Case ReportGNQ-209P Mutation in Metastatic Uveal Melanoma andTreatment Outcome

Nagla Abdel Karim,1 Ihab Eldessouki ,1 Ahmad Taftaf ,1 Deeb Ayham,1 Ola Gaber ,1

Abouelmagd Makramalla,2 and Zelia M. Correa3

1Department of Hematology-Oncology, University of Cincinnati, Cincinnati, OH, USA2Department of Interventional Radiology, University of Cincinnati, Cincinnati, OH, USA3Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, USA

Correspondence should be addressed to Ihab Eldessouki; ihab_del@yahoo.com

Received 28 November 2017; Accepted 11 March 2018; Published 4 April 2018

Academic Editor: Raffaele Palmirotta

Copyright © 2018 Nagla Abdel Karim et al. *is is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Metastatic prognosis in uveal melanoma is assessed by gene expression profiling (GEP) testing of the tumor cells, usually obtainedby fine needle aspiration (FNA). GEP has demonstrated high accuracy in distinguishing class I and II tumors, both havingdifferent metastatic potential. Transcriptomic studies identified distinct mutations including somatic mutations in GNAQ andGNA11, detected in more than 80%, and contribute to the upregulation of the mitogen-activated protein kinase (MAPK) pathwayand the development of uveal melanoma (UM). *e role of these mutations in treatment selection and possible benefit fromtargeted therapy are somewhat unclear. However, until the discovery of novel agents, local versus systemic therapies remainoptions for treatment that can still be considered for disease control in certain cases. We report a series of patients with metastaticUMwith distinct mutational profiles. One had significant liver metastases with provenGNQ-209Pmutation on tissue biopsy whileperipheral blood molecular profiling did not show these mutations. *e other three cases had no GNQ-209P mutation. All casesreceived nab-paclitaxel (Abraxane) as a treatment drug, and we record their responses to treatment and their molecular-profiling results.

1. Introduction

Uveal melanoma (UM) is significantly less common thancutaneous melanoma and has a distinct molecular patho-genesis. Meanwhile, it is the most common primary in-traocular tumor in adults [1]. Despite the high success rate ofdisease control with local therapy, the potential for de-veloping metastases remains high even after a prolongedperiod of remission [2–4]. *e predominant target organ formetastasis is the liver although disease involvement of theskin, bone, brain, and lungs has also been reported [5, 6].Key mutations in the disease are GNAQ and GNA11 mu-tations. It was reported that 83% of the cases have somaticmutations in GNAQ or GNA11 [7]. GNAQ gene is the genecoding for the alpha subunit of heterotrimeric G proteins.*e latter proteins couple seven-transmembrane domain

receptors to intracellular signaling machinery [8], and theyare composed of three subunits, namely, alpha, beta, andgamma. *e alpha subunit is the G-protein molecularswitch, activated when it is bound to guanosine triphosphate(GTP), and when GTP is hydrolyzed to guanosine di-phosphate (GDP), it is deactivated [9]. *e alpha subunit hasa key glutamine that contacts the GTP molecule, located atposition 209 (Q209) in Gαq and is substituted when mutatedto either leucine or proline [10–13]. At this point, the alphasubunit is locked in a constitutively active state, and itsGTPase activity is blocked [14–16]. Taxanes work by pre-venting microtubule disassembly, so the mitotic functions areinhibited, leading to cell death [17]. *ey have shown rea-sonable activity in several phase II studies [18]. Nab-paclitaxelis a solvent-free formula that renders the drug more com-petent in the treatment of UM. Multiple therapeutic

HindawiCase Reports in Oncological MedicineVolume 2018, Article ID 4256365, 5 pageshttps://doi.org/10.1155/2018/4256365

approaches for metastatic UM have been studied althoughnone has shown any impact on the overall survival, and thusstandard of care has not yet been established for these pa-tients. In our report, we present the case of a patient withmetastatic uveal carcinoma to the liver who was successfullytreated with nab-paclitaxel, allowing for recovery from life-threatening spontaneous tumor lysis.

2. Methods

GNAQ and GNA11 mutations were assessed by genomichybridization on paraffin-embedded blocks obtained fromthe primary tumor tissue. Mutations were followed up bycirculating tumor DNA in plasma using next-generationsequencing using serial blood samples.

3. Case Presentation

*is is a 75-year-old man with a history of choroidalmelanoma of the right eye diagnosed in 1984 and treated byradioactive Co-60 plaque. *irty years later, he presentedwith progressive abdominal distention, early satiety, andweight loss of 20 pounds over a period of 6 months. He wasseen by his primary care physician who requested a CT scanof the abdomen that showed a large hepatic mass measuring34 cm by 26 cm, replacing the majority of the liver withoutretroperitoneal or mesenteric lymphadenopathy (Figure 1).Hepatic tumor biopsy revealed metastatic melanoma con-sistent with his primary choroidal melanoma. While com-pleting his diagnostic workup, the patient developedgeneralized weakness prompting his hospital admission dueto acute renal failure, hyperkalemia, and spontaneous tumorlysis. He started hemodialysis promptly followed by theadministration of weekly nab-paclitaxel 150mg/m2 and thenreduced to 75mg/m2 thereafter due to severe neutropenia.*e patient recovered his renal function as serum creatinineimproved from 4.93mg/dl to 0.69mg/dl (normal values0.60–1.20mg/dl) and demonstrated clinical improvement ofhis generalized weakness, abdominal distention, and edemaof the legs after three doses of nab-paclitaxel. A repeatabdominal CT scan one month after the therapy revealed

a good response to treatment with significant decrease intumor burden. *is is donated by full clinical recovery andtotal resolution of tumor lysis manifestations. However,according to RECIST criteria, the response can be minimalfollowed bymaintained stable disease. CTscan of the abdomenafter 4 cycles of nab-paclitaxel revealed shrinkage of the hepaticlesion to 24×15 cm in maximum diameter (approximately 7%decrease in the largest lesion per RECIST criteria) (Figure 2).*is patient is still alive and continues to have excellentfunctional status, ECOG performance status of I, and no signsor symptoms of disease progression for 32 months now.

Our patient with this metastatic uveal melanoma withextensive liver metastases with GNQ-209Pmutation on thetissue biopsy (Figures 3 and 4) and undetectable mutationson the peripheral blood molecular profiling in serialfollow-up samples suggests marked response to nab-paclitaxel. *is can be understood by the dramatic tu-mor response on CT scans which was accompanied clin-ically by spontaneous tumor lysis syndrome followed byvery prolonged disease control up to 30 months indicatingnab-paclitaxel efficacy. All other patients with metastaticocular melanoma, who did not have the GNQ-209P mu-tation, did not respond and did not have prolonged sur-vival when treated with nab-paclitaxel.

Our patient has received 8 cycles of Abraxane withinitial minimal response followed by no increase and stabletumor size in the following imaging scans. In an attempt toachieve further response, the patient received an anti-PD-L1in a clinical trial for 9 cycles. No further reduction in tumorsize was achieved, and the patient was disqualified from thestudy after he developed sarcoidosis/interstitial pneumo-nitis. He was then restarted on Abraxane, achieving clinicaland radiological stabilization of his disease with no majortoxicities, and remains fully functional. He has received todate 12 cycles of Abraxane (in addition to the prior cycles ofAbraxane received initially).

4. Discussion

UM has a high potential for developing a rapidly progressivecourse despite local or systemic therapies [1]. Even with

Figure 1: Abdominal CT scan at diagnosis. Figure 2: CT scan 24 months after the treatment.

2 Case Reports in Oncological Medicine

several FDA-approved agents for advanced cutaneousmelanoma, there is a lack of agents that show survival benefitin patients with advanced UM. *is issue is likely twofoldfrom the rare occurrence of the disease itself as well as a lackof complete understanding regarding the pathogenesis andimmunobiology that underlies this disease process. Currentstudies are ongoing to uncover these uncertainties in hopesof ultimately identifying potentially treatable targets andmore effective treatments [19, 20]. Until a standard of care isestablished, however, existing treatment options must beapplied on a case-by-case basis [21, 22].

In metastatic disease, different approaches have beenstudied including surgical resection in suitable candidates inaddition to local versus systemic infusion of cytotoxic agents.A comprehensive review of the role of metastectomy in se-lected surgical candidates showed improved survival in pa-tients who had a complete liver metastases resection comparedto patients for whom a complete resection was not feasible[23]. Local therapies including the hepatic arterial infusion ofmelphalan or fotemustine revealed in randomized trial,a significant improvement in progression-free survival (PFS)but not overall survival when compared to the systemic in-fusion of the same agents [24]. In contrast, a retrospectivestudy from Mayo Clinic showed only improvement in overallsurvival among patients treated with different local therapiesin comparison to different systemic agents including bev-acizumab, ipilimumab, and kinase inhibitors [25]. Systemicchemotherapy options have shown minimal benefit in treat-ment. Single agents such as cisplatin or paclitaxel versus

combined agents such as the BOLD regimen (bleomycin +vincristine + lomustine + dacarbazine) plus recombinantinterferon alpha 2-b have been studied with no more than20% response rate (RR) and absence of survival advantages[7, 26]. A similar study to ours that was presented at theASCO annual meeting shows clinically useful responses intwo of four patients with metastatic ocular melanomatreated with nab-paclitaxel [27]. In terms of targeted ther-apy, the ability to understand the genetic characteristic ofUM has helped in identifying different mutations and keysignaling pathways that can permit therapeutic interventionat a site specific to the pathway abnormality. UM is geneticallycharacterized by frequent, mutually exclusive mutations inguanine nucleotide-binding protein G(q) subunit alpha(GNAQ) and guanine nucleotide-binding protein subunitalpha-11 (GNA11) which can be detected in 83% of patientswith UM [12]. GNAQ stimulates the mitogen-activatedprotein kinase (MAPK), which is parallel to the conse-quence of mutations in the BRAF or NRAS oncogenes incutaneous melanomas. Furthermore, GNAQ stimulates thetranscriptional coactivator YAP that is essential for UM cellproliferation. *e aforementioned MAPK pathway is highlyinterconnected with the PI3K/ACT pathway, and both ofthem converge on the same downstream targets. MEKinhibitor, PI3K inhibitor, mTOR inhibitor, and YAP in-hibitor each represent novel therapeutic target for UM, andstudies are ongoing to uncover the role of these agentseither as a single or dual inhibition approach in patientswith advanced disease or early disease associated with high-risk features [10, 20, 28].

Our patient presented with acute renal failure secondary tospontaneous tumor lysis, and there was an urgent need fordisease control, which was achieved by using systemic che-motherapy with nab-paclitaxel. *e absence of standard ofcare in these patients and the extrapolated data from the phaseIII trial of nab-paclitaxel when compared to dacarbazine [29]in patients with cutaneous melanoma led to the use of thisagent in our patient who was not a candidate for cisplatin. Inhis case, the tissue from the liver biopsy was insufficient to run

Figure 3: Liver biopsy (H&E).

Figure 4: Liver biopsy (MART).

Table 1: Different types of genomic mutations in patients withmetastatic melanoma of the liver.

Casenumber Age (years) Gender Genomic mutation

1 75 Male GNAQ-Q209P by tissue testing

2 77 Female GNAQ-Q209L by peripheralcirculating DNA

3 70 Female GNAQ-Q209L4 78 Female Kit H580y

Table 2: Comparison between GNAQ-Q209P and GNAQ-Q209L.

Mutations Location ofmutation

Frequency of mutations amongGNAQ-mutated primary uveal

melanomaGNAQ-Q209P Exon 5 ∼64%GNAQ-Q209L Exon 5 ∼33%

Case Reports in Oncological Medicine 3

molecular testing, so we used a liquid biopsy (circulatingtumor DNA) obtained from the patient, to search for genomicalterations that came back negative for mutations; however,subsequent liver biopsy revealedGNAQ exon 5Q209mutationwhere theGNA11mutation or amplification was not detected.

In comparison to this case (Case 1), we had other patients(Case 2, 3, and 4) in our institution, in whom a diagnosisof metastatic UM was made. All patients started ontreatment with nab-paclitaxel, but they had metastaticdisease that continued to progress. In patients (Cases 2 and3), a molecular testing of DNA circulating in the bloodrevealed GNAQ/Q209L mutation while our patient (Case 1)had GNAQ-Q209P (Tables 1 and 2). *is might draw ourattention that GNQ-209P might be a predictive marker ofsensitivity to nab-paclitaxel in metastatic uveal melanoma.

5. Conclusion

Although our understanding of the molecular underpinningsof UM continues to improve and certain targeted agents areshowing promise, genomic alteration studies might play a rolein treatment selection. As we see from the cases we present,GNAQ-Q209P and not Q209L mutation could be associatedwith a considerable disease control when treated with nab-paclitaxel chemotherapy. We suggest the implication of mo-lecular profiling with specific attention to the status of not onlyGNAQ but also the exon 209P or Q209L for personalized useof therapies in future clinical trials designed to treat patientswith metastatic UM. Such clinical trials are needed to provethe efficacy and survival advantages of nab-paclitaxel in pa-tients with metastatic UM and to study its role in comparisonto the evolving targeted or immunotherapeutic agents. Ingeneral, reports of rare and less commonly encountered casescan have a pivotal effect on the collective clinical experienceand drug research.

Conflicts of Interest

*e authors declare that they have no conflicts of interest.

Acknowledgments

*e authors thank their colleagues in the pathology de-partment who helped with this work.

References

[1] A. D. Singh, L. Bergman, and S. Seregard, “Uveal melanoma:epidemiologic aspects,” Ophthalmology Clinics of NorthAmerica, vol. 18, no. 1, pp. 75–84, 2005.

[2] J. Scotto, J. F. Fraumeni, and J. A. Lee, “Melanomas of the eyeand other noncutaneous sites: epidemiologic aspects,” Journal ofthe National Cancer Institute, vol. 56, no. 3, pp. 489–491, 1976.

[3] E. Kujala, T. Ma¨kitie, and T. Kivela¨, “Very long-termprognosis of patients with malignant uveal melanoma,” In-vestigative Opthalmology and Visual Science, vol. 44, no. 11,p. 4651, 2003.

[4] M. Diener-West, S. M. Reynolds, D. J. Agugliaro et al.,“Development of metastatic disease after enrollment in theCOMS trials for treatment of choroidal melanoma:

collaborative ocular melanoma study group report no. 26,”Archives of Ophthalmology, vol. 123, no. 12, pp. 1639–1643,2005.

[5] *e Collaborative Ocular Melanoma Study Group, “Assess-ment of metastatic disease status at death in 435 patients withlarge choroidal melanoma in the Collaborative Ocular Mel-anoma Study (COMS): COMS report no. 15,” Archives ofOphthalmology, vol. 119, no. 5, pp. 670–676, 2001.

[6] S. Bakalian, J. C. Marshall, P. Logan et al., “Molecular pathwaysmediating liver metastasis in patients with uveal melanoma,”Clinical Cancer Research, vol. 14, no. 4, pp. 951–956, 2008.

[7] C. D. Van Raamsdonk, K. G. Griewank, M. B. Crosby et al.,“Mutations in GNA11 in uveal melanoma,” New EnglandJournal of Medicine, vol. 363, no. 23, pp. 2191–2199, 2010.

[8] S. R. Neves, P. T. Ram, and R. Iyengar, “G protein pathways,”Science, vol. 296, no. 5573, pp. 1636–1639, 2002.

[9] D. Markby, R. Onrust, and H. Bourne, “Separate GTP bindingand GTPase activating domains of a G alpha subunit,” Science,vol. 262, no. 5141, pp. 1895–1901, 1993.

[10] C. D. Van Raamsdonk, V. Bezrookove, G. Green et al.,“Frequent somatic mutations of GNAQ in uveal melanomaand blue naevi,” Nature, vol. 457, no. 7229, pp. 599–602,2009.

[11] S. Lamba, L. Felicioni, F. Buttitta et al., “Mutational profile ofGNAQQ209 in human tumors,” PLoS One, vol. 4, no. 8, articlee6833, 2009.

[12] M. D. Onken, L. A. Worley, M. D. Long et al., “Oncogenicmutations in GNAQ occur early in uveal melanoma,” In-vestigative Opthalmology and Visual Science, vol. 49, no. 12,pp. 5230–5234, 2008.

[13] J. Bauer, E. Kilic, J. Vaarwater, B. C. Bastian, C. Garbe, andA. De Klein, “Oncogenic GNAQ mutations are not correlatedwith disease-free survival in uveal melanoma,” British Journalof Cancer, vol. 101, no. 5, pp. 813–815, 2009.

[14] C. A. Landis, S. B. Masters, A. Spada, A. M. Pace,H. R. Bourne, and L. Vallar, “GTPase inhibiting mutationsactivate the alpha chain of Gs and stimulate adenylyl cyclasein human pituitary tumours,” Nature, vol. 340, no. 6236,pp. 692–696, 1989.

[15] G. Kalinec, A. J. Nazarali, S. Hermouet, N. Xu, and J. S. Gutkind,“Mutated alpha subunit of the Gq protein induces malignanttransformation in NIH 3T3 cells,” Molecular and CellularBiology, vol. 12, no. 10, pp. 4687–4693, 1992.

[16] J. Sondek, D. G. Lambright, J. P. Noel, H. E. Hamm, andP. B. Sigler, “GTPase mechanism of Gproteins from the 1.7-Acrystal structure of transducin α - GDPAIF−4,”Nature, vol. 372,no. 6503, pp. 276–279, 1994.

[17] P. B. Schiff and S. B. Horwitz, “Taxol stabilizes microtubules inmouse fibroblast cells,” Proceedings of the National Academyof Sciences, vol. 77, no. 3, pp. 1561–1565, 1980.

[18] R. A. Leon-Ferre and S. N. Markovic, “Nab-paclitaxel inpatients with metastatic melanoma,” Expert Review of Anti-cancer 1erapy, vol. 15, no. 12, pp. 1371–1377, 2015.

[19] J. J. Luke, P. L. Triozzi, K. C. McKenna et al., “Biology ofadvanced uveal melanoma and next steps for clinical thera-peutics,” Pigment Cell and Melanoma Research, vol. 28, no. 2,pp. 135–147, 2015.

[20] S. S. Agarwala, A. M. M. Eggermont, S. O’Day, and J. S. Zager,“Metastatic melanoma to the liver: a contemporary and com-prehensive review of surgical, systemic, and regional therapeuticoptions,” Cancer, vol. 120, no. 6, pp. 781–789, 2014.

[21] N. A. Karim, J. Schuster, I. Eldessouki et al., “Pulmonarysarcomatoid carcinoma: University of Cincinnati experience,”Oncotarget, vol. 9, no. 3, 2018.

4 Case Reports in Oncological Medicine

[22] N. Karim, I. Eldessouki, M. Yellu, T. Namad, J. Wang, andO. Gaber, “A case study in advanced lung cancer patients withvimentin over expression,” Clinical Laboratory, vol. 63, no. 10,2017.

[23] J. F. Pingpank, M. S. Hughes, H. R. Alexander et al., “A phaseIII random assignment trial comparing percutaneous hepaticperfusion with melphalan (PHP-mel) to standard of care forpatients with hepatic metastases from metastatic ocular orcutaneous melanoma,” Journal of Clinical Oncology, vol. 28,no. 18, p. LBA8512, 2010.

[24] J. C. Moser, J. S. Pulido, R. S. Dronca, R. R. McWilliams,S. N. Markovic, and A. S. Mansfield, “*e Mayo Clinic ex-perience with the use of kinase inhibitors, ipilimumab, bev-acizumab, and local therapies in the treatment of metastaticuveal melanoma,” Melanoma Research, vol. 25, no. 1,pp. 59–63, 2015.

[25] L. E. Flaherty, J. M. Unger, P. Y. Liu, W. C. Mertens, andV. K. Sondak, “Metastatic melanoma from intraocular pri-mary tumors,” American Journal of Clinical Oncology, vol. 21,no. 6, pp. 568–572, 1998.

[26] T. Kivela, S. Suciu, J. Hansson et al., “Bleomycin, vincristine,lomustine and dacarbazine (BOLD) in combination withrecombinant interferon alpha-2b for metastatic uveal mela-noma,” European Journal of Cancer, vol. 39, no. 8,pp. 1115–1120, 2003.

[27] T. J. Smith, S. Temin, E. R. Alesi et al., “American Society ofClinical Oncology provisional clinical opinion: the integrationof palliative care into standard oncology care,” Journal ofClinical Oncology, vol. 30, no. 8, pp. 880–887, 2012.

[28] E. M. Hersh, M. Del Vecchio, M. P. Brown, and R. F. Kefford,“Phase 3, randomized, open-label, multicenter trial of nab-paclitaxel (nab-P) vs dacarbazine (DTIC) in previously un-treated patients with metastatic malignant melanoma(MMM),” Pigment Cell & Melanoma Research, vol. 25, p. 863,2012.

[29] P. J. Hesketh, M. G. Kris, E. Basch et al., “Antiemetics:American Society of Clinical Oncology clinical practiceguideline update,” Journal of Clinical Oncology, vol. 35, no. 28,pp. 3240–3261, 2017.

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