Trastuzumab Use in Breast Cancer: Clinical Issues

John Horton, MB, ChB

Disclosures

Cancer Control. 2002;9(6) 

In This Article

Metastatic Breast Cancer

The most commonly used schedule for trastuzumab is a "loading" intravenous dose of 4 mg/kg given as a 90-minute infusion and followed by a weekly "maintenance" dose of 2 mg/kg that can be given over 30 minutes if the initial dose was well tolerated.[10] Studies of higher loading and maintenance doses have not demonstrated increased activity,[3] but the mean half-life of trastuzumab increases and clearance decreases with increasing doses, and the half-life of trastuzumab in the serum is now estimated to be approximately 30 days.[18] Gelmon et al[19] have reported that a loading dose of 8 mg/kg followed by a maintenance dose of 6 mg/kg given every 3 weeks provides serum trastuzumab concentrations equivalent to those achieved by the "standard" weekly dosing regimen. This alternate dosing regimen will likely be shown to be as effective and is more convenient than the weekly dosing regimen. It is now being incorporated into some clinical trials, including adjuvant trials, and it seems a reasonable choice to be included in standard clinical practice.

Two large trials have evaluated the antitumor effectiveness of trastuzumab alone in patients with HER2 overexpressing metastatic tumors. The first was a "salvage" trial and included 222 patients with prior chemotherapy.[2] Nevertheless, trastuzumab monotherapy gave a response rate (complete [CR] and partial [PR]) of 15%, and responses lasted 9.1 months. A trial by Vogel et al[3] studied patients at an earlier stage and reported a response rate (CR and PR) of 26% and clinical benefit (CR, PR, and stable >6 months) occurring in 38% of patients treated, with a median duration of response of 18.8 months. This salutary response rate suggests that trastuzumab alone might be a reasonable choice for those patients with a relatively limited extent of metastatic disease (eg, having similar tumor spread characteristics as patients who might be considered for hormonal therapy). Such early treatment with trastuzumab monotherapy would not seem to abrogate the effectiveness of later treatment with trastuzumab plus chemotherapy. In a phase II study by Burris et al,[20] patients were treated initially with trastuzumab alone and obtained a 21% incidence of response. Subsequent treatment with paclitaxel plus carboplatin induced responses in 11 of 20 responses. This rate is consistent with reports of combined trastuzumab-chemotherapy treatment given as "first-line" therapy.[4]

The seminal report by Slamon et al[4] demonstrated the now well-known information that, in patients with HER2-overexpressing metastatic breast cancer, the addition of trastuzumab to chemotherapy increases response rates, prolongs the duration of remissions, and lengthens survival in comparison to treatment with chemotherapy alone. Deserving reemphasis is the finding that the chemotherapy-trastuzumab combination was associated with a 5-month longer median survival even though 67% of patients randomized to receive chemotherapy alone initially subsequently received trastuzumab. This suggests that "early" use of trastuzumab, ie, given with the first line of chemotherapy in patients with metastatic disease, is optimal.

Trastuzumab adds to the clinical benefit of several other chemotherapeutic drugs besides the doxorubicin/cyclophosphamide doublet and paclitaxel therapies reported by Slamon and associates. Taxanes have been further studied ( Table 3 ),[21,22,23] and combinations of trastuzumab with vinorelbine produce response rates that are often over 60% ( Table 4 ).[24,25,26] Response rates are always highest in those patients who have IHC 3+ or FISH+ test results.

Other agents that have been successfully combined with trastuzumab include gemcitabine[27] and cape-citabine.[28] Despite the known association of cardiac toxicity with anthracycline-containing regimens, studies are in progress using liposome-encapsulated doxorubicin[29] and epirubicin[30] ( Table 5 ).

Of great current interest is the use of trastuzumab with platinum plus taxane combinations ( Table 6 ). Pegram et al[31] demonstrated a 24% incidence of response and a 48% incidence of clinical benefit in chemoresistant HER2-positive breast cancer using trastuzumab plus cisplatin. Since then, tolerance and toxicity concerns concerning cisplatin have stimulated evaluation of carboplatin-taxane doublets given either weekly[20] or every 3 weeks. As examples, investigators at UCLA[32] have evaluated a combination of docetaxel plus carboplatin given each 3 weeks together with weekly trastuzumab. In their patients who were FISH+, there was a 64% response rate (CR plus PR) to that combination in comparison to a 41% rate for those who were FISH-. A US Oncology group entered 196 patients with metastatic breast cancer who were HER2, 2+, 3+ or FISH+ into a study (N. Robert, MD) personal communication, September 2002) comparing paclitaxel given every 3 weeks plus weekly trastuzumab vs paclitaxel plus carboplatin given every 3 weeks plus week-ly trastuzumab. The combination arm was more toxic but provided more responses that were of significantly longer duration than the paclitaxel/trastuzumab-alone arm. These data support trials of this approach for adjuvant therapy in high-risk breast cancer patients.

Many questions arise regarding optimal management of patients with tumors that are characterized as being both estrogen receptor (ER)-positive and HER2-positive. This combination of tumor characteristics has implications both for prognosis and for predicting response to treatment. The Naples GUN adjuvant trial[35] suggested that use of tamoxifen in such patients might be detrimental to survival, but this study contains many flaws. Many clinicians believe that the response of breast cancer patients to hormone therapy with tamoxifen is diluted in HER2-positive patients. Lipton et al[36] have described a shorter time to progression in patients with metastatic breast cancer treated with hormones who had elevated levels of circulating HER2 in comparison with those who did not. Ellis et al[37] evaluated responses to neoadjuvant tamoxifen or letrozole in postmenopausal patients with locally advanced HER1/2-positive tumors who were also ER-positive, and compared outcomes to patients who had ER-positive, HER1/2-negative tumors.

The numbers are small but suggest that an aromatase inhibitor might be capable of at least partially ameliorating primary tamoxifen resistance. Two important studies are now in progress that will assess whether trastuzumab can enhance responses to aromatase inhibitors in postmenopausal women with HER2-positive and ER-positive metastatic tumors. One is a phase II study that evaluates the combination of letrozole plus trastuzumab. Another is a phase III study that compares anastrozole alone to anastrozole plus trastuzumab. In the adjuvant therapy situation, it seems reasonable to recommend the appropriate adjuvant hormonal therapy based on the ER-positivity of the tumor for patients with clinically localized ER-positive and HER2-positive tumors and not modify the approach based on the HER2-positivity.

When trastuzumab is prescribed for patients with HER2-positive metastatic breast cancer, either alone or in combination with cytotoxic chemotherapy, the drug is usually continued for as long as clinical benefit ensues, even if the cytotoxic therapy component of the intervention is discontinued because of toxicity or intolerance. Thus, in the absence of severe toxicity (eg, cardiac toxicity), the drug may be administered for long periods, sometimes several years. Questions arise, however, when the breast cancer progresses. Should trastuzumab be stopped or continued? Should an alternate hormone or cytotoxic agent be used -- alone or with trastuzumab? Since trastuzumab is a growth inhibitor, should it be continued indefinitely akin to the policy of ensuring life-long androgen blockade in patients with metastatic prostate cancer even in the face of progressive metastatic disease?[38]

A decision on continuing trastuzumab after progression from management with trastuzumab alone or if combined with a hormone is relatively easy. There is an excellent chance of clinical response occurring if a drug combination of proven effectiveness (eg, trastuzumab plus a taxane or vinorelbine or a taxane/carboplatin doublet) were prescribed, and such an approach will generally be indicated. What approach should be used, however, if a patient has responded to a combined trastuzumab-chemotherapy approach and has then progressed?

One relevant clinical study in progress randomizes treatments to patients who have progressed after trastuzumab plus a taxane between vinorelbine alone and vinorelbine plus trastuzumab. Until data from such important trials are at hand, we are forced to rely on the retrospective data collection on first and second-line use of trastuzumab reported by Mackey et al[39] recognizing the inherent limitations of nonprospective data. First-line trastuzumab monotherapy was associated with a response rate of 41%, and the combination of trastuzumab plus a taxane 38%. Second-line trastuzumab therapy provided similar objective response rates, ie, 38% with a combination with a taxane and 27% with a combination with vinorelbine ( Table 7 ). The similarity of the reported outcomes between first-and second-line usage suggests that it is reasonable to consider a different trastuzumab/chemotherapy combination as second-line treatment after failure or progression from an initial trastuzumab-chemotherapy combination. There are no good data to help direct use of third or later lines of trastuzumab combined with chemotherapy, so clinical judgment needs to be used. If the disease progression is relatively slow and the patient is in good clinical condition, then trial of a third trastuzumab/ chemotherapy combination could be considered. However, if there was no response to prior trastuzumab/chemotherapy combinations and disease progression is rapid, then it is probably reasonable to discontinue trastuzumab. In situations where the central nervous system (CNS) is the sole site of progression and systemic metastasis is well controlled, there is logic to continuing the trastuzumab with or without other chemotherapy treatment while managing the CNS metastasis appropriately.

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