title: 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 [Rs]=0.94, P<0.001, and Rs=0.73, P=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=0.76 [95% confidence interval, 0.64-0.90], P=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=0.68 [95% confidence interval, 0.48-0.97], P=0.031).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands s.dalm@erasmusmc.nl.
authors.forename: Simone U
authors.initials: SU
authors.lastname: Dalm
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, The Netherlands; and.
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, The Netherlands; and.
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.affiliation: Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Melis
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Carolien H M
authors.initials: CH
authors.lastname: van Deurzen
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, The Netherlands; and.
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.affiliation: Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, The Netherlands; and.
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use; D001345:Autoradiography; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000628:therapy*; D005260:Female; D006801:Humans; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin / Q000187:drug effects*; D019718:Receptors, CXCR4 / Q000187:drug effects*; D017481:Receptors, Somatostatin / Q000187:drug effects*; D016019:Survival Analysis; D013629:Tamoxifen / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D019718:Receptors, CXCR4; D017481:Receptors, Somatostatin; C574734:SSTR2 protein, human; D013629:Tamoxifen
keywords: CXCR4; GRPR; PRS/PRRT; SSTR2; breast cancer