The impact of a genomic assay (Oncotype DX) on adjuvant treatment recommendations in early breast cancer

Breast cancer is the most common malignancy in Australian women and most of these tumours are hormone receptor-positive (HR+).1-3 Adjuvant therapy for invasive breast cancer has been shown to improve survival.4 For early-stage, HR+, human epidermal growth factor receptor 2-negative (HER2−) cancer, this therapy may consist of hormonal therapy (HT), or a combination of chemotherapy and hormonal therapy (CHT). It is accepted that the vast majority of patients with HR+, HER2− tumours should receive HT; however, the threshold for use of CHT is difficult to define because this group includes patients with a spectrum of recurrence risks.4,5 A large number of patients in whom the disease would not recur still receive CHT because accurate tools to help define the benefit of adjuvant chemotherapy have not been available.6,7

The 21-gene Oncotype DX breast cancer assay (Genomic Health) was developed on mRNA extracted from archived tumour samples of 447 patients from three studies. The expression patterns of 21 genes were used to develop an algorithm that yields a recurrence score. The score has been validated to quantify the risk of distant recurrence in patients treated with tamoxifen and who had both HR+, lymph node-negative or lymph node-positive disease, as well as to predict the magnitude of benefit from the addition of chemotherapy to tamoxifen treatment.8-11 The assay has been widely available in the United States since 2004, and is available in Australia for $4000. There have been a number of studies examining the effect of the Oncotype DX assay on clinical decision making.12-17 The results have been fairly consistent, showing a shift in the treatment decision in about 30% of patients.12-15,17

These studies have largely focused on decisions made by individual practitioners. In Australia, the multidisciplinary meeting (MDM) has become the standard forum for determining treatment recommendations. A national goal is for all patients to have their treatment decisions discussed in an MDM before definitive treatment recommendations are made.18 In this study, we have assessed the effect of recurrence score information on treatment recommendations in the MDM.

Fifteen patients chose not to follow the recommendation of the MDM. In the node-negative group, 10/101 patients decided against the post-assay treatment recommendation: four opted for CHT instead of HT, four selected HT instead of CHT, and two refused all therapy. In the node-positive group, 5/50 opted for a different therapy than the post-assay recommendation: two selected CHT instead of HT, and three selected HT instead of CHT.

This first decision-impact study of the Oncotype DX breast cancer assay in Australia provides evidence that recurrence score information influenced MDM treatment recommendations for both the node-negative and node-positive groups.

In patients with node-negative tumours, those initially receiving a CHT recommendation were more likely to change to HT than the reverse (change rates of 40% v 17%; P = 0.02), as reported by others.12-15 However, unlike in other studies, a high proportion (more than two-thirds) of patients initially received a recommendation of HT alone and hence there was no overall change in chemotherapy use (12 patients changed from HT to CHT and 12 from CHT to HT). The high proportion of patients with node-negative tumours and with an initial recommendation of HT in this study appears to reflect an approach among this group of clinicians of basing treatments primarily on the degree of hormone sensitivity of the tumour, with the understanding that these patients would gain little extra benefit from chemotherapy. A number of these patients had unexpectedly high recurrence score results, which suggests that such an approach may sometimes lead to undertreatment.

In patients with node-positive tumours, those initially receiving a CHT recommendation were also more likely to change to HT than the reverse (change rates of 32% v 8%), although the difference in rates was not significant (P = 0.14). In contrast to the node-negative group, almost three-quarters of the patients with node-positive tumours received an initial recommendation for CHT, and there was a statistically significant reduction in recommendations for CHT post-assay (from 74% to 52%, P = 0.003). The reduction in CHT recommendations in the node-positive group is consistent with results seen in other studies of the impact of Oncotype DX assay on adjuvant decision making in patients with node-positive tumours.13,16 This suggests that in terms of reducing possible overtreatment, the Oncotype DX assay might have its greatest impact in this group.

While confirmation of the impact of the recurrence score on chemotherapy benefit in RCTs is pending (eg, TAILORx [NCT00310180], RxPONDER [NCT01272037]), our data suggest that use of the assay can spare patients potentially unnecessary treatment as well as identify patients for whom potentially lifesaving therapy might otherwise be omitted. In both patients with node-negative and those with node-positive tumours, changes in recommendations were made in directions consistent with the recurrence score categories, suggesting that assay results had a strong impact on final decisions. As the recurrence score has been validated to predict both distant recurrence risks and responsiveness to chemotherapy in both the node-negative and node-positive groups, these shifts in treatment recommendations arguably allow physicians to direct individual patients toward therapies that ultimately may be associated with better health outcomes. The result is more precise individualisation of therapy from both the MDM and the treating physician.

In both the node-negative and node-positive groups, about 10% of patients elected not to follow the post-assay treatment recommendation. Patient treatment decisions went against the MDM recommendations, both toward CHT and toward HT. Reasons for not following treatment recommendations might include patient preference, patient anxiety about one treatment regimen or the other, and varying levels of patient trust in the Oncotype DX recurrence score assay.

The lack of routine assessment of Ki-67 levels may be seen as a limitation of this study. A report in 2011 suggested that an assessment of Ki-67 levels, along with ER, PR and HER2 status, could provide similar prognostic information to the Oncotype DX assay.19 However, a subsequent international working group concluded that large variations in analytic methods have limited the routine reliance on immunohistochemical assessment of Ki-67 in clinical practice.20

Another limitation of our study is that MDMs at only three academic breast cancer units in Melbourne participated. Therefore, our results (which reflect the collective opinions of participating physicians) may not reflect nationwide practices. Attendance at the MDMs may have varied, and other factors such as the passage of time could have affected the second MDM recommendation, although the time between assessments was generally about 3 weeks. There may have been other biases.

In conclusion, this study provides evidence that the Oncotype DX assay influences treatment recommendations for HR+ early-stage invasive breast cancer in the Australian MDM setting. Most of the recommended changes were toward lower intensity treatment regimens. The health economic impact of this assay in Australia remains to be investigated, but the impact of this shift on quality of life should not be underestimated.