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There are limited data in endometrial cancer for nodal control and appropriate treatment volume for non-surgically resected nodes treated with chemoradiotherapy (CRT) for patients who are not candidates for upfront extrafascial hysterectomy.Patients (n = 105) with clinical stage ≥ II endometrial cancer who were not candidates for upfront extrafascial hysterectomy treated with preoperative CRT were retrospectively reviewed. CRT included pelvic nodes to the common iliac for node-negative disease and para-aortic nodes to the renal vessel for any node-positive disease. Involved nodes most commonly received a boost of 55 Gy in 25 fractions ± additional 4-6 Gy sequential boost for nodes2 cm.Of the included 95 patients, 55 patients were node positive, with a total of 300 positive nodes. At a median follow-up of 25 months (interquartile range 9-46), the 3-year regional control was 91%. The 3-year involved nodal control rate was 96%. Involved nodal control was significantly higher in type I histology, nodes2 cm and by radiation dose (75% for55 Gy, 98% for 55 Gy in 25 fractions and 89% for55 Gy, P = 0.03). The 3-year para-aortic failure rate for node negative patients treated with pelvis-only CRT was significantly higher with positron emission tomography/computed tomography (PET/CT) versus computed tomography (CT)-based staging (0% versus 20%).This is the largest study examining regional control rates of involved lymph nodes with CRT for patients who were not candidates for upfront extrafascial hysterectomy. Nodal failure was low following CRT and dose ≥55 Gy in 25 fractions seems to be adequate for involved nodes.

OBJECTIVE: To examine the association between (GWG) and epithelial ovarian cancer (EOC). METHODS: We compared GWG between 670 incident EOC cases to 1551 community controls from a population-based, case-control study conducted in Pennsylvania, Ohio, and New York from 2003–2008. Multivariable unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) associated with GWG adjusting for potential confounders. To explore the potential effect of maternal long-term weight retention after childbearing, we restricted analyses to women who began their childbearing years as normal/underweight and examined differences in EOC risk between those who were normal/underweight versus those who were overweight/obese at study baseline reference date. RESULTS: Average GWG per full term pregnancy did not differ between cases and controls. Among women who were normal/underweight at study baseline, greater average GWG was not associated with EOC (OR=0.9, 0.8, 0.7 for quartiles 2, 3 and 4 of GWG gain, respectively compared to quartile 1). In contrast, among women who were overweight/obese at study baseline, greater average GWG was positively associated with EOC (OR=1.4, 1.8, 1.2, for quartiles 2, 3, and 4 compared to quartile 1; interaction P=0.04). CONCLUSION: We posit that maternal post-partum weight retention and not gestational weight gain itself among normal/underweight women may impact subsequent risk of EOC. If our hypothesis is supported in other studies designed to assess this question directly, then counseling women on the importance of healthy weight management after a pregnancy could provide another means to help women reduce their risk of this often-fatal malignancy.

Purpose The role of neoadjuvant chemoradiation therapy in locally advanced type II endometrial cancer is controversial. We thus aimed to present our experience with the hypothesis that neoadjuvant chemoradiation therapy is associated with similarly high rates of downstaging and locoregional control for type II endometrial cancer and type I endometrial cancer. Methods and Materials Thirty-four patients with type II endometrial cancer with clinical evidence of cervical ± parametrium involvement treated with neoadjuvant external beam radiation therapy (45-50.4 Gy in 25-28 fractions) and high-dose-rate brachytherapy with a median total dose of 20 Gy (range, 15-27.5) in 4 fractions (range, 3-5) and concurrent platinum chemotherapy ± adjuvant chemotherapy from 2008 to 2018 were retrospectively reviewed. Patients with type I pathologic diagnoses and those treated with definitive (rather than preoperative) intent were excluded. Results Pathologic characteristics were as follows: 38% were carcinosarcoma, 18% serous, and 24% clear cell. Ninety-four percent of patients were downstaged to an extrafascial hysterectomy, and 94% had negative surgical margins. The 2-year local control, regional control, distant control, disease-free survival, and overall survival were 87.8%, 81.3%, 76.3%, 52.5%, and 63.7%, respectively. There was 1 subacute grade 3 and 1 late grade 3 small bowel obstruction, directly attributable to radiation therapy. Conclusions Neoadjuvant chemoradiation therapy effectively downstages the majority of locally advanced type II endometrial cancers, thereby increasing the likelihood of achieving complete resection with negative margins.

Purpose Vulvar squamous cell carcinoma (VSCC) is a relatively rare malignancy. Human papillomavirus has been implicated as a causative factor for a subset of these patients. The purpose of this study was to evaluate whether p16-positivity (a human papillomavirus surrogate) predicts for better response rates in women who undergo surgery followed by adjuvant radiation therapy (RT). Methods and Materials We retrospectively analyzed data from women with VSCC who were treated with adjuvant RT. p16-Positivity was defined as diffuse strong immunoreactivity within the tumor. Time to event outcomes was performed with Kaplan-Meier and cumulative incidence methodologies. Results Thirty-nine women were identified. Ten had positive results for p16 (p16+), and 29 had negative results (p16−). The median follow-up was 25.7 months. The median age at diagnosis was 59 years for women with p16+ tumors and 74 years for women with p16− tumors (P = .022). The distribution of stage did not differ by p16 status. The indications for adjuvant RT were close/positive margins in 19 women, positive nodes in 9 women, and both in 11 women. There were 21 recurrences: 15 vulvar, 3 isolated nodal, 2 synchronous vulvar/nodal, and 1 distant metastasis. In-field relapse rates at 3 years were lower in p16+ patients (32.5%) than in p16− patients (59.1%, P = .072). This trend was also observed in progression-free survival (P = .062). A p16+ status and a lower International Federation of Gynecology and Obstetrics stage were associated with fewer in-field relapses and improved progression-free survival in multivariable analyses. The p16 status was not a predictor of overall survival. Conclusions p16-Positivity appears to be a prognostic factor for in-field relapse rates in patients with VSCC appropriately treated with adjuvant RT.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.

PURPOSE. Brachytherapy is integral to vaginal cancer treatment and is typically delivered using an intracavitary single-channel vaginal cylinder (SCVC) or an interstitial brachytherapy (ISBT) applicator. Multi-channel vaginal cylinder (MCVC) applicators allow for improved organ-at-risk (OAR) sparing compared to SCVC while maintaining target coverage. We present clinical outcomes of patients treated with image-based high dose-rate (HDR) brachytherapy using a MCVC. METHODS AND MATERIALS. Sixty patients with vaginal cancer (27% primary vaginal and 73% recurrence from other primaries) were treated with combination external beam radiotherapy (EBRT) and image-based HDR brachytherapy utilizing a MCVC if residual disease thickness was 7 mm or less after EBRT. All pts received 3D image-based BT to a total equivalent dose of 70–80 Gy. RESULTS. The median high-risk clinical target volume was 24.4 cm(3) (interquartile range [IQR], 14.1), with a median dose to 90% of 77.2 Gy (IQR, 2.8). After a median follow-up of 45 months (range, 11–78), the 4-year local-regional control, distant control, DFS, and OS rates were 92.6%, 76.1%, 64.0%, and 67.2%, respectively. The 4-year LRC rates were similar between the primary vaginal (92%) and recurrent (93%) groups (p = 0.290). Pts with lymph node positive disease had a lower rate of distant control at 4 years (22.7% vs. 89.0%, p < 0.001). There were no Grade 3 or higher acute complications. The 4-year rate of late Grade 3 or higher toxicity was 2.7%. CONCLUSIONS. Clinical outcomes of pts with primary and recurrent vaginal cancer treated definitively in a systematic manner with combination EBRT with image-guided HDR BT utilizing a MCVC applicator demonstrate high rates of local control and low rates of severe morbidity. The MCVC technique allows interstitial implantation to be avoided in select pts with ≤7 mm residual disease thickness following EBRT while maintaining excellent clinical outcomes with extended 4-year follow-up in this rare malignancy.

OBJECTIVE. The aim of this study was to examine the significance of lymphovascular space invasion (LVSI) with a sarcomatous component on the tumor characteristics and clinical outcomes of women with uterine carcinosarcoma (UCS). METHODS. This was a secondary analysis of a prior multicenter retrospective study that examined women with stage I–IV UCS who underwent primary hysterectomy. Archived histopathology slides were reviewed and LVSI was scored as follows: LVSI with a carcinomatous component alone (LVSI-carcinoma; n = 375, 76.8%) or LVSI containing a sarcomatous component with or without a carcinomatous component (LVSI-sarcoma; n = 113, 23.2%). Qualitative metrics of LVSI were correlated to clinicopathological factors and survival outcome. RESULTS. Tumors in the LVSI-sarcoma group were more likely to have sarcoma dominance (82.1 vs. 26.4%) heterologous sarcomatous component (51.3 vs. 37.9%), low-grade carcinoma (42.5 vs. 22.4%), and large tumor size (81.0 vs. 70.2%) in the primary tumor site compared with tumors in the LVSI-carcinoma group (all p < 0.05). On multivariate analysis, LVSI-sarcoma was independently associated with decreased progression-free survival (5-year rates: 34.9 vs. 40.8%, adjusted hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.36–2.50, p < 0.001), and cause-specific survival (5-year rates: 41.8 vs. 55.9%, adjusted HR 1.95, 95% CI 1.39–2.75, p < 0.001) compared with LVSI-carcinoma. Postoperative radiotherapy for women with LVSI-sarcoma had a higher reduction rate of recurrence/progression of disease (54% reduction, p = 0.04) compared with postoperative radiotherapy for women with LVSI-carcinoma (26% reduction, p = 0.08). CONCLUSION. In UCS, the presence of a sarcomatous component in LVSI is particularly prevalent when a tumor has sarcoma dominance. Our study suggests that LVSI containing a sarcomatous component may be a predictor of decreased survival for women with UCS.

Purpose Vaginal brachytherapy (VBT) alone has been shown to be a viable adjuvant treatment strategy for most patients with Stage I endometrioid endometrial cancer. We sought to examine our institutional data following practice pattern changes resulting from the publications of GOG-99 and PORTEC-2. Methods and Materials We retrospectively analyzed women who underwent adjuvant VBT after surgical staging for Stage 1 endometrioid endometrial cancer at our institution from 2007 to 2014. Results We identified 297 women. Median time to last followup or death was 52.3 months (interquartile range: 32.3–72.3 months). By International Federation of Gynecology and Obstetrics 2009 staging, 162 patients (54.5%) had Stage IA and 128 (43.1%) had Stage IB disease. Ninety-nine (33.3%) patients had Grade 1, 153 (51.5%) had Grade 2, and 45 (15.2%) had Grade 3 disease. According to GOG-249 and PORTEC-2 criteria, 167 (56.2%) and 127 (42.7%) patients were with high–intermediate–risk disease. Two women had Stage IB Grade 3 disease. The most common high-dose-rate–VBT regimen was 2100 cGy/three fractions to a depth of 5 mm. Four (two acute and two late) (1.3%) Grade 3 genitourinary toxicities were reported: three episodes of vaginal dehiscence (after second course of VBT, 2 months after completion of VBT, and 1 year after completion of VBT) and one episode of radiation necrosis. Twenty-one (7%) women recurred: three recurred in the vagina, two recurred in the pelvic lymph nodes, and 16 recurred distantly. Conclusions Outcomes appear consistent with published randomized data in women with high–intermediate–risk endometrial cancer who are treated with brachytherapy alone. Recurrence and complication rates were minimal.

OBJECTIVE: To identify risk factors for venous thromboembolism (VTE) and to examine the association of VTE and survival in women with uterine carcinosarcoma. METHODS: This multicenter retrospective study examined 906 women who underwent primary surgical treatment for stage I-IV uterine carcinosarcoma. Time-dependent analyses were performed for cumulative incidence of VTE after surgery on multivariate models. RESULTS: There were 72 (7.9%) women who developed VTE after surgery with 1-, 2-, and 5-year cumulative incidences being 5.1%, 7.3%, and 10.2%, respectively. On multivariate analysis, older age (hazard ratio [HR] per year 1.03, P = 0.012), non-Asian race (HR 6.28, P< 0.001), large body habitus (HR per kg/m(2) 1.04, P = 0.014), residual disease at surgery (HR 3.04, P = 0.003), tumor size ≥5 cm (HR2.73, P = 0.003), and stage IV disease (HR2.12, P = 0.025) were independently associated with increased risk of developing VTE. A risk pattern analysis identified that obese Non-Asian women with large tumors (13.7% of population) had the highest incidence of VTE (2-year cumulative rate, 26.1%) whereas Asian women with no residual disease (47.1% of population) had the lowest (2-year cumulative rate, 1.6%) (P< 0.001). Presence of carcinoma/sarcoma in metastatic sites was significantly associated with increased risk of VTE compared to carcinoma alone (2-year rates, 31.2% versus 8.4%, P = 0.049). VTE was independently associated with decreased progression-free survival on multivariate models (5-year rates, 24.9% versus 47.2%, HR 1.46,95%CI 1.05–2.04, P = 0.026). CONCLUSION: Our study suggests that VTE represents a surrogate marker of aggressive tumor behavior and diminished patient condition in uterine carcinosarcoma; obese Non-Asian women with large tumors carry a disproportionally high risk of VTE, suggesting that long-term prophylaxis may benefit this population.

OBJECTIVE: To examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. METHODS: We retrospectively examined 148 women with recurrent uterine carcinosarcoma who received salvage chemotherapy within a cohort of 906 uterine carcinosarcomas. An independent association of salvage chemotherapy type and SAR was examined with multivariate analysis. RESULTS: There were 71 (48.0%) women who received a taxane/platinum regimen. On univariate analysis, women who received a taxane/platinum doublet had a higher 2-year SAR rate compared to women who received non-taxane/platinum regimens (55.5% versus 34.8%, P < 0.001). On multivariate analysis, use of taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35 to 0.91, P = 0.02). When stratified by disease-free interval, women with a disease-free interval ≥6 months who received a taxane/platinum doublet had a higher 2-year SAR rate compared to those who received non-taxane/platinum regimens (61.9% versus 40.0%, HR 0.46, 95% CI 0.28 to 0.75, P = 0.002); conversely, in women with a disease-free interval

Purpose Previous studies of stage II endometrial cancer have included cancers with cervical glandular involvement, a factor no longer associated with risk of recurrence. In order to better assess relapse patterns and the impact of adjuvant therapy, a retrospective analysis was conducted for patients with modern stage II endometrial cancer, defined as cervical stromal invasion. Materials and methods Patients diagnosed with surgically staged FIGO stage II endometrial cancer at the UPMC Hillman Cancer Center from 1990–2013 were reviewed. Factors associated with rates of locoregional control (LRC), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS) were analyzed using the log rank test. Results 110 patients with FIGO stage II disease were identified. Most (84.5%) received EBRT±BT, with 13.6% receiving BT alone. With a median follow-up of 64.6months, the 5-year actuarial rates of LRC, DM, DFS, and OS were 94.9%, 85.1%, 67.9%, and 75.0%, respectively. With 5 locoregional failures, the only factor predictive of LRC was pelvic lymph node dissection. Characteristics associated with DM included age, LVSI, depth of myometrial invasion, and receipt of chemotherapy. Factors predictive of both DFS and OS were age, grade, adverse histology, LVSI, depth of myometrial invasion, and receipt of chemotherapy. Conclusions This represents the largest single-institution study for modern stage II endometrial cancer, confirming high rates of pelvic disease control after surgery and adjuvant therapy. With most patients receiving adjuvant radiotherapy, the predominant mode of failure, albeit low in absolute number, remains distant metastases.

BACKGROUND: To examine recurrence patterns in women with stage I uterine carcinosarcoma (UCS) stratified by adjuvant therapy pattern. METHODS: We examined 443 cases of stage I UCS derived from a retrospective cohort of 1192 UCS cases from 26 institutions. Adjuvant therapy patterns after primary hysterectomy-based surgery were correlated to recurrence patterns. RESULTS: The most common adjuvant therapy was chemotherapy alone (41.5%) followed by chemotherapy/radiotherapy (15.8%) and radiotherapy alone (8.4%). Distant-recurrence was the most common recurrence pattern (5-year cumulative rate, 28.1%) followed by local-recurrence (13.3%). On multivariate analysis, chemotherapy but not radiotherapy remained an independent prognostic factor for decreased risk of local-recurrence (5-year cumulative rates 8.7% versus 19.8%, adjusted-hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25–0.83, P = 0.01) and distant-recurrence (21.2% versus 38.0%, adjusted-HR 0.41, 95%CI 0.27–0.62, P < 0.001). The chemotherapy/radiotherapy group had a lower 5-year cumulative local-recurrence rate compared to the chemotherapy alone group but it did not reach statistical significance (5.1% versus 10.1%, adjusted-HR 0.46, 95%CI 0.13–1.58, P = 0.22). Radiotherapy significantly decreased local-recurrence when tumors had high-grade carcinoma, sarcoma component dominance, and deep myometrial tumor invasion (all, P < 0.05); and combining radiotherapy with chemotherapy was significantly associated with decreased local-recurrence compared to chemotherapy alone in the presence of multiple risk factors (5-year cumulative rates, 2.5% versus 21.8%, HR 0.12, 95%CI 0.02–0.90; P = 0.013) but not in none/single factor (P = 0.36). CONCLUSION: Adjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.

Purpose We evaluated the long-term outcome and toxicity of adjuvant intensity modulated radiation therapy (IMRT) for high-risk endometrial carcinoma via a retrospective institutional review of patients treated in this setting with extended follow-up. Methods and materials Patients with endometrial cancer who underwent comprehensive surgical staging followed by adjuvant IMRT with or without sequential chemotherapy between 1999 and 2010 were reviewed. Median doses delivered with IMRT and brachytherapy were 45 Gy in 25 fractions and 10 Gy in 2 fractions; 10.2% received extended field and 94.5% received vaginal brachytherapy. Kaplan-Meier estimates are provided for rates of locoregional (in-field) relapse, distant metastasis, and disease-free survival, and overall survival. Gastrointestinal (GI) and genitourinary (GU) toxicity reported were graded with the Common Terminology Criteria for Adverse Events, version 4.03. Results A total of 128 patients were identified. Median age at diagnosis was 64 years. Most patients (82.8%) had endometrioid adenocarcinoma followed by papillary serous (10.2%), clear cell (4.7%), and carcinosarcoma (2.3%). International Federation of Gynecology and Obstetrics staging distribution was as follows: IA, 13.3%; IB, 32.8%; II, 30.4%; IIIA, 5.5%; IIIC1, 9.4%; and IIIC2, 8.6%. Most (85.9%) underwent nodal dissections (28.1% pelvic only and 57.8% pelvic and para-aortic). Two patients (1.6%) experienced acute grade 3 GI toxicity; no other acute grade ≥3 GI/GU toxicities were noted. With a median follow-up of 57.0 months, 5-year locoregional relapse was 2.5%: vagina (n = 3), parametrium (n = 1), pelvic node (n = 1). Five-year estimates of distant metastasis, disease-free survival, and overall survival were 16.5%, 73.4%, and 77.4%, respectively. Five-year actuarial rates of late grade 3 GI and GU toxicities were 3.2% and 0.0%. The 5-year rate of symptomatic pelvic insufficiency fracture was 4.4%. Conclusions This study represents the largest cohort of endometrial cancer patients with extended follow-up receiving adjuvant IMRT. High rates of pelvic disease control and limited late toxicities demonstrate safety and efficacy of this approach in the setting of extended follow-up.

Benign breast disease is a spectrum of common disorders. The majority of patients with a clinical breast lesion will have benign process. Management involves symptom control when present, pathologic-based and imaging-based evaluation to distinguish from a malignant process, and counseling for patients that have an increased breast cancer risk due to the benign disorder.

Objective Previous studies suggest that breastfeeding reduces epithelial ovarian cancer (EOC) risk. However, the effects of age, timing and episode details on the EOC-breastfeeding relationship have not been examined. The objective of this study was to examine the association between breastfeeding factors and epithelial ovarian cancer. Methods We examined breastfeeding factors among parous women in a population-based, case-control study conducted in Pennsylvania, Ohio, and New York from 2003 to 2008. We compared 689 incident EOC cases to 1572 community controls. Multivariable unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) associated with breastfeeding patterns adjusting for potential confounders. Results Compared to never breastfeeding, breastfeeding any offspring was associated with a 30% reduction in EOC risk (OR = 0.70; 95%CI = 0.58–0.85). That association lasted more than 30 years (OR = 0.69, 95%CI = 0.53–0.88). An average breastfeeding episode of 3 months was also associated with reduced risk (OR = 0.73, 95%CI = 0.58–0.80). A greater number of breastfeeding episodes was associated with greater risk reduction (OR = 0.78, 95%CI = 0.64–0.96 and OR = 0.49, 95%CI = 0.36–0.68 1–2 and 3+ episodes, respectively, compared to never breastfed, trend p = 0.01). Longer breastfeeding duration was also associated with reduced risk (OR = 0.75 and 0.62 for less than and greater than 1-year total duration, respectively, compared to never breastfed). An earlier age at first breastfeeding was further associated with increased protection (OR = 0.50–0.80, for first episode at age Conclusions Breastfeeding for as few as 3 months is associated with reduced EOC risk. Although this association decreases over time, it persists for more than 30 years. Longer cumulative duration, increasing number of breastfeeding episodes, and earlier age at first breastfeeding episode are each associated with increased benefit.

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. Significance: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene. See related commentary by Choi and Brown, p. 439

RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P

To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma.A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes.Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P0.001).Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

Background: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality. Methods: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years. Results: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18–1.52) and without (HR=1.22, 95% CI: 1.12–1.33) further adjustment for residual disease, respectively. Conclusion: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.

Contains fulltext : 170949.pdf (Publisher’s version ) (Closed access) BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis. RESULTS: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81). CONCLUSIONS: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.

Purpose Many patients with endometrial cancer cannot undergo surgery and instead receive definitive radiation therapy (RT). We investigate the correlation between MRI response to RT and clinical outcomes. Methods and Materials Women with inoperable, clinical Stage I endometrial cancer were treated with definitive brachytherapy (BT) with/without pelvic RT (PRT). Patients underwent MRI with functional diffusion-weighted imaging before and after RT. A radiologist retrospectively classified cases as complete, partial, or indeterminate response (CR, PR, or IR, respectively) vs. disease progression. Local control was clinicopathologically defined. Results From 2007 to 2017, 50 women underwent definitive RT. Thirty-five (70%) received BT alone (median dose 37.5 Gy). For combined therapy, the median PRT and BT doses were 45 and 25 Gy, respectively. Median gross tumor volume and high-risk clinical target volume were 7.1 cc and 90.0 cc, respectively. Median followup among living patients was 20 months. All patients underwent post-RT MRI with T1/T2 sequencing at a median of 3.2 months after RT; 40 patients (80%) underwent functional diffusion-weighted imaging sequences. On initial post-RT MRI, CR was documented in 42 patients (84%), IR in 1 patient (2%), and PR in seven patients (14%). At median followup of 16.3 months, no CR patients had uterine failure. Among eight patients with initial PR/IR, all were found to be clinicopathologically no evidence of disease at the uterus on further evaluation. Conclusions Definitive RT with BT or BT + PRT is associated with high response rates on MRI. Overall, initial CR predicted for excellent outcome with no infield failure.

OBJECTIVE: To examine clinico-pathological characteristics and outcomes of uterine carcinosarcoma (UCS) in women aged ≥80 years. METHODS: This is a secondary analysis of a previous multicenter retrospective study examining 906 women with stage I–IV UCS who underwent primary hysterectomy. Patient demographics, treatment types, tumor characteristics, and survival were examined across aged ≥80 (n = 82 [9.1%]), aged 60–79, (n = 526 [58.1%]), and aged < 60 (n = 298 [32.9%]). RESULTS: Women in the aged ≥80 group were more likely to be Caucasian, undergo simple hysterectomy without lymphadenectomy, and receive no postoperative therapy (all, P < 0.05). Tumors in the aged ≥80 group were more likely to have high-grade carcinoma, heterologous sarcoma, and sarcoma dominance but less likely to have lympho-vascular space invasion (all, P < 0.05). Lymphadenectomy did not improve survival in the aged ≥80 group (P > 0.05), whereas lymphadenectomy was protective for survival in the younger groups (both, P < 0.05). Postoperative chemotherapy was associated with improved progression-free survival (PFS) in the aged ≥80 group (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.22–0.89, P = 0.021). With chemotherapy treatment, women in the aged ≥80 group had PFS similar to those in the aged 60–79 group (HR 0.97, 95%CI 0.51–1.83, P = 0.92). In contrast, without chemotherapy treatment, women in the aged ≥80 group had significantly decreased PFS compared to the aged 60–79 group (HR 1.62, 95%CI 1.09–2.40, P = 0.016). Similar associations were observed for postoperative radiotherapy. CONCLUSION: Nearly 10% of women with UCS are aged ≥80 that are characterized by aggressive tumor factors. Postoperative therapy but not extensive surgery may improve survival in this age group.

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09, 95% CI = 0.97–1.22, p = 0.15, N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13, 95% CI = 1.03–1.24, p = 0.01, N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Aim: To explore inflammatory biomarkers secreted by adipose stem cells (ASCs) in omental, retroperitoneal and subcutaneous adipose tissues of women with endometrial cancer. Patients & Methods: ASCs were collected from 22 women, aged 35-83 years, undergoing hysterectomy for endometrial cancer. Angiopoietin-2, EGF, IL-8, leptin, VEGFA, VEGFC and VEFGD levels in the ASC-conditioned media were analyzed by Luminex. Results: We found a significant difference between the three depots for IL-8 (p

Purpose Human papillomavirus (HPV) is implicated as a causative factor in vulvar squamous cell carcinoma (VSCC). This study evaluates if p16-positivity, a surrogate for HPV, predicts for better response rates to chemoradiation therapy and survival. Materials and methods We conducted a retrospective chart review of women treated with neoadjuvant or definitive chemoradiation (CRT) therapy from 2000 to 2016 for VSCC. p16 stain-positivity was defined as diffuse strong “block” immunoreactivity within invasive tumor. Results Seventy-three women with median follow-up of 13.4 months were analyzed. Thirty-three (45.2%) had p16+ tumors. Median age was 73 years (range: 37–89); with p16+ tumors, the median age was 60 years vs 73 years for women with p16− tumors (p The complete clinical response (cCR) rate for p16+ tumors was 63.6% vs 35.0% for p16− tumors (p = 0.014). The pathologic complete response (pCR) rate for women treated neoadjuvantly was 53.8% vs 31.4% for p16+ vs p16−, respectively (p = 0.067). The combined complete response (cCR orpCR [CCR]) rate was 63.6% for p16+ and 30.0% for p16− (p = 0.004). Two-year vulvar control (VC) for women with p16+ tumors was 75.5% vs. 49.5% for p16− (p = 0.008). In women with p16+ tumors who achieved CCR, 2-year VC was 92.3% vs 52.1% for CIR (p = 0.009). For p16− tumors, 2-year VC was 67.3% vs 41.1% for CCR and CIR (p = 0.072). No woman with a p16+ tumor developed distant metastases vs. 7 with p16− tumor (p = 0.013). OS was not statistically different between p16+ cohorts, but was improved for p16− patients with CR vs CIR, 72.9% vs 18.8% (p = 0.026). Conclusions p16-positive tumors appear to have better clinical and pathologic response rates and clinical outcomes.

PURPOSE: To propose a categorization model of uterine carcinosarcoma (UCS) based on tumor cell types (carcinoma and sarcoma) and sarcoma dominance. METHODS: This secondary analysis of a prior multicenter retrospective study examined 889 cases of UCS with available histologic evaluation. Based on survival outcome, cases were clustered into three groups: low-grade carcinoma with nondominant homologous sarcoma [type A, n = 96 (10.8%)], (1) low-grade carcinoma with heterologous sarcoma or any sarcoma dominance and (2) high-grade carcinoma with nondominant homologous sarcoma [type B, n = 412 (46.3%)], and high-grade carcinoma with heterologous sarcoma or any sarcoma dominance [type C, n = 381 (42.9%)]. Tumor characteristics and outcome were examined based on the categorization. RESULTS: Women in type C category were more likely to be older, obese, and Caucasian, whereas those in type A category were younger, less obese, Asian, and nulligravid (all P < 0.01). Type C tumors were more likely to have metastatic implants, large tumor size, lymphovascular space invasion with sarcoma cells, and higher lymph node ratio, whereas type A tumors were more likely to be early-stage disease and small (all P < 0.05). On multivariate analysis, tumor categorization was independently associated with progression-free survival (5-year rates: 70.1% for type A, 48.3% for type B, and 35.9% for type C, adjusted P < 0.01) and cause-specific survival (5-year rates: 82.8% for type A, 63.0% for type B, and 47.1% for type C, adjusted P < 0.01). CONCLUSION: Characteristic differences in clinicopathological factors and outcomes in UCS imply that different underlying etiologies and biological behaviors may be present, supporting a new classification system.

OBJECTIVE: To examine significance of sarcoma dominance (SD) patterns In uterine carcinosarcoma (UCS). METHODS: This is a secondary analysis of multicenter retrospective study examining women with stages I-IV UCS who underwent primary surgery. SD was defined as >50% of sarcoma component in uterine tumor. SD patterns were grouped as homologous sarcoma without SD (homo/non-dominance, n = 351), heterologous sarcoma without SD (hetero/non-dominance, n = 174), homologous sarcoma with SD (homo/dominance, n = 175), and heterologous sarcoma with SD (hetero/dominance, n = 189), and correlated to tumor characteristics and survival. RESULTS: SD patterns were significantly associated with age, body habitus, carcinoma type, tumor size, depth of myometrial invasion, and nodal metastasis (all, P < 0.05). On univariate analysis, SD was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (both, P < 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homo/dominance 1.35–1.69, and hetero/dominance 1.47–1.64) and CSS (adjusted-HR ranges: 1.52–1.84 and 1.66–1.81, respectively) compared to homo/non-dominance (all, P < 0.05). Among stage I-III disease, when tumors had SD, adding radiotherapy to chemotherapy was significantly associated with improved PFS (adjusted-HR: homo/dominance 0.49, and hetero/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P < 0.05); contrary, this association was not observed with absence of SD (all, P > 0.05). CONCLUSION: In UCS, SD impacts survival in homologous but not in heterologous type. Regardless of sarcoma types, SD was associated with decreased survival in UCS; adding radiotherapy to chemotherapy may be an effective postoperative strategy.

Uterine carcinosarcomas are an aggressive and rare form of endometrial cancer. Omentectomy is not part of routine staging, but biopsy is often done because omental disease is a known poor prognostic indicator. We sought to define the role of routine omental sampling during surgical staging.Patients who underwent staging for uterine carcinosarcoma at our institution from January 2000 to December 2013 were identified. Clinical and pathological data were abstracted. Univariate and multivariable Cox proportional hazard regression analysis was used to identify significant predictors of progression-free (PFS) and overall survival (OS). Logistic regression was used to identify predictors of omental disease.We identified 153 patients. The median age was 65 years (range, 40-87 years), and 88.9% were Caucasian. Omental sampling was performed in 106 (69.3%) patients. Of these, 17(16%) had pathologically confirmed omental disease, and 6 (35.3%) with microscopic disease. On multivariable analysis, tumor size (P = 0.024) and postoperative radiation (P = 0.041) were significant predictors of progression-free survival, and omental disease (P = 0.002), residual disease (P = 0.03), and tumor size (P = 0.025) were significant predictors of OS. Median OS was 11.4 versus 128.7 months for those who did and did not have omental disease, respectively (P0.001). The median OS for those who had omental sampling (127.7 months) versus those who did not (71.3 months) was not significantly different (P = 0.7432).Although survival was not significantly different between those who did and did not have omental sampling, omental disease had a significant impact on survival. Of those with omental disease, 35% had microscopic disease that could be missed if routine biopsy is not performed, suggesting a role for routine omental sampling.

Background:\ud \ud Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.\ud Methods:\ud \ud We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.\ud Results:\ud \ud Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01–1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01–1.11) and borderline (pOR = 1.15; 95% CI: 1.02–1.29) tumours.\ud Conclusions:\ud \ud Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

Uterine carcinosarcoma (UCS) is a rare type of high-grade endometrial cancer (EC) that has been understudied with population-based statistics due to its rarity. This study examined temporal trends in the proportion of UCS among women with EC.This is a retrospective observational study examining The Surveillance, Epidemiology, and End Results program between 1973-2013. Primary EC cases were eligible for analysis, and a time-specific proportion of UCS was examined during the study period.UCS was seen in 11,000 (4.7%) women among 235,849 primary EC cases. Mean age at UCS diagnosis increased from 65.9 to 71.7 years between 1973-1989 and then decreased from 71.7 to 67.0 years between 1989-2013 (both, p0.001). Proportion of Black women significantly increased during the study period (11.9%-20.0%, p0.001), whereas the proportion of White women decreased from 86.0% to 60.5% between 1987-2013 (p0.001). There was a significant increase in the proportion of UCS among primary EC from 1.7% to 5.6% between 1973-2013 (p0.001). Among type II ECs (n=76,118), the proportion of UCS also increased significantly from 6.0% to 17.5% between 1973-2013 (p0.001). An increasing proportion of UCS was seen in both young and older women but the magnitude of interval increase was larger in the older age group between 1973-2013 (60 years, from 1.3% to 3.3%. p0.001; and ≥60 years, from 2.6% to 7.0%, p0.001).Our study demonstrated that the proportion of UCS has significantly increased among EC, accounting for more than 5% in recent years.

Importance Cytotoxic CD8+tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+TILs in epithelial ovarian cancer. Design, Setting, and Participants This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Exposures Following immunohistochemical analysis, CD8+TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures Overall survival time. Results The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+TILs, respectively (Pvalue for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germlineBRCA1pathogenic mutation, but were not prognostic forBRCA2mutation carriers. Evaluation of uncategorized CD8+TIL counts showed a near-log-linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Context Cervical cancer affects 12 000 women in the United States annually. However, despite its prevalence, there remains no good methodology to detect its recurrence. Objective To identify the role of cervicovaginal high-risk human papilloma virus (hr-HPV) testing in predicting cervical cancer recurrence. Design This is a retrospective study of patients who underwent hr-HPV testing as part of their routine surveillance for cervical cancer. Standard statistical analyses, including χ2 test and multivariable logistic regression, were performed with IBM SPSS 19.0. Results A total of 133 patients were identified, of whom 107 (80%) had squamous cell carcinoma. Ninety patients (68%) had bulky disease and were treated primarily with chemoradiation and brachytherapy. Of patients whose disease recurred, 5 patients (42%) had tested positive for hr-HPV during their surveillance period, compared to 13 patients (11%) for whom disease did not recur (relative risk: 3.88, P = .002). On multivariate logistic regression, hr-HPV status remained significantly predictive of disease recurrence (odds ratio: 12.3, P = .02, 95% confidence interval: 1.5–99.6). Using 2 × 2 table analysis, we found that while cervicovaginal cytology has limited specificity (5.7%) in predicting recurrence, the combination of cytology with hr-HPV testing increases the specificity of testing to 89.3%. Conclusions Persistence of hr-HPV is a risk factor for disease recurrence. High-risk–HPV testing is not routinely used during surveillance for cervical cancer, but this study suggests that large, prospective trials investigating the role of hr-HPV testing in cervical cancer surveillance are needed.

Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

Functional loss of expression of breast cancer susceptibility gene 1(BRCA1) has been implicated in genomic instability and cancer progression. There is emerging evidence that BRCA1 gene product (BRCA1) also plays a role in cancer cell migration. We performed a quantitative proteomics study of EOC patient tumor tissues and identified changes in expression of several key regulators of actin cytoskeleton/cell adhesion and cell migration (CAPN1, 14-3-3, CAPG, PFN1, SPTBN1, CFN1) associated with loss of BRCA1 function. Gene expression analyses demonstrate that several of these proteomic hits are differentially expressed between early and advanced stage EOC thus suggesting clinical relevance of these proteins to disease progression. By immunohistochemistry of ovarian tumors with BRCA1(+/+) and BRCA1(null) status, we further verified our proteomic-based finding of elevated PFN1 expression associated with BRCA1 deficiency. Finally, we established a causal link between PFN1 and BRCA1-induced changes in cell migration thus uncovering a novel mechanistic basis for BRCA1-dependent regulation of ovarian cancer cell migration. Overall, findings of this study open up multiple avenues by which BRCA1 can potentially regulate migration and metastatic phenotype of EOC cells.

Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

Purpose: Hypofractionated whole breast irradiation (HF-WBI) following breast conserving surgery for early stage breast cancer is now recommended for women over 50 years of age by the American Society for Radiation Oncology (ASTRO). Herein, we explored the rate of HF-WBI utilization and its associated patterns of care using the National Cancer Data Base (NCDB), a comprehensive oncology outcomes database which captures 70% of all newly diagnosed cancer patients in the US. Methods: We utilized NCDB to identify women aged ≥50 diagnosed with T1N0/T1Nx invasive breast cancer or Tis (DCIS) who underwent breast conserving surgery and adjuvant whole breast external beam radiation therapy. HF-WBI was defined when a definitive radiation dose (≥40 Gy) was delivered in ≤23 fractions. We evaluated factors associated with the use of HF-WBI through exploratory univariate and multivariable analyses. Results: A total of 311,071 patients from 1998-2011 met inclusion criteria. The commonest HF-WBI regimen was 42.56 Gy in 16 fractions. The rate of HF-WBI utilization increased over time from 0.4% in 1998 to 16.5% in 2011 (p Factors Associated with Increased Use of HF-WBIAssociation with HF-WBIOdds Ratio of HF-WBI Use (95% confidence interval)Year of Diagnosis (2011 vs. prior to 2009)7.14 (6.85-7.52)Age (Decade, 80+ years)6.45 (6.06-6.90)Facility Type: Academic4.00 (3.69-4.33)Location (Mountain Region)1.82 (1.68-1.97)Grade 11.40 (1.33-1.47)Race: White1.38 (1.25-1.53)Income Quartile 4 (>$46K/year)1.30 (1.21-1.40)Comorbidity Index (High, 2)1.15 (1.02-1.31)Invasive Cancer1.09 (1.04-1.14)Laterality (Right Side)1.05 (1.02-1.09)Distance from Treatment Facility1.002 per mile (1.002-1.002) Conclusions: This comprehensive patterns of care study of HF-WBI in women ≥50 years old with early stage breast cancer from a national database identified a substantial increase in the utilization of this technique with time. Advancing patient age and treatment at academic facility were also strong predictors of delivery of HF-WBI. Disparities in utilization of HF-WBI and overall employment of this technique, even in later years, remain suboptimal. Strategies to identify and break barriers to the adoption of HF-WBI should be explored. Citation Format: Malolan S Rajagopalan, Craig Lehocky, John C Flickinger, Dwight E Heron, Paniti Sukumvanich, Joseph L Kelley, Gretchen M Ahrendt, Sushil Beriwal. Utilization of hypofractionated radiation therapy for early stage breast cancer in women over 50 years of age [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-02.

ABSTRACT Aim: Lymphadenectomy or lymph node dissection is a topic of controversy in endometrial cancer (EC) treatment. Materials & methods: Associations between lymph node dissections and clinical factors were retrospectively examined in obese, endometrioid endometrial cancer patients with early-stage disease between 1995 and 2005. Overall, EC-specific and recurrence-free survival were also evaluated. Results: Out of 192 patients, 61 (32%) did not have a lymph node examination, 55 (29%) had less than ten lymph nodes removed and 76 (39%) had ≥10 removed. Lymph node dissection count was not significantly associated with overall, EC-specific or recurrence-free survival. Conclusion: Analysis revealed no significant associations between ≥10 dissected lymph nodes and survival outcomes among obese, EC patients, which supports the need for additional investigation of the merit of lymphadenectomy among these patients.

Purpose To investigate the clinical feasibility and treatment outcomes of image-based high-dose-rate (HDR) brachytherapy using an intracavitary multichannel vaginal cylinder for the definitive treatment of vaginal cancers. Methods and Materials A total of 41 patients with vaginal cancer (24% primary vaginal and 76% recurrence from other gynecologic primaries) treated with definitive radiotherapy ± chemotherapy including image-based HDR brachytherapy with a multichannel vaginal cylinder were included in the study. Image-based brachytherapy was completed using either CT- (41%) or MR-based planning (59%) with each fraction. The high-risk clinical target volume was defined based on the pre- and postexternal beam radiotherapy gross tumor volume. Doses were converted to equivalent dose of 2 Gy per fraction. Endpoints examined were dose–volume parameters and early clinical outcomes. Results The median high-risk clinical target volume was 24.2 cc (interquartile range [IQR], 12.6), with a median dose to 90% ( D 90 ) of 77.1 Gy (IQR, 3.4). The median dose to 2 cc ( D 2 cc ) for the bladder, rectum, and sigmoid were 59.4 Gy (IQR, 5.6), 58.2 Gy (IQR, 4.1), and 52.3 Gy (IQR, 5.5), respectively. After a median followup of 16 months (range, 3–35), complete clinical response was documented in 98% of the patients. The 2-year local, regional, and distant control; and disease-free and overall survival were 93%, 100%, 81%, 78%, and 88%, respectively. The 2-year actuarial rate of late Grade 3 or higher toxicity was 4% overall with 0%, 0%, 0%, and 4% for vaginal, bladder, urethral, and gastrointestinal, respectively. Conclusions Image-based HDR brachytherapy using an intracavitary multichannel cylinder seems feasible in definitive vaginal cancer treatment. The described clinical implementation shows promising early clinical outcomes with high rates of local control and little toxicity, which should be validated with extended followup.

Purpose Positron emission tomography/computed tomography (PET/CT) is commonly used for nodal staging in locally advanced cervical cancer; however the false negative rate for para-aortic disease are 20% to 25% in PET-positive pelvic nodal disease. Unless surgically staged, pelvis-only treatment may undertreat para-aortic disease. We have treated patients with PET-positive nodes with extended field intensity modulated radiation therapy (IMRT) to address the para-aortic region prophylactically with concomitant boost to involved nodes. The purpose of this study was to assess regional control rates and recurrence patterns. Methods and Materials Sixty-one patients with cervical cancer (stage IBI-IVA) diagnosed from 2003 to 2012 with PET-avid pelvic nodes treated with extended field IMRT (45 Gy in 25 fractions with concomitant boost to involved nodes to a median of 55 Gy in 25 fractions) with concurrent cisplatin and brachytherapy were retrospectively analyzed. The nodal location was pelvis-only in 41 patients (67%) and pelvis + para-aortic in 20 patients (33%). There were a total of 179 nodes, with a median number of positive nodes of 2 (range, 1-16 nodes) per patient and a median nodal size of 1.8 cm (range, 0.7-4.5 cm). Response was assessed by PET/CT at 12 to 16 weeks. Results Complete clinical and imaging response at the first follow-up visit was seen in 77% of patients. At a mean follow-up time of 29 months (range, 3-116 months), 8 patients experienced recurrence. The sites of persistent/recurrent disease were as follows: cervix 10 (16.3%), regional nodes 3 (4.9%), and distant 14 (23%). The rate of para-aortic failure in patients with pelvic-only nodes was 2.5%. There were no significant differences in recurrence patterns by the number/location of nodes, largest node size, or maximum node standardized uptake value. The rate of late grade 3+ adverse events was 4%. Conclusions Extended field IMRT was well tolerated and resulted in low regional recurrence in node-positive cervical cancer. The dose of 55 Gy in 25 fractions was effective in eradicating disease in involved nodes, with acceptable late adverse events. Distant metastasis is the predominant mode of failure, and the OUTBACK trial may challenge the presented paradigms.

Introduction: In 2012, University of Pittsburgh Medical Center (UPMC) introduced a hysterectomy clinical pathway to reduce the number of total abdominal hysterectomies performed for benign gynecological indications. This study focused on exploring physician and patient factors impacting the utilization of hysterectomy clinical pathways.Methods: An online survey with 24 questions was implemented to explore physicians’ attitudes and perceived barriers toward implementing the pathway. A survey consisting of 27 questions was developed for patients to determine the utility of a pathway-based educational tool for making surgery decisions and to measure satisfaction with the information provided. Descriptive statistics were used to describe survey results, while thematic analysis was performed on verbal feedback submitted by respondents. Results: Physician respondents found the clinical pathway to be practical, beneficial to patients, and up-to-date with the latest evidence-based literature. Key barriers to the use of the pathway that were identified by physicians included perceived waste of time, inappropriateness for some of the patient groups, improper incentive structure, and excessive bureaucracy surrounding the process. Overall, patient respondents were satisfied with the tool and found it to be helpful with the decision-making process of choosing a hysterectomy route. Conclusions: Physicians and patients found the developed tools to be practical and beneficial. Findings of this study will help to use pathways as a unifying framework to shape future care of patients needing hysterectomy and add value to their care.

Background and Objectives To examine survival of women with stage IV uterine carcinosarcoma (UCS) who received neoadjuvant chemotherapy followed by hysterectomy. Methods This is a nested case-control study within a retrospective cohort of 1192 UCS cases. Women who received neoadjuvant chemotherapy followed by hysterectomy based-surgery for stage IV UCS (n = 26) were compared to those who had primary hysterectomy-based surgery without neoadjuvant chemotherapy for stage IV UCS (n = 120). Progression-free survival (PFS) and cause-specific survival (CSS) were examined. Results The most common regimen for neoadjuvant chemotherapy was carboplatin/paclitaxel (53.8%). Median number of neoadjuvant chemotherapy cycles was 4. PFS was similar between the neoadjuvant chemotherapy group and the primary surgery group (unadjusted-hazard ratio [HR] 1.19, 95% confidence interval [CI] 0.75-1.89, P = 0.45). Similarly, CSS was comparable between the two groups (unadjusted-HR 1.13, 95%CI 0.68-1.90, P = 0.64). When the types of neoadjuvant chemotherapy regimens were compared, women who received a carboplatin/paclitaxel regimen had better survival outcomes compared to those who received other regimens: PFS, unadjusted-HR 0.38, 95%CI 0.15-0.93, P = 0.027; and CSS, unadjusted-HR 0.21, 95%CI 0.07-0.61, P = 0.002. Conclusion Our study found that there is no statistically significant difference in survival between women with stage IV UCS who are tolerated neoadjuvant chemotherapy and those who undergo primary surgery.

Objectives Management of endometrial cancer consists of surgical staging with adjuvant therapy guided by risk factors, though some women cannot undergo surgery due to comorbidities. We present a series of women treated with definitive high-dose rate image-guided tandem and cylinder brachytherapy (HDR-IGBT) alone. Methods Patients with grade 1–2, clinical stage I endometrial adenocarcinoma, Results From 2007 to 2016, 45 patients were treated to a median dose of 37.5Gy. The median gross tumor volume (GTV) and clinical target volume (CTV) were 5.9cm 3 (range, 0.7–18.7) and 80.9cm 3 (17.2–159.0), respectively. The median cumulative dose to 90% (D90) of the GTV was 132.8Gy (76.5–295.6) equivalent 2Gy dose, and the median CTV D90 was 49.7Gy (34.5–57.2). Median follow-up among living patients was 18.6months (3.0–64.3). Cessation of vaginal bleeding occurred in 98%. Among those with post-treatment MRI (64%), complete radiographic response was demonstrated in 90%. The 2-year LRC, cancer-specific survival, and overall survival rates were 90%, 86%, and 97%, respectively. No grade 3+ acute or late toxicity was observed. Conclusions HDR-IGBT alone for treatment of early-stage, medically inoperable endometrial cancer is feasible with excellent response rates and clinical results. This approach also allows sparing of critical organs and ensures target coverage, which contributed to the low toxicity rate and high LRC in comparison with 2D point-based series.

Purpose Definitive radiotherapy is a viable option for medically inoperable patients with early stage endometrial cancer. We present our experience using image-based brachytherapy (BT). Methods and Materials Patients with medically inoperable clinical Stage I endometrial adenocarcinoma received definitive BT with or without external beam radiotherapy. High-dose-rate BT was delivered using MRI- or CT-based planning for each fraction. For patients with an MRI, gross tumor volume (GTV) was contoured although dose was still prescribed to the clinical treatment volume (CTV), including the entire uterus, cervix, and upper 1–2 cm of vagina. Equivalent 2 Gy doses (EQD 2 ) were calculated. Results Thirty-eight patients were treated from 2007 to 2013, 20 receiving BT alone with a median dose of 37.5 Gy in five to six fractions. For combined therapy, median external beam and BT doses were 45 and 25 Gy in four to five fractions. With 15-month median followup, the 2-year actuarial local control and overall survival were 90.6% and 94.4%. No Grade 2–5 late toxicities were observed. Mean CTV D 90 EQD 2 for BT alone and combined therapy was 48.6 ± 5.6 and 72.4 ± 6.0 Gy, whereas mean GTV D 90 EQD 2 was 172.3 ± 59.6 and 138.0 ± 64.6 Gy. Conclusions Image-based BT is feasible for medically inoperable early stage endometrial cancer with excellent early results. Despite low CTV doses, high doses delivered to GTV with BT likely accounts for high local control. Endometrial cancer guidelines for image-based planning are needed to define target volumes based on risk with differential dose delivery.

Purpose For locally-advanced uterine cancer clinically extending to the cervix, two treatment paradigms exist: surgical staging radical hysterectomy with tailored adjuvant therapy or neoadjuvant therapy followed by a less extensive simple hysterectomy. Currently, insufficient data exists to guide consensus guidelines and practical application of preoperative radiotherapy. Materials and methods Retrospective IRB approved cohort study from 1999 to 2014 of 36 endometrial cancer patients with clinical involvement of cervix±parametria treated with neoadjuvant external beam radiotherapy (45–50.4Gy in 25–28 fractions) and image-based HDR brachytherapy (5–5.5Gy times 3–4 fractions)±chemotherapy followed by extrafascial hysterectomy performed at a median of 6weeks after radiotherapy. Results All patients had clinical cervical extension, 50% also had parametria extension, and 31% had nodal involvement. At the time of surgery 91% had no clinical cervical involvement, 58% had no pathologic cervical involvement, and all had margin negative resection. The pathologic complete response rate was 24%. Median follow-up from the time of surgery was 20months (range: 0–153). The 3-year local control, regional control, distant control, disease free survival and overall survival rates were 96%, 89%, 84%, 73%, and 100%. The 3-year rate of grade 3 complications was 11%, with no grade 4+ toxicity. Conclusions Neoadjuvant radiation therapy±chemotherapy followed by extrafascial hysterectomy appears to be a viable option for patients with endometrial cancer clinically extending to the cervix and parametria. The HDR brachytherapy schema of 5–5.5Gy times 3–4 fractions, for a cumulative EQD 2 of 60–70Gy, is well tolerated with high rates of clinical and pathological response.