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Recommendations for use of Trastuzumab (Herceptin®)

Summary of trial or study results

Trastuzumab in early breast cancer

Disease-free survival

All five trials in early breast cancer reported statistically significant improvements in disease-free survival in favour of trastuzumab. In the larger studies (BCIRG 0064 p0.001; HERA7 p0.001; NCCTG-N9831;6 NSABP-B316 p0.001) the relative rate of recurrence was reduced by 40 52% among women receiving chemotherapy with trastuzumab compared to women receiving chemotherapy alone. The absolute difference in disease-free survival between women receiving trastuzumab and women receiving chemotherapy alone was between 5.5% and 12.8%. Three trials reported on distant recurrence and all showed significant improvements in women receiving trastuzumab. The relatively short follow-up must be taken into account; longer follow-up is needed to examine the effect of trastuzumab on the incidence of disease recurrence in the central nervous system.7

Overall survival

Three trials6,8 in early breast cancer have reported significant improvements in overall survival in favour of trastuzumab (HERA p=0.001; NCCTG-N9831; NSABP-B31 p=0.015). At a median follow-up of 12 36 months overall survival was improved by 24 33%. Absolute risk reductions ranged from 0.47 6.85%, although due to the short follow-up benefits are likely to be small. A recent update of results from one trial8 demonstrated a statistically significant improvement in overall survival of 41% in favour of trastuzumab, although this result has been reported in abstract form only.

Preoperative trastuzumab

A number of small phase II trials have investigated preoperative trastuzumab with chemotherapy. Pathologic complete response (pCR) rates ranged from 7 47%.20,32-34 One randomised phase III study9 (42 patients) found that preoperative trastuzumab and chemotherapy was safe and effective. This study closed early due to improved interim results in women receiving trastuzumab and chemotherapy (pCR 65.2%) compared to chemotherapy alone (pCR 26.3%, p=0.016). A subgroup analysis of the HERA study reported significant improvements in disease-free survival in women receiving trastuzumab with chemotherapy preoperatively. One trial found benefit to adding trastuzumab to primary systemic therapy in women with locally advanced breast cancer. At a median follow-up of 43 months, 4-year progression-free survival was 81% and overall survival was 86%.20 Further research is required to establish whether the pCR rate will translate into significant disease-free and overall survival. Currently there are no data on optimal dose, long-term survival, and safety for the use of pre-operative trastuzumab.

Trastuzumab in metastatic breast cancer

Progression-free survival

Three trials in metastatic breast cancer investigated the addition of trastuzumab to chemotherapy,10-12 although data on progression-free survival are only available for two trials (M77001;11 Slamon12). Both trials showed a statistically significant improvement in progression free survival in favour of women receiving trastuzumab with chemotherapy (M77001: median 11.7 vs 6.1 months, p=0.001; Slamon: median 7.4 vs 4.6 months, p=<0.001). Improvements were also seen in time to treatment failure, duration of response and overall response.

Overall survival

Two trials in metastatic breast cancer reported data on overall survival (M77001;11 Slamon12). Both trials showed a significant improvement in overall survival in favour of women receiving trastuzumab with chemotherapy (M77001: 31.2 vs 22.7 months, p=0.032; Slamon: median 25.1 vs 20.3 months, p=0.046). One trial12 showed a 20% reduction in the risk of death at a median follow-up of 30 months. Improvements in survival were seen in both studies despite substantial cross-over of patients from chemotherapy alone to chemotherapy with trastuzumab after disease progression.

Adverse events

cardiotoxicity

Cardiac dysfunction (CD) has been observed in patients receiving trastuzumab alone or in combination with chemotherapy. Two trials in metastatic breast cancer11,12 and five in early breast cancer5-7 have reported data related to CD. The incidence of symptomatic or asymptomatic CD was significantly higher among patients receiving trastuzumab in combination with an anthracycline (27%) compared with an anthracycline alone (8%). Serious CD was seen in 0.5 4% of women receiving adjuvant trastuzumab with a non-anthracycline.12 Congestive heart failure associated with trastuzumab usually responded to cessation of therapy and management. Longer follow-up is needed to determine possible long-term cardiotoxicity associated with trastuzumab.

other adverse events

Two trials11,12 in metastatic breast cancer have reported higher rates of infection, leukopenia, anaemia and neutropenia in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone, although fewer patients receiving trastuzumab discontinued treatment due to adverse events.11 In one trial, 10% of women with metastatic breast cancer receiving trastuzumab in combination with chemotherapy developed isolated central nervous system (CNS) metastases as first site of tumour progression.35 It is unclear whether CNS metastases are associated with the biology of HER2-positive breast cancer or develop as a result of trastuzumab treatment. A low incidence of transfusion-related reactions associated with trastuzumab treatment has also been reported.

Trials in early breast cancer5,6 have reported little difference in adverse effects other than CD. The follow-up periods reported were insufficient for information on longer term side effects to be ascertained.

Cardiac monitoring

Eligibility criteria for entry into the most recent trials included in this guideline required patients to have a (LVEF) >50%. Patients were screened prior to commencement of trastuzumab and at 3-monthly intervals for the duration of treatment.6 Initial screening included a cardiac questionnaire, physical examination, 12-lead electrocardiogram and an assessment of LVEF by echocardiography.7 Decline in LVEF was the primary indictor of CD and was assessed using either multi-gated acquisition (MUGA) or echocardiogram. Degree of symptoms was usually classified using the New York Heart Association (NYHA) classification or the National Cancer Institute Common Toxicity Criteria.

Quality of life

Formal analyses of quality of life for patients receiving trastuzumab are limited. One study36 reported a statistically significant improvement in quality of life in women with metastatic disease receiving chemotherapy and trastuzumab compared with chemotherapy alone (51% vs 36%). Women receiving trastuzumab also reported improvements in fatigue and physical and role functioning (not significant). Further research is required to determine the short-and long-term effects of trastuzumab on quality of life.

Assessment of HER2 status

Assessment of HER2 status should be performed on samples obtained by core or surgical biopsy.

Trials used immunohistochemistry (IHC) to detect over-expression of the HER2 protein, or in-situ hybridisation (ISH) to detect the amplified gene. ISH includes fluorescence in-situ hybridisation (FISH) and chromogenic in situ hybridisation (CISH). Trials in metastatic breast cancer defined HER2-positive as an IHC score of 2+ or 3+ or as FISH-positive. A reanalysis of randomised trial data found that patients with IHC scores of 3+ were more likely than those with scores of 2+ to respond to trastuzumab. Retesting of the tumours by FISH also found that patients who did not respond to trastuzumab were more likely to be FISH-negative. FISH-positive patients had higher overall response rates and longer survival compared with FISH-negative patients.37 Trials in early breast cancer defined HER2-positive as an IHC score of 3+, FISH-positive or CISH-positive.

In Australia, eligibility for trastuzumab by patients with metastatic breast cancer is dependent on an IHC score of 3+ or a positive ISH test (FISH or CISH). For patients with an IHC score of 2+, subsequent confirmation by ISH is required. Eligibility for trastuzumab by patients with early breast cancer is dependent on a positive ISH test.

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