Caris Life Sciences, Inc. · NASDAQ:CAI
Caris Life Sciences — Technical Presentation (2011)
19 slides from Caris Life Sciences's technical presentation, Jun 1, 2011
Slide 1: High Yield of Lynch Syndrome Screening in Pre-Cancerous Colorectal Polyps: A Study of 898 Patients
High Yield of Lynch Syndrome Screening in Pre-Cancerous Colorectal Polyps: A Study of 898 Patients Mark Redston and Richard Lash Caris Research Institute, Caris Life Sciences Newton, MA and Irving, TX 1
Slide 2: Lynch Syndrome (LS) Screening
Lynch Syndrome (LS) Screening • LS is the most common form of HNPCC; accounts for 2-5% of CRC • Caused by germline mutations in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2) • Traditionally identified by family and personal history criteria, and then characterized and diagnos
Slide 3: Laboratory Screening for LS in CRC
Laboratory Screening for LS in CRC All CRC MMR IHC Testing IHC Intact MLH1 Deficient MSH2/MSH6/PMS2 Deficient BRAF/MLH1 Methylation Testing BRAF Mutated or BRAF Wild type and MLH1 Hypermethylated No MLH1 Hypermethylation Not LS Probable LS © 2010 Caris Life Sciences, Inc. All rights reserved. 3
Slide 4: MMR Loss in Adenomas from LS patients
MMR Loss in Adenomas from LS patients • Relatively few studies of MMR and MSI status in adenomas • About 40-70% of adenomas from known LS patients have the expected loss of MMR expression by IHC • More frequent in adenomas with high grade dysplasia (HGD) • Anecdotal experience that most adenomas adj
Slide 5: Hypothesis
Hypothesis • Routine laboratory screening for LS in HGD adenomas will yield patients with probable LS • Diagnosis of LS prior to the development of CRC allows an opportunity to institute increased colonoscopic screening and potentially achieve a normal life expectancy • Began offering reflex MMR IHC
Slide 6: Purpose of Study
Purpose of Study • To determine the prevalence of MMR IHC defects and probable LS in a large cohort of patients with HGD adenomas in a community practice setting • To compare the rate of detection with that of CRC in the same population 6 © 2010 Caris Life Sciences, Inc. All rights reserved.
Slide 7: Methods
Methods • Case selection – All newly diagnosed HGD adenomas were eligible for routine MMR IHC testing beginning March 15, 2010 – All cases with stains performed through Nov. 14, 2010 were included • IHC staining – MLH1 –ES05 (Dako); Dako platform – PMS2 – A16-4 (BioCare); Dako platform – MSH2 – G219
Slide 8: MMR IHC Interpretation and Scoring
MMR IHC Interpretation and Scoring • Adequacy of internal positive control staining – 2-3+ nuclear positivity in crypt base epithelial cells and/or lymphocytes/germinal center cells • Absent MMR staining – No nuclear positivity in any tumor cells • Markedly reduced MMR staining – 2-3+ nuclear positi
Slide 9: Identification of Cases
Identification of Cases 984 Eligible HGD adenomas Mar 15-Nov 14, 2010 87 (8.8%) Not Tested 898 (91.2%) MMR IHC 21 (2.1%) (1.1%) Median age: 65 Declined Other Age range: 21-93 by Clinician Conditions Male: 59.9% Right colon: 27.3% 16 (1.6%) 15 (1.5%) Insufficient Synchronous Tissue CRC 9 © 2010 Caris
Slide 10: MMR IHC in HGD Adenomas
MMR IHC in HGD Adenomas H&E MSH2 MSH6 H&E MLH1 PMS2 10 © 2010 Caris Life Sciences, Inc. All rights reserved.
Slide 11: MMR IHC in HGD Adenomas
MMR IHC in HGD Adenomas H&E MSH2 MSH6 MLH1 PMS2 11 © 2010 Caris Life Sciences, Inc. All rights reserved.
Slide 12: Classification of MLH1 Deficient Cases
Classification of MLH1 Deficient Cases • Probable LS – Age < 50 or – Positive personal or family history • two or more 1st or 2nd degree relatives with CRC or other LS-associated cancer • one 1st degree relative with LS-associated cancer < age 50 • personal history CRC or other LS-associated cancer
Slide 13: Prevalence of Probable Lynch Syndrome Amongst HGD Adenomas
Prevalence of Probable Lynch Syndrome Amongst 898 HGD Adenomas MMR Intact Probable LS Probable MLH1 Methylation Frequency 832 (92.7%) 27 (3.0%) 39 (4.3%) 95% C.I. 91.0-94.4 1.9-4.1 3.0-5.7 Median Age (years) 65 56; p<0.05 74; p<0.01 Female Gender 320 (38.5%) 12 (44.4%); p=NS 28 (71.8%); p<0.05 Right
Slide 14: Prevalence of Probable Lynch Syndrome Amongst HGD Adenomas
Prevalence of Probable Lynch Syndrome Amongst 898 HGD Adenomas MMR Defect Probable LS Cases Proportion MLH1/PMS2 Deficient (n =44; 4.8%) MLH1 Positive family/personal history 3 0.3% MLH1 Age < 50 2 0.2% MSH2/MSH6 Deficient 15 1.7% MSH6 Deficient 3 0.3% PMS2 Deficient 4 0.4% Total 27 3.0% 14 © 2010 C
Slide 15: Comparison of LS Screening in HGD Adenomas vs CRC
Comparison of LS Screening in HGD Adenomas vs CRC MMR Defect HGD Adenoma CRC* (898 Cases) (1046 Cases) MLH1/PMS2 Deficient 44 (4.8%) 121 (11.6%) MLH1 Positive family/personal history 3 (0.3%) 6 (0.6%) MLH1 Age < 50 2 (0.2%) 6 (0.6%) MSH2/MSH6 Deficient 15 (1.7%) 14 (1.4%) MSH6 Deficient 3 (0.3%) 6 (
Slide 16: Age Distribution of Probable LS in HGD Adenoma Patients
Age Distribution of Probable LS in 898 HGD Adenoma Patients 35 30 25 Percent 20 Prevalence 15 Total Cases 10 5 0 <50 50-59 60-69 70-79 >79 Age (years) 16 © 2010 Caris Life Sciences, Inc. All rights reserved.
Slide 17: Family and Personal History Characteristics of LS Patients
Family and Personal History Characteristics of LS Patients 27 Probable LS 21 with Family and Personal History Data 4 (19.0%) 7 (33%) 10 (48%) Amsterdam Revised No Features Criteria Bethesda of LS/HNPCC 17 © 2010 Caris Life Sciences, Inc. All rights reserved.
Slide 18: Conclusions
Conclusions 1. The prevalence of LS among patients with newly diagnosed HGD adenomas in the community practice setting is similar to CRC patients in the same population (3.0% vs. 3.6%). 2. The prevalence of LS is highest in HGD adenoma patients under age 50, however, more than 50% are older than age
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end 19 © 2010 Caris Life Sciences, Inc. All rights reserved.