Background:
Human epidermal growth factor receptor (HER2) expression is associated with increased disease recurrence and treatment resistance1. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) prolongs progression-free and overall survival (PFS) for patients with HER2-low and -ultralow breast cancer; however, there is a major clinical challenge in identifying patients who will respond to T-DXd2-4. At the cellular level, HER2 internalization and recycling affect uptake and tumor response to antibody-based therapies5. Statins, cholesterol-depleting drugs, can enhance cell-surface HER2 protein levels in breast cancer cells and enhance HER2-antibody complex internalization and efficacy6,7.
Hypothesis/Objective:
We aim to employ image-based optimization of statin administration to enhance T-DXd efficacy in HER2-low and -ultralow patient-derived breast tumor models, which will be used to inform a future clinical trial.
Methods:
Models: Female nu/nu mice were implanted subcutaneously with a mixture of HER2-positive JIMT1 and HER2-negative MDA-MB-231 breast cancer cells (4:1 ratio). MDA-MB-231 cells were implanted into the third mammary fat pad of female nu/nu mice. Statin administration: Lovastatin (4.15 or 8.3 mg/kg) was orally administered 12 h prior to and at the same time as T-DXd (acute schedule) or daily for 7 days per cycle of T-DXd. PET/CT: Animals (n=4-5/group) randomized into lovastatin (acute or daily) or saline cohorts were administered [64Cu]Cu-NOTA-trastuzumab (200 µCi) or [89Zr]Zr-DFO-trastuzumab (170 µCi) and imaged on a Mediso nanoScan preclinical PET/CT. Imalytics software was used to quantify changes in trastuzumab uptake. Biodistribution and immunohistochemical staining were performed on excised tumors at the terminal imaging time point. Independent t-tests were performed to compare imaging and biodistribution data between groups, which are presented as mean±S.D. Therapy: Groups included saline, lovastatin, T-DXd, and T-DXd/lovastatin. Animals (n=10/group) received T-DXd (5 mg/kg, i.v.) weekly every 3 weeks and lovastatin (4.15 mg/kg) 12 h before and simultaneously with T-DXd each cycle. Clinical cohort: Kaplan-Meier analysis was used to compare progression-free survival (PFS) for HER2-low breast cancer patients receiving T-DXd with or without statin treatment from a retrospective cohort of patients treated with standard-of-care T-DXd (n=131).
Results:
PET/CT demonstrated that both acute and daily statin administration significantly increased trastuzumab uptake in HER2-low tumors (Fig. 1A, 1B). T-DXd/statin significantly extended the survival of mice compared to single-agent T-DXd and control treatments in the HER2-low model (Fig. 1C). Retrospective clinical data showed that HER2-low advanced breast cancer patients treated with T-DXd while taking statins had significantly improved PFS compared to non-statin users (Fig. 2A, 290 days vs. 140 days, P=0.0098).
[89Zr]Zr-DFO-trastuzumab PET showed baseline heterogeneity in HER2 expression within MDA-MB-231 HER2-ultralow tumors (10.89±5.19 %ID/mL) and revealed the highest percent increase in trastuzumab uptake from baseline occurs after 2 statin doses (Fig. 2B-D, 6.87% mean increase, P=0.041). We observed from imaging that statin increased and stabilized trastuzumab uptake in HER2-ultralow tumors, while control tumors had a gradual wash-out of trastuzumab (Fig. 2B, 2D). Biodistribution data (Fig. 2C) indicated that lovastatin administration increased trastuzumab tumor uptake in HER2-ultralow tumors in comparison to the liver (P=0.03) and kidneys (P=0.02) (Fig. 2E).
Ongoing tissue staining is being performed to determine changes in HER2 protein levels after statin administration in HER2-low and -ultralow breast tumors. We are currently investigating therapeutic efficacy of T-DXd/statin in HER2-low and -ultralow breast cancer patient-derived xenografts with additional data to be presented at the time of presentation.
Conclusion:
Trastuzumab PET imaging indicates that 2 doses of lovastatin significantly increased trastuzumab uptake in both HER2-low and -ultralow breast tumors. Our preclinical data demonstrate that T-DXd/lovastatin treatment increases response for heterogeneous, HER2-low tumors. Based on these data, acute dosing of statins will be utilized for ongoing preclinical therapy studies and in a planned clinical trial treating patients with advanced HER2-low and -ultralow breast cancer with T-DXd/lovastatin.
Image/Figure:
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Image/Figure Caption:
Figure 1. Statin administration increases trastuzumab uptake and improves T-DXd treatment efficacy in HER2-low breast tumors.
A. Immunohistochemical staining shows HER2 intra-tumoral heterogeneity in a HER2-low (HER2 IHC 2+) admixed breast tumor model.
B. Representative PET images obtained with [64Cu]Cu-NOTA-trastuzumab show that both chronic (7X, daily) and acute (2X, daily) schedule of statin administration increases trastuzumab uptake in the HER2-low breast tumors compared to control. Female nu/nu mice were implanted s.c. with a mixture of JIMT1:MDA-MB2-31 (4:1) cancer cells and were treated orally with lovastatin (4.15 mg/kg) or saline every 24 h for 7 d prior to and at time of (daily) or 12 h prior and at time of (acute) radiolabeled trastuzumab. [64Cu]Cu-NOTA-trastuzumab (7.4MBq, 200 µCi) was administered intravenous, and mice were imaged with PET/CT 20 h post-injection. [64Cu]Cu-NOTA-trastuzumab purity was >95% by instant thin layer chromatography. PET images represented as maximum intensity projections with maximum intensity = 0.4MBq/mL.
C. Survival probability for the admixed breast tumor model shows combination lovastatin + T-DXd significantly extends survival compared to single-agent T-DXd, lovastatin, and saline control. Female nu/nu mice were implanted s.c. with a mixture of JIMT1:MDA-MB-231 cancer cells (4:1) and were assigned to different groups: saline, lovastatin, T-DXd, T-DXd plus lovastatin. Mice were treated with three doses of T-DXd (5 mg/kg of mice, i.v., administered 28 days apart). Lovastatin (4.15 mg/kg) was orally administered 12 h before and at the same time as T-DXd with each cycle. Mice were sacrificed once tumors became ulcerated or reached >1,500 mm3.
Author
Shannon Elizabeth Lynch
Washington University in St. Louis