Third Annual Early Age Onset Colorectal Cancer Symposium - Optimizing Outcomes For EAO-CRC

Improving Outcomes For EAO-CRC
Advancing Earliest Stage Diagnosis:
Recognizing Symptoms and Signs of CRC
Thomas K. Weber MD FACS State University of New York Health Sciences

Advancing Earliest Possible Stage Diagnosis:
Recognizing Symptoms & Signs of Young Adult CRC
Thomas Weber, MD FACS
Professor of Surgery State University of New York Health Sciences
Center
President, Colon Cancer Challenge Foundation

SATURDAY MARCH 21st, 2015
http://events.coloncancerchallenge.org

Siegel et al, Journal of the National Cancer Institute
(2017) 109(8):
• “From 1989-90 to 2012-2013 the
proportion of rectal cancers
diagnosed in adults younger than
age 55 doubled from 14.6% to
29.2%. Compared with adults born
circa 1950, those born circa 1990
have double the risk of colon
cancer and quadruple the risk of
rectal cancer. As nearly one-third of
rectal cancer patients are younger
than age 55, screening initiation
before 50 years should be
considered.”

Early Age Onset Colorectal Cancer
A 21st Century Epidemiologic Challenge
• “A study of initial presentation of young onset CRC
patients without established risk factors found
that 86% were symptomatic at the time of
diagnosis” *
• Siegel et al Can Epi Biomark 18(6) 1695-8

Let Us Not Forget
“I spent a year, maybe more, going to multiple doctors with my
complaints. I received lot’s of sincere “reassurance”. But I did not
receive a diagnosis. I did not receive a diagnosis until someone finally
did a rectal exam. That exam took 30 seconds and told me and my
new doctor all we needed to know. But I lost a lot of time.”
A Survivor

Increasing Earliest Possible Stage Diagnosis of
YA CRC
• Young Onset CRC is more likely to be detected at an advanced stage1
• Young Onset CRC patients are significantly more likely to present with
stage III/IV disease compared with patients with older-onset disease
(colon cancer 63% vs. 49%; rectal cancer 57% vs 46%) 2
1. Ahnen et al Mayo Clin Proc 2016:89:216-24
2. You YN et al Arch Int med 2012;172:287-89

Trends in young adults by stage at diagnosis
Source: SEER 9 delay-adjusted rates, 1975-2012; 3-year moving average.
0
0.5
1
1.5
2
2.5
3
Colon
Localized
Regional
Distant
0
0.5
1
1.5
2
2.5
3
Rectum
Localized
Regional
Distant
Incidencerateper100,000
3.6% annually,
2003-2012
3.0% annually,
2003-2012

Increasing Earliest Possible Stage Diagnosis of YA
CRC
What is the Problem?
It is a complex , multifactorial problem…
Rich in opportunity to improve the situation and save
lives…..
• Pre-symptomatic strategies
• And…..
• Rapid, effective response for the symptomatic patient

CRC
Pre-Symptomatic Strategies
Primary Strategies: Risk Assessment Driven
• Family History : Lynch, MYH, FAP
• Family History: First Degree Relative History of CRC
and or Adenomatous Polyps
• Personal History of CRC or Adenomatous Polyps
• Inflammatory Bowel Disease
• Take a family history! And HC Systems must be able
to ACT on that information. EMR?

CRC
Strategies to Improve Timely Diagnosis
For Symptomatic Patients
• Provider Related Delays
• Patient Related Delays

Delays in Diagnosis of Young-Onset
CRC
Patient Related Delays
• “On average, symptomatic young patients wait approximately 6
months before seeking medical care” Ahnen et al
• Lack of recognition
• Embarrassment and fear
• Denial
• Lack of access to care

Delays in Diagnosis of Young-Onset
CRC
Provider Related Delays
• “Once young patients do present with colorectal symptoms they may
encounter physician-related delays”
• Missed symptoms
• Missed diagnosis
• Affecting 15-50% of cases*
*Ahnen et al Mayo Clin Proc 2016:89:216-24

Colorectal Cancer Symptoms & Signs*
• Bleeding from the rectum
• Blood in the stool / Dark or black stools
• Change in the shape of stool
• Cramping abdominal pain
• Constipation and or Urgency
• Decreased appetite and weight loss
• Anemia
* http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-signs-and-symptoms

Cancer Risk of Rectal Bleeding*
• Rectal bleeding: Twenty-one primary studies provided PPVs on rectal
bleeding as a single presenting symptom.13,14,17,18,21,22,24,27-34,36,37,39-41,43
• In more than half of these studies the risk of cancer was equal to or
greater than5% 12-15,17-19,21,23-26,28-37,39-43
• Del Giudice et al Canadian Family Physician 2014 e405

The Clinical Significance / Cancer Risk of
Rectal Bleeding
• “ The rate of CRC among men and women with rectal bleeding is
approximately 25 times that of the general population”*
* Lawrensen R et al. Risk of colorectal cancer in general practice patients presenting with rectal bleeding Eur J
Cancer Care 2006: 15:267-271

Liang and Church
• “Rectal bleeding is a common symptom,(of CRC) especially in
combination with anemia and should be thoroughly investigated.
• “The presence of a second symptom doubles the absolute risk of CRC
in individuals for all age groups.”

Risk Assessment Tool for Colorectal Cancers

The Development of an Ovarian Cancer
Symptom Index Goff et al.

Professor William Hamilton
University of Exeter, U.K. Clinical Practice Research Datalink:
National Health Service (NHS): 64 Million Patients

Positive predictive values (95% confidence
intervals) for colorectal cancer in men and
women aged 18 to 49 years for individual risk
markers and for pairs of risk markers in
combination.
Rectal
bleeding
Rectalmass
Changein
bowelhabit
Constipation
Diarrhoea
Abdominal
pain
Nausea
and/or
vomiting
Low
haemoglobin
Raised
inflammatory
markers
Lowmean
redcell
volume
0.4
(0.3, 0.6)
0.6
(0.3, 1.1)
0.5
(0.2, 1.0)
0.1
(0.1, 0.2)
0.1
(0.1, 0.1)
0.1
(0.1, 0.1)
0.1
(0.1, 0.1)
0.1
(0.1, 0.1)
0.1
(0.1, 0.1)
0.1
(0.1, 0.2)
PPV as a single
symptom
1.8
(-)
17
(-)
0.3
(-)
5.8
(-)
0.4
(-)
0.4
(-)
1.3
(-)
13
(-)
1.4
(-)
8.0
(-)
Rectal bleeding
5.6
(-)
6.3
(-)
6.1
(-)
5.1
(-)
7.0
(-)
1.3
(-)
5.6
(-)
7.0
(-)
2.9
(-)
Rectal mass
1.2
(-)
0.3
(-)
6.1
(-)
0.3
(-)
0.3
(-)
5.1
(-)
0.4
(-)
2.1
(-)
Change in
bowel habit
0.3
(0.1, 0.7)
1.8
(-)
0.3
(0.1, 0.6)
0.5
(-)
0.4
(-)
1.0
(-)
5.1
(-)
Constipation
0.1
(0.1, 0.2)
0.2
(0.1, 0.3)
0.1
(-)
0.4
(-)
0.3
(0.1, 0.6)
0.7
(-)
Diarrhoea
0.2
(0.1, 0.3)
0.1
(0.1, 0.3)
0.5
(0.3, 1.2)
0.3
(0.2, 0.6)
0.7
(-)
Abdominal
pain
0.1
(0.1, 0.2)
0.3
(-)
0.2
(-)
0.2
(-)
Nausea and/or
vomiting
0.4
(0.2, 0.6)
0.2
(0.2, 0.4)
Low
haemoglobin
0.4
(0.2, 0.7)
Raised
inflammatory
markers

Frequency of selected features in cases and controls in the whole study population
Diarrhoea
Abdominal
pain
Rectal
bleeding
Change in
bowel
habit
Raised Inf
markers
Low Hb
Raised
platelets
Raised
white cell
count
Raised
hepatic
enzymes
Low MCV
Cases 3047 3040 2654 730 3115 1802 1678 1472 1392 1102
Controls 531 1534 201 65 575 572 206 488 1019 290
0
500
1000
1500
2000
2500
3000
3500
Cases Controls
Positive
LR
(95% CI)
13.8
(12.6, 15)
4.8
(4.5, 5)
31.6
(27.5,
36.5)
26.9
(20.9,
34.6)
13
(11.9,
14.2)
7.6
(6.9, 8.3)
19.5
(16.9,
22.5)
7.2
(6.5, 8)
3.3
(3, 3.5)
9.1
(8, 10.3)

Young Adult Colorectal Cancer Symptom
Index : Risk Score
• We have the Ovarian Cancer Symptom Index model
• We have the progress reported by Deborah Alsina, Bowel Cancer U.K.
with Professor William Hamilton
• We have a “charge” from the NCCRT to move forward as “rapidly as
practical” to develop tools to identify those at increased risk and
dramatically improve earliest possible stage diagnosis
• FOR ADDITIONAL CONSIDERATION: We have a body of published
literature confirming the cancer risk associated with prolonged rectal
bleeding especially if there are symptoms & signs of anemia.

Young Adult Colorectal Cancer Symptom
Index : Risk Score
• Take action based on the data we have including the NHS data.
• Provider Education initiatives: Medical Schools, Residency, CME
• HCS (Health Care Systems) Quality of Care Metrics. If 80% of your YA CRC
patients are diagnosed at Stage III & IV – NOT acceptable
• NCCRT: Progress with the Family Health History & Early Age Onset Task
Group: Special Satellite Session November 2017 NCCRT Annual Meeting.
Move forward as “rapidly as practical” to develop tools to identify those at
increased risk and dramatically improve earliest possible stage diagnosis
• Explore complimentary research on the critical symptoms and signs for
Young Adult CRC – as Decision Support for HC Providers.
• Case & Control data sets in the U.S. setting as well as the Patient Survey
Concept

Advancing Prevention & Earliest Possible Stage
Diagnosis:
What “Action Steps” Can We Take NOW!
To Reduce YA CRC Diagnosis
And Improve Survival

Diagnosis
• Consumer & Provider Awareness of YA CRC
• Risk Assessment and Evidence Based Action: Family Health History
• Adaptation of the Screening Guidelines to the Current Reality
• Assessing SYMPTOMS is not Screening. It is DIAGNOSIS
• Decision Support Tools (Prof Hamilton) Recognizing CRC Symptoms &
Signs
• What is driving these dramatic increases? The “Epi Challenge”

Constructive Next Steps
 The application and utilization of current evidence-
based, risk-driven CRC surveillance and screening
guidelines would save lives. Nb 74% age 40-49. This
includes improving the use of family history
documentation; the “Forgotten Question.”
 Research and validation of a YA CRC Symptoms & Signs
Index. Barbara Goff’s Ovarian Cancer Symptom index.
 The identification of suitable patient cohorts for the
study of suspected and novel etiologic drivers of these
incidence trends. Nb CDC enhanced comorbidity Cancer
Registries program.
1. Chang et al. Mod Path 2012;25:1128-39

Diagnosis
• 1. “Are we there yet?” Is the risk of rectal or colon cancer for a 40 or
45 year old NOW equal to that of a 50 year old in 1990?
• Decision Support Tools (Prof Hamilton) Recognizing CRC Symptoms &
Signs
• What is driving these dramatic increases? The “Epi Challenge”

0
10
20
30
40
50
60
70
80
1974
1977
1980
1983
1986
1989
1992
1995
1998
2001
2004
2007
2010
2013
Colon
40-44 years
45-49 years
50-54 years
55-59 years
0
5
10
15
20
25
30
35
40
1974
1977
1980
1983
1986
1989
1992
1995
1998
2001
2004
2007
2010
2013
Rectum
40-44 years
45-49 years
50-54 years
55-59 years
Colon and Rectal Cancer Incidence Trends by Age and Birth Cohort
R. Siegel et al

Siegel et al, Journal of the National Cancer
Institute (2017) 109(8):
“Beginning screening at age 45 years is not supported by a recent review of
the evidence for CRC screening (49,50) (USPSTF) and would add
approximately 20 million people to the screening-eligible population.
Yet it is worth noting that in 2013 there were about 10 400 new CRCs
diagnosed in adults age 40 to 49 years and 12 800 cases in adults age 50 to
54 years, similar to the total number of cervical cancers (12 300) (51), for
which screening of 95 million women age 21 to 65 years is recommended
(52).
Moreover, Cancer Intervention and Surveillance Modeling Network (CISNET)
researchers recently reported that beginning screening at age 45 years is
“more effective and provided a more favorable balance between life-years
gained and screening burden than starting at age 50 years” (49). Endoscopic
screening could be particularly useful in stemming the tide of tumors in the
distal colon and rectum (53), which are preponderant in young patients.”

Diagnosis
• 1. “Are we there yet?” Is the risk of rectal or colon cancer for a 40 or 45 year old
NOW equal to that of a 50 year old in 1990?
• 2. Can we better inform “risk”? If you are 42 years old and your BMI is 42, you
have diabetes, smoke and do not exercise – YOUR CRC risk at 42 might well equal
that of the standard (new normal) 50 year old. We need to know. This is a CISNET
modeling problem – that has an answer.
• Decision Support Tools (Prof Hamilton) Recognizing CRC Symptoms & Signs
• What is driving these dramatic increases? The “Epi Challenge”. “Why?”

Diagnosis
NOW equal to that of a 50 year old in 1990?
• Assessing SYMPTOMS is not Screening. It is DIAGNOSIS!
• Decision Support Tools (Prof Hamilton) Recognizing CRC Symptoms & Signs.

Diagnosis of Young Adult CRC : A Strategic Outline
• Adaptation of the Screening Guidelines to the Current Reality:
NOW equal to that of a 50 year old in 1990? (It’s close - see
• Assessing SYMPTOMS is not Screening. It is DIAGNOSIS!
• Decision Support Tools (Prof Hamilton) Recognizing CRC Symptoms & Signs.
T. Weber MD for the Young Adult CRC Research Consortium

The COVINA Group
March 11th, 2017 NYC

The “Other Agenda”
For EAO CRC 2017: Based on the Covina Group Discussions
• To come to a consensus on the top priority Action Items:
Screening Guidelines : Family Health History : Earlier Diagnosis of
the Symptomatic Patient : The Causes – “The Epi Challenge”
• To lay out a road map of the constructive “Next Steps we plan to take.
• Build on the unique to date awareness prompted by Rebecca Siegel’s
article and the media attention it has received e.g. NY Times article
• Launch the formation of the Young Adult CRC Research Consortium.
• The COVINA Declaration?
• Support tools for patients and their Care Givers: The Provider Buddy “App”
for Patients, Care Givers & Providers

Early Age Onset Colorectal Cancer
A 21st Century Cancer Control Challenge:
Summary
• Early Age Onset CRC is a significant and growing national and international cancer
control challenge.
• Characterized by delayed, late stage diagnosis and poor outcomes.
• The reasons for the global increase in EAO CRC are unknown but not unknowable.
• Risk clarification and stratification will save lives. FAMILY HEALTH HISTORY.
National Health Care System Issue / Challenge!
• Symptom recognition and ACTION is essential. SURVEY > RISK INDEX > A Health
Care Provider and Consumer / Patient Issue / Challenge!
• 75% of EAO CRC in 40-49 age group. Revision of Screening Guidelines to
incorporate additional risk factors e.g. Obesity, Diabetes, Smoking etc.
• EAO CRC presents an opportunity for the Lombardi Cancer Center Care
Community to help lead efforts to understand, prevent and effectively treat as
early as possible, a leading cause of young adult cancer death.

FUTURE TRENDS: US COLON & RECTAL CA BY AGE GROUP
A
Colon Cancer
Rectal Cancer

Advancing Earliest Stage Diagnosis: The Genetics
of Early Age Onset CRC Tumor Testing: Improving
Access to Targeted Molecular Therapies and
Clinical Trials
Julia A. Smith MD PhD Laura and Isaac Perlmutter Cancer Center

Julia A. Smith, M.D., Ph.D.
• Clinical Director, Cancer Screening Program
Laura and Isaac Perlmutter Cancer Center
• Director, NYU and Bellevue Lynne Cohen
Foundation & Caring Together Project for
Woman with Increased Risk for Cancer

Hereditary CRC Syndromes
Why bother understanding your risk?

25% of CRC are associated with a
Family History
• 10% are associated with a well recognized genetic
syndrome
• Data accumulating
• HNPCC, FAP, MYH polyposis, PJS
• Bloom’s syndrome, HPS, JPC, 1307K APC

First, Know Your Risk
• Contributing Factors - overview
– Family History/Genetics
– Personal Medical History
• Associated Medical Diseases
• Personal History of Exposure
– Lifestyle
• Diet
• Exercise
• Cigarettes
• Alcohol

Factors Suggestive of Hereditary Cancer
• Young age at diagnosis
• Red flags or unusual cancers
– Ovarian, male breast, pancreatic, melanoma, sarcoma, gastric, brain
• Multiple primaries in same individual
• Family clustering of certain cancers
– Colon/endometrial, breast/ovarian, melanoma/pancreatic
• Multiple colorectal adenomas in same family
• Ancestry
– Specific at risk population
– Relative of a known mutation carrier

@ 50 y/o:
• Population lifetime risk: 1.8%
• With 1 affected relative: 3.4%
• With 2 or >: 6.9%

Hereditary Colorectal Cancer Syndromes
• Nonpolyposis
– HNPCC : CRC +/- EC
• CRC: 25% by age 50, 80% by age 70
• EC: 20% by age 50, 60% by age 70
• Red flag – early onset EC esp. w/ fhx CRC or EC
– Other HNPCC associated cancers
• Gastric, ovarian
• Renal, biliary, small bowel, pancreas, brain, sebaceous adenoma
• Red flag – onset at <50 of 2 or > HNPCC related cancers

Hereditary Colorectal Cancer Syndromes
• Polyposis: 3 syndromes, degree & type
– FAP
• CRC risk 93% by age 50, >99% by age 70
– AFAP
• Lifetime risk of CRC 80-100%
– MAP – MYH associated polyposis
• Specific penetrance/risk not known

Hereditary CRC Syndromes Risk of 2nd
Cancer
• HNPCC
– 30% within 10 yr of initial diagnosis
– 50% within 15 yrs (CRC, EC, 2nd CRC)
• FAP
– duodenal or periampullary ca: 4-12% risk
– Thyroid, pancreatic, gastric, bile duct, adrenal, CNS
(medulloblastoma): increased but small (2%)
– 1.6% risk hepatoblastoma in children < 5 y/o

Lynch Syndrome Increases
Risk of Second Cancer
0
20
40
60
Within 10 yrs Within 15 yrs
General Population
Lynch
RiskofCancer(%)
3.5%
30%
5%
50%

Lynch Syndrome Increases CRC and
Endometrial Cancer Risks
0
20
40
60
80
100
CRC by age
50
CRC by age
70
EC by age 50 EC by age 70
General Population
Lynch
RiskofCancer(%)
0.2%
>25%
2%
Up to 80%
0.2%
20%
1.5%
Up to 71%

Assessment
• Family history
– Expanded pedigree
– Types of cancer
– Polyp history
– Age at diagnosis
– Medical record documentation
• Detailed medical and surgical history
– Personal history of cancer
– Previous colon history including polyp number and type
– Past medical illnesses
– Carcinogen exposure
• Focused physical exam
– Gyn for women including endometrail/ovarian
– Dermatologic
– Head/neck (including thyroid)
– Cononoscopy/EGD

Risk Counseling
Educate, Assess risk, Manage risk
• Provide accurate information on genetic, biologic, environmental risk
• Provide understanding of the genetic basis to allow participation in
decision making
• Formulate options and recommendations for prevention and screening
• Psychosocial support to adjust to risk assessment and adhere to
recommendations
• Must be tailored to individual’s age, education, level of risk, personal
exposure to the disease, social environment

Genetic Testing
• Selection based on personal and familial characteristics that determine probability of carrying
a mutation
• Psychosocial readiness to receive results
• Review of possible genetic test results
– True-positive (carrier)
– True-negative (not carrier but identified in family member)
– Indeterminate (neg & family members neg or unk)
– Inconclusive (MUS)
• Decision made on multifactorial grounds
– Level of risk
– Cost
– Perceived risk-benefit ratio

HNPCC
Surveillance Guidelines
• Colon
– Colonoscopy:
Starting at age 20-25 every 1-2 yr
After age 40 every year
• EC/Ov
– Endometrial aspiration, TVUS, CA-125:
Starting at age 25-35 every 1-2 yrs

Adenomatous Polyposis Syndromes
Surveillance Guidelines
• Colon/rectum (FAP)
– Sigmoidoscopy annually starting age 10-12
• Colon/rectum (AFAP)
– Colonoscopy q 1-3 yr begin late teens or early 20s
• Stomach/duodenum (FAP/AFAP)
– EGD q 1-3 yr begin age 20-25 or time of dx

Management of CRC
• Surgical prevention
• Enhanced surveillance
• Chemoprevention ?
ASA
NSAIDs
OCP

Lifestyle Modification
• Some data:
cigs
weight control
healthy diet
exercise

Remember
• Think
• Plan
• Advocate
• Team work
• It’s never too late
• And get your colonoscopy

Advancing Earliest Stage Diagnosis: New and
“In the Pipeline” Treatments for CRC
Joshua Raff MD White Plains Hospital Center for Cancer, Director, Digestive Cancer
Program

Joshua P. Raff, M.D.
Director, Digestive Cancer Program
New and ‘In the Pipeline’
Therapies
March 12, 2017,

Treatment Overview for Early Stage
Surgery Adjuvant Chemo
NeoAdjuvant
Chemo +Radiation
Surgery
Adjuvant
Chemo
Rectal Cancer
Colon Cancer

Treatment Overview for Advanced Disease
Chemo
Biologics
Occasional
Surgery
Occasional
Radiation
Palliative
Therapies

Drugs Used For CRC in the US
5 Fluorouracil
Capecitabine
5Fu LV
Capecitabine
Oxaliplatin
5fu LV Oxaliplatin
Capecitabine
Irinotecan
Cetuximab
Panitumumab
Bevacizumab
Ramucirumab
Ziv-Aflibercept
Regorafenib
Trifluridine +Tipiracil
NeoAdjuvant
(Rectal Only)
Adjuvant
(Both)
Advanced
(Both)

Drugs Used For CRC in the US
5 Fluorouracil
Xeloda
5Fu LV
Xeloda
Eloxatin
5fu LV Eloxatin
Xeloda
Camptosar
Erbitux
Vecitbix
Avastin
Cyramza
Zaltrap
Stivarga
Lonsurf
NeoAdjuvant
(Rectal Only)
Adjuvant
(Both)
Advanced
(Both)

Colorectal
Cancer
Host
Immune
Response
Genetics
Cell
Signal
Pathways
Gut
Microbe
Milieu

Host
Immune
Response
Cell
Signal
Pathways

Overview of cellular signaling
pathways involved in colorectal cancer
J Natl Cancer Inst (2009) 101 (19): 1308-1324.

Molecularly Targeted Approaches
VEGF – Bevacizumab, Ramucirumab,
Zif-Aflibercept
EGFR – Cetuximab, Panitumumab
Regorafenib - a multi-target inhibitor: VEGFR1,
VEGFR2, VEGFR3, PDGFRβ, Kit, RET, Raf-1
MTOR, MEK
IDO, BRAF
WnT, PDGFR
FGFR
These – and
many more –
currently being
studied

Types of Immunotherapies in GI Ca
Immune Checkpoint Inhibition
Monoclonal Antibodies
Cancer Vaccines
Adoptive Cell therapy
Oncolytic Virus therapy
Adjuvant Immunotherapies
Cytokines

Mismatch Repair (MMR) & MicroSatellite
Instability (MSI)
• Mismatch Repair enzyme system - recognize and
repair errors which occur during DNA replication
• Impaired or deficient mismatch repair genes (MMR-D)
leads to inconsistent DNA patterns of certain areas of
chromosomes, called microsatellites
• Normal State is MMR-P (proficient), and MS Stable
• Micro Satellite Instability-High (MSI-H) is the condition of
DNA inconsistency resulting from impaired MMR genes
• MSI caused by MMR-D represents a distinct pathway of
carcinogenesis, ie cancer formation.

MMR / MSI, & Hereditary Syndromes
• The hereditary syndromes involving mutations of
mismatch repair enzymes (MLH1, MSH2, MSH6, and
PMS2) is often referred to as Lynch syndrome, but other
classifications exist including HNPCC (Hereditary Non-
Polypotic Colon Cancer) – 5% of CRC
• MSI-H Associated more with: Right Side colon cancer,
poorly differentiated tissue, Crohn's-like host
response, Tumor Infiltrated Lymphocytes,
• MSI-H cancer appears to be more antigenic than MSS
malignancies and has a special susceptibility to
immunotherapeutic strategies.

T Cell Inhibition
http://www.genscript.com/immune-checkpoint-inhibitors.html

Immune Checkpoint Inhibition
http://www.genscript.com/immune-checkpoint-inhibitors.html
Pembrolizumab
Nivolumab
Atezolimumab
Ipilimumab

J Clin Oncol 34, 2016 (suppl; abstr 103); J Clin Oncol 35, 2017 (suppl 4S; abstract 519)
28 patients
MMR-D / MSI-H
At least 2 prior Chemos
25 patients
MMR-P
At least 2 prior Chemos
Pembrolizumab
PD-1 Inhibitor
(Keytruda)
10mg/kg q 3wk
RR SD PFS OS
50% 39% N/R N/R
0% 16% 2.4 6m
o
74 patients
MMR-D / MSI-H
At least 1 prior Chemo
Nivolumab
PD-1 Inhibitor
(Opdivo)
3mg/kg q 2wk
RR SD PFS OS
31% 37% 9.6 N/R
PD-1 Inhibitors in Metastatic CRC
with MMR / MSI

Atezolimimab + Bevacicumab in MSI-H
• Ph Ib study Atezolimumab 1200 mg q3w plus Bev 15 mg/kg q3w
• Ten MSI-high mCRC pts; 2L; median follow-up of 11.1 mo.
• Confirmed ORR was 30%; dCR 90%; Median OS had not been reached
• One AE led to discontinuation of Atezo and 3 AEs led to d/c of bev
J Clin Oncol 35, 2017 (suppl 4S; abstracts 673, 676, 767 )
Pertuzumab + Trastuzumab in HER2+
• ph IIA study HER2+ heavily treated mCRC; 2L, med 4 prior
• standard doses of pertuzumab + trastuzumab only NO CHEMO
• 34 patients; median follow-up of 5.2 mo
• 12 patients had PR; 3 with SD for >4 months
Activated T cells with chemotherapy
• 17 patients with mCRC ; first-line chemoimmunotherapy.
• XELOX + bevacizumab + ex vivo expanded αβ T lymphocytes
• mPFS 15.2 months; Immunotherapy-assoc toxicity minimal
• ORR 70%: CR = 23.5%, PR = 47.1%, SD = 29.4% PD = 0

J Clin Oncol 35, 2017 (suppl 4S; abstracts 660, 673, 676, 677, 767 )
• MABp1 (Xilonix; IL-1a Ab)
• Cobimetinib (anti-MEK)+ Atezolimumab
• Napabucasin (Stemness Inhibitor)
• Nindetanib (anti VEGFR, PDGFR and FGFR)
• Vemurafenib – for BRAFV600 mutated and
extended RAS wild-type mCRC
• Anti-KRAS siRNA nanoparticles (preclinical)
Other Agents Showing Promise

Immune and Stromal Classification of
Colorectal Cancer Is Associated with
Molecular Subtypes and Relevant for
Precision Immunotherapy
• Retrospectively analyzed the composition and the
function of
• 1,388 colorectal cancer tumors from three
independent cohorts
• Prospectively validated findings using
immunohistochemistry.
• Found four distinct subclasses based upon
molecular and tumor micro-environment features
Etienne Becht et al. Clin Cancer Res 2016;22:4057-4066

Immune and stromal signatures of the four molecular subgroups of colorectal cancer.
Etienne Becht et al. Clin Cancer Res 2016;22:4057-4066©2016 by American Association for Cancer Research

Immune and stromal signatures of
the four molecular subgroups of
colorectal cancer.
CMS1 characterized by overexpression of genes specific to
cytotoxic lymphocytes.
CMS2 (canonical ) and CMS3 (metabolic ) subtypes have
intermediate prognosis exhibit low immune and inflammatory
signatures : target cellular pathways, and or strategies to up-
regulate immune response
CMS4 is a poor-prognosis mesenchymal subgroup, expresses
markers of lymphocytes and of cells of monocytic origin. The
mesenchymal subgroup also displays an angiogenic,
inflammatory, and immunosuppressive signature
Etienne Becht et al. Clin Cancer Res 2016;22:4057-4066

Colorectal Cancer - Summary
• Clarify best pre- and post-operative regimens
• Shift focus on to molecular and immuno therapies
• Genetic Counseling & DNA testing – more routine
• Testing of tumor tissue is now routine
• MMR, MSI – to predict respone from Immune Checkpoint Inhibitors
• KRAS, NRAS, – to predict response from Cetuximab, Panitumumab
• BRAF – for prognostic and possible Vemurafenib response
• Pembrolizumab or Nivolumab for MMR-D/MSI-H:
- Very promising !
• Many other molecular and immuno therapies, alone
or in combinations – showing promise
• Integrated Tumor Analysis – to predict subclasses
and refine therapeutic strategies

A New Hope for ColoRectal Cancer
Refine Genomic &
Molecular Analysis
Target
Cellular
Processes
Alter the Tumor
Micro- Environment
Zhuzh up
Host
Immune
Response

Advancing Earliest Stage Diagnosis: What Are
We Going To Do To Advance The Cause?
Jacen Roberts CRC Survivor and Advocate
Daniella Burgess Fight Colorectal Cancer

News 12 Video
• http://longisland.news12.com/news/study-colon-rectal-
cancers-on-the-rise-for-millennials-1.13195725#autoplay=true

Jacen’s Story
• Diagnosed with Stage IV rectal cancer in January of 2014 after 6-7 years of irregular bowel
movements and constipation.
• He has undergone 8 FOLFOX treatments, 25 radiation treatments and a lower anterior
resection in 2014 along with a liver resection in 2015.
• After having genetic testing performed in early 2016, Jacen was confirmed to be Lynch
positive. As of October 2016, his bi-annual CT scans and annual scopes have ALL come back
clean and he is in remission.
• Attended the Early Age Onset Colorectal Cancer (EAO CRC) Summit for the past two years
and become a vocal member of the CCCF Community.
• Recently begun his journey as a CRC Advocate by telling his story to News 12 Long Island. He
is dedicated to sharing his story with as many people under the age of 50 as possible – and
SAVING LIVES.
• Jacen lives in North Babylon, NY loves music, cooking and comes from a close knit family.

Where do we go from here?
• Where do go from here?
– Patient Education
• Signs and Symptoms
• Personal advocacy
– Physician Education
• AMA

Fight Colorectal Cancer
get behind a cure.®

About Me!
• Two-time survivor
• Diagnosed at age
17 with stage III in
2001
• Diagnosed at age
25 with stage I in
2008
• Dx Lynch in 2013

ABOUT
FIGHT CRC
• National nonprofit
advocacy
organization
founded in 2005.
• Focus on 4 areas:
– Advocacy/policy
– Research
– Awareness
– Patient Education

ADDRESSING
“UNDER 50”
THE ORG
ROLE
1
Multidisciplinary task force to be
convened in summer 2017
2 Collaborations across the community
Continue funding early-onset research3
Share real life stories4

ADDRESSING
“UNDER 50”
THE
ADVOCATE
ROLE
1
Share your story to raise awareness
and educate others
2
Discuss your family history and
encourage others to do so as well
Participate in clinical trials to continue
the research for treatment &
survivorship care
3
Advocate for more research funding4
Support the growing body of evidence
that will influence guidelines in the
future
5

POLICY
CHANGE
• Advocate on March 15
through Virtual Lobby Day
• Become a policy advocate
year-round
– Blue Star States
– August Recess Challenge
– Call-on Congress
• Sign up at
FightCRC.org/Advocate

CRC
RESEARCH
• Participate in a clinical trial
• Volunteer for focus groups
soliciting patient feedback
• RATS group for those
interested in the science

AWARENESS
• Add your story to the One Million Strong community at
FightCRC.org/OneMillionStrong
• Engage on social media! Tag us at @FightCRC

PATIENT
EDUCATION
• Share the free resources
- both digital and print
materials. Get them at
FightCRC.org/Resources
• Educate yourself during
webinars. Sign up on our
website at
FightCRC.org/SignUp

Interested in Attending the
4th Annual EAO CRC Summit in 2018?
Join our mailing list by visiting
http://coloncancerchallenge.org

Third Annual Early Age Onset Colorectal Cancer Symposium - Optimizing Outcomes For EAO-CRC

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Third Annual Early Age Onset Colorectal Cancer Symposium - Optimizing Outcomes For EAO-CRC

Similar to Third Annual Early Age Onset Colorectal Cancer Symposium - Optimizing Outcomes For EAO-CRC (20)

More from Colon Cancer Challenge Foundation

More from Colon Cancer Challenge Foundation (6)

Recently uploaded

Recently uploaded (20)

Third Annual Early Age Onset Colorectal Cancer Symposium - Optimizing Outcomes For EAO-CRC