Vinod Ravi

Feasibility of Large-Scale Genomic Testing to Facilitate Enrollment Onto Genomically Matched Clinical Trials

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Recurrent PTPRB and PLCG1 mutations in angiosarcoma

Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.

Inhibiting the VEGF-VEGFR pathway in angiosarcoma, epithelioid hemangioendothelioma, and hemangiopericytoma/solitary fibrous tumor

Purpose of review 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. Recent findings 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. Summary 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.

Universal Marker and Detection Tool for Human Sarcoma Circulating Tumor Cells

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.

Outcomes after definitive treatment for cutaneous angiosarcoma of the face and scalp

The aim of the present analysis was to retrospectively evaluate outcomes in patients with cutaneous angiosarcoma of the face/scalp treated curatively with surgery, radiation therapy (RT), or a combination of surgery and RT.

Treatment of tenosynovial giant cell tumor and pigmented villonodular synovitis

Purpose of review To review recent developments in the molecular pathogenesis of tenosynovial giant cell tumor (TGCT) or pigmented villonodular synovitis (PVNS) and its therapeutic implications. Recent findings TGCT or PVNS is a benign clonal neoplastic proliferation arising from the synovium characterized by a minor population of intratumoral cells that harbor a recurrent translocation. These cells overexpress CSF1, resulting in recruitment of CSF1R-bearing macrophages that are polyclonal and make up the bulk of the tumor. Inhibition of CSF1R using small molecule inhibitors such as imatinib, nilotinib or sunitinib can result in clinical, radiological and functional improvement in the affected joint. Summary Currently, surgery remains the treatment of choice for patients with TGCT/PVNS. Localized TGCT/PVNS is managed by marginal excision. Recurrences occur in 8–20% of patients and are easily managed by re-excision. Diffuse TGCT/PVNS tends to recur more often (33–50%) and has a much more aggressive clinical course. Patients are often symptomatic and require multiple surgical procedures during their lifetime. For patients with unresectable disease or multiple recurrences, systemic therapy using CSF1R inhibitors may help delay or avoid surgical procedures and improve functional outcomes.

Localized and metastatic myxoid/round cell liposarcoma: Clinical and molecular observations

Myxoid liposarcoma (MLPS), a disease especially of young adults with potential for local recurrence and metastasis, currently lacks solid prognostic factors and therapeutic targets. The authors of this report evaluated the natural history and outcome of patients with MLPS and commonly deregulated protein biomarkers.

The role of chemotherapy in advanced solitary fibrous tumors: a retrospective analysis

BackgroundPatients with advanced solitary fibrous tumors (SFTs) have a poor prognosis; treatment options for recurrent disease are particularly limited. Several novel targeted agents have recently shown promise against advanced SFTs, but the relative efficacy of new agents is difficult to assess because data on the efficacy of conventional chemotherapy for SFTs are limited. We thus sought to estimate the efficacy of conventional chemotherapy for SFTs by reviewing data on tumor response to therapy and progression-free survival from SFT patients who received this therapy.MethodsWe retrospectively analyzed the clinical outcomes of 21 patients with grossly measurable, advanced SFTs (unresectable metastatic disease or potentially resectable primary tumors) who received conventional chemotherapy and follow-up at The University of Texas MD Anderson Cancer Center between January 1994 and June 2007. Best tumor response to therapy was assessed using the Response Evaluation Criteria In Solid Tumors 1.1. The Kaplan-Meier method was used to estimate median progression-free survival (PFS) duration.ResultsOf 21 patients, 4 received more than 1 regimen of chemotherapy, for a total of 25 treatments. Doxorubicin-based chemotherapy was given in 15 cases (60%), gemcitabine-based therapy in 5 cases (20%), and paclitaxel in 5 cases (20%). First-line chemotherapy was delivered in 18 cases (72%). No patients had a complete or partial response, 16 (89%) had stable disease, and 2 (11%) had disease progression. Five patients (28%) maintained stable disease for at least 6 months after first-line treatment. The median PFS duration was 4.6 months. The median overall survival from diagnosis was 10.3 years.ConclusionConventional chemotherapy is effective in controlling or stabilizing locally advanced and metastatic SFTs. Our findings can serve as a reference for tumor response and clinical outcomes in the assessment of novel treatments for SFTs.

Surgical Treatment of Primary Cardiac Sarcomas: Review of a Single-Institution Experience

BACKGROUND 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. METHODS 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. RESULTS 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%). CONCLUSIONS Primary cardiac sarcoma is a rare but lethal disease. Surgical intervention is associated with acceptable surgical mortality in this high-risk group of patients.

When patients and families feel abandoned

PurposePatients with serious illness derive a sense of security by forming strong, healing relationships with their providers. These bonds are particularly strong in life-threatening illnesses, such as cancer, which carry the stigma of death and suffering. These strong relationships create expectations in patients that are not necessarily shared by their clinicians. Providers often focus on treating disease and emphasize technically excellent, “evidence-based” practice while failing to fully appreciate the power of the patient–provider relationship. In contrast, vulnerable patients expect much more than technical competence, including open and clear communication, security, continuity, and access. Patients are often left feeling abandoned when their providers do not meet their expectations, even when their care is technically sound.Methods/resultsIn this paper, we describe scenarios that can lead to feelings of abandonment and discuss strategies to avoid and respond to them.ConclusionsThese strategies can help us maintain healing relationships with our patients by maintaining their trust, confidence, and satisfaction. Cultivating relational aspects of medical practice requires an interchange and takes time. Experienced doctors know this and continue to do so because being present and staying with the patient during difficult times is a pillar of moral and ethical training and a fundamental attribute of a good physician.