Recurrent Uterine Serous Carcinoma Research Articles

Phase II/III study of paclitaxel/carboplatin alone or combined with either trastuzumab and hyaluronidase-oysk or pertuzumab, trastuzumab, and hyaluronidase-zzxf in HER2 positive, stage I-IV endometrial serous carcinoma or carcinosarcoma (NRG-GY026).

TPS5641 Background: Uterine serous carcinoma and uterine carcinosarcoma are rare, high-risk uterine cancer subtypes that overexpress HER2 in up to 40% and 10% of cases, respectively. Phase II data demonstrated a benefit in adding trastuzumab in HER2 positive advanced and recurrent uterine serous carcinoma. Dual anti-HER2 therapy has the potential for further improvement in survival. Methods: This is a non-blinded, three-arm randomized phase II/III study. The primary objective is to evaluate the efficacy of trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA) or a fixed dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive uterine serous carcinoma or carcinosarcoma. The primary outcome of the phase II component is PFS. Depending on the phase II results, the study will progress to a phase III study of either two or three study arms. Patients in the control arm (Arm 1) receive carboplatin and paclitaxel every 3 weeks for 6 cycles. Patients on Arm 2 receive carboplatin and paclitaxel with trastuzumab and hyaluronidase-oysk every 3 weeks for 6 cycles plus one year of maintenance trastuzumab and hyaluronidase-oysk. Patients enrolled on Arm 3 receive carboplatin and paclitaxel with trastuzumab, pertuzumab, and hyaluronidase-zzxf every 3 weeks for 6 cycles plus one year of maintenance trastuzumab, pertuzumab, and hyaluronidase-zzxf . Those with an ongoing partial response may continue maintenance therapy for up to three years. Patients are eligible if they are diagnosed with chemo-naïve, non-recurrent stage IA-IVB myoinvasive uterine serous or carcinosarcoma. All tumors must be HER2 positive as defined by the ASCO/CAP Breast Cancer 2018 guidelines (testing performed locally). Tumors may also be HER2 positive based on next generation sequencing testing. Patients may have measurable, non-measurable, or no measurable disease and may have a plan for vaginal brachytherapy . Key exclusion criteria include severe heart disease or interstitial lung disease. The phase II portion of this study is open and enrolling. Clinical trial information: NCT05256225 .

In Vivo and In Vitro Efficacy of Trastuzumab Deruxtecan in Uterine Serous Carcinoma.

Uterine serous carcinoma (USC) is a rare, biologically aggressive variant of endometrial cancer with a high recurrence rate and poor prognosis. HER2 overexpression (3+ positivity) by IHC and/or FISH ERBB2 gene amplification is detected in approximately one-third of patients with USC. Clinical trials incorporating trastuzumab with standard chemotherapy have recently demonstrated improved progression-free and overall survival in advanced-stage or recurrent USC that overexpresses HER2. However, a large number of patients with USC eventually developed resistance to trastuzumab. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload recently approved by the Food and Drug Administration (FDA) for multiple tumor indications. Here, we investigated the in vitro and in vivo efficacy of T-DXd in primary USC cell lines and xenografts with different HER2 expression. T-DXd-induced cell growth suppression in HER2-overexpressing cell lines in vitro, increased early and late apoptosis as assessed by annexin and propidium iodide staining, and, similarly to trastuzumab, T-DXd-induced significant antibody-dependent cellular cytotoxicity in the presence of peripheral blood lymphocytes. While negligible activity was detected against USC cell lines with low HER2 expression, T-DXd demonstrated significant bystander killing against USC tumors with low/negligible HER2 when such cells were admixed with HER2 3+ tumor cells in vitro. T-DXd showed tumor growth suppression in in vivo USC PDX models that overexpress HER2 at 3+ levels, prolonging survival when compared with controls, with minimal toxicity. Future clinical trials are warranted in patients with USC failing trastuzumab treatment.

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.

Phase II trial of maintenance niraparib in patients with stage III,stage IV or platinum-sensitive recurrent uterine serous carcinoma (330)

<b>Objectives:</b> Uterine serous carcinoma (USC) accounts for up to 40% of endometrial cancer-related deaths. Patients with USC share many genomic and clinical characteristics with serous ovarian cancer patients. This study aims to determine the efficacy of Niraparib in women with advanced or platinum-sensitive recurrent USC. We also aim to describe the safety profile of this regimen. We hypothesize that Niraparib maintenance will be a well-tolerated treatment and show a significant response in patients with USC. <b>Methods:</b> We are conducting a Phase II prospective non-randomized cohort study recruiting 45 patients with newly diagnosed stage III, IV, or platinum-sensitive recurrent USC who will receive 300 mg of Niraparib daily for one year or until disease progression. Dose reductions to 200 mg and 100 mg will be allowed based on treatment side effects. Newly diagnosed patients receive standard platinumbased treatment +/- radiation followed by Niraparib maintenance. Women with recurrent USC will receive platinum-based therapy followed by Niraparib maintenance. Platinum sensitivity is defined as achieving a complete or partial response and disease progression >6 months after completion of their last dose of platinum-based chemotherapy. Patients must have achieved a partial, stable, or complete tumor response following the last chemotherapy, minimal of 3 cycles, and physician choice of platinum-based regimen. Patients must be recruited within 12 weeks of completing chemotherapy or 14 weeks if they are receiving adjuvant radiation therapy. The primary outcome will be progression-free survival (PFS) at one year. Secondary outcomes include PFS at three years, treatment-related adverse events, quality of life measures using Functional Assessment of Cancer Therapy and EQ-5D-5L Euroqol, overall survival (OS), and overall response rate at 2 and 3 years. Mutational burden and loss of heterozygosity will be evaluated for all patients using FoundationOne testing. This trial will employ a Simon two-stage minimax design to test the null hypothesis that the one-year response rate is <20% (which would not be clinically meaningful) versus the alternative hypothesis that the one-year response rate is ≥40%. A treatment "success" will be defined as the patient being alive and progressionfree at one-year post-treatment. This design corresponds to testing the null hypothesis that the true objective response rate is 20% or less versus the alternative hypothesis that the true response rate is 40% or greater, with alpha=0.05 and power=0.90. To date, we have recruited six patients at Northwell and are opening additional sites for recruitment.

Evaluation of the efficacy and treatment sequence of paclitaxel and gemcitabine-loaded microparticles in a serous-like endometrial cancer cell line: a novel treatment strategy

<h3>Objectives:</h3> Uterine serous carcinoma (USC) presents a clinical challenge due its propensity to present at advanced stages, high recurrence rate and development of chemoresistance. The majority of patients with advanced disease will progress or recur following first-line platinum-based chemotherapy. As a result, new treatment strategies are urgently needed. Poly (lactic-co-glycolic acid)-based (PLGA) microparticles (MP) are a promising tool for delivery of chemotherapy due to prolonged drug elution over a period of several weeks, offering the benefit of sustained anti-cancer activity in the target tissue while limiting systemic toxicity. This is an attractive treatment strategy for USC, which can be accessed vaginally, allowing for the delivery of drug-loaded MP directly to the tumor. Previous work demonstrates paclitaxel and gemcitabine can be successfully loaded to PLGA-MP for drug delivery. <h3>Methods:</h3> The human endometrial cancer (EC) cell line KLE, representing a poorly differentiated serous-like EC was obtained from ATCC. Cells were treated with paclitaxel-loaded MP only (PMP), gemcitabine-loaded MP only (GMP), PMP-GMP sequence (PG), GMP-PMP sequence (GP) and PMP-GMP delivered concurrently (C). Blank MP (BMP) were used as control for each treatment. Cells were then collected at 6-days post-treatment for isolation of protein and assessment of cytotoxicity by cell viability assay. Protein lysates were analyzed for expression of multiagent chemoresistance protein AXL and paclitaxel resistance protein beta III tubulin (TUBB3) and apoptotic protein cleaved-PARP by Western Blot. <h3>Results:</h3> We observed morphologic changes and a decrease in cell density in all treatment regimens versus controls. These changes were most marked in the two-drug combination regimens. A significant increase in cleaved-PARP was observed in all treatments compared to controls. Chemoresistance proteins AXL and TUBB3 were not expressed in controls. AXL expression was increased in all treatment regimens. TUBB3 expression was significantly greater in PMP and GP regimens compared to PG (p=0.05). All treatment regimens were associated with a significantly decrease in cell viability versus controls (p<0.001). GMP containing regimens produced a greater decrease in cell viability compared to single agent paclitaxel. C treatment produced a significantly greater decrease in cell viability compared to all other regimens (p<0.001). <h3>Conclusions:</h3> PMP and GMP demonstrated significant cytotoxicity in a serous-like EC cell line. Concurrent PMP-GMP administration elicited the greatest decrease in cell viability. TUBB3 expression was markedly less when cells received PG, indicating the sequence of paclitaxel followed by gemcitabine may counteract paclitaxel resistance observed with single agent paclitaxel and alternate sequencing. Chemotherapy delivered via MP is an attractive treatment strategy for advanced and recurrent USC. Future <i>in vivo</i> studies are needed to validate this new treatment approach.

A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma

Objective: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial carcinoma characterized by frequent TP53 mutations (>90%), often concomitantly with oncogenic mutations or amplifications that can increase replication stress. We hypothesized that USCs would therefore be uniquely sensitive to further interference of cell cycle regulation by Wee1 inhibition. This 2-stage single-arm phase 2 study was conducted to assess the activity of the oral Wee1 inhibitor adavosertib as monotherapy in recurrent USCs.

Is platinum-free interval relevant in recurrent uterine serous carcinoma?

Objective: Uterine serous carcinoma (USC) behaves aggressively and carries a poor prognosis. The study objective was to delineate platinum-free interval and other variables that may pose a prognostic impact on patients with recurrent USC.

Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort study

BackgroundHuman epidermal growth factor receptor 2 (HER2) has emerged as an important prognostic and therapeutic target in advanced stage and recurrent uterine serous carcinoma (USC). The significance of tumoral HER2 expression in early-stage disease has not been established. MethodsThis multi-center cohort study included women with stage I USC treated from 2000 to 2019. Demographic, treatment, recurrence, and survival data were collected. Immunohistochemistry (IHC) was performed for HER2 and scored 0–3+. Equivocal IHC results (2+) were further tested with fluorescence in-situ hybridization (FISH). HER2 positivity was defined as 3+ IHC or FISH positive. ResultsOne hundred sixty-nine patients with stage I USC were tested for HER2; 26% were HER2-positive. There were no significant differences in age, race, stage, adjuvant therapy, or follow-up duration between the HER2-positive and negative cohorts. Presence of lymph-vascular space invasion was correlated with HER2-positive tumors (p = .003).After a median follow-up of 50 months, there were 43 (25.4%) recurrences. There were significantly more recurrences in the HER2-positive cohort (50.0% vs 16.8%, p < .001). HER2 positive tumors were associated with worse progression-free (PFS) and overall survival (OS) (p < .001 and p = .024). On multivariate analysis, HER2 positive tumors were associated with inferior PFS (aHR 3.50, 95%CI 1.84–6.67; p < .001) and OS (aHR 2.00, 95%CI 1.04–3.88; p = .039) compared to HER2-negative tumors. ConclusionsGiven its significant association with worse recurrence and survival outcomes, HER2 positivity appears to be a prognostic biomarker in women with stage I uterine serous carcinoma. These data provide support for clinical trials with anti-HER2-directed therapy in early-stage disease.

A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma.

6009 Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial carcinoma characterized by TP53 mutations ( &gt; 90%), often concomitantly with oncogenic mutations or amplifications that can increase replication stress. As such, USC may therefore be uniquely sensitive to further interference of cell cycle regulation by Wee1 inhibition. This two-stage single arm Phase 2 study was conducted to assess the activity of the Wee1 inhibitor adavosertib as monotherapy in recurrent USC. Methods: Women with recurrent USC (defined as non-carcinosarcoma uterine cancers with any serous component) were eligible. Patients (pts) were required to have had at least one prior platinum-based chemotherapy regimen; those with known MSI-H/MMRd disease were required to have received prior PD1/PDL1 therapy or to be ineligible for such therapy. There was no upper limit on the number of prior lines pts could have received. All pts were required to have RECIST measurable disease. Pts received adavosertib 300mg daily on days 1 through 5 and 8 through 12 of a 21-day cycle. Coprimary endpoints were objective response and progression-free survival at 6 months (PFS6). Results: Between OCT-11-2018 and SEP-30-2019, 35 pts enrolled on study. Median follow-up is 4.6 months. The median number of prior lines was 3 (range 1-8). 34 pts were considered evaluable for response. In these pts, 9 confirmed and 1 unconfirmed responses were observed, for an ORR of 29.4% (95% CI 15.1-47.5%). The PFS at 6 months was 58.7% (95% CI: 39.5-73.7%). The median PFS is 6.1 months and the median duration of response is 9.0 months. Frequently observed Grade 3 or higher related adverse events included neutropenia (32.3%), anemia (20.6%), and fatigue (23.5%). Immunohistochemistry and targeted next-generation sequencing were performed to investigate potential biomarkers of response. Conclusions: Adavosertib monotherapy demonstrates promising clinical activity in women with USC. The observed monotherapy activity is higher than in other diseases, and additional exploration of the biology of Wee1 inhibition in USC is needed. Further studies of adavosertib in this patient population are planned. Clinical trial information: NCT03668340.

Recurrent uterine serous carcinoma with a germline pathogenic BRCA2 variant treated using olaparib: A case report

A germline pathogenic variant in BRCA2 was secondarily found through genomic sequencing of uterine serous carcinoma. Clinical response to olaparib was observed in recurrent uterine serous carcinoma with a germline BRCA2 mutation. Here, we report, for the first time, a long-term clinical response to olaparib in a patient with uterine serous carcinoma and a germline pathogenic BRCA2 variant.

Targeting human epidermal growth factor receptor 2 (HER2) in gynecologic malignancies.

The purpose of this review is to describe the role of the human epidermal growth factor receptor 2 (HER2) as a biomarker and potential target in gynecologic malignancies and to describe contemporary updates in the use of anti-HER2 treatments for these cancers. Approximately 25-30% of all patients with uterine serous carcinoma overexpress tumoral HER2. The anti-HER2 antibody trastuzumab represents an effective, targeted therapy with significant efficacy in the treatment of HER2-positive breast and gastric cancer. Recently, trastuzumab efficacy has also been demonstrated in a randomized controlled trial of women with advanced or recurrent uterine serous carcinoma. Additionally, trastuzumab may be effective in women with HER2-positive uterine carcinosarcoma. The role of anti-HER2 therapy is unclear in women with other gynecologic malignancies but is being evaluated. HER2 amplification/overexpression is an effective therapeutic target in select gynecologic malignancies, and especially in the rare endometrial cancer subtype, uterine serous carcinoma. As anti-HER2-targeted therapies become increasingly available, more treatment options may become available for women with HER2-positive disease.

Is there a role for for minnelide in uterine serous cancers?

Objectives: Most women with uterine serous carcinoma (USC) have a high risk of advanced stage disease and/or recurrence, and in these settings, there are few effective therapies. There is a need for effective therapy in the recurrent USC. Minnelide is bioavailable prodrug of Triptolide, which was isolated in the Chinese herb, Thunder god vine (Tripterygium wilfordii). Minnelide is currently in phase II clinical trials for pancreatic and GI cancers. The purpose of this study was to explore the effect of Minnelide on USC in preclinical models.

Distant Cutaneous Manifestations of a Primary Gynecologic Malignancy

Uterine cancer is the most common gynecologic cancer in the United States. While most cases are diagnosed early and recurrence is rare with adequate treatment, late stage disease has a much worse prognosis, with 5-year survival rates of 25-45%. We report the presentation of recurrent uterine serous carcinoma with metastasis to the skin. An 80-year-old postmenopausal female with a history of endometrial intraepithelial carcinoma was diagnosed with recurrent metastatic disease 3 years after her initial presentation. During hospital admission, she was noted to have clusters of rubbery cutaneous nodules with an erythematous vesicular appearance on the left breast. Biopsy of the lesions showed metastatic serous adenocarcinoma consistent with gynecologic origin. Cutaneous metastasis is a rare finding in uterine cancer. This case highlights the importance of maintaining a wide differential diagnosis and high level of suspicion when evaluating skin lesions in the setting of uterine pathology. J Clin Gynecol Obstet. 2017;6(3-4):71-74 doi: https://doi.org/10.14740/jcgo461w

Targeted Therapy in Uterine Serous Carcinoma: An Aggressive Variant of Endometrial Cancer

Uterine serous carcinoma (USC) is a highly aggressive variant of endometrial cancer. Although it only represents less than 10% of all cases, it accounts for a disproportionate number of deaths from endometrial cancer. Comprehensive surgical staging followed by carboplatin and paclitaxel chemotherapy represents the mainstay of USC therapy. Vaginal cuff brachytherapy is also of potential benefit in USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. These results emphasize the relevance of these novel therapeutic targets for biologic therapy of chemotherapy-resistant recurrent USC.

A phase I study of imatinib mesylate and paclitaxel in patients with advanced (stage IIIC/IV) or recurrent uterine papillary serous carcinoma (UPSC)

16025 Background: Uterine serous carcinoma (USC) is a rare, aggressive uterine tumor biologically distinct from typical endometrial cancers. Imatinib mesylate (IM)-associated kinases (kit, abl, PDGFR-B) are overexpressed and activated in most tumors from patients (pts) with USC. Single agent paclitaxel (TAX) has a good response rate but short duration of response in pts with USC. The purpose of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of escalated doses of IM with a fixed dose of TAX. Methods: Pts with newly diagnosed (stage IIIC/IV) or recurrent USC were eligible (pts were required to have tumors that expressed at least one of the IM-targeted kinases by immunohistochemistry). Measurable disease was not required. TAX was administered at 175 mg/m2 every three weeks. One dose reduction to 135 mg/m2 was allowed. IM was given daily (400 mg, 500 mg or 600 mg). A 3+3 design was implemented. Pts with measurable disease were treated until progression or treatment associated toxicity. Pts with no measurable disease were treated for six cycles. Results: 11 pts were enrolled. The median age was 62 years (47–79). A total of 50 cycles were administered. Three pts were treated at the first dose level (400 mg), 6 pts treated at the second dose level (500 mg), and 2 pts were treated at the highest dose level (600 mg). Three DLTs were observed (1 at 500 mg level and 2 at 600 mg level) including: rash, neutropenia, and fatigue. IM 500 mg daily and TAX 175 mg/m2 every three weeks was the MTD. There were 3 serious adverse events not related to treatment (infection, dyspnea, pain). Neutropenia was the most common grade 3 or 4 toxicity but only one patient required TAX dose reduction. 8 pts were evaluated for efficacy (2 with measurable disease, 6 with no measurable disease). 1 (of 2) pts with measurable disease had a partial response and was treated for 13 cycles. Of the 6 pts with no measurable disease, 2 recurred (5 and 10 months). The median disease free interval for the pts without recurrent disease was 22 months (6–30). Conclusion: Combination therapy of IM and TAX is well tolerated with minimal side effects in pts with advanced or recurrent USC. Initiation of the phase II component of this study is warranted to better evaluate efficacy. No significant financial relationships to disclose.