Targeting KRAS in gynecological malignancies.

Cervical, endometrial, and ovarian cancers stand prominently as the leading gynecological malignancies of the female reproductive system. The conventional therapeutic modalities for gynecological malignancies have predominantly encompassed surgery, chemotherapy, and radiotherapy. However, efficacy of these approaches remains limited in cases of relapse or drug resistance. KRAS is one of the most frequently mutated oncogenes in human cancers. The KRAS gene encodes a small guanosine triphosphatase protein that acts as a molecular switch for crucial intracellular signaling pathways. KRAS mutations are deeply involved in the occurrence and development of gynecological malignancies. The present review aims to expound upon the role of oncogenic KRAS as a biomarker, elucidating various therapeutic approaches under investigation targeting the KRAS pathway in gynecological tumors.

Artificial intelligence-based risk stratification, accurate diagnosis and treatment prediction in gynecologic oncology.

As data-driven science, artificial intelligence (AI) has paved a promising path toward an evolving health system teeming with thrilling opportunities for precision oncology. Notwithstanding the tremendous success of oncological AI in such fields as lung carcinoma, breast tumor and brain malignancy, less attention has been devoted to investigating the influence of AI on gynecologic oncology. Hereby, this review sheds light on the ever-increasing contribution of state-of-the-art AI techniques to the refined risk stratification and whole-course management of patients with gynecologic tumors, in particular, cervical, ovarian and endometrial cancer, centering on information and features extracted from clinical data (electronic health records), cancer imaging including radiological imaging, colposcopic images, cytological and histopathological digital images, and molecular profiling (genomics, transcriptomics, metabolomics and so forth). However, there are still noteworthy challenges beyond performance validation. Thus, this work further describes the limitations and challenges faced in the real-word implementation of AI models, as well as potential solutions to address these issues.

Association between cholelithiasis, cholecystectomy, and risk of breast and gynecological cancers: Evidence from meta-analysis and Mendelian randomization study.

BACKGROUND: Observational studies have shown that cholelithiasis and cholecystectomy are associated with the risk of breast cancer (BC) and gynecological cancers, but whether these relationships are causal has not been established and remains controversial. METHODS: Our study began with a meta-analysis that synthesized data from prior observational studies to examine the association between cholelithiasis, cholecystectomy, and the risk of BC and gynecological cancers. Subsequently, a two-sample Mendelian randomization (MR) analysis was conducted utilizing genetic variant data to investigate the potential causal relationship between cholelithiasis, cholecystectomy, and the aforementioned cancers. RESULTS: The results of the meta-analysis demonstrated a significant association between cholecystectomy and the risk of BC (risk ratio [RR] = 1.04, 95% confidence interval [CI]: 1.01-1.06, p = 0.002) and endometrial cancer (EC) (RR = 1.26, 95% CI: 1.02-1.56, p = 0.031). Conversely, no significant association was observed between cholelithiasis and the risk of BC, EC, and ovarian cancer. The MR analysis revealed no discernible causal connection between cholelithiasis and overall BC (p = 0.053), as well as BC subtypes (including estrogen receptor-positive/negative). Similarly, there was no causal effect of cholecystectomy on BC risk (p = 0.399) and its subtypes. Furthermore, no causal associations were identified between cholelithiasis, cholecystectomy, and the risk of gynecological cancers (ovarian, endometrial, and cervical cancer [CC]) (all p > 0.05). CONCLUSION: This study does not support a causal link between cholelithiasis and cholecystectomy and an increased risk of female cancers such as breast, endometrial, ovarian, and CC.

The prognostic value of MEK pathway-associated estrogen receptor signaling activity for female cancers.

BACKGROUND: Other than for breast cancer, endocrine therapy has not been highly effective for gynecologic cancers. Endocrine therapy resistance in estrogen receptor positive gynecologic cancers is still poorly understood. In this retrospective study, we examined the estrogen receptor (ER) signaling pathway activities of breast, ovarian, endometrial, and cervical cancers to identify those that may predict endocrine therapy responsiveness. METHODS: Clinical and genomic data of women with breast and gynecological cancers were downloaded from cBioPortal for Cancer Genomics. Estrogen receptor alpha (ESR1) expression level and sample-level pathway enrichment scores (EERES) were calculated to classify patients into four groups (low/high ESR1 and low/high EERES). Correlation between ESR1/EERES score and survival was further validated with RNAseq data from low-grade serous ovarian cancer. Pathway analyses were performed among different ESR1/EERES groups to identify genes that correlate with endocrine resistance, which are validated using Cancer Cell Line Encyclopedia gene expression and Genomics of Drug Sensitivity in Cancer data. RESULTS: We identified a novel combined prognostic value of ESR1 expression and the corresponding estrogen response signaling (EERES score) for breast cancer. The combined prognostic value (ESR1/EERES) may be applicable to other gynecologic cancers. More importantly, we discovered that ER signaling can cross-regulate MEK pathway activation. We identified downstream genes in the MEK pathway (EPHA2, INAVA, MALL, MPZL2, PCDH1, and TNFRSF21) that are potential endocrine therapy response biomarkers. CONCLUSION: This study demonstrated that targeting both the ER and the ER signaling activity related MEK pathway may aid the development of endocrine therapy strategies for personalized medicine.

Expanding the Spectrum of NR4A3 Fusion-Positive Gynecologic Leiomyosarcomas.

Recurrent gene fusions have been observed in epithelioid and myxoid variants of uterine leiomyosarcoma. PGR::NR4A3 fusions were recently described in a subset of epithelioid leiomyosarcomas exhibiting rhabdoid morphology. In this study, we sought to expand the clinical, morphologic, immunohistochemical, and genetic features of gynecologic leiomyosarcomas harboring NR4A3 rearrangements with PGR and novel fusion partners. We identified 9 gynecologic leiomyosarcomas harboring PGR::NR4A3, CARMN::NR4A3, ACTB::NR4A3, and possible SLCO5A1::NR4A3 fusions by targeted RNA sequencing. Tumors frequently affected premenopausal women, involving the uterine corpus, uterine cervix, or pelvis. All were similarly characterized by lobules of monomorphic epithelioid and/or spindled cells arranged in sheets, cords, trabeculae, and micro- and macrocysts associated with abundant myxoid matrix and hemorrhage, creating labyrinth-like or pulmonary edema-like architecture. Myogenic differentiation with frequent estrogen receptor and progesterone receptor staining and no CD10 expression characterized all tumors. All cases showed high NR4A3 RNA expression levels and NOR1 (NR4A3) nuclear staining similar to salivary gland acinic cell carcinomas and a subset of extraskeletal myxoid chondrosarcomas harboring NR4A3 rearrangements. NOR1 (NR4A3) immunohistochemistry may serve as a useful diagnostic marker of NR4A3 fusion-positive gynecologic leiomyosarcomas.

Association between gynecologic cancer and Alzheimer's disease: a bidirectional mendelian randomization study.

BACKGROUND: Alzheimer's disease (AD) manifests with a higher rate of occurrence in women. Previous epidemiological studies have suggested a potential association between AD and gynecological cancers, but the causal relationship between them remains unclear. This study aims to explore the causal link between 12 types of gynecological cancers and AD using a bidirectional Mendelian randomization (MR) approach. METHODS: We obtained genetic correlation tools for AD using data from the most extensive genome-wide association study. Genetic correlation data for 12 types of gynecological cancers were also sourced from the Finnish Biobank. These cancers include breast cancer (BC), cervical adenocarcinoma (CA), cervical squamous cell carcinoma (CSCC), cervical cancer (CC), endometrial cancer (EC), ovarian endometrioid carcinoma (OEC), ovarian cancer (OC), ovarian serous carcinoma (OSC), breast carcinoma in situ (BCIS), cervical carcinoma in situ (CCIS), endometrial carcinoma in situ (ECIS), and vulvar carcinoma in situ (VCIS). We used the inverse-variance weighted (IVW) model for causal analysis and conducted horizontal pleiotropy tests, heterogeneity tests, MR-PRESSO tests, and leave-one-out analyses to ensure the robustness of our results. We also applied replication analysis and meta-analysis to further validate our experimental results. RESULTS: The study found that EC (P_IVW =0.037, OR [95% CI] = 1.032 [1.002, 1.064]) and CCIS (P_IVW = 0.046, OR [95% CI] = 1.032 [1.011, 1.064]) increase the risk of AD, whereas OC was negatively correlated with AD (P_IVW = 0.016, OR [95% CI] = 0.974[0.954, 0.995]). In reverse MR analysis, AD increased the risk of CC (P_IVW = 0.039, OR [95% CI] = 1.395 [1.017, 1.914]) and VCIS (P_IVW = 0.041, OR [95% CI] = 1.761 [1.027, 2.021]), but was negatively correlated with OEC (P_IVW = 0.034, OR [95% CI] = 0.634 [0.417, 0.966]). Sensitivity analysis results demonstrated robustness. These findings were further substantiated through replication and meta-analyses. CONCLUSIONS: Our MR study supports a causal relationship between AD and gynecological cancers. This encourages further research into the incidence of gynecological cancers in female Alzheimer's patients and the active prevention of AD.

The emerging roles of long non-coding RNA (lncRNA) H19 in gynecologic cancers.

Long non-coding RNA (lncRNA) H19 has gained significant recognition as a pivotal contributor to the initiation and advancement of gynecologic cancers, encompassing ovarian, endometrial, cervical, and breast cancers. H19 exhibits a complex array of mechanisms, demonstrating dualistic effects on tumorigenesis as it can function as both an oncogene and a tumor suppressor, contingent upon the specific context and type of cancer being investigated. In ovarian cancer, H19 promotes tumor growth, metastasis, and chemoresistance through modulation of key signaling pathways and interaction with microRNAs. Conversely, in endometrial cancer, H19 acts as a tumor suppressor by inhibiting proliferation, inducing apoptosis, and regulating epithelial-mesenchymal transition. Additionally, H19 has been implicated in cervical and breast cancers, where it influences cell proliferation, invasion, and immune evasion. Moreover, H19 has potential as a diagnostic and prognostic biomarker for gynecologic cancers, with its expression levels correlating with clinical parameters and patient outcomes. Understanding the functional roles of H19 in gynecologic cancers is crucial for the development of targeted therapeutic strategies and personalized treatment approaches. Further investigation into the intricate molecular mechanisms underlying H19's involvement in gynecologic malignancies is warranted to fully unravel its therapeutic potential and clinical implications. This review aims to elucidate the functional roles of H19 in various gynecologic malignancies.

ChatGPT accurately performs genetic counseling for gynecologic cancers.

OBJECTIVE: Artificial Intelligence (AI) systems such as ChatGPT can take medical examinations and counsel patients regarding medical diagnosis. We aim to quantify the accuracy of the ChatGPT V3.4 in answering commonly asked questions pertaining to genetic testing and counseling for gynecologic cancers. METHODS: Forty questions were formulated in conjunction with gynecologic oncologists and adapted from professional society guidelines and ChatGPT version 3.5 was queried, the version that is readily available to the public. The two categories of questions were genetic counseling guidelines and questions pertaining to specific genetic disorders. The answers were scored by two attending Gynecologic Oncologists according to the following scale: 1) correct and comprehensive, 2) correct but not comprehensive, 3) some correct, some incorrect, and 4) completely incorrect. Scoring discrepancies were resolved by additional third reviewer. The proportion of responses earning each score were calculated overall and within each question category. RESULTS: ChatGPT provided correct and comprehensive answers to 33/40 (82.5%) questions, correct but not comprehensive answers to 6/40 (15%) questions, partially incorrect answers to 1/40 (2.5%) questions, and completely incorrect answers to 0/40 (0%) questions. The genetic counseling category of questions had the highest proportion of answers that were both correct and comprehensive with ChatGPT answering all 20/20 questions with 100% accuracy and were comprehensive in responses. ChatGPT performed equally in the specific genetic disorders category, with 88.2% (15/17) and 66.6% (2/3) correct and comprehensive answers to questions pertaining to hereditary breast and ovarian cancer and Lynch syndrome questions respectively. CONCLUSION: ChatGPT accurately answers questions about genetic syndromes, genetic testing, and counseling in majority of the studied questions. These data suggest this powerful tool can be utilized as a patient resource for genetic counseling questions, though more data input from gynecologic oncologists would be needed to educate patients on genetic syndromes.

Molecular landscape of ERBB2/HER2 gene amplification among patients with gynecologic malignancies; clinical implications and future directions.

OBJECTIVE: Investigate the prevalence of ERBB2/HER2 gene amplification among patients with gynecologic malignancies. METHODS: The American Association of Cancer Research (AACR) Genomics Evidence of Neoplasia Information Exchange (GENIE) (version 13.1) database was accessed and patients with endometrial, ovarian, and cervical cancer were identified. Patients with available data on the presence of copy-number gene alterations were selected for further analysis. Incidence of ERBB2 amplification following stratification by tumor site and histology was evaluated. Data from the OncoKB database, as provided by cBioPortal, was utilized to determine presence of pathogenic genomic alterations. RESULTS: A total of 6961 patients who met the inclusion criteria were identified: 49.1% with ovarian cancer, 45.2% with endometrial cancer and 5.7% with cervical cancer respectively. Overall incidence of ERBB2 amplification was 3.8%. Highest incidence of ERBB2 amplification was observed among patients with mucinous ovarian (14.4%), uterine serous (13.2%), uterine clear cell (9.4%), and uterine carcinosarcoma (7.9%). ERBB2 amplification was rare among patients with TP53 wild-type endometrioid endometrial cancer (0.4%). High incidence of mutations in genes of the PI3K pathway was observed among patients with ERBB2 amplified tumors. CONCLUSION: ERBB2 amplification is frequently encountered among patients with uterine serous carcinoma, and mucinous ovarian carcinoma. In addition, a high incidence was also observed among those with uterine clear cell carcinoma, and uterine carcinosarcoma. For patients with endometrioid endometrial carcinoma, incidence of ERBB2 amplification is low, especially in the absence of TP53 mutations.

Alpelisib for PIK3CA-mutated advanced gynecological cancers: First clues of clinical activity.

OBJECTIVE: Recurrent gynecological tumors (e.g., endometrial, and ovarian cancers) are incurable diseases; therefore, new treatment options are urgently needed. The PTEN-AKT-PI3K pathway is frequently altered in these tumors, representing a potential treatment target. Alpelisib is an α-specific PI3K inhibitor approved in PIK3CA-mutated advanced breast cancer. We report outcomes from a large series of patients with PIK3CA-mutated gynecological cancers prospectively treated with alpelisib within a controlled program. METHODS: From April 2021 to December 2022, 36 patients with PIK3CA-mutated advanced gynecological cancers received alpelisib 300 mg orally once daily. Objective response (ORR) and disease control (DCR) rates provided measure of the antitumor activity of alpelisib, the primary objective of the study. RESULTS: Included patients had endometrial (17/36 [47%]), ovarian (10/36 [28%]), or other gynecological cancers (9/36 [25%]). Most patients had received 2-3 prior systemic treatments (endometrial, 47·2%; ovarian, 60%; other, 56%), and presented with visceral metastases at baseline (82%, 70%, and 56%, respectively). Overall, 17 different PIK3CA mutations were found, including 53% in the kinase domain (most commonly H1047R) and 36% in the helical domain (most commonly E545K). Overall, the ORR was 28% and DCR was 61%, with the greatest benefit observed in patients with endometrial cancer (35% and 71%, respectively). CONCLUSION: Alpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers.

Impact of pharmacogenomic profiles on post-surgical pain following laparotomy for gynecologic pathology.

OBJECTIVES: The aim of this prospective study was to compare perioperative opioid use in women by status of CYP2D6, a highly polymorphic pharmacogene relevant to opioid metabolism. METHODS: Patients undergoing laparotomy were prospectively recruited and provided a preoperative saliva swab for a pharmacogenomic (PGx) gene panel. Postoperative opioid usage and pain scores were evaluated via chart review and a phone survey. Pharmacogenes known to be relevant to opioid metabolism were genotyped, and opioid metabolizing activity predicted by CYP2D6 genotyping. Patient and procedural factors were compared using Fisher's exact and Kruskal-Wallis tests. RESULTS: The 96 enrolled patients were classified as ultra-rapid (N = 3, 3%), normal (58, 60%), intermediate (27, 28%), and poor (8, 8%) opioid metabolizers. There was no difference in surgical complexity across CYP2D6 categories (p = 0.61). Morphine Milligram Equivalents (MME) consumed during the first 24 h after peri-operative suite exit were significantly different between groups: ultrarapid metabolizers had the highest median MME (75, IQR 45-88) compared to the other three groups (normal metabolizers 23 [8-45], intermediate metabolizers 48 [20-63], poor metabolizers 31 [12-53], p = 0.03). Opioid requirements were clinically greater in ultrarapid metabolizers during the second 24 h and last 24 h but were statistically similar (p = 0.07). There was no difference in MME prescribed at discharge (p = 0.22) or patient satisfaction with pain control (p = 0.64) between groups. CONCLUSIONS: A positive association existed between increased CYP2D6 activity and in-hospital opioid requirements, especially in the first 24 h after surgery. This provides important information to further individualize opioid prescriptions for patients undergoing laparotomy for gynecologic pathology.

The microRNA Let-7 and its exosomal form: Epigenetic regulators of gynecological cancers.

Many types of gynecological cancer (GC) are often silent until they reach an advanced stage, and are therefore often diagnosed too late for effective treatment. Hence, there is a real need for more efficient diagnosis and treatment for patients with GC. During recent years, researchers have increasingly studied the impact of microRNAs cancer development, leading to a number of applications in detection and treatment. MicroRNAs are a particular group of tiny RNA molecules that regulate regular gene expression by affecting the translation process. The downregulation of numerous miRNAs has been observed in human malignancies. Let-7 is an example of a miRNA that controls cellular processes as well as signaling cascades to affect post-transcriptional gene expression. Recent research supports the hypothesis that enhancing let-7 expression in those cancers where it is downregulated may be a potential treatment option. Exosomes are tiny vesicles that move through body fluids and can include components like miRNAs (including let-7) that are important for communication between cells. Studies proved that exosomes are able to enhance tumor growth, angiogenesis, chemoresistance, metastasis, and immune evasion, thus suggesting their importance in GC management.

Circulating Tumor DNA (ctDNA) and Its Role in Gynecologic Malignancies.

OPINION STATEMENT: Circulating tumor DNA (ctDNA) refers to small fragments of DNA released into the bloodstream by cancer cells. It is obtained through "liquid biopsy;" which most commonly refers to plasma or blood samples, but can be obtained from a number of bodily fluids including ascitic fluid, saliva, and even urine and stool. ctDNA is detected via polymerase chain reaction (PCR) or next-generation sequencing (NGS). The DNA from these samples is analyzed for the detection of point mutations, copy-number alterations, gene fusion, and DNA methylation. These results have the potential for use in cancer diagnosis, determining prognosis, targeting gene-specific therapies, and monitoring for/predicting disease recurrence and response to treatment. ctDNA offers an alternative to tissue biopsy; it is less invasive and can be monitored serially over time without multiple procedures. Moreover it may have the ability to detect disease recurrence or predict behavior in a way that solid tissue biopsies, tumor marker surveillance, and imaging cannot. Recent explosion in interest in ctDNA shows promising developments for widespread adoption of these techniques in cancer care. However, the use of ctDNA in diagnosis and treatment of gynecologic malignancies is currently limited, compared to adoption in other solid-organ tumors such as breast and colorectal cancers. Compared to other cancer types, there appear to be fewer comprehensive studies and clinical validations specifically focusing on the use of ctDNA in gynecologic cancers. More research is needed in this area to advance the potential for use of ctDNA in ovarian, endometrial, and cervical cancers before this can be routinely adopted to improve care for patients with gynecologic malignancies.

Genetic risk assessment in breast and gynecologic malignancies- what's to know in 2024?

PURPOSE OF REVIEW: Hereditary cancer risk assessment and counseling have become integral in oncology care, especially in breast and gynecologic malignancies where genetic test results impact management. However, a large number of patients who could benefit from genetic testing are not getting tested. As such, genetic risk assessment and counseling methods have had to evolve to meet the needs of this expanding patient population. RECENT FINDINGS: "Mainstreaming" genetic testing is an initiative to incorporate genetic testing into routine cancer care in lieu of the traditional genetic counseling model to improve uptake of testing while minimizing expansion of genetic counselor and clinic resources. These models have performed well in various institutions demonstrating an improvement in clinical efficacy. However, missed opportunities from the preventive care standpoint, a core value of cancer genetics risk assessment, have become apparent. The focus of these models is on the patient's cancer diagnosis and comprehensive/familial genetic risk assessment is not often completed. SUMMARY: Identifying patients at an increased risk of cancer, even in the absence of a hereditary cancer predisposition syndrome, is important in tailoring screening and preventive measures. As we look to the future, we need to critically approach mainstreaming and determine how to reincorporate comprehensive genetic risk assessment into our models.

Real-world efficacy and safety of low-dose pembrolizumab in patients with advanced and refractory gynecologic cancers.

OBJECTIVE: The approved standard dose of pembrolizumab (200 mg administrated every 3 weeks) for cancer treatment imposes a significant financial burden on patients. However, no study has analyzed the clinical outcomes of low-dose pembrolizumab among individuals diagnosed with gynecologic cancer. The primary objective of this study was to assess the effectiveness and safety of a low-dose pembrolizumab regimen in real-world clinical practice. METHODS: We retrospectively assessed the efficacy and safety data of patients with gynecologic malignancies who received pembrolizumab between 2017 and 2022 at Kaohsiung Chang Gung Memorial Hospital. Furthermore, we conducted a comparative analysis of the objective response rate (ORR) and progression-free survival (PFS) between patients with deficient mismatch repair (dMMR) and proficient MMR (pMMR). RESULTS: A total of thirty-nine patients were included and received pembrolizumab at fixed dosages of 50 mg (5.1%), 100 mg (84.6%) and 200 mg (10.3%) per cycle. Compared to the pMMR group, the dMMR group exhibited a tendency toward improved ORR (45.5% vs. 13.0%, p = 0.074), and notably, the median duration of response remained unreached. There was no significant difference in PFS between the dMMR and pMMR groups; however, the patients with dMMR in tumor tissue had a trend of better survival (p = 0.079). Incidence of immune-related adverse events (irAEs) of any grade was observed in 13 patients (33.3%), with 3 individuals (7.7%) experiencing grade 3 or 4 events. CONCLUSION: Low-dose pembrolizumab may be a cost-effective and safe treatment option without compromising clinical outcomes in patients with refractory gynecologic cancers.

Genetics and beyond: Precision Medicine Real-World Data for Patients with Cervical, Vaginal or Vulvar Cancer in a Tertiary Cancer Center.

Advances in molecular tumor diagnostics have transformed cancer care. However, it remains unclear whether precision oncology has the same impact and transformative nature across all malignancies. We conducted a retrospective analysis of patients with human papillomavirus (HPV)-related gynecologic malignancies who underwent comprehensive molecular profiling and subsequent discussion at the interdisciplinary Molecular Tumor Board (MTB) of the University Hospital, LMU Munich, between 11/2017 and 06/2022. We identified a total cohort of 31 patients diagnosed with cervical (CC), vaginal or vulvar cancer. Twenty-two patients (fraction: 0.71) harbored at least one mutation. Fifteen patients (0.48) had an actionable mutation and fourteen (0.45) received a recommendation for a targeted treatment within the MTB. One CC patient received a biomarker-guided treatment recommended by the MTB and achieved stable disease on the mTOR inhibitor temsirolimus for eight months. Factors leading to non-adherence to MTB recommendations in other patient cases included informed patient refusal, rapid deterioration, stable disease, or use of alternative targeted but biomarker-agnostic treatments such as antibody-drug conjugates or checkpoint inhibitors. Despite a remarkable rate of actionable mutations in HPV-related gynecologic malignancies at our institution, immediate implementation of biomarker-guided targeted treatment recommendations remained low, and access to targeted treatment options after MTB discussion remained a major challenge.

The prognostic impact of peritoneal tumour DNA in gastrointestinal and gynaecological malignancies: a systematic review.

Peritoneal metastases from various abdominal cancer types are common and carry poor prognosis. The presence of peritoneal disease upstages cancer diagnosis and alters disease trajectory and treatment pathway in many cancer types. Therefore, accurate and timely detection of peritoneal disease is crucial. The current practice of diagnostic laparoscopy and peritoneal lavage cytology (PLC) in detecting peritoneal disease has variable sensitivity. The significant proportion of peritoneal recurrence seen during follow-up in patients where initial PLC was negative indicates the ongoing need for a better diagnostic tool for detecting clinically occult peritoneal disease, especially peritoneal micro-metastases. Advancement in liquid biopsy has allowed the development and use of peritoneal tumour DNA (ptDNA) as a cancer-specific biomarker within the peritoneum, and the presence of ptDNA may be a surrogate marker for early peritoneal metastases. A growing body of literature on ptDNA in different cancer types portends promising results. Here, we conduct a systematic review to evaluate the prognostic impact of ptDNA in various cancer types and discuss its potential future clinical applications, with a focus on gastrointestinal and gynaecological malignancies.

Pharmacogenetics as a predictor chemotherapy induced peripheral neuropathy in gynecologic cancer patients treated with Taxane-based chemotherapy.

BACKGROUND: This study investigated whether there are pharmacogenomic markers predictive of chemotherapy induced peripheral neuropathy (CIPN) as a result of taxane-based chemotherapy. METHODS: Patients were enrolled from August 2020 to November 2020 in a prospective, case-control trial evaluating pharmacogenetic predictors of CIPN. All women were treated with at least 3 cycles of taxane-based chemotherapy for histologically confirmed gynecologic malignancies. Buccal saliva samples were used to test for 32 drug metabolism variations. All testing was performed by ⍺LPHA-GENOMIX laboratories. Fisher's Exact test was used to assess for event differences of categorical variables. RESULTS: Of 102 enrolled patients, 58%, 28%, and 14% had ovarian, endometrial, or cervical cancers, respectively. The median age was 67, 72% were Caucasian and 25% were African American. 16% of patients were treated with 3-4 cycles, 57% received 5-7 cycles, and 27% received 8 or more cycles of chemotherapy that included paclitaxel. Grade 2 CIPN was experienced by 51 patients. There was no difference in age, race, disease site, or number of chemotherapy cycles (p > 0.05) between those who did or did not develop CIPN. CYP2D6 genotype (p = 0.009) and CYP3A5 genotype (p = 0.023) had different frequencies among those with and without CIPN. Patients classified as having poor or intermediate function of CYP2D6 had increased risk of CIPN (OR 1.63, 95% CI 1.04-2.57, p = 0.026). There was no difference in CYP2D6 phenotype by race (p = 0.29). No patients with normal function of CYP3A5 developed CIPN. There were no Caucasians with normal function of CYP3A5, but 28% of African Americans had normal CYP3A5 function (p < 0.001). CONCLUSIONS: Pharmacogenomics appear associated with the development of CIPN and may be able to help personalize treatment decision making.

Systematic mapping review of guidelines for BRCA1/2 genetic testing globally: investigating geographic and regional disparities in health equity for women and families at risk for hereditary ovarian cancer.

OBJECTIVE: Identification of persons at risk for hereditary syndromes through genetic testing prior to cancer diagnosis may proactively reduce the cancer burden morbidity and mortality. Using a framework of health equity, this study characterizes the global landscape of publication and reference to BRCA1/2 genetic testing guidelines (GTG). METHODS: This study used a systematic literature search supplemented by an International Gynecologic Cancer Society (IGCS) informal survey and cross referenced with Myriad Genetics records, to identify published GTG, their country of origin, and countries referencing them. RESULTS: Of 1011 identified publications, 166 met the inclusion criteria, from which 46 unique guidelines were identified, published by 18 countries and two regions (Europe and the UK). Authorship from the USA accounted for 63% of publications on GTG. Systematic mapping reviews revealed 34 countries with published and/or referenced guidelines, the IGCS survey revealed 22 additional countries, and coordination with Myriad Genetics revealed additional information for two countries and primary information for one country. Of the 57 countries evaluated, 33% published their own guidelines and reference guidelines from another country/region, 5% published their own guidelines without referencing another country/region, and 61% only referenced a guideline from another country/region. No data were available for 138 of 195 countries, disproportionately from Africa, the Middle East, Eastern Europe, and Southeast Asia. CONCLUSIONS: Global geographic disparities in the publication and referencing of GTG exist, with a large emphasis on North American and European guidelines in the published literature. These disparities highlight a need for uniform BRCA GTG to improve global health equity.

Human leukocyte antigen-G in gynaecological tumours.

Gynaecological tumours that threaten the health of women, especially when advanced and recurrent, have remained mostly intractable to existing treatments. Therefore, new therapeutic targets are urgently needed. Human leukocyte antigen-G (HLA-G) is a nonclassical major histocompatibility complex class I molecule typically expressed in foetuses for protection against destruction by the maternal immune system. HLA-G is also expressed under pathological conditions, such as in solid tumours, and may participate in tumour development and serve as a novel immune checkpoint in cancer. Furthermore, it is expressed in most gynaecological tumours. Therefore, inhibiting HLA-G and its receptors to block the immune escape pathway could represent a new strategy in cancer immunotherapy. To the best of our knowledge, this review is the first to summarize recent research findings on HLA-G in gynaecological oncology. We highlight the fact that HLA-G is expressed in gynaecological tumour tissues, wherein it inactivates immune effectors involved in tumour progression. Further studies on HLA-G in gynaecological oncology are needed to incorporate HLA-G into the design and evaluation of immunotherapy for malignant gynaecological diseases.