Detecting a Cancer Signal Using aMulti-Cancer Early Detection (MCED) Test
Circulating Cell-free Genome Atlas (CCGA) Substudy 3: Clinical Validation1
CCGA: Prospective, observational, case-control study divided into 3 substudies for discovery, training, and validation2

15,254 participants from 142 sites 2
56% with cancer
44% without cancer

Blood samples
All participants

Tissue samples
Participants
with cancer only

MCED Test result

Follow-up
for 5 years(vitals & cancer status)

CCGA3: Cancer Signal Detection1
Speciﬁcity 99.5%(95% CI: 99.0–99.8%)(95% CI: 28.6–79.9%)

0.5% false-positive rate inparticipants without cancer*Estimated value (adiustedto SEER cancer incidence
and stage distribution inthe 50-79 y age group) 3, aSensitivity 51.5%(95% CI: 49.6–53.3%)
Sensitivity of 12 prespeciﬁed cancers that
account for ~2/3 of US cancer deaths 4,b76%
53%
All cancer stages

Stage I-II

68%

Stage I-III

Diversity of Cancer Signals Detected1
MCED Test Sensitivity

75%

Sensitivity<25%
25% – <50%50% – <75%
≥75%

50%

Unknown Primary (17/18)

Liver/Bile-duct (43/46)

Esophagus (85/100)

Head and Neck (90/105)

Multiple Primaries (16/19)

Ovary (54/65)

Pancreas (113/135)

Anus (18/22)

88.7%

Colon/Rectum (169/206)

Cervix (20/25)

Urothelial Tract (8/10)

Lung (302/404)

Plasma Cell Neoplasm (34/47)

Stomach (20/30)

Gallbladder (12/17)

Sarcoma (18/30)

Other (30/59)

High Accuracy ofPredicted Cancer
Signal Origin

Lymphoma (98/174)

Melanoma (6/13)

Lymphoid Leukemia (21/51)

Bladder (8/23)

Uterus (44/157)

Breast (160/524)

Kidney (18/99)

Myeloid Neoplasm (2/10)

0%

Thyroid (0/14)

25%

Prostate (47/420)

Sensitivity (±95% CI)

100%c>50 AJCC
cancer types5
including a majoritythat don't haverecommended
screenings

High rate of correctly identiﬁed Cancer Signal
Origins across multiple cancer types, giving
you a roadmap for where to explore further(95% Cl: 87.0–90.2%)

Clinical validation supports use of this MCED test in a clinical setting in addition to single-cancer
screening tests in adults with elevated cancer risk (such as being 50+ years of age.)
MCED tests do not detect a signal for all cancers and not all cancers can bedetected in the blood. False positive and false negative results do occur.

Adverse Events10 serious AEs

0.4%

related toblood draw

participants (20/5309)
with AEs related
to blood draw

3 ⁄20 e17⁄20 dmildAEs

moderate
AEs

Participants by highest-grade AE

Overview of CCGA Substudies
Samples divided among 3 pre-speciﬁed CCGA substudies1

Discovery 6
Whole Genome Methylation
identiﬁed as method forfurther development(of ten classiﬁers—
using different cfDNA
features across three
prototype MCED assays)

Training: n=1785
Validation: n=1015

Assay Reﬁnement andInitial Validation 7

Further Assay Reﬁnement
and Clinical Validation 1

Targeted Methylation
identiﬁed key informative
methylation regions

Further reﬁned for use
as screening tool

Training and validation of
the machine-learning classiﬁer
to differentiate cancer vs
non-cancer and predict
signal origin

Clinical validation supporting
commercial product launch

Training: n=3133
Validation: n=1354

n=4077 conﬁrmed status analysis set(cancer=2823; non-cancer=1254)

a Estimated PPV value was adjusted using SEER cancer incidence data3, as PPV is impacted by population incidence and speciﬁcity. PPV in thePATHFINDER study was 43.1%8.
bAnus, Bladder, Colon/rectum, Esophagus, Head and neck, Liver/bile duct, Lung, Lymphoma, Ovary, Pancreas, Plasma cell neoplasm, Stomach.
cThe graph shows 24 cancer classes plus 3 additional classes (other, unknown primary, and multiple primaries). The 24 cancer classes plus the"other" class used for sensitivity reporting correlate with the >50 AJCC cancer types.
d17 participants with 19 mild AEs: dizziness (n=8), bruising (n=2), hematoma and bruising (n=1), lightheaded (n=2), lightheaded and nausea(n=1), feeling warm (n=1). syncope (n=1), multiple attempts for blood draw (n=1).
e3 participants with 3 moderate AEs: syncope (n=2) and vasovagal reaction (n=1); 1 participant with syncope also reported a mild AE of vomiting.
Abbreviations: AE: adverse event; AJCC: American Joint Committee on Cancer; CCGA: The Circulating Cell-free Genome Atlas study (1, 2. and 3indicate substudies); CI: conﬁdence interval; MCED: multi-cancer early detection; PPV: positive predictive value; PSA: prostate speciﬁc antigen;
SEER: Surveillance, Epidemiology. and End Results Program.

References
1. Klein EA, et al. Ann Oncol. 2021;32(9):1167-1177. DOI: 10.1016/j.annonc.2021.05.806.
2. GRAIL, LLC. The Circulating Cell-Free Genome Atlas Study. https://clinicaltrials.gov/ct2/show/NCT02889978.
3. SEER Stat Database: Incidence - SEER 18 Regs Research Data, Nov 2017 Sub. Includes persons aged 50+ diagnosed 2006-2015.
4. American Cancer Society. Cancer Facts & Figures 2021. Atlanta: American Cancer Society; 2021.
5. Amin MB, et al. (Eds.). AJCC Cancer Staging Manual (8th edition). Springer International Publishing: American Joint Commission on Cancer; 2017.
6. Jamshidi A, et al. Cancer Cell. 2022;40(12):1537-1549.e12. DOI: 10.1016/j.ccell.2022.10.022.
7. Liu MC, et al. Ann Oncol. 2020;31(6):745-759. DOI: 10.1016/j.annonc.2020.02.011.
8. Schrag D, et al. Lancet. 2023;402:1251-1260. DOI: 10.1016/S0140-6736(23)01700-2.

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