Prognostic and predictive impact of stroma cells defined by PDGFRb expression in early breast cancer: results from the randomized SweBCG91RT trial

Abstract

Purpose Predictive biomarkers are needed to aid the individualization of radiotherapy (RT) in breast cancer. Cancer-associated fibroblasts have been implicated in tumor radioresistance and can be identified by platelet-derived growth factor receptor-beta (PDGFRb). This study aims to analyze how PDGFRb expression affects RT benefit in a large randomized RT trial. Methods PDGFRb was assessed by immunohistochemistry on tissue microarrays from 989 tumors of the SweBCG91RT trial, which enrolled lymph node-negative, stage I/IIA breast cancer patients randomized to RT after breast-conserving surgery. Outcomes were analyzed at 10 years for ipsilateral breast tumor recurrence (IBTR) and any recurrence and 15 years for breast cancer specific death (BCSD). Results PDGFRb expression correlated with estrogen receptor negativity and younger age. An increased risk for any recurrence was noted in univariable analysis for the medium (HR 1.58, CI 95% 1.11–2.23, p = 0.011) or PDGFRb high group (1.49, 1.06–2.10, p = 0.021) compared to the low group. No differences in IBTR or BCSD risk were detected. RT benefit regarding IBTR risk was significant in the PDGFRb low (0.29, 0.12–0.67, p = 0.004) and medium (0.31, 0.16–0.59, p < 0.001) groups but not the PDGFRb high group (0.64, 0.36–1.11, p = 0.110) in multivariable analysis. Likewise, risk reduction for any recurrence was less pronounced in the PDGFRb high group. No significant interaction between RT and PDGFRb-score could be detected. Conclusion A higher PDGFRb-score conferred an increased risk of any recurrence, which partly can be explained by its association with estrogen receptor negativity and young age. Reduced RT benefit was noted among patients with high PDGFRb, however without significant interaction.

Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer

“…Our murine data are also in agreement with findings in human breast cancer, showing reduced levels of PDGFRα and the concomitant increase in PDGFRβ expression as the disease progresses, which also acts as a strong marker of high-risk ductal carcinoma in situ (DCIS) [43]. In another clinical study, high expression of PDGFRβ correlated with oestrogen receptor (ER) negativity and increased risk of recurrence [44]. Thus, these findings suggest that our two murine TNBC progression models mirror clinically relevant findings.…”

Germline Variants in Angiogenesis-Related Genes Contribute to Clinical Outcome in Head and Neck Squamous Cell Carcinoma

“…PDGFRB upregulation has been linked to poor outcome, treatment resistance, and metastasis in several cancers [ 54 , 55 , 56 ]. Recently, in a large study on early-stage breast cancer, high PDGFRB expression was associated with the risk of recurrence after RT [ 57 ]. In oral cancer, a positive correlation was found between elevated PDGFRB levels and lymph node metastases [ 58 ].…”

Cancer‐associated fibroblasts in breast cancer: Challenges and opportunities

“…The expression of PDGFRβ in stromal cells was also negatively correlated with the radiotherapy benefit, RFS and breast cancer‐specific survival [102, 103, 105]. Moreover, stromal PDGFRβ expression had a better prognostic value among young and premenopausal patients with breast cancer [102, 103].…”

“…In breast cancer, the expression of PDGFRβ in stromal cells was positively correlated with the histopathological grade and HER2 expression, but negatively correlated with estrogen receptor (ER) expression [102,103], reducing the efficacy of tamoxifen [104]. The expression of PDGFRβ in stromal cells was also negatively correlated with the radiotherapy benefit, RFS and breast cancer-specific survival [102,103,105]. Moreover, stromal PDGFRβ expression had a better prognostic value among young and premenopausal patients with breast cancer [102,103].…”