Taxane-pretreated Metastatic Breast Cancer Research Articles

Efficacy and safety of nanoparticle albumin-bound paclitaxel in taxane-pretreated metastatic breast cancer patients.

Taxanes are the basic components of breast cancer chemotherapy. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) shows improved antitumor effects because of more targeted delivery. However, the effects of nab-paclitaxel have not been systematically studied in patients with metastatic breast cancer (MBC) pretreated with taxanes. Considering the limited treatment options for MBC, this study retrospectively evaluated the clinical efficacy and adverse effects of nab-paclitaxel in patients with taxane-pretreated MBC. Patients who had previously received taxanes and subsequently received nab-paclitaxel chemotherapy for MBC at Jiangsu Cancer Hospital between October 2014 and April 2022 were included for analysis. The primary end point was progression-free survival (PFS), and the secondary end points were the objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and side effects. A total of 236 female patients with MBC were included. The median PFS was 7.20months (95% confidence interval [CI], 6.63-7.80months), and the ORR, DCR, and CBR were 29.55% (95% CI, 23.50%-35.60%), 83.64% (95% CI, 78.70%-88.60%), and 56.36% (95% CI, 49.80%-63.00%), respectively. Following nab-paclitaxel treatment, the median PFS of patients who were sensitive to taxanes during previous treatments was significantly longer than that of patients who were resistant to taxanes (7.57months vs. 4.43months, p<.001). The most common adverse events were sensory neuropathy (89.83%), neutropenia (48.73%), leukopenia (46.61%), and anemia (35.59%). Nab-paclitaxel demonstrated clinical activity in taxane-pretreated patients with MBC. This beneficial effect was observed both in patients who were sensitive and resistant to taxanes during previous treatments. These results suggest nab-paclitaxel as the preferred chemotherapy regimen in patients with MBC, regardless of their sensitivity to taxanes during previous treatments.

Maintenance chemotherapy after 6 cycles of platinum-doublet regimen in anthracycline-and taxane-pretreated metastatic breast cancer.

Background/AimsSequential monotherapy is recommended for anthracycline-and taxane-resistant metastatic breast cancer (MBC), but combination chemotherapy is considered in patients with visceral crisis. Cisplatin-doublet chemotherapy is a combination regimen for MBC, but prolonged treatment is challenging because of toxicity. We analyzed the role of single-agent maintenance chemotherapy after cisplatin-doublet chemotherapy for MBC.MethodsFrom January 2011 to December 2017, 96 anthracycline- and taxane-resistant MBC patients were retrospectively reviewed, and 49 patients with a sustained clinical benefit during the initial 6 cycles of cisplatin-doublet chemotherapy were enrolled for study. Patients were treated with gemcitabine-cisplatin (gemcitabine, 1,250 mg/m2, intravenously [IV], days 1 to 8; cisplatin 60 mg/m2, IV, day 1) or capecitabine-cisplatin (capecitabine 2,500 mg/m2, orally, days 1 to 14; cisplatin 60 mg/m2, IV, day 1) during the induction period. After 6 cycles, 16 patients were switched to single-maintenance treatment (gemcitabine or capecitabine) and the doublet regimen was continued in 24 patients. Survival outcomes (progression-free survival [PFS] and overall survival [OS]) were analyzed.ResultsAmong the 49 patients who showed a clinical benefit during cisplatin-doublet therapy, 24 were maintained on the doublet regimen, 16 were switched to single-maintenance treatment, and chemotherapy was suspended until disease progression in nine patients. The single-maintenance chemotherapy group showed superior survival than the chemotherapy holiday and doublet regimen groups (median PFS 15.43 months vs. 8.37 and 10.67 months, respectively, p = 0.008; median OS 43.67 months vs. 22.17 and 22.33 months, respectively, p = 0.014).ConclusionsPatients showing a clinical benefit during 6 cisplatin-doublet chemotherapy cycles may have a sustained survival benefit from single-maintenance chemotherapy.

Phase II, Multicenter, Single-arm Trial of Eribulin as First-line Therapy for Patients With Aggressive Taxane-pretreated HER2-Negative Metastatic Breast Cancer: The MERIBEL Study

BackgroundEribulin has efficacy in patients with progression after ≥ 1 chemotherapeutic regimen for metastatic breast cancer (MBC). A short disease-free interval (DFI) and previous use of taxanes in the neoadjuvant or adjuvant setting have been associated with worse outcomes for patients receiving first-line chemotherapy for HER2-negative MBC. The aim of the present trial was to evaluate the efficacy and safety of eribulin as first-line therapy for patients with HER2-negative MBC with these poor prognostic factors. Patients and MethodsEribulin monotherapy was administered until disease progression or unacceptable toxicity. The principal selection criteria were HER2 negativity without previous chemotherapy for MBC, the previous use of taxanes for early-stage breast cancer, and a DFI of < 36 months (subsequently amended to 48 months). The primary endpoint was the investigator-assessed time to progression. The secondary endpoints included overall survival, progression-free survival, objective response rate, clinical benefit rate, duration of response, and toxicity profile. A total of 53 patients were enrolled and received ≥ 1 dose of eribulin. ResultsThe median patient age was 47 years (range, 23-82.8 years). The median DFI was 15.7 months (range, 0.1-46.4 months). The median investigator-assessed time to progression was 4.1 months (range, 0.2-27.8 months; 95% confidence interval, 3.2-6.2 months). The objective response and clinical benefit rate was 20.8% and 26.4%, respectively. All-grade and grade 3/4 adverse events developed in 96.2% and 69.8% of patients, respectively. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and anemia. ConclusionEribulin is effective and safe as first-line therapy for aggressive taxane-pretreated HER2-negative MBC.

Cyclophosphamide, Methotrexate, and 5-Fluorouracil as Palliative Treatment for Heavily Pretreated Patients with Metastatic Breast Cancer: A Multicenter Retrospective Analysis.

PurposeThis study aimed to evaluate the efficacy and safety of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy beyond standard treatment for anthracycline- and taxane-pretreated metastatic breast cancer (MBC).MethodsWe consecutively enrolled 158 MBC patients who underwent CMF chemotherapy in a palliative setting at two academic hospitals in Korea between 2002 and 2016.ResultsThe median age of the 158 enrolled patients was 51 years (range, 30–77 years). The enrolled patients were treated with a median of 5 lines of systemic treatment (range, 2–11) before CMF therapy, and the median time from diagnosis of MBC to CMF administration was 36.0 months (range, 7.1–146.7 months). The median number of cycles of CMF treatment was 3 (range, 1–19), and the relative dose intensity was 90.4%. The toxicity profile was mild, with an observed 3.1% of grade 2 and 5.0% of grade 3/4 neutropenia. Among 147 patients (93.0%) whose response to CMF was evaluated, the response rate was 10.9% (16/147), with complete response (CR) in one and partial response (PR) in 15. In addition, the disease control rate (calculated as CR+PR+stable disease) was 44.2% (65/147). The median progression-free survival and overall survival were 3.1 months (95% confidence interval [CI], 2.7–3.6) and 9.4 months (95% CI, 7.1–11.6), respectively.ConclusionCMF therapy is effective and tolerable as salvage treatment for heavily pretreated MBC.

A meta-analysis of combination therapy versus single-agent therapy in anthracycline- and taxane-pretreated metastatic breast cancer: results from nine randomized Phase III trials.

Nowadays, the philosophy of treating metastatic breast cancer (MBC) is slowly evolving. Especially for the anthracycline- and taxane-pretreated MBC patients, no standard therapy exists in this setting. Whether to choose doublet agents or single agent as salvage treatment remains fiercely debated. Thus, we conducted a meta-analysis to resolve this problem. Databases including PubMed, EMBASE, and Cochrane library were searched for Phase III randomized clinical trials (published before August 2015) comparing the efficacy and adverse effects between the combination therapy and single-agent therapy in anthracycline- and taxane-pretreated MBC patients. The primary end point was the overall survival (OS), and the secondary end points were the progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 toxicities. The pooled hazard ratio (HR) and pooled risk ratio (RR) were used to evaluate the efficacy. Analyses were also performed to estimate the side effects and safety of both groups. In all, nine eligible randomized clinical trials were included in this meta-analysis. Improvements were proven in the doublet agents group on OS (HR 0.90, 95% confidence interval [CI] 0.84–0.96, P=0.002), PFS (HR 0.81, 95% CI 0.76–0.88, P<0.001), and ORR (RR 1.72, 95% CI 1.34–2.21, P<0.001). Notably, subgroup analysis failed to favor the targeted agent-based combination in terms of OS (HR 1.08, 95% CI 0.89–1.31, P=0.365), PFS (HR 1.09, 95% CI 0.88–1.35, P=0.433), and ORR (RR 1.60, 95% CI 0.69–3.71, P=0.278) compared with single agent. In addition, although more hematological and gastrointestinal toxicities were observed in the doublet agents group, they were acceptable and manageable. Taken together, when compared with single-agent therapy, doublet agents should be considered a treatment option because of the superior efficacy and the manageable safety profile for the prior anthracycline- and taxane-treated MBC patients.

Capecitabine in elderly patients with metastatic breast cancer.

Capecitabine is the reference treatment for anthracycline- and/or taxane-pretreated metastatic breast cancer (MBC). This study examined its efficacy, tolerability and impact on the quality of life of elderly patients with MBC. Between January 2002 and December 2009, 75 consecutive elderly patients with MBC received first-line chemotherapy with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks. Endpoints were efficacy, tolerability and clinical-benefit response measured every 3 cycles. Median age was 76 years (range 65-88); median ECOG performance status was 1 (range 0-2); 51 patients (68%) had received adjuvant chemotherapy and all patients had received hormonal therapy. Median exposure was 6 cycles. After 3 cycles, 11 patients (14.7%) had a partial response, one patient experienced a complete response, and 49 patients (65.3%) had stable disease, amounting to a disease control rate of 81.3%. Stable disease was maintained in 45 patients (60%) after 6 cycles, in 21 patients (28%) after 9 cycles, and in 13 patients (17.3%) after 12 cycles. A clinical-benefit response was experienced by 42 patients (56%), indicating a positive impact on quality of life. Treatment was well tolerated, the most common grade 3 events being diarrhea (12%) hand-foot syndrome (8%), and mucositis (8%). Adverse events were managed with dose adjustments and supportive therapy when required. Our results indicate that capecitabine is active and well tolerated in elderly patients with MBC. This dosing regimen warrants further study in the first-line setting for patients with less aggressive MBC who are not candidates for combination therapy.

Characterization of Durable Responder for Capecitabine Monotherapy in Patients With Anthracycline- and Taxane-Pretreated Metastatic Breast Cancer

BackgroundThe purpose of this study was to evaluate predictive factors and the clinical characteristics of durable responders to capecitabine monotherapy in heavily-treated patients with metastatic breast cancer (MBC). Patients and MethodsBetween December 2000 and May 2012, a total of 236 evaluable patients with MBC who had been treated with second- or greater-line palliative capecitabine monotherapy after a previous treatment regimen with anthracycline and taxane were included. Capecitabine (1250 mg/m2 twice daily) was administered for 2 weeks followed by a 1-week rest period. ResultsThe response rate was 23.3% and median progression-free survival (PFS) was 4.7 months (95% confidence interval, 4.0-5.5). Among 236 patients, 33 patients (14.0%) showed durable response (>12 months) to capecitabine monotherapy. Patients with durable response showed significantly greater incidence of estrogen receptor (ER) positivity (81.8% vs. 59.1%; P = .012), single-organ metastasis (51.5% vs. 32.0%; P = .047), and absence of lymph node metastasis (75.8% vs. 54.2%; P = .023), compared with patients without durable response. In multivariate analysis, ER positivity and single-organ metastasis retained a significant association with better PFS to capecitabine monotherapy (hazard ratio [HR], 0.51; P < .001 and HR, 0.62; P = .004). ConclusionOur data suggest that ER positivity and single-organ metastasis can be useful predictive markers for better PFS to second- or greater-line palliative capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients.

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer patients: prospective evaluation of activity, safety, and quality of life

BackgroundA prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC).Patients and methodsFifty-two women with HER2-negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m2 as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal.ResultsAll of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%–61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52–86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0–11.6 months, range 5–21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment.ConclusionOur results showed that single-agent nab-paclitaxel 260 mg/m2 every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen is a valid therapeutic option for that ‘difficult to treat’ patient population represented by women who at the time of disease relapse have already received the most active agents in the adjuvant and/or metastatic setting (ie, conventional taxanes).

Abstract OT3-1-08: The PROCEED trial KCSG BR11-01: Phase III multicenter randomized open label study of irinotecan plus capecitabine versus capecitabine in patients previously treated with anthracycline and taxane for HER2 negative metastatic breast cancer

Abstract Background: Most patients with metastatic breast cancer (MBC) experience disease progression after being treated with an anthracycline or taxane. Irinotecan, a semisynthetic agent derived from the natural alkaloid camptothecin is metabolized to the active metabolite SN-38 which targets topoisomerase I leading to single and double strand DNA breaks. Irinotecan as a single agent demonstrated tumor activity with an objective response rate ranging from 5 to 23% in patients with MBC refractory to taxane and anthracycline. Irinotecan increased the activity of 5-FU, the active metabolite of capecitabine, and overcomes the negative effect of thymidylate synthase overexpression, which is the main target of an active metabolite of 5-FU. A phase II study that evaluated the efficacy and safety of irinotecan and capecitabin combination (IX) showed that the median progression free survival (PFS) was 7.6 months (95% CI, 5.0-10.2months), and the median OS was 22.6 months (95% CI, 15.4 – 29.8 months) with good tolerability in anthracycline and taxane pretreated MBC patients. Based on these results, we planned to conduct a multicenter, randomized phase III study which assesses the efficacy of irinotecan and capecitabine combination therapy compared with capecitabine alone in patients with anthracycline and taxane resistant MBC. Methods: In this trial, patients with HER2 normal tumor who previously received anthracycline and taxane based chemotherapies are enrolled. Eligible patients are randomly assigned in a 1:1 ratio to receive irinotecan plus capecitabine or capecitabine alone. The primary end point of this trial is PFS and a total number of accrual patients will be 222. Randomization is done using a random block size permutation method and stratified by hormone receptor status (negative vs. positive), first line vs. ≥second lines, visceral metastasis (negative vs. positive). Patients receive irinotecan at 80 mg/m2 on day 1 and 8 every 3 weeks and capecitabine 1000mg/m2 bid from day 1 to day 14 every 3 weeks. In control arm, patients receive capecitabine 1250mg/m2 bid from day 1 to day 14 every 3 weeks. Response will be assessed using RECIST1.1 criteria and toxicity will be graded according to NCI-CTCAE 4.0 criteria. Study Status: A total of 107 patients consented for the study since June 2011, and accrual is ongoing. Clinical trial information: NCT01501669. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-08.

Efficacy and safety of ixabepilone plus capecitabine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer

Data on chemotherapy regimens in elderly patients with metastatic breast cancer (MBC) are limited. The aim of this retrospective pooled analysis was to determine efficacy and safety of ixabepilone plus capecitabine versus capecitabine alone in patients with MBC aged ≥ 65 years. A total of 1973 patients with MBC previously treated with or resistant to anthracyclines and taxanes were randomized in two open-label, multinational, phase 3 studies (study 046 and study 048). Patients received ixabepilone (40 mg/m(2) as a 3-hour intravenous infusion every 3 weeks) plus oral capecitabine (1000 mg/m(2) administered twice each day), or capecitabine alone (1250 mg/m(2) twice each day). In total, 251 randomized patients were aged ≥ 65 years (ixabepilone plus capecitabine, n=116; capecitabine monotherapy, n=135). Efficacy results were consistent in patients aged <65 and ≥ 65 years with respect to the observed improvement in progression-free survival and objective response rate with ixabepilone plus capecitabine compared with capecitabine alone. No significant differences in overall survival between arms were observed for either subgroup. In the ixabepilone plus capecitabine arm, grade 3/4 hematologic adverse events (AEs) were similar in both subgroups except leukopenia and febrile neutropenia, which had a higher incidence in patients aged ≥ 65 years. The majority of grade 3/4 nonhematologic AEs were similar in the two subgroups, including fatigue, peripheral sensory neuropathy, and hand-foot syndrome. The combination of ixabepilone plus capecitabine maintains its efficacy in elderly patients with anthracycline and taxane pretreated MBC, with a similar safety profile to patients aged < 65 years.

Trastuzumab plus capecitabine vs. lapatinib plus capecitabine in patients with trastuzumab resistance and taxane-pretreated metastatic breast cancer

The purpose of this prospective, nonrandomized, controlled study was to compare the regimen of continuously administering trastuzumab and capecitabine (HX) with the regimen of lapatinib plus capecitabine (LX) for metastatic breast cancer (MBC) patients who are resistant to trastuzumab and have previously received taxane treatment. The patients in the HX group received trastuzumab (6 mg/kg every 21 days following a loading dose of 8 mg/kg on cycle 1) and capecitabine (2,000 mg/m(2)/day, days 1 to 14 every 21 days). The patients in the LX group received lapatinib (1,250 mg/day) and capecitabine (2,000 mg/m(2)/day, days 1 to 14 every 21 days). The median progression-free survival (PFS) of the patients in the HX and LX groups was 4.5 vs. 6.0 months, respectively (p = 0.006). The proportion of patients having a PFS ≥ 6 months in the HX and LX groups was 30 vs. 55 %, respectively (p = 0.005). The incidence rate of new brain metastases during treatment was 12 and 3 % in the HX and LX groups, respectively, which was not significantly different (p = 0.16). In conclusion, application of the lapatinib plus capecitabine regimen in MBC patients with a trastuzumab-resistant tumor can more effectively control the disease compared with continuous administration of trastuzumab plus capecitabine.

Chemotherapy in Patients with Anthracycline- and Taxane-Pretreated Metastatic Breast Cancer: An Overview.

Anthracyclines and taxanes are cytotoxic agents that are commonly used for the treatment of breast cancer, including in the adjuvant, neoadjuvant, and metastatic setting. Each drug class of is associated with cumulative and potentially irreversible toxicity, including cardiomyopathy (anthracyclines) and neuropathy (taxanes). This may either limit the duration of therapy for advanced disease, or prevent retreatment for recurrence if previously used as component of adjuvant or neoadjuvant therapy. Several classes of cytotoxic agents have been evaluated in patients with anthracycline and taxane-pretreated metastatic breast cancer (MBC), including other antitubulins (vinorelbine, ixabepilone, eribulin), antimetabolites (capecitabine, gemcitabine), topoisomerase I inhibitors (irinotecan), platinum analogues (cisplatin, carboplatin), and liposomal doxorubicin preparations. No trials have shown an overall survival advantage for combination chemotherapy in this setting, indicating that single cytotoxic agents should usually be used, expect perhaps in patients with rapidly progressive disease and/or high tumor burden.

Abstract PD09-05: Single nucleotide polymorphism of XRCC1 which participates in DNA repair mechanism predicts clinical outcome in relapsed or metastatic breast cancer patients treated with S1 and oxaliplatin chemotherapy: Results from multicenter prospective study (TORCH_KCSG BR07-03)

Abstract Background: S1 and oxaliplatin (SOX) combination chemotherapy is an effective regimen in anthracycline and taxane pretreated metastatic breast cancer (MBC) patients with manageable toxicities (KCSG BR07-03, SABCS 2011 #Abst P3-16-06). The aim of this study was to investigate the association of the single nucleotide polymorphisms (SNPs) and clinical outcome in MBC treated with SOX chemotherapy. Patients and Methods: A total of 87 MBC patients previously treated with or resistant to anthracycline and taxane chemotherapy were enrolled in this prospective multicenter trial. The patients received S-1 80mg/m2/day (day 1–14) and oxaliplatin 130 mg/m2 (day 1) every 3 weeks till progression. Among the 87 patients, 77 patients were available for SNP analysis. Germline DNA from peripheral blood (PB) mononuclear cells was extracted. SNPs in 4 genes from pathways that may influence cellular sensitivity to S1 and oxaliplatin (TS, ERCC, XPD, and XRCC) were genotyped from PB sample using PCR-restriction fragment length polymorphism. Results: Overall response rate (RR) was 38.5% (95% CI: 27.7–49.3) and disease control rate was 67.9% (95% CI:57.5–78.3) to SOX. Median time-to-progression (TTP) and overall survival (OS) were 6.0 mo (95% CI: 5.1–6.9 mo) and 19.4 mo (95% CI: not estimated), respectively. XRCC1 Arg194Trp SNP which participates in DNA repair mechanism showed correlation with the clinical outcome. RR was tend to higher in XRCC1 Arg194Trp CC genotype compared with CT or TT genotype (50.0 % vs 35.1% or 12.5%, P = 0.121). TTP of patients with CC genotype in XRCC1 Arg194Trp was significantly longer than the TTP of patients with CT or TT genotype (median TTP: 6.4 mo in CC, 5.9 mo in CT, 3.0 mo in TT, P = 0.007) as well as overall survival (OS) (median OS: not reached in CC, 13.9 mo in CT, 7.1 mo in TT, P = 0.006). After adjusting for hormone receptor status, performance status, and visceral involvement, prognostic value of XRCC1 Arg194Trp SNP remained significant (Hazard Ratio=1.322 and 4.484, P = 0.016). Other SNPs were not significantly associated with survival or toxicities. Conclusion: XRCC1 Arg194Trp SNP is associated with clinical outcome of MBC patients treated with SOX chemotherapy. Further studies of the relationship between germline polymorphisms in XRCC1 and functional mechanism researches are warranted. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-05.

Capecitabine and oxaliplatin in combination as first- or second-line therapy for metastatic breast cancer: a Wisconsin Oncology Network trial

Several cytotoxic chemotherapy regimens are active against metastatic breast cancer; however, benefits are modest and overall prognosis remains limited. For anthracycline and taxane-pretreated metastatic breast cancer, there remains a relative paucity of therapies with significant activity. This Phase II study evaluated the combination of capecitabine and oxaliplatin (XELOX) among patients with metastatic breast cancer being treated in the first- or second-line setting. Patients received oxaliplatin 85 mg/m(2) on days 1 and 15, and capecitabine 1,500 mg/m(2) twice daily on days 1-7 and 15-21 of a 28-day cycle. Patients were treated until progression or intolerable toxicity. The primary objective was to estimate the objective response rate by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria with tumor assessments every 8 weeks. Ten patients were treated of which 3 had received prior neurotoxic therapy in the metastatic setting. There were no confirmed complete responses, 5 patients had partial response, 4 patients had stable disease for at least 24 weeks, and one patient was unevaluable. Median time to progression (TTP) was 10.4 months (95% lower confidence bound [LCB]: 5.75 months), median progression-free survival (PFS) was 14.2 months (95% LCB: 6.14 months), and median overall survival (OS) was 19 months (95% LCB: 12.8 months). Multiple patients experienced pain syndromes and unusual neuropathies. Other common toxicities included fatigue, diarrhea, and nausea. XELOX is a promising regimen for anthracycline-pretreated metastatic breast cancer although careful patient selection is indicated and alternate dosing schedules should be explored to minimize neurologic morbidity.

Vinorelbine and capecitabine in anthracycline- and/or taxane-pretreated metastatic breast cancer: sequential or combinational?

The difference between combinational and pre-planned sequential therapies using regimens that include non-anthracycline and taxane in the first-line setting remains unclear. The purpose of this study is to explore the interaction between vinorelbine (N) and capecitabine (X) in breast cancer cells and to compare the simultaneous or sequential administration of the two drugs in patients with metastatic breast cancer (MBC) as first-line treatment. First, we explored the effects of vinorelbine on thymidine phosphorylase (TP) and thymidylate synthase (TS) expression in breast cancer cells. Next, we designed a prospective randomized phase II trial of MBC patients comparing the combinational and pre-planned sequential administration of vinorelbine and capecitabine in the first-line metastatic setting. The primary end point was progression-free survival (PFS). The correlation between clinical characteristics and class III β-tubulin expression and patient survival was also explored. Vinorelbine upregulates TP and downregulates TS in breast cancer cells, thereby further sensitizing tumor cells to capecitabine, which indicated the proper order for sequential therapy should be N → X. Sixty patients were eligible for the phase II trial. No significant difference was observed between the combinational arm and the sequential arm in terms of progression-free survival (PFS), overall response rate (ORR), and overall survival (OS). Only in the subgroup of patients with liver metastases were median PFS and OS significantly prolonged in the combinational arm (8.5 vs. 6.4 months, P = 0.041 and 23.8 vs. 13.9 months, P = 0.028, respectively). No association between class III β-tubulin expression and patient outcome was identified. Grade 3/4 adverse events were more common in the combinational arm. Both the NX regimen and pre-planned sequential N → X regimen are acceptable as first-line treatments with comparable efficacies for MBC patients previously treated with anthracyclines and/or taxanes. Sequential monotherapies are recommended as the preferred approach to first-line chemotherapy for most MBC patients in the absence of an imminent visceral crisis and the need for rapid symptom and/or disease control.

IS2-5 - Phase II Trial of TS-1 in Combination with Oxaliplatin (SOX) in Patients with Metastatic Breast Cancer (MBC) Previously Treated with Anthracycline and Taxane Chemotherapy [TORCH] [Korean Cancer Study Group (KCSG) BR07-03

ABSTRACT Background Oxaliplatin, a platinum analogue, is an active drug in advanced anthracycline and taxane-pretreated breast cancer patients as a single agent and with 5-fluorouracil (5-FU) combination. TS-1 was developed by the scientific theory of both potentiating antitumor activity of 5-FU and reducing gastrointestinal toxicity. This trial was carried out to evaluate the efficacy and safety of TS-1 in combination with oxaliplatin in metastatic breast cancer (MBC) patients previously treated with anthracycline (A) and taxane (T) chemotherapy (CTx). Methods Between October 2007 and October 2009, MBC patients were enrolled in this prospective multicenter trial. Eligible criteria included age >18 years, at least one measurable lesion, prior treatment with A and T CTx, and ECOG PS 0-2. TS-1 40 mg/m2 bid on D1-14 with oxaliplatin 130 mg/m2 on D1 were administered every 3 weeks till disease progression. Primary end-point was response rate (RR), and secondary end-points were time-to-progression (TTP), overall survival (OS), duration of response (DOR) and toxic effects. Response was evaluated every 6 weeks according to the RECIST criteria v.1.0 and toxicity was assessed with NCICTCAE v.3.0. (ClinicalTrials.gov identifier NCT00527930.) Results A total of 87 patients were enrolled. Median age was 48 (range 30–71) years. Nineteen patients (21.8%) had de novo stage IV and 68 patients (78.2%) had recurrent disease. Forty-eight patients (55.2%) had ≥3 disease sites. Fifty-four patients (62.1%) were hormone receptor positive, and 25 patients (28.7%) were triple negative. Five patients received prior anti-HER2 therapy. A total of 525 cycles were administered (median 6, range: 1–22+ cycle). In per-protocol analysis, the overall RR was 38.5% (CR 0%, PR 38.5%) and the disease control rate (CR, PR, and SD) was 67.9%. Median TTP, OS, and DOR were 6.0, 19.4, 6.6 months, respectively. The RR did not differ by triple negativity (39.1% in TNBC versus 38.2% in non-TNBC, P = 0.361). Reported grade 3 or 4 toxic effects (per cycle) were neutropenia (10.3%), thrombocytopenia (5.5%), diarrhea (1.9%), vomiting (1.9%), and stomatitis (0.2%). There was no treatment-related death. Conclusions SOX is an effective regimen in anthracycline and taxane pretreated MBC patients with manageable toxic effects.

Mitomycin C in Combination with Vinorelbine in Anthracycline- and/or Taxane-Pretreated Patients with Metastatic Breast Cancer

Background: Patients with metastatic breast cancer (MBC) with disease progression after anthracycline-and/or taxane-containing therapy need an effective drug regimen with low toxicity. Mitomycin C (MMC) and vinorelbine (VNR) are suitable candidates for combination therapy in the second-/third-line treatment of MBC. This study evaluates the safety and efficacy of an MMC/VNR combination chemotherapy in pretreated patients with MBC. Patients and Methods: In a phase II trial, patients with anthracycline-and/or taxane-pretreated MBC were treated with MMC 8 mg/m² (day 1) and VNR 25 mg/m² (days 1 and 8) every 4 weeks for up to 6 cycles or until disease progression. Results: In 51 eligible patients, 13 (26%) partial remissions (PRs), 20 (39%) stable diseases (SDs) and 18 (35%) progressive diseases (PDs) were observed. The median progression-free survival (PFS) was 5.0 months. The main grade 3/4 toxicities were neutrocytopenia (41%), granulocytopenia (37%), and thrombocytopenia (4%). Other hematological and non-hematological toxicities were mostly mild. Conclusion: The combination of MMC and VNR is an effective and relatively well-tolerated regimen for anthracycline- and/or taxane-pretreated patients with MBC and is suitable for outpatient therapy.

Capecitabine in Elderly Patients with Metastatic Breast Cancer

Capecitabine is the reference treatment for anthracycline- and/or taxane-pretreated metastatic breast cancer (MBC). This study examined its efficacy, tolerability and impact on the quality of life of elderly patients with MBC. Between January 2002 and December 2009, 75 consecutive elderly patients with MBC received first-line chemotherapy with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks. Endpoints were efficacy, tolerability and clinical-benefit response measured every 3 cycles. Median age was 76 years (range 65-88); median ECOG performance status was 1 (range 0-2); 51 patients (68%) had received adjuvant chemotherapy and all patients had received hormonal therapy. Median exposure was 6 cycles. After 3 cycles, 11 patients (14.7%) had a partial response, one patient experienced a complete response, and 49 patients (65.3%) had stable disease, amounting to a disease control rate of 81.3%. Stable disease was maintained in 45 patients (60%) after 6 cycles, in 21 patients (28%) after 9 cycles, and in 13 patients (17.3%) after 12 cycles. A clinical-benefit response was experienced by 42 patients (56%), indicating a positive impact on quality of life. Treatment was well tolerated, the most common grade 3 events being diarrhea (12%) hand-foot syndrome (8%), and mucositis (8%). Adverse events were managed with dose adjustments and supportive therapy when required. Our results indicate that capecitabine is active and well tolerated in elderly patients with MBC. This dosing regimen warrants further study in the first-line setting for patients with less aggressive MBC who are not candidates for combination therapy.

Gemcitabine in combination with vinorelbine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer

To evaluate the efficacy and safety of gemcitabine in combination with vinorelbine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC). Elderly patients with MBC received gemcitabine 1,000 mg m(-2) and vinorelbine 25 mg m(-2) on days 1 and 8 every 3 weeks for a maximum of 6 cycles. The primary end points were objective response and toxicity. The secondary end points included progression-free survival (PFS), overall survival (OS), and prognostic factors associated with disease control, PFS, and OS. Fifty-one patients with a median age of 73 years (range, 65-84 years) were included. The response rate according to Response Evaluation Criteria in Solid Tumors was 33.3% (95% confidence interval [CI], 20.4 to 46.2%). At a median follow-up of 16.2 months, median PFS and OS were 6.2 (95% CI, 4.6 to 7.8) and 17.0 months (95% CI, 14.5 to 19.5), respectively. Grade 3 to 4 adverse events included neutropenia (25.5%), anemia (13.7%), thrombocytopenia (9.8%), fatigue (5.9%), constipation (3.9%), neuropathy (3.9%), and hepatotoxicity (3.9%). Neutropenic fever occurred in 2 patients. There was one toxic death due to massive gastrointestinal hemorrhage. The study of prognostic factors did not reveal any predictive factor of disease control, while response to treatment and Eastern Cooperative Oncology Group performance status was the main factor conditioning PFS and OS, respectively. Gemcitabine in combination with vinorelbine is active and safe in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer.

P3-16-06: Phase II Trial of TS-1 in Combination with Oxaliplatin (SOX) in Patients with Metastatic Breast Cancer (MBC) Previously Treated with Anthracycline and Taxane Chemotherapy [TORCH] [Korean Cancer Study Group (KCSG) BR07-03

Abstract Background Oxaliplatin, a platinum analogue, is an active drug in advanced anthracycline and taxane-pretreated breast cancer patients as a single agent and with 5-fluorouracil (5-FU) combination. TS-1 was developed by the scientific theory of both potentiating antitumor activity of 5-FU and reducing gastrointestinal toxicity. This trial was performed to evaluate the efficacy and safety of TS-1 in combination with oxaliplatin in metastatic breast cancer (MBC) patients previously treated with anthracycline and taxane chemotherapy. Methods: Between October 2007 and October 2009, MBC patients were enrolled in this prospective multicenter trial. Eligible criteria included age ≥18 years, at least one measurable lesion, prior treatment with anthracycline and taxane chemotherapy, and ECOG Performance Status 0–2. TS-1 40 mg/m2 b.i.d. on days 1–14 with oxaliplatin 130 mg/m2 on day 1 were administered every 3 weeks till disease progression. Primary end-point was response rate, and secondary end-points were time-to-progression (TTP), overall survival (OS), duration of response (DOR) and toxicities. Response was evaluated every 6 weeks according to the RECIST criteria v. 1.0 and toxicity was assessed with NCICTCAE v.3.0.(ClinicalTrials.gov identifier NCT00527930). Results: A total of 87 patients were enrolled. Median age was 48 years (range 30–71 years). Nineteen patients (21.8%) had de novo stage IV and 68 patients (78.2%) had recurrent disease. Thirty-five patients (40.2%) received two-lines of prior chemotherapy in palliative setting. Forty-eight patients (55.2%) had ≥ 3 disease sites. Fifty-four patients (62.1%) were hormone receptor positive, and 25 patients (28.7%) were triple negative. Five patients received prior anti-HER2 therapy. A total of 525 cycles were administered (median 6 cycles, range: 1 ∼ 22+ cycle). In per-protocol analysis, overall response rate was 38.5% (95% CI: 27.7−49.3) (CR 0%, PR 38.5%) and disease control rate (CR, PR, and SD) was 67.9% (95% CI: 57.5−78.3). Median TTP, OS, and DOR were 6.0 months (95% CI: 5.1−6.9 months), 19.4 months (95% CI: not estimated), 6.6 months (95% CI: 3.7−9.6 months), respectively. RR was not different by triple negativity (39.1% in TNBC vs. 38.2% in non-TNBC, P=0.361). TTP was not different according to the number of prior chemotherapy regimens. Reported grade 3 or 4 toxicities (per cycle) were neutropenia (10.3%), thrombocytopenia (5.5%), diarrhea (1.9%), vomiting (1.9%), and stomatitis (0.2%). There was no treatment-related death. Conclusions: SOX is an effective regimen in anthracycline and taxane pretreated MBC patients with manageable toxicities. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-06.