Caris Life Sciences, Inc. · NASDAQ:CAI
Caris Life Sciences — Technical Presentation (2021)
37 slides from Caris Life Sciences's technical presentation, 2021
Slide 1: Molecular Variances Between Rectal and Left-Sided Colon Cancers
Molecular Variances Between Rectal and Left-Sided Colon Cancers Mohamed E. Salem1, Heinz-Josef Lenz2, Joanne Xiu3, Wafik S. El- Deiry4, Zoran Gatalica3, Jimmy J. Hwang5, Philip A. Philip6, Anthony F. Shields6, and John L. Marshall1 1Lombardi Comprehensive Cancer Center, Georgetown University, Washin
Slide 2: Disclosure
Disclosure • Research grant funding from Bayer and Taiho • Consultant for of Genentech, Bayer and Taiho • Speaker’s Bureau Member: Genentech, Bayer and Taiho
Slide 3: Background
Background Colorectal cancer (CRC) is a heterogeneous disease with different genetic alterations and clinical behavior CRC was recently classified into four consensus molecular subtypes (CMSs) with distinguishing features1 CMS 1-4 tumors have different carcinogenic pathways and genomic pattern
Slide 4: Background
Background Recent retrospective analysis of CALGB 80405 showed that left-sided colon tumors respond differently to biologics compared to right-sided colon tumors1, likely due to molecular differences In the CALGB 80405 analysis, rectal cancers were included as part of the “left-sided” tumors H
Slide 5: Objective
Objective To identify the molecular variations among left-sided CRC tumors: Rectal cancers Sigmoid colon cancers Descending colon cancers (plus splenic flexure)
Slide 6: Methods
Methods Retrospective analysis of 1,730 CRC tumors that were profiled by Caris Life Sciences between 2009 and 2016 was performed All samples were independently reviewed by at least one pathologist, in addition to the local pathologist Only primary tumors were included in the current analysis
Slide 7: CONSORT Diagram
CONSORT Diagram
Slide 8: CONSORT Diagram
CONSORT Diagram Colorectal tumors profiled between 2009 and 2016 (N = 10,570)
Slide 9: CONSORT Diagram
CONSORT Diagram Colorectal tumors profiled between 2009 and 2016 (N = 10,570) Excluded (N = 8,840) Metastatic tumors (457) + Rectosigmoid tumors (227) + Transverse colon tumors (116) + Tumor origin not confirmed (8,040)
Slide 10: CONSORT Diagram
CONSORT Diagram Colorectal tumors profiled between 2009 and 2016 (N = 10,570) Excluded (N = 8,840) Metastatic tumors (457) + Rectosigmoid tumors (227) + Transverse colon tumors (116) + Tumor origin not confirmed (8,040) Primary tumors with clearly defined origins (N = 1,730)
Slide 11: CONSORT Diagram
CONSORT Diagram Colorectal tumors profiled between 2009 and 2016 (N = 10,570) Excluded (N = 8,840) Metastatic tumors (457) + Rectosigmoid tumors (227) + Transverse colon tumors (116) + Tumor origin not confirmed (8,040) Primary tumors with clearly defined origins (N = 1,730) Rectum (N = 872)
Slide 12: CONSORT Diagram
CONSORT Diagram Colorectal tumors profiled between 2009 and 2016 (N = 10,570) Excluded (N = 8,840) Metastatic tumors (457) + Rectosigmoid tumors (227) + Transverse colon tumors (116) + Tumor origin not confirmed (8,040) Primary tumors with clearly defined origins (N = 1,730) Sigmoid colon Rectum (N
Slide 13: CONSORT Diagram
CONSORT Diagram Colorectal tumors profiled between 2009 and 2016 (N = 10,570) Excluded (N = 8,840) Metastatic tumors (457) + Rectosigmoid tumors (227) + Transverse colon tumors (116) + Tumor origin not confirmed (8,040) Primary tumors with clearly defined origins (N = 1,730) Splenic flexure - Sigmoi
Slide 14: CONSORT Diagram
CONSORT Diagram Colorectal tumors profiled between 2009 and 2016 (N = 10,570) Excluded (N = 8,840) Metastatic tumors (457) + Rectosigmoid tumors (227) + Transverse colon tumors (116) + Tumor origin not confirmed (8,040) Primary tumors with clearly defined origins (N = 1,730) Splenic flexure - Right
Slide 15: CONSORT Diagram
CONSORT Diagram Colorectal tumors profiled between 2009 and 2016 (N = 10,570) Excluded (N = 8,840) Metastatic tumors (457) + Rectosigmoid tumors (227) + Transverse colon tumors (116) + Tumor origin not confirmed (8,040) Primary tumors with clearly defined origins (N = 1,730) Splenic flexure - Right
Slide 16: Multi-platform profiling
Multi-platform profiling Immunohistochemistry (IHC): Next-Generation Sequencing ALK PGP Illumina MiSeq platform Illumina TruSeq Amplicon Cancer AR PR cMET PTEN Hotspot panel EGFR RRM1 All tumor samples micro-dissected ER TLE3 ERCC1 TOP2A Average depth of coverage > 1500X Her2/Neu TOPO1 A
Slide 17: Results
Results 17
Slide 18: Patient characteristics
Patient characteristics Primary tumor Splenic flexure - Sigmoid colon Rectum location descending colon (N=460) (N=872) (N=125) Median Age (yr.) 62 60 60 Female 50% 44% 37% Sex (%) 50% 56% 63% Male
Slide 19: Next-Generation Sequencing
Next-Generation Sequencing 19
Slide 20: Mutation Frequency Comparison Between Rectal and Descending Colon Tumors
Mutation Frequency Comparison Between Rectal and Descending Colon Tumors 80% 70% Rectum 60% Sigmoid Descending 50% 40% 30% 20% 10% 0% indicates a significant difference between rectal and descending colon tumors (p < 0.05)
Slide 21: Mutation Frequency Comparison Between Rectal and Sigmoid Colon Tumors
Mutation Frequency Comparison Between Rectal and Sigmoid Colon Tumors 80% 70% Rectum 60% Sigmoid Descending 50% 40% 30% 20% 10% 0% No significant differences were found between rectal and sigmoid colon tumors
Slide 22: Mutation Frequency Comparison Between Sigmoid Colon and Descending Colon Tumors
Mutation Frequency Comparison Between Sigmoid Colon and Descending Colon Tumors 80% Rectum 70% Sigmoid 60% Descending 50% 40% 30% 20% 10% 0% indicates a significant difference between Sigmoid Colon and Descending colon tumors (p < 0.05)
Slide 23: Frequency of microsatellite instability in left-sided CRC
Frequency of microsatellite instability in left-sided CRC P = 0.015 Rectum Sigmoid 8% 7% Descending 7% 6% 5% 4% 4% 3% 2% 1% 1% 0% Splenic Flexure/Descending Sigmoid Rectal Tumors Colon Microsatellite instability was tested with Microsatellite Instability fragment analysis (Promega)
Slide 24: Tumor Mutation Load (TML)
Tumor Mutation Load (TML) 40 35 30 25 23.0 20 15 10 6.5 7.4 5 0 10% 8.8% Mean TML per MB 5% 4.2% 1.6% 0% Splenic Flexure/Descending Sigmoid Rectum % of cases with TML ≥ 17 mutation/megabase TML was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. On
Slide 25: Correlation of MSI with TML
Correlation of MSI with TML Stadler, et. al., (2016) J of Clin Oncol, 34(18):2141-7 Salem et al. Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers. Unpublished data 25
Slide 26: Her2/Neu: Overexpression and Amplification
Her2/Neu: Overexpression and Amplification 6% 5% 5% Rectum Sigmoid 4% 3% Descending 3% 3% 3% 2% 2% 1% 1% 0% IHC CISH There were no significant differences in Her2 overexpression or amplification between rectal, sigmoid colon and descending colon cancers Threshold for positivity -Her2 IHC: ≥ 3+ an
Slide 27: IHC - Protein Overexpression
IHC - Protein Overexpression 100% Rectum Sigmoid 80% Descending 60% 40% 20% 0% ERCC1 MGMT PTEN TLE3 TOP2A TOPO1 TS TUBB3 indicates a significant difference between rectal and descending colon tumors (p < 0.05) indicates a significant difference between rectal and sigmoid colon tumors (p < 0.05)
Slide 28: Rectal vs. Descending Colon vs. Right-Sided Colon Cancers
Rectal vs. Descending Colon vs. Right-Sided Colon Cancers Presented by:
Slide 29: Mutation Frequency Comparison Between Rectal and Right-sided Colon Cancers
Mutation Frequency Comparison Between Rectal and Right-sided Colon Cancers 80% 70% Rectum Descending 60% Right 50% 40% 30% 20% 10% 0% Indicates a significant difference between rectal cancers vs. right-sided colon tumors (p < 0.05)
Slide 30: Frequency of Microsatellite Instability
Frequency of Microsatellite Instability P < 0.0001 Rectum P = 0.0296 Descending 25% 22% Right 20% P = 0.0152 15% 10% 7% 5% 1% 0% Microsatellite Instability Right Colon Descending Colon Rectum (N = 112) (N = 42) (N = 134) Deficient 25 3 1 MSI Proficient 87 39 133
Slide 31: Her2/Neu : Overexpression and Amplification
Her2/Neu : Overexpression and Amplification P = 0.0328 6.0% 5.4% 5.0% Rectum 4.0% Descending 3.4% Right 3.0% 2.7% 2.0% 1.4% 1.3% 1.0% 1.0% 0.0% IHC CISH Descending Descending Right Colon Rectum Right Colon Rectum Colon Colon Positive N 3 1 16 Positive N 2 2 15 IHC- CISH- Negative N 218 98 574 Negati
Slide 32: IHC - Protein Overexpression
IHC - Protein Overexpression 100% Rectum Descending 80% Right 60% 40% 20% 0% indicates a significant difference between right-sided colon vs. rectal tumors (p < 0.05) Presented by:
Slide 33: Limitations
Limitations • This was a retrospective analysis • Potential effects of treatments including chemoradiation are unknown • Limited clinical information was available for analyzed tumors • A large number of samples were excluded due to a lack of definitive tumor location information
Slide 34: Primary Site Effects (left colon vs. rectal)
Abstract # 675 Primary Site Effects (left colon vs. rectal) Figure 1. Overall survival among all pts OS of all pts. Left-sided colon pts had similar OS as rectal pts Median OS 18.7 mos left-sided colon versus 18.1 mos rectal Adjusted HR 1.02 (0.95-1.10) p=0.559 34
Slide 35: Conclusions
Conclusions • CRCs carry a continuum of molecular alterations from right to left, rather than having a sharp, clear-cut distinction
Slide 36: Conclusions
Conclusions • Rectal cancers have molecular features that are different from left-sided colon tumors • Clinical trials should stratify patients based on the location of the primary tumor (right vs. left) as well as molecular features • Better understanding of disease biology may help to identify the
Slide 37: THANK YOU
THANK YOU