Can You Compete in Early Cancer Detection?

Learning Objectives • Discuss the benefits, limitations, and potential harms of current cancer-screening recommendations and protocols • Describe how cell-free DNA (cfDNA) can be used for the early detection of multiple cancer types • Evaluate recent clinical data on available and emerging noninvasive multi-cancer screening tests and their utility in early cancer detection • Design a practical protocol for integration of patient counseling and multi-cancer screening into workflow protocols in the primary care setting

ADDRESSING THE UNMET NEEDS OF UNDIAGNOSED CANCERS IN THE US

By the Numbers US Cancer

Cancer is the 2

nd leading cause of death in the US.1

More than

609,000 lives are estimated to be lost to cancer in 2023.2

40

65

of Americans will be diagnosed with cancer in their lifetimes.3

of Americans ≥21 years old are not up-to-date on at least 1 routine cancer screening.4

%

%

US, United States.

1. Murphy SL, et al. NCHS Data Brief. 2021;427:1-8; 2. NCI: SEER*Explorer. https://seer.cancer.gov/statfacts/; 3. National Cancer Institute (NCI). www.cancer.gov/aboutcancer/understanding/statistics; 4. Prevent Cancer Foundation. 2023. www.preventcancer.org/2023/02/65-of-americans-21-years-of-age-and-older-report-not-being-up-to-date-on-atleast-one-routine-cancer-screening/.

5-Year Relative Survival Rates 5-Year Relative Survival Rate, %

Stratified by Age, Race, and Stage

100 80 60 40 20 0

<15

15-39

40-64

Agec,1

65-74

≥75

Whitea

Hispanicb Asian/ Pacific Islander a

Racec,1

Black a

Native Localized Regional American/ Alaska Native a

Staged,2

5-year relative survival rate is 3x higher for tumors detected at a localized stage than for those detected at a distant stage.2 Overall 5-Year Survival Rate With Any Malignancy: 68.7%3 a

Non-Hispanic; bAny race; c2013-2019; d2011-2017.

1. NCI: SEER*Explorer. https://seer.cancer.gov/explorer/; 2. Centers for Disease Control and Prevention. US Cancer Statistics Data Brief, no. 25. 2021. Atlanta, GA. www.cdc.gov/cancer/uscs/about/data-briefs/no25-incidence-relative-survival-stage-diagnosis.htm; 3. NCI: NCI Cancer Stat Facts. https://seer.cancer.gov/statfacts/.

Distant

The USPSTF Recommendations for Screening Asymptomatic Patients1-3 Cancer

Screening

Criteria

Breast

Biennial screening mammography

Women aged 40-74 years

• Cervical cytology every 3 years • Cervical cytology every 3 years OR • High-risk human papillomavirus (hrHPV) every 5 years OR • hrHPV + cervical cytology every 5 years • Stool-based testing – Annual fecal immunochemical test (FIT) or high-sensitivity guaiacbased testing – sDNA-FIT (stool DNA test with FIT) every 1 to 3 years • Colonoscopy every 10 years • Computed tomography colonography every 5 years • Flexible sigmoidoscopy – Every 5 years – Every 10 years + annual FIT

Women aged 21-29 years

Cervical

Colorectal

Lung

Annual LDCT

Prostate

Prostate-specific antigen (PSA) testing

Women aged 30-65 years

• Age 45-75 years • Certain populations aged 76-85 years

Age 50-80 years and ≥20 pack per year history of smoking and currently smoke or quit within the past 15 years Men aged 55-69 years when elected with shared decision-making

Year Published Draft Recommendation Statement (May 2023) 2018; update in progress

2021

2021 2018

USPSTF, US Preventive Services Task Force; LDCT, low-dose computed tomography.

1. USPSTF. www.uspreventiveservicestaskforce.org/uspstf/recommendation-topics/uspstf-a-and-b-recommendations; 2. USPSTF. www.uspreventiveservicestaskforce.org/uspstf/draftupdate-summary/breast-cancer-screening-adults; 3. USPSTF. www.uspreventiveservicestaskforce.org/uspstf/recommendation/prostate-cancer-screening.

USPSTF Recommendations The USPSTF currently recommends AGAINST screening asymptomatic patients for ovarian, pancreatic, testicular, and thyroid cancers (estimated to account for 11% of all cancer deaths in 2023).

USPSTF. www.uspreventiveservicestaskforce.org/uspstf/recommendation-topics.

Successes of Cancer Screening

Reductions in Age-Adjusted Mortality Rates 2011-20201 BREAST CANCER

LUNG CANCER

ê 1.3% annually Since its peak in 1989, female screening resulted in a 20% ê in overall mortality2

ê 4.1% annually Early diagnosis ê mortality rates at 10 years by 39% compared with no intervention3

COLORECTAL CANCER

PROSTATE CANCER

ê 2.0% annually

ê 1.2% annually

1. NCI Cancer Stat Facts. https://seer.cancer.gov/statfacts/; 2. Beau AB, et al. J Clin Oncol. 2018;36(30):2988-2994; 3. Pastorino U, et al. Ann Oncol. 2019;30(7):1162-1169.

Many Cancers Are Not Detected by a Preventive Screening Test

25%

• Current screening recommendation is ”one organ at a time”2 • Some populations are not benefiting from current guideline recommendations because they are not included in the guidelines

18%

– eg, mortality rate among adults <50 years with colorectal cancer é 1.2% annually (2004-2020)3

% Cancers1 Diagnosed cancers with no preventive screening test

57%

Detected via conventional screening

Screenable cancers not detected by screening

• Only 1/3 of cancers found in the National Lung Screening Trial (NLST) were lung cancera,4

a

N=53,299 people in the US. 1. NORC at the University of Chicago. 2021. www.norc.org/PDFs/GRAIL/State-Specific%20PCDSs%20chart%201213.pdf; 2. Ahlquist DA. NPJ Precis Oncol. 2018;2:23; NCI SEER*Explorer. https://seer.cancer.gov/explorer/; 4. Chang ET, et al. J Clin Oncol. 2023;41(suppl 16):10633.

3.

Modeled Data Demonstrate Late-Stage Cancer Diagnoses and Deaths Can Be Reduced by Adding MCED to Usual Care Deaths Within 5 Yearsa,1 Averted vs No MCED N %

MCED Screening Interval

N

Annual

308

85

21

Biennial

324

69

17

None

393

0

0

The addition of MCED to routine cancer would result in 3x as many cancers diagnosed as routine screening alone, with at least 17% fewer cancer deaths per year.b,2 a

Deaths within 5 years of original diagnosis to account for lead time; bindividuals aged 50-79 years who have been screened.

1. Sasieni P, et al. Ann Oncol. 2021;32(suppl 5):1135P; 2. Sasieni P, et al. Br J Cancer. 2023;129(1):72-80.

MCED Testing Could Detect Cancers Not Assessed by Traditional Single Organ Screening Modalities

Many Cancers Are Potentially Missed With Conventional Screening Crude Incidence Rate Per 100,000a

1250 1000

Invasive cancer targeted via conventional screening Invasive cancers not targeted by screening

973

12X

750

3X

500

25X

250 0

326

323 90

13 Cervical b (30-65 Years)

a

1067

Colorectal c (50-74 Years)

Breast d (50-74 Years)

All rates are crude per 100,000 from Surveillance, Epidemiology and End Results; bRecommended cervical cancer screening every 3 years with cytology alone, every 5 years with highrisk HPV testing alone, or every 5 years with cotesting; cRecommended colorectal cancer screening choice of approved modality; dRecommended breast cancer screening biennial mammography.

Clarke CA, et al. Cancer Cell. 2021;39(4):447-448.

Adding MCED to Recommended Screening Could Detect More Cancers and Be More Cost-effective Current Screening (67M)

With Added MCED screening (Estimated)

Total diagnostic costs1

$16.9 billion

$3.0 billion

Cost per cancer found1

$89,042

$7,060

An MCED test ordered during a preventive care exam could have detected up to an additional 11% of breast cancer cases and up to 58% of unscreened cancers that are the leading causes of cancer death.2 1. Hackshaw A, et al. Br J Cancer. 2021;125(10):1432-1442; 2. Hathaway C, et al. Front Oncol. 2021;11:688455.

SCIENCE OF MCED

Traditional Tissue vs Liquid Biopsy Traditional Tissue Biopsy1,2

Liquid Biopsy3-5

• Usually invasive • Only possible if tumor is visible and accessible • Can be costly, risky, and potentially painful • Only provides detailed information about cancer at the site and the time of biopsy

• Noninvasive • Can characterize across all tumor stages • Can produce real-time information for diagnosis, metastases, prognoses • May indicate potential treatment response

1. Sharma S, et al. Pathology. 2021;53(7):809-817; 2. Rodríguez J, et al. Oncol Ther. 2021;9(1):89-110; 3. Mathai RA, et al. J Clin Med. 2019;8(3):372-373; 4. Aarthy R, et al. Mol Diagn Ther.

2015;19(6):339-350; 5. Pinzani P, et al. Clin Chem Lab Med. 2021;59(7):1181-1200.

Cell-Free DNA (cfDNA) Apoptosis

Apoptotic bodies Point mutations Copy number alterations Protein biomarkers

Necrosis

Rearrangements CH3

Secretion

Methylation changes

CH3

Exosomal DNA

CH3, methyl group.

Cisneros-Villanueva M, et al. Br J Cancer. 2022;126(3):391-400; Wan JCM, et al. Nat Rev Cancer. 2017;17(4):223-238.

cfDNA anomalies that can be measured and characterized in assays

DNA Methylation as a Tumor Biomarker • Cancer is associated with epigenetic changes (eg, DNA methylation) that can alter: – The 3-dimensional conformation of the genome – Protein-DNA interactions – Expression patterns (silencing, activation)

• Changes in DNA methylation patterns: – Can contribute to tumorigenesis or progression • ctDNA ctDNA, circulating tumor DNA; Me, methylation.

Locke WJ, et al. Front Genet. 2019;10:1150.

– Can be identified and characterized via nextgeneration sequencing + machine learning

MCED vs Genetic Testing • MCED Testing is SCREENING • Genetic Testing is RISK CALCULATION

Validation of the Assays

Understanding Sensitivity & Specificity Sensitivity

Specificity

Examples

the test's ability to detect a truepositive sample (eg, a patient with a particular cancer)

the test’s ability to detect a true negative (eg, a patient who does not have that particular cancer)

98% Sensitivity would

Negative Predictive Values (NPV)

98% Specificity would

Positive Predictive Values (PPV) assessment of the utility of the test in clinical practice, measured as the percentage of all positive samples that are true positives Trevethan R. Front Public Health. 2017;5:307.

percentage of all negative samples that are true negatives

produce 2 false-negative results for every 100 samples from patients with cancer.

result in 2 false-positive signals for every 100 samples from patients with no cancer.

The Power of Aggregate Prevalence for Selected Cancers 1000

PPV, %

60

600

Liver (588) Pancreas (500)

400

0

1

40

95%

0 2

Prevalence, % GI, gastrointestinal; NNS, number needed to screen.

Ahlquist, DA. NPJ Precis Oncol. 2018;2:23.

97%

Universal (33)

Pan-GI (83)

0

99%

20

Colorectal (167)

200

Specificity

l Esophagus l Stomach l Liver l Pancreas l Colorectal l Pancreas-GI l Universal

Stomach (833)

800

NNS

80

Esophagus (1000)

3

0

1

2

Prevalence, %

3

cfDNA-Based MCED Assays That Have Received FDA Breakthrough Device Designationa Tumor Protein biomarkers

CancerSEEK1,2 § 8 cancers § Methylated cfDNA (16 genes) + protein biomarkers

OverC MCDBT2,3 § 5+ cancers § Deep methylation sequencing Me

Galleri1,2 § >50 cancers § >100,000 differentially methylated regions

cfDNA biomarkers

aAs of September 2023, Galleri is the only commercially available test in the US that analyzes cfDNA methylation patterns.

MCDBT, multi-cancer detection blood test.

1. Hackshaw A, et al. Cancer Cell. 2022;40(2):109-113; 2. Liu MC. Br J Cancer 2021;124(9):1475-1477; 3. Gao Q, et al. J Clin Oncol. 2021;39(suppl 3):459.

Criteria Important for a Cancer Screening Test Specificity and Sensitivity

Criteria1

High specificity

High sensitivity a

Why Important To minimize falsepositives and thereby reduce unnecessary workup, overdiagnosis, overtreatment

Test

Specificity

Sensitivity (Range)

Cancers investigated

CancerSEEK (+PET-CT)

99.6%

15.6%

All cancers except skin, CNS, leukemias

Galleri

99.5%

40.7% (Stages 1-3) 51.9% (All cancers)

>50 cancer types

PATHFINDERc,4

Galleri

99.5%

51.9%d

>50 cancer types

Thunder IIe,5 Validation Set

OverC MCDBT

98.3%

80.6%

Lung, colon/rectum, liver, ovary, pancreas, and esophagus

Trial DETECT-Aa,2 CCGA Substudy 3b,3

To detect early tumors that may be curable by surgery

N=10,006 women with no prior cancer history; bN=4077 (with cancer=2823) + (noncancer=1254); cN=6578 patients ≥50 years old with or without additional risk factors for cancer (smoking history, genetic predisposition, or prior diagnosis of successfully treated cancer); dSensitivity determined from the CCGA study; eN=639 (with cancer=351) + (noncancer=288).

ASCO, American Society of Clinical Oncology; CCGA, Circulating Cell-free Genome Atlas; CNS, central nervous system; ESMO, European Society for Medical Oncology; PET-CT, positron emission tomography-computed tomography.

1. Duffy MJ, et al. Clin Chem Lab Med. 2021;59(8):1353-1361; 2. Lennon AM, et al. Science. 2020;369(6499):eabb9601; 3. Klein EA, et al. Ann Oncol. 2021;32(9):1167-1177; 4. Schrag D, et al. Lancet. 2023;402(10409):1251-1260; 5. Gao Q, et al. J Clin Oncol. 2021;39(suppl 3):459.

Criteria Important for a Cancer Screening Test PPV and NPV

Criteria1

Why Important

Trial DETECT-Aa,2

High PPV

To reduce unnecessary workup, overdiagnosis, overtreatment

High NPV

To reduce the probability of missing potentially curable tumors

Test

PPV

NPV

CancerSEEK (+PET-CT)

28.3%

99.1%

CCGA Substudy 3b,3

Galleri

44.4%

99.4%

PATHFINDERc,4

Galleri

43.1%

98.5%

Thunder IId,5 Validation Set

OverC MCDBT

N/A

N/A

aN=10,006 women with no prior cancer history; bN=4077 (with cancer=2823) + (noncancer=1254); cN=6578 patients ≥50 years old with or without additional risk factors for cancer

(smoking history, genetic predisposition, or prior diagnosis of successfully treated cancer); dN=639 (with cancer=351) + (noncancer=288).

AACR, American Association for Cancer Research; N/A, not available.

1. Duffy MJ, et al. Clin Chem Lab Med. 2021;59(8):1353-1361; 2. Lennon AM, et al. Science. 2020;369(6499):eabb9601; 3. Klein EA, et al. Ann Oncol. 2021;32(9):1167-1177; 4. Schrag D, et al. Lancet. 2023;402(10409):1251-1260; 5. Gao Q, et al. J Clin Oncol. 2021;39(3_suppl):459.

Criteria Important for a Cancer Screening Cancer Signal of Origin (CSO) Identification

a

Criteria1

Why Important

Ability to localize site of tumor

To minimize imaging for localizing tumor site

Test

Specificity

Sensitivity (Range)

PPV

NPV

CSO

CancerSEEK (+PET-CT)

99.6%

15.6%

28.3%

99.1%

—

CCGA Substudy 3b,3

Galleri

99.5%

40.7% (Stages 1-3) 51.5% (All cancers)

44.4%

99.4%

88.7%

PATHFINDERc,4

Galleri

99.5%

51.9%d

43.1%

98.5%

88%

Thunder IIe,5 Validation Set

OverC MCDBT

98.3%

80.6%

—

—

81%

Real-World Experiencef,6

Galleri

Trial DETECT-Aa,2

91%

N=10,006 women with no prior cancer history; bN=4077 (with cancer=2823) + (noncancer=1254); cN=6578 patients ≥50 years old with or without additional risk factors for cancer (smoking history, genetic predisposition, or prior diagnosis of successfully treated cancer); dSensitivity determined from the CCGA study; eN=639 (with cancer=351) + (noncancer=288); fN=53,744 MCED tests delivered.

1. Duffy MJ, et al. Clin Chem Lab Med. 2021;59(8):1353-1361; 2. Lennon AM, et al. Science. 2020;369(6499):eabb9601; 3. Klein EA, et al. Ann Oncol. 2021;32(9):1167-1177; 4. Schrag D, et al. Lancet. 2023;402(10409):1251-1260; 5. Gao Q, et al. J Clin Oncol. 2021;39(suppl 3):459; 6. Westgate C, et al. J Clin Oncol. 2023;41(suppl 16):10519.

Criteria Important for a Cancer Screening Cancer Signal of Origin (CSO) Identification

Criteria1

Why Important

Ability to localize site of tumor

To minimize imaging for localizing tumor site

Test

Specificity

Sensitivity (Range)

PPV

NPV

CSO

CancerSEEK (+PET-CT)

99.6%

15.6%

28.3%

99.1%

—

Galleri

99.5%

40.7% (Stages 1-3) 51.5% (All cancers)

44.4%

99.4%

88.7%

PATHFINDERc,4

Galleri

99.5%

51.9%d

43.1%

98.5%

88%

Thunder IIe,5 Validation Set

OverC MCDBT

98.3%

80.6%

—

—

81%

Trial DETECT-Aa,2 CCGA Substudy 3b,3

Real-World Experiencef,6

Galleri

91%

According to the Galleri real-world data presented by Westgate et al at the ASCO 2023 Annual Meeting, the cancer signal of origin (CSO) prediction demonstrated 91% accuracy for 53,744 tests. a

N=10,006 women with no prior cancer history; bN=4077 (with cancer=2823) + (noncancer=1254); cN=6578 patients ≥50 years old with or without additional risk factors for cancer (smoking history, genetic predisposition, or prior diagnosis of successfully treated cancer); dSensitivity determined from the CCGA study; eN=639 (with cancer =351) + (noncancer =288); fN=53744 MCED tests delivered.

1. Duffy MJ, et al. Clin Chem Lab Med. 2021;59(8):1353-1361; 2. Lennon AM, et al. Science. 2020;369(6499):eabb9601; 3. Klein EA, et al. Ann Oncol. 2021;32(9):1167-1177; 4. Schrag D, et al. Lancet. 2023;402(10409):1251-1260; 5. Gao Q, et al. J Clin Oncol. 2021;39(3_suppl):459; 6. Westgate C, et al. J Clin Oncol. 2023;41(suppl 16):10519.

What We’ve Learned About cfDNA-Based MCEDs So Far • Cancer at all stages can be identified by analyzing methylated cfDNA with machine learning • Other notes: – HPV-mediated misdiagnosis of CSO has been reported6 – False positives have resulted from clonal B cell expansion7

Test

Specificity Sensitivity

PPV

NPV

CSO

FPR

FNR

Diagnostic Mammography1,2

88.9%

86.9%

4.4%

—

N/A

12.1%

0.08%

Low-dose CT3-5

>75%

>80%

3.3%43.5%

97.7% -100%

N/A

27%

6.2%

Pap Smear6-8

85.5%

29.7%

62.6%

59.8%

N/A

40.2%

37.4%

FNR, false negative rate; FPR, false positive rate.

1. Lehman CD, et al. Radiology. 2017. 283(1):49-58; 2. Nelson HD, et al. Ann Intern Med. 2016. 164(4):226-235; 3. Jonas DE, et al. JAMA. 2021. 325(10):971-987; 4. Pinsky PF. Lung Cancer Manag. 2014;3(6):491-498; 5. The National Lung Screening Trial Research Team. N Engl J Med. 2013. 368(21):1980-1991. 6. Vahedpoor Z, et al. Taiwan J Obstet Gynecol. 2019. 58(3):345348; 7. Myers DA, Wood B. Cancer Res. 2023;83(suppl 7):6503; 8. Xiang J, et al. Cancer Res. 2023;83(suppl 7):779.

Ongoing cfDNA-Based MCED Clinical Trials • CancerSEEK: ASCEND1, DETECTASCEND-22 • GALLERI: STRIVE, SUMMIT, PATHFINDER 2, REFLECTION3 • OverC MCDBT: PREDICT, PRESCIENT3 • HarbingerHx: CORE-HH4 • PanSeerX: FuSion Project5 • Guardant LUNAR-2: SHIELD6 1. Duffy MJ, et al. Clin Chem Lab Med. 2021;59(8):1353-1361; 2. WCG CenterWatch. www.centerwatch.com/clinical-trials/listings/290326/ascend-2-detecting-cancers-earlier-throughelective-plasma-based-cancerseek-testing-ascertaining-serial-cancer-patients-to-enable-new-diagnostic-ii-detect-ascend-2/?featured=true. 3. ClinicalTrials.gov. https://clinicaltrials.gov/; 4. Gregg JP, et al. J Clin Oncol. 2023;41(suppl 16):e15035; 5. Suo C, et al. Cancer Res. 2023;83(suppl 7):4194; 6. Nguyen HA, et al. J Clin Oncol. 2023;41(suppl 16):TPS1610.

MCED IMPLEMENTATION INTO PRIMARY CARE PRACTICE

Overcoming Challenges Associated With Lack of MCED Guidelines MCED testing should be used to complement recommended screening approaches to identify cancers they do not cover, NOT in place of current screening.

• Who should take an MCED Test?1 • ≥50 years • Family or personal history of cancer • History of childhood cancer • Known genetic mutations • Risk factors

• Who is NOT eligible1 – Pediatric populations (<21 years) – Pregnant patients – Active cancer diagnosis or treated for cancer in last 3 years 1. Putcha G, et al. JCO Precis Oncol. 2021:574-576; 2. Multicancer Early Detection Consortium. June 27, 2023. https://static1.squarespace.com/static/615c87aaea640d19cc98840b/t/6499fcaddf755715cc844f39/168781329396 9/MCED+Consortium+Care+Delivery+Paper_Final.pdf.

Risk Factors2

• Age • Alcohol • Cancer-causing substances (environmental exposures such as tobacco smoke) • Chronic inflammation • Diet • Hormones • Immunosuppression • Infectious agents • Overweight/Obesity • Radiation • Sunlight • Tobacco

Considerations When Discussing MCED With Patients Potential Advantages

Potential Disadvantages

Increased and earlier cancer detection rate, including asymptomatic patients1,2

Currently not covered by most insurance (commercial or government-sponsored)1

Trials demonstrate improving efficiency of testing with increased PPV, decreased NNS1

“No Cancer Detected” does not rule out future cancer diagnosis. Sensitivity limited.

Screening of organ sites currently without a screening modality2

Consequential cancers found sooner, but patient may not live any longer3

Screening for multiple cancers at the same time1

Possible harm from unnecessary diagnostic procedures due to false positives or missed diagnoses due to false negatives1,2

Less invasive procedures and potentially improved success of treatments2

Overdiagnosis and overtreatment of cancers that would have otherwise never bothered the patient2,3

May help reduce health disparities by increasing participation rates through improved access to screening2

Inequities will increase if tests are not widely available, affordable, and acceptable to minority groups2

1. Klein EA, et al. Ann Oncol. 2021;32(9):1167-1177; 2. Multicancer Early Detection Consortium. June 27, 2023. https://static1.squarespace.com/static/615c87aaea640d19cc98840b/t/6499fcaddf755715cc844f39/1687813293969/MCED+Consortium+Care+Delivery+Paper_Final.pdf; 3. Welch HG, Kramer B. STAT. January 12, 2022. www.statnews.com/2022/01/12/medicare-shouldnt-cover-liquid-biopsies-early-cancer-detection/.

MCED Is Not Always Covered by Insurance • Currently covered by a few; out of pocket for Galleri is $949 • Medicare Multi-Cancer Early Detection Screening Coverage (originally 2021, reintroduced March 2023 (House of Representatives) and June (Senate) 20231 – Not passed yet

• Cancer Moonshot Initiative: develop plans to quickly evaluate utility and benefits of MCED tests2 – Early 2022, added goal of reducing cancer death rate by half within 25 years and improving lives of people with cancer and cancer survivors

• National Cancer Institute (NCI) Vanguard Study on Multi-Cancer Detection evaluating MCED assays for purpose of cancer screening 1. Prevent Cancer Foundation. www.preventcancer.org/multi-cancer-early-detection/coverage-and-legislation/#coverage-act; 2. American Association for Cancer Research. Cancer Discov. 2022;12(4):876.

MCED Workflow (Galleri) • Galleri is the only currently available test • To order an MCED test for eligible patients1: – Order using test requisition via provider portal or email – Kits include 2x 10-mL Streck cfDNA blood collection tubes (fasting not required) • Fill both tubes (samples <3 mL will be rejected)

– Collected blood can be stored at 6°C -37°C (48.2°F-98.6°F) for <7 days (Standard Kit) • Extreme Temperatures Kit – for when samples may be exposed to extreme temperatures in transita

– Results given to provider within 10 business days of sample receipt (via online Provider Portal or automatic fax notification)

Temperatures are considered extreme when <6°C/48.2°F or >37°C/98.6°F. Grail. www.galleri.com/hcp. a

Follow-up for a Positive Cancer Signal Test Result Should Be Individualized • Based on: – Data supporting the specific test, the invasiveness of additional diagnostic evaluations, the potential efficacy of available treatments – Further workups may include laboratory tests, imaging (CT, MRI, PET, US, X-ray) bone scans, or tissue biopsy (see next slide)

CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; US, ultrasound.

Nadauld LD, et al. Cancers (Basel). 2021;13(14):3501.

Clinical Care Pathways Following a “Signal Detected” Result Cancer Signal Origin Prediction

Proposed First-line Procedures Blood workup including peripheral blood smear, CBC with differential; chemistry tests including creatinine clearance, protein electrophoresis of blood/urine

Multiple myeloma Upper GI (esophagus, stomach) Colorectal Head and neck Pancreas, gallbladder Ovary Lung Liver, bile duct

Endoscopy Colonoscopy Physical exam, fiber optic exam, ultrasound CT abdomen with IV contrast, MRCP, GI referral Abdominal/pelvic exam, ultrasound (preferred) CT chest with or without IV contrast Ultrasound, CT, GI referral

Blood work

Diagnostic mammography with ultrasound (MRI if mammography screening within last 3 months)

Breast Lymphoid neoplasm Indeterminate

CT (neck, chest, abdomen, pelvis) with IV contrast, PET-CT CT (neck, chest, abdomen, pelvis) with IV contrast, PET-CT

For your reference, this chart is on your handout or available at www.ExchangeCME.com for easy download.

CBC, complete blood count; IV, intravenous; MRCP, magnetic resonance cholangiopancreatography.

Adapted from Nadauld LD, et al. Cancers (Basel). 2021;13(14):3501.

Successful Implementation of MCED Screening in a US-based Health System A Case Study

1

Assess Patient Eligibility

Patient Registration via online form or provider referral

2

Pretest Counseling & Ordering MCED Test

MCED Team notified of eligible patients

3

MCED Test Processing

4

Result Delivery

Patient blood sample taken

Patients Screened for eligibility Patients called for pretest counseling within 2 business days

Blood sent to test manufacturer

Results inputted into test manufacturer portal (~2 weeks after blood received) and delivered to MCED Team

A. “Cancer Signal Detected”

MCED Team develops diagnostic plan within 24 hours

Patient notified and Diagnostic tests scheduled

N=925 MCED test orders (from 3777 total referrals: 2931 patient, 846 provider).

CSD, cancer signal detected.

Agarwal G, et al. J Clin Oncol. 2023;41(suppl 16):1526.

MCED test ordered for interested patients

B. “No Cancer Signal Detected” Diagnostic results and next steps discussed with patient if confirmed positive

Patient notified and additional health screenings discussed as needed

Median time from CSD result to: • Patient notification of result: 22.8 hours • Initial diagnostic evaluation: 3.1 days • Cancer diagnosis (6/925): 8.7 days • Initiation of treatment or first postdiagnosis specialist visit: 33 days

Summary • MCED can successfully detect a cancer signal and its point of origin • MCED tests are intended to complement other screening strategies, not to be used instead of current cancer screening methods • Statistical modeling indicates that adding MCED testing to usual screening protocols could result in – 3x as many cancers diagnosed compared with routine screening alone – 17% fewer cancer deaths per year

• Lack of guidelines and insurance coverage are significant barriers to overcome