The biological and prognostic heterogeneity of breast cancer is widely recognized [1, 2]. This diversity determines a great deal of the risk of relapse of each tumor, and therefore, the different election of complementary treatment, especially in early stages [3, 4].
Right now, to the prognostic value of the “burden tumor”, meaning the size of the tumor and the node involvement, should be added other tumor biological factors. As in other published studies, in our population, tumor size, as well as node involvement turned out to be survival prognostic factors, in univariate analysis, as well as in multivariate analysis, maintaining their independent prognostic value . In contrast, ER and PR expression and HER2 overexpression lost their independent prognostic value in multivariate analysis. Nevertheless, one of the limitations of our study in this assessment is the small percentage of patients with known HER2 overexpression.
In the same way, the prognostic value of tumor grade has been highlighted . It maintained significance in uni- and multivariate analyses, but exclusively in tumors undifferentiated (G3), increasing 6.36 times the risk of death by breast cancer (p = 0.02). Other studies have not given this prognostic quality to tumor grade either , recommending the routine study of the Ki-67 antigen expression and giving more value to this one. Despite, other studies have limited this worthiness to women with hormone-sensitive tumors which are moderately differentiated . A recent publication has reported a correlation between higher Ki-67 value and Erb-B2, triple negative and luminal B-HER2 negative tumors. Besides histological grade was not informative for estimating proliferation in luminal B HER2 negative, being necessary other tools like Ki-67 index .
We also observed that Ki-67 was a factor related with survival in multivariate analysis. Several meta-analyses demonstrated the prognostic influence of this factor [6, 7, 11, 14–16]. Two of them [14, 15], which included 12,155 and 32,825 patients, respectively, led to the same conclusion even when different inclusion criteria, different Ki-67 assessment methods and different cut-points were used. In spite of these differences, the results on the prognostic value of Ki-67 were consistent.
In search of elements that can help us to identify those women with a favorable prognosis in order to avoid overtreatment, we have continued to study this marker [6, 16, 17]. Using samples of randomized studies, where a second Ki-67 centralized analysis was performed, Luporsi recently recognized Ki-67 as an independent prognostic factor of free relapse survival. It reached a level of evidence IB . It did not achieve the IA level because none of the revised studies had been specifically designed to be evaluated it as a prognostic factor.
A more recent meta-analysis about the prognostic significance of Ki-67 recognizes that the debate is still open, even when most of the studies have established their relation with the free relapse survival and the specific breast cancer survival. However, the biggest inconvenient to establish a standard has been its measurement [6, 7]. The published recommendations about its determination will help this purpose .
When we divided our series of 680 patients in tumor subtypes by IHC, according to the Saint Gallen criteria,  and we studied the prognosis of them, with and without node involvement, we observed that luminal B N0 patients had the worse prognosis. We tried to identify which of the variables that categorized them as Luminal B, the absence of PR expression, the HER 2 overexpression or Ki-67 ≥14 levels were the ones that conferred this worse prognosis.
Of the 87 patients with luminal B tumors, those with PR expression, absence of HER 2 overexpression and high levels of Ki-67, underwent the majority of relapses. Even though, there is not the unique research with similar outcome regarding HER2 overexpression . From our point of view, this fact underlines the value of Ki-67 even more.
As early as 2005, Urruticoechea reviewed 40 studies that included more than 11,000 patients and he found that Ki-67 was a prognostic factor in N0 patients in the uni- and multivariate analysis . A later report, which studied breast cancer prognostic factors after 5 and 10 years in patients with pT1N0M0 tumors, demonstrated that Ki-67 had a prognostic value and that it was the only factor that did not lose this value over time .
In the genomic era, because of the cost and availability of gene microarrays, IHC classification of the tumors represents a surrogated marker of gene profiles in the daily routine and determination of Ki-67 takes on a great significance [3, 4].
Ki-67 is the most important cell proliferation marker in Oncotype, which constitutes the biggest determinant in the gene expression profiles [21, 22]. These genomic profiles are applied to predict the risk of relapse, especially in hormone-sensitive patients. However, comparing two of the most accepted, PAM 50 and Oncotype, they had differences in the risk classification of the patients . There was no display of benefit in the prediction of the relapse risk by Oncotype face to face an IHC profile, IHC4, consisting in ER, PR, HER 2 and Ki-67 expression and supposing a great accessibility in the daily routine, besides supposing IHC a great economical saving . The lack of a greater exactitude in the relapse prediction in Oncotype, before IHC in which Ki-67 is included, has also been reflected in other studies [24, 25].
Although some reports have manifested the predictive value on Ki-67 [26–29], there is no agreement on the matter [16, 30, 31], even when its association with complete pathological responses in neoadjuvant treatment with evidence level IIA is recognized .
In summary, on the current rise of the gene expression profile studies and their use in the calculation of relapse risk in breast cancer , we must not forget that the classification of tumors based in TNM system and IHC including Ki-67 assessment has not lost its prognostic value, keeping greater efficiency and accessibility, and being able to be used with security and lower cost in the clinical routine. Classical factors as size of tumor, nodal involvement and tumor grade sustain their prognostic role. However, it should be completed now with new biological tumor parameters. Ki-67 has been demonstrated as an independent and additional predictor of survival in multivariable analysis. In the genomic era Luminal B node negative breast cancer by IHC has proved being a prognostic factor. Conversely, neither progesterone-receptor expression nor HER2 status has shown it in this group. Standardizing Ki67 right assessment will improve estimation of breast cancer recurrence risk.