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Trastuzumab has demonstrated clinical efficacy in the treatment of HER2‐positive serous endometrial cancer (EC), which led to its incorporation into standard‐of‐care management of this aggressive disease. Acquired resistance remains an important challenge, however, and its underlying mechanisms in EC are unknown. To define the molecular changes that occur in response to anti‐HER2 therapy in EC, targeted next‐generation sequencing (NGS), HER2 immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) were performed on pre‐ and post‐treatment tumour samples from 14 patients with EC treated with trastuzumab or trastuzumab emtansine. Recurrent tumours after anti‐HER2 therapy acquired additional genetic alterations compared with matched pre‐treatment ECs and frequently showed decreased HER2 protein expression by IHC (7/14, 50%). Complete/near‐complete absence of HER2 protein expression (score 0/1+) observed post‐treatment (4/14, 29%) was associated with retained HER2 gene amplification (n = 3) or copy number neutral status (n = 1). Whole‐exome sequencing performed on primary and recurrent tumours from the latter case, which exhibited genetic heterogeneity of HER2 amplification in the primary tumour, revealed selection of an early HER2‐non‐amplified clone following therapy. Our findings demonstrate that loss of target expression, by selection of HER2‐non‐amplified clones or, more commonly, by downregulation of expression, may constitute a mechanism of resistance to anti‐HER2 therapy in HER2‐positive EC. © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Low‐grade serous ovarian cancer was initially described as a distinct type of rare epithelial ovarian cancer 20 years ago; however, only recently have physicians begun to leverage the understanding of the clinical behavior and molecular profile of this disease for treatment. The use of routine next‐generation sequencing has allowed a deeper understanding of the molecular drivers of this disease and shown how molecular alterations in mitogen‐activated protein kinase pathway genes such as KRAS and BRAF can affect overall prognosis and disease behavior. The use of targeted therapies, including MEK inhibitors, BRAF kinase inhibitors, and other investigational targeted therapies are changing the way this disease is viewed and treated. In addition, endocrine therapy can provide prolonged disease stability with generally mild toxicity, as well as promising response rates in recent studies examining combination therapy with CDK 4/6 inhibitors in the upfront and recurrent setting. Once seen merely as a chemo‐resistant form of ovarian cancer, recent studies have worked to harness the unique features of low‐grade serous ovarian cancer to provide individualized treatment options for patients with this disease. The use of routine next‐generation sequencing has allowed for a deeper understanding of the molecular drivers of low‐grade serous ovarian cancer and shown how molecular alterations in mitogen‐activated protein kinase pathway genes such as KRAS and BRAF can affect overall prognosis and disease behavior. The use of targeted therapies, including MEK inhibitors, BRAF kinase inhibitors, and other investigational targeted therapies, as well as novel endocrine strategies, are changing the way this disease is viewed and treated. [ABSTRACT FROM AUTHOR]

Summary: We report a case of a 47‐year‐old woman with a history of acral lentiginous melanoma, left great toe subungual primary, metastatic to the lungs, brain, and spleen, presenting with lower urinary tract symptoms. She had also palpated and removed a dark mass from her vaginal canal. Magnetic resonance imaging (MRI) showed polypoidal lesions within the urinary bladder and the endometrium. The suspected differential diagnosis was endometrial and bladder melanoma metastases, based on her cancer history and MRI findings. The patient underwent cystoscopy with transurethral resection of the bladder tumor and endometrial biopsy, and pathology was consistent with metastatic melanoma. Bladder and endometrial metastatic lesions are exceedingly rare. Herein, we describe an unusual case of metastatic melanoma concurrent to the urinary bladder and endometrium. [ABSTRACT FROM AUTHOR]