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Increase in incidence of colorectal cancer
among young adults in the US
Rebecca Siegel, MPH
Surveillance & Health Services...
Among <50 years: 13,000 cases and 3,000 deaths
Estimated numbers of new cases & deaths in 2015
Top 5 cancers, ages 20-49 years
Lung (18%)
Colorectum (12%)
Brain (8%)
Leukemia (7%)
Pancreas (5%)
Breast (26%)
Lung (15%)...
Anatomy of the colorectum
(right-sided colon)
(left-sided colon)
Subsite distribution by age at diagnosis
0-49 years 50+ years
Proximal 25% 43%
Distal 27% 23%
Rectum 41% 28%
Other 8% 6%
R...
0
50
100
150
200
250
300
350
400
Age-specificincidencerateper100,000
Age at diagnosis
Men
Women
Source: SEER 18 registries...
0
10
20
30
40
50
60
70
1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011
Rate...
The American Surgeon, Oct
2003
SEER 9, 5,383 patients 20-39 yrs
1973-1999
Cancer Epidemiol, Biomarkers, &
Prevention, June...
Incidence trends by age: 50+ versus 20-49
Source: SEER 9 registries, 1975-2011; 2-yr moving average.
0
2
4
6
8
10
12
14
19...
Trends by anatomic subsite in ages 20-49
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2...
Incidence trends by stage at diagnosis, ages 20-49 years
Source: SEER 9 registries, 1975-2011; 2-year moving average.
0
0....
Trends by histologic subtype, 20-49 years
Mucinous
Signet-ring cell
Adenocarcinoma, NOS
Source: SEER 9 registries and Join...
Incidence trends by 10-year age group
40-49
2% per year
30-39
2% per year
20-29
3% per year
0
5
10
15
20
25
30
1975-
76
19...
Incidence trends in ages 50-59 years
0
5
10
15
20
25
30
35
40
1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010...
Incidence trends by race/ethnicity, ages 20-49 years
0
2
4
6
8
10
12
14
Non-Hispanic white
Colon and
Rectum
Colon
Rectum
0...
Stage distribution: early vs. later onset
33%
38%
25%
3%
41%
34%
19%
6%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Localized Re...
Five-year relative survival
Data Source: Trends, SEER 9 registries; Stage-specific, SEER 18 registries, 2007-2011.
0%
10%
...
Mortality trends in ages 20-49 years
0
0.5
1
1.5
2
2.5
3
3.5
4
Deathsper100,000
20-49 years
Source: National Center for He...
Factors that influence population cancer trends
Detection/imaging
practices
Risk factors
Screening behaviors MortalityInci...
Colorectal cancer risk factors: medical and family history
Relative risk
Family history
1 first-degree relative 2.2
More t...
Increase risk: Relative risk Trend
Alcohol consumption (heavy vs.
nondrinkers)
1.6
Obesity 1.2
Red meat consumption 1.2
Pr...
Trends in obesity and diabetes
0
5
10
15
20
25
1971-74 1976-80 1988-94 1999-02 2003-06 2007-08 2009-10 2011-12
Percent
Age...
Obesity and colorectal cancer: pooled relative risk
Ning et al. A quantitative analysis of body mass index and colorectal ...
Lifestyle changes
Changes in dietary patterns
Trends in beverage consumption
Nielsen et al. Changes in beverage intake between 1977 and 2001. Am J Prev Med 2004.
0
2
4
...
State patterns in obesity and CRC incidence rates
Obesity prevalence, ages 18-49, 2001 CRC incidence rates, ages 20-49, 20...
Most colorectal cancers are due to unknown risk factors
Source: The Cancer Atlas, 2nd Edition
Up to 87% of colorectal canc...
Strategies for reducing colorectal cancer risk
 Maintain a healthy weight
 Be physically active
 Consume a healthy diet...
Who should begin screening before 50?
High risk Age to begin
Familial adenomatous polyposis (FAP) 10-12 years
Lynch syndro...
Who else should begin screening before 50?
Increased risk Age to begin
Cancer/adenomas in a first-degree
relative
40 years...
Conclusions
• CRC incidence rates continue to increase in young adults
• Know when to begin screening based on your family...
Acknowledgements
• Kim Miller, MPH
• Ann Goding-Sauer, MPH
• Stacey Fedewa, MPH
Thank you!
American Cancer Society CRC screening guidelines
• Increase unestablished during previous evidence review
• In beginning s...
Percentage of individuals who develop CRC by specific age
0.00%
0.50%
1.00%
1.50%
2.00%
2.50%
3.00%
3.50%
4.00%
4.50%
5.00...
Harms & limitations of colonoscopy screening
• 33% of patients report at least 1 GI symptom following the
procedure
• Seri...
35-39
30-34
25-29
20-24
0
2
4
6
8
10
12
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
20-49
Canada_20_49
UK_20_49
0
2...
Screening test use in ages 40-49 years
0
2
4
6
8
10
12
14
2000 2003 2005 2008 2010 2013
Ever routine endoscopy
0
2
4
6
8
1...
US meat consumption per person, 1909-2012
Defining Body Mass Index (BMI)
Weight
(kg)
Height
(m)2
BMI =
For children & adolescents, obesity is
defined as a BMI > the...
40-49
30-39
20-29
Incidence trends by age group and subsite
0
2
4
6
8
10
12
14
16
1975-76
1977-78
1979-80
1981-82
1983-84
...
State variation in incidence rates by age
50+ years20-49 years
What is a colon adenomatous polyp?
Polyps begin in the cells of glandular
structures lining the colon. Most polyps are
ben...
The growth and stages of CRC
ACS screening guidelines – average risk
Men and women, ages 50+ Frequency
Fecal occult blood test (FOBT)
with at least 50%...
Trends in the use of screening tests (ages 50-75)
0
10
20
30
40
50
60
70
80
2000 2003 2005 2008 2010 2013
Percentage
Any e...
Changes in dietary patterns
Then…
THE CLINICAL CHALLENGES OF EAO-
CRC :
REDUCING LATE STAGE DIAGNOSIS;
IMPROVING SURVIVAL
Y. Nancy You, MD, MHsc
Assistant P...
• Persistently increasing incidence
• Majority between ages of 40-49
• Predominately located in distal colon and rectum
• ...
39 year-old dental hygienist
Single mother; estranged family
Grandmother, colon cancer in
60’s
Intermittent rectal bleedin...
COLORECTAL CANCER TRENDS
39 YEAR-OLD, STAGE IV RECTAL CANCER
5/year 0
Chemo
10-12/year0
Liver
surgery
#1
Liver
surgery
#2
...
CLINICAL CHALLENGES OF EAO-CRC
OUTLINE
• What are the clinical challenges ?
• How can we improve ?
CLINICAL CHALLENGES OF EAO-CRC
WHAT ARE THE CHALLENGES
 Interrupts adulthood
 Stresses support network
 Hereditary? Gen...
CLINICAL CHALLENGES OF EAO-CRC
WHAT ARE THE CHALLENGES
 Multiple treatments
 Many modalities
 Long time
 Treatment-rel...
CLINICAL CHALLENGES OF EAO-CRC
OUTLINE
• What are the clinical challenges ?
• Focusing on Survival
• How can we improve ?
Bleyer et al. Nature Reviews Oncology. 2007.
CLINICAL CHALLENGES OF EAO-CRC
SURVIVAL : SEER 1993-1998
CLINICAL CHALLENGES OF EAO-CRC
OUTLINE
• What are the clinical challenges ?
Focusing on Survival
• What influences surviva...
You et al. Arch Int Med.
CLINICAL CHALLENGES OF EAO-CRC
NCDB, 1998-2007
Age 18-49 Years (N=64,068) vs. Age 50+ Years (N=52...
Age-adjusted CRC death
rate has declined between
1975-2005
Factors thought to contribute to the
decline in death rate:
CLI...
All CRC
~ 5%
“Hereditary”
Burt et al. Gastroenterology 2000.
CLINICAL CHALLENGES OF EAO-CRC
SUBGROUPS OF CRC & SCREENING G...
All CRC
~ 5%
“Hereditary”
CLINICAL CHALLENGES OF EAO-CRC
SUBGROUPS OF CRC & SCREENING GUIDELINES
Start Frequency
High Risk...
You et al. ASCRS Annual Meeting 2013.
• 223 CRC patients aged 18-50
• Stratify by Tumor mismatch repair (MMR) status & Fam...
All CRC
~ 5%
“Hereditary”
CLINICAL CHALLENGES OF EAO-CRC
SUBGROUPS OF CRC & SCREENING GUIDELINES
Goal
High Risk
(“Heredita...
70
Ampullary,
Pancreas,
Hepatoblastoma
Colon and
Rectum
Familial Adenomatous Polyposis Surveillance
Thyroid
Brain
Desmoid
/
W...
Biliary,
Pancreas
Colon and
Rectum
Lynch Syndrome Surveillance
UrinaryTract
Brain
Skin
Uterine &
Ovary
Why Hereditary Synd...
All CRC
~ 5%
“Hereditary”
CLINICAL CHALLENGES OF EAO-CRC
SUBGROUPS OF CRC & SCREENING GUIDELINES
Goal
High Risk
(“Heredita...
CLINICAL CHALLENGES OF EAO-CRC
OUTLINE
• What are the clinical challenges ?
• What influences survival and how can we impr...
THE IMPACT OF YOUNG AGE ON SURVIVAL IN
PATIENTS WITH METASTATIC COLORECTAL
CANCER: ANALYSIS FROM THE ARCAD
CLINICAL TRIALS...
Overall Survival
Age in Years
RelativeHazard
1.0
1.2
1.4
1.6
1.8
20 40 60 80
p < 0.0001
Progression-Free Survival
Age in Y...
You et al. In Press JAMA Surgery
NCDB,
2003 to 2005
OR for
Chemo
(95% CI)
OR for Multi-
agent
regimen
(95% CI)
5-year
Adju...
NCDB,
2003 to
2005
OR for
Chemo
(95% CI)
OR for Multi-
agent
regimen
(95% CI)
5-year Adjusted
Relative
Survival (No
chemo)...
CLINICAL CHALLENGES OF EAO-CRC
OUTLINE
• What are the clinical challenges ?
• What influences survival and how can we impr...
0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0%
Benefits
Positive feelings
Family distress
Recurrence distress
...
EORTC CR-29 (SCORE > 3)
*P<0.05
34.2
19.5
57.3
23.0
20.5
13.4
40.2
16.4
0 10 20 30 40 50 60 70
* Anxiety
* Body image
* Ma...
CLINICAL CHALLENGES OF EAO-CRC
SUMMARY
• Key challenge : improve survival
• Factors that influence survival
Stage of disea...
THANK YOU
ynyou@mdanderson.org
THE CLINICAL CHALLENGES OF EAO-CRC :
REDUCING LATE STAGE DIAGNOSIS;
IMPROVING SURVIVAL
Hereditary Colorectal Cancer
Syndromes and the Contribution
to Early Age Onset Colorectal
Cancer
Fay Kastrinos MD, MPH
Col...
Sporadic
(~75%)
Familial
colorectal cancer
(~20%)
Inherited colorectal cancer
syndromes (~5%)
Epidemiology of
Colorectal C...
Hereditary Colorectal Cancer
Syndromes
• Lynch Syndrome/ Hereditary
Nonpolyposis Colorectal Cancer (HNPCC)
• Familial Aden...
Genes Associated with a
High Risk of Colorectal Cancer
Gene Syndrome Hereditary Pattern Predominant Cancer
Tumor suppresso...
How common is CRC in adults
younger than 50?
• ~10% of CRCs arise in men and women <50
yrs
140,000 new cases, 2014
• Incid...
How common are inherited CRC
syndromes in EAO-CRC?
• ~10% of EAO-CRC is attributed to known
inherited CRC syndromes
– 14,0...
Lynch Syndrome
 Most prevalent hereditary CRC syndrome
 5% of all CRC
 Defective DNA Mismatch Repair
 Mutations in MLH...
Lynch Syndrome Results
From Failure of Mismatch
Repair (MMR) Genes
Base pair
mismatch
Normal
DNA repair
Defective DNA
repa...
Mismatch Repair Failure Leads
to Microsatellite Instability (MSI)
Normal
Microsatellite
instability Addition of
nucleotide...
Lynch Syndrome Clinical
Features
 Striking family history affecting
multiple generations
 Early (but variable) age at CR...
Lynch Syndrome
• Sine qua non is identification of a germline mutation
• Families originally identified based
on Amsterdam...
Clinical Criteria for the Identification of
Lynch Syndrome
• Revised Bethesda Guidelines
– Incorporates MSI testing, extra...
Lynch syndrome and EAO-CRC
• Lynch syndrome accounts for 3-4% of ALL
CRCs, regardless of ages
• What % of EAO-CRC is due t...
Lynch syndrome and EAO-CRC
• US study examining the prevalence of Lynch
syndrome
– Unselected, population-based sample
– Y...
Lynch syndrome and EAO-CRC
• Spanish study examining the prevalence of
Lynch syndrome
– Unselected, population-based sampl...
Summary of Lynch syndrome and
contribution on EAO-CRC
• 3-4 % of all CRCs, regardless of age, are due
to Lynch syndrome
• ...
Hereditary GI Cancer Syndromes:
How good are we at identifying
families with germline mutations?
Proband
HEREDITARY GI CAN...
Hereditary GI cancer syndromes:
What have we learned from
clinical genetic testing?
• Ability to define new conditions fro...
Original Contribution. JAMA. 2005;293(16):1979-1985.
Lower Cancer Incidence in Amsterdam-I Criteria Families Without Misma...
• Families fulfill AC-I criteria
– Suspected Lynch syndrome but no mutation
• Lower CRC incidence than Lynch syndrome
– SI...
• Genetic etiology is largely unknown
– Has a monogenic component
• likely caused by high-penetrance mutations
– ?Polygeni...
HOWEVER….
• Phenotype varies from “classic” to “attenuated”
• 30% are de novo cases: no family history
• Classic FAP easy ...
Variations of classic phenotypes are
common: Attenuated FAP
• Attenuated polyposis is a phenotypically distinct variant of...
• Polyp phenotype more so “attenuated”
• Autosomal recessive pattern of inheritance
• Biallelic mutation carriers: 53 fold...
MYH associated polyposis
• ~3% of EAO-CRC is due to MYH mutations
– Compared to <1% of all CRC cases, regardless of
age
• ...
Germline Testing
Proband
HEREDITARY GI CANCER SYNDROME
Pedigree
Clinical Criteria
+/- tumor testing
+
Stepwise Approach fo...
Germline p53 Mutations and
Early Age Onset Cancers
• Li-Fraumeni syndrome
– caused by p53 mutations
• Lifetime risk of can...
• 457 patients with CRC ≤40 years old
• 1.3% carried a p53 gene mutation
– Comparable to the prevalence of APC gene
mutati...
Advances in Genetic Testing for
Inherited CRC
• Next Generation Sequencing (NGS) allows for simultaneous
assessment of man...
Expanded Commercial Cancer
Genetic Testing
47%
Uptake of NGS Panel Testing in EAO-CRC
LaDuca H et al. Genet Med. 2014 Nov;16(11):830-7
NGS Panel Testing in EAO-CRC
Additional Results from NGS Panel
Testing in EAO-CRC
Pilot study
• To determine the frequency and clinical phenotype
of patients undergoing genetic testing for Lynch
syndrome ...
Overall Panel Testing Results
Total cohort 343 patients
No mutation found 277 (81%)
All mutation carriers 66 (19%)
Lynch m...
Summary & Future Directions
• 85 % of EAO-CRC are not explained by known inherited CRC
syndromes
• NGS Panel testing will ...
Thank you!
Fay Kastrinos, MD, MPH
212-305-1021
Kate McNamara, MD
CCCF Research Scholar
University of Toronto
CCCF Annual Research Scholar Award
Zane Cohen Center for Digestive Diseases
Research Treatment Education Support
Gastrointestinal Cancers
Research Groups
Fam...
Genetics of Early Age Onset Colorectal Cancer (EAO-CRC)
age-standardized incidence rate per 100,000 43.7
age-standardized mortality rate per 100,000 15.9
estimated new cases in 2...
EAO-CRC incidence and mortality in the US
● approximately 10% of colorectal cancers have early-onset
NEW CASES DEATHS
Male...
CRC incidence and mortality in Canada
● incidence and mortality rates are higher in Canada than in the US
● second leading...
EAO-CRC incidence and mortality in Canada
● approximately 6% of colorectal cancers have early-onset
NEW CASES DEATHS
Male ...
CRC incidence trends in the US
● CRC ASIR have been decreasing on average 3.1% per year since 2002
SEER 9 Incidence & U.S....
CRC incidence is increasing in young adults
Age (y) 1973
Incidence
1999
Incidence
EAPC
Colon 20-40 1.8 2.1 0.75**
60+ 179 ...
CRC incidence trends among young non-hispanic white adults (20-49yrs)
by age and anatomic subsite,1992 to 2005
Age n APC
M...
CRC incidence and mortality trends in Canada
● CRC ASIR has been decreasing on average 0.8% per year in males, 2001-2010
●...
CRC incidence is increasing in young adults
Cancer Care Ontario. Colorectal cancer incidence increasing among adolescents ...
Hereditary CRC risk
• familial cases comprise approximately 30% of all CRC
• mutations in highly penetrant CRC susceptibil...
Hereditary CRC syndromes
POLYPOSIS
adenomatous polyposis syndromes
Familial Adenomatous polyposis (FAP) – AD, mutation in ...
POLYPOSIS
adenomatous polyposis syndromes
Familial Adenomatous polyposis (FAP) – AD, germline mutation in APC
Attenuated F...
POLYPOSIS
hamartomatous polyposis
Peutz-Jeghers syndrome (PJS) - AD, germline mutations in STK11
 GI polyps in 90-100% of...
hyperplastic/serrated polyposis
Serrated polyposis syndrome
 uncertain genetic etiology; unclear hereditary predispositio...
NONPOLYPOSIS
Lynch syndrome (LS) – AD, mutation in DNA mismatch repair (MMR) gene
(MLH1, MSH2, MSH6, PMS2) or EPCAM
 usua...
Hereditary CRC syndromes and EAO-CRC
Chang et al. 2012 ≤40 surgical patients, Stanford Univ hosp 75 total; 13(17%) IHC def...
FGICR and EAO-CRC
Lynch Syndrome n=87
1.MMR (or EPCAM) gene mutation
2.IHC deficient tumor
• 71 germline mutations
• 12 VU...
Br J Surg. 2013 Dec;100(13):1719-31. doi: 10.1002/bjs.9316.
Systematic review of the impact of registration and screening ...
J Exp Clin Cancer Res. 2014 Jan 2;33:1. doi: 10.1186/1756-9966-33-1.
Early-onset colorectal cancer patients without family...
Clinicopathologic features of non-familial EAO-CRC
Early-onset (≤40
years) colorectal
adenocarcinoma
(%) (N=55)
Control (>...
PLoS One. 2014 Aug 1;9(8):e103159.
Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a
morphologica...
Am J Surg Pathol. 2009 Apr;33(4):572-82. doi: 10.1097/PAS.0b013e31818afd6b.
Clinical, pathologic, and molecular features o...
Exploring the genetics of EAO-CRC
Next-generation sequencing (NGS)
 rare variant hypothesis
▪ undiscovered moderately penetrant genetic variants
cause increased CRC risk
de novo dominant
...
Whole genome sequencing
vs
Exome sequencing
Whole genome
 expensive
 IT issues
 complete sequence
Exome
 cheaper
 mor...
Nat Genet. 2011 May; 43(5): 442–446.
Exome sequencing identifies GRIN2A as frequently mutated in
melanoma
Xiaomu Wei,1 Vij...
Nat Genet. 2013 Feb;45(2):136-44.
Germline mutations affecting the proofreading domains of POLE and POLD1
predispose to co...
POLE L424V variant
• pedigree SM2702, only variant shared by all 3 affected individuals
• present in 12 additional unrelat...
Hum Mutat. 2013 Jul;34(7):1026-34. doi: 10.1002/humu.22333. Epub 2013 May 20.
Exome resequencing identifies potential tumo...
analysis strategy 1
 search for protein-truncating variants in subset of 1,138 genes from pathways implicated in CRC
 on...
Cancer Genetics 208 (2015) 35-40
Systematic search for rare variants in Finnish
early-onset colorectal cancer patients
Tom...
RESULTS
 no genes with rare loss-of-function (LoF) variants present in more than one EOA-CRC patient
 ADAMTS4, CYTL1, SY...
The Toronto EAO-CRC cohort
FGICR
Undefined conditions n=122
• 97 complete testing
• 5 partial testing
• 20 no testing
• co...
rare variant hypothesis
▪ undiscovered moderately penetrant genetic variants
cause increased CRC risk
perhaps not one sin...
References
Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC C...
Thank you
Jiyoung Ahn, PhD, RD
Associate Professor
Dept. of Population Health
NYU School of Medicine
Early Age Onset Colorectal Canc...
16
3
Human microbiome
• Human microbiome, totality of human microbiota.
• Our understanding of microbiome has been limited...
16
4
World Health Organization
Group 1 infectious agents that cause cancer
Bacteria
Helicobacter pylori (H. pylori)
Viruse...
16
5
• Recently completed study of microbiome and
colorectal cancer
- published in Journal of National Cancer Institute
• ...
16
6
Gut microbiome and CRC
• Gut microbiome plays key roles in inflammation and in the
breakdown of otherwise indigestibl...
16
7
• Hospital based case-control study
- 47 CRC cases and 94 non-cancer controls
- recruited 3 hospitals in Washington D...
16
8
Microbiome Assay and Data Analysis
- Compared overall gut microbiome diversity and microbial taxa
abundances in CRC c...
16
9
Inter-individual variability of gut microbiome
Ahn et al, JNCI, 2013
20 different health subjects
17
0
Gut microbiome diversity in CRC and controls
500 1000 1500 2000 2500 3000
6
7
8
9
Shannon Index in Colorectal Cancer ...
17
1
Taxonomic differences in CRC and controls
Case
Cont
Ahn et al, JNCI, 2013
17
2
Fusobacterium increases CRC risk
• Multivariate OR=3.74, p=0.0035.
• Fusobacterium is gram negative
inflammatory bact...
17
3
Clostridia decreases in CRC patients
• Clostridia depleted in CRC cases
(Multivariate OR = 0.8, P=0.005).
• Clostridi...
17
4
High fiber intake decreases CRC risk
0.6
0.7
0.8
0.9
1
1.1
CRC Risk
<15 g/day, 15-20 g/day, 20-24 g/day, 24-30 g/day ...
17
5
Low Fiber Intake
High fiber intake and high clostridia
High Fiber Intake
High fiber intake - for high vs. low Clostri...
17
6
Summary
• CRC risk was associated
- with decreased gut microbiome diversity;
- increased presence of Fusobacterium;
-...
17
7
NYU Human Microbiome Cohort:
Human Microbiome and Colorectal Tumor (HMAC) Study
(supported by Dept. Population Health...
17
8
Implications
• Learn about the causes of CRC.
• Identifying people at high risk for CRC.
• Possible prevention of CRC...
17
9
Research Team
• NYU: Richard Hayes, Mitchell Bernstein, George Miller, Zhiheng Pei
• My group: Christine Domminiani, ...
18
0
Each body site
has a different
and unique
microbiome
HMP data
18
1
Shared common structure of human microbiome
Catonella
Dialister
Eubacterium
Filifactor
Gemella
Granulicatella
Megasph...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Thomas K Weber, MD FACS
Professor of Surgery
Stat...
Incidence trends by age: 50+ versus 20-49
Source: SEER 9 registries, 1975-2011; 2-yr moving average.
0
2
4
6
8
10
12
14
19...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• We have a major cancer control /
epidemiologic ...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• “A study of initial presentation of young
onset...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• For almost a quarter of a century our
collectiv...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• However…………..
• At least 75% of EAO-CRC patient...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• So…………..
• We are facing a new problem…
• A Fre...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• I have no links whatsoever to this man…
However
NO RELATION!
HOWEVER……
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• A Potentially Useful Construct:
• “Th...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Known Knowns……The Basics
• Health Insurance: what...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Known Knowns……The Basics
• A POSITIVE family hist...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
in YOUNG ...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especiall...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especiall...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especiall...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
What DO we know about the
Unknown Knowns……?
• Any...
COloRECtal Transdisciplinary Study NCI
GAME-ON Consortium
• •Global study n= 52,649
• •OncoArray consortium n= 45,000
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Measuring the Exposome
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especiall...
GWAS, SNPS,THE “EXPOSOME” and
Colorectal Cancer
• GWAS SNP studies have been…..disappointing
• If 21,000 is “underpowered”...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• “But there are also unknown unknowns.
There are...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• “But there are also unknown unknowns.
There are...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• How Can We Move Forward?
• No Health Insurance
• No Primary Physician
• INEFFECTIVE PRIMARY CARE & OTHER
PHYSICIANS
• Positive Family History
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Evidenced Based Score Card
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especiall...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
Unknown Knowns……What is the true risk –
especiall...
Evidenced Based Score Card
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• “There are also unknown unknowns.
There are thi...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• “There are also unknown unknowns.
There are thi...
Incidence trends by race/ethnicity, ages 20-49 years
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Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
And How Do We Advance Knowledge About
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Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
And How Do We Advance Knowledge About
Young Adult...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
And How Do We Advance Knowledge About
Young Adult...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
One Thing We All SHOULD Know:
• If you are sympto...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
SUMMARY?
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
“You Never Know…”
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• We know a great deal
• There are clear opportun...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• Known RISK FACTORS need to be
validated in YOUN...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
RISK
• Identification
• Clarification
• Mitigatio...
Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
THANK YOU!
Martha Raymond, MA, CPN
Early Age Onset Colorectal Cancer Summit
March 21, 2015
Memorial Sloan Kettering Cancer Center
New...
Quality of Life After an EAO-CRC
Diagnosis:
Knowledge Gaps and
Opportunities
Susan K. Peterson, PhD, MPH
Professor, Behavi...
Cancer Survivorship
• Cancer survivorship = the state or process
of living after a diagnosis of cancer
• Encompasses not o...
Measuring Quality of Life
• Physical functioning
• Health status
• Sexuality and fertility
• Emotional adjustment
• Psycho...
• Establish autonomy and independence
– Achieve emotional independence from adults
– Self-esteem and identity development
...
The Impact of an Illness
• Changes in mobility and physical functioning
• Changes in physical appearance
• Separation from...
Research on Quality of Life (QOL)
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Young Adult Cancer Survivors
N=523 young survivors, age 15-39
• Compared to peers, YCS had lower physical and
social functioning; psychosocial, emotion...
N=8375 survivors, diagnosed age 15-39
• Compared to peers, 30% of those age 40-64 report
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• About half or fewer may achieve
recommended levels of physical activity (PA)
(ages 20-44)
• About half may be overweight...
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• Psychological and Spiritual
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Cancer Can Promote Psychological
Growth: Resilience Concept
• Some people can transform their lives by
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• Racial/ethnic minority and medically underserved cancer
survivors have greater disparities in cancer outcomes
and access...
Including “Previvors” in the Discussion
About EAO-CRC
• Previvors = at increased risk of hereditary CRC, no CRC diagnosis
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72% seek health information online
-Used phone: 31% cell phone, 52%
smartphone
- 19% smartphone owners
download Pew Intern...
Computer and mobile technology use in the U.S.
Pew Internet Research Project, 2014
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• In general, young adult cancer survivors not well-
represented in QOL studies of survivors
– Especially EAO-CRC
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• Subgroups of young adult cancer survivors
have specific needs
– Those diagnosed at youngest ages
– Underserved
– Fertili...
• Health care system may not be responsive to needs
of EAO-CRC
– Cancer treatment settings may reflect pediatric vs. older...
National Cancer Institute, National Institutes of Health, 1R42 CA126453,
1R41-CA126453-01
Seed Money Grant, Duncan Family ...
*
• Cancer survivorship = the state or process
of living after a diagnosis of cancer
• Encompasses not only the physical b...
*
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• Changes in mobility and physical functioning
• Changes in physical appearance
• Separation from peers and usual activi...
Research on Quality of Life (QOL)
in
Young Adult Cancer Survivors
N=523 young survivors, age 15-39
• Compared to peers, YCS had lower physical and
social functioning; psychosocial, emotion...
N=8375 survivors, diagnosed age 15-39
• Compared to peers, 30% of those age 40-64 report
poor/fair health vs. controls
• >...
• About half or fewer may achieve
recommended levels of physical activity (PA)
(ages 20-44)
• About half may be overweight...
20
32
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– Dissatisfaction with initial diagnosis delay
• Patient fac...
• Practical
– Financial
• Inadequate or gaps in health insurance
• Difficulty navigating health insurance coverage
• Work ...
• Psychological and Spiritual
– Managing distress & emotions related to cancer,
treatment, and fear of recurrence
– Social...
*
• Some people can transform their lives by
responding to an illness in ways that
enhance the quality and meaning of thei...
• Racial/ethnic minority and medically underserved cancer
survivors have greater disparities in cancer outcomes
and access...
*
• Previvors = at increased risk of hereditary CRC, no CRC diagnosis
• Bowel function and QOL in children with FAP who un...
72% seek health information online
-Used phone: 31% cell phone, 52%
smartphone
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download Pew Intern...
* Computer and mobile technology
use in the U.S.
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2014
Clauser,
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Early age onset_colorectal_cancer_2015

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The Early Age Onset (EAO) Colorectal Cancer (CRC) Summit was a novel meeting designed for Early Age Onset (EAO) colorectal cancer (CRC) survivors, affected families as well as physicians and scientists who were interested in advancing their understanding of the rapidly increasing incidence of rectal and colon cancer among young adults under 50 years of age.

Co-hosted by the Colon Cancer Challenge Foundation and the CME office of Memorial Sloan Kettering Cancer Center the program provided an opportunity to hear leading clinicians and scientists on the epidemiology, pathogenesis, genomics and lifestyle challenges of EAO-CRC.

The course also included lectures as well as workshops and panel discussions designed to facilitate multidisciplinary consensus regarding the priorities of EAO-CRC prevention, clinical care and research moving forward.

Published in: Healthcare
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Early age onset_colorectal_cancer_2015

  1. 1. Increase in incidence of colorectal cancer among young adults in the US Rebecca Siegel, MPH Surveillance & Health Services Research Program March 21, 2015
  2. 2. Among <50 years: 13,000 cases and 3,000 deaths Estimated numbers of new cases & deaths in 2015
  3. 3. Top 5 cancers, ages 20-49 years Lung (18%) Colorectum (12%) Brain (8%) Leukemia (7%) Pancreas (5%) Breast (26%) Lung (15%) Colorectum (8%) Cervix uteri (7%) Ovary (5%) Colorectum (10%) Testis (9%) Prostate (9%) Melanoma (8%) NHL (7%) Incidence Mortality Breast (36%) Thyroid (12%) Melanoma (7%) Colorectum (5%) Cervix uteri (5%) Men Women Men Women
  4. 4. Anatomy of the colorectum (right-sided colon) (left-sided colon)
  5. 5. Subsite distribution by age at diagnosis 0-49 years 50+ years Proximal 25% 43% Distal 27% 23% Rectum 41% 28% Other 8% 6% Right side Left side
  6. 6. 0 50 100 150 200 250 300 350 400 Age-specificincidencerateper100,000 Age at diagnosis Men Women Source: SEER 18 registries, 2007-2011. Age-specific incidence rates by sex 90% of cases 20-49 years: 11 per 100,000 vs. 50+ years: 140 per 100,000
  7. 7. 0 10 20 30 40 50 60 70 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 Rateper100,000 Year of diagnosis Colorectum, 3% per year Colon, 3% per year Rectum, 2% per year Incidence trends overall, 1975-2011 Source: SEER 9 registries, 1975-2011. Declines during 2002-2011:
  8. 8. The American Surgeon, Oct 2003 SEER 9, 5,383 patients 20-39 yrs 1973-1999 Cancer Epidemiol, Biomarkers, & Prevention, June 2009 SEER 13, 20,646 patients 20-49 yrs 1992-2005 The American Surgeon, Sept 1998 LSU Medical Ctr, 37 patients < 40 1976-1997 Awareness of the increase in early-onset disease
  9. 9. Incidence trends by age: 50+ versus 20-49 Source: SEER 9 registries, 1975-2011; 2-yr moving average. 0 2 4 6 8 10 12 14 1975- 76 1980- 81 1985- 86 1990- 91 1995- 96 2000- 01 2005- 06 2010- 11 Rateper100,000 Men Women 45% 2% per year Since 1993-1994 0 50 100 150 200 250 300 1975- 76 1980- 81 1985- 86 1990- 91 1995- 96 2000- 01 2005- 06 2010- 11 Rateper100,000 Men Women Ages 50+ Ages 20-49
  10. 10. Trends by anatomic subsite in ages 20-49 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11 Rateper100,000 2.6 in 1991 4.9 in 2011 Source: SEER 9 registries, 1975-2011; 2-yr moving average. Proximal colon Rectum Distal colon
  11. 11. Incidence trends by stage at diagnosis, ages 20-49 years Source: SEER 9 registries, 1975-2011; 2-year moving average. 0 0.5 1 1.5 2 2.5 3 1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11 Colon Localized Regional Distant 0 0.5 1 1.5 2 2.5 3 1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11 Rectum Localized Regional Distant Rateper100,000 3.6% per year from 2002-2011 2.9% per year from 2002-2011
  12. 12. Trends by histologic subtype, 20-49 years Mucinous Signet-ring cell Adenocarcinoma, NOS Source: SEER 9 registries and Joinpoint Regression Program.
  13. 13. Incidence trends by 10-year age group 40-49 2% per year 30-39 2% per year 20-29 3% per year 0 5 10 15 20 25 30 1975- 76 1980- 81 1985- 86 1990- 91 1995- 96 2000- 01 2005- 06 2010- 11 Rateper100,000people 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 20-29 years Source: SEER 9 registries, 1975-2011; 2-year moving average. 20-29 years 5% 30-39 years 20% 40-49 years 75% Increase during 2002-2011:
  14. 14. Incidence trends in ages 50-59 years 0 5 10 15 20 25 30 35 40 1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11 Rectum 55-59 50-54 0 10 20 30 40 50 60 70 80 1975-76 1980-81 1985-86 1990-91 1995-96 2000-01 2005-06 2010-11 Rateper100,000 Colon 50-54 55-59 Source: SEER 9 registries, 1975-2011; 2-yr moving average. 2.4% per year since 1996
  15. 15. Incidence trends by race/ethnicity, ages 20-49 years 0 2 4 6 8 10 12 14 Non-Hispanic white Colon and Rectum Colon Rectum 0 2 4 6 8 10 12 14 1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09 2010-11 Non-Hispanic black 0 2 4 6 8 10 12 14 1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09 2010-11 Asian/Pacific Islanders 0 2 4 6 8 10 12 14 1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09 2010-11 Hispanic Colorectal Colon Rectum Non-Hispanic white 2.3 1.6 3.4 Hispanic 2.1 2.0 2.2 Asian/Pac Islander 0.7 0.8 stable Non-Hispanic black stable stable 1.9 Average annual % increase from 2002-2011: Source: SEER 13 registries, 1992-2011; 2-year moving average. AAPCs based on Joinpoint Regression Program.
  16. 16. Stage distribution: early vs. later onset 33% 38% 25% 3% 41% 34% 19% 6% 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% Localized Regional Distant Unknown 20-49 years 50+ years Source: SEER 18 registries, 2007-2011.
  17. 17. Five-year relative survival Data Source: Trends, SEER 9 registries; Stage-specific, SEER 18 registries, 2007-2011. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 55% 68% Trend 94 76 19 90 70 12 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Localized Regional Distant 20-49 years 50+ years By stage
  18. 18. Mortality trends in ages 20-49 years 0 0.5 1 1.5 2 2.5 3 3.5 4 Deathsper100,000 20-49 years Source: National Center for Health Statistics, National Vital Statistics System. 0 20 40 60 80 100 120 50+ years
  19. 19. Factors that influence population cancer trends Detection/imaging practices Risk factors Screening behaviors MortalityIncidence Treatment Increase in: Incidence Mortality Risk factor ↑ ↑ Screening ↑ ↓ Detection/imaging practice ↑ Possible artifactual ↑ Effective treatment No effect ↓
  20. 20. Colorectal cancer risk factors: medical and family history Relative risk Family history 1 first-degree relative 2.2 More than 1 relative 4.0 Relative with diagnosis before age 45 3.9 Medical history Inflammatory bowel disease Crohn disease 2.6 Ulcerative colitis Colon 2.8 Rectum 1.9 Diabetes 1.2
  21. 21. Increase risk: Relative risk Trend Alcohol consumption (heavy vs. nondrinkers) 1.6 Obesity 1.2 Red meat consumption 1.2 Processed meat consumption 1.2 ? Smoking (current vs. never) 1.2 Colorectal cancer risk factors: behavioral Decrease risk: Relative risk Trend Physical activity (colon) 0.7 Milk/total dairy consumption 0.8 Fruit consumption 0.9 ? Vegetable consumption 0.9 ? Total dietary fiber (10 g/day) 0.9 ?
  22. 22. Trends in obesity and diabetes 0 5 10 15 20 25 1971-74 1976-80 1988-94 1999-02 2003-06 2007-08 2009-10 2011-12 Percent Ages 6-11 Ages 12-19 6% Obesity prevalence 6 16 0 2 4 6 8 10 12 14 16 18 20 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 Rateper1,000 167% Diabetes, ages 0-44 years 21% Source: National Health and Nutrition Examination Survey. Source: National Health Interview Survey.
  23. 23. Obesity and colorectal cancer: pooled relative risk Ning et al. A quantitative analysis of body mass index and colorectal cancer: findings from 56 observational studies. Obesity Reviews 2010. Relative risk (95% CI) BMI <23.0 BMI > 30 Subsite Colon 1.0 1.49 (1.35, 1.63) Rectum 1.0 1.26 (1.17, 1.37) Sex Men 1.0 1.53 (1.44, 1.62) Women 1.0 1.25 (1.14,
  24. 24. Lifestyle changes
  25. 25. Changes in dietary patterns
  26. 26. Trends in beverage consumption Nielsen et al. Changes in beverage intake between 1977 and 2001. Am J Prev Med 2004. 0 2 4 6 8 10 12 14 2-18 yrs 19-39 yrs 2-18 yrs 19-39 yrs Sweetened beverages Milk Percentoftotaldailycalorieintake 1977-78 1989-91 1994-96 1999-01
  27. 27. State patterns in obesity and CRC incidence rates Obesity prevalence, ages 18-49, 2001 CRC incidence rates, ages 20-49, 2007-2011 Pearson’s r = 0.57 Source: Behavioral and Risk Factors Surveillance System Source: US Cancer Statistics, WONDER Online Database
  28. 28. Most colorectal cancers are due to unknown risk factors Source: The Cancer Atlas, 2nd Edition Up to 87% of colorectal cancers worldwide are due to unknown risk factors.
  29. 29. Strategies for reducing colorectal cancer risk  Maintain a healthy weight  Be physically active  Consume a healthy diet  Limit alcohol consumption  Consume recommended levels of calcium  Avoid tobacco products  Screening at 50, OR earlier with a family history of adenomas or CRC
  30. 30. Who should begin screening before 50? High risk Age to begin Familial adenomatous polyposis (FAP) 10-12 years Lynch syndrome 20-25 years* Inflammatory bowel disease (ulcerative colitis or Crohn disease) Varies depending on age at onset *Or 10 years before youngest case in immediate family
  31. 31. Who else should begin screening before 50? Increased risk Age to begin Cancer/adenomas in a first-degree relative 40 years OR 10 years before youngest case Cancer in > 2 second-degree relatives 40 years
  32. 32. Conclusions • CRC incidence rates continue to increase in young adults • Know when to begin screening based on your family history • Increase awareness to hasten follow-up of symptomatic young adults 1. Rectal bleeding 2. Abdominal pain 3. Change in bowel habits • Critical need for further research to elucidate the cause of this trend
  33. 33. Acknowledgements • Kim Miller, MPH • Ann Goding-Sauer, MPH • Stacey Fedewa, MPH
  34. 34. Thank you!
  35. 35. American Cancer Society CRC screening guidelines • Increase unestablished during previous evidence review • In beginning stages of guideline review; independent, systematic review of the literature, including harms & benefits of screening • Current evidence may justify earlier screening • Benefits must outweigh harms at the population level  rare before 50 (0.3%)  3 serious adverse events (perforation, adverse reaction to sedation) per 1,000 colonoscopies  cost
  36. 36. Percentage of individuals who develop CRC by specific age 0.00% 0.50% 1.00% 1.50% 2.00% 2.50% 3.00% 3.50% 4.00% 4.50% 5.00% 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 95+ Age (years)
  37. 37. Harms & limitations of colonoscopy screening • 33% of patients report at least 1 GI symptom following the procedure • Serious adverse event rate: 2.8 per 1,000 • Adverse reaction to the sedative • Bleeding if a polyp or tissue sample is taken • Perforation of the colon wall • Screening won’t detect all cancers
  38. 38. 35-39 30-34 25-29 20-24
  39. 39. 0 2 4 6 8 10 12 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 20-49 Canada_20_49 UK_20_49 0 20 40 60 80 100 120 140 160 180 200 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 50-85+ Canada_50plus UK_50plus Incidence trends in Canada and the UK by age, through 2007
  40. 40. Screening test use in ages 40-49 years 0 2 4 6 8 10 12 14 2000 2003 2005 2008 2010 2013 Ever routine endoscopy 0 2 4 6 8 10 12 14 2000 2003 2005 2008 2010 2013 Ever diagnostic endoscopy Source: NHIS
  41. 41. US meat consumption per person, 1909-2012
  42. 42. Defining Body Mass Index (BMI) Weight (kg) Height (m)2 BMI = For children & adolescents, obesity is defined as a BMI > the 95th percentile based on age/sex-specific growth charts developed by CDC
  43. 43. 40-49 30-39 20-29 Incidence trends by age group and subsite 0 2 4 6 8 10 12 14 16 1975-76 1977-78 1979-80 1981-82 1983-84 1985-86 1987-88 1989-90 1991-92 1993-94 1995-96 1997-98 1999-00 2001-02 2003-04 2005-06 2007-08 2009-10 Colon 0 2 4 6 8 10 12 14 16 1975-76 1977-78 1979-80 1981-82 1983-84 1985-86 1987-88 1989-90 1991-92 1993-94 1995-96 1997-98 1999-00 2001-02 2003-04 2005-06 2007-08 2009-10 Rectum Source: SEER 9 registries, 1975-2011; 2-year moving average. Rateper100,000 40-49 3% per year 2% per year 20-29 30-39
  44. 44. State variation in incidence rates by age 50+ years20-49 years
  45. 45. What is a colon adenomatous polyp? Polyps begin in the cells of glandular structures lining the colon. Most polyps are benign, but one kind is the cause of greater concern–the colon adenomatous polyp (adenoma). This growth is associated with DNA changes in the lining of the colon. Polyps can become cancerous if undetected or ignored.
  46. 46. The growth and stages of CRC
  47. 47. ACS screening guidelines – average risk Men and women, ages 50+ Frequency Fecal occult blood test (FOBT) with at least 50% test sensitivity for cancer, or fecal immunochemical test (FIT) with at least 50% test sensitivity for cancer Annual Stool DNA test Every 3 years Flexible sigmoidoscopy Every 5 years Double contrast barium enema Every 5 years Colonoscopy Every 10 years CT colonography Every 5 years
  48. 48. Trends in the use of screening tests (ages 50-75) 0 10 20 30 40 50 60 70 80 2000 2003 2005 2008 2010 2013 Percentage Any exam Colonoscopy (10 yrs) FOBT (past year) Sigmoidoscopy (5 yrs)
  49. 49. Changes in dietary patterns Then…
  50. 50. THE CLINICAL CHALLENGES OF EAO- CRC : REDUCING LATE STAGE DIAGNOSIS; IMPROVING SURVIVAL Y. Nancy You, MD, MHsc Assistant Professor Department Of Surgical Oncology Medical Director Familial High-risk Gastrointestinal Cancer Clinic University Of Texas MD Anderson Cancer Center March 21, 2015
  51. 51. • Persistently increasing incidence • Majority between ages of 40-49 • Predominately located in distal colon and rectum • Advanced-stage disease at presentation CLINICAL CHALLENGES OF EAO-CRC UNIQUE FEATURES OF EAO-CRC: SUMMARY
  52. 52. 39 year-old dental hygienist Single mother; estranged family Grandmother, colon cancer in 60’s Intermittent rectal bleeding > 1 year ER visit x 3, no work-up CLINICAL CHALLENGES OF EAO-CRC AN ILLUSTRATION
  53. 53. COLORECTAL CANCER TRENDS 39 YEAR-OLD, STAGE IV RECTAL CANCER 5/year 0 Chemo 10-12/year0 Liver surgery #1 Liver surgery #2 Chemo + Radiation 5/year 1 11/year 1 Rectal surgery #1 Chemo Rectal surgery #2; Liver surgery #3 8/year 3 – 3/year 4 Chemo Chemo Hospice 2/year 2
  54. 54. CLINICAL CHALLENGES OF EAO-CRC OUTLINE • What are the clinical challenges ? • How can we improve ?
  55. 55. CLINICAL CHALLENGES OF EAO-CRC WHAT ARE THE CHALLENGES  Interrupts adulthood  Stresses support network  Hereditary? Genetic?  Delay in self referral  Variable access to care  Late-stage at diagnosis 39 year-old dental hygienist Single mother; estranged family Grandmother, colon cancer in 60’s Intermittent rectal bleeding > 1 year ER visit x 3, no work-up
  56. 56. CLINICAL CHALLENGES OF EAO-CRC WHAT ARE THE CHALLENGES  Multiple treatments  Many modalities  Long time  Treatment-related toxicities/adverse effects  Variable survival outcome  Quality of survival 5/year 0 Chemo 10-12/year0 Liver surgery #1 Liver surgery #2 Chemo + Radiation 5/year 1 11/year 1 Rectal surgery #1 Chemo Rectal surgery #2; Liver surgery #3 8/year 3 – 3/year 4 Chemo Chemo Hospice 2/year 2
  57. 57. CLINICAL CHALLENGES OF EAO-CRC OUTLINE • What are the clinical challenges ? • Focusing on Survival • How can we improve ?
  58. 58. Bleyer et al. Nature Reviews Oncology. 2007. CLINICAL CHALLENGES OF EAO-CRC SURVIVAL : SEER 1993-1998
  59. 59. CLINICAL CHALLENGES OF EAO-CRC OUTLINE • What are the clinical challenges ? Focusing on Survival • What influences survival and how can we improve ?  Stage of disease  Treatment  Quality of life
  60. 60. You et al. Arch Int Med. CLINICAL CHALLENGES OF EAO-CRC NCDB, 1998-2007 Age 18-49 Years (N=64,068) vs. Age 50+ Years (N=524,801)
  61. 61. Age-adjusted CRC death rate has declined between 1975-2005 Factors thought to contribute to the decline in death rate: CLINICAL CHALLENGES OF EAO-CRC AGE-ADJUSTED DEATH RATE: DECLINED 1975-2005
  62. 62. All CRC ~ 5% “Hereditary” Burt et al. Gastroenterology 2000. CLINICAL CHALLENGES OF EAO-CRC SUBGROUPS OF CRC & SCREENING GUIDELINES 3-5%
  63. 63. All CRC ~ 5% “Hereditary” CLINICAL CHALLENGES OF EAO-CRC SUBGROUPS OF CRC & SCREENING GUIDELINES Start Frequency High Risk (“Heredita ry”) Hereditary syndromes; Inflammatory bowel syndrome etc Teen-25; 8 years of disease Every 1-2 years Increased Risk (“Familial ”) Family history; Prior polyp or cancer Age 40, or 10 years before the youngest case in the immediate family, Every 3-5 years Average Risk (“Sporadi Age 50 Every 7-10 years American Cancer Society
  64. 64. You et al. ASCRS Annual Meeting 2013. • 223 CRC patients aged 18-50 • Stratify by Tumor mismatch repair (MMR) status & Family history CLINICAL CHALLENGES OF EAO-CRC APPLYING TO EAO-CRC SUBGROUPS
  65. 65. All CRC ~ 5% “Hereditary” CLINICAL CHALLENGES OF EAO-CRC SUBGROUPS OF CRC & SCREENING GUIDELINES Goal High Risk (“Hereditary”) Defined and effective prevention, surveillance strategies exist Make the diagnosis • Clinical suspicion • Proband and family diagnosis /Registry
  66. 66. 70
  67. 67. Ampullary, Pancreas, Hepatoblastoma Colon and Rectum Familial Adenomatous Polyposis Surveillance Thyroid Brain Desmoid / Why Hereditary Syndrome Should Not Be Missed
  68. 68. Biliary, Pancreas Colon and Rectum Lynch Syndrome Surveillance UrinaryTract Brain Skin Uterine & Ovary Why Hereditary Syndrome Should Not Be Missed
  69. 69. All CRC ~ 5% “Hereditary” CLINICAL CHALLENGES OF EAO-CRC SUBGROUPS OF CRC & SCREENING GUIDELINES Goal High Risk (“Hereditary”) Defined and effective prevention, surveillance strategies exist Make the diagnosis • Clinical suspicion • Proband and family diagnosis /Registry Increased Risk (“Familial”) Guidelines for screening younger than age 50 exist Know family history Engage in screening Average Risk (“Sporadic”) Symptom to diagnosis time
  70. 70. CLINICAL CHALLENGES OF EAO-CRC OUTLINE • What are the clinical challenges ? • What influences survival and how can we improve ?  Stage of disease  Treatment  Quality of life
  71. 71. THE IMPACT OF YOUNG AGE ON SURVIVAL IN PATIENTS WITH METASTATIC COLORECTAL CANCER: ANALYSIS FROM THE ARCAD CLINICAL TRIALS PROGRAM CHRISTOPHER H. LIEU, LINDSAY RENFRO, AIMERY DE GRAMONT, TIMOTHY S. MAUGHAN, MATTHEW T. SEYMOUR, LEONARD SALTZ, RICHARD M. GOLDBERG, DAN SARGENT, S. GAIL ECKHARDT, CATHY ENG 75 Courtesy of Dr Cathy Eng CLINICAL CHALLENGES OF EAO-CRC SAME TREATMENT, WORSE OUTCOME ? Lieu et al. JCO 2014
  72. 72. Overall Survival Age in Years RelativeHazard 1.0 1.2 1.4 1.6 1.8 20 40 60 80 p < 0.0001 Progression-Free Survival Age in Years RelativeHazard 1.0 1.1 1.2 1.3 1.4 20 40 60 80 20,000 patients enrolled to 22 first-line phase III trials ARCAD Foundation Colorectal Database OS 1-year: 28% increased risk of death (REF: age 57) p < 0.0001 PFS 1-year: 28% increased risk of progression (REF: age 61) Lieu et al. JCO 2014
  73. 73. You et al. In Press JAMA Surgery NCDB, 2003 to 2005 OR for Chemo (95% CI) OR for Multi- agent regimen (95% CI) 5-year Adjusted Relative Survival (No chemo) 5-year Adjusted Relative Survival (Chemo) Stage I Aged 65-75 (n=8,991) 1 1 96.8 -- Aged18-49 (n=1,926) 2.88 (2.21-3.77) 1.38 (0.71-2.68) 98.4 -- Stage II low risk Aged 65-75 (n=4822) 1 1 89.2 95.4 Aged18-49 (n=1636) 4.22 (3.70-4.81) 1.67 (1.34-2.09) 93.3 95.2 CLINICAL CHALLENGES OF EAO-CRC OVER-TREATMENT, NO BETTER OUTCOME ?
  74. 74. NCDB, 2003 to 2005 OR for Chemo (95% CI) OR for Multi- agent regimen (95% CI) 5-year Adjusted Relative Survival (No chemo) 5-year Adjusted Relative Survival (Chemo) Stage II high risk Aged 65-75 (n=6189) 1 1 74.6 85.8 Aged18-49 (n=1447) 3.69 (3.23-4.20) 1.77 (1.46-2.14) 78.9 87.7 Stage III Aged 65-75 (n=11202) 1 1 39.1 71.0 Aged18-49 (n=4780) 2.42 (2.18-2.68) 1.75 (1.58-1.93) 54.7 0.64(0.57-0.71) 73.7 0.84(0.79-0.9) CLINICAL CHALLENGES OF EAO-CRC OVER-TREATMENT, NO BETTER OUTCOME ? You et al. In Press JAMA Surgery
  75. 75. CLINICAL CHALLENGES OF EAO-CRC OUTLINE • What are the clinical challenges ? • What influences survival and how can we improve ?  Stage of disease  Treatment  Quality of life
  76. 76. 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% Benefits Positive feelings Family distress Recurrence distress Appearance concerns Financial problems Sexual dysfunction Sexual disinterest Social avoidance Fatigue Physical pain Cognitive problems Negative feelings QUALITY OF LIFE IN ADULT CANCER SURVIVORS (QLACS) % of Scores ≥ 4 per Domain YS LS • 830 (68%) survivors responded • 282 Young-onset (43.4 ± 6.1 years) • 548 Later-onset (62.6 ± 7.5 years) • Mean years from diagnosis: 10.8 years* * * * * * * *
  77. 77. EORTC CR-29 (SCORE > 3) *P<0.05 34.2 19.5 57.3 23.0 20.5 13.4 40.2 16.4 0 10 20 30 40 50 60 70 * Anxiety * Body image * Male sexual function * Female sexual function Percent of Respondents Reporting Score > 3 Young-Onset Survivors Late-Onset Survivors CLINICAL CHALLENGES OF EAO-CRC FUNCTIONAL OUTCOMES & CANCER SURVIVORSHIP
  78. 78. CLINICAL CHALLENGES OF EAO-CRC SUMMARY • Key challenge : improve survival • Factors that influence survival Stage of disease :  Reduce late-stage diagnosis Treatment :  Optimize benefit (response) vs. risk (toxicity) Quality of life :  Maximize quality
  79. 79. THANK YOU ynyou@mdanderson.org THE CLINICAL CHALLENGES OF EAO-CRC : REDUCING LATE STAGE DIAGNOSIS; IMPROVING SURVIVAL
  80. 80. Hereditary Colorectal Cancer Syndromes and the Contribution to Early Age Onset Colorectal Cancer Fay Kastrinos MD, MPH Columbia University Medical Center Herbert Irving Comprehensive Cancer Center Hereditary GI Cancer Risk and Prevention Program, Director
  81. 81. Sporadic (~75%) Familial colorectal cancer (~20%) Inherited colorectal cancer syndromes (~5%) Epidemiology of Colorectal Cancer
  82. 82. Hereditary Colorectal Cancer Syndromes • Lynch Syndrome/ Hereditary Nonpolyposis Colorectal Cancer (HNPCC) • Familial Adenomatous Polyposis (FAP) • MYH Associated Polyposis (MAP) • Hamartomatous Polyposis Syndromes
  83. 83. Genes Associated with a High Risk of Colorectal Cancer Gene Syndrome Hereditary Pattern Predominant Cancer Tumor suppressor genes APC FAP/ Attenuated polyposis Dominant Colon, intestine, etc. STK11 Peutz-Jeghers Dominant Multiple (including intestine) PTEN Cowden Dominant Multiple (including intestine) BMPR1A Juvenile polyposis Dominant Gastrointestinal SMAD4 (DPC4) Juvenile polyposis Dominant Gastrointestinal Repair/Stability genes hMLH1, hMSH2, hMSH6, PMS2 Lynch Dominant Multiple (including colon, uterus, and others) MYH (MutYH) Attenuated polyposis Recessive Colon
  84. 84. How common is CRC in adults younger than 50? • ~10% of CRCs arise in men and women <50 yrs 140,000 new cases, 2014 • Incidence in US is 7 per 100,000 people/year (<50) vs 130 per 100,000 people/year (≥50) 14,000 10% <50 years
  85. 85. How common are inherited CRC syndromes in EAO-CRC? • ~10% of EAO-CRC is attributed to known inherited CRC syndromes – 14,000 ~1,400 total cases • Likely underestimated – This has not been comprehensively studied • What about the pool of “at-risk” individuals? 10%
  86. 86. Lynch Syndrome  Most prevalent hereditary CRC syndrome  5% of all CRC  Defective DNA Mismatch Repair  Mutations in MLH1, MSH2, MSH6, PMS2  Lifetime risk of CRC ~60%; endometrial cancer ~40- 60%  Risk is markedly lower if colonoscopies begin early
  87. 87. Lynch Syndrome Results From Failure of Mismatch Repair (MMR) Genes Base pair mismatch Normal DNA repair Defective DNA repair (MMR+) T CTA C A G C T G T C G A C A G C T G T CTA C A G C T G A G A T G T C T A C
  88. 88. Mismatch Repair Failure Leads to Microsatellite Instability (MSI) Normal Microsatellite instability Addition of nucleotide repeats
  89. 89. Lynch Syndrome Clinical Features  Striking family history affecting multiple generations  Early (but variable) age at CRC diagnosis (mean 45 years)  Multiple primary cancers  Extracolonic cancers:  Endometrium  Ovary  Urinary tract  Stomach  small bowel  sebaceous carcinomas of skin
  90. 90. Lynch Syndrome • Sine qua non is identification of a germline mutation • Families originally identified based on Amsterdam Criteria (AC-I) • ≥ 3 cases of CRC • ≥ 2 generations affected • at least one CRC< 50 years • no evidence of FAP • 50% of AC-I families do not have a MMR mutation • Testing only those who meet AC fails to detect 50%
  91. 91. Clinical Criteria for the Identification of Lynch Syndrome • Revised Bethesda Guidelines – Incorporates MSI testing, extracolonic cancers – Cumbersome criteria to apply regularly which makes uptake low – Testing those who meet any of the Bethesda criteria would fail to detect 30% of gene mutations carriers
  92. 92. Lynch syndrome and EAO-CRC • Lynch syndrome accounts for 3-4% of ALL CRCs, regardless of ages • What % of EAO-CRC is due to Lynch syndrome? • Few studies have examined random samples of the prevalence among CRC patients <50 years
  93. 93. Lynch syndrome and EAO-CRC • US study examining the prevalence of Lynch syndrome – Unselected, population-based sample – Young-onset CRC cases diagnosed <50 years – Identified through the CCFR • Results: 195 eligible subjects – Mean age of diagnosis: 43 years – 5.6% (11/195) had MMR gene associated with Lynch syndrome Limburg PJ et al. Clin Gastroenterol Hepatol. 2011;9(6):497-502
  94. 94. Lynch syndrome and EAO-CRC • Spanish study examining the prevalence of Lynch syndrome – Unselected, population-based sample – Young-onset CRC cases diagnosed <50 years – Identified through 2 surgical centers in Spain • Results: 140 eligible subjects – Mean age of diagnosis: 44.1 years – 7.8 (11/140) had MMR gene associated with Lynch syndrome Giraldez MD et al. Clin Cancer Res. 2010; 16: 5402-5413.
  95. 95. Summary of Lynch syndrome and contribution on EAO-CRC • 3-4 % of all CRCs, regardless of age, are due to Lynch syndrome • 6-8% of EAO-CRC are due to Lynch syndrome • Largest impact for at-risk individuals – Early identification of mutation carriers prevents cancer
  96. 96. Hereditary GI Cancer Syndromes: How good are we at identifying families with germline mutations? Proband HEREDITARY GI CANCER SYNDROME Germline Testing Pedigree Clinical Criteria +/- tumor testing + ?
  97. 97. Hereditary GI cancer syndromes: What have we learned from clinical genetic testing? • Ability to define new conditions from existing ones • Familial Colorectal Cancer Type X • Identification of new gene mutations • MYH associated polyposis
  98. 98. Original Contribution. JAMA. 2005;293(16):1979-1985. Lower Cancer Incidence in Amsterdam-I Criteria Families Without Mismatch Repair Deficiency: Familial Colorectal Cancer Type X Noralane M. Lindor, MD; Kari Rabe, MS; Gloria M. Petersen, PhD; Robert Haile, PhD; Graham Casey, PhD; John Baron, MD; Steve Gallinger, MD; Bharati Bapat, PhD; Melyssa Aronson, MSc, CGC; John Hopper, PhD; Jeremy Jass, MD; Loic LeMarchand, MD, PhD; John Grove, PhD; John Potter, MD, PhD; Polly Newcomb, PhD; Jonathan P. Terdiman, MD; Peggy Conrad, MS; Gabriella Moslein, MD; Richard Goldberg, MD; Argyrios Ziogas, PhD; Hoda Anton-Culver, PhD; Mariza de Andrade, PhD; Kim Siegmund, PhD; Stephen N. Thibodeau, PhD; Lisa A. Boardman, MD; Daniela Seminara, PhD, MPH Ability to define new conditions from existing ones
  99. 99. • Families fulfill AC-I criteria – Suspected Lynch syndrome but no mutation • Lower CRC incidence than Lynch syndrome – SIR 2.3 (1.7-3.0) vs SIR 6.1 (5.2-7.2) • Incidence may be lower for other cancers • Families should not be described or counseled as having Lynch syndrome • Lynch Syndrome ≠ Familial CRC Type X Familial Colorectal Cancer Type X
  100. 100. • Genetic etiology is largely unknown – Has a monogenic component • likely caused by high-penetrance mutations – ?Polygenic component: Is there an interaction of multiple low-penetrance genetic variants • Clinical characteristics such as lower risk of CRC and fewer associated extracolonic cancers suggest this • More similar to sporadic CRC? • Represents a novel form of familial CRC and families are resource for research Familial Colorectal Cancer Type X
  101. 101. HOWEVER…. • Phenotype varies from “classic” to “attenuated” • 30% are de novo cases: no family history • Classic FAP easy to recognize • Penetrance for adenomas and cancer near 100% in APC+ gene mutation carriers Familial Adenomatous Polyposis
  102. 102. Variations of classic phenotypes are common: Attenuated FAP • Attenuated polyposis is a phenotypically distinct variant of FAP • Arises from mutations in proximal or distal portions of APC gene Characteristics • Mean age at CRC diagnosis: 54 years • Cumulative risk of CRC by the age of 80 yr is ~69% • Proximal>>distal colon polyps and 75% of tumors occur in the proximal colon *The prevalence of APC mutations is likely similar in EAO-CRC*
  103. 103. • Polyp phenotype more so “attenuated” • Autosomal recessive pattern of inheritance • Biallelic mutation carriers: 53 fold excess risk of CRC • Up to 80% increased risk of CRC in lifetime • Monoallelic mutation carriers: OR 1.15 • Mutational hotspots: –White, Northern Europeans : Y165C G382D –Indian/Pakistani: E466X MYH associated polyposis (MAP): A newer entity in inherited CRC risk account for 80% of all mutations Jenkins MA, et al. Cancer Epidemiol Biomarkers Prev 2006; 15:312-4 Win AK, et al. Fam Cancer 2011; 10:1-9
  104. 104. MYH associated polyposis • ~3% of EAO-CRC is due to MYH mutations – Compared to <1% of all CRC cases, regardless of age • ~30% of biallelic MYH carriers develop CRC without polyps – According to population-based studies • Recommendation that all early-onset CRC should be tested for MUTYH mutations Riegert-Johnson DL et al. Genet Test. 2007;11:361–365. Giraldez MD et al. Clin Cancer Res. 2010; 16: 5402-5413.
  105. 105. Germline Testing Proband HEREDITARY GI CANCER SYNDROME Pedigree Clinical Criteria +/- tumor testing + Stepwise Approach for Inherited CRC Syndromes • Requires recognition of cancer syndromes by providers –Diagnosis may be missed –Additional genes with other cancer syndromes increase CRC risk • Time consuming process, multiple decisions –Test and re-test –Complex decision-making for patients
  106. 106. Germline p53 Mutations and Early Age Onset Cancers • Li-Fraumeni syndrome – caused by p53 mutations • Lifetime risk of cancer is ~70-100% • Carriers develop early onset cancers – Leukemias, brain tumors, sarcomas, breast cancer, adenocortical cancers – Reports of gastric and CRC
  107. 107. • 457 patients with CRC ≤40 years old • 1.3% carried a p53 gene mutation – Comparable to the prevalence of APC gene mutations associated with FAP • None of the patients met clinical criteria for Li-Fraumeni Syndrome
  108. 108. Advances in Genetic Testing for Inherited CRC • Next Generation Sequencing (NGS) allows for simultaneous assessment of many cancer susceptibility genes with multi- gene panel testing: – Breast, colon, ovarian, pancreas…. • The role of NGS panel testing and its yield over traditional genetic testing strategies are unclear • Will change the conventional approach to genetic evaluation
  109. 109. Expanded Commercial Cancer Genetic Testing
  110. 110. 47% Uptake of NGS Panel Testing in EAO-CRC LaDuca H et al. Genet Med. 2014 Nov;16(11):830-7
  111. 111. NGS Panel Testing in EAO-CRC
  112. 112. Additional Results from NGS Panel Testing in EAO-CRC
  113. 113. Pilot study • To determine the frequency and clinical phenotype of patients undergoing genetic testing for Lynch syndrome using a 25- gene hereditary cancer panel • 343 non-consecutive subjects with banked blood samples • Validation study ongoing MLH1 APC BRCA1 PTEN RAD51C MSH2 MYH BRCA2 TP53 RAD51D MSH6 BMPR1A PALB2 CDH1 BRIP1 PMS2 SMAD4 CHEK2 CDKN2A BARD1 EPCAM STK11 ATM CDK4 NBN Yurgelun M et al. J Clin Oncol 32, 2014 (suppl 15s; abstr 1509)
  114. 114. Overall Panel Testing Results Total cohort 343 patients No mutation found 277 (81%) All mutation carriers 66 (19%) Lynch mutation 48 (14%) Any non-Lynch mutation 19 (6%) Non-Lynch CRC* mutation 3 BRCA1/2 mutation 10 Other† mutation 9 Rows not mutually exclusive due to 4 subjects having ≥1 pathogenic mutation * APC, biallelic MYH, BMPR1A † ATM, BARD1, BRIP1, CHEK2, NBN
  115. 115. Summary & Future Directions • 85 % of EAO-CRC are not explained by known inherited CRC syndromes • NGS Panel testing will redefine the contribution of known cancer- related genes in EAO-CRC • Continued research efforts are necessary in affected individuals and family members – Gene discovery – Screening and surveillance recommendations
  116. 116. Thank you! Fay Kastrinos, MD, MPH 212-305-1021
  117. 117. Kate McNamara, MD CCCF Research Scholar University of Toronto
  118. 118. CCCF Annual Research Scholar Award
  119. 119. Zane Cohen Center for Digestive Diseases Research Treatment Education Support Gastrointestinal Cancers Research Groups Familial Gastrointestinal Cancer Registry (FGICR) Ontario Pancreas Cancer Study (OPCS) Ontario Familial Colorectal Cancer Registry (OFCCR) Soft Tissue Sarcoma Research Program (STSRP) Diseases Lynch Syndrome (LS) Familial Adenomatous Polyposis (FAP) MYH - Associated Polyposis (MAP) Peutz-Jeghers Syndrome (PJS) Juvenile Polyposis (JP) Hereditary Hemorrhagic Telangiectasia (HHT) Hereditary Diffuse Gastric Cancer Syndrome (HDGC) Pancreatic Cancer
  120. 120. Genetics of Early Age Onset Colorectal Cancer (EAO-CRC)
  121. 121. age-standardized incidence rate per 100,000 43.7 age-standardized mortality rate per 100,000 15.9 estimated new cases in 2014 136,830 % of all new cancer cases 8.2% estimated deaths in 2014 50,310 % of all cancer deaths 8.6% CRC incidence and mortality in the US ● third leading cause of cancer incidence in both males and females ● second leading cause of cancer mortality in both males and females SEER 9 Incidence & U.S. Mortality 1975-2011, All Races, Both Sexes.
  122. 122. EAO-CRC incidence and mortality in the US ● approximately 10% of colorectal cancers have early-onset NEW CASES DEATHS Male Female Male Female Age (yrs) Count % Count % Count % Count % 0-49 7,270 10 6,250 10 1,840 7 1,450 6 50-64 22,890 32 16,570 25 6,780 26 4,590 19 65-79 27,950 39 23,050 35 10,100 38 7,710 32 80+ 13,720 19 19,130 29 7,550 29 10,290 43 Estimated Numbers of New Colorectal Cancer Cases and Deaths by Age and Sex, United States, 2014 Siegel, R., DeSantis, C. and Jemal, A. (2014), Colorectal cancer statistics, 2014. CA: A Cancer Journal for Clinicians, 64: 104–117. doi: 10.3322/caac.21220
  123. 123. CRC incidence and mortality in Canada ● incidence and mortality rates are higher in Canada than in the US ● second leading cause of cancer incidence and mortality in males ● third leading cause of cancer incidence and mortality in females age-standardized incidence rate per 100,000 48.9 age-standardized mortality rate per 100,000 17.9 estimated new cases in 2014 24,400 % of all new cancer cases 12.8% estimated deaths in 2014 9,300 % of all cancer deaths 11.5% Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2014. Toronto, ON: Canadian Cancer Society; 2014.
  124. 124. EAO-CRC incidence and mortality in Canada ● approximately 6% of colorectal cancers have early-onset NEW CASES DEATHS Male Female Male Female Age (yrs) Count % Count % Count % Count % 0-29 45 <1% 45 <1% 10 <1% 5 <1% 30-49 720 5 660 6 175 3.5 145 3.5 50-59 2,100 15 1,550 14 580 11.5 390 10 60-69 4,000 29.5 2,500 23 1,250 25 700 18 70-79 4,000 29.5 2,800 26 1,500 30 1,000 25.5 80+ 2,800 20.5 3,300 30.5 1,450 29 1,650 42 Estimated Numbers of New Colorectal Cancer Cases and Deaths by Age and Sex, Canada, 2011 Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2014. Toronto, ON: Canadian Cancer Society; 2014.
  125. 125. CRC incidence trends in the US ● CRC ASIR have been decreasing on average 3.1% per year since 2002 SEER 9 Incidence & U.S. Mortality 1975-2011, All Races, Both Sexes. Rates are Age-Adjusted.
  126. 126. CRC incidence is increasing in young adults Age (y) 1973 Incidence 1999 Incidence EAPC Colon 20-40 1.8 2.1 0.75** 60+ 179 204.4 0.26 Rectum 20-40 0.8 1.4 3.15** 60+ 86 72.1 -0.73** Race/ethnicity n APC All races M 10,913 1.5** F 9,733 1.6** Non-Hispanic White M 6,748 2.0** F 5,626 2.2** Non-Hispanic Black M 1,409 −0.2 F 1,456 −0.6 Hispanic M 1,307 2.7** F 1,250 1.1 Asian American/ Pacific Islander M 1,284 1.2 F 1,239 0.6 Subsite APC Rectum 2.6** Sigmoid 0.4 Descending colon -1.8** Colon excluding rectum -0.2 • O’Connell et al. Young adults 20-40y, SEER 1973-1999 • Meyer et al. Young adults <40y, SEER 1973-2005 • Seigel et al. Young adults 20-49y, SEER 1992-2005
  127. 127. CRC incidence trends among young non-hispanic white adults (20-49yrs) by age and anatomic subsite,1992 to 2005 Age n APC M 20-29 249 5.2* 30-39 1,419 3* 40-49 5,080 1.5* F 20-29 240 5.6* 30-39 1,125 2* 40-49 4,261 2.1* Subsite n APC M Proximal 2,054 0 Distal 1,609 1.5* Rectum 2,609 3.5* F Proximal 1,548 0.8 Distal 1,619 2.3* Rectum 2,065 2.9* CRC incidence is increasing in young adults Seigel et al. • O’Connell et al. Young adults 20-40y, SEER 1973-1999 • Meyer et al. Young adults <40y, SEER 1973-2005
  128. 128. CRC incidence and mortality trends in Canada ● CRC ASIR has been decreasing on average 0.8% per year in males, 2001-2010 ● CRC ASIR has been decreasing on average 0.6% per year in females, 2001-2010 Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2014. Toronto, ON: Canadian Cancer Society; 2014.
  129. 129. CRC incidence is increasing in young adults Cancer Care Ontario. Colorectal cancer incidence increasing among adolescents and young adults. August 2009. Available at https://www.cancercare.on.ca/cancerfacts.
  130. 130. Hereditary CRC risk • familial cases comprise approximately 30% of all CRC • mutations in highly penetrant CRC susceptibility genes account for 5-10% of all CRC • etiology of remaining 20-25% of inherited CRC is not completely understood
  131. 131. Hereditary CRC syndromes POLYPOSIS adenomatous polyposis syndromes Familial Adenomatous polyposis (FAP) – AD, mutation in APC Attenuated FAP (AFAP) - AD, APC mutations at 5’ or 3’ ends of gene or in certain locations of exon 9 MUTYH-associated polyposis (MAP) – AR, biallelic mutations in MUTYH Polymerase-proofreading associated polyposis – AD, mutation in POLE or POLD1 hamartomatous polyposis Peutz-Jeghers syndrome (PJS) - AD, mutations in STK11 Juvenile Polyposis syndrome (JPS) - AD, mutation in SMAD4 or BMPR1A Cowden syndrome (PTEN hamartoma tumor syndrome) - AD, germline mutation in PTEN hyperplastic/serrated polyposis Serrated polyposis syndrome – uncertain genetic etiology; unclear hereditary predisposition Hereditary mixed polyposis syndrome NONPOLYPOSIS Lynch syndrome (LS) – AD, mutation in DNA mismatch repair (MMR) gene (MLH1, MSH2, MSH6, PMS2) or EPCAM Biallelic Mismatch Repair deficiency Other (Li-Fraumeni, Bloom syndrome)
  132. 132. POLYPOSIS adenomatous polyposis syndromes Familial Adenomatous polyposis (FAP) – AD, germline mutation in APC Attenuated FAP (AFAP) - AD, germline APC mutations at 5’ or 3’ ends of gene or in certain locations of exon 9 10 to 99 synchronous adenomas emergence of adenomas and CRC development delayed 10 to 20 years CRC risk 70% by age 80  100s to 1000s of synchronous adenomas beginning in adolescence  CRC risk >95% by age 50 if untreated MUTYH-associated polyposis (MAP) - AR, biallelic mutations in MUTYH  variable phenotype, most commonly 20 to 99 polyps but may present with <10 or >500  CRC risk >40% by age 60 Polymerase-proofreading associated polyposis (PPAS) – AD, mutation in POLE or POLD1  10 to 100 adenomas, may present with other polyp histology  CRC risk undefined
  133. 133. POLYPOSIS hamartomatous polyposis Peutz-Jeghers syndrome (PJS) - AD, germline mutations in STK11  GI polyps in 90-100% of cases  mucocutaneous pigmentation in >95% of cases most commonly perioral and buccal mucosa  lifetime CRC risk 40%  elevated risk for gastric, small bowel , breast, lung, pancreatic, and gynecologic cancers Juvenile Polyposis syndrome (JPS) - AD, mutation in SMAD4 or BMPR1A  multiple juvenile polyps in colon, small bowel, and stomach  CRC risk 20% by age 35 and up to 70% by age 60 Cowden syndrome (PTEN hamartoma tumor syndrome) - AD, germline mutation in PTEN  range of phenotypes, colon polyps present in up to 95%, <10 to 100s of polyps, various histology  lifetime CRC risk may be up to 15%
  134. 134. hyperplastic/serrated polyposis Serrated polyposis syndrome  uncertain genetic etiology; unclear hereditary predisposition Hyperplastic Mixed Polyposis Syndrome newly described, poorly characterized oligopolyposis, mixed poly histology including adenomatous, serrated, hyperplastic and mixed types
  135. 135. NONPOLYPOSIS Lynch syndrome (LS) – AD, mutation in DNA mismatch repair (MMR) gene (MLH1, MSH2, MSH6, PMS2) or EPCAM  usually few (<10) early-onset adenomas, accelerated adenoma-carcinoma sequence  lifetime CRC risk dependent on MMR gene mutation ranging 25-75% for MLH1/MSH2 mutations and lower risks for other gene mutations  associated with extracolonic malignancies – endometrial, gastric, ovarian, urinary tract, small bowel, brain, hepatobiliary  pedigrees characterized by Amersterdam criteria (3 affected, 2 generations, first-degree relatives) Biallelic Mismatch Repair deficiency – AD, biallelic mutations in MMR genes  more commonly associated with brain and hematologic malignancies at very early-age Other (Li-Fraumeni, Bloom syndrome)
  136. 136. Hereditary CRC syndromes and EAO-CRC Chang et al. 2012 ≤40 surgical patients, Stanford Univ hosp 75 total; 13(17%) IHC def, 2(3%) FAP, 1(1%) JPS, 1(1%) LFS, 3(4%) IBD Steinhager et al. 2012 <50 surgical patients, MSKCC 198 total; 17 (9%) LS and 7 (3.5%) VUS Limburg et al 2011 <50 CCFR 155 total; 18 (12%) IHC def Perea et al. 2010 ≤45 surgical patients ,2 hospitals in Spain 43 total; 8(19%) LS and 1(2%)FAP, 26(60%) sporadic Jasperson et al. 2010 ≤35 3 US CRC registries 86 total; 21(24%) LS, 1(1%) FAP, 1(1%) LFS 48(56%) sporadic Losi et al. 2005 <45 surgical patients, 2 hospitals in Italy 71 total; 7 (10%) LS Terdiman et al. 2002 ≤35 high risk clinic, USCF 43 total; 13(30%) LS US population based registry 23 total; 0 (0%) LS hereditary CRC syndromes account for greater proportion of EAO-CRC
  137. 137. FGICR and EAO-CRC Lynch Syndrome n=87 1.MMR (or EPCAM) gene mutation 2.IHC deficient tumor • 71 germline mutations • 12 VUS Classic FAP n=84 1. >100 adenomas 2. 100 adenomas + 1⁰ relative with FAP • 43 germline mutations: 41 APC, 2 biallelic MUTYH • 10 VUS AFAP n=8 • 8 germline mutations: 4 APC, 4 biallelic MUTYH JPS n=6 • 2 germline mutations: 1 SMAD4, 1 BMPR1A • 1 VUS other Biallelic MMR deficiency n=4 • 3 germline mutations • 1 VUS Bloom syndrome n=1 • 1 germline mutation IBD n =11 Undefined conditions n=122 • 97 complete testing • 5 partial testing • 20 no testing high-risk familial ▪ FCCTX common familial risk non-familial
  138. 138. Br J Surg. 2013 Dec;100(13):1719-31. doi: 10.1002/bjs.9316. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Barrow P1, Khan M, Lalloo F, Evans DG, Hill J. METHODS • English-language studies describing CRC incidence and/or mortality in patients with FAP or LS • comparison of : screened and unscreened patients OR time periods before and after establishment of the registry RESULTS  FAP – 33/33 studies report reduction of CRC incidence and mortality with registration and screening  LS – 9/10 studies report reduction of CRC incidence and mortality with registration and screening
  139. 139. J Exp Clin Cancer Res. 2014 Jan 2;33:1. doi: 10.1186/1756-9966-33-1. Early-onset colorectal cancer patients without family history are "at very low risk" for lynch syndrome. Stigliano V1, Sanchez-Mete L, Martayan A, Diodoro M, Casini B, Sperduti I, Anti M.
  140. 140. Clinicopathologic features of non-familial EAO-CRC Early-onset (≤40 years) colorectal adenocarcinoma (%) (N=55) Control (>40 years of age) colorectal adenocarcinoma (%) (N=73) P value Tumor location Right colon 11 (20) 31 (42) 0.007 Left colon and rectum 44 (80) 42 (58) Sigmoid 24 (44) 33 (45) Rectum 20 (36) 9 (12) Tumor stage I 6 (11) 14 (19) 0.21 II 14 (26) 21 (29) III 20 (36) 28 (38) IV 15 (27) 10 (14) Tumor grade Low 40 (73) 63 (86) 0.06 High 15 (27) 10 (14) Perineural invasion 16 (29) 8 (11) 0.009 Venous invasion 12 (22) 4 (6) 0.006 Mucinous histology present 42 (76) 11 (15) 0.22 absent 13 (24) 62 (85) Signet ring histology present 7 (13) 1 (1) 0.021 absent 48 (87) 72 (99) ● more frequent location in distal colon and rectum ● later stage at presentation ● more frequent aggressive histologic features  venous invasion  perineural invasion  mucinous histology  signet ring histology Chang DT, Pai RK, Rybicki LA, et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features. Mod Pathol 2012 Aug;25(8):1128–1139
  141. 141. PLoS One. 2014 Aug 1;9(8):e103159. Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study. Kirzin S1, Marisa L2, Guimbaud R3, De Reynies A2, Legrain M4, Laurent-Puig P5, Cordelier P6, Pradère B7, Bonnet D8, Meggetto F6, Portier G7, Brousset P9, Selves J9. METHODS • surgical patients at university hospital in France 1999-2005 ▪ 39 MSS tumor <45y cases ▪ 9 MSI tumor <45y cases ▪ 36 MSS tumor >60y cases ▪ 14 MSI tumor >60y cases RESULTS • absence of BRAF mutations and methylator phenotype in EAO-CRC • 49 signaling pathways upregulated in EAO-CRC CONCLUSIONS  EAO-CRC is distinct clinico-molecular entity MSS young MSS old MSI young MSI old KRAS mut 14 (37%) 16 (44%) 3 (33%) 4 (29%) WT 24 (63%) 20 (56%) 6 (67%) 10 (71%) BRAF V600E mut 0 (0%) 5 (14%) 0 (0%) 5 (36%) WT 39 (100%) 31 (86%) 9 (100%) 9 (64%) TP 53 mut 17 (44%) 17 (47%) 0 (0%) 5 (36%) WT 22 (56%) 19 (53%) 9 (100%) 9 (64%) PIK- 3CA mut 5 (21%) 2 (6%) 4 (80%) 3 (27%) WT 19 (79%) 32 (94%) 1 (20%) 8 (73%) CIMP unmethylated 38 (100%) 29 (81%) 9 (100%) 5 (38%) methylated 0 (0%) 7 (19%) 0 (0%) 8 (62%)
  142. 142. Am J Surg Pathol. 2009 Apr;33(4):572-82. doi: 10.1097/PAS.0b013e31818afd6b. Clinical, pathologic, and molecular features of early-onset colorectal carcinoma. Yantiss RK1, Goodarzi M, Zhou XK, Rennert H, Pirog EC, Banner BF, Chen YT. METHODS • surgical patients UMass Memorial Healthcare and Weill Cornell Medical College 2000-2007  24 patients <40y  15 patients 40-40y  30 patients >50y RESULTS • more frequent AMACR expression in patients <40y • 4 micro-RNA species significantly overexpressed in patients <40y (miR-21, miR-20a, miR-181b, mi-203) CONCLUSIONS  posttranscriptional regulation of mRNA may be particularly important for the development of CRC in young patients
  143. 143. Exploring the genetics of EAO-CRC Next-generation sequencing (NGS)
  144. 144.  rare variant hypothesis ▪ undiscovered moderately penetrant genetic variants cause increased CRC risk de novo dominant recessive biallelic somatic
  145. 145. Whole genome sequencing vs Exome sequencing Whole genome  expensive  IT issues  complete sequence Exome  cheaper  more manageable  coding regions  incomplete sequence
  146. 146. Nat Genet. 2011 May; 43(5): 442–446. Exome sequencing identifies GRIN2A as frequently mutated in melanoma Xiaomu Wei,1 Vijay Walia,1,12 Jimmy C Lin,2,12 Jamie K Teer,3 Todd D Prickett,1 Jared Gartner,1 Sean Davis,4 NISC Comparative Sequencing Program,5 Katherine Stemke- Hale,6 Michael A Davies,6,7 Jeffrey E Gershenwald,8,9 William Robinson,10 Steven Robinson,10 Steven A Rosenberg,11 and Yardena Samuels1 Science. 2009 Apr 10;324(5924):217 Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Jones S1, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, Klein AP. Nat Genet. 2011 Jun 19;43(7):663-7. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Comino-Méndez I1, Gracia-Aznárez FJ, Schiavi F, Landa I, Leandro-García LJ, Letón R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gómez-Graña A, de Cubas AA, Inglada-Pérez L, Maliszewska A, Taschin E, Bobisse S, Pica G, Loli P, Hernández-Lavado R, Díaz JA, Gómez-Morales M, González-Neira A, Roncador G, Rodríguez-Antona C, Benítez J, Mannelli M, Opocher G, Robledo M, Cascón A. Nature. 2011 Jan 27; 469(7331): 539–542. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma Ignacio Varela,1 Patrick Tarpey,1 Keiran Raine,1 Dachuan Huang,2 Choon Kiat Ong,2 Philip Stephens,1 Helen Davies,1 David Jones,1 Meng-Lay Lin,1 Jon Teague,1 Graham Bignell,1 Adam Butler,1 Juok Cho,1 Gillian L. Dalgliesh,1 Danushka Galappaththige,1 Chris Greenman,1 Claire Hardy,1 Mingming Jia,1 Calli Latimer,1 King Wai Lau,1 John Marshall,1 Stuart McLaren,1 Andrew Menzies,1 Laura Mudie,1 Lucy Stebbings,1 David A. Largaespada,3 L.F.A. Wessels,4 Stephane Richard,5,6 Richard J Kahnoski,7 John Anema,7 David A. Tuveson,8 Pedro A. Perez-Mancera,8 Ville Mustonen,8 Andrej Fischer,9,10 David J. Adams,11 Alistair Rust,11 Waraporn Chan-on,2 Chutima Subimerb,2 Karl Dykema,12 Kyle Furge,12 Peter J. Campbell,1 Bin Tean Teh,2,14 Michael R. Stratton,1,15 and P. Andrew Futreal1 Exome sequencing and cancer genetics
  147. 147. Nat Genet. 2013 Feb;45(2):136-44. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Palles C1, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, Kemp Z, Spain SL, Guarino E, Salguero I, Sherborne A, Chubb D, Carvajal-Carmona LG, Ma Y, Kaur K, Dobbins S, Barclay E, Gorman M, Martin L, Kovac MB, Humphray S; CORGI Consortium; WGS500 Consortium, Lucassen A, Holmes CC, Bentley D, Donnelly P, Taylor J, Petridis C, Roylance R, Sawyer EJ, Kerr DJ, Clark S, Grimes J, Kearsey SE, Thomas HJ, McVean G, Houlston RS, Tomlinson I. • whole genome sequencing and linkage analysis • COloreRectal Gene Identification (CORGI) study; recruits from UK Clinical Genetics Departments • 20 discovery phase samples:  15 unrelated probands diagnosed with ≥10 colorectal adenomas before age 60  relative with >5 colorectal adenomas for 3 probands, and 2 affected relatives for 1 proband • 3,805 white UK validation phase samples enriched for family history of CRC and early-onset • 6,721 white UK control samples without personal history of CRC
  148. 148. POLE L424V variant • pedigree SM2702, only variant shared by all 3 affected individuals • present in 12 additional unrelated cases from validation phase and no controls • additional genotyping in 12 families showed all carriers developed colorectal tumors POLD1 S478N variant • pedigree SM1645, shared by both of the 2 affected individuals • present in additional proband plus additional unrelated case from validation phase and no controls • additional genotyping in SM1645 and proband family showed all carriers developed colorectal tumors  dominantly-inherited high penetrance susceptibility for colorectal adenoma and carcinoma  mutations map to proof-reading (exonuclease) domain of DNA polymerases ε and δ; predicted to impair correction of mispaired bases inserted during DNA replication
  149. 149. Hum Mutat. 2013 Jul;34(7):1026-34. doi: 10.1002/humu.22333. Epub 2013 May 20. Exome resequencing identifies potential tumor-suppressor genes that predispose to colorectal cancer. Smith CG1, Naven M, Harris R, Colley J, West H, Li N, Liu Y, Adams R, Maughan TS, Nichols L, Kaplan R, Wagner MJ, McLeod HL, Cheadle JP. METHODS • exome sequencing of 50 germline DNA samples • unrelated sporadic CRC patients from UK national multicenter randomized controlled trials COIN and COIN-B
  150. 150. analysis strategy 1  search for protein-truncating variants in subset of 1,138 genes from pathways implicated in CRC  oncogenes excluded  search for LOH by Sanger sequencing of matched tumor DNA when available 32 variants in 31 genes 5 variants with somatic biallelic inactivation FANCM, LAMB4, PTCHD3, LAMC3, TREX2 analysis strategy 2  search for protein-truncating variants in all genes  initially limited search to 18 EAO-CRC cases in sample set  expanded to include all cases 173 variants in 159 genes in EAO-CRC additional 331 variants in additional 305 genes in remainder
  151. 151. Cancer Genetics 208 (2015) 35-40 Systematic search for rare variants in Finnish early-onset colorectal cancer patients Tomas Tanskanen a, Alexandra E. Gylfe a, Riku Katainen a, Minna Taipale b,e, Laura Renkonen-Sinisalo a,c, Heikki J€arvinen c, Jukka-Pekka Mecklin d, Jan B€ohm d, Outi Kilpivaara a, Esa Pitk€anen a, Kimmo Palin a, Pia Vahteristo a, Sari Tuupanen a, Lauri A. Aaltonen a,* METHODS • exome sequencing • unselected surgical patients from 9 Finnish hospitals 1994-1998 • discovery set of 22 non-familial EAO-CRC cases <40y • validation set of 95 familial CRC cases
  152. 152. RESULTS  no genes with rare loss-of-function (LoF) variants present in more than one EOA-CRC patient  ADAMTS4, CYTL1, SYNE1 LoF variants in one EAO-CRC patient and familial CRC cases  ACSL5 p.Pro71Leu, INTS5 p.Pro922Leu missense variants in 2 EAO-CRC patients and no familial CRC cases  MCTP2, ARHGAP12, ATM, DONSON, ROS1 each with homozygous variants in one EOA-CRC patient  no compound heterozygous LoF variants CONCLUSIONS  results suggest genetic heterogeneity in unexplained EAO-CRC
  153. 153. The Toronto EAO-CRC cohort FGICR Undefined conditions n=122 • 97 complete testing • 5 partial testing • 20 no testing • complete testing • no polyposis • no significant family history: ▪ pedigree does not meet Amsterdam or Revised Bethesda criteria ▪ no relative with EAO-CRC (≤35y) ▪ no first degree relative with CRC • germline and tumor DNA available  30 EAO-CRC germline and tumor exomes
  154. 154. rare variant hypothesis ▪ undiscovered moderately penetrant genetic variants cause increased CRC risk perhaps not one single variant but unique combinations ; OR the interaction of certain variant(s) with environmental exposures and/or epigenetic alterations, etc….
  155. 155. References Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed November 15, 2014. American Cancer Society. Colorectal Cancer Facts and Figures 2014-2016. Atlanta: American Cancer Society; 2014. Canadian Cancer Society's Advisory Committee on Cancer Statistics (2014). Canadian Cancer Statistics 2014. Toronto, ON: Canadian Cancer Society. Siegel R, Desantis C, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Mar-Apr 64(2):104-17. Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010 Feb 1;116(3):544-73. Cheng L, Eng C, Neiman LX, Kapadia AS, Du XL. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976-2005. Am J Clin Oncol. 2011 Dec;34(6):573-80 Surveillance Epidemiology and End Results. Fast Stats, http:// seer.cancer.gov/faststats. Accessed November 15, 2014. Bailey CE, Hu CY, You YN, et al. Increasing Disparities in the Age-Related Incidences of Colon and Rectal Cancers in the United States, 1975-2010. JAMA Surg. 2014 Nov 5:1-6. Siegel RL, Jemal A, Ward EM. Increase in incidence of colorectal cancer among young men and women in the United States. Cancer Epidemiol Biomarkers Prev. 2009 Jun;18(6):1695-8. You YN, Xing Y, Feig BW, Chang GJ, Cormier JN. Young-onset colorectal cancer: is it time to pay attention? Arch Intern Med. 2012 Feb 13;172(3):287-9. Pignone M, Rich M, Teutsch SM, et al. Screening for colorectal cancer in adults at average risk: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2002 Jul 16;137(2):132-41. Whitlock EP, Lin JS, Liles E, Beil TL, Fu R. Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2008 Nov 4;149(9):638-58. Myers EA, Feingold DL, Forde KA, et al. Colorectal cancer in patients under 50 years of age: A retrospective analysis of two institutions' experience. World J Gastroenterol. 2013 Sep 14;19(34):5651-7. Kirzin S, Marisa L, Guimbaud R, et al. Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study. PLoS One. 2014 Aug 1;9(8):e103159. Chang DT, Pai RK, Rybicki LA, et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features. Mod Pathol 2012 Aug;25(8):1128–1139 Yantiss RK, Goodarzi M, Zhou XK, et al. Clinical, pathologic, and molecular features of early-onset colorectal carcinoma. Am J Surg Pathol 2009 Apr;33(4):572–582 Fante R, Benatti P, di Gregorio C, et al. Colorectal carcinoma in different age groups: a population-based investigation. Am J Gastroenterol. 1997;92:1505–1509. Minardi AJ, Sittig KM, Zibari GB, McDonald JC. Colorectal cancer in the young patient. Am Surg. 1998;64:849–853. Domergue J, Ismail M, Astre C, et al. Colorectal carcinoma in patients younger than 40 years of age. Montpellier Cancer Institute experience with 78 patients. Cancer. 1988;61:835–840. Palmer ML, Herrera L, Petrelli NJ. Colorectal adenocarcinoma in patients less than 40 years of age. Dis Colon Rectum. 1991;34:343–346. Chiang JM, Chen MC, Changchien CR, et al. Favorable influence of age on tumor characteristics of sporadic colorectal adenocarcinoma: patients 30 years of age or younger may be a distinct patient group. Dis Colon Rectum. 2003 Jul;46(7):904-10. Parramore JB, Wei JP, Yeh KA (1998) Colorectal cancer in patients under forty: presentation and outcome. Am Surg 64: 563–567 discussion 567–568 Liang JT, Huang KC, Cheng AL, Jeng YM, Wu MS, et al. (2003) Clinicopathological and molecular biological features of colorectal cancer in patients less than 40 years of age. Br J Surg 90: 205–214 Berg M, Danielsen SA, Ahlquist T, Merok MA, Agesen TH, et al. (2010) DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset. PLoS One. 2010 Nov 12;5(11):e13978. Alsop K, Mead L, Smith LD, Royce SG, Tesoriero AA, et al. (2006) Low somatic K-ras mutation frequency in colorectal cancer diagnosed under the age of 45 years. Eur J Cancer 42: 1357–1361 Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67. Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet. 2001;17:502–10. Wang WY, Barratt BJ, Clayton DG, Todd JA. Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet. 2005;6:109–118. Bodmer W1, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet. 2008 Jun;40(6):695-701. doi: 10.1038/ng.f.136. Frayling I, Beck NE, Ilyas M, Dove-Edwin I, Goodman P, Beck JA, et al. The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history. Proc Natl Acad Sci USA. 1998 Sep 1;95(18):10722–7. Fearnhead N, Wilding JL, Winney B, Tonks S, Bartlett S, Bicknell DC, et al. Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas. Proc Natl Acad Sci USA. 2004 Nov 9;101(45):15992–7. Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 2011 Jun 19;43(7):663–7. Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. 2009 Science Apr 10;324(5924):217 Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. Smith CG, Naven M, Harris R, Colley J, West H, Li N, et al. Exome resequencing identifies potential tumor-suppressor genes that predispose to colorectal cancer. Hum Mutat. 2013 Jul;34(7):1026-34. Newcomb PA, Baron J, Cotterchio M, Gallinger S, Grove J, Haile R, et al. Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomarkers Prev. 2007 Nov;16(11):2331-43.
  156. 156. Thank you
  157. 157. Jiyoung Ahn, PhD, RD Associate Professor Dept. of Population Health NYU School of Medicine Early Age Onset Colorectal Cancer Summit, March 2005 Gut Microbiome, Fiber Intake, and Risk of Colorectal Cancer
  158. 158. 16 3 Human microbiome • Human microbiome, totality of human microbiota. • Our understanding of microbiome has been limited. • Bacterial DNA sequencing opened new possibility to study microbiome comprehensively and accurately. Ahn et al, Cancer Cause and Control, 2012
  159. 159. 16 4 World Health Organization Group 1 infectious agents that cause cancer Bacteria Helicobacter pylori (H. pylori) Viruses Epstein-Barr Virus (EBV) Hepatitis B Virus (HBV) Hepatitis C Virus (HCV) Human Herpesvirus 8 (HHV-8) Human Immunodeficiency Virus (HIV) Human Papillomavirus (HPV) Human T-Cell Lymphotrophic/Leukemia Virus Type 1 (HTLV-1)
  160. 160. 16 5 • Recently completed study of microbiome and colorectal cancer - published in Journal of National Cancer Institute • Large scale on-going effort on - NYU Human Microbiome Study Cohort Overview of talk
  161. 161. 16 6 Gut microbiome and CRC • Gut microbiome plays key roles in inflammation and in the breakdown of otherwise indigestible food compounds, such as fiber. • Animal studies (Infect Immun 1998, mBio 2013) - mice develops fewer colon tumors under germ-free conditions - fecal transplant from CRC mice results in tumor formation • Systematic epidemiologic surveys of gut microbiome with cases and controls are lacking. • We tested the hypothesis that altered gut microbiome is associated with risk of CRC.
  162. 162. 16 7 • Hospital based case-control study - 47 CRC cases and 94 non-cancer controls - recruited 3 hospitals in Washington DC area - matched by age, gender, and BMI • Diet and demographic questionnaires • In-home 2 day fecal collection • 16s rRNA gene sequencing microbiome assay Study Design
  163. 163. 16 8 Microbiome Assay and Data Analysis - Compared overall gut microbiome diversity and microbial taxa abundances in CRC cases and controls
  164. 164. 16 9 Inter-individual variability of gut microbiome Ahn et al, JNCI, 2013 20 different health subjects
  165. 165. 17 0 Gut microbiome diversity in CRC and controls 500 1000 1500 2000 2500 3000 6 7 8 9 Shannon Index in Colorectal Cancer Cases and Controls Sequences Per Sample ShannonIndex Controls Cases Less diverse in cases than in controls Ahn et al, JNCI, 2013 P = 0.02
  166. 166. 17 1 Taxonomic differences in CRC and controls Case Cont Ahn et al, JNCI, 2013
  167. 167. 17 2 Fusobacterium increases CRC risk • Multivariate OR=3.74, p=0.0035. • Fusobacterium is gram negative inflammatory bacteria. • Consistent with our result, two studies reported that Fusobacterium is enriched in human colorectal cancer tissue compared to adjacent normal tissue (Genome Research 2012 and Science 2013). Ahn et al, JNCI, 2013
  168. 168. 17 3 Clostridia decreases in CRC patients • Clostridia depleted in CRC cases (Multivariate OR = 0.8, P=0.005). • Clostridia ferment dietary fiber to short chain fatty acid (butyrate), anti-carcinogenic components. Ahn et al, JNCI, 2013
  169. 169. 17 4 High fiber intake decreases CRC risk 0.6 0.7 0.8 0.9 1 1.1 CRC Risk <15 g/day, 15-20 g/day, 20-24 g/day, 24-30 g/day 30+ g/day Dietary Fiber Intakes Lancet 2003, JAMA 2005 • Non-digestible plant component of complex carbohydrates
  170. 170. 17 5 Low Fiber Intake High fiber intake and high clostridia High Fiber Intake High fiber intake - for high vs. low Clostridia: multivariate OR=1.24 (p=0.009) Domminiani et al, PLOS ONE, 2015 Clostridia Overall diversity Genera (unsupervised clustering)
  171. 171. 17 6 Summary • CRC risk was associated - with decreased gut microbiome diversity; - increased presence of Fusobacterium; - depletion of fiber–fermenting Clostridia. • High fiber intake  Clostridia  CRC.
  172. 172. 17 7 NYU Human Microbiome Cohort: Human Microbiome and Colorectal Tumor (HMAC) Study (supported by Dept. Population Health, NYU Cancer Institute, and NCI) Ongoing Recruitment (~ 500 recruited, 3000 planned) - GI clinic and colonoscopy centers at NYULMC and other 3 sites in US. - Fecal/oral/tissue sample collection - Comprehensive diet/demographic questionnaires - Detailed clinical and pathology information Follow up for future tumor assessment - Annual follow up questionnaire and medical chart verification
  173. 173. 17 8 Implications • Learn about the causes of CRC. • Identifying people at high risk for CRC. • Possible prevention of CRC by tailored bacterial and diet modifications.
  174. 174. 17 9 Research Team • NYU: Richard Hayes, Mitchell Bernstein, George Miller, Zhiheng Pei • My group: Christine Domminiani, Xiaozhou Fan, Jing Wu, Ryan Shanly, Elong Zhang • NCI: Mark Purdue, Rashimi Sinha, Jim Goedert, Neal Freedman • ACS: Susan Gapstur, Eric Jacobs • CDC: Jean Shapirio Grant Support • NIH R01 CA 164964 (PI. Ahn): Microbiome-pancreas cancer • NIH U01 CA182370 (MPI. Ahn/Pei): Microbiome-esophagus cancer • NIH R03 CA159414 & NIH R21 CA183887 (PI. Ahn): Microbiome-CRC • NIH R01 CA 164964 (PIs. Hayes/Pei): Microbiome-HNC • NYU Abu Dhabi (PI. Ahn): Microbiome - CVD • NIH R21 ES021194 (PI. Ahn) & NIH R21 ES021242 (PI. Ahn): Diet studies www.NYUMGEL.org (Ahn – Diet, microbiome and genetic epidemiology lab)
  175. 175. 18 0 Each body site has a different and unique microbiome HMP data
  176. 176. 18 1 Shared common structure of human microbiome Catonella Dialister Eubacterium Filifactor Gemella Granulicatella Megasphaera Parvimonas Selenomonas Streptococcus Veillonella Aggregatibacter Camplylobacter Haemophilus Kingella Neisseria Capnocytophaga Porphyromonas Prevotella Tannerella Actinomyces Bifidobacterium Slackia Fusobacterium LeptotrichiaFusobacteria (5.0%) Firmicutes (52.3%) Proteobacteria (19.7%) Bacteroidetes (15.6%) Actinobacteria(7.3%) SR1 (0.07%) TM7 (0.06%) Cyanobacteria (0.01%) Spirochaetes (0.01%) Tenericutes (0.01%) Synergistetes (0.0001%) HumanOralBacteria Ahn et al, PLoS ONE, 2011 Phyla Genera
  177. 177. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge Thomas K Weber, MD FACS Professor of Surgery State University of New York Health Sciences Center Brooklyn, New York
  178. 178. Incidence trends by age: 50+ versus 20-49 Source: SEER 9 registries, 1975-2011; 2-yr moving average. 0 2 4 6 8 10 12 14 1975-76 1977-78 1979-80 1981-82 1983-84 1985-86 1987-88 1989-90 1991-92 1993-94 1995-96 1997-98 1999-00 2001-02 2003-04 2005-06 2007-08 2009-10 Rateper100,000 Men Women 45% 2% per year Since 1993-1994 0 50 100 150 200 250 300 1975-76 1977-78 1979-80 1981-82 1983-84 1985-86 1987-88 1989-90 1991-92 1993-94 1995-96 1997-98 1999-00 2001-02 2003-04 2005-06 2007-08 2009-10 Rateper100,000 Men Women Ages 50+ Ages 20-49
  179. 179. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • We have a major cancer control / epidemiologic challenge • The “seismic” nature of this challenge are illustrated by very simple “30,000 feet” observations.
  180. 180. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • “A study of initial presentation of young onset CRC patients without established risk factors found that 86% were symptomatic at the time of diagnosis” * • Siegel et al Can Epi Biomark 18(6) 1695-8
  181. 181. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge
  182. 182. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge
  183. 183. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • For almost a quarter of a century our collective “conditioned reflexes” have been wired to think “genetic hereditary syndrome” when we see a young (under 50) solid tumor patient in general and especially with breast and colorectal cancer. • However…………..
  184. 184. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge
  185. 185. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • However………….. • At least 75% of EAO-CRC patients DO NOT report positive family history of the disease • Dr Kastrinos shared Dr Limburg’s Colorectal CFR data indicating less than 6% of < 50 patients carried a Lynch Syndrome gene mutation.
  186. 186. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • So………….. • We are facing a new problem… • A Fresh Challenge….... • A novel opportunity to advance our understanding of the basic biology of the pathophysiology of solid tumor malignancy in the young.
  187. 187. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • I have no links whatsoever to this man…
  188. 188. However NO RELATION!
  189. 189. HOWEVER…… Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • A Potentially Useful Construct: • “There are known knowns. These are things we know that we know. • There are known unknowns. That is to say, there are things that we know we don't know. • But there are also unknown unknowns. There are things we don't know we don't know.”
  190. 190. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge Known Knowns……The Basics • Health Insurance: what are the dimensions of this problem? What specific strategies could address this? Do related pre-existing issues impact it” • No Primary Care Physician: again – the dimensions? • Remember – in NYC > 80% unscreened had insurance AND a primary care physician
  191. 191. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge Known Knowns……The Basics • A POSITIVE family history for CRC and or Lynch related malignancies • A positive history for Inflammatory Bowel Disease - IBD
  192. 192. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge Unknown Knowns……What is the true risk – in YOUNG ADULTS?
  193. 193. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge Unknown Knowns……What is the true risk – especially in the young? • Exercise vs. Sedentary Lifestyle?? • Obesity? • Red Meat? • Milk? • Fast Foods? • That’s NOT ME!
  194. 194. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge Unknown Knowns……What is the true risk – especially in the young? • Diabetes • Sleep Patterns? • Sitting Position? • Alcohol? • Tobacco? • Recreational Drugs ?
  195. 195. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge Unknown Knowns……What is the true risk – especially in the young? • Microbiome? • Periodontal Disease? • Our Environment? • The Exposome?
  196. 196. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge What DO we know about the Unknown Knowns……? • Any Data?
  197. 197. COloRECtal Transdisciplinary Study NCI GAME-ON Consortium • •Global study n= 52,649 • •OncoArray consortium n= 45,000 • •Diverse populations • •Harmonizing epidemiologic data • •Developing integrated risk prediction model
  198. 198. Measuring the Exposome
  199. 199. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge Unknown Knowns……What is the true risk – especially in the young? • Genetics…………………………….. • “Known Syndromes? • Unknown Genetic Elements and Syndromes • Unknown Unknowns?
  200. 200. GWAS, SNPS,THE “EXPOSOME” and Colorectal Cancer • GWAS SNP studies have been…..disappointing • If 21,000 is “underpowered” then ….? • GWAS / SNP approach has not focused on EAO-CRC (“enriched”) • The GWAS SNP approach contrasts with the whole exome / whole genome work discussed by Drs McNamara and Kastrinos.
  201. 201. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • “But there are also unknown unknowns. There are things we don't know we don't know.” • ? • ? • ? • ?
  202. 202. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • “But there are also unknown unknowns. There are things we don't know we don't know.” • Changing patterns of: Antibiotic Usage • Aspirin Use? • Attention Deficit Meds • In Utero Exposures – “Exposome” • Statins?
  203. 203. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • How Can We Move Forward?
  204. 204. • No Health Insurance • No Primary Physician • INEFFECTIVE PRIMARY CARE & OTHER PHYSICIANS • Positive Family History • Inflammatory Bowel Disease • Diabetes • High Calorie / Red Meat Containing / Processed Foods
  205. 205. Evidenced Based Score Card
  206. 206. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge Unknown Knowns……What is the true risk – especially in the young? • Diabetes • Sleep Patterns? • Sitting Position? • Alcohol? • Tobacco? • Recreational Drugs ?
  207. 207. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge Unknown Knowns……What is the true risk – especially in the young? • Microbiome? • Periodontal Disease? • Our Environment? • The Exposome?
  208. 208. Evidenced Based Score Card
  209. 209. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • “There are also unknown unknowns. There are things we don't know we don't know.” • ? • ? • ? • ?
  210. 210. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • “There are also unknown unknowns. There are things we don't know we don't know.” • Changing Patterns of: Antibiotic usage? • Aspirin? • Puberty and Menarche? • Attention Deficit Meds? • In-Utero Exposures?
  211. 211. Incidence trends by race/ethnicity, ages 20-49 years 0 2 4 6 8 10 12 14 Non-Hispanic white Colon and Rectum Colon Rectum 0 2 4 6 8 10 12 14 1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09 2010-11 Non-Hispanic black 0 2 4 6 8 10 12 14 1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09 2010-11 Asian/Pacific Islanders 0 2 4 6 8 10 12 14 1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09 2010-11 Hispanic Colorectal Colon Rectum Non-Hispanic white 2.3 1.6 3.4 Hispanic 2.1 2.0 2.2 Asian/Pac Islander 0.7 0.8 stable Non-Hispanic black stable stable 1.9 Average annual % increase from 2002-2011: Source: SEER 13 registries, 1992-2011; 2-year moving average. AAPCs based on Joinpoint Regression Program.
  212. 212. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge And How Do We Advance Knowledge About Young Adult CRC Unknowns? • Little or none of what we have reviewed has been directed to EAO-CRC • Our NCI / CDC Cancer Registries do NOT collect family history or other basic risk factor data
  213. 213. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge And How Do We Advance Knowledge About Young Adult CRC Unknowns? • Little or none of what we have reviewed has been directed to YOUNG ADULTS! • Our NCI / CDC Cancer Registries do NOT collect family history or other basic risk factor data.
  214. 214. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge And How Do We Advance Knowledge About Young Adult CRC Unknowns? • As Discussed at Yesterday’s Never Too Young Coalition Meeting: • An IRB guided, HIPAA Compliant, State of the Art Epidemiologic SURVEY of Young Adult Survivors – (and Families?) • MSKCC & MD Anderson – Genetic Alliance
  215. 215. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge One Thing We All SHOULD Know: • If you are symptomatic – or have positive “physical signs” • You Need / Your Patient Needs…….. • A DIAGNOSTIC EVALUATION! • Rectal Bleeding, Abdominal Pain, Change in Bowel Habit
  216. 216. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge SUMMARY?
  217. 217. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge “You Never Know…”
  218. 218. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • We know a great deal • There are clear opportunities to use that knowledge to inform patient choice and provider response / action. • Knowledge of RISK FACTORS can be immediately deployed to RISK REDUCTION strategies.
  219. 219. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge • Known RISK FACTORS need to be validated in YOUNG ADULTS. • Tackling UNKOWNS – requires resourcing our national / international cancer registries to address the problem • EAO-CRC Survivor Survey Project
  220. 220. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge RISK • Identification • Clarification • Mitigation / Reduction
  221. 221. Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge THANK YOU!
  222. 222. Martha Raymond, MA, CPN Early Age Onset Colorectal Cancer Summit March 21, 2015 Memorial Sloan Kettering Cancer Center New York, New York The Patient Perspective: Exploring the ‘New Normal’ of the Young Colon Cancer Patient
  223. 223. Quality of Life After an EAO-CRC Diagnosis: Knowledge Gaps and Opportunities Susan K. Peterson, PhD, MPH Professor, Behavioral Science 1st Early Age Onset Colorectal Cancer Summit New York, NY March 21, 2015
  224. 224. Cancer Survivorship • Cancer survivorship = the state or process of living after a diagnosis of cancer • Encompasses not only the physical but also the social, psychological, and spiritual/existential impact of cancer on one’s life and for the remainder of one’s life.
  225. 225. Measuring Quality of Life • Physical functioning • Health status • Sexuality and fertility • Emotional adjustment • Psychological and behavioral functioning • Spiritual/existential domains • Future outlook • Independence • School performance • Work performance • Social relationships • Family relationships
  226. 226. • Establish autonomy and independence – Achieve emotional independence from adults – Self-esteem and identity development – Acquire a set of values and an ethical system as a guide to behavior • Social and intimate relationships – More mature relations with peers – Prepare for marriage and family • Establish financial independence – Completion of school – Prepare for a career. Crucial Developmental Milestones in Young Adulthood
  227. 227. The Impact of an Illness • Changes in mobility and physical functioning • Changes in physical appearance • Separation from peers and usual activities • Increased dependence on parents at a time they would usually be practicing independence
  228. 228. Research on Quality of Life (QOL) in Young Adult Cancer Survivors
  229. 229. N=523 young survivors, age 15-39 • Compared to peers, YCS had lower physical and social functioning; psychosocial, emotional, and work/school functioning were similar to peers • Worse HRQOL associated with: < high school, no insurance, Hispanic ethnicity, active treatment (esp. chemo), younger age, greater symptom burden • Demands of normal physical, hormonal, cognitive changes + other normal developmental changes may contribute to lower levels of physical functioning and fatigue Smith, JCO, 2013 Health-related QOL in Young Cancer Survivors
  230. 230. N=8375 survivors, diagnosed age 15-39 • Compared to peers, 30% of those age 40-64 report poor/fair health vs. controls • > 1 diagnosis associated with poorer QOL • 45% of female CRC survivors report fair/poor health – Long-term issues with infertility, bowel function • Earlier age of diagnosis associated with more days of poor mental health compared with older age at diagnosis – Gap in psychological support for youngest survivors • Young age at diagnosis may have long-term QOL impact across lifespan Kirchhoff, JAYAO, 2014 Health-related QOL in Young Cancer Survivors
  231. 231. • About half or fewer may achieve recommended levels of physical activity (PA) (ages 20-44) • About half may be overweight or obese • More physically active compared to older survivors, less compared to age-related peers • Benefits of PA include improved QOL, symptom reduction, and improved survival/reduced recurrence risk in some cancers • Tobacco use may be higher compared to older survivors Health Behaviors in Young Adult Cancer Survivors
  232. 232. 20 32 39 39 12 29 18 21 9 0 1 0 2 0 3 0 5 0 4 0 0 1 2 3 Number of Risk Factors 4 Percent Affected Unaffected Prevalence of Risk Behaviors* for Colorectal Cancer Among Persons at Risk for Lynch Syndrome (n=429) Risk Behavior Index Score (M), Cancer-affected vs. unaffected 1.4 vs. 1.7 (p<0.01) *Smoking, alcohol use, dietary factors Burton, 2011
  233. 233. Unmet need rated by 70% or more - Sexuality/intimacy-related counseling - Adoption services - Retreats, camps N=879 young cancer survivors Needs were greater for younger survivors and those diagnosed at younger ages Unmet need rated by 50% or more - Diet, nutrition, exercise - Family counseling - Substance abuse counseling - Assistance with transportation, child care Unmet Information and Service Needs of Young Cancer Survivors
  234. 234. • Medical care – Perceived excellence in care after diagnosis – Dissatisfaction with initial diagnosis delay • Patient factors - still-maturing cognitive function, reliance on peers for information • Provider factors – not attributing symptoms to cancer, poor provider-patient communication – Side effects and symptoms • Fatigue, depression, nausea, weight gain/loss, bowel function, sexuality/fertility, changes in eating, decreased energy, body image concerns Zebrack, Psychosoc Onc, 2014 QOL Domains for Young Cancer Survivors
  235. 235. • Practical – Financial • Inadequate or gaps in health insurance • Difficulty navigating health insurance coverage • Work interruptions • Acquiring early debt & limited financial resources – School/ work disruption • Treatment takes precedence over work, school QOL Domains for Young Cancer Survivors
  236. 236. • Psychological and Spiritual – Managing distress & emotions related to cancer, treatment, and fear of recurrence – Social functioning and isolation • Disclosure and communication – Maintain/re-establish normalcy – Loss: job/school, appearance change, relationship changes ***Positive attitudes, beliefs, feelings emerge from cancer experience QOL Domains for Young Cancer Survivors
  237. 237. Cancer Can Promote Psychological Growth: Resilience Concept • Some people can transform their lives by responding to an illness in ways that enhance the quality and meaning of their lives • Resilience = process for identifying and developing resources or strengths to manage stressors in order to gain positive outcome from the experience • Positive growth: greater maturity, appreciation for life than population norms
  238. 238. • Racial/ethnic minority and medically underserved cancer survivors have greater disparities in cancer outcomes and access to survivorship care – AfricanAmericans: higher mortality for CRC – Uninsured or underinsured persons → more likely to be diagnosed with advanced cancer → less likely to receive standard care and survive → less likely to adhere to surveillance and survivorship care regimens • Uninsured/underinsured = predominantly Hispanic, recent immigrants, and the working poor – Lifestyle behaviors (e.g., obesity, low physical activity, tobacco use) related to cancer recurrence or mortality are more prevalent among racial/ethnic minority, lower resourced, and less educated survivors CDC, 2011; American Cancer Society, 2012 Health disparities in U.S. cancer survivors
  239. 239. Including “Previvors” in the Discussion About EAO-CRC • Previvors = at increased risk of hereditary CRC, no CRC diagnosis • Bowel function and QOL in children with FAP who underwent colectomy at age < 14 y • n=28, 56% female, mean colectomy age=12 y, current age=24 y • Reported more night incontinence, nighttime stools (p<0.05); daytime incontinence not different from adult sample • 60% reported feeling embarassed “always or sometimes” due to bowel concerns • 20% reported restrictions at school or work, 30% restrictions in sports due to bowel concerns • 36% worried ‘at least some’ about post-surgery cancer risk; greater in younger patients had greater worry • Younger patients reported more FAP surgery-related distress – Number of FAP-affected family members associated with higher distress • Body image and self-esteem scores in normal ranges Durno, Dis Colon Rectum (2012)
  240. 240. 72% seek health information online -Used phone: 31% cell phone, 52% smartphone - 19% smartphone owners download Pew Internet Research Project, 2012; 2014 Social and mobile media to reach EAO-CRC survivors
  241. 241. Computer and mobile technology use in the U.S. Pew Internet Research Project, 2014
  242. 242. Clauser, 2011
  243. 243. • In general, young adult cancer survivors not well- represented in QOL studies of survivors – Especially EAO-CRC • QOL needs for young adult survivors are specific and differ from older survivors e.g., social functioning, financial stress, sexuality, health information → Need better understanding of QOL in EAO-CRC → QOL measures specific to EAO-CRC → Resources targeted toward specific QOL support in EAO-CRC Gaps and Opportunities
  244. 244. • Subgroups of young adult cancer survivors have specific needs – Those diagnosed at youngest ages – Underserved – Fertility, sexuality considerations – Pre-vivors → Need better understanding of life-stage specific QOL in EAO- CRC → Resources targeted toward specific QOL support in EAO-CRC Gaps and Opportunities
  245. 245. • Health care system may not be responsive to needs of EAO-CRC – Cancer treatment settings may reflect pediatric vs. older adult divisions in care – Delay in initial diagnosis and treatment, despite persistent symptoms & health concerns • Delays in diagnosis → skepticism, mistrust → poor adherence to treatment, failure to seek future care → Resources needed for EAO-CRC that are appropriate for varied stages of life, development → Support for providers who care for EAO-CRC e.g., Focus Under Forty (ASCO, Livestrong), EAO- targeted survivorship care plans and services Gaps and Opportunities
  246. 246. National Cancer Institute, National Institutes of Health, 1R42 CA126453, 1R41-CA126453-01 Seed Money Grant, Duncan Family Institute for Cancer Risk Assessment and Prevention Cancer Center Support Grant (CA016672, PI: R. DePinho) National Cancer Institute, National Institutes of Health MarthaAskins, PhD Associate Professor and Pediatric Psychologist Psychosocial Director,Adolescent and Young Adult Program The Children’s Cancer Hospital at MD Anderson Cancer Center Acknowledgements
  247. 247. * • Cancer survivorship = the state or process of living after a diagnosis of cancer • Encompasses not only the physical but also the social, psychological, and spiritual/existential impact of cancer on one’s life and for the remainder of one’s life.
  248. 248. * • Physical functioning • Health status • Sexuality and fertility • Emotional adjustment • Psychological and *behavioral functioning • Spiritual/existential *domains • Future outlook • Independence • School performance • Work performance • Social relationships • Family relationships
  249. 249. • Establish autonomy and independence – Achieve emotional independence from adults – Self-esteem and identity development – Acquire a set of values and an ethical system as a guide to behavior • Social and intimate relationships – More mature relations with peers – Prepare for marriage and family • Establish financial independence – Completion of school – Prepare for a career. *
  250. 250. * • Changes in mobility and physical functioning • Changes in physical appearance • Separation from peers and usual activities • Increased dependence on parents at a time they would usually be practicing independence
  251. 251. Research on Quality of Life (QOL) in Young Adult Cancer Survivors
  252. 252. N=523 young survivors, age 15-39 • Compared to peers, YCS had lower physical and social functioning; psychosocial, emotional, and work/school functioning were similar to peers • Worse HRQOL associated with: < high school, no insurance, Hispanic ethnicity, active treatment (esp. chemo), younger age, greater symptom burden • Demands of normal physical, hormonal, cognitive changes + other normal developmental changes may contribute to lower levels of physical functioning and fatigue Smith, JCO, 2013 *
  253. 253. N=8375 survivors, diagnosed age 15-39 • Compared to peers, 30% of those age 40-64 report poor/fair health vs. controls • > 1 diagnosis associated with poorer QOL • 45% of female CRC survivors report fair/poor health – Long-term issues with infertility, bowel function • Earlier age of diagnosis associated with more days of poor mental health compared with older age at diagnosis – Gap in psychological support for youngest survivors • Young age at diagnosis may have long-term QOL impact across lifespan Kirchhoff, JAYAO, 2014 *
  254. 254. • About half or fewer may achieve recommended levels of physical activity (PA) (ages 20-44) • About half may be overweight or obese • More physically active compared to older survivors, less compared to age-related peers • Benefits of PA include improved QOL, symptom reduction, and improved survival/reduced recurrence risk in some cancers • Tobacco use may be higher compared to *
  255. 255. 20 32 39 39 12 29 18 21 9 0 1 0 2 0 3 0 5 0 4 0 0 1 2 3 Number of Risk Factors 4 Percent Affected Unaffected * Risk Behavior Index Score (M), Cancer-affected vs. unaffected 1.4 vs. 1.7 (p<0.01) *Smoking, alcohol use, dietary factors Burton, 2011
  256. 256. Unmet need rated by 70% or more - Sexuality/intimacy-related counseling - Adoption services - Retreats, camps N=879 young cancer survivors Needs were greater for younger survivors and those diagnosed at younger ages Unmet need rated by 50% or more - Diet, nutrition, exercise - Family counseling - Substance abuse counseling - Assistance with transportation, child care *
  257. 257. • Medical care – Perceived excellence in care after diagnosis – Dissatisfaction with initial diagnosis delay • Patient factors - still-maturing cognitive function, reliance on peers for information • Provider factors – not attributing symptoms to cancer, poor provider-patient communication – Side effects and symptoms • Fatigue, depression, nausea, weight gain/loss, bowel function, sexuality/fertility, changes in eating, decreased energy, body image concerns Zebrack, Psychosoc Onc, 2014 *
  258. 258. • Practical – Financial • Inadequate or gaps in health insurance • Difficulty navigating health insurance coverage • Work interruptions • Acquiring early debt & limited financial resources – School/ work disruption • Treatment takes precedence over work, school *
  259. 259. • Psychological and Spiritual – Managing distress & emotions related to cancer, treatment, and fear of recurrence – Social functioning and isolation • Disclosure and communication – Maintain/re-establish normalcy – Loss: job/school, appearance change, relationship changes ***Positive attitudes, beliefs, feelings emerge from cancer experience *
  260. 260. * • Some people can transform their lives by responding to an illness in ways that enhance the quality and meaning of their lives • Resilience = process for identifying and developing resources or strengths to manage stressors in order to gain positive outcome from the experience • Positive growth: greater maturity, appreciation for life than population norms
  261. 261. • Racial/ethnic minority and medically underserved cancer survivors have greater disparities in cancer outcomes and access to survivorship care – African Americans: higher mortality for CRC – Uninsured or underinsured persons → more likely to be diagnosed with advanced cancer → less likely to receive standard care and survive → less likely to adhere to surveillance and survivorship care regimens • Uninsured/underinsured = predominantly Hispanic, recent immigrants, and the working poor – Lifestyle behaviors (e.g., obesity, low physical activity, tobacco use) related to cancer recurrence or mortality are more prevalent among racial/ethnic minority, lower resourced, and less educated survivors CDC, 2011; American Cancer Society, 2012 *
  262. 262. * • Previvors = at increased risk of hereditary CRC, no CRC diagnosis • Bowel function and QOL in children with FAP who underwent colectomy at age < 14 y • n=28, 56% female, mean colectomy age=12 y, current age=24 y • Reported more night incontinence, nighttime stools (p<0.05); daytime incontinence not different from adult sample • 60% reported feeling embarassed “always or sometimes” due to bowel concerns • 20% reported restrictions at school or work, 30% restrictions in sports due to bowel concerns • 36% worried ‘at least some’ about post-surgery cancer risk; greater in younger patients had greater worry • Younger patients reported more FAP surgery-related distress – Number of FAP-affected family members associated with higher distress • Body image and self-esteem scores in normal ranges Durno, Dis Colon Rectum (2012)
  263. 263. 72% seek health information online -Used phone: 31% cell phone, 52% smartphone - 19% smartphone owners download Pew Internet Research Project, 2012; 2014 * Social and mobile media to reach EAO-CRC survivors
  264. 264. * Computer and mobile technology use in the U.S. Pew Internet Research Project, 2014
  265. 265. Clauser,

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