DNA-Based Liquid Biopsy for Evaluating Surgical and Postsurgical Outcomes in Gynecologic Malignancies: A Systematic Review.

1
Introduction
Liquid biopsy refers to a minimally invasive diagnostic technique that involves the analysis of circulating biomarkers, such as, circulating tumor cells (CTCs), cell‐free DNA (cfDNA), and exosomes, present in bodily fluids, primarily blood [1]. Unlike traditional tissue biopsies, liquid biopsies can be performed repeatedly with minimal discomfort, providing real‐time insights into tumor biology and dynamics. This innovative approach holds significant potential for early cancer detection, monitoring disease progression, and assessing therapeutic responses [2]. Among these, DNA‐based liquid biopsy approaches, particularly those examining ctDNA and cfDNA, have shown promise in diagnosing, monitoring, and predicting outcomes in various diseases [3]. DNA‐based analyses can detect tumor‐specific mutations, alterations in methylation patterns, and changes in copy number variations (CNVs), offering potential for early relapse detection and treatment resistance assessment [4]. Gynecologic malignancies encompass a range of cancers affecting the female reproductive organs, including ovarian, endometrial, and cervical cancers. These cancers pose substantial health challenges due to their often‐late diagnosis and complex treatment requirements [5]. Ovarian cancer, known for its poor prognosis, is frequently diagnosed at advanced stages [6]. Endometrial cancer, the most common gynecologic malignancy, generally has a better prognosis but still presents diagnostic and therapeutic challenges [7]. Cervical cancer, largely preventable through vaccination and screening, remains a significant health burden, especially in low‐resource settings. Effective management of these malignancies necessitates accurate diagnostic tools and reliable methods for monitoring treatment efficacy and disease recurrence [8]. Liquid biopsies offer a transformative approach to managing gynecologic malignancies by enabling the detection of surgical and post‐surgical outcomes with high precision [9]. Pre‐surgical liquid biopsy analyses can aid in determining tumor burden and guiding surgical planning [10]. Post‐surgical assessments through liquid biopsy can identify residual disease and early signs of recurrence, providing critical information for timely intervention. Furthermore, liquid biopsies can monitor treatment response and disease progression over time, facilitating personalized treatment strategies and potentially improving patient outcomes [11]. This study aims to explore the application of liquid biopsy in the detection of surgical and post‐surgical outcomes in gynecologic malignancies. By reviewing recent advancements and clinical applications, we seek to evaluate the effectiveness of liquid biopsy, specifically CTCs and cfDNA in predicting surgical success, identifying residual disease, and monitoring recurrence in patients with ovarian, endometrial, and cervical cancers. Our goal is to highlight the potential of liquid biopsies to revolutionize the management of gynecologic malignancies, ultimately improving patient care and prognosis through more accurate and timely diagnostic methods.

2
Material and Methods
2.1
Study Design
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines [12]. The objective of this review was to evaluate the effectiveness of DNA‐based liquid biopsy techniques, including circulating tumor DNA (ctDNA) and cell‐free DNA (cfDNA), in assessing surgical and postsurgical outcomes in patients diagnosed with gynecologic malignancies, which encompass cervical, ovarian, uterine, vaginal, and vulvar cancers.

2.2
PICO Framework
To systematically address the research question, we utilized the PICO framework, which stands for Population, Intervention, Comparison, and Outcomes:
Population (P): Patients diagnosed with gynecologic malignancies, specifically those with cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, vaginal cancer, and vulvar cancer who underwent or will undergo surgery.

Intervention (I): The use of DNA‐based liquid biopsy techniques, particularly focusing on circulating ctDNA and cfDNA.

Comparison (C): While the review does not focus on direct comparisons between interventions, studies included assessed the effectiveness of ctDNA and cfDNA in evaluating surgical outcomes, postoperative outcomes, residual disease, and minimal residual disease in comparison to standard monitoring techniques.

Outcomes (O): The primary outcomes of interest are surgical outcomes, postsurgical outcomes, postoperative outcomes, and the presence of residual disease or minimal residual disease as assessed by DNA‐based liquid biopsy techniques.

2.3
Searching Strategy
A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science databases until May, 2, 2025 to identify relevant studies. The search aimed to include articles examining the role of DNA‐based liquid biopsies, specifically ctDNA and cfDNA, in assessing surgical or postsurgical outcomes in gynecologic malignancies. The search query is outlined in Table 1.

2.4
Eligibility Criteria
Studies included in this review were selected based on predetermined criteria. The inclusion criteria consisted of peer‐reviewed articles published in English that examined the relationship between ctDNA and cfDNA and surgical or postsurgical outcomes in patients with gynecologic malignancies. This encompassed original research articles. The exclusion criteria comprised review articles, editorials, conference papers, case reports/series and commentaries, as well as studies that did not focus on DNA‐based liquid biopsy or lacked data on surgical or postsurgical outcomes.
Two independent reviewers screened the titles and abstracts of the articles retrieved from the search to determine their eligibility based on the established criteria. Full‐text articles were obtained for further evaluation for studies that met the inclusion criteria. In instances of discrepancies, discussions were held to reach a consensus, with a third reviewer consulted as necessary to resolve conflicts.

2.5
Data Extraction
Data extraction was conducted using a standardized form to collect essential information from each included study. The extracted data included study characteristics, such as reference, year, country, study design, and sample size. Details on cancer type, type of liquid biopsy (ctDNA or cfDNA), and biopsy sample were documented, along with information on the specific surgical interventions involved. Biopsy timing (pre‐surgical or post‐surgical) was noted, and key findings were summarized. Additionally, outcomes assessments related to postsurgical metrics, including recurrence rates, survival, and residual disease status were recorded.

2.6
Quality Assessment
The quality of the included cohort studies was evaluated using the Newcastle‐Ottawa Scale (NOS), which assesses methodological rigor across three domains: Selection, Comparability, and Outcome. In the Selection domain, studies were examined for representativeness, appropriateness of the comparison group, accurate measurement of exposure, and confirmation that outcomes were not present at baseline to establish a clear temporal relationship. In the Comparability domain, control for key confounders, such as cancer stage and patient demographics, was assessed, and points were awarded for adequate adjustments. The Outcome domain evaluated the reliability of outcome assessment methods, sufficiency of follow‐up duration, and completeness of follow‐up, with points assigned for adequate observation periods and minimal attrition. Each study received a total score out of nine, with higher scores indicating stronger methodological quality. Studies were categorized as low, moderate, or high quality, providing a basis for evaluating the strength of evidence across the included studies. To evaluate the quality of the included case–control studies, we used the NOS. This tool assesses methodological quality across three domains: selection of study groups (4 items), comparability of cases and controls (1 item), and ascertainment of exposure (3 items). Each item is awarded a star if the study meets predefined quality standards, with a maximum possible score of nine stars indicating the highest quality and lowest risk of bias.

2.7
Data Synthesis and Analysis
A narrative synthesis of the findings was performed to summarize the collective evidence regarding the role of DNA‐based liquid biopsies in evaluating surgical and postsurgical outcomes in gynecologic malignancies.

3
Results
3.1
Searching Strategy
A systematic search was conducted using PubMed, Scopus, and Web of Science databases, yielding 416 records: 167 from PubMed, 136 from Scopus, and 113 from Web of Science. After removing 177 duplicate records, 239 unique studies underwent screening. During title/abstract screening, 135 records were excluded due to irrelevance, leaving 104 studies for full‐text retrieval. One report could not be retrieved, resulting in 103 studies assessed for eligibility. Of these, 71 records were excluded: one was non‐English, and 70 were review articles, book chapters, conference papers, or case reports, which did not meet inclusion criteria. Ultimately, 32 studies were included in the final analysis. This rigorous process ensured only the most relevant studies, aligned with predefined criteria, were incorporated into the review (Figure 1).

3.2
Bibliographic Analysis
Between 2017 and 2025, a total of 32 observational studies of gynecologic malignancies were published, encompassing 3210 patients (n = 3210). The research timeline spans a nine‐year period (2017–2025), with the earliest cohort reports appearing in Italy and Australia in 2017 and the most recent multi‐center and case–control series emerging in 2025. Studies were conducted across 19 countries, but repeat contributions came predominantly from the United States (n = 6 studies), China (n = 5), Spain (n = 3), Canada (n = 3), South Korea (n = 2), and Germany (n = 2), underscoring sustained research capacity and collaborative networks in these regions. Nine distinct cancer classifications were examined across these 32 studies. Endometrial cancer was the most frequently studied subtype (n = 9 studies, 28.1%), followed by epithelial ovarian cancer (n = 7, 21.9%), broadly defined ovarian cancer (n = 6, 18.8%), and serous ovarian cancer (n = 4, 12.5%). Mixed endometrial/ovarian cohorts accounted for n = 2 studies (6.2%), while advanced epithelial ovarian cancer, Stage II–IV ovarian cancer, Stage I endometrial cancer, and uterine cancer each appeared in n = 1 study (3.1% apiece). When patients are summed by cancer type, endometrial cancers comprised the largest group (n = 1233), followed by general ovarian cancer cohorts (n = 683) and epithelial ovarian cancer studies (n = 447). Serous ovarian cancer investigations enrolled 470 patients, while the two mixed endometrial/ovarian cohorts together included (n = 88). Smaller series addressed advanced epithelial ovarian cancer (n = 66), Stage I endometrial cancer (n = 101), Stage II–IV ovarian cancer (n = 31), and uterine cancer (n = 91) (Figure 2).

3.3
Quality Assessment
The methodological quality of the 31 cohort studies included in this review was assessed using the NOS, with scores ranging from 5 to 9 out of a possible 9 stars and a median score of 7. This range reflects considerable variability in methodological rigor, with particular strengths in exposure definition and outcome confirmation balanced by recurrent limitations in control selection and confounder adjustment.
Three studies [13, 14, 15] achieved the maximum score of 9 out of 9 stars. These studies demonstrated excellence across all NOS domains, including representativeness of the exposed cohort, appropriate selection of non‐exposed controls, rigorous exposure ascertainment, confirmation of outcome absence at baseline, comprehensive comparability adjustments for key confounders, standardized outcome assessment, sufficient follow‐up duration, and complete follow‐up reporting. An additional eight studies [16, 17, 18, 19, 20, 21, 22, 23] scored 8 out of 9 stars, indicating similarly robust design and reporting but with one domain—most often comparability or non‐exposed cohort selection—rated slightly lower. Seventeen studies (55%) scored 6 or 7 stars, reflecting moderate quality. These studies generally provided clear definitions of exposure and appropriately confirmed the absence of the outcome at baseline; however, they frequently lacked a detailed description of the non‐exposed comparison groups and often adjusted for only a single confounder rather than multiple key variables. Only five of these studies received the full two stars for comparability. Three studies [24, 25, 26] scored 5 out of 9 stars and exhibited notable weaknesses such as incomplete follow‐up reporting, inadequate non‐exposed cohort selection, and, in one case, missing ascertainment of exposure or outcome domains. Across all included studies, the most consistent strengths were in the representativeness of the exposed cohorts, the ascertainment of exposure, and the standardized assessment of outcomes during follow‐up. Every study clearly confirmed that participants were free of the outcome at study entry, minimizing baseline selection bias in that respect. Nevertheless, the selection of non‐exposed cohorts was inadequately described in more than half of the studies, which may have introduced selection bias. While the duration of follow‐up was generally adequate, nine studies (29%) did not fully report the completeness of follow‐up, and a few had follow‐up periods that may have been too short to capture longer‐term outcomes. Although the majority of studies demonstrated moderate to high methodological quality—with three studies achieving perfect 9/9 ratings and eight others scoring 8/9—recurring limitations in non‐exposed cohort selection, incomplete adjustment for potential confounders, and occasional gaps in follow‐up reporting should be considered when interpreting the cumulative evidence of this systematic review (Table 2, Figure 3). Only one study employed a case–control design and received a moderate quality rating of 5 out of 9 stars on the Newcastle‐Ottawa Scale. Its strengths included a clear case definition, consistent exposure assessment methods, and complete follow‐up. However, limitations were noted, such as the use of hospital‐based controls, absence of confounder adjustment, and potential bias due to non‐blinded exposure assessment [44].

3.4
DNA‐Based Liquid Biopsy for Surgical and Postsurgical Outcome Assessment in Gynecologic Malignancies: Prognostic and Predictive Insights
This systematic review analyzes 32 studies on the application of DNA‐based liquid biopsies, including cell‐free DNA (cfDNA) and circulating tumor DNA (ctDNA), for assessing surgical and postsurgical outcomes in gynecologic malignancies. Liquid biopsies are increasingly valued for their non‐invasive approach to capturing real‐time tumor dynamics, offering critical insights into prognosis, recurrence, and treatment efficacy. The synthesis of these studies is organized into three primary themes, including predicting recurrence and patient prognosis, monitoring surgical outcomes and treatment response, and enhancing diagnostic accuracy through pre‐surgical assessments. These themes reflect the diverse yet complementary roles that liquid biopsies play in the continuum of care for patients with gynecologic cancers, underscoring their utility in both early and advanced stages of disease management.
3.4.1
Recurrence Prediction and Prognosis
Several studies emphasize the prognostic value of ctDNA and cfDNA for recurrence risk across different gynecologic cancers. In endometrial cancer, Recio et al. [27] demonstrated that ctDNA‐positive patients had notably higher recurrence rates, with ctDNA positivity associated with significantly worse recurrence‐free survival (RFS). This finding aligns with Liu et al. [28], who reported that post‐surgical ctDNA positivity in endometrial cancer had high predictive accuracy for recurrence at 1 and 2 years (AUCs of 0.87–0.89). Similarly, Jamieson et al. [30] observed a high recurrence risk in patients with persistent ctDNA postoperatively, further highlighting ctDNA's value in predicting outcomes. In a multicenter prospective cohort of 83 endometrial cancer patients, Lindemann et al. [13] found pre‐operative ctDNA positivity in 19.3% of cases; these patients experienced higher recurrence rates (37.5% vs. 11.9%) and significantly reduced 24‐month disease‐free survival (61.4% vs. 87.6%). CtDNA positivity independently predicted recurrence (HR = 5.49, p = 0.010) and disease‐specific death (HR = 7.04), underscoring its strong prognostic utility.
In ovarian cancer, Kallio et al. [29] found that detectable ctDNA after surgery predicted faster progression and reduced overall survival, with ctDNA recurrence detection preceding standard imaging methods in some cases. Heo et al. [19] also identified persistent ctDNA mutations as a predictor of poor prognosis, with a significantly higher hazard ratio (HR = 10.7). Furthermore, in studies by Zhu et al. [32] and Dobilas et al. [24], higher post‐surgical ctDNA levels were linked to increased recurrence risk, with ctDNA serving as a marker of residual disease in patients with serous ovarian cancer. For endometrial cancer, Casas‐Arozamena et al. [31] showed that elevated combined cfDNA/ctDNA levels were associated with a high recurrence risk group, suggesting the combined biomarker approach may strengthen recurrence predictions.
In a retrospective study of stage II–IV ovarian cancer patients, Shu et al. [16] reported 100% MRD positivity pre‐treatment and a drop to 25.8% post‐treatment; persistent MRD positivity post‐therapy correlated with markedly shorter progression‐free survival (5.8 vs. 24.7 months, HR = 6.678, p = 0.01), highlighting ctDNA‐based MRD as a powerful predictor of relapse. Jamieson et al. [15] evaluated 44 patients with mixed gynecologic malignancies and detected preoperative ctDNA in 27% (6/24 endometrial, 6/17 ovarian). Advanced disease was more common in ctDNA+ patients (67% vs. 29%), and 62% of those who relapsed remained ctDNA+ post‐operatively, supporting ctDNA's role in early relapse prediction.
Preoperative cfDNA levels were also found to have prognostic value. In ovarian cancer, Hou et al. [36] reported that pre‐surgical ctDNA positivity predicted relapse better than CA125, while Feng et al. [39] demonstrated that ctDNA sensitivity and specificity were high for relapse detection. Additionally, studies on endometrial cancer, such as by Lukasiewicz et al. [38] and Bolivar et al. [42], observed correlations between high ctDNA levels and advanced stage, suggesting ctDNA's prognostic role even before surgery. Zhang et al. [22] assessed 107 epithelial ovarian cancer patients and showed that post‐surgical MRD ctDNA positivity was significantly associated with relapse (HR = 3.4). CtDNA outperformed CA125 for relapse prediction (AUC 0.78 vs. 0.66), with a PPV of 0.62 and NPV of 0.83, further validating its prognostic superiority (Table 3, Figure 4).

3.4.2
Monitoring Surgical Outcomes and Treatment Response
Liquid biopsies have also been instrumental in assessing surgical efficacy and tracking treatment response. Multiple studies found ctDNA levels effective in monitoring residual disease and response to surgical intervention. For instance, in ovarian cancer patients, Heitz et al. [37] demonstrated that ctDNA mutation allele frequency (MAF) measurements after surgery more accurately reflected tumor burden than CA125 or HE4, particularly in patients achieving complete tumor resection. Hou et al. [36] also showed that ctDNA was a superior indicator of recurrence over CA125, with 100% sensitivity and specificity in detecting relapse.
Glueck et al. [14] conducted a prospective cohort in 66 advanced epithelial ovarian cancer patients, finding ctDNA detectable in 96% pre‐operatively and 81% at day 10 post‐surgery. In those with residual disease, median ctDNA was 367.38 copies/mL (2.84% VAF) and increased post‐operatively in 7/8 patients. In contrast, patients without residual disease saw a drop to 0.92 copies/mL (0.017% VAF) in 17/19 cases. These dynamics underscore ctDNA's utility for real‐time surgical outcome assessment. Van den Berg et al. [17] applied cfDNA methylation profiling (MeD‐seq) in 49 epithelial ovarian cancer cases undergoing primary or interval debulking; their perioperative analysis suggested methylation signatures not only distinguished advanced disease from healthy controls but also reflected surgical impact and possibly host immune response.
In studies focused on treatment monitoring, Jamieson et al. [30] noted that ctDNA levels cleared in patients before CA125 normalization, suggesting earlier detection of treatment response. Similarly, in a study by Christie et al. [43], recurrent ovarian cancer cases displayed ctDNA‐based reversion mutations linked to platinum resistance, providing insights into chemotherapy response and potential for personalized treatment adjustments. Meanwhile, Han et al. [40] reported concordance between plasma and ascites ctDNA, supporting ctDNA's utility in comprehensive molecular monitoring (Table 3, Figure 4).

3.4.3
Diagnostic Accuracy for Pre‐Surgical Assessments
In the diagnostic realm, several studies have shown that cfDNA and ctDNA can enhance the detection of malignancy pre‐surgery. Vanderstichele et al. [20] reported that nucleosome footprinting of cfDNA was useful in distinguishing invasive ovarian carcinoma from benign or borderline cases (AUC = 0.81). In another ovarian cancer study, Zhang et al. [18] found that a cfDNA‐based decision tree model, combining cfDNA with CA125, achieved a high diagnostic accuracy (AUC = 0.98), supporting its potential for distinguishing malignant from benign tumors preoperatively. Rajaram et al. [44] compared preoperative plasma cfDNA in ovarian tumor cases and found mean cfDNA levels of 1330 ± 1705.4 ng/mL in malignant versus 748.5 ± 444.8 ng/mL in benign and 448.5 ± 203.9 ng/mL in borderline tumors. Higher cfDNA correlated with advanced‐stage and high‐grade serous carcinoma, and fair concordance was observed between cfDNA p53 mutations and tissue p53 status.
Additional studies on endometrial cancer highlighted similar findings. In Casas‐Arozamena et al. [41], high cfDNA and ctDNA levels in uterine aspirates effectively differentiated high‐risk tumors, while in Cicchillitti et al. [26], cfDNA levels were higher in patients with aggressive endometrial cancer grades. These results suggest cfDNA's potential role in preoperative risk assessment. Likewise, Braicu et al. [21] observed that the CNI‐score from cfDNA was highly specific and sensitive for primary epithelial ovarian cancer, proving useful in detecting both primary and recurrent cases with a pre‐surgical diagnostic focus. Jamieson et al. [15] also reported pre‐surgical ctDNA detection in 27% of mixed gynecologic malignancies, with a higher positivity rate among advanced cases (35% in ovarian vs. 25% in endometrial), reinforcing ctDNA's role in preoperative stratification (Table 3, Figure 4).

4
Discussion
This systematic review highlights the growing role of DNA‐based liquid biopsies, specifically ctDNA and cfDNA, in predicting surgical and postsurgical outcomes for gynecologic malignancies. The 25 studies included in this review collectively underscore the clinical utility of liquid biopsies as non‐invasive biomarkers that offer significant insights into prognosis, recurrence, and treatment monitoring across various gynecologic cancers, including endometrial, ovarian, and uterine cancers.
Liquid biopsies, particularly those utilizing ctDNA and cfDNA, have gained traction as minimally invasive diagnostic tools for evaluating surgical and post‐surgical outcomes in cancer treatment, including gynecologic malignancies. Studies have demonstrated that liquid biopsies hold promise in detecting minimal residual disease and in tracking tumor dynamics, offering the potential for early intervention and improved patient management [45]. By capturing tumor DNA through non‐invasive methods, these tests reduce the need for repeat tissue biopsies and enable real‐time monitoring, aligning with a growing emphasis on precision medicine [46]. A recent study highlights how ctDNA can be used to detect recurrence early, allowing clinicians to adjust postoperative care based on molecular signs of cancer recurrence. This approach improves patient outcomes by informing treatment plans without additional surgical procedures, showcasing the utility of liquid biopsies in refining post‐surgical management and reducing invasive follow‐ups [47]. By providing a snapshot of the tumor's molecular profile, liquid biopsies might help surgeons make better pre‐operative decisions, potentially lowering the risk of adverse outcomes. Integrating liquid biopsies into pre‐surgical planning can improve precision by identifying molecular indicators that could predict surgical success or complications [48].
The results of this study illustrate that ctDNA and cfDNA are promising tools for predicting recurrence and long‐term survival outcomes. For instance, studies have shown that ctDNA positivity post‐surgery is associated with a higher risk of recurrence and shorter disease‐free survival across endometrial and ovarian cancers. This finding aligns with similar prognostic studies in solid tumors, where ctDNA levels have shown high sensitivity in detecting minimal residual disease and predicting recurrence earlier than conventional imaging techniques. Importantly, ctDNA appears to have a high predictive accuracy in these cancers, suggesting that liquid biopsies may serve as early indicators for patients at increased recurrence risk. This early prediction could allow clinicians to identify high‐risk patients and consider adjuvant therapies more promptly, potentially improving patient outcomes.
Several studies emphasized the capacity of ctDNA and cfDNA to monitor surgical effectiveness and treatment response, with ctDNA levels reflecting tumor burden more accurately than traditional markers such as CA125 in ovarian cancer. The results from studies where ctDNA was monitored pre‐ and post‐surgery suggest that ctDNA dynamics correlate closely with tumor reduction, underscoring its value as a marker of residual disease. This is particularly beneficial in gynecologic cancers, where complete cytoreduction is crucial for improved outcomes. By tracking ctDNA levels over time, clinicians can better assess the success of surgery and gauge the need for further intervention. Additionally, the ability of liquid biopsies to detect response to chemotherapy offers a compelling alternative for ongoing surveillance, potentially reducing the reliance on repeated imaging and allowing for more personalized treatment adjustments.
This review also found evidence supporting the diagnostic utility of liquid biopsies for pre‐surgical assessments, with cfDNA and ctDNA contributing to distinguishing malignant from benign cases. Studies using cfDNA levels and methylation patterns before surgery demonstrated good accuracy in risk stratification, which could help tailor surgical planning. Enhanced diagnostic accuracy before surgery may not only facilitate early intervention but also guide clinicians in selecting appropriate therapeutic strategies, particularly for high‐risk cases that may benefit from more aggressive approaches.
Despite these promising findings, certain limitations exist in the current body of research on DNA‐based liquid biopsies in gynecologic cancers. Quality assessments using the NOS revealed that although most studies were of moderate to high quality, variability existed in the adjustment for confounding factors and follow‐up adequacy. The lack of consistent adjustment for factors such as age, tumor stage, and treatment history could potentially influence outcomes. Moreover, while ctDNA and cfDNA demonstrated strong predictive capacities, variations in study protocols, including differences in liquid biopsy sampling time points and methods of DNA quantification, may limit direct comparisons across studies.
Furthermore, it is important to note specific biological and technical limitations of liquid biopsies. The study by Lindemann and colleagues [13] found that preoperative ctDNA was only detected in 19% of patients, meaning that in 81% of cases ctDNA was not detectable despite the presence of disease. This highlights a sensitivity limitation that may hinder the diagnostic accuracy of liquid biopsies, particularly for patients with low tumor burden or early‐stage disease. Such limitations can also affect the reliability of methylation analysis and mutation profiling, potentially leading to incomplete molecular characterization of tumors. Additionally, issues such as low ctDNA shedding, variability in cfDNA background levels, and challenges in distinguishing tumor‐derived DNA from normal cfDNA remain unresolved hurdles. Future challenges in this field include improving detection sensitivity, enhancing standardization of molecular assays, and addressing cost‐effectiveness concerns before liquid biopsies can be fully integrated into routine clinical practice [49, 50].
To fully realize the clinical potential of DNA‐based liquid biopsies in gynecologic malignancies, future studies should focus on standardizing methodologies, particularly around sampling frequency, collection protocols, and DNA analysis methods. Additionally, more longitudinal studies with larger sample sizes and diverse populations are needed to validate the prognostic and diagnostic value of ctDNA and cfDNA across different stages of gynecologic cancers. There is also a need to explore the integration of liquid biopsy data with other clinical markers and imaging results to enhance decision‐making frameworks for personalized treatment.

5
Conclusion
Overall, this review supports the potential of DNA‐based liquid biopsies as a valuable tool for assessing surgical and postsurgical outcomes in gynecologic malignancies. The ability of ctDNA and cfDNA to predict recurrence, assess treatment response, and provide diagnostic insights pre‐surgery marks a significant advancement in personalized oncology. With further research and validation, these non‐invasive biomarkers may offer a more comprehensive and real‐time approach to managing gynecologic cancers, ultimately improving patient outcomes and facilitating tailored treatment approaches.

Funding
The authors declare that no funds, grants, or other support was received during the preparation of this manuscript.

Ethics Statement
The authors have nothing to report.

Consent
The authors have nothing to report.

Conflicts of Interest
The authors declare no conflicts of interest.