Anthracycline-resistant Breast Cancer Research Articles

A comparison of platinum-based chemotherapy versus capecitabine-based chemotherapy in the treatment of breast cancer metastasis to the liver.

e12595 Background: Liver metastasis have long been known to indicate an unfavourable disease course in breast cancer (BC). A variety of drugs have been used in first choice for anthracycline-resistant and/or taxane-resistant breast cancer. This study aimed to systematically investigate the impact of different treatments. Methods: Between January 2003 and December 2013, we examined the clinical outcome of breast cancer patients with liver metastases from database in China National Cancer Center. 284 patients who received platinum or capecitabine based chemotherapy as first-line treatment were analyzed and followed up until December 2018. Results: Overall, 284 patients (female:280/284 (98.6%); male:4/284 (1.4%)) breast cancer with liver metastasis were available for this analysis. 205/ 284 patients (72.2%) received capecitabine-based chemotherapy including docetaxel/capecitabine (TX) and vinorelbine/capecitabine(NX), while 79/284 patients (27.8%) received platinum-based chemotherapy including docetaxel/ platinum (TP) and vinorelbine/platinum(NP).The median PFS (10.1 vs 8.3 months; P = .329; 95%), and the median overall survival (OS) (35.3 vs 19.8 months; P = .012) in the TX/NX group appeared to be longer compared with those in the NP/TP group, among which NP group seemed to be the poorest. Patients aged ≥50 years who were postmenopausal were more likely to benefit from the TX/NX regimens in terms of OS, however hormone receptor and human epidermal growth factor receptor 2 status did not affect differences in PFS and OS between the TX/NX and TP/NP groups. Conclusions: Capecitabine-based chemotherapy for advanced breast cancer with liver metastasis led to longer OS than platinum-based chemotherapy. These findings should be validated in more prospective cohorts.

Abstract OT2-01-20: Phase IIB study of neoadjuvant panitumumab combined with carboplatin and paclitaxel (PaCT) for anthracycline-resistant triple-negative breast cancer (TNBC)

Abstract BACKGROUND: Approximately 50% of patients with TNBC treatedwithstandardtaxane/anthracycline-based neoadjuvant chemotherapy (NACT)have chemo-insensitive disease (CID), i.e., residual disease burden (RCB)-II/III at the time of surgery, and 40-80% of patients develop recurrence within 3 years. Recent developments in molecular profiling have identified subsets of TNBC with distinct, targetable molecular features. We developed a clinical trial to identify and characterize CID (ARTEMIS: A Randomized, TNBC-Enrolling trial to confirm Molecular profiling Improves Survival). In ARTEMIS, patients with localized TNBC will undergo a pretreatment biopsy, then begin anthracycline-based NACT. During NACT, we use molecular profiling and response assessment to identify CID and allocate patients to alternative therapies to overcome CID. Epidermal growth factor receptor (EGFR) is overexpressed in 25-30% of TNBC. In preclinical studies, suppression of EGFR signaling has shown efficacy in controlling cancers through suppression of the stem cell population, enhanced apoptosis via MAPK/PI3K signaling, and modulation of epithelial-mesenchymal transition (EMT). Moreover, in a phase II trial of triple negative inflammatory breast cancer, neoadjuvant PaCT yielded significantly higher pathologic complete response (pCR) rates than historic control. Taken together, we hypothesize that using PaCT to suppress EGFR in TNBC will enhance the pCR rate. OBJECTIVES: Primary objective: determine pCR and RCB-0/I rates in TNBC patients with CID given PaCT. Secondary objective: determine the benefit of using baseline genomic signatures to develop an alternative second phase of NACT. TRIAL DESIGN AND STATISTICAL METHODS: Patients with >10% volume reduction for non-CID or <80% for CID will enroll in a biomarker-guided, experimental, nonrandomized phase II study and be given PaCT (panitumumab 2.5 mg/kg, carboplatin AUC 5, paclitaxel 80 mg/m2). Because pCR rates in pts with CID with additional cycles of taxane-based therapy are low (∼5%), a 20% response rate (RCB-0 or RCB-I) will be considered clinically meaningful. A two-stage Gehan-type design will be employed. If at least 1 of 14 patients responds, 23 more patients will be added, for a total of 37 patients. This design has a 49% chance of terminating after the first stage if the true response rate is 0.05, 23% if the rate is 0.10, 10% if the rate is 0.15, and 4% if the rate is 0.20. If accrual continues to the second stage and 37 patients are enrolled, the 95% confidence interval for a 0.20 response rate will be 0.10 to 0.35. BRIEF ELIGIBILITY CRITERIA: Inclusion: localized TNBC; enrolled in ARTEMIS trial; adequate organ, bone marrow, and cardiac parameters; Exclusion: pregnant or lactating, known or suspected metastasis. CORRELATIVE SCIENCE: Circulating tumor cells (CTCs) and cell free (cf) DNA in baseline and subsequent blood samples, EGFR expression (immunohistochemistry), stem cell/EMT/apoptosis marker changes in tissue and CTCs, PD-L1 glycosylation for EGFR sensitivity. Citation Format: Lim B, Helgason T, Hess KR, Piwnica-Worms H, Yang W, Adrada BE, Rauch GM, Gilcrease M, Symmans FW, Huo L, Mittendorf EA, Thompson A, Stacy M-TL, Debu T, Ueno NT. Phase IIB study of neoadjuvant panitumumab combined with carboplatin and paclitaxel (PaCT) for anthracycline-resistant triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-20.

Genome-wide profiling of long non-coding RNA expression patterns in anthracycline-resistant breast cancer cells.

Long non-coding RNAs (lncRNAs) are involved in cancer progression. In the present study, we analyzed the lncRNA profiles in adriamycin-resistant and -sensitive breast cancer cells and found a group of dysregulated lncRNAs in the adriamycin-resistant cells. Expression of the dysregulated lncRNAs was correlated with dysregulated mRNAs, and these were enriched in GO and KEGG pathways associated with cancer progression and chemoresistance development. Among these lncRNA-mRNA interactions, some lncRNAs may cis‑regulate neighboring protein-coding genes and be involved in chemoresistance. We then validated that the lncRNA NONHSAT028712 regulated nearby CDK2 and interfered with the cell cycle and chemoresistance. Furthermore, we identified another group of lncRNAs that trans-regulated genes by interacting with different transcription factors. For example, NONHSAT057282 and NONHSAG023333 modulated chemoresistance and most likely interacted with the transcription factors ELF1 and E2F1, respectively. In conclusion, in the present study, we report for the first time the lncRNA expression patterns in adriamycin-resistant breast cancer cells, and provide a group of novel lncRNA targets that mediate chemoresistance development in both cis- and trans-action modes.

Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer.

BackgroundDrug resistance in breast cancer is the major obstacle to effective treatment with chemotherapy. While upregulation of multidrug resistance genes is an important component of drug resistance mechanisms in vitro, their clinical relevance remains to be determined. Therefore, identifying pathways that could be targeted in the clinic to eliminate anthracycline-resistant breast cancer remains a major challenge.MethodsWe generated paired native and epirubicin-resistant MDA-MB-231, MCF7, SKBR3 and ZR-75-1 epirubicin-resistant breast cancer cell lines to identify pathways contributing to anthracycline resistance. Native cell lines were exposed to increasing concentrations of epirubicin until resistant cells were generated. To identify mechanisms driving epirubicin resistance, we used a complementary approach including gene expression analyses to identify molecular pathways involved in resistance, and small-molecule inhibitors to reverse resistance. In addition, we tested its clinical relevance in a BR9601 adjuvant clinical trial.ResultsCharacterisation of epirubicin-resistant cells revealed that they were cross-resistant to doxorubicin and SN-38 and had alterations in apoptosis and cell-cycle profiles. Gene expression analysis identified deregulation of histone H2A and H2B genes in all four cell lines. Histone deacetylase small-molecule inhibitors reversed resistance and were cytotoxic for epirubicin-resistant cell lines, confirming that histone pathways are associated with epirubicin resistance. Gene expression of a novel 18-gene histone pathway module analysis of the BR9601 adjuvant clinical trial revealed that patients with low expression of the 18-gene histone module benefited from anthracycline treatment more than those with high expression (hazard ratio 0.35, 95 % confidence interval 0.13–0.96, p = 0.042).ConclusionsThis study revealed a key pathway that contributes to anthracycline resistance and established model systems for investigating drug resistance in all four major breast cancer subtypes. As the histone modification can be targeted with small-molecule inhibitors, it represents a possible means of reversing clinical anthracycline resistance.Trial registrationClinicalTrials.gov identifier NCT00003012. Registered on 1 November 1999.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0676-6) contains supplementary material, which is available to authorized users.

Cross-platform meta-analysis of multiple gene expression profiles identifies novel expression signatures in acquired anthracycline-resistant breast cancer.

Anthracyclines are among the most effective and commonly used chemotherapeutic agents. However, the development of acquired anthracycline resistance is a major limitation to their clinical application. The aim of the present study was to identify differentially expressed genes (DEGs) and biological processes associated with the acquisition of anthracycline resistance in human breast cancer cells. We performed a meta-analysis of publically available microarray datasets containing data on stepwise-selected, anthracycline‑resistant breast cancer cell lines using the RankProd package in R. Additionally, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to analyze GO term enrichment and pathways, respectively. A protein-protein interaction (PPI) network was also generated using Cytoscape software. The meta-analysis yielded 413 DEGs related to anthracycline resistance in human breast cancer cells, and 374 of these were not involved in individual DEGs. GO analyses showed the 413 genes were enriched with terms such as 'response to steroid metabolic process', 'chemical stimulus', 'external stimulus', 'hormone stimulus', 'multicellular organismal process', and 'system development'. Pathway analysis revealed significant pathways including steroid hormone biosynthesis, cytokine-cytokine receptor interaction, drug metabolism-cytochrome P450, metabolism of xenobiotics by cytochrome P450, and arachidonic acid metabolism. The PPI network indicated that proteins encoded by TRIM29, VTN, CCNA1, and karyopherin α 5 (KPNA5) participated in a significant number of interactions. In conclusion, our meta-analysis provides a comprehensive view of gene expression patterns associated with acquired resistance to anthracycline in breast cancer cells, and constitutes the basis for additional functional studies.

Weekly paclitaxel in escalating doses in a patient with anthracycline-resistant, triple-negative, metastatic breast cancer with severe liver dysfunction

Liver dysfunction in a patient with anthracycline-resistant breast cancer and liver metastases with poor performance status (PS) represents a serious situation. Taxanes are the drugs of choice, but once the transaminase enzyme levels are raised more than 10-times the upper limit of normal (>10 ULN), paclitaxel administration is contraindicated. We present the report of one such case who had a gratifying response to escalating doses of weekly paclitaxel thus suggesting that even patients with severe liver dysfunction can derive benefits from such a strategy. The patient, a 54-year-old lady with breast cancer metastatic to the liver and bones and previous receipt of anthracycline-based therapy, presented to us with a PS of 3. Her liver functions (LFT) were: serum bilirubin 2.2 mg% (0.3–1.1 mg%), aspartate aminotransferase 375 IU/L (0–25 IU/L), alanine aminotransferase 369 IU/L (0–35 IU/L) and alkaline phosphatase 363 IU/L (38–126 IU/L). She was started on weekly paclitaxel 20 mg/m2 and zoledronate. After the first dose, the LFTs rose marginally but the skin lesions stabilized. Dose was subsequently escalated to 40 mg/m2. At the end of the 10th week, her PS improved to 1 and the disease showed a partial response. LFTs improved markedly. However, 5 days after the administration of the 13th dose, the disease progressed and paclitaxel had to be discontinued. It is possible to derive maximum palliative benefit with escalating doses of weekly paclitaxel even in patients whose liver functions are deranged with transaminase levels (>10 ULN) and in whom conventional administration of paclitaxel is contraindicated.

How Circulating Tumor Cells Escape From Multidrug Resistance

Resistance to anthracyclines is responsible for treatment failure in most patients with metastatic breast cancer. According to recent studies, the expression of specific drug transporters (MRPs) on circulating tumor cells is predictive of prognosis in different cancer types. We observed that patients whose circulating tumor cells expressed MRP1 and MRP2, two drug-export pumps responsible for anthracyclines efflux, who received conventional anthracyclines had a significantly shorter time to progression compared with patients sharing same characteristics who received non pegylated liposomal doxorubicin (P < 0.005). These results may highlight a new appealing role of the liposomal doxorubicin formulation, not only because of its reduced cardiac toxicity but especially referring to its theoretical efficacy in anthracycline-resistant breast cancer patients.

Metnase Mediates Resistance to Topoisomerase II Inhibitors in Breast Cancer Cells

DNA replication produces tangled, or catenated, chromatids, that must be decatenated prior to mitosis or catastrophic genomic damage will occur. Topoisomerase IIα (Topo IIα) is the primary decatenating enzyme. Cells monitor catenation status and activate decatenation checkpoints when decatenation is incomplete, which occurs when Topo IIα is inhibited by chemotherapy agents such as the anthracyclines and epididophyllotoxins. We recently demonstrated that the DNA repair component Metnase (also called SETMAR) enhances Topo IIα-mediated decatenation, and hypothesized that Metnase could mediate resistance to Topo IIα inhibitors. Here we show that Metnase interacts with Topo IIα in breast cancer cells, and that reducing Metnase expression significantly increases metaphase decatenation checkpoint arrest. Repression of Metnase sensitizes breast cancer cells to Topo IIα inhibitors, and directly blocks the inhibitory effect of the anthracycline adriamycin on Topo IIα-mediated decatenation in vitro. Thus, Metnase may mediate resistance to Topo IIα inhibitors, and could be a biomarker for clinical sensitivity to anthracyclines. Metnase could also become an important target for combination chemotherapy with current Topo IIα inhibitors, specifically in anthracycline-resistant breast cancer.

Dose-independent synergistic response with gemcitabine and cisplatin in anthracycline-resistant breast cancer and reversal of resistance to gemcitabine with addition of paclitaxel

Dose-independent synergistic response with gemcitabine and cisplatin in anthracycline-resistant breast cancer and reversal of resistance to gemcitabine with addition of paclitaxel

Changes of Topoisomerase IIα Expression in Breast Tumors after Neoadjuvant Chemotherapy Predicts Relapse-Free Survival

To assess the value of changes in the expression of topoisomerase IIalpha (TopoII) and the proto-oncogene erbB-2 (HER-2) as predictors of relapse-free survival in women with operable breast cancer treated with anthracycline-based neoadjuvant chemotherapy. Seventy-seven patients with primary breast cancer who had undergone neoadjuvant anthracycline-based chemotherapy were included in the present study. TopoII and HER-2 were measured by immunohistochemistry in prechemotherapy and postchemotherapy (at the time of surgery) tumor specimens, and the value of their changes as predictors of relapse-free survival were evaluated by Kaplan-Meier and Cox proportional hazard regression analyses. Neoadjuvant chemotherapy resulted in a significant reduction in the percentage of cells expressing TopoII (P < 0.0001). No significant change was observed for HER-2. TopoII and HER-2 expression before chemotherapy predicted tumor response to treatment. Changes in TopoII expression after chemotherapy were strongly associated with a poor relapse-free survival (P < 0.0001) in a Cox multivariate analysis adjusted for other clinicopathologic prognostic factors. Changes in TopoII expression after anthracycline-based neoadjuvant chemotherapy is an independent predictor of a poor relapse-free survival in patients with breast cancer. Tumor cells displaying an increased TopoII expression after treatment may be responsible for relapses, and may, therefore, define a group of patients with anthracycline-resistant breast cancer.

Treatment of Anthracycline-Resistant Breast Cancer

The anthracyclines are commonly used for the treatment of early stage and advanced stage breast cancer, but many patients develop resistance to therapy. The definition of anthracycline resistance varies considerably in the literature, but in most cases includes disease progression during or within 6–12 months after completion of anthracycline therapy. Some authors have distinguished true anthracycline resistance (defined as progression during anthracycline therapy) from anthracycline pretreatment (defined as progression after completion of therapy).

Locoregional treatment outcomes for inoperable anthracycline-resistant breast cancer

Purpose: To assess the therapeutic outcomes and treatment-related morbidity of patients treated with radiation for inoperable breast cancer resistant to anthracycline-containing primary chemotherapy. Methods and Materials: We analyzed the medical records of breast cancer patients treated on five consecutive institutional trials who had been designated as having inoperable locoregional disease after completion of primary chemotherapy, without evidence of distant metastases at diagnosis. The cohort for this analysis was 38 (4.4%) of 867 patients enrolled in these trials. Kaplan-Meier statistics were used for survival analysis, and prognostic factors were compared using log-rank tests. The median follow-up of surviving patients was 6.1 years. Results: Thirty-two (84%) of the 38 patients were able to undergo mastectomy after radiotherapy. For the whole group, the overall survival rate at 5 years was 46%, with a distant disease-free survival rate of 32%. The 5-year survival rate for patients who were inoperable because of primary disease extent was 64% compared with 30% for those who were inoperable because of nodal disease extent ( p = 0.0266). The 5-year rate of locoregional control was 73% for the surgically treated patients and 64% for the overall group. Of the 32 who underwent mastectomy, the 5-year rate of significant postoperative complications was 53%, with 4 (13%) requiring subsequent hospitalization and additional surgical revision. Preoperative radiation doses of ≥54 Gy were significantly associated with the development of complications requiring surgical treatment (70% vs. 9% for doses <54 Gy, p = 0.0257). Conclusion: Despite the poorer prognosis of patients with inoperable disease after primary chemotherapy, almost one-half remained alive at 5 years and one-third were free of distant disease after multidisciplinary locoregional management. These patients have high rates of locoregional recurrence after preoperative radiotherapy and mastectomy, and the morbidity associated with this approach may limit dose-escalation strategies. Alternative therapeutic strategies such as novel systemic agents, use of planned myocutaneous repair for closure, or radiation combined with radiosensitizing agents, should be considered in this class of patients.

Lack of activity of stealth liposomal doxorubicin in the treatment of patients with anthracycline-resistant breast cancer.

We conducted a single-institution phase II clinical trial to determine the objective response rate, duration of response, time to progression, and overall survival in patients with anthracycline-resistant breast cancer treated with Doxil. Patients with metastatic breast cancer were eligible if they had disease progression while receiving an anthracycline-containing regimen or developed evidence of metastatic disease during or within 6 months after the last cycle of an anthracycline-containing adjuvant regimen. Prior treatment with liposomal doxorubicin was not allowed. Patients received a dose of 50 mg/m(2) infused every 4 weeks via a peripheral vein or central line. Doxil was administered for a total of six cycles or until disease progression. We treated 11 patients with stage IV breast cancer of whom two had never received chemotherapy for their metastatic disease. Most had a performance status of 1 and had visceral involvement as their dominant site of disease. All patients had received prior therapy with doxorubicin. No clinical evidence of congestive heart failure or cardiac toxicity was observed. The most common toxicities were nonhematologic and were mostly grade 1/2. These included fatigue, nausea, vomiting, and stomatitis. Significant myelosuppression was only observed in one patient. No complete or partial response was observed. There were two patients who had a minimal response and two other patients who had evidence of stable disease. Doxil was well tolerated with minimal toxicity. However, the lack of antitumor activity in anthracycline-resistant breast cancer patients indicates that further evaluation in this patient population is not warranted.

Docetaxel in Patients with Anthracycline-Resistant Advanced Breast Cancer

Objective: To better determine docetaxel activity in patients with well-defined anthracycline-resistant breast cancer. Methods: From October 1996, we carried out a phase II trial in 69 heavily pretreated patients with advanced breast cancer with docetaxel 100 mg/m² by a 1-hour infusion on day 1, with cycles repeated every 3 weeks. Patients were classified as having primary anthracycline resistance (n = 32), secondary anthracycline resistance (n = 7), anthracycline pretreatment (n = 22) or no anthracycline pretreatment (n = 8). Results: Among 68 evaluable patients, we observed 6 (9%) complete responses and 27 (40%) partial responses, for an overall response rate of 49% (95% confidence interval 37–61%); the disease remained stable in 17 patients (25%). Responses according to the above subgroups were as follows: primary anthracycline resistance 41%, secondary anthracycline resistance 43%, anthracycline pretreatment 64% and no anthracycline pretreatment 43%. The median time to response, median time to progression and median overall survival were 2, 7 and 10 months, respectively. Myelosuppression was the dose-limiting toxicity, with grade 4 neutropenia occurring in 47% of the patients and neutropenic fever in 12%. G-CSF was added in the case of grade 4 febrile neutropenia; a 25% reduction in the dose of docetaxel was required in 4 patients. Other side effects were mild. Conclusions: The results of the present trial confirm the high activity of docetaxel in heavily pretreated patients with advanced breast cancer, including those with strictly defined anthracycline resistance.

A unified definition of clinical anthracycline resistance breast cancer.

The purpose of the study was to determine the response rates (RR) and duration to second- and third-line chemotherapy programmes in patients with anthracycline-resistant breast cancer, utilizing various definitions of anthracycline resistance. This was a retrospective analysis performed on 1335 patients with metastatic breast cancer who participated in consecutive clinical trials of first line, anthracycline-containing combination chemotherapy (ACCC) at the University of Texas MD Anderson Cancer Center between July 1973 and April 1980. Anthracycline-resistant groups were identified using definitions of anthracycline resistance found in the literature: progressive disease as best response to ACCC (Group 1, n = 56 patients); progressive disease while receiving ACCC after an intervening response to the drug (Group 2, n = 84); progressive disease within 6 months of last dose of ACCC (Group 3, n = 233); and progressive disease within 12 months of last dose of ACCC (Group 4, n = 272). Second- and third-line therapies administered to these patients included methotrexate, doxorubicin, mitoxantrone, bisantrene, vinblastine, vindesine, melphalan, mitomycin, cisplatin, etoposide and others, but not taxanes. The distribution of patients' characteristics was similar between the four groups, as was the use of second- and third-line regimens. Response rate (RR) to second-line chemotherapy were 5% and 7.7% for Group 1 and Group 2 respectively. In contrast, RR to second-line chemotherapy were 21.6% and 15% for Group 3 and 4. The differences in response rate between the combination of Groups 1 and 2 and Groups 3 or 4 were significant (P = 0.005 and P = 0.04 respectively). These results indicate that strictly defined anthracycline resistance as defined in Groups 1 and 2 is associated with resistance to many other cytotoxic drugs. The definitions used in Groups 3 and 4 include many patients with responsive tumours, and a more favourable prognosis. © 2000 Cancer Research Campaign

Cost-utility analysis of chemotherapy using paclitaxel, docetaxel, or vinorelbine for patients with anthracycline-resistant breast cancer.

Paclitaxel, docetaxel, and vinorelbine have been approved for chemotherapy in patients with advanced breast cancer that is resistant to anthracyclines. Selecting which agent to use is difficult because each possesses advantages and disadvantages related to clinical response, toxicity, method of administration, and cost. A cost-utility analysis was therefore performed to create a rank order on the basis of effectiveness, quality of life, and economic considerations. Eighty-eight anthracycline-resistant breast cancer patients who had received paclitaxel (n = 34), docetaxel (n = 29), or vinorelbine (n = 25) during the past 2 years were identified. Total resource consumption was collected, which included expenditures for chemotherapy, supportive care, laboratory tests, management of adverse effects, and all related physician fees. Utilities from 25 oncology care providers and 25 breast cancer patients were estimated using the time trade-off technique. The economic estimates from the chart review and clinical data from the literature were then modeled using the principles of decision analysis. Each of the three drugs led to a similar duration of quality-adjusted progression-free survival (paclitaxel, 37.2 days; docetaxel, 33.6 days; vinorelbine, 38.0 days). Vinorelbine was the least costly strategy, with an overall treatment expenditure of Can $3,259 per patient, compared with Can $6,039 and Can $10,090 for paclitaxel and docetaxel, respectively. Palliative chemotherapy with vinorelbine in anthracycline-resistant metastatic breast cancer patients has economic advantages over the taxanes and provides at least equivalent quality-adjusted progression-free survival. These benefits are largely related to its lower drug acquisition cost and better toxicity profile.

The efficacy of chemotherapy with docetaxel and paclitaxel in anthracycline-resistant breast cancer (Review).

This review was performed to determine the efficacy of commonly used cytotoxic agents in the management of anthracycline-resistant breast cancer, using a stringent and uniform definition of drug resistance. We reviewed the reports of second- and third-line chemotherapy after anthracycline-containing regimens published over the last two decades. Only studies with sufficient information on the timing of progressive disease in relation to anthracycline therapy were considered. All assessable studies were reviewed individually, and the data obtained with taxanes in anthracycline-resistant breast cancer were also pooled to estimate the activity. The great majority of published studies on second- and third-line chemotherapy lack useful information about anthracycline resistance. Among the few studies with sufficient information about anthracycline resistance, several definitions were used. We reanalyzed those reports utilizing a uniform definition of anthracycline resistance: progression while receiving an anthracycline. Only studies using paclitaxel or docetaxel reported an activity in this anthracycline-resistant population, allowing a response rate between 6-50% and 32-57% for both agents respectively. The activity of other cytotoxic agents in anthracycline-resistant breast cancer could not be determined because a lack of accurate data using the stringent definition. Both paclitaxel and docetaxel have substantial antitumor activity in patients with clearly defined anthracycline-resistant breast cancer. The activity of other cytotoxic agents in this group of patients remains to be established.

Docetaxel: a taxoid for the treatment of metastatic breast cancer.

The pharmacology, pharmacokinetics, clinical trials, adverse effects, and dosage and administration of docetaxel are reviewed. Docetaxel, a taxoid for the treatment of metastatic breast cancer, blocks the ability of tumor cells to divide in the M phase of the cell cycle. The drug has demonstrated superior cytotoxic activity in the treatment of a variety of cancers and enhanced activity in combination with other drugs. The pharmacokinetics of docetaxel appear to be linear. There seems to be a large interpatient variation in docetaxel biotransformation rates. Docetaxel has FDA-approved labeling for use in the treatment of patients with locally advanced or metastatic breast cancer whose disease has progressed during anthracycline-based therapy or who have relapsed during anthracycline-based adjuvant therapy. Phase II trials established the drug's role in first-line and second-line treatment of advanced breast cancer and as therapy for anthracycline-resistant advanced breast cancer, and they suggested a role for the agent in combination chemotherapy. The dose-limiting toxicity in all studies has been neutropenia. Other commonly noted adverse effects include mucositis, hypersensitivity reactions, and neuropathy. The recommended dosage for patients with metastatic or locally advanced breast cancer and normal hepatic function is 60-100 mg/m2 i.v. infused over one hour every three weeks. Docetaxel is not recommended for patients with liver metastases or impaired liver function because clearance of the drug is impaired. Docetaxel is effective in the treatment of metastatic and anthracycline-resistant breast cancer and may have a role in combination with other agents and in neoadjuvant and adjuvant therapy.

Ifosfamide given by continuous-intravenous infusion in association with vinorelbine in patients with anthracycline-resistant metastatic breast cancer: A phase I–II clinical trial

Vinorelbine (VNR) is highly active in metastatic breast cancer (MBC) and has shown an overall response rate of 40%-50% as first-line treatment. In vitro, a synergy has been observed between this drug and ifosfamide (IFX). In addition, the pharmacokinetics of IFX suggest that it may have greater activity when given by continuous-intravenous infusion (c.i.v.i.). The aim of this study was, therefore, to assess the antitumor efficacy and toxicity of the combination of bolus VNR and c.i.v.i. IFX as second-line therapy in anthracycline-resistant breast cancer patients. Forty-two patients with MBC who had already received anthracycline-based chemotherapy were treated with a regimen consisting of IFX, by c.i.v.i. for 72 hours and bolus VNR. The courses were repeated every three weeks for a maximum of eight cycles. Four dose intensification steps were planned: IFX, 1.5 g/m2 on days 1-3 + VNR, 30 mg/m2 on day 1 (six patients); IFX, 2 g/m2 on days 1-3 + VNR, 25 mg/m2 on day 1 (six patients); IFX, 1.8 mg/m2 on days 1-3 + VNR, 25 mg/m2 on days 1 and 8 (six patients); IFX, 2 g/m2 on days 1-3 + VNR, 25 mg/m2 on days 1 and 8 (24 patients). Sodium-2-mercaptoethane sulfonate (mesna) was associated with IFX at an infusion ratio of 1:1 and, once the infusion was completed, per os every four hours for three times. All of the 42 patients entered were assessable for toxicity, and 41 of them for response. Neutropenia was the most frequently-occurring toxicity, but only five patients at the highest dose level (11.9%) presented grade 4, and none of those at the first three steps. Other significant toxic effects were mild (only grade I-II). The median relative dose intensity was 95% at the highest dose level and all of the treatments were administered on an out-patient basis. The overall response rate was 36.5% with a CR rate of 4.8% (two of 41 patients, all at the highest dose level) and a PR rate of 31.7% (13 of 41 patients). The median response duration was 7.0 months (range 2-13 months). The present phase I-II study shows that the IFX and VNR combination is an active and well-tolerated treatment in MBC and provides an alternative to taxanes for patients previously treated with anthracyclines.

Anthracycline-Resistant Breast Cancer.

The management of breast cancer requires the judicious use of cytotoxic therapy, hormone therapy, radiotherapy, analgesics, and other forms of physical and psychological support for optimal palliation of symptoms and prolongation of survival. Patients with low-risk metastatic breast cancer often benefit from hormone therapy as initial management; other patients are best treated with early introduction of cytotoxic therapy. Combination chemotherapy is superior to single-agent treatment, and anthracycline-containing regimens are more effective than the rest. The development of primary or secondary resistance to anthracycline therapy represents an adverse prognostic indicator, associated, until recently, with poor response to subsequent cytotoxic therapy and short survival. Prior to the development of taxanes, response to second- and third-line chemotherapy for patients with primary anthracycline resistance was observed in 5% of patients. Paclitaxel and docetaxel retain substantial antitumor activity in anthracycline-resistant breast cancer, and vinorelbine is also moderately effective in this subset of patients. Attempts to reverse P-glycoprotein-related drug resistance, while encouraging in the laboratory, have not been successful in the clinic. A number of novel therapeutic interventions, many that bypass traditional mechanisms of drug resistance, are currently in clinical developments, with encouraging preliminary results.