Editorial
Hereditary Colon Cancer Syndromes: Optimal Management in 2017
Christos Fountzilas and Virginia Kaklamani*
Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 7979 Wurzbach Road, San Antonio, TX 78229, USA
*Corresponding author: Virginia Kaklamani, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, 7979 Wurzbach Road, San Antonio, TX 78229, USA
Published: 24 Apr, 2017
Cite this article as: Fountzilas C, Kaklamani V. Hereditary
Colon Cancer Syndromes: Optimal
Management in 2017. Clin Oncol. 2017;
2: 1264.
Editorial
Colorectal Cancer (CRC) is the third most common cancer in the United States [1]. Almost onethird
of the cases show familiar predisposition and a genetic syndrome is identified in approximately
5% of newly diagnosed patients [2]. Hereditary colorectal cancer syndromes can be divided into polyposis and non-polyposis (Table 1); the most common is Lynch Syndrome (LS) secondary to Mismatch Repair (MMR) gene mutations causing Microsatellite Instability (MSI). Mutations in one
of the MMR genes are highly prevalent in the western hemisphere; the prevalence is estimated to
range between 1:370 and 1:3100 [3,4]. The cumulative incidence for CRC at 70 years in patients with
LS can be up to 70% [5,6]; the risk depends on the genotype, with the highest risk for MLH1 and
MSH2 mutation carriers (72 vs. 54 and 18% for MSH6 and MPS2 mutation carriers respectively) [7].
The CRC risk by age 40 approaches 100% for APC mutation carriers. Patients and/or families that
meet clinical criteria for LS but tumors lack MMR gene mutations are considered to have familial
colorectal cancer type X [8].
Who should be tested and how?
There is evidence that almost one-third of LS cases will be missed if only patients fulfilling
clinical (Amsterdam [9] and revised Bethesda [10]) criteria are tested [11]. Screening all patients who develop CRC before the age of 70 and patients above the age of 70 who fulfill the revised
Bethesda criteria using tumor PCR for detection of MSI or immunohistochemistry for lack of
expression of MMR proteins is recommended by the National Comprehensive Cancer Network
(NCCN) and is cost-effective [12,13]. As 12% of sporadic CRC cases have MSI secondary to biallelic MLH1 promoter methylation or a CpG island hypermethylation phenotype, specialized testing through simultaneous detection of somatic MLH1 promoter methylation or BRAFV600 mutation is
required [14-16]. Mutation specific testing is advised if one of the polyposis syndromes is suspected [17].
Simultaneous detection of multiple different germline pathogenic mutations through Next-
Generation Sequencing (NGS) is an alternative method for detection of carriers. In patients with
suspected LS who had germline DNA testing at a commercial laboratory, 5.6% had mutations in
non-MMR genes; 21% of those cases were in BRCA1/2 and 13% in other high-penetrance cancer
predisposition genes [18]. Two-thirds were in moderate-penetrance genes and monoallelic MUTYH mutations. In a recent study, the prevalence of germline mutations for high- and moderatepenetrance
genes detected by NGS was 10%; half of those patients carried a high-penetrance gene
mutation [19]. Three percent of the overall study population had an MMR gene mutation and 2% a mutation not related to LS. Ninety-seven percent of the patients with MMR gene mutation met
clinical criteria for testing but the clinical history was not suggestive of the genotype in one-third of
the patients with non-MMR gene mutations. For example, half of the patients with APC or MUTYH
mutation lacked diffuse colorectal polyposis. It should be noted though that in about two-thirds of
those patients, the mutation was in a gene not typically associated with CRC like BRCA1/2. Onethird
of the patients had a Variant of Unknown Significance (VUS). In another study incorporating
germline NGS testing for cancer susceptibility genes, 16% of patients with early onset CRC (age <50
years) were found to have a genetic cancer syndrome; half of the patients had LS [20]. Three percent of the cases had a mutation not specifically related to CRC and in half of these cases the mutation
was in a moderate-penetrance gene. In 23 (31%) of the 72 patients with a pathogenic mutation,
testing was not recommended based on NCCN guidelines; in 60% of those cases the mutation was in
a colon cancer related gene like APC or MUTYH. One-third of the patients had a VUS. It is currently
unclear whether NGS should be used for detection of hereditary CRC syndromes but it appears that
it is most useful for detection of non-MMR gene mutations.
Primary prevention of CRC
Intensive early endoscopic surveillance and/or prophylactic
colectomy are recommended for the major hereditary CRC
syndromes [17]. Screening colonoscopy every 3 years in non-affected
MMR mutation carriers resulted in a decrease in CRC incidence
and mortality [21,22]. The time from development of adenoma to
development of carcinoma is significantly accelerated in patients
with LS (3 vs. 10 years in sporadic cases), providing rational for more
frequent screening colonoscopy (every 1-2 years) [23]. Polyps in
Familiar Adenomatous Polyposis (FAP) appear at the mean age of 15
years necessitating initiation of endoscopic screening at puberty [24].
Endoscopic screening (and subsequent surgery) decreases the risk of
developing CRC and improves survival [25,26]. Timely prophylactic
total colectomy with or without rectal sparring is recommended in
patients with FAP [17].
Chemoprevention has been evaluated as primary prophylaxis in
patients with hereditary CRC syndromes with the most promising
agents being Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).
Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor,
significantly decreased adenoma formation in patients with large or
multiple adenomas at baseline by 33 to 45% in phase III trials but
its cardiovascular safety remains a concern [27,28]. In a randomized,
double blind, placebo-controlled trial, 77 individuals with FAP with
at least 5 colonic polyps were randomized to celecoxib or placebo
[29]. Celecoxib resulted in a significant decrease in the number and
polyp size from baseline (28 vs. 4.5% and 30.7 vs. 4.9% respectively).
In a second randomized placebo-controlled trial, 22 individuals with
FAP who had at least 5 adenomatous polyps were randomized to the
NSAID sulindac or placebo [30]. Treatment with sulindac resulted in
a 44% decrease in the number and 35% decrease in the size of polyps
compared to placebo. In a follow up study from the same group
enrolling phenotypically normal (e.g. with no polyps) individuals with
genetically confirmed FAP, treatment with sulindac did not decrease
the number or size of polyps significantly compared to placebo [31].
In a double-blind, randomized phase III study of low-dose aspirin vs.
placebo conducted in Japan, aspirin decreased mean polyp volume
compared to placebo, although not significantly [32]. This study was
underpowered for the primary outcome. NDAID plus the ornithine
decarboxylase inhibitor eflornithine have shown synergistic effects
in colon cancer chemoprevention in a murine FAP model [33]. The
combination of celecoxib plus eflornithine compared to celexicob
alone has been studied in a phase III trial [34]. The combination
resulted in a decrease in the adenoma number and size compared
to celecoxib alone but this did not reach statistical significance (13
vs. 1% and 40 vs. 27% respectively). CPP FAP-310 is an ongoing
randomized, double blind, phase III trial evaluating the eflornithine
and sulindac combination (compared to each as monotherapy) in
individuals with FAP [35].
A summary of syndrome-specific primary recommendations
is provided in Table 2. The evidence for screening for extracolonic malignancies is weak.
CRC treatment
There is a concern for decreased efficacy of flouoropyrimidinecontaining
chemotherapy as adjuvant therapy in stage II/III CRC
in cases with a deficient MMR system [36,37]. Recent data reassure
on the effectiveness of oxaliplatin-fluoropyrimidine containing
regimens, but it appears that the mechanism of MMR deficiency
does play a role, with LS cases showing no benefit [38]. The evidence
though to withhold adjuvant chemotherapy in patients with LS when
otherwise indicated (stage III, high-risk stage II) is inadequate.
An exciting new development is the use of MSI status of the
tumor as a predictive biomarker for response to immune checkpoint
inhibitors. Response to immune checkpoint inhibitors has been
linked to high mutation and thus high neoantigen tumor burden in
melanoma and non-small cell lung cancer [39,40]. MSI-high CRC has
a higher mutational and neoantigen load compared to non-MSI-high
CRC and shows evidence of having an immune active environment
with upregulation of many negative immune checkpoint pathways
[41-43]. In a phase II study by Le and colleagues, 32 patients with
refractory metastatic CRC were treated with pembrolizumab at
the dose of 10 mg/kg every 2 weeks; 11 had MSI-high tumors [43].
The overall response rate in these patients was 40% and the disease
control rate was 90%. On the contrary, best response for patients with
proficient MMR tumors was stable disease in 11% of the patients.
Results appear similar with nivolumab in the CheckMate 142 trial
[44].
Table 1
Table 2
Conclusions
Identification of hereditary CRC syndromes in the clinic is important not only for unaffected family members but also for the patients themselves. Universal screening of patients with CRC for evidence of MMR deficiency/MSI is sensitive and cost-effective. Intensive endoscopic surveillance and/or prophylactic surgery are recommended for carriers. MSI status can be a predictive marker for response to immunotherapy and provide new treatment options.
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