VOLUME 32 䡠 NUMBER 32 䡠 NOVEMBER 10 2014
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
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O N C O L O G Y
region of the tumor without significant cytologic atypia [H&E, ⫻400 optical magnification]; Fig 1C, high power view of tumor cells with significant atypia including enlarged, vesicular nuclei and prominent nucleoli [H&E, ⫻400]; Fig 1D, focus of single cell necrosis [H&E, ⫻100 optical magnification]; Fig 1E, mitotic figures [H&E, ⫻200, arrows point to mitoses]; Fig 1F, tumor cells with S100 expression by immunostain [S100, ⫻200 optical magnification]). One year later she had a recurrence within the surgical bed after an initial R0 resection. Subcentimeter lung nodules were noted on cross-sectional imaging. Resection of residual disease within the right scapula was performed confirming lymph node involvement. Several months later the lung nodules had enlarged. Lung metastatectomy confirmed pulmonary involvement. At the time of presentation at our center, she had disease noted in lung and in the soft tissues
Dramatic Response to Pazopanib in a Patient With Metastatic Malignant Granular Cell Tumor Case Report A 65-year-old woman with malignant granular cell tumor metastatic to lung, lymph node, and soft tissue presented for evaluation. Her performance status was excellent. Eighteen months previously she had resection of a 6.2 cm malignant granular cell tumor from the right periscapular area with no osseous involvement, or involvement of the glenohumeral joint (Fig 1A, low power view demonstrating nests of large cells with abundant eosinophilic cytoplasm [H&E, ⫻40 optical magnification]; Fig 1B, high power view of nests of tumor cells in a
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Fig 1. Journal of Clinical Oncology, Vol 32, No 32 (November 10), 2014: pp e107-e110
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on May 27, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
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by fluorescent in situ hybridization with an average of more than four copies per cell in 51% of cells examined. KRAS was not mutated by direct sequence analysis. We did not independently validate the microarray analysis since this was performed for clinical purposes and not on a research protocol. Dasatinib, an inhibitor of various receptor tyrosine kinases and nonreceptor tyrosine kinases such as SRC, was chosen as the initial systemic agent. Although she experienced minimal toxicity she developed objective progression on scans after two cycles. Next, pazopanib was initiated at 800 mg a day on a 28-day cycle. After two cycles, she exhibited objective signs of response. Before pazopanib (Fig 2A), computed tomography demonstrated multiple pulmonary nodules. After treatment (Fig 2B), nodules decreased in size or resolved. The axial and sagittal contrast-enhanced magnetic resonance imaging before therapy (Figs 3A and 3C) demonstrated avidly enhancing right axillary and chest wall masses surrounding and within the surgical bed. After therapy (Figs 3B and 3D), sites of disease showed decrease in size and internal necrosis. As seen in prior studies with pazopanib, our patient experienced an increase in systolic and diastolic blood pressures requiring initiation of antihypertensive therapy. She experienced diarrhea, which was controlled with loperamide HCl simethicone and tincture of opium. No other toxicities required medical treatment. At this time, after three cycles, the patient continues on pazopanib. The patient’s tumor response to pazopanib has been evaluated at 2-month intervals and, as of the fourth month, the tumors continue to decrease in size and contrast enhancement in both the soft tissues and lungs. Long-term follow-up data are pending.
Table 1. Overexpressed Genes and Signal Ratio Gene
Ratio
SRC MET VEGFA TOP2A GNRH1 PDGFC ABCG2 BRCA1 OGFR POLA1 VHL ASNS SSTR2 TYMS MSH2 LYN
6.89 4.19 3.80 3.02 2.93 2.92 2.75 2.71 2.55 2.39 2.23 2.11 2.04 2.03 1.80 1.68
surrounding the primary surgical bed. Due to the lack of known effective systemic treatments for this rare cancer, a Target Now assay (Caris Life Sciences, Phoenix, AZ) was performed on the original musculoskeletal primary tumor. The submitted specimens included 55 unstained slides. An Illumina-based whole genome (29K) microarray analysis was performed from formalin-fixed paraffin-embedded samples. Briefly, the process involves total RNA extraction from the selected samples followed by conversion to cDNA, and the final assay involves cDNA-mediated annealing, selection, extension, and ligation. Gene expression is compared between tumor samples and selected control tissues. This analysis revealed significant (P ⱕ .001) overexpression of 16 genes including SRC, MET, and VEGFA (Table 1). By the same microarray analysis, KIT, platelet-derived growth factor receptor alpha (PDGFRA), and platelet-derived growth factor receptor beta (PDGFRB) were not overexpressed. Increased gene copy number, but not amplification, of epidermal growth factor receptor was observed
A
Discussion Granular cell tumors, which are thought to be of schwann cell derivation,1 typically occur in the skin, soft tissue, and mucosal surfaces. The vast majority of granular cell tumors pursue a benign clinical course. Malignant granular cell tumors are exceedingly rare, representing less than 2% of granular cell tumors.2 Histologically, malignant granular cell tumors resemble their benign counterparts
B
Fig 2. e108
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Diagnosis in Oncology
A
B
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Fig 3.
and are composed of large tumor cells with abundant granular cytoplasm. Although the presence of metastasis represents the only definitive criterion for diagnosing malignancy, histologic criteria exist for distinguishing benign, atypical, and malignant granular cell tumors. The most widely accepted criteria entail evaluation of six histologic features: increased mitotic activity (greater than two mitoses per 10 high power fields), necrosis, tumor cell spindling, vesicular nuclei with prominent nucleoli, increased nucleus to cytoplasm ratio, and pleomorphism.3 The presence of three or more criteria is consistent with malignancy, while the presence of one to two defines an atypical granular cell tumor. Benign granular cell tumors lack these atypical features, or contain only focal pleomorphism. Malignant granular cell tumors are associated with an aggressive course, with 39% of patients dead of disease at 3 years.3 Half of the patients in this series experienced metastases and 32% had local recurrence. www.jco.org
Treatment for this rare disease involves surgical extirpation for localized disease. For patients with unresectable or metastatic presentation, options are limited. To the authors’ knowledge, there are no documented responses to systemic treatment for malignant granular cell tumor. In the absence of known effective treatment, we felt it was necessary to obtain objective molecular data before treatment initiation. Our microarray analysis revealed increased expression of SRC (6.89-fold change) and VEGFA (3.8-fold change). Dasatinib, a kinase inhibitor of the Src family (FYN, LCK, SRC, YES), c-kit, PDGFR ephrin receptors, and the BCR/ABL fusion protein, was initiated primarily because SRC was the most overexpressed gene in this patient’s tumor profiling analysis. Unfortunately, this was ineffective as evidenced by progression on first objective tumor assessment. Although the exact mode of resistance is unclear, it is possible that SRC inhibition led to an increase of other proliferative factors via feed-back loops © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on May 27, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
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Conley et al
or by coactivation of other important pathways such as the epidermal growth factor receptor pathway, which did exhibit over expression in this patient’s sample. More importantly, it could be that, while SRC was the most upregulated gene, it was not the primary driver in the survival of this particular tumor. Pazopanib, a potent receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3, which was recently approved for treatment of advanced soft tissue sarcomas, was used due to increased expression of VEGFA.4,5 The vascular endothelial growth factor (VEGF) pathway is critical to angiogenesis in the host and for tumor growth, invasion, and metastasis.6,7,8 VEGFA is a glycoprotein capable of binding to VEGFR-1 and VEGFR-2, which in turn leads to dimerization of the receptor and subsequent downstream activation of several key pathways including phospholipase C gamma-protein kinase/Raf-MAP kinase and PI3K.8 In a cell-free assay system, pazopanib has been shown to inhibit VEGFR2 with an IC50 of 0.03 mol/L, while the selectivity for Src was low with an IC50 of 3.09 mol/L.9 This is in contrast to dasatinib, which has high selectivity to SRC and weak selectivity for VEGFR-2.10 Even though pazopanib is an effective inhibitor of VEGF receptors, it also inhibits c-KIT, PDGFR-␣, PDGFR-, FGFR-1, FGFR-3, ITK, LCK, and c-FMS. Based on the Target Now analysis, KIT expression was low and c-KIT was negative by immunohistochemistry. PDGFRA was underexpressed compared with controls and PDGFRB revealed no change in expression. Furthermore, pazopanib and dasatinib are known to be potent inhibitors of c-kit and PDGFR and yet only pazopanib administration resulted in radiographic response. Therefore, it is unlikely that activity of this drug occurred solely due to inhibition of c-kit or PDGFR. The use of a molecular profiling assay may have been useful in this case because several overexpressed genes with therapeutic targets were identified. However, this may not reflect the tumor biology of other patients with malignant granular cell tumors. Furthermore, it is possible that the overexpressed genes were not the driving force behind the response to pazopanib, especially since this agent targets multiple tyrosine kinase receptors. Without appropriate cell lines or mouse models of this disease, it is difficult to ascertain the exact mode of action responsible for tumor response exerted by pazopanib in this case. Malignant granular cell tumor is an uncommon disease that is poorly understood with respect to its clinical course, biology, and treatment options. Here, to our knowledge, we report the first documented response of a malignant granular cell tumor to a systemic agent, specifically, a tyrosine kinase inhibitor (pazopanib). Even though a molecular profiling assay was used in this case, for a gene assay to be considered standard of care it should be validated in the target patient population. When available, clinical trials are the best tools to assess the efficacy of a given agent for a selected disease process. Unfortunately, clinical trials evaluating treatment for malignant granular cell tumor do not exist because of its rarity. Perhaps, however,
there is hope for patients afflicted with an orphan cancer such as this utilizing personalized medicine through genetic analysis.
Anthony P. Conley Moffitt Cancer Center, Tampa, FL
Stephanie Koplin Aurora Cancer Care, Milwaukee, WI
Jamie T. Caracciollo and Damon R. Reed Moffitt Cancer Center, Tampa, FL
Nicolas P. Webber Aurora Cancer Care, Milwaukee, WI
Steven Attia Mayo Clinic Florida, Jacksonville, FL
ACKNOWLEDGMENT
We thank Raheela Ashfaq, MD, Director of Oncologic Profiling, of Caris Life Sciences for her assistance with the manuscript. We also thank Scott Okuno, MD, and Vinod Ravi, MD, for their review of this article. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Fisher ER, Wechsler H: Granular cell myoblastoma: A misnomer—Electron microscopy and histochemical evidence concerning its schwann cell derivation and nature (granular cell schwannoma). Cancer 15:936-954, 1962 2. Enzinger RM, Weiss SW. Granular cell tumor, in Enzinger RM, Weiss SW (eds): Soft Tissue Tumors (ed 3). St Louis, MO, Mosby, 1995, pp 864-875 3. Fanburg-Smith JL, Meis-Kindblom JM, Fante R, et al: Malignant granular cell tumor of soft tissue: Diagnostic criteria and clinicopathologic correlation. Am J Surg Pathol 22:779-794, 1998 4. Jefferson E: FDA approves Votrient for advanced soft tissue sarcoma. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm302065.htm 5. Van Der Graaf WT, Blay JY, Chawla SP, et al: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): A randomized, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879-1886, 2012 6. Olsson AK, Dimberg A, Kreuger J, et al: VEGF receptor signaling: In control of vascular function. Nat Rev Mol Cell Biol 7:359-371, 2006 7. Eng L, Azad AK, Habbous S, et al: Vascular endothelial growth factor pathway polymorphisms as prognostic and pharmacogenetic factors in cancer: A systematic review and meta-analysis. Clin Cancer Res 18:4526-4537, 2012 8. Hicklin DJ, Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011-1027, 2005 9. Kumar R, Knick VB, Rudolph SK, et al: Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6:2012-2021, 2007 10. Lombardo LJ, Lee FY, Chen P, et al: Discovery of N-(2-chloro-6-methyl-phenyl)-2(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a Dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47:6658-6661, 2004
DOI: 10.1200/JCO.2012.47.1078; published online ahead of print at www.jco.org on February 18, 2014
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© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
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O N C O L O G Y
region of the tumor without significant cytologic atypia [H&E, ⫻400 optical magnification]; Fig 1C, high power view of tumor cells with significant atypia including enlarged, vesicular nuclei and prominent nucleoli [H&E, ⫻400]; Fig 1D, focus of single cell necrosis [H&E, ⫻100 optical magnification]; Fig 1E, mitotic figures [H&E, ⫻200, arrows point to mitoses]; Fig 1F, tumor cells with S100 expression by immunostain [S100, ⫻200 optical magnification]). One year later she had a recurrence within the surgical bed after an initial R0 resection. Subcentimeter lung nodules were noted on cross-sectional imaging. Resection of residual disease within the right scapula was performed confirming lymph node involvement. Several months later the lung nodules had enlarged. Lung metastatectomy confirmed pulmonary involvement. At the time of presentation at our center, she had disease noted in lung and in the soft tissues
Dramatic Response to Pazopanib in a Patient With Metastatic Malignant Granular Cell Tumor Case Report A 65-year-old woman with malignant granular cell tumor metastatic to lung, lymph node, and soft tissue presented for evaluation. Her performance status was excellent. Eighteen months previously she had resection of a 6.2 cm malignant granular cell tumor from the right periscapular area with no osseous involvement, or involvement of the glenohumeral joint (Fig 1A, low power view demonstrating nests of large cells with abundant eosinophilic cytoplasm [H&E, ⫻40 optical magnification]; Fig 1B, high power view of nests of tumor cells in a
A
B
C
D
E
F
Fig 1. Journal of Clinical Oncology, Vol 32, No 32 (November 10), 2014: pp e107-e110
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on May 27, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
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Conley et al
by fluorescent in situ hybridization with an average of more than four copies per cell in 51% of cells examined. KRAS was not mutated by direct sequence analysis. We did not independently validate the microarray analysis since this was performed for clinical purposes and not on a research protocol. Dasatinib, an inhibitor of various receptor tyrosine kinases and nonreceptor tyrosine kinases such as SRC, was chosen as the initial systemic agent. Although she experienced minimal toxicity she developed objective progression on scans after two cycles. Next, pazopanib was initiated at 800 mg a day on a 28-day cycle. After two cycles, she exhibited objective signs of response. Before pazopanib (Fig 2A), computed tomography demonstrated multiple pulmonary nodules. After treatment (Fig 2B), nodules decreased in size or resolved. The axial and sagittal contrast-enhanced magnetic resonance imaging before therapy (Figs 3A and 3C) demonstrated avidly enhancing right axillary and chest wall masses surrounding and within the surgical bed. After therapy (Figs 3B and 3D), sites of disease showed decrease in size and internal necrosis. As seen in prior studies with pazopanib, our patient experienced an increase in systolic and diastolic blood pressures requiring initiation of antihypertensive therapy. She experienced diarrhea, which was controlled with loperamide HCl simethicone and tincture of opium. No other toxicities required medical treatment. At this time, after three cycles, the patient continues on pazopanib. The patient’s tumor response to pazopanib has been evaluated at 2-month intervals and, as of the fourth month, the tumors continue to decrease in size and contrast enhancement in both the soft tissues and lungs. Long-term follow-up data are pending.
Table 1. Overexpressed Genes and Signal Ratio Gene
Ratio
SRC MET VEGFA TOP2A GNRH1 PDGFC ABCG2 BRCA1 OGFR POLA1 VHL ASNS SSTR2 TYMS MSH2 LYN
6.89 4.19 3.80 3.02 2.93 2.92 2.75 2.71 2.55 2.39 2.23 2.11 2.04 2.03 1.80 1.68
surrounding the primary surgical bed. Due to the lack of known effective systemic treatments for this rare cancer, a Target Now assay (Caris Life Sciences, Phoenix, AZ) was performed on the original musculoskeletal primary tumor. The submitted specimens included 55 unstained slides. An Illumina-based whole genome (29K) microarray analysis was performed from formalin-fixed paraffin-embedded samples. Briefly, the process involves total RNA extraction from the selected samples followed by conversion to cDNA, and the final assay involves cDNA-mediated annealing, selection, extension, and ligation. Gene expression is compared between tumor samples and selected control tissues. This analysis revealed significant (P ⱕ .001) overexpression of 16 genes including SRC, MET, and VEGFA (Table 1). By the same microarray analysis, KIT, platelet-derived growth factor receptor alpha (PDGFRA), and platelet-derived growth factor receptor beta (PDGFRB) were not overexpressed. Increased gene copy number, but not amplification, of epidermal growth factor receptor was observed
A
Discussion Granular cell tumors, which are thought to be of schwann cell derivation,1 typically occur in the skin, soft tissue, and mucosal surfaces. The vast majority of granular cell tumors pursue a benign clinical course. Malignant granular cell tumors are exceedingly rare, representing less than 2% of granular cell tumors.2 Histologically, malignant granular cell tumors resemble their benign counterparts
B
Fig 2. e108
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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Diagnosis in Oncology
A
B
C
D
Fig 3.
and are composed of large tumor cells with abundant granular cytoplasm. Although the presence of metastasis represents the only definitive criterion for diagnosing malignancy, histologic criteria exist for distinguishing benign, atypical, and malignant granular cell tumors. The most widely accepted criteria entail evaluation of six histologic features: increased mitotic activity (greater than two mitoses per 10 high power fields), necrosis, tumor cell spindling, vesicular nuclei with prominent nucleoli, increased nucleus to cytoplasm ratio, and pleomorphism.3 The presence of three or more criteria is consistent with malignancy, while the presence of one to two defines an atypical granular cell tumor. Benign granular cell tumors lack these atypical features, or contain only focal pleomorphism. Malignant granular cell tumors are associated with an aggressive course, with 39% of patients dead of disease at 3 years.3 Half of the patients in this series experienced metastases and 32% had local recurrence. www.jco.org
Treatment for this rare disease involves surgical extirpation for localized disease. For patients with unresectable or metastatic presentation, options are limited. To the authors’ knowledge, there are no documented responses to systemic treatment for malignant granular cell tumor. In the absence of known effective treatment, we felt it was necessary to obtain objective molecular data before treatment initiation. Our microarray analysis revealed increased expression of SRC (6.89-fold change) and VEGFA (3.8-fold change). Dasatinib, a kinase inhibitor of the Src family (FYN, LCK, SRC, YES), c-kit, PDGFR ephrin receptors, and the BCR/ABL fusion protein, was initiated primarily because SRC was the most overexpressed gene in this patient’s tumor profiling analysis. Unfortunately, this was ineffective as evidenced by progression on first objective tumor assessment. Although the exact mode of resistance is unclear, it is possible that SRC inhibition led to an increase of other proliferative factors via feed-back loops © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on May 27, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e109
Conley et al
or by coactivation of other important pathways such as the epidermal growth factor receptor pathway, which did exhibit over expression in this patient’s sample. More importantly, it could be that, while SRC was the most upregulated gene, it was not the primary driver in the survival of this particular tumor. Pazopanib, a potent receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3, which was recently approved for treatment of advanced soft tissue sarcomas, was used due to increased expression of VEGFA.4,5 The vascular endothelial growth factor (VEGF) pathway is critical to angiogenesis in the host and for tumor growth, invasion, and metastasis.6,7,8 VEGFA is a glycoprotein capable of binding to VEGFR-1 and VEGFR-2, which in turn leads to dimerization of the receptor and subsequent downstream activation of several key pathways including phospholipase C gamma-protein kinase/Raf-MAP kinase and PI3K.8 In a cell-free assay system, pazopanib has been shown to inhibit VEGFR2 with an IC50 of 0.03 mol/L, while the selectivity for Src was low with an IC50 of 3.09 mol/L.9 This is in contrast to dasatinib, which has high selectivity to SRC and weak selectivity for VEGFR-2.10 Even though pazopanib is an effective inhibitor of VEGF receptors, it also inhibits c-KIT, PDGFR-␣, PDGFR-, FGFR-1, FGFR-3, ITK, LCK, and c-FMS. Based on the Target Now analysis, KIT expression was low and c-KIT was negative by immunohistochemistry. PDGFRA was underexpressed compared with controls and PDGFRB revealed no change in expression. Furthermore, pazopanib and dasatinib are known to be potent inhibitors of c-kit and PDGFR and yet only pazopanib administration resulted in radiographic response. Therefore, it is unlikely that activity of this drug occurred solely due to inhibition of c-kit or PDGFR. The use of a molecular profiling assay may have been useful in this case because several overexpressed genes with therapeutic targets were identified. However, this may not reflect the tumor biology of other patients with malignant granular cell tumors. Furthermore, it is possible that the overexpressed genes were not the driving force behind the response to pazopanib, especially since this agent targets multiple tyrosine kinase receptors. Without appropriate cell lines or mouse models of this disease, it is difficult to ascertain the exact mode of action responsible for tumor response exerted by pazopanib in this case. Malignant granular cell tumor is an uncommon disease that is poorly understood with respect to its clinical course, biology, and treatment options. Here, to our knowledge, we report the first documented response of a malignant granular cell tumor to a systemic agent, specifically, a tyrosine kinase inhibitor (pazopanib). Even though a molecular profiling assay was used in this case, for a gene assay to be considered standard of care it should be validated in the target patient population. When available, clinical trials are the best tools to assess the efficacy of a given agent for a selected disease process. Unfortunately, clinical trials evaluating treatment for malignant granular cell tumor do not exist because of its rarity. Perhaps, however,
there is hope for patients afflicted with an orphan cancer such as this utilizing personalized medicine through genetic analysis.
Anthony P. Conley Moffitt Cancer Center, Tampa, FL
Stephanie Koplin Aurora Cancer Care, Milwaukee, WI
Jamie T. Caracciollo and Damon R. Reed Moffitt Cancer Center, Tampa, FL
Nicolas P. Webber Aurora Cancer Care, Milwaukee, WI
Steven Attia Mayo Clinic Florida, Jacksonville, FL
ACKNOWLEDGMENT
We thank Raheela Ashfaq, MD, Director of Oncologic Profiling, of Caris Life Sciences for her assistance with the manuscript. We also thank Scott Okuno, MD, and Vinod Ravi, MD, for their review of this article. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Fisher ER, Wechsler H: Granular cell myoblastoma: A misnomer—Electron microscopy and histochemical evidence concerning its schwann cell derivation and nature (granular cell schwannoma). Cancer 15:936-954, 1962 2. Enzinger RM, Weiss SW. Granular cell tumor, in Enzinger RM, Weiss SW (eds): Soft Tissue Tumors (ed 3). St Louis, MO, Mosby, 1995, pp 864-875 3. Fanburg-Smith JL, Meis-Kindblom JM, Fante R, et al: Malignant granular cell tumor of soft tissue: Diagnostic criteria and clinicopathologic correlation. Am J Surg Pathol 22:779-794, 1998 4. Jefferson E: FDA approves Votrient for advanced soft tissue sarcoma. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm302065.htm 5. Van Der Graaf WT, Blay JY, Chawla SP, et al: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): A randomized, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879-1886, 2012 6. Olsson AK, Dimberg A, Kreuger J, et al: VEGF receptor signaling: In control of vascular function. Nat Rev Mol Cell Biol 7:359-371, 2006 7. Eng L, Azad AK, Habbous S, et al: Vascular endothelial growth factor pathway polymorphisms as prognostic and pharmacogenetic factors in cancer: A systematic review and meta-analysis. Clin Cancer Res 18:4526-4537, 2012 8. Hicklin DJ, Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011-1027, 2005 9. Kumar R, Knick VB, Rudolph SK, et al: Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6:2012-2021, 2007 10. Lombardo LJ, Lee FY, Chen P, et al: Discovery of N-(2-chloro-6-methyl-phenyl)-2(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a Dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47:6658-6661, 2004
DOI: 10.1200/JCO.2012.47.1078; published online ahead of print at www.jco.org on February 18, 2014
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© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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