César Serrano

Retrospective cohort study evaluating the impact of intraperitoneal morcellation on outcomes of localized uterine leiomyosarcoma.

Uterine leiomyosarcoma (ULMS) is identified in 0.1% to 0.2% of hysterectomy specimens of presumed leiomyoma. To date, there is no preoperative technique that reliably differentiates ULMS from uterine leiomyoma. Increasing use of minimally invasive approaches for the management of leiomyomas may result in inadvertently morcellated ULMS with resultant intraperitoneal dissemination of tumor. The objective of this study was to assess the impact of intraperitoneal morcellation on the outcomes of patients with ULMS.

Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients.

Purpose: KIT is the major oncogenic driver of gastrointestinal stromal tumors (GIST). Imatinib, sunitinib, and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here, we explore the KIT-inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in patients with GIST. Experimental Design: The cellular and in vivo activities of ponatinib, imatinib, sunitinib, and regorafenib against mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib–KIT costructure was also determined. The clinical activity of ponatinib was examined in three patients with GIST previously treated with all three FDA-approved agents. Results: In engineered and GIST-derived cell lines, ponatinib potently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinib also induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nmol/L ponatinib was sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nmol/L. This inhibitory profile could be rationalized on the basis of structural analyses. Ponatinib (30 mg daily) displayed encouraging clinical activity in two of three patients with GIST. Conclusion:Ponatinib possesses potent activity against most major clinically relevant KIT mutants and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinib in patients with GIST. Clin Cancer Res; 20(22); 5745–55. ©2014 AACR.

Recent advances in the treatment of gastrointestinal stromal tumors.

Constitutively activating mutations in the KIT and platelet-derived growth factor receptor α (PDGFRA) RTKs play a crucial role in the biology of gastrointestinal stromal tumors (GISTs), and this disease has served as an effective model for targeting gain-of-function kinase mutations in cancer. Imatinib has entered the clinical arena in the last decade and substantially improved the outcome in these formerly untreatable cancers. However, most advanced GISTs responding to imatinib progress within 2–3 years due to heterogeneous subclones harboring a range of imatinib-resistant secondary KIT mutations. Sunitinib, and more recently, regorafenib, have obtained US Food and Drug Administration approval for the treatment of GISTs after imatinib failure, and thus expanded the treatment options in resistant disease. Within this framework, we present an evaluation of current GIST management, emphasizing the most recent advances in the field together with a discussion on future steps to be taken in refractory disease.

KRAS and KIT Gatekeeper Mutations Confer Polyclonal Primary Imatinib Resistance in GI Stromal Tumors: Relevance of Concomitant Phosphatidylinositol 3-Kinase/AKT Dysregulation

Introduction KIT juxtamembrane oncogenic mutations (encoded by KIT exon 11) are found in 67% of GI stromal tumors (GISTs) and are inhibited potently by imatinib. Virtually all patients with these mutations therefore achieve clinical benefit when treated with imatinib. Imatinib resistance in KIT exon 11–mutant GISTs typically occurs after 18 to 24 months of response or disease stabilization, most often resulting from expansion of multiple tumor clones harboring secondary KIT kinase domain mutations. However, approximately 10% of patients with GISTs have primary imatinib resistance, defined by clinical progression within 3 to 6 months after initiating therapy. Such GISTs typically lack KIT and platelet-derived growth factor receptor alpha (PDGFRA) mutations, or contain particular mutations, such as PDGFRA D842V, that are intrinsically imatinib resistant. To our knowledge, this is the first report of polyclonal heterogeneity—including KRAS mutation— as a mechanism of primary imatinib resistance in a patient with GIST.

Imatinib Is Not a Potential Alternative Treatment for Uterine Leiomyosarcoma

To the Editor: We read with great interest the article written by Raspollini et al. ([1][1]). The authors studied a series including 32 cases of uterine leiomyosarcomas, which showed a 50% rate of positive immunostaining for KIT. Based on these results,the authors suggested the possibility of

Angiosarcoma of the Ovary: Is It Always a Lethal Disease?

A previously healthy 23-year-old woman was admitted to our emergency department (Vall d’Hebron University Hospital, Barcelona, Spain) with diffuse acute abdominal pain. A history of dysmenorrhea lasting 2 months was also reported. Laboratory data revealed hemoglobin of 8.1 mg/dL as the unique finding. An ultrasonography examination and a computed tomography scan of the abdomen and pelvis showed a right adnexal heterogeneous mass measuring 106 135 167 mm. Tumor markers such as CA-125, carcinoembryonic antigen, -human chorionic gonadotropin, and -fetoprotein were in the range of normality. Subsequently, the patient underwent a diagnostic laparotomy during which an ovarian malignancy was confirmed. Therefore, a debulking surgery for ovarian cancer was performed. An optimal surgical cytoreduction without macroscopic residual disease was achieved. The surgical specimen revealed a 14-cm-long mass in the left adnexa. A histologic evaluation determined that the ovarian parenchyma had been vastly replaced by a high-grade neoplasm composed of pleomorphic spindle cells with a high mitotic index, scattered necrosis, and hemorrhage. Some areas with vessel-like structures were discernible (Fig 1A). In addition, involvement of the sigma, rectum, vesicouterine peritoneum, omentum, and a peritoneal implant was confirmed. An immunohistochemistry profile demonstrated positive staining to vimentin, CD31 (Fig 1C), and CD34, as well as a lack of immunoreactivity to epithelial markers, corroborating the diagnosis of angiosarcoma. All of these findings were compatible with stage-IIIC cancer according to the International Federation of Gynecology and Obstetrics staging system. Given the intrinsic aggressiveness of this type of sarcoma, the work-up prior to the systemic treatment included a whole-body positron emission tomography/computed tomography study, which unexpectedly showed that the disease had spread to the pelvic and retroperitoneal lymph nodes, peritoneum, and liver (Figs 1B and 2A). After the diagnosis of recurrent angiosarcoma as metastatic disease, the patient was treated with six cycles of epirubicin 60 mg/m on days 1 through 2 and ifosfamide 1.8 g/m on days 1 through 5, with mesna and granulocyte colony-stimulating factor. According to RECIST (Response Evaluation Criteria in Solid Tumors), a partial response involving 90% tumor volume shrinkage was achieved after three cycles of treatment (Fig 1D), which

Emerging therapies for urothelial cancer.

Urothelial carcinoma is one of the leading causes of death in Europe and the United States. Despite its chemosensitivity, median overall survival for advanced disease is still nearly 1 year. Most second-line chemotherapeutic agents tested have been disappointing. Thus, new treatment strategies are clearly needed. This review focuses on emerging therapies in urothelial carcinoma. Results from recent clinical trials, investigating the activity of new generation cytostatic agents, as well as results from studies assessing the toxicity and efficacy of novel targeted therapies, are discussed. In this setting, anti-epidermal growth factor receptor, angiogenesis, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors account for the majority of phase I and II trials.

Novel Insights into the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GIST) have emerged as a compelling clinical and biological model for the rational development of therapeutic strategies targeting critical oncogenic events over the past two decades. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial driver for GIST tumor initiation, transformation, and cancer cell proliferation. Three tyrosine kinase inhibitors (TKIs) with KIT inhibitory activity – imatinib, sunitinib, and regorafenib – are approved to treat advanced GIST and have successfully exploited this addiction to KIT oncogenic signaling, demonstrating remarkable activity in a disease that historically had no successful systemic therapy options. However, GIST refractory to approved TKIs remain an unmet clinical need, as virtually all patients with metastatic GIST eventually progress on any given therapy. The main and best-established mechanism of resistance is the polyclonal expansion of multiple subpopulations harboring different secondary KIT mutations. The present review aims at summarizing current and forthcoming treatment directions in advanced imatinib-resistant GIST supported by a strong biological rationale.

Soft Tissue and Uterine Leiomyosarcoma

Leiomyosarcoma (LMS) is one of the most common subtypes of soft tissue sarcoma in adults and can occur in almost any part of the body. Uterine leiomyosarcoma is the most common subtype of uterine sarcoma. Increased awareness of this unique histology has allowed for the development of drugs that are specific to LMS and has begun to shed light on the similarities and possible unique aspects of soft tissue and uterine LMS. In this review, we summarize the current understanding of the epidemiology, diagnosis, genomics, and treatment options for LMS.

Hormone dependency in metastatic low-grade leiomyosarcoma following uterine smooth muscle tumour of uncertain malignant potential

Uterine leiomyosarcoma (ULMS) usually follows an aggressive clinical course, although a small proportion of ULMS exhibit a more indolent course, which in turn reflects heterogeneity within this disease and the need to identify and characterise this distinct subgroup. The role of hormone therapy in ULMS is yet to be elucidated. We report a patient with well-differentiated metastatic ULMS on hormone replacement therapy (HRT) at the time of the diagnosis. The withdrawal of the HRT led to a significant decrease in the tumour burden and symptomatic improvement. The patient further benefited from aromatase inhibitor treatment once the benefit from the HRT withdrawal reached a plateau. The present case report describes for the first time hormone-dependency for tumour growth in a ULMS. We propose that a subset of ULMS that follow a protracted/indolent course might depend on hormone stimulation for tumour proliferation, and antihormone treatment can therefore be useful in these patients.