Abstract
Background: Standard therapy for HER2+ breast cancers includes HER2 inhibition. While HER2 inhibitors have modestly improved outcomes, they have not had nearly the original anticipated therapeutic efficacy, with only a modest improvement in survival in both the metastatic and adjuvant setting. An important intrinsic resistance mechanism to HER2 inhibition in some breast cancers is dynamic upregulation of HER3. Increase in HER3 expression that occurs in response to HER2 inhibition allows for continued growth signaling through HER2:HER3 heterodimers, promoting tumor escape. We hypothesized that a non-invasive method to image changes in HER3 expression would be valuable to identify those breast cancers that dynamically upregulate HER3 in response to HER2 inhibition. We further hypothesized that this imaging method could identify those tumors that would benefit by further addition of a HER3 inhibitor. Methods: In cells treated with the HER2 inhibitor lapatinib, we evaluate changes in HER3 expression and viability. Mouse HER2+ breast cancer models treated with lapatinib were imaged with a peptide-based HER3-specific PET imaging agent (Ga-68-HER3P1) to assess for dynamic changes in tumoral HER3 expression and uptake confirmed by biodistribution. Subsequently, HER2+ cell lines were treated with the HER2 inhibitor lapatinib as well HER3-specific siRNA to assess for changes in viability and correlate with HER3 expression upregulation. For all statistical comparisons, p<0.05 was considered statistically significant. Results: Ga68-HER3P1 PET imaging of mice implanted with the HER2+ breast cancer cell lines MDA-MB453 or HCC-1569 prior to and after treatment with lapatinib demonstrated a significant increase in SUV in MDA-MB453 tumors only, consistent with in vitro findings. The addition of HER3 siRNA to lapatinib increased therapeutic efficacy in MDA-MB453 cells, but not in HCC-1569 cells. Conclusion: HER3 PET imaging can be used to visualize dynamic changes in HER3 expression that occur in HER2+ breast cancers with HER2 inhibitor treatment and identify those likely to benefit by the addition of combination HER3 and HER2 inhibition.
Initial experience of dedicated breast PET imaging of ER+ breast cancers using [F-18]fluoroestradiol
