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Prat A.,Vall dHebron Institute of Oncology | Prat A.,University of Barcelona | Bianchini G.,San Raffaele Cancer Center | Thomas M.,Roche Holding AG | And 14 more authors.
Clinical Cancer Research | Year: 2014

Purpose: We report a retrospective exploratory analysis of the association of the research-based prediction analysis of microarray 50 (PAM50) subtype predictor with pathologic complete response (pCR) and event-free survival (EFS) in women enrolled in the NeOAdjuvant Herceptin (NOAH) trial. Experimental Design: Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded core biopsies from 114 pretreated patients with HER2-positive (HER2+ ) tumors randomized to receive neoadjuvant doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/ fluorouracil (CMF), or the same regimen in combination with trastuzumab for one year. A control cohort of 42 patients with HER2-negative tumors treated with AT-CMF was also included. The PAM50 subtypes, the PAM50 proliferation score, and the PAM50 risk of relapse score based on subtype (RORS) and subtype and proliferation (RORP) were evaluated. Results: HER2-enriched (HER2-E) tumors predominated within HER2 + disease, although all PAM50 intrinsic subtypes were identified across the three cohorts. The OR for achieving pCR with trastuzumabbased chemotherapy for HER2+/HER2-E and HER2 +/RORP-high were 5.117 (P = 0.009) and 8.469 (P = 0.025), respectively, compared with chemotherapy only. The pCR rates of HER2+ /HER2-E and HER2 + / RORP-high after trastuzumab-based chemotherapy were 52.9% and 75.0%, respectively. A statistically nonsignificant trend was observed for more pronounced survival benefit with trastuzumab in patients with HER2+ /HER2-E and HER2 + /RORP-high tumors compared with patients with HER2+ /non-HER2-E and HER2 + /non-RORP-high tumors, respectively.Conclusions: As determined by EFS and pCR, patients with HER2 + /HER2-E tumors, or HER2 + / RORP-high tumors, benefit substantially from trastuzumab-based chemotherapy. The clinical value of this genomic test within HER2 + disease warrants further investigation. Clin Cancer Res; 20(2); 511-21. © 2014 American Association for Cancer Research.

Stern H.M.,Genentech | Stern H.M.,Infinity Pharmaceuticals Inc. | Gardner H.,Astrazeneca | Burzykowski T.,International Drug Development Institute | And 17 more authors.
Clinical Cancer Research | Year: 2015

Purpose: To investigate the clinical relevance of PTEN in HER2-amplified and HER2-nonamplified disease. Experimental Design: We assessed PTEN status in two large adjuvant breast cancer trials (BCIRG-006 and BCIRG-005) using a PTEN immunohistochemical (IHC) assay that was previously validated in a panel of 33 breast cancer cell lines and prostate cancer tissues with known PTEN gene deletion. Results: In the HER2-positive patient population, absence of tumor cell PTEN staining occurred at a rate of 5.4% and was independent of ER/PR status. In contrast, 15.9% of HER2-negative patients exhibited absence of PTEN staining with the highest frequency seen in triple-negative breast cancer (TNBC) subgroup versus ER/PR-positive patients (35.1% vs. 10.9%). Complete absence of PTEN staining in tumor cells was associated with poor clinical outcome in HER2-positive disease. Those patients whose cancers demonstrated absent PTEN staining had a significant decrease in disease-free survival (DFS) and overall survival (OS) compared with patients with tumors exhibiting any PTEN staining patterns (low,moderate, or high). Trastuzumab appeared to provide clinical benefit even for patients lacking PTEN staining. In the HER2-negative population, there were no statistically significant differences in clinical outcome based on PTEN status. Conclusions: This study is the largest to date examining PTEN status in breast cancer and the data suggest that the rate and significance of PTEN status differ between HER2-positive and HER2-negative disease. Furthermore, the data clearly suggest that HER2-positive patients with PTEN loss still benefit from trastuzumab. © 2015 AACR.

Von Minckwitz G.,C o GBG Forschungs GmbH | Von Minckwitz G.,Universitats Frauenklinik Frankfurt | Schmitt W.D.,Charite University Hospital | Loibl S.,C o GBG Forschungs GmbH | And 18 more authors.
Clinical Cancer Research | Year: 2013

Purpose: The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described. Experimental Design: Participants of the GeparTrio study with primary breast cancer randomly received neoadjuvant response-guided [8 cycles TAC (docetaxel/doxorubicin/cyclophosphamide) in responding and TAC-NX (vinorelbine/capecitabine) in nonresponding patients] or conventional (6 cycles TAC) chemotherapy according to interim response assessment. Ki-67 levels were centrally measured immunohistochemically after neoadjuvant treatment if tumor tissue was available. Here, we analyze 1,151 patients having a pathologic complete response (pCR; n, 484), or residual disease with low (0-15%), intermediate (15.1-35%), or high (35.1-100%) posttreatment Ki67 levels in 488, 77, and 102 patients, respectively. Results: Patients with high posttreatment Ki67 levels showed higher risk for disease relapse (P < 0.0001) and death (P < 0.0001) compared with patients with low or intermediate Ki67 levels. Patients with low Ki67 levels showed a comparable outcome to patients with a pCR (P = 0.211 for disease-free and P = 0.779 for overall survival). Posttreatment Ki67 levels provided more prognostic information than pretreatment Ki67 levels or changes of Ki67 from pre- to posttreatment. Information on pCR plus posttreatment Ki67 levels surmount the prognostic information of pCR alone in hormone-receptorpositive disease [hazard ratios (HR), 1.82-5.88] but not in hormone-receptor-negative disease (HR: 0.61-1.73). Patients with conventional and response-guided treatment did not show a different distribution of posttreatment Ki67 (P = 0.965). Conclusions: Posttreatment Ki67 levels provide prognostic information for patients with hormone-receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy. Levels were not prognostic for outcome after response-guided chemotherapy. High posttreatment Ki67 indicates the need for innovative postneoadjuvant treatments. © 2013 American Association for Cancer Research.

Huober J.,Brustzentrum Kantonsspital St. Gallen | Huober J.,University of Tubingen | Von Minckwitz G.,German Breast Group | Denkert C.,Charite - Medical University of Berlin | And 11 more authors.
Breast Cancer Research and Treatment | Year: 2010

In order to explore the effect of neoadjuvant chemotherapy (NACT) on clinical mid-course and pathological complete response (pCR) at surgery in different biological breast cancer subtypes. The GeparTrio study included 2,072 patients with operable or locally advanced breast cancer. After two cycles with docetaxel, doxorubicin and cyclophosphamide (TAC) patients were randomized according to their clinical response. Clinical and biological factors were assessed for predicting clinically mid-course response and pCR at surgery. The overall pCR rate, defined as no invasive residuals in breast and axilla, was 20.5%. The highest pCR rate of 57% was observed in patients below 40 years of age with triple negative or grade 3 tumors. Independent factors for mid-course response and pCR were: young age, non-T4 tumors, high grade, and hormone receptor status, the strongest single predictive factor. Within the biological subtypes, grading was an independent factor to predict pCR for luminal tumors, clinical tumor stage for the HER2 like tumors and age for the triple negative ones. Grading gave independent information for mid-course response within the triple negative group. No factor predicted mid-course response within the other groups. Grading and age can identify subgroups within the luminal and triple negative patients who have an increased benefit from NACT. © 2010 Springer Science+Business Media, LLC.

Meyer P.,University of Rostock | Landgraf K.,University of Rostock | Hogel B.,Red Cross | Eiermann W.,Frauenklinik Vom Roten Kreuz | Ataseven B.,Frauenklinik Vom Roten Kreuz
PLoS ONE | Year: 2012

Recently, BRCA1 germline mutations were found in a high proportion (14-34%) of patients with triple-negative breast cancer (TNBC). BRCA2 was either not analyzed or showed much lower mutation frequencies. Therefore, we screened a group of TNBC patients (n = 30) of white European descent for mutations in BRCA2 as well as in BRCA1. Cases were unselected for age of disease-onset (median age at breast cancer diagnosis was 58 years, ranging from 37 to 74 years), family history of cancer and BRCA1 and BRCA2 mutation status. Half of the patients (15/30) showed a family history of breast and/or ovarian cancer. A high frequency of deleterious germline mutations was observed in BRCA2 (5/30; 16.7%), and only one case showed a BRCA1 mutation (3.3%). Although the study group was small, these results point to BRCA2 mutations being important in TNBC. © 2012 Meyer et al.

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