High PDGFRb Expression Predicts Resistance to Radiotherapy in DCIS within the SweDCIS Randomized Trial

Abstract

Purpose: This study analyzes the potential of stromal platelet-derived growth factor receptor-beta (PDGFRb) expression as biomarker for radiotherapy (RT) benefit on ipsilateral breast events (IBE) in ductal carcinoma in situ (DCIS). Improved identification of DCIS patients refractory to adjuvant whole-breast RT is needed. Predictive biomarker studies in DCIS have focused on tumor cell features rather than the tumor-associated stroma, despite growing evidence of its influence on therapy efficiency. Experimental Design: Samples from the Swedish randomized radiotherapy DCIS trial (SweDCIS) were subjected to IHC analysis for stromal PDGFRb expression. IBE incidence at 10 years after breast-conserving surgery was the primary endpoint. Interactions between marker and treatment were analyzed. Results: PDGFRb score was predictive for RT benefit with regard to IBE (Pinteraction = 0.002 and Pinteraction = 0.008 adjusted multivariably). Patients of the PDGFRblow group had a strong benefit from RT regarding IBE risk [HR, 0.23; 95% confidence interval (CI), 0.12–0.45; P < 0.001] with an absolute risk reduction of 21% (cumulative risk 7% vs. 28%) at 10 years. No significant risk reduction by RT was observed for patients of the PDGFRbhigh group (HR, 0.83; 0.51–1.34; P = 0.444; cumulative risk 22% vs. 25%). The RT response–predictive effect of stromal PDGFRb was equally strong in analyses for in situ and invasive IBE when analyzed separately (in situ IBE: P = 0.029; invasive IBE: P = 0.044). Conclusions: Results suggest high stromal PDGFRb expression as a novel biomarker identifying DCIS patients who are refractory to standard whole-breast adjuvant RT. The data imply previously unrecognized fibroblast-mediated modulation of radiosensitivity of DCIS, which should be further explored from mechanistic and targeting perspectives.

Pancreatic ductal adenocarcinoma cells regulated the gemcitabine‐resistance function of CAFs by LINC00460

“…PDGFR‐β participates in the regulation of the cell function of fibroblasts, and PDGFR‐β + CAFs are associated with a worse prognosis in pancreatic cancer. 33 , 34 , 35 , 36 , 37 , 38 In line with these reports, we found that PDGFR was highly expressed in CAFs but was rarely expressed in PDAC tumor cells. Further results showed that knockdown of LINC00460 increased the proliferation of CAFs and activated the PDGFR signaling pathway, and this effect could be reversed by treatment with crenolanib (PDGFR inhibitor).…”

“…PDGFR‐α and PDGFR‐β are expressed at similar levels in fibroblasts. PDGFR‐β participates in the regulation of the cell function of fibroblasts, and PDGFR‐β + CAFs are associated with a worse prognosis in pancreatic cancer 33–38 . In line with these reports, we found that PDGFR was highly expressed in CAFs but was rarely expressed in PDAC tumor cells.…”

Radiation‐induced effects on TGF‐β and PDGF receptor signaling in cancer‐associated fibroblasts

“…In the context of radiation or radiotherapy, there are few or no published records on the effects of radiation on the expression of PDGF and/or PDGFRs in stromal cells. In a recent study by Strell et al performed on mammary ductal carcinoma in situ (DCIS) patient samples, authors found an association between high tissue expression of PDGFR‐β and reduced RT sensitivity, indicating a potential role of PDGFR‐β positive cells in radiotherapy resistance 55 . Results from our study indicate that exposure of CAFs to intermediate or high radiation doses does not have a significant impact on PDGFR‐β expression or signaling in CAFs, suggesting that radiation exposure does not trigger PDGFR‐mediated tumor radioresistance.…”

ASPM induces radiotherapy resistance by disrupting microtubule stability leading to chromosome malsegregation in non-small cell lung cancer

“…RT resistance remains a major cause of failure of clinical cancer therapy [33][34][35]. Knowledge of the mechanisms underlying RT resistance is urgently needed so that patients who have RT-resistant disease (and hence are unlikely to respond to RT) can be spared the morbidity and expense of ineffective treatment, ideally before that treatment is begun.…”