• Case describes a response to sunitinib in clear cell ovarian cancer. • Discussion of unique molecular characteristics of clear cell ovarian cancers; • Practical points regarding dosing and toxicity when using sunitinib discussed

Alifrangis, C

Fotopoulou, C

Gabra, H

Krell, J

Thornton, A

Gynecologic Oncology Reports

English

PubMed

Spiral - Imperial College Digital Repository

Gynecologic Oncology Reports 18 (2016) 42–44Contents lists available at ScienceDirectGynecologic Oncology Reportsj ourna l homepage: www.e lsev ie r .com/ locate /gynorCase reportResponse to sunitinib (Sutent) in chemotherapy refractory clear cellovarian cancerC Alifrangis a, A Thornton a, C Fotopoulou c, J Krell a,b, H Gabra a,b,⁎a Dept. of Medical Oncology, Hammersmith Hospital, United Kingdomb Division of Cancer, Imperial College London, United Kingdomc Dept. of Gynaecology, Imperial College London, United Kingdoma r t i c l e i n f oArticle history:Received 11 August 2016Received in revised form 19 September 2016Accepted 3 November 2016Available online 6 November 2016Keywords:Targeted therapyClear cellDrug resistance1. IntroductionClear cell ovarian cancer (OCCA) is an uncommon subtype of epithe-lial ovarian cancer accounting for less than 10% of clinical cases in mostreported cohorts (Fujiwara et al., 2016). Whereas the precursor cell ofthe more common high grade serous ovarian (HGS) cancer has beenhypothesised to be secretory epithelium of the distal fallopian tubethe precursor of clear cell ovarian cancer is less clear. The recent associ-ation of clear cell histology (Wentzensen et al., 2016) with previousareas of endometriosis has pointed towards an entirely different cellof origin and indeed molecular characterisation has confirmed this fun-damental disparity between HGS and OCCA.The poor response rates to cytotoxic chemotherapy in the setting ofadvanced disease in the order of 10–30% (Magazzino et al., 2011) andmolecular characteristics of these tumours (Anon, 2013) haveprompted investigators to propose treatment of OCCA with sunitinibmaleate, a multi-active RTK inhibitor with selectivity for PDGFRa,VEGFR and c-MET, as a potential therapeutic option in this disease(Friedlander et al., 2016). To our knowledge only one previously pub-lished report demonstrating activity of sunitinib in clear cell ovariancancer exists (Anglesio et al., 2011). This report illustrates a responseto sunitinib in a patient with parenchymal hepatic deposits and chemo-therapy refractory OCCA.⁎ Corresponding author at: Dept. ofMedical Oncology, Hammersmith Hospital, Du CaneRoad, W12 0HS London, United Kingdom.E-mail address: costi@doctors.org.uk (C. Alifrangis).http://dx.doi.org/10.1016/j.gore.2016.11.0012352-5789/© 2016 The Authors. Published by Elsevier Inc. This is an open access article under1.1. Case descriptionA 59 year old patient was discussed at the gynaecologic oncologymulti-disciplinary meeting having presented with abdominal disten-sionwith radiological features of an ovarianmalignancy. A CT scan dem-onstrated a complex 16 cm × 13 cmmass arising in the pelvis from theright ovary. Her baseline serum tumour marker ca125 was 34 U/ml Shehad no medical history of note and was previously fit and well. HerECOG performance status was 1. There was no family history ofmalignancy.A primary debulking procedure was carried out including Total ab-dominal hysterectomy, Bilateral salpingo-oophorectomy, omentectomyand peritoneal stripping, to no residual macroscopic disease. The histo-pathologic assessment of the tumour revealed a FIGO Stage IIIA2 clearcell ovarian carcinoma by virtue of omental involvement. There wasno background of co-existing endometriosis noted. A course of adjuvantchemotherapy with carboplatin and paclitaxel was prescribed but fol-lowing thefirst cycle of platinumdoublet therapy the patient developeda significantmyocardial infarction, and a worsening of her performancestatus to ECOG P2. Adjuvant treatment was then withheld and the pa-tient was placed on outpatient surveillance.15months later she reported increasing lethargy and abdominal dis-tension. A CT scan performed at this time demonstrated a recurrence ofher disease with multiple parenchymal liver deposits, the largest mea-suring 3 cm in diameter, peritoneal deposits and lymphadenopathy atthe porta hepatis. A modified retreatment regiment of platinum con-taining chemotherapywith nitrate cover was utilised. The patient toler-ated this well with no further cardiac events. Unfortunately after2 cycles a re-staging CT demonstrated progression in the size of thenodal disease and hepatic deposits - the largest lesion measuring5.5 cm in diameter.At this point sunitinib was obtained and the patient agreed to self-fund its off license use in the setting of chemotherapy refractory disease.Sunitinib was commenced at a dose of 50 mg od in the intermittent dos-ing schedule as per the Motzer et al. pivotal study in renal cell carcinoma(Motzer et al., 2007). After four weeks of treatment themain toxicity wasgrade I-II fatigue. Unfortunately the patientwas then admittedwith rectalbleeding and the sunitinib withheld. Colonoscopy and Oesophogastricduodenoscopy failed to identify a bleeding focus, and the bleeding settledwith conservativemanagement. However given the possible contributionof sunitinib, a decision was made that it should be discontinued. Duringthe CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Fig. 1. A) Pre treatment CT CAP demonstrating hepatic deposit measuring 55 mm. B) Following 4 weeks of sunitinib this now measures 25 mm.43C. Alifrangis et al. / Gynecologic Oncology Reports 18 (2016) 42–44this admission the patient underwent a re-staging CTwhich demonstrat-ed a reduction in the size and volume of the multiple hepatic parenchy-mal metastatic deposits compared to the pre treatment imaging. Thelargest of these reduced in size from 55–25 mmwith a concomitant im-provement in symptoms of right upper quadrant discomfort. A represen-tative image is shown in Fig. 1. The patient has now been off treatmentand on follow up for 2 months. She has unfortunately since declined inher performance status and no further treatment is planned. She is cur-rently being supported by the community palliative care team.2. DiscussionTo our knowledge this Is only the third report in the literature dem-onstrating that sunitinib monotherapy can provoke a response in che-motherapy refractory clear cell ovarian cancer. Pre-clinical data hasdemonstrated distinct molecular characteristics of these tumours,more similar in their somatic mutation burden to clear cell renal carci-noma than the more common high grade serous subtype. Specificallyin comparison to more common types of EOC, somatic mutations inp53 are usually absent, with high levels of activation of PI3Kinase path-way signalling, either through inactivation of PTEN or throughmissensevariants causing activation in PIK3CA. Other interesting mutationsenriched for in OCCA include inactivation of the chromatin remodellinggene ARID1A which is a member of the SWI/SNF complex, notably alsorecurrently inactivated in clear cell renal carcinoma (Friedlander et al.,2016; Jones et al., 2010; Rauh-Hain and Penson, 2008; Anon, 2013).There is a clear rationale to target angiogenesis and multiple RTKsgiven the overexpression of the IL6-HIF-STAT3 pathway in these can-cers compared to high grade serous ovarian cancer (Anglesio et al.,2011).Previous phase II studies of sunitinib in ovarian carcinomahave beenundertaken in unselected ovarian cancer histological groups. A phase IIstudy in relapsed epithelial ovarian/fallopian/Primary peritoneal cancer(Biagi et al., 2011) recruited 30 patients. Three patients had a measur-able response - all in the platinum sensitive population and all on inter-mittent rather than continuous lower dose (37.5 mg) dosing regimens.The AGO study group have since evaluated the 50 mg intermittent reg-imen compared to continuous dosing of 37mg in a phase 2 study in theplatinum resistant setting. 73 patients recruited into the study(Baumann et al., 2012) and in the non-continuous dosing group therewere 6 responses compared to 2 responses in the continuous group. In-terestingly in renal cell carcinoma the intermittent sunitinib dosing reg-imen has a confirmed efficacy signal over the continuous regimen(Motzer et al., 2012). One other published study has specifically exam-ined the role of sunitinib in OCCA where the above molecular findingsperhaps provide more of a biological justification than in other groupsof EOC. In the study reported by Bowtell and colleagues two partial re-sponses to sunitinib were reported in chemotherapy refractory OCCA,both in patients with large volume nodal or visceral disease outsidethe pelvis. A further study reported the short term response of a singlepatient to sunitinib in the fifth line setting (Rauh-Hain and Penson,2008). The eagerly awaited GOG254 sunitinib phase II study, althoughnot published has been presented in abstract form. This demonstratedan overall response rate of 7% in OCCA. Given the pre-clinical data andencouraging reports of responses in chemotherapy refractory patientssuch as that presented here this is clearly disappointing. One could spec-ulate that a biomarker for a sensitive subgroup exists, but this has notyet been elucidated. It may be that alternative or combination strategiesare necessary to improve on the response rates in the GOG254 studyand recent data has however demonstrated other avenues that maybe clinically relevant to extend this efficacy spectrum of small moleculeinhibitors in this disease. The epistatic relationship between the SWI/SNF complex and PIK3CA mutations in OCCA have been shown con-verge on and drive IL-6 signalling and a panPI3K inhibitor has shown ef-ficacy in pre-clinical models of OCCA (Chandler et al., 2015).Furthermore a recent paper demonstrated a novel synthetic lethal rela-tionship between inhibition of the EZH2 methyltransferase in ARID1Amutant tumours (Bitler et al., 2015). A strategy to target IL-6 usingmonoclonal antibodies such as the approved therapy for rheumatoid ar-thritis Tocilizumab has just entered early stage trials in ovarian cancer(Dijkgraaf et al., 2015) and one could foresee its particular applicabilityin OCCA given the data presented above.In terms of practical use of this agent the report presented here alsohighlights the specific toxicities that treating oncologists should beaware of, specifically thewell reported complication of gastro-intestinalbleeding events. In our patient this necessitated stopping the drug de-spite an impressive response in the burden of hepatic parenchymal me-tastases. It must be noted that this is an unusual toxicity with the mostcommon adverse events seen being fatigue, diarrhea, nausea and dia-stolic hypertension (Motzer et al., 2012). It is useful to note that in thepivotal studies in renal cancer the discontinuation rate due to AE's isaround 15% with approximately 40% of patients requiring dose adjust-ment to manage these toxicities.In summary sunitinib used off license in clear cell histology has demon-stratedmeaningful and encouraging responses in patients with otherwisechemotherapy refractory disease. This has not however been replicatedwidely in a recently reported phase II study. In the absence of validatedbiomarkers to identify responders to sunitinibnovel strategies are urgentlyneeded. Early data exists for alternative small molecule inhibitors whichmay give hope in this population of chemo-refractory patients.Consent and conflict of interest statementsInformed consent for publication of this casewas obtained inwritingfrom the patient prior to publication.44 C. Alifrangis et al. / Gynecologic Oncology Reports 18 (2016) 42–44None of the authors has any conflicting interests regarding thismanuscript.ReferencesAnglesio, M.S., et al., 2011. IL6-STAT3-HIF signaling and therapeutic response to the an-giogenesis inhibitor sunitinib in ovarian clear cell cancer. Clin. Cancer Res. 17 (8),2538–2548.Baumann, K.H., et al., 2012. A phase II trial (AGO 2.11) in platinum-resistant ovarian can-cer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage,schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosinekinase inhibitor monotherapy. Ann. Oncol. 23 (9), 2265–2271.Biagi, J.J., et al., 2011. A phase II study of sunitinib in patients with recurrent epithelialovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group study.Ann. Oncol. 22 (2), 335–340.Bitler, B.G., et al., 2015. Synthetic lethality by targeting EZH2methyltransferase activity inARID1A-mutated cancers. Nat. Med. 21 (3), 231–238.Chandler, R.L., et al., 2015. Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling. Nat.Commun. 6, 6118.Dijkgraaf, E.M., et al., 2015. A phase I trial combining carboplatin/doxorubicin with toci-lizumab, an anti-IL-6R monoclonal antibody, and interferon-alpha2b in patientswith recurrent epithelial ovarian cancer. Ann. Oncol. 26 (10), 2141–2149.Friedlander, M.L., et al., 2016. Molecular profiling of clear cell ovarian cancers: identifyingpotential treatment targets for clinical trials. Int. J. Gynecol. Cancer 26 (4), 648–654.Fujiwara, K., Shintani, D., Nishikawa, T., 2016. Clear-cell carcinoma of the ovary. Ann.Oncol. 27 (Suppl. 1), i50–i52.Jones, S., et al., 2010. Frequent mutations of chromatin remodeling gene ARID1A in ovar-ian clear cell carcinoma. Science 330 (6001), 228–231.Magazzino, F., et al., 2011. Surgical and medical treatment of clear cell ovarian cancer: re-sults from the multicenter Italian Trials in Ovarian Cancer (MITO) 9 retrospectivestudy. Int. J. Gynecol. Cancer 21 (6), 1063–1070.Motzer, R.J., et al., 2007. Sunitinib versus interferon alfa inmetastatic renal-cell carcinoma.N. Engl. J. Med. 356 (2), 115–124.Motzer, R.J., et al., 2012. Randomized phase II trial of sunitinib on an intermittent versuscontinuous dosing schedule as first-line therapy for advanced renal cell carcinoma.J. Clin. Oncol. 30 (12), 1371–1377.The Cancer Genome Atlas Research Network, 2013. Comprehensive molecular character-ization of clear cell renal cell carcinoma. Nature 49 (7456), 43–49.Rauh-Hain, J.A., Penson, R.T., 2008. Potential benefit of sunitinib in recurrent and refracto-ry ovarian clear cell adenocarcinoma. Int. J. Gynecol. Cancer 18 (5), 934–936.Wentzensen, N., et al., 2016. Ovarian cancer risk factors by histologic subtype: an analysisfrom the ovarian cancer cohort consortium. J. Clin. 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Response to sunitinib (Sutent) in chemotherapy refractory clear cell ovarian cancer

Response to sunitinib (Sutent) in chemotherapy refractory clear cell ovarian cancer

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