Antitumor Response of VEGFR2- and VEGFR3-Amplified Angiosarcoma to Pazopanib

Ravi, Vinod; Sanford, Eric M.; Wang, Wei Lien; Ross, Jeffrey S.; Ramesh, Naveen; Futreal, Andrew; Patel, Shreyaskumar; Stephens, P. J.; Miller, Vincent A.; Ali, Siraj M.

doi:10.6004/jnccn.2016.0058

Cited by 33 publications

(26 citation statements)

References 14 publications

(27 reference statements)

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“…Similarly, angiosarcomas lack standard evidence‐based therapies for recurrent disease and are enriched for 4q12amp . Clinical history was not available for our angiosarcoma cases, but orthogonal support for 4q12amp actionability has been seen in a previously reported case treated with pazopanib on the basis of KDR and FLT4 ( VEGFR3 ) amplification and subsequent durable response . Given the lack of rationally matched therapies for advanced sarcoma of all stripes, we believe that defining 4q12amp subset of sarcomas is an initial step in evaluating the targetability of this alteration for the benefit of these patients.…”

Section: Discussionmentioning

confidence: 96%

The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA

Dişel

Madison²,

Abhishek

et al. 2019

The Oncologist

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Purpose Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large‐scale analysis is lacking. We assess the pan‐cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon. Experimental Design Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186–315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases. Results Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6–344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months. Conclusion We define 4q12amp as a significant event across the pan‐cancer landscape, comparable to known pan‐cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy. Implications for Practice Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan‐cancer drug development strategy.

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Section: Discussionmentioning

confidence: 96%

The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA

Dişel

Madison²,

Abhishek

et al. 2019

The Oncologist

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“…The ANGIOTAX phase II trial suggested the utility of paclitaxel in advanced angiosarcomas [5] . Ravi et al report good response to treatment with pazopanib in a patient with angiosarcoma with amplification of vascular endothelial growth factor receptor (VEGFR) and that had not responded to sorafenib [19] .…”

Section: Discussionmentioning

confidence: 99%

Bilateral ovarian angiosarcoma arising from the mature cystic teratomas – A case report and review of the literature

Kúdela

Ňachajová

Biringer

et al. 2018

International Journal of Surgery Case Reports

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HighlightsWe present the first case of bilateral ovarian angiosarcoma arising from the mature teratomas.Due to widespread disease, we performed limited surgical procedure consisting of bilateral adnexectomy and omentectomy.This work summarizes the current knowledge in the diagnosis and treatment of angiosarcomas arising in the mature teratomas.Promising results are expected from the trials devoted to antiangiogenic strategies in treatment of aggressive sarcomas.

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“…Furthermore, it has been reported that positive immunohistochemical staining for VEGF occurs in 14% of primary angiosarcomas and of its 3 known receptors, VEGFR3 has been shown to be present in 50% of all angiosarcomas (5). Given the potential involvement of these signalling pathways in the pathogenesis of post-radiotherapy angiosarcoma, it seems reasonable to consider the use of VEGF antagonists such as bevacizumab (humanized monoclonal antibody targeting VEGF-A), sorafenib (an inhibitor of VEGFR1, VEGFR2, VEGRF3 among other receptors) (15), pazopanib (an inhibitor of VEGF2 and VEGF3) (16,17), apatinib (an inhibitor of VEGF2) (18) or even thalidomide (known to suppress VEGF) (19) in the treatment of angiosarcoma.…”

Section: Discussionmentioning

confidence: 99%

A radiation-induced and radiation-sensitive, delayed onset angiosarcoma arising in a precursor lymphangioendothelioma

et al. 2017

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An 83-year-old female was treated with mastectomy and postoperative radiotherapy for breast cancer 30 years prior to developing a new small patch of thickening and scaliness on her left upper back, within the previous radiotherapy field. Serial excision biopsies revealed this to be a lymphangioendothelioma with no suggestion of malignancy. In early 2006 the lesion began to enlarge and take on a more erythematous plaque-like appearance. She was reviewed by a specialist dermatologist and an excision biopsy revealed a low-grade cutaneous angiosarcoma; this was approximately 38 years after radiotherapy to this region, the longest reported period between irradiation and in-field angiosarcoma development (the previous being 16 years). To our knowledge, this is the first case of post-radiotherapy angiosarcoma with a diagnosed precursor lesion. The lesion was treated with surgical excision and adjuvant radiotherapy. After further in-and out of-field recurrences, low dose radiotherapy elicited a surprisingly rapid and complete response within the treated areas; this was unusual in that these tumours are characteristically radiation-resistant. The radiosensitive case we report here raises the possibility that radiation should be more widely considered in the therapy of this disease. Methods of treatment of this rare malignancy are discussed.

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Antitumor Response of VEGFR2- and VEGFR3-Amplified Angiosarcoma to Pazopanib

Abstract: This exceptional response to pazopanib treatment suggests that a subset of patients with angiosarcoma with genomic alterations in vascular signaling genes may respond well to pazopanib.

Cited by 33 publications

References 14 publications

The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA

The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA

Bilateral ovarian angiosarcoma arising from the mature cystic teratomas – A case report and review of the literature

A radiation-induced and radiation-sensitive, delayed onset angiosarcoma arising in a precursor lymphangioendothelioma

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