Breast Cancer Subtypes
Further evidence has accrued in the last 2 years to support the use of multi-gene signatures to make distinctions among patients with luminal disease. Many different multi-gene assays provide prognostic information, primarily derived from their sampling of proliferation genes, which emphasizes the need for some measure of proliferation in any surrogate classification.
The 21-gene RS is accepted as providing not only prognostic, but also predictive information regarding the utility of cytotoxic therapy in addition to endocrine therapy for patients with luminal disease. This and perhaps other multi-gene assays can help define a group of patients for whom chemotherapy is futile because the biological nature of the tumour is such that it is substantially unresponsive to such agents. Existing studies of the 21-gene RS involve retrospective analysis of previously conducted randomized clinical trials,[75,76] which included both HER2-positive and HER2-negative cohorts. A recent report demonstrated excellent 5-year outcome without chemotherapy for a 'good prognosis' 70-gene signature cohort.
In those areas of the world where multi-gene assays are readily available, clinical practice has developed to rely on the results to guide decisions about inclusion of chemotherapy in the treatment of patients with ER-positive, HER2-negative disease. The 70-gene assay returns a dichotomous result, while 21-gene RS is continuous. An unresolved question is the level of RS which should justify cytotoxic therapy: only high RS values (>31) were significantly associated with chemotherapy benefit in the prospective/retrospective studies,[75,76] while substantially lower values are being investigated in ongoing prospective trials and are being used in clinical practice. For many societies, the cost of these multi-gene assays remains prohibitive.
The possibility that multi-gene expression assays may become more widely available was discussed by some Panellists after the meeting during the preparation of this manuscript. Cost-effectiveness studies have been carried out in the United States,[98,99] Canada,[100–104] Israel, the UK and Germany.[107,108] These studies have yielded varying estimates ranging from cost-saving to an incremental cost-effectiveness ratio (ICER) of ~US $60 000 per quality-adjusted life year (QALY). One Japanese study of the 70-gene assay found an ICER of US $40 000 per QALY. Such assessments will be sensitive not only to the cost of the test, but to the net proportion of patients in whom testing leads to the omission of cytotoxic therapy, and to the cost of the cytotoxic regimen which would otherwise have been given. These reports have largely worked from the perspective of the health care system or third-party payer, and thus offer hope that such bodies may increasingly support multi-gene testing. It has recently been reported that the UK National Institute for Clinical Excellence, having reached a confidential pricing arrangement with the supplier, has issued a draft recommendation that the 21-gene RS be used for women with node-negative disease for whom the indication for chemotherapy is otherwise uncertain1. Meanwhile, in many settings patients can only access multi-gene testing by large personal out-of pocket payments, and therefore, from a global perspective for the immediate future multi-gene testing remains inaccessible for the majority of women with early breast cancer. It is for these women that the Panel believed that the approach adopted by successive St Gallen Panels based on the available clinico-pathological testing, and now expressed in the surrogate IHC-based classification shown in Table 2 will be more widely applicable at lesser cost, notwithstanding its limited validation.
The main reason for attempting distinction between 'Luminal A-like' (more endocrine sensitive, indolent, better prognosis) and 'Luminal B-like' (less endocrine sensitive, more aggressive, worse prognosis) tumours was recognized to be the differing implications for the utility or futility of adjuvant cytotoxic therapy between these groups. Evidence was presented that the clarity of distinction between 'Luminal A-like' and 'LuminalB-like' tumours could be improved by the requirement for substantial PgR positivity in the definition of 'Luminal A-like' disease. Adding this restriction will have the effect of reducing the number of patients classified as 'Luminal A-like' and thus increasing the number for whom cytotoxic therapy is generally recommended. Recognizing that high-quality pathology and quality assurance programmes are important for the interpretation of these tests, it was noted that the absolute values of each IHC parameter/cut-point may vary between laboratories, and that pending improved standardization local experience might best define the locally useful cut-points between 'high' and 'low' Ki-67 and PgR.
Ann Oncol. 2013;24(9):2206-2223. © 2013 Oxford University Press
Copyright European Society for Medical Oncology. Published by Oxford University Press. All rights reserved.