Endometrial cancer is the most common gynecologic malignancy in developed countries and approximately 7% of the women with endometrial cancer are below the age of 45. Management of endometrial cancer in young women who desire to maintain fertility presents a unique set of challenges since the standard surgical treatment based on hysterectomy and salpingo-oophorectomy is often not compatible with the patient’s goals. A fertility-preserving approach can be considered in selected patients with early stage and low-grade endometrial cancer. An increasing amount of data suggest that oncologic outcomes are not compromised if a conservative approach is utilized with close monitoring until childbearing is completed. If a fertility-preserving approach is not possible, assisted reproductive technologies can assist patients in achieving their fertility goals.

Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) are two rare histologic variants of uterine carcinoma, with distinct molecular profiles and aggressive metastatic potential. As the effectivity of traditional platinum-based chemotherapy for USC and UCS is low, and there are high rates of resistance and recurrence, the development of novel targeted therapeutics is needed. Human epidermal growth factor receptor 2 (HER2) has proven to be an oncogene of increasing interest in these cancers, as HER2 protein overexpression and/or c-ERBB2 gene amplification ranges from ~30 to 35% in USC, and between ~15 and 20% in UCS. This review summarizes the existing clinical and preclinical evidence, as well as ongoing clinical trials of HER2-targeting therapeutics, and identifies potential areas of further development and inquiry.

Antibody–drug conjugates (ADCs) are a new class of targeted anti-cancer therapies that combine a monoclonal tumor-surface-receptor-targeting antibody with a highly cytotoxic molecule payload bonded through specifically designed cleavable or non-cleavable chemical linkers. One such tumor surface receptor is human epidermal growth factor 2 (HER2), which is of interest for the treatment of many gynecologic tumors. ADCs enable the targeted delivery of a variety of cytotoxic therapies to tumor cells while minimizing delivery to healthy tissues. This review summarizes the existing literature about HER2-targeting ADC therapies approved for use in gynecologic malignancies, relevant preclinical studies, strategies to address ADC resistance, and ongoing clinical trials.

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

Purpose: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. Patients and Methods: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. Results: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. Conclusions: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.

To examine clinicopathologic characteristics and oncologic outcomes of patients diagnosed with Mullerian adenosarcoma and to evaluate ovarian preservation as a practical management option in early-stage disease. A retrospective review was performed of 31 patients treated for uterine, ovarian, or cervical adenosarcoma at our institution between 1/2000–3/2020. Recurrence-free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards regression. Median age was 51 years (IQR: 41–68). Primary sites included uterine corpus (n = 23, 74.2%), uterine cervix (n = 7, 22.6%), and ovary (n = 1, 3.2%). Surgical management primarily consisted of total hysterectomy +/- bilateral adnexectomy +/- lymph node dissection. Fifteen (48.1%) patients underwent lymph node dissection; no patients had positive nodes. Ovaries were preserved in 6 (19.4%). Twenty-two (71.0%) patients received no adjuvant therapy, 4 (12.9%) received chemotherapy, 1 (3.2%) received chemoradiation, and 3 (9.7%) received hormonal therapy. Sarcomatous overgrowth (p = 0.04), high grade histology (p = 0.002), and greater depth of myometrial invasion (p = 0.001) were associated with decreased RFS. None of the 6 patients with ovarian preservation had recurrences. At last follow up, 21 patients (67.7%) had no evidence of disease, 7 (22.6%) were deceased due to disease, and 3 (9.7%) were deceased due to non-cancerous reasons. Uterine adenosarcoma appears to have a relatively good prognosis, especially in the absence of risk factors, such as sarcomatous overgrowth, high grade histology, and deep myometrial invasion. Ovarian preservation may be a feasible management option with non-inferior outcomes for premenopausal women with early-stage disease. Future studies including larger patient cohorts are needed for this rare disease.