Breast Cancer

, Volume 16, Issue 4, pp 295–300

The role of trastuzumab in the management of HER2-positive metastatic breast cancer: an updated review

Authors

    • Department of Breast and Endocrine SurgeryTokai University School of Medicine
  • Yasuhiro Suzuki
    • Department of Breast and Endocrine SurgeryTokai University School of Medicine
  • Yuki Saito
    • Department of Breast and Endocrine SurgeryTokai University School of Medicine
  • Shinobu Umemura
    • Department of PathologyTokai University School of Medicine
Special Feature New strategy for HER-2 testing and trastuzumab therapy

DOI: 10.1007/s12282-009-0142-8

Cite this article as:
Tokuda, Y., Suzuki, Y., Saito, Y. et al. Breast Cancer (2009) 16: 295. doi:10.1007/s12282-009-0142-8
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Abstract

Currently, trastuzumab is one of the key drugs in the treatment strategy for HER2-positive breast cancer. Although metastatic breast cancer is unlikely to be cured, some HER2-positive patients have survived for a long time with complete response to trastuzumab therapy. In HER2-positive metastatic breast cancer, single agent trastuzumab is effective and less toxic. Combination of trastuzumab with cytotoxic drugs is also effective. Therefore, major guidelines recommend using trastuzumab as a key drug in the management of HER2-positive metastatic breast cancer. However, many clinical questions still need to be solved. In this article, recent evidence was reviewed to find some answers about these issues.

Keywords

Metastatic breast cancerHER2-positiveTrastuzumab

Introduction

Currently, trastuzumab is one of the key drugs in the treatment strategy for HER2-positive breast cancer. Although metastatic breast cancer is unlikely to be cured, some patients have survived for a long time with complete response to trastuzumab therapy [1]. In HER2-positive metastatic breast cancer, single agent trastuzumab is effective with favorable toxicity. Combination of trastuzumab with cytotoxic drugs is also effective. Therefore, major guidelines recommend using trastuzumab as a key drug in the treatment strategy of HER2-positive metastatic breast cancer. However, many clinical questions still need to be solved. In this article, recent evidence is reviewed to find some answers about these issues.

Trastuzumab combined with hormone therapy for HER2 and hormone receptor-positive breast cancer

To select proper treatment, tumor biology and clinical factors should be considered for each patient. Approximately half of breast cancers are HER2-positive as well as hormone receptor-positive. Generally, endocrine therapy is preferred for initial treatment of hormone receptor-positive metastatic breast cancer because of its favorable toxic profile. The National Comprehensive Cancer Network (NCCN) guideline recommends trastuzumab for beyond first-line therapy in patients refractory to standard endocrine therapy [2]. However, preclinical [3] and clinical [4] evidence suggests that HER2 positivity gives intrinsic resistance to hormone therapy. The targeting of both hormone receptors and HER2 signaling pathways in hormone receptor and HER2-positive breast cancers may overcome resistance to anti-estrogen therapy. Thus, another option for HER2-positive and hormone receptor-positive metastatic breast cancer patients is the combination of trastuzumab and endocrine therapy.

In terms of this issue, a randomized trial was conducted [5]. The TAnDEM study randomly assigned 208 postmenopausal patients with HER2-positive and hormone receptor-positive metastatic breast cancer to anastrozole alone or anastrozole plus trastuzumab. Anastrozole 1 mg was administered daily, and trastuzumab 4 mg/kg of loading dose was administered on week 1 followed by 2 mg/kg weekly until disease progression. Crossover to receive trastuzumab was actively offered to all patients who progressed on anastrozole alone. A preliminary analysis reported that benefits of combination showed a significantly better overall response rate (20 vs. 7%) as well as progression-free survival (4.8 vs. 2.4 months, P = 0.0016). Seventy percent of the patients initially assigned to anastrozole alone received trastuzumab later during the course of the disease. Overall survival of the combination group was 28.5 months compared with 23.9 months for the anastrozole alone group (P = 0.325). Cardiac toxicity developed in 13 of 103 patients of the combination group compared with 2 of 104 patients of the anastrozole alone group. Therefore, combinations of hormone therapy plus trastuzumab for patients with HER2-positive metastatic breast cancer seem to be safe and have promising efficacy.

Trastuzumab alone versus trastuzumab plus chemotherapy as first-line treatment

Trastuzumab monotherapy has shown efficacy and is well tolerated. Thus, the NCCN guideline recommends both trastuzumab alone and combination of trastuzumab and chemotherapy as first-line treatment for HER-positive metastatic breast cancer patients [2]. However, the clinical question of whether trastuzumab monotherapy followed by trastuzumab and chemotherapy at disease progression has equal efficacy to an initial combination therapy of trastuzumab and chemotherapy remains to be answered. A randomized phase III study of trastuzumab monotherapy followed by docetaxel and trastuzumab versus the combination of trastuzumab and docetaxel as first-line treatment was conducted in Japan.

A result of the first-analysis was reported at the San Antonio Breast Cancer Symposium in 2008 [6]. Eligible patients had HER2-positive metastatic breast cancer with a measurable tumor based on RECIST, ECOG performance status 0 or 1, and left ventricular ejection fraction more than 50%. Patients with prior chemotherapy for metastatic breast cancer, adjuvant trastuzumab and docetaxel were excluded. The patients were randomly assigned to sequential weekly trastuzumab 2 mg/kg (loading 4 mg/kg) alone followed by a combination of docetaxel (60 mg/m2 every 3 weeks) and trastuzumab at disease progression or concurrent combination of trastuzumab and docetaxel. Primary endpoints were time to progression of trastuzumab alone and combination of trastuzumab and docetaxel and overall survival. Secondary endpoints were overall response rates, progression-free survival of sequential trastuzumab monotherapy followed by docetaxel and trastuzumab, time to treatment failure of trastuzumab monotherapy versus the initial combination group and safety in both arms.

The planned sample size was 80 patients in each group. The Independent Data Management Committee recommended stopping recruitment because there was a significant difference in death rate. Finally, 112 patients were enrolled, and 107 patients were analyzed. Statistically significant progression-free survival was observed for the trastuzumab and docetaxel group compared with the trastuzumab monotherapy group (HR: 4.24, P < 0.0001). In terms of overall survival, the results suggested that the combination group was superior to the sequential group (HR: 2.72, P = 0.0352), though the number of deaths was insufficient. Time to treatment failure was significantly superior in the combination group. Overall response rates were 67.9% for the combination group, 14.8% for trastuzumab monotherapy and 47.2% for sequential trastuzumab and docetaxel. According to the above evidence, a combination of trastuzumab and cytotoxic drugs could be considered as standard for first-line therapy.

Trastuzumab combined with anthracyclines

In preclinical studies, cisplatin, thiotepa and etoposide were found to be synergistic with trastuzumab. Additive interactions were observed with doxorubicin, paclitaxel, methotrexate and vinblastine [7]. Thus, to determine the efficacy and safety of trastuzumab in combination with chemotherapy as a first-line treatment for patients with HER-2-overexpressing metastatic breast cancers, a randomized, placebo-controlled, multicenter, multinational phase III trial was designed [8]. Patients without prior anthracycline treatment were randomly grouped to receive trastuzumab plus anthracycline (doxorubicin or epirubicin)/cyclophosphamide (AC) or AC alone. Cyclophosphamide (600 mg/m2) was administered in combination with doxorubicin (80 mg/m2) or epirubicin (75 mg/m2). Chemotherapy was repeated every 3 weeks for six cycles. Patients with prior anthracycline treatment in the adjuvant setting received either trastuzumab plus paclitaxel or just paclitaxel. Paclitaxel (175 mg/m2) was administered by IV infusion over a 3-h period, after premedication. Four hundred sixty-nine HER-2-overexpressing breast cancer patients without prior chemotherapy for metastatic disease were enrolled.

The overall response rates were 60% for trastuzumab plus AC and 42% for AC alone. Median duration of response was 9.1 months for trastuzumab plus AC and 6.5 months for AC alone (P = 0.0025). Median time to progression was 8.1 months for trastuzumab plus AC and 6.0 months for AC alone. Median overall survival was 31 months for trastuzumab plus AC and 21 months for AC alone. Therefore, trastuzumab plus concomitant anthracyclines demonstrated significant clinical activity.

A syndrome of cardiac dysfunction was reported more commonly with trastuzumab plus AC (27%; NYHA class III or IV) than with AC alone (8%), paclitaxel alone (1%), or trastuzumab plus paclitaxel (13%). To date, the mechanism of adverse effects of trastuzumab on cardiac function has not been fully explained. These results led to the general recommendation that combined use of anthracyclines and trastuzumab should be avoided. However, combining trastuzumab with anthracyclines is still attractive. Thus, some recent trials showed impressive efficacy and no significant cardiotoxicity with the combination. At the neoadjuvant setting, trastuzumab was used concurrently with fluorouracil, epirubicin and cyclophosphamide without significant cardiotoxicity [9]. For metastatic breast cancer, epirubicin or liposomal doxorubicin was also investigated to obtain more than 60% overall response rates without significant cardiotoxicity [1012] (Table 1).
Table 1

Trastuzumab plus anthracyclines: clinical trials in metastatic breast cancer

References

Regimen

N

ORR (%)

Untch et al. [10]

Epirubicin/cyclophosphamide (60/600 mg/m2)

26

62

 

Epirubicin/cyclophosphamide (90/600 mg/m2)

25

64

Theodoulou et al. [11]

Myocet® (60 mg/m2, q3w)

33

58

Cortes et al. [12]

Myocet® (50 mg/m2, q3w)

69

98

 

Paclitaxel (80 mg/m2, qw)

  
Amrubicin is a third generation, totally synthetic anthracycline (Fig. 1). In preclinical studies, amrubicin demonstrated a higher level of anti-tumor activity than conventional anthracyclines without showing any evidence of the cumulative cardiac toxicity [13]. Therefore, the authors investigated the combination of amrubicin and trastuzumab in a human tumor xenograft model with HER2-positive cancer. The data suggested a therapeutic advantage in the administration of trastuzumab in combination with amrubicin (Fig. 2). This promising combination warrants further clinical evaluation in the treatment of HER2-positive breast cancer [14].
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Fig. 1

Structures of anthracyclines

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Fig. 2

Effects of trastuzumab and amrubicin on HER2-positive human tumor xenografts in athymic nude mice. A tumor fragment of HER2-positive human gastric cancer xenograft (4-1 ST [22]) was subcutaneously inoculated into female Balb/cA athymic nude mice. Mice were randomly divided into experimental groups when each tumor had reached a palpable size (100–300 mm3). Five weeks after tumor inoculation, mice bearing the tumors were treated with a single intravenous administration of trastuzumab (36 mg/kg) (T), amrubicin (25 mg/kg) (A) or trastuzumab plus amrubicin (T + A). Mean tumor weight (g) of T + A was significantly reduced to 0.233 ± 0.27, compared with that of control (3.152 ± 0.83) (P < 0.0001), T (2.697 ± 0.64) (P < 0.0001) and A (0.870 ± 0.31) (P = 0.001)

Trastuzumab plus taxanes

In the pivotal trial [8], patients with prior anthracycline treatment in the adjuvant setting received either trastuzumab plus paclitaxel or just paclitaxel. Compared to paclitaxel alone, combined therapy had a significantly higher response rate (38 vs. 16%) and time to disease progression (7 vs. 3 months), and a trend toward better median overall survival (22 vs. 18 months).

A similar antitumor efficacy has been reported with trastuzumab plus docetaxel [15]. In a phase II trial, 186 metastatic breast cancer patients without prior chemotherapy were randomly assigned to docetaxel with or without trastuzumab. Trastuzumab plus docetaxel demonstrated significantly better response rates (61 vs. 34%), time to disease-progression (12 vs. 6 months), and median overall survival (31 vs. 23 months).

In the phase II HERTAX trial, 101 metastatic breast cancer patients without prior chemotherapy were randomly assigned to combined therapy with trastuzumab plus docetaxel (100 mg/m2 every 3 weeks) or trastuzumab monotherapy at the same dose followed by docetaxel alone at progression. Progression-free survival, the primary endpoint, was defined as the time from treatment initiation until disease progression or death for combined therapy, and from treatment initiation until disease progression on subsequent docetaxel or death for the sequential monotherapy. In a preliminary report from the 2008 ASCO meeting [16], combined therapy demonstrated a significantly higher overall response rate (73 vs. 50%), but there was no significant benefit to combined therapy in terms of progression-free survival (9.4 vs. 10.8 months), and the difference in median overall survival was not significant (30.5 vs. 20.2 months). According to the UpToDate systematic review [17], serial administration of trastuzumab alone followed by taxane monotherapy at disease progression is an acceptable alternative and is a preferred strategy for indolent and/or relatively asymptomatic disease.

Trastuzumab plus taxane versus trastuzumab plus vinorelbine

Combinations of vinorelbine and trastuzumab are also active for patients with taxane-refractory metastatic breast cancer. Although this combination of trastuzumab with vinorelbine appears to be as active as combinations of trastuzumab with a taxane, its place in the treatment algorithm for HER2-positive metastatic breast cancer is uncertain. In one study, the TRAVIOTA, efficacy of trastuzumab plus vinorelbine for first-line treatment was compared with that of trastuzumab plus taxane for HER2-positive metastatic breast cancer [18]. Eighty-one patients were randomly assigned to trastuzumab plus vinorelbine 25 mg/m2/week (n = 41) or trastuzumab plus paclitaxel (80 mg/m2/week) (n = 14), docetaxel (35 mg/m2/week) (n = 24) or paclitaxel (175 mg/m2) plus carboplatin (AUC 6) (n = 2). Median time to disease-progression was 8.5 months for trastuzumab plus vinorelbine and 6.0 months for trastuzumab plus taxane (P = 0.09). Overall response rates were 51% for trastuzumab plus vinorelbine and 40% for trastuzumab plus taxane, though the difference was not significant because of the small sample size. In terms of toxicity, alopecia was less frequent in the combination with vinorelbine than that with taxanes. Thus, the combination with vinorelbine could be chosen by some patients.

Trastuzumab continuation beyond progression

An important clinical question is whether trastuzumab should be continued after progression on the first trastuzumab-containing regimen. A preclinical study showed that the combination of trastuzumab with taxanes was more effective than cytotoxic chemotherapy alone after being refractory to trastuzumab [19].

A German trial, the GBG-26/BIG3-05 trial, randomly assigned 156 patients with progressive metastatic breast cancer under trastuzumab-based first-line therapy to capecitabine 2,500 mg/m2 daily for 14 of every 21 days with or without trastuzumab. Trastuzumab 6 mg/kg was administered every 3 weeks. The trial was prematurely closed because of slow accrual. However, a preliminary report showed that the overall response rate was 48% for the combination group and 27% for capecitabine alone (P = 0.011) [20]. Median time to disease-progression, a primary endpoint, was 8.2 months for the combination group and 5.6 months for the capecitabine alone group (HR = 0.69, P = 0.034). Median overall survival was 25.5 months for the combination and 20.4 months for the capecitabine group (HR = 0.76, P = 0.26). Therefore, continuing trastuzumab beyond progression appears to improve the efficacy of second-line capecitabine treatment.

Trastuzumab plus lapatinib versus lapatinib monotherapy

A benefit for continued trastuzumab after progression was also suggested in a randomized trial, EGF104900, presented at the 2008 ASCO meeting [21]. The trial assigned 296 patients with progressive metastatic breast cancer under trastuzumab-based therapy to lapatinib alone (1,500 mg, daily) and lapatinib (1,000 mg, daily) plus continuation of trastuzumab. The overall response rate was 10.3% for combined therapy and 6.9% for lapatinib alone (P = 0.46). Clinical benefit rates were 24.7 and 12.4% for combined therapy and lapatinib alone, respectively (P = 0.01). Median progression-free survival was 2.8 months for combined therapy and 1.9 months for lapatinib alone (P = 0.008), although overall survival was not significantly different.

In conclusion, according to the data obtained so far, the authors recommend a treatment algorithm as shown in the Fig. 3. Hormone receptor-positive patients with favorable prognosis such as bone or soft tissue metastases only are recommended to be treated by endocrine therapy and concurrent trastuzumab. Hormone receptor- negative patients, hormone receptor-positive and endocrine refractory patients, or hormone receptor-positive patients with unfavorable prognosis should be treated by trastuzumab combined with chemotherapy. After disease progression on a first-line trastuzumab-containing regimen, trastuzumab should be continued with a second- or third-line chemotherapy. After approval of lapatinib in Japan, the regimen of capecitabine and lapatinib is also an option for patients progressive on a trastuzumab-containing regimen.
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Fig. 3

Algorithm for treatment selection for HER2-positive metastatic breast cancer

Copyright information

© The Japanese Breast Cancer Society 2009