Original StudyA Validated Model for Identifying Patients Unlikely to Benefit From the 21-Gene Recurrence Score Assay
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.
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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)
TAILORx: Trial Assigning Individualized Options for Treatment (Rx)
Clin Breast Cancer
(2006)- et al.
Prediction of Oncotype DX and TAILORx risk categories using histopathological and immunohistochemical markers by classification and regression tree (CART) analysis
Breast
(2013) - et al.
Prediction of the Oncotype DX recurrence score: use of pathology-generated equations derived by linear regression analysis
Mod Pathol
(2013) - et al.
Histopathologic variables predict Oncotype DX recurrence score
Mod Pathol
(2008) - et al.
A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer
N Engl J Med
(2004) - et al.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer
J Clin Oncol
(2006) - et al.
Is oncotype DX recurrence score (RS) of prognostic value once HER2-positive and low-ER expression patients are removed?
Breast J
(2013) - et al.
Routine pathologic parameters can predict Oncotype DX recurrence scores in subsets of ER positive patients: who does not always need testing?
Breast Cancer Res Treat
(2012) - et al.
Routine histopathologic characteristics can predict oncotype DX(TM) recurrence score in subsets of breast cancer patients
Cancer Invest
(2013) - et al.
Risk of recurrence and chemotherapy benefit for patients with node-negative, estrogen receptor-positive breast cancer: recurrence score alone and integrated with pathologic and clinical factors
J Clin Oncol
(2011)
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Selecting Patients for Oncotype DX Testing Using Standard Clinicopathologic Information
2020, Clinical Breast CancerCitation Excerpt :The Gage model uses 2 rules to classify patients into groups likely to either benefit or not from adjuvant chemotherapy (Table 1). Using grade as recorded in the original pathology report (without review) and ER and PR status from EORLA, each case was categorized as either: LOW (low grade and PR+ [> 1%]) or HIGH (high grade or low ER [< 20%]).25 University of Tennessee probability scores were calculated using the online tool, which incorporated patient age, tumor size, grade, and LVI status as recorded in the original report and ER/PR status (positive or negative) as designated by ASCO/CAP cut-offs.26
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2019, BreastCitation Excerpt :We [8] and others [10–13] have shown that utilization of the ODX test in the United States was influenced by socioeconomic status and race. For the past few years, several institution-based studies, restricted to limited number of patients from respective institutions, were published utilizing some of the pathologic variables available from pathology reports to predict ODX score [17,25–32] (summary of select studies presented in Table 5). Recently published studies implied that ordering of ODX test for every eligible ER+/HER2-negative/lymph node-negative female patients with invasive breast carcinoma might not contribute to clinical management decisions.
Prediction of Oncotype Dx recurrence score using clinical parameters: A comparison of available tools and a simple predictor based on grade and progesterone receptor
2019, Hematology/ Oncology and Stem Cell TherapyImpact of 21-Gene Expression Assay on Staging Estrogen Receptor–Positive HER2-Negative Breast Cancer
2019, Clinical Breast Cancer