In vitro fit and direct statistical analysis of the xenograft breast data (S1); Population fit of the tumor growth data that were measured by BL, under the Gomp-Exp model and initial volume Vi fixed by the conversion rule inferred from the correlation between volume and BL (S2); Population fits of the breast xenograft data under different growth theories (S3); Population fits of the kidney isograft data under different growth theories (S4); Second kidney data set used for fitting the data (S5); Individual fits of primary tumor and metastatic burden kinetics Breast animal model (S6); Individual fits of primary tumor and metastatic burden kinetics. Kidney animal model (S7); Link between experimental and model survival (S8); Surgery benefit on survival and metastatic burden reduction as a function of resection size, for varying values of metastatic potential (S9); Population fits of the ortho-surgical metastasis animal models for a dissemination coefficient d(Vp) = ??Vyp and various values of y (S10); Population fits of the ortho-surgical metastasis animal models for various values of the signal-to-cell ratio V0 (S11).
ARTICLE ABSTRACTRapid improvements in the detection and tracking of early-stage tumor progression aim to guide decisions regarding cancer treatments as well as predict metastatic recurrence in patients following surgery. Mathematical models may have the potential to further assist in estimating metastatic risk, particularly when paired with in vivo tumor data that faithfully represent all stages of disease progression. Herein, we describe mathematical analysis that uses data from mouse models of spontaneous metastasis developing after surgical removal of orthotopically implanted primary tumors. Both presurgical (primary tumor) growth and postsurgical (metastatic) growth were quantified using bioluminescence and were then used to generate a mathematical formalism based on general laws of the disease (i.e., dissemination and growth). The model was able to fit and predict pre/postsurgical data at the level of the individual as well as the population. Our approach also enabled retrospective analysis of clinical data describing the probability of metastatic relapse as a function of primary tumor size. In these data-based models, interindividual variability was quantified by a key parameter of intrinsic metastatic potential. Critically, our analysis identified a highly nonlinear relationship between primary tumor size and postsurgical survival, suggesting possible threshold limits for the utility of tumor size as a predictor of metastatic recurrence. These findings represent a novel use of clinically relevant models to assess the impact of surgery on metastatic potential and may guide optimal timing of treatments in neoadjuvant (presurgical) and adjuvant (postsurgical) settings to maximize patient benefit. Cancer Res; 76(3); 535–47. ©2015 AACR.