Topo2α protein expression predicts response to anthracycline combination neo-adjuvant chemotherapy in locally advanced primary breast cancer.
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ABSTRACT: Background
this study aimed to identify predictors of response to anthracycline-based chemotherapy (5-fluoro-uracil, epirubicin, cyclophosphamide (FEC)) in locally advanced primary breast cancer (LAPC).Methods
a total of 91 LAPC patients were treated with six cycles of FEC before surgery. Protein expression of nine biomarkers (topoisomerase2α (Topo2α), ER, PR, HER2, Ki67, p53, EGFR, CK5/6 and CK14) was assessed in pre-chemotherapy core biopsies using immunohistochemistry (IHC) and results correlated with clinical and pathological response.Results
clinical (cCR) and pathological (pCR) complete response were seen in 34.1% (n=31) and 20% (n=18), respectively. Pathological complete response was concordant with cCR in 14/31 cases; in four cases of cPR with palpable residual breast tumours, histology showed fibrous tissue only (pCR). On univariate analysis, pre-chemotherapy high expression of Topo2α protein (P=0.031), and negativity for ER and EGFR (P=0.001 and P=0.005, respectively) correlated with pCR. Positivity for p53 also showed significance (P=0.015), whereas basal phenotype, HER2, and all the clinicopathological variables of LAPC included in this study did not show significant correlation with response. On multivariate analysis, Topo2α expression had the strongest correlation with pCR (P=0.021) followed by EGFR (P=0.044).Conclusion
the study suggests that pre-chemotherapy Topo2α protein expression measured by IHC strongly correlates with pathological CR to neo-adjuvant anthracyclines in this group of LAPC studied.
SUBMITTER: Mukherjee A
PROVIDER: S-EPMC3008601 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionMicroRNAs (miRNAs) are small non-coding RNA that plays a vital role in cancer progression. Neo-adjuvant chemotherapy (NAC) has become the standard of care for locally advanced breast cancer. The aim of this study was to evaluate miRNA alterations during NAC using multiple samples of tissue and serum to correlate miRNA expression with clinico-pathological features and patient outcomes.MethodsTissue and serum samples were collected from patients with locally advanced breast cancer undergoing NAC at four time points: time of diagnosis, after the first and fourth cycle of doxorubicin/cyclophosphamide treatment, and after the fourth cycle of docetaxel administration. First, we evaluated the miRNA expression profiles in tissue and correlated expression with clinico-pathological features. Then, a panel of four miRNAs (miR-451, miR-3200, miR-21, and miR-205) in serum samples was further validated using quantitative reverse-transcription polymerase chain reaction (RT-qPCR). The alterations in serum levels of miRNA, associations with clinical and pathological responses, correlation with clinico-pathological features, and survival outcomes were studied using Friedman, Mann-Whitney U, and Spearman, Wilcoxon signed-ranks tests. P≤0.05 was considered statistically significant.ResultsWe analyzed 72 tissue samples and 108 serum samples from 9 patients and 27 patients, respectively. MicroRNA expression profiling of tumor versus normal tissue revealed more than 100 differentially expressed miRNAs. Serum miR-451 levels were significantly decreased during treatment, and higher serum levels were associated with improved clinical and pathological responses and disease-free survival. This is one of the early reports on miR-3200 in response to treatment in breast cancer, as serum levels of miR-3200 found to decline during NAC, and higher serum levels were associated with lower residual breast cancer burden and relapse rates at time of diagnosis.ConclusionVariations in serum miRNA levels during NAC treatment may be therapeutically significant for predicting response and survival outcomes.
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Project description:PurposeThe role of zoledronic acid (ZOL), a bone-targeted bisphosphonate, in the treatment of patients with breast cancer remains an active area of study. Here, we report the long-term outcomes of a randomized placebo-controlled phase II clinical trial in which ZOL treatment was added to neoadjuvant chemotherapy in women with locally advanced breast cancer.Methods120 women with clinical stage II-III (≥ T2 and/or ≥ N1) newly diagnosed breast cancer were randomized to receive either 4 mg intravenous ZOL every 3 weeks for 1 year (17 total doses) beginning with the first dose of neoadjuvant chemotherapy, or chemotherapy alone. Clinical endpoints included time to recurrence (TTR), time to bone recurrence (TTBR), time to non-bone recurrence (TTNBR), breast cancer survival (BCS) and overall survival (OS).ResultsWith a median follow-up interval of 14.4 years, there were no significant differences in any of the clinical endpoints studied between the control and ZOL groups in the overall study population. However, ER+/HER2- patients younger than age 45 who were treated with ZOL had significantly worse TTR and TTNBR with a trend towards worse TTBR, BCS and OS (TTR: P = 0.024, HR 6.05 [1.26-29.1]; TTNBR: P = 0.026, HR 6.94 [1.26-38.1]; TTBR: P = 0.054, HR 6.01 [0.97-37.1]; BCS: P = 0.138, HR 4.43 [0.62-31.7]; OS: P = 0.138, HR 4.43 [0.62-31.7]). These differences were not seen in older ER+/HER2- patients or triple-negative patients of any age.ConclusionAddition of ZOL to neoadjuvant therapy did not significantly affect clinical outcomes in the overall study population but was associated with increased extra-skeletal recurrence and a trend towards worse survival in ER+/HER2- patients younger than age 45. These findings suggest caution when using zoledronic acid in young, premenopausal women with locally advanced breast cancer and warrant further investigation. Clinical Trial Registration Number NCT00242203, Date of Registration: 10/17/2005.
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Project description:Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer.Patients with rectal cancer with high risk features for local or systemic failure on magnetic resonance imaging are randomized to either a standard arm or an experimental arm. The standard arm consists of chemoradiation (1.8 Gy x 25 or 2 Gy x 25 with capecitabine) preoperatively, followed by selective postoperative adjuvant chemotherapy. Postoperative chemotherapy is optional and may be omitted by participating institutions. The experimental arm includes short-course radiotherapy (5 Gy x 5) followed by full-dose chemotherapy (capecitabine and oxaliplatin) in 6 cycles before surgery. In the experimental arm, no postoperative chemotherapy is prescribed. Surgery is performed according to TME principles in both study arms. The hypothesis is that short-course radiotherapy with neo-adjuvant chemotherapy increases disease-free and overall survival without compromising local control. Primary end-point is disease-free survival at 3 years. Secondary endpoints include overall survival, local control, toxicity profile, and treatment completion rate, rate of pathological complete response and microscopically radical resection, and quality of life.Following the advances in rectal cancer management, increased focus on survival rather than only on local control is now justified. In an experimental arm, short-course radiotherapy is combined with full-dose chemotherapy preoperatively, an alternative that offers advantages compared to concomitant chemoradiotherapy with or without postoperative chemotherapy. In a multi-centre setting this regimen is compared to current standard with the aim of improving survival for patients with locally advanced rectal cancer.ClinicalTrials.gov NCT01558921.
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Project description:Introduction: MicroRNAs (miRNAs) are small non-coding RNA that play a vital role in cancer progression. Neo-adjuvant chemotherapy (NAC) has become the standard of care for locally advanced breast cancer. The aim of this study was to evaluate miRNA alterations during NAC using multiple samples of tissue and serum to correlate miRNA expression with clinico-pathological features and patient outcomes. Methods: Tissue and serum samples were collected from patients with locally advanced breast cancer undergoing NAC at four time points: time of diagnosis, after the first and fourth cycle of doxorubicin/cyclophosphamide treatment, and after the fourth cycle of docetaxel administration. First, we evaluated the miRNA expression profiles in tissue and correlated expression with clinico-pathological features. Then, a panel of four miRNAs (miR-451, miR-3200, miR-21, and miR-205) in serum samples was further validated using quantitative reverse-transcription polymerase chain reaction (RT-qPCR). The alterations in serum levels of miRNA, associations with clinical and pathological responses, correlation with clinico-pathological features, and survival outcomes were studied using Friedman, Mann-Whitney U, Spearman, Wilcoxon signed-ranks tests. Pâ¤0.05 was considered statistically significant. Results: We analyzed 32 tissue samples and 108 serum samples from 8 patients and 27 patients, respectively. MicroRNA expression profiling of tumor versus normal tissue revealed more than 100 differentially expressed miRNAs. Serum miR-451 levels were significantly decreased during treatment, and higher serum levels were associated with improved clinical and pathological responses and disease-free survival. The serum levels of miR-3200 declined during NAC, and higher serum levels were associated with lower residual breast cancer burden and relapse rates. Conclusion: Variations in serum miRNA levels during NAC treatment may be therapeutically significant for predicting response and survival outcomes. Serum and tissue from a total of 27 consecutive patients diagnosed with locally advanced breast cancer undergoing NAC treatment were collected however microarray data were generated from tissue biopsy of 5 patients at four timepoints for both Normal and tumor. Additionally 3 tissue from only tumor at four timepoints and 6 patients at two timepoint T1 and T4
2015-10-31 | E-GEOD-70754 | biostudies-arrayexpress
Project description:Introduction: MicroRNAs (miRNAs) are small non-coding RNA that play a vital role in cancer progression. Neo-adjuvant chemotherapy (NAC) has become the standard of care for locally advanced breast cancer. The aim of this study was to evaluate miRNA alterations during NAC using multiple samples of tissue and serum to correlate miRNA expression with clinico-pathological features and patient outcomes. Methods: Tissue and serum samples were collected from patients with locally advanced breast cancer undergoing NAC at four time points: time of diagnosis, after the first and fourth cycle of doxorubicin/cyclophosphamide treatment, and after the fourth cycle of docetaxel administration. First, we evaluated the miRNA expression profiles in tissue and correlated expression with clinico-pathological features. Then, a panel of four miRNAs (miR-451, miR-3200, miR-21, and miR-205) in serum samples was further validated using quantitative reverse-transcription polymerase chain reaction (RT-qPCR). The alterations in serum levels of miRNA, associations with clinical and pathological responses, correlation with clinico-pathological features, and survival outcomes were studied using Friedman, Mann-Whitney U, Spearman, Wilcoxon signed-ranks tests. P≤0.05 was considered statistically significant. Results: We analyzed 32 tissue samples and 108 serum samples from 8 patients and 27 patients, respectively. MicroRNA expression profiling of tumor versus normal tissue revealed more than 100 differentially expressed miRNAs. Serum miR-451 levels were significantly decreased during treatment, and higher serum levels were associated with improved clinical and pathological responses and disease-free survival. The serum levels of miR-3200 declined during NAC, and higher serum levels were associated with lower residual breast cancer burden and relapse rates. Conclusion: Variations in serum miRNA levels during NAC treatment may be therapeutically significant for predicting response and survival outcomes.
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Project description:Triple-negative breast cancer (TNBC) constitutes a heterogeneous breast cancer subgroup with poor prognosis; survival rates are likely to be lower with TNBC compared to other breast cancer subgroups. For this disease, systemic adjuvant chemotherapy regimens often yield suboptimal clinical results. To improve treatment regimens in TNBC, identification of molecular biomarkers may help to select patients for individualized adjuvant therapy. Evidence has accumulated that determination of the methylation status of the PITX2 gene provides a predictive value in various breast cancer subgroups, either treated with endocrine-based therapy or anthracycline-containing chemotherapy. To further explore the validity of this novel predictive candidate biomarker, in the present exploratory retrospective study, determination of the PITX2 DNA-methylation status was assessed for non-metastatic TNBC patients treated with adjuvant anthracycline-based chemotherapy by molecular analysis of breast cancer tissues. The PITX2 DNA-methylation status was determined in fresh-frozen tumor tissue specimens (n=56) by methylation-specific qRT-PCR (qMSP) and the data related to disease-free and overall survival, applying an optimized DNA-methylation score of 6.35%. For non-metastatic TNBC patients treated with adjuvant systemic anthracycline-based chemotherapy, a low PITX2 DNA-methylation status (<6.35) defines TNBC patients with poor disease-free and overall survival. Univariate and multivariate analyses demonstrate the statistically independent predictive value of PITX2 DNA-methylation. For non-metastatic TNBC patients, selective determination of the PITX2 DNA-methylation status may serve as a cancer biomarker for predicting response to anthracycline-based adjuvant chemotherapy. The assay based on methylation of the PIXT2 gene can be applied to frozen and routinely available formalin-fixed, paraffin-embedded (FFPE) breast cancer tumor tissues that will not only define those TNBC patients who may benefit from anthracycline-based chemotherapy but also those who should be spared the necessity of such potentially toxic treatment. Such patients should be allocated to alternative treatment options.
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Project description:Breast cancer is characterized by considerable metabolic diversity. A relatively high percentage of patients diagnosed with breast carcinoma do not respond to standard-of-care treatment, and alteration in metabolic pathways nowadays is considered one of the major mechanisms responsible for therapeutic resistance. Consequently, there is an emerging need to understand how metabolism shapes therapy response, therapy resistance and not ultimately to analyze the metabolic changes occurring after different treatment regimens. The most commonly applied neoadjuvant chemotherapy regimens in breast cancer contain an anthracycline (doxorubicin or epirubicin) in combination or sequentially administered with taxanes (paclitaxel or docetaxel). Despite several efforts, drug resistance is still frequent in many types of breast cancer, decreasing patients' survival. Understanding how tumor cells rapidly rewire their signaling pathways to persist after neoadjuvant cancer treatment have to be analyzed in detail and in a more complex system to enable scientists to design novel treatment strategies that target different aspects of tumor cells and tumor resistance. Tumor heterogeneity, the rapidly changing environmental context, differences in nutrient use among different cell types, the cooperative or competitive relationships between cells pose additional challenges in profound analyzes of metabolic changes in different breast carcinoma subtypes and treatment protocols. Delineating the contribution of metabolic pathways to tumor differentiation, progression, and resistance to different drugs is also the focus of research. The present review discusses the changes in glucose and fatty acid pathways associated with the most frequently applied chemotherapeutic drugs in breast cancer, as well the underlying molecular mechanisms and corresponding novel therapeutic strategies.
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Project description:BackgroundStage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence.MethodsIn this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life.ResultsOf the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group.ConclusionsChemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.).
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