Rare cancers are usually defined as an incidence of <6/100,000 persons per year. Gynecological oncology is characterized by a paradoxical high prevalence of rare cancer subtypes, especially in ovarian tumors. Ovarian germ cell tumors, clear cell ovarian cancer and gestational trophoblastic disease encompass this set of gynecologic tumors. The WHO classification distinguishes epithelial cell tumors (85% of malignant tumors) from non-epithelial tumors, sex cord stromal tumors (8% of malignant tumors), and germ cell tumors (6% of malignant tumors). The current treatment for these tumors is similar to that for ovarian cancer but advancing quickly to incorporate targeted therapy. Gestational trophoblastic tumors are usually curable, even when widely metastatic disease is present. Ovarian clear-cell carcinoma (OCCC) remains a challenging disease characterized by intrinsic chemoresistance and distinct molecular features. A more biologically aligned treatment strategy has emerged. Continued integration of molecular selection and microenvironmental modulation will likely define the next phase of therapeutic development in OCCC. The clinical features, staging, and current treatment of each of these tumors is reviewed.

Background Twin molar pregnancy (TMP) represents one of the most complex and high-risk entities within the spectrum of gestational trophoblastic disease. Characterized by the coexistence of a potentially viable fetus and molar trophoblastic tissue, TMP poses significant diagnostic, obstetric, and oncologic challenges.Objective To provide a structured diagnostic and management framework for TMP, integrating clinical, biochemical, imaging, genetic, and pathological findings to support early recognition and informed clinical decision-making.Methods This narrative review synthesizes contemporary evidence from cohort studies and diagnostic guidelines, focusing on the clinical presentation, imaging characteristics, genetic evaluation, and outcomes associated with TMP.Results Early diagnosis is frequently hindered by overlapping features with partial hydatidiform mole and placental mesenchymal dysplasia, particularly as placental components merge with advancing gestation. Common clinical manifestations include vaginal bleeding, uterine enlargement disproportionate to gestational age, and systemic complications related to markedly elevated human chorionic gonadotropin levels, such as early-onset preeclampsia, hyperthyroidism, and theca lutein cysts. Ultrasonography remains the primary diagnostic modality, while magnetic resonance imaging provides additional value in complex cases. Genetic testing, including invasive fetal karyotyping and post-pregnancy molecular analysis, is essential for accurate classification and counseling. Management should be individualized, prioritizing maternal safety while recognizing the potential for favorable perinatal outcomes in selected cases. Current evidence suggests that continuation of pregnancy does not independently increase the risk of postmolar gestational trophoblastic neoplasia, which appears to be primarily driven by intrinsic trophoblastic biology.Conclusion TMP remains a rare but clinically challenging condition requiring a high index of suspicion and a multidisciplinary approach. Early diagnosis, individualized management, and rigorous postmolar surveillance are essential to optimize maternal and perinatal outcomes.

Gestational trophoblastic neoplasia (GTN) is a highly curable malignancy arising from placental trophoblasts, yet a small subset of patients develops multidrug resistance with limited therapeutic options. The discovery of high programmed death-ligand 1 (PD-L1) expression across trophoblastic tumors has provided a compelling biological rationale for immunotherapy, particularly immune checkpoint blockade targeting the PD-1/PD-L1 axis. To summarize current evidence on immunotherapy in GTN, integrating biological foundations, clinical experiences, and ongoing clinical trials, and to discuss future perspectives toward individualized, fertility-preserving management. A narrative review was conducted according to structured PRISMA-based principles. Literature was retrieved from PubMed, Scopus, and Web of Science from 2000 to 2025 using predefined descriptors related to GTN and immunotherapy. Eligible studies included clinical trials, case series, case reports, and translational research addressing immune checkpoint inhibitors in GTN. GTN exhibits high PD-L1 expression, mirroring the immune-privileged nature of the placenta. Checkpoint inhibitors alone, such as pembrolizumab, avelumab, or the combination of camrelizumab plus apatinib (that potently suppresses the kinase activity of vascular endothelial growth factor 2), have demonstrated complete and durable responses in approximately 70–80

Objectives: To evaluate the potential associations of the type of complete hydatidiform mole (CHM) initial treatment (hysterectomy or uterine evacuation) with GTN development, need for chemotherapy, and treatment outcome in women aged ≥ 40 years. Methods: This multicentric retrospective cohort study included women ≥ 40 years with CHM, initially treated between 1990 and 2018, at four different centers. Data collected included patient demographics and clinical characteristics. The outcome variables were post-CHM GTN development, need for chemotherapy for hCG normalization, surgical complications, and time to remission. Univariate and multivariate analyses were performed using chi-square, Mann-Whitney, Fisher's exact tests, and Poisson regression. Results: 275 women with CHM aged ≥ 40 years were included in the analysis. Median patient age was significantly higher among hysterectomy patients (47 × 44 years, p = 0.01). Multivariate analysis showed that compared with uterine evacuation (244/275, 89%), hysterectomy (31/275, 11%) was associated with an 83% lower risk of GTN [RR = 0.17 95% CI = (0.04-0.71); p = 0.015] and a 92% lower risk of requiring chemotherapy [RR: 0.08 (0.01-0.64), p = 0.016]. Median time to hCG normalization did not statistically differ between treatments. No significant differences were observed between hysterectomy and uterine evacuation in terms of FIGO staging (p = 0.221) or prognostic risk score (p = 0.576). Resistance to first-line chemotherapy (17/72; 23.6%) and relapse (3/72; 4.1%) were observed only in patients undergoing initial uterine evacuation. Hysterectomy complications occurred in 45.1% (14) of the patients. Conclusions: CHM initial treatment with hysterectomy was associated with a lower risk for GTN occurrence and need for chemotherapy in women aged 40 years or older. However, shared decision-making about surgery should be tailored to each patient and their risk factors and preferences. Further, larger controlled studies are required to support our findings.

OBJECTIVE:Dual immune checkpoint blockade (ICB) may synergize with palliative radiotherapy (RT) to improve responses in patients with recurrent/metastatic gynecologic cancer. We conducted an open label prospective phase I trial to assess the safety and tolerability of ICB plus RT. METHODS:Patients with recurrent/metastatic endometrial, ovarian, cervical, vaginal or vulvar cancer were eligible. The safety lead-in cohort A was treated with programmed death ligand (PD-L1) inhibitor durvalumab 1500 mg IV q4 weeks and palliative RT of 25 Gy in 5 fractions to a single abdominopelvic lesion. Cohort B also received 4 cycles of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab 75 mg IV. The primary endpoint was the rate of dose-limiting toxicities (DLTs) in patients on protocol 8 weeks after RT. Secondary endpoints included the overall response rate (ORR) in non-irradiated lesions. RESULTS:16 patients were enrolled, with 12 able to be assessed for the primary endpoint. Zero DLTs occurred in cohort A and 1 in cohort B. One patient in cohort B with platinum resistant ovarian cancer with two metastatic sites (a pelvic mass irradiated prior to trial enrollment and a peritoneal nodule irradiated on protocol) had a dramatic reduction in disease burden and remains off all therapy >3 years. The ORR of non-irradiated lesions was 0 %. CONCLUSIONS:Combining durvalumab, tremelimumab and RT to a single lesion had limited DLTs but no response in non-irradiated lesions in unselected patients with recurrent gynecologic malignancies. One patient with oligometastatic disease experienced prolonged durable benefit. CLINICAL TRIAL INFORMATION:NCT03277482.

5513 Background: Preclinical studies have demonstrated synergism with simultaneous inhibition of the estrogen receptor (ER), CDK4/6 and PI3K pathways. Metformin suppresses PI3K signaling directly via activation of the AMP-activated protein kinase (AMPK) and indirectly via downregulating the insulin/IGF-1 signaling pathway. We conducted a phase 2 study of letrozole/abemaciclib/metformin in ER positive EC. Methods: Patients (pts) with recurrent ER positive (≥1% immunoreactive tumor nuclei) endometrioid EC, measurable disease, any number of prior therapies and any prior hormonal therapy but no prior CDK4/6 inhibitor received abemaciclib 150 mg PO bid, metformin 500mg PO qd and letrozole 2.5 mg PO qd until progression or unacceptable toxicity. Primary endpoints were objective response (OR) rate (ORR) and progression-free survival (PFS) rate at 6 months (PFS6). A safety lead-in was included, and target accrual was 25 pts; if there were ≥6 ORs or ≥9 pts without disease progression or death at 6 months, letrozole/abemaciclib/metformin would be considered worthy of further investigation. Correlative studies included pharmacokinetic (PK) analyses of metformin alone and in combination with letrozole/abemaciclib, molecular profiling using Oncopanel targeted NGS, and progesterone receptor (PrgR) expression by IHC. Results: As of 10/4/2024, all 25 pts received protocol therapy. Median follow up was 17 months, median number of prior lines was 2 and 18 (72%) pts had previously received hormonal therapy. Eight pts exhibited OR: 3 complete responses (CRs) and 5 partial responses (PRs),ORR 32% (95% CI 14.9% to 53.5%). Sixteen (64%) pts had stable disease (SD) and 1(4%) pt progressive disease (PD) as best response. Kaplan Meier estimate of PFS6 was 69.7% and median PFS was beyond 19.3 months. Most common G3+ treatment-related toxicities were G3 neutropenia (24%) and G3 fatigue (16%). No pts discontinued therapy because of toxicity. PK analyses demonstrated that metformin plasma concentrations were ~3-fold higher when combined with letrozole/abemaciclib compared to metformin monotherapy. Molecular profiling showed no objective responses in TP53 mutated ECs and no objective responses in pts with NSMP ECs with RB1 or CCNE1 alterations; median PFS was only 3.8 months in these tumors. All objective responses were observed in pts with NSMP ECs without RB1 and CCNE1 alterations; these pts exhibited an ORR of 50% and PFS6 of 87.5%. There were no MMRD and no POLE -mutated tumors. Responses were observed regardless of PrgR expression. Conclusions: Addition of metformin (at plasma concentrations sufficient to inhibit the PI3K pathway) to letrozole/abemaciclib is feasible and safe, and appears to induce deeper responses (including complete responses) and more prolonged PFS than letrozole/abemaciclib alone. NSMP tumors without RB1 and CCNE1 alterations derive the most benefit from this regimen. Clinical trial information: NCT03675893 .

Objective To assess the performance of pembrolizumab for the treatment of Gestational Trophoblastic Neoplasia (GTN). Methods The Medical Subject Headings related to immunotherapy/pembrolizumab and GTN were used alone or in combination to retrieve relevant articles. The authors searched in EMBASE, MEDLINE/PubMed, Elsevier's Scopus, and Web of Science until November/2024. The authors included any randomized controlled trials, cohort studies, case series, and case reports focusing on pembrolizumab treatment in GTN. Meta-analysis of proportions was carried out employing a random-effects model. The meta-analysis employed the inverse variance method, with the arcsine link function for the analysis of proportional data. All analyses were performed using Stata 18. For all analyses, a p-value < 0.05 indicated statistical significance. This study was registered on PROSPERO (CRD42023493329). Results A total of 550 studies were identified after a literature search among which 15 original studies were included in the systematic review and in the meta-analysis. Pembrolizumab induced complete sustained remission in 71.59% (95% CI 53.27-84.78%; I-2 = 0.00%, H-2 = 1.00, p = 0.90) of cases. The subgroups meta-analysis showed pembrolizumab had similar performance, regardless of age (< 40 vs. >= 40-years-old, p = 0.38), GTN histopathology (Placental Site Trophoblastic Tumor [PSTT], Epithelioid Trophoblastic Tumor [ETT]/noninvasive mole/others versus invasive mole/choriocarcinoma, p = 0.48), time from diagnosis to the beginning of immunotherapy (< 4 vs. >= 4-years, p = 0.84), pembrolizumab combined with chemotherapy (yes vs. no, p = 0.66). Conclusions Pembrolizumab seems an effective treatment for patients with high-risk GTN with chemoresistant or relapsed disease, including cases of PSTT/ETT, notwithstanding patient age, time to initiate immunotherapy and whether or not it was associated with chemotherapy.

5515 Background: Clear cell ovarian carcinoma (CCOC) is a chemoresistant subtype of ovarian cancer. Immune checkpoint inhibitors have been reported to have clinical activity in CCOC. Additionally, CCOC harbors molecular alterations suggesting a role for anti-angiogenic agents. We therefore conducted a single-arm two-stage phase 2 trial to investigate the clinical activity of the combination of the PD-1 inhibitor pembrolizumab with the anti-angiogenic tyrosine kinase inhibitor lenvatinib in patients (pts) with CCOC. Methods: Pts with CCOC and measurable disease received pembrolizumab 200 mg IV every 3 weeks and lenvatinib 20 mg daily. Pts could have received an unlimited number of prior therapies; prior bevacizumab and immune checkpoint inhibitors were allowed, but prior lenvatinib was exclusionary. Malignant bowel involvement was not allowed. Co-primary endpoints were objective response rate (H 0 5%; H a 25%) and rate of PFS at 6 months (mo) per RECIST v1.1 (H 0 10%; H a 30%), restricting the probabilities of type I and type II errors to 10% and 10%, respectively. Two pts with objective responses or 3 pts progression-free and alive at 6 mos were needed to proceed from stage 1 (n=18) to stage 2 (n=13); 5 pts with objective responses or 6 pts progression-free and alive at 6 mos were needed to declare the combination worthy of further study. Results: Data cut-off occurred 22-Oct-2024. Of 30 enrolled pts, 83.3% were white; the mean age among all pts was 54.1 years. 30% of pts (9/30) experienced a confirmed response (2 CR, 7 PR); an additional 3 pts (10%) experienced unconfirmed PRs and 4 pts (13.3%) had SD ≥6 mo. As of data cut-off, 3 pts (10%) had not yet reached their first radiographic assessments, and 17 pts were still receiving study therapy. With a median of 9.72 mo of follow up, 16 pts were alive and progression-free at 6 months. The estimated 6-month PFS was 75.96% (95% CI 53.82-88.51%). Median PFS was 10.9 mo. The estimated 12-month PFS was 48.86% (95% CI 23.67-70.04%). The most common any-grade TRAEs were hypertension (71%), hypothyroidism (66%), and fatigue (60%). There were no unanticipated TRAEs. Conclusions: The combination of pembrolizumab/lenvatinib demonstrates encouraging evidence of clinical activity in CCOC, with 9 pts experiencing a confirmed response and 16 pts alive and progression-free at 6 months. As both co-primary endpoints of the study were met, enrollment closed with 30 pts. Updated data for all pts will be reported. There were no new safety signals. Clinical trial information: NCT05296512 .

OBJECTIVE:To compare the effectiveness and safety of home-based versus hospital-based chemotherapy with 8-day methotrexate/folinic acid (MTX/FA) for low-risk gestational trophoblastic neoplasia (GTN). METHODS:Retrospective multiple-cohort study with patients receiving first-line MTX/FA for low-risk GTN at either the Botucatu Trophoblastic Disease Center-UNESP, Brazil (home-based treatment - 80 patients) or the New England Trophoblastic Disease Center, USA (hospital-based treatment - 61 patients), from 1995 to 2020. Follow-up was ≥12 months. Study variables were pre-treatment hCG, FIGO staging/risk score, sustained complete response, failure due to resistance/recurrence/toxicity, number of chemotherapy cycles, time to remission, and survival. RESULTS:There was no significant difference between treatment settings regarding pre-treatment hCG, GTN stage, sustained complete remission rate (home: 72.5 %, vs. hospital: 78.7 %, p = 0.52), resistance rate (home: 20 % vs. hospital: 15 %, p = 0.56), and rate of toxicity requiring a shift in single-agent chemotherapy (home: 3.5 % vs. hospital: 3.3 %, p = 1.00). The remission rate remained consistent after multivariate adjustment for age and FIGO risk score. However, there was a significant difference in median risk score (home: 2 vs. hospital: 1, p < 0.01) and median number of cycles (home: 3 cycles vs. hospital: 2 cycles; p < 0.01). Time to remission was 14 days longer with home treatment (home: 57 days vs. hospital: 41 days; p < 0.01). All patients survived. CONCLUSION:Home- and hospital-based treatments showed similar sustained complete remission rate, with no change in frequency of toxicity-related failure and survival. Low-risk GTN treatment with 8-day-MTX/FA at home is feasible, produces outcomes similar to those observed in a hospital setting and offers a more flexible and patient-centered approach to care.

Hydatidiform mole is a trophoblastic disorder resulting from abnormal fertilization. Diagnosis is established through a combination of clinical findings, elevated serum human chorionic gonadotropin (hCG) levels, and characteristic features on transvaginal ultrasound. Timely and accurate diagnosis is essential for initiating prompt treatment and preventing medical complications. Uterine evacuation, preferably via vacuum aspiration, is the treatment of choice due to its high efficacy and safety profile. Adjunctive techniques, such as hysteroscopy and intraoperative ultrasonography, enhance the safety and effectiveness of uterine evacuation and should be available to patients, especially at specialized referral centers equipped to manage this diagnosis. In selected cases, particularly in women with fulfilled reproductive goals or those at a high risk of developing post-molar gestational trophoblastic neoplasia (GTN), total abdominal hysterectomy is appropriate. Postoperative follow-up with serial measurements of hCG is essential for monitoring remission and for the early detection of post-molar GTN, which develops in approximately 20% of cases of complete molar pregnancies and 1–4% of partial molar pregnancies. This article provides a comprehensive review of the diagnosis of hydatidiform mole and the surgical techniques employed in the treatment of this condition, emphasizing individualized care and the use of appropriate surgical strategies to treat complications associated with this trophoblastic disease.

Gestational trophoblastic neoplasia (GTN) is a group of rare but highly curable pregnancy-related tumors, especially in low-risk cases. However, around 25% of patients with GTN develop either resistant or recurrent disease after initial chemotherapy. To enhance the understanding of the mechanisms driving treatment failures and to develop more personalized and effective therapeutic strategies, this review explored diverse factors influencing low-risk GTN prognosis. These factors include FIGO (International Federation of Gynecology and Obstetrics) risk score, histology, patient age, pregnancy type, human chorionic gonadotropin (hCG) levels, disease duration, tumor characteristics, metastasis, Doppler ultrasonography, and consolidation chemotherapy. Additionally, the review examined independent risk determinants for disease recurrence and resistance to single-agent chemotherapy in patients with low-risk GTN. In most previous studies on the risk factors related to low-risk GTN, resistance and recurrence have typically been examined independently, despite their overlapping and interrelated nature. Furthermore, they often involve small sample sizes, suffer from methodological shortcomings, and exhibit limited statistical power.Studies utilizing multivariate analysis have shown that independent risk determinants for resistance to firstline treatment include FIGO score, metastatic disease, pre-treatment hCG level, interval between antecedent pregnancy and GTN diagnosis, tumor size, uterine artery pulsatility index (UAPI), choriocarcinoma, lung metastases, lung nodule size, and clearance hCG quartile. The independent predictive factors associated with recurrence include lung metastases, lung nodule size, interval between antecedent pregnancy and chemotherapy, interval from first chemotherapy to hCG normalization, post-delivery low-risk GTN, number of chemotherapy courses to achieve hCG normalization, and number of consolidation chemotherapy cycles. However, while these identified predictive factors offer valuable guidance, the variability in definitions and populations across studies may have implications for the generalizability of their findings. A comprehensive approach using clear definitions and taking into account multiple predictive factors may be necessary for accurately assessing the risk of resistance and recurrence in patients with low-risk GTN.

The selection of optimal therapies for patients with ovarian cancer is difficult, especially in recurrent disease. An implantable microdevice (IMD) is a new technology to evaluate in situ drug responses in cancer. An IMD, about the size of a grain of rice, is implanted into human or murine solid tumors and releases microdoses of up to 20 compounds in spatially distinct regions of the tumor. Histologic analysis of tissue surrounding the IMD is used to quantitate tumor response. Using IMDs, we can measure tumor sensitivity to multiple drugs or drug combinations in parallel, directly in the tumor with its native microenvironment. Previous studies showed that measurement of local drug response with IMDs in solid tumors correlates with systemic drug response in animal models. We are conducting a clinical trial (NCT04701645) to evaluate the safety and feasibility of IMD implantation in patients with ovarian cancer undergoing surgical resection for clinical indications. Several IMDs, each with 16 standard-of-care drugs and controls, are implanted into a tumor 24-72 hours prior to surgery using a percutaneous delivery needle under CT guidance. After the mass is resected, the tumor tissue containing the IMDs is formalin-fixed, sectioned, and stained to evaluate cellular responses to drug treatment. The aim of the trial is to assess the safety and the feasibility of IMDs in ovarian cancer. Four patients have enrolled to date (histologies: 2 high-grade serous, 1 clear cell, 1 granulosa cell) with 3-4 IMDs implanted per patient. No adverse events attributable to the IND were observed. Of 14 total devices, 10 provided evaluable histology information (4 were dislodged from the tumor ex vivo during pathology processing). Several assays are being applied to evaluate the effects of each drug on the tumor tissue, including 1) immunohistochemistry for apoptosis (cleaved caspase 3, CC3); 2) cyclic immunofluorescence for protein markers; 3) spatial transcriptomics. Regions of interest are selected adjacent to each drug reservoir, and imaging methods quantitate different cell types and markers of drug response. Initial results from three patients demonstrate moderate induction of apoptosis via CC3 staining with a subset of drugs, but minimal CC3 staining for other drugs, in each patient’s tumor. Cyclic immunofluorescence staining is completed on tissue from the first two patients, and a spatial transcriptomics panel is completed on tissue from one patient, both technically successful, and data analysis is ongoing. Additional patients are being enrolled to the clinical trial. In summary, our clinical trial experience indicates that IMDs are safe to implant into tumors of patients with ovarian cancer and that it is feasible to retrieve the IMDs after surgery and obtain informative measurements of mRNA and protein responses in ovarian cancers exposed to different drugs. IMDs may represent an effective new technology for functional precision medicine in ovarian cancer. Citation Format: Elizabeth H. Stover, Sharath K. Bhagavatula, Christine A. Dominas, Sebastian W. Ahn, Samantha E. Martin, David L. Kolin, Michelle S. Hirsch, Madeline Polak, Alexis Rabbitt, Jeanette Gardner, Kimberley MacNeill, Zuzana Tatarova, Michael Worley Jr., Kevin M. Elias, Joyce F. Liu, Ursula A. Matulonis, Stuart G. Silverman, Neil S. Horowitz, Oliver Jonas. Clinical trial of an implantable microdevice to evaluate drug responses in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B012.

BACKGROUND:There are limited data around adjuvant radiotherapy following surgical management for patients with early-stage uterine carcinosarcoma (UCS). We compared outcomes for patients with early-stage UCS who underwent adjuvant chemotherapy (CT) and pelvic external beam radiotherapy (EBRT) vs. CT and vaginal brachytherapy (VBT) vs. radiation therapy (EBRT or VBT) alone. METHODS:A retrospective analysis was performed of patients diagnosed with FIGO stage I-II UCS from 2002 to 2020 who received adjuvant radiotherapy, with or without CT, following definitive surgery. Clinical and treatment characteristics and clinical outcomes were assessed. Kaplan-Meier method and log-rank test was used for clinical outcomes. Cox proportional-hazards modeling was used for multivariable analysis. RESULTS:98 patients were analyzed, of whom 38 received CT + EBRT, 31 received CT + VBT, and 29 received RT-alone (18 EBRT, 11 VBT). For the CT + EBRT, CT + VBT, and RT-alone groups, median follow up was 93.5, 50.2, and 143.0 months, and 3-year PFS was 78.7 %, 67.6 %, and 58.2 %, respectively. CT + EBRT was associated with improved PFS compared to RT alone (p = 0.01), but not compared to CT + VBT (p = 0.22). There were 4 locoregional recurrences in the CT + EBRT group (10.5 %), 8 in the CT + VBT group (25.8 %), and 5 in the RT-alone group (17.2 %). On multivariable analysis, RT-alone trended towards shorter time to progression (TTP) compared to CT + EBRT (p = 0.05), with similar TTP compared to CT + VBT (p = 0.83). CONCLUSIONS:In one of the largest retrospective cohorts of early-stage UCS, adjuvant CT + EBRT, but not CT + VBT, improved outcomes compared to RT-alone. Larger prospective studies are needed to investigate the role of different radiation modalities in UCS.

Antibody-drug conjugates (ADC) are emerging therapies with promising results in the treatment of solid tumors. In this study, we aimed to evaluate biomarker expression of ADCs, including folate receptor alpha (FOLR1), Nectin-4, trophoblast cell surface antigen 2 (Trop-2), and tissue factor (TF) in a diverse cohort of gestational trophoblastic disease. Immunohistochemistry for FOLR1, Nectin-4, Trop-2, and TF was evaluated in tissue microarray of 18 complete hydatidiform moles (CHM) and whole tissue sections of 62 gestational trophoblastic neoplasia (GTN) by 2 gynecologic pathologists. Western blotting for FOLR1, Nectin-4, and Trop-2 was performed in JEG-3 and JAR choriocarcinoma cell lines, 2 CHM and 3 GTN clinical samples. Results: The overall immunohistochemical positive rate in GTN was 11% for FOLR1, 59% for Nectin-4, 38% for Trop-2, and 26% for TF. Choriocarcinomas showed 27% positivity for FOLR1, 75% for Nectin-4, 40% for Trop-2, and 25% for TF. Epithelioid trophoblastic tumors (ETT) were positive for Nectin-4 in 58%, for Trop-2 in 79%, and for TF in 67% of cases. Placental site trophoblastic tumors were positive only for Nectin-4 (23% of cases). In CHM, only Nectin-4 revealed a higher degree of expression and limited staining for the other markers. Western blotting showed FOLR1 expression in CHM, JEG-3, and JAR; Nectin-4 in CHM and PSTT; and Trop-2 in CHM, JEG-3, and choriocarcinoma. Conclusion: A subset of GTN shows expression for FOLR1, Nectin-4, Trop-2, and TF, particularly choriocarcinoma and ETT. These results suggest that patients with GTN could potentially benefit from ADC treatment.

PURPOSE:In a phase II study, letrozole/abemaciclib demonstrated an objective response rate of 30% and a median progression-free survival (PFS) of 9.1 months in recurrent estrogen receptor-positive endometrial cancer (EC). While tissue-based tumor profiling revealed several mechanistically relevant candidate baseline genomic predictors of response, circulating tumor DNA (ctDNA) is a less invasive alternative to monitor therapeutic efficacy and define acquired resistance. METHODS:Serial plasma specimens were obtained at baseline, C2D1, C3D1, C8D1, the time of objective response, and the time of progression. Samples were analyzed using the Guardant Reveal assay to assess methylation-based tumor fraction (TF), with the Guardant360 assay providing genotyping of >700 genes in samples with detectable ctDNA. Treatment response was assessed using a measure of the relative change in TF pre- versus on-treatment. RESULTS:A total of 99 of 102 (97%) samples from 28 patients were successfully analyzed. Patients with above median baseline TF exhibited worse median PFS (2.0 months v 16.5 months, P < .005, hazard ratio [HR], 24.1) and worse overall survival (OS) (10.7 months v not yet reached, P < .005, HR, 14.8). Patients with molecular response (MR) after the first or second cycle of letrozole/abemaciclib therapy had significantly better median PFS and OS regardless of the cutoff used for definition of MR. ctDNA analysis of postprogression specimens identified several acquired genomic alterations associated with resistance to letrozole/abemaciclib therapy in more than half of the patients, including PI3K pathway, receptor tyrosine kinase (FGFR1,2 and ERBB2 alterations), cell cycle pathway (RB1 and CCNE1 alterations), and ESR1 and MAPK pathway alterations. Two of the three patients with mismatch repair-deficient ECs acquired ESR1 mutations at the time of progression. CONCLUSION:Baseline and on-treatment ctDNA dynamics may provide an early indication of benefit from letrozole/abemaciclib in EC. ctDNA at the time of progression may identify resistance alterations that may inform subsequent therapy.

Gestational trophoblastic neoplasia (GTN) is primarily treated with chemotherapy, but surgery plays a key role at different steps in disease management, including initial diagnosis, primary therapy, and salvage options. Initial diagnosis is usually made by electric or manual vacuum aspiration for molar pregancy or uterine curettage for other forms of GTN. Excisional procedures of localized disease, whether second curettage or hysterectomy, can obviate chemotherapy, but patients still require monitoring for relapse. Resection remains a useful adjunct for either the management of isolated foci of chemoresistant disease or the management of bleeding complications.