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Von Minckwitz G.,German Breast Group GBG Forschungs GmbH
Oncology (Williston Park, N.Y.) | Year: 2012

Neoadjuvant treatment with a sequential anthracycline-taxane-based chemotherapy in combination with trastuzumab (Herceptin) is currently a preferred therapy for patients with HER2-positive breast cancer. This approach is based on the higher pathologic complete response (pCR) of 40% seen with the addition of trastuzumab, compared with a 17% pCR with chemotherapy alone. The pCR can be increased to 75% with dual HER2-receptor blockade and chemotherapy. Higher pCR rates are found in hormone-receptor-negative tumors. Patients with a pCR after chemotherapy and trastuzumab showed a significantly better outcome compared with those who did not have a pCR. The need for additional or alternate treatment options is great in patients who do not achieve a pCR. Addition of lapatinib (Tykerb) or pertuzumab (Omnitarg) to trastuzumab is a therapeutic option. Recent findings suggest pCR might not be the appropriate surrogate for long-term outcome in patients with hormone receptor-positive and HER2-positive tumors. Source

Darb-Esfahani S.,Charite - Medical University of Berlin | Kronenwett R.,Sividon Diagnostics | Kronenwett R.,Heinrich Heine University Dusseldorf | Von Minckwitz G.,German Breast Group GBG Forschungs GmbH | And 14 more authors.
British Journal of Cancer | Year: 2012

Background:Biomarkers predictive of pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) of breast cancer are urgently needed.Methods:Using a training/validation approach for detection of predictive biomarkers in HER2-negative breast cancer, pre-therapeutic core biopsies from four independent cohorts were investigated: Gene array data were analysed in fresh frozen samples of two cohorts (n86 and n55). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed in formalin-fixed, paraffin-embedded (FFPE) samples from two neoadjuvant phase III trials (GeparTrio, n212, and GeparQuattro, n383).Results:A strong predictive capacity of thymosin beta 15 (TMSB15A) gene expression was evident in both fresh frozen cohorts (P0.0001; P0.0042). In the GeparTrio FFPE training cohort, a significant linear correlation between TMSB15A expression and pCR was apparent in triple-negative breast cancer (TNBC) (n61, P0.040). A cutoff point was then defined that divided TNBC into a low and a high expression group (pCR rate 16.0% vs 47.2%). Both linear correlation of TMSB15A mRNA levels (P0.017) and the pre-defined cutoff point were validated in 134 TNBC from GeparQuattro (pCR rate 36.8% vs 17.0%, P0.020). No significant predictive capacity was observed in luminal carcinomas from GeparTrio and GeparQuattro.Conclusion:In TNBC, TMSB15A gene expression analysis might help to select patients with a high chance for pCR after NACT. © 2012 Cancer Research UK. Source

Marme F.,University of Heidelberg | Marme F.,Universitats Frauenklinik Heidelberg | Lederer B.,German Breast Group GBG Forschungs GmbH | Blohmer J.-U.,Sankt Gertrauden Krankenhaus | And 15 more authors.
European Journal of Cancer | Year: 2016

Background Pathologic complete response after neoadjuvant chemotherapy (NACT) correlates with overall survival (OS) in primary breast cancer. A recently described staging system based on pre-treatment clinical stage (CS), final pathological stage (PS), estrogen receptor (ER) status and nuclear grade (NG) leads to a refined estimation of prognosis in unselected patients. Its performance in luminal type breast cancers has not been determined. This study investigates the clinical utility of this CPS + EG score when restricted to hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) patients and compares the results to a cohort of unselected patients. Methods The CPS + EG score was calculated for 6637 unselected patients and 2454 patients with HR + /HER2- tumours who received anthracycline/taxane-based NACT within 8 prospective German trials. Results Five-year disease-free survival (DFS) and OS were 75.6% and 84.1% for the unselected cohort and 80.6% and 87.8% for the HR + /HER2- subgroup, respectively. The CPS + EG system distinguished different prognostic groups with 5-year DFS ranging from 0% to 91%. The CPS + EG system leads to an improved categorisation of patients by outcome compared to CS, PS, ER or NG alone. When applying the CPS + EG score to the HR + /HER2- subgroup, a shift to lower scores was observed compared to the overall population, but 5-year DFS and OS for the individual scores were identical to that observed in the overall population. Conclusions In HR + /HER2- patients, the CPS + EG staging system retains its ability to facilitate a refined stratification of patients according to outcome. It can help to select candidates for post-neoadjuvant clinical trials in luminal breast cancer. © 2015 Elsevier Ltd. All rights reserved. Source

Darb-Esfahani S.,Charite - Medical University of Berlin | von Minckwitz G.,German Breast Group GBG Forschungs GmbH | von Minckwitz G.,University Womens Hospital | Denkert C.,Charite - Medical University of Berlin | And 12 more authors.
BMC Cancer | Year: 2014

Background: Gross cystic disease fluid protein 15 (GCDFP-15), which is regulated by the androgen receptor (AR), is a diagnostic marker for mammary differentiation in histopathology. We determined the expression of GCDFP-15 in breast cancer subtypes, its potential prognostic and predictive value, as well as its relationship to AR expression.Methods: 602 pre-therapeutic breast cancer core biopsies from the phase III randomized neoadjuvant GeparTrio trial (NCT00544765) were investigated for GCDFP-15 expression by immunohistochemistry. Expression data were correlated with disease-free (DFS) and overall survival (OS) time as well as pathological complete response (pCR) to neoadjuvant chemotherapy.Results: 239 tumors (39.7%) were GCDFP-15 positive. GCDFP-15 expression was positively linked to hormone receptor (HR) and HER2 positive tumor type, while most triple negative carcinomas were negative (p < 0.0001). GCDFP-15 was also strongly correlated to AR expression (p 0.001), and to the so-called molecular apocrine subtype (HR-/AR+, p < 0.0001). Higher rates of GCDFP-15 positivity were seen in tumors of lower grade (<0.0001) and negative nodal status (p = 0.008). GCDFP-15 positive tumors tended to have a more favourable prognosis than GCDFP-15 negative tumors (DFS (p = 0.052) and OS (p = 0.044)), which was not independent from other factors in multivariate analysis. GCDFP-15 expression was not linked to pCR. Histological apocrine differentiation was frequent in molecular apocrine carcinomas (60.7%), and was associated with GCDFP-15 within this group (p = 0.039).Conclusions: GCDFP-15 expression is higher in tumors with favorable prognostic features. GCDFP-15 expression is further a frequent feature of AR positive tumors and the molecular apocrine subtype. It might have reduced sensitivity as a diagnostic marker for mammary differentiation in triple negative tumors as compared to HR or HER2 positive tumor types. © 2014 Darb-Esfahani et al.; licensee BioMed Central Ltd. Source

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