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The Community Oncologist

Clinical Efficacy of Taxane–Trastuzumab Combination Regimens for HER-2–Positive Metastatic Breast Cancer

Department of Medicine, Division of Medical Oncology, Duke University Comprehensive Cancer Center, Durham, North Carolina, USA

Key Words. Trastuzumab • Metastatic breast cancer • Docetaxel • Paclitaxel • Carboplatin

Correspondence: Kimberly L. Blackwell, M.D., Box 3893, Durham, North Carolina 27710, USA. Telephone: 919-668-1748; Fax: 919-681-0874; e-mail: black034{at}mc.duke.edu

Received October 25, 2007; accepted for publication April 4, 2008.

Disclosure: K. Blackwell has acted as a consultant to AstraZeneca and Pfizer and has a financial interest in Novartis (speakers bureau). No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

	Learning Objectives

Top Learning Objectives Abstract Introduction Rationale for Taxane-Trastuzumab... Efficacy of Taxane-Trastuzumab... The Addition of Platinum... Conclusions Author Contributions Acknowledgments References

 
After completing this course, the reader will be able to:

1. Evaluate the results of trials assessing the efficacy of monotherapy and doublet therapy of the taxanes, paclitaxel and docetaxel, plus trastuzumab in HER-2–positive MBC patients.
   
2. Administer the optimal dosing schedule of taxanes in HER-2–positive MBC patients.
   
3. Explain the possible benefits and toxicity of using anthracycline-sparing platinum chemotherapy in combination with taxane–trastuzumab therapy for HER-2–positive MBC.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Rationale for Taxane-Trastuzumab... Efficacy of Taxane-Trastuzumab... The Addition of Platinum... Conclusions Author Contributions Acknowledgments References

 
The taxanes docetaxel (Taxotere®; Sanofi-Aventis U.S. LLC, Bridgewater, NJ) and paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ) are highly active agents in metastatic breast cancer and may represent a safer alternative to anthracycline-based regimens when combined with the human epidermal growth factor receptor (HER)-2–targeted agent trastuzumab (Herceptin®; Genentech Inc., South San Francisco, CA). A number of preclinical and early clinical studies have evaluated the feasibility, duration, and appropriate dosing schedule(s) for taxane–trastuzumab combinations in HER-2–positive metastatic breast cancer. Preclinical studies of the taxanes in combination with trastuzumab demonstrate synergistic interactions of trastuzumab with docetaxel and additive interactions with paclitaxel. Even though not supported by head-to-head studies, clinical trial results indicate the response rates with docetaxel–trastuzumab combinations may be higher than those with paclitaxel–trastuzumab, although there is a lack of clear crosstrial differences in other clinical benefits. Weekly taxane–trastuzumab regimens have been shown to offer superior disease control. Results from two large, phase III trials that examined the addition of carboplatin to a taxane–trastuzumab doublet did not demonstrate a difference in survival with carboplatin. In one study, the addition of carboplatin to paclitaxel–trastuzumab therapy resulted in a higher response rate and longer progression-free survival time; in the second study, the docetaxel–trastuzumab and docetaxel–trastuzumab–carboplatin combinations were equally effective. Ongoing correlative studies of taxanes, as well as newer formulations such as nanoparticle albumin-bound paclitaxel, in combination with trastuzumab will inform clinical practice regarding the optimal agent, schedule, and use of these highly effective regimens.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Rationale for Taxane-Trastuzumab... Efficacy of Taxane-Trastuzumab... The Addition of Platinum... Conclusions Author Contributions Acknowledgments References

 
Breast cancer represents a heterogeneous array of different disease subtypes that have unique molecular phenotypes and distinct clinical features [1]. Despite advances in the treatment of early-stage breast cancer, approximately one third of patients will eventually develop metastatic breast cancer (MBC) [2]. The prognosis of patients with MBC is poor, with a median survival time of 26 months [3]. Recently, advances in understanding the biology of breast cancer have led to the classification of breast tumors based upon their molecular features and the advent of targeted therapies for the treatment of both early and metastatic cancer. Targeted agents and their promise of better patient outcomes with respect to safety, survival, and quality of life may change the clinical course for many MBC patients.

The human epidermal growth factor receptor (HER)-2/neu gene is a member of a gene family that encodes for transmembrane receptor tyrosine kinases, including the epidermal growth factor receptor. Approximately 20%–30% of human breast tumors overexpress the HER-2/neu gene, and patients with HER-2–overexpressing tumors experience early progression and a poor prognosis in the metastatic setting [4, 5]. Trastuzumab (Herceptin®; Genentech Inc, South San Francisco, CA), a humanized monoclonal antibody directed against the extracellular domain of HER-2, has been developed for the treatment of HER-2–overexpressing breast cancers. In the pivotal phase III randomized trial in patients with MBC, the combination of trastuzumab with either doxorubicin (Adriamycin®; Pfizer Inc, New York, NY) plus cyclophosphamide (Cytoxan®; Bristol Myers Squibb, Princeton, NJ) (AC) or single-agent paclitaxel resulted in longer times to progression (TTP), higher response rates, and higher survival rates than with chemotherapy alone [6]. However, the combination of trastuzumab and AC also resulted in an unexpectedly high risk for cardiotoxicity: the frequency of congestive heart failure was greatest among patients receiving simultaneous anthracycline and trastuzumab therapy. Recognition of this effect, compounded by the widespread use of anthracycline adjuvant therapy, prompted the development of nonanthracycline-containing targeted regimens for the treatment of women with HER-2–positive MBC.

The taxanes docetaxel (Taxotere®; Sanofi-Aventis U.S. LLC, Bridgewater, NJ) and paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ) are highly active agents in MBC and may represent a safer alternative to anthracycline-based regimens when combined with trastuzumab. The rationale for combining taxanes with trastuzumab for the treatment of patients with HER-2–positive MBC is based on in vitro preclinical synergy, favorable results as monotherapies, safety considerations, and demonstrated benefit in early clinical trials. This review summarizes this rationale and presents efficacy data from taxane–trastuzumab combination regimens and schedules in HER-2–positive MBC. Recent data from studies that investigated the triple combination of a taxane with trastuzumab and a platinum compound in MBC are also discussed in light of a potential clinical application.

	RATIONALE FOR TAXANE–TRASTUZUMAB COMBINATION THERAPY

Top Learning Objectives Abstract Introduction Rationale for Taxane-Trastuzumab... Efficacy of Taxane-Trastuzumab... The Addition of Platinum... Conclusions Author Contributions Acknowledgments References

 
Preclinical Interactions Between Trastuzumab and Taxanes
A multiple drug effect/combination index model allowing for the quantization of synergism or antagonism between chemotherapy agents has been useful in the preclinical identification of rational combinations of drugs for specific diseases [7]. Applying this model to HER-2–overexpressing breast cancer cell lines, Pegram and colleagues reported synergistic cytotoxic interactions over a wide range of clinically achievable concentrations of trastuzumab and docetaxel, including with the addition of carboplatin [8, 9]. The synergy between trastuzumab and docetaxel was higher in cell lines with higher HER-2 expression levels [10]. In contrast, additive interactions between trastuzumab and paclitaxel were found in each HER-2–overexpressing cell line. The differences between docetaxel and paclitaxel in preclinical interactions with trastuzumab may be based on inherent mechanistic differences between the taxanes.

Trastuzumab and Taxanes as Monotherapies in MBC
Several multicenter trials in patients with MBC found response rates to single-agent trastuzumab in the range of 12%–34%, depending on the method used to determine HER-2 status and on prior treatment received by patients [11–13]. Response rates also varied with the degree of HER-2 overexpression, with a higher objective response rate among those patients who had HER-2/neu gene amplification or HER-2 3+ overexpression by immunohistochemistry [11, 13]. Although trastuzumab monotherapy is not approved as first-line treatment for HER-2–positive MBC, considering its tolerability profile and nearly equivalent response rate to chemotherapy it may offer a viable first-line option for some women with HER-2–overexpressing MBC. As described, cardiomyopathy is the most significant toxicity associated with trastuzumab, particularly when administered in combination with anthracyclines and in patients with pre-existing cardiac disease or risk factors [14]. Trastuzumab-associated cardiac dysfunction requires careful monitoring of the ejection fraction with timely recognition and treatment of heart failure, accordingly.

Paclitaxel is a highly active agent in MBC and has been evaluated in multiple trials. As first-line treatment for MBC, paclitaxel has achieved objective response rates in the range of 29%–63% [15–17]; in second-line treatment, response rates are in the range of 21%–56% [17–20]. The overall survival (OS) time with first-line paclitaxel monotherapy is in the range of 10.1–11.7 months [15, 16]. The second taxane proven to have considerable efficacy in the treatment of breast cancer is docetaxel. Three phase III trials that examined its use in anthracycline-resistant and anthracycline-refractory MBC patients each found a significantly higher overall response rate for single-agent docetaxel (30%–43%) in comparison with other combination therapies [21–23]. In one trial, a significant survival benefit was observed in women given docetaxel (11.4 months) compared with those given the previously established second-line therapy of mitomycin plus vinblastine (8.7 months; p = .001) [21]. The dose-limiting toxicity for both docetaxel and paclitaxel is neutropenia [24, 25].

Recently, results from the only phase III trial directly comparing paclitaxel with docetaxel as monotherapy in patients with MBC were reported [26]. All 449 patients had progressed on prior anthracycline-based chemotherapy and were randomly assigned to receive either docetaxel (100 mg/m²) or paclitaxel (175 mg/m²) every 3 weeks until disease progression. Patients treated with docetaxel had a significantly longer median TTP (5.7 months versus 3.6 months; hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.33–2.02; p < .001) and OS time (15.4 versus 12.7 months; HR, 1.41; 95% CI, 1.15–1.73; p = .03) than those treated with paclitaxel. There was no significant difference in the objective response rates in the two treatment arms, and although docetaxel demonstrated a survival benefit, it was also associated with more serious grade 3–4 toxicities than paclitaxel. Clinical application of these results remains challenging given the subsequent adoption of weekly dosing schedules for many chemotherapeutic agents in the metastatic setting, including the taxanes and trastuzumab.

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane®, Abraxis Bioscience, Los Angeles, CA and AstraZeneca Pharmaceuticals, Wilmington, DE), developed to ameliorate hypersensitivity reactions, has been compared with paclitaxel and docetaxel in patients with MBC. In the key phase III trial in 460 patients, there was a benefit with nab-paclitaxel every 3 weeks over paclitaxel every 3 weeks in terms of the response rate (33% versus 19%; p = .001) and TTP (23 versus 16.9 weeks; p = .006), but the median OS times were similar [27]. Gradishar et al. [28] recently reported interim results of a randomized phase II trial of 302 patients comparing docetaxel against three different schedules of nab-paclitaxel. The response rates of every-3-weeks nab-paclitaxel and docetaxel were comparable. Weekly nab-paclitaxel had a significantly greater response rate than the every-3-weeks regimens. Survival data for this study are not yet mature [28].

	EFFICACY OF TAXANE–TRASTUZUMAB COMBINATIONS

Top Learning Objectives Abstract Introduction Rationale for Taxane-Trastuzumab... Efficacy of Taxane-Trastuzumab... The Addition of Platinum... Conclusions Author Contributions Acknowledgments References

 
The favorable preclinical synergy, activity as monotherapy, and nonoverlapping toxicities serve as the basis for examining combinations of a taxane and trastuzumab in patients with HER-2–overexpressing MBC. The efficacy, treatment duration, and appropriate dosing schedule for these combinations are still under investigation in this setting.

Phase II
Small, phase II trials that have evaluated trastuzumab–taxane combinations as first-line therapy in MBC have reported response rates of 50%–70% for trastuzumab in combination with docetaxel [29–31], and 62%–81% for trastuzumab in combination with paclitaxel [32–35]. Two larger, randomized, phase II multicenter trials have corroborated an advantage of adding trastuzumab to a taxane as first-line therapy in patients with HER-2–positive MBC (Table 1). In the M77001 phase II study in HER-2–positive MBC, 186 patients were randomly assigned to receive six cycles of docetaxel (100 mg/m²) every 3 weeks either with or without trastuzumab (Table 1) [36, 37]. An analysis performed at 24 months after enrollment found that the addition of trastuzumab to docetaxel produced a significantly higher response rate (61% versus 34%; p = .0002), significantly longer TTP (11.7 versus 6.1 months; p = .0001), and significantly longer OS time (31.2 versus 22.7 months; p = .03) than with docetaxel alone [36]. Importantly, a subsequent 36-month analysis demonstrated that the survival difference of 8.5 months for upfront trastuzumab was sustained, even with 57% of patients initially randomized to receive docetaxel alone having crossed over to receive trastuzumab [37]. An unplanned analysis that compared the patients who crossed over to trastuzumab after docetaxel with the patients who never received trastuzumab found a survival advantage of 13.7 months [36]. These data suggest that there is an advantage to initiating trastuzumab therapy early in the treatment course of HER-2–positive breast cancer. The combination of docetaxel and trastuzumab therapy was generally well tolerated, but there were higher incidences of grade 3–4 leukopenia (20% versus 15%) and neutropenia (32% versus 22%) in the combination arm than in the docetaxel-alone arm. Only one patient (1%) in the trastuzumab plus docetaxel arm experienced heart failure.

Weekly nab-paclitaxel plus trastuzumab (4 mg/kg loading, followed by 2 mg/kg weekly maintenance) in HER-2–overexpressing women is currently being studied in the ION-04–012 phase II trial for first-line locally advanced breast cancer and MBC. Though the trial is still accruing, there have been no concerning safety signals at a median weekly dose of nab-paclitaxel of 125 mg/m². The rate of grade 3 sensory neuropathy is approximately 7%. Efficacy data are pending [39].

Phase III
In the pivotal phase III trial in MBC that examined the addition of trastuzumab to either AC or paclitaxel, trastuzumab in combination with paclitaxel (175 mg/m² every 3 weeks) resulted in significantly longer median TTP (6.9 months) than with paclitaxel alone (3.0 months; p < .001) (Table 2) [6]. Statistically significant advantages in the response rate (41% versus 17%; p < .001) and response duration (10.5 versus 4.5 months; p < .01) were also seen in the group who received trastuzumab, but there was no survival difference between treatment groups (22.1 versus 18.4 months; p = .17). The combination of paclitaxel and trastuzumab resulted in cardiac dysfunction in 13% of patients; only 1% of patients in the paclitaxel-alone group experienced cardiac dysfunction [6].

Optimal Dosing for Taxanes in Combination with Trastuzumab
At present, the dosing schedules approved by the U.S. Food and Drug Administration for the taxanes in MBC are 60–100 mg/m² for docetaxel as a 1-hour infusion every 3 weeks and 175 mg/m² for paclitaxel as a 3-hour infusion every 3 weeks. In an effort to increase the therapeutic results while reducing toxicity, dose-dense regimens are being explored that administer effectively higher doses of taxane per unit of time (i.e., mg/m² per week).

Trials that have specifically examined weekly regimens of lower dose docetaxel (33–40 mg/m²) in combination with trastuzumab for HER-2–overexpressing MBC have reported objective response rates in the range of 50%–70% [29, 31, 41–43]. Rates varied by the degree of HER-2 expression [29, 31] and this regimen yielded efficacy comparable with that seen with the every-3-weeks dosing regimen (Table 3).

	THE ADDITION OF PLATINUM TO TAXANE–TRASTUZUMAB REGIMENS IN MBC

Top Learning Objectives Abstract Introduction Rationale for Taxane-Trastuzumab... Efficacy of Taxane-Trastuzumab... The Addition of Platinum... Conclusions Author Contributions Acknowledgments References

 
Phase II
Phase II trials that examined the combination of docetaxel and carboplatin as first-line treatment in patients with MBC found that administration every 3 weeks resulted in overall response rates of approximately 60% and a median TTP of 10 months [47, 48]. More recently, trials that examined carboplatin with paclitaxel every 3 weeks as first-line treatment in MBC found the combination to be active and reasonably well tolerated, with response rates in the range of 43%–62% and a median TTP of 5–9 months [49–52]. A retrospective review by Perez of phase II/III carboplatin trials in patients with MBC showed that carboplatin–docetaxel and carboplatin–paclitaxel combinations had response rates of 53%–62%, greater efficacy than when carboplatin or the taxanes were used alone in this patient population [53].

Noncomparative phase II trials that have examined the triple combination of a taxane with trastuzumab and a platinum compound as first-line treatment in patients with HER-2–positive MBC have also shown promising results. In the parallel phase II North Central Cancer Treatment Group (NCCTG) 983252 study, women with MBC were randomized to receive the triple combination of either trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance), paclitaxel (200 mg/m²), and carboplatin (area under the concentration–time curve [AUC], 6 mg/ml per minute) every 3 weeks or weekly trastuzumab (4 mg/kg loading dose, followed by 2 mg/kg maintenance), paclitaxel (80 mg/m²), and carboplatin (AUC, 2 mg/ml per minute) [54]. Although the parallel design of the NCCTG 983252 trial does not permit direct comparisons between the two arms, a greater clinical benefit for the weekly schedule was suggested by a higher overall response rate (81% versus 65%, respectively), longer median progression-free survival time (14.7 versus 9.9 months), and longer OS time (3.2 versus 2.3 years). Grade 4 neutropenia (70% versus 10%) and grade 3-4 febrile neutropenia (16% versus 2%) occurred more frequently with the every-3-weeks schedule, but grade 3 neurosensory toxicity was less frequent (2% versus 19%). These data are in concordance with a pilot trial designed to assess the feasibility and toxicity of an induction course of trastuzumab followed by weekly paclitaxel plus carboplatin, which reported an overall response rate of 84% with the weekly triple combination, a median TTP of 14.2 months, and a median OS time of 32.2 months [55].

Several phase II clinical trials supported by the Breast Cancer International Research Group (BCIRG 101 and BCIRG 102) and conducted by Pegram et al. [56] and Slamon et al. [57] have demonstrated a high degree of efficacy with the triple combination of docetaxel, trastuzumab, and carboplatin or cisplatin in women with HER-2–overexpressing MBC (Table 2). Dosing schedules from these trials included trastuzumab at 4 mg/kg loading dose, followed by 2 mg/kg maintenance, with every-3-weeks schedules of docetaxel (75 mg/m²) and a platinum salt, either cisplatin (BCIRG 101) or carboplatin (BCIRG 102) at an AUC of 6 mg/ml per minute; each trial enrolled 62 patients. Objective responses were reported in 58% of patients (95% CI, 44%–70%) in the carboplatin trial and 79% of patients (95% CI, 66%–89%) in the cisplatin trial. The median TTP were 12.7 months and 9.9 months, respectively [56]. With a median follow-up of 37.7 months for the cisplatin trial, the median OS time for all patients was 28.1 months. After a median follow-up of 34.3 months for the carboplatin trial, the median OS time for all patients had not yet been reached (55% of patients remained alive at 34.3 months) [57]. In terms of tolerability, 65% of patients in the carboplatin trial and 16% of patients in the cisplatin trial developed grade 4 neutropenia. The rates of febrile neutropenia were 16% and 13%.

Phase III
These provocative phase II data served as the basis for several larger, randomized, phase III trials in MBC that have directly examined the benefit of adding carboplatin to a taxane–trastuzumab regimen. One such trial was conducted by the U.S. Oncology Group and evaluated the efficacy and safety of paclitaxel and trastuzumab with or without carboplatin as first-line therapy for 196 women with HER-2–overexpressing MBC (Fig. 1, Table 2) [58]. The investigators reported a significantly higher response rate with carboplatin (52%) than with trastuzumab and paclitaxel alone (36%; p = .04). A 3.6-month longer median progression-free survival time was also observed for patients treated with the triplet therapy compared with patients receiving paclitaxel and trastuzumab (HR, 0.66; 95% CI, 0.59–0.73; p = .03). These superior clinical outcomes were most evident in patients with HER-2 3+ overexpression as determined by immunohistochemistry. Despite a significantly higher incidence of grade 4 neutropenia with the triple regimen (p < .01), both regimens were reported as well tolerated.

View larger version (28K): [in this window] [in a new window]   Figure 1. BCIRG 007 and U.S. Oncology phase III studies of taxane–trastuzumab–platinum combinations in HER-2–overexpressing metastatic breast cancer patients. Abbreviations: AUC, area under the concentration–time curve; BCIRG, Breast Cancer International Research Group; C, carboplatin; H, trastuzumab; HER, human epidermal growth factor receptor; q3w, every 3 weeks; T, taxane.

Based on the results from these two randomized, phase III trials, it remains unclear whether the addition of a platinum agent to taxane–trastuzumab therapy for MBC is warranted. While the BCIRG 007 trial objective response rates with docetaxel plus trastuzumab (72%), with or without carboplatin, appear greater than those reported with paclitaxel plus trastuzumab (52% with carboplatin, 36% without), the BCIRG investigators failed to show significance among the groups despite a larger cohort. One possible suggestion for the similar clinical benefit observed among treatment groups in the BCIRG 007 trial may be that approximately 10% of patients were pretreated with taxane therapy prior to enrollment. The U.S. Oncology trial design specifically excluded patients who received prior taxane therapy; thus, it is possible that taxane-naive patients showed a synergistic response to the combination therapy that was not seen in the partially taxane-pretreated groups of the BCIRG 007 study. Additionally, more patients in the U.S. Oncology trial (40% in the TCH arm and 51% in the TH arm, compared with 36.4% in the TCH arm and 26.7% in the TH arm of the BCIRG 007 study) had been pretreated with hormonal therapies, indicating a patient population with a higher prevalence of favorable estrogen receptor and progesterone receptor expression that had also received less overall cytotoxic therapy and was perhaps primed to demonstrate a response when challenged with triplet conventional chemotherapy.

As a result of these data, and in light of emerging clinical practice favoring weekly taxane–trastuzumab therapy, it follows that, if the side-effect profile of adding a platinum agent is elected for an individual patient, the drug would be optimally given as part of a similar weekly regimen. Attention should be given to using G-CSF in the appropriate patients, especially when dosing carboplatin.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Rationale for Taxane-Trastuzumab... Efficacy of Taxane-Trastuzumab... The Addition of Platinum... Conclusions Author Contributions Acknowledgments References

 
Cardiac toxicity continues to limit the use of trastuzumab in MBC patients, specifically in patients with prior anthracycline exposure or other risk factors for cardiomyopathy. As alternatives to anthracyclines, both docetaxel and paclitaxel are now considered among the most active agents in MBC. Their combinations with trastuzumab are well-tolerated and effective therapy options for women with HER-2–positive MBC, particularly in a weekly dosing schedule. Preclinical assessment of the taxanes in combination with trastuzumab demonstrates the synergy of trastuzumab with either docetaxel or carboplatin and additivity with paclitaxel. Similarly, phase II and III trials indicate that response rates with docetaxel–trastuzumab combinations are likely higher than those with paclitaxel, although no clear crosstrial differences between other efficacy endpoints have emerged.

Given the preclinical synergy between carboplatin and trastuzumab, the addition of carboplatin to taxane-and trastuzumab-containing regimens should offer additional antitumor activity. Two large studies support that carboplatin added to taxane- and trastuzumab-based regimens may improve some clinical parameters, but neither study demonstrated a survival benefit for the addition of carboplatin. In the BCIRG 007 trial, no added benefit was found with trastuzumab, docetaxel, and carboplatin over trastuzumab plus docetaxel alone. These results with the triplet combinations are disappointing in relation to survival advantages seen with other doublet chemotherapy regimens in non-HER-2–positive MBC [60, 61]. Accordingly, trials that further examine taxane–trastuzumab therapy with or without a platinum in combination with novel agents, including the dual tyrosine kinase inhibitor lapatinib, the mammalian target of rapamycin inhibitor everolimus, and the anti–vascular endothelial growth factor agent bevacizumab, are currently accruing HER-2–positive women.

Overall, because there have been no head-to-head comparisons of docetaxel and paclitaxel used in combination with trastuzumab for the treatment of HER-2–positive MBC, and no large trials have fully examined the combination of trastuzumab with newer taxane formulations, such as nab-paclitaxel, we await the results of ongoing, well-designed correlative studies to instruct clinicians further regarding the optimal schedule, taxane, and use of these highly effective regimens.

	AUTHOR CONTRIBUTIONS

Top Learning Objectives Abstract Introduction Rationale for Taxane-Trastuzumab... Efficacy of Taxane-Trastuzumab... The Addition of Platinum... Conclusions Author Contributions Acknowledgments References

 
Conception/design: Karen Bullock, Kimberly Blackwell

Financial support: Karen Bullock, Kimberly Blackwell

Administrative support: Karen Bullock, Kimberly Blackwell

Provision of study materials or patients: Karen Bullock, Kimberly Blackwell

Collection/assembly of data: Karen Bullock, Kimberly Blackwell

Data analysis and interpretation: Karen Bullock, Kimberly Blackwell

Manuscript writing: Karen Bullock, Kimberly Blackwell

Final approval of manuscript: Karen Bullock, Kimberly Blackwell

	ACKNOWLEDGMENTS

Top Learning Objectives Abstract Introduction Rationale for Taxane-Trastuzumab... Efficacy of Taxane-Trastuzumab... The Addition of Platinum... Conclusions Author Contributions Acknowledgments References

 
The authors acknowledge the assistance of medical writer Fiona Herr, Ph.D., of Aranmore Medical Communications.

	REFERENCES

Top Learning Objectives Abstract Introduction Rationale for Taxane-Trastuzumab... Efficacy of Taxane-Trastuzumab... The Addition of Platinum... Conclusions Author Contributions Acknowledgments References

 

1. Slamon DJ, Romond EH, Perez EA. Advances in adjuvant therapy for breast cancer. Clin Adv Hematol Oncol 2006;4(suppl 1):4–9.
2. Polychemotherapy for early breast cancer: An overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 1998;352:930–942.[CrossRef][Medline]
3. Gennari A, Conte P, Rosso R et al. Survival of metastatic breast carcinoma patients over a 20-year period: A retrospective analysis based on individual patient data from six consecutive studies. Cancer 2005;104:1742–1750.[CrossRef][Medline]
4. Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–182.[Abstract/Free Full Text]
5. Press MF, Bernstein L, Thomas PA et al. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: Poor prognosis in node-negative breast carcinomas. J Clin Oncol 1997;15:2894–2904.[Abstract]
6. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792.[Abstract/Free Full Text]
7. Chou TC, Motzer RJ, Tong Y et al. Computerized quantitation of synergism and antagonism of Taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: A rational approach to clinical protocol design. J Natl Cancer Inst 1994;86:1517–1524.[Abstract/Free Full Text]
8. Pegram MD, Konecny GE, O'Callaghan C et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004;96:739–749.[Abstract/Free Full Text]
9. Pegram M, Hsu S, Lewis G et al. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 1999;18:2241–2251.[CrossRef][Medline]
10. Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639–2648.[Abstract/Free Full Text]
11. Vogel CL, Cobleigh MA, Tripathy D et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719–726.[Abstract/Free Full Text]
12. Baselga J, Carbonnell X, Casteneda-Soto N et al. Updated efficacy and safety analyses of 3-weekly Herceptin monotherapy in women with HER2-positive metastatic breast cancer; results from twelve-months of follow-up to a phase II study. Breast Cancer Res Treat 2004;88(suppl 1):S126.
13. Baselga J, Tripathy D, Mendelsohn J et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 1996;14:737–744.[Abstract/Free Full Text]
14. Herceptin® (trastuzumab) [prescribing information]. 2005, Genentech, South San Francisco, CA, Available at http://www.gene.com/gene/products/information/oncology/herceptin/insert.jsp. Accessed February 3, 2008.
15. Wilson WH, Berg SL, Bryant G et al. Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: A phase I/II trial of 96-hour infusion. J Clin Oncol 1994;12:1621–1629.[Abstract/Free Full Text]
16. Nabholtz JM, Gelmon K, Bontenbal M et al. Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 1996;14:1858–1867.[Abstract/Free Full Text]
17. Seidman AD, Tiersten A, Hudis C et al. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol 1995;13:2575–2581.[Abstract]
18. Fountzilas G, Athanassiades A, Giannakakis T et al. A phase II study of paclitaxel in advanced breast cancer resistant to anthracyclines. Eur J Cancer 1996;32A:47–51.
19. Holmes FA, Walters RS, Theriault RL et al. Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 1991;83:1797–1805.[Abstract/Free Full Text]
20. Abrams JS, Vena DA, Baltz J et al. Paclitaxel activity in heavily pretreated breast cancer: A National Cancer Institute Treatment Referral Center trial. J Clin Oncol 1995;13:2056–2065.[Abstract/Free Full Text]
21. Nabholtz JM, Senn HJ, Bezwoda WR et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group. J Clin Oncol 1999;17:1413–1424.[Abstract/Free Full Text]
22. Sjöstrom J, Blomqvist C, Mouridsen H et al. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: A randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer 1999;35:1194–1201.[CrossRef][Medline]
23. Bonneterre J, Roché H, Monnier A et al. Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. Br J Cancer 2002;87:1210–1215.[CrossRef][Medline]
24. Taxotere® (docetaxel) [prescribing information]. 2006, Sanofi-Aventis U.S. LLC, Bridgewater, NJ, Available at http://products.sanofi-aventis.us/Taxotere/taxotere.html. Accessed February 3, 2008.
25. Taxol® (paclitaxel) [prescribing information]. 2003, Bristol Myers Squibb, Princeton, NJ, Available at http://www.bms.com/cgi-bin/anybin.pl?sql=select%20PPI%20from%20TB_PRODUCT_PPI%20where%20PPI_SEQ=19&key=PPI. Accessed February 3, 2008.
26. Jones SE, Erban J, Overmoyer B et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005;23:5542–5551.[Abstract/Free Full Text]
27. Gradishar WJ, Tjulandin S, Davidson N et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005;23:7794–7803.[Abstract/Free Full Text]
28. Gradishar W, Krasnojon D, Cheparov S et al. Randomized comparison of weekly or every-3-week (q3w) nab-paclitaxel compared to q3w docetaxel as first-line therapy in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol 2007;25;(18) (Suppl):1032.
29. Esteva FJ, Valero V, Booser D et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:1800–1808.[Abstract/Free Full Text]
30. Montemurro F, Choa G, Faggiuolo R et al. Safety and activity of docetaxel and trastuzumab in HER2 overexpressing metastatic breast cancer: A pilot phase II study. Am J Clin Oncol 2003;26:95–97.[CrossRef][Medline]
31. Tedesco KL, Thor AD, Johnson DH et al. Docetaxel combined with trastuzumab is an active regimen in HER-2 3+ overexpressing and fluorescent in situ hybridization-positive metastatic breast cancer: A multi-institutional phase II trial. J Clin Oncol 2004;22:1071–1077.[Abstract/Free Full Text]
32. Fountzilas G, Tsavdaridis D, Kalogera-Fountzila A et al. Weekly paclitaxel as first-line chemotherapy and trastuzumab in patients with advanced breast cancer. A Hellenic Cooperative Oncology Group phase II study. Ann Oncol 2001;12:1545–1551.[Abstract/Free Full Text]
33. Gasparini G, Morabito A, DeSio L et al. Preliminary clinical results of a randomized phase IIb study of weekly paclitaxel +/- trastuzumab as first-line therapy of patients with HER-2/neu positive metastatic breast cancer. Breast Cancer Res Treat 2003;82(suppl 1):S51.
34. John M, Hindenburg H. Weekly paclitaxel plus trastuzumab in metastatic breast cancer; a multicentre German trial. Eur J Cancer Suppl 2003;1:S139–S140.
35. Seidman AD, Fornier MN, Esteva FJ et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001;19:2587–2595.[Abstract/Free Full Text]
36. Marty M, Cognetti F, Maraninchi D et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol 2005;23:4265–4274.[Abstract/Free Full Text]
37. Marty M, Cognetti F, Maraninchi D et al. Superior long-term survival benefits of trastuzumab plus docetaxel compared to docetaxel alone in patients with HER2-positive metastatic breast cancer: Patients surviving more than 4 years in the M77001 study. Breast Cancer Res Treat 2006;100(suppl 1):S103.[CrossRef]
38. Wardley A, Anton-Torres A, Pivot X et al. Trastuzumab plus docetaxel with or without capecitabine in patients with HER2-positive advanced/metastatic breast cancer: First efficacy results from the Phase II MO16419 (CHAT) study. Breast Cancer Res Treat 2006;100(suppl 1):S101.
39. Mirtsching B, Chidiac T, Cosgriff T. International Oncology Network. First line treatment of metastatic breast cancer with weekly abraxane (nab-paclitaxel: A 130 nm albumin-bound particle): A preliminary analysis of the phase II international oncology network ION-04-012 study. J Clin Oncol 2006;24;(18) (suppl):10707.
40. Extra JM, Antoine EC, Vincent-Salomon A et al. Favourable effect of trastuzumab (Herceptin) treatment in metastatic breast cancer patients: Results from the French Hermine cohort study. Breast Cancer Res Treat 2006;100(suppl 1):S102.
41. Raab G, Brugger W, Harbeck N et al. Multi-center randomized phase II study of docetaxel (Doc) given q3w vs. q1wk plus trastuzumab (Tra) as first line therapy for Her2 overexpressing adjuvant anthracycline pretreated metastatic breast cancer (MBC). Breast Cancer Res Treat 2002;76(suppl 1):S114.
42. Bines J, Murad A, Lago S et al. Weekly docetaxel (Taxotere) and trastuzumab (Herceptin) as primary therapy in stage III, Her2 overexpressing breast cancer—a Brazilian multicenter study. Breast Cancer Res Treat 2003;82(suppl 1):S56.
43. Raff JP, Rajdev L, Malik U et al. Phase II study of weekly docetaxel alone or in combination with trastuzumab in patients with metastatic breast cancer. Clin Breast Cancer 2004;4:420–427.[Medline]
44. John M, Kriebel-Schmitt R, Staunch M et al. Weekly paclitaxel plus trastuzumab shows promising efficacy in advanced breast cancer. Breast Cancer Res Treat 2003;82:S49.
45. Gori S, Colozza M, Mosconi AM et al. Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer. Br J Cancer 2004;90:36–40.[CrossRef][Medline]
46. Seidman A, Berry D, Cirrincione C et al. CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour (h) infusion versus standard (S) 3 h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC. J Clin Oncol 2004;22:512.
47. Perez EA, Suman VJ, Fitch TR et al. A phase II trial of docetaxel and carboplatin as first-line chemotherapy for metastatic breast cancer: NCCTG study N9932. Oncology 2005;69:117–121.[CrossRef][Medline]
48. Brufsky A, Matin K, Cleary D. A phase II study of carboplatin and docetaxel as first line chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 2002;21:52b.
49. Fountzilas G, Athanassiadis A, Kalogera-Fountzila A et al. Paclitaxel by 3-h infusion and carboplatin in anthracycline-resistant advanced breast cancer. A phase II study conducted by the Hellenic Cooperative Oncology Group. Eur J Cancer 1997;33:1893–1895.[CrossRef][Medline]
50. Perez EA, Hillman DW, Stella PJ et al. A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma. Cancer 2000;88:124–131.[CrossRef][Medline]
51. Fountzilas G, Athanassiades A, Papadimitriou V et al. Paclitaxel and carboplatin as first-line chemotherapy for advanced breast cancer. Oncology (Williston Park) 1998;12(suppl 1):45–48.[Medline]
52. Loesch D, Robert N, Asmar L et al. Phase II multicenter trial of a weekly paclitaxel and carboplatin regimen in patients with advanced breast cancer. J Clin Oncol 2002;20:3857–3864.[Abstract/Free Full Text]
53. Perez EA. Carboplatin in combination therapy for metastatic breast cancer. The Oncologist 2004;9:518–527.[Abstract/Free Full Text]
54. Perez EA, Suman VJ, Rowland KM et al. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer 2005;6:425–432.[Medline]
55. Burris H 3rd, Yardley D, Jones S et al. Phase II trial of trastuzumab followed by weekly paclitaxel/carboplatin as first-line treatment for patients with metastatic breast cancer. J Clin Oncol 2004;22:1621–1629.[Abstract/Free Full Text]
56. Pegram MD, Pienkowski T, Northfelt DW et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 2004;96:759–769.[Abstract/Free Full Text]
57. Slamon D, Yeon CH, Pienkowski T et al. Survival analysis from two open-label non-randomized phase II trials of trastuzumab (H) combined with docetaxel (T) and platinums (C, cisplatin or carboplatin) (TCH) in women with HER2+ advanced breast cancer (ABC). J Clin Oncol 2004;22:642.
58. Robert N, Leyland-Jones B, Asmar L et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2006;24:2786–2792.[Abstract/Free Full Text]
59. Pegram M, Forbes J, Pienkowski T et al. BCIRG 007: First overall survival analysis of randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin as first line therapy in HER2 amplified metastatic breast cancer (MBC). J Clin Oncol 2007;25:968S.
60. O'Shaughnessy J, Miles D, Vukelja S et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 2002;20:2812–2823.[Abstract/Free Full Text]
61. Albain KS, Nag S, Calderillo-Ruiz G et al. Global phase III study of gemcitabine plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): First report of overall survival. J Clin Oncol 2004;22;(5) (suppl):510.

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