[show abstract][hide abstract] ABSTRACT: PURPOSE:
To assess the prognostic value of the PAM50 risk-of-recurrence (ROR) score on late distant recurrence (beyond 5 years after diagnosis and treatment) in a large cohort of postmenopausal, endocrine-responsive breast cancer patients.EXPERIMENTAL DESIGN: The PAM50 assay was performed on formalin-fixed paraffin-embedded whole-tumor sections of patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG-8). RNA expression levels of the PAM50 genes were determined centrally using the nCounter Dx Analysis System. Late distant recurrence-free survival (DRFS) was analyzed using Cox models adjusted for clinical and pathologic parameters.RESULTS: PAM50 analysis was successfully performed in 1,246 ABCSG-8 patients. PAM50 ROR score and ROR-based risk groups provided significant additional prognostic information with respect to late DRFS compared with a combined score of clinical factors alone (ROR score: ΔLRχ2 15.32, P < 0.001; ROR-based risk groups: ΔLRχ2 14.83, P < 0.001). Between years 5 and 15, we observed an absolute risk of distant recurrence of 2.4% in the low ROR-based risk group, as compared with 17.5% in the high ROR-based risk group. The DRFS differences according to the PAM50 ROR score were observed for both node-positive and node-negative disease.CONCLUSION: PAM50 ROR score and ROR-based risk groups can differentiate patients with breast cancer with respect to their risk for late distant recurrence beyond what can be achieved with established clinicopathologic risk factors.
Clinical Cancer Research 02/2014; · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background:To investigate the clinical utility of pretreatment plasma fibrinogen levels in malignant pleural mesothelioma (MPM) patients.Methods:A retrospective multicenter study was performed in histologically proven MPM patients. All fibrinogen levels were measured at the time of diagnosis and clinical data were retrospectively collected after approval of the corresponding ethics committees.Results:In total, 176 MPM patients (mean age: 63.5 years±10.4 years, 38 females and 138 males) were analysed. Most patients (n=154, 87.5%) had elevated (390 mg dl(-1)) plasma fibrinogen levels. When patients were grouped by median fibrinogen, patients with low level (627 mg dl(-1)) had significantly longer overall survival (OS) (19.1 months, confidence interval (CI) 14.5-23.7 months) when compared with those with high level (OS 8.5; CI 6.2-10.7 months). In multivariate survival analyses, fibrinogen was found to be an independent prognostic factor (hazard ratio 1.81, CI 1.23-2.65). Most interestingly, fibrinogen (cutoff 75th percentile per 750 mg dl(-1)) proved to be a predictive biomarker indicating treatment benefit achieved by surgery within multimodality therapy (interaction term: P=0.034). Accordingly, only patients below the 75th percentile benefit from surgery within multimodality therapy (31.3 vs 5.3 months OS).Conclusions:Fibrinogen is a novel independent prognostic biomarker in MPM. Most importantly, fibrinogen predicted treatment benefit achieved by surgery within multimodality therapy.British Journal of Cancer advance online publication, 16 January 2014; doi:10.1038/bjc.2013.815 www.bjcancer.com.
British Journal of Cancer 01/2014; · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Adjuvant cisplatin-based chemotherapy only marginally improves survival in patients with completely resected non-small-cell lung cancer (NSCLC). We have evaluated the predictive value of mutations in TP53, encoding the tumour suppressor p53, in the International Adjuvant Lung Cancer Trial (IALT), a randomized trial of adjuvant cisplatin-based chemotherapy against observation. TP53 (exons 4 to 8) was sequenced in 524 archived specimens of IALT patients with a median follow-up of 7.5 years. Predictive analyses were based on Cox models adjusted for clinical and pathological variables. P-values ≤ 0.01 were considered as significant. Mutations were detected in 221 patients (42%) and had no predictive value for the effect of chemotherapy (interaction between TP53 and treatment: p=0.17 for Overall Survival (OS); p=0.06 for Disease-Free Interval, (DFS)). However, among patients with mutations, outcome appeared worse in treatment compared to observation arms (HR for OS= 1.36 (95%CI [0.97-1.31), p=0.08; DFS= 1.40 (95%CI [1.01-1.95]), p= 0.04). When grouping mutations into classes according to predicted effects on protein structure, the tendency towards worse outcomes was restricted to “structure” mutations affecting residues of the hydrophobic core that are not located at the p53 protein-DNA interface (HR for death in this class vs wild-type T53 = 1.66; 95% CI [1.10-2.52], p=0.02). Overall, TP53 mutations are not significant predictors of outcome in this trial of cisplatin-based chemotherapy, although a specific class of structural mutations may be associated with a tendency towards worse outcomes upon treatment.
[show abstract][hide abstract] ABSTRACT: Surgical excision of colorectal cancer at early clinical stages is highly effective, but 20-30% of patients relapse. Therefore, it is of clinical relevance to identify patients at high risk for recurrence, who would benefit from adjuvant chemotherapy. The objective of this study was to identify prognostic and/or predictive methylation markers in stage II colorectal cancer patients. Therefore, we selected six gene promoters (FZD9, PCDH10 (protocadherin 10), SFRP2, SPARC (secreted protein acidic and rich in cysteine), UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), and WIF1) for methylation analysis in formalin-fixed, paraffin-embedded primary tumor samples of colorectal cancer patients (n=143) who were enrolled in a prospective randomized phase III trial of the Austrian Breast and Colorectal cancer Study Group. Patients were randomized to adjuvant chemotherapy with 5-fluorouracil and leucovorin or surveillance only. Survival analyses revealed that combined evaluation of three promoters (PCDH10, SPARC, and UCHL1) showed differential effects with regard to disease-free survival and overall survival in the two treatment groups (significance level 0.007). In the chemotherapy arm, a statistically insignificant trend for patients without methylation toward longer survival was observed (P=0.069 for disease-free survival and P=0.139 for overall survival). Contrary, patients in the surveillance arm without methylation in their gene promoters had shorter disease-free survival and overall survival (P=0.031 for disease-free survival and P=0.003 for overall survival), indicating a prognostic effect of methylation in this group (test for interaction, P=0.006 for disease-free survival and P=0.018 for overall survival). These results indicate that promoter methylation status of PCDH10, SPARC, and UCHL1 may be used both as prognostic and predictive molecular marker for colorectal cancer patients and, therefore, may facilitate treatment decisions for stage II colorectal cancer.Modern Pathology advance online publication, 6 December 2013; doi:10.1038/modpathol.2013.204.
[show abstract][hide abstract] ABSTRACT: Background:ER+/HER2- breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy.Methods:A total of 1702 postmenopausal ER+/HER2- breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan-Meier method and Cox regression analysis were used in an early (0-5 years) and late time interval (>5 years post diagnosis).Results:EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up.Conclusion:The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.British Journal of Cancer advance online publication, 24 October 2013; doi:10.1038/bjc.2013.671 www.bjcancer.com.
British Journal of Cancer 10/2013; · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: CALGB 9633 was a randomized trial of observation versus adjuvant chemotherapy for patients with stage IB non-small cell lung cancer (NSCLC). In CALGB 9633, the presence of mucin in the primary tumor was associated with shorter disease-free survival (DFS; hazard ratio (HR)=19, p=0.002) and overall survival (OS; HR=19, p=0.004).
To validate these results, mucin staining was performed on primary tumor specimens from 780 patients treated on IALT, 351 on JBR.10 and 150 on ANITA. The histochemical technique using mucicarmine was performed. The prognostic value of mucin for DFS and OS was tested in a Cox model stratified by trial and adjusted for clinical and pathological factors. A pooled analysis of all 4 trials was performed for the predictive value of mucin for benefit from adjuvant chemotherapy.
The cross-validation group had 48% squamous, 37% adenocarcinoma and 15% other NSCLC compared with 29%, 56%, and 15%, respectively in CALGB. Among 1262 patients with assessable results, mucin was positive in IALT 24%, JBR.10 30%, ANITA 22% compared with 45% in CALGB. Histology was the only significant covariate (p<0.0001) in multivariate analysis with mucin seen more commonly in adenocarcinoma (56%) compared with squamous (5%) and other NSCLC (15%). Mucin was a borderline negative prognostic factor for DFS (HR=12 [10-15], p=0.06) but not significantly so for OS (HR=11 [0.9-14], p=0.25). Prognostic value did not vary according to histology: HR=13 [10-16] in adenocarcinoma vs. 16 [12-22] for DFS in other histology (interaction p=0.69). Mucin status was not predictive for benefit from adjuvant chemotherapy (test of interaction: DFS p=0.27; OS p=0.49).
Mucin was less frequent in the cross-validation group due to its higher percentage of squamous cell carcinomas. The negative impact of mucin was confirmed for DFS but not for OS. Mucin expression was not predictive of overall survival benefit from adjuvant chemotherapy.
Lung cancer (Amsterdam, Netherlands) 08/2013; · 3.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: The enzyme uridine diphospho glucuronosyltansferase 2B17 (UGT2B17) glucuronidates several endogenous and exogenous compounds, including carcinogens from tobacco smoke like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanl (NNAL). UGT2B17 shows a remarkable copy number variation (CNV) and an association between deletion genotype and increased risk of lung adenocarcinoma in women has been previously reported. Methods: We investigated the UGT2B17 CNV by PCR in 453 Austrian lung cancer patients and in 449 healthy donors and analyzed the impact on lung cancer susceptibility and outcome. Results: Copy numbers of UGT2B17 were 44.4% (+/+), 42.2% (+/-) and 13.5% (-/-) in lung cancer patients and 43.0% (+/+), 46.3% (+/-) and 10.7% (-/-) among healthy donors. The null genotype was not significantly more frequent among women with adenocarcinoma compared to healthy women (p=0.59). There was no association with overall survival (p=0.622) and no significant sex-associated (p=0.423) or histology-related impact on development of lung cancer. Conclusion: UGT2B17 deletion genotype was not associated with a significant risk for lung cancer development or outcome in our Central European patient cohort. Our study indicates that UGT2B17 is not a crucial factor in lung carcinogenesis among Caucasians and shows the importance of investigating such markers in large cohorts from different populations.
[show abstract][hide abstract] ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer-related death. Most patients present with an advanced stage of disease that has a dismal outcome, with a median survival of approximately 6 months. Evidently, there is a clear need for the development of new agents with novel mechanisms of action in this disease. A number of biological agents modulating different signal transduction pathways are currently in clinical development, inhibiting angiogenesis and targeting epidermal growth factor receptor, cell cycle, matrix metalloproteinases, cyclooxygenase-2, mammalian target of rapamycin, or proteasome. This is the first systematic review of the literature to synthesize all available data coming from trials and evaluate the efficacy and safety of molecular targeted drugs in unresectable and metastatic pancreatic cancer. However, it should be stressed that although multiple agents have been tested, only 9 phase 3 trials have been conducted and one agent (erlotinib) has been approved by the Food and Drug Administration for use in clinical practice. As knowledge accumulates on the molecular mechanisms underlying carcinogenesis in the pancreas, the anticipated development and assessment of molecularly targeted agents may offer a promising perspective for a disease which, to date, remains incurable.
[show abstract][hide abstract] ABSTRACT: Pertuzumab is a monoclonal antibody that represents the first among a new class of agents known as human epidermal growth factor receptor (HER) dimerization inhibitors. This is the first systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to synthesize all available data of pertuzumab in breast cancer. The search strategy retrieved 11 studies that evaluated pertuzumab. One study was conducted in the neoadjuvant setting (417 patients), whereas all the others dealt with patients with recurrent, metastatic, or refractory disease (1023 patients). Six studies were conducted in HER2(+) breast cancer population (1354 patients), whereas 5 studies (86 patients) were conducted in HER2(-) (or unknown HER2 status) disease. Pertuzumab is the most recent agent approved by the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patients with HER2(+) metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. This approval has been based on data from a phase III Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study. The antitumor activity with the significant reduction in the risk of progression or death, as reflected upon the increase of 6.1 months in median progression-free survival, indicates that pertuzumab may provide an avenue for achieving additional benefit for patients with HER2(+). Moreover, pertuzumab seems to have a putative role in the management of patients with HER2 who are resistant to trastuzumab. The promising role of pertuzumab in the neoadjuvant and adjuvant settings remains to be further investigated and established in the future.
Clinical Breast Cancer 06/2013; · 2.42 Impact Factor
[show abstract][hide abstract] ABSTRACT: PURPOSEWe undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non-small-cell lung cancer (NSCLC). METHODSKRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model. RESULTS: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02). CONCLUSIONKRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT.
Journal of Clinical Oncology 04/2013; · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation.
We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage.
We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance.
Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).
New England Journal of Medicine 03/2013; 368(12):1101-10. · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background:The mesenchymal-epithelial transition (MET) pathway is frequently altered in tumours. The purpose of our study was to determine the prognostic value of tumour MET expression levels in patients with triple-negative breast cancer (TNBC), in order to strengthen the rationale for targeted therapy of TNBC using MET inhibitors.Methods:We determined expression of MET in formalin-fixed paraffin-embedded surgical specimens of TNBC by immunohistochemistry. Recurrence-free and overall survival was analysed with Cox models adjusted for clinical and pathological factors.Results:Immunostaining for MET was classified as high in 89 of 170 (52%) tumours. MET expression was more frequently observed in G3 carcinomas (P=0.02) but was not significantly associated to any of the other clinical or pathological parameters. High MET expression predicted shorter survival of the patients. Multivariate Cox proportional hazards regression analyses identified MET to be an independent prognostic factor for recurrence (adjusted hazard ratio (HR) for recurrence 3.43; 95% confidence interval (CI) 1.65-7.12; P=0.001) and death (adjusted HR for death 3.74; 95% CI 1.65-8.46; P=0.002).Conclusion:These results provide further evidence that the MET pathway could be exploited as a target for TNBC.British Journal of Cancer advance online publication, 19 February 2013; doi:10.1038/bjc.2013.31 www.bjcancer.com.
British Journal of Cancer 02/2013; · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Evaluation of DNA repair proteins might provide meaningful information in relation to prognosis and chemotherapy efficacy in Non-Small Cell Lung Cancer (NSCLC) patients. The role of Poly(ADP-Ribose) Polymerase (PARP) in DNA repair of platinum adducts has not been firmly established. We used a DNA repair functional test based on antibody recognition of cisplatin intrastrand platinum adducts on DNA. We evaluated the effect of PARP inhibition on DNA repair functionality in a panel of cisplatin cell lines treated by the clinical-grade pharmacological inhibitor CEP8983 (a 4-methoxy-carbazole derivate) and the commercially available inhibitor PJ34 (phenanthridinone). We determined PARP1 protein expression in whole tumor sections from the International Adjuvant Lung cancer Trial (IALT)-bio study and tested a 3-marker PARP1/MSH2/ERCC1 algorithm combining PARP1 tumor status with previously published data. Chemosensitivity of cisplatin in NSCLC cell lines was correlated with the accumulation of cisplatin DNA adducts (P=0.0004). Further, the pharmacological inhibition of PARP induced a 1.7 to 2.3-fold increase in platinum adduct accumulation (24h) in A549 cell line suggesting a slow-down of platinum DNA-adduct repair capacity. In parallel, PARP1 inhibition increased the sensitivity to cisplatin treatment. In patient samples, PARP1 expression levels did not influence patient survival or the effect of platinum-based post-operative chemotherapy in the global IALT-bio population (interaction P=0.79). Among cases with high expression of all three markers (triple positive), untreated patients had prolonged survival with a median DFS of 7.8 years, (HR=0.34, 95%CI [0.19-0.61], adjusted P=0.0003) compared to triple negative patients (1.4 years). Remarkably, triple positive patients suffered from a detrimental effect (4.9-year reduction of median DFS) by post-operative cisplatin-based chemotherapy (HR=1.79, 95%CI [1.01-3.17], adjusted P=0.04, chemotherapy vs. control). Combinatorial sub-group analysis of the 3 markers further suggested that PARP1 tumor positivity might constitute a molecular context with high theranostic interest of ERCC1 and MSH2 in NSCLC. In conclusion, our data confirm that platinum DNA adduct accumulation is linked to chemosensitivity, which increase by pharmacological PARP inhibitors points to a role of PARP-dependent DNA repair in the process. We further suggest DNA repair biomarkers should be analyzed in a larger context of multiple DNA repair pathway regulation.
Lung cancer (Amsterdam, Netherlands) 02/2013; · 3.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background
We critically evaluated the available evidence on genomic tests in breast cancer to define their prognostic ability and likelihood to determine treatment benefit.DesignIndependent evaluation of six genomic tests [Oncotype Dx™, MammaPrint(®), Genomic Grade Index, PAM50 (ROR-S), Breast Cancer Index, and EndoPredict] was carried out by a panel of experts in three parameters: analytical validity, clinical validity, and clinical utility based on the principles of the EGAPP criteria.Panel statementsThe majority of the working group members found the available evidence on the analytical and clinical validity of Oncotype Dx™ and MammaPrint(®) to be convincing. None of the genomic tests demonstrated robust evidence of clinical utility: it was not clear from the current evidence that modifying treatment decisions based on the results of a given genomic test could result in improving clinical outcome.Conclusions
The IMPAKT 2012 Working Group proposed the following recommendations: (i) a need to develop models that integrate clinicopathologic factors along with genomic tests; (ii) demonstration of clinical utility should be made in the context of a prospective randomized trial; and (iii) the creation of registries for patients who are subjected to genomic testing in the daily practice.
[show abstract][hide abstract] ABSTRACT: Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (1, KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (2, KP1339) are promising redox-active anticancer drug candidates which were investigated with X-ray absorption near edge structure spectroscopy. The analysis was based on the concept of the coordination charge and ruthenium model compounds representing possible coordinations and oxidation states in vivo. 1 was investigated in citrate saline buffer (pH 3.5) and in carbonate buffer (pH 7.4) at 37°C for different time intervals. Interaction studies on 1 with glutathione in saline buffer and apo-transferrin in carbonate buffer were undertaken and the coordination of 1 and 2 in tumor tissues was studied too. The most likely coordinations and oxidation states of the compound under the before mentioned conditions were assigned. Microprobe X-ray fluorescence of tumor thin sections showed the strong penetration of the ruthenium into the tumor tissue, with the highest concentrations near blood vessels and in the edge regions of the tissue samples.
Journal of Medicinal Chemistry 01/2013; · 5.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Overexpression of () is associated with aggressive disease in acute myeloid leukemia (AML). Despite of its clinical importance, little is known about the mechanism through which confers resistance to antileukemic drugs. Here, we show that a human myeloid cell line constitutively overexpressing after infection with a retroviral vector (U937_EVI1) was partially resistant to etoposide and daunorubicin as compared to empty vector infected control cells (U937_vec). Similarly, inducible expression of in HL-60 cells decreased their sensitivity to daunorubicin. Gene expression microarray analyses of U937_EVI1 and U937_vec cells cultured in the absence or presence of etoposide showed that 77 and 419 genes were regulated by and etoposide, respectively. Notably, mRNA levels of 26 of these genes were altered by both stimuli, indicating that regulated genes were strongly enriched among etoposide regulated genes and vice versa. One of the genes that were induced by both and etoposide was , which in addition to its function as a cell cycle regulator plays an important role in conferring chemotherapy resistance in various tumor types. Indeed, overexpression of in U937 cells mimicked the phenotype of overexpression, similarly conferring partial resistance to antileukemic drugs.
PLoS ONE 01/2013; 8(2):e56308. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Controversy exists regarding CYP2D6 genotype and tamoxifen efficacy. Methods: A matched case-control study was conducted utilizing the Austrian Breast and Colorectal Cancer Study Group Trial 8 that randomized post-menopausal women with estrogen receptor positive breast cancer to tamoxifen for 5 years (Arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (Arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and TNM stage. Genotyping was performed for alleles associated with no (PM; *3, *4, *6); reduced (IM; *10, and *41); and extensive (EM: absence of these alleles) CYP2D6 metabolism. Findings: The common CYP2D6 *4 allele was in Hardy Weinberg Equilibrium. In Arm A during the first 5 years of therapy, women with 2 poor alleles (PM/PM: OR=2.45, 95% CI: 1.05-5.73, p=0.04) and women with one poor allele (PM/IM or PM/EM: OR=1.67, 95% CI: 0.95-2.93, p=0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3-5 when patients remained on tamoxifen (Arm A) or switched to anastrozole (Arm B), PM/PM tended towards a higher likelihood of a disease event relative to EM/EM (OR= 2.40, 95% CI: 0.86-6.66, p=0.09) among women on Arm A but not among women on Arm B (OR= 0.28; 95% CI: 0.03-2.30). CONCLUSION: In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration, and not after switching to anastrozole.
Clinical Cancer Research 12/2012; · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: PI3K/AKT/mTOR pathway is a crucial mediator of tumor progression. As the PI3K/Akt pathway is heavily deregulated in breast cancer, the application of mTOR inhibitors in breast cancer patients seems warranted. This is the first systematic review according to PRISMA guidelines to synthesize all available data of mTOR inhibitors in all subcategories of breast cancer. The search strategy retrieved 16 studies evaluating everolimus (1492 patients), seven studies examining temsirolimus (1245 patients), one study evaluating sirolimus (400 patients) and two studies evaluating MKC-1 (60 patients). The Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study has marked a turning point in the evaluation of everolimus in the treatment of estrogen receptor positive breast cancer. Given the positive results, everolimus has entered NCCN 2012 guidelines, and its approval of its combination with exemestane by FDA and EMA is imminent. In addition, the promising antitumor activity and long-term disease control further suggest that mTOR inhibition with everolimus may provide an avenue for achieving long-lasting benefit from trastuzumab-based therapy in HER2-positive patients. Regarding temsirolimus, it seems that the agent may play, in the future, a role in the treatment of metastatic breast cancer; importantly, however, there is an unmet need to find its optimal target subpopulation.