Clinical Relevance of Targeting the Gastrin-Releasing Peptide Receptor, Somatostatin Receptor 2, or Chemokine C-X-C Motif Receptor 4 in Breast Cancer for Imaging and Therapy

Abstract

Imaging and therapy using radioligands targeting receptors overexpressed on tumor cells is successfully applied in neuroendocrine tumor patients. Because expression of the gastrin-releasing peptide receptor (GRPR), somatostatin receptor 2 (SSTR2), and chemokine C-X-C motif receptor 4 (CXCR4) has been demonstrated in breast cancer, targeting these receptors using radioligands might offer new imaging and therapeutic opportunities for breast cancer patients. The aim of this study was to correlate messenger RNA (mRNA) expression of GRPR, SSTR2, and CXCR4 with clinicopathologic and biologic factors, and with prognosis and prediction to therapy response, in order to identify specific breast cancer patient groups suited for the application of radioligands targeting these receptors. Methods: First, we studied GRPR and SSTR2 expression in 13 clinical breast cancer specimens by in vitro autoradiography and correlated this with corresponding mRNA levels to investigate whether mRNA levels reliably represent cell surface expression. Next, GRPR, SSTR2, and CXCR4 mRNA levels were measured by quantitative reverse transcriptase polymerase chain reaction in 915 primary breast cancer tissues and correlated with known clinicopathologic and biologic factors, disease-free survival, distant metastasis-free survival, and overall survival (DFS, MFS, and OS, respectively). In 224 adjuvant hormonal treatment-naïve estrogen receptor (ER, ESR1)-positive patients who received tamoxifen as first-line therapy for recurrent or metastatic disease, the expression levels of the receptors were correlated with progression-free survival. Results: Our results showed a significant positive correlation between GRPR and SSTR2 expression analyzed by in vitro autoradiography and by quantitative reverse transcriptase polymerase chain reaction (Spearman's rank correlation coefficient [R s ] 5 0.94, P , 0.001, and R s 5 0.73, P 5 0.0042, respectively). Furthermore, high GRPR and SSTR2 mRNA levels were observed more frequently in ESR1-positive specimens, whereas high CXCR4 expression was associated with ESR1-negative specimens. Also, high mRNA expression of CXCR4 was associated with a prolonged DFS, MFS, and OS (multivariate hazard ratio MFS 5 0.76 [95% confidence interval, 0.64-0.90], P 5 0.001), whereas high mRNA levels of GRPR were associated with a prolonged progression-free survival after the start of first-line tamoxifen treatment (multivariate hazard ratio 5 0.68 [95% confidence interval, 0.48-0.97], P 5 0.031). Conclusion: Our data indicate that imaging and therapy using GRPR or SSTR2 radioligands might especially be beneficial for ESR1-positive breast cancer and CXCR4 radioligands for ESR1-negative breast cancer.

Prospects of Targeting the Gastrin Releasing Peptide Receptor and Somatostatin Receptor 2 for Nuclear Imaging and Therapy in Metastatic Breast Cancer

“…When we associated receptor mRNA expression levels of primary BCs and metastases with clinico-pathological factors, we observed a significantly higher GRPR and SSTR2 expression in both ESR1 -positive primary BC and metastases. These findings are in agreement with our previous findings [10] and findings by Kumar et. al.…”

“…Prior to this, we evaluated whether mRNA expression levels of tumor tissue properly represent radioligand binding, by correlating in vitro autoradiography results with mRNA expression levels of selected primary tumors and corresponding metastases with varying mRNA receptor expression. In line with previously published findings [10], we demonstrated that there was a high correlation between mRNA expression of the receptors and radiotracer binding, which suggests that mRNA expression levels can be used as a surrogate for radiotracer binding.…”

“…Regarding BC, multiple studies have demonstrated overexpression of the gastrin releasing peptide receptor (GRPR) and the somatostatin receptor 2 (SSTR2). In line with this, several pre-clinical as well as clinical studies demonstrated feasibility of imaging and/or treatment of BC with GRPR and SSTR2 radioligands with promising results, and indicated specific BC patients groups that can benefit from the application of these radioligands [6–10]. …”

Review: Receptor Targeted Nuclear Imaging of Breast Cancer

“…Since BC is a very heterogeneous disease, SSTR expression between BC subtypes may vary. We and others showed higher SSTR expression in ER-positive BC compared to ER-negative BC, identifying ER-positive BC subtypes as the most suitable subtypes for SSTR-mediated imaging [68,69,70,71]. If we only focus on these BC subtypes, which account for the majority of the breast tumors, SSTR-mediated BC imaging might be more successful.…”

ProCA1.GRPR: A New Imaging Agent in Cancer Detection

“…GRPR is also expressed in lymph node metastases from breast cancer, whereas the GRPR expression level in normal lymph node tissue is very low. In addition, GRPR mRNA levels are correlated with smaller pathologic tumor size, positive estrogen receptor 1, progesterone receptor status and negative HER2 status [11,12].…”