Detect residual disease early. Treat with confidence.

Personalized and tumor-informed ctDNA monitoring and MRD assessment

Surveillance ProgramUse Signatera alongside CEA to detect recurrence earlier while it may still be resectable, and reduce false positives

Medicare draft

coverage*

*Medicare draft coverage for Surveillance Program: Stage II-III colorectal cancer patients

Use Signatera after surgery to evaluate the need for adjuvant chemotherapy and avoid unnecessary treatment

MRD Program

*Medicare draft coverage for MRD Program: Stage II-III colon cancer and Stage IIA rectal cancer patients

• Each patient gets a personalized custom-built assay to reflect their unique tumor

• Signatera targets 16 tumor-derived variants for each patient

• Clonal mutations are selected that occured early and persist throughout tumor evolution

Clonal/truncal

Sub-clonal/branch

TUMOR MUTATION

Sur

ger

y

1 w 2 w 3 w 4 w 5 w 6 w 7 wWEEKS MONTHS

2 m 3 m 4 m 5 m 6 m

Adjuvant treatment window

MRD Program

Treatment decision based on risk assessment5

Signatera validated with high PPV and NPV1

Signatera status is the only significantpredictor of risk

PPV: Postive Predictive Value NPV: Negative Predictive Value

Evaluate the need for adjuvant chemotherapy after surgery to avoid unnecessary treatment

Stage II ColonStage IIA Rectal Stage III Colon

Observe Treat

Low risk High risk

3 months 6 months

Low risk High risk

97%

70%

Without additional adjuvant treatment

With additional adjuvant treatment

100%

80%

60%

40%

20%

0%

Rel

apse

rat

e

12%3%

Single test after treatment

Serial testing after treatment

100%

80%

60%

40%

20%

0%

Rel

apse

rat

e

ctDNActDNA

Longitudinal

First time point after treatment

30 day time point pre-adjuvant

Stage II (T4 vs T1-T3)

Tumor grade (High vs low)

MMR status (MSI-H vs MSI-L)

17.5

43.5

7.2

1.55

1.36

0.73

0 5 10 15 20 25 30 35 40 45 50

Sig

nate

ra

Hazard ratio

1

6

7

8

*Medicare draft coverage for MRD Program: Stage II-III colon cancer and Stage IIA rectal cancer patients

MRD Program (first 6 months)

Series of assays in the adjuvant windowMedicare

draft coverage*

Surveillance Program

Serial testing with same frequency as CEA

Significant lead time over CT and CEA

88%

Speci�citySensitivity

69%

98%*

64%

Signa

tera

Signa

tera

CEA

CEA

100%

80%

60%

40%

20%

0%

Surveillance Program (after 6 months)

*Patient-level specificity 98%. Test-level specificity 99.7%.

Determine response to treatment earlier than previously possible

Actionable results5

>97% of patients will relapse without treatment

Consider directed imaging (PET/MRI) to locate the disease while potentially resectable

12-14% patients will relapse. Patients who remain negative 2 years post treatment have risk reduced to 3%.

Continue monitoring with reassurance

Detect recurrence while it may be resectable, and triage indeterminate nodules

Signatera is more accurate than CEA with fewer false positives1,9,10

Signatera detects recurrence earlier than CT imaging1

Average lead time vs CT

Maximum lead time vs CT

8.7 months

16.5 months

ctDNA High risk ctDNA Reduced risk

*Medicare draft coverage for Surveillance Program: Stage II-III colorectal cancer patients

9 m 1 y 2 y 3 y 4 y 5 yYEARS

q3mo q6mo

MONTHS

6 m

Medicare draft

coverage*

Personalized monitoring and MRD assessment across solid tumors

How Signatera works

Days from surgery

Rel

apse

-fre

e su

rviv

al + +++ ++ ++++++++++ + +++++++++++++++++++++ ++ +

++++

p < 0.001

0

0.00

0.25

0.50

0.75

1.00ctDNA negative

ctDNA positive(n=17)

(n=47)

300 600 900

Bladder4

100% sensitivity to relapseAverage lead time 2.8 mos

JOURNAL OF CLINICAL ONCOLOGY

Rel

apse

-fre

e su

rviv

al +++++ ++++ +++++++++++++++ +++ + +++++++

p < 0.0050.00

0.25

0.50

0.75

1.00

0 250 500 750 1000

Days from surgery

ctDNA negative

ctDNA positive(n=14)

(n=10)

Lung3

92% sensitivity to relapseAverage lead time 4.0 mos

NATURE

0

Days from surgery

0.00

0.25

0.50

0.75

1.00

ctDNA negative

ctDNA positive(n=16)

(n=33)

750 1500 2250 3000

Rel

apse

-fre

e su

rviv

al

Breast2

89% sensitivity to relapseAverage lead time 9.5 mos

CLINICAL CANCER RESEARCH

HR, 35.84 p < 0.001

ctDNA negative

(n=15)

(n=60)

HR, 43.5 p < 0.001

0.00

0.25

0.50

0.75

1.00

0 1 2 3

ctDNA positive

Years from surgery

Rel

apse

-fre

e su

rviv

al

JAMA ONCOLOGY

Colon1

88% sensitivity to relapseAverage lead time 8.7 mos

The personalized and tumor informed approach

Signatera validated across tumor types

Mut

atio

n VA

F (%

)

Days after surgery

1.00

0.1

0.01

0.001 Trea

tmen

t

ctDNA ( – )

ctDNA ( + )

Clonal/truncal

Sub-clonal/branch

Sequence tumor tissue to identify unique signature of tumor mutations

Custom design and manufacture personalized mPCR assay for each patient, targeting the top 16clonal mutations found in tumor

Use personalized assay to testpatient’s blood for presence ofcirculating tumor DNA (ctDNA)

REFERENCES

1. Reinert T, Henriksen TV, Christensen E, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 2019;5(8):1124–1131. 2. Coombes RC, Page K, Salari R, et al. Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence Clin Cancer Res. 2019;;25(14):4255-426. 3. Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017;545:446-451. 4. Christensen E, Birkenskamp-Demtroder K, Sethi H, et al. Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma. J Clin Oncol. 2019; 37(18):1547-1557. 5. National Comprehensive Cancer Network. Colon Cancer V. Plymouth Meeting, PA: National Comprehensive Cancer Network. 2019. 6. Aoyama, Oba K, Honda M, et al. Impact of postoperative complications on the colorectal cancer survival and recurrence: analyses of pooled individual patients’ data from three large phase III randomized trials. Cancer Med. 2017;6(7):1573–1580. 7. Yothers G, O’Connell MJ, Lopatin M, et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol. 2013;31(36):4512-4519. 8. Sinicrope FA, Foster NR, Thibodeau SN, et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-Fluorouracil-based adjuvant therapy. J Natl Cancer Inst. 2011;103(11):863–875. 9. Purandare NC, Dua SG, Arora A, et al. Colorectal cancer — patterns of locoregional recurrence and distant metastases as demonstrated by FDG PET/CT. Indian J Radiol Imaging. 2010;20(4):284-288. 10. Advance Staff. Colorectal cancer monitoring. Elite Healthcare. 2016;25(9):14. https://www.elitecme.com/resource-center/laboratory/colorectal-cancer-monitoring/

This test was developed by Natera, Inc., a laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA). This test has not been cleared or approved by the US Food and Drug Administration (FDA). Although FDA does not currently clear or approve laboratory-developed tests in the US, certification of the laboratory is required under CLIA to ensure the quality and validity of the tests. © 2019 Natera, Inc. 2010_12_06_NAT-8020037

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