Metastatic Endometrial Carcinoma Research Articles

Abstract CT292: Phase II study of pembrolizumab in combination with lenvatinib in patients with triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other tumor types and brain metastases

Abstract Background: Many patients develop brain metastasis during the course of their disease and it represents the cause of death in more than half of them. The prognosis and survival of patients with brain metastases remains poor with limited palliative treatment options. Thus, there is a need to develop new strategies for the therapeutic management of patients with brain metastases. Inflammatory stimuli originating from CNS tumors may increase the permeability of the blood-brain barrier and promote immune cell activation and infiltration into tumors. Several studies have demonstrated now the efficacy of immune checkpoint inhibitors in patients with melanoma with active brain metastases. The modulation of VEGF-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. Lenvatinib is an oral, potent multiple receptor tyrosine kinase inhibitor that selectively inhibits VEGFRs, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other pro-angiogenic and oncogenic pathway-related receptor tyrosine kinases. The combination of lenvatinib and pembrolizumab is approved for patients with metastatic endometrial carcinoma and renal cancer, and it is investigated in other tumor types with promising preliminary results. We hypothesize that pembrolizumab and lenvatinib will be an effective treatment for TNBC, NSCLC, and other solid tumor types with brain metastases by decreasing angiogenic tumor activity and improving antitumor T-cell activity. Methods: This is a single-center, open-label, multi-cohort Phase II study evaluating the efficacy and safety of pembrolizumab in combination with lenvatinib in patients with solid tumors and brain metastases. The study has 3 cohorts: triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other solid tumor types with established or preliminary clinical evidence of efficacy of programmed cell death-1 (PD-1) and angiogenesis inhibitors. Eligible patients will have at least 1 unirraditated or progressing brain metastasis of 0.5-2 cm on brain MRI. The study is conducted using a Simon’s optimal two-stage design, and approximately 87 patients will be enrolled concurrently (n=29 per cohort). Pembrolizumab (200 mg intravenously on Day 1 of each cycle) and lenvatinib (20 mg orally once daily) are administered in 21-day cycles for a maximum of 24 months. The primary endpoint is intracranial objective response rate at 4 months as assessed by the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Exploratory analyses will include evaluation of tissue and blood-based immune-related correlates of response to the pembrolizumab and lenvatinib combination. The first patient was enrolled in January 2022 and accrual of patients is ongoing (NCT05064280). Citation Format: Ecaterina E. Dumbrava, Emma J. Montazari, Uyen M. Vu, Tiantian Cai, Mehmet Altan, Nuhad K. Ibrahim, Debra N. Yeboa, Jing Li, Frederick F. Lang, Gisela Sanchez, Isabella C. Glitza, Barbara J. O'Brien, Rashmi K. Murthy, Jianbo Wang, Tanisha T. Darko, Denisse Velazquez, Komal Shah, Funda Meric-Bernstam, Hussein Tawbi, Jordi Rodon. Phase II study of pembrolizumab in combination with lenvatinib in patients with triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other tumor types and brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT292.

Evaluation of potential biomarkers for lenvatinib plus pembrolizumab among patients with advanced endometrial cancer: results from Study 111/KEYNOTE-146

BackgroundLenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations...

Case report: prolonged durable clinical benefit and low toxicity from combination endocrine therapy in a patient with recurrent endometrial carcinoma

BackgroundEndometrial carcinoma is the most common gynecologic cancer, with increasing incidence and mortality. Combination endocrine therapy comprised of tamoxifen and progestational agents has demonstrated promising results in treating recurrent disease. This case report describes the prolonged clinical benefit of treatment with tamoxifen and megestrol acetate in a woman with recurrent, metastatic endometrial endometrioid carcinoma positive for estrogen (ER) and progesterone receptors (PR).CaseA 71-year-old gravida 1 para 1 woman presented with postmenopausal bleeding and vaginal discharge. Pelvic ultrasound and magnetic resonance imaging confirmed a 4.7 cm endometrial mass. The patient underwent a total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and cystoscopy; pathology revealed a FIGO stage IA grade 1 ER/PR-positive endometroid endometrial adenocarcinoma. She continued under active surveillance for approximately 42 months until she experienced bone metastases in her pelvis, for which she received radiation therapy. Five months later, pulmonary metastases were detected, and she received six cycles of carboplatin and paclitaxel. She then started megestrol acetate and tamoxifen and has remained clinically stable with minimal side effects and reasonable quality of life for approximately 57 months.ConclusionOur case suggests that combination endocrine therapy has the potential to provide substantial long-term clinical benefit in women with recurrent endometrial cancer and bone metastases, despite multiple prior treatments, allowing patients to experience stable disease and quality of life. In patients with recurrent endometrioid, ER/PR-positive disease, endocrine therapy alone or in combination with other targeted therapies are regimens that may be considered due to their low overall toxicity.

A rare case of paraneoplastic Guillain-Barré syndrome in a patient with endometrial cancer

Introduction: Guillain-Barré syndrome is an acute, inflammatory polyradiculoneuropathy of autoimmune aetiology. It is a rare disease seen in 1 in 100,000 person-years. Up to 20% of those affected develop severe disability; mortality in Guillain-Barré syndrome is 5%. Guillain-Barré, associated with many malignancies as a paraneoplastic phenomenon, has been reported – especially in haematological malignancies such as lymphoma and leukaemia. Solid tumours associated with paraneoplastic Guillain-Barré syndrome are breast and lung cancers. The association between paraneoplastic Guillain-Barré syndrome and gynaecological malignancies are rare, and only a handful of cases have been previously reported in gynaecological cancers. Case description: We discuss a 65-year-old Sri Lankan female patient diagnosed with metastatic endometrial carcinoma who presented with paraneoplastic Guillain-Barré syndrome. The patient was treated appropriately and eventually recovered from her condition. Conclusion: Paraneoplastic Guillain-Barré syndrome is a rare phenomenon that clinicians can easily miss, and it has rarely been described in gynaecological cancers. Our patient was diagnosed with this rare phenomenon. The timely recognition and prompt treatment of this potentially life-threatening condition with multiple complications is essential in managing patients with malignancies and neuropathy. Further studies on paraneoplastic Guillain-Barré syndrome are needed as cases may be underreported.

815P Clinical outcome of metastatic endometrial carcinoma patients treated with chemotherapy: ENDOVIE, a GINECO national observational cohort study

815P Clinical outcome of metastatic endometrial carcinoma patients treated with chemotherapy: ENDOVIE, a GINECO national observational cohort study

Should we abandon hormonal therapy in endometrial cancer? Outcomes of recurrent and metastatic endometrial cancer treated with systemic progestins.

The objective of this study is to determine primary survival endpoints in women with recurrent and metastatic endometrial carcinoma (RMEC) treated with progestins. A retrospective chart review was conducted at The Ottawa Hospital using electronic medical records. Inclusion criteria were a diagnosis of RMEC between 2000 and 2019, endometrioid histology, and ≥one line of progestin treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Of 2342 cases reviewed, 74 met inclusion criteria. Sixty-six (88.0%) patients received megestrol acetate and 9 (12.0%) received a progestin alternative. The distribution of tumors by grade was: 1: 25 (33.3%), 2: 30 (40.0%), and 3: 20 (26.7%). The PFS and OS for the entire study sample was 14.3 months (95% CI 6.2-17.9) and 23.3 months (14.8-36.8), respectively. The PFS for patients with Grade 1-2 RMEC was 15.7 months (8.0, 19.5), compared to 5.0 months (3.0, 23.0) with Grade 3 disease. The OS for patients with Grade 1-2 versus Grade 3, was 25.9 months (15.3, 40.3) versus 12.5 months (5.7, 35.9), respectively. Thirty-four (45.9%) and 40 (54.1%) patients were treated with 0 and ≥1 line of chemotherapy. The PFS for chemotherapy-naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy-naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed. This real-world data on RMEC suggests there is a role for progestins in select subgroups of women. The PFS for chemotherapy-naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy-OS was 29.1 months (17.9, 61.1) for chemotherapy-naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed.

Possible applications for combined lenvatinib and pembrolizumab in advanced endometrial carcinoma

Endometrial cancer is one of the most common gynaecological cancers in both the United States and the Russian Federation, and the rate continues to rise. Although early-stage endometrial cancer is associated with a favourable 5-year survival rate (96%), this rate in patients with distant metastases accounts for only 18%. A combination of paclitaxel and carboplatin is standard first-line therapy for advanced, recurrent and metastatic endometrial carcinoma. Pembrolizumab, a monoclonal antibody targeting the programmed death-1 receptor, is approved for therapy of metastatic solid tumors with high microsatellite instability that have progressed aft er previous therapy and have no alternative treatment options. Lenvatinib is an oral multikinase inhibitor that blocks vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor alpha, RET and KIT. Phase II and III studies (KEYNOTE-146/ Study111 and KEYNOTE-775) on the combination of lenvatinib and pembrolizumab in advanced endometrial carcinoma, irrespective of MMR and MSI status, have shown new potential for the treatment of this pathology. Th e results obtained, including progression-free and overall survival, allow the combination of lenvatinib and pembrolizumab to be considered a new standard for the treatment of this pathology.

Response to first line platinum-based chemotherapy in mismatch repair deficient (MMRd)/ microsatellite instability high (MSI-high) endometrial carcinoma

BackgroundAround 15% of metastatic endometrial carcinoma (EC) are MMRd/MSI-H improving response to immune checkpoint inhibitors (ICI). So far, few data existed considering the chemotherapy (CT) sensitivity in MMRd/MSI-H EC, especially response to first-line platinum-based treatment. Patients and methodsWe performed a multicentric retrospective analysis reporting the response to first line platinum CT in MMRd/MSI-H EC patients. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) with first line platinum-based CT. ResultsA total of 112 patients MMRd/MSI-H EC from 8 centers were identified. Median overall survival was 58.0 months (95% CI: 45.3–95.1). Among them, 78 patients received first line platinum CT in recurrent/metastatic setting. With a median follow up of 32.6 months (min: 0.03; max: 135.0), ORR and DCR (disease control rate) were 50% (95% CI: 38.5–61.5) and 68% (95% CI: 56.4–78.1), respectively. Median PFS and OS from first line platinum-based CT was 7.8 months (95% CI: 6.0–9.0) and 51.9 months (95% CI: 28.0-NE), respectively. Median PFS with ICI in second line (n = 48) was 10.7 months (95% CI: 3.4-NE) from ICI initiation. ConclusionORR in first line metastatic MMRd/MSI-H EC is consistent with efficacy in an all comer metastatic EC population.

557P Tumour mutation burden is a dispensable test in endometrial carcinoma patients whose molecular classification is known

The panel of NCCN Guidelines recommend that Pembrolizumab is useful in patients of recurrent, metastatic, or high-risk endometrial carcinoma with TMB-H or MSI-H at second-line therapy according to the finding of KEYNOTE158, which makes TMB (tumor mutation burden) a key biomarker for the immunotherapy of endometrial carcinoma. TMB is typically calculated from data of whole exome sequencing or targeted sequencing of a panel of a few hundred genes, which means great economic burden for patients. In the initial design of molecular classification, mutation frequency served as one of the important references, thus we explored the proportion of TMB-H patients in subtypes. Publicly available data from publicly available data from the Cancer Genome Atlas (n=507) was analyzed to define the subtypes and calculate the TMB. We also retrospectively analyzed 79 endometrial carcinoma patients (WSB cohort) who performed NGS (733 gene panel) and evaluated for subtypes and TMB. We adopted two methods to define TMB-H and non-TMB-H. In method one, we set cutoff as 10, the same as KEYNOTE158, and the patient with TMB higher than 10 is considered to be a TMB-H patient. According to method one, POLE-mut and MSI-H endometrial carcinoma account for 96.76% (179/185) of TMB-H patients in TCGA cohort and 96.15% (25/26) in WSB cohort. In method two, patients who ranked in the top quartile of TMB were considered as TMB-H. We found that 96.85% (123/127) and 100% (20/20) of TMB-H patients in TCGA and WSB cohort were POLE-mut and MSI-H endometrial carcinoma. In both methods, only one POLE-mut patients (1/49) were non-TMB-H in TCGA cohort and all POLE-mut patients in WSB cohort were TMB-H (3/3). For patients whose molecular classification is known, TMB detection is a dispensable test. Immunotherapy may be admissible for POLE-mut and MSI-H patients without the performance of TMB detection.

Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0–31.0) in cervical cancer and 12.0% (90% CI 3.4–28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1–25.7) in cervical cancer and 3.6 weeks (95% CI 3.6–15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0–67.0) and 37.4 weeks (95% CI 19.0–50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity.Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97).

KEYNOTE-C93/GOG-3064/ENGOT-en15: A phase 3, randomized, open-label study of first-line pembrolizumab versus platinum-doublet chemotherapy in mismatch repair deficient advanced or recurrent endometrial carcinoma.

TPS5623 Background: Carboplatin-paclitaxel chemotherapy (with trastuzumab for HER2+ uterine serous carcinoma) is the standard of care first-line systemic treatment for recurrent or metastatic endometrial carcinoma (EC), which has a 5-year relative survival rate of only 17%. Worse survival outcomes have been shown for the mismatch repair deficient (dMMR) subtype of EC. Pembrolizumab (pembro), an anti-PD-1 antibody, showed compelling antitumor activity in previously treated, advanced MSI-H/dMMR EC in the phase 2 KEYNOTE-158 study (ORR, 48%; median duration of response [DOR], not reached; O’Malley JCO 2022). KEYNOTE-C93/GOG-3064/ENGOT-en15 (NCT05173987) is a phase 3, randomized, open-label study evaluating first-line pembro versus carboplatin-paclitaxel chemotherapy in patients with dMMR advanced or recurrent EC. Methods: Patients aged ≥18 years with histologically confirmed stage III/IV recurrent EC including carcinosarcoma (mixed Mullerian tumor), radiographically evaluable disease (measurable or nonmeasurable per RECIST v1.1), no prior systemic therapy (prior radiation with or without radiosensitizing chemotherapy > 2 weeks before first dose or prior hormonal therapy ≥1 week before randomization is permitted), and an ECOG PS ≤1 are eligible. Patients must have central confirmation of dMMR status. Approximately 350 patients will be randomized 1:1 to receive pembro 400 mg IV Q6W for 18 cycles (̃2 years) or carboplatin AUC 5 or 6 mg/mL/min IV Q3W and paclitaxel 175 mg/m2 IV Q3W for 6 cycles (with option for > 6 cycles). Trastuzumab is permitted for patients in the chemotherapy arm with HER2+ serous EC. Randomization is stratified by disease status (newly diagnosed advanced EC vs recurrent EC) and histology (endometrioid vs nonendometrioid). Treatment will continue for the specified number of cycles or until PD or unacceptable toxicity. Patients in the chemotherapy arm have the option to receive pembro following confirmed PD by blinded independent central review (BICR). Tumor imaging will be performed Q9W from randomization to week 54 and Q12W thereafter. AEs will be assessed from randomization to 30 days (90 days for serious AEs) after treatment discontinuation and graded per NCI CTCAE version 5.0. Dual primary endpoints are PFS per RECIST v1.1 by BICR and OS. Secondary endpoints are ORR, disease control rate, and DOR per RECIST v1.1 by BICR; PFS per RECIST v1.1 by investigator review; PFS2 (ie, time from randomization to PD per investigator assessment or death from any cause after start of subsequent anticancer therapy); safety; and patient-reported outcomes. PFS and OS will be estimated by the Kaplan-Meier method, with treatment differences assessed by the stratified log-rank test and HRs with 95% CIs determined using a Cox proportional hazard model. Enrollment is ongoing. Clinical trial information: NCT05173987.

Biomarker associations of immune checkpoint inhibitor versus chemotherapy effectiveness in first-line metastatic endometrial carcinomas: A real-world study.

5596 Background: Limited evidence exists comparing outcomes of single-agent anti-PD1 immune checkpoint inhibitors (ICPI) vs. chemotherapy in the 1st line among metastatic endometrial carcinoma (mEC) patients. dMMR, MSI status, and Tumor Mutational Burden (TMB) have been characterized as predictive biomarkers of ICPI response in many solid tumors, including mEC. We sought to evaluate ICPI vs. chemotherapy effectiveness in 1st line mEC, stratified by TMB ≥ 10 mut/MB and MSI as assessed by next-generation sequencing. Methods: Following a prespecified analysis plan, this study used the nationwide (̃280 US cancer clinics) de-identified, EHR-derived, Flatiron Health-Foundation Medicine mEC clinico-genomic database (FH-FMI CGDB), with tissue CGP between 1/2011 - 6/2021. Cohort inclusion criteria: recurrent mEC patients with stage I-III at original diagnosis, 1st line ICPI or platinum chemotherapy treatment with TMB and MSI assessments available. Adjusted hazard ratios (aHR) from multivariable Cox proportional hazard models were utilized for time to next treatment (TTNT) and overall survival (OS) comparisons between 1L chemotherapy and 1L ICPI from start of 1L treatment stratified by TMB (≥ 10 vs. < 10) and adjusted for ECOG, BMI, and stage at diagnosis. Results: Among the 1st line cohort, patients received either Chemotherapy (n = 139, 87%) or first-line ICPI (n = 20, 13%). While the overlap between the TMB ≥ 10 (n = 46) population and MSI-H (n = 39) populations was high, with 38/46 (83%) of TMB ≥ 10 classified as MSI-H and 38/39 (97%) of MSI-H with a TMB ≥ 10, there were also 8 (17%) TMB ≥ 10 patients who were MSS. TMB ≥ 10 was associated with more favorable TTNT (aHR: 0.11 [0.03 - 0.44]) and OS (aHR: 0.1 [0.01 - 0.82]) on single-agent ICPIs vs. chemotherapy; however, TMB < 10 patients exhibited no observed differences in TTNT (aHR: 1.66 [0.79 - 3.48]) or OS (aHR: 1.79 [0.66 - 4.8]) between treatments. MSI-H pts were associated with more favorable TTNT (aHR: 0.1 [0.02 - 0.39]) and OS (aHR: 0.1 [0.01 - 0.86]) on single-agent ICPIs over chemotherapy; however, MSS pts did not observe differences in TTNT (aHR: 1.5 [0.65 - 3.5]) or OS (aHR: 2.14 [0.63 - 7.26]) between ICPI vs. chemotherapy. Conclusions: Recurrent 1st line mEC patients with TMB ≥ 10 and/or MSI-H exhibit more favorable outcomes on single-agent ICPI than standard chemotherapy in real-world settings. These findings warrant prospective randomized validation. Future studies should assess the utility of a combined biomarker approach across TMB and MSI status to identify the broadest group of patients who might benefit from ICPI.

Investigation of Molecular Features Involved in Clinical Responses and Survival in Advanced Endometrial Carcinoma Treated by Hormone Therapy.

Hormone therapy (HT) is an effective treatment for metastatic endometrial carcinoma (mEC), with limited toxicity and low cost. We focused on molecular analysis of mECs treated by HT and, for the first time to date, we compared the genomic profiles of paired metastasis and primary ECs. The main objective was to identify predictive factors of the response to HT as well as specific altered signaling pathways driving mEC biology. From 1052 patients with EC treated by HT in two French cancer centers, 32 with endometrioid EC and 6 with high grade serous EC were included. We evaluated hormone receptors (HR) and mismatch repair proteins expression by immunohistochemistry and gene alterations by targeted next-generation sequencing and array-based comparative genomic hybridization. Several variables were tested in univariate and multivariate analyses to identify potential associations with (i) the clinical benefit of HT (CBHT) and (ii) a longer response (>18 months) (LRHT) and overall survival (OS). We compared the biological and genomic profiles of 11 primary/metastatic EC pairs. Thirty tumors (78.9%) were HR-positive and 6 (15.8%) showed microsatellite instability (MSI). The genomic profiles of 34 tumors showed an average altered genome of 3.26%, DNA repair homologous recombination deficiency in five tumors (14.7%), and 17 regions significantly targeted by amplification/deletion. Thirty-three tumors had 273 variants (158 genes, median of 7 mutations/sample), including 112 driver mutations. TP53, PTEN, PPP2R1A, ARID1A, FGFR2, and PIK3CA were the most frequently mutated. Based on the genomic status, nine oncogenic pathways were altered in more than 25% of primary EC. Clinically, 22 (57.9%) and 6 (15.8%) patients presented CBHT and LRHT, respectively. Neither oncogenic pathways alterations nor the variables tested were associated with CBHT and LRHT. Only patient’s age, mitotic index and the presence of at least one HR were associated with OS. Paired analysis of the primary/metastatic samples showed that among the 22 mutations acquired in the metastatic counterparts, the most frequently targeted genes were involved in pathways that might confer a selective advantage to cancer metastasis including hormone resistance. In conclusion, only patient’s age, mitotic index and the presence of at least one HR were associated with OS. The identification of gene mutations newly acquired in metastasis might help to better understand the formation of EC metastasis and select the best actionable candidates for HT-treated patients at the metastatic stage.

Case Report: Metastatic Signet-Ring-Cell Carcinoma of the Bladder From Breast Invasive Lobular Carcinoma Detected by Computed Tomography

Secondary bladder tumors are relatively rare among all bladder tumors, while bladder metastases from breast cancer have been rarely reported. Furthermore, signet-ring differentiation may appear in the metastases from a breast invasive lobular carcinoma regardless of whether the primary breast tumor had signet-ring cells, which may cause diagnostic uncertainty. We report a case of a 55-year-old female patient with diffuse bladder thickening as the chief complaint and no specific clinical manifestations. While the cystoscopy showed multiple scattered red protuberances, the biopsy suggested signet-ring-cell carcinoma. The gastroscopy results suggested poorly differentiated adenocarcinoma with signet-ring cells. Considering the patient’s history of invasive lobular carcinoma of the breast, chronic myeloid leukemia, and metastatic endometrial carcinoma from the breast, we performed an immunohistochemical analysis and the results indicated that signet-ring-cell carcinomas of the stomach and bladder originated from the invasive lobular carcinoma of the breast. We performed positron emission tomography/computed tomography and the results showed that there were multiple bone metastases already present. This was the first English case report of invasive lobular carcinoma of the breast metastasizing to the uterus, stomach, bladder, and bones with multiple signet-ring-cell variations. This study shares our reasons for misdiagnosing and opinions on diagnosing and treating for this kind of cases.

A randomized phase II trial of everolimus and letrozole or hormonal therapy in women with advanced, persistent or recurrent endometrial carcinoma: A GOG Foundation study

BackgroundBlocking the PI3K/AKT/mTOR pathway decreases resistance to hormonal therapy in endometrial carcinoma (EC). ObjectiveIn this study, the aim was to assess the efficacy and tolerability of everolimus(E)/letrozole (L) or medroxyprogesterone acetate(M)/tamoxifen(T) in the treatment of metastatic EC. Study designThis single stage, open-label two arm randomized phase II trial accrued women with advanced/persistent/recurrent EC. Treatment with E (10 mg daily) and L (2.5 mg daily) or T (20 mg twice daily) and M (200 mg daily alternating weeks) was randomly assigned, and stratified by prior adjuvant therapy. Treatments were administered orally. Primary endpoint was response rate. ResultsBetween February 2015 and April 2016, everolimus/letrozole (n = 37) or MT (n = 37) was assigned to 74 patients. Median follow-up was 37 months. Eight (22%; 95% CI 11% to 37%) patients responded on EL (one CR) and nine (25%; 95% CI 14% to 41%) patients responded on MT (three CRs). Median PFS for EL and MT arms was 6 months and 4 months, respectively. On EL, chemo-nave patients demonstrated a 28 month median PFS; prior chemotherapy patients had a 4-month median PFS. On MT, patients without prior therapy had a 5-month median PFS; those with prior chemotherapy demonstrated a 3-month PFS. Common grade 3 adverse events were anemia (9 [24%] patients EL vs 2 [6%] MT) and mucositis (2 [5%] vs 0 [0%]). Grade 3/4 thromboembolic events were observed with MT but not with EL (0 [0%] vs 4 [11%]). ConclusionsEL and MT demonstrated clinically meaningful efficacy in recurrent EC patients. The higher PFS observed in chemo-naïve patients is worthy of confirmation in future studies.

PULMONARY ROCKS! A CASE OF PULMONARY ALVEOLAR MICROLITHIASIS

TOPIC: Diffuse Lung Disease TYPE: Fellow Case Reports INTRODUCTION: Pulmonary alveolar microlithiasis (PAM) is an extremely rare lung disease characterized by the development of calcium phosphate deposits (microliths) within the alveolar spaces. Genetic mutations in the SLC34A2 gene (solute carrier family 34 member 2 gene), which encodes for a sodium-phosphate co-transporter, have been described as the cause of the disease. This co-transporter is located on type II alveolar pneumocytes and is responsible for removing phosphate ions from the alveolar space. Without effective transport, phosphate ions bind to calcium ions leading to calcium phosphate deposits within the alveoli. Over time this often leads to pulmonary fibrosis and progressive respiratory failure. Here, we present a case of pulmonary alveolar microlithiasis that was initially suspected to be metastatic endometrial carcinoma. CASE PRESENTATION: A 37-year-old female presented to gynecology clinic for evaluation of abnormal uterine bleeding. Endometrial biopsy showed endometrioid adenocarcinoma of the uterus. Staging CT scans revealed bilateral adnexal masses, metastatic disease in the liver, peritoneal carcinomatosis, and concern for lymphangitic carcinomatosis in the lungs due to calcification of the pleura and diaphragm. Liver biopsy confirmed metastatic disease of ovarian primary consistent with synchronous stage IV ovarian cancer. She underwent chemotherapy with carboplatin and paclitaxel as well as abdominal hysterectomy and debulking surgery with good response; however, repeat CT chest showed persistent pulmonary disease with innumerable calcified micronodules and extensive pleural, fissural, and interlobular calcifications. Transbronchial biopsies were obtained and revealed diffuse intra-alveolar laminated concentric deposits consistent with microliths and diagnostic of pulmonary alveolar microlithiasis. At the time of diagnosis her pulmonary function testing showed mild restriction. She has no family history of pulmonary disease and had no pulmonary symptoms. Calcium supplements were discontinued, and she was treated with a low phosphorus diet. She continues to undergo monitoring for the development of symptoms as well as monitoring of her pulmonary function. DISCUSSION: PAM is an extremely rare genetic disease caused by a defective sodium-phosphate co-transporter that leads to the accumulation of microliths within the alveolar spaces. Pulmonary fibrosis and progressive respiratory failure is the typical cause of death, although the rate of progression is variable. There is no known effective treatment except for lung transplant. A low phosphorus diet, bisphosphonates, and repeated bronchoalveolar lavage have been studied without clear clinical benefit. CONCLUSIONS: (See Discussion) REFERENCE #1: Castellana G, Castellana G, Gentile M, Castellana R, Resta O. Pulmonary alveolar microlithiasis: review of the 1022 cases reported worldwide. Eur Respir Rev. 2015 Dec;24(138):607-20. REFERENCE #2: Saito A, McCormack FX. Pulmonary Alveolar Microlithiasis. Clin Chest Med. 2016;37(3):441-448. doi:10.1016/j.ccm.2016.04.007. DISCLOSURES: No relevant relationships by Carlos Cardenas, source=Web Response No relevant relationships by Sakda Sathirareuangchai, source=Web Response No relevant relationships by Andrew Tomlinson, source=Web Response

801P Response to first-line platinum chemotherapy in microsatellite instability high (MSI-H) metastatic endometrial carcinoma

Between 17 to 25% of recurrent or metastatic endometrial carcinoma (EC) are MSI-H which results in improved response to immune checkpoint inhibitors (ICI). However, little is known regarding chemotherapy sensitivity in MSI-H EC, especially response to first-line platinum-based treatment.

The role of immunotherapy in the management of metastatic/recurrent female reproductive system neoplasms

In 2019 malignant neoplasms of the female reproductive system (ovarian cancer, (OC), endometrial carcinoma (EC) and cervical cancer (CC) were diagnosed in 58 860 patients – 17.6% of all malignant tumors in women in Russia. The morbidity and mortality rates from these neoplasms remain high over the past 10 years. This article provides a detailed review of the current evidence base for the use of various immunotherapeutic agents in mentioned malignant neoplasms. It has been demonstrated that in relapsed OC (ROC), the only proved indication for immunotherapy is tumors with microsatellite instability (MSI), whereas PD-L1 does not have an independent role in this disease. MSI occurs in approximately 8% of patients with metastatic OC. A significantly higher frequency MSI — up to 25% is detected in metastatic EC. MSI-positive subtype of the disease is characterized by an extremely high sensitivity to immunotherapy - the rate of objective response with pembrolizumab exceeds 50%. For MS-stable EC, the combination of pembrolizumab and lenvatinib is an effective therapeutic option. In advanced CC, on the other hand, PD-L1 has a predictive role for immunotherapy efficacy — the KEYNOTE-158 study showed that about 15% of patients with extensively pretreated metastatic PD-L1-positive CC can achieve long-term remission with pembrolizumab compared to 0% in PD-L1 negative tumors. Current evidence shows that PD-L1 expression can be observed in ≥ 30% of patients.

Abstract 658: CRABP2 - a novel biomarker for high risk endometrial cancer

Abstract Introduction: The incidence of endometrial cancer (EC) is rising - a consequence of the current obesity epidemic. An improved understanding of obesity-induced EC is needed to manage this growing cohort of patients. Here-in we present Cellular Retinoic Acid Binding Protein 2 (CRABP2), which was identified as an obesity-related gene in the BDII/Han rat spontaneous EC model, as a novel biomarker in high-risk EC. Methods:BDII/Han rats were fed either a high (N=12) or low calorie (N=7) diet for 15 months. RNA-seq, - differential gene expression and gene set enrichment analysis (GSEA) were performed on endometrial tumors from both groups. The association between CRABP2 mRNA expression and standard clinico-pathological features was examined in human EC using the TCGA. Following dichotomization of patients based on their CRABP2 mRNA expression using regression tree analysis, univariate and multivariate Cox regression survival analyses were performed. Differential gene expression analysis and GSEA were performed on human tumors stratified according to CRABP2 expression levels. In-silico findings were validated using immunohistochemistry (IHC) assessing CRABP2 expression in normal endometrium, primary and metastatic endometrial carcinoma. Results:Weight gain in high fat diet (HFD) rats was double that of normal chow diet rats (50 g vs. 25 g). The incidence of cancer was similar in both groups (4/7-57% vs. 4/12-33%; p=0.37). 368 differentially expressed genes (DEGs) were identified between both groups. CRABP2 was upregulated in tumors from the HFD group. Regression tree analysis identified 60 (11%) tumors in the TCGA with increased CRABP2 mRNA expression. Increased CRABP2 expression was associated with serous EC (p<0.001), grade 3 (p<0.001) and advanced stage (p=0.015). Univariate Cox regression analysis revealed that high CRABP2 expression is associated with reduced overall survival (HR=2.67, 95% CI 1.64-4.33, p<0.001). This remained true following multivariate cox regression analysis in which age, histological type, stage and grade were confounded for (HR=2.06, 95% CI 1.24-3.41, p=0.004). 224 DEGs were identified between CRABP2 high (N=60) and low (N=468) tumors in the TCGA. GSEA analysis revealed an enrichment of pathways involved in developmental biology and embryonic stem cell-like gene expression signatures in the CRABP2-high cohort. IHC confirmed increased expression of cytoplasmic CRABP2 in EC compared to normal endometrium. CRABP2 expression was significantly increased in serous compared to endometrioid cancer (p<0.05) and a comparison between primary and metastatic serous carcinoma demonstrated increased expression in metastatic cases. Conclusion: A HFD increased CRABP2 expression in rat EC. In humans, increased expression of CRABP2 is associated with high-risk EC. Transcriptomic analysis and validation using IHC suggests that CRABP2 and retinoic acid signalling may be an important therapeutic target in advanced EC. Citation Format: Donagh Egan, Bruce Moran, Michael Wilkinson, William Gallagher, Xavier Matias-Guiu, Walter Kolch, Carel LeRoux, Donal Brennan. CRABP2 - a novel biomarker for high risk endometrial cancer [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 658.

Metastatic endometrial carcinoma responsive to pembrolizumab

Carcinoma of the endometrium is the second most common and the fourth leading cause of mortality due to gynecological cancer among women worldwide. About 80% of endometrial carcinomas present as localized disease and have a 5-year survival rate of more than 95%. Most of the recurrent and metastatic endometrial cancers have a poor prognosis, and the response to chemotherapy is poor. The treatment options for advanced and recurrent endometrial carcinoma are limited. Several trials investigated the role of immune checkpoint inhibitors in endometrial cancer. Based on these trials, pembrolizumab was approved for individuals with unresectable recurrent or metastatic disease. In the current era of advancing immunotherapy, identification of mismatch repair deficiency or microsatellite instability status can predict response to drugs like pembrolizumab. Here, we report a 62-year-old lady with metastatic endometrial cancer who progressed on first-line therapy with lung and lymph nodal metastases. She was oxygen dependent and was bedridden. As she was not fit for chemotherapy, and her MSI status was found to be unstable, she was treated with pembrolizumab and had a remarkable recovery.