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PURPOSE No combined immunotherapy and antiangiogenic therapy have been investigated in exclusively programmed death-ligand 1 (PD-L1)–positive advanced cervical cancer (CA). We investigated the efficacy and safety of sintilimab plus anlotinib as second-line or later therapy for PD-L1–positive recurrent or metastatic (R/M) CA. PATIENTS AND METHODS Patients with PD-L1–positive (Combined Positive Score ≥ 1) R/M CA who progressed after at least one prior systemic chemotherapeutic regimen or could not tolerate chemotherapy were eligible for the phase II trial. The patients received 200 mg sintilimab once on day 1 and 10 mg anlotinib once daily on days 1-14 every 3 weeks. The primary end point was investigator-confirmed objective response rate (ORR) per RECIST v1.1. Secondary end points included progression-free survival (PFS), overall survival, and disease control rate. Biomarkers were explored. RESULTS Forty-two patients were enrolled. The ORR was 54.8% (95% CI, 38.7 to 70.2). In 39 efficacy-evaluable patients, the ORR was 59.0% (95% CI, 42.1 to 74.4); the disease control rate was 94.9% (95% CI, 82.7 to 99.4). The median PFS was 9.4 months (95% CI, 8.0 to 14.6). The median overall survival was not reached. Furthermore, 85.8% of the patients experienced treatment-related adverse events. The most frequent treatment-related adverse events were hypothyroidism (33.3%), elevated aspartate aminotransferase levels (21.4%), and hypertension (19.0%). Patients with altered PIK3CA, PI3K-AKT signaling, or KMT2D had a higher ORR, whereas those with altered STK11 and/or JAK2 had a significantly shorter PFS. CONCLUSION Sintilimab plus anlotinib as second-line or later therapy is efficacious and safe for patients with advanced CA who have failed prior chemotherapy.

Cervical cancer patients who develop distant metastasis are rarely curable with very limited treatment options. Chemotherapy is often administered but with limited efficacy. Immunotherapy and anti-angiogenesis therapy are recommended for selected cases of recurrent or metastatic cervical cancers. The clinical efficacy of inhibitors targeting HER2, a commonly mutated gene in cervical cancer, has not been elucidated. Herein, we report a metastatic cervical adenocarcinoma patient carrying HER2 G292R who benefited from pyrotinib after progression on radio-chemotherapy, achieving complete response (CR) with a progression-free survival of 25 months and counting. Our study sheds light on the treatment options for previously treated metastatic cervical adenocarcinoma patients harboring activating HER2 mutations.

Purpose: This study aimed to analyze genomic alteration profiles and immune characteristics of a cohort of Chinese cervical cancer patients to understand why certain patients benefited from molecular targeted therapies, immunotherapy and their prognostic significance.Methods: PD-L1 expression, and clinicopathological information from 98 cervical cancer samples. Differences in PD-L1 expression and gene mutations between squamous cell carcinoma (SCC) and adenocarcinoma (AC) were analyzed by chi-square test or Fisher's exact test. Differences in gene mutations between our cohort and the Cancer Genome Atlas (TCGA) cohort were tested by Fisher's exact test. Logistic regression was used to analyze factors influencing TMB-high.Results: Positive PD-L1 expression was significantly higher in cervical SCC than in cervical AC (87% vs. 39%, p < 0.001). Frequently mutated genes in cervical cancer included PIK3CA, KMT2D, and KMT2C genes, among others. PIK3CA gene mutation rates were significantly higher in SCC than in AC (p = 0.004). TERT gene mutation rate was significantly higher in our cohort than TCGA cohort (12% vs. 1%, p < 0.001). The independent predictors of TMB-high were KMT2C and LRP1B gene mutations (p < 0.05). we also found the PTEN mutations were associated with worse survival (median PFS, 12.16 vs. 21.75 months, p = 0.0024)Conclusion: Cervical SCC and AC have different molecular profiling and immune characteristics, suggesting that targeted treatments for SCC and AC patients may improve clinical outcomes. KMT2C and LRP1B gene mutations are independent predictors of TMB-high status in cervical cancer. We have also proposed the prognostic value of PTEN mutations.

Background Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis. It is meaningful to develop alternative targets for eliminating cancer stem cells (CSCs) properties, suppressing metastasis, and alleviating chemoresistance in cervical cancer. This study clarifies the role of CENPK in cervical cancer stemness and chemoresistance and its clinical significance in cancer progression. Methods Human cervical cancer cell lines, xenografts, and clinical samples were used for expression and functional analysis. CENPK expression in cervical cancer was analyzed by bioinformatics based on a microarray and TCGA database and immunohistochemistry based on 119 paraffin-embedded cervical cancer specimens and 35 paraffin-embedded adjacent normal tissues in a tissue chip. Results CENPK served as an oncogene by promoting CSCs properties, DNA damage repair, epithelial-mesenchymal transition and DNA replication, thus inducing cisplatin/carboplatin resistance, cell metastasis and proliferation in cervical cancer. Intriguingly, targeting CENPK markedly prolonged the survival time of cervical cancer-bearing mice, and improved chemotherapy sensitivity of cervical cancer cells in vivo. CENPK also interacted with tumor suppressor gene SOX6 to activate Wnt signaling and inactivate p53 signaling. CENPK modulated expression of key regulators in CSCs properties, DNA damage repair, epithelial-mesenchymal transition and DNA replication by disrupting SOX6-β-catenin interaction, promoting β-catenin expression and nuclear translocation, and facilitating SOX6-mediated p53 ubiquitination and nuclear export, thus stimulating cervical cancer stemness, chemoresistance, metastasis and proliferation by. Interestingly, the RAD21/SMC3 complex, downstream targets of β-catenin, enhanced CENPK transcription to form a positive regulatory circuit through Wnt signaling. Facilitation of Wnt signaling by iRhom2 further activated the CENPK/SOX6-β-catenin-RAD21/SMC3 loop and conferred cervical cancer progression, suggesting a Wnt-p53 pathway crosstalk. Importantly, CENPK was upregulated in cervical cancer, correlated with cancer recurrence, and independently predicted poor patient prognosis. Conclusions This work identifies CENPK as a prognostic indicator and highlights targeting of CENPK as a novel strategy in the treatment of cervical cancer.

Locations of selected eight core points in the treatment regimen. (DOCX 600 kb)

Silver-needle warm acupuncture conducted Multi-Function Moxibustion Apparatus with specially designed heat pipe. (DOCX 722 kb)

SPIRIT checklist. (DOC 122 kb)

Informed consent materials. (DOCX 17 kb)