Comparing 68Ga-Pentixafor,18F-FDG PET/CT and chemokine receptor 4 immunohistochemistry staining in breast cancer : a prospective cross sectional study

Abstract

BACKGROUND : CXCR4 is a chemokine receptor that is frequently overexpressed in invasive breast cancer and plays a major role in tumor proliferation, aggressiveness and metastasis. The aim of this prospective study was to establish the value of CXCR4-directed PET imaging in patients with breast cancer using the novel CXCR4-targeted PET probe 68Ga-Pentixafor by comparing it with 18F-FDG PET/CT (n = 40). MATERIALS AND METHODS : In this prospective cross-sectional study, fifty-one patients with breast cancer aged 36–81 (median (Q1-Q3) 51 (42.5–63)), n = 47 (92%) with initially diagnosed and n = 4 (8%) patients with recurrent breast cancer, underwent CXCR4-targeted PET imaging using 68Ga-Pentixafor. Maximum standardized uptake values (SUVmax), total lesion glycolysis (TLG) or total lesion uptake (TLU), metabolic tumor volume (MTV) and tumor-to-background ratios (TBR) of tumor lesions were measured and correlated with pathological prognostic factors, molecular subtypes and CXCR4 immunohistochemistry (IHC) staining. 18F-FDG PET/CT images were available in 40 of 51 cases (82%) and were compared semi-quantitatively. The patients were followed up for a median of 11 months (range 4–80 months) to determine whether CXCR4 expression correlated with survival. RESULTS : 68Ga-Pentixafor-PET/CT was visually positive in 49/51 (96%) of the cases; in addition, [18F]FDG demonstrated a higher SUVmax compared to 68Ga-Pentixafor. The mean SUVmax was 7.26 ± 2.84 and 18.8 ± 9.1 for 68Ga-Pentixafor and [18F]FDG, respectively. Thirty-seven percent (18/51) of patients had triple-negative breast cancer and 25/51 (49%) had estrogen receptor (ER+) disease. There was a statistically significant correlation between tumor grade, proliferative index (Ki-67) and SUVmax obtained from 68Ga-Pentixafor PET p = 0.002. There was no correlation between the SUVmax obtained from 68Ga-Pentixafor and PET molecular subtypes, estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2) status; however, triple-negative breast cancers had more avid 68Ga-Pentixafor accumulation compared to luminals A and B. The median (Q1–Q3) 68Ga-Pentixafor TLU was significantly higher in HIV-positive (376 (219–881)) compared to HIV-negative (174 (105–557)) breast cancer patients. CONCLUSIONS : In conclusion, 68Ga-Pentixafor had a sensitivity of 96% and a specificity of 100% for detecting primary breast cancer; in addition, 68Ga-Pentixafor exhibited significantly higher uptake in patients with higher tumor grade, high proliferative index and triple-negative breast cancer (TNBC), as well as HIV-infected breast cancer patients, highlighting the potential clinical utility and prognostic role of CXCR4-targeted PET imaging in aggressive breast cancer. Notably, 68Ga-Pentixafor complements 18F-FDG by detecting more metastasis in the brain and the skull where FDG has limitations, while 18F-FDG remains superior for detecting skeletal metastasis. Future research should further explore the potential of CXCR4-targeted PET imaging in selecting patients with triple-negative breast cancer and high-grade breast cancer who may benefit from CXCR4-targeted therapies, particularly in the context of HIV co-infection.

SIMPLE SUMMARY : This prospective cross-sectional study explored the complementary role of 68Ga-Pentixafor in 18F-FDG in patients with breast cancer using PET/CT imaging. 68Ga-Pentixafor-PET/CT was visually positive in 49/51 (96%) of the cases; however, 18F-FDG demonstrated higher tracer accumulation compared to 68Ga-Pentixafor. Indicators of prognosis in breast cancer, such as the proliferative index (Ki67) and Bloom Richardson grade, were correlated with a higher uptake (SUVmax) of 68Ga-Pentixafor. Also, HIV-infected patients with breast cancer and patients with triple-negative breast cancer had a higher accumulation of 68Ga-Pentixafor in primary tumors. Lastly, 68Ga-Pentixafor detected more brain and skull metastasis compared to 18F-FDG, whereas 18F-FDG detected more bone marrow metastasis. Therefore 68Ga-Pentixafor cannot replace 18F-FDG in the detection of breast cancer but plays a complementary role by detecting lesions in sites where 18F-FDG is limited by physiological tracer accumulation. 68Ga-Pentixafor has a role in the prognostication of patients and selecting potential candidates for therapies targeting CXCR4, particularly in the setting of HIV co-infection.