Persistent cervical cancer disparities among American Indian/Alaska Native women: a systematic scoping review exploring the state of the science in this population.

PURPOSE: American Indian/Alaska Native (AI/AN) populations experience significantly higher incidence and mortality rates of cervical cancer. The objective of this systematic scoping review is to characterize the volume and nature of research being conducted specific to the AI/AN population regarding cervical cancer and related clinical themes. METHODS: This scoping review was conducted in collaboration with the Pacific Northwest Evidence-based Practice Center. Search strategies identified eligible publications from 1990 through 4 February 2022. Two reviewers independently abstracted study data, including clinical area, number of participants and percent inclusion of AI/AN, intervention or risk factor, outcomes reported, Indian Health Service (IHS) Region, and funding source. We used published algorithms to assess study design. RESULTS: Database searches identified 300 unique citations. After full-text evaluation of 129 articles, 78 studies and 9 secondary publications were included (total of 87). Approximately 74% of studies were observational in design, with cross-sectional methodology accounting for 42.7% of all included studies. The most common clinical theme was cervical cancer screening. The most common intervention/exposure was risk factor, typically race (AI/AN compared with other groups) (69%). For studies with documented funding sources, 67% were funded by the US Government. CONCLUSION: Of the small number of publications identified, the majority are funded through government agencies, are descriptive and/or cross-sectional studies that are hypothesis generating in nature, and fail to represent the diversity of the AI/AN populations in the US. This systematic scoping review highlights the paucity of rigorous research being conducted in a population suffering from a greater burden of disease.

Ultrasonographic evaluation of endometrial stripe thickness is insufficient to rule out uterine serous carcinoma.

PURPOSE: Uterine serous carcinoma (USC) is a rare endometrial cancer representing less than 10% of uterine cancers but contributing to up to 50% of the mortality. Delay in diagnosis with this high-grade histology can have significant clinical impact. USC is known to arise in a background of endometrial atrophy. We investigated endometrial stripe (EMS) thickness in USC to evaluate current guidelines for postmenopausal bleeding in the context of this histology. METHODS: Retrospective chart review was conducted using ICD-9 and ICD-10 codes over an 18-year period. We included 139 patients with USC and compared characteristics of patients with EMS ≤ 4 mm and EMS > 4 mm. Chi-square or Fisher's exact tests were used to compare proportions and two-tailed t-tests to compare means. A p-value of < 0.05 was considered statistically significant. RESULTS: Most patients were white, obese, and multiparous. Thirty-two (23%) had an EMS ≤ 4 mm; 107 (77%) had an EMS > 4 mm. There were no statistically significant differences in age at diagnosis or presenting symptoms between groups, and postmenopausal bleeding was the most common symptom in each group. CONCLUSION: Nearly 25% of patients with USC initially evaluated with transvaginal ultrasound were found to have an EMS ≤ 4 mm. If transvaginal ultrasound is used to triage these patients, one in four women will potentially experience a delay in diagnosis that may impact their prognosis.

Ovarian preservation compared to oophorectomy in premenopausal women with early-stage, low-grade endometrial Cancer: A cost-effectiveness analysis.

OBJECTIVES: Standard treatment for endometrial cancer is a hysterectomy, bilateral salpingo-oophorectomy, and lymph node assessment. In premenopausal women, removal of the ovaries may not be necessary and could increase the risk of all-cause mortality. We sought to estimate the outcomes, costs, and cost-effectiveness of oophorectomy versus ovarian preservation in premenopausal women with early-stage, low-grade endometrial cancer. METHODS: A decision-analytic model was designed using TreeAge software comparing oophorectomy to ovarian preservation in premenopausal women with early-stage, low-grade endometrial cancer. We used a theoretical cohort of 10,600 women to represent our population of interest in the United States in 2021. Outcomes included cancer recurrences, ovarian cancer diagnoses, deaths, rates of vaginal atrophy, costs, and quality-adjusted life years (QALYs). The cost-effectiveness threshold was set at $100,000/QALY. Model inputs were derived from the literature. Sensitivity analyses were conducted to evaluate the robustness of the results. RESULTS: Oophorectomy resulted in more deaths and higher rates of vaginal atrophy, while ovarian preservation resulted in 100 cases of ovarian cancer. Ovarian preservation resulted in lower costs and higher QALYs making it cost effective when compared to oophorectomy. Sensitivity analyses demonstrated the probability of cancer recurrence after ovarian preservation and probability of developing ovarian cancer were the most impactful variables in our model. CONCLUSION: Ovarian preservation is cost-effective in premenopausal women with early-stage, low-grade endometrial cancer when compared to oophorectomy. Ovarian preservation may prevent surgical menopause, which may improve quality of life and overall mortality without compromising oncologic outcomes, and should be strongly considered in premenopausal women with early stage disease.

Acceptability of human papillomavirus self-collection and the role of telehealth: a prospective, randomized study stratified by menopausal status.

OBJECTIVE: We investigated the utility of telehealth instruction versus mail-based written instruction in facilitating high-risk human papillomavirus (hrHPV) self-collection among post-menopausal patients compared with pre-menopausal patients, as well as the impact on acceptability and feasibility. METHODS: We conducted a prospective, randomized study of people eligible for cervical cancer screening, stratified by menopausal status, to undergo standard written or telehealth-based instructions for hrHPV self-collection. English speaking individuals residing in Oregon, with a cervix, eligible for primary hrHPV testing, and with access to a video-capable device were included. Patients with prior hysterectomy, trachelectomy, diagnosis of cervical cancer, or pelvic radiation for gynecologic cancer were excluded. We compared preference for and opinions about self-collection and hrHPV test results, by randomization group and stratified by menopausal status using descriptive statistics. RESULTS: Among 123 patients enrolled, 61 identified as post-menopausal with a median age of 57 years. While the majority of post-menopausal participants who received telehealth instructions found it helpful, only 6.1% considered telehealth instructions necessary to complete self-testing. There was no difference in opinion of telehealth by menopausal status. Overall, 88.5% of post-menopausal participants preferred self-collection to provider-collection. There were no significant differences between pre- and post-menopausal participants in terms of test preference, discomfort, ease of use, or perceptions of self-collection. CONCLUSION: Telehealth instruction did not add significant value to patients participating in hrHPV self-collection, nor did it alter the acceptability of hrHPV-self collection among an English-speaking cohort. Compared with prior experiences with provider-collected screening, hrHPV self-collection was preferred by both pre- and post-menopausal participants. There were no significant differences in preference for provider- versus self-collection when stratified by menopausal status.

Success Rates of Sentinel Lymph Node Mapping for Endometrial Cancer in Patients with Body Mass Index < 45 Compared with Body Mass Index ≥ 45.

STUDY OBJECTIVE: The objective is to evaluate the rate of sentinel lymph node (SLN) mapping in patients with body mass index (BMI [kg/m2]) BMI ≥ 45 compared with < 45. DESIGN: A retrospective chart review. SETTING: Three urban referral-based settings-1 academic and 2 community based. PATIENTS: Patients age ≥ 18 years, with endometrial intraepithelial neoplasia or clinical stage 1 endometrial cancer who underwent robot-assisted total laparoscopic hysterectomy with attempted SLN mapping between January 2015 and December 2021. INTERVENTIONS: Robot-assisted total laparoscopic hysterectomy with attempted SLN mapping. MEASUREMENTS AND MAIN RESULTS: A total of 933 subjects were included: 795 (85.2%) with BMI < 45 and 138 (14.8%) with BMI ≥ 45. Comparing the BMI < 45 with BMI ≥ 45 group, bilateral mapping was successful in 541 (68.1%) vs 63 (45.7%), respectively. Unilateral mapping was successful in 162 (20.4%) vs 33 (23.9%), respectively. Failure to map occurred in 92 (11.6%) vs 42 (30.4%) (p <.001), respectively. Exploratory analysis also suggested an inverse relationship between success rate of bilateral SLN mapping and BMI, with patients with BMI < 20 having bilateral SLN mapping rates of 86.5% and patients with BMI ≥ 61 having rates of 20.0%. The steepest decline in bilateral SLN mapping rates was from BMI group 46 to 50 compared to 51 to 55, at 55.4% to 37.5%, respectively. Adjusted odds ratio (compared with those with BMI < 30) for those in the BMI 30 to 44 group was 0.36 (95% confidence interval 0.21-0.60) and for those in the BMI ≥ 45 group was 0.10 (95% confidence interval 0.06-0.19). CONCLUSION: There is a statistically significant lower rate of SLN mapping in patients with a BMI ≥ 45 than BMI < 45. Understanding the success of SLN mapping in patients with morbid obesity is essential for preoperative counseling, surgical planning, and developing a risk-appropriate postoperative treatment plan.

Hysterectomy with a general gynecologist vs gynecologic-oncologist in the setting of endometrial intraepithelial neoplasia: a cost-effectiveness analysis.

BACKGROUND: Standard treatment for patients with endometrial intraepithelial neoplasia (EIN) is a hysterectomy, which has a 43% risk of concomitant endometrial cancer on final pathology. General gynecologists and gynecologic-oncologists perform hysterectomies; however, patients who have a hysterectomy for EIN with a general gynecologist and are found to have cancer may require a second surgery by a gynecologic-oncologist to complete staging. There is ongoing discussion regarding whether patients with EIN should be provided the option to receive the initial hysterectomy with a gynecologic-oncologist. OBJECTIVE: This study aimed to better understand if patients with EIN should be initially referred to a gynecologic-oncologist for treatment. We examined the cost-effectiveness of hysterectomy by general gynecologists vs gynecologic-oncologists for patients with EIN. STUDY DESIGN: We created a decision-analytical model using TreeAge Pro software to compare outcomes between hysterectomies by general gynecologists and those by gynecologic-oncologists in patients with EIN. Our theoretical cohort contained 200,000 patients, an estimate of the number of individuals diagnosed with EIN each year in the United States. Outcomes included costs, quality-adjusted life years, primary lymph node dissection, secondary lymph node dissection, surgical site infection, and perioperative mortality. We assumed that surgical morbidity and mortality were the same under generalist and specialist care and applied costs of travel and lost work for those seeing a gynecologic-oncologist. We performed univariable sensitivity analyses and multivariable probabilistic sensitivity analysis to assess the model's robustness given the uncertainty of model inputs. RESULTS: In our theoretical cohort of 200,000 patients with EIN, hysterectomy with a gynecologic-oncologist was associated with a decrease of 10,811 second surgeries for lymph node dissection, 87 surgical site infections, and 9 perioperative mortalities. When hysterectomy was performed by a general gynecologist, 9 fewer patients had a lymph node dissection because of perioperative mortalities that occurred before lymph node dissection with a gynecologic-oncologist. Hysterectomy with a gynecologic-oncologist was the dominant, cost-effective strategy because it saved $116 million and increased quality-adjusted life years by 180. In our univariable analyses, hysterectomy with a gynecologic-oncologist was cost-saving and increased quality-adjusted life years over a wide range of probabilities and costs for lymph node dissection, surgical site infection, and perioperative mortality. However, hysterectomy with a gynecologic-oncologist was only a cost-effective and cost-saving strategy in just over 50% of multivariable simulations, demonstrating that there is significant uncertainty in the model's cost-effectiveness. CONCLUSION: In our model, hysterectomy with a gynecologic-oncologist for patients with EIN was associated with cost savings and increased quality-adjusted life years. Our study supports that patients undergoing hysterectomy for EIN at institutions using Mayo criteria to determine need for lymphadenectomy may benefit from surgery with a gynecologic-oncologist rather than a general gynecologist to reduce costs and adverse events associated with a second surgery.

HPV self-collection: what are we waiting for? Exploration of attitudes from frontline healthcare providers.

OBJECTIVE: Polymerase chain reaction based human papilloma virus (HPV) self-collection for cervical cancer screening is well established. It is utilized worldwide, accepted by patients, is cost-effective, has comparable sensitivity to provider-collected samples, and increases screening rates, however clinical practice in the United States has not shifted to include HPV self-collection. This study sought to examine provider knowledge and attitudes to better understand why HPV self-collection is not being utilized. METHODS: An observational, qualitative study was conducted. Data were collected with semi-structured focus groups and individual interviews with Oregon healthcare providers. Focus groups and interviews were continued until data saturation was achieved. A grounded theory method was used for analysis, a cyclical process of coding data, memo-writing, and theoretical sampling to the point of saturation. RESULTS: Eighteen healthcare providers participated in the focus group and interviews. They represented 14 of 36 counties across Oregon and 50% were physicians, 33% were nurse practitioners, and 94% worked within family medicine. All providers performed cervical cancer screening according to current American Society for Colposcopy and Cervical Pathology guidelines. Five overarching themes emerged: provider concerns, clinical and provider barriers, patient perspective and barriers, process-based themes, and barriers to cervical cancer screening. Nearly all providers stated they will offer HPV self-collection to most of their patients once available. CONCLUSION: While providers identified concerns and barriers for initiating HPV self-collection, there was a strong desire to implement HPV self-collection and acceptance within patient populations was assumed. Providers indicated the need for HPV self-collection to be incorporated into national screening guidelines along with best practices on how to successfully implement this modality to further increase cervical cancer screening rates.

Does obesity influence the preferred treatment approach for early-stage cervical cancer? A cost-effectiveness analysis.

OBJECTIVE: Abdominal radical hysterectomy in early-stage cervical cancer has higher rates of disease-free and overall survival compared with minimally invasive radical hysterectomy. Abdominal radical hysterectomy may be technically challenging at higher body mass index levels resulting in poorer surgical outcomes. This study sought to examine the influence of body mass index on outcomes and cost effectiveness between different treatments for early-stage cervical cancer. METHODS: A Markov decision-analytic model was designed using TreeAge Pro software to compare the outcomes and costs of primary chemoradiation versus surgery in women with early-stage cervical cancer. The study used a theoretical cohort of 6000 women who were treated with abdominal radical hysterectomy, minimally invasive radical hysterectomy, or primary chemoradiation therapy. We compared the results for three body mass index groups: less than 30 kg/m2, 30-39.9 kg/m2, and 40 kg/m2 or higher. Model inputs were derived from the literature. Outcomes included complications, recurrence, death, costs, and quality-adjusted life years. An incremental cost-effectiveness ratio of less than $100 000 per quality-adjusted life year was used as our willingness-to-pay threshold. Sensitivity analyses were performed broadly to determine the robustness of the results. RESULTS: Comparing abdominal radical hysterectomy with minimally invasive radical hysterectomy, abdominal radical hysterectomy was associated with 526 fewer recurrences and 382 fewer deaths compared with minimally invasive radical hysterectomy; however, abdominal radical hysterectomy resulted in more complications for each body mass index category. When the body mass index was 40 kg/m2 or higher, abdominal radical hysterectomy became the dominant strategy because it led to better outcomes with lower costs than minimally invasive radical hysterectomy. Comparing abdominal radical hysterectomy with primary chemoradiation therapy, recurrence rates were similar, with more deaths associated with surgery across each body mass index category. Chemoradiation therapy became cost effective when the body mass index was 40 kg/m2 or higher. CONCLUSION: When the body mass index is 40 kg/m2 or higher, abdominal radical hysterectomy is cost saving compared with minimally invasive radical hysterectomy and primary chemoradiation is cost effective compared with abdominal radical hysterectomy. Primary chemoradiation may be the optimal management strategy at higher body mass indexes.

Women's perspectives on receiving and expanding access to essential health services in pharmacies in the United States.

BACKGROUND: Expanding reproductive health services in community pharmacies is a promising strategy for reaching underserved communities. Limited information exists on women's attitudes to receive these services and if interest may differ in urban and rural locations. OBJECTIVE: We sought to determine whether there were differences by rural location in women's perspectives and willingness to receive essential preventative and diagnostic reproductive health services in community pharmacies. METHODS: We conducted a cross-sectional national survey of women in November 2020. The survey consisted of demographic data, women's experiences receiving essential preventative health services, and questions regarding perspectives on and interest in receiving these services in community pharmacies. Descriptive statistics assessed differences in survey responses between rural and urban communities. RESULTS: Our sample size consisted of 867 women. We received 544 responses for a response rate of 62.7%. Rural women were as likely as their urban counterparts to delay receiving preventative care owing to concerns about insurance or how they would pay for services (P = 0.45). Rural women were less likely than urban women to have received the human papillomavirus vaccine (P = 0.02) or have had regular cervical cancer screenings (P = 0.04). Overall, both rural and urban women want to receive preventative reproductive health services in community pharmacies. CONCLUSION: Expanded access to reproductive health services in community pharmacies has the potential to improve access and health screening, particularly in underserved rural areas.

Trastuzumab with carboplatin/paclitaxel for treatment of advanced stage and recurrent uterine papillary serous carcinoma: A cost-effectiveness analysis.

OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is a variant of endometrial cancer that is aggressive and associated with poor outcomes. We sought to evaluate the cost effectiveness of carboplatin/paclitaxel alone versus carboplatin/paclitaxel with trastuzumab among patients with Her2/neu-positive advanced or recurrent UPSC. METHODS: We designed a Markov model in TreeAge Pro 2019 software to simulate management of a theoretical cohort of 4000 patients with Her2/neu-positive advanced or recurrent uterine papillary serous carcinoma (UPSC) followed for four years. In the carboplatin/paclitaxel with trastuzumab strategy, we included the cost of testing for Her2/neu status. We obtained all model inputs from the literature and a societal perspective was assumed. Outcomes included progression-free survival, progression, UPSC-specific mortality, cost, and quality-adjusted life years (QALYs). The intervention was considered cost effective if the incremental cost-effectiveness ratio (ICER) was below the willingness-to-pay threshold of $100,000 per QALY. Sensitivity analyses were used to determine the robustness of the results. RESULTS: In our theoretical cohort of 4000 women, treatment with the addition of trastuzumab resulted in 637 fewer deaths and 627 fewer cases of progression compared with treatment with carboplatin/paclitaxel alone. Treatment with trastuzumab was associated with an additional cost of $144,335,895, but was associated with an increase of 2065 QALYs. The ICER was $69,903 per QALY, which was below our willingness-to-pay threshold. Sensitivity analysis demonstrated that this treatment strategy was cost-effective until the cost of 6 months of treatment surpassed $38,505 (baseline input: $27,562). CONCLUSION: We found that the addition of trastuzumab to carboplatin/paclitaxel was a cost-effective treatment strategy for patients with advanced/recurrent Her2/neu-positive UPSC.

Cost-effectiveness of second curettage for treatment of low-risk non-metastatic gestational trophoblastic neoplasia.

OBJECTIVE: Low-risk non-metastatic gestational trophoblastic neoplasia (GTN) has been treated with single agent chemotherapy, but second curettage is emerging as an alternative strategy with reported cure rates of 40%. We sought to estimate the cost-effectiveness of second curettage as the first line treatment of low-risk GTN. METHODS: A decision-analytic model was created using TreeAge software to compare costs and outcomes for women with WHO staged low-risk GTN undergoing treatment with 5-day methotrexate (MTX), biweekly pulsed actinomycin-D, or second curettage. Probabilities were derived from the literature. Outcomes of interest included side effects from chemotherapy, need for additional agents, hemorrhage, uterine perforation, and cure rates. Utilities were applied to discounted life expectancy at a rate of 3% to generate quality adjusted life years (QALYs). Sensitivity analyses were then performed in order to assess the robustness of our assumptions. RESULTS: Of the three treatment arms, MTX was associated with the lowest cost and had similar QALYs to the other studied modalities. Second curettage was associated with 49 additional cures when applied to a theoretic cohort of 1000 women, as well as an additional 83 hemorrhages and 17 uterine perforations. Sensitivity analysis on the cure rate of second curettage revealed that second curettage was not cost-effective over MTX unless its probability of cure was 98%. CONCLUSION: Our study found 5-day MTX was the cost-effective strategy for treatment of women with low-risk, non-metastatic GTN when compared to second curettage and actinomycin-D. In a carefully selected patient population, second curettage may be an additional treatment strategy.

Gynecologic cancer incidence and mortality among American Indian/Alaska Native women in the Pacific Northwest, 1996-2016.

OBJECTIVES: Compare the incidence and mortality of gynecologic cancers among American Indian/Alaska Native (AI/AN) women to the Non-Hispanic White (NHW) population in the Pacific Northwest. METHODS: Age-adjusted cancer incidence (1996-2016) and mortality (2006-2016) rates were calculated from population-based state cancer registry and death certificate data obtained from Washington, Oregon, and Idaho, and corrected for AI/AN misclassification. Incidence and mortality rate ratios (RR) were calculated to compare AI/AN and NHW women with gynecologic cancers. RESULTS: Across all gynecologic cancer sites, AI/AN women were diagnosed at a younger age compared to NHW women. AI/AN women had a higher incidence of cervical cancer compared to NHW women with a RR of 1.53 (95% CI: 1.34, 1.75). For all age groups, AI/AN women had a higher incidence of cervical cancer and the disparity was greatest in the 50-64 age group with a RR of 1.76 (95% CI: 1.36, 2.30). Cervical cancer mortality was greater among AI/AN women, with an all-ages RR of 1.79 (95% CI: 1.30, 2.46); the disparity was greatest in the 50-64 age group (RR: 2.88, 95% CI: 1.89, 4.38). For uterine cancer, AI/AN women had similar incidence rates as NHW women but higher mortality rates (RR: 1.35, 95% CI: 1.03-1.75). Incidence and mortality for ovarian cancer were similar between groups. CONCLUSION: Our analysis of gynecologic cancers among AI/AN in the PNW found significant disparities relative to NHW women in cervical cancer incidence and mortality. These disparities persist despite advances in prevention strategies.

A contemporary framework of health equity applied to gynecologic cancer care: A Society of Gynecologic Oncology evidenced-based review.

Health disparities are defined as the preventable difference in the burden of disease, injury, and violence, or opportunity to achieve optimal health that socially disadvantaged populations experience compared to the population as a whole. Disparities in incidence and cancer outcomes for women with gynecologic malignancies have been well described particularly for American women of Black race. The etiology of these disparities has been tied to socio-economics, cultural, educational and genetic factors. While access to high quality treatment has been primarily linked to survival from cervical and ovarian cancer, innate biologic distinctions have been principally cited as reasons for differences in incidence and mortality in cancers of the uterine corpus. This article will update the framework of disparities to incorporate a broader understanding of the social determinants of health and how they affect health equity by addressing the root causes of disparities within the health care system. Special populations are identified who are at risk for health inequities which include but are not limited to Black race, underserved racial and ethnic minorities (e.g. indigenous peoples, low English fluency), trans/gender nonconforming people and rural populations. Each of these populations at risk have unique structural barriers within the healthcare system impacting gynecologic cancer outcomes. The authors provide practical recommendations for practitioners aimed at eliminating cancer related outcome disparities.

Complete Resection Is Essential in the Surgical Treatment of Gestational Trophoblastic Neoplasia.

OBJECTIVE: The aim of this study was to determine the utility of surgery in patients with gestational trophoblastic neoplasia (GTN). MATERIALS AND METHODS: We performed a retrospective institutional review board-approved analysis of all patients with GTN at a single institution from 1985 to 2015 and compared all patients who underwent surgery as definitive management for their disease to a matched cohort of those who did not. Kaplan-Meier curves were used to estimate progression-free survival (PFS) and overall survival (OS). RESULTS: Sixty-nine patients underwent a total of 94 surgeries as definitive treatment for GTN. Nineteen patients had multiple surgeries. Progression-free survival and OS were improved in patients with complete macroscopic surgical resection (n = 61) compared with patients with gross residual disease (n = 33) (median PFS 91.2 months vs 3.3 months, and median OS not reached at 108.8 months vs 66.3 months, respectively; P < 0.05). The nature of the surgery (emergent vs planned) and site of metastatic disease did not influence PFS or OS. Of the 61 patients with no visible residual disease, 17 received adjuvant chemotherapy and 44 did not; there were no observed differences in PFS or OS. Patients who underwent surgery as part of definitive treatment (n = 69 patients) were compared with patients with GTN over the same period who received chemotherapy alone (n = 33 patients). Median PFS was improved in the surgical group (5.9 vs 5.1 months, P < 0.01), but OS was not significantly different (P = 0.37). CONCLUSIONS: Complete resection results in improved outcomes in patients who undergo surgery for GTN, whether emergent or planned, independent of disease site, and should be considered as an important component of treatment in some situations.

Importance of PCR-based Tumor Testing in the Evaluation of Lynch Syndrome-associated Endometrial Cancer.

Lynch syndrome (LS) is a hereditary cancer syndrome caused by a germline mutation in a DNA mismatch repair gene, usually MLH1, MSH2, MSH6, or PMS2. The most common cancers associated with LS are colorectal adenocarcinoma and endometrial carcinoma. Identification of women with LS-associated endometrial cancer is important, as these women and their affected siblings and children are at-risk of developing these same cancers. Germline testing of all endometrial cancer patients is not cost effective, and screening using young age of cancer diagnosis and/or presence of family history of syndrome-associated is underutilized and ineffective. Therefore, most groups now advocate for tumor tissue testing to screen for LS, with germline testing targeted to women with abnormal tissue testing results. Immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 is used in many clinical laboratories for this tumor screening step, as immunohistochemistry is relatively inexpensive and is technically more accessible for smaller clinical labs. PCR-based tissue testing, whereas technically more challenging, does play an important role in the identification of these patients. MLH1 methylation analysis identifies women with tumor MLH1 loss who likely have sporadic endometrial cancer and do not need heightened cancer prevention surveillance. High levels of microsatellite instability have been identified in tumors with retained positive expression of mismatch repair proteins. Somatic sequencing of mismatch repair genes from tumor DNA, whereas not currently available in most clinical laboratories, is helpful in resolution of cases in which germline sequencing fails to identify a mutation in a mismatch repair gene. The tumor tissue testing approach can help to identify most women at-risk for germline mutations in a LS gene, but not all patients will be captured using this approach. Clinical suspicion can still play a pivotal role in accurately identifying a subset of these patients.

Salvage chemotherapy for gestational trophoblastic neoplasia: Utility or futility?

OBJECTIVE: To determine the efficacy of chemotherapy after failed initial treatment in patients with high risk gestational trophoblastic neoplasia (GTN). METHODS: We performed a retrospective IRB-approved chart review of all patients with GTN seen at a single institution from 1985 to 2015, including all patients who failed initial treatment. We summarized clinical characteristics with descriptive statistics and estimated progression-free survival (PFS) and overall survival (OS) with the Kaplan-Meier method. RESULTS: Of 68 identified patients, 38 required >2 chemotherapy regimens. Patients were treated for GTN (n=53), including choriocarcinoma, persistent GTN, and invasive mole; for placental site trophoblastic tumor (PSTT) (n=5); and for intermediate trophoblastic tumor (ITT) (n=10). Patients with GTN had a median of 2 salvage regimens, median PFS of 4.0months, and median OS was not reached at median follow-up of 71.2months. Active regimens included EMACO, MAC, BEP, platinum- and etoposide-based combination therapies, and ICE; 8 of 53 patients died of disease (DOD). Patients with PSTT had a median of 3 salvage regimens, median PFS of 2.8months, and median OS of 38.8months. Active regimens included ICE and EMA-EP; 4 of 5 patients DOD. Patients with ITT had a median of 3 salvage regimens, median PFS of 4.1months, and median OS of 38.2months. Active regimens included liposomal doxorubicin, platinum-containing regimens, EMA-CO, and EMA-EP; 7 of 10 patients DOD. CONCLUSIONS: Several salvage chemotherapy regimens demonstrate activity in high risk GTN. Multiple regimens may be required and cure is not universal.

Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort.

Hereditary endometrial carcinoma is associated with germline mutations in Lynch syndrome genes. The role of other cancer predisposition genes is unclear. We aimed to determine the prevalence of cancer predisposition gene mutations in an unselected endometrial carcinoma patient cohort. Mutations in 25 genes were identified using a next-generation sequencing-based panel applied in 381 endometrial carcinoma patients who had undergone tumor testing to screen for Lynch syndrome. Thirty-five patients (9.2%) had a deleterious mutation: 22 (5.8%) in Lynch syndrome genes (three MLH1, five MSH2, two EPCAM-MSH2, six MSH6, and six PMS2) and 13 (3.4%) in 10 non-Lynch syndrome genes (four CHEK2, one each in APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, NBN, PTEN, and RAD51C). Of 21 patients with deleterious mutations in Lynch syndrome genes with tumor testing, 2 (9.5%) had tumor testing results suggestive of sporadic cancer. Of 12 patients with deleterious mutations in MSH6 and PMS2, 10 were diagnosed at age >50 and 8 did not have a family history of Lynch syndrome-associated cancers. Patients with deleterious mutations in non-Lynch syndrome genes were more likely to have serous tumor histology (23.1 vs 6.4%, P=0.02). The three patients with non-Lynch syndrome deleterious mutations and serous histology had mutations in BRCA2, BRIP1, and RAD51C. Current clinical criteria fail to identify a portion of actionable mutations in Lynch syndrome and other hereditary cancer syndromes. Performance characteristics of tumor testing are sufficiently robust to implement universal tumor testing to identify patients with Lynch syndrome. Germline multi-gene panel testing is feasible and informative, leading to the identification of additional actionable mutations.

Defective DNA Mismatch Repair Influences Expression of Endometrial Carcinoma Biomarkers.

Endometrial endometrioid carcinomas are related to estrogen excess and express estrogen and progesterone receptors. However, hormone receptor expression can be variable from tumor to tumor, and this variability is not always explained by differences in tumor grade. Variable expression of other biomarkers that may be used in the diagnostic work-up of endometrial cancer has also been noted. We hypothesized that mismatch repair (MMR) defects may contribute to this variability. A total of 411 unselected endometrial carcinomas were evaluated for immunohistochemical expression of DNA MMR proteins and MLH1 methylation. Loss of immunohistochemical expression of MLH1, MSH2, MSH6, or PMS2 was defined as MMR deficient; positive expression was defined as MMR intact. A case-control cohort of 80 Grade 2 endometrioid carcinomas was selected from this set (40 MMR deficient, 40 MMR intact). Cases were matched for histotype, grade, and age. Estrogen receptor, progesterone receptor, CK7(+), CK20, and Pax-8 immunohistochemistry was evaluated. The median percentage of CK7 tumor cells was significantly lower in the MMR deficient group compared with the MMR intact group. The mean percentage of tumor cells exhibiting estrogen receptor expression was similar in both the MMR-deficient and MMR intact groups. However, there was greater variability in the MMR-deficient group. Our study shows that MMR defects influence the expression of clinically important biomarkers for endometrioid-type endometrial carcinoma as decreased cytokeratin 7 expression is more commonly associated with MMR deficiency.

Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for Lynch syndrome.

OBJECTIVE: Determine factors impacting the uptake of genetic counseling and results of genetic testing following universal tumor testing for Lynch syndrome in patients with endometrial cancer. METHODS: The study population consisted of two unselected cohorts of endometrial cancer patients, 408 identified retrospectively and 206 identified prospectively. Immunohistochemistry for mismatch repair protein expression and/or microsatellite instability analysis was performed on these tumors. MLH1 methylation analysis was performed on tumors with loss of MLH1 protein. Tumor studies were considered suggestive of Lynch Syndrome if they showed immunohistochemical loss of MSH2, MSH6 or PMS2, loss of MLH1 without MLH1 promoter methylation, and/or microsatellite instability. Participants with suggestive tumor studies were contacted and offered genetic counseling and testing. RESULTS: In the retrospective cohort, 11% had tumor studies suggestive of Lynch syndrome, and 42% was seen for genetic counseling. A germline mutation was detected in 40%, and one had a variant of uncertain significance. In the prospective cohort, 8.7% of patients had tumor testing suggestive of Lynch syndrome; 72% were seen for genetic counseling. Germline mutations were found in 40%, and one had a variant of uncertain significance. Common challenges included timing of re-contact, age, perceived lack of relevance, inability to travel and limited insurance coverage. CONCLUSIONS: There are several barriers to genetic counseling and testing follow-up after universal tumor testing, and uninformative genetic test results present a management challenge. It is important to consider these limitations when implementing an approach to screening endometrial cancer patients for Lynch syndrome.

Cervical Cancer: Preventable Deaths Among American Indian/Alaska Native Communities.

American Indian/Alaska Native (AI/AN) individuals have twice the mortality rate of cervical cancer than the general US population. Participation in prevention programs such as cervical cancer screening and human papillomavirus (HPV) vaccination are under-utilized in this population. There are high rates of established cervical cancer risk factors among this community, with AI/AN people having a higher likelihood of infection with high-risk HPV strains not included in the 9-valent vaccine. There is a need for more robust and urgent prevention and treatment efforts in regard to cervical cancer in the AI/AN community.