title: Pathological Complete Response to Neoadjuvant Trastuzumab Is Dependent on HER2/CEP17 Ratio in HER2-Amplified Early Breast Cancer.
abstract: Purpose:To evaluate whether pathologic complete response (pCR) to neoadjuvant trastuzumab is dependent on the level of HER2 amplification.Experimental Design:114 HER2-overexpressing early breast cancer patients who had received neoadjuvant trastuzumab were included in this study. Absolute HER2 and chromosome 17 centromere (CEP17) were measured byin situhybridization analysis, and associations were examined between HER2/CEP17 ratio and tumor pCR status (commonly defined by ypT0 ypN0, ypT0/is ypN0, and ypT0/is).Results:In trastuzumab-treated patients, ypT0 ypN0 was achieved in 69.0% of patients with high-level amplification (HER2/CEP17 ratio > 6), but only in 30.4% of tumors with low-level amplification (ratio ≤ 6;P= 0.001). When pCR was defined by ypT0/is ypN0 or ypTis, 75.9% and 82.8% of tumors with high-level amplification had a complete response, whereas only 39.1%, and 38.3% with low-level amplification achieved pCR (P= 0.002 andP< 0.001, respectively). Logistic regression revealed that tumors with high-level amplification had a significantly higher probability achieving ypT0 ypN0 (OR, 5.08; 95% confidence interval, 1.86-13.90;P= 0.002) than tumors with low-level amplification, whereas no other clinicopathologic parameters were predictive of pCR. The association between high-level HER2 amplification and pCR was almost exclusively confined to hormone receptor (HR)-positive tumors (ypT0 ypN0: 62.5% vs. 24.0%,P= 0.014; ypT0/is ypN0: 75.0% vs. 28.0%,P= 0.005; and ypT0/is: 87.5% vs. 28.0%,P< 0.001), and was largely absent in HR-negative tumors.Conclusions:An HER2/CEP17 ratio of >6 in the pretherapeutic tumor biopsy is associated with a significantly higher pCR rate, particularly in HER2/HR copositive tumors, and can be used as a biomarker to predict response before neoadjuvant trastuzumab is initiated.Clin Cancer Res; 23(14); 3676-83. ©2017 AACR.
authors.affiliation: Department of Obstetrics and Gynecology, Cancer Comprehensive Center, Medical University of Vienna, Vienna, Austria. christian.singer@meduniwien.ac.at.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Singer
authors.affiliation: Department of Obstetrics and Gynecology, Cancer Comprehensive Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Yen Y
authors.initials: YY
authors.lastname: Tan
authors.affiliation: Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Fitzal
authors.affiliation: Department of Internal Medicine 1, Division of Oncology, Cancer Comprehensive Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Guenther G
authors.initials: GG
authors.lastname: Steger
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Egle
authors.affiliation: Institute of Pathology, Sozialmedizinisches Zentrum Ost, Vienna, Austria.
authors.forename: Angelika
authors.initials: A
authors.lastname: Reiner
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Margaretha
authors.initials: M
authors.lastname: Rudas
authors.affiliation: Institute for Clinical Pathology, Barmherzige Schwestern Hospital, Linz, Austria.
authors.forename: Farid
authors.initials: F
authors.lastname: Moinfar
authors.affiliation: Institute for Clinical Pathology, Barmherzige Schwestern Hospital, Linz, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Gruber
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
authors.forename: Edgar
authors.initials: E
authors.lastname: Petru
authors.affiliation: Department of Internal Medicine 1, Division of Oncology, Cancer Comprehensive Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Rupert
authors.initials: R
authors.lastname: Bartsch
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Tendl
authors.affiliation: Department of Internal Medicine 3-Hematology and Oncology, Kepler University Hospital, Linz, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Fuchs
authors.affiliation: Department of Obstetrics and Gynecology, Cancer Comprehensive Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Seifert
authors.affiliation: Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Ruth
authors.initials: R
authors.lastname: Exner
authors.affiliation: Department of Internal Medicine, Division of Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Marija
authors.initials: M
authors.lastname: Balic
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bago-Horvath
authors.affiliation: Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Filipits
authors.affiliation: Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Gnant
mesh_terms: D000328:Adult; D000368:Aged; D054316:Biomarkers, Pharmacological; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002503:Centromere / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D054316:Biomarkers, Pharmacological; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human