2.3.1 DNA methylation

In cervical cancer, researchers have primarily focused on the hypermethylation of promoter CpG islands and tumor suppressor genes. High CpG island methylation in the SOX17 promoter region is closely associated with cervical carcinogenesis and serves as a critical biomarker for malignant transformation process [56]. Tumor suppressor genes, such as PAX1, ASCL1, LHX8, and ST6GALNAC5, exhibit increased DNA methylation in cervical cancer, with higher levels correlating with disease progression [57, 58]. DNA methylation typically occurs in the pre-cancer stage and peaks after hrHPV-induced carcinogenesis [59, 60]. As an early event in tumorigenesis, abnormal DNA methylation of both the host and HPV genomes during persistent hrHPV infection may facilitate HPV DNA integration, leading to the dysfunction of tumor suppressor genes and the promotion of cervical cancer progression [55]. HPV integration alters host methylation patterns, with significant differences between integrated and non-integrated samples in genes such as tumor suppressors BARX2 and IRX4 and oncogenes SIM2 and CTSE [46]. Further research is needed to understand the relationship between HPV integration and host gene methylation in order to develop new screening strategies.

2.3.2 Histone modifications

Histone modifications regulated by histone acetylases (HAT) and histone deacetylases (HDAC) are dynamic and reversible [55]. In cervical cancer cells, the HAT-active factor p300 enhances the acetylation of H3K27, H3K9, and H4K16, whereas Tip60 enhances H3K27 and H4K5 acetylation, thereby influencing the expression of HPV E6/E7 by affecting RNA polymerase II recruitment to the HPV18 long control region (LCR) [61]. These activities underscore the dual role of acetylation in promoting or inhibiting cervical cancer progression. Furthermore, acetylation of histones H3 and H4 is associated with activation of HPV16 gene expression in cervical cancer cells [62]. Research has also indicated that HDAC1 collaborates with the nuclear matrix protein SMAR1 to suppress E6 transcription by inhibiting the recruitment of the tumor promoter c-Fos to the E6 promoter, thereby hindering cervical cancer development [63]. Emerging evidence highlights the importance of super-enhancers (SE) in HPV transcription and cervical cancer induction [64], with the SE marker H3K27ac detected as highly enriched in cervical cancer cells with tandem HPV integration [65], driving the expression of cellular oncogenes. Tandem integration of the HPV genome can form SE-like elements that drive E6/E7 transcription and promote cervical cancer, which are crucial for cervical cancer progression [65].

2.3.3 Non-coding RNAs (ncRNAs)

Numerous studies have demonstrated that aberrant expression of miRNAs is associated with the progression of cervical cancer. For instance, miR-34a inhibits cell proliferation and induces apoptosis by targeting the oncogene SIRT1, whereas the miR-200 family reduces tumor invasion and metastasis by inhibiting genes associated with epithelial-mesenchymal transition (EMT) [66]. Circular RNAs (circRNAs) play a crucial role in cervical cancer progression by acting as “miRNA sponges” and sequestering miRNAs to regulate their target mRNAs [67]. They also contribute to oncogenesis by modulating pathways, such as the N6-methyladenosine-dependent IGF2BP2/FOXM1 pathway and MAPK pathways [55]. Long non-coding RNAs (LncRNAs) regulate the malignant transformation of cervical epithelial cells. For instance, HOTAIR interacts with polycomb repressive complexes to increase H3K27me3 modifications and silence tumor suppressor genes [68]. Conversely, DINO, another lncRNA, can reduce cervical cancer cell activity by activating TP53 via the ATM/CHK2 signaling pathway [69].

2.3.4 Three-dimensional (3D) chromatin remodeling

The 3D chromatin genome structure plays a key role in cell function and gene regulation [70]. High-throughput chromosomal conformation capture (Hi-C) techniques provide genome-wide chromatin interactions and facilitate the identification of dynamic changes in genome architecture in cellular biological functions [70]. Combining Hi-C technology with RNA sequencing (RNA-seq) revealed significant changes in the number and boundaries of topologically associated domains (TADs) near HPV16 integration sites and chromosomes containing these sites, supporting the looping-based model of HPV integration [48, 71]. The loop span distribution varied between normal and cervical cancer samples, with a higher percentage of cis-element interactions (promoters or enhancers) in cervical carcinoma [54]. HPV-CCDC106 integration has recently been shown to alter local chromosomal structure by dividing one TAD into two smaller TADs and hijacking an enhancer from PEG3 to CCDC106 via 3D genome structure remodeling [72]. Additionally, another study conducted a multi-omics analysis and identified seven HPV breakpoint-induced cellular SEs (BP-cSEs) generated by HPV integration within HPV-human hybrid extrachromosomal DNAs, leading to the intra- and inter-chromosomal regulation of genes associated with tumorigenic pathways [73]. The TADs around each BP-cSE changed noticeably, potentially affecting local intra-chromosomal interactions and the transcriptional activities of related genes. These results support the hypothesis that HPV genome interactions with chromatin regulatory factors alter the chromatin structure and promote tumorigenesis. The epigenetic alterations in cervical cancer are shown in Figure 1B.

4.1.1 Photodynamic therapy (PDT)

PDT uses a photosensitizer and specific light wavelengths to produce reactive oxygen species that kill tumor cells and is effective in treating various grades of CIN with high remission and low recurrence rates [133-136]. 5-aminolevulinic acid PDT (ALA-PDT), a second-generation photosensitizer, has shown complete response rates of 93.9% for CIN1, 92.4% for CIN2, and 82.4% for CIN3, with 12-month clearance rates of 86.4%, 85.5%, and 80.4%, respectively [137]. These results suggest that PDT can be recommended for women of childbearing age or for those seeking minimally invasive treatment.

4.1.2 Therapeutic HPV vaccines

Therapeutic vaccine strategies aim to generate T-cell-mediated immunity by specifically targeting HPV E6/E7, which is continuously expressed in infected and cancer cells [138]. VGX-3100, a DNA plasmid-based vaccine, has shown efficacy in eliminating HPV-16/18-associated HSIL and long-term viral clearance [139, 140]. This dual benefit of lesion reduction and viral elimination using VGX-3100 makes it a promising treatment option for HPV-related cervical lesions. PepCan, a peptide-based vaccine, is currently being evaluated in a phase II trial for HSIL (NCT02481414). Larger trials will provide clinical evidence for the use of therapeutic vaccines as noninvasive treatments for cervical precancerous lesions. Notably, an important consideration for therapeutic vaccines is their dependence on an intact immune system, posing potential issues for patients with immunosuppressive diseases, such as organ transplant recipients and HIV+ patients [141].

4.1.3 Gene-editing therapy of HPV integration

With the advent of gene-editing technologies, identifying optimal targets within viral integration sequences, and reducing potential oncogenic risks can reduce the HPV infection load and reverse cervical lesions [142]. Tools such as CRISPR/Cas9 [143-147], transcription activator-like effector nucleases (TALEN) [148], and zinc-finger nucleases (ZFN) [149] offer precise targeting and cleavage of integrated viral sequences, showing promise in preclinical studies for inhibiting malignant phenotypes in HPV-driven cervical carcinogenesis. Furthermore, clinical trials of gene-editing technology, such as TALEN-T512 (NCT03226470, ChiCTR2100042757), are ongoing to evaluate the efficacy and safety of gene-editing techniques for the treatment of HSIL. These findings highlight the potential of gene editing as a targeted therapeutic approach to address persistent HPV infections and associated lesions and represent a significant advancement in HPV-related cancer treatment. Further research is essential to validate these approaches for widespread clinical use.

4.2.1 Minimally invasive surgery (MIS) or open surgery?

In the era of MIS, laparoscopic procedures have gained popularity among gynecologic oncologists and patients. However, the results of several major studies cast doubt on the indications for MIS in cervical cancer. In 2018, the initial results of Laparoscopic Approach to Cervical Cancer (LACC), a global multicenter prospective phase III randomized controlled trial, indicated that compared to open surgery for radical hysterectomy, MIS was associated with a lower rate of overall survival (OS) and a lower disease-free survival (DFS) (3-year OS, 93.8% vs. 99.0%; 4.5-year DFS, 86.0% vs. 96.5%) [152]. Recently, after 4.5 years of follow-up, the final results of this trial were released, showing consistent findings with the initial results (4.5-year OS was 90.6% in the MIS group vs. 96.2% in the open surgery group, respectively) and a higher local recurrence risk in the MIS group (hazard ratio [HR] = 4.70) [153]. This landmark trial resulted in a global sensation. Similarly, findings from a population-based study using the National Cancer Database (NCDB) [154] and a large meta-analysis [155] were consistent with the LACC trial findings of worse oncological outcomes with MIS. These results have led to revised guidelines favoring open surgery, and real-world studies have shown a decline in laparoscopic surgery for cervical cancer since 2018 [156].

Patients often prefer MIS owing to its rapid recovery and reduced complications. A study found that MIS for early-stage cervical cancer is linked to better perioperative outcomes and a lower incidence of postoperative lymphadenitis [157]. However, quality-of-life assessments showed no difference compared to open surgery in the LACC trial [158]. In addition, no statistical difference in complications was reported at 90 days after surgery between the MIS and open surgery groups, although there was a greater proportion in the latter after LACC trial [159]. This evidence aligns with the SUCCOR database analysis [160], which indicates that open surgery does not increase heighten the occurrence of postoperative complications.

Despite the findings of the LACC trial, which should be duly considered owing to its level I evidence, many gynecologic oncologists continue to endorse MIS for specific cases of cervical cancer. Numerous real-world studies have indicated that MIS is safe and effective for early-stage low-risk cervical cancer, particularly for tumors with a diameter of ≤ 2 cm [161-167]. The 2023 guidelines issued by the European Society of Gynaecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP), supported MIS as a potential option for low-risk tumors (with a diameter of less than 2 cm and negative margins after conization), considering it acceptable for lymph node staging [168]. However, these recommendations are mostly based on patients with cervical squamous cell carcinoma, leaving it uncertain whether MIS is available for adenocarcinoma due to its distinct biological background [169]. Although a study has shown no significant differences in DFS and OS when comparing MIS to open surgery for patients with FIGO 2009 stage IB1-IIA2 cervical adenocarcinoma [157], future studies are required to further explore the role of MIS in managing early-stage cervical adenocarcinoma.

Rather than abandoning MIS, surgeons have refined laparoscopic techniques in accordance with tumor-free principles to mitigate poor prognoses. These modifications include avoiding the use of uterine manipulators and vaginal incisions under pneumoperitoneum and thoroughly irrigating the pelvic cavity and vaginal stump before suturing to prevent peritoneal contamination and tumor seeding [170-176]. However, the evidence presented by the LACC trial should not be ignored in favor of earlier level II-III data from smaller retrospective studies when guiding clinical decision making.

In China, where the disease burden is substantial and surgeons are highly skilled in performing laparoscopic procedures, reversion to open surgery may not be optimal. The necessity for additional research to elucidate the mechanisms underlying these contemporary findings and to identify patient subgroups that could benefit from MIS remains critical. Prospective trials focusing on East Asian populations involving large cohorts should be prioritized to provide robust data. Currently, several clinical trials are underway to compare the efficacy of MIS and open radical hysterectomy for cervical cancer, intending to identify patient populations that would derive the greatest benefit from MIS [161, 177–180]. These efforts will be instrumental in refining the surgical guidelines and improving patient outcomes.

4.2.2 Radical surgery or conservational surgery?

The concept of “less is more” in treating esCC prioritizes the enhancement of quality of life while ensuring effective tumor control [181]. Radical trachelectomy with pelvic lymph node dissection has been recognized as a viable and safe option for patients with esCC (Stage IB1-IB2) desiring fertility preservation, especially for tumors smaller than 2 cm [182, 183]. By 2023, there will be a significant shift towards less extensive surgical interventions for low-risk esCC patients, challenging traditional radical surgical treatments. The ConCerv trial, a prospective, single-arm, multicenter study on conservative surgery for low-risk esCC, demonstrated that patients meeting specific criteria could opt for conization [184]. In this trial, low-risk esCC was defined as including no lympho-vascular space invasion (LVSI), negative conization margins, squamous cell carcinoma (any grade) or usual-type adenocarcinoma (grade 1 or 2 only), tumor size ≤ 2 cm, invasion depth ≤ 10 mm, and no metastatic lesions on imaging. Based on these promising results, the 2023 National Comprehensive Cancer Network (NCCN) guidelines recommend conservative surgery for patients meeting the ConCerv criteria. Specifically, cone biopsy with negative margins plus pelvic lymphadenectomy or sentinel lymph node (SLN) mapping is suggested for those wishing to preserve fertility, whereas extrafascial hysterectomy plus pelvic lymph node dissection or SLN mapping is recommended for those without fertility requirements. Additionally, the SHAPE trial results demonstrated that simple hysterectomy had similar prognostic outcomes to radical hysterectomy, with a lower incidence of postoperative urinary complications in low-risk esCC patients, who were defined similarly to the ConCerv criteria [185]. The LESSER trial in Brazil further indicated the efficacy and safety of simple hysterectomy in esCC patients with tumor diameters of less than 2 cm [186]. Based on these findings, discussions with specialists have advocated conservative surgery for esCC, suggesting that, with strict patient evaluation and selection, conservative surgery, including conization and simple hysterectomy, can be a viable option without compromising tumor outcomes [187-190]. Further large-scale clinical trials are necessary to support the broader implementation of conservative surgery for esCC and ensure that this approach can be safely and effectively integrated into clinical practice.

4.3.1 Chemotherapy combined with CCRT

Several decades of development have firmly established the significant role of CCRT in the treatment of laCC through several key trials, from cisplatin monotherapy (GOG64 trial) [193] and the cisplatin-paclitaxel combination chemotherapy (GOG204 trial) [194], to cisplatin-based CCRT (RTOG90-01 trial) [195]. In recent years, research on induction chemotherapy before CCRT has emerged, and its efficacy has been further verified, potentially altering the standard of care for laCCs. The Gynecologic Cancer Inter Group (GCIG) INTERLACE trial, a phase III multicenter randomized controlled trial, found that dose-dense weekly paclitaxel and carboplatin induction chemotherapy followed by CCRT reduced the recurrence risk by 35% and mortality by 39% compared to CCRT alone, with acceptable toxicity of induction chemotherapy and high compliance with radiotherapy [196]. Another study indicated that neoadjuvant chemotherapy (NACT) plus CCRT increased complete response rates (CRR) and reduced distant metastasis rates in laCC patients with tumors larger than 4 cm [197]. Similar findings have been previously reported [198, 199]. These results support the use of induction chemotherapy followed by CRT as a new standard of care. Notably, all these trials used paclitaxel and carboplatin/cisplatin (TC/TP) as NACT regimens. However, a study using cisplatin-gemcitabine in NACT did not show the same benefits and reported challenges in continuing chemotherapy during CCRT, leading to delays in initiating CCRT [200], which may have contributed to the observed inferior outcomes in the NACT group. These results highlight the importance of carefully considering drug toxicity and patient tolerance when selecting NACT regimens, and the combination of paclitaxel and platinum may offer a more suitable option owing to its manageable side effect profile [196-198]. Furthermore, the dose-dense weekly schedule demonstrated in the INTERLACE trial could be well-tolerated by patients and accommodate a short interval between NACT and CCRT, with only a 7-day gap, thus optimizing treatment efficacy and patient compliance [196]. Furthermore, findings from the OUTBACK trial, a multicenter, open-label, randomized phase III trial, revealed that there was no significant difference in the 5-year OS rates between CCRT alone and CCRT followed by adjuvant chemotherapy (71% vs. 72%), but increased short-term toxicity was reported in the CCRT followed by adjuvant chemotherapy group [201]. These findings suggest that adjuvant chemotherapy may not effectively eliminate residual lesions after CCRT in patients with laCC. Together, these findings suggest that using an appropriate chemotherapy regimen, with careful consideration of the interval between chemotherapy and CCRT, as well as the treatment sequence, can enhance the effectiveness of CCRT in patients with laCC. This approach may be particularly suitable for many patients with laCC and can help alleviate the economic burden on LMICs with limited radiotherapy resources. Future research should focus on determining the optimal sequence of chemotherapy and CCRT, and identifying patient subgroups that would benefit the most from specific sequencing strategies.

4.3.2 NACT followed by radical surgery

In the context of NACT combined with surgery for aCC, the current consensus leans against its effectiveness. Although some postoperative improvements have been reported, NACT has not demonstrated significant benefits for OS or PFS. Both the EORTC-55994 study [202] and the Tata Memorial Center study (NCT00193739) [203] for patients with stage IB2-IIB concluded that NACT followed by radical surgery was not superior to CCRT. Recent research suggests that chemotherapy may beneficially remodel the anti-tumor microenvironment (anti-TME) in responsive patients [204], indicating that combining immunotherapy with NACT could be more advantageous before radical surgery. Two recent clinical trials have focused on the clinical response rate to NACT combined with immune checkpoint inhibitors (ICIs) in patients with laCC. The NACI phase II trial demonstrated that adding the anti-PD-1 (anti-programmed cell death protein 1) antibody camrelizumab to platinum-based NACT improved the pathological complete response (pCR) rate in untreated patients with laCC (stage IB3, IIA2, or IIB/IIIC1r), with an objective response rate (ORR) of 98% and a pCR of 38% in the overall population [205]. Preliminary multiomic analysis of samples from patients with pCR demonstrated that NACT induces a state transition to epithelial-immune system, which may contribute to the response to ICIs [206]. Based on these results, a phase III clinical trial comparing neoadjuvant chemo-immunotherapy followed by radical surgery with CCRT is currently underway (NCT04516616). Similarly, another phase II trial, NATIC (ChiCTR2200065392), also supported that the combination of the anti-PD-1 antibody Tislelizumab with NACT is safe and effective in laCC (stage IB3-IIA2), resulting in a pCR of 60.9% and an ORR of 73.9% and reduced rates of postoperative adjuvant therapy (26.1%) and adjuvant radiotherapy (17.4%) [207]. These studies suggest that NACT combined with ICIs could become the standard treatment for resectable laCC, although a longer follow-up is needed to support long-term survival outcomes. Overall, while NACT followed by surgery does not significantly improve survival outcomes for patients with laCC, long-term data are necessary for a comprehensive evaluation of the combined approach of ICIs with NACT.

4.3.3 Target therapy

Bevacizumab is a representative drug that targets vascular endothelial growth factor (VEGF), a key factor in tumor growth and metastasis, and has proven effective in treating cervical cancer. The GOG227 trial in 2009 supported the confirmed tolerability and activity of bevacizumab in second- and third-line (2/3L) treatment for patients with r/mCC [191]. In 2014, another trial, GOG240, established the role of bevacizumab in cervical cancer and was the first phase III clinical study of an anti-angiogenesis targeted therapy for cervical cancer treatment [208]. The preliminary results showed that patients with r/mCC receiving chemotherapy plus bevacizumab had a higher mOS (17.0 months vs. 13.3 months) and an improved ORR (48% vs. 36%) compared to those receiving chemotherapy alone. The results confirmed the benefits of combining bevacizumab and demonstrated the long-term efficacy and tolerability of anti-angiogenic therapy in r/Mcc [208]. The combination of chemotherapy and bevacizumab has become the preferred first-line (1L) treatment option for r/mCC, with single-agent bevacizumab serving as a second-line (2L) alternative [209]. Subsequent clinical trials confirmed the efficacy of bevacizumab combined with platinum-based chemotherapy for aCC [210] and standard pelvic CCRT in laCC [211]. The toxicity and decreased quality of life caused by bevacizumab cannot be ignored, although some studies indicate that patients who discontinue treatment because of toxicity still have longer survival times than those with progressive disease (PD) [212]. Future trials should include supportive care interventions. In addition to bevacizumab, other VEGF/VEGFR inhibitors have been evaluated in patients with aCC in clinical trials. The CIRCCa trial, a randomized, double-blind, placebo-controlled phase II trial, demonstrated significant efficacy when cediranib (a potent tyrosine kinase inhibitor of VEGFR1, 2, and 3) was added to TC chemotherapy, showing a median progression-free survival (mPFS) of 8.1 months versus 6.7 months in the treatment of r/mCC [213]. However, there was no difference in OS between the cediranib and placebo groups, and the treatment was accompanied by an increase in toxic effects. Although cediranib did not benefit treatment-naïve patients, it may be used as an alternative for patients who experience PD after receiving bevacizumab in a previous trial. Further clinical trials focusing on this population of patients treated with cediranib can be developed.

Non-VEGF-dependent angiogenesis inhibitors, such as the angiopoietin axis inhibitors apatinib, trebananib, and anlotinib, as well as vascular-disrupting agents targeting the existing tumor vasculature, are being explored [214]. Apatinib, a novel tyrosine kinase inhibitor targeting tumor angiogenesis, has been indicated as a 2L treatment for patients with aCC, with an ORR of 15.0% [215]. EGFR is one of the most common therapeutic targets for cervical cancer. A phase II trial, MITO CERV-2, evaluated the efficacy of cetuximab (an anti-EGFR monoclonal antibody) combined with TC chemotherapy in the treatment of patients with r/mCC [216]. Although no increased OS was found in all participants, CR was observed in 27% of patients without PIK3CA mutations but in none of the patients with one or more PIK3CA mutations, suggesting a correlation between these mutations and cetuximab resistance. Dual-drug therapy targeting the PI3K/Akt/mTOR and RAS/RAF/MEK/ERK pathways was tested in a phase II trial in recurrent cervical cancer, but the trial was terminated due to discontinuation of drug development, and no survival data have been reported [217]. The feasibility of targeted therapies focusing on these signal transduction pathways relevant to cervical carcinogenesis, as well as homologous recombination deficiency (HRD) and the Notch binary cell fate decision pathway, requires further clinical evidence [218].

4.3.4 Immunotherapy

A pivotal advancement in addressing the therapeutic challenges associated with aCC has been the advent of immunotherapies. The year 2023 witnessed the publication of numerous clinical trials, heralding a new era in aCC treatment. Immunotherapy has been recognized as a groundbreaking modality in contemporary oncology, offering promising avenues for tumor control and, in certain cases, a potential cure [219]. Current immunotherapeutic strategies include ICIs, antibody-drug conjugates (ADCs), and adoptive cell therapy (ACT) [220, 221]. Although pembrolizumab (an ICI) and Tisotumab Vedotin (TV, an ADC) are currently the only immunotherapies approved by the Food and Drug Administration (FDA) for cervical cancer, ongoing research is vigorously exploring additional immunotherapeutic agents and methodologies to enhance the clinical efficacy of immunotherapy in cervical cancer management.

4.4.1 Small cell neuroendocrine cervical carcinoma (SCNCC)

NECC, particularly SCNCC, is a rare but highly aggressive subtype of cervical cancer, accounting for less than 5% of cases [270]. Unlike the local spread observed in cervical squamous cell carcinoma and adenocarcinoma, SCNCC tends to spread early, both locally and distantly, leading to high mortality and poor prognosis. The 5-year DFS rates were 36.8% for FIGO stages I-IIA, 9.8% for stages IIB-IVA, and virtually zero for stage IVB [271, 272]. Currently, specific treatment recommendations for SCNCC are not defined separately in the FIGO and ESGO guidelines. A comprehensive treatment approach involving surgery, chemotherapy, and radiotherapy is recommended [273-275]. However, there is no standard initial treatment for SCNCC at different stages. According to the NCCN guidelines, for early-stage SCNCC (stage IA-IB2), the initial treatment options include surgery, chemoradiation brachytherapy, or NACT depending on the tumor size. Non-surgical methods are primarily recommended as the 1L treatment for locally advanced tumors (stage IB3–IVA).

Although small-sample retrospective studies comparing the prognosis of radical surgery and direct chemoradiation in stage I-II patients have produced inconsistent results [276, 277], a recent large retrospective study involving 1,288 participants from the Surveillance, Epidemiology, and End Results (SEER) registry cohort and a Chinese multi-institutional registry found that surgery is a protective factor in patients with locally advanced SCNCC (stage IB3-IIA2) [278]. This study represents the largest retrospective analysis to date examining the prognostic differences between various treatment regimens in patients with SCNCC. In the absence of high-quality prospective trials, surgery followed by systemic therapy is currently considered the preferred treatment for resectable early-stage SCNCC, including locally advanced disease (IB3-IIA2).

Studies have demonstrated that chemotherapy is crucial in patients with SCNCC. All patients were advised to undergo chemotherapy, including postoperative adjuvant chemotherapy for early-stage disease, NACT for locally advanced disease, and systemic therapy for advanced disease [270]. Etoposide combined with platinum (EP) is the 1L treatment for at least five cycles [279], referenced from small cell lung cancer (SCLC) treatments. In addition to the EP regimen, irinotecan combined with cisplatin (IP) is recommended as 1L treatment for locally advanced SCNCC [271]. Immunotherapy and targeted therapies may also offer benefits, particularly for patients with recurrent or metastatic SCNCC; however, there are no approved targeted therapies for SCNCC. A retrospective analysis showed that the combined topotecan, paclitaxel, and bevacizumab (TPB) regimen in recurrent SCNCC resulted in an mPFS of 7.8 months, compared to 4.0 months in the TB group (P = 0.001), with 23% of patients in the TPB group achieving a CR [280]. Based on this evidence, the NCCN guidelines now recommend the TPB regimen as the 1L treatment for recurrent or metastatic SCNCC. Several other small retrospective studies have also supported a significant improvement in PFS with VEGF inhibitors as 1L or 2L therapy [281, 282]. In the context of SCLC treatment, several key targets in the HR pathway, such as PARP [283], ATR [284], Chk1 [285], and Wee1 [286], have shown promise. These targets have not been reported in SCNCC. However, the prevalence of PARP expression in SCNCC suggests its potential as a therapeutic target [287]. An ongoing phase II clinical trial (NCT04701307) is currently investigating the effectiveness of the PARP inhibitor niraparib in combination with the PD-1 inhibitor dostarlimab for the treatment of recurrent SCLC and other high-grade neuroendocrine carcinomas, including SCNCC. This trial may provide further insights. Upregulation of phosphorylated ATR, Chk1/2, and BRCA1 in the HR pathway has been observed in hrHPV-infected cells [270]. Additionally, SCNCC exhibits three HPV integration modes that activate host oncogenes, which may offer valuable molecular standards for clinical care [288].

Nearly all SCNCC cases are PD-L1 negative and exhibit microsatellite stability (MSI) [287], which requires careful consideration when using ICIs. However, recent studies have suggested that the effectiveness of ICIs is not solely dependent on PD-L1 expression, particularly when used in combination therapies. Results from two phase III clinical trials in patients with SCLC indicated that the addition of PD-1 inhibitors such as atezolizumab and durvalumab to 1L chemotherapy significantly improved OS and PFS [289, 290]. As a result, the NCCN guidelines also recommend combining EP with atezolizumab/durvalumab as 1L therapy for patients with recurrent/metastatic SCNCC. Small preliminary studies and case reports on previously treated patients with SCNCC have shown encouraging results with nivolumab combined therapy or monotherapy, as well as ACT, whereas pembrolizumab monotherapy exhibited limited antitumor activity [291-295]. Further trials are required to validate the efficacy of combination therapies in a larger patient population.

4.4.2 GCA

The International Endocervical Adenocarcinoma Criteria and Classification (IECC), introduced in 2018, categorized cervical adenocarcinomas into two main groups based on HPV status and morphology: HPV-associated cervical adenocarcinomas (HACA) and non-HPV-associated cervical adenocarcinomas (NHACA) [296]. Notably, NHACA displays unique morphological and molecular traits, resulting in poor prognosis and presenting different potential targets for future therapies. This subtype is frequently detected at an advanced stage, partly because of its reliance on HPV testing for cervical cancer screening, leading to higher rates of lymph node metastasis and reduced prognosis. Currently, treatment strategies for cervical cancer are not differentiated based on HPV status, and there is a paucity of evidence supporting distinct therapeutic approaches for NHACA. Clinicians generally adhere to the treatment protocols for stage-matched cervical adenocarcinomas.

GCA is the most prevalent subtype of NHACA and the second most common cervical adenocarcinoma, accounting for approximately 10% [297]. NGS analyses have identified frequent TP53 and STK11 mutations in GCA [298, 299]. Notably, STK11 mutations are closely associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by mucocutaneous pigmentation and gastrointestinal polyposis [298]. Studies have indicated that 11%-17% of female patients with PJS develop GCA, and approximately 50% of patients with GCA also present with PJS [300, 301]. This underscores the significant role of genetic susceptibility in GCA pathogenesis. At diagnosis, 40% to 100% of GCA patients are in stages II to IV, with 75% demonstrating distant metastases [297, 302]. Even at stage I, GCA is associated with a poor prognosis, as evidenced by a 5-year survival rate of only 42%, in stark contrast to the 91% observed in usual-type cervical adenocarcinoma [297]. GCA has exhibited primary resistance to both chemotherapy and radiotherapy and locally advanced GCA may not respond optimally to CCRT, highlighting the imperative need for novel therapeutic strategies [303, 304]. Molecular genetic analyses revealed that 14.7% of GCA cases exhibited ERBB2 amplification, suggesting that HER2-targeted therapies may be beneficial [305, 306]. Clinical outcomes for patients with ERBB2 alterations treated with trastuzumab have been promising, paralleling experiences with HER2-positive endometrial, breast, and gastric cancers [307, 308]. Moreover, Claudin-18.2 (CLDN18.2) in GCA can be as high as 65%, indicating its potential as a therapeutic target [308]. Zolbetuximab, a pioneering monoclonal antibody targeting CLDN18.2, has been investigated for 1L treatment in patients with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma [309, 310]. Although specific therapeutic outcomes for cervical cancer have not been published, it is plausible to anticipate that zolbetuximab could offer substantial clinical benefits to patients with CLDN18.2-positive GCA.