Tumor growth inhibition modeling of individual lesion dynamics and interorgan variability in HER2-negative breast cancer patients treated with docetaxel

Information on individual lesion dynamics and organ location are often ignored in pharmacometric modeling analyses of tumor response. Typically, the sum of their longest diameters is utilized. Herein, a tumor growth inhibition model was developed for describing the individual lesion time-course data from 183 patients with metastatic HER2-negative breast cancer receiving docetaxel. The interindividual variability (IIV), interlesion variability (ILV), and interorgan variability of parameters describing the lesion time-courses were evaluated. Additionally, a model describing the probability of new lesion appearance and a time-to-event model for overall survival (OS), were developed. Before treatment initiation, the lesions were largest in the soft tissues and smallest in the lungs, and associated with a significant IIV and ILV. The tumor growth rate was 2.6 times higher in the breasts and liver, compared with other metastatic sites. The docetaxel drug effect in the liver, breasts, and soft tissues was greater than or equal to 1.2 times higher compared with other organs. The time-course of the largest lesion, the presence of at least 3 liver lesions, and the time since study enrollment, increased the probability of new lesion appearance. New lesion appearance, along with the time to growth and time-course of the largest lesion at baseline, were identified as the best predictors of OS. This tumor modeling approach, incorporating individual lesion dynamics, provided a more complete understanding of heterogeneity in tumor growth and drug effect in different organs. Thus, there may be potential to tailor treatments based on lesion location, lesion size, and early lesion response to provide better clinical outcomes.