Survival In Uterine Serous Carcinoma Research Articles

Human epidermal growth factor 2 (HER2) amplification in uterine serous carcinoma: an analysis of prognosis and immune microenvironment.

Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. Anti-human epidermal growth factor receptor 2 (HER2) therapy has demonstrated its promising effects on HER2-positive USC. However, data on prognostic relevance and immune microenvironment are limited in HER2-positive USC. This study aimed to determine the clinicopathologic features, prognosis, and the immune microenvironment trait in HER2 status in USC. We applied immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and multi-color immunofluorescence to investigate HER2 expression and amplification, PD-L1 expression, and tumor infiltration lymphocytes (TIL) in 77 USC (61 pure and 16 mixed-type USC). HER2 IHC 1 + , 2 + , and 3 + were found in 26, 18, and 10 USC, respectively. HER2 staining frequently had an incomplete membrane (basolateral or "U"-shaped) pattern. Twenty-three cases (23/54, 42.6%) showed an intra-tumor heterogeneous staining. HER2 amplification was present in 16/77 (20.8%) USC. HER2 amplification was significantly associated with deep myometrial invasion (> 1/2), and increased intra-epithelial and stromal density of CD20 + or CD8 + TIL (all P < 0.05), but not with USC subtypes (pure versus mixed-type), PD-L1 expression, CD4 + TIL, CD68 + histiocytes, or the CD4 + /CD8 + ratio (p > 0.05). HER2 amplification was associated with poor overall and progression-free survival in USC, but lost the prognostic significance on multivariate analysis. We concluded that HER2 amplified USC had adverse clinical outcomes, but showed the potential active immune microenvironment. Our findings raised the possibility of the combined anti-HER2 and immunotherapy for HER2-positive USC in the future.

Monitoring Treatment Response, Early Recurrence, and Survival in Uterine Serous Carcinoma and Carcinosarcoma Patients Using Personalized Circulating Tumor DNA Biomarkers.

Uterine serous carcinoma (USC) and carcinosarcomas (CSs) are rare, highly aggressive variants of endometrial cancer. No reliable tumor biomarkers are currently available to guide response to treatment or detection of early recurrence in USC/CS patients. Circulating tumor DNA (ctDNA) identified using ultrasensitive technology such as droplet digital polymerase chain reaction (ddPCR) may represent a novel platform for the identification of occult disease. We explored the use of personalized ctDNA markers for monitoring USC and CS patients. Tumor and plasma samples from USC/CS patients were collected at the time of surgery and/or during the treatment course for assessment of tumor-specific somatic structural variants (SSVs) by a clinical-grade next-generation sequencing (NGS) platform (i.e., Foundation Medicine) and a droplet digital PCR instrument (Raindance, ddPCR). The level of ctDNA was quantified by droplet digital PCR in plasma samples and correlated to clinical findings, including CA-125 serum and/or computed tomography (CT) scanning results. The genomic-profiling-based assay identified mutated "driver" target genes for ctDNA analysis in all USC/CS patients. In multiple patients, longitudinal ctDNA testing was able to detect the presence of cancer cells before the recurrent tumor was clinically detectable by either CA-125 or CT scanning. Persistent undetectable levels of ctDNA following initial treatment were associated with prolonged progression-free and overall survival. In a USC patient, CA-125 and TP53 mutations but not PIK3CA mutations become undetectable in the plasma at the time of recurrence, suggesting that more than one customized probe should be used for monitoring ctDNA. Longitudinal ctDNA testing using tumor-informed assays may identify the presence of residual tumors, predict responses to treatment, and identify early recurrences in USC/CS patients. Recognition of disease persistence and/or recurrence through ctDNA surveillance may allow earlier treatment of recurrent disease and has the potential to change clinical practice in the management of USC and CS patients. CtDNA validation studies in USC/CS patients prospectively enrolled in treatment trials are warranted.

WT1 expression associated with platinum-sensitivity and improved progression-free survival in uterine serous carcinoma

Objectives: Wilms tumor gene 1 (WT1) expression is a hallmark of ovarian serous carcinoma (OSC) and considered to be diagnostic marker of these tumors, differentiating them from uterine serous carcinoma (USC), traditionally thought to rarely express WT1. However, recent data indicates a significant percentage of USC may express WT1, limiting its use as a differentiating marker between these two tumors. Additionally, the clinical implications of WT1 positivity in USC remain unclear. Methods: A multicenter retrospective analysis of patients with USC was conducted from 2000 - 2019. Inclusion criteria were patients who had undergone comprehensive surgical staging/tumor debulking with archival tissue available for WT1 assessment via immunohistochemistry (IHC). Platinum-sensitive patients were defined as those recurring >6 months from last platinum-based chemotherapy. Differences in the frequencies of stage, race, chemosensitivity and sites of disease recurrence were identified using Pearson's chi-square test. Progression free survival (PFS) and overall survival (OS) analysis was performed using Kaplan-Meier estimates. Multivariate analysis (MVA) was performed using Cox proportional hazards model. Results: WT1 status was evaluated in 61 patients with USC. 13 (21.3%) were positive for WT1 by IHC. Of these 61 patients, 56 had follow-up information available for review and were included in final analysis. The mean age was 67-years and the majority of patients were African American (97%). Stage distribution included 32% stage I, 5% stage II, 25% stage III and 38% stage IV. The majority of patients were designated as platinum-sensitive (63%). 36 (64%) patients recurred during the study period, 8 (62%) of the WT1 positive and 28 (65%) of the WT1 negative cohort. The most common location of recurrence was the abdomen followed by the pelvis and extra-abdominopelvic sites. There was no difference in the stage (p=0.158), race (p=0.227) or distribution of recurrence sites (p=0.581) between WT1 positive and WT1 negative tumors. Platinum-sensitivity was significantly improved in WT1 positive (92.3%) vs. WT1 negative tumors (55.8%) (p=0.016). For the entire cohort, the median PFS was 20 months and the median OS was 29 months. The median PFS and OS did not differ significantly based on WT1 status (p=0.544 and p=0.759, respectively). However, we did observe a trend towards improved PFS among WT1 positive tumors (21 vs. 16 months, respectively). On MVA, stage (p Download : Download high-res image (147KB) Download : Download full-size image Conclusions: WT1 positivity is observed in over 20% of USC, limiting its utility to differentiating OSC and USC. Additionally, WT1 status holds prognostic significance as expression was associated with improved platinum-sensitivity and a clinically significant 5-month improvement in PFS.

Impact of positive cytology in uterine serous carcinoma: A reassessment

ObjectivesThe aim of this study was to evaluate the prognostic value of peritoneal cytology status among other clinicopathological parameters in uterine serous carcinoma (USC). MethodsA retrospective study of 148 patients diagnosed with uterine serous carcinoma from 1997 to 2016 at two academic medical centers in the Detroit metropolitan area was done. A central gynecologic pathologist reviewed all available slides and confirmed the histologic diagnosis of each case of USC. We assessed the prognostic impact of various clinicopathological parameters on overall survival (OS) and endometrial cancer-specific survival (ECSS). Those parameters included race, body mass index (BMI), stage at diagnosis, tumor size, lymphovascular invasion (LVSI), peritoneal cytology status, receipt of adjuvant treatment, and comorbidity count using the Charlson Comorbidity Index (CCI). We used Cox proportional hazards models and 95% confidence intervals for statistical analysis. ResultsPositive peritoneal cytology had a statistically significant effect on OS (HR: 2.09, 95% CI: [1.19, 3.68]) and on ECSS (HR: 2.02, 95% CI: [1.06 – 3.82]). LVSI had a statistically significant effect on both OS (HR: 2.27, 95% CI: [1.14, 4.53]) and ECSS (HR: 3.45, 95% CI: [1.49, 7.99]). Black or African American (AA) race was also found to have a significant effect on both OS (HR: 1.92, 95% CI: [1.07, 3.47]) and ECSS (HR: 2.01, 95% CI: [1.02, 3.98]). Other factors including BMI and tumor size > 1 cm did not show a statistically significant impact on OS or ECSS. ConclusionsPeritoneal washings with positive cytology and LVSI are important prognostic tools that may have a significant impact on overall survival in USC and can be used as independent negative prognosticators to help guide adjuvant treatment.

Abstract 911: In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma

Abstract Objective: Uterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2 overexpressing tumors at a distinct epitope from that bound by trastuzumab and pertuzumab after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A against primary USC cell lines and xenografts. Methods: Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for C-erbB2 gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability and bystander killing in USC cell lines after exposure to DHES0815A, the non-targeted ADC, and the unconjugated antibody (i.e. MHES0488A) were evaluated using flow cytometry-based-assays. In vivo activity of DHES0815A was tested against HER2/neu overexpressing USC xenografts. Results: High HER2/neu protein expression was seen in 25% (3/12) of the primary USC cell lines. USC cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (p&amp;lt;0.001). DHES0815A did not induce significant bystander killing of HER2/neu negative tumors when admixed with HER2/neu positive tumors. DHES0815A caused growth-inhibition and increased survival in USC HER2/neu overexpressing xenografts when compared to controls (p&amp;lt;0.01). Conclusions: DHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy. Citation Format: Joan Tymon R. Tymon-Rosario, Elena Bonazzoli, Stefania Bellone, Arancha Manzano, Paola Manara, Luca Zammataro, Silvia Pelligra, Adele Guglielmi, Barbara Gnutti, Burak Zeybek, Justin Harold, Dennis Mauricio, Elena Ratner, Peter Schwartz, Alessandro D. Santin. In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 911.

Exploring molecular profiles and survival in hormone receptor-positive uterine serous carcinoma.

5579 Background: Hormone receptor (HR) positivity has been reported as a good prognostic indicator in endometrial cancer. This study investigated estrogen receptor (ER) and progesterone receptor (PR) positivity as indicators of platinum response and improved survival in uterine serous carcinoma (USC), and determined differences in molecular profiles between these tumors and hormone receptor negative tumors. Methods: Tumor profiling was done with immunohistochemistry (IHC), next generation sequencing (NGS), and whole transcriptome sequencing (WTS). PD-L1 expression was determined by IHC using SP-142 (cut-off &gt;1%). Microsatellite instability (MSI) status was evaluated with IHC and NGS, and tumor mutational burden (TMB) by totaling somatic mutations per tumor (high if &gt; 10 mutations/ MB). Immune-cell fraction was determined with QuantiSeq. We used insurance claims data to calculate Kaplan-Meier estimates for overall survival (OS). Statistical significance was determined with chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. Results: 2806 USC tumors were available for molecular profiling with 717 HR+/966 HR-, 1559 ER+/1059 ER- and 805 PR+/1809 PR-. Median OS for HR+ patients was longer than patients who were HR- regardless of treatment (1152 v 797 days; hazard ratio 0.68, 95% CI 0.58-0.80, p &lt; 0.01). This OS benefit of HR positivity remained for patients receiving platinum therapy (1134 v 889 days; hazard ratio 0.75, 95% CI 0.58-0.98, p &lt; 0.01). HR+ status trended towards improved OS in those treated with hormone therapy (407 vs 771 days, hazard ratio 0.78, 95% CI 0.59-1.02, p = 0.07). In addition to increased androgen receptor expression (54.2 vs 6.2%, p = &lt; 0.001), PTEN mutations were more common in the HR+ group (10.3 vs 5.1%, p = 0.016). This resulted in in more frequent alterations of the PI3K pathway when compared to HR- tumors 64.5 vs 52.2%, p = &lt; 0.001). PD-L1, TMB, and MSI status were similar between the two cohorts. Checkpoint inhibitor gene expression was notable for higher IDO expression in the HR+ group, but lower CD80, CD86, HAVCR2, IFNG, and PDC1 expression. The immune micro-environment was notable for less B-cells and M1 macrophages, but more M2 macrophages. Breaking the ER and PR positive cohort down to individual expression of each gene resulted in similar OS and molecular findings. Conclusions: HR positivity is associated with improved survival in allcomers with USC and those treated with platinum therapy, and there was a trend to improved OS with hormone therapy. More data is needed to determine if HR status is a prognostic marker for IO treatment response. This cohort had a distinct molecular profile compared to HR- tumors.

Family history of cancer associated with improved survival in uterine serous carcinoma

Family history of cancer associated with improved survival in uterine serous carcinoma

High expression of the p53 isoform \u03b3 is associated with reduced progression-free survival in uterine serous carcinoma

BackgroundUterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial carcinoma. Large-scale comprehensive efforts have resulted in an improved molecular understanding of its pathogenesis, and the p53 pathway has been proposed as a key player and is potentially targetable. Here we attempt to further portray the p53 pathway in USC by assessing p53 isoform expression.MethodsWe applied quantitative Real-Time PCRs (RT-qPCR) for expression analyses of total p53 mRNA as well as quantitative distinction of p53β, p53γ, and the total mRNA of amino-terminal truncated Δ40p53 and Δ133p53 in a retrospective cohort of 37 patients with USC. TP53 mutation status was assessed by targeted massive parallel sequencing. Findings were correlated with clinical data.ResultsThe p53 isoform expression landscape in USCs was heterogeneous and dominated by total Δ133p53, while the distinct p53β and p53γ variants were found at much lower levels. The isoform expression profiles varied between samples, while their expression was independent of TP53 mutation status. We found high relative p53γ expression to be associated with reduced progression-free survival (PFS).ConclusionsThis is the first indication that elevated p53γ expression is associated with reduced PFS in USC. This single-center study may offer some insight in the landscape of p53 isoform expression in USC, but further validation studies are crucial to understand the context-dependent and tissue-specific role of the p53 isoform network in gynecological cancer.

Impact of tubal ligation on routes of dissemination and overall survival in uterine serous carcinoma

ObjectiveAbdominal peritoneal implants are characteristic of uterine serous carcinoma (USC). The presumed mechanism of dissemination is retrograde transit via the fallopian tube. We assessed the impact of tubal ligation (TL) on the metastatic profile and survival of USC patients. MethodsPatient risk factors, process-of-care variables, and disease-specific parameters were annotated. Categorical variables were compared using the χ2 test. Overall survival (OS) was estimated via the Kaplan–Meier method. ResultsAmong 211 USC patients, fallopian tube status was documented in 142 patients; 35 had a history of TL and 107 did not. When comparing patients with and without TL, positive peritoneal cytology was present, respectively, in 18.8% vs 45.0% (P=.01) and stage IV disease in 14.3% vs 34.6% (P=.02). Using Cox models, age was the sole significant determinant of OS in stage I/II USC. By contrast, age, lymphovascular space involvement, positive cytology, and TL independently and adversely affected survival in stage III/IV USC. Adjusting for these factors in a multivariable model, the association between TL and OS among patients with advanced disease yielded a hazard ratio of 8.61 (95% CI, 3.08–24.03; P<.001). The prevalence of lymphatic metastasis and nodal tumor burden was significantly greater in patients who underwent ligation. ConclusionPatients with TL had significantly lower rates of positive cytology and stage IV disease than patients without TL. The lymphatic system appeared to be the dominant mode of spread after TL and was associated with a paradoxic worsening of OS, perhaps reflecting a delay in diagnosis.

The impact of race on survival in uterine serous carcinoma: A hospital-based study

Objective Although less common than endometrioid carcinoma, uterine serous carcinoma (USC) accounts for a disproportionate number of endometrial cancer-related deaths. It is relatively more common in black compared to white women. The aim of our study is to analyze the impact of race on survival in USC. Methods We conducted a retrospective review in women with USC managed at two large urban medical centers. Clinical and histopathologic parameters were retrieved. Recurrence and survival data were obtained from medical records and the Surveillance, Epidemiology, and End Results (SEER) registry. Differences in overall survival between African American and Caucasian women were compared using Kaplan–Meier curves and log rank test for univariate analysis. Cox regression models for multivariate analyses were built to evaluate the relative impact of the various prognostic factors. Results One hundred seventy-two women with USC were included in this study, including 65 Caucasian women and 107 African American women. Both groups were similar with respect to age, stage at diagnosis, angiolymphatic invasion ( p = 0.79), and the depth of myometrial invasion ( p = 0.36). There was no statistical difference in overall survival between African American and Caucasian patients in univariate analysis ( p = 0.14). In multivariate analysis, stage at diagnosis, angiolymphatic invasion, and depth of myometrial invasion, but not race, were significantly associated with overall survival. Conclusion In this study, African American women with USC had a similar survival to Caucasian women. This suggests that the racial differences seen in USC at a larger population level may be diminished in hospital-based studies, where women are managed in a uniform way.