Anticancer effect of zoledronic acid in endocrine-resistant breast cancer cells via HER-2 signaling.

HER-2 overexpression is a major mechanism involved in endocrine-resistant breast cancer, which has very limited treatment options. Zoledronic acid (ZA) is a drug in the bisphosphonate group used to treat osteoporosis. ZA was reported to exhibit activity in various cancers, with higher efficacy associated with estrogen-deprivation states. ZA inhibits cell proliferation in lung cancer through the epidermal growth factor receptor signaling pathway. Because endocrine-resistant breast cancer cells overexpress HER-2 and grow independently without estrogen, ZA may exert anticancer effects in these cell types. The inhibitory effects and mechanisms of ZA in endocrine-resistant cells through HER-2 signaling were investigated. The efficacy of ZA was higher in the endocrine-resistant breast cancer cells when compared with the wild-type cells. ZA also exhibited a synergistic effect with fulvestrant and may circumvent fulvestrant resistance. ZA decreased phosphorylated ERK (pERK) levels in resistant cell lines and attenuated HER-2 signaling in tamoxifen- and fulvestrant-resistant cells. ZA significantly decreased HER-2 levels and its downstream signaling molecules, including pAKT and pNF-κB in fulvestrant-resistant breast cancer cells. This inhibitory effect may explain the lower IC50 values of ZA in fulvestrant-resistant cells compared with tamoxifen-resistant cells. Moreover, ZA inhibited the migration and invasion in the resistant cell lines, suggesting an ability to inhibit tumor metastasis. The results indicate that ZA has potential for repurposing as an adjuvant treatment for patients with endocrine-resistant breast cancer.

Immunogenicity of ChAdOx1-nCoV-19 vaccine in solid malignancy patients by treatment regimen versus healthy controls: A prospective, multicenter observational study.

Background: Limited data exists regarding the efficacy of ChAdOx1-nCoV-19 vaccine against Severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) in solid cancer patients. We aimed to assess the immunogenicity of the ChAdOx1-nCoV-19 vaccine and the impact of different anticancer therapies for solid malignancies on immune response. Methods: This prospective, longitudinal observational study of immunogenicity following ChAdOx1-nCoV-19 vaccination among 385 solid cancer patients on active cancer treatment was conducted in two oncology centers. Participants received the first dose between June 18 and July 27, 2021 and the second dose at 8-10 weeks later. Blood samples were evaluated for total immunoglobulins against the receptor-binding of SARS-CoV-2 spike protein (anti-RBD total-Ig) before, and 4-week after the first- and second-doses. The primary endpoint was the geometric mean titers (GMT) of antibody among solid cancer patients compared to healthy controls and the impact of different cancer treatment types. Findings: Among solid cancer patients, the antibody level increased more slowly to significantly lower levels than achieved in healthy controls. The GMT at 4-weeks post-vaccination in cancer vs. healthy were 224.5 U/ml (95%CI 176.4-285.6) vs. 877.1 U/ml (95%CI 763.5-1008), p<0.0001), respectively. For different types of cancer treatments, chemotherapy agents, especially anthracyclines (GMR 0.004; 95%CI 0.002-0.008), paclitaxel (GMR 0.268; 95%CI 0.123-0.581), oxaliplatin (GMR 0.340; 95%CI 0.165-0.484), and immunotherapy (GMR 0.203; 95%CI 0.109-0.381) showed significantly lower antibody response. Anti-HER2, endocrine therapy and 5-fluouracil or gemcitabine, however, had less impact on the immune response. Interpretation: Suboptimal and heterogeneous immunologic responses were observed in cancer patients being treated with different systemic treatments. Immunotherapy or chemotherapy significantly suppressed the antibody response. Funding: Quality Improvement Fund, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society and Center of Excellence in Clinical Virology at Chulalongkorn University and Chulalongkorn Medical Oncology Research Fund.