Prognostic value of Bcl-2 in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy.
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ABSTRACT:
SUBMITTER: Vargas-Roig LM
PROVIDER: S-EPMC5527786 | biostudies-other | 2008 Jun
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Prevention of bone metastases is a major issue for breast cancer patients, as it would improve quality of life in a population where long survival is anticipated. PATIENTS AND METHODS:Early breast cancer patients, who had been treated with anthracycline-based chemotherapy within two randomized trials, were included in the study. We evaluated, by quantitative reverse transcription-polymerase chain reaction, 819 formalin-fixed paraffin-embedded tumor tissue samples for mRNA expression of RANK, OPG, and RANKL, as well as their ratios, for potential prognostic significance for the development of bone metastases and also for disease-free survival (DFS) and overall survival. RESULTS:Median age was 52.7years, whereas 54.2% of the patients were postmenopausal and 78.3% estrogen receptor/progesterone receptor positive. After a median follow-up of 119.9months, 226 patients (27.6%) had died and 291 patients (35.5%) had disease progression. Low mRNA expression of RANKL was associated with postmenopausal status and greater number of positive lymph nodes (P=.002 and P<.001, respectively). In the univariate analysis, low RANKL mRNA expression was found to be an unfavorable factor for DFS [hazard ratio (HR)=1.33, 95% confidence interval (CI) 1.05-1.68, Wald's P=.018] and bone metastasis-free survival (HR=1.67, 95% CI 1.09-2.56, P=.018), although it did not retain its significance in the multivariate analysis. CONCLUSIONS:Low RANKL mRNA expression in early breast cancer patients is of prognostic significance for increased risk for relapse and bone metastases and might potentially guide clinical decision-making for the use of anti-RANKL agents in the treatment of early breast cancer patients at high risk for metastatic spread, provided that our findings are validated in independent cohorts.
| S-EPMC5491451 | biostudies-literature
Project description:BackgroundTumor-infiltrating lymphocytes (TILs) have been shown to be of prognostic value in several cancer types. In early breast cancer, TILs have a prognostic utility, as well, especially in HER2-positive and triple-negative breast cancer. TILs presence is broadly associated with improved survival; however, there is controversy regarding TILs subpopulations.Patients and methodsEarly-stage breast cancer patients treated with anthracycline-based chemotherapy within two randomized trials were included in the study. We evaluated, by qRT-PCR, 826 tumor tissue samples for mRNA expression of CD3, CD8, and FOXP3 for potential prognostic significance in terms of disease-free survival (DFS) and overall survival (OS).ResultsAfter a median follow-up of 133.0 months, 255 patients (30.9%) had died and 314 (38.0%) had disease progression. In the univariate analysis, high CD3 and CD8 mRNA expression was found to be of favorable prognostic value for DFS (P = 0.007 and P = 0.016, respectively). In multivariate analyses, the association of high CD8 mRNA expression with increased DFS was retained (HR = 0.77, 95% CI 0.60-0.998, Wald's P = 0.048), whereas that of high CD3 mRNA expression was of marginal statistical significance (HR = 0.77, 95% CI 0.59-1.01, P = 0.059). Moreover, a significant interaction was observed between HER2 status and CD3 mRNA expression with respect to DFS (interaction P = 0.032). In the HER2-positive subgroup, the hazard ratio associated with high CD3 mRNA expression was of greater magnitude (HR = 0.48, 95% CI 0.30-0.76, P = 0.002) compared with the hazard ratio presented above, for the entire cohort. No significant findings were observed for FOXP3 in terms of DFS, while none of the studied markers were of prognostic value for OS.ConclusionsHigh CD3 and CD8 mRNA expression in early-stage breast cancer patients is of prognostic value for decreased risk of relapse and, in the future, could potentially be of importance in deciding the most appropriate therapeutic strategy in light of the recent immune-related treatment developments.
| S-EPMC6198219 | biostudies-literature
Project description:The response to neoadjuvant chemotherapy in breast cancer patients is usually assessed by pCR and RCB score. However, the prognostic value of these parameters is still in discussion. We showed recently that an epirubicin/docetaxel therapy is associated with an increase in the cell death marker high-mobility group box 1 protein (HMGB1) in the circulation. Here, we investigate whether this increase correlates with the long-term outcome. Thirty-six early breast cancer patients under neoadjuvant epirubicin/docetaxel combination chemotherapy were included in this study. To determine the immediate effect of this treatment on HMGB1, we collected blood samples before and 24-96 h after the initial dose. This time course was then compared to the 5-year follow-up of the patients. HMGB1 levels varied before chemotherapy between 4.1 and 11.3 ng/mL and reacted differently in response to therapy. Some patients showed an increase while others did not show any changes. Therefore, we subdivided the patient collective into two groups: patients with an at least 1.1 ng/mL increase in HMGB1 and patients with smaller changes. The disease-free survival was longer in the HMGB1 increase group (56.2 months vs. 46.6 months), but this difference did not reach significance. The overall survival (OS) was significantly better in patients with an increase in HMGB1 (log rank P = 0.021). These data suggest that an immediate increase in HMGB1 levels correlates with improved outcome in early breast cancer patients receiving neoadjuvant chemotherapy, and may be a valuable complementary biomarker for early estimation of prognosis.
| S-EPMC5055166 | biostudies-literature
Project description:IntroductionReliable predictive and prognostic markers for routine diagnostic purposes are needed for breast cancer patients treated with neoadjuvant chemotherapy. We evaluated protein biomarkers in a cohort of 116 participants of the GeparDuo study on anthracycline/taxane-based neoadjuvant chemotherapy for operable breast cancer to test for associations with pathological complete response (pCR) and disease-free survival (DFS). Particularly, we evaluated if interactions between hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression might lead to a different clinical behavior of HR+/HER2+ co-expressing and HR+/HER2- tumors and whether subgroups of triple negative tumors might be identified by the help of Ki67 labeling index, cytokeratin 5/6 (CK5/6), as well as cyclooxygenase-2 (COX-2), and Y-box binding protein 1 (YB-1) expression.MethodsExpression analysis was performed using immunohistochemistry and silver-enhanced in situ hybridization on tissue microarrays (TMAs) of pretherapeutic core biopsies.ResultspCR rates were significantly different between the biology-based tumor types (P = 0.044) with HR+/HER2+ and HR-/HER2- tumors having higher pCR rates than HR+/HER2- tumors. Ki67 labeling index, confirmed as significant predictor of pCR in the whole cohort (P = 0.001), identified HR-/HER- (triple negative) carcinomas with a higher chance for a pCR (P = 0.006). Biology-based tumor type (P = 0.046 for HR+/HER2+ vs. HR+/HER2-), Ki67 labeling index (P = 0.028), and treatment arm (P = 0.036) were independent predictors of pCR in a multivariate model. DFS was different in the biology-based tumor types (P < 0.0001) with HR+/HER2- and HR+/HER2+ tumors having the best prognosis and HR-/HER2+ tumors showing the worst outcome. Biology-based tumor type was an independent prognostic factor for DFS in multivariate analysis (P < 0.001).ConclusionsOur data demonstrate that a biology-based breast cancer classification using estrogen receptor (ER), progesterone receptor (PgR), and HER2 bears independent predictive and prognostic potential. The HR+/HER2+ co-expressing carcinomas emerged as a group of tumors with a good response rate to neoadjuvant chemotherapy and a favorable prognosis. HR+/HER2- tumors had a good prognosis irrespective of a pCR, whereas patients with HR-/HER- and HR-/HER+ tumors, especially if they had not achieved a pCR, had an unfavorable prognosis and are in need of additional treatment options.
| S-EPMC2790846 | biostudies-literature
Project description:BackgroundEPIC1 is an oncogenic long non-coding ribonucleic acid (RNA) that promotes cell growth and cell-cycle progression and inhibits apoptosis in several cancer cell lines. However, clinical studies on EPIC1 in breast cancer, specifically in the neoadjuvant setting, are relatively few.MethodsPatients treated with weekly paclitaxel-cisplatin-based neoadjuvant chemotherapy after core-needle biopsy were included in the study. Real-time quantitative polymerase chain reaction assays were performed to detect EPIC1 expression.ResultsAmong all patients included in this study (n = 111), higher EPIC1 expression was associated with estrogen receptor negativity, human epidermal growth factor receptor 2 positivity, higher Ki67 index, and higher histologic grade. Multivariate analysis suggested that EPIC1 expression was an independent predictive factor for pathological complete response, with a significant interaction between EPIC1 expression and age. The Kaplan-Meier Plotter dataset suggested that the EPIC1 high-expression group showed a worse 10-year distant metastasis-free survival and post-progression survival when compared with the EPIC1 low-expression group. The Cancer Genome Atlas dataset suggested that the overall survival in the EPIC1 high-expression group was inferior to that in the EPIC1 low-expression group, specifically in hormone receptor (HorR)-positive patients and patients aged <50 years. Pathway analysis revealed the top pathways that indicated the potential mechanisms of EPIC1 in chemoresistance, including the daunorubicin and doxorubicin metabolic processes.ConclusionsOur study suggests that EPIC1 may be a promising biomarker for both neoadjuvant chemosensitivity and long-term clinical outcomes in breast cancer, specifically in the HorR-positive premenopausal subgroup. It may also help identify candidate responders and determine treatment strategies.
| S-EPMC7383657 | biostudies-literature
Project description:BackgroundTP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial.Methods450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup.ResultsOf 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019).ConclusionsOur study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes.
| S-EPMC5356512 | biostudies-literature
Project description:BACKGROUND:The relationship between chemotherapy-related toxicities and prognosis is unclear. Previous studies have examined the association of myelosuppression parameters or neuropathy with survival and reported conflicting results. This study aims to investigate 13 common chemotherapy toxicities and their association with relapse-free survival and breast cancer-specific survival. METHODS:Chemotherapy-related toxicities were collected prospectively for 6,248 women with early-stage breast cancer from four randomised controlled trials (NEAT; BR9601; tAnGo; Neo-tAnGo). Cox proportional-hazards modelling was used to analyse the association between chemotherapy-related toxicities and both breast cancer-specific survival and relapse-free survival. Models included important prognostic factors and stratified by variables violating the proportional hazards assumption. RESULTS:Multivariable analysis identified severe neutropenia (grades ?3) as an independent predictor of relapse-free survival (hazard ratio (HR)?=?0.86; 95% confidence interval (CI), 0.76-0.97; P?=?0.02). A similar trend was seen for breast cancer-specific survival (HR?=?0.87; 95% CI, 0.75-1.01; P?=?0.06). Normal/low BMI patients experienced more severe neutropenia (P?=?0.008) than patients with higher BMI. Patients with fatigue (grades ?3) showed a trend towards reduced survival (breast cancer-specific survival: HR?=?1.17; 95% CI, 0.99-1.37; P?=?0.06). In the NEAT/BR9601 sub-group analysis by treatment component, this effect was statistically significant (HR?=?1.61; 95% CI, 1.13-2.30; P?=?0.009). CONCLUSIONS:This large study shows a significant association between chemotherapy-induced neutropenia and increased survival. It also identifies a strong relationship between low/normal BMI and increased incidence of severe neutropenia. It provides evidence to support the development of neutropenia-adapted clinical trials to investigate optimal dose calculation and its impact on clinical outcome. This is important in populations where obesity may lead to sub-optimal chemotherapy doses.
| S-EPMC4693418 | biostudies-literature
Project description:BackgroundZinc finger E-box binding homeobox 1 (ZEB1) is a molecule involved in the progression of epithelial-to-mesenchymal transition (EMT) in various kinds of cancers. Here, we aimed to determine whether the expression of the ZEB1 protein is related to the response of patients to neoadjuvant therapy as well as their survival outcome.MethodsImmunohistochemistry (IHC) was performed on paraffin-embedded tumor samples from core needle biopsy before neoadjuvant therapy (NAT). Univariate and multivariate logistic regression analyses were used to analyze the associations between the protein expression of ZEB1 and the pathological complete response (pCR) outcome. Kaplan-Meier plots and log-rank tests were used to compare disease-free survival (DFS) between groups. A Cox proportional hazards model was used to calculate the adjusted hazard ratio (HR) with a 95% confidential interval (95% CI).ResultsA total of 75 patients were included in the IHC test. High ZEB1 protein expression was associated with a low pCR rate in both univariate (OR = 0.260, 95% CI 0.082-0.829, p = 0.023) and multivariate (OR = 0.074, 95% CI 0.011-0.475, p = 0.006) logistic regression analyses. High ZEB1 protein expression was also associated with a short DFS according to both the log-rank test (p = 0.023) and Cox proportional hazard model (HR = 9.025, 95% CI 1.024-79.519, p = 0.048). In hormone receptor positive (HorR-positive) patients, high ZEB1 protein expression was also associated with a lower pCR (OR = 0.054, 95% CI 0.007-0.422, p = 0.005) and a poorer DFS (HR = 10.516, 95% CI 1.171-94.435, p = 0.036) compared with low ZEB1 protein expression. In HER2-overexpressing patients, ZEB1 protein expression was also associated with poor survival (p = 0.042).ConclusionsOur results showed that high ZEB1 protein expression was a negative predictive marker of pCR and DFS in neoadjuvant therapy in breast cancer patients and in HorR-positive and HER2-overexpressing subgroups.Trial registration NCT, NCT02199418. Registered 24 July 2014-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02199418?term=NCT02199418&rank=1. NCT, NCT 02221999. Registered 21 August 2014-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02221999?term=NCT02221999&rank=1.
| S-EPMC6441148 | biostudies-literature
Project description:ObjectiveTo validate the prognostic value of tumor regression grading (TRG) and to explore the associated factors of TRG for advanced gastric cancer (AGC) with neoadjuvant chemotherapy (NACT) plus surgery.MethodsTwo hundred forty-nine AGC patients treated with NACT followed by gastrectomy at the Mayo Clinic, USA and the Fujian Medical University Union Hospital, China between January 2000 and December 2016 were enrolled in this study. Cox regression was used to identify covariates associated with overall survival (OS) and recurrence-free survival (RFS). Logistic regression was used to reveal factors predicting tumor regression grading.ResultsFor patients with TRG 0-1, the 3- and 5-year OS rates were 85.2% and 74.5%, respectively, when compared to 56.1% and 44.1% in patients with TRG 2 and 28.2% and 23.0% in patients with TRG 3, respectively (p<0.001). TRGs were independent risk factors for OS. Similar findings were observed in RFS. Multivariable analysis revealed that an oxaliplatin-based regimen (p=0.017) was an independent predictor of TRG. The oxaliplatin-based regimen was superior to the nonoxaliplatin-based regimen for OS (38.4 months vs 19.5 months, respectively; p=0.01). Subgroup analyses by histological subtype indicated that the oxaliplatin-based regimen improved the OS in nonsignet ring cell carcinoma compared to the nonoxaliplatin-based regimen (53.7 months vs 19.5 months, respectively; p=0.011). However, similar findings were not observed in RFS.ConclusionTRG was an independent factor of AGC treated with neoadjuvant chemotherapy plus surgery. Oxaliplatin-based neoadjuvant chemotherapy regimens improve tumor response and may have an overall survival benefit for patients with nonsignet ring cell carcinoma.
| S-EPMC8352744 | biostudies-literature
Project description:PurposePIK3CA, encoding for subunit p110a of phosphatidylinositol 3 kinase, is frequently mutated in breast cancer. PIK3CA mutation was predictive for pathological complete response (pCR) in human epidermal growth factor 2 positive breast cancer. This study explores the association of PIK3CA mutation and pCR in triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy.Materials and methodsA total of 92 patients with TNBC derived from a prospectively randomized phase II trial GeparSixto study (NCT01426880). Exon 9 and exon 20 of PIK3CA mutations were evaluated by using classical Sanger method with formalin-fixed paraffin-embedded tumor tissues.ResultsSeven of 90 tumors (7.8%) were detectable with a PIK3CA H1047R mutation. Overall, PIK3CA H1047R mutation was significantly associated with a lower pCR rate (14.3% vs. 56.6%; odds ratio, 0.128; 95% confidence interval [CI], 0.015 to 1.108; p=0.047). In carboplatin- containing treatment patients, H1047R mutation trended to predict a lower pCR rate (20% vs. 62.5%; p=0.146). In a multivariable analysis, H1047R mutation trended to predict a lower pCR rate (hazard ratio, 0.1; 95% CI, 0.01 to 1; p=0.056).ConclusionTNBC with a PIK3CA H1047R mutation was less likely to achieve pCR after anthracycline-based neoadjuvant chemotherapy. Development of H1047R mutant selective inhibitors might be helpful to conquer this subtype of breast cancer.
| S-EPMC7373870 | biostudies-literature