Recurrence dynamics does not depend on the recurrence site

Abstract

Introduction: The dynamics of breast cancer recurrence and death, indicating a bimodal hazard rate pattern, has been confirmed in various databases. A few explanations have been suggested to help interpret this finding, assuming that each peak is generated by clustering of similar recurrences and different peaks result from distinct categories of recurrence.

Methods: The recurrence dynamics was analysed in a series of 1526 patients undergoing conservative surgery at the National Cancer Institute of Milan, Italy, for whom the site of first recurrence was recorded. The study was focused on the first clinically relevant event occurring during the follow up (ie, local recurrence, distant metastasis, contralateral breast cancer, second primary tumour), the dynamics of which was studied by estimating the specific hazard rate.

Results: The hazard rate for any recurrence (including both local and distant disease relapses) displayed a bimodal pattern with a first surge peaking at about 24 months and a second peak at almost 60 months. The same pattern was observed when the whole recurrence risk was split into the risk of local recurrence and the risk of distant metastasis. However, the hazard rate curves for both contralateral breast tumours and second primary tumours revealed a uniform course at an almost constant level. When patients with distant metastases were grouped by site of recurrence (soft tissue, bone, lung or liver or central nervous system), the corresponding hazard rate curves displayed the typical bimodal pattern with a first peak at about 24 months and a later peak at about 60 months.

Conclusions: The bimodal dynamics for early stage breast cancer recurrence is again confirmed, providing support to the proposed tumour-dormancy-based model. The recurrence dynamics does not depend on the site of metastasis indicating that the timing of recurrences is generated by factors influencing the metastatic development regardless of the seeded organ. This finding supports the view that the disease course after surgical removal of the primary tumour follows a common pathway with well-defined steps and that the recurrence risk pattern results from inherent features of the metastasis development process, which are apparently attributable to tumour cells.

Figure 1

Hazard rate estimates for selected events in 1526 patients undergoing conservative surgery. Each point represents the measure of the hazard rate of the given event within a three-month interval. The smoothed curve was obtained by a Kernel-like smoothing procedure. (a) Hazard rate for any recurrence (including both local and distant disease relapses). (b) The hazard rate for recurrence is split into its components: local recurrence (red line) and distant metastasis (blue line). (c) Hazard rate for contralateral breast cancer. (d) Hazard rate for second primary cancer.

Figure 2

Hazard rate for selected events in 1526 patients undergoing conservative surgery. The same events as in Figure 1 were analysed by a formal flexible regression modelling strategy considering B-spline bases with degrees of freedom ranging from 4 to 10 and selecting the best models according to the Akaike Information Criterion. Vertical lines represent point-wise confidence interval for the model estimated hazards, according to standard asymptotic theory.

Figure 3

Hazard rate for distant metastasis in different sites. Distant metastases were categorised as bone, viscera and soft tissue recurrences. Soft tissue metastases also included the supra-clavicular lymph node recurrences. Because of the limited number of events to a single visceral site, recurrences to lung, liver or CNS were merged to obtain a more suitable collection of cases, representative of the visceral recurrence. Vertical lines represent point-wise confidence intervals for the model estimated hazards, according to standard asymptotic theory.