Abstract P1-05-19: Modeling Cancer Recurrence and the Therapeutic Effect of Adjuvant Systemic Therapy

Abstract

Abstract Despite complete surgical removal of early stage cancers, recurrence can occur at distant locations in time spans ranging from months to decades. This is due to the presence of disseminated cancer cells that can ultimately transition into active growth leading to recurrence. Systemic adjuvant therapy can decrease the incidence of distant relapse and lead to improved survival in some cancers. In this study, data on natural recurrence patterns of different breast cancer subtypes is used to build a probabilistic model of distant recurrence. The central hypothesis of this model is that after initial local therapy, a fraction of patients will have the presence of one or more disseminated dormant metastatic foci (DMF). The transition of DMF into actively growing metastatic foci (AMF) is described using a stochastic model. DMF of individual breast cancer subclasses each have a distinct probability per unit time of entering active growth. Fitting of this model to clinical trial data of early stage breast cancers treated with surgery alone demonstrates that DMF present in estrogen receptor negative (ER−) cancers and Luminal B cancer have greater probabilities of transition to active growth per unit time than Luminal A breast cancers. Clinical trial data were then used to determine the effect of adjuvant therapy on the dynamics of tumor recurrence. The data strongly support a model in which adjuvant chemotherapy works by eliminating only a fraction of DMF that have transitioned into AMF during the time of chemotherapy treatment. Thus short duration adjuvant chemotherapy would have greater efficacy in ER−, HER+ and Luminal B breast cancers, which have fast dynamics of recurrence, and little effect in Luminal A breast cancers with far slower dynamics of recurrence. Similarly, analysis of adjuvant hormonal therapy trial data, demonstrate that hormonal therapy also affects only DMF that transition into active growth during the period of hormonal therapy. This model can explain why extended duration therapy of up to 5 years is more effective than shorter duration of adjuvant hormonal therapy. Interestingly some adjuvant treatments, such as trastuzumab for HER2+ breast cancers, affect recurrence rates in a way that suggest that these interventions directly kill DMF. This model of tumor recurrence has several clinical implications that could inform future clinical trial design. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-19.