Analysis of trastuzumab and chemotherapy in advanced breast cancer after the failure of at least one earlier combination: An observational study

Breast cancer remains the main cause of cancer morbidity and mortality in women in most countries all over the world [1, 2]. While localised disease is potentially curable, even in stage I and II disease, 30 % of patients can be expected to experience a relapse [3]. Especially at risk for cancer recurrence are patients of young age, nodal positive tumours and individuals with aggressive tumour phenotypes, defined as high or intermediate grade, endocrine receptor negative and/or her2/neu positive [4, 5]. When metastatic disease develops, appropriate therapeutic strategies are necessary to lengthen the patient's survival while not further reducing her quality of life.

In her2/neu positive tumours, a combination of chemotherapy and trastuzumab has proven to produce superior response rates and a longer time to progression than chemotherapy alone [6–10]. Trastuzumab is a monoclonal humanized antibody targeting the epidermal growth factor receptor 2 (her2/neu), resulting in an anti-tumour activity whose exact mechanism of action is not yet fully understood. Antibody dependent cytotoxicity (ADCC) is part of this mechanism, but also the blocking of post-receptor pathways and the inhibition of homo- and hetero-dimerization are thought to play a crucial role [11–13]. A benefit however can only be found in tumours with her2/neu 3+ over-expression in immunohistochemistry or in cells with her2/neu gene amplification, which is usually analysed by FISH (fluorescence in situ hybridisation) [14]. Paclitaxel plus trastuzumab was the first combination regimen established [15]. While in vitro studies were able to demonstrate an additive anti-tumour effect of this combination, other substances (vinorelbine, docetaxel, and cisplatin) showed a synergistic effect [16]. In vivo, it was possible to demonstrate, that vinorelbine plus trastuzumab regimens are not only superior to paclitaxel containing regimens in terms of toxicity [17], but also in terms of response and survival [9, 10, 16, 18]. A recent study found docetaxel plus trastuzumab highly superior to docetaxel monotherapy as first line palliative treatment with little additional toxicity [19].

Today, a first line palliative combination of chemotherapy and trastuzumab can already be deemed standard. Still, it is not established whether or not patients do achieve a benefit from continuing trastuzumab treatment combined with a different chemotherapeutic agent after the failure of one earlier combination, as the way a resistance to trastuzumab develops is not yet understood entirely. Because of limited resources, also pharmacoeconomic aspects must be taken in account.

At our centre, patients were routinely treated with trastuzumab also in the second line and beyond second line setting. Individuals were observed prospectively, and we are reporting our experiences with trastuzumab treatment after the failure of at least one earlier trastuzumab containing therapy regimen.

All data were collected at the Department of Internal Medicine I, Division of Oncology at the Medical University of Vienna, Vienna, Austria. Treatment was performed in accordance with the ethical regulations of the Medical University of Vienna.

While there is some evidence from different other, mostly retrospective, trials reporting a benefit from continued trastuzumab treatment beyond disease progression with a changed chemotherapy regimen only [22–24], a discontinuation after disease progression is still standard of care. Though the here presented study is limited by the relatively small number of patients included, we are clearly able to strengthen existing evidence that there is a benefit for at least some patients.

The reported decline in response rates from 42.6% in first line treatment to 30% in beyond second line compares to the expected drop of response rates with every further line of chemotherapy or endocrine therapy in palliative treatment. Stable disease and objective response combined, clinical benefit rates were 85.2% in first line, 68.5% in second line and 58.3% in beyond second line. As some other groups, we believe this to be the more significant parameter in judging the efficacy of palliative treatment, as a stabilisation of the disease without excessive toxicity often appears more important than objective remission [25, 26]. The high clinical benefit rate of nearly 60% even beyond second line must be seen as a clear sign of a benefit that most patients gain from treatment continuation. It is also obvious from our here presented data that this benefit is not paid for by excess toxicity, as apart from a possible drop in cardiac output rate, no other major toxicity linked to trastuzumab was observed. This was especially important to us, as some patients included in this trial were treated with trastuzumab for more than 3 years. Notably, we did not find a case of symptomatic congestive heart failure. All other toxicities were well within the range expected from the different chemotherapy regimens. Still, in one patient, treatment had to be discontinued because of a drop in ejection fraction below 50%. So while trastuzumab based regimens are well tolerated also in medium and long term treatment, a monitoring of cardiac function remains essential. Echocardiography only in the case of symptoms appears not to be sufficient.

Of special interest is the fact, that we did not find a statistical significant difference in TTP between first line, second line and beyond second line trastuzumab based combinations. Although we rather expected to observe a shortening of time to disease progression with every further line of therapy, as this is the usual development in the metastatic setting, we believe this to be another sign of a potential benefit from continued combination treatment. TTP data from the different treatment lines (median 6 months in 1^st line, 2^nd line and beyond 2^nd line) compare favourably to the data reported in the pivotal trastuzumab trial with median 6.9 months in combination with paclitaxel as first line therapy [27]. As median overall survival was not yet reached, we believe that our survival data will be well beyond the median 25.4 months presented in the pivotal trial. These results are intriguing and somewhat unexpected, but still the necessity for larger, especially randomised, trials remains.

A big problem lies in the fact, that the mechanism of resistance to trastuzumab is not yet fully understood. If tumour cells are able to switch the main growth pathway from the her2/neu receptor to the EGFR or other signal transduction pathways, a continued treatment would not necessarily lead to a benefit. On the other hand, if no complete resistance develops, a discontinuation of trastuzumab might cause a massive overshoot in tumour growth, in which case only combination partners should be switched [28, 29]. With limited resources available, also economic aspects must be taken on account.

In conclusion, we are definitely able to strengthen evidence that her2/neu positive patients do profit from continued trastuzumab therapy, with a clinical benefit rate of 68.5% in the second line. We are to our best knowledge the first group reporting a similar TTP in 1^st line, 2^nd line and beyond 2^nd line treatment, making our data especially noteworthy. Further, this is among the first studies reporting a beneficial role of trastuzumab combination even beyond second line. Albeit the here presented data, randomised trials are still warranted to make a final conclusion regarding treatment continuation possible.