Original ResearchPrimary metastatic breast cancer in the era of targeted therapy – Prognostic impact and the role of breast tumour surgery
Introduction
In the developed countries, about 25% of the total population of breast cancer patients cannot be cured due to advanced stage or recurrent disease. Approximately 6% suffer from primary metastatic breast cancer (PMBC, also termed de novo metastatic cancer), i.e. test positive for metastatic disease synchronously, at the time of their first diagnosis of a mammary carcinoma [1], [2], [3]. Hence, approximately one out of four patients entering a palliative stage has stage IV disease (M1) disease at presentation. This incidence has remained unchanged during the last 25 years [4], while the prognosis of PMBC seems to have improved slightly, but steadily over time [2], [4], [5].
Although survival differences between PMBC and secondary metastatic breast cancer (SMBC) have been shown in retrospective studies, the prognostic relevance might have changed in the era of antibody treatment. Moreover, the impact of primary breast surgery remains controversial, in spite of a large number of studies on this topic [3], [6], [7]. We reanalysed two large prospective non-interventional studies conducted in Germany between 2000 and 2011 for patients with advanced/metastatic breast cancer (ABC) whose treatment for primary stage IV disease included antibody treatment [8], [9], [10]. The data from both projects were pooled in order to obtain a sufficiently large cohort for prognostic and subgroup analysis.
The main objectives of this pooled analysis are as follows: First, to characterise patients with PMBC and analyse the impact of this initial stage on long-term prognosis, compared to patients with SMBC. Second, to further characterise subgroups of PMBC patients with respect to the chosen local therapy approach, and analyse the impact of initial breast surgery on the long-term prognosis.
Section snippets
Data sources and study design
All data were retrieved from two large prospective non-interventional studies, enrolling patients with ABC receiving antibody treatment:
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ML16684 (started in 2000): Observational study on trastuzumab (Herceptin®) in HER2-positive ABC, predominantly without palliative cytotoxic pre-treatment. In the majority of patients, trastuzumab was combined with chemotherapy (mostly a taxane), but monotherapy or combination of trastuzumab with antihormonal therapy was permitted as well.
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ML21165 (started in
Patient characteristics
Between 2000 and 2011, a total of 2401 evaluable patients were recruited and documented in both observational studies (Fig. 1). Five-hundred and seventy out of these (24%) presented with PMBC. Characteristics of the patients according to their initial cM0/cM1 status are shown in Table 1. Although there was no difference with respect to median age, we identified more patients aged over 70 years in the PMBC group. As expected, PMBC patients presented with distinctly more advanced T and N status
Discussion
The prognosis of PMBC has been subject to a variety of cohort studies during the last decades, suggesting a continuous improvement of long-term outcome over time [1], [3]. It remains unclear, whether this trend is mainly caused by improved therapy options, or a changing profile of disease characteristics. Especially, the growing insight on the molecular biology of breast cancer, influencing both diagnostic profiling and therapeutic options, may require additional studies on the PMBC population.
Role of the funding source
The data sources, non-interventional studies ML16684 and ML21165, had been sponsored by Roche Germany, which granted access to the database. Support for data analysis and third-party writing assistance by WiSP Research Institute, Langenfeld, Germany was provided by Roche Germany.
Conflict of interest statement
Marcus Schmidt: Honoraria Roche Pharma AG, Non-Financial Support Roche Pharma AG.
Marc Thill: Honoraria Roche Pharma AG.
Claus Richard Lattrich: Employee Roche Pharma.
Stella Keitel: Employee Roche Pharma.
Axel Hinke: Honoraria Roche Pharma AG.
Andreas Kutscheidt: Honoraria Roche Pharma AG.
All other authors declare no conflict of interest.
References (24)
- et al.
Surgical resection of the primary tumour is associated with improved survival in patients with distant metastatic breast cancer at diagnosis
Eur J Clin Oncol
(2009) - et al.
Impact of trastuzumab treatment beyond disease progression for advanced/metastatic breast cancer on survival - results from a prospective, observational study in Germany
Breast
(2014) - et al.
Survival differences among women with de novo stage IV and relapsed breast cancer
Ann Oncol
(2010) - et al.
Does aggressive local therapy improve survival in metastatic breast cancer?
Surgery
(2002) - et al.
Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: an open-label randomised controlled trial
Lancet Oncol
(2015) - et al.
Breast cancer with synchronous metastases: trends in survival during a 14-year period
J Clin Oncol
(2004) - et al.
Fifteen-Year trends in metastatic breast cancer survival in Greece
Breast Cancer Res Treat
(2010) - et al.
Improvement of survival in patient with primary metastatic breast cancer over a 10-year periode: prospective analyses based on Individual patient date from a multicenter data bank
J Cancer Ther
(2013) - et al.
Metastasis of breast cancer
(2007) - et al.
Gesamtüberleben im zeitlichen Verlauf
Senologie
(2009)
Primary metastatic breast cancer: the impact of locoregional therapy
Breast Care
Trastuzumab in advanced breast cancer – a decade of experience in Germany
BMC Cancer
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