prognostic information to enhance treatment decisions -...

Prognostic information to enhance treatment decisions

Facilitating an integrated approach to the diagnosis and treatment of breast cancerThis guide provides an explanation of the Prosigna Patient Report generated by the nCounter® Dx Analysis System, which may help interpret and present results.

Intended use: The Prosigna Breast Cancer Prognostic Gene Signature Assay is an in vitro diagnostic assay which is performed on the NanoString nCounter® Dx Analysis System using FFPE breast tumor tissue previously diagnosed as invasive breast carcinoma. This qualitative assay utilizes gene expression data, weighted together with clinical variables to generate a risk category and numerical score, to assess a patient’s risk of distant recurrence of disease.1 Special conditions for use: Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients.1

ProsignaTM Annotated Patient Report

2

Number of patients Nodal status

1047 Node-negative

382 Node-positive

Low risk

0 100

High riskIntermediate risk

Low Risk

16

NanoString Technologies, Inc. 530 Fairview Avenue N | Suite 2000 | Seattle, Washington 98109 | 1-206-378-6266 | nanostring.com

Patient Specimen Comments

For more information, visit PROSIGNA.com or e-mail [email protected]

Assay Description:The Prosigna™ breast cancer gene signature assay measures the expression of 58 different genes to report the Prosigna Score, which is used along with the patient’s nodal status to assign a risk classification defined by prespecified Prosigna Score cutpoints.The Prosigna Score is derived from a proprietary algorithm based on the PAM50 gene signature1, and includes information on the correlation of the tumor’s gene expression with four prototypical PAM50 molecular profiles, as well as proliferation and the pathologic tumor size.

† Data apply to patients being treated with endocrine therapy for 5 years as in the tested patient population. See Package Insert for further information on therapeutic regimens and tested patient population. It is unknown whether these findings can be extended to other patient populations or treatment schedules. ‡Average DR rate observed in ABCSG-8 for patients within 10 Prosigna Score units.

ID #: Date Reported:

Tumor Size: ≤ 2cmLymph Nodes: node-negative

* The Prosigna Score ranges from 0 through 100 and correlates with the probability of distant recurrence (DR) in the tested population. Risk classification is provided to guide the interpretation of the Prosigna Score using cutoffs related to clinical outcome.

Patient Prosigna Score*:

Clinical Trial Results:Probability of Distant Recurrence: In the clinical validation study, patients who were node-negative, with a Prosigna Score of 16 were in the low risk group.The low risk population averaged a 3% probability of distant recurrence at 10 years.

The Prosigna algorithm was used in retrospective analysis of the ABCSG-8 clinical trial which included more than 1400 patients with varying risks of distant recurrence. The retrospectively fitted model relating Prosigna Score to 10-year distant recurrence for node-negative patients in the ABCSG-8 study is displayed below.†

© 2013 NanoString Technologies, Inc.

Intermediate risk10% [7%-14%]

Low risk3% [2%-6%]

High risk16% [11%-22%]

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Modeled probability95% Con�dence Interval (CI)Observed probability‡

Prosigna score

GroupAverage[95% CI]


Probability of DR for node-negative Patients Prespecified Patient Risk Group



Clinical Trial Results:Clinical Validation StudyPrognosis for node-negative breast cancer patients was determined based on the probability of distant recurrence (DR) for this patient population in the validation study ABCSG-8. This study analyzed 1,047 node-negative samples using a prospectively defined analysis plan. The data shown are for post-menopausal women with hormone receptor-positive, node-negative, Stage I and II breast cancer that received 5 years of endocrine therapy.*

DRFS by Risk Group for node-negative Patients3

ABCSG-82




Low Risk [95% CI] Intermediate Risk [95% CI] High Risk [95% CI]

3% [2%-6%] 10% [7%-14%] 16% [11%-22%]

The Prosigna Score classifies node-negative patients as low, intermediate, or high-risk based on prespecified thresholds that indicate probability of DR at 10 years. In the ABCSG-8 clinical validation study, the probability of DR at 10 years for low-risk, node-negative patients was 3% (95% CI: 2%–6%), while the probability of DR at 10 years for high-risk patients was 16% (95% CI: 11%–22%).

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Follow-up Time (Years)

REFERENCES: 1. Parker JS, et al., Supervised Risk Predictor of Breast Cancer Based on Intrinsic Subtypes. Journal of Clinical Oncology, v27 No. 8 (2009) 1160-1167

2. Prosigna Package Insert

3. Gnant M, et al., P2-10-02, Clinical Validation of the PAM50 risk of recurrence (ROR) score for predicting residual risk of distant recurrence (DR) after endocrine therapy in postmenopausal women with HR+ early breast cancer (EBC): An ABCSG study, SABCS 2012.

* See Package Insert for further information on therapy regimens and tested patient population. It is unknown whether these findings can be extended to other patient populations or treatment schedules.

2 3

The patient’s tumor size and nodal status are required to determine her Prosigna Score and risk group.1

The Prosigna Score is derived from a proprietary algorithm and is reported on a scale from 0 to 100. Risk group and the Prosigna Score are dependent on the patient’s nodal status.1

Page 1 of the Prosigna Patient Report provides two customized outputs to determine your patient’s probability of distant recurrence over 10 years:

• Prosigna Score: Derived from a proprietary algorithm based on the PAM50 gene signature, the Prosigna Score is a numerical value on a 0 to 100 scale that correlates with the probability of distant recurrence within 10 years1

• Risk group: Based on the Prosigna Score and nodal status, risk group is provided to allow interpretation of the Prosigna Score by using cutoffs related to clinical outcome in tested patient populations1

Prosigna assay results are based on a large validation data set of postmenopausal women with early-stage breast cancer, including both node-negative and node-positive patients (see table at right).1 The Prosigna Patient Report is customized and includes only those results relevant to your patient’s nodal status.

of the Prosigna Patient Report provides context for your patient’s reported risk group based on the results of a large clinical validation study, ABCSG-8.1 Both the Prosigna Score and risk group add statistically significant prognostic information beyond other clinical variables for node-negative and node-positive patients (P<0.0001).1,2

• Node-negative patients: 10-year distant recurrence-free survival (DRFS) rates were >95% for the low-risk group, 90.4% for the intermediate-risk group, and <85% for the high-risk group1

• Node-positive patients: 10-year DRFS rates were 94.2% for the low-risk group and 75.8% for the high-risk group1

The data and table in the Clinical Trial Results section reflect results seen in your patient’s nodal status and risk group from the broader ABCSG-8 validation study population.

Risk group Node-negative Node-positive

Low 487 (47%) 158 (41%)

Intermediate 335 (32%) N/A

High 225 (21%) 224 (59%)

Number of patients by risk group and nodal status in the clinical validation study1

Understanding the Prosigna™ Patient Report

The Kaplan-Meier plot shows the probability of distant recurrence (DR) for each risk group, based on DRFS within the similar nodal status patient population from the clinical validation study.1

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Low risk

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Low Risk

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Low risk3% [2%-6%]

High risk16% [11%-22%]

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Prosigna score



Probability of DR for node-negative Patients Prespecified Patient Risk Group



Clinical Trial Results:Clinical Validation StudyPrognosis for node-negative breast cancer patients was determined based on the probability of distant recurrence (DR) for this patient population in the validation study ABCSG-8. This study analyzed 1,047 node-negative samples using a prospectively defined analysis plan. The data shown are for post-menopausal women with hormone receptor-positive, node-negative, Stage I and II breast cancer that received 5 years of endocrine therapy.*

DRFS by Risk Group for node-negative Patients3

ABCSG-82




Low Risk [95% CI] Intermediate Risk [95% CI] High Risk [95% CI]

3% [2%-6%] 10% [7%-14%] 16% [11%-22%]

The Prosigna Score classifies node-negative patients as low, intermediate, or high-risk based on prespecified thresholds that indicate probability of DR at 10 years. In the ABCSG-8 clinical validation study, the probability of DR at 10 years for low-risk, node-negative patients was 3% (95% CI: 2%–6%), while the probability of DR at 10 years for high-risk patients was 16% (95% CI: 11%–22%).

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Low Risk

16














Low risk3% [2%-6%]

High risk16% [11%-22%]

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Prosigna score


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A Patient Prosigna ScoreThe Prosigna Score section contains two key pieces of information specific to your patient1: 1. Prosigna Score provided as a numerical value on a 0 to 100 scale 2. Risk group (low, intermediate, or high) based on cutoffs related to clinical outcome

Based on a clinical validation study involving over 1400 patients, the Prosigna Score and risk group add statistically significant prognostic information beyond other clinical variables (P<0.0001).1,2 This information can be used in combination with other patient risk factors to determine whether adjuvant chemotherapy may be required.3,4

B Probability of Distant RecurrenceEstimation of risk is derived from the rate of 10-year DR within the node-negative clinical trial population. There is a continuous relationship between Prosigna Score and predicted 10-year risk of DR, which can be used to extrapolate your patient’s predicted 10-year risk of DR.1,4

A

C

Node-negative Prosigna™ Patient Report

The Prosigna Score is related to an individual patient’s 10-year risk of DR.1

• Low risk: <10% predicted risk1

• Intermediate risk: 10% to 20% predicted risk1

• High risk: >20% predicted risk1

To determine the relationship between the Prosigna Score and estimated 10-year risk of DR, plot your patient’s score along the x-axis, then draw a horizontal line to the y-axis.

B

C Clinical Trial Results Prosigna has been validated in a large clinical validation study (N=1478) that includes both node-negative and node-positive patients.1,2 Results from the node-negative patient population are presented on page 2 of the Prosigna Patient Report, so you can interpret your patient’s Prosigna Score in the context of the results seen in similar patients from the clinical validation study.

Summary of ABCSG-8 study• Samples: 1478 FFPE breast tumor samples from postmenopausal women with hormone receptor–

positive breast cancer who were randomized prior to treatment to 2 years of adjuvant tamoxifen, followed by either 3 years of anastrozole or 3 years of adjuvant tamoxifen1,2

• Objective: Determine if the Prosigna Score and risk group add prognostic information beyond other clinical variables1,2

• Conclusions: The Prosigna Score and risk group add statistically significant prognostic information beyond other clinical variables (P<0.0001). Risk groups stratify patients according to DRFS, with 10-year DRFS rates of >95% for the low-risk group, 90.4% for the intermediate-risk group, and <85% for the high-risk group1,2

The Kaplan-Meier plot shows the 10-year DRFS rate for each risk group within the node-negative patient population from the ABCSG-8 clinical validation study. Both the intermediate- and high-risk groups are significantly different from the low-risk group.1

Page 2 of the Prosigna Patient Report contains prognostic information from the node-negative patients in the ABCSG-8 clinical validation study (n=1047).

6

Low risk

0 100

High risk

Low Risk

16





Due to small sample size of patients with scores greater than 80 in the clinical validation study, the exact relationship of the Prosigna Score to probabilityof DR could not be established with a retrospective model fitting.† Data apply to patients being treated with endocrine therapy for 5 years as in the tested patient population. See Package Insert for further information

on therapeutic regimens and tested patient population. It is unknown whether these findings can be extended to other patient populations or treatment schedules. ‡Average DR rate observed in ABCSG-8 for patients within 10 Prosigna Score units.


Tumor Size: ≤ 2cmLymph Nodes: node-positive (1-3 nodes)

* The Prosigna Score ranges from 0 through 100 and correlates with the probability of distant recurrence (DR) in the tested population. Risk classification is provided to guide the interpretation of the Prosigna Score using cutoffs related to clinical outcome. Prosigna Scores greater than 80 are considered high risk, and the score is not reported.


Clinical Trial Results:Probability of Distant Recurrence: In the clinical validation study, patients who were node-positive (1-3 nodes), with a Prosigna Score of 16 were in the low risk group.The low risk population averaged a 6% probability of distant recurrence at 10 years.

The Prosigna algorithm was used in retrospective analysis of the ABCSG-8 clinical trial which included more than 1400 patients with varying risks of distant recurrence. The retrospectively fitted model relating Prosigna Score to 10-year distant recurrence for node-positive (1-3 nodes) patients in the ABCSG-8 study is displayed below.†


Low risk6% [3%-12%]


High risk24% [19%-31%]

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Tumor Size: ≤ 2cmLymph Nodes: node-positive (1-3 nodes)


Probability of DR for node-positive (1–3 nodes) Patients Prespecified Patient Risk Group

Clinical Trial Results:Clinical Validation StudyPrognosis for node-positive (1–3 nodes) breast cancer patients was determined based on the probability of distant recurrence (DR) for this patient population in the validation study ABCSG8. This study analyzed 382 node-positive (1–3 nodes) samples using a prospectively defined analysis plan. The data shown are for post-menopausal women with hormone receptor-positive, node-positive (1–3 nodes), Stage II breast cancer that received 5 years of endocrine therapy.*

DRFS by Risk Group for node-positive (1–3 nodes) Patients3




ABCSG-82


Low Risk [95% CI] High Risk [95% CI]

6% [3%–12%] 24% [19%–31%]

The Prosigna Score classifies node-positive (1–3 nodes) patients as low or high risk based on prespecified thresholds that indicate probability of DR at 10 years. In the ABCSG-8 clinical validation study, the probability of DR at 10 years for low-risk, node-positive (1–3 nodes) patients was 6% (95% CI: 3%–12%), while the probability of DR at 10 years for high-risk patients was 24% (95% CI: 19%–31%).

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D Patient Prosigna Score1

The analysis for node-positive patients was limited to two risk categories since the ABCSG-8 study included a smaller number of node-positive patients (n=382) relative to the number of node-negative patients (n=1047). The scale and cutoffs between risk groups differ for node-negative and node-positive patients, as shown below.

To determine the relationship between the Prosigna Score and estimated 10-year risk of DR, plot your patient’s score along the x-axis, then draw a horizontal line to the y-axis. Due to the small sample size of node-positive patients with scores >80, the exact relationship of the Prosigna Score to probability of DR could not be established beyond 80.1

Node-positive Prosigna™ Patient Report

All node-positive patients are classified into one of 2 risk groups based on their Prosigna Score. The cutoff between low risk and high risk is 40.1

Low risk

0 100


Low risk

0 100

High risk

Node-negative

Node-positive

The Kaplan-Meier plot shows the 10-year DRFS rate for each risk group within the node-positive patient population from the ABCSG-8 clinical validation study. The high-risk group is significantly different from the low-risk group.1

E Clinical Trial Results Prosigna has been validated in a large clinical validation study (N=1478) that includes both node-negative and node-positive patients.1,2 Results from the node-positive patient population are presented on page 2 of the Prosigna Patient Report, so you can interpret your patient’s Prosigna Score in the context of the results seen in similar patients from the clinical validation study.

Summary of ABCSG-8 study• Samples: 1478 FFPE breast tumor samples from postmenopausal women with hormone receptor–

positive breast cancer who were randomized prior to treatment to 2 years of adjuvant tamoxifen, followed by either 3 years of anastrozole or 3 years of adjuvant tamoxifen1,2

• Objective: Determine if the Prosigna Score and risk group add prognostic information beyond other clinical variables1,2

• Conclusions: The Prosigna Score and risk group add statistically significant prognostic information beyond other clinical variables (P<0.0001). Risk groups stratify patients according to DRFS, with 10-year DRFS rates of 94.2% for the low-risk group and 75.8% for the high-risk group1,2

D

EPage 2 of the Prosigna Patient Report contains prognostic information from the node-positive patients in the ABCSG-8 clinical validation study (n=382).

Contact us to learn how Prosigna™ can enhance your clinical practice

References: 1. Prosigna [Package Insert]. Seattle, WA: NanoString Technologies, Inc; 2013. 2. Gnant M, Filipits M, Mlineritsch B, et al. Clinical validation of the PAM50 risk of recurrence (ROR) score for predicting residual risk of distant-recurrence (DR) after endocrine therapy in postmenopausal women with HR+ early breast cancer (EBC): an ABCSG study. Presented at: San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract P2-10-02. 3. Data on file. NanoString Technologies, Inc. 4. Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol. 2013;31(22):2783-2790.

For more information, visit Prosigna.com or e-mail [email protected]

US contact information: NanoString Technologies, Inc. 530 Fairview Ave N, Suite 2000 Seattle, WA 98109

Phone: 888-358-NANO (888-358-6266) Fax: 206-378-6288Web site: nanostring.com

© 2013 NanoString Technologies, Inc. All rights reserved. NanoString, the NanoString Technologies logo, nCounter, Prosigna and the Prosigna logo are trademarks and/or registered trademarks of NanoString Technologies, Inc. in various jurisdictions.

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