We report the experience with 2,000 consecutive patients with advanced cancer who underwent testing on a genomic testing protocol, including the frequency of actionable alterations across tumor ...types, subsequent enrollment onto clinical trials, and the challenges for trial enrollment.
Standardized hotspot mutation analysis was performed in 2,000 patients, using either an 11-gene (251 patients) or a 46- or 50-gene (1,749 patients) multiplex platform. Thirty-five genes were considered potentially actionable based on their potential to be targeted with approved or investigational therapies.
Seven hundred eighty-nine patients (39%) had at least one mutation in potentially actionable genes. Eighty-three patients (11%) with potentially actionable mutations went on genotype-matched trials targeting these alterations. Of 230 patients with PIK3CA/AKT1/PTEN/BRAF mutations that returned for therapy, 116 (50%) received a genotype-matched drug. Forty patients (17%) were treated on a genotype-selected trial requiring a mutation for eligibility, 16 (7%) were treated on a genotype-relevant trial targeting a genomic alteration without biomarker selection, and 40 (17%) received a genotype-relevant drug off trial. Challenges to trial accrual included patient preference of noninvestigational treatment or local treatment, poor performance status or other reasons for trial ineligibility, lack of trials/slots, and insurance denial.
Broad implementation of multiplex hotspot testing is feasible; however, only a small portion of patients with actionable alterations were actually enrolled onto genotype-matched trials. Increased awareness of therapeutic implications and access to novel therapeutics are needed to optimally leverage results from broad-based genomic testing.
Primary cardiac sarcomas are rare, aggressive, and usually lethal. Surgical management protocols are not defined because of the lack of extensive experience in treating these patients. In this study, ...we reviewed our outcomes with primary cardiac sarcoma, and we make recommendations regarding management.
Review of the Houston Methodist Hospital cardiac tumor database from 1990 to 2015 (25 years) yielded 131 primary cardiac evaluations of possible cardiac sarcoma. From these we identified 95 patients who underwent surgical excision. A computer search of cardiac sarcomas yielded 131 tumors that were coded as primary cardiac sarcoma or possible primary cardiac sarcoma. Retrospective data collection and clinical outcomes were evaluated for all 95 patients. Medical records and follow-up material were requested for all patients through clinic visits and contacting the physician of the patient, the hospital record department, and the cardiac tumor board after previous approval. The procedures were performed using an institutional review board-approved cardiac tumor protocol, and the patients gave full consent.
All 95 patients were diagnosed as having primary cardiac sarcoma by histologic appearance. Age ranged from 15 to 84 years at the time of presentation (mean, 44 years). Male patients made up 57% of the sample. The most common site for the cardiac sarcoma was the right atrium (37 patients) followed by the left atrium (31 patients). Postoperative 1-year mortality was 35% (33 patients). The most common tumor histologic type was angiosarcoma (40%) followed by spindle cell sarcoma (11%).
Primary cardiac sarcoma is a rare but lethal disease. Surgical intervention is associated with acceptable surgical mortality in this high-risk group of patients.
Angiosarcoma, epithelioid hemangioendothelioma, and Kaposi sarcoma are classified according to the line of differentiation that these neoplastic cells most closely resemble: the endothelial cell. ...Although these malignant vascular sarcomas demonstrate immunohistochemical and ultrastructural features typical of this lineage, they vary dramatically in presentation and behavior, reflecting oncologic mechanisms unique to each. Antineoplastic therapies offer significant benefit, but because of the rarity of these cancers, novel therapies are slow to develop, and treatment options for these cancers remain limited. Antiangiogenic approaches that have shown benefit in other malignancies have not fully realized their promise in vascular tumors, suggesting that these tumors do not depend entirely on either angiogenic growth factors or on neighboring endothelia that are affected by these agents. Nonetheless, translational studies have begun to unravel these distinct pathologies, identifying novel translocation products, targets of oncogenic virulence factors, and genomic mutations that hijack angiogenic signaling and drive malignant growth. Concurrently, an elaborate and highly regulated model of angiogenesis and lymphangiogenesis involving vascular endothelial growth factor-receptor tyrosine kinase and TGF-β and Notch pathways has emerged that informs treatment of these tumors as well as cancer in general. This review summarizes the literature on malignant vascular sarcomas in the context of current models of angiogenesis and, in light of recent clinical trial data, could help clinician-scientists generate novel therapeutic approaches.
To date, no specific marker exists for the detection of circulating tumor cells (CTC) from different types of sarcomas, though tools are available for detection of CTCs in peripheral blood of ...patients with cancer for epithelial cancers. Here, we report cell-surface vimentin (CSV) as an exclusive marker on sarcoma CTC regardless of the tissue origin of the sarcoma as detected by a novel monoclonal antibody. Utilizing CSV as a probe, we isolated and enumerated sarcoma CTCs with high sensitivity and specificity from the blood of patients bearing different types of sarcoma, validating their phenotype by single cell genomic amplification, mutation detection, and FISH. Our results establish the first universal and specific CTC marker described for enumerating CTCs from different types of sarcoma, thereby providing a key prognosis tool to monitor cancer metastasis and relapse.
Right-side heart sarcomas tend to be bulky, infiltrative, and difficult to treat. We have previously examined our outcomes with right heart sarcomas. Surgical resection with R0 margins showed better ...survival than positive margins but in only one third of cases could R0 status be achieved. The hypothesis for this study was that preoperative neoadjuvant chemotherapy would shrink the tumor margins and allow an increase in R0 resection, and hence, better survival.
Review of our cardiac tumor database from 1990 to 2015 yielded 133 primary cardiac sarcoma cases. Of these, we identified 44 patients with primary right-side heart sarcomas. Prospective database and retrospective data collection and clinical outcomes were evaluated for all 44 patients. Primary outcomes included 30-day mortality and morbidity and long-term survival. We used univariate and multivariate analyses to identify independent predictors of overall survival.
There were 27 male and 17 female patients with a mean age of 41 ± 12.7 years (range, 15 to 67). Seventy-three percent of the patients (32 of 44) received neoadjuvant chemotherapy. The most common tumor histology was angiosarcoma in 30 of 44 (68%). Thirty-day mortality was 4.5%, and statistically similar between the two groups. The median survival of patients who had R0 resection was 53.5 months compared with 9.5 months for R1. Neoadjuvant chemotherapy led to a doubling of survival (20 versus 9.5 months).
Neoadjuvant chemotherapy followed by radical surgery is a safe and effective strategy in patients with primary right-side heart sarcoma. This multimodality treatment enhances resectability (R0 resection) that translates into improved patient survival.
Background
Angiosarcomas are rare mesenchymal sarcomas that can present as primary cutaneous or noncutaneous disease. They express a variety of vascular endothelial growth factor receptors. The ...authors hypothesized that the treatment of angiosarcoma with pazopanib, a multikinase inhibitor with activity against vascular endothelial growth factor receptors, would result in disease response and prolonged disease stabilization.
Methods
This was an open‐label, phase 2 trial of pazopanib in patients who had incurable angiosarcoma. The co‐primary end points were response according to the Response Evaluation Criteria in Solid Tumors and progression‐free survival (PFS) at 3 months. The starting dose of pazopanib was 800 mg daily.
Results
Twenty‐nine patients were accrued between 2011 and 2018, and 22 patients were evaluable for response. Toxicities were similar to those identified in prior reports. There was one partial response (3%), and the clinical benefit rate (including complete responses, partial responses, and stable disease) was 48%, which was observed more frequently in patients who had cutaneous disease. The median PFS was 14.4 weeks, and the 3‐month PFS rate determined by Kaplan–Meier estimate was 54.6% (95% CI, 36.0%–82.9%), meeting the primary study objective. The Kaplan–Meier overall survival estimate was 16.1 months.
Conclusions
Pazopanib therapy in patients who had incurable angiosarcoma was associated with meaningful disease control, especially in those who had cutaneous disease with limited objective responses.
Lay Summary
Angiosarcoma is a rare cancer that can be found on the skin or in internal organs.
This study tested pazopanib, an oral targeted medication, to determine its benefit in patients with angiosarcoma who could not undergo the removal of their tumors by surgery.
Pazopanib treatment was safe, and no new side effects were reported.
The study showed that pazopanib controlled tumor growth in one half of patients at 3 months and was more common in angiosarcomas of the skin; it led to tumor shrinkage in a minority of patients (1 of 29).
Pazopanib therapy in incurable angiosarcoma was associated with meaningful disease control, especially in patients with cutaneous disease who had limited objective responses. Toxicity in this patient population was consistent with prior reports.
Complete surgical resection is the optimal treatment for malignant and complex benign left heart tumors. Anatomic inaccessibility and relationship with vital cardiac structures, makes complete ...resection of these complex tumors with standard surgical technique suboptimal. We employ autotransplantation in these cases to allow optimal anatomic exposure for complete resection and accurate reconstruction.
From 1998 to 2013, 35 cardiac autotransplants were done in 34 patients. Demographics, tumor histology, operative notes, hospital data, pathology reports, morbidity, and short and long-term mortality data were analyzed. Mortality follow-up was complete in all patients.
Of the 34 patients, there were 26 primary cardiac sarcomas, 1 isolated malignant melanoma metastasis to the intracavitary left ventricle, and 7 benign cases. The benign group had no operative deaths and 100% 2-year survival. Overall 30-day, 1-year, and 2-year procedural survival was 85%, 59%, and 44%, respectively. For primary malignant tumors, survival at 1 and 2 years was 46% and 28%. Among patients with primary malignant tumors, 19 had isolated cardiac autotransplantation and 7 had autotransplantation plus pneumonectomy. Operative mortality (and median survival) for cardiac autotransplantation with and without pneumonectomy was 43% (55 days) and 11% (378 days), respectively. For primary sarcomas, microscopically positive or negative resection margins did not impact survival.
Cardiac autotransplantation is a feasible and safe technique for resection of complex left-sided tumors when done as an isolated procedure in experienced centers. Addition of concomitant pneumonectomy carries a high rate of mortality and should be avoided. Further studies are needed to validate these results.
This review highlights the current body of knowledge regarding the role of the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) in angiosarcoma, epithelioid hemangioendothelioma ...(EHE), and hemangiopericytoma/solitary fibrous tumor (HPC/SFT). Therapeutic agents that target this pathway are reviewed.
Several phase II trials in advanced soft tissue sarcoma patients have investigated the efficacy of bevacizumab, an anti-VEGF antibody, as well as sunitinib, sorafenib, and pazopanib, VEGFR tyrosine kinase inhibitors (TKIs). Although response rates and progression-free survival periods were generally low, several angiosarcoma, EHE, and HPC/SFT patients demonstrated response or durable disease stabilization on these therapies. Biological mechanisms underlying the activity of these agents in angiosarcoma, EHE, and HPC/SFT are poorly understood. Some angiosarcoma tumors, however, harbor specific activating mutations in VEGFR2, which may be effectively targeted by VEGFR TKIs.
Inhibition of the VEGF/VEGFR pathway may be a rational and effective therapy for certain patients with angiosarcoma, EHE, and HPC/SFT, but more studies are needed to confirm these findings and to identify which patients will benefit from these agents.
Kaposiform hemangioendothelioma (KHE), a rare form of vascular neoplasm, is typically seen in children. In this paper, we report a unique case of KHE replacing bone marrow tissue mimicking ...myeloproliferative neoplasm with additional involvement in the lung, liver, and brain in a 60-year-old Caucasian woman. The patient was initially seen in the hematology department for the chief complaint of epigastric pain and anemia. Abdominal magnetic resonance imaging (MRI) revealed mild splenomegaly with iron deposition secondary to extramedullary hematopoiesis. Additional workup was inconclusive. Subsequent bone marrow and lung biopsies eventually revealed bone marrow with extensive grade 3 fibrosis and multiple foci of low-grade vasoformative neoplasm in the lung suggestive of KHE. Although rare, KHE can present as an aggressive disease with indolent behavior in adults and can be distinguished from other vascular malignancies based on histopathology and imaging findings.
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