The last part of our discussion, on the analyzed biomarkers, focuses on HER2, the transmembrane glycoprotein with intracellular tyrosine kinase activity belonging to the EGFR family, which becomes active by homo- and heterodimerization, by which HER2-HER3 plays an important role in carcinogenesis through the activation of the PI3K/protein kinase B/mammalian target of the rapamycin pathway.83,84 HER2 overexpression has been found in ~13%–23% of breast cancers and is associated with poor survival.85 According to the 2015 St Gallen recommendations and ASCO and CAP guidelines, the HER2 IHC staining score in the triple-negative phenotype could be 0 or 1+ or equivocal (2+) and negative according to the ISH test. The ERBB2 gene copy is closely associated with HER2 protein expression, but studies show that only around 20% of tumors with positive immunostaining in ≤50% of cells showed gene amplification compared with 85.7% of tumors presenting positive staining in >50% of cells.7,10,11,86

Therefore, it is highly probable that the triple-negative phenotype bearing an amplified ERBB2 gene would not have the same clinical behavior as a tumor without staining or with incomplete staining in <10% of the tumor cells. In breast cancer, HER2 overexpression is an independent negative prognostic factor directly correlated with tumor grade and lymph node involvement and inversely correlated with ER expression.87 Not many studies addressed the question of clinical relevance of HER2 score in nonmetastatic triple negative breast cancer population and the results are inconclusive. In 119 non-metastatic TNBCs, patients with a HER2-neu score of 0 had a significantly poorer outcome in terms of DFS and OS compared with those with a HER2 score of 1 or 2 (P=0.0021, P=0.0105).88 In our previous analysis of 47 patients with early-stage TNBC, we found the median EFS to be shorter in the HER2-positive, ISH-negative cases (29.2 months) than in the HER2-negative ones (31.8 months), without reaching significance (P=0.9).89

In our triple-negative patients, HER2 expression was marginally correlated with lymphovascular invasion (P=0.072) and significantly with histopathological type (P=0.001). In relapsed patients, some differences existed in HER2 expression: 88.9% (16 patients) were negative and 11.1% had weak expression (P=0.559) with no significant differences between the mean EFS of the subgroups.

Of the biomarkers examined in the present study, only EGFR was found to be significantly directly correlated with the triple-negative phenotype. In the literature, EGFR and CK5/6 co-expression are described in approximately half of triple-negative tumors, as they stand for the poor prognostic basal-like subtype.34,90 Regarding less specific biomarkers, TNBC appeared to be associated with p53 expression and high Ki67 levels in >50% of cases.91

As for outcomes, the only biomarker whose expression was inversely correlated with relapse in our specific population was that of CK5/6. Patients considered to be CK5/6 negative had five times higher risk of relapse than those displaying biomarker expression. Lastly, for our target population, we proposed a prognostic score based on CK5/6 and E-cad expression, but the differences between the identified subgroups did not reach statistical significance. Among previous scores assessing roughly the same types of IHC biomarkers in non-metastatic TNBC patients is the study of Kashiwagi et al, who evaluated the prognostic role of E-cad and Ki67 in 138 triple-negative patients undergoing adjuvant chemotherapy. The combination of E-cad negative and high Ki67 was associated with worse OS (P<0.001).92 In another study of E-cad, AR, and Ki67 expression in a small cohort (N=45) of primary operable TNBC patients, AR-negative and Ki67-positive patients had a significantly poorer OS (P=0.0202).49 In 102 Japanese patients with invasive TNBC who underwent primary surgery, analysis of the prognostic role of histological factors, such as pathological tumor size and nodal status, along with basal-like specific marker expression (EGFR, CK5/6, CK14, and CK35), led to the creation of three leader scores, of which the three groups of patients had statistically different risks of relapse and breast cancer-specific deaths, respectively.93 In a recent analysis of 99 cases of TNBC, CK5/6 expression was inversely correlated with AR and Ki67 levels, and it was associated with a better outcome than for CK5/6-negative patients (HR =0.39; P=0.02). Moreover, E-cad expression was found to be an independent favorable prognostic biomarker (P=0.05).56

In agreement with these results, the population that expressed both biomarkers in our study displayed the longest EFS, whereas those that did not express any biomarker showed the poorest outcomes. This finding might be explained by the absence of differences in CK5/6 expression in triple-negative compared with non-triple-negative patients as well as because there is no established cutoff for CK5/6 positivity. Furthermore, in several studies, the threshold was 1%, whereas our cutoff of 10% was fixed by the institutional internal laboratory. The participation of E-cad in our score as a good prognostic biomarker is as expected, as the absence of expression was found to be associated with poorer outcomes in other studies,32 seemingly correlated with the basal-like subtype.49


Given the published research, our preliminary analyses were designed to investigate a plethora of biomarkers correlated with various clinical and histopathological prognostic factors, but whose correlations with relapse or survival without relapse had not yet been confirmed. Due to the small number of TNBC patients and even smaller number of those patients tested for each biomarker, the results in our study were often statistically insignificant.

Other teams have assessed several scores to identify patients with good prognoses within this population, but none of them has yet been validated. Each of our score component biomarkers (CK5/6 and E-cad) has been assessed as a constituent of such scores, but to our knowledge, these two have not been assessed solely together.

Other limitations of our study include the lack of standardization for the IHC assessment of biomarkers, other than the assessment of hormone receptors or HER2, and lack of guidelines for interpretation and reproducibility, which leads to discordant results.

We will add inferential statistical tests to identify other factors that might be included in our score. The final analysis will also contain the application of the score in borderline tumors, such as ER 1%–10%, PR 1%–10%, and non-expressing HER2 population, to identify the subgroups of very bad prognoses.


We would like to thank Mr Everardo D Saad for his written contribution and Mr Sorin S Opris for his assistance in preparing the article.


The authors report no conflicts of interest in this work.

Silvia Mihaela Ilie,1 Xenia Elena Bacinschi,1,2 Inga Botnariuc,2 Rodica Maricela Anghel1,2

1University of Medicine and Pharmacy “Carol Davila,” Bucharest, Romania; 2Department of Oncology-Radiotherapy, Institute of Oncology “Prof Dr Alexandru Trestioreanu,” Bucharest, Romania  


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Source: Breast Cancer: Targets and Therapy.
Originally published November 23, 2018.