PurposeUterine serous carcinoma is a rare, aggressive variant of endometrial cancer. Trastuzumab is a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2)/neu, a receptor overexpressed in 30% of uterine serous carcinoma. This multicenter, randomized phase II trial compared carboplatin-paclitaxel with and without trastuzumab in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu.MethodsEligible patients had primary stage III or IV or recurrent HER2/neu-positive disease. Participants were randomly assigned to receive carboplatin-paclitaxel (control arm) for six cycles with or without intravenous trastuzumab (experimental arm) until progression or unacceptable toxicity. The primary end point was progression-free survival, which was assessed for differences between treatment arms via one-sided log-rank tests.ResultsFrom August 2011 to March 2017, 61 patients were randomly assigned. Forty progression-free survival–related events occurred a...

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Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu

Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study.

Endometrial cancer comprises a heterogeneous group of tumors, with distinct risk factors, clinical presentation, histopathological features and molecular characteristics. Currently, treatment of metastatic or recurrent disease is based on conventional chemotherapy combination regimens. Advances in the understanding of the molecular pathology of the two types of endometrial carcinoma--type I (endometrioid) and type II (non-endometrioid)--have underpinned the first steps in the development and testing of targeted therapies. Of the potential therapeutic targets identified to date, clinical trials have only assessed the efficacy of inhibition of the EGFR, VEGFR and PI3K/PTEN/AKT/mTOR signaling pathways; responses to these targeted therapies were modest. Despite the striking molecular differences between type I and type II endometrial cancers, most clinical trials have not taken this diversity into account. The identification of activating mutations of kinases (for example PIK3CA and FGFR2) and loss of function of genes related to DNA repair (for example PTEN) may lead to more biology-driven clinical trials exploiting the concepts of oncogene addiction and synthetic lethality.

Emerging therapeutic targets in endometrial cancer

Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. Endometrioid endometrial carcinomas constitute approximately 85% of newly diagnosed cases; serous carcinomas represent approximately 3-10% of diagnoses; clear cell carcinoma accounts for <5% of diagnoses; and uterine carcinosarcomas are rare, biphasic tumors. Longstanding molecular observations implicate PTEN inactivation as a major driver of endometrioid carcinomas; TP53 inactivation as a major driver of most serous carcinomas, some high-grade endometrioid carcinomas, and many uterine carcinosarcomas; and inactivation of either gene as drivers of some clear cell carcinomas. In the past decade, targeted gene and exome sequencing have uncovered additional pathogenic aberrations in each histotype. Moreover, an integrated genomic analysis by The Cancer Genome Atlas (TCGA) resulted in the molecular classification of endometrioid and serous carcinomas into four distinct subgroups, POLE (ultramutated), microsatellite instability (hypermutated), copy number low (endometrioid), and copy number high (serous-like). In this review, we provide an overview of the major molecular features of the aforementioned histopathological subtypes and TCGA subgroups and discuss potential prognostic and therapeutic implications for endometrial carcinoma.

Molecular Genetics of Endometrial Carcinoma.

Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu

Uterine papillary serous carcinoma (UPSC) is a highly aggressive variant of endometrial cancer with features similar to high-grade ovarian cancer. Patients tend to be elderly, thin, have a high grade tumor with extensive extrauterine disease at the time of diagnosis. The transmembrane receptor encoded by the HER-2 cellular oncogene is amplified in several types of human carcinomas and provides an attractive therapeutic target. HER-2/neu, the transmembrane receptor encoded by the c-erbB2 gene, is overexpressed by immunohistochemistry in <25% of ovarian cancers and 20-30% of breast cancers, and <10% of endometrial cancer. There are prognostic and therapeutic implications associated with the overexpression of this transmembrane protein. Herceptin, a humanized murine monoclonal antibody directed against the extracellular domain of the HER-2/neu protein, is being used to treat breast cancer that overexpresses HER-2/neu. We reviewed all patients diagnosed with UPSC between 1999-2001. Twenty-six patients were identified, and 19 patients had specimens available for evaluation. We performed immunohistochemical analysis (Herceptest, Dako, Carpinteria, CA) on 19 paraffin embedded blocks of UPSC tumors looking for HER-2/neu over expression. Five out of 19 (26%) stained heavily (3+) for HER-2/neu receptor protein. Four of these five patients had advanced disease at diagnosis. Two of these patients were subsequently treated with Herceptin; one with complete response and one with stable disease based on CT scan and CA-125 findings. Targeting HER-2/neu may be beneficial for a select group of patients with UPSC. We are continuing to evaluate samples for HER-2/neu over expression by fluorescence in situ hybridization (FISH).

HER-2/neu overexpression in uterine papillary serous cancers and its possible therapeutic implications.

P018 TROPION-Breast03: Datopotamab deruxtecan (Dato-DXd) ± durvalumab vs investigator’s choice of therapy (ICT) for triple-negative breast cancer (TNBC) with residual disease following neoadjuvant therapy

Development and validation of a risk calculator for adverse perioperative outcomes for women with ovarian cancer

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HER-2/neu overexpression in uterine papillary serous cancers and its possible therapeutic implications.

P018 TROPION-Breast03: Datopotamab deruxtecan (Dato-DXd) ± durvalumab vs investigator’s choice of therapy (ICT) for triple-negative breast cancer (TNBC) with residual disease following neoadjuvant therapy

Development and validation of a risk calculator for adverse perioperative outcomes for women with ovarian cancer