Prospective Evaluation of the Impact of the 21‐Gene Recurrence Score Assay on Adjuvant Treatment Decisions for Women with Node‐Positive Breast Cancer in Ontario, Canada

The 21‐gene Recurrence Score assay is a reverse transcriptase polymerase chain reaction test based on the expression of 21 genes (16 breast cancer genes and 5 reference genes). The recurrence score is used to assign patients with ER+, HER2‐, lymph node‐negative and ‐positive early‐stage breast cancer into groups of low, intermediate, and high risk of distant recurrence and to determine the likelihood of chemotherapy benefit. This article reports results of a single‐center, prospective cohort study of women with ER+, HER2‐, node‐positive early‐stage breast cancer and characterizes the effect of the 21‐gene Recurrence Score assay on recommendations made for adjuvant chemotherapy.

Abstract

Background.

The 21‐gene Recurrence Score (RS) assay is only reimbursed in Ontario for node‐negative and micrometastatic node‐positive (N+) early‐stage breast cancer (EBC). We carried out a prospective study to evaluate the impact of the assay on treatment decisions for women with N+ EBC.

Subjects, Materials, and Methods.

Women with estrogen receptor‐positive, human epidermal growth receptor 2‐negative EBC and one to three positive axillary lymph nodes, who were candidates for adjuvant chemotherapy in addition to hormonal treatment, but in whom the benefit of chemotherapy was uncertain, were eligible. The primary objective was to characterize how the results of the RS assay affected physicians’ recommendations for adjuvant chemotherapy. Secondary objectives were to characterize changes in the physicians’ and patients’ level of confidence in treatment recommendations, to determine whether the results of the RS assay affected patients’ treatment preferences, and to determine the final treatment administered.

Results.

Seventy‐two patients were recruited; the mean age was 61. RS was <18 in 55%, between 18 and 30 in 36%, and ≥31 in 9% of patients. Treatment recommendations changed in 36% of all evaluable patients. The most significant change was in the group with a low RS. Physicians’ and patients’ confidence in treatment recommendations increased in 49% and 54% of cases, respectively. Upfront chemotherapy was recommended to 79% of patients before the assay; 42% ultimately received chemotherapy.

Conclusion.

The RS assay resulted in a substantial decrease in the number of patients who received chemotherapy and in an increase in physicians’ and patients’ confidence in the adjuvant treatment recommendations.

Implications for Practice.

This is the first decision impact study to include exclusively women with ER‐positive, HER2‐negative, early‐stage breast cancer with 1–3 positive lymph nodes, a population typically treated with adjuvant chemotherapy. This study provides evidence that, in these patients, the Oncotype Dx Recurrence Score assay influences systemic treatment decisions. Most of the changes in treatment recommendation resulted in withdrawal of chemotherapy or change in recommendation from a chemotherapy regimen with anthracyclines to a taxane‐only regimen. If prospective studies confirm that these decisions result in good outcomes, a reduction in the use of chemotherapy might result in pharmacoeconomic savings.

Introduction

Survival of women with early‐stage breast cancer (EBC) has improved significantly since the early 1980s, an improvement attributed in part to the use of adjuvant systemic therapy [1], [2]. Although the standard treatment for women with estrogen receptor‐positive (ER+), human epidermal growth receptor 2‐negative (HER2−) EBC is adjuvant endocrine therapy, women with regional lymph node involvement will, in most cases, also be offered chemotherapy based on their higher risk of disease recurrence [2], [3], [4]. The addition of adjuvant chemotherapy to tamoxifen reduces the risk of breast cancer recurrence and mortality in ER+ disease by approximately 30% and 20%, respectively, at the cost of increased treatment toxicity. It is known that not all patients derive the same benefit from adjuvant chemotherapy, but so far there have been few predictive markers of chemotherapy benefit [5], [6].

The 21‐gene Recurrence Score (RS) assay (Genomic Health, Redwood City, CA) is a reverse‐transcriptase polymerase chain reaction test based on the expression of 21 genes (16 breast cancer genes and 5 reference genes), which reports a recurrence score used to assign patients with ER+, HER2−, lymph node‐negative and ‐positive EBC to groups with low risk (RS ≤17), intermediate risk (RS 18–30), and high risk (RS >30–100) of distant recurrence and to determine the likelihood of chemotherapy benefit [7], [8].

Although the RS assay has been validated in published trials of women with node‐positive, ER+ EBC using archived tumors from prior clinical trials, in Ontario, the largest province in Canada, with a population of 13.6 million, the standard of care for that group of patients is to receive third‐generation anthracycline‐taxane chemotherapy regimens [4], [9], [10], [11], [12].

Currently in Ontario, the RS assay is only reimbursed by the single‐payer provincial government for node‐negative and micrometastatic node‐positive EBC. Therefore, we conducted a single‐center, prospective cohort study of women with ER+, HER2− EBC, with one to three positive lymph nodes, with the primary objective of characterizing the impact of the 21‐gene RS assay in recommendations for adjuvant chemotherapy made by medical oncologists in an academic cancer center in Ontario.

Subjects, Materials, and Methods

Patient Population

The study included women over 18 years of age, diagnosed with T stage 1–3, lymph node positive (one to 3 nodes), M stage M0, ER+, HER2− breast cancer. All patients underwent surgical resection with adequate evaluation of axillary lymph nodes, either a sentinel lymph node biopsy or full axillary dissection. Positive involvement of one to three lymph nodes had to be confirmed by histologic examination, and patients with only micrometastatic disease were excluded. Patients’ performance status (PS) had to be adequate (Eastern Cooperative Oncology Group [ECOG] PS 0 or 1), and they had to be candidates for treatment with chemotherapy but represent a population for which the benefit of adding chemotherapy to hormonal therapy was either unclear or not large enough to warrant the risk of undergoing chemotherapy, in the treating physician's judgement.

Exclusion criteria were as follows: a prior history of breast cancer in the same breast, more than one operable primary breast tumor, multicentric tumors, <2 mm of invasive tumor, and previous neoadjuvant chemotherapy.

Intervention

All eligible consenting patients underwent an initial consultation with their medical oncologist, who discussed the patient's treatment alternatives prior to ordering the 21‐gene RS assay. After the discussion, the physician completed a baseline questionnaire indicating the therapeutic strategy he or she would recommend to the patient based upon the available clinical and pathologic data (chemotherapy regimen recommended, if any, and hormonal treatment) and his or her confidence level in the treatment recommendation on a 5‐point scale. In addition, the patient also completed a baseline questionnaire indicating whether she believed chemotherapy to be an adequate treatment (yes, no, or unsure) based on the previous discussion with the physician and her level of confidence in the treatment plan (on a 5‐point scale). After consultation, the patient's tumor sample was sent to Genomic Health, and after the RS was available, approximately 3 weeks later, the patient returned to discuss the final treatment choice.

Both the physician and the patient completed separate follow‐up questionnaires (similar to the baseline questionnaires) after the results of the 21‐gene RS assay were known and shared with the patient and a final treatment recommendation was made. Two to 4 weeks after the visit after the assay, the actual treatment administered to the patient was documented. This information was obtained from the medical chart and chemotherapy records.

Patients were enrolled in the study approximately 1 month before starting adjuvant therapy. The choice of adjuvant chemotherapy and/or hormonal therapy was at the discretion of the treating physician. Patients referred to the study center specifically for the study and had the discussions before and after the test with a medical oncologist at the study center, but the final treatment decision was made by the referring medical oncologist. For this study, the 21‐gene RS assay was provided free of charge by the study sponsor, Genomic Health.

Outcomes

The primary outcome was a change in the oncologists’ treatment recommendation after the results of the 21‐gene RS assay became available. Secondary outcomes were to characterize whether the results of the RS assay affected the physician's expressed level of confidence in the treatment recommendations, to characterize whether the results of the RS assay affected the treatment preference of the patient by evaluating changes in the patient's treatment preferences and changes in the expressed level of the patient's confidence in the treatment plan, and to assess the actual treatment administered to patients in comparison with the physician's initial treatment recommendation.

Sample Size

A change in the physician's treatment recommendation after knowledge of the result of the 21‐gene RS assay could represent a change in the treatment recommendation from chemotherapy plus hormonal therapy to hormonal therapy alone or a change from hormonal therapy alone to the addition of chemotherapy to hormonal therapy. It was assumed that enrollment of 70 subjects would yield approximately 63 evaluable patients (90% of those enrolled). The sample size justification for this study is based upon anticipating an overall treatment decision change rate of 26% [15]. With at least 60 evaluable patients, a 26% decision change rate has a 95% confidence interval (CI) of 15.6%–38.8% (a CI width of 23.2%), with the lower limit still considered to be clinically significant.

Statistical Analysis

Patient and tumor characteristics were recorded for all patients. Categorical variables were summarized as counts and percentages, and continuous measures as medians and ranges. Continuous variables were also reported as categories when applicable (e.g., age as 10‐year intervals and tumor size as ≤2, >2–5, and >5 cm). The continuous RS for each patient was described by using histograms and categorized into three risk groups: low, intermediate, and high. For RS, the groupings were >18, 18–30, and ≥31, respectively.

The primary outcome, change in physicians’ treatment recommendations, was measured by the change from the treatment recommendation indicated on the physician questionnaire before the assay to the treatment recommendation indicated on the physician questionnaire after the assay. The proportion of patients for whom the treatment recommendation changed and the 95% CI were calculated overall and by Recurrence Score group. McNemar's test was used to compare the proportion of patients recommended chemotherapy upfront before the assay versus the proportion after the assay. The analysis was repeated comparing the treatment recommendation before the assay with the final treatment decision, as well as comparing the patient's treatment preferences before and after the assay.

The proportions of patients for whom the physician's level of confidence decreased, remained the same, and increased were reported. The proportions of patients whose own level of confidence decreased, remained the same, and increased were reported. The changes in physicians’ and patients’ level of confidence in the treatment recommendation were analyzed by the Wilcoxon signed‐rank test.

All hypothesis tests were conducted at a two‐sided α level of 0.05. Analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC). The study was approved by the institutional review board of Sunnybrook Health Sciences Centre.

Results

Seventy‐two women were enrolled in the study from October 24, 2014, to May 18, 2016; one withdrew consent while waiting for the results of the RS assay. The baseline characteristics of the 71 participants are presented in Table 1.

Table 1. Baseline characteristics of study participants (n = 71).

^aOnly the five most common comorbidities are presented.

Abbreviations: ER+, estrogen receptor positive; HER2−, human epidermal growth receptor 2 positive; PR−, progesterone receptor negative; PR+, progesterone receptor positive.

Eight participants were not staged with computed tomography scans and bone scan to rule out metastatic disease, probably because their disease was not considered high risk enough to warrant staging. Two women were found to be ineligible for the study after the 21‐gene RS assay was ordered (one had five positive lymph nodes and other was found to have metastatic disease).

Twenty‐nine women were referred to the study center specifically for participation in the study; two of these women discussed the 21‐gene RS assay results with the referring medical oncologist prior to their follow‐up visit with the study center oncologist. This constituted a violation of the study protocol, and therefore the patients were not considered in the analysis of the study outcomes, which included 67 assessable patients. The enrollment flow chart is presented as supplemental online Figure 1. Figure 1 shows the distribution of the RS scores for the 69 patients eligible for the study. According to RS, 38 (55%) of eligible patients were categorized as having a low risk of recurrence, 23 (36%) as having an intermediate risk, and 6 (9%) as having a high risk.

Figure 1.

Distribution of 21‐gene RS assay recurrence scores by risk categories.

The primary outcome measure was change in physician's treatment recommendations from before the RS assay to after the assay (Table 2). The recommendation changed for 36% of patients (95% CI, 24%–48%) after physicians received the RS result. The most significant change in treatment recommendation was in the group with a low RS (<18), with 47% of the recommendations changing from upfront chemotherapy followed by hormonal treatment, recommended before the assay, to hormonal treatment only, recommended after the assay. Upfront chemotherapy was recommended to 79% women before the assay; 52% were still recommended chemotherapy after the assay (net reduction, 27%; relative reduction, 34%; p < .0002), but only 42% ultimately received chemotherapy (net reduction, 37%; relative reduction, 47%; p < .0001).

Table 2. Change in physician's treatment recommendation and actual treatment received.

Physicians were asked to specify chemotherapy and/or hormonal treatment recommended after their discussion of treatment options with the patient, before and after results of the 21‐gene RS assay were known. The overall change in treatment recommendation was either a change from no chemotherapy recommended before the RS assay to chemotherapy recommended after the assay or a change from chemotherapy recommended before the RS assay to chemotherapy not recommended after the RS assay. The actual treatment initiated to the patient was also captured.

Abbreviations: CI, confidence interval; RS, recurrence score.

Interestingly, the 21‐gene RS assay also influenced the chemotherapy regimens administered to patients (Table 3): the two most recommended chemotherapy regimens before the assay were three cycles of 5‐fluouracil, epirubicin, and cyclophosphamide every 21 days followed by three cycles of docetaxel every 21 days (FEC‐D) and four cycles of docetaxel plus cyclophosphamide (TC), each recommended to 34% of participants; after the assay, the most commonly administered chemotherapy regimen was TC (28%), followed by FEC‐D (16%).

Table 3. Physician's choice of chemotherapy regimen versus actual treatment received.

Abbreviations: AC‐T (wk), 3 cycles of AC every 3 weeks followed by 12 cycles of paclitaxel weekly; CMF, six cycles of cyclophosphamide, methotrexate, and 5‐fluouracil every 28 days; dd AC‐T, four cycles of doxorubicin plus cyclophosphamide every 14 days followed by four cycles of paclitaxel every 14 days; FEC‐D, three cycles of 5‐fluouracil, epirubicin, and cyclophosphamide every 21 days followed by three cycles of docetaxel every 21 days; RS, recurrence score; TC, four cycles of docetaxel plus cyclophosphamide every 21 days.

Fifty‐three percent (95% CI, 40%–65%) of patients changed their treatment preference after receiving the RS result (Table 4). There was an elevated proportion of patients (41%) who felt unsure if chemotherapy was an appropriate treatment before the test; this proportion decreased to 23% after the RS assay. Upfront chemotherapy was considered the indicated treatment by 42% of patients before the assay and by 30% after the assay (net reduction, 12%; relative reduction, 29%; p < .0008).

Table 4. Change in the number of patients who believed chemotherapy to be an appropriate treatment for their disease.

Patients were asked to indicate if they believed adjuvant chemotherapy to be the right treatment for them, after discussion of the treatment options with their physician, before and after 21‐gene RS assay results were known (response options: Yes, No, Unsure).

^aOne patient did not answer the questionnaire after the assay.

Abbreviations: CI, confidence interval; RS, recurrence score.

Physicians’ confidence in recommendations (Fig. 2A) increased in 49% of cases, decreased in 10%, and stayed the same in 40% (p < .001). After knowledge of the RS results, 88% of physicians either agreed or strongly agreed with the statement, “I am confident in my treatment recommendation,” compared with 64% of physicians before the test.

Figure 2.

Changes in physicians’ and patients’ confidence levels in treatment recommendations. (A): Physicians were asked to indicate how strongly they agreed or disagreed with the statement “I am confident in my treatment recommendation before/after ordering Oncotype Dx^” on a 5‐point scale (1 = strongly disagree, 2 = disagree, 3 = neither disagree nor agree, 4 = agree, 5 = strongly agree), before and after ordering the 21‐gene RS assay and discussing treatment options with the patients. (B): Patients were asked to indicate how strongly they agreed or disagreed with the following statement: “It's clear what choice of treatment is best for me before/after receiving the result of the Oncotype Dx test” on a 5‐point scale (1 = strongly disagree, 2 = disagree, 3 = neither disagree nor agree, 4 = agree, 5 = strongly agree), before and after receiving the 21‐gene RS assay results and discussing treatment options with their physicians.

Abbreviation: RS, recurrence score.

Patients’ confidence in their choices (Fig. 2B) increased in 54% of cases, decreased in 14%, and stayed the same in 32% (p < .001). After knowledge of the RS results, the percentage of patients who were unsure regarding their treatment decreased from 41% to 23%; 74% patients either agreed or strongly agreed with the statement, “It's clear what choice of treatment is best for me after receiving the results of the Oncotype assay,” compared with 38% of patients before the test.

Discussion

This is the first decision impact study in Canada to include women with ER+, HER2−, node‐positive (one to three positive lymph nodes) EBC. Traditionally, adjuvant chemotherapy is recommended, in addition to hormonal treatment, to this group of patients [2].

In this study, treatment recommendations of medical oncologists from an academic cancer center in Ontario were influenced by the results of the 21‐gene RS assay. The change in treatment recommendations was higher than we had hypothesized initially, based on the results of an Australian decision impact study that enrolled 101 patients with node‐negative disease and 50 patients with node‐positive disease (one to three positive nodes) from three academic centers in Melbourne. In that study, 26% of patients with node‐positive tumors had their treatment changed after receiving the RS results [15]. In fact, the change rate in treatment recommendations found in our study was closer to the one reported in the German decision impact study, which included 244 patients with node‐negative disease and 122 patients with node‐positive disease (one to three positive nodes) and found a change rate of 39% in the node‐positive cohort [11].

Overall, the change in the treatment recommendations occurred in the direction of omitting chemotherapy, with the most significant change occurring in the group with a low RS (<18). All patients with RS in the high‐risk category (≥31) were recommended upfront chemotherapy after RS testing, but treatment recommendations for patients in the intermediate RS (18–30) category remained basically unaffected by the results of the RS assay, with most patients still receiving a recommendation for adjuvant chemotherapy after testing. Previous decision impact studies that included women with ER+, HER2−, node‐positive (one to three lymph nodes) EBC found a similar consistency between RS category and change in treatment recommendation (decrease in chemotherapy use in the low‐RS group and hesitancy in chemotherapy withdrawal for patients in the intermediate‐RS category) [11], [13].

If we consider the actual treatment initiated in patients, the relative reduction in chemotherapy use was even higher, which means that treatment decision changed between the discussion after the test and the beginning of treatment. Twenty‐nine patients were referred to the study center, specifically for study participation, whereas treatment was initiated by the referring medical oncologist, who might not have agreed with the recommendation made at our institution. Patients’ preferences might have also played a role; most of the reduction in chemotherapy use from the recommendations after the test to the treatments initiated occurred in the intermediate RS category. A survey of 160 U.S. medical oncologists (71% from community‐based practices, 25% from academic settings) also revealed a higher change in treatment recommendations after receiving the RS assay results (51% of patients) in the clinical practice setting, with treatment recommendation changing from upfront chemotherapy to hormonal treatment only in 33% of patients [14].

We did not offer study participation to all women with ER+, HER2− EBC and one to three positive lymph nodes treated our center during the study period. Only women who, in the treating medical oncologist's view, were less likely to benefit from adjuvant chemotherapy were included in the study. This resulted in a highly selected population of predominantly postmenopausal women with several comorbidities, including significant cardiovascular risk factors, but good performance status. Most tumors were small, with only one lymph node involved with macrometastatic disease, grade 1 or 2, and both ER+ and progesterone receptor‐positive. The 21‐gene RS assay results were predominantly in the low‐risk category. The distribution of RS results observed in this study is similar to other decision impact studies published but skewed to lower values compared with the initial validation studies using archived tissue from prior clinical trials [9], [10], [11], [13], [14], [15]. These studies have shown that the RS result provides additional prognostic and predictive information beyond histopathological characteristics. For the postmenopausal women with estrogen receptor‐positive, node‐positive EBC enrolled in the phase III SWOG‐8814 trial, randomized to tamoxifen alone versus chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen, the RS result was prognostic of disease‐free survival and overall survival. Ten‐year disease‐free survival estimates were 60%, 49% and 43%, for patients with low, intermediate, and high RS, respectively. In the chemotherapy arm, patients with lower RS results had little disease‐free survival benefit from chemotherapy compared with tamoxifen alone; patients with high RS results benefited from anthracycline‐based chemotherapy [9]. In the ECOG 2197 trial, all patients received adjuvant chemotherapy (either doxorubicin‐cyclophosphamide or doxorubicin‐docetaxel) followed by 5 years of hormonal treatment (tamoxifen or aromatase inhibitor), if hormone receptor‐positive. Patients with node‐positive disease (one to three positive nodes) with a low RS result had lower 5‐year recurrence rates than patients with high scores (5% vs. 25%); the RS value continued to be a highly significant predictor of distant recurrence after 10 years [10]. An analysis of the 306 postmenopausal women with ER+, node positive breast cancer enrolled in the ATAC trial and treated with tamoxifen or anastrozole showed that patients with low, intermediate, and high RS values had an average 9‐year risk of distant recurrence of 17%, 28%, and 49%, respectively [15]. In the cohort of patients with node‐positive disease who participated in the NSABP B‐28 trial and received tamoxifen plus adjuvant chemotherapy (randomized to docetaxel, doxorubicin, and cyclophosphamide or dose‐dense doxorubicin and cyclophosphamide followed by dose‐dense paclitaxel [dd AC‐P] or dd AC‐P with gemcitabine added to paclitaxel), the RS result was shown to be a significant predictor of outcome for disease‐free and overall survival, distant recurrence‐free interval, and breast cancer‐specific survival. Multivariable analysis showed that the RS result was independent of other prognostic indicators, including the number of nodes, tumor size, tumor grade, treatment, and whether or not the patient had a mastectomy [16].

In the present study, we also found that the 21‐gene RS assay influenced not only the decision of administering adjuvant chemotherapy but also the chemotherapy regimen administered. RS testing resulted in a decrease in the use of third‐generation regimens that included anthracyclines (such as FEC‐D) and an increase in the use of taxane‐only regimens (such as TC), sparing this specific group of patients from the well‐known toxicities of anthracycline chemotherapy. Although we acknowledge that modifying the chemotherapy regimen choice based on molecular profiling has not been addressed in other studies, the concept of modifying intensity of treatment based on risk of recurrence is well established in breast cancer, for example in HER2‐positive disease [17]. In decision‐making regarding adjuvant chemotherapy for breast cancer, medical oncologists consider both patient and disease characteristics; the results of the present observational study suggest that the RS assay was viewed as one more factor to take into consideration when making that decision [12].

The outcomes from prospective trials of molecular profiling tests in patients with node‐positive disease are needed before these assays are incorporated into standard practice [2], [18]. The results of a prospective randomized study (RxPONDER trial) that aims to validate the assay for the population of patients with lymph node‐positive disease are still pending; therefore, it is not possible to know for sure if the treatment decisions made based on RS results in our study represent best practice. The first results from the TAILORx trial, a multicenter, prospective trial of 10,253 women with ER+, HER2−, node‐negative EBC are reassuring: for the 1,626 participants with RS <11 who received hormonal therapy alone, 5‐year freedom from distant recurrence was 99.3% (95% CI, 98.7%–99.6%) [19]. More recently, the 5‐year results of the MINDACT trial confirmed the value of genomic profiling for women with EBC and zero (80% of patients enrolled) or one to three (20% of patients enrolled) positive lymph nodes [20]. In that phase III study, the MammaPrint, a 70‐gene signature, was used in addition to standard clinical‐pathological criteria to select patients for adjuvant chemotherapy. A total of 6,693 women were enrolled; women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk received chemotherapy. Patients with discordant risk results were randomized to receive adjuvant chemotherapy or no chemotherapy. The 5‐year distant metastasis‐free survival for the patients deemed clinically high risk but genomically low risk who were randomized not to receive chemotherapy was 94.7% (95% CI, 92.5%–96.2%); patients in the clinically and genomically low‐risk group had a 5‐year metastasis‐free survival close to 98% without chemotherapy. Whereas the MINDACT trial randomized the patients who received chemotherapy to anthracycline‐based chemotherapy versus taxane‐only chemotherapy, the TAILORx and RxPonder trials both included the option of second‐ and third‐generation chemotherapy regimens (with and without anthracyclines) at the discretion of the treating physician after discussion with the patient.

Furthermore, data from the U.S. Surveillance, Epidemiology, and End Results program registry have shown that among patients with up to three positive nodes (n = 4,691), 5‐year breast cancer‐specific mortality was 1.0%, 2.3%, and 14.3% in patients with RS <18 (57% of patients), 18–30 (36%), and ≥31 (7%), respectively [21]. Chemotherapy use was reported in 23%, 47%, and 75% of patients in the low, intermediate, and high RS groups, respectively. The West German Study Group phase III PlanB trial showed 3‐year disease‐free survival to be 97.9% in 348 women with one to three positive lymph nodes and a 21‐gene RS ≤11 who received endocrine therapy only [22].

As in the decision impact study for node‐negative ER+, HER2− EBC in Ontario, we included an option for unsure preference in the patient's questionnaires before and after the assay [23]. This decision might have resulted in an overestimate of the proportion of patients for whom the RS changed treatment preferences. Nevertheless, RS results seem to have had a positive influence on the confidence levels of treatment decisions both for physicians and patients.

Conclusion

This study provides evidence that the Oncotype Dx RS assay influences the treatment decisions of medical oncologists in Ontario, in a selected population of patients with ER+, HER2−, lymph‐node positive (one to three positive nodes) EBC. Most of the changes in treatment recommendation resulted in withdrawal of chemotherapy or a change in recommendation to a less toxic chemotherapy regimen. Provided that prospective studies confirm that these decisions result in good outcomes, a reduction in the use of chemotherapy might result in pharmacoeconomic savings. Therefore, the next step will be to determine the cost‐effectiveness of the assay in Ontario for patients with ER+ EBC with one to three positive lymph nodes.

See http://www.TheOncologist.com for supplemental material available online.

Author Contributions

Conception/design: Sofia Torres, Maureen Trudeau, Sonal Gandhi, Ellen Warner, Sunil Verma, Kathleen I. Pritchard, Teresa Petrella, Mark Hew‐Shue, Calvin Chao, Andrea Eisen

Provision of study material or patients: Sofia Torres, Maureen Trudeau, Sonal Gandhi, Ellen Warner, Sunil Verma, Kathleen I. Pritchard, Teresa Petrella, Calvin Chao, Andrea Eisen

Collection and/or assembly of data: Sofia Torres, Mark Hew‐Shue

Data analysis and interpretation: Sofia Torres, Maureen Trudeau, Ellen Warner, Kathleen I. Pritchard, Andrea Eisen

Manuscript writing: Sofia Torres

Final approval of manuscript: Sofia Torres, Maureen Trudeau, Sonal Gandhi, Ellen Warner, Sunil Verma, Kathleen I. Pritchard, Teresa Petrella, Mark Hew‐Shue, Calvin Chao, Andrea Eisen

Disclosures

Sofia Torres: Genomic Health, Inc. (RF); Maureen Trudeau: Genomic Health, Inc., Pfizer (RF); RNA Diagnostics, Pfizer (SAB); RNA Diagnostics (OI); Sunil Verma: Amgen, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Merck, Roche, Spectrum Health (SAB); Kathleen I. Pritchard: AstraZeneca, Pfizer, Roche, Novartis, Eisai (RF); AstraZeneca, Pfizer, Roche, Amgen, Novartis, GlaxoSmithKline, Eisai (SAB); Novartis (C/A, H); Teresa Petrella: Merck, Bristol‐Myers Squibb, Novartis, Roche (SAB, C/A); Roche, Merck (RF); Calvin Chao: Genomic Health, Inc. (E, OI); Andrea Eisen: Genomic Health, Inc. (RF). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board