Abstract
The report addresses the role of the hazard function in the analysis of disease-free survival data in breast cancer. An investigation on local recurrences after mastectomy provided evidence that uninterrupted growth is inconsistent with clinical findings and that tumor dormancy could be assumed as working hypothesis to understand the clinical course of the disease. Additionally, it was deemed that the lag-time between primary tumor removal and tumor recurrence is dynamically dependent on the subclinical metastasis development within the host-tumor system and, therefore, may be informative about the biology of the disease. Accordingly, the hazard function, which estimates the event risk pattern through the time, was adopted to analyze survival data. The multipeak pattern of the hazard function suggested that the process metastasis development has discontinuous features. A new paradigm of breast cancer metastatic development was proposed, involving the notions of tumor homeostasis, tumor quiescence in specific metastatic microscopic phases and surgery-related acceleration of the metastatic process. All analyses by prognostic factors (e.g., by menopausal status) or treatment modalities (e.g., by adjuvant chemotherapy) or other parameters (e.g., site of metastasis), provided coherent data in agreement with the model. The hazard rate function allowed addressing several clinical questions including meaning of ipsilateral breast tumor recurrence (IBTR), oncologic effect of delayed breast reconstruction, surgery related metastasis acceleration, possible role of anti-inflammatory drugs and body mass index (BMI) to modulate the recurrence risk. We conclude that the hazard function is a powerful tool to investigate the post-surgical course of early breast cancer and other operable tumors and to make inferences on their biology.
Highlights
One could assume that at the time of primary tumor removal, microscopic metastatic foci may be in different biological steady states, most of which are dormancy states and that they start growing at the time of primary tumor surgical removal, thereafter, producing the observed clustered hazard pattern
The analysis approach by means of the hazard function allowed addressing several additional clinical questions including the meaning of ipsilateral breast tumor recurrence (IBTR), delayed breast reconstruction, surgery related metastasis acceleration, possible role of perioperative anti-inflammatory drugs and body mass index (BMI) to modulate the recurrence risk
We found a bimodal pattern matching to the corresponding dynamics following primary tumor removal in node positive (N+) patients
Summary
Metastases or local recurrence appear at variable time intervals (from a few months to many years) after primary treatment. The question was resolved for local recurrences after mastectomy by the analysis we carried out on the time to recurrence in 122 patients who underwent periodical follow-up examinations [3] This investigation provided evidence that the hypothesis of uninterrupted growth involves a statistically significant departure from observed data and, should be rejected. The results, suggested that a time span of tumor dormancy followed by quite rapid growth could provide a more reasonable description of the observed recurrence pattern Following this main conceptual change of the understanding of local recurrences, the question emerged whether tumor dormancy was able to explain the metastatic course for distant recurrences as well. In breast cancer, the recurrence-free survival curves provide the percentage of patients who remain recurrence-free at a given time after primary tumor removal. One could assume that at the time of primary tumor removal, microscopic metastatic foci may be in different biological steady states, most of which are dormancy states and that they start growing at the time of primary tumor surgical removal, thereafter, producing the observed clustered hazard pattern
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