Download editorial Rectal Cancer: Age Matters in the Affairs

JNCI J Natl Cancer Inst (2016) 108(1): djv325
doi:10.1093/jnci/djv325
First published online October 12, 2015
Editorial
editorial
Rectal Cancer: Age Matters in the Affairs of Stage
Joanne Ngeow, Charis Eng
Affiliations of authors: Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre, Singapore (JN); Oncology Academic Clinical Program, DukeNUS Graduate Medical School, Singapore (JN); Genomic Medicine Institute (JN, CE) and Taussig Cancer Institute (CE), Cleveland Clinic, Cleveland, OH; Department
of Genetics and Genome Sciences and Germline High Risk Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH (CE).
Correspondence to: Charis Eng, MD, PhD, Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195 (e-mail: [email protected]).
“Aging is not lost youth but a new stage of opportunity and
strength.”
–Betty Friedan
The American Cancer Society estimates that 132 700 new colorectal (CRC) cases will be seen in 2015 (1), making CRC one of the
top three most common cancers in the United States as well as
a major health burden worldwide. It is encouraging that in the
United States CRC incidence rates appear to be leveling off, even
declining in recent years (2). This decline is largely attributed to
the success of colonoscopic screening in patients over the age
of 50 years. It allows for the early detection and removal of colorectal polyps before they progress to cancer and is the mainstay
of CRC prevention efforts. However, recent literature suggests a
worrisome trend of rising incidence of CRC in young individuals (3–6), a population that is not included in current population screening guidelines. These observations have important
public health implications, but these studies suffer from a lack
of uniformity in defining young CRC with studies including
patients under the age of 40 or 50 years, with the majority of
these studies being done at single centers, making it difficult for
policy makers to fully appreciate the public health implications.
The heterogeneity in studies has led to conflicting results as to
what clinicopathological features are prognostic in young CRC
patients, if any.
It is in this context that the article by Meyer et al. in this
issue of the Journal is timely (7). The authors used the population-based data from the US Surveillance, Epidemiology, and
End Results (SEER) program of the National Cancer Institute
to compare clinicopathological characteristics among patients
with young rectal cancer (defined as age <50 years) diagnosed
between 1988 and 2008. They included patients with stage I-III
disease, without any history of prior radiotherapy and at least
one lymph node examined with a standard rectal cancer operation, to help ensure that patients had received similar perioperative care. One in 10 patients included was under the age
of 50 years, with 2.1% under the age of 40 years, and 7.5% age
40 to 49 years. The approximately 10% incidence of young rectal
cancers is consistent with that of other studies (8). Adjusting
for factors such as number of lymph nodes harvested and other
clinicopathological factors, the authors found age to be statistically significantly predictive of lymph node positivity (LN+). For
each T stage, LN+ was inversely associated with age. Intriguingly,
for patients under the age of 40 years compared with patients
age 60 to 69 years (the majority of cases), they were 2-fold, 1.5fold, and 1.3-fold more likely to be LN+ for T1, T2, and T3 disease,
respectively.
A study using population-based data such as the SEER
database is limited by available clinical data. As the authors
acknowledged, it is not known how these patients came to diagnosis—were they discovered on diagnostic or screening evaluations? Older patients are far more likely to have their rectal
cancers detected presymptomatically as part of screening, and
there are studies to suggest their doctors are also less likely to
ignore early symptoms compared with the young. Although the
authors account for this by stratifying by T stage, reporting that
age is predictive of LN+ status regardless of T stage, it remains
unclear how late presentation in younger patients could affect
these results, except to attribute to different underlying biology.
Regardless of these limitations, the results of this study have
significant clinical implications. Given the higher propensity
amongst young rectal cancer patients to be occult LN+ even for
T1 disease, this will need to be taken into account for choice
of surgical intervention. Although preoperative neoadjuvant
chemoradiotherapy is recommended for the management of
resectable rectal cancer, it is not uniformly practiced and the
results here give further impetus for this to be standard of care
in fit young rectal cancer patients.
Given the results from this article and others, there is certainly a growing consensus that “young CRC” is a clinical entity
in need of both research and health policy attention. To aid future
research into this area, it will be important that future studies
address this issue by first addressing what uniform definitions we
will use. Amongst the definitions to be defined, what age should
be considered the threshold for “young CRC”? A review of studies
Received: October 4, 2015; Accepted: October 7, 2015
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up to 2003 revealed that approximately 70% of references defined
‘‘young’’ as patients younger than age 40 years (9), but this trend
appears to be reversing with increasing numbers of studies using
younger than age 50 years (10), which is the cutoff used by the
Amsterdam criteria for identifying patients who may be at risk
of Lynch Syndrome (LS). In another recently published study, and
an important one, the authors using SEER data divided patients
into three age groups to better understand what cutoffs would be
useful. They grouped the case patients as age 21 to 40, age 41 to
50, and older than age 50 years (11). In this study, they included all
CRC patients and found that patients with CRC diagnosed at age
21 to 40 years had later stage presentation and more aggressive
pathological features but better survival. CRC patients age 41 to
50 years had the best CRC survival, in contrast to patients in the
other two age groups. What this study highlights is that there is
certainly heterogeneity in CRC patients under the age of 50 years
and perhaps future CRC studies would need to look at the three
groups separately rather than as a single cutoff.
Is “young CRC” a good catchall for both young rectal and
young colon-only cancers? Should we consider them similarly with regards to biology and management? As the authors
highlight, we do not yet understand the molecular differences
between CRCs seen in young vs elderly patients and between
“young rectal” vs “young colon” cancers. Important host-environment factors remain to be interrogated and understood,
including the interaction of host genetics with innate immunity,
the tumor and its microenvironment, and the gut microbiome,
in disease initiation and progression.
What we do know is that approximately 5% of all CRCs are due
to a heritable cause. Indeed, LS accounts for approximately 3% of
all incident cases of CRC. Almost certainly, part of the 10% “young
CRC” in this study have an inherited cancer syndrome. What of
the rest? It is important that all these patients also be assessed
for cancer predisposition syndromes. For LS, universal testing
of the molecular phenotype of mismatch gene repair deficiency
through either microstatellite instability or immunohistochemistry has been shown to be a cost-effective screening tool for
detection of LS (12–14). For the other hereditary CRC syndromes,
it remains challenging, and clinicians will need to pay particular
attention to family history as well as detailed personal history for
all CRC patients under the age of 50 years to identify who might
require referral for genetic risk assessment (15). A recent study
found a high prevalence of hereditary cancer predisposition syndromes in patients under the age of 35 years and recommend
that any CRC patient age 35 years or younger receive genetic testing in the setting of genetic counseling (16). Of the 193 patients
with evaluable data, 35% had an identifiable hereditary cancer
syndrome, including 23 with Lynch Syndrome, 22 with mutationnegative Lynch Syndrome, 16 with familial adenomatous polyposis, two with constitutional mismatch repair deficiency, two with
biallelic MUTYH mutations, and one with Li-Fraumeni Syndrome.
While knowing the index case’s mutation will allow family
members to undergo predictive testing such that only those
affected need receive increased surveillance starting at an early
age, unfortunately, the majority of young CRC patients do not
have a family history (17). An absence of family history therefore does not preclude early onset CRC in an individual, nor does
it exclude de novo occurrence of heritable cancer. This underscores the need for further research to better understand the
etiology of early-onset CRC. Apart from LS and the other hereditary CRC syndromes, we have, at present, no other means of
rapidly identifying those at increased genetic risk, which leads
to the last question. How should we best screen these patients
without adding substantial burden to the healthcare system? In
this era of value-based healthcare in the era of genomic medicine, the answer may lie in using molecular multitarget DNAbased stool screening to first identify that subset that requires
colonoscopy (18).
“Age is opportunity no less,
Than youth itself, though in another dress,
And as the evening twilight fades away,
The sky is filled with stars, invisible by day.”
-- Henry Wadsworth Longfellow, Morituri Salutamus, 1875
Notes
Disclosure of potential conflict of interest: CE is a member of
the Strategic Advisory Board of N-of-One. Otherwise, no author
had any financial or personal relationships that could inappropriately influence or bias this work. JN was awarded the NMRC
(Singapore) Transition Award. CE is the Sondra J. and Stephen
R. Hardis Chair of Cancer Genomic Medicine at the Cleveland
Clinic and is an American Cancer Society Clinical Research
Professor.
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