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This study aimed to evaluate the homologous recombination repair pathway deficiency (HRD) in ovarian high-grade serous carcinoma (HGSC).In the ovarian cancer data from The Cancer Genome Atlas, we identified genes differentially expressed between tumours with and without HRD genomic scars and named these genes "HRDness signature". We performed SNP array, RNA sequencing, and methylation array analyses on 274 HGSC tumours for which targeted sequencing of 51 genes and clinical data were available to generate JGOG3025-TR2 dataset. The HRDness signature was tested on external datasets, including the JGOG3025-TR2 cohort, by computational scoring and machine-learning prediction.High scores and positive predictions of the HRDness signature were significantly associated with BRCA alterations, genomic scar scores, and better survival. On the other hand, among cases with high scores and/or positive predictions, those with BRCA1 methylation showed poorer survival. In the JGOG3025-TR2 cohort, HRD status was significantly associated with the use of olaparib after relapse and progression-free survival after its initiation.The HRDness gene expression signature is associated with a good prognosis, while BRCA1 methylation is associated with a poor prognosis. The newly generated JGOG3025-TR2 dataset will be useful in future HGSC studies.

Introduction: The epithelial cells of the endometrium undergo rapid proliferation and shedding each month under the influence of estrogen and progesterone. Recent studies have demonstrated pervasive driver mutations in the endometrium with ageing. However, previous observations have been limited to the microscopic scale, and it is still unclear how clonal expansion occurs over the entire endometrium and what driver mutations are responsible therein. To address these issues, we performed multisampling of the endometrium with extensive spatial mapping. Methods: We collected multiple endometrial glands from normal endometrium in a 5mm lattice in 19 patients who underwent hysterectomy (3-31 samples per case), followed by DNA extraction, detected somatic mutations by whole exome sequencing, to identify large clones that spread across samples based on shared mutations. Results: In total, 216 bulk endometrial glands were analyzed. The number of detected somatic mutations per sample ranged from 6 to 98 (mean±SD: 37.8±16.0), and most of the samples had at least one known driver gene mutation (mean±SD: 4.38±2.27). The mutational signature analysis revealed the predominance of the age-related SBS1 and SBS5 signatures. dN/dS analysis identified 21 genes that were positively selected in normal endometrium, including PIK3CA, PIK3R1, KRAS, PPP2R1A, ARHGAP35, and FBXW7, most of which are also known as driver genes for endometrial cancer. The number of mutations and their frequency for each driver gene did not differ by background diseases: endometriosis, endometriosis-associated ovarian cancer and other non-endometrial related diseases. We found clones showing a large expansion involving multiple samples in 8 cases, most of which harbored one or more driver mutations, such as PIK3CA and KRAS. The size of the largest clone carrying a KRAS mutation, which was found in a 32-year-old woman with cervical cancer, spanned as long as 10 mm in diameter. This suggests that clonal expansion in the endometrium could be very rapid even in healthy women, which contrasts to the observations that clonal expansion in other organs is usually seen in aged individuals. Conclusion: We confirmed the high frequency of driver mutations in the normal endometrium, most of which overlapped to those found in endometrial cancers, suggesting that these driver genes are involved in the early phase of the development in the endometrial cancer. Some of the driver-mutated clones expanded in macroscopic size. Our findings provide an interesting insight into the clonal structure and underlying genetic variation in the normal endometrium. Citation Format: Koichi Watanabe, Nobuyuki Kakiuchi, Shiro Takamatsu, Sachiko Kitamura, Mana Taki, Koji Yamanoi, Ryusuke Murakami, Ken Yamaguchi, Junzo Hamanishi, Hiroko Tanaka, Satoru Miyano, Masaki Mandai, Seishi Ogawa. Clonal expansion with driver mutations in normal human endometrium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 128.

Background: Since the advent of high-throughput sequencing technologies, multi-omics data along with large-scale drug sensitivity screening data on cancer cell lines from the NCI-60 panel and the CCLE (Cancer Cell Line Encyclopedia) project have been established and widely used for cancer research. Although we previously reported the utility of homologous recombination deficiency (HRD), commonly found in ovarian and breast cancer, as a clinical biomarker across cancer types (PMID:35613413), whether HRD status in cancer cell lines can be an indicator of drug sensitivity to platinum agents or PARP inhibitors has not been fully investigated. Methods: From CCLE publicly available datasets, BRCA1/2 gene mutations and their loss of heterozygosity (LOH) status, HRD score, mutational signature 3 (SBS3), and BRCA1 methylation silencing were analyzed. In vitro drug screening data were obtained from the GDSC (Genomics of Drug Sensitivity in Cancer), CTRP (Cancer Therapeutic Response Portal), and PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) databases. We additionally analyzed anticancer drug response in cell line-derived xenograft models using the dataset of ROADMAPS (Responses to Oncology Agents and Dosing in Models to Aid Preclinical Studies). Results: A total of 1260 cell lines from the CCLE were analyzed. HRD score and SBS3 were positively correlated (ρ=0.36). These scores were higher in samples with BRCA1 methylation and BRCA1/2 mutations involving locus-specific LOH (referred to collectively as BRCA alteration), but not in samples with BRCA1/2 mutations lacking locus-specific LOH. Per-drug correlation analysis between cell line HRD scores and the areas under the drug response curve (AUCs) showed statistically significant (p Conclusion: When comparing in vitro drug sensitivity among cancer cell lines, HRD correlates with resistance rather than with response to platinum or PARP inhibitors. Thus, the association between HRD status and drug sensitivity of cancer cells is substantially different between tumors in dish culture and in clinical settings. This study provides critical insights that should be considered when using cancer cell lines and underscores the need for experimental models that better reflect efficacy in clinical tumors. Citation Format: Shiro Takamatsu, Noriomi Matsumura. Homologous recombination deficiency in the CCLE cell lines correlates with in vitro resistance to platinum agents and PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2773.

Objective Carcinosarcoma (CS) of the uterus or ovary is a rare, biphasic tumor comprising epithelial and mesenchymal elements, and exhibits more aggressive clinical features than its carcinoma counterpart. Four molecular subtypes of CS were recently established based on genomic aberration profiles (POLE, MSI, CNH, and CNL) and shown to be associated with multiple clinicopathological parameters, including patient outcomes. However, the role of the immune microenvironment in CS remains unclear. Here, we investigated the influence of the immune cells that infiltrate CS to better understand the immunological status of gynecological CS. Methods Tumor immune microenvironmental analyses on CS samples were performed using immune cell profiling with RNA-seq, transcriptomic subtyping with microenvironmental genes, and T-cell receptor repertoire assay. Carcinoma and sarcoma elements from CS samples were also assessed separately. Results Relying on estimations of tumor-infiltrating cell types from RNA-seq data, POLE and MSI (hypermutator) tumors showed an enrichment of M1 macrophages, plasma cells and CD8+ T cells, whereas CNH and CNL (non-hypermutator) tumors had high levels of M2 macrophages. Further subclassification by immune-related, non-cancer genes identified a fraction of tumors with distinct patient outcomes, particularly those with the CNH genomic aberration subtype. T-cell heterogeneity was independently correlated with prolonged progression-free survival. Differential analysis of carcinoma and sarcoma elements identified many shared mutations but there was little overlap in the T-cell receptor repertoire between the two elements. Conclusions Tumor immune microenvironmental analyses could offer potential clinical utility in the stratification of gynecological CS above classification by genomic aberration subtype alone.

[Background] In cancer therapy, higher-resolution tumor-agnostic biomarkers that predict response to immune checkpoint inhibitor (ICI) therapy are needed. Mutation signatures reflect underlying oncogenic processes that can affect tumor immunogenicity, and thus potentially delineate ICI treatment response among tumor types. [Methods] Based on mutational signature analysis, we developed a stratification for all solid tumors in The Cancer Genome Atlas (TCGA). Subsequently, we developed a new software (Genomic Subtyping and Predictive Response Analysis for Cancer Tumor ICi Efficacy, GS-PRACTICE) to classify new tumors submitted to whole-exome sequencing. Using existing data from 973 pan-cancer ICI-treated cases with outcomes, we evaluated the subtype-response predictive performance. [Results] Systematic analysis on TCGA samples identified eight tumor genomic subtypes, which were characterized by features represented by smoking exposure, ultraviolet light exposure, APOBEC enzyme activity, POLE mutation, mismatch repair deficiency, homologous recombination deficiency, genomic stability, and aging. The former five subtypes were presumed to form an immune-responsive group acting as candidates for ICI therapy because of their high expression of immune-related genes and enrichment in cancer types with FDA approval for ICI monotherapy. In the validation cohort, the samples assigned by GS-PRACTICE to the immune-reactive subtypes were significantly associated with ICI response independent of cancer type and TMB high or low status. [Conclusions] The new tumor subtyping method can serve as a tumor-agnostic biomarker for ICI response prediction and will improve decision making in cancer treatment., あらゆる固形がんを8種に分類するプログラムを開発 --がん治療薬である免疫チェックポイント阻害剤の効果を事前予測--. 京都大学プレスリリース. 2022-07-27.

Immunotherapy has experienced remarkable growth recently. Tertiary lymphoid structures (TLSs) and B cells may play a key role in the immune response and have a survival benefit in some solid tumors, but there have been no reports about their role in endometrial cancer (EC). We investigated the clinicopathological and pathobiological characteristics of the tumor microenvironment (TME) in EC. Patients with EC at Kyoto University Hospital during 2006–2011 were retrospectively included. In 104 patients with EC who met study inclusion criteria, 81 (77.9%) had TLSs, which consisted of areas rich in CD20+ B cells, CD8+ T cells, CD4+ T cells, and CD38+ plasma cells. The absence of TLS was independently associated with tumor progression (HR, 0.154; 95% CI, 0.044–0.536; P = 0.003). Patients with TLSs that included CD23+ germinal centers had better PFS. All tumor infiltrating lymphocytes were counted in the intratumor site. The number of CD20+ B cells was significantly larger in patients with TLSs than in those without TLS (P + B cells numbers were positively correlated with other TLSs. The larger number of CD20+ B cell was associated with better PFS (P = 0.015). TLSs and B cell infiltration into tumors are associated with favorable survival outcomes in patients with EC. They may represent an active immune reaction of the TME in endometrial cancer.

The improvement of the quality of life (QOL) of gynecological cancer patients is a critical purpose in cancer treatment. At present, there is no other methodology to evaluate QOL other than patients reported outcomes using QOL questionnaires. Therefore, management of QOL is not performed clinically because there is no objective and easy method to evaluate QOL. In this study, we extracted the worst symptom of QOL in gynecological cancer patients and examined whether QOL can be evaluated by lifelogs objectively. Lifelogs (diets, sleep duration, the number of steps, pulse rate, voice, and so on) and QOL questionnaires (EORTC-qlq-c30, PHQ9, and so on) were collected from 139 gynecological cancer patients at our hospital using mobile applications. Scales of symptoms and functions were calculated from EORTC-qlq-c30. Logistic regression analyses and calculation of feature impact in the predictive model depicting receiver operating characteristic (ROC) curve were performed to extract symptoms and functions that contributed most to global health status (GHS) indicating a general QOL status. Fatigue-related metabolites in patient serum were measured by ELISA. Correlations between each lifelog, fatigue scale, and fatigue-related metabolites were examined. A computational model to detect high fatigue scale status was developed using lifelogs. The fatigue scale was the highest among all treatment periods. The fatigue scale, appetite loss scale, and physical functioning scale were symptoms that deteriorate QOL frequently in gynecologic cancer patients (odds ratio: 0.9708, 0.9797, and 1.0374, respectively; 95% CI: 0.9493 to 0.9927, 0.9677 to 0.9919, and 1.0155 to 1.0597, respectively). ROC curve indicated that an accurate prediction of GHS using scales of symptoms and functions (area under the curve, AUC: 0.85). From the scales of symptoms and functions, the fatigue scale showed the highest feature impact to predict GSH. Several lifelogs were significantly correlated with fatigue scores (p In summary, fatigue is a significant problem contributing to the decline in QOL of gynecological cancer patients. Fatigue can be monitored and diagnosed using digital data using lifelogs. These findings lead to the development of future management strategies of QOL for cancer patients. Citation Format: Ken Yamaguchi, Nozomi higashiyama, Akihiko Ueda, Shiro Takamatsu, Masayo Ukita, Mana Taki, Koji Yamanoi, Junzo Hamanishi, Masaki Mandai. Development of a computational algorithm to detect fatigue of gynecologic cancer patients using lifelogs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5261.

Objective: Tertiary lymphoid structures (TLSs) are known to be a marker of peripheral inflammation. While high densities of TLSs were reported to be associated with longer patient survival in several cancer types, there is no direct evidence where B cells in TLSs(TLBs) are derived from and whether these clones are consistent with tumor infiltrating B cells (TIBs), in endometrial cancer. Methods: We analyzed the pathological distribution of TLSs and TIBs in human endometrial cancer samples using immunohistochemistry of a series of B cell markers and evaluated the relationship with patients’ clinical outcomes. Additionally, we micro-dissected six pairs of tumor nests and their neighbor TLSs and analyzed the clonal consistency between TLBs and TIBs using the sequencing of complementarity-determining region (CDR) of B cell receptor (BCR). Results: In 104 patients with endometrial cancer, TLSs were detected in 81 patients (78%), and the absence of TLS was related to worse progression-free survival (PFS) (HR, 0.15, P Conclusion: TLSs and TIBs are associated with better prognosis in endometrial cancer. Common B cell clones were found in the advanced stage cases, suggesting that B cells may have gradually acquired immunospecificity in TLSs. Citation Format: Haruka Suzuki, Junzo Hamanishi, Meng Qin, Masayo Ukita, Akihiko Ueda, Shunsuke Kawahara, Koji Yamanoi, Taito Miyamoto, Shiro Takamatsu, Mana Taki, Yoko Hosoe, Takashi Kobayashi, Ken Yamaguchi, Masaki Mandai. Clonal relationship of B cells between tertiary lymphoid structures (TLSs) and tumor infiltrating lymphocytes (TILs) in advanced endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6109.

Homologous recombination repair (HRR) pathway deficiency (HRD) is involved in the tumorigenesis and progression of high-grade serous ovarian carcinoma (HGSOC) as well as in the sensitivity to platinum chemotherapy drugs. In this study, we obtained data from The Cancer Genome Atlas (TCGA) on HGSOC and identified scores for the loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions, and calculated the HRD score. We then investigated the relationships among the score, genetic/epigenetic alterations in HRR-related genes, and the clinical data. We found that BRCA1/2 mutations were enriched in the group with HRD scores ≥63. Compared with the groups with scores ≤62, this group had a good prognosis; we thus considered HRD scores ≥63 to be the best cutoff point for identifying HRD cases in HGSOC. Classification of HGSOC cases by the HRD status revealed a better prognosis for HRD cases caused by genetic alterations (genetic HRD) than those caused by epigenetic changes and those caused by undetermined reasons (p = 0.0002). Among cases without macroscopic residual tumors after primary debulking surgery, 11 of 12 genetic HRD cases survived after the median observation period of 6.6 years, showing remarkably high survival rates (p = 0.0059). In conclusion, HGSOC can be classified into subtypes with different prognoses according to HRD status. This classification could be useful for personalized HGSOC treatment.

[Background] Genomic alterations in BRCA1/2 and the ‘genomic scar' signatures are associated with homologous recombination DNA repair deficiency (HRD) and serve as therapeutic biomarkers for sensitivity to platinum and PARP inhibitors in breast and ovarian cancers. However, the clinical significance of these biomarkers in other homologous recombination repair (HRR) pathway genes or in other cancer types is not fully understood. [Method] From the TCGA and the AACR GENIE project databases, we obtained clinical and genomic data of patients with multiple solid cancers, evaluated both locus-specific LOH in HRR pathway gene mutations and two genomic scar signature scores (HRD score and mutational signature 3), identified potential HRD cases, and examined the efficacy of DNA-damaging drugs in these HRD cases. [Results] Germline and somatic gene mutations in the HRR pathway genes with locus-specific LOH were significantly enriched in cases having high genomic scar scores, whereas those without the LOH were not enriched. Somatic mutations without the LOH were remarkably enriched in hypermutated cases and considered to be passenger mutations. The mutation rate and frequency with LOH in the HRR pathway genes varied widely by cancer type. When stratifying patients by gender and presence of TP53 mutation, the correlation between the two genomic scar scores and the resulting optimal cutoff values for biallelic HRR pathway gene alterations differed greatly. The potential HRD cases that were selected by the two genomic scar cutoffs and biallelic HRR pathway gene alterations showed significantly high gene expression-based HRD scores. In Cox proportional hazard multivariate analyses with covariates of age, stage, gender, HRD, and TP53 mutation, HRD was a good prognostic factor in the group with DNA-damaging agents, but a poor one in the group without the agents. [Conclusion] Increased attention on locus-specific LOH in HRR pathway gene alterations and the differences in genomic scar signatures stratified by gender and TP53 mutation is newly warranted in order to properly assess HRD in a pan-cancer manner. The results in the present study proved the clinical significance of HRD across cancer types and may contribute to the development of personalized medicine based on HRD. Citation Format: Shiro Takamatsu, JB Brown, Koji Yamanoi, Ken Yamaguchi, Junzo Hamanishi, Takashi Kobayashi, Masaki Mandai, Noriomi Matsumura. Identification of a clinically significant pan-cancer biomarker for homologous recombination deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 366.

Background: Homologous recombination repair (HRR) pathway deficiency (HRD) is deeply involved in the tumorigenesis and progression of high-grade serous ovarian carcinoma (HGSOC) as well as in the sensitivity to platinum chemotherapy drugs. Until now, the proposed cutoff value for the HRD score, determined by calculating genomic scar signature scores associated with HRD, namely, the loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST), has been ≥ 42 based on a combined dataset of HGSOC and breast cancer. In this study, we propose a rational method to classify HGSOC based on HRD status and investigated its clinical significance. Methods: We obtained data from The Cancer Genome Atlas (TCGA) on HGSOC and determined the HRD score as the sum of LOH, TAI, and LST scores. We then investigated the relationships among the score, genetic alterations in HRR-related genes, and the clinical data. Results: BRCA1/2 mutations were enriched in the group with HRD scores ≥ 63. BRCA1/2 mutations represented 38% of the cases with HRD scores ≥ 63 (49/128), 10% with HRD scores between 42 and 62 (12/118), and 10% with HRD scores 41 and below (5/50); no enrichment of BRCA1/2 mutation cases with HRD scores from 42 to 62 was observed compared with those with scores ≤ 41. Compared with the groups with scores ≤ 62, this group had a good prognosis (p < 0.0001); we thus considered HRD scores ≥ 63 to be the best cutoff point for identifying HRD cases in HGSOC. Among the other HRR pathway gene mutations, only CHEK1 homozygous deletions and PTEN homozygous deletions were associated with high HRD scores (p = 0.0038 and p = 0.035, respectively). In terms of promoter methylation, BRCA1 methylations and RAD51C methylations were associated with high HRD scores (p < 0.0001 and p = 0.029, respectively). Classification of HGSOC cases by the HRD status revealed a better prognosis for HRD cases caused by genetic alterations (HRD-G) than those caused by epigenetic changes (HRD-E), those caused by undetermined reasons (HRD-U), and non-HRD cases (p < 0.0001). A combined analysis of HRD status and residual tumor after primary debulking surgery revealed that, among cases without macroscopic residual tumors, 11 of 12 HRD-G cases survived after the median observation period of 6.6 years, showing remarkably higher survival rates than HRD-E, HRD-U, and non-HRD cases (p = 0.0059). Conclusion: HRD score ≥ 63 is an optimal cut-off to define HRD in HGSOC. HGSOC can be classified into subtypes with different prognoses according to HRD status. This classification could be useful for personalized HGSOC treatment. Citation Format: Noriomi Matsumura, Hisamitsu Takaya, Shiro Takamatsu, Hidekatsu Nakai. Homologous recombination deficiency status-based classification of high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A49.

Background: Microsatellite instability (MSI) and tumor mutation burden (TMB) are being considered as predictive biomarkers for PD-1 and PD-L1 blockade immunotherapy. However, in ovarian clear-cell carcinoma (OCC), which demonstrates characteristic resistance to standard chemotherapy, the extent of MSI and TMB and their subsequent prognostic capability are unresolved. The aim of this study is to investigate TMB and MSI in OCC for improved therapy decision making. Methods: Tumor-normal paired whole-exome data of 55 OCC patients (Itamochi et al., Br J Cancer 2017) were analyzed. Sequence data preprocessing was performed in accordance with GATK best practice workflows using BWA, Picard, the GATK toolkit, and SAMtools. Somatic SNVs and indels were detected by using Mutect and VarScan. Resulting variants were annotated by ANNOVAR, and exonic or splicing variants were extracted. SNVs with allele frequency >= 2.0% were kept and further processed by the combination of the pathogenicity prediction values obtained from SIFT, PolyPhen-2, and PROVEAN; SNVs annotated as deleterious or damaging by at least one of the tools were retained. The TMB of each sample was evaluated by the total number of nonsynonymous SNVs called by the preannotation pipeline. A threshold defining high TMB was derived from the inflection point on the right tail of the TMB distribution; the resulting value was positioned at the 85th percentile of TMB values. MSI was calculated using MSIsensor, with the MSI-high classification threshold set as per the software’s documentation. Results: Among the 55 OCC cases, 11 (20%) had at least one or a combination of either MSI-high status, mismatch repair (MMR) mutations, or TMB-high status. Specifically, three had MSI-high status, five had MMR gene mutations, and eight had TMB-high status. MSI-high samples showed elevated TMB (p= 0.052 Fisher-T). TMB was also elevated in MMR-mutated samples (p=0.018 Fisher-T). Among the three samples with MSI-high status, only one contained a deleterious mutation in MMR gene MSH6. One TMB-high sample had a POLE1 mutation. Critically, discrete- and continuous-valued survival analyses using MSI and TMB as independent variables did not suggest correlation with patient prognosis. Conclusion: Within gynecologic oncology, MSI and TMB are correlated with prognosis in uterine endometrial cancer subtypes, though here they have demonstrated relatively reduced prognostic ability in OCC so far as examined by the samples available for this study. Thus, OCC patients are warranted the consideration of immune checkpoint inhibitor therapy at an earlier stage of treatment, and further studies to improve the resolution between MSI/TMB/MMR and phenotypical aspects should be encouraged. Citation Format: Shiro Takamatsu, Noriomi Matsumura, J.B. Brown, Hiroaki Itamochi, Junzo Hamanishi, Ken Yamaguchi, Toru Sugiyama, Tsukasa Baba, Masaki Mandai. Microsatellite instability and tumor mutation burden as factors in ovarian clear-cell carcinoma therapy selection [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A27.

Malignant psoas syndrome (MPS) is a rare and unique cancer-associated syndrome caused by the malignant involvement of the psoas major muscle, and is characterized by ipsilateral lumbosacral plexopathy and painful hip flexion. The pain in MPS is often distressing and intractable, and there is no established effective treatment approach. Herein, the present study reports on three cases of MPS associated with gynecological malignancies, wherein symptom improvement was observed following chemotherapy or radiotherapy. Among 39 cases documented in the literature, female genital tract malignancies were the most frequent causes of MPS; however, the condition may be under-diagnosed, owing to the lack of general recognition. Considering the development of recent high-precision radiation therapy, palliative radiotherapy may serve an important role in the management of MPS. For physicians treating gynecological cancers, early detection of MPS is clinically important as this may allow patients to receive possible therapies and improve their quality of life in end-stage cancer. Further prospective studies should be performed to evaluate effective therapeutic approaches for MPS.