This is the largest prospective study on the impact of the Oncotype
DX assay on adjuvant decision-making as of today and, in particular, the first that reported prospective data in women with node-positive EBC [23
Overall, treatment recommendations changed in 30% of node-negative cases after RS results were known. This is quiet consistent with findings from the prospective studies by Lo et al. [11
] (32%) and Albanell et al. [12
The predominant change in our study was from a recommendation of CHT to HT alone in 18% of N0 cases, which compares well with the findings from all reported prospective decision impact studies. The lower overall shift in treatment recommendations of 23% reported for N0 patients from the Australian study recently [15
] can be explained by the much lower proportion of patients of 30% with an initial recommendation for CHT, whereas 47% of all N0 patients in our study were recommended CHT before Oncotype
DX based on traditional criteria.
The change rate of 39% from pre- to post-test recommendation in patients with N+ disease in our study was higher than the rate of 30% in the N0 subset. But the difference was not statistically significant (P
= 0.116, chi-square). The predominant change was from CHT to HT in 28% of all N+ cases and 37% of the 92 N+ patients with an initial recommendation for CHT. This is remarkable if one implies that the decision to omit chemotherapy in patients with 1–3 positive lymph nodes is considered more deeply and eventually hesitantly. Even if data indicate that patients with 1–3 positive nodes have a moderately elevated risk of recurrence, especially if they have low RS values [1
], some will regard chemotherapy as mandatory regardless of the number of positive nodes [8
Four other studies reported about the clinical use of Oncotype
DX in N+ disease. A UK study including patients with nodal micrometastases did not report results of this particular subgroup [13
]. A web-based physicians' survey [22
] reported a higher change rate of 51% in a probably highly selected population of 138 N+ ER-positive patients—92.6% had 1–3 positive nodes—with a change from CHT to HT in 33%. A prospective Japanese study reported on 90 patients including a subset of 17 patients with 1–3 positive nodes [14
]. Recommendations changed in 12 (71%) women, all from CHT to HT. In the 50 patients with 1–3 positive lymph nodes from the Australian study [15
], the overall change rate was 26%: 12 patients to HT and 1 to CHT.
In our study physicians seemed to be hesitant omitting chemotherapy in patients with intermediate RS: HT was recommended in 13% of patients initially recommended CHT but 60% of patients with initial recommendation for HT were advised CHT post-test. Also, 32% of patients with initial CHT recommendation were not advised to omit chemotherapy despite a low RS result and initial HT recommendation was revised to CHT post-test in three women with low RS values.
This may be explained by a large adjuvant study that had been ongoing in Germany defining an RS of 11 as the threshold for omitting chemotherapy in hormone receptor-positive EBC. It may also reflect that the use of Oncotype
DX is not as widespread in German clinical practice as it is, e.g. in the United States [27
]. This goes along with a lower reported increased confidence of physicians' after the test when compared with respective numbers from the United States (76%) [11
] and the Spanish study (60%) [12
]. A score combining pathological and clinical factors with the RS has been shown to improve the prognostic value compared with the RS alone and to substantially reduce the proportion of patients with intermediate risk which may help treatment decisions. However, RS alone is a better predictor of the benefit of chemotherapy [28
Importantly, 45 patients—all with low or intermediate RS values—did not follow their physician's post-test recommendation, the majority (82%) of them deciding against chemotherapy regardless of the nodal status. This may have been the result of patients pondering their actual numeric relative risk of recurrence with HT alone and the potential benefit to be gained by CHT. Interestingly, Lo et al. [11
] could demonstrate that patients perceived their actual risk of recurrence to be lower after knowing the RS result.
When comparing the initial treatment recommendation and treatment actually given, the use of adjuvant chemotherapy decreased with the limitation that it is assumed that without Oncotype
DX all patients would have accepted their physician's initial treatment recommendation. This was even more pronounced for the subgroup of patients with 1–3 positive nodes. A reduction in chemotherapy usage may translate into actual pharmacoeconomic savings from the sick funds' perspective as indicated by results of our group reported here and in more detail in a separate publication [26
]. While the outcome data of using Oncotype
DX in clinical routine practice are pending, assumptions have to be based on consistent data from multiple prospectively designed studies of archival specimens from randomized clinical trials with a long-term follow-up [2
]. Findings from various health care systems [21
] show that using the Oncotype
DX assay as a decision aid in ER-positive EBC is, at minimum, cost-effective.
Grade and Ki-67 are frequently used as key markers to guide adjuvant treatment decisions and the St Gallen consensus recommends Ki-67 to discriminate luminal A and B tumors, although the relevant cut-off is debated. We carried out a retrospective analysis to assess the potential value of the RS in assumed low-risk patients with G1-2 with Ki-67 <15% and in assumed high-risk patients with G3 with Ki67 ≥15% for the patients where data were available. There were relevant shifts in treatment recommendations in both directions post-test. These results may be explained by a limited concordance among pathologists regarding grade and a high interobserver variability in Ki-67 assessment [29
]. The adjuvant PlanB study recently reported a 68% concordance between local and central grading [30
]. The correlation between the RS and Ki-67 by central assessment in PlanB was weak (r = 0.34) [31
] and the current data indicate that Ki-67 is not predictive of the benefit of adjuvant chemotherapy in node-negative EBC [32
The RS has been demonstrated to provide additional prognostic and predictive information beyond classical and histopathological criteria in N0 and N+ hormone receptor-positive disease [2
] Recently, a score derived from immunohistochemical staining of ER, PgR, HER2 and Ki-67 (IHC4) was reported to deliver similar prognostic information as the RS if obtained by an optimized and centralized testing method [33
]. Correlation between the IHC score and the RS was modest (r = 0.7). Moreover, this still has to prove the test of applicability in broad routine clinical practice. Lack of reproducibility of IHC assays is an issue of major concern as are the ~20% of immunohistochemically false HR-negative patients [34
] and the ~20% of potentially inaccurate HER2 tests [35
]. Also, the IHC4 is only a prognostic score while the RS also has predictive importance quantifying the benefit of adjuvant chemotherapy.
In conclusion, our results confirm that the RS had an impact on physicians' and patients' adjuvant decision-making in both node-negative and node-positive ER-positive disease. This resulted in a substantial reduction of adjuvant chemotherapy usage and should thus support efforts to improve the access for patients with ER-positive EBC to the test.