Health Professionals: More About the EGAPP™ Tumor Gene Expression Profiling To Predict Risk of Breast Cancer Recurrence Recommendation

EGAPP™ Evidence Review at a Glance

Test	Application	Quality of Evidence Adequacy of information to address:				Overall Recommen-dation*
		Analytic Validity	Clinical Validity	Clinical Utility	Cost Effective-ness
Oncotype DX Estrogen positive only	Prognostic	Inade-quate	Adequate to demonstrate impact on — Disease recurrence Response to chemotherapy	Inade-quate	Inade-quate	Insufficient evidence to recommend for or against use
Mamma Print Estrogen positive or negative	Prognostic	Inade-quate	Adequate to demonstrate association with — Future metastases but Inadequate to assess the added value to standard risk stratification the population to which the test would best apply	No evidence identified	No evidence identified
H:I Ratio Test Estrogen positive only	Prognostic	Inadequate	Inadequate	No evidence identified	No evidence identified

*Overall recommendation was decided on the basis of (a) evidence indicating a low level of certainty of net health benefits, and (b) Contextual Factors .

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Considerations for Practice

• Information on analytic validity is limited by the lack of a gold standard against which gene expression profiling tests can be directly compared. Therefore, computing estimates of analytic false positive or false negative rates is not possible.
• The EGAPP Working Group found preliminary evidence of potential benefit of Oncotype Dx test results to some women who face decisions about treatment options:
  • Reduced adverse events because of low risk women avoiding chemotherapy

  However, they could not rule out the potential for harm for others:

  • Breast cancer recurrence that might have been prevented
• Clinicians must decide on a case by case basis if using GEP adds value and is relevant to a particular patient
• If use of GEP is considered, counseling and educational materials should be provided to the patient to address potential benefits and harms, and how results may affect decisions regarding therapy
• Categorization and cut-offs for “recurrence risk scores” vary significantly among different test approaches
• Clinical trials are needed to fully understand the impact of chemotherapy on outcomes of women classified into low, intermediate, or high risk groups
  • Two randomized prospective clinical trials are underway: TAILORx and MINDACT
• Other organizations, including the American Society of Clinical Oncology and the National Comprehensive Cancer Network have endorsed use of breast cancer GEP.

Note: See Contextual Factors for more information.

Note: See Public Health Implications for additional information that is not part of the EGAPP™ recommendation.

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Testing Information

Breast cancer GEP tests reviewed by EGAPP:

Note: Additional GEP may be available or in development.
Oncotype DX®

• Intended for use with other conventional risk assessment approaches to predict likelihood of distant breast cancer recurrence in women of any age with node negative, stage I or II, ER–positive breast cancer to be treated with tamoxifen.
• Results reported as Recurrence Score™ (RS; scale of 0–100) that correlates to patient-specific “Average rate of Distant Recurrence”

Risk Category	Recurrence Score	10-year Distant Recurrence Rate after 5 Years of Tamoxifen
Low	<18	<12%
Intermediate	18-30	12-21%
High	≥31	21-33%

MammaPrint:

• Intended for use in women aged 61 years or younger with primary invasive (Stage I or II) breast cancer who are lymph node negative and have a ≤ 5 cm, ER-positive or ER-negative tumor.
• Not intended “to predict or detect response to therapy, or to help select the optimal therapy for patients.”
• Test results reported as chance to develop distant metastases at 10 years without adjuvant treatment:
  • Low Risk = 13%
  • High Risk = 56%

H:I Ratio Test (Quest — Breast Cancer Gene Expression Ratio Assay):

• Test measures the ratio of the expression of the homeobox geneB13 (HOXB13) and the interleukin-17B receptor gene (IL17BR)
• Designed to predict tumor recurrence risk for women on tamoxifen monotherapy, for whom alternative therapies (aromatase inhibitors, chemotherapy) might be considered.
• H:I ratio is a “continuous marker of recurrence in untreated ER-positive/node-negative patients”.
• Reported as chance of breast cancer recurrence at 5 years:
  • Low ≈ 10–27%
  • High ≈ 28–60% or greater

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Contextual Factors

Additional contextual issues were taken into account in the final recommendation statement because the EGAPP™ Working Group found insufficient evidence to support a recommendation for or against using tumor gene expression profiles to improve outcomes in women with breast cancer.

• Use of breast cancer GEP has potential for significant benefit (reduced adverse events because of low risk women avoiding chemotherapy), but also harm (breast cancer recurrence that might have been prevented).
• Provision of firm guidance to physicians on how to use results of breast cancer GEP will require data from trials such as the TAILORx and MINDACT prospective trials.
• It is uncertain if changes reported in chemotherapy treatment decisions based on breast cancer gene expression profiling are the result of patient compliance with physician recommendations, weighing of risks and benefits, or the effects of test marketing.
• Improved understanding of risk tolerance in women is needed to identify women who might benefit most from test use, and also to guide discussion regarding test risks and benefits.
• Comparative effectiveness data will be needed to determine if the potential improvement in clinical outcomes suggested by current evidence also applies to new breast cancer GEP tests that are developed and marketed.

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Research Gaps

The EGAPP™ Working Group identified the need for research to address the following:

• Better quality data regarding analytic validity of tests, including external proficiency testing
• Pre-analytic issues related to sample preparation, transport and processing given reported rates of testing failures related to sample quality
• Clinical validation studies to include: typical patient populations, relevant ethnic groups, and calibration against actual observed risk
• Studies to assess women’s understanding and use of the risk information in decision making
• Development and evaluation of management algorithms based on GEP results and other prognostic factors
• Additional cost-effectiveness analyses

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Public Health Implications of Tumor Gene Expression Profiling To Predict Risk of Breast Cancer Recurrence not part of the EGAPP™ recommendation.

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