Update on clinical data combining capecitabine with targeted agents in newly diagnosed colorectal cancer

Colorectal cancer (CRC) is a worldwide public health problem, with nearly 800,000 new cases diagnosed each year, resulting in approximately 500,000 deaths. When advanced metastatic disease is diagnosed, CRC is associated with a poor prognosis, and 5-year survival rates are in the range of 5%-8%. Chemotherapy has been the mainstay approach for patients with advanced CRC. For nearly 40 years, the main drug used for this disease was the fluoropyrimidine 5-fluorouracil (5-FU). Significant advances have been made in chemotherapy treatment options for patients with metastatic disease, such that improvements in 2-year survival are now being reported with median survival rates of 21 months to 24 months. Over the past 10 years, 3 new cytotoxic chemotherapy agents have been approved by the FDA for metastatic CRC. These compounds include the topoisomerase I inhibitor irinotecan, the third-generation platinum analogue oxaliplatin, and the oral fluoropyrimidine capecitabine. Since 2004, 3 novel biologic agents have been approved by the FDA, and they include the anti-epidermal growth factor receptor antibodies cetuximab and panitumumab and the anti-vascular endothelial growth factor bevacizumab. The oral fluoropyrimidine capecitabine has been effectively and safely combined with irinotecan (CAPIRI) and/or oxaliplatin (CAPOX). Three randomized phase III studies have now shown that CAPOX is equivalent to FOLFOX (5-FU/leucovorin/oxaliplatin)-based regimens. Significant interest has centered around combining capecitabine-based cytotoxic regimens with the biologic agents, and specifically, bevacizumab and cetuximab. This review will update the current status of these capecitabine-based combination regimens.     

晚期乳腺癌紫杉类耐药及其新型抗微管治疗

紫杉类药物原发性或继发性耐药已成为不可避免的棘手难题.伊沙匹隆对经多线治疗包括紫杉类耐药的乳腺癌患者有效.艾日布林用于治疗接受过二线以上化疗的晚期乳腺癌患者.新型抗微管药物有望成为既往接受过紫杉类药物标准化疗的晚期乳腺癌患者的有效方案.     

In the End What Matters Most? A Review of Clinical Endpoints in Advanced Breast Cancer

Many agents are being studied for the treatment of metastatic breast cancer (MBC), yet few studies have demonstrated longer overall survival (OS), the primary measure of clinical benefit in MBC. This paper examines the key endpoints in clinical trials and U.S. Food and Drug Administration (FDA) approvals of drugs for MBC. PubMed was searched (1980 to October 2009) for reports of phase III trials investigating chemotherapy and/or targeted therapy agents in MBC. FDA approval histories (1996-2009) for cytotoxic and biological agents indicated for MBC were reviewed. Of the 73 phase III MBC trials reviewed, a strikingly small proportion of trials demonstrated a gain in OS duration (12%, n = 9). OS gains were less frequently noted in first-line trials (8%) than in trials of second-line plus other lines of therapy (22%). Few trials were designed with the capacity to detect OS effects. Among 37 phase III trials conducted in the last 15 years, only three systemic therapies were approved for first-line use and nine were approved for use as second-line or other lines of therapy. Of these, only four were supported by results showing longer survival times. There is substantial discordance among the design and conduct of clinical trials, FDA drug approval, and the current view of OS as the ultimate measure of clinical benefit. There is an urgent need to reassess standards for clinical benefit in MBC and to establish guidelines for study design and conduct and drug approval. In the end, what matters most is ensuring rapid access to safe and effective oncology treatments.     

Targeting angiogenesis in metastatic breast cancer

Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC.     

Advances in the treatment of metastatic colorectal cancer

The overall 5-year survival rate for patients with metastatic colorectal cancer (CRC) is less than 10%. Median survival with 5-fluorouracil (5-FU)/leucovorin (LV) therapy is approximately 12 months. Recent additions to the chemotherapy armamentarium for this disease have begun to prolong median survival times. In trials in which patients are exposed to all three approved chemotherapy agents, oxaliplatin, irinotecan, and 5-FU/LV, or capecitabine during the course of their disease, median survival has reached 20 months. The addition of oxaliplatin and irinotecan to 5-FU/LV regimens has also led to the maintenance of quality of life for longer intervals than were traditionally observed with 5-FU/LV alone. Current standard first-line regimens for metastatic CRC are FOLFOX (infusional 5-FU/LV with oxaliplatin) and FOLFIRI (infusional 5-FU/LV with irinotecan). The addition of bevacizumab to a two-drug regimen (irinotecan with 5-FU/LV) prolongs median survival to 20 months, with a modest amount of additional toxicity. Improvements in this median survival have not yet been realized with modifications to the current standard regimens; however, the oral agent capecitabine appears to be a reasonable substitute for infusional 5-FU/LV in combination regimens or as a single agent, with the advantage of reducing the inconvenience of the long infusion time. Ongoing investigations will identify a place for capecitabine, epidermal growth factor inhibitors, and new cytotoxics in the treatment of metastatic CRC.     

Ixabepilone plus capecitabine for breast cancer patients with an early metastatic relapse after adjuvant chemotherapy: two clinical trials

BackgroundDespite recent advances in treating patients with metastatic breast cancer (MBC), outcomes remain poor. Ixabepilone is a semisynthetic analogue of epothilone B with low susceptibility to multiple mechanisms of tumor-cell resistance. This review examined the results of 2 phase III clinical trials of ixabepilone in patients with drug-resistant or heavily pretreated, locally advanced breast cancer or MBC.Patients and MethodsIn both studies, women with locally advanced breast cancer or MBC pretreated with, or resistant to, taxanes or anthracyclines were randomly assigned to ixabepilone plus capecitabine, or capecitabine alone, until disease progression or unacceptable toxicity occurred.ResultsIxabepilone plus capecitabine significantly prolonged progression-free survival (PFS) compared with capecitabine alone. The median PFS was prolonged by 1.5 months and 1.8 months in the 2 studies (hazard ratio, < 0.8 in both studies; P ≥ .001). These observations remained valid within several patient subsets: those receiving ixabepilone as first-line therapy, those with taxane-resistant disease, and those with particularly poor prognostic features. Ixabepilone plus capecitabine significantly improved overall survival (OS) compared with capecitabine in patients with symptomatic disease (12.3 vs. 9.5 months, respectively; P = .015). Peripheral neuropathy with ixabepilone was generally reversible and was effectively managed by dosage reduction in most patients. Ixabepilone did not exacerbate capecitabine-induced hand-foot syndrome or diarrhea.ConclusionThe results of these 2 large phase III trials suggest that ixabepilone plus capecitabine may improve treatment outcomes for patients with locally advanced breast cancer or MBC resistant to, or heavily pretreated with, taxanes or anthracyclines, even in those with poor prognostic features.     

Capecitabine monotherapy: review of studies in first-line HER-2-negative metastatic breast cancer

The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2-negative MBC.     

Phase II trial of simple oral therapy with capecitabine and cyclophosphamide in patients with metastatic breast cancer: SWOG S0430

Background.

Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens. We evaluated a simple oral combination of capecitabine with cyclophosphamide (CPA) for MBC.

Methods.

The trial was designed to determine whether or not combination therapy would achieve a 42% response rate (RR) using the Response Evaluation Criteria in Solid Tumors (RECIST) in MBC. Patients with two or fewer prior chemotherapy regimens for MBC were eligible. Those with estrogen receptor–positive MBC had to have progressed on endocrine therapy. Patients had measurable disease or elevated mucin (MUC)-1 antigen and received CPA, 100 mg daily on days 1–14, and capecitabine, 1,500 mg twice daily on days 8–21, in 21-day cycles.

Results.

In 96 eligible patients, the median progression-free survival (PFS) interval was 5.9 months (95% confidence interval [CI], 3.7–8.0 months) and median overall survival (OS) time was 18.8 months (95% CI, 13.1–22.0 months). The RR was 36% (95% CI, 26%–48%) in 80 patients with measurable disease. The MUC-1 antigen RR was 33% (95% CI, 20%–48%), occurring in 15 of 46 patients with elevated MUC-1 antigen. Toxicity was mild, with no treatment-related deaths.

Conclusions.

PFS, OS, and RR outcomes with capecitabine plus CPA compare favorably with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone. The addition of these other agents to capecitabine does not improve OS time in MBC patients, and this single-arm study does not suggest that the addition of CPA to capecitabine has this potential in an unselected MBC population. When OS prolongation is the goal, clinicians should choose single-agent capecitabine.     

An update on the current and emerging targeted agents in metastatic colorectal cancer

Over the past 8 to 10 years, significant advances have been made in the treatment of metastatic colorectal cancer (mCRC). In particular, the development of the targeted biologic agents bevacizumab, cetuximab, and panitumumab, and their integration with cytotoxic chemotherapy regimens has led to improvements in clinical efficacy. Despite these gains, the overall impact of current targeted agents in the treatment of mCRC has been relatively modest, and while 2-year survival has improved, no gains have been made, as of yet, in 5-year survival. Intense efforts continue to be focused on developing novel targeted agents with a different spectrum of activity. Presently, five novel targeted molecules are in phase III trials, including the antiangiogenesis agents aflibercept and ramucirumab, two novel receptor tyrosine kinase inhibitors, regorafenib and brivanib, and the Akt inhibitor perifosine. There are an additional 52 phase II trials investigating a wide range of other candidate molecules. The potential list of approved targeted agents in mCRC seems likely to increase over the next 5 to 10 years. To maximize their potential clinical impact, however, it will be critically important to introduce efficient molecular diagnostic methodologies into the drug development process for the identification and validation of predictive biomarkers for chemosensitivity. This article reviews the development of targeted agents for the treatment of mCRC, including the three molecules currently approved by the US Food and Drug Administration (FDA), as well as the main non-FDA-approved therapeutics currently undergoing phase II and III clinical testing.     

Clinical Development of Ixabepilone and Other Epothilones in Patients with Advanced Solid Tumors

Chemotherapy efficacy in patients with solid tumors is influenced by primary and acquired multidrug resistance (MDR). Epothilones represent a novel class of microtubule inhibitors with lower susceptibility to drug resistance and efficacy in taxane‐resistant tumors. While other epothilones are currently under investigation, ixabepilone is the first epothilone B analogue approved by the U.S. Food and Drug Administration. Ixabepilone has been shown to have preclinical activity in chemotherapy‐sensitive and chemotherapy‐resistant tumor models, and synergistic antitumor activity with other chemotherapeutic and targeted agents. Single‐agent ixabepilone has demonstrated clinical activity in multiple solid tumors including advanced breast, lung, prostate, pancreatic, renal cell, and ovarian cancers. Most notably, efficacy has been demonstrated in patients with metastatic breast cancer (MBC) progressing after treatment with anthracyclines and taxanes. A phase III trial in anthracycline‐ and taxane‐resistant MBC showed superior disease control with ixabepilone plus capecitabine versus capecitabine monotherapy, resulting in its approval. Ixabepilone is also active in chemotherapy‐naïve and taxane‐resistant hormone‐refractory prostate cancer and platinum‐resistant non‐small cell lung cancer. Neutropenia and peripheral sensory neuropathy are the most common adverse events associated with treatment. This review discusses the challenges of MDR and the data that support the use of epothilones in this setting, focusing on ixabepilone.     

Emerging approaches for treating HER2-positive metastatic breast cancer beyond trastuzumab

Because metastatic breast cancer (MBC) is incurable in most cases, the goals of treatment are improvement in quality of life, management of symptoms, and prolonged survival. The human epidermal growth factor receptor 2 (HER2) is overexpressed in up to 30% of breast tumors, and before the development of HER-targeted therapy, HER2 positivity was predictive of poorer clinical outcomes. Trastuzumab and pertuzumab (anti-HER2 monoclonal antibodies), lapatinib (a small molecule inhibitor of HER2 and the epidermal growth factor receptor [EGFR]) are approved for treating HER2-positive MBC in the United States. Although trastuzumab plus chemotherapy is currently regarded as the first-line standard of care for HER2-positive MBC, it is not without shortcomings; these include its association with certain adverse events (e.g. cardiotoxic effect) and development of resistance. A number of investigational agents that target HER2 and other members of that receptor family are in clinical development for patients with HER2-positive MBC whose disease has progressed on trastuzumab. In addition, in an effort to overcome treatment resistance, clinical trials are evaluating combination therapy (investigational HER-targeted agents with trastuzumab or lapatinib). This review discusses recently completed and ongoing phase II and III clinical trials of investigational HER-targeted agents in the setting of trastuzumab-progressive, HER2-positive MBC.     

Cytotoxic drugs for patients with breast cancer in the era of targeted treatment: back to the future?

BackgroundDespite current trend of targeted therapy development, cytotoxic agents are a mainstay of treatment of patients with breast cancer. We reviewed recent advances in cytotoxic therapy for patients with metastatic breast cancer (MBC).Materials and methodsMedline searches were conducted for English language studies using the term ‘MBC’ and ‘cytotoxic drugs’. The data search was restricted to the period 2000–2011.ResultsSeveral novel cytotoxic compounds, all microtubule inhibitors, have been approved for clinical use in MBC: (i) nab-paclitaxel, reported to improve tumour response and decrease hypersensitivity reactions in comparison with other taxanes; (ii) ixabepilone, shown to have clinical benefit in taxane- and anthracycline-resistant disease and (iii) eribulin, shown to improve overall survival in heavily pre-treated patients, when compared with best available standard treatment. Agents, such as larotaxel, vinflunine, trabectidin and formulations, including cationic liposomal paclitaxel or paclitaxel poliglumex, are currently under evaluation in phase II/III trials.ConclusionToxicity and chemotherapy resistance are still major limitations in the treatment of patients with MBC. Further research into new cytotoxic compounds is needed in order to maximise benefit, whilst minimising toxicity.     

Treatment beyond taxanes,emerging new cytotoxic agents

Until recently, taxanes were considered the first choice of therapy for patients with metastatic breast cancer (MBC). However, the clinical utility of the taxanes is limited in some patients by the emergence of drug resistance. Moreover, these agents are increasingly used as adjuvant therapy, increasing the population of patients with prior exposure once the disease has metastasised. Current approved treatment options after prior taxane therapy include capecitabine, liposomal doxorubicin and nab-paclitaxel – as single agents and/or in combination. Vinorelbine and gemcitabine may also be used. Most recently, the epothilones, a novel group of microtubule-stabilising agents, have shown promising activity in patients with MBC, including those resistant to taxanes and other cytotoxic drugs. Currently, three epothilone B synthetic derivatives, ixabepilone (BMS-247550), patupilone (EPO906), and sagopilone (ZK-EPO) are in development. This article will examine the latest data for these next-generation cytotoxics in the treatment of MBC.     

Optimizing ixabepilone treatment schedules in patients with advanced or metastatic breast cancer

The epothilone B analog, ixabepilone, demonstrates low susceptibility to drug resistance mechanisms and has demonstrated clinically meaningful efficacy in patients refractory to other chemotherapeutic options. Ixabepilone is approved by the FDA for treatment of patients with metastatic breast cancer (MBC) progressing after taxanes and anthracyclines, either in combination with capecitabine or as monotherapy if the patient has already progressed on capecitabine. Ixabepilone is generally well tolerated at the approved dose and administration schedule of 40 mg/m(2) every 3 weeks. The most commonly observed dose-limiting adverse events (AEs) associated with ixabepilone are myelosuppression and peripheral neuropathy. Dose modification including dose reduction and dosing schedule modification may be utilized to manage toxicities, but this must be based on careful hematologic, neurologic, and liver function monitoring. Other ixabepilone dose schedules are being evaluated to further improve the risk/benefit profile. Weekly and daily schedules of ixabepilone have shown useful efficacy and reasonable tolerability. A recent phase II trial compared the tolerability of ixabepilone dosed once weekly (16 mg/m(2) on Days 1, 8, and 15 of each 28-day cycle) or every 3 weeks (40 mg/m(2) on Day 1 of each 21-day cycle) in patients with MBC. Preliminary data showed that both dosing schedules had an acceptable safety profile; however, more AEs were reported in patients receiving ixabepilone every 3 weeks. Ixabepilone is also being evaluated in combination with other anticancer agents (e.g., bevacizumab and lapatinib), in earlier breast cancer settings and in other indications.     

The role of capecitabine in first-line treatment for patients with metastatic breast cancer

Capecitabine is an important drug in the therapeutic armamentarium for metastatic breast cancer. A comprehensive worldwide clinical trial program involving >10,000 patients with locally advanced and metastatic breast cancer has provided evidence for the current treatment strategies. On the basis of data demonstrating consistent activity across several trials in patients with heavily pretreated breast cancer, capecitabine was approved in the U.S. in 1998 for the treatment of patients with metastatic disease resistant to paclitaxel and anthracycline-containing therapy, with later European Union approval for single-agent capecitabine in the metastatic setting. Capecitabine plus docetaxel (XT) was approved by the U.S. Food and Drug Administration for the treatment of metastatic breast cancer in 2001 on the basis of the large phase III trial comparing XT with docetaxel alone, which showed a survival advantage for combination therapy compared with single-agent therapy. This was shortly followed by European approval for the combination in metastatic breast cancer. The clinical utility of capecitabine in the management of breast cancer is supported by its convenient oral dosing schedule and favorable safety profile, as well as its excellent clinical activity in primary and metastatic breast cancer. Recently, clinical trials have studied single-agent capecitabine as first-line treatment and evaluated other capecitabine-containing combinations with cytotoxic and novel targeted agents.     

Redefining adjuvant chemotherapy in patients with stage III colon cancer: X-ACT trial

The current standard adjuvant chemotherapy for suitable patients with stage III colon cancer is the combination of oxaliplatin and 5-fluorouracil plus folinic acid (5-FU/LV). However, until recently and for many years prior to this, the accepted standard adjuvant chemotherapy was 6-8 months of bolus 5-FU/LV. However, bolus treatment was associated with significant toxicity, namely stomatitis, diarrhea and neutropenia, in addition to multiple hospital visits for drug administration for patients. The X-ACT trial (Xeloda in Adjuvant Colon Cancer Therapy) compared traditional bolus 5-FU/LV (as per the Mayo Clinic regimen) with capecitabine, in the adjuvant treatment of 1987 stage III colon cancer patients. The main safety, efficacy and pharmacoeconomic results have all been published, and the updated 5-year efficacy results have also recently been presented. This trial demonstrated that capecitabine was at least as effective as bolus 5-FU/LV in terms of disease-free and overall survival, with trends towards superiority for both. Moreover, there was much less toxicity associated with capecitabine, apart from hand-foot syndrome which was significantly more prevalent. On the basis of the X-ACT trial, capecitabine was approved by the US FDA, the National Institute for Clinical Excellence and the Scottish Medicines Consortium as monotherapy for the adjuvant treatment of stage III colon cancer.     

Redefining adjuvant chemotherapy in patients with stage III colon cancer: X-ACT trial

The current standard adjuvant chemotherapy for suitable patients with stage III colon cancer is the combination of oxaliplatin and 5-fluorouracil plus folinic acid (5-FU/LV). However, until recently and for many years prior to this, the accepted standard adjuvant chemotherapy was 6–8 months of bolus 5-FU/LV. However, bolus treatment was associated with significant toxicity, namely stomatitis, diarrhea and neutropenia, in addition to multiple hospital visits for drug administration for patients. The X-ACT trial (Xeloda in Adjuvant Colon Cancer Therapy) compared traditional bolus 5-FU/LV (as per the Mayo Clinic regimen) with capecitabine, in the adjuvant treatment of 1987 stage III colon cancer patients. The main safety, efficacy and pharmacoeconomic results have all been published, and the updated 5-year efficacy results have also recently been presented. This trial demonstrated that capecitabine was at least as effective as bolus 5-FU/LV in terms of disease-free and overall survival, with trends towards superiority for both. Moreover, there was much less toxicity associated with capecitabine, apart from hand–foot syndrome which was significantly more prevalent. On the basis of the X-ACT trial, capecitabine was approved by the US FDA, the National Institute for Clinical Excellence and the Scottish Medicines Consortium as monotherapy for the adjuvant treatment of stage III colon cancer.     

The Place for Eribulin in the Treatment of Metastatic Breast Cancer

Treatment of metastatic breast cancer (MBC) remains one of the major challenges in cancer care. Chemotherapeutic agents currently approved for the treatment of invasive disease may exhibit initial efficacy; however, the development of resistance to therapy and concerns over tolerability are common and generally limit treatment options available to physicians and patients. Novel chemotherapeutic agents are, therefore, necessary to increase survival, delay disease progression, and improve tolerability. Eribulin mesylate (E7389) is a novel microtubule dynamics inhibitor with a unique mechanism of action that has shown antitumor efficacy and a manageable tolerability profile in clinical trials. Importantly, eribulin is the only single agent to date that has been shown to prolong overall survival in patients with heavily pretreated MBC. This review will discuss eribulin, with focus on the potential it has to address the specific treatment needs of patients with MBC who are refractory to conventional chemotherapies.     

Treatment of metastatic breast cancer: second line and beyond

Increasing use of standard chemotherapy, especially anthracycline- and taxane-based therapies, in early-stage breast cancer has led to a corresponding increase in heavily pretreated and/or treatment-resistant cases of metastatic breast cancer (MBC). Thus, second and later lines of MBC therapy frequently involve the clinically challenging picture of progressive disease and limited treatment options. While several prognostic factors have been identified to aid treatment selection in MBC patients, treatment is palliative and aimed at prolonging survival, controlling symptoms, and maximizing patients' quality of life. No globally accepted standard exists for meeting these goals, and treatment patterns vary according to region. The list of available agents for the treatment of MBC is increasing with newer chemotherapeutic agents and molecular-targeted therapies. Within recent years, several single-agent and combination chemotherapy regimens have been shown to improve progression-free survival and reduce symptoms of disease in clinical studies in patients with resistant and/or heavily pretreated MBC. However, at present, the demonstrated benefits of these medical interventions have usually not included extension of overall survival times. It is hoped that in the near future, ongoing refinements to treatment approaches used in second-line settings and beyond will allow meaningful improvements in symptom control and survival in MBC.     

Landmark trials in the medical oncology management of metastatic breast cancer

Significant advances in the management of metastatic breast cancer (MBC) have guided more personalized treatment according to disease biology and led to improved survival outcomes and quality of life for patients. In this review, we discuss landmark clinical trials in medical oncology that have shaped the current standard of care for MBC. Combinations of endocrine therapy with cyclin-dependent kinase 4/6 inhibitors have led to substantial improvements in overall survival, thus becoming standard first-line treatment for patients with HR-positive MBC. Inhibition of the PI3K and mTOR pathway is another promising strategy to overcome resistance to endocrine therapy. HER2-targeted therapies have also evolved with the addition of pertuzumab to trastuzumab plus a taxane demonstrating remarkable overall survival advantage in patient with HER2-positive MBC. In second or later line therapies, novel anti-HER2 antibody-drug conjugates and TKIs have durable antitumor activity, survival benefit, and encouraging efficacy in the subgroup of patients with brain metastases. Triple negative breast cancer remains the most challenging subtype due to lack of druggable targets. Immunotherapy for patients with PDL-1 expression on tumor infiltrating immune cells and poly (ADP-ribose) polymerase inhibitors for those with germline BRCA1/2 mutations are the latest approved targeted strategies in this population. Numerous obstacles still exist in treating MBC, especially for patients whose disease develops resistance to available agents. Future research is eagerly awaited to address the optimal sequence or combination of therapies and to identify better biomarkers to guide precision medicine.