current treatment of locally advanced and metastatic breast cancer in the asia–pacific region:...

10
REVIEW ARTICLE Current treatment of locally advanced and metastatic breast cancer in the Asia–Pacific region: Challenges and limitations Louis WC CHOW 1,2,3 and Young-Hyuck IM 2,4 1 Asian Breast Cancer Society, 2 Organization for Oncology and Translational Research; 3 UNIMED Medical Institute, Hong Kong, China; and 4 Samsung Medical Center, Kangnam-Ku, Seoul, Korea Abstract Over the past decade, the management of breast cancer has improved substantially with advances in understanding the tumor biology and the introduction of several new, more effective agents. As a result, the performance of breast-conservation surgery has increased, and the use of neoadjuvant therapy to downstage locally advanced breast cancer has become more common in the Asia–Pacific region. For patients with metastatic breast cancer, treatment typically follows Western clinical experience, but the use of specific drugs and regimens is variable throughout the region. Anthracycline-based and/or taxane-based regimens are commonly used for the first-line treatment of locally advanced and metastatic breast cancer. However, a number of challenges and barriers have emerged that are unique to the treatment of patients with breast cancer in the Asia–Pacific region. These include differences in the safety and tolerability profiles of standard chemotherapeutic agents between Asian–Pacific and Western women; the variable availability of, and cost of anticancer agents; the high prevalence of Chinese herbal medicines and alternative therapies used by women with breast cancer, and the prohibitive costs of conducting clinical trials in some countries in the region. Key words: breast cancer, chemotherapy, China, Japan, Korea, surgery. INTRODUCTION The incidence and mortality of breast cancer in the Asia–Pacific region is rising rapidly and may surpass that of Western countries over the next decade. 1,2 In areas such as Japan, recent reports have indicated an increased breast cancer incidence of 40% to 50% since the year 2000, 3,4 and Korea has experienced a doubling of breast cancer cases over the past 15 years. 4 The rising incidence of breast cancer, particularly among young women, represent a growing heath and economic concern in highly populated countries such as China and India. 3,5,6 Advances in understanding of the etiology of breast cancer and the introduction of more effective therapies have led to substantial improvement in the management of this disease. This article reviews advances in the man- agement of locally advanced and metastatic breast cancer with a special emphasis on clinical experience in the Asia–Pacific region. Current challenges and barriers to effective treatment of breast cancer in the Asia–Pacific region are also discussed. Future directions in metastatic breast cancer management are highlighted. SURGERY Over the past 15 years, there has been a considerable shift in the frequencies of different surgical methods used to treat patients with breast cancer in the Asia–Pacific region. These methods include extensive radical mastec- tomy, radical mastectomy, modified radical mastectomy, simple mastectomy and breast-conserving surgery. The frequency of extensive and radical mastectomy, which once accounted for 80% of all surgeries for breast cancer in Asian–Pacific women, decreased significantly in the Correspondence: Dr Louis WC Chow, UNIMED Medical Institute, 10/F No. 72 Gloucester Road, Wanchai, Hong Kong. Email: [email protected] Conflict of Interest: No conflict of interest has been declared by Louis Chow or Young-Hyuck Im. Asia–Pacific Journal of Clinical Oncology 2008; 4(Suppl. 3): S14–S23 doi:10.1111/j.1743-7563.2008.00195.x © 2008 The Authors Journal Compilation © Blackwell Publishing Asia Pty Ltd

Upload: louis-wc-chow

Post on 28-Sep-2016

213 views

Category:

Documents


1 download

TRANSCRIPT

Page 1: Current treatment of locally advanced and metastatic breast cancer in the Asia–Pacific region: Challenges and limitations

REVIEW ARTICLE

Current treatment of locally advanced and metastatic breastcancer in the Asia–Pacific region: Challenges and limitations

Louis WC CHOW1,2,3 and Young-Hyuck IM2,4

1Asian Breast Cancer Society, 2Organization for Oncology and Translational Research; 3UNIMED Medical Institute, HongKong, China; and 4Samsung Medical Center, Kangnam-Ku, Seoul, Korea

Abstract

Over the past decade, the management of breast cancer has improved substantially with advances inunderstanding the tumor biology and the introduction of several new, more effective agents. As a result, theperformance of breast-conservation surgery has increased, and the use of neoadjuvant therapy to downstagelocally advanced breast cancer has become more common in the Asia–Pacific region. For patients withmetastatic breast cancer, treatment typically follows Western clinical experience, but the use of specific drugsand regimens is variable throughout the region. Anthracycline-based and/or taxane-based regimens arecommonly used for the first-line treatment of locally advanced and metastatic breast cancer. However, anumber of challenges and barriers have emerged that are unique to the treatment of patients with breastcancer in the Asia–Pacific region. These include differences in the safety and tolerability profiles of standardchemotherapeutic agents between Asian–Pacific and Western women; the variable availability of, and costof anticancer agents; the high prevalence of Chinese herbal medicines and alternative therapies used bywomen with breast cancer, and the prohibitive costs of conducting clinical trials in some countries in theregion.

Key words: breast cancer, chemotherapy, China, Japan, Korea, surgery.

INTRODUCTION

The incidence and mortality of breast cancer in theAsia–Pacific region is rising rapidly and may surpassthat of Western countries over the next decade.1,2 Inareas such as Japan, recent reports have indicated anincreased breast cancer incidence of 40% to 50% sincethe year 2000,3,4 and Korea has experienced a doublingof breast cancer cases over the past 15 years.4 The risingincidence of breast cancer, particularly among youngwomen, represent a growing heath and economicconcern in highly populated countries such as China andIndia.3,5,6

Advances in understanding of the etiology of breastcancer and the introduction of more effective therapies

have led to substantial improvement in the managementof this disease. This article reviews advances in the man-agement of locally advanced and metastatic breastcancer with a special emphasis on clinical experience inthe Asia–Pacific region. Current challenges and barriersto effective treatment of breast cancer in the Asia–Pacificregion are also discussed. Future directions in metastaticbreast cancer management are highlighted.

SURGERY

Over the past 15 years, there has been a considerable shiftin the frequencies of different surgical methods usedto treat patients with breast cancer in the Asia–Pacificregion. These methods include extensive radical mastec-tomy, radical mastectomy, modified radical mastectomy,simple mastectomy and breast-conserving surgery. Thefrequency of extensive and radical mastectomy, whichonce accounted for 80% of all surgeries for breast cancerin Asian–Pacific women, decreased significantly in the

Correspondence: Dr Louis WC Chow, UNIMED MedicalInstitute, 10/F No. 72 Gloucester Road, Wanchai, HongKong. Email: [email protected] of Interest: No conflict of interest has been declaredby Louis Chow or Young-Hyuck Im.

Asia–Pacific Journal of Clinical Oncology 2008; 4(Suppl. 3): S14–S23 doi:10.1111/j.1743-7563.2008.00195.x

© 2008 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

Page 2: Current treatment of locally advanced and metastatic breast cancer in the Asia–Pacific region: Challenges and limitations

mid-1990s with an increase in modified radical mas-tectomy.7 Furthermore, breast-conserving therapy hasbecome an established and more widely accepted form oftreatment, with overall survival rates of 86–100% forpatients with stage 0, I, or II disease – comparable to thesurvival rates associated with mastectomy.4,7–9 From theearly to mid-1990s to 2008, the frequency of breast-conserving surgery has increased by approximately 20%,from 10.0 to 12.1% in China, and by >600%, from 5.1 to39.1% in Korea (Fig. 1).4,7 In Hong Kong, women aged<40 years are more likely to undergo breast-conservingtreatment than are women aged �40 years.10

The increased performance of breast-conservingsurgery is due to the identification of smaller tumors andearlier-stage disease during screening programs and theuse of neoadjuvant therapy.10–12 In China, the number ofwomen diagnosed with operable early-stage diseaseincreased by 15% from the early 1990s to 2000.7 Neo-adjuvant therapy is effective for the downstaging oftumors, resulting in the conversion of often unresectabletumors to resectable tumours.13–15 In a study of 30Chinese women with stage IIA or IIIA breast cancer,neoadjuvant therapy with epirubicin and paclitaxelresulted in tumor downstaging in 87% of patients. Aninitial tumor size of 4.0 cm decreased to 0.8 cm after

neoadjuvant therapy, allowing 60% of patients tobecome eligible for breast-conserving surgery.12 Otherstudies in Chinese women have demonstrated the feasi-bility of breast-conserving surgery in patients withlocally advanced breast cancer following neoadjuvanttherapy with anthracycline-containing regimens.16

Similar results were demonstrated in Japanese womenwho received weekly doses of paclitaxel, with 100% ofpatients with stage II disease and tumors measuring>3 cm downstaged, becoming eligible for breast-conserving surgery.17 Combination therapy with doc-etaxel 70 mg/m2 every three weeks and trastuzumab hasbeen shown to be effective as neoadjuvant chemo-therapy for patients with human epidermal growthfactor receptor 2 (HER2) overexpressing operablebreast cancer.18 In a phase II study conducted by theJapan East Cancer Center Breast Cancer Consortium,21 patients with operable breast cancer received fourcycles of docetaxel 70 mg/m2 every three weeksand trastuzumab as primary chemotherapy prior tosurgery.18 At the time of the report, 19 patients hadcompleted surgery. The pathological complete response(pCR) rate was 21% [95% CI 6%–46%] and the overallresponse rate (ORR) was 90% [95% CI 67%–99%].The most common toxicities observed with this regimenincluded grade 3 or 4 neutropenia (67%), leukopenia(48%) and febrile neutropenia (10%).18

LOCALLY ADVANCEDBREAST CANCER

Despite an increase in the frequency of early-stage breastcancer, characterized by a nonpalpable lesion at diagno-sis, 60–79% of patients in the Asia–Pacific regionpresent with stage II or III disease.19,20 Among Chinesewomen living in Singapore, a country with breast cancerscreening, the median tumor size is 2 cm.19 As mostwomen are diagnosed with locally advanced diseaseand, therefore, with larger tumors, and are given apoorer prognosis, the use of chemotherapy (neoadjuvantchemotherapy) to shrink or downstage tumors is com-mon practice in the Asia–Pacific region.13

Neoadjuvant chemotherapy provides significantoverall response rates in locally advanced breast cancerand broadens the therapeutic options. In a study of 173Chinese patients with tumors measuring >4 cm, neoad-juvant treatment with the combination of 5-fluorouracil600 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide600 mg/m2 (FEC) or single-agent doxorubicin 75 mg/m2

resulted in an overall response rate of 75% with meanreductions of tumor size of 57.2% and 87.5% in

1990 1992 1994 1996 1998 2000 2002 2004

0.0

0.2

0.4

0.6

0.8

1.0

Year

Figure 1 Changes in surgical modalities used for the treat-ment of breast cancer in Korea from 1990 to 2005. BCS,breast conserving surgery; ERM, extensive radical mastec-tomy; MRM, modified radical mastectomy; Recon, recon-structive surgery; RM, radical mastectomy; SM, simplemastectomy. Data adapted with permission from Yu et al.7

Treatment of breast cancer in Asia–Pacific S15

© 2008 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

Asia–Pac J Clin Oncol 2008; 4(Suppl. 3): S14–S23

Page 3: Current treatment of locally advanced and metastatic breast cancer in the Asia–Pacific region: Challenges and limitations

patients receiving FEC and doxorubicin, respectively.16

However, neoadjuvant therapy did not improve theoverall 5-year probability of survival, regardless ofregimen.

To improve the therapeutic response and allow formore conservative surgical options, chemosensitivitytesting has been developed to individualize treatment bydetermining a patient’s in vitro response to therapy priorto its administration.21 Chemosensitivity testing using anin vitro adenosine triphosphate bioluminescence assayof a patient’s cancer cells demonstrated a higher thera-peutic response (83% vs 17%), a greater reduction oftumor size (75% vs 26%) and greater pCR (17% vs 0%)to individually tailored therapy than to standard regi-mens.21 The findings from this pilot study warrantfurther investigation to determine the potential role ofchemosensitivity testing in the management of breastcancer.

The combination of anti-hormonal and targeted anti-growth factor agents is also being investigated as apotential neoadjuvant therapy. This combination isassociated with greater anti-tumor activity than endo-crine therapy alone in vitro.22 A clinical trial, the Cele-coxib Anti-Aromatase Neoadjuvant trial evaluated theeffectiveness of combining anti-hormonal and targetedagent in postmenopausal Asian–Pacific women withhormone receptor (HR)-positive breast cancer.15 Thisstudy involved 82 patients who were randomly assignedto receive either exemestane 25 mg/day and celecoxib400 mg b.i.d. (group A, n = 30), exemestane 25 mg/day(group B, n = 24), or letrozole 2.5 mg/day (group C,n = 28). Clinical responses were similar across all treat-ment groups: 58.6% of group A, 54.5% of group B, and62.0% of group C responded. Five patients achieved acomplete clinical response; of these, three were observedin the combination therapy arm. A similar decrease inthe tumor area was also observed across treatmentgroups: 61.8% change in tumour area for group A,58.1% for group B, and 55.7% for group C. The dif-ferences were statistically significant only when group Cwas compared with group B (P = 0.025). The toxicityprofiles among the groups were as expected with theseagents. These results indicate that aromatase inhibitortherapy is effective in treating postmenopausal HR-positive breast cancer and may be safely used preopera-tively. Additional studies are needed to further assess theimpact of adding a cyclooxygenase-2 inhibitor to anti-hormonal therapy in this patient population.

Similarly, a clinical trial conducted at the Universityof Hong Kong Medical Centre evaluated the efficacyof neoadjuvant therapy with letrozole 2.5 mg/day plus

imatinib 400 mg b.i.d. in postmenopausal women withhormone-sensitive and invasive breast cancer.23 In thistrial, the addition of imatinib, a selective tyrosine kinaseinhibitor, produced a 30% improvement in the responserate compared with aromatase inhibition with letrozolealone. Of 10 evaluable patients, 90% achieved partialresponses and 10% had stable disease. One patientachieved a pCR. Although these tumor responses arepromising, the treatment regimen was associated withsignificant toxicity including grade 3 neutropenia, skinrash, dermatitis, hypokalemia, shortness of breath,acute coronary syndrome and acute chronic gastritis.Further studies evaluating lower doses of imatinib incombination with letrozole are needed.

METASTATIC BREAST CANCER

Most clinical findings regarding the efficacy and toler-ability of hormonal therapy and chemotherapy inpatients with metastatic breast cancer have beenobtained from trials enrolling Western women. Theexperience with these drugs and regimens is variablein the Asia–Pacific region. Due to differences in actualor anticipated tolerability among women in the Asia–Pacific region, chemotherapy regimens are oftenchanged by altering the dose or schedule.24 However theefficacy and tolerability of combination therapy andregimens, including new targeted agents in Asia–Pacificwomen with metastatic breast cancer, has been the focusof recent reports.18,25–28

Endocrine therapy with agents such as tamoxifen orthe aromatase inhibitors (i.e., anastrozole, letrozole andexemestane) are the mainstay of treatment for post-menopausal women with estrogen-receptor (ER) posi-tive and/or progesterone-receptor (PR) positive breastcancer.29–32 Clinical trials have shown that anastrozoleand tamoxifen yield equivalent overall response rates(ORRs), although anastrozole was associated with asignificantly longer time to progression in at least oneNorth American study.30,31 In another clinical trial, letro-zole significantly prolonged the median time to progres-sion by 57% when compared to patients receivingtamoxifen.32

Unfortunately, the efficacy of endocrine therapy isoften limited by de novo or acquired resistance. Down-regulation of the ER may be the best second-lineor third-line hormonal therapy for patients withER-positive tumors who fail therapy with tamoxifen oraromatase inhibitors.33,34 Fulvestrant, a steroid analog of17-b-estradiol, binds to the ER, has no agonist activityand leads to degradation of the ER.33 Approximately

S16 LWC Chow and Y-H Im

© 2008 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

Asia–Pac J Clin Oncol 2008; 4(Suppl. 3): S14–S23

Page 4: Current treatment of locally advanced and metastatic breast cancer in the Asia–Pacific region: Challenges and limitations

30–35% of the patients who had progressive diseasewhile receiving an aromatase inhibitor or who devel-oped aromatase inhibitor resistance demonstrated aclinical benefit from fulvestrant.33,34

Emerging data from preclinical and clinical studiessuggest that resistance to endocrine therapy may bemediated in part by growth factor signaling pathways.22

The combination of trastuzumab and endocrine therapywith either letrozole or anastrozole has demonstratedpromising anti-tumor activity in preliminary studiesinvolving women with ER-positive and HER2, overex-pressing tumors.22,35 Preliminary data from a phase II/IIIstudy comparing anastrozole 1 mg daily with orwithout trastuzumab given as a 4 mg/kg loading dosefollowed by 2 mg/kg weekly until disease progression in205 women with hormone-dependent HER2, positivemetastatic breast cancer has been reported.22 The com-bination of anastrozole and trastuzumab was associatedwith an improvement in progression-free survival from2.4–4.8 months (P = 0.0016); however, no differencewas observed in overall survival between the two treat-ment arms. The safety and efficacy of letrozole 2.5 mgdaily and trastuzumab given as a 4 mg/kg or 8 mg/kgloading dose followed by 2.5 mg/kg or 6.5 mg/kg everythree weeks was evaluated in a phase II study involving30 patients with metastatic breast cancer.35 The combi-nation was associated in an ORR of 26%. Ongoingstudies are evaluating the safety and efficacy of combi-nation therapy with trastuzumab plus letrozole or tras-tuzumab plus fulvestrant in women with hormone-dependent HER2, positive metastatic breast cancer.Data from these studies are reviewed elsewhere.22

Chemotherapy is the mainstay of treatment forpatients with hormone-unresponsive, rapidly progress-ing metastatic breast cancer. A review of 21 studiesenrolling >6300 women with metastatic breast cancershowed that the overall response and overall survivalwere improved in patients receiving taxane-containingregimens.36 However, in an analysis of nearly 4000patients in eight studies, taxane-based regimens yieldedbetter response rates and greater progression-free sur-vival, but not overall survival, than anthracycline-basedcombinations.37 A randomized phase III trial comparedthe taxanes, docetaxel and paclitaxel, in 449 patientswith metastatic breast cancer who progressed after ananthracycline-based regimen, and showed a significantincrease in ORR, median time to progression, andoverall survival in the patients receiving docetaxel.38

Regimens of docetaxel in combination with doxorubi-cin, capecitabine or cisplatin have shown efficacy inwomen with metastatic breast cancer.39–41

For patients with tumors that overexpress the HER2receptor, regimens containing trastuzumab that targetsHER2 are considered the standard of care in both themetastatic and adjuvant setting.42,43 In clinical trials, tras-tuzumab used as a single agent or in combination withchemotherapy has demonstrated substantial clinicalbenefit in the treatment of women with metastatic breastcancer.44,45 When compared with standard chemotherapyalone, the combination of trastuzumab plus standardchemotherapy resulted in a longer time to disease pro-gression (TTP) (median, 7.4 vs 4.6 months; P < 0.001),a higher rate of objective response (50% vs 32%,P < 0.001), a longer duration of response (median, 9.1 vs6.1 months; P < 0.001), a lower rate of death at 1 year(22% vs 33%, P = 0.008), longer survival (median sur-vival, 25.1 vs 20.3 months; P = 0.046) and a 20% reduc-tion in the risk of death in women with HER2-positivemetastatic breast cancer.42 Despite the clinical benefitassociated with trastuzumab, the risk of cardiotoxicityis a concern with this agent, particularly when trastu-zumab is used concurrently or sequentially with ananthracycline or other cardiotoxic agents such as thetaxanes and cyclophosphamide as well as in patientswith pre-existing cardiac disease.46 Trastuzumab-induced cardiotoxicity differs from traditionaldoxorubicin-induced cardiotoxicity, that is, it appears tobe at least partially reversible and is not related to thecumulative dose. Thus, clinicians should assess the ejec-tion fraction prior to initiating trastuzumab, avoid theconcurrent administration of trastuzumab with anthra-cyclines and monitor patients for symptoms and cardiacfunction during and for several years after therapy withtrastuzumab-containing regimens.

Several recent studies have evaluated the safety andefficacy of trastuzumab in combination with chemo-therapy in Japanese women with locally advanced andmetastatic breast cancer.18,26–28 A phase II trial conductedby the Japan Breast Cancer Research Network evaluatedthe safety and efficacy of trastuzumab in combinationwith capecitabine in women with HER2-overexpressingadvanced breast cancer.28 A total of 59 patients wereenrolled, of whom 86% had received prior chemo-therapy as part of adjuvant (21.4%) or metastatic treat-ment (48.2%), or both (16.1%). The combination oftrastuzumab and capecitabine resulted in an ORR of50% with higher response rates (63–65%) observed inpatients treated with trastuzumab and capecitabine asfirst-line therapy for metastatic disease, and those withHER2+3-positive tumors. Patients receiving first-linetherapy with trastuzumab and capecitabine had longermedian TTP (280 vs 130 days, P < 0.05) and overall

Treatment of breast cancer in Asia–Pacific S17

© 2008 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

Asia–Pac J Clin Oncol 2008; 4(Suppl. 3): S14–S23

Page 5: Current treatment of locally advanced and metastatic breast cancer in the Asia–Pacific region: Challenges and limitations

survival (780 days vs 480 days, P < 0.05) than didpatients receiving this treatment as second-line or third-line therapy. The treatment-related adverse events weregrade 1–2 hand-foot syndrome (30.4%), nausea (25%),diarrhea (10.7%), stomatitis (10.7%), fatigue (7.1%)and vomiting (5.4%). One patient reported grade 1cardiotoxicity with this combination.28

Another phase II study evaluated the combination ofdocetaxel and trastuzumab in Japanese women withHER2-positive metastatic breast cancer.27 A total of 40patients were enrolled and received 2–6 cycles of doce-taxel (70 mg/m2 every three weeks) and trastuzumab(4 mg/kg loading dose followed by 2 mg/kg weekly).The primary endpoint was a tumor response. Themedian follow-up was 20.8 months (range 0.6–30.9 months). The combination of docetaxel and tras-tuzumab was associated with an ORR of 65% and themedian TTP was 6.8 months (range 0.6–21.2 months).Common treatment-related toxicities included grade 3or 4 leukopenia and neutropenia, which were manage-able by reducing the dose of docetaxel or by treatmentwith granulocyte colony-stimulating factor. In fourpatients, left ventricular ejection fraction decreased bymore than 10% from baseline.

More recently, lapatinib, a small molecular dualinhibitor of epidermal growth factor receptor (EGFR)and HER2 tyrosine kinases has been shown to be effec-tive in patients with HER positive metastatic breastcancer, particularly those who have progressed while ontrastuzumab.47–49 In phase I/II studies, lapatinib demon-strated promising activity in patients with HER2-positive breast cancer and was associated with grade 1/2diarrhea and skin rash, and a low incidence of car-diotoxicity.48 The activity of lapatinib has been con-firmed in phase III trial comparing lapatinib andcapecitabine to capecitabine alone in women withHER2-positive, locally advanced or metastatic breastcancer previously treated with regimens containinganthracycline, taxane and trastuzumab.47,49 This studyinvolved 399 patients with HER2-positive breast cancerwho were randomized to lapatinib 1250 mg/day con-tinuously plus capecitabine 2000 mg/m2 days 1–14 of a21-day cycle or capecitabine 2500 mg/m2 on the sameschedule. The primary endpoint was TTP as determinedby an independent review panel. The addition of lapa-tinib to capecitabine prolonged TTP (hazard ratio [HR]:0.57, 95% CI, 0.43–0.77; P < 0.001). Lapatinib therapywas associated with fewer cases of central nervoussystem involvement at first progression compared withcapecitabine alone (4% lapatinib plus capecitabine vs13% capecitabine, P = 0.045). Ongoing clinical trials

are exploring the efficacy of lapatinib in combinationwith conventional chemotherapeutic agents (paclitaxel[Taxol], capecitabine and platinoids), hormone therapy(letrozole) and other target therapies (trastuzumab) inadvanced breast cancer or in neoadjuvant and adjuvantsettings.50

Basal-like tumors typically show a low or a completelack of expression of HER2 and ER and exhibit the highexpression of genes characteristic to the basal epithelialcells. They might share much clinical and biologicalbehavior with triple-negative breast cancers, which rep-resent the lack of expression of ER, PR and HER2.These tumors are characterized by more aggressive clini-cal behavior and poor prognosis than the other sub-types, which is likely to reflect this subtype’s highproliferative capacity as well as the lack of targetedtherapies such as conventional hormonal or anti-HER2therapies.51 As a result, these patients are currentlytreated with regimens combining chemotherapy andanti-angiogenic therapy (e.g., bevacizumab plus capeci-tabine or paclitaxel).52,53 Unfortunately, while both regi-mens increase the response rate, neither increases overallsurvival.52,53

The goals of future developments in treating womenwith metastatic breast cancer are to improve efficacyand reduce toxicity. The weekly administration oftaxanes has received growing interest as a way toincrease efficacy and/or decrease toxicity. The weeklydocetaxel showed a reduction in myelosuppressionwithout improving efficacy. However, weekly paclitaxeldemonstrated a higher response rate (28% vs 40%,P = 0.017) and prolonged TTP (5 months vs 9 months,P = 0.0008) with more neurotoxicity.54–59 Clinical trials,including a randomized phase III study, have shown thatpatients receiving nanoparticle albumin–bound pacli-taxel have a longer time to progression with feweradverse events.56,60,61

There is currently no standard therapy for patientswho do not respond or become refractory to anthracy-cline and taxane-based therapy for metastatic breastcancer. Many of the agents that have been used forsecond-line therapy against metastatic breast cancerinclude common chemotherapeutic drugs such as cap-ecitabine, gemcitabine, vinorelbine and vinflunine.62–65

Epothilones are novel microtubule targeting agents thatinduce tumor cell apoptosis by binding to beta-tubulinand stabilizing microtubules involved in mitosis.However, their mechanism of microtubule bindingis different from that of paclitaxel and they exhibita higher therapeutic indices and lower susceptibility tomultidrug-resistant (MDR)-1/p-glycoprotein-mediated

S18 LWC Chow and Y-H Im

© 2008 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

Asia–Pac J Clin Oncol 2008; 4(Suppl. 3): S14–S23

Page 6: Current treatment of locally advanced and metastatic breast cancer in the Asia–Pacific region: Challenges and limitations

resistance, which makes epothilones an attractive drugclass for patients with taxane-resistant malignan-cies.66,67 Of the epothilones currently under clinicaldevelopment, ixabepilone, a semi-synthetic analog ofnatural epothilone B, has demonstrated single agentanti-tumor activity in phase II studies across a spec-trum of breast cancer patients, including thosewith treatment-naive, anthracycline-resistant, taxane-refractory breast cancer.68–71 The combination of ixa-bepilone and capecitabine has demonstrated superiorefficacy compared to capecitabine monotherapy in aphase III randomized study involving patients withadvanced breast cancer or metastatic breast cancer resis-tant to the anthracyclines or taxanes.72 Other novelagents including the taxoid, larotaxel (XRP9881) andsunitinib have also demonstrated activity in phase IItrials involving patients with taxane-resistant breastcancer, as well as, women with metastatic breast cancerpreviously treated with an anthracycline and taxane.73,74

CHALLENGES AND BARRIERS TOEFFECTIVE TREATMENT

Barriers to the management of breast cancer in the Asia–Pacific region include a lack of awareness of the diseaseamong government and health-care practitioners, incon-sistent adherence to treatment guidelines on the part ofhealth-care practitioners, lack of diagnostic equipmentand specialists (particularly in rural areas), patients’ lackof access to treatment because of its high cost, and thelack of reimbursement programs. These issues are com-plicated by a low level of disease awareness and thesocial stigma associated with breast cancer in the generalpopulation.

Lack of access to testing and specialists

In many countries in the Asia–Pacific region, the cost ofdiagnostic equipment and testing is a barrier to effectivedisease management. Physicians may have only limitedaccess to equipment and genetic testing methods and thetrained specialists required for the diagnosis and moni-toring of breast cancer. As a result many women withthe disease go entirely without diagnosis or treatment.The lack of resources and medical facilities that providea comprehensive breast cancer service is particularlyacute in the rural areas of China, India and the Philip-pines. Such conditions pose significant barriers to theeffective prevention and management of breast cancer.

Insurance and monetary reimbursement

Although safe and effective therapy is available for themanagement of breast cancer, the high cost of therapy

and the lack of reimbursement for treatment and diag-nostic testing represent major obstacles to the manage-ment of this disease in the Asia–Pacific region. The costof traditional chemotherapy may be as high as US$3000and diagnostic testing to determine the hormone andHER2 receptor status of a tumor can cost an additionalUS$500. The costs associated with diagnostic testingand therapies are rarely covered by the government ormedical insurance, leaving individuals responsible forpayment on a fee-for-service basis. Thus, access to treat-ment is often limited to those who can afford it.75,76

Currently, only Korea, Taiwan, Singapore and Australiaprovide reimbursement for most of the chemotherapyand targeted agents used to treat patients with breastcancer.

Insufficient clinical experience

There is limited clinical experience of many chemothera-peutic agents in Asian–Pacific women with breastcancer. Economic barriers prevent many countries fromconducting their own clinical trials, and these countriesrely on dosing regimens that have been calibrated on thebasis of trial data from studies conducted primarily inWestern women. Accumulating evidence suggests thatcertain ethnic groups seem to absorb the chemicals dif-ferently and few comparative data are available on theethnic differences in the tolerability profiles of standardchemotherapies, which can differ between Western andAsian–Pacific women.77 These differences may be due togenetic variations resulting in altered pharmacokineticsof the drug, the lower body mass index of Asian womencompared with Western women, and the prevalent useof alternative therapies during treatment for breastcancer.77–79

Alternative medicines

The use of complementary and alternative medicines,particularly traditional Chinese or herbal medicines,to treat women with breast cancer is very prevalent inthe Asia–Pacific region.80 In a study in urban Shanghai,87% of 1065 women used Chinese herbal medicine(Table 1).80 While some preclinical data suggest thatsome traditional Chinese herbal medications displayanti-tumor activity, the efficacy of most Chinese herbalmedicines and alternative therapies has not been evalu-ated in controlled clinical trials.81–84 In a recent phase Istudy Yip et al. showed that the herbal medicine KY88composed of Fructus Schisandrae displayed immuno-modulatory effects in 23 patients infected with hepatitisB virus.85 However, herbal remedies and alternativemedicines are often complex mixtures produced without

Treatment of breast cancer in Asia–Pacific S19

© 2008 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

Asia–Pac J Clin Oncol 2008; 4(Suppl. 3): S14–S23

Page 7: Current treatment of locally advanced and metastatic breast cancer in the Asia–Pacific region: Challenges and limitations

quality assurance regulations.81 Safety concerns existover the possible adverse effects conferred by theseherbal and alternative medicines especially when theyare consumed in large quantities, and about their inter-action with conventional treatments for breast can-cer.80,81 Patients may not disclose their use of herbalor alternative medicines to their oncologists, furthercontributing to their potential for adverse effects. There-fore, the treatment of patients using Chinese herbalmedicines or alternative therapies represents a signifi-cant challenge.

CONCLUSION

The treatment of breast cancer in the Asia–Pacific regionis driven by a variety of factors, including its cost, theavailability of the drugs, and differences in patient char-acteristics, including their potential ethnic differences.The clinical experience in the Asia–Pacific region is vari-able across different countries but overall does not differmuch from that in the West. Yet regimens and dosages ofagents used to treat breast cancer are generally based onclinical data and experience derived from studies con-ducted in the USA and the EU. Clinical responses andtheir toleration of chemotherapy may differ betweenAsian–Pacific and Western women, but currently there isa lack of comparative trials defining the differencesamong ethnicities. Several factors may contribute to thedifferences in outcomes of Asian–Pacific and Westernwomen with breast cancer, including economic differ-ences and the use of alternative medicines. Cliniciansneed to be aware of the high use of Chinese herbal and

alternative medicines by women in the Asia–Pacificregion, as these medicines can potentially interactwith concurrent conventional chemotherapies to causeadverse drug–drug interactions and adverse effects.Clinical studies are needed to further evaluate and opti-mize the efficacy and safety profiles of breast cancertherapies in women in the Asia–Pacific region. Suchtrials would aid in the individualization and optimiza-tion of therapy for breast cancer patients in the Asian–Pacific region.

REFERENCE

1 Ferlay J, Autier P, Boniol M, Heanue M, Colombet M,Boyle P. Estimates of the cancer incidence and mortality inEurope in 2006. Ann Oncol 2007; 18: 581–92.

2 Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer sta-tistics, 2002. CA Cancer J Clin 2005; 55: 74–108.

3 Yang L, Parkin DM, Ferlay J, Li L, Chen Y. Estimates ofcancer incidence in China for 2000 and projections for2005. Cancer Epidemiol Biomarkers Prev 2005; 14: 243–50.

4 Son BH, Kwak BS, Kim JK et al. Changing patterns in theclinical characteristics of Korean patients with breastcancer during the last 15 years. Arch Surg 2006; 141:155–60.

5 Yang L, Parkin DM, Li LD, Chen YD, Bray F. Estimationand projection of the national profile of cancer mortality inChina: 1991–2005. Br J Cancer 2004; 90: 2157–66.

6 Suen D, Chow LW. Prognostic contribution of the HER-2oncogene overexpression to the Nottingham PrognosticIndex in breast cancer. Biomed Pharmacother 2006; 0:293–7.

7 Yu KD, Di GH, Wu J et al. Development and trends ofsurgical modalities for breast cancer in China: a review of16-year data. Ann Surg Oncol 2007; 14: 2502–9.

8 Yau TK, Chan K, Chant M et al. Wide local excision andradiotherapy for the treatment of ductal carcinoma in situof the breast: the Hong Kong experience. Clin Oncol(R Coll Radiol) 2006; 18 :447–52.

9 Fan J, Wang L, Wang XJ et al. Breast conservative therapyin east part of China: a retrospective cohort study. J CancerRes Clin Oncol 2006; 132: 573–8.

10 Kwong A, Cheung P, Chan S, Lau S. Breast cancer inChinese women younger than age 40: are they differentfrom their older counterparts? World J Surg 2008;Available from: http://www.springerlink.com/content/K5185021735264ru DOI: 10.1007/s00268-008-9589-6.

11 Chow LW, Au GK, Poon RT. Breast conservation therapyfor invasive breast cancer in Hong Kong: factors affectingrecurrence and survival in Chinese women. Aust N Z J Surg1997; 67: 94–7.

12 Zhou B, Yang DQ, Qiao XM et al. [Feasibility of breastconservation surgery after neoadjuvant chemotherapy for

Table 1 The use of Chinese herbal and alternative medicinesby Chinese women with breast cancer. Data adapted fromCui et al.80

Type of alternative medicine Prevalence of use (%)

Traditional Chinese medicine 86.7Chinese herbal medicine 86.4Acupuncture 4.9

Supplements 84.8Ginseng 62.9Omega-3 fatty acid 27.0Ganoderma 18.9Shark cartilage 17.6Lecithin 11.6Melatonin 6.6Honey tonic 5.6Megavitamins 0.0

S20 LWC Chow and Y-H Im

© 2008 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

Asia–Pac J Clin Oncol 2008; 4(Suppl. 3): S14–S23

Page 8: Current treatment of locally advanced and metastatic breast cancer in the Asia–Pacific region: Challenges and limitations

breast cancer]. Zhonghua Yi Xue Za Zhi 2005; 85: 769–72.

13 Akashi-Tanaka S, Omatsu M, Shimizu C et al. Favorableoutcome in patients with breast cancer in the presence ofpathological response after neoadjuvant endocrine therapy.Breast 2007; 16: 482–8.

14 Sarid D, Ron IG, Sperber F et al. Neoadjuvant treatmentwith paclitaxel and epirubicin in invasive breast cancer: aphase II study. Clin Drug Investig 2006; 26: 691–701.

15 Chow LW, Yip AY, Loo WT, Lam CK, Toi M. Celecoxibanti-aromatase neoadjuvant (CAAN) trial for locallyadvanced breast cancer. J Steroid Biochem Mol Biol 2008;111: 13–17.

16 Chow LW, Day W, Ng KC. Neoadjuvant chemotherapy forChinese women with locally advanced breast cancer. AmSurg 2001; 67: 412–16.

17 Watatani M, Ueda K, Daito K et al. Clinical experience ofweekly paclitaxel-based treatment as preoperative chemo-therapy for patients with primary breast cancer. BreastCancer 2004; 11: 187–93.

18 Sano M, Tabei T, Suemasu K et al. [Multicenter phase IItrial of thrice-weekly docetaxel and weekly trastuzumabas preoperative chemotherapy in patients with HER2-overexpressing breast cancer – Japan East Cancer CenterBreast Cancer Consortium (JECBC) 02 Trial]. Gan ToKagaku Ryoho 2006; 33: 1411–15 (Japanese).

19 Lim SE, Back M, Quek E, Iau P, Putti T, Wong JE. Clinicalobservations from a breast cancer registry in Asian women.World J Surg 2007; 31: 1387–92.

20 Hebert JR, Ghumare SS, Gupta PC. Stage at diagnosis andrelative differences in breast and prostate cancer incidencein India: comparison with the United States. Asian Pac JCancer Prev 2006; 7: 547–55.

21 Lau GI, Loo WT, Chow LW. Neoadjuvant chemotherapyfor breast cancer determined by chemosensitivity assayachieves better tumor response. Biomed Pharmacother2007; 61: 562–5.

22 Gligorov J, Azria D, Namer M, Khayat D, Spano JP. Noveltherapeutic strategies combining antihormonal and bio-logical targeted therapies in breast cancer: focus on clinicaltrials and perspectives. Crit Rev Oncol Hematol 2007; 64:115–28.

23 Chow LW, Yip AY, Loo WT, Toi M. Evaluation of neoad-juvant inhibition of aromatase activity and signal transduc-tion in breast cancer. Cancer Lett 2008; 262: 232–8.

24 Yip AY, Chow LW. Clinical experience with docetaxel forChinese breast cancer patients: hematological toxicity pro-files. Breast Cancer 2006; 13: 192–6.

25 Saji S, Toi M, Morita S et al. Dose-finding phase I andpharmacokinetic study of capecitabine (Xeloda) in combi-nation with epirubicin and cyclophosphamide (CEX) inpatients with inoperable or metastatic breast cancer.Oncology 2007; 72: 330–7.

26 Nishimura R, Okumura Y, Arima N. Trastuzumab mono-therapy versus combination therapy for treating recurrent

breast cancer: time to progression and survival. BreastCancer 2008; 15: 57–64.

27 Sato N, Sano M, Tabei T et al. Combination docetaxeland trastuzumab treatment for patients with HER-2-overexpressing metastatic breast cancer: a multicenter,phase-II study. Breast Cancer 2006; 13: 166–71.

28 Yamamoto D, Iwase S, Kitamura K, Odagiri H, YamamotoC, Nagumo Y. A phase II study of trastuzumab andcapecitabine for patients with HER2-overexpressingmetastatic breast cancer: Japan Breast Cancer ResearchNetwork (JBCRN) OO Trial. Cancer Chemother Pharma-col 2008; 61: 509–14.

29 Howell A, Dowsett M. Endocrinology and hormonetherapy in breast cancer: aromatase inhibitors versus anti-oestrogens. Breast Cancer Res 2004; 6: 269–74.

30 Nabholtz JM, Buzdar A, Pollak M et al. Anastrozole issuperior to tamoxifen as first-line therapy for advancedbreast cancer in postmenopausal women: results of a NorthAmerican multicenter randomized trial. Arimidex StudyGroup. J Clin Oncol 2000; 18: 3758–67.

31 Bonneterre J, Thurlimann B, Robertson JF et al.Anastrozole versus tamoxifen as first-line therapy foradvanced breast cancer in 668 postmenopausal women:results of the tamoxifen or arimidex randomized groupefficacy and tolerability study. J Clin Oncol 2000; 18:3748–57.

32 Mouridsen H, Gershanovich M, Sun Y et al. Superiorefficacy of letrozole versus tamoxifen as first-line therapyfor postmenopausal women with advanced breastcancer: results of a phase III study of the InternationalLetrozole Breast Cancer Group. J Clin Oncol 2001; 19:2596–606.

33 Perey L, Paridaens R, Hawle H et al. Clinical benefitof fulvestrant in postmenopausal women with advancedbreast cancer and primary or acquired resistance to aro-matase inhibitors: final results of phase II Swiss Group forClinical Cancer Research Trial (SAKK 21/00). Ann Oncol2007; 18: 64–9.

34 Ingle JN, Suman VJ, Rowland KM et al. Fulvestrant inwomen with advanced breast cancer after progression onprior aromatase inhibitor therapy: North Central CancerTreatment Group Trial N0032. J Clin Oncol 2006; 24:1052–6.

35 Marcom PK, Isaacs C, Harris L et al. The combination ofletrozole and trastuzumab as first or second-line biologicaltherapy produces durable responses in a subset of HER2positive and ER positive advanced breast cancers. BreastCancer Res Treat 2007; 102: 43–9.

36 Ghersi D, Wilcken N, Simes RJ. A systematic review oftaxane-containing regimens for metastatic breast cancer.Br J Cancer 2005; 93: 293–301.

37 Piccart-Gebhart MJ, Burzykowski T, Buyse M et al.Taxanes alone or in combination with anthracyclines asfirst-line therapy of patients with metastatic breast cancer.J Clin Oncol 2008; 26: 1980–6.

Treatment of breast cancer in Asia–Pacific S21

© 2008 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

Asia–Pac J Clin Oncol 2008; 4(Suppl. 3): S14–S23

Page 9: Current treatment of locally advanced and metastatic breast cancer in the Asia–Pacific region: Challenges and limitations

38 Jones SE, Erban J, Overmoyer B et al. Randomizedphase III study of docetaxel compared with paclitaxelin metastatic breast cancer. J Clin Oncol 2005; 5542–51.

39 Aihara T, Takatsuka Y, Itoh K et al. Phase II study ofconcurrent administration of doxorubicin and docetaxelas first-line chemotherapy for metastatic breast cancer.Oncology 2003; 64: 124–30.

40 Ahn JH, Kim SB, Sohn HJ, Lee JS, Kang YK, Kun KW.Docetaxel and cisplatin combination chemotherapy inmetastatic breast cancer patients with previous exposure toanthracyclines. Breast 2005; 14: 304–9.

41 O’Shaughnessy J, Miles D, Vukelja S et al. Superior sur-vival with capecitabine plus docetaxel combination therapyin anthracycline-pretreated patients with advanced breastcancer: phase III trial results. J Clin Oncol 2002; 20: 2812–23.

42 Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemo-therapy plus a monoclonal antibody against HER2 formetastatic breast cancer that overexpresses HER2. N EnglJ Med 2001; 344: 783–92.

43 Marty M, Cognetti F, Maraninchi D et al. Randomizedphase II trial of the efficacy and safety of trastuzumabcombined with docetaxel in patients with human epidermalgrowth factor receptor 2-positive metastatic breast canceradministered as first-line treatment: the M77001 studygroup. J Clin Oncol 2005; 23: 4265–74.

44 Cobleigh MA, Vogel CL, Tripathy D et al. Multinationalstudy of the efficacy and safety of humanized anti-HER2monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressedafter chemotherapy for metastatic disease. J Clin Oncol1999; 17: 2639–48.

45 Vogel CL, Cobleigh MA, Tripathy D et al. Efficacy andsafety of trastuzumab as a single agent in first-line treat-ment of HER2-overexpressing metastatic breast cancer.J Clin Oncol 2002; 20: 719–26.

46 Ewer SM, Ewer MS. Cardiotoxicity profile of trastuzumab.Drug Saf 2008; 31: 459–67.

47 Geyer CE, Forster J, Lindquist D et al. Lapatinib pluscapecitabine for HER2-positive advanced breast cancer.N Engl J Med 2006; 355: 2733–43.

48 Burris H III, Yardley D, Jones S et al. Phase II trial oftrastuzumab followed by weekly paclitaxel/carboplatin asfirst-line treatment for patients with metastatic breastcancer. J Clin Oncol 2004; 22: 1621–9.

49 Cameron D, Casey M, Press M et al. A phase III random-ized comparison of lapatinib plus capecitabine versuscapecitabine alone in women with advanced breast cancerthat has progressed on trastuzumab: updated efficacy andbiomarker analyses. Breast Cancer Res Treat 2008; 11 Jan.[Epub ahead of print].

50 Bilancia D, Rosati G, Dinota A, Germano D, Romano R,Manzione L. Lapatinib in breast cancer. Ann Onco 2007;18 (Suppl. 6): vi26–30.

51 Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer:a critical review. J Clin Oncol 2008; 26: 2568–81.

52 Miller K, Wang M, Gralow J et al. Paclitaxel plus bevaci-zumab versus paclitaxel alone for metastatic breast cancer.N Engl J Med 2007; 357: 2666–76.

53 Miller KD, Chap LI, Holmes FA et al. Randomized phaseIII trial of capecitabine compared with bevacizumab pluscapecitabine in patients with previously treated metastaticbreast cancer. J Clin Oncol 2005; 23: 792–9.

54 Lu CH, Lin YC, Chang HK. Weekly paclitaxel in womenwith heavily pretreated metastatic breast cancer: a retro-spective analysis of cases treated at the Chang GungMemorial Hospital. Chang Gung Med J 2007; 30: 33–40.

55 Blum JL, Dees EC, Vukelja SJ et al. Phase II trial of capecit-abine and weekly paclitaxel in patients with metastaticbreast cancer previously treated with every-3-week taxanetherapy. Clin Breast Cancer 2007; 7: 465–70.

56 Blum JL, Savin MA, Edelman G et al. Phase II study ofweekly albumin-bound paclitaxel for patients with meta-static breast cancer heavily pretreated with taxanes. ClinBreast Cancer 2007; 7: 850–6.

57 Clavarezza M, Del Mastro L, Venturini M. Taxane-containing chemotherapy in the treatment of early breastcancer patients. Ann Oncol 2006; 17 (Suppl. 7): vii22–6.

58 Eniu A, Palmieri FM, Perez EA. Weekly administration ofdocetaxel and paclitaxel in metastatic or advanced breastcancer. Oncologist 2005; 10: 665–85.

59 Seidman AD, Berry D, Cirrincione C et al. CALGB 9840:phase III study of weekly (W) paclitaxel (P) via 1-hour(h)infusion versus standard (S) 3h infusion every third week inthe treatment of metastatic breast cancer (MBC), with tras-tuzumab (T) for HER2 positive MBC and randomized forT in HER2 normal MBC. J Clin Oncol 2004; 22: No 14S(Suppl. 15): 512.

60 Gradishar WJ, Tjulandin S, Davidson N et al. Phase III trialof nanoparticle albumin-bound paclitaxel compared withpolyethylated castor oil-based paclitaxel in women withbreast cancer. J Clin Oncol 2005; 23: 7794–803.

61 Ibrahim NK, Samuels B, Page R et al. Multicenter phase IItrial of ABI-007, an albumin-bound paclitaxel, in womenwith metastatic breast cancer. J Clin Oncol 2005; 23:6019–26.

62 Schaller G, Fuchs I, Gonsch T et al. Phase II study ofcapecitabine plus trastuzumab in human epidermal growthfactor receptor 2 overexpressing metastatic breast cancerpretreated with anthracyclines or taxanes. J Clin Oncol2007; 25: 3246–50.

63 Chow LW, Yip AY, Lang BH. A phase II trial of vinorelbineand pegylated liposomal doxorubicin in patients with pre-treated metastatic breast cancer. Am J Clin Oncol 2007;30: 133–8.

64 Pajk B, Cufer T, Canney P et al. Anti-tumor activityof capecitabine and vinorelbine in patients withanthracycline- and taxane-pretreated metastatic breast

S22 LWC Chow and Y-H Im

© 2008 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

Asia–Pac J Clin Oncol 2008; 4(Suppl. 3): S14–S23

Page 10: Current treatment of locally advanced and metastatic breast cancer in the Asia–Pacific region: Challenges and limitations

cancer: findings from the EORTC 10001 randomizedphase II trial. Breast 2008; 17: 180–5.

65 Campone M, Cortes-Funes H, Vorobiof D et al. Vinflunine:a new active drug for second-line treatment of advancedbreast cancer. Results of a phase II and pharmacokineticstudy in patients progressing after first-line anthracycline/taxane-based chemotherapy. Br J Cancer 2006; 95:1161–6.

66 Altmann KH, Pfeiffer B, Arseniyadis S, Prattt BA, NicolaouKC. The chemistry and biology of epothilones – the wheelkeeps turning. Chem Med Chem 2007; 2: 396–423.

67 Lee FY, Borzilleri R, Fairchild CR et al. BMS-247550: anovel epothilone analog with a mode of action similar topaclitaxel but possessing superior antitumor efficacy. ClinCancer Res 2001; 7: 1429–37.

68 Denduluri N, Low JA, Lee JJ et al. Phase II trial of ixabepi-lone, an epothilone B analog, in patients with metastaticbreast cancer previously untreated with taxanes. J ClinOncol 2007; 25: 3421–7.

69 Low JA, Wedam SB, Lee JJ et al. Phase II clinical trial ofixabepilone (BMS-247550), an epothilone B analog, inmetastatic and locally advanced breast cancer. J Clin Oncol2005; 23: 2726–34.

70 Thomas E, Perez EA, Mukhopadhyay P et al. Phase II trialof ixabepilone in patients with metastatic breast cancer(MBC) who are resistant to an anthracycline, a taxaneand capecitabine [Abstract 660]. J Clin Oncol 2006; 24(Suppl.): 42s.

71 Roche H, Yelle L, Cognetti F et al. Phase II clinical trial ofixabepilone (BMS-247550), an epothilone B analog, asfirst-line therapy in patients with metastatic breast cancerpreviously treated with anthracycline chemotherapy. J ClinOncol 2007; 25: 3415–20.

72 Thomas ES, Gomez HL, Li RK et al. Ixabepilone pluscapecitabine for metastatic breast cancer progressing afteranthracycline and taxane treatment. J Clin Oncol 2007;25: 5210–7.

73 Dieras V, Limentani S, Romieu G et al. Phase II multicenterstudy of larotaxel (XRP9881), a novel taxoid, in patientswith metastatic breast cancer who previously receivedtaxane-based therapy. Ann Oncol 2008; 19: 1255–60.

74 Burstein HJ, Elias AD, Rugo HS et al. Phase II studyof sunitinib malate, an oral multitargeted tyrosinekinase inhibitor, in patients with metastatic breast cancer

previously treated with an anthracycline and a taxane.J Clin Oncol 2008; 26: 1810–6.

75 Gross A. Asia’s Cancer Markets. Published in Vivo: TheBusiness and Medicine Report. Pacific Bridge Medical,Bethesda, MD; October 1997. Available from: http://www.pacificbridgemedical.com/publications_asia.html

76 Chu PC, Hwang JS, Wang JD, Chang YY. Estimation ofthe financial burden to the National Health Insurance forpatients with major cancers in Taiwan. J Formos MedAssoc 2008; 107: 54–63.

77 Ma B, Yeo W, Hui P, Ho WM, Johnson PJ. Acute toxicityof adjuvant doxorubicin and cyclophosphamide for earlybreast cancer – a retrospective review of Chinese patientsand comparison with an historic Western series. RadiotherOncol 2002; 62: 185–9.

78 Lal S, Wong ZW, Jada SR et al. Novel SLC22A16 poly-morphisms and influence on doxorubicin pharmacokinet-ics in Asian breast cancer patients. Pharmacogenomics2007; 8: 567–75.

79 Lal S, Wong ZW, Sandanaraj E et al. Influence of ABCB1and ABCG2 polymorphisms on doxorubicin disposition inAsian breast cancer patients. Cancer Sci 2008; 99: 816–23.

80 Cui Y, Shu XO, Gao Y et al. Use of complementary andalternative medicine by Chinese women with breast cancer.Breast Cancer Res Treat 2004; 85: 263–70.

81 Cassidy A. Are herbal remedies and dietary supplementssafe and effective for breast cancer patients? Breast CancerRes 2003; 5: 300–2.

82 Loo WT, Chen JP, Chow LW, Chou JW. Effects of shugan-sanjie tang on matrix metalloproteinases 1, 3 and 9 andtelomerase reverse transcriptase expression in human breastcells in vitro. Biomed Pharmacother 2007; 61: 601–5.

83 Kang JX, Liu J, Wang J, He C, Li FP. The extract ofhuanglian, a medicinal herb, induces cell growth arrest andapoptosis by upregulation of interferon-beta and TNF-alpha in human breast cancer cells. Carcinogenesis 2005;26: 1934–9.

84 Wang X, Wei Y, Yuan S et al. Potential anticancer activityof tanshinone IIA against human breast cancer. Int JCancer 2005; 116: 799–807.

85 Yip AY, Loo WT, Chow LW. Fructus Schisandrae(wuweizi) containing compound in modulating humanlymphatic system – a Phase I minimization clinical trial.Biomed Pharmacother 2007; 61: 588–90.

Treatment of breast cancer in Asia–Pacific S23

© 2008 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

Asia–Pac J Clin Oncol 2008; 4(Suppl. 3): S14–S23