Abstract
Ipsilateral breast tumor relapse (IBTR) often occurs in breast cancer patients after their breast conservation therapy. The IBTR status' classification (true local recurrence versus new ipsilateral primary tumor) is subject to error and there is no widely accepted gold standard. Time to IBTR is likely informative for IBTR classification because new primary tumor tends to have a longer mean time to IBTR and is associated with improved survival as compared with the true local recurrence tumor. Moreover, some patients may die from breast cancer or other causes in a competing risk scenario during the follow-up period. Because the time to death can be correlated to the unobserved true IBTR status and time to IBTR (if relapse occurs), this terminal mechanism is non-ignorable. In this paper, we propose a unified framework that addresses these issues simultaneously by modeling the misclassified binary outcome without a gold standard and the correlated time to IBTR, subject to dependent competing terminal events. We evaluate the proposed framework by a simulation study and apply it to a real data set consisting of 4477 breast cancer patients. The adaptive Gaussian quadrature tools in SAS procedure NLMIXED can be conveniently used to fit the proposed model. We expect to see broad applications of our model in other studies with a similar data structure.
Highlights
Breast conservation therapy (BCT) is a breast conserving surgery followed by moderatedose radiation therapy to eradicate the microscopic residual disease and it offers similar overall survival and disease-free survival rates as does mastectomy in breast cancer patients[1]
The ipsilateral breast tumor relapse (IBTR) status is classified as either true local recurrence tumor (TR, residual cancer cells grow gradually to detectable size) or new ipsilateral primary tumor (NP, first occurrence of cancer independently arising in the preserved breast) by some diagnostic tests
This phenomena can be visualized in the large gap between curves in the right panel of Figure 2 and the explanation is that the patient with IBTR, especially those with TR relapse, are more likely to die from breast cancer and less likely to die from other causes
Summary
Breast conservation therapy (BCT) is a breast conserving surgery followed by moderatedose radiation therapy to eradicate the microscopic residual disease and it offers similar overall survival and disease-free survival rates as does mastectomy in breast cancer patients[1]. In the presence of a single imperfect diagnostic test, some additional information on the misclassification structure is required in order to make the model identifiable and to adjust for potential bias due to misclassification[11]. To this end, Nagelkerke et al.[12] suggested modeling the unobserved true disease status as a function of an instrumental variable, which is an additional parameter to increase the outcome degrees of freedom. We proposed the model framework for a binary outcome classified by a single imperfect diagnostic test and the correlated time to IBTR, in the presence of two competing risks, i.e., breast cancer death and other cause death.
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