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Biomarkers for Treatment Prediction, Prognosis and Early Detection of Gynecologic Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: 15 December 2025 | Viewed by 13742

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Special Issue Editors

Dr. Brian S Finkelman

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Guest Editor

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Interests: cancer biomarkers; HER2; endometrial cancer; breast cancer; gynecologic cancer; prediction modeling; prognostic risk-stratification

Dr. Rachelle P Mendoza

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Guest Editor

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Interests: gynecology; cytology; pathology; oncology; placenta

Dr. Hani Katerji

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Guest Editor

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Interests: breast cancer; gynecologic cancer; prognostic and predictive breast and gynecologic cancer biomarkers

Special Issue Information

Dear Colleagues,

Biomarkers play an essential role in the early detection, prognosis, and prediction of treatment response in cancer. Biomarkers are based on qualitative and/or quantitative assessment of biomolecules, such as DNA, RNA, and proteins. Biomarker detection can be performed on a variety of tissue samples, including tumor tissue derived from biopsies or surgical specimens, as well as less invasive samples such as blood, cervical Pap smears, and vaginal secretions, among others.

In gynecologic cancers—including cancers of the uterine corpus, uterine cervix, fallopian tube, ovary, vagina, and vulva—biomarkers have increased in clinical relevance in recent years. For instance, molecular testing for high-risk subtypes of human papilloma virus (HPV) has transformed cervical cancer screening, while testing for HER2 expression has recently increased therapy options for some patients with endometrial serous carcinoma.

This Special Issue of Cancers encompasses new research articles and up-to-date reviews on all aspects of biomarkers and their relationship to treatment prediction, prognosis, and early detection of gynecologic cancer. Special attention will be given to submissions with clinical relevance.

Dr. Brian S Finkelman
Dr. Rachelle P Mendoza
Dr. Hani Katerji
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

biomarkers
endometrial cancer
uterine cancer
cervical cancer
ovarian cancer
vulvar cancer
treatment prediction
prognosis
early detection

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Published Papers (10 papers)

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Research

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19 pages, 828 KiB

Open AccessArticle

Clinical Application of Next-Generation Sequencing for Molecular Classification in the Management of Endometrial Cancer: An Observational Cohort Study

by Sabrina Paratore, Angela Russo, Giusi Blanco, Katia Lanzafame, Eliana Giurato, Giovanni Bartoloni, Marco D’Asta, Mirella Sapienza, Valeria Solarino, Valentina Vinci, Giulia Maria Bonanno, Giuseppe Ettore and Roberto Bordonaro

Cancers 2025, 17(11), 1806; https://doi.org/10.3390/cancers17111806 - 28 May 2025

Abstract

Background/Objectives: Endometrial cancer (EC) is the most common malignancy of the female genital tract. In 2013, The Cancer Genome Atlas analyzed the molecular profile of endometrial tumors identifying four risk classes (POLE ultramutated, mismatch repair-deficient, copy-number low-microsatellite stable, and copy-number high-serous-like. This classification is reshaping the current understanding of EC, enabling more refined risk stratification and uncovering potential therapeutic targets tailored to specific molecular subgroups. In the context of these four categories, it is possible to identify different molecular alterations that correlate with different prognoses. Methods and Results: We retrospectively analyzed tissue samples from eighty-five EC patients, performing multigene profiling using a 50-gene next-generation sequencing (NGS) panel to categorize them into distinct molecular subtypes; we observed the following distribution: 5.9% POLE, 25.8% mismatch repair-deficient/microsatellite instability (MMRd/MSI), 11.8% p53abn/TP53mut, and 56.5% NSMP. A favorable concordance (97.6%) was shown in MSI NGS-based analysis and MMR IHC results, and the agreement rate of p53 IHC and TP53 mutation was 92.3%. When we analyzed the correlation between molecular subtypes and clinicopathological features, we found that molecular subtypes significantly differentiated by grade, FIGO stage, and lymphovascular invasion (LVSI). These findings seem to support the effectiveness of our NGS-based classifier and its reliability in distinguishing both MSI and TP53 mutated cancers. This study also explored mutations in PIK3CA, PTEN, KRAS, ERBB2, and ESR1 genes, noting their potential as targets for treatments. PIK3CA mutations were linked to favorable features, such as early disease stage and absence of LVSI. Conclusions: Our study highlights the potential of a medium-complexity NGS panel for supporting the molecular classification of endometrial cancer, complementing the existing diagnostic algorithms. By identifying additional biomarkers, we provided valuable insights into the genomic landscape of EC. However, further exploration of the molecular profiles is needed to validate these findings and improve the identification of patients at a higher risk of unfavorable outcomes. Full article

(This article belongs to the Special Issue Biomarkers for Treatment Prediction, Prognosis and Early Detection of Gynecologic Cancer)

12 pages, 1827 KiB

Open AccessArticle

Correlation Between Intravascular Platelet Aggregation in Tumors and Hypoxia-Inducible Factor 1 Alpha Expression in Epithelial Ovarian Cancer: Implications for Prognosis and Staging

by Jung Min Ryu, Yoon Young Jeong, Sun-Jae Lee and Youn Seok Choi

Cancers 2025, 17(3), 345; https://doi.org/10.3390/cancers17030345 - 21 Jan 2025

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Abstract

Background/Objectives: This study aimed to evaluate the association between intravascular platelet aggregation in tumors and ovarian carcinoma prognosis and investigate underlying mechanisms. Methods: A retrospective analysis was conducted on 144 patients with ovarian carcinoma. Immunohistochemical staining for CD42b, hypoxia-inducible factor-1α (HIF-1α), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) was performed using tissue microarrays to assess intravascular platelet aggregation. Staining grades ranged from 1 to 3 for CD42b (platelet aggregation or microthrombus) and 0 to 3 for HIF-1α, PDGF, and VEGF. Results: Among the patients, 25 (17.4%) had grade 1 (no platelet aggregation), 85 (59.0%) had grade 2 (platelet aggregation), and 34 (23.6%) had grade 3 (microthrombus). The grade of intravascular platelet aggregation in ovarian carcinoma was statistically significantly associated with a poor prognosis (p = 0.037). In addition, in patients with more advanced stages of ovarian cancer, higher levels of intravascular platelet aggregation were observed. Additional analysis revealed a correlation between platelet aggregation and HIF-1α expression (correlation coefficient = 0.226, p= 0.006), while PDGF and VEGF showed no significant correlations. Conclusions: Intravascular platelet aggregation in tumors is associated with advanced stages and poor prognosis in ovarian carcinoma. The results of our study suggest a potential association with hypoxia induced by intravascular platelet aggregation in ovarian carcinoma. Full article

(This article belongs to the Special Issue Biomarkers for Treatment Prediction, Prognosis and Early Detection of Gynecologic Cancer)

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12 pages, 2014 KiB

Open AccessArticle

Expression of CK17 and SOX2 in Vulvar Intraepithelial Neoplasia: A Comprehensive Analysis of 150 Vulvar Lesions

by Nikki B. Thuijs, Féline O. Voss, Patricia C. Ewing-Graham, Shatavisha Dasgupta, Johannes Berkhof, Johan Bulten, Koen van de Vijver and Maaike C. G. Bleeker

Cancers 2024, 16(23), 3966; https://doi.org/10.3390/cancers16233966 - 26 Nov 2024

Viewed by 840

Abstract

Background: Recently, the immunohistochemical markers cytokeratin 17 (CK17) and SRY-box2 (SOX2) have been evaluated as adjuncts for the diagnosis of high-grade vulvar intraepithelial neoplasia (VIN). In the present study, the aim was to assess CK17 and SOX2 expression in VIN by studying 150 vulvar lesions, originally reported as high-grade VIN and to assess the diagnostic accuracy. Methods: All slides (H&E, p16^INK4a, p53, Ki-67, CK17, and SOX2 stains) were independently assessed by six pathologists and the final diagnosis was reached in consensus meetings, as follows: 46 human papillomavirus (HPV)-independent VIN (including 30 p53 mutant and 16 p53 wild-type lesions), 58 high-grade squamous intraepithelial lesions (HSILs), 4 low-grade SILs (LSILs), 37 non-dysplastic lesions, and 5 lesions where the histology was inconclusive. Results: CK17 positivity was observed in 100% p53 wild-type HPV-independent VIN, compared to 73% p53 mutant HPV-independent VIN, 14% HSILs, 0% LSILs, and 24% non-dysplastic lesions. SOX2 positivity was observed in 13% p53 wild-type HPV-independent VIN, 43% p53 mutant HPV-independent VIN, 2% HSILs, 0% LSILs, and 3% non-dysplastic lesions. The highest diagnostic accuracy (89%) for HPV-independent VIN was obtained when combining p53 and CK17 immunohistochemistry. The addition of SOX2 did not further increase diagnostic accuracy. Conclusion: To conclude, aside from p53, both CK17 and SOX2 can be of value for reaching an accurate diagnosis of HPV-independent VIN. Full article

(This article belongs to the Special Issue Biomarkers for Treatment Prediction, Prognosis and Early Detection of Gynecologic Cancer)

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13 pages, 4467 KiB

Open AccessArticle

ZNF281 Facilitates the Invasion of Cervical Cancer Cell Both In Vivo and In Vitro

by Ye Chong, Kun Zhang, Yuting Zeng, Qian Chen, Qian Feng, Nan Cui, Pengsheng Zheng, Litao Ruan and Wei Hua

Cancers 2024, 16(21), 3717; https://doi.org/10.3390/cancers16213717 - 4 Nov 2024

Cited by 1 | Viewed by 1215

Abstract

Background: Cervical cancer is the fourth most common cancer among women worldwide. The zinc finger transcription factor 281 (ZNF281)/ZBP-99 protein specifically binds to GC-rich DNA sequences and regulates gene expression, and it has been shown to promote tumor progression. In this study, we aim to investigate the function and molecular mechanism of ZNF281 in uterine cervical carcinoma. Methods: We conducted immunohistochemistry and Western blot assays to determine the expression of ZNF281 in eight human cervical cancer tissues. And, xenograft experiments involving the injection of HeLa cells into nude mice was used to determine the function of ZNF281 on proliferation. Transwell assays were used to detect the migration and invasion of HeLa cells after indicated that ZNF281 overexpression. Results: Our results indicated that ZNF281 protein levels were higher in cervical cancer tissues compared to normal cervical tissues. Additionally, ZNF281 was expressed in human cervical carcinoma cell lines, including HeLa, SiHa, C-33 A, CaSki, and HT-3, and is localized in both the cell nucleus and cytoplasm. ZNF281 overexpression did not influence HeLa cell proliferation or tumor size in situ. Moreover, nude mice injected with ZNF281-overexpressing cell lines developed more tumor lesions in the lungs compared to those injected with control cell lines. Conclusions: These findings suggest that ZNF281 is associated with tumor metastasis without affecting cell proliferation, both in vivo and in vitro. Full article

(This article belongs to the Special Issue Biomarkers for Treatment Prediction, Prognosis and Early Detection of Gynecologic Cancer)

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11 pages, 2070 KiB

Open AccessArticle

Analysis of Clinicopathological and Molecular Features of Microcystic, Elongated, and Fragmented Pattern Invasion in Endometrioid Endometrial Cancer

by Xiaobo Zhang, Bo Han and Danhua Shen

Cancers 2024, 16(20), 3555; https://doi.org/10.3390/cancers16203555 - 21 Oct 2024

Viewed by 1518

Abstract

Background: Microcystic, elongated, and fragmented (MELF) invasion is a special invasion pattern in endometrioid endometrial cancer (EEC). This study aimed to investigate the clinical, pathological, and molecular features of the MELF pattern and its prognostic value in patients with EEC. Materials and Methods: The clinical and pathological data of 342 patients with EEC were retrospectively collected at Peking University People’s Hospital from January 2019 to December 2022. Some key clinicopathological features were evaluated, including the tumor grade, Federation of Gynecology and Obstetrics (FIGO) staging, cervical stromal involvement, lymph node status, and lymphatic vascular space infiltration (LVSI). Immunohistochemical staining and molecular tests were performed, and the relevant literature was reviewed. Results: The MELF pattern was more prevalent in low-grade EEC. A significant correlation was found between the MELF pattern and advanced FIGO staging, LVSI, the depth of myometrial invasion, cervical stromal involvement, and lymph node metastasis (LNM). The incidence of mismatch-repair-deficient (MMRd) proteins was much higher in the MELF group than in the no-MELF group. Molecular testing revealed that, after copy number—low (CNL), microsatellite instability—high (MSI-H) was the second-most frequent subtype in the MELF group. The recurrence risk did not significantly differ between the MELF and no-MELF groups, but the differences among the four molecular subtypes were statistically significant. However, the MELF group experienced a shorter recurrence time. Among the four molecular subtypes, the recurrence risk was the highest in the CNH subgroup, followed by the MSI-H subgroup. Conclusions: MELF is a special invasion pattern in EEC and is associated with distinct clinicopathological and molecular characteristics, including the latest 2023 FIGO staging. Further research is warranted to explore its implications for treatment strategies and patient outcomes. Full article

(This article belongs to the Special Issue Biomarkers for Treatment Prediction, Prognosis and Early Detection of Gynecologic Cancer)

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11 pages, 1279 KiB

Open AccessArticle

Isotopic Composition of C, N, and S as an Indicator of Endometrial Cancer

by Tomasz Zuzak, Anna Bogaczyk, Agnieszka Anna Krata, Rafał Kamiński, Piotr Paneth and Tomasz Kluz

Cancers 2024, 16(18), 3169; https://doi.org/10.3390/cancers16183169 - 16 Sep 2024

Cited by 1 | Viewed by 1220

Abstract

Objectives: The metabolic pathway of cancerous tissue differs from healthy tissue, leading to the unique isotopic composition of stable isotopes at their natural abundance. We have studied if these changes can be developed into diagnostic or prognostic tools in the case of endometrial cancer. Methods: Measurements of stable isotope ratios were performed using isotope ratio mass spectrometry for nitrogen, carbon, and sulfur isotopic assessment. Uterine tissue and serum samples were collected from patients and the control group. Results: At a natural abundance, the isotopic compositions of all three of the studied elements of uterus cancerous and healthy tissues are different. However, no correlation of the isotopic composition of the tissues with that of serum was found. Conclusions: Differences in the isotopic composition of the tissues might be a potential prognostic tool. However, the lack of a correlation between the differences in the isotopic composition of the tissues and serum seems to exclude their application as diagnostic biomarkers, which, however, might be possible if a position-specific isotopic analysis is performed. Full article

(This article belongs to the Special Issue Biomarkers for Treatment Prediction, Prognosis and Early Detection of Gynecologic Cancer)

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11 pages, 1751 KiB

Open AccessArticle

Ascites and Serum Interleukin-10 Levels as a Prognostic Tool for Ovarian Cancer Outcomes

by Paul Adrien Guigue, Yoav Brezinov, Amber Yasmeen, Maroua Mbarik, Shannon Salvador, Susie Lau, Walter Henri Gotlieb and Melica Nourmoussavi Brodeur

Cancers 2024, 16(16), 2840; https://doi.org/10.3390/cancers16162840 - 14 Aug 2024

Cited by 1 | Viewed by 1270

Abstract

Interleukin-10 (IL-10) has been shown to be present at high levels in the ascites of ovarian cancer (OC) patients; however, little is known about its prognostic value. We sought to correlate IL-10 levels in ascites and sera of OC patients with clinicopathologic characteristics and oncologic outcomes. IL-10 levels and clinical data from biobanked ascites and serum samples of OC patients were evaluated. Receiver operating characteristic curves were used to quantify marker performance and identify IL-10-high and IL-10-low groups. Correlations between IL-10 levels and clinicopathologic data were performed. Survival outcomes were calculated, while the factors affecting them were also investigated. A total of 106 patients had ascites samples, of which 44 serum samples were also available. Mean ascites IL-10 levels were significantly higher in patients with serous histology compared to endometrioid histology (p = 0.024). Fold-change in ascites IL-10 during treatment positively correlated with clinical response, as determined by a change in serum cancer antigen (CA)-125 levels (p = 0.0126). Median progression-free survival (PFS) and overall survival (OS) were shorter in patients with high compared with low ascites IL-10 levels (PFS: 18 versus 60 months; p = 0.007, OS: 42 versus 85 months; p = 0.029). A significant positive correlation was seen between ascites and sera IL-10 levels (p = 0.019). In multivariable analyses, a high ascites IL-10 level was associated with a significantly worse prognosis (PFS hazard ratio (HR) = 1.93; p = 0.02). Patients with high ascites levels of IL-10 have worse outcomes, which are likely reflective of the immunosuppressive effect of IL-10. This highlights its potential role as an immunomodulator in the tumor microenvironment, leading to OC immune evasion. Full article

(This article belongs to the Special Issue Biomarkers for Treatment Prediction, Prognosis and Early Detection of Gynecologic Cancer)

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12 pages, 1517 KiB

Open AccessArticle

Expression of Potential Antibody–Drug Conjugate Targets in Cervical Cancer

by Michael R. Mallmann, Sina Tamir, Katharina Alfter, Dominik Ratiu, Alexander Quaas and Christian M. Domroese

Cancers 2024, 16(9), 1787; https://doi.org/10.3390/cancers16091787 - 6 May 2024

Viewed by 2459

Abstract

(1) Background: There is a huge unmet clinical need for novel treatment strategies in advanced and recurrent cervical cancer. Several cell membrane-bound molecules are up-regulated in cancer cells as compared to normal tissue and have revived interest with the introduction of antibody–drug conjugates (ADCs). (2) Methods: In this study, we characterize the expression of 10 potential ADC targets, TROP2, mesotheline, CEACAM5, DLL3, folate receptor alpha, guanylatcyclase, glycoprotein NMB, CD56, CD70 and CD138, on the gene expression level. Of these, the three ADC targets TROP2, CEACAM5 and CD138 were further analyzed on the protein level. (3) Results: TROP2 shows expression in 98.5% (66/67) of cervical cancer samples. CEACAM5 shows a stable gene expression profile and overall, 68.7% (46/67) of cervical cancer samples are CEACAM-positive with 34.3% (23/67) of cervical cancer samples showing at least moderate or high expression. Overall, 73.1% (49/67) of cervical cancer samples are CD138-positive with 38.8% (26/67) of cervical cancer samples showing at least moderate or high expression. (4) Conclusions: TROP2, CEACAM5 or CD138 do seem suitable for further clinical research and the data presented here might be used to guide further clinical trials with ADCs in advanced and recurrent cervical cancer patients. Full article

(This article belongs to the Special Issue Biomarkers for Treatment Prediction, Prognosis and Early Detection of Gynecologic Cancer)

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22 pages, 2705 KiB

Open AccessArticle

Circulating Adipocytokines and Insulin Like-Growth Factors and Their Modulation in Obesity-Associated Endometrial Cancer

by Irene Ray, Carla S. Möller-Levet, Agnieszka Michael, Simon Butler-Manuel, Jayanta Chatterjee, Anil Tailor, Patricia E. Ellis and Lisiane B. Meira

Cancers 2024, 16(3), 531; https://doi.org/10.3390/cancers16030531 - 26 Jan 2024

Cited by 3 | Viewed by 2023

Abstract

The rising global incidence of uterine cancer is linked to the escalating prevalence of obesity. Obesity results in alterations in adipocytokines and IGFs, driving cancer progression via inflammation, increased cell proliferation, and apoptosis inhibition, although the precise mechanisms are still unclear. This study examined a set of six markers, namely, adiponectin, leptin, IL6, TNFα, IGF1, and IGF2 and compared them between fifty age-matched endometrial cancer patients (study group) and non-cancer patients with benign gynaecological conditions (control group). We also assessed the relationship of these markers with obesity and explored the correlation between these markers and various tumour characteristics. In the cancer population, these markers were also assessed 24 h and 6 months post-surgery. Remarkably, low adiponectin levels were associated with a 35.8% increase in endometrial cancer risk. Interestingly, compared to control subjects where IGF levels decreased after menopause, post-menopausal women in the study group showed elevated IGF1 and IGF2 levels, suggesting a potential influence of endometrial cancer on the IGF system, particularly after menopause. Lastly, it is noteworthy that a discernible inverse relationship trend was observed in the levels of adipocytokines and IGFs 6 months post-surgery. This indicates that treatment for endometrial cancer may have a differential impact on adipocytokines and IGFs, potentially holding clinical significance that merits further investigation. Full article

(This article belongs to the Special Issue Biomarkers for Treatment Prediction, Prognosis and Early Detection of Gynecologic Cancer)

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18 pages, 1606 KiB

Open AccessReview

Insulin-like Growth Factor 1 (IGF1) and Its Isoforms: Insights into the Mechanisms of Endometrial Cancer

by Abdul Muzhill Hannaan Abdul Hafizz, Norfilza Mohd Mokthar, Reena Rahayu Md Zin, Nigel P. Mongan, Mohd Nazzary Mamat @ Yusof, Nirmala Chandralega Kampan, Kah Teik Chew and Mohamad Nasir Shafiee

Cancers 2025, 17(1), 129; https://doi.org/10.3390/cancers17010129 - 3 Jan 2025

Viewed by 1561

Abstract

Endometrial cancer (EC) is a common gynaecological malignancy associated with metabolic dysfunctions such as obesity, diabetes and insulin resistance, as well as hormonal imbalances, particularly involving oestrogen and progesterone. These factors disrupt normal cellular metabolism, heightening the risk of developing endometrioid EC (EEC), the most prevalent subtype of EC. The insulin-like growth factor-1 (IGF1) pathway, a key regulator of growth, metabolism, and organ function, is implicated in EC progression. Recent research highlights the distinct roles of IGF1 isoforms, including IGF1-Ea, IGF1-Eb, and IGF1-Ec, in promoting tumour growth, metastasis, and hormone signalling interactions, particularly with oestrogen. This review examines the function and clinical significance of IGF-1 isoforms, emphasising their mechanisms in gynaecological physiology and their contributions to EC pathogenesis. Evidence from other cancers further underscores the relevance of IGF1 isoforms in driving tumour behaviours, offering valuable insights into their potential as biomarkers and therapeutic targets. Understanding these mechanisms provides opportunities for novel approaches to the prevention, diagnosis, and treatment of EC, improving patient outcomes and advancing the broader field of hormone-driven cancers. Full article

(This article belongs to the Special Issue Biomarkers for Treatment Prediction, Prognosis and Early Detection of Gynecologic Cancer)

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