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Medscape Medical News > Oncology

Multigene Testing a 'Must' for Young Patients With

Colorectal Cancer
Roxanne Nelson, BSN, RN
December 15, 2016

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Multigene panel testing should be considered for all

EDITORS' RECOMMENDATIONS
Not on Anyone's Radar: Colorectal
Cancer in Young Adults
Why Is Colorectal Cancer
Targeting the Young?
patients with colorectal cancer (CRC) who are diagnosed
younger than age 50 years, new findings suggest.
Among 450 patients with early-onset CRC, 16% had a
pathogenic mutation, and testing with a multigene panel
identified mutations that might have been otherwise MOST POPULAR ARTICLES
missed. According to ONCOLOGIST/HEMATOLOGISTS

A third of these patients 1. Indications for Adjuvant Radiation

Colorectal Cancer Alarm:
Rates Rising in Young
Adults
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harbored pathogenic mutations that did not meet Therapy in Breast Cancer
National Comprehensive Cancer Network (NCCN)
2. Postmastectomy Implants? Radiotherapy
Guidelines for at least one of the genes in which they Affects Outcomes
were found to have a mutation.
3. More Frequent Creatinine Checks for
"Genetic counseling and testing with a broad multigene Some Patients on Oral Anticoagulation?
panel should be considered for all patients with early-
onset CRC due to their high prevalence of hereditary 4. WHO Urges Trump to Expand
cancer syndrome," the authors conclude. Obamacare, Ensure Healthcare for All
The study was published online December 15 in JAMA 5. Top Cancer Doc: I Have HIV -- Stigma
Oncology. Can Be Devastating

Early-onset cancer is a hallmark of inherited cancer predisposition, but genetic testing is still VIEW MORE
not yet universal. "Tumor screening for Lynch syndrome is being done at many but not all
hospitals for all colorectal cancer patients, and patients with abnormal tumor screening
are referred to cancer genetics to consider genetic testing for Lynch syndrome," said lead
author Heather Hampel, MS, CGC, associate director, Division of Human Genetics, Ohio State
University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J.
Solove Research Institute, Columbus.

"Patients with normal tumor screening are generally only referred to cancer genetics if they
have a strong family history or polyposis," she told Medscape Medical News. "What our study
has found is that all of the colorectal cancer patients diagnosed under age 50 should be
referred to cancer genetics for consideration of a multigene panel test of hereditary cancer
susceptibility genes, including more than just testing for Lynch syndrome. I would guess that
the majority of these patients are not being seen in cancer genetics currently."

Beyond Lynch Syndrome

CRC is typically a disease that occurs in older adults, with only 10% of patients diagnosed
before age 50 years.

Hereditary cancer syndromes are implicated in approximately 5% of all CRC cases, the
authors note in their paper. Although the prevalence of genetic predisposition is likely higher
among individuals who develop cancers at an early age, younger patients with CRC are
significantly less likely than their counterparts with young-onset breast cancer to undergo
genetic evaluation.

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Stories by germline
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Support Tied to deficiency genes
In Fossil Rarity, MLH1, MSH2
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at Cancer Top Cancer Doc: I Have Multigene Testing a
PMS2, Live Longer . Lynch syndrome
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with Is the HIV -- Stigma Can Be 'Must' for Young Patients
Outcomes Year-Old Beast Future Devastating With CRC
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NCCN guidelines suggest that all patients with CRC diagnosed at age younger than 50 years
consider genetic testing for Lynch syndrome.

However, the prevalence of other hereditary cancer syndromes among younger patients is
relatively unknown because of limited studies, which have also generally been confined to
select populations, the authors note.

Pathogenic Mutations Revealed

In the current study, Hampel and colleagues sought to determine the prevalence and
spectrum of germline mutations in 25 genes associated with various hereditary cancer
syndromes by using a multigene panel.

Among the 450 patients in the cohort, the mean age at cancer diagnosis was 42.5 years,
and 8.2% of patients (n = 37) had an additional malignancy.

Nearly one fifth (19.1%) reported having at least 1 first-degree relative with colon cancer,
and a family history of other cancers, including cancer of the endometrium, breast, ovary,
and/or pancreas, was also reported.

Most patients (n = 402 [89.3%]) had MMR-proficient tumors, with 10.7% (n = 48) harboring
tumors that were MMR deficient.

Mulitigene testing also revealed 75 pathogenic or gene mutations that were likely to be
pathogenic in 72 patients (16%). There were 36 patients (8%) with Lynch syndrome only,
while 2 (0.4%) had Lynch syndrome along with another hereditary cancer syndrome.

In addition, 34 patients (7.6%) had a different hereditary cancer syndrome.

A total of 61 patients (13.6%) had mutations in high- or moderate-penetrance genes, and 11

(2.4%) had mutations in low-penetrance genes.

The authors also found that patients with pathogenic mutations were more likely to have a
family history of colon cancer (45.8% vs 14%; P < .001) and endometrial cancer (11.1% vs
2.9%; P = .005) when compared with patients lacking mutations.

Patients with Lynch syndrome also tended to be diagnosed at earlier stages compared with
those who had a different type of hereditary cancer syndrome (51.4% vs 25.7%; P = .047).

Even though many of the detected mutations were in genes that have already been linked
to CRC risk, the authors point out that 18.1% of patients had mutations in genes that are not
generally associated with CRC.

Testing Family Members Important

Hampel also pointed out that most patients do have access to multigene testing. "There are
multiple laboratories providing this type of genetic testing and the cost has decreased
significantly over the past few years so it is much more accessible," she said. "Most insurers
will cover genetic testing for individuals with early-onset CRC, and most of the laboratories
even have financial hardship programs that cover the costs of testing completely for
uninsured or underinsured patients who meet certain criteria."

If a patient is positive for pathogenic mutations, it is essential that family members be

tested as well.

"Cascade testing is when we follow the mutation through the family, testing at-risk relatives
like siblings, children, parents, aunts/uncles, and cousins who are over age 18," Hampel
explained. "It is a critical component of the study, so we are actively trying to provide
genetic counseling and testing to as many relatives as possible."

"Many of them have not developed cancer yet, so this testing

can save their lives by identifying who is at increased risk and Many of them
needs intensive cancer surveillance and prevention options," have not
she added. developed cancer yet
so this testing can
Proceed With Caution
save their lives
Heather Hampel
In an accompanying editorial, Eduardo Vilar, MD, PhD, from the
University of Texas MD Anderson Cancer Center in Houston,
and Elena M. Stoffel, MD, from the University of Michigan, Ann
Arbor, reiterate that the current findings show the benefit of incorporating multigene panel
genetic testing.

Use of such a panel will "increase the diagnosis of individuals with genetic predisposition to
cancer and will expand current knowledge regarding the associated phenotypes, further
supporting the cost-effectiveness of testing that can guide management for patients with
cancer and their at-risk relatives," they write.

However, they caution that important questions remain. For example, variants of uncertain
significance are common and are identified in nearly 1 in 3 of these patients, thus leaving
both patients and healthcare professionals with "uncertain" results.

Another question concerns the actual risk associated with the genes. "What is the relative
(and absolute) increase in CRC risk associated with mutations in the 'other' cancer genes not
previously associated with CRC, and how should this information influence recommendations
for colonic and extracolonic screening and surveillance?" the editorialists ask.

Because most younger patients with CRC lacked a pathogenic mutation in any of the 25
cancer genes on the panel, this raises the issue of other novel cancer genes, or
combinations of genes, or gene-environment interactions that might explain the increase in
incidence of CRC in those under the age of 50 years, they note.

"We are entering a 'brave new world' of research aimed at clarifying the functional
significance of germline variants in high- and moderate-risk genes and how these interact
with exposures and lifestyle factors," Dr Vilar and Dr Stoffel conclude.

The study was funded by the Ohio Colorectal Cancer Prevention Initiative, which is
supported by a grant from Pelotonia, an annual cycling event in Columbus, Ohio, that
supports cancer research at The Ohio State University Comprehensive Cancer CenterJames
Cancer Hospital and Solove Research Institute (Hampel, Paskett, Shields). The study was
also funded in part by the National Cancer Institute. Ms Hampel discloses consulting for
Invitae and receiving research funding from Myriad Genetics Inc and honoraria from Beacon
LBS. Several coauthors also disclose relationships with industry, as noted in the paper. The
editorialists have disclosed no relevant financial relationships..

JAMA Oncol. Published online December 15, 2016. Full text, Editorial

Follow Medscape Oncology on Twitter: @MedscapeOnc

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Cite this article: Multigene Testing a 'Must' for Young Patients With Colorectal
Cancer. Medscape . Dec 15, 2016.

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