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Molecular Diagnostics and the Future of Cancer Care

George W. Sledge, MD – Executive Vice President & Chief Medical Officer

March 7, 2025

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U.S. Cancer in 2024

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2,001,140 new cases diagnosed in the U.S.

611,720 people died from the disease in the U.S.

Source: https://www.cancer.gov/about-cancer/understanding/statistics

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Estimated Increase in Cancer Incidence

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Source: UICC, https://www.uicc.org/what-we-do/thematic-areas/cancer-and-ageing

2050 Incidence

2030 Incidence

2022 Incidence

30 Million

20 Million

10 Million

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The Deteriorating Oncology Workforce

15,959 oncologists engaged in cancer care in the U.S.
23% are 64 and older
57% feel burned out from work weekly or more often
21% “Likely” or “Definite” they would leave their current practice within 2 years
Significant Maldistribution: 70% of U.S. counties lack

a single active cancer treatment trial

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Source: ASCO, State of Cancer Care in America, https://society.asco.org/research-data/reports-studies/state-cancer-care-america

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Cancer Care: The Story Until Now

Change from nonspecific to targeted therapies
Targeted therapies (usually) require measurable targets.

We call these biomarkers.

The last two decades have seen

dominance by biomarker-based therapies
an explosion in new systemic therapies
improved survival in many (but not all) cancers

Disparities in survival still bedevil us.

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Cancer Statistics 2025

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Source: Siegel, RL, et al. (2025) CA Cancer J Clin 75, 10-45. PMID 39817679.

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The FDA Approved 59 New Oncology Drugs / Indications in 2024

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– more than one new drug or indication per week –

This pace is an incredible educational and financial burden for doctors and patients.

https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancerhematologic-malignancies-approval-notifications

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Leading Cancer Drugs Worldwide by Revenue in 2023

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Source: Statista, 2024: https://www.statista.com/statistics/288538/top-cancer-drugs-based-on-revenue/

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National Cancer Costs in the United States

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Source: https://www.statista.com/statistics/1313989/projection-on-cancer-care-costs-us/

Projection

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Adherence to GuidelinesRequires a Multi-Technology Approach

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MAXIMIZING CLINICAL UTILITY WITH

100+ FDA-APPROVED THERAPY ASSOCIATIONS

HER2-targeted therapy temozolomide

sacituzumab-govitecan

MAXIMIZING CLINICAL UTILITY WITH

94+ FDA-APPROVED THERAPY ASSOCIATIONS

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First Generation Biomarkers

Singleton biomarkers�
Simple to perform�
Required pathologist interpretation�
Gateway biomarkers�
Largely failure biomarkers

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Best-in-Class Profiling Reveals a More Comprehensive Molecular Blueprint

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Analyzing DNA, RNA, and proteins to reveal a more complete molecular blueprint to guide precise and individualized treatment decisions.

Next-Generation Sequencing

— DNA —

Illumina NovaSeq System

23,000+ full gene coverage (whole exome coverage)
1,500x for clinical genes
SNVs, Indels, CNAs, Karyotyping, Viruses
~250,000 exonic/intronic/intergenic SNPs – gLOH, gene loss or amplification
Genomic signatures: gLOH, HRD*, TMB and MSI
HLA genotype*

Next-Generation Sequencing

— RNA —

Illumina NovaSeq System

23,000+ full gene coverage (whole transcriptome coverage); 61,000 transcripts
17 million read count
Gene fusions and variant transcripts
Novel translocation detection independent of intronic breakpoint

Immunohistochemistry

— Protein —

Ventana & Dako IHC

20+ clinically relevant IHCs (optimized across 25 tumor types)
Additional 50+ antibodies for RUO
Multiple FDA approved CDx PD-L1 tests for different disease types (per label)
Controls on every IHC
4 μm cuts to preserve tissue

Standard of Care + Clinical Trial Biomarkers
Immunotherapy	Targeted Therapy	Chemotherapy/Hormonal Therapies	Clinical Trials

DNA

Whole Exome Sequencing

SNVs, Indels, CNAs, Karyotyping, Viruses

RNA

Whole Transcriptome Sequencing

Gene Fusions & Variant Transcripts

Protein

Immunohistochemistry

Tumor-Relevant Protein Biomarkers*

Transcription & Gene Regulation

Translation

*Certain tests or features are not available in all locations. See website for details.

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Caris Assure^™ For Therapy Selection

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______________________

Technology

Circulating Nucleic Acids Sequencing (cNAS)

______________________

Application

Biomarker Analysis (Including Resistance Mutations) �______________________

Biological Coverage

Plasma: cfDNA, cfRNA

White Blood Cells: gDNA, mRNA

______________________

Variant Coverage (Pathogenic & Likely Pathogenic)

Tumor-Derived Incidental Germline* Incidental CH

______________________

Genes & Depth

23,000+ 8,000x (Raw Average For Clinically Relevant Genes)

______________________

Next-Generation Sequencing

Whole Exome

Whole Transcriptome

______________________

Alterations

SNV INDEL CNA Fusions

______________________

Genomic Signatures/Other

bTMB HLA Genotyping MSI

______________________

Sample Quantity

2 Tubes Whole Blood

______________________

Performance In Advanced/Metastatic Patients�Compared To Matched Tissue Collected Within 30 Days;

Based On ≥5 Ng Of cNAS Input� Clinically Actionable SNV & INDEL:

Sensitivity 93.8%

Specificity >99%

PPV 96.8%

� Incidental Germline*:

Sensitivity >99%

Specificity >99%

PPV >99%

Whole Exome & Whole Transcriptome Sequencing From Blood

*Not a replacement for comprehensive germline testing. Incidental pathogenic alterations are reported, including ACMG recognized cancer genes. Negative results do not imply the patient does not harbor a germline mutation..

Caris Assure™ for therapy selection is intended for patients with previously diagnosed solid malignant neoplasms when tissue is not feasible and is to be used by qualified healthcare professionals. RNA results are intended for investigational purposes only. Not available in all locations.

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Caris Assure^™Enables Calling Confidence

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cfDNA

cfRNA

gDNA

mRNA

Plasma

Buffy Coat

Incidental Germline Assessment

By analyzing genomic material (gDNA/mRNA) from white blood cells

More Results

More Often

WES and WTS analysis of both cfDNA and cfRNA as well as gDNA and mRNA

Fewer False Positives

Due to high specificity and analysis of white blood cells for CH mutations

Fewer Missed Mutations

Due to more tumor-derived material inputs, concordance to tissue and high sensitivity

Caris Assure™ is intended for patients with previously diagnosed solid malignant neoplasms when tissue is not feasible and is to be used by qualified healthcare professionals. RNA results are intended for investigational purposes only. Not available in all locations.

Not a replacement for comprehensive germline testing. Incidental pathogenic alterations are reported, including ACMG recognized cancer genes. Negative results do not imply the patient does not harbor a germline mutation.

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Artificial Intelligence

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Artificial Intelligence applied to large datasets can find new patterns that define disease and identify new drug targets.

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Caris GPSai^™ v3.0: Appropriate Identification

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Multiple neural networks

300K parameters each

90 Oncotree categories

26 major, 64 sub-categories

98% prediction sensitivity

With top two probabilities

Excellent PPV and NPV

Simultaneous WES and WTS of DNA and RNA from microdissected FFPE tumor samples in a single assay

Training

>230K non-CUP

Independent validation

>23K non-CUP, 417 CUP

Prospective validation

Additional >3K cases

Genomic Probability Score

MI Tumor Seek Hybrid^™

Deep Learning

Processing of WES/WTS data using multiple deep neural networks to create models for tissue identification

Generation of a probability score based on hybrid WES/WTS profiling data to help identify tissue of origin

23,000+ gene coverage

Genomic alterations, signatures

WES

1,500x for clinical genes

WTS

17 million read count

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Caris GPSai Identifies 90 Unique Cancer Types with > 95% Accuracy

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Caris GPSai Analysis Changes Therapy Options

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Signatures Change Lives

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Original Diagnosis:

Undifferentiated pleomorphic sarcoma

Original Chart Note:

“Since final diagnosis from University of *** consider pleomorphic undifferentiated sarcoma, I discussed with patient treatment choice such as supportive versus palliative chemotherapy which is not for cure.”

�

GPSai Prediction:

Lymphoma

IHC staining confirms lymphoma diagnosis – follicular lymphoma

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Sequencing Costs Continues to Fall

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When Should Sequencing Improve Outcome?

When a patient is relatively healthy

Good PS, longer expected lifespan

When the patient’s cancer has multiple molecularly targetable lesions and these lesions have drugs that work
When the test is ordered
When the doctor understands and can make use of the results

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Use of Genomic Testing is Increasing

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Cumulative Incidence of Patients Undergoing Next-Generation Sequencing (NGS) Testing, 2015-2022

Source: Chehade, CH, et al. (2024) JAMA Network Open 7, e2423186. PMID 39023888.

There is increasing use of NGS, but significant racial / ethnic, socioeconomic and insurance-related disparities.

(Shading represents 95% CI)

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Healthcare Disparities in Genomic Testing

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Round Up the Usual Suspects: Race and Ethnicity, Insurance, Region, Age, Poverty, Rural

1) Scheinson, DM, et al. (2021) JAMA Network Open 4, e2138219. PMID 34882180.

2) Zhao, T, et al. (2024) Cancer Res Commun 4, 303-311. PMID: 38276870.

Association of Panel Size with Area Deprivation Index (ADI) and Urban / Rural Status²

Demographic Differences in NGS Testing Stratified by Pre- and Post- National Coverage Determination (NCD) Periods¹

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We Have Met the Enemy, and It Is Us

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Blacks and Latinx patients with advanced NSCLC have lower timely NGS testing rates than non-Latinx whites.

“We observed at the practice level that both within- and across-practice inequities were meaningful contributors to total inequity for timely NGS testing.

At the physician level, across-physician inequity was the dominant contributor to total inequity in NGS testing.”

Source: Vidal, GA, et al. (2024) Racial and ethnic inequities at the practice and physician levels in timely next-generation sequencing for patients with advanced non–small-cell lung cancer treated in the US community setting.

JCO Oncol Pract 20, 370-377. PMID: 38194619

Doctors Are an Important Part of the Problem

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What Happens When Genomic Testing is Performed?

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In 11,085 patients receiving

genomic testing at Caris Life

Sciences, no difference in overall

survival was seen between

black and white patients.

Source: Heath, E, et al. (2024) Health disparities among patients with cancer who received molecular testing for biomarker-directed therapy. Cancer Res Commun 4, 2598-2609. PMID 39172022.

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Healthcare Disparity Fixes

Technological

Fix the EHR: Improve ease of ordering and clinical decision support

Educational

Professional Societies

More disparities research
Organizational

Quality Measures

Governmental

Medicare National Coverage Determination
Eliminate insurance barriers

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Thank You

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