Open Access

Molecular biomarkers for facilitating genome‑directed precision medicine in gynecological cancer (Review)

  • Authors:
    • Takeo Minaguchi
    • Ayumi Shikama
    • Azusa Akiyama
    • Toyomi Satoh
  • View Affiliations

  • Published online on: August 17, 2023
  • Article Number: 426
  • Copyright : © Minaguchi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Prominent recent advancements in cancer treatment include the development and clinical application of next‑­generation sequencing (NGS) technologies, alongside a diverse array of novel molecular targeting therapeutics. NGS has enabled the high‑speed and low‑cost sequencing of whole genomes in individual patients, which has opened the era of genome‑based precision medicine. The development of numerous molecular targeting agents, including anti‑VEGF antibodies, poly (ADP‑ribose) polymerase inhibitors and immune checkpoint inhibitors, have all improved the efficacy of systemic cancer therapy. Accumulating bench and translational research evidence has led to identification of various cancer‑related biomarker profiles. In particular, companion diagnostics have been developed for some of these biomarkers, which can be clinically applied and are now widely used for guiding cancer therapies. Selecting biomarkers accurately will improve therapeutic efficacy, avoid overtreatment, enable earlier diagnosis and reduce the cost of preventing and treating gynecological cancer. Therefore, biomarkers are fast becoming indispensable tools in the practice of genome‑directed precision medicine. In the present review, the current evidence of cancer‑related biomarkers in the field of gynecological oncology, their molecular interpretations and future perspectives are outlined. The aim of the present review is to provide potentially useful information for the formulation of clinical trials.


Notable advancements that have been encountered in the field of cancer treatment over the preceding decades include the development of next-generation sequencing (NGS) technologies and the clinical application of various molecularly-targeting therapeutics. NGS has enabled the high-speed and low-cost sequencing of whole genomes in individual patients, which opened the era of genome-based precision medicine (1). In addition, the development of numerous molecular targeting agents, such as anti-VEGF antibodies, multikinase inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint blockers has improved the efficacy of systemic cancer therapy by combining with conventional chemotherapeutics and with different types of targeting agents (2). This improvement in efficacy has even been observed for patients with advanced or metastatic tumors with inflamed phenotypes (2). Accumulating research evidence has led to the detailed elucidation of a number of oncogenic signaling pathways, e.g. cell cycle regulation, apoptotic signaling, kinase signaling, DNA damage response, DNA mismatch repair, and immune checkpoint signaling, resulting in the identification of a variety of cancer-associated biomarkers. Cancer-associated biomarkers can in turn be utilized for a number of specific purposes, including predicting patient prognosis, predicting tumor response to chemotherapeutic and molecular targeting agents, early diagnosis or prevention of cancer and aiding precise diagnoses. In addition, companion diagnostics have been developed using some of the biomarker profiles, which can be applied clinically and are now becoming widely utilized for guiding cancer treatment (3). These include BRACAnalysis (Myriad Genetics), myChoice (Myriad Genetics) and FoundationOne CDx (Foundation Medicine) (3). Selecting the appropriate biomarkers are predicted to improve treatment efficacy, avoid overtreatment and reduce the cost of preventing and treating gynecological malignancies, rendering biomarkers essential tools in precision medicine. In the present review, current evidence of cancer-related biomarkers in the gynecological oncology field was summarized. This will be based on findings extracted from clinical trials, their molecular interpretations and future perspectives.

Biomarkers for predicting patient prognosis

Biomarkers used for predicting prognosis prior to commencing treatment are expected to be beneficial for stratifying patients based on the recurrence risks, to designate the optimal combination of treatment modalities and therapeutics.

Endometrial cancer (EC)

ECs were conventionally classified into two groups, type I and II, based on clinicopathological, epidemiological and endocrinological features (4). Type I EC is characterized by low-grade endometrioid histology and tend to more frequently develop in younger and obese women. In addition, the pathogenesis of this type of EC is associated with unopposed estrogen, superficial myometrial invasion, early stage at diagnosis and favorable prognosis. By contrast, type II EC is characterized by high-grade, non-endometrioid histology, tend to occur in older and more slender-shaped women, deep myometrial invasion, advanced stages and poorer prognosis. Commonly mutated genes in type I tumors include PTEN, PI3K catalytic subunit α, KRAS, AT-rich interactive domain-containing protein 1A and β-catenin 1, whilst TP53 is more frequently mutated in type II tumors (5). This dualistic classification system has been pivotal for understanding this entire disease entity in terms of EC pathogenesis. However, this categorizing model is considered incomplete, due to intergroup overlapping caused by tumor diversity and heterogeneity (5).

In 2013, molecular analyses of 232 endometrial carcinomas by The Cancer Genome Atlas (TCGA) program on the results of exome sequencing, microsatellite instability (MSI) testing and microarray of somatic copy number alterations resulted in the proposal of classifying EC into four genomic categories. They are POLE-ultramutated [1], microsatellite instability hypermutated [2], copy-number low [3] and copy-number high [4], each showing distinct progression-free survival (PFS) profiles (6). Of note, POLE is a catalytic subunit of DNA polymerase ε, which is involved in nuclear DNA replication and repair.

In 2015, a more clinically applicable, cost-effective classification system, named ‘ProMisE’, was developed using the same TCGA data and applied it to a new cohort of cases (7). The four categories of POLE-mutated [POLE exonuclease domain mutation (EDM) was determined by sequencing] [1], p53 wild-type [2], DNA mismatch repair deficiency [determined by immunohistochemistry (IHC) testing of MutL homolog 1 (MLH1), MutS homolog (MSH)2, MSH6 and postmeiotic segregation increased 2 (PMS2)] [3] and p53 abnormal (p53 status was determined by p53 IHC) [4] revealed significantly different overall (OS; P=0.0082, n=141), disease-specific (P=0.0378, n=139) and recurrence-free survival (RFS; P=0.0358; n=133; Fig. 1).

In 2017, the ProMisE molecular classification system was confirmed in a large cohort of 319 EC samples, showing distinct OS (P<0.0001), disease-specific (P<0.0001) and PFS (P<0.0001) (8). In particular, the POLE EDM group had the most favorable outcome, whereas the p53 abnormal group had the worst outcome. To conclude, using these genome-based risk factors to stratify the patients into the various adjuvant therapeutic regimens may improve treatment outcome and reduce overtreatment. However, prospective studies, such as PORTEC-4a (Molecular Profile-based Versus Standard Adjuvant Radiotherapy in Endometrial Cancer; NCT03469674) and TAPER (Tailored Adjuvant Therapy in POLE-mutated and p53-wildtype Early Stage Endometrial Cancer; NCT04705649), are currently on-going, from which additional results are expected (9,10).

Biomarkers for predicting tumor response to chemo-therapeutic and molecular targeting agents

Biomarkers used for predicting the efficacy of systemic therapeutics are expected to be useful, especially for advanced or aggressive tumors, where localized therapies alone are insufficient.

Ovarian cancer

The majority of ovarian cancer cases are diagnosed already at advanced stages and chemosensitivity is one of its most important prognostic factors. NGS was previously performed on 393 patients with ovarian carcinoma who received primary surgery. They were also prospectively followed-up for survival analysis. Multivariate logistic regression on 281 high-grade serous carcinoma (HGSC) cases adjusted for germline or somatic BRCA mutations, age at diagnosis, optimal cytoreduction and neoadjuvant chemotherapy was performed. It was found that the presence of any TP53 mutations were associated with platinum sensitivity, which was defined as time to progression after the completion of adjuvant platinum chemotherapy (odds ratio, 0.41; 95% confidence interval, 0.17–0.99; P=0.048) (11). This observation suggests that the presence of TP53 mutations may predict platinum sensitivity in patients with HGSC.

The PARP inhibitor olaparib was previously evaluated in a phase I trial in 60 refractory solid tumors (12). An expansion cohort of this trial was studied further in patients with ovarian cancer harboring germline breast cancer gene (BRCA)1/2 mutations, revealing significant associations between platinum-free interval and the maximal % tumor response rate after olaparib treatment (radiological change, P=0.001, n=38; cancer antigen 125 change, P=0.002, n=46) (13). This finding suggests that platinum sensitivity of patients with germline BRCA1/2 mutations may predict the response to PARP inhibitors.

The efficacy of maintenance olaparib therapy was also evaluated by the PAOLA-1 phase 3 trial, which compared olaparib treatment with placebo in patients with newly diagnosed stage III/IV ovarian cancer who showed a response to first-line platinum-taxane plus bevacizumab followed by maintenance bevacizumab (14). The hazard ratio (HR; 95% CI) for disease progression or death for olaparib vs. placebo was 0.33 (0.25–0.45) in homologous-recombination deficiency (HRD)-positive tumors and 1.00 (0.75–1.35) in HRD-negative tumors. Tumor HRD status was determined by Miriad myChoice CDx testing, which is designed based on germline/somatic BRCA1/2 mutations and/or positive genomic instability scores using DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissues. This finding suggests that HRD positivity can be used to predict the efficacy of adding maintenance PARP inhibitors into the primary treatment strategy for advanced ovarian cancer.

The safety and activity of niraparib monotherapy was evaluated by the QUADRA phase 2 trial in patients with relapsed high-grade serous ovarian cancers treated with ≥3 chemotherapy regimens (15). In patients whose tumors were platinum-sensitive to the most recent line of platinum therapy (n=105), the overall response rate was 26% in HRD-positive tumors compared with 4% in HRD-negative or unknown tumors. HRD status was also determined using the Miriad myChoice CDx testing. This finding suggests that HRD positivity can also be applied to predict the effectiveness of PARP inhibitor monotherapy for patients with recurrent platinum-sensitive serous ovarian cancer.


The PORTEC-3 is a phase III trial that investigated the benefit of chemoradiotherapy compared with radiotherapy alone for high-risk endometrial cancer (endometrioid G3 stage IA with lymphovascular space invasion; endometrioid G3 stage IB; endometrioid stage II–III; and non-endometrioid stage I–III) (16). Using tissue samples from this trial, the prognostic value of a molecular classification system similar to ProMisE (7) was evaluated. Significant improvement in the RFS was found with the addition of adjuvant chemotherapy to radiotherapy for p53 abnormal tumors (5-year RFS, 59 vs. 36%; P=0.019; n=93) (17). p53 status was evaluated by IHC and if applicable, the TP53 mutational status was also analyzed by NGS. This finding suggests that the p53 mutational status can be used to predict tumor chemosensitivity or enhancing effect of radiosensitivity by chemotherapy in patients with high-risk EC.

KEYNOTE-028 is a phase Ib trial in patients with programmed death ligand 1 (PD-L1)-positive advanced solid tumors, including EC, who were treated with the anti-programmed cell death 1 (PD-1) monoclonal antibody pembrolizumab. Data from this trial found that higher response rates and longer PFS are significantly associated with higher T-cell-inflamed gene-expression profile (GEP), PD-L1 expression and tumor mutational burden (TMB; T-cell-inflamed GEP, P=0.012 and 0.017, n=203; PD-L1, P=0.018 and 0.005, n=198; TMB, P=0.018 and 0.051, n=77) (18). T-cell inflamed GEP was evaluated based on the normalized expression values of 18 selected genes using RNA extracted from FFPE tumor tissues (19). PD-L1 expression was evaluated by IHC, which was used to calculate the combined positive score [CPS; the number of PD-L1-positive cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells ×100]. TMB was assessed by whole-exome sequencing using DNA isolated from the FFPE tissues. This finding suggests that higher T-cell-inflamed GEP, PD-L1 expression and/or TMB may predict the efficacy of pembrolizumab in advanced EC.

The KEYNOTE-158 phase II trial assessed pembrolizumab monotherapy in previously treated, advanced but incurable solid tumors (n=790), including EC (n=82). TMB was evaluated in FFPE tumor tissues using the FoundationOne CDx assay (20). TMB-high was defined as ≥10 mutations per megabase. The response rates of TMB-high and TMB-low groups were found to be 29 vs. 6%, suggesting that TMB can be used to predict the efficacy of pembrolizumab in patients with previously treated, advanced EC.

The KEYNOTE-775 phase III trial assessed the efficacy of lenvatinib, a multikinase inhibitor of VEGFR1-3 and other receptor tyrosine kinases, combined with pembrolizumab or chemotherapy, in 827 patients with advanced EC who had previously received ≥ one platinum-based chemotherapy regimen (21). PFS was found to be longer in the lenvatinib plus pembrolizumab group compared with that in the lenvatinib plus chemotherapy group in both mismatch repair (MMR) proficient (HR, 0.60; 95% CI, 0.50–0.72; P<0.001) and in all patients (HR, 0.56; 95% CI, 0.47–0.66; P<0.001). In addition, OS was longer with in the lenvatinib plus pembrolizumab group compared with that in the lenvatinib plus chemotherapy group in both MMR proficient (HR, 0.68; 95% CI, 0.56–0.84; P<0.001) and all patients (HR, 0.62; 95% CI, 0.51–0.75; P<0.001). MMR status was determined by IHC staining of MLH1, MSH2, MSH6 and PMS2 proteins. These results suggest that lenvatinib plus pembrolizumab is efficacious for advanced EC irrespective of the MMR status. However, it should be noted that lenvatinib was discontinued due to drug-related adverse events in 22.7% of the patients, where the most frequent grade ≥3 adverse event was hypertension (37.9%) and was clinically significant for lenvatinib (21). Accordingly, considering the results of tumor assessment in terms of MSI/MMR status, T-cell-inflamed GEP and PD-L1 expression, coupled with using TMB for predicting pembrolizumab efficacy, may still be important even for this regimen in case of switching to pembrolizumab monotherapy.

Cervical cancer

KEYNOTE-826 phase III trial assessed the efficacy of pembrolizumab compared with placebo in 617 patients with persistent, recurrent or metastatic cervical cancer who were also receiving platinum-based chemotherapy with or without bevacizumab. PFS (P<0.001) and OS (P<0.001) were found to be significantly longer with pembrolizumab compared with those in placebo (22). The HR (95% CI) for disease progression or death were 0.94 (0.52–1.70) for PD-L1 CPS <1, compared with 0.68 (0.49–0.94) for CPS 1 to <10 and 0.58 (0.44–0.77) for CPS ≥10. Likewise, the HR for death were 1.00 (0.53–1.89) for PD-L1 CPS <1, compared with 0.67 (0.46–0.97) for CPS 1 to <10 and 0.61 (0.44–0.84) for CPS ≥10. These findings suggest that PD-L1 expression can be used to predict the efficacy of adding concurrent pembrolizumab to chemotherapy in persistent, recurrent or metastatic cervical cancer.

Biomarkers for the early diagnosis/prevention of cancer

Biomarkers that can facilitate the early diagnosis or prevention of cancer are expected to enable the provision of an optimal cost-effective and ideal healthcare plan.

Cervical cancer

High risk (HR)-human papilloma virus (HPV) DNA genotyping is more sensitive compared with cytology, rendering them useful for long-term risk prediction. By contrast, cytology has high specificity (apart from atypical squamous cells of undetermined significance) and is useful for estimating immediate risk, but has lower sensitivity and lower negative predictive value compared with HR-HPV DNA genotyping (23). HPV 16 or 18 infections have the highest risk of cervical intraepithelial neoplasia (CIN) 3 and occult cancer development, requiring colposcopy with targeted biopsy even when cytology results turn out negative (24).

Cyclin-dependent kinase inhibitor 2A (p16 INK4A) is a cyclin-dependent kinase inhibitor that can inhibit cyclin-dependent kinases 4 and 6, inducing G1 cell cycle arrest. Degradation of the tumor suppressor retinoblastoma (Rb) protein by the HR-HPV oncoprotein E7 and E2F upregulation result in a feedback loop, leading to the increased expression of p16 (25). p16 IHC staining has been reported to be 86.7% sensitive and 82.8% specific for ≥CIN 2 (CIN 2 or worse) diagnoses, rendering this useful for distinguishing high-grade CIN from ≤CIN 1 (26). When p16 staining is combined with H&E staining, the sensitivity for high-grade CIN is increased by 13%, decreasing the false-negative rate by 50% (27).

Ovarian cancer

Hereditary breast and ovarian cancer (HBOC) is an autosomal dominant hereditary cancer predisposition syndrome that is caused by pathogenic germline BRCA1/2 variants. The life-time risk for developing ovarian cancer in individuals harboring BRCA1 mutations is 39–48%, compared with 11–20% in those harboring BRCA2 mutations (2831). To date, an effective screening method for improving the survival rate of ovarian cancer has remained elusive (3236). Women with HBOC are recommended to receive risk-reducing salpingo-oophorectomy (RRSO), which has been shown to reduce mortality according to results from large-population prospective studies (37,38). Specifically, RRSO reduced mortality in individuals with BRCA1 mutations aged 35–40 years and in individuals with BRCA2 mutations aged 40–45 years. This appeared to be due to later ovarian cancer onset in carriers of BRCA2 mutations compared with their BRCA1 counterparts (37), after childbearing age (39). Serous tubal intra-epithelial carcinoma (STIC) is an early precursor for high-grade serous carcinoma of fallopian tube origin and is incidentally found in RRSO specimens (4042). Coupling IHC results of p53 and Ki-67 with histological morphology has been found to improve the reproducibility of successfully pathologically diagnosing STIC (43). Ki-67 is a nuclear non-histone protein that is expressed during the G1, S and G2 phases, with peak expression at the M phase of the cell cycle but is typically absent at the G0 phase (44).


Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition condition. It is diagnosed by the presence of germline pathogenic variants in one of the MMR genes MLH1, MSH2, MSH6, PMS2 and epithelial cell adhesion molecule (45). LS is screened by MMR IHC and/or MSI testing on tumor tissues (46,47), specifically the loss of MLH1, MSH2, MSH6 and PMS2 expression (47). Detection of the loss MLH1 expression is followed by MLH1 promoter methylation testing, where the presence of its hypermethylation would be deemed as a sporadic tumor instead of LS (47,48). MSI testing is conducted by comparing the PCR amplicons of microsatellite repeats in the tumor and those in the corresponding normal control. The life-time risks of developing colorectal cancer and EC in women with LS are 30–52 and 28–60%, respectively (4953). However, although risk-reducing surgery for preventing EC in women with LS can reduce the incidence (54), it has not been reported to reduce mortality (55).

Molecular interpretations

BRCA1, BRCA2, BRCA1-associated RING Domain 1, RAD51, BRCC36, BRCC45 etc. make up the BRCA1/BRCA2-containing complex (BRCC), which is involved in the homologous recombination-mediated repair of DNA double-strand breaks (Fig. 2) (56,57). Tumors with the loss of heterozygosity in either the BRCA1 or 2 gene correspondingly show defects in repairing double-strand DNA breaks, and are sensitive to inhibitors of PARP1, an enzyme that contributes to repairing single-strand DNA breaks, by causing the synthetic lethality of tumor cells. Tumors with HRD tend to show genomic instability, accumulate DNA damage, undergo cell cycle arrest and apoptosis in a wild-type p53-dependent manner, which is pivotal for the DNA damage response (5860). Acquisition of p53 aberrations, which appear to be an early and requisite event during BRCA-related carcinogenesis (61,62), overcomes cell cycle arrest and circumvents apoptosis, causing dysregulated proliferation (5860). p53 dysfunction also causes defects in DNA damage repair, leading to sensitivity to DNA-damaging chemotherapeutics, such as platinum agents.

Tumors with MMR deficiency show high MSI and TMB, which promotes the T-cell inflammatory phenotype and activation of the PD1/PD-L1-mediated immune checkpoint pathway (Fig. 3) (63). These tumors are sensitive to immune checkpoint inhibitors, such as anti-PD1 antibodies. Endometrial carcinomas with POLE mutations can be treated by surgery alone, leading to favorable prognoses. Surgery alone also avoids the need of overtreatment to maintain a good quality of life (QOL). By contrast, endometrial carcinomas with p53 aberrations tend to have the worst prognosis. They may be treated with conventional adjuvant therapies based on clinicopathological risk factors or pembrolizumab plus lenvatinib, combined with surgery.

Persistent infection with high-risk HPVs causes cervical carcinogenesis due to the chronic overexpression of viral oncoproteins E6 and E7, which degrade and inactivate tumor suppressors p53 and Rb, respectively. This in turn regulates a variety of cellular functions, such as apoptosis, cell cycle arrest, DNA damage response, immune system response, differentiation, transformation and immortalization. Therefore, whilst cytological changes are the results of cellular transformation, the presence of high-risk HPV DNA can reflect both the resultant status and future risk of transformation. Degradation of Rb by E7 and E2F upregulation results in a feedback loop, leading to p16 overexpression, which then supports the histological diagnosis for ≥CIN2 (Fig. 4).

Future perspectives

Clinical studies are currently ongoing to investigate the advantage of risk stratification using molecular biomarkers over conventional clinicopathological factors for the treatment of EC (Table I). PORTEC-4a phase III randomized trial is currently recruiting patients (9). It compares standard adjuvant vaginal brachytherapy with adjuvant treatment assignment (observation, vaginal brachytherapy or external beam radiotherapy) based on integrated clinicopathological and molecular risk profiles. It also performs the same evaluations as ProMisE for stage I–II EC (9). TAPER is a single-arm prospective cohort study that is also recruiting patients. It intends to investigate whether early-stage EC with POLE mutations or wild-type p53 carries a lower risk of pelvic recurrence at 3 years following no or de-escalated adjuvant therapy (10). The RAINBO trial (NCT05255653), which consists of four clinical trials investigating novel adjuvant therapies, is also recruiting patients (64). Patients are assigned to one of the following trials according to the molecular profile of their tumor: i) p53 abnormal to the p53abn-RED trial; ii) MMR deficient to the MMRd-GREEN trial; iii) no specific molecular profile to the NSMP-ORANGE trial; and iv) POLE mutant to the POLEmut-BLUE trial. The p53abn-RED randomized phase III trial compares adjuvant chemoradiation with/without 2 years of following treatment with olaparib. The MMRd-GREEN randomized phase III trial compares adjuvant pelvic external-beam radiotherapy with/without combined and following durvalumab, a human monoclonal anti-PD-L1 antibody, for 1 year. The NSPM-ORANGE randomized phase III trial compares adjuvant pelvic external-beam radiotherapy with/without 2-year following treatment with progestogens. The POLEmut-BLUE phase II single-arm trial evaluates the de-escalation of adjuvant therapy: No adjuvant therapy for stage I–II and no adjuvant therapy or adjuvant pelvic external-beam radiotherapy for stage III. The results of these studies are expected to provide useful evidence for formulating genome-based therapeutic strategies for EC. In terms of ovarian cancer, the most compelling evidence on the application of biomarkers is for HGSC. However, ovarian cancer is comprised of a variety of histological types. A comprehensive molecular classification system beyond pathological morphology needs to be constructed, in a manner that is applicable for risk stratification and therapeutic selection. Additionally, although the majority of ovarian cancers are diagnosed at advanced stages at present, an effective surveillance method for early detection remains elusive. Therefore, biomarkers for such utility are eagerly anticipated. For cervical cancer, considering the global effort for the prevalence of HPV vaccination, biomarkers for increased efficiency and economical screening instead of those for efficacious treatment will be needed in the near future.

Table I.

Selected studies on biomarkers for patient prognosis and tumor response in gynecological oncology.

Table I.

Selected studies on biomarkers for patient prognosis and tumor response in gynecological oncology.

BiomarkerTarget diseaseSample sizeStudy for identifierStudy phasePublished year(Refs.)
MSI, POLEm, copy numberStage I–IV EC232Observational 2013(6)
dMMR, POLEm, p53Stage I–IV EC133, 139, 141Observational 2015(7)
dMMR, POLEm, p53Stage I–IV EC319Observational 2017(8)
dMMR, POLEm, p53Stage I–II ECrecruitingInterventionalNCT03469674 (POTEC-4a)3 (9)
POLEm, p53Stage I–II ECrecruitingInterventionalNCT04705649 (TAPER) (10)
dMMR, POLEm, p53Stage I–III ECrecruitingInterventionalNCT05255653 (RAINBO)2, 3 (64)
p53High-risk, stage IB-III EC93ObservationalNCT00411138 (PORTEC-3)32020(17)
T-cell-inflamed GEP, PD-L1, TMBPD-L1+ advanced solid tumors (including EC)203, 198, 77ObservationalNCT02054806 (KEYNOTE-028)1b2019(18)
TMB (FoundationOne CDx)Advanced, incurable solid tumors (including EC)790 (82)ObservationalNCT02628067 (KEYNOTE-158)22020(20)
p53HGSC281Observational 2021(11)
PFI gBRCAm+ OC38, 46Observational 2010(13)
HRD (myChoice CDx)Stage III–IV OC667ObservationalNCT02477644 (PAOLA-1)32019(14)
HRD (myChoice CDx)Recurrent, platinum-sensitive HGSC105ObservationalNCT02354586 (QUADRA)22019(15)
PD-L1 Persistent/recurrent/metastatic CC617ObservationalNCT03635567 (KEYNOTE-826)32021(22)

[i] Refs, references; MSI, microsatellite instability; POLEm, polymerase epsilon mutation; EC, endometrial cancer; dMMR, DNA mismatch repair deficiency; GEP, gene-expression profile; PD-L1, programmed cell death ligand 1; TMB, tumor mutation burden; CDx, companion diagnostics; HGSC, high-grade serous ovarian cancer; PFI, platinum-free interval; gBRCAm, germline BRCA mutation; OC, ovarian cancer; HRD, homologous recombination deficiency; CC, cervical cancer.


The present review provided an overview for the current evidence on the use of cancer-related biomarkers for gynecological malignancies. Due to the recent acceleration in the advancements of human genomics and therapeutic developments, the knowledge and application of biomarkers are fast becoming essential for maximizing therapeutic efficacy and patient QOL whilst minimizing overtreatment and waste of limited resources. Several biomarkers have been suggested to be viable for guiding therapies, such as companion diagnostics based on the data from mainly observational studies (Table I). However, currently ongoing and future prospective interventional studies are warranted. They are expected to provide robust evidence on potentially effective and beneficial biomarkers that are applicable for the prevention, diagnosis and treatment of gynecological cancers, to further facilitate genome-directed precision medicine.


Not applicable.


Funding: No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

TM performed the literature search and drafted the manuscript. AS, AA and TS critically reviewed the manuscript. TS revised the manuscript. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

TS received participant/speaker/advisor/chair payments from Aska Pharmaceutical, AstraZeneca, Bayer Yakuhin, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Fuji Pharma, GE HealthCare, Johnson & Johnson, Kyowa Kirin, Merck, Mochida Pharmaceutical, Nippon Kayaku, Nobelpharma, Otsuka Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical, Tsumura and Yakult Honsha. AS received speaker/chair payments from AstraZeneca, Eisai, Johnson & Johnson, Medtronic, Merck, Sanofi S.A., Taiho Pharmaceutical and Takeda Pharmaceutical. AA received speaker payments from MSD and Takeda Pharmaceutical.



Friedman AA, Letai A, Fisher DE and Flaherty KT: Precision medicine for cancer with next-generation functional diagnostics. Nat Rev Cancer. 15:747–756. 2015. View Article : Google Scholar : PubMed/NCBI


Yang W, Lei C, Song S, Jing W, Jin C, Gong S, Tian H and Guo T: Immune checkpoint blockade in the treatment of malignant tumor: Current statue and future strategies. Cancer Cell Int. 21:5892021. View Article : Google Scholar : PubMed/NCBI


Herzog TJ, Vergote I, Gomella LG, Milenkova T, French T, Tonikian R, Poehlein C and Hussain M: Testing for homologous recombination repair or homologous recombination deficiency for poly (ADP-ribose) polymerase inhibitors: A current perspective. Eur J Cancer. 179:136–146. 2023. View Article : Google Scholar : PubMed/NCBI


Bokhman JV: Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 15:10–17. 1983. View Article : Google Scholar : PubMed/NCBI


Murali R, Soslow RA and Weigelt B: Classification of endometrial carcinoma: More than two types. Lancet Oncol. 15:e268–e278. 2014. View Article : Google Scholar : PubMed/NCBI


Cancer Genome Atlas Research Network, . Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, et al: Integrated genomic characterization of endometrial carcinoma. Nature. 497:67–73. 2013. View Article : Google Scholar : PubMed/NCBI


Talhouk A, McConechy MK, Leung S, Li-Chang HH, Kwon JS, Melnyk N, Yang W, Senz J, Boyd N, Karnezis AN, et al: A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer. 113:299–310. 2015. View Article : Google Scholar : PubMed/NCBI


Talhouk A, McConechy MK, Leung S, Yang W, Lum A, Senz J, Boyd N, Pike J, Anglesio M, Kwon JS, et al: Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer. 123:802–813. 2017. View Article : Google Scholar : PubMed/NCBI


PORTEC-4a. Molecular profile-based versus standard adjuvant radiotherapy in endometrial cancer (PORTEC-4a). 25–2023


Tailored Adjuvant Therapy in POLE-mutated and p53-wildtype Early Stage Endometrial Cancer (TAPER). 25–2023


Ghezelayagh TS, Pennington KP, Norquist BM, Khasnavis N, Radke MR, Kilgore MR, Garcia RL, Lee M, Katz R, Leslie KK, et al: Characterizing TP53 mutations in ovarian carcinomas with and without concurrent BRCA1 or BRCA2 mutations. Gynecol Oncol. 160:786–792. 2021. View Article : Google Scholar : PubMed/NCBI


Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, et al: Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 361:123–134. 2009. View Article : Google Scholar : PubMed/NCBI


Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, De Greve J, Lubinski J, Shanley S, Messiou C, et al: Poly(ADP)-ribose polymerase inhibition: Frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 28:2512–2519. 2010. View Article : Google Scholar : PubMed/NCBI


Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, Fujiwara K, Vergote I, Colombo N, Mäenpää J, et al: Olaparib plus Bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 381:2416–2428. 2019. View Article : Google Scholar : PubMed/NCBI


Moore KN, Secord AA, Geller MA, Miller DS, Cloven N, Fleming GF, Hendrickson AEW, Azodi M, DiSilvestro P, Oza AM, et al: Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): A multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 20:636–648. 2019. View Article : Google Scholar : PubMed/NCBI


de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, Colombo A, et al: Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): Final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 19:295–309. 2018. View Article : Google Scholar : PubMed/NCBI


Leon-Castillo A, de Boer SM, Powell ME, Mileshkin LR, Mackay HJ, Leary A, Nijman HW, Singh N, Pollock PM, Bessette P, et al: Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: Impact on prognosis and benefit from adjuvant therapy. J Clin Oncol. 38:3388–3397. 2020. View Article : Google Scholar : PubMed/NCBI


Ott PA, Bang YJ, Piha-Paul SA, Razak ARA, Bennouna J, Soria JC, Rugo HS, Cohen RB, O'Neil BH, Mehnert JM, et al: T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 37:318–327. 2019. View Article : Google Scholar : PubMed/NCBI


Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, Kang SP, Shankaran V, et al: IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 127:2930–2940. 2017. View Article : Google Scholar : PubMed/NCBI


Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung HC, Kindler HL, Lopez-Martin JA, Miller WH Jr, et al: Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 21:1353–1365. 2020. View Article : Google Scholar : PubMed/NCBI


Makker V, Colombo N, Herraez AC, Santin AD, Colomba E, Miller DS, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, et al: Lenvatinib plus Pembrolizumab for advanced endometrial cancer. N Engl J Med. 386:437–448. 2022. View Article : Google Scholar : PubMed/NCBI


Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Usta EH, Yañez E, et al: Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 385:1856–1867. 2021. View Article : Google Scholar : PubMed/NCBI


Schiffman M, Kinney WK, Cheung LC, Gage JC, Fetterman B, Poitras NE, Lorey TS, Wentzensen N, Befano B, Schussler J, et al: Relative performance of HPV and cytology components of cotesting in cervical screening. J Natl Cancer Inst. 110:501–508. 2018. View Article : Google Scholar : PubMed/NCBI


Perkins RB, Guido RS, Castle PE, Chelmow D, Einstein MH, Garcia F, Huh WK, Kim JJ, Moscicki AB, Nayar R, et al: 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 24:102–131. 2020. View Article : Google Scholar : PubMed/NCBI


Serrano M, Hannon GJ and Beach D: A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 366:704–707. 1993. View Article : Google Scholar : PubMed/NCBI


Galgano MT, Castle PE, Atkins KA, Brix WK, Nassau SR and Stoler MH: Using biomarkers as objective standards in the diagnosis of cervical biopsies. Am J Surg Pathol. 34:1077–1087. 2010. View Article : Google Scholar : PubMed/NCBI


Bergeron C, Ordi J, Schmidt D, Trunk MJ, Keller T and Ridder R; European CINtec Histology Study Group, : Conjunctive p16INK4a testing significantly increases accuracy in diagnosing high-grade cervical intraepithelial neoplasia. Am J Clin Pathol. 133:395–406. 2010. View Article : Google Scholar : PubMed/NCBI


Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, Jervis S, van Leeuwen FE, Milne RL, Andrieu N, et al: Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 317:2402–2416. 2017. View Article : Google Scholar : PubMed/NCBI


Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, et al: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet. 72:1117–1130. 2003. View Article : Google Scholar : PubMed/NCBI


Chen S and Parmigiani G: Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 25:1329–1333. 2007. View Article : Google Scholar : PubMed/NCBI


Chen J, Bae E, Zhang L, Hughes K, Parmigiani G, Braun D and Rebbeck TR: Penetrance of breast and ovarian cancer in women who carry a BRCA1/2 mutation and do not use risk-reducing salpingo-oophorectomy: An updated meta-analysis. JNCI Cancer Spectr. 4:pkaa0292020. View Article : Google Scholar : PubMed/NCBI


Pinsky PF, Yu K, Kramer BS, Black A, Buys SS, Partridge E, Gohagan J, Berg CD and Prorok PC: Extended mortality results for ovarian cancer screening in the PLCO trial with median 15years follow-up. Gynecol Oncol. 143:270–275. 2016. View Article : Google Scholar : PubMed/NCBI


Jacobs IJ, Menon U, Ryan A, Gentry-Maharaj A, Burnell M, Kalsi JK, Amso NN, Apostolidou S, Benjamin E, Cruickshank D, et al: Ovarian cancer screening and mortality in the UK collaborative trial of ovarian cancer screening (UKCTOCS): A randomised controlled trial. Lancet. 387:945–956. 2016. View Article : Google Scholar : PubMed/NCBI


Marchetti C, De Felice F, Perniola G, Lecce F, Vertechy L, Monti M, Musio D, Muzii L, Tombolini V and Panici PB: Screening program in ovarian cancer: A logical step in clinical management? A meta-analysis. Curr Probl Cancer. 42:235–240. 2018. View Article : Google Scholar : PubMed/NCBI


Jacobs IJ, Skates SJ, MacDonald N, Menon U, Rosenthal AN, Davies AP, Woolas R, Jeyarajah AR, Sibley K, Lowe DG and Oram DH: Screening for ovarian cancer: A pilot randomised controlled trial. Lancet. 353:1207–1210. 1999. View Article : Google Scholar : PubMed/NCBI


Henderson JT, Webber EM and Sawaya GF: Screening for ovarian cancer: Updated evidence report and systematic review for the US preventive services task force. JAMA. 319:595–606. 2018. View Article : Google Scholar : PubMed/NCBI


Finch AP, Lubinski J, Møller P, Singer CF, Karlan B, Senter L, Rosen B, Maehle L, Ghadirian P, Cybulski C, et al: Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 32:1547–1553. 2014. View Article : Google Scholar : PubMed/NCBI


Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, Garber JE, Neuhausen SL, Matloff E, Eeles R, et al: Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 304:967–975. 2010. View Article : Google Scholar : PubMed/NCBI


NCCN Guidelines Genetic/Familial High-risk Assessment, . Breast, Ovarian, and Pancreatic. NCCN Clinical Practice Guidelines in Oncology. 2023. 25–2023


Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE, Feltmate CM, Berkowitz RS and Muto MG: Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol. 25:3985–3990. 2007. View Article : Google Scholar : PubMed/NCBI


Powell CB, Kenley E, Chen LM, Crawford B, McLennan J, Zaloudek C, Komaromy M, Beattie M and Ziegler J: Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: Role of serial sectioning in the detection of occult malignancy. J Clin Oncol. 23:127–132. 2005. View Article : Google Scholar : PubMed/NCBI


Shaw PA, Rouzbahman M, Pizer ES, Pintilie M and Begley H: Candidate serous cancer precursors in fallopian tube epithelium of BRCA1/2 mutation carriers. Mod Pathol. 22:1133–1138. 2009. View Article : Google Scholar : PubMed/NCBI


Vang R and Shih IM: Serous tubal intra-epithelial carcinoma: What do we really know at this point? Histopathology. 81:542–555. 2022. View Article : Google Scholar : PubMed/NCBI


Lopez F, Belloc F, Lacombe F, Dumain P, Reiffers J, Bernard P and Boisseau MR: Modalities of synthesis of Ki67 antigen during the stimulation of lymphocytes. Cytometry. 12:42–49. 1991. View Article : Google Scholar : PubMed/NCBI


Latham A, Srinivasan P, Kemel Y, Shia J, Bandlamudi C, Mandelker D, Middha S, Hechtman J, Zehir A, Dubard-Gault M, et al: Microsatellite instability is associated with the presence of lynch syndrome pan-cancer. J Clin Oncol. 37:286–295. 2019. View Article : Google Scholar : PubMed/NCBI


Hendriks YM, de Jong AE, Morreau H, Tops CM, Vasen HF, Wijnen JT, Breuning MH and Bröcker-Vriends AH: Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): A guide for clinicians. CA Cancer J Clin. 56:213–225. 2006. View Article : Google Scholar : PubMed/NCBI


Crosbie EJ, Ryan NAJ, Arends MJ, Bosse T, Burn J, Cornes JM, Crawford R, Eccles D, Frayling IM, Ghaem-Maghami S, et al: The Manchester international consensus group recommendations for the management of gynecological cancers in Lynch syndrome. Genet Med. 21:2390–2400. 2019. View Article : Google Scholar : PubMed/NCBI


Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, et al: Guidelines on genetic evaluation and management of Lynch syndrome: A consensus statement by the US multi-society task force on colorectal cancer. Gastroenterology. 147:502–526. 2014. View Article : Google Scholar : PubMed/NCBI


Stoffel E, Mukherjee B, Raymond VM, Tayob N, Kastrinos F, Sparr J, Wang F, Bandipalliam P, Syngal S and Gruber SB: Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology. 137:1621–1627. 2009. View Article : Google Scholar : PubMed/NCBI


Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, Liu B, Kinzler KW and Vogelstein B: Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet. 6:105–110. 1997. View Article : Google Scholar : PubMed/NCBI


Barrow E, Robinson L, Alduaij W, Shenton A, Clancy T, Lalloo F, Hill J and Evans DG: Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: A report of 121 families with proven mutations. Clin Genet. 75:141–149. 2009. View Article : Google Scholar : PubMed/NCBI


Hampel H, Stephens JA, Pukkala E, Sankila R, Aaltonen LA, Mecklin JP and de la Chapelle A: Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: Later age of onset. Gastroenterology. 129:415–421. 2005. View Article : Google Scholar : PubMed/NCBI


Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, Peltomäki P, Mecklin JP and Järvinen HJ: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 81:214–218. 1999. View Article : Google Scholar : PubMed/NCBI


Schmeler KM, Lynch HT, Chen LM, Munsell MF, Soliman PT, Clark MB, Daniels MS, White KG, Boyd-Rogers SG, Conrad PG, et al: Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. 354:261–269. 2006. View Article : Google Scholar : PubMed/NCBI


NCCN Guidelines, . Genetic/Familial High-risk Assessment: Colorectal. NCCN Clinical Practice Guidelines in Oncology 2023. 25–2023


Dong Y, Hakimi MA, Chen X, Kumaraswamy E, Cooch NS, Godwin AK and Shiekhattar R: Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell. 12:1087–1099. 2003. View Article : Google Scholar : PubMed/NCBI


Christou CM and Kyriacou K: BRCA1 and its network of interacting partners. Biology. 2:40–63. 2013. View Article : Google Scholar : PubMed/NCBI


Brugarolas J and Jacks T: Double indemnity: p53, BRCA and cancer. p53 mutation partially rescues developmental arrest in Brca1 and Brca2 null mice, suggesting a role for familial breast cancer genes in DNA damage repair. Nat Med. 3:721–722. 1997. View Article : Google Scholar : PubMed/NCBI


Patel KJ, Yu VP, Lee H, Corcoran A, Thistlethwaite FC, Evans MJ, Colledge WH, Friedman LS, Ponder BA and Venkitaraman AR: Involvement of Brca2 in DNA repair. Mol Cell. 1:347–357. 1998. View Article : Google Scholar : PubMed/NCBI


Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW, Harris CC, Ried T and Deng CX: Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell. 3:389–395. 1999. View Article : Google Scholar : PubMed/NCBI


Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, et al: Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol. 31:161–169. 2007. View Article : Google Scholar : PubMed/NCBI


Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, Stewart C, Fereday S, Caldas C, Defazio A, et al: Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol. 221:49–56. 2010. View Article : Google Scholar : PubMed/NCBI


Dudley JC, Lin MT, Le DT and Eshleman JR: microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 22:813–820. 2016. View Article : Google Scholar : PubMed/NCBI


Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features (RAINBO). 25–2023

Related Articles

Journal Cover

Volume 26 Issue 4

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
Spandidos Publications style
Minaguchi T, Shikama A, Akiyama A and Satoh T: Molecular biomarkers for facilitating genome‑directed precision medicine in gynecological cancer (Review). Oncol Lett 26: 426, 2023
Minaguchi, T., Shikama, A., Akiyama, A., & Satoh, T. (2023). Molecular biomarkers for facilitating genome‑directed precision medicine in gynecological cancer (Review). Oncology Letters, 26, 426.
Minaguchi, T., Shikama, A., Akiyama, A., Satoh, T."Molecular biomarkers for facilitating genome‑directed precision medicine in gynecological cancer (Review)". Oncology Letters 26.4 (2023): 426.
Minaguchi, T., Shikama, A., Akiyama, A., Satoh, T."Molecular biomarkers for facilitating genome‑directed precision medicine in gynecological cancer (Review)". Oncology Letters 26, no. 4 (2023): 426.