title: Tumor angiogenesis as prognostic and predictive marker for chemotherapy dose-intensification efficacy in high-risk breast cancer patients within the WSG AM-01 trial.
abstract: The goal of this analysis was to characterize the survival impact of angiogenesis in the patients with high-risk breast cancer, particularly the predictive impact on benefit from dose intensification of adjuvant chemotherapy. Formalin-fixed tissue sample of 152 patients treated as part of the WSG AM-01 trial by either high-dose or conventional dose-dense chemotherapy were analyzed. Angiogenic activity was measured using microvessel count and vascular surface area (VSA) determined by the expression of vascular markers CD31 (n = 128) and CD105/endoglin (n = 130). Protein molecular breast cancer subclasses were analyzed by k-means clustering (k = 5). The univariate impact of factors on event-free (EFS) and overall survival (OS) was tested by log-rank statistics and quantified by univariate Cox analysis. Multivariate survival analysis included factors significant in univariate analysis, as well as interactions was performed for EFS. Both VSA/CD31 (P = 0.004) and VSA/CD105 (P = 0.003) were significantly higher among cases with increased Ki-67. A significant association with molecular subtypes was also found for VSA/CD105: in patients with basal-like/Her-2 subtypes, mean was 1.72 versus 1.24 in patients with other subtypes (P < 0.001). Elevated VSA/CD105 was associated with both significantly decreased EFS (P = 0.01) and OS (P = 0.02). Increased tumor size and positive Her-2 status were also prognostic for poorer EFS. The benefit of dose intensification for EFS was seen in those low-VSA/CD105 patients. The result was evident both in univariate and in multivariate survival analysis including all factors that were significant at the univariate level. Expression of angiogenesis markers may mirror or confer resistance to chemotherapy in the patients with breast cancer, particularly within the context of dose intensified chemotherapy. Highly angiogenic tumors may not derive sufficient benefit from dose intensification of chemotherapy alone. Our findings may serve as a rationale for further exploring anti-angiogenic treatment options in the patients with such highly angiogenic tumor subtypes.
authors.affiliation: West German Study Group, Ludwig Weber Str. 15, 41061 Mönchengladbach, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Gluz
authors.forename: Peter
authors.initials: P
authors.lastname: Wild
authors.forename: Cornelia
authors.initials: C
authors.lastname: Liedtke
authors.forename: Ronald
authors.initials: R
authors.lastname: Kates
authors.forename: Heiko
authors.initials: H
authors.lastname: Mendrik
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ehm
authors.forename: Verena
authors.initials: V
authors.lastname: Artinger
authors.forename: Raihanatou
authors.initials: R
authors.lastname: Diallo-Danebrock
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ting
authors.forename: Svjetlana
authors.initials: S
authors.lastname: Mohrmann
authors.forename: Christopher
authors.initials: C
authors.lastname: Poremba
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nitz
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Gaumann
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D016000:Cluster Analysis; D018572:Disease-Free Survival; D000071063:Endoglin; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000096:biosynthesis
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C064206:ENG protein, human; D000071063:Endoglin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface