Metronomic Chemotherapy in Triple-Negative Metastatic Breast Cancer: The Future Is Now?
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ABSTRACT:
SUBMITTER: Cazzaniga ME
PROVIDER: S-EPMC5733132 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
Publications
Metronomic Chemotherapy in Triple-Negative Metastatic Breast Cancer: The Future Is Now?
Cazzaniga M E ME Cortesi L L Ferzi A A Scaltriti L L Cicchiello F F Ciccarese M M Torre S Della SD Villa F F Giordano M M Verusio C C Nicolini M M Gambaro A R AR Zanlorenzi L L Biraghi E E Casini E E Legramandi L L Rulli E E
International journal of breast cancer 20171203
Triple-negative breast cancer (TNBC) shows a very bad prognosis, even in early stages of disease. Metronomic chemotherapy refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen with no prolonged drug-free breaks that leads to antitumor activity. In the present article, we review preclinical and clinical data of metronomic administration of chemotherapy agents with or without biological agents in TNBC cell lines and patients, contextually re ...[more]
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Project description:Triple negative breast cancer (TNBC) accounts for 15%-20% of all breast cancer, and is still defined as what it is not. Currently, TNBC is the only type of breast cancer for which there are no approved targeted therapies and maximum tolerated dose chemotherapy with taxanes and anthracycline-containing regimens is still the standard of care in both the neoadjuvant and adjuvant settings. In the last years, metronomic chemotherapy (MC) is being explored as an alternative to improve outcomes in TNBC. In the neoadjuvant setting, purely metronomic and hybrid approaches have been developed with the objective of increasing complete pathologic response (pCR) and prolonging disease free survival. These regimens proved to be very effective achieving pCR rates between 47%-60%, but at the cost of great toxicity. In the adjuvant setting, MC is used to intensify adjuvant chemotherapy and, more promisingly, as maintenance therapy for high-risk patients, especially those with no pCR after neoadjuvant chemotherapy. Considering the dismal prognosis of TNBC, any strategy that potentially improves outcomes, specially being the oral agents broadly available and inexpensive, should be considered and certainly warrants further exploration. Finally, the benefit of MC needs to be validated in properly designed clinical trials were the selection of the population is the key.
| S-EPMC5740099 | biostudies-literature
Project description:BackgroundMetastatic triple-negative breast cancer (mTNBC) is treated mainly with chemotherapy. However, resistance frequently occurs as tumours enter dormancy. Statins have been suggested as effective against cancer but as they prolong and promote dormancy, it is an open question of whether the concomitant use would interfere with chemotherapy in primary and mTNBC. We examined this question in animal models and clinical correlations.MethodsWe used a xenograft model of spontaneous metastasis to the liver from an ectopic tumour employing a mTNBC cell line. Atorvastatin was provided to sensitise metastatic cells, followed by chemotherapy. The effects of statin usage on outcomes in women with metastatic breast cancer was assessed respectively by querying a database of those diagnosed from 1999 to 2019.ResultsAtorvastatin had limited influence on tumour growth or chemotherapy effects in ectopic primary tumours. Interestingly, atorvastatin was additive with doxorubicin (but not paclitaxel) when targeting liver metastases. E-cadherin-expressing, dormant, breast cancer cells were resistant to the use of either statins or chemotherapy as compared to wild-type cells; however, the combination of both did lead to increased cell death. Although prospective randomised studies are needed for validation, our retrospective clinical analysis suggested that patients on statin treatment could experience prolonged dormancy and overall survival; still once the tumour recurred progression was not affected by statin use.ConclusionAtorvastatin could be used during adjuvant chemotherapy and also in conjunction with metastatic chemotherapy to reduce mTNBC cancer progression. These preclinical data establish a rationale for the development of randomised studies.
| S-EPMC8548312 | biostudies-literature
Project description:BACKGROUND:Chemotherapy resistance is a great obstacle in effective treatment for metastatic triple negative breast cancer (TNBC). The ability to predict chemotherapy response would allow chemotherapy administration to be directed toward only those patients who would benefit, thus maximizing treatment efficiency. Differentially expressed plasma proteins may serve as putative biomarkers for predicting chemotherapy outcomes. PATIENTS AND METHODS:In this study, 26 plasma samples (10 samples with partial response (S) and 16 samples with progression disease (R)) from patients with metastatic TNBC were measured by Tandem Mass Tag (TMT)-based proteomics analysis to identify differentially expressed proteins between the S and R group. Potential proteinswere validated with enzyme-linked immunosorbent assay (ELISA) in another 67 plasma samples. RESULTS:A total of 320 plasma proteins were identified, and statistical analysis showed that 108 proteins were significantly dysregulated between R and S groups in the screening stage. Bioinformatics revealed relevant pathways and regulatory networks of the differentially expressed proteins. Three differentially expressed proteins were validated by ELISA with 67 samples from TNBC patients. The R group had significantly higher plasma CAMK2A level than the S group (P=0.0074). The ROC curve analysis showed an AUC of 0.708, with sensitivity 48.4% and specificity 86.1%. In multivariate logistic regression analysis, the level of plasma CAMK2A was also significant for chemotherapeutic response (P=0.009, OR=0.152). Furthermore, the patients with higher CAMK2A level had shorter OS than those with lower CAMK2A level, which amounted to 13.9 and 28.9 months, respectively (P=0.034). In the multivariate Cox regression analysis, CAMK2A level still had significant effect on OS (P=0.031, HR=1.865). CONCLUSION:TMT-based proteomic analysis was able to identify potential biomarkers in plasma that predicted chemotherapy resistance in the metastatic TNBC. The plasma of CAMK2A level may serve as apotential predictive and prognostic biomarker for chemotherapy in metastatic TNBC.
| S-EPMC6958019 | biostudies-literature
Project description:Until recently, despite its heterogenous biology, metastatic triple negative breast cancer (TNBC) was treated as a single entity, with successive lines of palliative chemotherapy being the only systemic option. Significant gene expression studies have demonstrated the diversity of TNBC, but effective differential targeting of the four main (Basal-like 1 and 2, mesenchymal and luminal androgen receptor) molecular sub-types has largely eluded researchers. The introduction of immunotherapy, currently useful only for patients with PD-L1 positive cancers, led to the stratification of first-line therapy using this immunohistochemical biomarker. Germline BRCA gene mutations can also be targeted with PARP inhibitors in both the adjuvant and metastatic settings. In contrast, the benefit of the anti-Trop-2 antibody-drug conjugate (ADC) Sacituzumab govitecan (SG) does not appear confined to patients with tumours expressing high levels of Trop-2, leading to its potential utility for any patient with an estrogen receptor (ER)-negative, HER2-negative advanced breast cancer (ABC). Most recently, low levels of HER2 expression, detected in up to 60% of TNBC, predicts benefit from the potent HER2-directed antibody-drug conjugate trastuzumab deruxtecan (T-DXd), defining an additional treatment option for this sub-group. Regrettably, despite recent advances, the median survival of TNBC continues to lag far behind the approximately 5 years now expected for patients with ER-positive or HER2-positive breast cancers. We review the data supporting immunotherapy, ADCs, and targeted agents in subgroups of patients with TNBC, and current clinical trials that may pave the way to further advances in this challenging disease.
| S-EPMC10417818 | biostudies-literature
Project description:Conventional chemotherapy is generally administered in high doses followed by a treatment-free period to give the body needful time to recover. This "maximum tolerated dose" approach results in high response rates. However, long periods between therapy cycles can lead to development of resistance mechanisms and consequently disease progression. One of the most interesting alternative strategies is metronomic chemotherapy. This concept relies on the continuous administration of chemotherapy at low doses and aims at targeting endothelial cells in the tumor bed as well. Recently, metronomic chemotherapy has been incorporated into the recommendations issued by the German AGO expert panel (www.ago-online.de). A systematic review of PubMed/Medline, ClinicalTrials.gov, the European Clinical Trials Database (EudraCT) and the Cochrane Database was conducted. In the present review, we discuss the current evidence on metronomic chemotherapy in metastatic breast cancer.
| S-EPMC4873299 | biostudies-literature
Project description:Purpose: The IMpassion130 trial demonstrated the efficacy of adding atezolizumab to paclitaxel for advanced or metastatic triple-negative breast cancer (TNBC). The current study evaluated the cost-effectiveness of adding atezolizumab to nab-paclitaxel for TNBC from the perspective of Chinese health sector. Methods: A partitioned survival model was implemented for patients with TNBC. The survival data were derived from IMpassion130 trial. Direct costs and utility values were collected from the Chinese Drug Bidding Database and published literatures. The primary analysis outcomes were quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were performed to observe model stability. Results: In the base-case analysis, the ICER of atezolizumab plus nab-paclitaxel vs. nab-paclitaxel is respectively, $176,056/QALY, $118,146/QALY, and $323,077/QALY in the ITT, PD-L1(+) and PD-L1(-) group. Conclusion: Adding atezolizumab to nab-paclitaxel could improve survival time significantly in the PD-L1-positive group, but it is not a cost-effective strategy compared to nab-paclitaxel monotherapy for Chinese patients with advanced or metastatic triple-negative breast cancer in the current economic context of China.
| S-EPMC8585931 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) represents a heterogeneous breast cancer subtype with a poor prognosis. The optimal adjuvant chemotherapy regimen is still unknown. Although numerous large randomized trials have established the benefit of adjuvant anthracyclines and/or taxanes in TNBC, there is no preferred regimen for these patients. There is currently no guideline. Moreover, without knowing the optimal treatment backbone, it will not be possible to evaluate whether adding agents such as platinum or other novel therapies is beneficial for TNBC patients. Furthermore, the best duration of adjuvant treatment in TNBC is still unknown. This review will focus on results of clinical trials that analyzed the benefits of extending the duration of adjuvant treatment in TNBCs with maintenance treatments. We will further discuss promising results in favor of other new agents including capecitabine, metronomic treatment, and biological drugs.
| S-EPMC5527164 | biostudies-other
Project description:PurposeThe ASCENT trial demonstrated the efficacy of sacituzumab govitecan for the treatment of advanced or metastatic triple-negative breast cancer (TNBC). The current study evaluated the cost-effectiveness of receiving sacituzumab govitecan compared with standard of care chemotherapy from the United States payer perspective.MethodsA partitioned survival approach was used to project the disease course of advanced or metastatic TNBC. Two survival modes were applied to analyze two groups of patients. The survival data were gathered from the ASCENT trial. Direct medical costs were derived from the data of Centers for Medicare & Medicaid Services. Utility data was collected from the published literature. The incremental cost-utility ratio (ICUR) was the primary outcome that measured the cost-effectiveness of therapy regimen. One-way sensitivity and probabilistic sensitivity analysis were implemented to explore the uncertainty and validate the stability of results.ResultsIn the base-case, the ICUR of sacituzumab govitecan versus chemotherapy is $ 778,771.9/QALY and $ 702,281/QALY for full population group and brain metastatic-negative (BMN) group with the setting of classic survival mode. And in the setting of cure survival mode, the ICUR is $ 506,504.5/QALY for the full population group and $ 274,232.0/QALY for BMN population group. One-way sensitivity analyses revealed that the unit cost of sacituzumab govitecan and body weight were key roles that lower the ICUR value. Probabilistic sensitivity analyses also showed that reducing the unit price of sacituzumab govitecan can improve the likelihood of becoming cost-effective.ConclusionThe cost-effectiveness analysis suggested that from a US payer perspective, sacituzumab govitecan at current price is unlikely to be a preferred option for patients with advanced or metastatic TNBC at a threshold of $ 150,000/QALY.
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Project description:The optimal neoadjuvant chemotherapy (NACT) regimen in triple-negative breast cancer (TNBC) has not been clearly defined. Achieving a pathologic complete response (pCR) provides important prognostic information, and, especially in TNBC, is considered a surrogate endpoint for event-free survival. Thus, many neoadjuvant studies in TNBC focus on this as a primary endpoint, and such information may be used for accelerated US Food and Drug Administration approval. Current controversies in the field include: (1) the role of platinum-based compounds; (2) the optimal chemotherapy backbone; and (3) the benefits of additional therapy after surgery. Conflicting results of 2 major studies adding carboplatin to NACT have highlighted the need to balance potential benefits to disease outcomes against increased toxicity. While the PROGECT study suggests efficacy of a nonanthracycline-containing regimen, this is observational data, and evidence in the form of a clinical trial remains to be seen. Data surrounding optimal taxane use support the use of nab-paclitaxel in place of paclitaxel in limited clinical situations. Although bevacizumab may increase pCR rates, this has not translated into survival benefit. Capecitabine shows promise in patients who have not achieved pCR after NACT. The neoadjuvant setting remains an important model for drug development. This review will focus on the most important and most current neoadjuvant trials in women with TNBC.
| S-EPMC5865448 | biostudies-literature
Project description:The objective of the study was to detect changes in quality of life (QoL) in metastatic breast cancer patients treated with metronomic chemotherapy with daily low doses of cyclophosphamide and celecoxib.Patients included in a Phase II trial, treated with metronomic cyclophosphamide and celecoxib were included in the QoL study. Assessment of QoL was carried out every 2 months by the Functional Assessment of Cancer Therapy Breast (FACT-B) questionnaire, Brief Pain Inventory and Eastern Cooperative Oncologic Group scale. Data were analyzed at three time points: baseline (BL); middle of treatment (MT); and end of treatment (ET).A total of 20 patients were included. All patients were heavily pretreated. Treatment showed a good and safe therapeutic profile. With FACT-B questionnaire, no significant differences were observed during the response period (BL-MT). However, a significant increase was observed in the Emotional well-being and Additional concerns axes, when the last time point was included in the analysis (BL-MT-ET). A significant decrease in the proportion of patients with pain was found when comparing BL with ET (p = 0.046). The assessment with Eastern Cooperative Oncologic Group scale showed that 26.7% (4/15) of the patients improved their functional status and 40% (6/15) showed no changes, while 33.3% (5/10) worsened it.Patients treated metronomically for several months did not worsen their QoL. A high proportion of patients showed improvement or no changes and there were less patients with pain at the end of the treatment.
| S-EPMC4976839 | biostudies-other