Ovarian Cancer Risk Prediction - a Clinical Epidemiology Perspective.

Ovarian cancer is a rare and highly heterogeneous disease usually detected at late stages when outcomes are poor. Population-based screening approaches have not been successful at reducing ovarian cancer mortality, but preventive bilateral salpingo-oophorectomy is highly effective at preventing ovarian cancer in high-risk populations. Ovarian cancer risk prediction models may allow identification of populations at increased risk of ovarian cancer for preventive interventions or targeted early detection. We propose a life-course approach to ovarian cancer risk prediction based on the time at which a risk model should be applied and the risk factors that are available. The discriminative ability of ovarian cancer risk prediction models published so far is limited, with areas under the curve ranging from 0.58-0.65 for different combinations of risk factors and genetic susceptibility markers. Currently proposed absolute risk thresholds for preventive surgery are around 4% lifetime risk. The absolute risk predicted by ovarian cancer risk models ranges from 0.6-2.5% lifetime risk in the general population, highlighting the need to improve ovarian cancer risk prediction models and evaluating new preventive approaches that can be offered to individuals at lower risk.

How far is too far? Cancer prevention and clinical trial enrollment in geographically underserved patient populations.

Despite dedicated efforts to improve equitable access to cancer care in the United States, disparities in cancer outcomes persist, and geographically underserved patients remain at an increased risk of cancer with lower rates of survival. The critical evaluation of cancer prevention inequities and clinical trial access presents the opportunity to outline novel strategies to incrementally improve bookended access to gynecologic cancer care for geographically underserved patients. Cancer prevention strategies that can be addressed in the rural patient population mirror priorities in the Healthy People 2030 objectives and include increased identification of high risk individuals who may benefit from increased cancer screening and risk reduction, increasing the proportion of people who discuss interventions to prevent cancer, such as HPV vaccination, with their provider, and increasing the proportion of adults who complete evidence based cancer screening. Barriers to accrual to clinical trials for rural patients overlap significantly with the same barriers to obtaining health care in general. These barriers include: lack of facilities and specialized providers; lack of robust health infrastructure; inability to travel; and financial barriers. In this review, we will discuss current knowledge and opportunities to improve cancer prevention initiatives and clinical trial enrollment in geographically underserved populations with a focus on rurality.

What About the Others? Clinical Management of Gynecologic Cancer Risk in Patients With Moderate-Risk Hereditary Cancer Genes (ATM, BRIP1, RAD51C, RAD51D, and PALB2).

Hereditary cancer syndromes associated with gynecologic malignancies account for up to 18% of all cases of ovarian, uterine, and cervical cancers, and identification of these syndromes has implications for cancer screening and risk reduction techniques in affected patients. The associated cancer risks with moderate-penetrance genes are rapidly evolving and present variable risks for the provider counseling the patient. In this review, we detail the cancer risk and management of patients with germline PV in the moderate-risk hereditary cancer genes ATM, BRIP1, RAD51C, RAD51D, and PALB2.

Factors affecting adherence to a high-risk surveillance protocol among patients with Li-Fraumeni syndrome.

BACKGROUND: High-risk surveillance for patients with Li-Fraumeni syndrome (LFS) has shown a stage shift and improved overall survival, but is demanding. Our objective was to evaluate surveillance adherence in a population of patients with LFS presenting for high-risk care. METHODS: A retrospective analysis of surveillance adherence of adult patients with LFS at a single institution was performed. Adherence was defined by the duration from initial University of Virginia (UVA) LFS clinic visit to the time of first missed surveillance test. Two-sample t-tests and ANOVA tests were used to identify factors associated with duration of adherence. RESULTS: A total of 42 patients were evaluated in the UVA LFS clinic between 2017 and 2021. Of these, 21 patients met inclusion criteria. At the time of review, 6 patients (29%) were up to date with high-risk surveillance recommendations. The mean duration of adherence was 17 months. Female sex was found to be associated with longer duration of adherence (mean 21 mo vs. 3.5 mo for males, p = 0.02). A personal history or active diagnosis of cancer was also associated with increased adherence (p = 0.02). However, neither age (p = 0.89), geography (p = 0.84), or known family history of LFS (p = 0.08) were associated with duration of adherence. CONCLUSION: Female sex as well as a personal history of cancer were associated with longer duration of adherence to recommended high-risk surveillance among patients with LFS. Identification of barriers to surveillance will be essential moving forward to increase adherence and promote early detection of cancer, thereby reducing the morbidity and mortality of LFS.

Targeting immune checkpoints in gynecologic cancer: updates & perspectives for pathologists.

Checkpoint inhibitor-based immunotherapy is increasingly used in the treatment of gynecologic cancers, and most often targets the PD-1/PD-L1 axis. Pathologists should be familiar with the biomarkers required to determine candidacy for these treatments based on existing FDA approvals, including mismatch repair protein immunohistochemistry, microsatellite instability testing, tumor mutation burden testing, and PD-L1 immunohistochemistry. This review summarizes the rationale behind these treatments and their associated biomarkers and delivers guidance on how to utilize and readout these tests. It also introduces additional biomarkers which may provide information regarding immunotherapeutic vulnerability in the future such as neoantigen load; POLE mutation status; and immunohistochemical expression of immunosuppressive checkpoints like LAG-3, TIM-3, TIGIT, and VISTA; immune-activating checkpoints such as CD27, CD40, CD134, and CD137; enzymes such as IDO-1 and adenosine-related compounds; and MHC class I.

MLH1/PMS2-deficient Endometrial Carcinomas in a Universally Screened Population: MLH1 Hypermethylation and Germline Mutation Status.

MLH1/PMS2 loss due to epigenetic hypermethylation of the MLH1 promoter is the most common cause of mismatch repair deficiency in endometrial carcinoma, and typically provides reassurance against an associated germline mutation. To further characterize the genetic features of MLH1/PMS2-deficient endometrial cancers, the departmental database was searched for cases with dual MLH1/PMS2 loss and retained MSH2/6 expression which underwent MLH1 hypermethylation testing. Genetic testing results were obtained when available. One hundred seventeen endometrial cancers met inclusion criteria: 100 (85%) were MLH1-hypermethylated, 3 (3%) were low-level/borderline, 7 (6%) were nonmethylated, and 7 (6%) were insufficient for testing. Sixteen cases (12 MLH1-hypermethylated, 3 nonmethylated, and 1 insufficient for testing) underwent germline testing, 6 of which (37.5%) demonstrated germline variants of unknown significance (VUS) (MSH6, PMS2, POLD1, BRIP1, RAD51D, CHEK2) but no known deleterious mutations. Notably, however, the patients harboring the MSH6 and PMS2 germline VUS had clinical features concerning for Lynch syndrome. One nonmethylated, germline-normal case underwent somatic tumor testing, and demonstrated a somatic MLH1 mutation. In summary, MLH1-hypermethylation accounts for the vast majority of MLH1/PMS2-deficient cancers in a universally screened population, although MLH1 somatic and germline mutations can occur. Occasionally, patients with MLH1-hypermethlated tumors also bear germline VUS in other mismatch repair genes as well as genes implicated in other hereditary cancer syndromes, but their clinical relevance is unclear. Family and personal cancer histories must always be evaluated to determine the need for germline testing in women with loss of MLH1/PMS2, even in the setting of hypermethylation.

MHC class I loss in endometrial carcinoma: a potential resistance mechanism to immune checkpoint inhibition.

Major histocompatibility complex (MHC) class I is a membrane-bound protein complex expressed on nucleated human cells. MHC class I presents intracellular protein fragments to cytotoxic T cells and triggers an activation cascade upon neoantigen detection by these cells. MHC class I loss by tumor cells decreases tumor neoantigen presentation to the immune system and therefore represents a possible mechanism of immunotherapeutic resistance even among cancers that otherwise appear to be good candidates for checkpoint inhibition, such as mismatch repair (MMR)-deficient and PD-L1-positive malignancies. We herein assess MHC class I expression in a range of endometrial carcinomas, including MMR-deficient and PD-L1-positive cancers. Immunohistochemical staining for combined MHC class I A-, B-, and C-heavy chains was performed on 76 cases of endometrial carcinoma and was classified as present, subclonally lost, or diffusely lost. Tumoral PD-L1 expression, PD-L1 combined positive score, and CD3-positive T lymphocytes were also quantified. Forty-two percent of tumors showed loss of MHC class I expression, either in a subclonal (26%) or diffuse (16%) pattern. This included 46% of MMR-deficient and 25% of PD-L1-positive cancers. These findings suggest that tumoral MHC class I status may be an important factor to consider when selecting endometrial cancer patients for checkpoint inhibition.

Clinical significance of homologous recombination deficiency score testing in endometrial Cancer.

BACKGROUND: Homologous recombination deficiency (HRD) score is related to chemotherapy response in some cancers, but its role in endometrial cancer in not known. We determined frequency and clinical significance of alterations in the HR pathway in endometrial cancer. METHODS: 253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts (discovery and replication) were tested for HRD score using the Myriad HRD assay, microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation sequencing assay. HRD scores were also generated on endometrial cancer cell lines and in vivo response to olaparib was assessed. RESULTS: ROC curves were employed to determine optimal cutoffs of HRD in relation to survival impact in endometrial cancer and a cutoff of HRD ≥ 4 was suggested for DFS using the discovery cohort. Patients from two independent cohorts with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score < 4. Both cohorts were further separated into four groups according to molecular subtypes (TMB positive; MSI positive; HRD positive; all others). When grouped by molecular subtype, there was a significant difference between groups using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts. The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments. CONCLUSIONS: High HRD score was associated with worse DFS in our patient cohort. These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer.

LAG-3 and GAL-3 in Endometrial Carcinoma: Emerging Candidates for Immunotherapy.

LAG-3 is an immunosuppressive checkpoint molecule expressed on T cells. One of its ligands, GAL-3, can promote the progression of malignancy and has been identified on tumor cells. Both LAG-3 and GAL-3 are the targets of emerging immunotherapies, but have not been well-studied in endometrial carcinomas. LAG-3, CD3, and GAL-3 immunohistochemistry was performed on 75 endometrial cancers (25 nonmethylated mismatch repair-deficient, 25 MLH1-hypermethylated mismatch repair-deficient, and 25 mismatch repair-intact). LAG-3 and CD3 lymphocytes were averaged per high-power field. Tumoral GAL-3 expression was semiquantitatively scored. Tumor-infiltrating lymphocyte expression of LAG-3 and CD3 were positively correlated (Spearman ρ=0.521, P<0.001) and greater in mismatch repair-deficient compared with mismatch repair-intact tumors (LAG-3: P<0.001; CD3: P<0.001). The majority (64%) of endometrial carcinomas demonstrated ≥1% tumoral GAL-3 expression, with higher rates in mismatch repair-deficient versus intact tumors at the ≥1% (80% vs. 32%, P<0.001) and the ≥5% thresholds (52% vs. 16%, P=0.003). At the ≥5% threshold, nonmethylated mismatch repair-deficient cancers were more likely than intact tumors carcinomas to express GAL-3 (60% vs. 4/25 16%, P=0.003). LAG-3 lymphocytes were positively correlated with GAL-3 expression in nonmethylated mismatch repair-deficient endometrial carcinomas only (Spearman ρ=0.461, P=0.020). LAG-3 tumor-associated lymphocytes and GAL-3 neoplastic cells are common in endometrial carcinomas, particularly in nonmethylated mismatch repair-deficient cancers. This supports a role for immunotherapies targeting LAG-3 and/or GAL-3 in a subset of endometrial carcinomas, potentially in concert with other checkpoint inhibitors.

ß-catenin and PD-L1 expression in mismatch repair deficient endometrial carcinomas.

INTRODUCTION: Predictors of non-response in mismatch repair deficiency cancers are poorly understood. Upregulation of the canonical Wnt pathway has been associated with decreased immune cell infiltration in many cancer types. The relationship between Wnt/ß-catenin pathway activation and the programmed death-ligand 1 axis in endometrial cancer remains poorly characterized. This study evaluates ß-catenin expression in a well characterized cohort of endometrial cancers by mismatch repair status and programmed death-ligand 1 expression. METHODS: Whole sections of formalin-fixed, paraffin embedded tissue from 23 Lynch syndrome-associated carcinomas, 20 mutL homolog-1 (MLH1) promoter hypermethylated carcinomas, and 19 mismatch repair intact carcinomas were evaluated. Immunohistochemistry staining for ß-catenin and programmed death-ligand 1 was performed on all cases. Programmed death-ligand 1 expression was scored in both the tumor and the peri-tumoral immune compartment. Tumor staining was classified as positive when membranous (programmed death-ligand 1) staining was present in ≥1% of tumor cells. Immune stromal staining was scored as positive when ≥5% of peritumoral and intratumoral immune cells (including lymphocytes and macrophages) showed reactivity. RESULTS: Six tumors (6/62, 9.7%) demonstrated nuclear expression of ß-catenin (4 were Lynch syndrome-associated, 1 was MLH1 methylated, 1 was mismatch repair intact). The majority of tumors with nuclear ß-catenin expression demonstrated concomitant tumoral programmed death-ligand 1 expression (5/6, 83.3%) and were more likely to demonstrate tumoral programmed death-ligand 1 expression compared to tumors without nuclear ß-catenin expression (83.3% vs 39.3%, p=0.04). Both tumoral and immune cell expression of programmed death-ligand 1 was statistically significantly associated with mismatch repair deficient tumors. DISCUSSION: Tumors demonstrating nuclear ß-catenin expression were more likely to express tumoral programmed death-ligand 1 staining than tumors without nuclear ß-catenin expression. Nuclear ß-catenin expression could be a potential predictive biomarker for non-response to immune checkpoint inhibition in mismatch repair deficient tumors. Nuclear ß-catenin expression status should be considered as a translational endpoint in future clinical trials of immune checkpoint inhibition in endometrial cancer.

TIM-3 in endometrial carcinomas: an immunotherapeutic target expressed by mismatch repair-deficient and intact cancers.

The checkpoint molecule TIM-3 is a target for emerging immunotherapies and has been identified on a variety of malignancies. Mismatch repair-deficient endometrial carcinomas have demonstrated durable responses to other checkpoint inhibitors due to high neoantigen loads and robust tumor-associated immune responses. However, little is known about TIM-3 expression in this tumor type. Tumor-associated immune and tumoral expression of TIM-3 were evaluated by immunohistochemistry on 75 endometrial carcinomas [25 MLH1 promoter hypermethylated (MLH1-hypermethylated), 25 non-hypermethylated mismatch repair-deficient, and 25 mismatch repair-intact]. All cases showed at least focal immune staining, but moderate and robust immune cell expression were more often observed in mismatch repair-deficient vs intact cases [66 vs 12%, P = 0.00002]. While the majority (77%) of endometrial cancers showed ≥1% tumoral TIM-3 expression, the MLH1-hypermethylated subset was more likely to demonstrate >5% tumoral staining when compared to both mismatch repair-intact and non-methylated mismatch repair-deficient cancers [64 vs. 28% and 32%, respectively; P = 0.02 and P = 0.05]. Within the non-methylated mismatch repair-deficient subset, high-level expression was most often associated with MSH6 loss. Across mismatch repair subgroups, tumoral TIM-3 expression was more common among intermediate and high-grade vs. low-grade tumors using both the 1% (P = 0.02) and 5% expression cut-offs (P = 0.02). In conclusion, tumoral TIM-3 expression is common in both mismatch repair-intact and deficient endometrial cancers, with particularly high levels of expression identified in the setting of MLH1-hypermethylation, MSH6 loss, and intermediate to high histologic grade. Although focal immune cell expression was seen in all tumors, robust expression was significantly more common in the context of mismatch repair deficiency. These data support a potential role for checkpoint inhibitors targeting TIM-3 in a subset of endometrial cancers, including some mismatch repair-intact tumors which are not currently considered immunotherapy candidates.

Targetable Immune Regulatory Molecule Expression in High-Grade Serous Ovarian Carcinomas in African American Women: A Study of PD-L1 and IDO in 112 Cases From the African American Cancer Epidemiology Study (AACES).

African American women with high-grade serous ovarian carcinoma have worse outcomes compared with women of European descent. Although the discrepancy is partially attributed to differences in access to care, the tumor immune microenvironment may also contribute. Expression of targetable immune regulatory molecules such as programmed cell death ligand-1 (PD-L1) and indoleamine 2,3 dioxygenase (IDO) is of particular interest as it may help guide therapy in this population. Using cases from the largest study of African American women with ovarian cancer, the African American Cancer Epidemiology Study, we characterized PD-L1 and IDO expression in 112 high-grade serous ovarian carcinomas. Immunohistochemistry for PD-L1, IDO, CD8, FOX3p, and CD68 was performed. PD-L1 and IDO were scored as the percentage of positive tumor cells and tumor-associated immune cells. CD8 and FOX3p counts were averaged across 10 high-power fields. Cox proportional hazards regression was used to evaluate the association between PD-L1 and IDO expression and survival. Tumor cells were positive for PD-L1 and IDO in 29% and 58% of cases, respectively. The majority showed <10% staining, and no cases exceeded 25% positivity. The majority of PD-L1-positive cases coexpressed IDO. PD-L1 and IDO expression was associated with higher CD8 and FOX3p counts (P<0.05). No association was observed between PD-L1 and IDO and survival. In summary, expression of PD-L1 and IDO is seen in a subset of high-grade serous ovarian carcinoma from African American women and is correlated with elevated lymphocyte infiltration. While PD-L1 and IDO co-expression suggests a role for dual immunotherapy, diffuse expression of PD-L1 and IDO is rare, invoking caution regarding the potential for immunotherapeutic response.

Cases and evidence for panel testing in cancer genetics: Is site-specific testing dead?

Historically in cancer genetic counseling, when a pathogenic variant is found which explains the cancers in the family, at risk family members are offered site-specific testing to identify whether or not they have the previously identified pathogenic variant. Factors such as turnaround times, cost, and insurance coverage all made site-specific testing the most appropriate testing option; however, as turnaround times and costs have substantially dropped and the recognition of double heterozygous families and families with nontraditional presentations has increased, the utility of site-specific testing should be questioned. We present four cases where ordering site-specific testing would have missed a clinically relevant pathogenic variant which raises the question of whether or not site-specific testing should be regularly used in cancer genetic testing.

Indoleamine 2,3-dioxygenase in endometrial cancer: a targetable mechanism of immune resistance in mismatch repair-deficient and intact endometrial carcinomas.

Mismatch repair-deficient endometrial carcinomas are optimal candidates for immunotherapy given their high neoantigen loads, robust lymphoid infiltrates, and frequent PD-L1 expression. However, co-opting the PD-1/PD-L1 pathway is just one mechanism that tumors can utilize to evade host immunity. Another immune modulatory molecule that has been demonstrated in endometrial carcinoma is indoleamine 2,3-dioxygenase (IDO). We herein evaluate IDO expression in 60 endometrial carcinomas and assess results in relation to PD-L1 and mismatch repair status. IDO immunohistochemistry was performed on 60 endometrial carcinomas (20 Lynch syndrome (LS)-associated, 20 MLH1 promoter hypermethylated, and 20 mismatch repair-intact). Eight-five percent of endometrial carcinomas showed IDO tumor staining in >1% of cells. Twenty-five percent were positive in >25% of tumor cells and only 7% exceeded 50% staining. Mismatch repair-deficient cancers were more likely than mismatch repair-intact cancers to be >25% IDO-positive (35% vs. 5% p = 0.024). Differences were amplified when Lynch syndrome-associated cases were evaluated in isolation (50% Lynch syndrome-associated vs. 10% mismatch repair-intact and MLH1-hypermethylated, p = 0.001). Of the four cases showing >50% staining, three were Lynch syndrome-associated and one was MLH1-hypermethylated; no mismatch repair-intact cases had >50% staining. Forty-three percent of IDO-positive tumors were also positive for PD-L1, whereas only two cases showed tumoral PD-L1 in the absence of IDO. In summary, IDO expression is prevalent in endometrial carcinomas and diffuse staining is significantly more common in mismatch repair-deficient cancers, particularly Lynch syndrome-associated cases. Given that the majority of PD-L1 positive cancers also express IDO, synergistic combination therapy with anti-IDO and anti-PD1/PD-L1 may be relevant in this tumor type. Furthermore, anti-IDO therapy may be an option for a small subset of mismatch repair-intact cancers.

The Role of PD-1 Checkpoint Inhibition in Gynecologic Malignancies.

OPINION STATEMENT: Activity of PD-1 and PD-L1 inhibitors has been demonstrated in ovarian, endometrial, and cervical cancer, with a tolerable side effect profile and the highest response rate seen in mismatch repair-deficient endometrial cancers. Other biomarkers are under active investigation. Tumor testing for mismatch repair deficiency or high microsatellite instability for treatment with pembrolizumab should be considered an option for all women with progressive gynecologic malignancy.

Tumor-associated macrophage expression of PD-L1 in implants of high grade serous ovarian carcinoma: A comparison of matched primary and metastatic tumors.

OBJECTIVE: Data on PD-L1 expression in high grade serous ovarian carcinoma (HGSOC) is mixed. Some studies report robust tumor staining and others identify expression limited to tumor-associated macrophages (TAM). TAM PD-L1 expression is induced in HGSOC metastatic implants from patients who have undergone chemotherapy. However, it is unclear whether TAM acquisition of PD-L1 plays a role in treatment naïve tumors. We investigated PD-L1 expression in primary ovarian tumors and matched metastatic implants from predominantly treatment-naïve HGSOC. METHODS: Sixty one primary HGSOC were evaluated with PD-L1 and CD68 IHC: 40 on TMA and 21 on whole section. Whole section cases were matched to a metastatic implant. TAM were delineated by CD68. Membranous PD-L1 staining was scored separately for tumor cells and TAM. RESULTS: Eight percent of primary HGSOC demonstrated PD-L1 expression. In contrast, 74% showed PD-L1+ TAM. In the 16 treatment naïve cases, 13 (81.3%) demonstrated fidelity in intratumoral PD-L1 expression between the primary and metastatic site. Of the 21 matched pairs, only one case (4.8%) did not exhibit PD-L1 positive TAM in the metastatic implant and 19 (90.5%) showed fidelity across both locations. Intratumoral and immune infiltrate PD-L1 expression was not different in cases who received neoadjuvant chemotherapy compared to treatment naïve cases. CONCLUSIONS: PD-L1+ TAM are common in both primary and metastatic HGSOC however tumoral PD-L1 staining is rare. There was high fidelity of PD-L1 expression when comparing primary tumors and metastatic implants in treatment naïve specimens. Clinical trials are needed to determine whether tumor-associated staining correlates with clinical response to PD-1/PD-L1 inhibition.

Potential immunotherapy targets in recurrent cervical cancer.

OBJECTIVE: Our objective was to characterize the intra and peritumoral immune profile in recurrent cervical cancers to identify rational immunotherapy targets. METHODS: Archival pelvic exenteration specimens were examined using a validated multiplex immuno-fluorescent panel of antibodies against cluster of differentiation 8 (CD8), cluster of differentiation 68 (CD68), forkhead box P3 (FoxP3), programmed cell death protein 1 (PD1), and programmed death-ligand 1 (PD-L1, N=28). Clinical data were abstracted from the electronic medical record. RESULTS: Cytotoxic T cells, macrophages, and regulatory T cells were found in higher densities in peritumoral stroma (CD8+ density 497.7 vs 83.5, p<0.0001, CD68+ density 345.0 vs 196.7, p=0.04, FoxP3+ density 214.5 vs 35.6, p<0.0001). Antigen experienced T cells (PD1+) were higher in peritumoral compared to tumor tissue (median normalized fluorescence intensity 0.05 vs 0.0085, p<0.001). Although there was a higher median density of intratumoral cytotoxic T cells and macrophages compared to regulatory T cells (median density CD8+ 83.5 vs 35.6, p<0.05, median density 196.7 vs 35.6, p<0.05), the presence of macrophages correlated with the presence of regulatory T cells in tumors (r=0.58, p=0.001). CONCLUSIONS: While cytotoxic T cells are present in tumor tissue to varying degrees, their density is lower than in peritumoral stroma, suggesting intratumoral exclusion or destruction of T cells. Higher densities of intratumoral macrophages compared to regulatory T cells suggest macrophages may be important contributors to the immunosuppressive tumor environment. Future directions for combination therapy include altering T cell trafficking and targeting tumor associated macrophages (TAMs) to enhance intratumoral activated T cell density and effect a more robust immune response.

Current and future role of genetic screening in gynecologic malignancies.

The world of hereditary cancers has seen exponential growth in recent years. While hereditary breast and ovarian cancer and Lynch syndrome account for the majority of mutations encountered by gynecologists, newly identified deleterious genetic mutations continue to be unearthed with their associated risks of malignancies. However, these advances in genetic cancer predispositions then force practitioners and their patients to confront the uncertainties of these less commonly identified mutations and the fact that there is limited evidence to guide them in expected cancer risk and appropriate risk-reduction strategies. Given the speed of information, it is imperative to involve cancer genetics experts when counseling these patients. In addition, coordination of screening and care in conjunction with specialty high-risk clinics, if available, allows for patients to have centralized management for multiple cancer risks under the guidance of physicians with experience counseling these patients. The objective of this review is to present the current literature regarding genetic mutations associated with gynecologic malignancies as well to propose screening and risk-reduction options for these high-risk patients.

Endometrial Cancers With Activating KRas Mutations Have Activated Estrogen Signaling and Paradoxical Response to MEK Inhibition.

OBJECTIVES: The aims of this study were to determine if activating KRas mutation alters estrogen signaling in endometrial cancer (EC) and to explore the potential therapeutic impact of these alterations. METHODS: The Cancer Genome Atlas was queried for changes in estrogen-regulated genes in EC based on KRas mutation status. In vitro studies were conducted to evaluate estrogen receptor α (ERα) phosphorylation changes and related kinase changes in KRas mutant EC cells. The resulting effect on response to MEK inhibition, using trametinib, was evaluated. Immunohistochemistry was performed on KRas mutant and wild-type EC tumors to test estrogen signaling differences. RESULTS: KRas mutant tumors in The Cancer Genome Atlas showed decreased progesterone receptor expression (P = 0.047). Protein analysis in KRas mutant EC cells also showed decreased expression of ERα (P < 0.001) and progesterone receptor (P = 0.001). Although total ERα is decreased in KRas mutant cells, phospho-ERα S118 was increased compared with wild type. Treatment with trametinib in KRas mutant cells increased phospho-ERα S167 and increased expression of estrogen-regulated genes. While MEK inhibition blocked estradiol-stimulated phosphorylation of ERK1/2 and p90RSK in wild-type cells, phospho-ERK1/2 and phospho-p90RSK were substantially increased in KRas mutants. KRas mutant EC tumor specimens showed similar changes, with increased phospho-ERα S118 and phospho-ERα S167 compared with wild-type EC tumors. CONCLUSIONS: MEK inhibition in KRas mutant cells results in activation of ER signaling and prevents the abrogation of signaling through ERK1/2 and p90RSK that is achieved in KRas wild-type EC cells. Combination therapy with MEK inhibition plus antiestrogen therapy may be necessary to improve response rates in patients with KRas mutant EC.