Elsevier

Clinical Breast Cancer

Volume 15, Issue 6, December 2015, Pages 467-472
Clinical Breast Cancer

Original Study
A Validated Model for Identifying Patients Unlikely to Benefit From the 21-Gene Recurrence Score Assay

https://doi.org/10.1016/j.clbc.2015.04.006Get rights and content

Abstract

Background

Predicting recurrence risk and chemotherapy benefit in early-stage breast cancer can be challenging, and Oncotype DX (ODX) is often used to gain insight. However, it is still unclear whether ODX can benefit in all cases. To clarify ODX's usefulness we sought to develop a model using readily available pathologic markers to help clinicians make that determination.

Patients and Methods

Clinical pathologic data from 221 hormone receptor-positive, HER2-negative invasive breast cancer patients was used to create a model. The model was then validated on a second institution's set of 319 patients.

Results

The model has 2 simple rules: low grade and positive progesterone receptor tumors (LG+PR) are low risk, and high grade or low estrogen receptor (ER) (ER < 20%) tumors (HG/LER) are high risk. The TAILORx (Trial Assigning Individualized Options for Treatment (Rx)) trial thresholds of Recurrence Score (RS) ≤ 10, when chemotherapy is of little benefit, and RS ≥ 26 when chemotherapy might be beneficial were used to judge model performance. Impressively, the misclassifications of an HG/LER patient who has an RS ≤ 10 were 0% and 2%, and for LG+PR patients who had an RS ≥ 26 were 0% and 2.6%. In the validation set, 28% (66 of 232) of the indeterminate group (neither in the HG/LER nor the LG+PR groups) had an RS ≤ 10 or an RS ≥ 26; this group might clinically benefit from ODX.

Conclusion

A simple 2-rule model based on readily available pathologic data was developed and validated, which categorized patients into high and low risk for recurrence. Identification of patients who are unlikely to benefit from ODX testing could result in significant cost avoidance.

Introduction

Adjuvant chemotherapy treatment decisions are straightforward in early-stage breast cancer patients with good prognostic findings and with poor prognostic findings. The dilemma is the patient with conflicting clinicopathologic data, for whom the benefit of giving or withholding chemotherapy is unclear. This dilemma has fueled our demand for technology that allows us to predict, with greater accuracy, tumor responsiveness, risk of recurrence, and mortality. The promise of tumor genomic signatures is to provide biological information above and beyond current clinical and pathological data and ultimately solve this problem.

The 21-gene Recurrence Score (RS) assay (Oncotype DX [ODX], Genomic Health, Redwood City, CA) is a 21-gene reverse transcriptase-polymerase chain reaction assay first introduced in 2004 to provide additional clinical information regarding the risk of recurrence of estrogen receptor (ER)-positive (ER+) breast cancers.1 Tumor expression of these genes (representing proliferation, invasion, HER2, and ER-related genes) is analyzed and calculated, using a weighted formula, into a single RS, which is classified into 1 of 3 risk categories: low, RS ≤ 17; intermediate, RS 18 to 30; or high, RS ≥ 31. In 2006, work was published predicting the 10-year survival benefit of chemotherapy as a function of the ODX recurrence score.2

In the series that established the RS as a valuable test, patients were included who clearly were on either end of the spectrum of favorable and unfavorable clinicopathology. It is therefore possible that the published performance of this test is driven largely by the results of patients for whom we could have easily predicted the prognosis and benefit of chemotherapy. This raises the concern that, in the very patients with conflicting clinicopathologic findings for whom additional information is most needed, the ODX test is weaker in its predictive power than implied in the published reports.

The type of patients for whom ODX is ordered is evolving. Experience is allowing oncologists to identify patients for whom it is unlikely to provide additional information to aid in treatment decisions. This experience can be captured and enhanced in a model. We sought to develop such a model that can be used to guide clinicians as to when not to order the test (at significant savings of $4400), because the chances that the RS would contribute more information about the patient's prognosis and chemotherapy responsiveness would be minimal.

Section snippets

Patients and Methods

All ER+, lymph node-negative breast cancer patients with complete clinicopathologic data who underwent ODX testing at Anne Arundel Medical Center (AAMC) between 2006 and July 2013 were included in our study. A developmental set of 221 patients (evaluated using the same staining and computer-aided slide-reading methodology, with proven high interpathologist reliability) was used to develop the current model. It was then tested on a “superset” which included an additional 108 patients with

Anne Arundel Medical Center Data Set Results

In the developmental set (n = 221), 17% (n = 37) were high-grade or low ER (the HG/LER group) and 33% (n = 73) were low-grade and positive PR (the LG+PR group). The remaining 50% (n = 111), had grade, ER, and PR results that rendered them indeterminate according to our model's rules.

All 37 HG/LER patients had an RS > 11, with most (31 of 37; 84%) with an RS ≥ 26 (Table 1). Similarly, all LG+PR patients had RS < 26, with most (60 of 73; 82%) with RS < 18. The indeterminate patients (those

Discussion

The model presented herein reliably classified many patients into a group for which the ODX test would provide little actionable information. ODX testing of HG/LER tumors consistently resulted in an RS that has a proven benefit of adding chemotherapy (RS ≥ 26) or a value at which chemotherapy benefit is indeterminate (RS 11-25). The same finding can be found in LG+PR tumors; in this population, tumors consistently resulted in an RS that has no proven benefit of adding chemotherapy (RS < 11) or

Conclusion

The potential effect of the implementation of our model would be a significant savings in the cost of breast cancer care. Since its introduction in 2004 to December of 2007, ODX has been ordered on > 175,000 patients by > 7500 physicians19 at the cost of approximately $4000 per test20 Ordering ODX as recommended by Genomic Health (“newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer”19) and/or using the National Comprehensive Cancer

Disclosure

The authors have stated that they have no conflicts of interest.

Acknowledgments

The authors thank Dr Carol Tweed and Dr Thomas Sanders for their reviews of this report. We also appreciate the AAMC Oncology and Hematology Group for their aid identifying patients who received the ODX test. Additionally we thank an anonymous reviewer for bringing to our attention the work on the importance of the IHC results for PR in characterizing a breast cancer patient's prognosis.

References (21)

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