Uterine Serous Carcinoma Research Articles

Preclinical testing of farletuzumab ecteribulin (FZEC [MORAb-202]) and MORAb-109, folate receptor α and mesothelin targeting antibody-drug conjugates (ADCs), in rare gynecologic cancers.

e17634 Background: Rare gynecologic cancers, such as ovarian carcinosarcoma (OCS), uterine serous carcinoma (USC) and ovarian clear cell adenocarcinoma (OCCA), have limited treatment options and molecular alterations that drive cell proliferation and drug resistance, resulting in poor overall survival. The anti-microtubule agent (AMA) paclitaxel is used in first-line treatment of most gynecologic cancers; however, the AMA eribulin is known to have additional anticancer properties (Goto et al. Anticancer Res 38:2929, 2018; Ho et al. Cancer Res 82:4457, 2022). Eribulin ADCs have been developed for targeted delivery to limit toxicity and maximize response. FZEC is an anti-folate receptor α (FRA)-eribulin ADC (Shimizu et al. Clin Cancer Res 27:3905, 2021) and MORAb-109 targets eribulin to mesothelin (MSLN; Albone et al. Annals Oncol 31:S491, 2020). Here we provide preclinical data to support clinical trials of FZEC and MORAb-109 in rare gynecologic cancers. Methods: Fresh tumor tissue from patients consented to the WEHI Stafford Fox Rare Cancer Program was used to establish a cohort of patient-derived xenograft (PDX) models of high-grade serous ovarian carcinoma (HGSOC), OCS, USC and OCCA. PDX models were screened for FRA and MSLN expression by IHC and quantified by HALO software, and 15 models were selected for in vivo testing. Tumor-bearing mice were treated with eribulin (1 mg/kg TIW 3 wks), FZEC (12.5 mg/kg Q14Dx3) or MORAb-109 (25 mg/kg Q14Dx3) and compared to standard of care treatments. Results: About 80% of HGSOC PDX models were FRA positive with no difference between models from chemonaïve samples vs multiple lines of prior treatment. FRA expression was frequent in USC and OCCA models, with MSLN seen in a smaller subset. Despite most (80%) models being cisplatin refractory, 11/15 responded to eribulin with the 4 non-responders having high MDR1 expression and being from previously treated patients. Overall, responses to FZEC and MORAb-109 appeared to correlate with FRA and MSLN expression; importantly, some models with moderate to high target antigen expression showed deeper and more durable responses to FZEC and MORAb-109 compared to eribulin. Conclusions: Responses to FZEC and MORAb-109 correlated with FRA and MSLN expression, with equivalent or better activity compared to eribulin in target-positive PDX models of HGSOC, USC and OCCA. [Table: see text]

Preliminary results of a phase II trial with sacituzumab govitecan-hziy in patients with recurrent endometrial carcinoma overexpressing Trop-2.

5599 Background: Despite recent advances, there remains a significant need for targeted, efficacious treatments for advanced and recurrent endometrial carcinoma (EC). Trop-2 has been demonstrated to be overexpressed in several EC including grade 3 endometrioid adenocarcinoma (96%), and uterine serous carcinoma (65%). Trop-2 overexpression has been found to confer a worse prognosis and predicts disease recurrence. Sacituzumab govitecan-hziy (SG) is an antibody-drug conjugate comprised of a humanized anti-Trop-2 antibody conjugated with the active metabolite of irinotecan, a topoisomerase-I inhibitor. SG is currently FDA-approved for use in metastatic urothelial cancer and metastatic triple-negative breast cancer. Methods: We report results from the stage 1 of an open-label non-randomized phase 2 trial (NCT04251416) established to evaluate the clinical activity of SG in patients with persistent or recurrent EC of epithelial origin with Trop-2 overexpression. Criteria for study participation included radiographically confirmed and measurable persistent or recurrent EC, progression after or during platinum-based chemotherapy, and at least 2+ staining of Trop-2. One target lesion by RECIST v1.1 and adequate bone marrow, renal, and hepatic function were required. Patients were at least two weeks beyond prior treatment, major surgery, or high dose systemic corticosteroid use. Patients were given 10mg/kg of SG administered as an intravenous infusion once weekly on days 1 and 8 of 21-day treatment cycles. This 3-week cycle was continued without rest until disease progression or unacceptable toxicity. Results: Twenty-one patients were enrolled into stage 1. Ten patients (48%) had uterine serous carcinoma, seven (33%) had endometrioid adenocarcinoma, three (14%) had carcinosarcoma, and one patient had mixed serous and clear cell histology. All patients received at least one prior line of chemotherapy, (median 3 lines, range 1-6). At the time of submission, 20 patients were response-evaluable (Table); seven (35%) achieved objective response (5 out of 7 confirmed). Eighteen patients were evaluable for durable disease control; 7 (39%) achieved it. Follow-up durations had a median (IQR) of 15.6 (5.7–22.5) months. Median OS was 22.5 months, and median PFS was 5.7 months. The treatment was well-tolerated with no new or unexpected safety signals reported. Conclusions: Sacituzumab govitecan shows remarkable clinical activity against some of the most historically challenging and chemotherapy-resistant endometrial pathologies and demonstrates a favorable safety profile. With these promising results, we will begin the stage 2 expansion of this phase 2 trial. Clinical trial information: NCT04251416 . [Table: see text]

Trastuzumab emtansine (T-DM1) in advanced cancers with HER2 mutations or amplification: Results from the Molecular Screening and Therapeutics (MoST) Program substudy.

3127 Background: The antibody-drug conjugate T-DM1 is widely used for the treatment of HER2-positive metastatic breast cancer. Its activity in other advanced solid tumors harboring HER2 alterations identified by comprehensive genomic profiling (CGP) needs further characterization. Methods: The MoST program provides a precision oncology framework for screening patients (pts) by CGP to identify genomic alterations with potential to match to biomarker-directed clinical trials. This multi-center, single-arm phase 2 trial (ACTRN12619001265167) enrolled adult pts with refractory solid tumors (excluding breast and gastroesophageal cancers) with HER2 alterations. This trial recruited 2 groups of 16 pts (group 1: mutations, group 2: genomic amplification, defined as copy number ≥ 6 copies). The primary composite endpoint was objective tumor response (OTR) assessed by RECIST 1.1 and time-to-progression (TTP) ratio (defined as TTP on T-DM1: TTP1 on prior line of systemic therapy). Anti-tumor activity of T-DM1 was confirmed if ≥3 of each 16 pt group achieved an OTR. Key secondary endpoints were progression-free and overall survival (PFS and OS) and safety as assessed by CTCAE 5.0. Results: 32 pts had a median age of 64 years (interquartile range [IQR] 53 to 69); 94% an ECOG PS ≤1; 53% female; and median 2 (IQR 1 to 3.5) prior lines of systemic therapy. The cohort included non-small cell lung cancer (NSCLC, n=12), colorectal (CRC, n=5), salivary gland (SGC, n=5), ovarian (n=3), uterine (n=2), gallbladder (n=2), and 1 each of bladder, pancreas and cervix cancers. After a median follow-up of 17 months (mo), the primary endpoint was met with 7 pts (22%) achieving an OTR, including 3 pts (19%) in group 1 (2 NSCLC and 1 SGC) and 4 pts (25%) in group 2 (3 SGC, and 1 uterine serous carcinoma [USC]). Fourteen of 29 TTP-evaluable pts (48%) achieved a TTP ratio ≥1.3, including 10 pts without an OTR: equating to 53% (n=17) deriving clinical benefit. The median PFS and OS were 4.5 (95% CI 2.1 to 7.0) and 18.23 mo (95% CI 8.11 to not reached) respectively and 6 mo PFS rate 44% (95% CI 26 to 60%). The (NSCLC) responders in group 1 harbored exon 20 insertions (Y772_A775dup and G778_P780dup ) and the SGC, a L755S mutation. None of the S310Y/F mutations (n=5, including 2 NSCLCs) had an OTR. The USC was ERBB2 amplified (18 copies) on CGP, discordant with in situ hybridisation (ISH) testing results. Overall, 4 pts had CGP-amplified, ISH negative tumors, of whom 2 achieved an OTR. No responses were seen in CRC pts (all RAS/ BRAF-wildtype and IHC 2-3+). No new safety concerns for T-DM1 were reported. Conclusions: T-DM1 has anti-tumor activity across a heavily treated, diverse range of cancer types with HER2 alterations identified by CGP, including several unidentified by standard ISH testing. We await results from our partner trial in the first line advanced NSCLC setting to corroborate the group 1 findings. Clinical trial information: ACTRN12619001265167 .

Laparoscopy with or without robotic assistance does not negatively impact long-term oncologic outcomes in patients with uterine serous carcinoma

ObjectivesWe sought to compare outcomes between minimally invasive surgery (MIS) and laparotomy in patients with clinical stage I uterine serous carcinoma (USC). MethodsPatients who underwent surgery for newly diagnosed USC between 11/1/1993 and 12/31/2017 were retrospectively identified and assigned to either the MIS cohort or the laparotomy cohort. Patients with conversion to laparotomy were analyzed with the MIS cohort. Chi-square and Mann-Whitney tests were used to compare categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival and compared using the log-rank test. ResultsIn total, 391 patients met inclusion criteria; 242 underwent MIS (35% non-robotic and 65% robotic-assisted laparoscopies) and 149 underwent laparotomy. Age, BMI, stage, and washings status did not differ between cohorts. Patients who underwent MIS were less likely to have lymphovascular space invasion (LVSI; 35.1% vs 48.3%), had fewer nodes removed (median, 9 vs 15), and lower rates of paraaortic nodal dissection (44.6% vs 65.1%). Rates of adjuvant therapy did not differ between cohorts.Median follow-up times were 63.0 months (MIS cohort) vs 71.0 months (laparotomy cohort; P = .04). Five-year PFS rates were 58.7% (MIS) vs 59.8% (laparotomy; P = .1). Five-year OS rates were 65.2% (MIS) compared to 63.5% (laparotomy; P = .2). On multivariable analysis, higher stage, deep myometrial invasion, and positive washings were associated with decreased PFS. Age ≥ 65 years, higher stage, LVSI, and positive washings were associated with shorter OS. ConclusionsMIS does not compromise outcomes in patients with newly diagnosed USC and should be offered to these patients to minimize surgical morbidity.

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.

Uterine serous carcinoma: assessing association between genomics and patterns of metastasis.

Uterine serous carcinoma (USC) is an aggressive subtype of endometrial carcinoma which has been increasing at alarming rates, particularly among Asian, Hispanic and Black women. USC has not been well characterized in terms of mutational status, pattern of metastases and survival. To investigate the association between sites of recurrence and metastases of USC, mutational status, race, and overall survival (OS). This single-center retrospective study evaluated patients with biopsy-proven USC that underwent genomic testing between January 2015 and July 2021. Association between genomic profile and sites of metastases or recurrence was performed using χ2 or Fisher's exact test. Survival curves for ethnicity and race, mutations, sites of metastasis/recurrence were estimated using the Kaplan-Meier method and compared with log-rank test. Cox proportional hazard regression models were used to examine the association between OS with age, race, ethnicity, mutational status, and sites of metastasis/recurrence. Statistical analyses were performed using SAS Software Version 9.4. The study included 67 women (mean age 65.8 years, range 44-82) with 52 non-Hispanic women (78%) and 33 Black women (49%). The most common mutation was TP53 (55/58 women, 95%). The peritoneum was the most common site of metastasis (29/33, 88%) and recurrence (8/27, 30%). PR expression was more common in women with nodal metastases (p=0.02) and non-Hispanic women (p=0.01). ERBB2 alterations were more common in women with vaginal cuff recurrence (p=0.02), while PIK3CA mutation was more common in women with liver metastases (p=0.048). ARID1A mutation and presence of recurrence or metastases to the liver were associated with lower OS (Hazard Ratio (HR): 31.87; 95%CI: 3.21, 316.9; p<0.001 and HR: 5.66; 95%CI: 1.2, 26.79; p=0.01, respectively). In the bivariable Cox model, the presence of metastasis/recurrence to the liver and/or the peritoneum were both independent significant predictors of OS (HR: 9.8; 95%CI: 1.85-52.7; p=0.007 and HR: 2.7; 95%CI: 1.02-7.1; p=0.04, respectively). TP53 is often mutated in USC, which most commonly metastasize and recur in the peritoneum. OS was shorter in women with ARID1A mutations and with metastasis/recurrence to the liver. The presence of metastasis/recurrence to liver and/or peritoneum were independently associated with shorter OS.

Abstract CT247: A Phase 1/2a, multicenter, open-label, non-randomized first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1303 in patients with advanced/metastatic solid tumors

Abstract Background: Epidermal growth factor receptor 2 (EGFR2 or HER2) has shown gene amplification/over-expression in more than 30% of all human cancers, including breast cancer, gastric, colon, salivary gland, bladder, and uterine serous carcinoma, and its overexpression in tumors is associated with poor prognosis. DB-1303 (developed by DUALITYBIO INC.) is an antibody-drug conjugate (ADC) comprised of a humanized anti-HER2 IgG1 monoclonal antibody (BAT0606), covalently linked to a proprietary DNA topoisomerase I inhibitor (P1003) via a cleavable linker containing maleimide tetrapeptide (GGFG), with a drug-to-antibody ratio (DAR) of approximately 8. Preclinical studies demonstrated a favorable safety profile and a potent antitumor activity of DB-1303 compared with approved HER2-ADC. These studies warrant further clinical development of the study drug. Methods: This is a global first-in-human Phase 1/2a study (NCT05150691) to assess the safety, tolerability, and anti-tumor activities of the study drug DB-1303 in patients with pretreated advanced/metastatic solid tumors. Patients should have histologically confirmed HER2-positive or HER2-expressing cancers who failed previously systemic therapies, ECOG 0-1, and adequate organ function. The dose escalation part will evaluate seven ascending dose levels of DB-1303 (accelerated titration design for the first dose level and “3+3” design for the rest dose levels) to determine recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD). The study drug will be administrated iv infusion Q3W, and dose-limiting toxicity (DLT) will be assessed during Cycle 1 (1st 3 weeks). Phase 2a part will initiate after MTD and/or RP2D are determined. Phase 2a part only enrolls the patients with HER2-positive gastric, esophageal, or gastroesophageal junction adenocarcinoma, colorectal cancers, HER2 overexpression and HER2-low endometrial carcinoma, hormone receptor-positive (HR+)/HER2-low breast cancer, HER2-positive breast cancer, and activating HER2-mutated NSCLC. The study treatment of DB-1303 will continue until disease progression, withdrawal of consent, or unacceptable toxicity. Tumor responses will be assessed every 6-9 weeks with RECIST v1.1. The study planned to enroll 253 patients from sites in the United States, Australia, and China (88 patients in Phase I and 165 patients in Phase 2a). Citation Format: Erika Hamilton, Jian Zhang, Liming Liu, Jie Gao, Rong Shi, Shengxue Liu, Gu Wei, Yang Qiu, Kathleen Moore. A Phase 1/2a, multicenter, open-label, non-randomized first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1303 in patients with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT247.

Abstract 2438: Loss of galectin 3 reveals its potential roles in the aggressive pathology of uterine serous carcinoma

Abstract Objective: Uterine serous cancer (USC) represents about 10% of all uterine cancers, yet it accounts for up to 40% of all uterine cancer deaths. This lethality is due in part to the highly aggressive clinical course of this disease. Recently, galectin 3 (Gal3), a glycoprotein, was shown to contribute to malignant features in other tumors including ovarian cancer. In this study, we test the hypothesis that Gal3 facilitates malignant features in USC and might provide an opportunity for therapeutic intervention. Methods: The TCGA database was used to define the relationship between LGALS3 mRNA expression and prognosis. Gal3 knockout cells were established via CRISPR/Cas9-mediated deletion from USC cell lines, ARK1 and ARK2 (Gal3-KO). Gal3’s role in cell proliferation, cell cycle, and cell death were assessed. Gal3’s influence on apoptotic priming was done by BH3 profiling. Gal3 small molecule inhibitors (SMIs) were used to as an orthogonal approach to genetic knockdown. The effect of Gal3 loss on migration, invasion, and angiogenesis was assessed with transwell, Matrigel-invasion and HUVEC (human umbilical vein endothelial cells) tube-forming assays. The impact of Gal3 loss on cancer stem cells (CSC), phenotypically characterized by CD44, CD117, and ALDH activity, was measured by flow cytometry, and functionally by colony-forming and sphere-forming assays. An in vivo limiting dilution tumorigenic assay was performed with ARK1 Gal3-CTRL and KO cells in immunocompromised mice. Statistical analysis was done and a significance level of p &amp;lt; 0.05 was used. Results: The TCGA database revealed a worse prognosis for patients with USC and high LGALS3 mRNA. Cell Counts revealed Gal3-KO cells proliferated at a slower rate compared to Gal3-CTRL cells, and the difference wasn’t attributed to an increase in cell death. Cell cycle analysis showed an extended G2/M arrest in Gal3-KO cells suggesting Gal3 may influence cell cycle checkpoints. Unlike SKOV3 ovarian cancer cells, loss of Gal3 did not affect apoptotic sensitivity of USC cells as determined by BH3 profiling. Gal3 knockout reduced the number of migrating and invading cells in vitro. Gal3 SMIs (GB1107 and TD139) often differed in their response when compared to the knockout strategy. Conditioned media (CM) from ARK2 Gal3-CTRL promoted tube formation and invasion of HUVECs. This effect was reduced with CM from ARK2 Gal3-KO cells, suggesting Gal3 influences the tumor vascular microenvironment. Gal3 loss markedly reduced CD117+ cells and cells displaying high ALDH activity. Functionally, these findings were supported by a reduction in the number and size of colonies and fewer spheres formed by Gal3-KO cells compared to Gal3-CTRL cells. ARK1 Gal3-KO cells formed fewer and smaller tumors compared to Gal3-CTRL in mice. Conclusion: Gal3 has the potential to promote the more aggressive features of USC and patients would likely benefit from an anti-Gal3 based strategy. Citation Format: Yusuke Matoba, Dominique T. Zarrella, Venkatesh Pooladanda, Eugene Kim, Shaan Kumar, Mengyao Xu, Xingping Qin, Raj Kumar, Artem Kononenko, Irva Veillard, Kristopher Sarosiek, Oladapo Yeku, David R. Spriggs, Bo R. Rueda. Loss of galectin 3 reveals its potential roles in the aggressive pathology of uterine serous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2438.

HER2+ endometrioid endometrial cancer possesses distinct molecular and immunologic features associated with a more active immune microenvironment and worse prognosis

ObjectiveHER2 status is not routinely evaluated in endometrioid endometrial cancer (E-EMCA), though it is frequently overexpressed or amplified in high grade E-EMCA and uterine serous carcinoma. Defining characteristics and survival outcomes of HER2+ E-EMCA could reveal subsets of patients who may benefit from targeted therapies. Methods2927 E-EMCA tumors from the Caris Life Sciences database were analyzed by next-generation sequencing and whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry for molecular and genomic features in a CLIA/CAP-certified laboratory (Caris Life Sciences, Phoenix, AZ). HER2 status was determined by transcriptomic cutoff extrapolated from uterine serous carcinoma. The relationship between HER2 status and patient outcomes was determined by Kaplan-Meier analysis. ResultsHER2 positivity was detected in 5.47% of E-EMCA. Differences in molecular alterations based on HER2 status were most apparent in microsatellite stable (MSS) tumors, which displayed increased TP53 mutations and loss of heterozygosity (LOH) and decreased PTEN and CTNNB1 mutations. HER2+ tumors had increased immune checkpoint gene expression and immune cell infiltration, particularly among MSS tumors. All HER2+ tumors displayed increased MAPK pathway activation scores (MPAS) and patients with HER2+ tumors experienced worse overall survival. ConclusionsHER2 positivity in E-EMCA corresponds with a unique molecular landscape, particularly in MSS tumors. HER2+ tumors are also associated with increased MAPK pathway activation and exhibit features of a more active immune microenvironment. These findings suggest a potential benefit of HER2 and MAPK targeted therapies as well as immunotherapies in this patient population.

HER2 IHC Expression and Gene Amplification in p53-aberrant High-grade Endometrial Endometrioid Carcinoma Suggests That This Population May Benefit From HER2 Testing and Targeted Therapy.

Among gynecologic cancers, uterine serous carcinoma (USC) has been shown to be human epidermal growth factor receptor 2 (HER2) amplified and trastuzumab has been included in the recent National Comprehensive Cancer Network (NCCN) guidelines for treatment of advanced stage or recurrent USC with HER2 overexpression/amplification. There is limited literature suggesting that a subset of high-grade endometrioid carcinomas with aberrant p53 expression may also be HER2 amplified and these patients could benefit from the addition of targeted therapy. We identified 59 p53-aberrant (mismatch repair proficient) FIGO 3 endometrioid carcinomas of the uterus. HER2 immunohistochemistry was performed in all 59 tumors and HER2 fluorescence in situ hybridization (FISH) was performed in 52 of the 59 cases. Four of the 59 cases were HER2 3+ by immunohistochemistry (6.7%), using the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2007, 2013, and 2018 criteria. HER2 FISH was performed in 3 of the 4 cases and was amplified in all 3. Nine, 8, and 7 tumors showed 2+ HER2 staining when applying 2018, 2013, and 2007 criteria, respectively, FISH was performed in 7 tumors and none were amplified. An additional 4 cases did not perfectly meet the 2018 ASCO/CAP criteria but were assigned a score of 2+, none were amplified by HER2 FISH. The remaining 42 cases showed 1+ or no staining for HER2, FISH was successfully performed in 38 tumors and none showed amplification. Approximately half of the tumors fulfilled criteria for HER2-low or HER2-very low (10 HER2-low and 20 HER2-very low). Our data shows that a subset of p53-aberrant high-grade endometrial endometrioid carcinoma express HER2 and these patients may benefit from the addition of targeted therapy. The role of targeted therapy in HER2-low gynecologic carcinoma is currently unexplored.

Type II endometrial cancer: Incidence, overall and disease-free survival in Martinique.

In Martinique, about 33 new cases of endometrial cancer are diagnosed per year with a high mortality rate (world standardised rate of 4.9/100,000 versus 2.3/100,000 in mainland France). The present study aimed to determine the incidence and mortality of type I and type II endometrial cancers (ECs), their overall survival (OS) and disease-free survival (DFS) between 2012 and 2016. This retrospective observational cohort study used data from the Martinique Cancer Registry (MCR). 191 patients with corpus uterine cancer were extracted between 2012 and 2016. Patients with either endometrioid endometrial carcinoma (EEC), uterine papillary serous carcinomas (UPSC), uterine clear cell carcinomas (UCCC) or uterine carcinosarcomas (UCS) were included. All other uterine cancers were excluded. Among the 163 included patients, 97 (60%) were type I and 66 (40%) were type II. The standardized incidence rate is 4.50/100,000 for type I vs. 2.66/100,000 for type II. Three years DFS for all types, type I and type II was 81.5% [74.2-86.9], 84.9% [75.4-91] and 76.7% [63.8-85.5] respectively. The five-years OS for all types, type I and type II was 47.0% [38.9-54.7] vs. 58.8% [47.3-68.5] vs. 22.8% [15.0-37.7] respectively. In Martinique, we report a high proportion of type II ECs, which has a poor prognosis with few treatment options.

Prognostic Value of Peritoneal Cytology in Stage I Serous and Clear Cell Carcinoma of the Endometrium

(1) Background: To investigate the relation between malignant peritoneal cytology and survival outcomes in patients who underwent primary staging surgery for stage I uterine serous (USC) or clear cell carcinoma (UCCC). (2) Methods: In this retrospective analysis, patients with stage I USC or UCCC who underwent staging surgery between 2010 and 2020 at the Peking Union Medical College Hospital were identified and reviewed. (3) Results: A total of 101 patients were included, and 11 patients had malignant cytology (10.9%). The median follow-up time was 44 months (range 6-120) with a total of 11 (10.9%) recurrences. Patients with malignant cytology had a higher likelihood of peritoneal recurrence and a shorter time to relapse (13 vs. 38 months, p = 0.022), as compared to patients with negative cytology. In univariate analysis, malignant cytology and serous histology had worse progression-free survival (PFS) and overall survival (OS) (all, p < 0.05). In sensitive analysis, the detrimental effects of malignant cytology on survival were more prominent in patients over 60 years old, those with serous histology, stage IB disease, and those who received hysteroscopy as a diagnostic test. (4) Conclusions: Stage I USC or UCCC patients with malignant peritoneal cytology had a higher recurrence and inferior survival.

Ipatasertib, an oral AKT inhibitor, in combination with carboplatin exhibits anti-proliferative effects in uterine serous carcinoma

Purpose Uterine serous carcinoma (USC) exhibits worse survival rates compared to the endometrioid subtype, and there is currently no effective treatment options for recurrence of this disease after platinum-based chemotherapy. Activation of PIK3CA/AKT/mTOR signaling pathway is a common biological feature in USC. Materials and Methods Ipatasertib (IPAT) is an investigational, orally administered, ATP-competitive, highly selective inhibitor of pan AKT that has demonstrated anti-proliferative activity in a variety of tumor cells and tumor models. In this study, we used IPAT, carboplatin and their combination to investigate the anti-tumor activity in SPEC-2 and ARK-1 cells. Results Our results indicate that IPAT combined with carboplatin at low doses was more effective at reducing proliferation, inducing apoptosis and causing cellular stress than IPAT or carboplatin alone. In particular, inhibition of the PIK3CA/AKT/mTOR pathway and induction of DNA damage were involved in the synergistic inhibition by combination treatment of cell viability in USC cells treated with the combination. Furthermore, IPAT in combination with carboplatin significantly reduced cell adhesion and inhibited cell invasion. Conclusions These findings suggest that the combination of IPAT and carboplatin has potential clinical implications for developing new USC treatment strategies.

Uterine Neoplasms, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org.

Association of Genomic Instability Score, Tumor Mutational Burden, and Tumor-Infiltrating Lymphocytes as Biomarkers in Uterine Serous Carcinoma.

Background: Uterine serous carcinomas represent 10% of uterine carcinomas but account for nearly 40% of deaths from the disease. Improved molecular characterization of these tumors is instrumental in guiding targeted treatment and improving outcomes. This study assessed the genomic instability score (GIS), tumor mutational burden (TMB), and tumor-infiltrating lymphocytes (TILs) in patients with USC. Methods: A retrospective cohort study evaluated patients with USC following staging surgery. The GIS and TMB were determined from archived specimens. We evaluated the tumoral expression of CD3, CD4, CD8, FOXP3, and CD68 using immunohistochemistry. T-tests were used to assess associations of TILs with the GIS. Results: We evaluated 53 patients with USC. The median GIS was 31 (range: 0−52) and a higher GIS was not associated with progression-free (PFS) or overall survival (OS). The median TMB was 1.35 mt/Mb; patients with TMB > 1.35 mt/Mb had improved PFS and OS (p = 0.005; p = 0.002, respectively). Tumors with increased CD3+ and CD4+ immune cells had a higher mean GIS (p = 0.013, p = 0.002). Conclusions: TMB > 1.35 mt/Mb was associated with improved survival in USC patients, whereas the GIS was not. Lower TMB thresholds may provide prognostic value for less immunogenic tumors such as USC. In this limited cohort, we observed that increased TIL populations were correlated with a higher GIS.

Stage I Clear Cell and Serous Uterine Carcinoma: What Is the Right Adjuvant Therapy?

This single-center study aimed to retrospectively evaluate the survival outcomes of patients with FIGO stage I clear cell and serous uterine carcinoma according to the type of adjuvant treatment received. The data were collected between 2003 and 2020 and only patients with stage I clear cell or serous uterine carcinoma treated with primary surgery were included. These were classified into three groups: No treatment or brachytherapy only (G1), radiotherapy +/- brachytherapy (G2), chemotherapy +/- radiotherapy +/- brachytherapy (G3). In total, we included 52 patients: 18 patients in G1, 16 in G2, and 18 in G3. Patients in the G3 group presented with poorer prognostic factors: 83.3% had serous histology, 27.8% LVSI, and 27.8% were FIGO stage IB. Patients treated with adjuvant radiotherapy showed an improved 5-year overall survival (OS) (p = 0.02) and a trend towards an enhanced 5-year progression-free survival (PFS) (p = 0.056). In contrast, OS (p = 0.97) and PFS (p = 0.84) in the chemotherapy group with poorer prognostic factors, were similar with increased toxicity (83.3%). Radiotherapy is associated with improved 5-year OS and tends to improve 5-year PFS in women with stage I clear cell and serous uterine carcinoma. Additional chemotherapy should be cautiously considered in serous carcinoma cases presenting poor histological prognostic factors.

Issue Information

Molecular OncologyVolume 17, Issue 1 p. 1-2 Issue InformationOpen Access Issue Information First published: 04 January 2023 https://doi.org/10.1002/1878-0261.13231AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Graphical Abstract Confocal microscopy image showing p-FAK-Y397 staining in ARK-1, a uterine serous carcinoma cell line. DAPI (blue), p-FAK-Y397 (green) and phalloidin (red). Read the research article by Isabel C. Lopez-Mejia, Jordi Pijuan et al. in pp. 98–118. Volume17, Issue1January 2023Pages 1-2 RelatedInformation

Defining the Optimal Treatment Strategy in Patients With Uterine Serous Carcinoma

AimsUterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with high rates of relapse and death. As adjuvant therapy might be beneficial in early-stage disease, the impact of standard complete surgical staging is questioned. Therefore, we wanted to explore the optimal treatment strategy for women diagnosed with USC. Materials and methodsA retrospective multicentre study of women diagnosed with primary USC in the UK and the Netherlands. Treatment strategy in relation to overall survival and progression-free survival was recorded and evaluated with Kaplan–Meier and Cox regression analysis. Furthermore, primary surgical staging and/or adjuvant treatment in relation to patterns of recurrence were evaluated. ResultsIn total, 272 women with a median age of 70 years were included. Most patients presented with International Federation of Gynecology and Obstetrics (FIGO) stage I disease (44%). Overall, 48% of patients developed recurrent disease, most (58%) with a distant component. Women treated with chemotherapy showed significantly better overall survival (hazard ratio 0.50, 95% confidence interval 0.31–0.81; P = 0.005) and progression-free survival (hazard ratio 0.48, 95% confidence interval 0.28–0.80; P = 0.04) in multivariable analysis. Furthermore, even in surgically staged women with FIGO stage IA disease, a high recurrence rate of 42% was seen. ConclusionWomen with USC who received adjuvant chemotherapy showed better survival rates compared with those who received other or no adjuvant treatment. The benefit of adjuvant chemotherapy was observed across all tumour stages, including surgically staged FIGO stage IA. These data question the role of surgical staging in the absence of macroscopic disease in USC.

Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness.

Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer (EC), characterized by its high propensity for metastases. In fact, while endometrioid endometrial carcinoma (EEC), which accounts for 85% of EC, presents a good prognosis, USC is the most frequently fatal. Herein, we used for the first time a peptide-based tyrosine-kinase-activity profiling approach to quantify the changes in tyrosine kinase activation between USC and EEC. Among the tyrosine kinases highly activated in USC, we identified focal adhesion kinase (FAK). We conducted mechanistic studies using cellular models. In a USC cell line, targeting FAK either by inhibitors PF-573228 and defactinib (VS-6063) or by gene silencing limits 3D cell growth and reduces cell migration. Moreover, results from our studies suggest that oxidative stress is increased in USC tumors compared to EEC ones. Reactive oxygen species (ROS) induce tyrosine phosphorylation of FAK and a concomitant tyrosine phosphorylation of paxillin, a mediator of FAK signal transduction. Mechanistically, by tracking hundreds of individual cells per condition, we show that ROS increased cell distance and migration velocity, highlighting the role of ROS-FAK-PAX signaling in cell migration. Both defactinib and ROS scavenger N-acetylcysteine (NAC) revert this effect, pointing toward ROS as potential culprits for the increase in USC cell motility. A proof of concept of the role of FAK in controlling cell growth was obtained in in vivo experiments using cancer-tissue-originated spheroids (CTOS) and a patient-derived orthotopic xenograft model (orthoxenograft/PDOX). Defactinib reduces cell proliferation and protein oxidation, supporting a pro-tumoral antioxidant role of FAK, whereas antioxidant NAC reverts FAK inhibitor effects. Overall, our data points to ROS-mediated FAK activation in USC as being responsible for the poor prognosis of this tumor type and emphasize the potential of FAK inhibition for USC treatment.

Neoadjuvant chemotherapy in patients with stage IVB uterine serous carcinoma: a Turkish multicentric study

The aim of this study was to evaluate the prognostic factors for and determine the effect of neoadjuvant chemotherapy (NACT) on oncologic outcome in stage IVB pure serous endometrial carcinoma patients who received taxane and platinum. Forty-two patients with 2009 International Federation of Gynecology and Obstetrics (FIGO) stage IVB uterine serous carcinoma were enrolled from six gynecologic oncology centers and a study group was created. The study group had a 2-year disease-free survival (DFS) of 32% and 2-year disease-specific survival (DSS) of 73%. On univariate analysis; lymphadenectomy (not performed vs. performed), paraaortic lymph node metastasis (positive vs. negative) and number of metastatic lymph node count (≤5 vs. >5) were found to have statistical significance for DFS (p < 0.001, p = 0.026 and p = 0.044, respectively). Adnexal metastasis (positive vs. negative) and type of cytoreductive surgery (maximal vs. optimal and suboptimal) had statistical significance for DSS (p = 0.041 and p = 0.015, respectively). Receiving NACT did not affect DFS and DSS in stage IVB uterine serous carcinoma patients. As our sample size was small, precise conclusions could not be made for suggesting the use of NACT in advanced stage uterine serous carcinoma. For more accurate results, more randomized controlled studies are needed in this patient group. IMPACT STATEMENT What is already known on this subject? Endometrial carcinoma is the most common type of gynecologic tract malignancies and usually it is diagnosed at early stages. Although the favorable prognosis, uterine serous carcinoma (USC), one of the rarest subtypes, has a poorer prognosis when compared to other histological subtypes. USC has a propensity to spread beyond pelvis. Due to this aggressive behavior, surgical intervention could not be feasible in advanced stage disease. What do the results of this study add? Our study evaluated the prognostic factors that affect survival in advanced stage USC patients. Also we investigated that neoadjuvant chemotherapy (NACT) could improve oncologic outcomes. Performing lymphadenectomy, presence of paraaortic lymph node and adnexal metastasis, number of metastatic lymph nodes and type of cytoreductive surgery improved survival in advanced stage USC patients. However, NACT did not have a statistical significance as a predictor for disease-specific survival (DSS) and disease-free survival (DFS). What are the implications of these findings for clinical practice and/or further research? Maximal surgical effort should be performed in advanced stage USC according to our results. On the other hand, NACT had no impact on DSS and DFS rates. For this reason, we could not be able to suggest the routine use of NACT in advanced stage USC. But more randomized controlled trials are warranted for confirmation of our results.