Metastatic breast cancer: an updating

https://doi.org/10.1016/j.biopha.2006.07.086Get rights and content

Abstract

This article reports on recent advances on metastatic breast cancer. Detection, prognostic factors, predictors of response to therapy and therapy, with particular regard to targeted therapies, were examined.

Detection

Unlike current guidelines that yet do not routinely recommend intensive clinical-instrumental post-operative follow-up of breast cancer patients, relatively large data collected in the last decades have shown that an intensive post-operative follow-up with ‘dynamic evaluation’ of a suitable tumour marker panel precedes a few months as average the clinical and/or instrumental sign of a pending relapse in most relapsed patients and largely limits the use of the common instrumental examinations.

Prognosis and therapy predictors

Disease-free interval (DFI)  24 months, adjuvant chemotherapy, liver and distant soft tissue involvement or DFI > 24 months and disease confined to bony skeleton are prognostic factors more often correlated with relatively poor or prolonged survival, respectively. Estrogen receptor (ER) expression in primary tumour and at the relapse correlates strongly with response to salvage hormone therapy and data from large trials showed that 38–59% of ER and/or PR+ post-menopausal patients had clinical benefit from first line tamoxifen or aromatase inhibitors. An inverse correlation of ER with epidermal growth factor receptor (EGFR) has been found. The co-expression of HER-2/neu and/or elevated serum HER-2/neu protein level were associated with a low rate and shorter duration of response of ER+ patients to first line hormone therapy. Accordingly, ER–EGFR– compared with ER–EGFR+ tumours are usually more responsive to endocrine therapy. High class III beta-tubulin expression or fall in insulin-like growth factor binding protein-3 (IGFBP-3) from baseline levels have been found to significantly predict resistance to chemotherapeutic agents.

Therapy

Liposomes as carrier of doxorubicin (Caelix, Evacet, Myocet) is one approach to decrease the anthracycline-related cardiac toxicity. Weekly paclitaxel or docetaxel and oral formulation of vinorelbine and 5-fluorouracil (5-FU) (capecitabine) provide new effective and well tolerated options that reach greater dose intensity and cumulative dose than with the conventional schedules. As to the so called ‘tailored’ or targeted therapies, the more potent and highly selective third generation of aromatase inhibitors (letrozole, anastrozole, exemestane) targeting ER+ tumours by estrogen deprivation, challenge tamoxifen as current standard first line therapy in postmenopausals. One pilot study showed that stimulation of cellular immunity by the addition of beta-interferon-interleukin-2 sequence in patients on clinical benefit on first line tamoxifen significantly prolonged median overall survival (OS) and duration of response compared to that observed in similar patients only treated with tamoxifen. Trastuzumab, a humanised monoclonal antibody to extracellular domain of HER-2, plus conventional chemotherapy has become a standard of care for women with overexpressing HER-2 tumours. Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor (VEGF) that in refractory metastatic breast cancer doubled the response rate of capecitabine although it did not affect survival. Finally, the so called ‘oligometastatic’ and a few stage IV diseases are conditions amenable to be rendered with no evidence of disease (NED) after local surgery and/or radiation. In both, as well as in complete responders to chemotherapy, minimal residual disease (m.r.d.) likely continues to be present. Recent data suggest that ‘biological’ therapy (immunomodulators and/or retinoids with or without hormone therapy), might be suitable to be successfully tested in these patients as maintenance treatment given soon after local intervention or chemotherapy.

Introduction

Many trials have been conducted in advanced or metastatic breast cancer patients and often the two terms have been used as synonymous. Indeed, as we recently reported [1] metastatic disease is one only of the three entities that advanced disease includes, i.e. locally advanced, locoregional and metastatic disease. These three entities differ as to the site, prognosis and therapeutic intervention [1]. Local and/or regional recurrences possibly undergo to radical excision and are easily detected by physical self examination and/or radiological study of the breast. Distant metastases are an incurable disease and systemic treatments are given for palliative rather than curative purposes. They are often detected occasionally in symptomatic or asymptomatic patients. The aim of this paper is to summarise some recent progress in metastatic disease.

Section snippets

Detection of metastatic disease

Current guidelines do not recommend routine use at regular intervals of any instrumental or laboratory test but mammography for early detection of relapse of breast cancer patients [2] and as above mentioned in most of them distant metastases are occasionally found out. This policy followed unfavourable result of two prospective randomised trials that were carried out in the nineties comparing clinical with clinical plus instrumental post-operative follow-up [3], [4]. In one of these two

Clinical outcome

Most patients with distant metastases have fatal outcome. Median survival of metastatic patients has been reported to range from 24 to 30 months with a small percentage of them surviving few months or a few years [12], [13]. Several prognostic factors have been defined to predict survival of patients with metastatic disease. Among them adjuvant chemotherapy, disease-free interval (DFI), dominant site of metastatic involvement, and occasionally menopausal and receptor status, serum LDH levels

Prediction of response to therapy

There are factors that can be useful to predict response to therapy with more accuracy when determined in metastatic cells than in primary tumour. Among them, enough evidence has been accumulated as to cellular expression of ER status and c-erbB2. The available data show that in 70–90% of relapsed patients ER remains as at the time of primary cancer [17], [19]. The 10–30% conversion rate from ER+ to ER– and from ER– to ER+ at the relapse is differently explained. One explanation based on

Therapy

This issue has been discussed in a recent report [1]. Therefore for completion here it will be focused on more recent developments.

Targeted therapy

The main targeted therapies in metastatic breast cancer are shown in Table 1.

Is minimal residual disease (m.r.d.) (‘oligometastatic disease’, stage IV with no evidence of disease (NED), and complete response to chemotherapy) a condition suitable for ‘biological’ maintenance therapy?

Conditions amenable to obtain m.r.d. in metastatic breast cancer are shown in Table 2. Recently, two particular breast cancer disease conditions have been considered: oligometastatic disease and stage IV with NED [72], [73]. Oligometastatic disease has been defined as ‘disease characterised by small tumour burden and by amenability to local therapies capable of controlling the detectable tumour site’. Stage IV with NED also has been defined as ‘locoregional or distant recurrence that have been

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