To our knowledge, this is the first time that the IHC4 and IHC4 + Clinical score has been tested for its ability to predict relapse in a cohort of patients who switched to an AI at 2–3 years, thus excluding those who relapsed early and more closely resembling the cohort who would potentially be considered for extended adjuvant therapy beyond 5 years. We found that patients with a IHC4 + Clinical score of ≥ 75th percentile have an approximately 50% risk of recurrence by 10 years after switching at 2–3 years. This may imply that this subgroup should continue adjuvant endocrine therapy beyond the total of 5 years.
Prediction of late relapse is a matter of considerable concern for patients who have switched therapies at 2–3 years and who remain disease-free after 2–3 years, since the current and planned randomised studies are insufficiently mature to assist their decision-making at the current time.
The IHC4 score has been confirmed as being predictive of early relapse by a number of groups, and is known to be especially valuable when combined with clinical prognostic scores [10]. Recently it has been compared with other scoring systems for its ability to predict both early and late recurrences [18, 19]; although the PAM50 risk of recurrence (ROR) score was superior in this study, the IHC4 has been found to be an important scoring system.
Our results confirm the prognostic importance of IHC4, alone and in conjunction with clinical scores. Although results from the calibration plot indicated that the prediction based on the published IHC4+C derived from TransATAC study was higher than the actual observed probability in some groups of predicted risk > 10%, One possible reason for this is that PathIES patients were treated with tamoxifen for 2–3 years, and remained recurrence-free before being randomised. Our results, nevertheless, demonstrated the prognostic value of IHC4 to segregate patients associated with differential risks of recurrence. The predictive value of the calculator might be improved by adjusting the weight estimates for each of the factors, given this is a different population and potential prognostic time dependency of some of the clinical pathological variables. Additional study using an independent cohort of patients is needed to investigate the robustness of the estimates.
Several other scoring systems have been advocated for their ability to predict late recurrence in patients with ER positive breast cancer. Sestak et al. [19] compared IHC4, recurrence score (RS) as well as the PAM50 ROR score in patients enrolled in the ATAC study: here, node status, tumour size and the ROR score, a gene expression profile test, were the factors best able to predict long-term relapse. More recently, the TransATAC group compared the breast cancer index (BCI) (both linear and cubic) the OncotypeDX, as well as the IHC4 score; here the BCI (linear) had the best predictive value [20]. The components of this score that were most important were HOXB13/IL17BR. The reason for these two factors being so important appears to be that HOXB3 can over-ride the tumour suppressor p21 whilst IL17 is now known to be the prime neutrophil-dependent growth promoter in breast cancer [21]. The importance of this ratio was also underscored by the reports on retrospective analysis of the ratio in the MA17 study and predicted those who may benefit from extended letrozole therapy [22]. Recently, TransATAC group reported that EndoPredict (EPclin), an alternative test combining an eight-gene signature (EP score) with tumour size and nodal status, provided more prognostic information than the OncotypeDX score for estimating late recurrence [23], which may partly due to the reason that the test includes the significant clinicopathological variables.
Previously, an assessment of the predictive effects, in terms of therapy, of Ki67 had been reported by Viale et al. [24]. This report suggested that high Ki67 levels predicted benefit from aromatase inhibition. However, this result was not amalgamated with the other three components of the IHC4 score, namely ER, PR and HER-2. In the current study, there were too few patients to enable an assessment of the IHC4 score for its capacity to predict which patients benefit from tamoxifen or exemestane after 2–3 years.
Recently, we carried out immunohistochemical staining for ER beta 1 and 2 in a subset of patients. Here, we found that, for those patients whose tumours expressed ER beta 1, the beneficial effect of simply continuing tamoxifen was similar to the patients who switched treatment to exemestane. Although requiring confirmation, this study suggests that it may be possible to ‘tailor’ treatment according to the primary tumour characteristics. This, combined with the IHC4 + clinical score, should enable us to optimise the type and duration of endocrine therapy.
There are a few caveats before translating these results into clinical practice; firstly, these patients did not receive trastuzumab; the study was initiated before the studies of adjuvant trastuzumab were mature and adjuvant trastuzumab became standard practice for patients whose tumours expressed HER-2; however, only 5% of patients had HER2 over-expressed tumours in this study. Secondly, Ki67 measurement, despite being the subject of a recent consortium statement remains a challenging analyte in tissue sections, due principally to heterogeneity of expression [25, 26]. Thus, all the Ki67 values were analysed and assessed in one central laboratory. Secondly, a large proportion of patients received chemotherapy in this study, and especially this substudy, and caution should be exercised in translating these results to patients who did not receive cytotoxic chemotherapy.
Finally, although tissue markers reflect the biology of breast cancers in large series such as this, they do not enable clinicians to accurately predict the type and duration of treatment for individual patients; this is reflected by our finding here that approximately 50% of those with the highest quartile of the IHC4 + clinical score have not yet relapsed.
Other methods of predicting effectiveness and duration of treatment include the assessment of cell-free DNA. Using sensitive detection methods it is possible to detect circulating DNA from apoptosis residual breast cancer cells. It has now been shown that copy number variation [27] and detection of mutations [28] potentially can predict which patients are resistant to therapy.
In summary, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2–3 years. Future, prospective studies are needed to define the role of IHC4 in selecting patients for long-term therapy.