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Annual Meeting Proceedings Part 1 - American Society of Clinical ...

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1512 Poster Discussion Session (Board #1), Sun, 8:00 AM-12:00 PM and<br />

11:30 AM-12:30 PM<br />

Routine universal screening for Lynch syndrome in colorectal cancer<br />

patients in the community setting. Presenting Author: Jeffrey M. Goldberg,<br />

Norton Cancer Institute, Louisville, KY<br />

Background: Identification <strong>of</strong> colorectal cancer (CRC) cases that are due to<br />

Lynch Syndrome (LS) is important to prevent secondary malignancies or<br />

development <strong>of</strong> additional malignancies among relatives. Utilization <strong>of</strong><br />

clinical criteria to select CRC patients for laboratory testing fails to identify<br />

a significant proportion <strong>of</strong> patients whose CRC is due to LS. Therefore,<br />

universal screening for LS among CRC patients has been advocated by the<br />

Evaluation <strong>of</strong> Genomic Applications in Practice and Prevention Working<br />

Group. However, the feasibility <strong>of</strong> routine universal screening has not been<br />

evaluated in a community-based, non-research setting. We implemented a<br />

universal screening protocol for LS as part <strong>of</strong> routine care <strong>of</strong> CRC at Norton<br />

Healthcare, a multi-institutional community-based healthcare organization.<br />

Methods: Beginning in October 2009, all resected CRC tumors<br />

automatically underwent immunohistochemistry analysis (IHC) for Lynch<br />

Syndrome-associated mismatch repair gene (MMR) expression. Selected<br />

patients who underexpressed MLH1 also underwent testing for the BRAF<br />

V600E mutation. Patients who had a BRAF V600E mutation were considered<br />

to have sporadic CRC. All other patients with abnormal IHC were<br />

automatically referred for genetic counseling. We retrospectively reviewed<br />

the outcomes <strong>of</strong> genetic counseling in all patients referred through this<br />

universal screening protocol. Results: Between October 2009 and December<br />

2011, 388 patients underwent resection <strong>of</strong> CRC, all <strong>of</strong> whom had IHC<br />

for MMR expression. Seventy patients were identified as having abnormal<br />

IHC. Sixty-two had MLH1/PMS2 underexpression, <strong>of</strong> which 18 underwent<br />

BRAF testing and 13 had a BRAF V600E mutation. Eight had MSH2/MSH6<br />

underexpression. Nine patients have been confirmed to have LS, 31 have<br />

been found not to have LS, and 19 are in the process <strong>of</strong> evaluation. Seven<br />

patients declined genetic counseling, and 4 died before they could be<br />

adequately evaluated. Conclusions: Universal screening for CRC due to LS,<br />

using IHC with select BRAF V600E mutation testing and automated<br />

referral for genetic counseling, is feasible in the community setting.<br />

Funded in part with federal funds: NCI, NIH, Contract No.<br />

HHSN261200800001.<br />

1514 Poster Discussion Session (Board #3), Sun, 8:00 AM-12:00 PM and<br />

11:30 AM-12:30 PM<br />

Use <strong>of</strong> clinical history (CH) for Lynch syndrome (LS) risk assessment: An<br />

economic decision analysis. Presenting Author: Sarmad Sadeghi, Cleveland<br />

Clinic Taussig Cancer Institute, Cleveland, OH<br />

Background: Previous studies comparing screening strategies (STs) for LS<br />

concluded that immunohistochemistry (IHC)-based STs are most cost effective.<br />

However, these analyses generally exclude clinical history (CH)-based criteria<br />

due to concerns for reliability, e.g. Amsterdam (Ams), Bethesda (Beth), MMRpro<br />

(Mpro), MMRpredict (Mpre) and PREMM (PRE). We conducted a comprehensive<br />

comparison <strong>of</strong> all STs. Methods: Using assumptions from published reports we<br />

performed a cost effectiveness analysis (CEA) with a societal viewpoint using<br />

TreeAge s<strong>of</strong>tware. 20 STs for proband (Pd) and general population (GP)<br />

screening in a cohort <strong>of</strong> 100,000 assumed a 3% LS prevalence (Prev) in Pd and<br />

0.23% in GP, 5 first degree relatives (FDRs) per LS diagnosis (Dx), 50% LS Prev<br />

in FDRs, and 90% genetic testing (GT) compliance in Pds and GP and 52% in<br />

FDRs. We used the number <strong>of</strong> LS Dxs as effectiveness measure (EM). Sensitivity,<br />

accuracy, and incremental cost effectiveness ratios (ICERs) were calculated.<br />

Results: The ST <strong>of</strong> Mpro followed by GT is highly sensitive and has an accuracy <strong>of</strong><br />

.997. Assuming 1-1.4 life years saved per Dx based on prior studies, this<br />

strategy is also cost effective. Strategies with greater sensitivity were dominated<br />

or not cost effective. Table shows results in order <strong>of</strong> increasing cost per Dx.<br />

Conclusions: This comprehensive comparison suggests that Mpro is an appropriate<br />

first step in screening for LS in Pds, and its routine use may be considered as<br />

a quality measure in the management <strong>of</strong> colorectal cancer. IHC � BRAF, GT<br />

should be reserved for Pds where CH is incomplete.<br />

ST Sensitivity LS in Pds LS in FDRs ICER<br />

No screening 0 0 0 -<br />

Ams, IHC, GT .17 493 641 -<br />

Ams, GT .2 594 772 -<br />

Mpre, IHC, GT .55 1,546 2,010 -<br />

Mpro, IHC, GT .72 1,994 2,593 $4.9K<br />

Beth, IHC, GT .66 1,838 2,389 -<br />

Mpre, GT .67 1,863 2,422 -<br />

PRE, IHC, GT .73 2,017 2,622 -<br />

Mpro, GT .88 2,403 3,124 $21.6K<br />

Beth, GT .8 2,214 2,878 -<br />

PRE, GT .89 2,430 3,159 $513K<br />

IHC � BRAF, GT .82 2,241 2,913 -<br />

IHC, GT .82 2,241 2,913 -<br />

MSI, GT .84 2,295 2,983 -<br />

PRE GP 4, GT age > 35 .89 110 144 -<br />

PRE GP 3, GT age > 30 .89 120 156 -<br />

PRE GP 2, GT age > 25 .89 129 168 -<br />

PRE GP 1, GT age > 20 .89 138 179 -<br />

MSI � IHC, GT .89 2,430 3,159 -<br />

MSI � IHC � BRAF, GT .89 2,430 3,159 -<br />

Up-front GT<br />

- � dominated.<br />

1 2,700 3,510 $1,053K<br />

Cancer Prevention/Epidemiology<br />

89s<br />

1513 Poster Discussion Session (Board #2), Sun, 8:00 AM-12:00 PM and<br />

11:30 AM-12:30 PM<br />

An alternative approach to identify women at risk for colorectal cancer.<br />

Presenting Author: Amanda S. Bruegl, University <strong>of</strong> Texas M. D. Anderson<br />

Cancer Center, Houston, TX<br />

Background: Hereditary colorectal cancer (CRC) is preventable; however,<br />

identification <strong>of</strong> individuals at sufficiently high risk to warrant heightened<br />

surveillance is difficult. Lynch Syndrome (LS) is an inherited cancer<br />

syndrome due to germline mutation in a DNA mismatch repair gene. For<br />

women with LS, the lifetime risk <strong>of</strong> endometrial cancer (EC) is 64% and<br />

CRC is 54%. Fifty percent <strong>of</strong> women with LS will present with EC or ovarian<br />

cancer prior to CRC. Therefore, women with LS associated EC represent an<br />

ideal group for CRC prevention. The optimal method to identify women with<br />

LS associated EC is not known. The purpose <strong>of</strong> this study was to determine<br />

the utility <strong>of</strong> Amsterdam II and <strong>Society</strong> <strong>of</strong> Gynecologic Oncology (SGO)<br />

Criteria (modified Bethesda criteria that use EC as the sentinel cancer) in<br />

identifying women with LS associated EC. Our ultimate goal is to identify<br />

women at increased risk <strong>of</strong> CRC. Methods: Immunohistochemistry (IHC) for<br />

DNA mismatch repair proteins and MLH1 methylation analyses were used<br />

to identify LS associated EC among 388 women. EC was designated as LS<br />

if there was loss <strong>of</strong> mismatch repair protein expression. Absence <strong>of</strong> MLH1<br />

methylation was required to confirm LS in tumors with MLH1 protein loss.<br />

Results: Fifty-nine (15.2%) <strong>of</strong> the EC patients tested had LS. These<br />

patients are summarized in the table. Conclusions: <strong>Clinical</strong> criteria to detect<br />

LS identify 17/59 (29%) - 44/59 (74%) <strong>of</strong> women who present with EC<br />

first. EC with MSH2 loss is most likely to occur in younger women and<br />

women with positive family history <strong>of</strong> EC and CRC, features classically<br />

associated with LS. In general, the MSH6 mutation is associated with older<br />

age at diagnosis and fewer familial CRCs, however, we found a large<br />

number <strong>of</strong> MLH1 (50%) and PMS2 (86%) cases diagnosed at greater than<br />

50 years with no family history <strong>of</strong> CRC. Our data suggest that classic<br />

clinical screening criteria are inadequate to detect patients with LS who<br />

present with EC, potentially missing up to 25% <strong>of</strong> these patients.<br />

Gene MLH1 MSH2 MSH6 PMS2 Total<br />

Total number 14 27 11 7 59<br />

Median age at diagnosis (range) 52 44 56 66 50<br />

(42-79) (33-81) (31-76) (45-87) (31-87)<br />

Diagnosis at greater than 50 years 7 8 9 6 30<br />

FH CRC 3 16 4 3 26<br />

Amsterdam criteria 3 13 0 1 17<br />

SGO criteria 11 22 7 4 44<br />

1515 Poster Discussion Session (Board #4), Sun, 8:00 AM-12:00 PM and<br />

11:30 AM-12:30 PM<br />

Next-generation sequencing to identify candidate gene for hereditary mixed<br />

polyposis syndrome. Presenting Author: Michele Caroline Gornick, University<br />

<strong>of</strong> Michigan, Ann Arbor, MI<br />

Background: Rare monogenic disorders are <strong>of</strong>ten due to mutations that are<br />

highly penetrant, extremely rare, and strongly disrupt normal biology.<br />

Hereditary mixed polyposis syndrome (HMPS, OMIM ID %601228), is<br />

characterized by a mixture <strong>of</strong> atypical juvenile polyps, hyperplasic polyps,<br />

sessile serrated adenomas and an increased risk <strong>of</strong> colorectal cancer.<br />

Polyps appear to be inherited in an autosomal dominant fashion. The<br />

putative susceptibility locus initially mapped to 15q13-14, however, the<br />

genetic basis <strong>of</strong> this syndrome is not well understood, and no mutation or<br />

associated variants have been identified. Methods: Germline DNA from four<br />

individuals from a family with clinically and pathologically confirmed<br />

HMPS was subjected to massively parallel sequencing (Illumina GAII).<br />

Affected individuals had an average <strong>of</strong> 30x coverage <strong>of</strong> their exome and 10x<br />

coverage <strong>of</strong> their genome. Sequence calls were filtered using the criteria <strong>of</strong><br />

� 4x coverage, quality score over depth � 50, depth <strong>of</strong> coverage � 360,<br />

allele balance � 0.75, number or MAPQ zero reads at locus � 4. Common<br />

variants were filtered out by excluding variants found in dbSNP (build131),<br />

1000 Genomes Project, the Exome Variant Server or 80 unaffected<br />

controls sequenced by hybrid capture and whole exome sequencing.<br />

Polyphen2 and SIFT were used to predict pathogenicity <strong>of</strong> the novel, shared<br />

variants, and validated by Sanger sequencing. Expression levels <strong>of</strong> novel<br />

variants were examined in available tumor samples using qRT-PCR.<br />

Results: From the 32 previously unidentified nonsense, missense or splice<br />

site variants shared by the family members whose whole genomes were<br />

sequenced, only 5 (4 missense, 1 nonsense) were predicted to be<br />

damaging, leading to a small subset <strong>of</strong> novel candidate genes including<br />

ZNF426, which may be responsible for HMPS within this family.<br />

Conclusions: HMPS extremely difficult to accurately diagnosis and the<br />

genetic basis is unknown. Using next-generation sequencing we were able<br />

to detect previously unidentified low frequency allelic variants including a<br />

novel candidate locus.<br />

Visit abstract.asco.org and search by abstract for the full list <strong>of</strong> abstract authors and their disclosure information.

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