Abstract PO5-03-06: Optimizing therapeutic regimens via digital twins to improve triple negative breast cancer response to neoadjuvant therapy

Abstract Introduction: Neoadjuvant systemic therapy (NAT) has been the standard-of-care of stage II-III, locally advanced triple-negative breast cancer (TNBC). However, about 50% of TNBC patients achieve a pathological complete response (pCR) to conventional neoadjuvant chemotherapy (NAC)1. Recently approved combination of NAC with the immunotherapy pembrolizumab, has improved the pCR rate by 7.5%2, although with a 44% risk of immune-related adverse reaction3. Aside from the need to develop new therapies with higher efficacy and lower toxicity, a critical barrier to improving TNBC response is the lack of rigorous ways to personally tailor therapeutic regimens. We seek to address this challenge by employing digital twins (i.e., mathematical models that provide virtual representation of individual patients and predict the changes at future time points) to systematically evaluate individual TNBC patient’s response to different NAT regimens, thereby patient-specifically optimizing treatments. Methods: A TNBC cohort (n = 139) from the ARTEMIS trial (NCT02276433)4 was used for this study. All patients received 4 cycles of Adriamycin/Cytoxan (A/C) every 2 weeks, followed by 12 cycles of weekly Taxol or experimental therapy in Phase II trials. All patients had surgery after NAT and post-surgical pathology to assess response status. For each patient, longitudinal MRIs were collected before, during, and after A/C. We have developed digital twins to integrate the longitudinal MRIs with a mechanism-based model to accurately predict TNBC response5. The model was based on a reaction-diffusion equation that describes the change in tumor cellularity due to migration, proliferation, and drug-induced death. With parameters personalized using MRIs, the patient-specific model (i.e., digital twin) significantly improved the accuracy to predict pCR5. We investigated patient-specific treatment optimization on 37 (19 pCR, 18 non-pCR) chemo-sensitive patients (≥ 70% volume decrease after A/C) who received only NAC. We evaluated the effect of altering the A/C/Taxol schedules on patient response. Specifically, each patient’s digital twin was used to predict the patient’s response to 128 clinically reasonable schedules of A/C/Taxol; i.e., 8 candidate A/C schedules combining with 16 candidate Taxol schedules (Table 1). The predicted response (pCR or non-pCR) from each alternative schedule was compared to the patient response from the actual treatment. Results: Without changing the total dose, shortening the duration of A/C/Taxol administration increased the treatment efficacy. The effectiveness of altering the schedules varied substantially in different patients. In particular, 8 patients who had non-pCR responses to their actual treatment were predicted to achieve pCR with the dense-dose Taxol (i.e., 4 cycles Taxol, 2 weeks per cycle), indicating a 21.62% improvement of pCR rate in the cohort. Discussion and conclusion: The preliminary results with our digital twin approach provided a unique opportunity of improving TNBC response to NAT through patient-specific optimization of therapeutic schedules. The ongoing effort focuses on accounting for toxicity and investigating the effects of altering therapy types and doses in combination with the schedules on the patient response. 1 Spring et al., Clin Cancer Res, 2020. 2 Schmid et al., NEJM, 2022. 3 Shah et al., Clin Cancer Res, 2022. 4 Yam et al., Clin Cancer Res, 2021. 5 Wu et al., Cancer Res, 2022. Table 1. Candidate therapeutic schedules Citation Format: Chengyue Wu, Ernesto Lima, Casey Stowers, Zhan Xu, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane Rauch, Thomas Yankeelov. Optimizing therapeutic regimens via digital twins to improve triple negative breast cancer response to neoadjuvant therapy abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-06.