Colorectal Cancer e An Update for

Primary Care Nurse Practitioners

Cyndy Simonson, MS, ANP-BC

ABSTRACT
The picture of colorectal cancer (CRC) is changing. Our understanding of factors that
drive the growth of CRC, the image of a CRC patient, and our approach to treating
CRC is all evolving. This article will bring the picture into clearer focus. We will start
with an update of the pathogenesis of CRC, review screening methods, look at a
meta-analysis of risk factors, then follow with new information about the concern of
younger patients developing CRC. We finish with a look at a new treatment option.
With this more focused view, nurse practitioners can screen more effectively for
colorectal cancer.

Keywords: cancer risk, cancer screening, colorectal cancer, early detection, nurse
practitioner
Ó 2018 Elsevier Inc. All rights reserved.

INTRODUCTION costs, and screening and early detection could help

control that cost.4

T he impact of colorectal cancer (CRC) is

substantial; it ranks as the third most com-
mon cancer for both men and women,1 as
well as the second most common cause of cancer
deaths for men and third for women in the United
States.2 It is estimated that 135,430 people will be
diagnosed with CRC and 50,260 people will die
from CRC in 2017.2 That is a sobering thought
because CRC remains one of the most preventable
cancers.2,3 CRC almost always develops slowly over
many years from benign growths in the colon or
rectum. With appropriate screening, lesions can be
identified and removed before they become
malignant.3,4 Siegel et al5 report that recent declines
in CRC incidence rates are likely driven by an
increase in colonoscopy screenings. They report that
in adults 50 to 75 years old, colonoscopy use has
increased from 19% in 2000 to 55% in 2013.5
Despite that increase, only 65% of adults in the
United States are following current screening
recommendations. CRC treatment contributes
approximately $14 billion annually to health care
American Association of Nurse Practitioners (AANP) members may
receive 1.0 continuing education contact hours, including 0.25
pharmacology credit, approved by AANP, by reading this article and
completing the online posttest and evaluation at aanp.inreachce.com.
PATHOGENESIS OF CRC
CRC can occur randomly (sporadic), from inherited
mutations in cancer-related genes (hereditary) or
from chronic inflammatory bowel diseases, such as
Crohn’s disease or ulcerative colitis. Sporadic tumors
account for most of CRC at about 94%, inherited
mutations account for 5%, and inflammatory bowel
diseases for 1%.6 In the sporadic group, about 25% of
tumors occur in patients who have a family history of
CRC (familial) but no identified familial genetic
CRC syndrome, indicating possible unidentified
cancer-related genes.1
Sporadic CRCs typically develop along 1 of 3
proposed genetic and morphologic pathways. The
first is the chromosomal instability or suppressor
pathway, accounting for about 70% of sporadic
CRCs. This pathway is characterized by genetic
alterations that interfere with tumor suppressor genes
(such as APC, KRAS, and p53) that activate path-
ways critical for carcinogenesis. These tumors are also
described as having microsatellite stability or intact
DNA mismatch repair systems. Second is the mi-
crosatellite instability (MSI) or mutator pathway,
accounting for about 15% of sporadic CRCs. This

344 The Journal for Nurse Practitioners - JNP Volume 14, Issue 4, April 2018
pathway is activated by disruption of the DNA
mismatch repair genes (MMR deficiency). The
mismatch repair system is responsible for proofing
newly created DNA, identifying and repairing
replication errors. When this system is inactivated,
DNA mutations increase rapidly, allowing malignant
cell lines to grow. The BRAF gene is an oncogene
and can direct cell growth. It is often mutated in MSI
tumors, facilitating malignant cell growth. These
tumors often arise in the proximal colon and have
increased mucin production, signet ring cells, and
low-grade differentiation. The third is the CpG island
methylator phenotype (CIMP) or serrated pathway,
which causes tumor suppressor genes to switch off,
allowing growth of malignant cell lines. This ac-
counts for 30%e40% of sporadic CRC. These tu-
mors are also often found in the proximal colon,
occur more often in females, and have poor
differentiation.1,3,6e9
Hereditary CRC can be subdivided into those
with or without colon polyps. The syndromes
characterized by polyps include familial adenomatous
polyposis (FAP), MYH-associated polyposis, Peutz-
Jeghers syndrome, Juvenile Polyposis syndrome,
phosphatase and tensin homolog (PTEN), and
hamartoma tumor (Cowden) syndrome. Those
commonly without polyps are referred to as heredi-
tary nonpolyposis CRC (Lynch syndrome). The 2
most common are hereditary nonpolyposis CRC and
FAP; both are autosomal dominant. FAP develops
most often from the chromosomal instability
pathway. This syndrome results in the development
of hundreds to thousands of polyps in the colon and
rectum beginning in adolescence. If untreated, 100%
of those affected will develop CRC by the age of 40
years. Prophylactic subtotal colectomy followed by
annual rectal endoscopy is recommended for affected
individuals, but can be delayed until the polyp
burden becomes too high to be safely managed by
colonoscopy. Hereditary nonpolyposis CRC de-
velops most often from the MSI pathway and is
associated with increased risk of CRC, synchronous
and metachronous CRCs, along with endometrial,
ovarian, gastric, small bowel, urinary tract, brain and
biliary cancers. National Comprehensive Cancer
Network guidelines recommend that these in-
dividuals begin annual or biennial screening
www.npjournal.org
colonoscopy at age 20e25 years, or 10 years before
the age at diagnosis of youngest family member
(whichever comes first).10e13
The pathway of development of CRC from in-
flammatory bowel disease is not yet well understood.
Chronic inflammation plays a role in the development
of CRC, and this is certainly important in the devel-
opment of CRC in inflammatory bowel disease. The
chromosomal instability pathway and the MSI
pathway also play important roles, but at different
times and frequencies than in sporadic CRC.14
All the pathways described earlier cause focal
changes that develop into benign polyps. These
typically grow slowly, may remain benign, or may
take decades to develop into malignancies. The 2
types of polys with the most potential for malignant
transformation are adenomas and sessile serrated
polyps. Tubulovillous and villous adenomas have the
greatest malignant potential and account for 60%e
70% of CRC. Sessile serrated polys account for
25%e35% of CRC. They are flat, may not bleed,
and grow in a way that can be difficult to detect
during colonoscopy.3,4
Our understanding of these pathways is rapidly
increasing, facilitating development of more targeted
and effective treatments, as well as the development
of more sensitive and specific screening methods to
detect early CRC and even developing benign and
precursor polyps.3,4
Another field of emerging study important to the
understanding of CRC pathogenesis and treatment is
the gut microbiota. The gut microbiota likely plays
an important role in the development of CRC, a role
in protecting from the development of CRC, as well
as a role in determining the response to treatment of
CRC. It is not within the scope of this article to
present an in-depth discussion of the gut microbiota,
but to note the developing field of research that will
likely enhance our understanding of CRC as well as
give us new targets for detection, prevention, and
treatment. For a more in-depth review, please refer
to Drewes et al.15
SCREENING FOR CRC
Screening remains the most important means to
prevent CRC. The primary care nurse practitioner
should be knowledgeable about CRC screening
The Journal for Nurse Practitioners - JNP 345
guidelines and apply them appropriately to patients.
There are several reliable resources for screening
guidelines, including the National Cancer Institute,
National Comprehensive Cancer Network, Amer-
ican Society for Clinical Oncology, American
Cancer Society, Centers for Disease Control and
Prevention, US Preventive Services Task Force,
American College of Gastroenterology, and the
American Society for Gastrointestinal Endoscopy.
The US Preventive Services Task Force guidelines
focus on asymptomatic individuals with average risk:
those without a history of (1) adenomatous polyps;
(2) inflammatory bowel disease or CRC; and (3) of
known familial genetic syndromes associated with
risk of CRC. They recommend screening in-
dividuals starting at age 50 and continuing until age
75. Individuals over age 75 should be screened based
on their condition and history, noting that in-
dividuals in this age group who have never been
screened benefit the most. They do not recommend
screening for individuals age 85 or older.16 The
American Cancer Society gives recommendations
for screening for individuals at average risk 17 and for
individuals at increased risk that can be found in
the Table.18
The screening methods used for CRC can be
divided into stool-based, direct visualization, and
serology. The stool-based tests include guaiac based
fecal occult blood test (gFOBT), fecal immuno-
chemical tests (FITs), and multitargeted stool DNA
testing (FIT-DNA). Direct visualization includes
flexible sigmoidoscopy and colonoscopy computed
tomography colonography.4,15 Serology includes
the SEPT9DNA. Different organizations and task
forces have different standards for which CRC
screening tests to use, when to use them, and how
often. Several organizations have collaborated to
provide tiered recommendation for those at average
risk for CRC, which is based on performance, costs,
and additional practical factors: The US Multi-
Society Task Force of Colorectal Cancer, which
represents the American College of
Gastroenterology, the American Gastroenterological
Association, and The American Society for
Gastrointestinal Endoscopy. They list colonoscopy
every 10 years and annual FIT as tier 1, computed
346 The Journal for Nurse Practitioners - JNP
tomography colonography every 5 years, FIT-DNA
every 3 years, and flexible sigmoidoscopy every 5 to
10 years for tier 2, and capsule colonoscopy every 5
years as tier 3. They do not recommend using the
SEPT9DNA test because of its performance and
cost issues. Their tiers are meant to be sequential if
the first recommendations of the provider are
declined by the patient, and should be risk stratified.
They also have recommendations for individuals at
increased risk of CRC. Please refer to their
guidelines for detailed recommendations.19 The US
Preventive Services Task Force does not rank the
available CRC screening tests. In evaluating
evidence for each test, they did not find any one test
more effective than another; however, they
recognize that there were variances in effectiveness,
strengths, and limitations.15 Please see their
recommendation statement for a detailed discussion.
Many sources note that the most effective screening
test is the one that patients will agree to do. Primary
care nurse practitioners should discuss screening
options with their patients and, based on the
patient’s risk, age, condition, ability to access health
care, and willingness to undergo screening, decide
together on the most effective screening steps
to take.
RISK FACTORS FOR CRC
There are multiple risk factors for CRC. They are
often divided into 2 categories e modifiable and
non-modifiable. Non-modifiable risk factors include
age, family history, ethnicity, and a personal history
of a predisposing genetic syndrome or inflammatory
bowel disease. Modifiable risk factors include lack of
physical exercise, a diet low in fruits, vegetables, and
fiber and high in fat, red meat, and processed meat,
smoking, drinking alcohol, and being overweight or
obese.10,20,21 Published literature has shown an
association for each of those risk factors, but not
always conclusive evidence. Johnson et al21
performed a meta-analyses of CRC risk factors and
identified factors that were statistically significant for
increasing the risk of CRC and some that were
statistically significant in decreasing the risk of CRC.
Those that showed the most statistically significant
increase in risk were having a personal history of
Volume 14, Issue 4, April 2018
Table. American Cancer Society Guidelines on Screening and Surveillance for the Early Detection of Colorectal
Adenomas and Cancer in People at Increased Risk or High Risk
Risk category When to test Recommended test(s) Comment
Increased Risk e People who have a history of polyps on prior colonoscopy
People with small rectal Same age as those at Colonoscopy, or other Those with hyperplastic
hyperplastic polyps average risk screening options at polyposis syndrome are at
same intervals as for increased risk for
those at average risk adenomatous polyps and
cancer and should have more
intensive follow-up
People with 1 or 2 small 5 to 10 years after the Colonoscopy Time between tests should be
(no more than 1 cm) polyps are removed based on other factors, such
tubular adenomas with as prior colonoscopy
low-grade dysplasia findings, family history, and
patient and doctor
preferences

People with 3 to 10 3 years after the polyps Colonoscopy Adenomas must have been
adenomas, or a large (at are removed completely removed. If
least 1 cm) adenoma, or colonoscopy is normal or
any adenomas with high- shows only 1 or 2 small
grade dysplasia or villous tubular adenomas with low-
features grade dysplasia, future
colonoscopies can be done
every 5 years
People with more than 10 Within 3 years after the Colonoscopy Doctor should consider
adenomas on a single polyps are removed possible genetic syndrome
exam (such as FAP or Lynch
syndrome)
People with sessile 2 to 6 months after Colonoscopy If entire adenoma has been
adenomas that are adenoma removal removed, further testing
removed in pieces should be based on doctor’s
judgment
Increased Risk e People who have had colorectal cancer
People diagnosed with At time of colorectal Colonoscopy to look at If the tumor presses on the
colon or rectal cancer surgery, or can be 3 to 6 the entire colon and colon/rectum and prevents
months later if person remove all polyps colonoscopy, CT colonoscopy
doesn’t have cancer (with IV contrast) or DCBE
spread that cannot be may be done to look at the
removed rest of the colon
People who have had Within 1 year after cancer Colonoscopy If normal, repeat in 3 years. If
colon or rectal cancer resection (or 1 year after normal then, repeat test every
removed by surgery colonoscopy to make 5 years. Time between tests
sure the rest of the colon/ may be shorter if polyps are
rectum was clear) found or there is reason to
suspect Lynch syndrome.
After low anterior resection
for rectal cancer, exams of the
rectum may be done every 3
to 6 months for the first 2 to 3
years to look for signs of
recurrence

continued

www.npjournal.org The Journal for Nurse Practitioners - JNP 347

Table. (continued)
Risk category When to test Recommended test(s) Comment
Increased Risk e People with a family history
Colorectal cancer or Age 40, or 10 years Colonoscopy Every 5 years
adenomatous polyps in before the youngest case
any first-degree relative in the immediate family,
before age 60, or in 2 or whichever is earlier
more first-degree relatives
at any age (if not a
hereditary syndrome)
Colorectal cancer or Age 40 Same test options as for Same test intervals as for
adenomatous polyps in those at average risk those at average risk
any first-degree relative
aged 60 or older, or in at
least 2 second-degree
relatives at any age
NOTE. The Bethesda criteria can be found in “Genetic Testing, Screening, and Prevention for People With a Strong Family History of Colorectal Cancer.”18 Available at:
https://www.cancer.org/cancer/colon-rectal-cancer/detection-diagnosis-staging/acs-recommendations.html.
Abbreviations: CT, computed tomography; DCBE, double contrast barium enema.

inflammatory bowel disease and a history of CRC in
a first-degree relative. Also statistically significant
were being overweight or obese, smoking, and red
meat consumption. Risk factors that showed a trend
toward higher risk but were not statistically
significant were alcohol and processed meat
consumption. Factors that showed a statistically
significant decrease in risk were increased level of
physical activity and fruit and vegetable consumption.
Postmenopausal hormone therapy use and aspirin/
NSAID use showed a trend toward decreased risk,
but were not statistically significant. Although they
did list limitations to their study, this information is a
good step toward building a statistical risk model of
CRC and can be useful in screening and counseling
patients.21 The National Cancer Institute has a colon
cancer risk assessment tool for men and women who
are between the ages of 50 and 85. It incorporates
family history, screening history, and lifestyle risk
factors to estimate the 5-year risk, the 10-year risk,
and the lifetime risk of CRC. This assessment can be
found at http://www.cancer.gov/
colorectalcancerrisk/.
CRC IN YOUNG ADULTS
The incidence of CRC has been declining in the
general population for several decades. In the young
adult population, however, CRC is rapidly
increasing, especially rectal cancer. Siegel et al22
report in their study of CRC incidence patterns in
the US from 1974e2013 that the incidence of CRC
has been rising for every generation born since 1950.
For example, individuals born in 1990 now have
twice the risk of CRC and 4 times the risk of rectal
cancer as individuals born in 1950. Researchers are
not sure of the reason for this increased risk in young
patients, but postulate that it may be related to
increasing obesity and a decrease in physical activity
in this age group as well.21 Younger patients are more
likely to be diagnosed with later-stage disease than are
older patients, largely because of delayed follow-up
of symptoms.21e23 It is very important for primary
care nurse practitioners to be aware of the rising rate
of CRC in individuals younger than 55, and
particularly rectal cancer in individuals in their
twenties and thirties. Symptoms in these patients
should be evaluated early. In particular, signs of rectal
bleeding in a younger patient should be
assessed promptly.
NEW TREATMENT TARGETS
One of the quickly emerging and exciting treatment
strategies for many cancers is immunotherapy. This is
true for CRC as well. The subset of CRC known as

348 The Journal for Nurse Practitioners - JNP Volume 14, Issue 4, April 2018
MSI- or MMR-deficient CRC is characterized by the
presence of tumor-infiltrating lymphocytes and an
increase in neoantigens in the tumor environment.
These characteristics, along with others, make these
CRCs good candidates for treatment with immune
checkpoint inhibitors. The immune system has an
ability to detect and destroy cancer cells. The cancer
cells learn to evade the immune system and continue to
survive and grow. In a normal immune environment,
T lymphocytes would detect neoantigens and prime
immune cells to recognize and destroy the tumors
expressing them. In a normal immune response, such
as fighting a bacterial infection, the immune system is
upregulated. When the threat is over, the immune
system down regulates. Cancer cells co-opt this system
by expressing cell surface molecules that bind with
immune cells and cause them to down regulate. This
allows the cancer cells to grow without detection by
the immune system. The immune checkpoint in-
hibitors bind with the cell surface markers on the
cancer cells and do not allow them to down regulate
the immune system. The immune system remains able
to detect and destroy cancer cells. Any immune cells
that have been down regulated by cancer cells can be
returned to normal function. Clinical trials of immune
checkpoint inhibitors used in MSI CRC have shown
significant responses. Even though MSI CRC is a small
subset of sporadic CRC, it is an important develop-
ment in treatment. Studies are also underway to see if
MSS or MRR intact CRC, a larger population of
CRC, might be made sensitive to immune therapies
as well.24,25
CONCLUSION
Primary care nurse practitioners play a key role in
identifying patients at risk for developing CRC. Using
new information about screening for CRC, risk factors
for CRC, and the rising incidence of CRC in younger
patients should help prevent CRC and identify CRC
at earlier, more treatable stages.
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Cyndy Simonson, MS, ANP-BC, AOCN is an oncology nurse
practitioner at (Un)Common Sense Solutions, Raleigh, NC, and
can be reached at Cyndy.simonson@gmail.com.In compliance
350 The Journal for Nurse Practitioners - JNP
with national ethical guidelines, the author reports no relationship
with business or industry that would pose a conflict of interest.
1555-4155/18/$ see front matter
© 2018 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.nurpra.2017.12.030
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