The impact of the 21-gene Recurrence Score assay on clinical decision-making in node-positive (up to 3 positive nodes) estrogen receptor-positive breast cancer patients

The current study suggests that Oncotype DX testing has a significant impact on oncologists’ decision to treat N1+ ER+ BC patients with chemotherapy. The use of Oncotype DX testing was associated with a reduction in the use of chemotherapy in this patient population by 65 % (with an adjusted OR of 0.16). All patients with high Recurrence Score results were treated with chemotherapy, whereas those with low Recurrence Score results rarely received chemotherapy.

Our findings, based on recent treatment patterns in N1+ ER+ BC patients in Israel, are consistent with findings from studies in node-negative populations around the world. These studies demonstrated that in 19–44 % of evaluated cases, recommendations for adjuvant treatment were changed after receiving the Recurrence Score results [15‐27]. Of the patients for whom treatment recommendations were changed, the most frequent change was from chemotherapy plus endocrine therapy to endocrine therapy alone (52–89 % of cases); however, a clinically relevant proportion of patients were identified as likely to derive a significant benefit from the addition of chemotherapy [15‐18, 20, 21, 23‐26].

The current study is also consistent with the limited available data on the impact of the Recurrence Score results on treatment recommendations in the N+ ER+ BC patient population [25‐29]. For example, in a recent analysis, in which treatment recommendations pre- and post-knowledge of Recurrence Score results were analyzed for a mixed patient population of whom only 15 % were N+, knowing the Recurrence Score results led to a 25 % overall change in treatment recommendations (up to 89 % of these changes were from chemotherapy plus endocrine therapy to endocrine therapy alone) [28]. Furthermore, in a recent physician survey, in which 160 medical oncologists in the United States provided information on their most recent N+ ER+ BC patient, 51 % of the medical oncologists changed their treatment recommendations after obtaining the Recurrence Score result, with the most frequent change (65 % of cases) being from chemotherapy plus endocrine therapy to endocrine therapy alone [29]. Our study is also consistent with a recent prospective study in Germany that showed a treatment recommendation change in 38.5 % of 122 evaluated N+ ER+ BC patients, with the most frequent change (72 % of cases) being from chemotherapy plus endocrine therapy to endocrine therapy alone [27].

Interestingly, our logistic regression analysis showed that the impact of Oncotype DX testing on reducing the odds of receiving chemotherapy was more pronounced in patients aged 40–55 years, than in patients >55 years of age, suggesting that in older patients, in whom chemotherapy treatment was less common overall, Oncotype DX testing had a lower impact on changing treatment decisions. These findings provide insight into the decision-making process in the molecular profiling era by highlighting the patient populations for whom oncologists tend to recommend chemotherapy before knowing the Recurrence Score results (due to high baseline risk for recurrence in younger patients overall), but given the opportunity to individualize treatment decisions, are likely to treat patients with endocrine therapy alone if the Recurrence Score result is low. Notably, these treatment patterns are consistent with the recent St. Gallen consensus document stating that chemotherapy is not necessarily mandated in patients with ER+, HER2 negative disease with 1–3 positive nodes [1].

From a patient’s perspective, Oncotype DX testing may prevent unnecessary chemotherapy and its associated toxicity, thereby affecting quality of life. Furthermore, 3 studies have recently demonstrated that patients report significantly lower conflict about their treatment decision and decreased situational anxiety after receiving their Recurrence Score result [15, 27, 30].

Reducing the proportion of patients receiving chemotherapy has economic implications. In the ER+ node-negative BC population in Israel, Klang et al. [18] have shown that Oncotype DX testing leads to reduced chemotherapy use, and estimated that Oncotype DX testing is associated with a net gain of 0.170 quality-adjusted life years (QALY) per patient (due to reducing disutility associated with chemotherapy and cancer recurrence) and that the cost-effectiveness ratio is $10,770 per QALY gained. There have been very few studies assessing the cost-effectiveness of Oncotype DX in the N+ ER+ BC population. The only study published to date is a UK-based analysis which showed that using Oncotype DX is likely to be cost-effective versus current clinical practice in this patient population [31]. As the current study shows significant reductions in chemotherapy use in the ER+ N1+ BC population, findings from a health economic analysis may be consistent with those from the UK study [31]. A formal assessment of the cost-effectiveness of using Oncotype DX in the Israeli ER+ N+ BC population is warranted and is currently being planned.

This study has several limitations. Most notably, the 2 patient groups were unbalanced with respect to baseline characteristics. Patients in the Oncotype DX group had, on average, smaller tumors, and the group had lower frequencies of patients with grade 3 tumors and those with 1, 2, and 3 positive nodes compared with controls. These differences probably stem from the discrepancy in the period of diagnosis (most of the Oncotype DX patients were diagnosed from 2008 onward, whereas most of the controls were diagnosed prior to 2008), and may therefore reflect earlier BC diagnosis in the Oncotype DX patients due to advances in BC awareness and screening over time. Since all of these characteristics impact chemotherapy use (Oncotype DX patients had characteristics associated with less chemotherapy use), we performed a multivariate logistic regression analysis (adjusting for age, tumor size, tumor grade, and nodal status) to assess the statistical significance of the observed reduction in chemotherapy use with Oncotype DX testing, and demonstrated that testing was significantly associated with reduced odds of receiving chemotherapy (after adjustment for these known imbalances). Although such an analysis is unlikely to capture all imbalances between the groups (i.e., factors not measured/included in the logistic regression model such as PR status), the calculated ORs strongly suggest that the observed reduction in chemotherapy use in the Oncotype DX group was statistically significant. Another limitation of this study stemming from the aforementioned difference in the period of diagnosis between the 2 groups is the potential shift in adjuvant treatment recommendations for this patient population over time. In addition, there may have been selection bias in the small proportion of control patients who were diagnosed after 2008 (i.e., after Oncotype DX was available in Israel for N+ patients), as these could represent a subgroup of patients for whom oncologists felt that the clinicopathologic characteristics were enough to recommend treatment without ordering Oncotype DX testing. Notably, the logistic regression analysis would have addressed this limitation to a large extent. Finally, the sample size of some of the subgroups in the Oncotype DX group (specifically, patients <40 years of age) was relatively small and therefore no conclusions could be drawn regarding these subgroups.