-gemcitabine based combination CT
FOLFORINOX (5FU, oxaliplatin, irinotecan) RR X3, OS 6.8 ↑to 11.1 m
Targeted therapy
G + erlotinib (tarceva= Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor)

GEM plus Erlotinib
6.24 months (GEM+ERL) vs. 5.91 months (GEM)
P=0.038
OS
vs. Gemcitabine (1000 mg/m2) + Placebo
Pts=569 (naïve advanced pancreatic cancer)
Gemcitabine (1000 mg/m2) +
Erlotinib (100 or 150 mg/die)

GEM plus Erlotinib

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
▲ 5.6 m
S+CRT= 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=47m)
CT/RT (split-course 40 Gy + bolus 5FU daily for 3 initial days of RT)
vs.
CT ( 5FU + 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
(189 pts): Gemcitabine (6 m) 13.4 22.8
(182 pts): observation 6.9 20.2 p<0.001 p=0.005
(cross over !)

Practical guidelines 2014
Rambam Medical Center
Chemoradiation Chemotherapy for most patients
Chemoradiation only is also an acceptable option. (might be 1st option for patients with R1 resection)
An option for no adjuvant therapy for the few “very good” patients = without any risk factor ( size↓, WD, R0, N0, perivascular/perineural involvement) or ”very frail” patients.
Chemotherapy: gemcitabine or 5FU (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

RRM1 → Gemcitabine
RRM1 (Ribonucleotide Reductase subunit M1) -involved in DNA synthesis and inhibited by gemcitabine
Thus, RRM1 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 -

BRCA1/2 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 patient-specific biomarker information to generate an evidence-based treatment approach
(= finding actionable or druggable targets).

A Retrospective Investigation to Evaluate the Use of Target Now® Assay in Selecting Treatment in Patients with Advanced Stage Pancreatic Cancer
The aim of the investigation was to retrospectively study the data from locally advanced and metastatic pancreatic cancer patients who have had their tumor profiled using the Target Now® commercial assay.
They all received at least one treatment line for advanced pancreatic cancer prior to TN-directed therapy.

Druggable targets reported included
Molecular Profiling Identifies Actionable Targets (n=20 patients)

Molecular Profiling Identifies Potential Therapeutic Options in Advanced Pancreatic Cancer (n=20 patients)

Molecular Profiling Guided Treatment Choices (n=20 patients)
The graph above shows the drugs recommended by the Target Now report
which were used alone or in combination in all lines (32) administered following receipt
of the molecular profiling information (1-4 lines per pt, median:1)

Nab-paclitaxel
Capecitabine
+ Irinotecan
Capecitabine
Gemcitabine
+Oxaliplatin
Nab-paclitaxel
Capecitabine
Capecitabine

During the progression of metastasis, cancer cells detach from the solid primary tumor, enter the blood stream, and travel to different tissues of the body ? Breakaway cancer cells in the peripheral blood: Circulating tumor cells (CTCs).
A real-time “liquid biopsy” in cancer patients
Circulating Tumor Cells

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

M Murtaza et al. Nature April 7 (2013), Cambridge, UK
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