Lapatinib and breast cancer: current indications and outlook for the future

Lapatinib is an oral dual erbB 1/2 tyrosine kinase inhibitor that inhibits human EGF receptor 2 (HER2) and blocks the EGF receptor. Studies have shown that in patients with metastatic HER2-positive breast cancer that is resistant to trastuzumab, the addition of lapatinib to capecitabine improves progression-free survival and appears to lengthen overall survival. Furthermore, lapatinib has been studied in patients with involvement of the CNS and has been associated with stable disease and some responses. Its combination with letrozole provided an improvement in progression-free survival compared with single-agent letrozole in women with hormone receptor-positive, HER2-positive metastatic breast cancer. More recently, data suggested that the combination of lapatinib with trastuzumab significantly improves overall survival in women with metastatic breast cancer compared with single-agent lapatinib. Current indications in the USA for the use of lapatinib are for the treatment of metastatic HER2-positive breast cancer, both in combination with capecitabine in patients who have received taxane, anthracycline and traztuzumab, and in combination with letrozole for postmenopausal patients with hormone receptor- and HER2-overexpressing breast cancer. Common side effects of lapatinib include diarrhea and rash. Studies to date have found a less than 2% risk for cardiotoxicity, although most cardiac events that occurred during the studies were not attributed to lapatinib. It is important to consider that most of the patients in existing studies had already been treated with trastuzumab with no significant cardiotoxicity; therefore, future studies will show how trastuzumab-naive patients tolerate lapatinib. Ongoing research is evaluating the role of lapatinib in the adjuvant setting as a single agent or in combination with trastuzumab.     

Expression of LC3B and FIP200/Atg17 in brain metastases of breast cancer

Background

Macroautophagy/autophagy is considered to play key roles in tumor cell evasion of therapy and establishment of metastases in breast cancer. High expression of LC3, a residual autophagy marker, in primary breast tumors has been associated with metastatic disease and poor outcome. FIP200/Atg17, a multi-functional pro-survival molecule required for autophagy, has been implicated in brain metastases in experimental models. However, expression of these proteins has not been examined in brain metastases from patients with breast cancer.

Methods

In this retrospective study, specimens from 44 patients with brain metastases of infiltrating ductal carcinoma of the breast (IDC), unpaired samples from 52 patients with primary IDC (primary-BC) and 16 matched-paired samples were analyzed for LC3 puncta, expression of FIP200/Atg17, and p62 staining.

Results

LC3-puncta⁺ tumor cells and FIP200/Atg17 expression were detected in greater than 90% of brain metastases but there were considerable intra- and inter-tumor differences in expression levels. High numbers of LC3-puncta⁺ tumor cells in brain metastases correlated with a significantly shorter survival time in triple-negative breast cancer. FIP200/Atg17 protein levels were significantly higher in metastases that subsequently recurred following therapy. The percentages of LC3 puncta⁺ tumor cells and FIP200/Atg17 protein expression levels, but not mRNA levels, were significantly higher in metastases than primary-BC. Meta-analysis of gene expression datasets revealed a significant correlation between higher FIP200(RB1CC1)/Atg17 mRNA levels in primary-BC tumors and shorter disease-free survival.

Conclusions

These results support assessments of precision medicine-guided targeting of autophagy in treatment of brain metastases in breast cancer patients.

     

ER+/HER2+ Breast Cancer Has Different Metastatic Patterns and Better Survival Than ER−/HER2+ Breast Cancer

BackgroundHuman epidermal growth factor receptor 2–positive (HER2⁺) breast cancer is generally treated with HER2-targeted therapy combined with chemotherapy. Patients with HER2⁺ and estrogen receptor–positive (ER⁺) cancer are additionally treated with long-term hormone therapy. This study examined the metastatic pattern and prognosis of both ER⁺/HER2⁺ and ER^?/HER2⁺ breast cancer.Patients and MethodsA total of 54,147 patients with HER2⁺ breast cancer from the National Cancer Data Base (NCDB, 2010-2013) and 31,946 patients with HER2⁺ breast cancer from the Surveillance, Epidemiology, and End Results Program (SEER, 2010-2014) were examined. Sites of metastasis and overall survival (OS) were examined in the NCDB, while OS and breast cancer–specific survival were examined in the SEER database.ResultsCompared to ER^?/HER2⁺ breast cancer, ER⁺/HER2⁺ breast cancer was more likely to metastasize to bone but less likely to brain, liver, and lung and less likely to result in multiple metastases. In univariate analysis based on the NCDB, patients with ER^?/HER2⁺ breast cancer had worse OS in all metastasis subsets, including patients who received HER2-targeted therapy. This poor survival for ER^?/HER2⁺ persisted in patients with metastasis to bone and lung, and multiple metastases. In multivariate analysis adjusting for age, tumor grade, surgery, chemotherapy, HER2-targeted therapy, and hormone therapy, ER^?/HER2⁺ patients with bone metastasis still had worse OS. In the SEER, ER^?/HER2⁺ patients had both worse OS and breast cancer–specific survival in univariate analysis.ConclusionThis large study showed patients with ER⁺/HER2⁺ and ER^?/HER2⁺ breast cancers had different metastatic patterns. Patients with ER^?/HER2⁺ breast cancer may require more aggressive treatment.     

Results of chemotherapy using ifosfamide with doxorubicin in advanced breast cancer

Summary Ifosfamide has single agent activity in advanced breast cancer and may potentiate the activity of doxorubicin. The combination of ifosfamide 5 g/m² and doxorubicin 40 mg/m² every 3 weeks for 4 cycles was used to treat 77 patients with advanced breast cancer. Fifty three patients had not received prior chemotherapy. All patients had one or more poor prognostic features, including tumor expression of epidermal growth factor receptor in 11/12 tested. The overall response rate was 74% (95% confidence intervals 62%-83%). The median survival was 9.4 months. The principal toxicities were febrile neutropenia and ifosfamide encephalopathy each in 6% of patients. A high percentage of the projected dose intensity was administered. This is a highly active combination with acceptable toxicity in advanced breast cancer, although the long term survival remains poor. Further exploration of ifosfamide in combination chemotherapy for advanced breast cancer is warranted.     

Final Results from Phase II Trial of Neoadjuvant Docetaxel and Capecitabine Given Sequentially or Concurrently for HER2-Negative Breast Cancers

BackgroundThe combination of docetaxel and capecitabine has been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer compared with docetaxel alone. We hypothesized that the combination of docetaxel and capecitabine, given concomitantly or sequentially, would present a nonanthracycline-based treatment option for patients with early stage and locally advanced breast cancer.Patients and MethodsPatients with stage I to stage IIIC, human epidermal growth factor receptor 2–negative (HER2^?) breast cancer were randomly assigned to receive either docetaxel followed by capecitabine (D → C) or docetaxel administered concomitantly with capecitabine (DC).ResultsBetween April 2007 and July 2009, 51 patients were accrued to the trial at an academic center, a county hospital, and community sites. Median tumor size was 3.8 cm and > 70% of patients had axillary lymph node involvement. Fifty-seven percent of patients accrued were African American. Twenty-one of the 51 subjects had triple-negative breast cancer. The pathologic complete response (pCR) rate was 8% in the D → C arm; 12% in the DC arm. The pCR rate among patients with triple-negative breast cancer was 19%.ConclusionThe combination of docetaxel and capecitabine has modest activity in the neoadjuvant setting. These results are consistent with other trials using this combination in the neoadjuvant setting.     

Cyclooxygenase-2 in tumor-associated macrophages promotes breast cancer cell survival by triggering a positive-feedback loop between macrophages and cancer cells

Tumor-associated macrophages (TAMs) play an important role in cancer cell survival, however, the mechanism of which remains elusive. In this study, we found that COX-2 was abundantly expressed in breast TAMs, which was correlated to poor prognosis in breast cancer patients. Ectopic over-expression of COX-2 in TAMs enhanced breast cancer cell survival both in vitro and in vivo. COX-2 in TAMs was determined to be essential for the induction and maintenance of M2-phenotype macrophage polarity. COX-2⁺ TAMs promoted breast cancer cell proliferation and survival by increasing Bcl-2 and P-gp and decreasing Bax in cancer cells. Furthermore, COX-2 in TAMs induced the expression of COX-2 in breast cancer cells, which in turn promoted M2 macrophage polarization. Inhibiting PI3K/Akt pathway in cancer cells suppressed COX-2⁺ TAMs-induced cancer cell survival. These findings suggest that COX-2, functions as a key cancer promoting factor by triggering a positive-feedback loop between macrophages and cancer cells, which could be exploited for breast cancer prevention and therapy.     

Metabolomics approach for predicting response to neoadjuvant chemotherapy for breast cancer

Breast cancer is a clinically heterogeneous disease, which necessitates a variety of treatments and leads to different outcomes. As an example, only some women will benefit from chemotherapy. Identifying patients who will respond to chemotherapy and thereby improve their long-term survival has important implications to treatment protocols and outcomes, while identifying non responders may enable these patients to avail themselves of other investigational approaches or other potentially effective treatments. In this study, serum metabolite profiling was performed to identify potential biomarker candidates that can predict response to neoadjuvant chemotherapy for breast cancer. Metabolic profiles of serum from patients with complete (n = 8), partial (n = 14) and no response (n = 6) to chemotherapy were studied using a combination of nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography–mass spectrometry (LC–MS) and statistical analysis methods. The concentrations of four metabolites, three (threonine, isoleucine, glutamine) from NMR and one (linolenic acid) from LC–MS were significantly different when comparing response to chemotherapy. A prediction model developed by combining NMR and MS derived metabolites correctly identified 80% of the patients whose tumors did not show complete response to chemotherapy. These results show promise for larger studies that could result in more personalized treatment protocols for breast cancer patients.     

The cyclooxygenase-2/thromboxane A2 pathway: a bridge from rheumatoid arthritis to lung cancer?

Patients with rheumatoid arthritis (RA) appear to be at a higher risk of lung cancer (LC). Although the connection between RA and LC has been an active area of research for many years, the molecular pathogenesis of the disease process remains unclear. The cyclooxygenase (COX)-2/thromboxane A2 (TxA2) pathway has been shown to play a potential role in LC development through an auto-regulatory feedback loop. An increased level of TxA2 has been found in RA patients, and intriguingly, the positive feedback loop for the COX-2/TxA2 pathway was shown to have a potential function in RA fibroblast-like synoviocytes (RA-FLS). Thus, the molecular basis of LC development in patients with RA has been at least in partly described. It is possible that COX-2-derived TxA2 could be monitored for the early detection of LC in RA patients, and targeting this molecular pathway may decrease the risk of LC in patients with RA.     

Sensitization of chemotherapy by anti-HER

This article reviews the current state of efforts targeting human epidermal growth factor receptor-2 (erbB2/HER2)in breast cancer therapy. The results of recently conducted clinical studies with trastuzumab and several other compounds are presented. Trastuzumab, a humanised monoclonal antibody(mAb)directed against the extracellular domain of HER2, has been shown to be active against HER2-overexpressing metastatic breast cancer, either as a single agent or when used in combination with chemotherapy. In preclinical models, trastuzumab has shown additive and even synergistic anti-tumor activity with the chemotherapeutic agents. In a large, randomised, phase III trial, the combination of trastuzumab and chemotherapy was shown to improve the response rate and survival in patients with metastatic breast cancer. The high incidence of cardiotoxicity seen with the combination of trastuzumab plus anthracycline drugs prompted several clinical studies combining trastuzumab with other chemotherapeutic agents, including taxanes, vinorelbine and platinum salts. This article summarises the available data on trastuzumab-based combination chemotherapies and novel drugs targeting HER2 and signal transduction molecules for the treatment of breast cancer.     

A Multicenter,Single-Arm Phase II Study of Pemetrexed Plus Doxorubicin Administered Every 21 Days in Patients With Advanced Breast Cancer

BackgroundDoxorubicin and pemetrexed have both shown single-agent activity in breast cancer. Preclinical and clinical evidence indicates that a combination of the 2 agents might have an additive or synergistic effect. A phase II trial was initiated to assess the antitumor activity and safety of pemetrexed plus doxorubicin in women with advanced breast cancer.Patients and MethodsAnthracycline-naive patients with advanced breast cancer received doxorubicin 50 mg/m² plus pemetrexed 500 mg/m² (both intravenously) on day 1 of 21-day cycles, as first-line therapy, with standard vitamin supplementation. Seventy-nine women were enrolled (median age, 55.3 years). Seventy-six patients (96.2%) had an Eastern Cooperative Oncology Group performance status of ≤ 1.ResultsAt baseline, 35 patients (44.3%) had visceral metastases. Three (4.2%) patients were HER2/neu positive, and 30 (42.3%) patients were HER2/neu negative. The objective response rate was 55.7% (95% exact CI, 44.1%-66.9%), including 2 (2.5%) complete responses. Median progression-free survival was 8 months (95% CI, 6.5-13.3 months). Two-year survival rate was 61.7% (95% CI, 49.7%-71.6%). Grade 3/4 drug-related toxicities in ≥ 10% patients included neutropenia (24.1%) and leukopenia (10.1%).ConclusionIn patients with advanced breast cancer, the combination of doxorubicin plus pemetrexed was well tolerated and showed promising antitumor activity that warrants further study.     

85例颅外转移性乳腺癌放疗疗效观察及预后分析

目的 观察颅外转移性乳腺癌的放疗疗效,探讨全病变放疗意义及预后相关因素。方法 回顾性分析2014—2019年间接受放疗的 85例颅外转移性乳腺癌患者的临床资料,其中全病变放疗 36例,非全病变放疗 49例。采用Kaplan-Meier法计算生存率并log-rank检验和单因素预后分析,Cox模型多因素预后分析。结果 全组中位随访时间26.7个月,2年局控(LC)、无进展生存(PFS)、总生存(OS)率分别为77%、26%、77%。全病变放疗预后显著优于非全病变放疗,2年LC率分别为91%和67%(P=0.001),2年PFS率分别为47%和8%(P<0.001),2年OS率分别为84%和71%(P=0.010)。多因素分析显示全病变放疗是LC、PFS、OS的独立预后因素。此外,接受放疗时是否仅有骨转移是LC的影响因素,激素受体状态是OS的影响因素。结论 全病变放疗可以延长颅外转移性乳腺癌患者的生存。仅有骨转移的患者接受放疗后LC更佳,激素受体阴性的患者长期生存较差。     

Synergistic effect of sequential administration of mitoguazone (MGBG) and gemcitabine in treating tissue cultured human breast cancer cells and mammary rat tumors

Modulation of cancer chemotherapeutic drugs has been attempted to increase efficacy and overcome resistance to the chemotherapeutic agent. Studies have shown schedule-dependent interactions in combined use of chemotherapeutic drugs. Mitoguazone (MGBG), an old drug with possible modulating activity, was used in combination with gemcitabine, a relatively new cancer drug, in treating tissue cultured human breast cancer cells and mammary rat tumors. Tissue cultured BOT-2 cancer cells were first treated with varying concentrations of gemcitabine and MGBG, independently. Combinations of the two drugs were then used with different scheduled administrations. Marked synergistic activity was found between gemcitabine and MGBG when the MGBG was given first, followed by gemcitabine 24 hours later. A non-toxic dose of MGBG enhanced the toxicity of gemcitabine by eight orders of magnitude using MTT assays in the tissue cultured human breast cancer cell study. The sequential administration of MGBG and gemcitabine also increased the survival rate of rats bearing mammary tumors in our pilot animal study.     

Impact of statin use on cancer recurrence and mortality in breast cancer: A systematic review and meta‐analysis

Statins have shown antineoplastic properties in preclinical studies with breast cancer cells. They inhibit the enzyme “HMG CoA reductase” and the expression of this enzyme in cancer cells has been implicated as a favorable prognostic factor in patients with breast cancer. After a search of MEDLINE and Embase from inception through November 2015, 817 abstracts were reviewed to identify studies that described an association between statin use and outcomes in breast cancer. A total of 14 studies which included 75,684 women were identified. In a meta‐analysis of 10 studies, statin use was associated with improved recurrence‐free survival (RFS; HR 0.64; 95% CI 0.53–0.79, I² = 44%). Furthermore, this RFS benefit appeared to be confined to use of lipophilic statins (HR 0.72; 95% CI 0.59–0.89) as hydrophilic statin use was not associated with improvement in RFS (HR 0.80; 95% CI 0.44–1.46). Statin users similarly showed improved overall survival in a meta‐analysis with substantial heterogeneity (8 studies, HR 0.66; 95% CI 0.44–0.99, I² = 89%). Statin users also had improved cancer‐specific survival, although this relationship was measured with less precision (six studies, HR 0.70; 95% CI 0.46–1.06, I² = 86%). In conclusion, breast cancer patients who use statins, or specifically, lipophilic statins show improved recurrence‐free survival. Statin users also had improved overall survival and cancer‐specific survival. These findings should be assessed in a prospective randomized cohort and the choice of statin, dose and biomarkers that may predict the efficacy of these drugs should be identified.     

Role of capecitabine (Xeloda®) in breast cancer

One rationale for the development of new treatment strategies for advanced breast cancer is to provide targeted antineoplastic therapy, while at the same time improving the quality of life of patients. One such drug, capecitabine (Xeloda^®), is an oral fluoropyrimidine 5-fluorouracil carbamate. Capecitabine is converted to 5-fluorouracil primarily in cancer tissue and it has been demonstrated to combine ease of administration, a manageable toxicity profile and potent antineoplastic activity. Capecitabine is widely used in metastatic breast cancer and offers symptom palliation and in combination with docetaxel (Taxotere^®) improved survival compared with docetaxel alone. Its toxicity profile includes hand–foot syndrome and stomatitis and diarrhea, whereas its hematologic side effects are mild. Capecitabine has been evaluated as a single agent in women with advanced breast cancer where it offers an overall response rate of 20–30%. Capecitabine is synergistic with other chemotherapeutic agents, such as the taxanes, where it increases the response rate to over 40%. This review will place the available data on the use of capecitabine in metastatic breast cancer as a single agent or as part of a combination regime in context.     

Long-term management of patients with metastatic renal cell carcinoma on targeted agents

Trastuzumab, a humanized monoclonal antibody directed against HER2, used alone or in combination with chemotherapy, has shown significant clinical benefit in improving survival in the metastatic setting, as well as halving the recurrence rate and improving survival in HER2-positive early breast cancer. Lapatinib is an orally active, reversible, small-molecule tyrosine kinase inhibitor that potently inhibits both HER1 and HER2 tyrosine kinase activity. This agent is the most advanced in terms of clinical trials and has been shown to have a favorable safety profile. Owing to the promising activity seen in advanced breast cancer, lapatinib is the ideal candidate for testing in the adjuvant setting. Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) is a four-arm randomized trial designed to compare trastuzumab and lapatinib in women with early-stage HER2-positive breast cancer. Specifically, ALTTO will examine which anti-HER2 agent is more effective and which is their best schedule of administration, namely, what benefit will be derived by taking the drugs separately, in tandem order or in combination. Overall, 8000 patients will be enrolled worldwide.     

Frequency of Immune Cell Subtypes in Peripheral Blood Correlates With Outcome for Patients With Metastatic Breast Cancer Treated With High-Dose Chemotherapy

BackgroundThe frequency of circulating leukocytes has been shown to be a prognostic factor in patients being treated for different types of cancer. In breast cancer, tumor-infiltrating leukocytes may predict patient outcome, but few studies have investigated such associations for circulating leukocytes.Patients and MethodsMultiparametric flow cytometry was used to examine the immunophenotypes of circulating peripheral blood mononuclear cells for 88 patients with metastatic breast cancer, which was then correlated to breast cancer–specific survival. Patients had been treated either with high-dose cyclophosphamide-containing regimens (group 1, n = 51 patients) or high-dose paclitaxel-containing regimens (group 2, n = 37 patients).ResultsThe frequency of peripheral blood CD14⁺ monocytes indicated prognosis for patients in group 1 (but not group 2), while higher levels of CD11c⁺ dendritic cells indicated a better prognosis for patients in group 2 (but not group 1). The frequency of a number of different CD4⁺ or CD8⁺ T cell subtypes also predicted prognosis for patients in group 2. For example, patients in group 2 with a higher frequency of circulating CD4⁺ or CD8⁺ naive T cells (CD45RA⁺CD95−CD27⁺CD28⁺) showed a poorer prognosis. In contrast, T cells were not associated with prognosis for patients in group 1.ConclusionCirculating leukocytes can predict clinical outcome for patients with breast cancer. Prediction of clinical outcome in this cohort of metastatic breast cancer patients was specific to the type of chemotherapy, and this finding is likely to apply to other therapies.     

SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival

In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox’ regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HR_interaction 6.98, 95% CI=3.3-14.4, P = 1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HR_interaction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.     

A systematic review of dual targeting in HER2-positive breast cancer

Background

Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15–20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer.

Materials and methods

A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included.

Results

This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described.

Conclusion

Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.     

Salvage Therapy with Capecitabine Plus Weekly Paclitaxel in Heavily Pretreated Advanced Breast Cancer

Background:The combination of intravenous paclitaxel (three-times weekly administration at a dose of 175 mg/m²) and oral capecitabine has been shown to be highly active in the treatment of advanced or metastatic breast cancer. Currently, there is much interest in the use of relatively low dose weekly paclitaxel infusions in this clinical setting. Aim:To assess the activity and safety of capecitabine plus weekly paclitaxel at a dose of 60 mg/m²in heavily pretreated metastatic breast cancer patients. Patients and methods:Patients were required to have pretreated metastatic breast cancer with measurable/ evaluable disease and a performance status of 0–2 (Eastern Cooperative Oncology Group score). Capecitabine was administered orally at a dosage of 1000 mg/m²twice daily on days 1–14, followed by a 7-day rest period. Paclitaxel was administered as a 1-hour intravenous infusion on a weekly basis at a dose of 60 mg/m². Twenty-one days of therapy represented one cycle. Results:The hypothesis of activity of the capecitabine-paclitaxel combination at the level of clinical interest (40% response rate) was accepted when the 15th response was observed and 33 patients were enrolled. The median progression-free survival and median overall survival estimates were 9.2 and 19.6 months, respectively. Therapy was generally well tolerated and manageable on an outpatient basis. The following grade 3/4 adverse events were observed: hand-foot syndrome (21.2%), neutropenia (12.1%), anemia, nausea/vomiting, stomatitis/ mucositis, and nail disorders (all occurred in 9.0%), and vascular/coagulation disorders (<1%). Conclusions:Oral capecitabine plus weekly paclitaxel at a dose of 60 mg/m²has a favorable activity and tolerability profile and is suitable for the treatment of heavily pretreated advanced breast cancer patients.