title: Her-2/neu and EGFR tyrosine kinase activation predict the efficacy of trastuzumab-based therapy in patients with metastatic breast cancer.
abstract: Her-2/neu overexpression in human breast cancer leads to an aggressive biological behavior and poor prognosis. Although the anti-Her-2/neu antibody trastuzumab (Herceptin(R)) has become a valuable therapeutic option for patients with Her-2/neu-overexpressing breast cancer, many patients do not benefit from this therapy. To evaluate the effect of receptor activation on tumor response, we have investigated the phosphorylation status of Her-2/neu and EGFR in 46 Her-2/neu-overexpressing tumor samples from trastuzumab-treated metastatic breast cancer patients by immunohistochemistry. Activated (p)tyr-1248 Her-2/neu was detected in 9 of 46 breast cancers (20%), and activated (p)tyr-845 and (p)tyr-1173 EGFR were both present in 6 tumors (13%) while EGFR was present in 16 cases (35%). ptyr-1248 Her-2/neu showed a trend to correlate with increased response to trastuzumab (p = 0.063), while ptyr-845, ptyr-1173 EGFR and EGFR did not. The presence of ptyr-1248 Her-2/neu and ptyr-845 or ptyr-1173 EGFR, however, was a strong predictor of both response to trastuzumab-based treatment (OR = 8.0, p = 0.021 and OR = 8.0, p = 0.021) and clinical benefit (OR = 5.47, p = 0.041 and OR = 6.22, p = 0.028 multivariate logistic regression analysis). Furthermore, ptyr-845 EGFR and ptyr-1248 Her-2/neu were both independent predictors of progression-free survival (RR = 0.21, p = 0.01 and RR = 0.45, p = 0.026, multivariate analysis). Patients with ptyr-845 EGFR positive tumors also tended toward increased overall survival (RR = 0.17, p = 0.082). Taken together, we have demonstrated that the determination of activated EGFR improves the utility of ptyr-1248 Her-2/neu staining in predicting the clinical outcome of patients undergoing trastuzumab treatment. We hypothesize that the activation state of both Her-2/neu and EGFR are key determinants for trastuzumab efficacy.
authors.affiliation: Ludwig Boltzmann Institute for Clinical and Experimental Oncology, Vienna, Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Hudelist
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Köstler
authors.forename: Klaus
authors.initials: K
authors.lastname: Czerwenka
authors.forename: Ernst
authors.initials: E
authors.lastname: Kubista
authors.forename: Johannes
authors.initials: J
authors.lastname: Attems
authors.forename: Ruth
authors.initials: R
authors.lastname: Müller
authors.forename: Daphne
authors.initials: D
authors.lastname: Gschwantler-Kaulich
authors.forename: Mahmood
authors.initials: M
authors.lastname: Manavi
authors.forename: Isabell
authors.initials: I
authors.lastname: Huber
authors.forename: Heinz
authors.initials: H
authors.lastname: Hoschützky
authors.forename: Christoph C
authors.initials: CC
authors.lastname: Zielinski
authors.forename: Christian F
authors.initials: CF
authors.lastname: Singer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000918:Antibody Specificity; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology*; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D019000:Phosphotyrosine / Q000378:metabolism; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015996:Survival Rate; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; D010455:Peptides; D019000:Phosphotyrosine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab