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  • 1
    Abstract: PURPOSE: We elucidated the value of tumor-infiltrating lymphocytes (TIL) as an independent predictor for pathologic complete response (pCR) rate and as a prognostic marker for disease-free survival (DFS) in patients with HER2-positive breast cancer in the neoadjuvant setting. EXPERIMENTAL DESIGN: We evaluated stromal TILs in 498 HER2-positive breast cancer samples of the neoadjuvant GeparQuattro (G4) and GeparQuinto (G5) trials. Levels of TILs were determined as a continuous parameter per 10% increase and as lymphocyte-predominant breast cancer (LPBC; 〉/= 60% TILs), and correlated with pCR rate and DFS. RESULTS: In the complete cohort, HER2-positive LPBC cases had a significantly increased pCR rates compared with non-LPBC types. They were significant predictors for pCR in univariate (10% TILs: OR 1.12, P = 0.002; LPBC: OR 2.02, P = 0.002) and multivariate analyses (10% TILs: OR 1.1, P = 0.014; LPBC: OR 1.87, P = 0.009). This effect was also detectable in the trastuzumab-treated (10% TILs: OR 1.12, P = 0.018; LPBC: OR 2.08, P = 0.013) but not in the lapatinib-treated subgroup. We identified a low-risk (pCR/LPBC) and a high-risk group (no pCR/no LPBC) regarding DFS. In triple-positive breast cancer, TILs are of more prognostic relevance than pCR. CONCLUSIONS: We could demonstrate the predictive and prognostic impact of TILs in HER2-positive breast cancer in the neoadjuvant setting. In combination with pCR rate, TILs may help to stratify prognostic subgroups, thereby guiding future therapy decisions. Clin Cancer Res; 22(23); 5747-54. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 27189162
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  • 2
    Abstract: BACKGROUND: The PI3K/AKT pathway and phosphatase and tensin homolog (PTEN) aberrations are common in breast cancer. We investigated the correlation between phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), PTEN, p4EBP1 (phosphorylated E4 binding protein 1), and pathologic complete response (pCR) in patients receiving neoadjuvant therapy. EXPERIMENTAL DESIGN: We retrospectively evaluated PIK3CA, PTEN, and p4EBP1 protein expression in centrally HER2-positive patients (n = 181) who received epirubicin cyclophosphamide/trastuzumab followed by docetaxel/trastuzumab alone or concomitant/followed by capecitabine within the GeparQuattro study. PTEN was assessed using the automated quantitative immunofluorescence analysis and was analyzed as a dichotomic variable. p4EBP1 was assessed by immunohistochemistry and used as a continuous and dichotomic variable. RESULTS: p4EBP1 was available from 137, PTEN from 108, and PIK3CA genotype from 83 patients. Overall, the pCR rate in PTEN-low tumors was 27.6%, and in PTEN-high tumors, it was 57.1% (P = 0.010). pCR rates were not statistically different between PIK3CA wild-type and mutant (35% vs. 22%) or p4EBP1 IRS 〈/= 4 and IRS 〉 4 (39% vs. 33%). pCR rate was 57.1% (8/14) in PTEN-high/PIK3CA wild-type and decreased to 15.4% in PTEN-low/PIK3CA-mutant tumors (P = 0.023). In multivariable analysis adjusted for baseline parameters, PTEN independently predicted pCR in the following cohorts: overall [OR, 7.54; 95% confidence interval (CI), 2.03-28.06; P = 0.003], PIK3CA wild-type (OR, 23.81; 95% CI, 1.75-324.05; P = 0.017), p4EBP1 IRS 〉 4 (OR, 11.53; 95% CI, 1.84-72.24; P = 0.009), and hormone receptor-positive (OR, 40.91; 95% CI, 2.93-570.44; P = 0.006). p4EBP1 was independently predictive for pCR in PIK3CA wild-type tumors (OR, 0.14; 95% CI, 0.03-0.78; P = 0.025). CONCLUSIONS: The study showed the potential role of PIK3CA genotype, PTEN, and p4EBP in predicting pCR after anthracycline-taxane-based chemotherapy and anti-HER2 treatment. Clin Cancer Res; 22(11); 2675-83. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 26758558
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  • 3
    Abstract: Purpose: Constitutively active WNT signaling is a hallmark of colorectal cancers and a driver of malignant tumor progression. Therapeutic targeting of WNT signaling is difficult due to high pathway complexity and its role in tissue homeostasis. Here, we identify the transcription factor ADNP as a pharmacologically inducible repressor of WNT signaling in colon cancer.Experimental Design: We used transcriptomic, proteomic, and in situ analyses to identify ADNP expression in colorectal cancer and cell biology approaches to determine its function. We induced ADNP expression in colon cancer xenografts by low-dose ketamine in vivo Clinical associations were determined in a cohort of 221 human colorectal cancer cases.Results: ADNP was overexpressed in colon cancer cells with high WNT activity, where it acted as a WNT repressor. Silencing ADNP expression increased migration, invasion, and proliferation of colon cancer cells and accelerated tumor growth in xenografts in vivo Treatment with subnarcotic doses of ketamine induced ADNP expression, significantly inhibited tumor growth, and prolonged survival of tumor-bearing animals. In human patients with colon cancer, high ADNP expression was linked to good prognosis.Conclusions: Our findings indicate that ADNP is a tumor suppressor and promising prognostic marker, and that ketamine treatment with ADNP induction is a potential therapeutic approach that may add benefit to current treatment protocols for patients with colorectal cancer. Clin Cancer Res; 23(11); 2769-80. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 27903678
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  • 4
    Abstract: Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.Results: The FGFR inhibitor-resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment. Clin Cancer Res; 23(18); 5527-36. (c)2017 AACR.
    Type of Publication: Journal article published
    PubMed ID: 28630215
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  • 5
    Abstract: Purpose: Approximately 40% of all glioblastomas have amplified the EGFR gene, and about half of these tumors express the EGFRvIII variant. The prognostic role of EGFRvIII in EGFR-amplified glioblastoma patients and changes in EGFRvIII expression in recurrent versus primary glioblastomas remain controversial, but such data are highly relevant for EGFRvIII-targeted therapies.Experimental Design:EGFR-amplified glioblastomas from 106 patients were assessed for EGFRvIII positivity. Changes in EGFR amplification and EGFRvIII status from primary to recurrent glioblastomas were evaluated in 40 patients with EGFR-amplified tumors and 33 patients with EGFR-nonamplified tumors. EGFR single-nucleotide variants (SNV) were assessed in 27 patients. Data were correlated with outcome and validated in 150 glioblastoma patients from The Cancer Genome Atlas (TCGA) consortium.Results: Sixty of 106 EGFR-amplified glioblastomas were EGFRvIII-positive (56.6%). EGFRvIII positivity was not associated with different progression-free or overall survival. EGFRvIII status was unchanged at recurrence in 35 of 40 patients with EGFR-amplified primary tumors (87.5%). Four patients lost and one patient gained EGFRvIII positivity at recurrence. None of 33 EGFR-nonamplified glioblastomas acquired EGFR amplification or EGFRvIII at recurrence. EGFR SNVs were frequent in EGFR-amplified tumors, but were not linked to survival.Conclusions: EGFRvIII and EGFR SNVs are not prognostic in EGFR-amplified glioblastoma patients. EGFR amplification is retained in recurrent glioblastomas. Most EGFRvIII-positive glioblastomas maintain EGFRvIII positivity at recurrence. However, EGFRvIII expression may change in a subset of patients at recurrence, thus repeated biopsy with reassessment of EGFRvIII status is recommended for patients with recurrent glioblastoma to receive EGFRvIII-targeting agents. Clin Cancer Res; 23(22); 6846-55. (c)2017 AACR.
    Type of Publication: Journal article published
    PubMed ID: 28855349
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  • 6
    Abstract: PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis and poor therapeutic response to current chemotherapy regimens in unselected patient populations. Recently, it has been shown that PDAC may be stratified into functionally and therapeutically relevant molecular subgroups and that some of these subtypes can be recapitulated by immunohistochemistry for KRT81 (QM/squamous/basal like) and HNF1A (non-QM, overlap with exocrine/ADEX subtype). EXPERIMENTAL DESIGN: We validated the different outcome of the HNF1A / KRT81 PDAC subtypes in two independent cohorts of surgically treated patients and examined the treatment response to chemotherapy in a third cohort of unresectable patients. The first two cohorts included 262 and 130 patients, respectively, and the third independent cohort comprised advanced-stage PDAC patients who were either treated with FOLFIRINOX (64 patients) or Gemcitabine (61 patients). RESULTS: In both cohorts with resected PDAC the HNF1A-positive subtype showed the best, the KRT81-positive subtype the worst and the double negative subtype an intermediate survival (p 〈0.013 and 〈0.009, respectively). In the chemotherapy cohort the survival difference between the double negative and the HNF1A-positive subtype was lost, while the dismal prognosis of KRT81-positive PDAC patients was retained (p 〈0.021). Patients with a KRT81-positive subtype did not benefit from FOLFIRINOX-therapy, while those with HNF1A-positive tumors responded better compared to Gemcitabine-based treatment (p 〈0.038). CONCLUSIONS: Immunohistochemical stratification recapitulating molecular subtypes of PDAC using HNF1A and KRT81 is associated with significantly differing outcomes and responses to chemotherapy. These results may pave the way towards future pretherapeutic biomarker based stratification of PDAC patients.
    Type of Publication: Journal article published
    PubMed ID: 29101303
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  • 7
    Abstract: Purpose: Colorectal cancers are composed of phenotypically different tumor cell subpopulations within the same core genetic background. Here, we identify high expression of the TALE transcription factor PBX3 in tumor cells undergoing epithelial-mesenchymal transition (EMT), analyze PBX3 regulation, and determine clinical associations in colorectal cancer.Experimental design: We used transcriptomic and in situ analyses to identify PBX3 expression in colorectal cancer and cell biology approaches to determine its regulation and function. Clinical associations were analyzed in independent tissue collections and gene expression datasets of colorectal cancers with recorded follow-up data.Results: PBX3 was expressed in tumor cells with high WNT activity undergoing EMT at the leading tumor edge of colorectal cancers, whereas stromal cells were PBX3 negative. PBX3 expression was induced by WNT activation and by the EMT transcription factors SNAIL and ZEB1, whereas these effects were mediated indirectly through microRNA miR-200. PBX3 was required for a full EMT phenotype in colon cancer cells. On the protein level, PBX3 expression indicated poor cancer-specific and disease-free survival in a cohort of 244 UICC stage II colorectal cancers, and was associated with metastasis in a case-control collection consisting of 90 cases with or without distant metastasis. On the mRNA level, high PBX3 expression was strongly linked to poor disease-free survival.Conclusions: PBX3 is a novel indicator of EMT in colorectal cancer, part of an EMT regulatory network, and a promising prognostic predictor that may aid in therapeutic decision making for patients with colorectal cancer. Clin Cancer Res; 24(8); 1974-86. (c)2018 AACR.
    Type of Publication: Journal article published
    PubMed ID: 29391352
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  • 8
    Abstract: Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance.Experimental Design: Whole-transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance.Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer (n = 469, P = 0.0036 for DMFS; n = 561, P = 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n = 132, P = 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivoConclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis. Clin Cancer Res; 24(8); 1987-2001. (c)2018 AACR.
    Type of Publication: Journal article published
    PubMed ID: 29386221
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  • 9
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; tumor ; carcinoma ; Germany ; FOLLOW-UP ; GENE-EXPRESSION ; PROTEIN ; DIFFERENTIATION ; TUMORS ; LINES ; TIME ; PATIENT ; primary ; ANTIGEN ; BIOLOGY ; ASSOCIATION ; MOLECULE ; BREAST ; breast cancer ; BREAST-CANCER ; antibodies ; antibody ; IDENTIFICATION ; PROGRESSION ; immunohistochemistry ; MALIGNANCIES ; DESIGN ; OVARIAN-CANCER ; CARCINOMA-CELLS ; BREAST-CARCINOMA ; PARAMETERS ; MULTIVARIATE ; CARCINOMAS ; FOLLOW-UP TIME ; P-SELECTIN ; CD24 ; CELL MONOCLONAL-ANTIBODIES ; protein expression
    Abstract: Purpose: CD24 is expressed in hematological malignancies as well as in a large variety of solid tumors including breast cancer. We aimed to evaluate CD24 protein expression in breast cancer and to correlate to clinicopatbological data including patient survival.Experimental Design: Primary breast carcinomas (201) with a mean clinical follow-up time of 53 months were immunostained using a monoclonal CD24 antibody (Ab-2, clone 24C02). The staining was evaluated as negative versus positive for statistical analysis.Results: In invasive breast carcinomas, CD24 expression was observed in 84.6% of cases. In univariate survival analyses, a significant association of CD24 expression with shortened patient overall survival (5-year survival rate 91.9% versus 83.8%; P = 0.031; log rank test) and disease-free survival (5-year progression rate 88.3% versus 57.0%; P = 0.0008) was demonstrated. In multivariate analyses CD24, tumor grading and nodal status were significant prognostic parameters for shortened disease-free survival.Conclusions: Our data suggest that CD24 expression in primary breast cancer as detected by immunohistochemistry might be a new marker for a more aggressive breast cancer biology
    Type of Publication: Journal article published
    PubMed ID: 14581365
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  • 10
    Keywords: CANCER ; GROWTH ; SURVIVAL ; carcinoma ; KINASE ; MODEL ; PATHWAY ; PATHWAYS ; DISEASE ; GENE ; PROTEIN ; ACTIVATION ; BASE ; protein kinase ; PROTEIN-KINASE ; treatment ; ASSOCIATION ; FREQUENCY ; polymorphism ; SIGNAL ; FREQUENCIES ; ACID ; STAGE ; DESIGN ; MUTATION ; MELANOMA ; METASTATIC MELANOMA ; SWEDEN ; MUTATIONS ; PARAMETERS ; MULTIVARIATE ; MALIGNANT-MELANOMA ; CANCER-RESEARCH ; B-RAF ; BRAF ; HIGH-FREQUENCY ; KINASE PATHWAYS ; N-RAS
    Abstract: Purpose: The RAS-RAF-mitogen-activated protein kinase pathways mediate the cellular response to growth signals. In melanocytes, BRAF is involved in cAMP-dependent growth signals. Recently, activating mutations in the BRAF gene, were reported in a large proportion of melanomas. We have studied mutations in the BRAF gene and their association with clinical parameters. Experimental Design: We analyzed exons 1, 11, and 15 of the BRAF gene and exons 1 and 2 of the N-ras gene for mutations in 38 metastatic melanomas by PCR-single-strand conformation polymorphism and direct sequencing. Kaplan-Meier survival and multivariate analyses were used to correlate mutations with various clinical parameters. Results: Mutations in exon 15 of the BRAF gene were detected in 26 (68%) melanomas. In 25 cases, mutation involved the "hot spot" codon 600(2) of the BRAF gene. Three melanomas without a BRAF mutation carried amino acid substituting base changes at codon 61 of the N-ras gene. In a multivariate proportional hazard (Cox) model, BRAF mutation, along with the stage of metastatic melanomas, showed a statistically significant hazard ratio of 2.16 (95% confidence interval 1.02-4.59; chi(2) for the model 6.94, degrees of freedom 2, P = 0.03) for diminished duration of response to the treatment. In a Kaplan-Meier survival model, cases with BRAF mutation showed longer disease-free survival (median of 12 months) than cases without mutation (median of 5 months), although this association was not statistically significant (Log-rank test P = 0.13). Conclusions: Our results, besides confirming the high frequency of BRAF mutations in metastatic melanomas, also underline the potential importance of these mutations in disease outcome
    Type of Publication: Journal article published
    PubMed ID: 12960123
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