Cyclophosphamide, Methotrexate And 5-fluorouracil Research Articles

Shilajit potentiates the effect of chemotherapeutic drugs and mitigates metastasis induced liver and kidney damages in osteosarcoma rats

Osteosarcoma is a primary malignant cancer of the bone identified by the direct formation of osteoid tissue or immature bone by cancer cells. The liver and kidneys represent two major secondary organs to which osteosarcoma metastasizes. In this study, we assessed Shilajit, a phytomineral diffusion traditionally used in Ayurvedic medicine, for its possible protective effects against metastasis induced liver and kidney damages in an osteosarcoma rat model. Osteosarcoma rats displayed typical dysregulation of serum levels of hepatic and renal functional markers (p < 0.05) including aspartate aminotransferase (AST)* and alanine aminotransferase (ALT), alkaline phosphatase (ALP), total proteins, albumin, bilirubin, creatinine, urea, and uric acid. Changes in functional markers were also positively correlated with marked histopathological alterations in liver and kidney tissues. Whereas Shilajit's treatment of osteosarcoma rates in combination with CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy drug cocktail significantly (p < 0.05) reversed the studied functional markers to their near-normal levels. Co-treatment of shilajit and drug cocktails also markedly alleviated histopathological changes in liver and kidney tissues. Correlation co-efficient analysis of hepatic and renal functional markers revealed a significant inter-association among these markers. Collectively, present data indicate that shilajit may potentiate the effects of chemotherapy drugs and mitigate the metastasis-induced liver and kidney damage in osteosarcoma. Thus, the findings of this study substantiate the beneficial health effects of shilajit and promote its regular consumption.

Effects of neoadjuvant therapies on genetic regulation of targeted pathways in ER+ primary ductal breast carcinoma: A meta-analysis of microarray datasets

Breast cancer arises as a result of multiple interactions between environmental and genetic factors. Conventionally, breast cancer is treated based on histopathological and clinical features. DNA technologies like the human genome microarray are now partially integrated into clinical practice and are used for developing new “personalized medicines” and “pharmacogenetics” for improving the efficiency and safety of cancer medications. We investigated the effects of four established therapies—for ER+ ductal breast cancer—on the differential gene expression. The therapies included single agent tamoxifen, two-agent docetaxel and capecitabine, or combined three-agents CAF (cyclophosphamide, doxorubicin, and fluorouracil) and CMF (cyclophosphamide, methotrexate, and fluorouracil). Genevestigator 8.1.0 was used to compare five datasets from patients with infiltrating ductal carcinoma, untreated or treated with selected drugs, to those from the healthy control. We identified 74 differentially expressed genes involved in three pathways, i.e., apoptosis (extrinsic and intrinsic), oxidative signaling, and PI3K/Akt signaling. The treatments affected the expression of apoptotic genes (TNFRSF10B [TRAIL], FAS, CASP3/6/7/8, PMAIP1 [NOXA], BNIP3L, BNIP3, BCL2A1, and BCL2), the oxidative stress-related genes (NOX4, XDH, MAOA, GSR, GPX3, and SOD3), and the PI3K/Akt pathway gene (ERBB2 [HER2]). Breast cancer treatments are complex with varying drug responses and efficacy among patients. This necessitates identifying novel biomarkers for predicting the drug response, using available data and new technologies. GSR, NOX4, CASP3, and ERBB2 are potential biomarkers for predicting the treatment response in primary ER+ ductal breast carcinoma.

Gentle Chemotherapy in Breast Cancer

Locally advanced breast cancer (LABC) includes patients with clinical stage III b and III c, as per NCCN (National Comprehensive Cancer Network), though some clinicians include clinical stage IIb and IIIa as well. The most commonly used oral chemotherapy in carcinoma breast is oral CMF (cyclophosphamide, methotrexate and 5-fluorouracil) regimen (or CMC (cyclophosphamide, methotrexate and capecitabine) regime). In this pilot study, we recruited 11 patients from October 2017 to June 2019 with locally advanced breast cancer without any metastasis and gave an oral CMC regime. The most common side effects encountered were neutropenia (myelosuppression), hand-foot syndrome and gastrointestinal disturbances like diarrhoea and mouth ulcers. More than 30% response was seen in six out of eleven patients, out of which three (27.2%) patients had complete clinical response after six cycles of oral chemotherapy. pCR (pathological complete response) was achieved in three (27.27%) patients who had complete clinical response (clinically as well as mammographically). With oral CMF, we observed a clinical response rate of 36% and pCR of 27% without any significant or disabling side effects. Hence, it is a safe and effective alternative to standard CAF (cyclophosphamide, anthracycline and 5-fluorouracil) regime in selected patients with locally advanced patients.

Effects of Metformin on the Survival Rate of CMF (Cyclophosphamide, Methotrexate and 5-fluorouracil)-treated Rats

Effects of Metformin on the Survival Rate of CMF (Cyclophosphamide, Methotrexate and 5-fluorouracil)-treated Rats

The Prosigna 50-gene profile and responsiveness to adjuvant anthracycline-based chemotherapy in high-risk breast cancer patients

The DBCG89D trial randomized high-risk early breast cancer patients to adjuvant CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil). Prosigna assays were performed by researchers with no access to clinical data. Time to distant recurrence (DR) was the primary endpoint, time to recurrence (TR) and overall survival (OS) secondary. Among the 980 Danish patients enrolled, Prosigna results were obtained in 686. Continuous ROR score was associated with DR for CMF (adjusted hazard ratio (HR) 1.20, 95% CI 1.09–1.33), and for CEF (HR 1.04, 95% CI 0.92–1.18), Pinteraction = 0.06. DR was significantly longer in CEF compared to CMF treated patients with Her2-enriched tumors (HR 0.58, 95% CI 0.38–0.86), but not in patients with luminal tumors. Heterogeneity of treatment effect was significant for TR and OS. In this prospective-retrospective analysis, patients with Her2-enriched breast cancer derived substantial benefit from anthracycline chemotherapy whereas anthracyclines are not an essential component of chemotherapy for patients with luminal subtypes. The benefit of CEF vs. CMF correlated with increasing ROR Score.

Abstract P2-18-07: Weight and body composition’s analysis in chemotherapy-treated women with breast cancer under nutritional follow up in a private oncology service in Brazil

Abstract INTRODUCTION: The obesity/overweight is closely related to poorer breast cancer prognosis, as well as higher mortality rates. In postmenopausal women, the main source of estrogen is in the adipose tissue. Due to that, overweight/obesity leads to an increase in breast cancer development and disease progression. This is a consequence of not only to high estrogen levels, but also to an increase in circulating factors that influence in inflammatory pathway activations and insulin resistance increase. OBJECTIVES: This study aims at analyzing weight and body composition variation in breast cancer women under nutritional monitoring during adjuvant chemotherapy (CT). METHOD/DESIGN: This is an observational, prospective study with estrogen receptor (ER) and/or progesterone receptor (PR) positives, HER2 negative breast cancer women, who underwent adjuvant CT, from 07/17/2018 to 06/19/2019. Nutritionists followed up these patients during all of CT cycles, and data on body composition were collected through bioelectric impedance in the first and last days of chemotherapy. In between cycles, body weight assessments, nutritional guidelines orientations adherence were checked against the information, which had been offered. RESULTS: 51 women were selected and 4 excluded according to study criteria (3 patients turned HER2 positive by FISH and 1 patient had metastatic cancer confirmation). By the data analysis, 36 patients completed chemotherapy. The CT regimens used were doxorrubicin, cyclophosphamide and paclitaxel (ACT) (59%), AC plus docetaxel (4%), cyclophosphamide, methotrexate and Fluorouracil (CMF) (10%), AC (6%) and docetaxel and cyclophosphamide (TC) (21%). The mean age was 51 years, with 12 women aged ≥ 60 years. At the beginning the mean Body Mass Index (BMI) was 27.94 kg / m2. 37% of them were classified as eutrophic, 33% were overweight and 30% obese, according to the World Health Organization (WHO) criteria. Weight gain was observed in 64% of patients, with a significant increase in lean mass (kg) as well as body water (in 75% of patients). There was a reduction in fat percentage due to the reduction of fat mass in kilos (52.8% of patients) and the increase of lean mass (kg). The mean BMI at the end of treatment was 27.08 kg / m2, with a decrease in obesity and eutrophic index (reduction of 5.8% and 32.9%, respectively) and an increase in overweight by 41.7%. If considered the weight variation per CT protocol, the women submitted to the ACT scheme had a higher prevalence of weight gain, distributed in lean mass (80%), body water (75%) and fat mass reduction in 55% of these patients. On the other hand, there was a reduction in the mean of BMI value between the first evaluation (26.7 kg / m2) and the last one (22.4 kg / m2), as well as a lower fat mass in 62.5% of women who were submitted to TC protocol. In addition, in CMF and AC protocol, only one patient in each regimen finished the treatment until the deadline. In this case, the results were immature and not been reported in this abstract. CONCLUSIONS: There was an improvement in body composition, considering lean and fat mass in the study population, probably due to the nutritional monitoring during all cycles of chemotherapy. Nutritional therapy certainly influenced adherence to better eating habits. Full data of the 51 patients will be presented during the meeting. It should reinforce the need of developing prospective controlled studies, targeting nutritional intervention in breast cancer treatment. Citation Format: Flavia Rocha Paes, Anna Nogueira Verano, Julia SM de Sá, Rafaela M Peixoto, Juliana CO Pena, Maria Clara A Zocrato, Patricia C Christo, Fernanda CMJ Oliveira, Bruno L Ferrari. Weight and body composition’s analysis in chemotherapy-treated women with breast cancer under nutritional follow up in a private oncology service in Brazil [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-18-07.

The role of radiation therapy and systemic therapies in elderly with breast cancer.

The focus of this review deals with the management of elderly patients with early stage breast cancer, discussing the role of systemic therapies [endocrine therapy (ET), chemotherapy, novel agents] and radiation therapy (RT). Several studies have evaluated in elderly low risk patients the possibility of omitting the RT but, at the same time, higher locoregional relapse (LR) rates without significant impact on overall survival (OS) were observed in all studies when RT was excluded. Technological improvements [intensity-modulated RT (IMRT), volumetric modulated arc therapy (VMAT), high dose brachy therapy (HDBT)] are very useful in order to reduce cosmetic outcome and improve quality of life of frail patients. The optimal sequence of ET, concomitant or sequential to RT, is currently under investigation, and specifically in the elderly it is questioned the possible choice of prolonged therapy after standard 5 years. Data regarding chemotherapy suggesting no benefit of OS in endocrine responsive diseases, whereas endocrine non-responsive breast cancer still showed a better outcome. Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen is recognized as the standard protocol, although age-dependent increase in therapy related mortality was reported. Neoadjuvant chemotherapy in elderly showed a lower ratio of pathological complete response in comparison to younger patients, but triple negative breast cancer patients showed a good prognosis regarding OS, comparable to younger patients. The risk of cardiotoxicity seems to increase with age, so the use trastuzumab in this setting is much debated. Currently, other anti-HER2 agents (pertuzumab, lapatinib) are used in neoadjuvant setting, but the data on elderly are still premature. Novel molecules are rapidly changing the clinical management of breast cancer patients but are tested especially in locally advanced and metastatic setting. Among these, particularly interesting are inhibitors of CDK4 and 6, alpelisib (PI3K enzymes mutations), immune checkpoint (PD1, PDL1, CTLA4) inhibitors, atezolizumab. Elderly patients are under-represented in clinical trials, although ageing can be frequently correlated with a decrease in the effectiveness of the immune system. For elderly women, treatment decisions should be individually decided, taking into account the geriatric assessment and limited life expectancy and tumor characteristics.

Secretory breast carcinoma in adulthood: A case report with literature review

Introduction. Secretory breast carcinoma is rare subtype of breast carcinoma which occurs primarily in children and young adults, so in the past it was called juvenile carcinoma. Case report. A 67-year-old female patient presented with mass of the right breast since one month. After physical, routine laboratory examination and mammography, core needle biopsy was performed and histopathological examination confirmed invasive carcinoma. Immunohistochemically, estrogen-receptors (ER) and progesteron-receptors (PR) showed weak positive reaction in 10% of tumor cells, while human epidermal growth factor receptor-2 (HER-2) was without expression. After an adequate preoperative preparation, operation was done ? quadrantectomy with sentinel lymph node biopsy. Postoperatively, the patient was treated with 6 cycles of cyclophosphamide, methotrexate and fluorouracil (CMF) combination, radiotherapy (60 Gy) and tamoxifen. After 5-year follow-up the patient had no signs of the disease. Conclusion. Secretory breast cancer is a rare subtype of invasive breast carcinoma with wide age range of occurrence and good prognosis despite its triplenegative immunophenotype. Although the therapeutic management is non-consensual for this breast cancer special type, surgery is considered the mainstay of the treatment as well as the adjuvant chemotherapy and radiation.

The Prosigna gene expression assay and responsiveness to adjuvant cyclophosphamide-based chemotherapy in premenopausal high-risk patients with breast cancer

BackgroundThe PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer.MethodsProsigna assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF).ResultsIn total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P < 0.001 for disease-free survival (DFS), P = 0.001 for overall survival (OS)). No statistically significant interaction of continuous ROR score and treatment on DFS and OS was found. A highly significant association was observed between intrinsic subtypes and C/CMF treatment for DFS (Pinteraction = 0.003 unadjusted, P = 0.001 adjusted) and OS (Pinteraction = 0.04). In the adjusted analysis treatment with C/CMF was associated with a reduced risk of DFS events in patients with basal-like (hazard ratio (HR) 0.14; 95% CI 0.06; 0.32) and luminal B (HR 0.48; 95% CI 0.27; 0.84) subtypes but not in patients with Human epidermal growth factor receptor-enriched (HR 1.05; 95% CI 0.56; 1.95) or luminal A (HR 0.61; 95% CI 0.32; 1.16) subtypes.ConclusionThe Prosigna ROR score and intrinsic subtypes were prognostic in high-risk premenopausal patients with breast cancer, and intrinsic subtypes identify high-risk patients with or without major benefit from adjuvant C/CMF treatment.

Abstract P2-10-04: Targeted sequencing in early breast cancer: Identification of novel candidate mutations predictive of anthracycline benefit

Abstract Background The use of chemotherapies such as anthracyclines and taxanes have improved overall and disease free survival in breast cancer. For all patients, anthracyclines can have significant toxicities including cardiotoxicity and leukemia. It is therefore essential to select the subset of patients who will receive the optimal overall benefit from anthracycline therapy and to identify molecular pathways driving resistance. To fully understand the impact of mutations in the context of current breast cancer therapy, requires a comprehensive mapping of key molecular events in the context of treatment. We sequenced 101 genes, that were prioritized based on not only gene frequency, but also taking into account the importance of amino acid substitution, type of mutation and network connectivity, in 692 primary tumours to both identify driver genes and pathway cassettes and to understand their clinical significance in response to anthracycline treatment. Methods We performed targeted sequencing in patients from the BR9601 (n=374) and CCTG MA.5 (n=703) clinical trials. The BR9601 and MA.5 clinical trials examined the effectiveness of combination chemotherapy consisting of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) with or without epirubicin. DNA was extracted, samples were sequenced using AmpliSeq Technology adapted to Illumina and somatic mutations were called using a novel mutation calling pipeline (ISOWN). A priori analyses were performed using distant recurrence free survival (DRFS) as the primary endpoint. Results: In 692 successfully analysed samples 509 (73.6%) samples exhibited at least one single nucleotide mutation (range 0-54). 94/101 genes were mutated in at least one patient. Only variants in PIK3CA, TP53, CDH1, TLE6, MLL3 and USH2A were detected in 5% or more of samples. TSC22D1, RB1 and ZNF565 were associated with increased risk of distant relapse in multivariate analyses corrected for clinic-pathological variables. No single genes were predictive of anthracycline treatment compared to CMF in multivariate analyses corrected for clinic-pathological variables. Signaling cassettes/modules were designed based on the pathway database, Reactome. Within the signaling cassettes one module was predictive of anthracycline failure. Patients with one or more mutations in this module had an increased risk of distant relapse (HR 0.52, 95% CI 0.29-0.95, p=0.034) when treated with an anthracycline containing chemotherapy regimen compared to CMF (HR 1.34 95% CI 1.05-1.72, p=0.019). Conclusions: We successfully performed a signaling pathway-based targeted sequencing analysis within predefined signaling modules. We identified a single signaling cassette linked to anthracycline resistance in early breast cancer. However, further work to validate this study in a separate clinical trial is warranted. Citation Format: Spears M, Kalatskaya I, Trinh QM, Liao L, Chong TM, Crozier C, Dion D, Heisler L, Timms L, Stein LD, Pritchard KI, Levine MN, Shepherd L, Twelves CJ, Bartlett JMS. Targeted sequencing in early breast cancer: Identification of novel candidate mutations predictive of anthracycline benefit [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-04.

Weight change during chemotherapy in breast cancer patients: a meta-analysis

BackgroundWeight gain during chemotherapy in women with breast cancer is commonly reported.However, there are important differences between studies that examined weight change during chemotherapy; e.g. type of chemotherapy, menopausal status, time between body weight measurements and sample size. The purpose of this meta-analysis was to quantify changes in body weight during chemotherapy for women with breast cancer, taking these differences into account.MethodsWe identified relevant studies using PubMed, Scopus and Embase databases. The search was limited to human studies published in English up to and including December 2015. Only studies among women with early stage breast cancer treated with chemotherapy, with reported body weight before and after chemotherapy and type of chemotherapy were included. Random-effect models were used, and heterogeneity between studies was explored through stratified analyses and meta-regression. Sensitivity analyses were done to explore whether a specific study markedly affected the results.ResultsIn total 25 papers were found, including data from 2620 women. Overall, body weight increased during chemotherapy: 2.7 kg (95% CI 2.0, 7.5) with a high degree of heterogeneity (I2 = 94.2%). Stratified analyses showed weight gain in all strata, but did not substantially reduce heterogeneity. Univariate meta-regression showed less weight gain in prospective studies compared to chart review studies (−2.0, 95% CI: -3.1, −0.8). Studies including cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimes showed a greater weight gain compared to those that did not (2.2, 95% CI: 1.1, 3.3); and papers published until the year 2000 showed a greater weight gain compared to those published after 2000 (1.9, 95% CI:-0.8, 3.1). In the multivariate models only studies including CMF regimes and studies published until 2000 were associated with significant weight gain of respectively 1.3 and 1.4 kg.ConclusionDespite the high heterogeneity, this meta-analysis shows significant weight gain during chemotherapy for women with breast cancer. Weight gain was more pronounced in papers published until 2000 and women receiving CMF as chemotherapy regime. Although weight gain after chemotherapy has decreased over the course of time, weight gain is still substantial and deserves clinical attention.

A nation-wide multicenter 10-year (1999-2008) retrospective study of chemotherapy in Chinese breast cancer patients.

Little information is available on the evolvement of chemotherapeutic regimens administered to Chinese females with breast cancer. We retrospectively analyzed demographic, pathological and chemotherapeutic data of 4211 breast cancer patients, who were randomly selected from representative hospitals of 7 traditional areas in China between 1999 and 2008. A total of 3271 cases (77.7%) received adjuvant chemotherapy, 558 (13.3%) received neoadjuvant chemotherapy, and 392 (9.3%) received chemotherapy for metastatic disease. In the adjuvant setting, higher percentage of patients with younger age, advanced stage, hormone receptor (HR) negative or HER2 positive disease received chemotherapy (P<0.001). The use of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) in adjuvant chemotherapy decreased significantly from 1999 to 2008, while the use of anthracycline-based (without taxanes) regimens increased in the first 5 years, followed by increased use of regimens containing both anthracyclines and taxanes. Women with locally advanced disease received more neoadjuvant chemotherapy. The percentage of neoadjuvant regimens containing anthracyclines and taxanes increased during this period. In first-line chemotherapy of metastatic disease, 87.5% of cases received combined chemotherapy, and platinum-based regimens were also major choices aside from anthracyclines and taxanes. In second-line chemotherapy, 80.3% received combined chemotherapy, and the combination of taxane and platinum was the most common choice. In conclusion, major changes have taken place in breast cancer chemotherapy in China during this 10-year interval, which reflected the incorporation of key evidence and guidelines into Chinese medical practice.

Impact of Sequencing Radiation Therapy and Chemotherapy on Long-Term Local Toxicity for Early Breast Cancer: Results of a Randomized Study at 15-Year Follow-Up

To compare long-term late local toxicity after either concomitant or sequential chemoradiation therapy after breast-conserving surgery. From 1997 to 2002, women aged 18 to 75years who underwent breast-conserving surgery and axillary dissection for early breast cancer and in whom CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy was planned were randomized between concomitant and sequential radiation therapy.Radiation therapy was delivered to the whole breast through tangential fields to 50Gy in 20 fractions over a period of 4weeks, followed by an electron boost.Surviving patients were tentatively contacted and examined between March and September 2014. Patients in whom progressive disease had developed or who had undergone further breast surgery were excluded. Local toxicity (fibrosis, telangiectasia, and breast atrophy or retraction) was scored blindly to the treatment received. A logistic regression was run to investigate the effect of treatment sequence after correction for several patient-, treatment-, and tumor-related covariates on selected endpoints. The median time to cross-sectional analysis was 15.7years (range, 12.0-17.8years). Of 206 patients randomized, 154 (74.8%) were potentially eligible. Of these, 43 (27.9%) refused participation and 4 (2.6%) had been lost to follow-up, and for 5 (3.2%), we could not restore planning data; thus, the final number of analyzed patients was 102. No grade 4 toxicity had been observed, whereas the number of grade 3 toxicity events was low (<8%) for each item, allowing pooling of grade 2 and 3 events for further analysis. Treatment sequence (concomitant vs sequential) was an independent predictor of grade 2 or 3 fibrosis according to both the National Cancer Institute Common Terminology Criteria for Adverse Events (odds ratio [OR], 4.05; 95% confidence interval [CI], 1.34-12.2; P=.013) and the SOMA (Subjective, Objective, Management and Analytic) scale (OR, 3.75; 95% CI, 1.19-11.79; P=.018), as well as grade 2 or 3 breast atrophy or retraction (OR, 3.87; 95% CI, 1.42-10.56; P=.008).No effect on telangiectasia was detected. At long-term follow-up, concomitant chemoradiation therapy has a detrimental effect on both fibrosis and retraction with an approximately 4-fold increase in the odds of grade 2 or 3 toxicity.

Time to initiation of adjuvant chemotherapy in patients with rapidly proliferating early breast cancer

AimTo evaluate the optimal time interval from definitive surgery to commencing chemotherapy in early breast cancer (EBC). Patients and methodsThe relationship between time to initiation of adjuvant chemotherapy (TTC), calculated in weeks, and disease-free (DFS) or overall survival (OS), was assessed in 921 EBC patients with rapidly proliferating tumours (thymidine labelling index >3% or G3 or Ki67 >20%), randomised in a phase III clinical trial (NCT01031030) to receive chemotherapy with or without anthracyclines (epirubicin→cyclophosphamide, methotrexate and fluorouracil (CMF) versus CMF→epirubicin versus CMF). DFS, OS and 95% confidence intervals (95% confidence interval (CI)) were calculated by the Kaplan–Meier method. Multivariate Cox analysis was performed in relation with nodal involvement, oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status, Ki67 value, type of adjuvant chemotherapy, menopausal status and tumour size. ResultsAt a median follow-up of 105months (range 2–188), a prolonged TTC resulted in a significant increase in the risk of relapse: hazard ratio (HR) 1.15 (95% CI 1.02–1.30, p=0.019). Using a backward elimination procedure, TTC, tumour size and nodal involvement remained significantly associated with DFS. A time-dependent receiver-operating characteristic (ROC) curve analysis was subsequently utilised to evaluate the best cut-off for TTC, identifying 7weeks as the best threshold for longer OS (p=0.043): 8-year OS 88% (95% CI 85–90) for patients with a TTC <7weeks and 78% (95% CI 68–87) for the other group. ConclusionsOur results confirm that a shorter TTC may reduce relapses and possibly also improve clinical outcome in patients with highly proliferating EBC.

Predicting Anthracycline Benefit: TOP2A and CEP17—Not Only but Also

Evidence supporting the clinical utility of predictive biomarkers of anthracycline activity is weak, with a recent meta-analysis failing to provide strong evidence for either HER2 or TOP2A. Having previously shown that duplication of chromosome 17 pericentromeric alpha satellite as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient-level pooled analysis of data from five trials comparing anthracycline-based chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy for early breast cancer. Fluorescent in situ hybridization for CEP17, HER2, and TOP2A was performed in three laboratories on samples from 3,846 of 4,864 eligible patients from five trials evaluating anthracycline-containing chemotherapy versus CMF. Methodologic differences did not affect HER2-to-CEP17 ratios but necessitated different definitions for CEP17 duplication: > 1.86 observed copies per cell for BR9601, NEAT, Belgian, and DBCG89D trials and > 2.25 for the MA.5 trial. Fluorescent in situ hybridization data were available in 89.3% (HER2), 83.9% (CEP17), and 80.6% (TOP2A) of 3,846 patient cases with available tissue. Both CEP17and TOP2A treatment-by-marker interactions remained significant in adjusted analyses for recurrence-free and overall survival, whereas HER2 did not. A combined CEP17 and TOP2A-adjusted model predicted anthracycline benefit across all five trials for both recurrence-free (hazard ratio, 0.64; 95% CI, 0.51 to 0.82; P = .001) and overall survival (hazard ratio, 0.66; 95% CI, 0.51 to 0.85; P = .005). This prospectively planned individual-patient pooled analysis of patient cases from five adjuvant trials confirms that patients whose tumors harbor either CEP17 duplication or TOP2A aberrations, but not HER2 amplification, benefit from adjuvant anthracycline chemotherapy.

Anthracycline-based induction chemotherapy followed by concurrent cyclophosphamide, methotrexate and 5-fluorouracil and radiation therapy in surgically resected axillary node-positive breast cancer.

The present study aimed to determine the toxicity and efficacy of 4 courses of anthracyclines-taxane (AT) chemotherapy followed by radiation therapy (XRT) concurrent with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in surgically resected axillary node-positive (N+) breast cancer. A total of 200 women with N+ breast cancer were treated with adriamycin and docetaxel followed by XRT concurrent with six courses of CMF. Two courses of dose-dense chemotherapy with ifosfamide, carboplatin and etoposide, supported by pegfilgrastim, were administered to patients with >5 histologically confirmed axillary lymph node metastases and patients with triple-negative disease. Additional treatments included 1 year of trastuzumab in human epidermal growth factor receptor 2-positive patients, 5 years of a luteinizing hormone-releasing hormone analogue in premenopausal women and 5 years of an aromatase inhibitor (AI) in estrogen receptor-positive (ER+) patients. The mean number of positive axillary lymph nodes was 4.4 (range, 2-37), 52% of the patients were premenopausal, 74% were ER+ and 26% had triple-negative disease. After a median follow-up of 73 months, grade 2 and 3 hematological toxicity was observed in 20% of the patients. The 10-year disease-free survival (DFS) and overall survival (OS) rates were 73 and 77%, respectively. There was no significant difference in DFS between ER+ and estrogen receptor-negative (ER-) patients (P>0.05), whereas the OS was better in ER+ vs. ER- patients (P<0.05) and in premenopausal vs. postmenopausal patients (P<0.005). In conclusion, induction AT concurrent CMF and XRT and dose-dense chemotherapy followed by AI in N+ high-risk breast cancer was associated with a low level of systemic and late cardiac toxicity and excellent local control, DFS and OS.

One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer

PurposeWe report the long-term results of a randomised trial comparing tamoxifen with tamoxifen plus cyclophosphamide, methotrexate and fluorouracil (CMF) in postmenopausal high-risk breast cancer patients. In addition, we analyse the prognostic and predictive value of centrally assessed subtypes. MethodsPostmenopausal patients with breast cancer and positive nodes, deep invasion or size exceeding 5cm were randomly assigned to 1year of tamoxifen, or cyclophosphamide 600mg/m2, methotrexate 40mg/m2 and fluorouracil 600mg/m2 intravenously on day 1 every 4weeks for nine cycles plus tamoxifen (CMFT). Tissue microarrays were constructed retrospectively and oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and proliferation-related Ki-67 antigen (Ki67) status were assessed. ResultsFrom October 1982 through March 1990 we randomised 1445 patients and 969 (67%) were eligible for the biomarker analysis. At 10-years 936 women had suffered a disease-free survival (DFS) event (tamoxifen, 495 events in 686 patients; CMFT, 441 events in 642 patients). The addition of CMF to tamoxifen significantly improved DFS (adjusted hazard ratio 0.82; 95% confidence interval (CI) 0.71–0.93; P=0.003) but not overall survival (adjusted hazard ratio 0.95; 95% CI 0.85–1.08; P=0.44). DFS was superior in Luminal A tumours (ER or PgR positive, HER2 negative and Ki67 ⩽14%) when compared to Luminal B or non-luminal (ER and PgR negative) tumours. There was no statistical evidence of heterogeneity by subtype in the benefit from CMF (Pinteraction=0.45). ConclusionCMF added to 1year of tamoxifen reduces the risk of a DFS event. The benefit from CMF was not significantly different in Luminal A and B subtypes.

Safety and tolerability of adjuvant dose dense chemotherapy in elderly patients with node-positive early breast cancer.

1093 Background: Intensive chemotherapy confers benefit to older and younger patients with early breast cancer (BC). We aim to characterize the feasibility and toxicity profile of adjuvant dose-dense chemotherapy (ADDC) in older women with early node positive (BC). Methods: Available data from women who received ADDC for BC within three randomized trials between 1997 and 2008 were retrieved from our electronic database. These trials included HE 10/97: epirubicin and cyclophosphamide, methotrexate and fluorouracil (CMF) with or without paclitaxel, HE 10/00: epirubicin and concurrent or sequential paclitaxel and CMF and HE 10/05: a sequential three arm study of epirubicin, paclitaxel and CMF compared with epirubin, CMF and either weekly paclitaxel or docetaxel. We identified women aged &gt;65 years and we looked at differences in tolerability and delivery of chemotherapy, toxicity, and treatment outcome. Results: From a total of 2,640 patients with a median age of 52 years, who received ADDC, we identified 453 patients (17%) &gt; 65 years, hormonal positive in 76%, all node negative. At least 90% of the planned doses were delivered in 37% of the elderly, compared to 49% of the younger patients (p &lt; 0.0001). Grade 3 and 4 hematological toxicity was observed in 32% of elderly patients compared to 21% of younger (p &lt; 0.0001). Febrile neutropenia occurred in 4.5% of elderly patients as opposed to 2% of younger (p &lt; 0.002). Elderly patients experienced more frequently grade 3 and 4 fatigue, mucositis and sensory neuropathy, though the incidence of these toxicities was relatively low (all p &lt; 0.0001). Relative dose intensities were significantly lower in elderly patients, mainly affected docetaxel and paclitaxel administration. Treatment discontinuation, regardless causality, was not different in both groups. At a median follow-up of 120 months, there was no significant difference in disease free survival. Conclusions: Elderly node positive BC patients treated with ADDC derive comparable clinical benefit as younger patients, mainly in the cost of increased risk of hematological toxicity. This should be taken into account in decision making and treatment individualization in high risk BC patients.

Association between delayed initiation of adjuvant CMF or anthracycline-based chemotherapy and survival in breast cancer: a systematic review and meta-analysis

BackgroundAdjuvant chemotherapy (AC) improves survival among patients with operable breast cancer. However, the effect of delay in AC initiation on survival is unclear. We performed a systematic review and meta-analysis to determine the relationship between time to AC and survival outcomes.MethodsPubMed, EMBASE, Cochrane Database of Systematic Reviews, and Web-of-Science databases (between January-1 1978 and January-29, 2013) were searched for eligible studies. Hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) from each study were converted to a regression coefficient (β) corresponding to a continuous representation per 4-week delay of AC. Most used regimens of chemotherapy in included studies were CMF (cyclophosphamide, methotrexate, and fluorouracil) or anthracycline-based. Individual adjusted β were combined using a fixed-effects or random-effects model depending on heterogeneity.ResultsWe included 7 eligible studies with 9 independent analytical groups involving 34,097 patients, 1 prospective observational study, 2 secondary analyses in randomized trials (4 analytical groups), and 4 hospital-/population-based retrospective study. The overall meta-analysis demonstrated that a 4-week increase in time to AC was associated with a significant decrease in both OS (HR = 1.15; 95% confidence interval [CI], 1.03-1.28; random-effects model) and DFS (HR = 1.16; 95% CI, 1.01-1.33; fixed-effects model). One study caused a significant between-study heterogeneity for OS (P < 0.001; I2 = 75.4%); after excluding that single study, there was no heterogeneity (P = 0.257; I2 = 23.6%) and the HR was more significant (HR = 1.17; 95% CI, 1.12-1.22; fixed-effects model). Each single study did not fundamentally influence the positive outcome and no evidence of publication bias was observed in OS.ConclusionsLonger time to AC is probably associated with worse survival in breast cancer patients.

Major Changes in Chemotherapy Regimens Administered to Breast Cancer Patients During 2000-2008 in the Netherlands

There is little information available on the patterns of chemotherapy regimens administered in daily practice to patients with early stage and metastatic or recurrent breast cancer. To determine the trends in type of chemotherapy regimens used in breast cancer patients, newly diagnosed breast cancer patients in the period 2000-2008 who received chemotherapy were identified from the Eindhoven Cancer Registry (ECR) and linked to the PHARMO RLS, including data on, e.g., in- and outpatient drug use. Chemotherapy regimens were classified based on the received combinations and sequences. Trends in the distribution of adjuvant chemotherapy regimens (for early-stage breast cancer) and palliative chemotherapy regimens (for metastatic or recurrent breast cancer) were determined and stratified by Her2/neu status when possible. In this study, 422 patients diagnosed with early-stage breast cancer received adjuvant chemotherapy. The use of CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) decreased from 90% in 2000 to almost none since 2005. Administration of regimens that included anthracyclines increased from 4% in 2000 to 96% in 2005, but decreased to 68% in 2008. The use of trastuzumab- and taxane-containing regimens (with or without anthracyclines) increased from 2005 onwards to 24% and 34%, respectively, in 2008. Among the 82 breast cancer patients who received palliative chemotherapy at diagnosis or after breast cancer recurrence, the use of CMF and anthracyclines (without taxanes) decreased, while the use of taxanes (with or without anthracyclines) increased (26% in 2008). Trastuzumab was used as palliative chemotherapy from 2003 onwards, with 22% of the metastatic breast cancer patients receiving trastuzumab-containing regimens in 2008, and bevacizumab was administered since 2007 with 19% of the patients receiving bevacizumab-containing regimens in 2008. In conclusion, major changes have taken place in the chemotherapeutic treatment of patients with early and recurrent breast cancer. These changes reflect the key findings from large clinical trials, as incorporated in the Dutch guidelines.