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Cytokeratin 5/6 fingerprinting in HER2-positive tumors identifies a poor prognosis and trastuzumab-resistant basal-HER2 subtype of breast cancer.

Martin-Castillo B, Lopez-Bonet E, Buxó M, Dorca J, Tuca-Rodríguez F, Ruano MA, Colomer R, Menendez JA - Oncotarget (2015)

Bottom Line: There is an urgent need to refine the prognostic taxonomy of HER2+ breast carcinomas and develop easy-to-use, clinic-based prediction algorithms to distinguish between good- and poor- responders to trastuzumab-based therapy.In the sub-cohort of HER2+ patients treated with trastuzumab-based adjuvant/neoadjuvant therapy, basal-HER2+ phenotype was found to be the sole independent prognostic marker for a significantly inferior time to treatment failure in multivariate analysis.A CK5/6-based immunohistochemical fingerprint may provide a simple, rapid, and accurate method for re-classifying women diagnosed with HER2+ breast cancer in a manner that can improve prognosis and therapeutic planning in patients with clinically aggressive basal-HER2+ tumors who are not likely to benefit from trastuzumab-based therapy.

View Article: PubMed Central - PubMed

Affiliation: Unit of Clinical Research, Catalan Institute of Oncology, Girona, Catalonia, Spain.

ABSTRACT
There is an urgent need to refine the prognostic taxonomy of HER2+ breast carcinomas and develop easy-to-use, clinic-based prediction algorithms to distinguish between good- and poor- responders to trastuzumab-based therapy. Building on earlier studies suggesting that HER2+ tumors enriched with molecular and morpho-immunohistochemical features classically ascribed to basal-like tumors are highly aggressive and refractory to trastuzumab, we investigated the prognostic and predictive value of the basal-HER2+ phenotype in HER2-overexpressing tumors. Our retrospective cohort study of a consecutive series of 152 HER2+ primary invasive ductal breast carcinomas first confirmed the existence of a distinct subgroup co-expressing HER2 protein and basal cytokeratin markers CK5/6, the so-called basal-HER2+ phenotype. Basal-HER2+ phenotype (≥10% of cells showing positive CK5/6 staining), but not estrogen receptor status, was significantly associated with inferior overall survival by univariate analysis and predicted worsened disease free survival after accounting for strong prognostic variables such as tumor size at diagnosis in stepwise multivariate analysis. In the sub-cohort of HER2+ patients treated with trastuzumab-based adjuvant/neoadjuvant therapy, basal-HER2+ phenotype was found to be the sole independent prognostic marker for a significantly inferior time to treatment failure in multivariate analysis. A CK5/6-based immunohistochemical fingerprint may provide a simple, rapid, and accurate method for re-classifying women diagnosed with HER2+ breast cancer in a manner that can improve prognosis and therapeutic planning in patients with clinically aggressive basal-HER2+ tumors who are not likely to benefit from trastuzumab-based therapy.

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Kaplan-Meier DFS curves of HER2+ patients stratified by ER status, lymph node status, HER2 phenotype, and CK5/6 phenotype
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Figure 3: Kaplan-Meier DFS curves of HER2+ patients stratified by ER status, lymph node status, HER2 phenotype, and CK5/6 phenotype

Mentions: The 5-year Kaplan-Meier estimate of DFS was 52% for patients with basal-HER2+ tumors, as compared with 77% for patients with luminal-HER2+, and 68% for HER2 + tumors (Figure 3). No statistical differences were found in 5-year estimated DFS between patients with luminal-HER2+ tumors and patients with HER2+. Notably, upon stratification of basal-HER2+ to underlying CK5/6 expression pattern, the 5-year Kaplan-Meier estimate of DFS was as low as 27% for patients with basal 2-HER2+ tumors (Figure 3), whereas the estimate of DFS in patients with basal 1-HER2+ tumors (75%) was not statistically different to those with basal CK-negative (luminal-HER2+ and HER2+) HER2+ patients.


Cytokeratin 5/6 fingerprinting in HER2-positive tumors identifies a poor prognosis and trastuzumab-resistant basal-HER2 subtype of breast cancer.

Martin-Castillo B, Lopez-Bonet E, Buxó M, Dorca J, Tuca-Rodríguez F, Ruano MA, Colomer R, Menendez JA - Oncotarget (2015)

Kaplan-Meier DFS curves of HER2+ patients stratified by ER status, lymph node status, HER2 phenotype, and CK5/6 phenotype
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466672&req=5

Figure 3: Kaplan-Meier DFS curves of HER2+ patients stratified by ER status, lymph node status, HER2 phenotype, and CK5/6 phenotype
Mentions: The 5-year Kaplan-Meier estimate of DFS was 52% for patients with basal-HER2+ tumors, as compared with 77% for patients with luminal-HER2+, and 68% for HER2 + tumors (Figure 3). No statistical differences were found in 5-year estimated DFS between patients with luminal-HER2+ tumors and patients with HER2+. Notably, upon stratification of basal-HER2+ to underlying CK5/6 expression pattern, the 5-year Kaplan-Meier estimate of DFS was as low as 27% for patients with basal 2-HER2+ tumors (Figure 3), whereas the estimate of DFS in patients with basal 1-HER2+ tumors (75%) was not statistically different to those with basal CK-negative (luminal-HER2+ and HER2+) HER2+ patients.

Bottom Line: There is an urgent need to refine the prognostic taxonomy of HER2+ breast carcinomas and develop easy-to-use, clinic-based prediction algorithms to distinguish between good- and poor- responders to trastuzumab-based therapy.In the sub-cohort of HER2+ patients treated with trastuzumab-based adjuvant/neoadjuvant therapy, basal-HER2+ phenotype was found to be the sole independent prognostic marker for a significantly inferior time to treatment failure in multivariate analysis.A CK5/6-based immunohistochemical fingerprint may provide a simple, rapid, and accurate method for re-classifying women diagnosed with HER2+ breast cancer in a manner that can improve prognosis and therapeutic planning in patients with clinically aggressive basal-HER2+ tumors who are not likely to benefit from trastuzumab-based therapy.

View Article: PubMed Central - PubMed

Affiliation: Unit of Clinical Research, Catalan Institute of Oncology, Girona, Catalonia, Spain.

ABSTRACT
There is an urgent need to refine the prognostic taxonomy of HER2+ breast carcinomas and develop easy-to-use, clinic-based prediction algorithms to distinguish between good- and poor- responders to trastuzumab-based therapy. Building on earlier studies suggesting that HER2+ tumors enriched with molecular and morpho-immunohistochemical features classically ascribed to basal-like tumors are highly aggressive and refractory to trastuzumab, we investigated the prognostic and predictive value of the basal-HER2+ phenotype in HER2-overexpressing tumors. Our retrospective cohort study of a consecutive series of 152 HER2+ primary invasive ductal breast carcinomas first confirmed the existence of a distinct subgroup co-expressing HER2 protein and basal cytokeratin markers CK5/6, the so-called basal-HER2+ phenotype. Basal-HER2+ phenotype (≥10% of cells showing positive CK5/6 staining), but not estrogen receptor status, was significantly associated with inferior overall survival by univariate analysis and predicted worsened disease free survival after accounting for strong prognostic variables such as tumor size at diagnosis in stepwise multivariate analysis. In the sub-cohort of HER2+ patients treated with trastuzumab-based adjuvant/neoadjuvant therapy, basal-HER2+ phenotype was found to be the sole independent prognostic marker for a significantly inferior time to treatment failure in multivariate analysis. A CK5/6-based immunohistochemical fingerprint may provide a simple, rapid, and accurate method for re-classifying women diagnosed with HER2+ breast cancer in a manner that can improve prognosis and therapeutic planning in patients with clinically aggressive basal-HER2+ tumors who are not likely to benefit from trastuzumab-based therapy.

Show MeSH
Related in: MedlinePlus