This confirmation study for N0/N1 chemo-naïve breast cancer patients, confirms the prognostic value of a previously defined index combining proliferation (previously cyclin A, in the present study Ki67), histological grade, and ER. Importantly, the KiGE-index separated chemo-naïve patients into groups with different risk, independent of menopausal status, lymph node status, and whether endocrine adjuvant treatment was given or not. The robustness of the index is strengthened by the fact that the evaluation of Ki67, histological grade, and ER was performed in different studies by different persons using different cut-points, that studies from three Swedish health care regions and one Danish region were included, and by the fact that different study designs were used (randomized, cohort and case-control studies). Furthermore, when analyzing Patient materials I–V separately (not the five sets), KiGE remained a significant prognostic factor (HR:s varied between 2.1 and 9.0) in all but one patient material (Patient material II, P=0.09; data not shown). We were also able to confirm the previous finding that the prognostic value of Ki67 is limited to ER-positive breast cancer and is most pronounced for the histological grade 2 subgroup. The latter findings are furthermore in line with gene expression analyses (Sotiriou et al. 2006; Ivshina et al. 2006; Teschendorff et al. 2007; Desmedt et al. 2008). However, a recent publication (Munzone et al. 2012) showed that within the group of patients with node-negative triple-negative breast cancer, Ki67 was associated with different prognosis when using a higher cut-point (35%). The KiGE-index is similar to the index proposed at the St. Gallen consensus meeting in 2011 (Goldhirsch et al. 2011), with Ki67 separating clinicopathologically classified ‘Luminal’ ER-positive breast cancer into ‘Luminal A’ and ‘Luminal B’ subgroups with different prognoses and thereby influence on the choice of therapy. Chemotherapy, with or without anti-HER2 therapy, is suggested for the ‘Luminal B’ subgroup, but not for the ‘Luminal A’ subgroup (Goldhirsch et al. 2011). According to the St. Gallen guidelines, not taking histological grade into consideration, patients with ER-positive low proliferating (and HER2 normal) tumors will be classified as having ‘Luminal A’ breast cancer. According to the KiGE-index, with the inclusion of histological grade, some of these patients will instead be considered as having worse prognosis. In this large patient material, patients with ER-positive, low Ki67, and histological 3 breast cancer (N=42) have a poor prognosis, with a five-year DDFS of 64% (95% CI: 47–76%). This subgroup constituted 6% (42/652) of the ER-positive (chemo-naïve) patients in our study (Patient materials I–V). In a recent publication by the International Ki67 in Breast Cancer Working Group (Dowsett et al. 2011), certain important drawbacks for Ki67 analyses were highlighted, including number of cancer cells being scored and cut-point used. Furthermore, the distribution of Ki67 values makes it difficult to define a cut-point. The inherent drawbacks with the evaluation of Ki67 may at least partly be overcome by also considering histological grade, as suggested in the present study. Our study was, probably due to low power, unable to demonstrate any prognostic importance of Ki67 in histological grade 1 breast cancer. Aleskandarany et al. however, demonstrated that patients with high Ki67 had a significantly worse prognosis than those with low Ki67, in a large study, including 494 histological grade 1 breast cancers (Aleskandarany et al. 2011). Therefore, we do not exclude the possibility that Ki67 has prognostic value in the histological grade 1 subgroup.
Identifying a subgroup of patients not in need of adjuvant chemotherapy, was found to be the top priority on a list of the most urgent research areas in breast cancer in a recent web-consultant study (Dowsett et al. 2007). The Early Breast Cancer Trialists´ Collaborative Group (Peto et al. 2012) demonstrated that the effect of chemotherapy was independent of age, node status, tumor size, differentiation, ER-status, and tamoxifen use. However, information on quantitative immunohistochemistry of proliferation was not included. Ki67 combined with ER-status and histological grade may be helpful in this respect. Breast cancer patients with histological grade 1 tumors or patients with ER-positive and histological grade 2 tumors with low Ki67 expression constitute 57% of the patients with N0/N1 cancers in this study, with a five-year DDFS of 92%. Adjuvant chemotherapy would have limited added value for this group. The identification of a low-risk group not in need of adjuvant chemotherapy is also the primary aim of two ongoing clinical trials (MINDACT and TAILORx) (Rutgers et al. 2011; Zujewski & Kamin 2008) evaluating the gene profiles MammaPrint® and Oncotype DX®. The MINDACT trial (Rutgers et al. 2011) is a prospective, randomized trial using the 70-gene signature (MammaPrint®) together with the common clinical-pathological criteria for selecting patients for adjuvant chemotherapy. It is being tested in patients with N0/N1 breast cancer. MINDACT has a null hypothesis of a five-year distant metastasis-free survival of 92%, which will be tested for the group of patients who have a low-risk gene prognosis signature and high clinical-pathological criteria, and who were randomized to use the 70-gene signature and thus receive no chemotherapy. In a pilot phase based on the first 800 patients from this trial, the low-risk group constituted 65% (Rutgers et al. 2011). This figure is in line with 57% being the percentage of low-risk patients in our study, who furthermore had the same five-year DDFS as the null hypothesis in the MINDACT trial (92%). Risk group stratification may be further modified by also considering other established prognostic factors, e.g. lymph node status, tumor size, age, and HER2-status. The incidence of recurrences in the low-risk group could thereby be further decreased, but with the consequence of a smaller low-risk group.
In conclusion, we have confirmed a prognostic index based on proliferation (Ki67), histological grade, and ER for identifying a low-risk group of patients with N0/N1 breast cancer. For this large low-risk group, with a five-year DDFS of 92%, adjuvant chemotherapy will have limited effect and may thus be avoided.