Early age onset_colorectal_cancer_2015

Increase in incidence of colorectal cancer among young adults in the US

Rebecca Siegel, MPHSurveillance & Health Services Research ProgramMarch 21, 2015

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%)

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

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%

Right side

Left side

20-2

425

-29

30-3

435

-39

40-4

445

-49

50-5

455

-59

60-6

465

-69

70-7

475

-79

80-8

485

+0

50

100

150

200

250

300

350

400

Age at diagnosis

Ag

e-s

pe

cif

ic in

cid

en

ce

ra

te p

er

10

0,0

00

Men

Women

Source: SEER 18 registries, 2007-2011.

Age-specific incidence rates by sex

90% of cases

20-49 years: 11 per 100,000vs.

50+ years: 140 per 100,000

19751977

19791981

19831985

19871989

19911993

19951997

19992001

20032005

20072009

20110

10

20

30

40

50

60

70

Year of diagnosis

Rate

per

100

,000

Colorectum, 3% per year

Colon, 3% per year

Rectum, 2% per year

Incidence trends overall, 1975-2011


Declines during 2002-2011:

The American Surgeon, Oct 2003

SEER 9, 5,383 patients 20-39 yrs1973-1999

Cancer Epidemiol, Biomarkers, & Prevention, June 2009

SEER 13, 20,646 patients 20-49 yrs1992-2005

The American Surgeon, Sept 1998

LSU Medical Ctr, 37 patients < 401976-1997

Awareness of the increase in early-onset disease

Incidence trends by age: 50+ versus 20-49

Source: SEER 9 registries, 1975-2011; 2-yr moving average.

1975-76

1978-79

1981-82

1984-85

1987-88

1990-91

1993-94

1996-97

1999-00

2002-03

2005-06

2008-090

2

4

6

8

10

12

14

Rate

per

100

,000

Men

Women

45%

2% per yearSince 1993-1994

1975-76

1978-79

1981-82

1984-85

1987-88

1990-91

1993-94

1996-97

1999-00

2002-03

2005-06

2008-090

50

100

150

200

250

300

Rate

per

100

,000

Men

Women

Ages 50+ Ages 20-49

Trends by anatomic subsite in ages 20-49

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

2009-100

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Rate

per

100

,000

2.6 in 1991

4.9 in 2011


Proximal colon

Rectum

Distal colon

Incidence trends by stage at diagnosis, ages 20-49 years

Source: SEER 9 registries, 1975-2011; 2-year moving average.

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

2009-100

0.5

1

1.5

2

2.5

3

Colon

LocalizedRegionalDistant

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

2009-100

0.5

1

1.5

2

2.5

3

Rectum

LocalizedRegionalDistant

Rate

per

100

,000

3.6% per year from 2002-2011

2.9% per year from 2002-2011

Trends by histologic subtype, 20-49 years

Mucinous

Signet-ring cell

Adenocarcinoma, NOS

Source: SEER 9 registries and Joinpoint Regression Program.

Incidence trends by 10-year age group

40-492% per year

30-392% per year

20-293% per year

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

2009-100

5

10

15

20

25

30

Rate

per

100

,000

peo

ple

1975-76

1978-79

1981-82

1984-85

1987-88

1990-91

1993-94

1996-97

1999-00

2002-03

2005-06

2008-090

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

20-29 years


20-29 years5%

30-39 years20%

40-49 years75%

Increase during 2002-2011:

Incidence trends in ages 50-59 years

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

2009-100

5

10

15

20

25

30

35

40

Rectum

55-59

50-54

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

2009-100

10

20

30

40

50

60

70

80

Colon

Rate

per

100

,000

50-54

55-59


2.4% per yearsince 1996

Incidence trends by race/ethnicity, ages 20-49 years

0

2

4

6

8

10

12

14

Non-Hispanic white

Colon and RectumColonRectum

1992-93

1995-96

1998-99

2001-02

2004-05

2007-08

2010-110

2

4

6

8

10

12

14

Non-Hispanic black

1992-93

1994-95

1996-97

1998-99

2000-01

2002-03

2004-05

2006-07

2008-09

2010-110

2

4

6

8

10

12

14

Asian/Pacific Is-landers

1992-93

1995-96

1998-99

2001-02

2004-05

2007-08

2010-110

2

4

6

8

10

12

14

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.

Stage distribution: early vs. later onset

Localized Regional Distant Unknown0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

33%

38%

25%

3%

41%

34%

19%

6%

20-49 years 50+ years


Five-year relative survival

Data Source: Trends, SEER 9 registries; Stage-specific, SEER 18 registries, 2007-2011.

1975-77

1978-80

1981-83

1984-86

1987-89

1990-92

1993-95

1996-98

1999-03

2004-2010

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

55%68%

Trend

Localized Regional Distant0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%94

76

19

90

70

12

20-49 years50+ years

By stage

Mortality trends in ages 20-49 years

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

2009-100

0.5

1

1.5

2

2.5

3

3.5

4

20-49 years

Deat

hs p

er 1

00,0

00

Source: National Center for Health Statistics, National Vital Statistics System.

0

20

40

60

80

100

120

50+ years

Factors that influence population cancer trends

Detection/imagingpractices

Risk factors

Screening behaviors

MortalityIncidence

Treatment

Increase in: Incidence Mortality Risk factor ↑ ↑ Screening ↑ ↓ Detection/imaging practice ↑ Possible artifactual ↑ Effective treatment No effect ↓

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

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 ?

Trends in obesity and diabetes

1971-74 1976-80 1988-94 1999-02 2003-06 2007-08 2009-10 2011-120

5

10

15

20

25

Ages 6-11

Ages 12-19

Perc

ent

6%

Obesity prevalence

0

2

4

6

8

10

12

14

16

18

20

6

16

Rate

per

1,0

00

167%

Diabetes, ages 0-44 years

21%

Source: National Health and Nutrition Examination Survey. Source: National Health Interview Survey.

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, 1.37)

Menopausal status

Premenopause

1.0 1.63 (1.21, 2.20)

Postmenopause

1.0 1.24 (1.02, 1.52)

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.

2-18 yrs 19-39 yrs 2-18 yrs 19-39 yrsSweetened beverages Milk

0

2

4

6

8

10

12

14

1977-781989-911994-961999-01

Perc

ent o

f tot

al d

aily

calo

rie in

take 11

5% 141%

38%

37%

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

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.

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

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

Who else should begin screening before 50?

Increased risk Age to begin

Cancer/adenomas in a first-degree relative

40 years OR10 years before youngest case

Cancer in > 2 second-degree relatives 40 years

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 bleeding2. Abdominal pain3. Change in bowel habits

• Critical need for further research to elucidate the cause of this trend

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 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

Percentage of individuals who develop CRC by specific age

15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 95+0.00%

0.50%

1.00%

1.50%

2.00%

2.50%

3.00%

3.50%

4.00%

4.50%

5.00%

Age (years)

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

35-39

30-34

25-2920-24

19781980

19821984

19861988

19901992

19941996

19982000

20022004

20060

2

4

6

8

10

12

20-49

Canada_20_49

UK_20_49

19781980

19821984

19861988

19901992

19941996

19982000

20022004

20060

20

40

60

80

100

120

140

160

180

200

50-85+

Canada_50plus UK_50plus

Incidence trends in Canada and the UK by age, through 2007

Screening test use in ages 40-49 years

2000 2003 2005 2008 2010 20130

2

4

6

8

10

12

14

Ever routine endoscopy

2000 2003 2005 2008 2010 20130

2

4

6

8

10

12

14

Ever diagnostic endoscopy

Source: NHIS

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 95th percentile based on age/sex-specific growth charts developed by CDC

40-49

30-39

20-29

Incidence trends by age group and subsite

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

2009-100

2

4

6

8

10

12

14

16

Colon

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

2009-100

2

4

6

8

10

12

14

16

Rectum


Rate

per

100

,000

40-49

3% per year

2% per year

20-29

30-39

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 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.

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% 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

Trends in the use of screening tests (ages 50-75)

2000 2003 2005 2008 2010 20130

10

20

30

40

50

60

70

80

Any examColonoscopy (10 yrs)FOBT (past year)Sigmoidoscopy (5 yrs)Pe

rcen

tage

Changes in dietary patterns

Then…

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

• 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-CRCUNIQUE FEATURES OF EAO-CRC: SUMMARY

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-CRCAN ILLUSTRATION

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 ChemoHospice

2/year 2

CLINICAL CHALLENGES OF EAO-CRCOUTLINE

• What are the clinical challenges ?

• How can we improve ?

CLINICAL CHALLENGES OF EAO-CRCWHAT 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

CLINICAL CHALLENGES OF EAO-CRCWHAT 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 ChemoHospice

2/year 2



• Focusing on Survival

• How can we improve ?

Bleyer et al. Nature Reviews Oncology. 2007.

CLINICAL CHALLENGES OF EAO-CRCSURVIVAL : SEER 1993-1998



Focusing on Survival

• What influences survival and how can we improve ?

Stage of disease

Treatment

Quality of life

You et al. Arch Int Med. 2011.

CLINICAL CHALLENGES OF EAO-CRCNCDB, 1998-2007 Age 18-49 Years (N=64,068) vs. Age 50+ Years (N=524,801)

Age-adjusted CRC death rate has declined between 1975-2005

Factors thought to contribute to the decline in death rate:

CLINICAL CHALLENGES OF EAO-CRCAGE-ADJUSTED DEATH RATE: DECLINED 1975-2005

All CRC

~ 5%“Hereditary”

Burt et al. Gastroenterology 2000.

CLINICAL CHALLENGES OF EAO-CRCSUBGROUPS OF CRC & SCREENING GUIDELINES

3-5%

All CRC



Start Frequency

High Risk (“Hereditary”)

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(“Sporadic”)

Age 50 Every 7-10 years

American Cancer Society

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-CRCAPPLYING TO EAO-CRC SUBGROUPS

All CRC



Goal


Defined and effective prevention, surveillance strategies exist

Make the diagnosis

• Clinical suspicion

• Proband and family diagnosis /Registry

70

Ampullary, Pancreas, Hepatoblastoma

Colon and Rectum

Familial Adenomatous Polyposis Surveillance

Thyroid

Brain

Desmoid

/

Why Hereditary Syndrome Should Not Be Missed

Biliary, Pancreas

Colon and Rectum

Lynch Syndrome Surveillance

UrinaryTract

Brain

Skin

Uterine & Ovary

Why Hereditary Syndrome Should Not Be Missed

All CRC



Goal


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




Stage of disease

Treatment

Quality of life

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

75Courtesy of Dr Cathy Eng

CLINICAL CHALLENGES OF EAO-CRCSAME TREATMENT, WORSE OUTCOME ?

Lieu et al. JCO 2014

p < 0.0001

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

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-CRCOVER-TREATMENT, NO BETTER OUTCOME ?

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 IIIAged 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-CRCOVER-TREATMENT, NO BETTER OUTCOME ?

You et al. In Press JAMA Surgery




Stage of disease

Treatment

Quality of life

Benefits

Positive feelings

Family distress

Recurrence distress

Appearance concerns

Financial problems

Sexual dysfunction

Sexual disinterest

Social avoidance

Fatigue

Physical pain

Cognitive problems

Negative feelings

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0%

QUALITY OF LIFE IN ADULT CANCER SURVIVORS (QLACS) % of Scores ≥ 4 per Domain

YS LS

830 (68%) survivors responded282 Young-onset (43.4 ± 6.1 years) 548 Later-onset (62.6 ± 7.5 years)Mean years from diagnosis: 10.8 years*

*

*

**

**

*

EORTC CR-29 (SCORE > 3)

*P<0.05

* Anxiety

* Body image

* Male sexual function

* Female sexual function

0 10 20 30 40 50 60 70

34.2

19.5

57.3

23.0

20.5

13.4

40.2

16.4

Late-Onset Survivors Young-Onset Survivors

Percent of Respondents Reporting Score > 3

CLINICAL CHALLENGES OF EAO-CRCFUNCTIONAL OUTCOMES & CANCER SURVIVORSHIP

CLINICAL CHALLENGES OF EAO-CRCSUMMARY

• 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

THANK YOU

[email protected]

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, MPHColumbia University Medical Center

Herbert Irving Comprehensive Cancer CenterHereditary GI Cancer Risk and Prevention Program, Director

Sporadic (~75%)

Familial colorectal cancer(~20%)

Inherited colorectal cancer syndromes (~5%)

Epidemiology of Colorectal Cancer

Hereditary Colorectal Cancer Syndromes

• Lynch Syndrome/ Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

• Familial Adenomatous Polyposis (FAP)

• MYH Associated Polyposis (MAP)

• Hamartomatous Polyposis Syndromes

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

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

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%

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

Lynch Syndrome Results From Failure of Mismatch

Repair (MMR) Genes

Base pair mismatch

Normal DNA repair

Defective DNA repair (MMR+)

T CT A C

A G C T G

T C G A C

A G C T G

T CT A C

A G C T G A G A T G

T C T A C

Mismatch Repair Failure Leads to Microsatellite Instability (MSI)

Normal

Microsatellite instability Addition of

nucleotide repeats

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

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%

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

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


• 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 syndromeLimburg PJ et al. Clin Gastroenterol Hepatol. 2011;9(6):497-502


• 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 syndromeGiraldez MD et al. Clin Cancer Res. 2010; 16: 5402-5413.

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

Hereditary GI Cancer Syndromes:How good are we at identifying

families with germline mutations?

Proband

HEREDITARY GI CANCER SYNDROME

Germline Testing

PedigreeClinical Criteria+/- tumor testing

+

?

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

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

• 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

• 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

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

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*

• 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 : Y165CG382D

– 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; 15:312-4Win AK, et al. Fam Cancer 2011; 10:1-9

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.

Germline Testing

Proband

HEREDITARY GI CANCER SYNDROME

PedigreeClinical 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

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

• 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

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

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 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)

Overall Panel Testing ResultsTotal 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

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

Thank you!

Fay Kastrinos, MD, MPH212-305-1021

Kate McNamara, MDCCCF Research ScholarUniversity of Toronto

CCCF Annual Research Scholar Award

Zane Cohen Center for Digestive Diseases Research Treatment Education Support

Gastrointestinal CancersResearch GroupsFamilial Gastrointestinal Cancer Registry (FGICR)Ontario Pancreas Cancer Study (OPCS)Ontario Familial Colorectal Cancer Registry (OFCCR)Soft Tissue Sarcoma Research Program (STSRP)

DiseasesLynch 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

Genetics of Early Age Onset Colorectal Cancer (EAO-CRC)

age-standardized incidence rate per 100,000 43.7age-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.

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

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 48.9age-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.

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


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.

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

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*


Seigel et al.

• O’Connell et al. Young adults 20-40y, SEER 1973-1999

• Meyer et al. Young adults <40y, SEER 1973-2005

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



Cancer Care Ontario. Colorectal cancer incidence increasing among adolescents and young adults. August 2009. Available at https://www.cancercare.on.ca/cancerfacts.

https://www.cancercare.on.ca/cms/one.aspx?pageId=8651

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

Hereditary CRC syndromesPOLYPOSIS adenomatous polyposis syndromesFamilial Adenomatous polyposis (FAP) – AD, mutation in APCAttenuated FAP (AFAP) - AD, APC mutations at 5’ or 3’ ends of gene or in certain locations of exon 9MUTYH-associated polyposis (MAP) – AR, biallelic mutations in MUTYHPolymerase-proofreading associated polyposis – AD, mutation in POLE or POLD1

hamartomatous polyposisPeutz-Jeghers syndrome (PJS) - AD, mutations in STK11Juvenile Polyposis syndrome (JPS) - AD, mutation in SMAD4 or BMPR1ACowden syndrome (PTEN hamartoma tumor syndrome) - AD, germline mutation in PTEN

hyperplastic/serrated polyposisSerrated polyposis syndrome – uncertain genetic etiology; unclear hereditary predispositionHereditary mixed polyposis syndrome

NONPOLYPOSISLynch syndrome (LS) – AD, mutation in DNA mismatch repair (MMR) gene (MLH1, MSH2, MSH6, PMS2) or EPCAM

Biallelic Mismatch Repair deficiencyOther (Li-Fraumeni, Bloom syndrome)

POLYPOSIS adenomatous polyposis syndromesFamilial 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

POLYPOSIShamartomatous polyposisPeutz-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%

hyperplastic/serrated polyposisSerrated 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

NONPOLYPOSISLynch 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)

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%) LSUS population based registry 23 total; 0 (0%) LS

hereditary CRC syndromes account for greater proportion of EAO-CRC

FGICR and EAO-CRCLynch Syndrome n=871.MMR (or EPCAM) gene mutation2.IHC deficient tumor • 71 germline mutations• 12 VUS

Classic FAP n=841. >100 adenomas2. 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

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

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.

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

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%)

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

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

recessive

biallelic somatic

Whole genome sequencingvs

Exome sequencing

Whole genome expensive IT issues complete sequence

Exome cheaper more manageable coding regions incomplete sequence

Nat Genet. 2011 May; 43(5): 442–446.

Exome sequencing identifies GRIN2A as frequently mutated in melanomaXiaomu 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 carcinomaIgnacio 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

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

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

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

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

Cancer Genetics 208 (2015) 35-40

Systematic search for rare variants in Finnish early-onset colorectal cancer patientsTomas 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

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

The Toronto EAO-CRC cohort

FGICRUndefined 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

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….

ReferencesFerlay 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):573-80Surveillance 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):1128–1139Yantiss 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):572–582Fante 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 567–568Liang 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: 205–214Berg 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):217Palles 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.

Thank you

Jiyoung Ahn, PhD, RD

Associate ProfessorDept. of Population HealthNYU School of Medicine

Early Age Onset Colorectal Cancer Summit, March 2005

Gut Microbiome, Fiber Intake, and Risk of Colorectal Cancer

163

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

164

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)

165

• 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

166

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.

167

• 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

168

Microbiome Assay and Data Analysis

- Compared overall gut microbiome diversity and microbial taxa abundances in CRC cases and controls

169

Inter-individual variability of gut microbiome

Ahn et al, JNCI, 2013

20 different health subjects

170

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

Sh

an

no

n In

de

x

ControlsCases

Less diverse in cases than in controls


P = 0.02

171

Taxonomic differences in CRC and controls

CaseCont


172

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).


173

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.


174

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

175

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)

176

Summary

• CRC risk was associated

- with decreased gut microbiome diversity;

- increased presence of Fusobacterium;

- depletion of fiber–fermenting Clostridia.

• High fiber intake Clostridia CRC.

177

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

178

Implications

• Learn about the causes of CRC.

• Identifying people at high risk for CRC.

• Possible prevention of CRC by tailored bacterial and diet modifications.

179

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)

http://www.NYUMGEL.org/

180

Each body site has a different and unique microbiome

HMP data

181

Shared common structure of human microbiome

CatonellaDialisterEubacteriumFilifactorGemellaGranulicatellaMegasphaeraParvimonasSelenomonasStreptococcusVeillonellaAggregatibacterCamplylobacterHaemophilusKingellaNeisseriaCapnocytophagaPorphyromonasPrevotellaTannerellaActinomycesBifidobacteriumSlackiaFusobacteriumLeptotrichiaFusobacteria (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%)

Hum

an Oral B

acteria

Ahn et al, PLoS ONE, 2011

Phyla Genera

Early Age Onset Colorectal Cancer A 21st Century Epidemiologic Challenge

Thomas K Weber, MD FACSProfessor of Surgery

State University of New YorkHealth Sciences Center

Brooklyn, New York

Incidence trends by age: 50+ versus 20-49


1975-76

1978-79

1981-82

1984-85

1987-88

1990-91

1993-94

1996-97

1999-00

2002-03

2005-06

2008-090

2

4

6

8

10

12

14

Rate

per

100

,000

Men

Women

45%

2% per yearSince 1993-1994

1975-76

1978-79

1981-82

1984-85

1987-88

1990-91

1993-94

1996-97

1999-00

2002-03

2005-06

2008-090

50

100

150

200

250

300

Rate

per

100

,000

Men

Women

Ages 50+ Ages 20-49


• We have a major cancer control / epidemiologic challenge

• The “seismic” nature of this challenge are illustrated by very simple “30,000 feet” observations.


• “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




• 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…………..



• 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.


• 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.


• 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:• “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.”


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


Known Knowns……The Basics• A POSITIVE family history for CRC and or

Lynch related malignancies• A positive history for Inflammatory Bowel

Disease - IBD


Unknown Knowns……What is the true risk – in YOUNG ADULTS?


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!



• Diabetes• Sleep Patterns?• Sitting Position?• Alcohol?• Tobacco?• Recreational Drugs ?



• Microbiome?• Periodontal Disease?• Our Environment?• The Exposome?


What DO we know about the Unknown Knowns……?

• Any Data?

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

Measuring the Exposome



• Genetics……………………………..• “Known Syndromes?• Unknown Genetic Elements and

Syndromes • Unknown Unknowns?

GWAS, SNPS,THE “EXPOSOME” andColorectal 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.


• “But there are also unknown unknowns. There are things we don't know we don't know.”

• ?• ?• ?• ?


• “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?


• How Can We Move Forward?

• 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

Evidenced Based Score Card



• Diabetes• Sleep Patterns?• Sitting Position?• Alcohol?• Tobacco?• Recreational Drugs ?



• Microbiome?• Periodontal Disease?• Our Environment?• The Exposome?

Evidenced Based Score Card


• “There are also unknown unknowns. There are things we don't know we don't know.”

• ? • ?• ?• ?


• “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?

Incidence trends by race/ethnicity, ages 20-49 years

0

2

4

6

8

10

12

14

Non-Hispanic white

Colon and RectumColonRectum

1992-93

1995-96

1998-99

2001-02

2004-05

2007-08

2010-110

2

4

6

8

10

12

14

Non-Hispanic black

1992-93

1994-95

1996-97

1998-99

2000-01

2002-03

2004-05

2006-07

2008-09

2010-110

2

4

6

8

10

12

14

Asian/Pacific Is-landers

1992-93

1995-96

1998-99

2001-02

2004-05

2007-08

2010-110

2

4

6

8

10

12

14

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.


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


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.


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


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


SUMMARY?


“You Never Know…”


• 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.


• 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


RISK• Identification• Clarification• Mitigation / Reduction


THANK YOU!

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

Quality of Life After an EAO-CRC

Diagnosis: Knowledge Gaps

andOpportunities

Susan K. Peterson, PhD, MPH

Professor, Behavioral Science

1st Early Age Onset Colorectal Cancer Summit

New York, NY

March 21, 2015

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.

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

• 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

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

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, 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

N=8375 survivors, diagnosed age 15-39

• Compared to peers, 30% of those age 40-64 reportpoor/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

• 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

Belanger, 2011; Hall, 2012

Health Behaviors in Young Adult Cancer Survivors

20

32

39 39

12

29

18

21

9

0

10

20

30

50

40

0 1 2 3

Number of Risk Factors

4

Perc

en

tAffectedUnaffected

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

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

• 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

• 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


• 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


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, appreciationfor life than population norms

• 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

Health disparities in U.S. cancer survivors

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

colectomyat 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;

greaterin 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)

72% seek health information online- Used phone: 31% cell phone, 52%

smartphone- 19% smartphone owners

downloadapps to manage or track health

Pew Internet Research Project, 2012; 2014

Social and mobile media to reach EAO-CRC survivors

Computer and mobile technology use in the U.S.

Pew Internet Research Project, 2014

Clauser, 2011

• 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 anddiffer 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

• 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 QOLsupport in EAO-CRC


• 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 →

pooradherence to treatment, failure to seek future care

→ Resources needed for EAO-CRC that areappropriate 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


National Cancer Institute, National Institutes of Health, 1R42 CA126453,1R41-CA126453-01

Seed Money Grant, Duncan Family Institute for Cancer Risk Assessmentand Prevention

Cancer Center Support Grant (CA016672, PI: R. DePinho)

National Cancer Institute, National Institutes of Health

Martha Askins, PhD

Associate Professor and Pediatric Psychologist Psychosocial

Director, Adolescent and Young Adult Program

The Children’s Cancer Hospital at MD Anderson Cancer Center

Acknowledgements

*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.

*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

• 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

*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

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, 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

N=8375 survivors, diagnosed age 15-39

• Compared to peers, 30% of those age 40-64 reportpoor/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

• 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

Belanger, 2011; Hall, 2012

* Health Behaviors in Young Adult

Cancer Survivors

20

32

39 39

12

29

18

21

9

0

10

20

30

50

40

0 1 2 3

Number of Risk Factors

4

Perc

en

tAffectedUnaffected

*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

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

• 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

• 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

• 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

* 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

• 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

survivorsCDC, 2011; American Cancer Society, 2012

*Health disparities in U.S. cancer survivors

* 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); daytimeincontinence not different from adult sample

• 60% reported feeling embarassed “always or sometimes” due to bowelconcerns

• 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)

72% seek health information online- Used phone: 31% cell phone, 52%

smartphone- 19% smartphone owners

downloadapps to manage or track health

Pew Internet Research Project, 2012; 2014

* Social and mobile media to reach EAO-CRC

survivors

* Computer and mobile technology use in the U.S.

Pew Internet Research Project, 2014

Clauser, 2011

• 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 survivorse.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

• 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 QOLsupport in EAO-CRC


• 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


National Cancer Institute, National Institutes of Health, 1R42 CA126453,1R41-CA126453-01

Seed Money Grant, Duncan Family Institute for Cancer Risk Assessmentand Prevention

Cancer Center Support Grant (CA016672, PI: R. DePinho)

National Cancer Institute, National Institutes of Health

Martha Askins, PhD

Associate Professor and Pediatric Psychologist Psychosocial

Director, Adolescent and Young Adult Program

The Children’s Cancer Hospital at MD Anderson Cancer Center

*Acknowledgements

What Is “Normal” After Cancer Treatment?

Those who have gone through cancer treatment describe the first few months as a time of change. It’s not so much “getting back to normal” as it is finding out what’s normal for you now. People often say that life has new meaning or that they look at things differently now. You can also expect things to keep changing as you begin your recovery.

Your new “normal” may include making changes in the way you eat, the things you do, and your sources of support.

From Facing Forward: Life After Cancer Treatment – National Institute of Health; National Cancer Institute, May 2014

What is the ‘New Normal’ ?

• A paradigm shift

• A work in progress

• Part of a club you never wanted to join

• There is no new normal

• Nothing about the new is normal

• I am constantly reminded of my life before cancer

and it stings a little more as time passes

A New Normal: Patient Insight

• 175 patients, survivors and caregivers

participated

• Study and interviews conducted during January

and February, 2015

• In person meetings; virtual town hall meetings;

telephone; and social media private chats

Study and Interview Format

Initial Thoughts: 'New Normal’

FearRegretPerspectiveAngerAnxietyControl Gratitude

Patient Survey Summary

• “ Every ache or pain makes me fear recurrence”

• “ I fear death and leaving my young children alone”

• “ Night terrors, pain and fear that I may die”

• “ Fear of unknown – what lies ahead”

• “ Fear that I will never regain my former self – that will never laugh and feel genuine joy again”

• “ Fear that my children may not remember me”

Fear: Patient Insight

• “I wish I had been a better person before diagnosis”

• “ I regret that I did not understand my symptoms”

• “ I wish I had not spent so much time at work”

• “ I should have insisted on a second medical opinion”

• “ I regret I didn’t have children before it was too late”

• “ I wasted too much time on stupidity – a big regret”

Regret: Patient Insight

• “I now see it as two lives - I had one life before cancer and one life after diagnosis”

• “ I no longer sweat the small stuff”

• “ My goal is to live meaningfully and

contribute”

• “ I am grateful - I appreciate every day - I try to live with integrity and purpose”

• “I am more spiritual and take time for

reflection”

Perspective: Patient Insight

• “I am angry and I grieve for what might have

been”

• “ Anger that the goals you have strived for throughout your life now seem so far out of reach”

• “ A mental screw game of constantly losing

friends”

• “Financially and emotionally bankrupt”

• “Why me? Why my family?”

• “ CRC robbed me of my chance to have a family and ‘normal’ intimacy”

Anger: Patient Insight

•“Constant feeling like someone punched me in the gut”

•“ I wake up in the middle of the night with full blown panic attacks”

•“ Survivors Guilt and the anxiety of knowing I may be next”

•“ I want to scream at people when they say I should get back to normal”

•“ My stress and anxiety are internalized – not healthy, but I don’t want to worry my family”

Anxiety: Patient Insight

• “Colon Cancer is an out-of-control roller coaster from Hell - You can’t get off once you’ve gotten on.”

• “ Lack of control over my own life is the most terrifying”

• “ I miss the days where life was predictable and I felt in control of most things – my family, finances, and work”

• “ I can’t control my bodily functions so now I leave the house with adult diapers, wipes, and clean clothes. I can’t control my body, but I can control my response.”

• “Self-conscious about my body image – 24/7”

Control: Patient Insight

• “ I may not make it to my ‘golden years’, but I will make every day now golden”

• “ Friends and family now call me courageous - I didn’t know how strong I was until I had cancer”

• “ I learned that volunteering and working to make change for other people with CRC is very rewarding”

• “ You will do anything to live – to be there with your loved ones and you understand what really is important and what is not ”

• “ I am grateful that I got to re-invent myself and my life – I am a much better person now”

Gratitude: Patient Insight

Go Live Your Life Music Video

Go Live Your LifeWade Hayes

https://www.facebook.com/l.php?u=https://www.youtube.com/watch?v%3DWs1_UzYguWs&h=UAQF9O-rl&s=1

• As a community what can we do to support and empower young CRC patients as they build their new normal?

• The needs are clear: Emotional, Physical, Psycho-Social, Family Support, Financial, Work/Career

Call To Action

• Thomas Weber, MD FACS

• Robin Mendelsohn, MD

• Cindy Borassi

• Colon Cancer Challenge Foundation

• Memorial Sloan Kettering Staff

• Survey and Town Hall Participants

• Fellow speakers

Thank you!