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  Table of Contents  
Year : 2019  |  Volume : 56  |  Issue : 3  |  Page : 274-275

TSC1/2 mutations as markers of response to everolimus in metastatic renal cell carcinoma: A case study

1 Department of Medical Oncology, Fortis Hospital, Bengaluru, Karnataka, India
2 Department of Clinical Genomics and Bioinformatics, Positive Bioscience, Mumbai, Maharashtra, India

Date of Web Publication19-Jul-2019

Correspondence Address:
Linu A Jacob
Department of Medical Oncology, Fortis Hospital, Bengaluru, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_732_18

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 » Abstract 

We report a case of a 67-year-old man with pazopanib-resistant metastatic renal cell carcinoma (mRCC) who showed an exceptional response to everolimus. Furthermore, this patient had TSC1 and TSC2 mutations. Only a subset of patients with mRCC respond to mTOR inhibitors and emerging evidences indicate that TSC1 and TSC2 mutations could be markers of response to mTOR inhibition. The current case study supports these accruing evidences.

Keywords: Everolimus, metastatic renal cell carcinoma, mTOR inhibitors, TSC1/2 mutations

How to cite this article:
Jacob LA, Shafi G. TSC1/2 mutations as markers of response to everolimus in metastatic renal cell carcinoma: A case study. Indian J Cancer 2019;56:274-5

How to cite this URL:
Jacob LA, Shafi G. TSC1/2 mutations as markers of response to everolimus in metastatic renal cell carcinoma: A case study. Indian J Cancer [serial online] 2019 [cited 2022 Jun 26];56:274-5. Available from:

 » Background Top

Mammalian target of rapamycin (mTOR) inhibitors is an option in patients with metastatic renal cell carcinoma (mRCC) who show resistance and a variable response to first line agents such as pazopanib.[1],[2] However, only a subset of patients with mRCC respond to mTOR inhibitors necessitating identification of reliable predictive markers of response.[3] The current case adds to data that are in accrual for the above contexts.

 » Case Presentation Top

A 67-year-old man who underwent left radical nephrectomy for renal cell carcinoma about 15 years back, presented with an insidious onset of gradually progressive pain about 5 months ago; ECOG performance status was 1 at baseline visit. There was pallor but no icterus, clubbing, cyanosis, or lymphadenopathy. Vital parameters were normal. Per abdomen, the liver was palpable 8 cm below the right costal margin in the mid-clavicular line. Respiratory system examination revealed reduced air entry with reduced movements in the right clavicular, supraclavicular, and suprascapular regions. Other systemic examinations were normal.

Chest X-ray showed right apical soft tissue opacity measuring 7 × 6.5 cm. CT thorax confirmed the right upper lobe mass of 6.7 cm near the apex with an erosion of right 1st and 2nd ribs and also revealed a small mass in left lower lobe and another 14 cm mass in the liver. Fine-needle aspiration from the liver mass confirmed metastatic clear cell carcinoma. On cardiac evaluation, the left atrium was dilated and there was trivial mitral regurgitation with good ejection fraction (68%). There was no evidence of local recurrence in left renal fossa on PET-CT [Figure 1].
Figure 1: Recurrence of metastatic renal cell carcinoma 15 years after nephrectomy with metastases in lung and liver

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The patient was initiated on pazopanib 800 mg/day along with bisphosphonates and received palliative radiotherapy to the rib lesions. There was a partial response to pazopanib treatment. Oral mucositis and anorexia were managed conservatively. After about 6 months, the patient developed a scalp nodule and a subsequent fine-needle aspiration cytology suggested metastatic clear cell carcinoma. In view of the progression, pazopanib was discontinued and everolimus 10 mg/day was initiated. The patient was monitored closely for adverse effects. Oral mucositis (Grade 1), hyperpigmentation of the skin of the legs and feet, and pedal edema were observed within the first month of treatment and were managed with supportive measures. A reassessment PET-CT after 6 months of everolimus treatment revealed partial response. Everolimus 10 mg/day was continued. Repeat PET-CT scans at 13 months, 20 months, and 32 months confirmed the persistent response [Figure 2]. Post completion of around 50 months of therapy on everolimus, the patient died in June 2017, due to progression of disease.
Figure 2: Stable response seen with Everolimus 10mg/day OD

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Because of the notable response to everolimus, we hypothesized that this patient's tumor may be characterized by mutations of the mTOR pathway. A comprehensive gene profiling using TEST® assay (Positive Bioscience, Mumbai, India) revealed 35 pathogenic genomic alterations, characterized by 21 somatic single-nucleotide variants including 5 splice-site variants and 4 frame-shift insertions/deletions. The mutations in TSC1 (Ile653Thrfs), TSC2 (Glu92Serfs) that lead to uncontrolled activation of the mTOR pathway were detected [Table 1].
Table 1: Oncogenic genomic alterations found in the patient

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 » Discussion Top

The current case confirms the findings of Uchida et al., that late recurrences (>5 years) of mRCC following nephrectomy may be low as compared to early recurrences (<5 years) but not rare.[4] Thus, it is important to ensure a careful follow-up for delayed recurrence in patients who are free of recurrence for more than 5 years after surgery for a primary lesion.

A number of evidences possibly and at least partly explain the response of this pazopanib-resistant patient to everolimus. Pazopanib-mediated blockage of the VEGF receptor results in hypoxia. The anti-angiogenic consequence of VEGF receptor blockade may lead to regression of blood vessels and an increase in HIF-1a levels through the mTOR pathway.[5] HIF-1a is known to upregulate VEGF genes in the tumor microenvironment. Interestingly, mTOR inhibition offsets the production of VEGF through complementary inhibition of the PTEN-AKT-mTOR pathway.[6] Another important adaptive mechanism of resistance to pazopanib is upregulation of fibroblast growth factor 2 (FGF2). FGF2 activates the FGF receptor inducing angiogenesis through the mTOR signaling pathway, along with several other pathways. Abrogating the mTOR pathway ameliorates angiogenesis induced by FGF2.

Along with a response to everolimus, the patient of the current study also had TSC1/2 mutations. Loss of TSC1/2 function is known to activate the mammalian target of rapamycin complex 1 (mTORC1) pathway.[7] Thus, it appears that TSC1/2 mutations may be putative markers of everolimus response in patients with mRCC. In a recent study, Kwiatkowski et al. note that TSC1 or TSC2 mutations were more common in mRCC patients who experienced clinical benefit from mTOR inhibitors than in those with rapid progression.[3]

Overall, functional studies to confirm the oncogenic role of particular TSC1/2 mutation along with additional data for the prognostic value of these mutations in predicting response to everolimus (and other mTOR inhibitors) and mRCC recurrence following nephrectomy are warranted and essential.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

Afriansyah A, Hamid AR, Mochtar CA, Umbas R. Targeted therapy for metastatic renal cell carcinoma. Acta Med Indones 2016;48:335-47.  Back to cited text no. 1
Buti S, Leonetti A, Dallatomasina A, Bersanelli M. Everolimus in the management of metastatic renal cell carcinoma: An evidence-based review of its place in therapy. Core Evid 2016;11:23-36.  Back to cited text no. 2
Kwiatkowski DJ, Choueiri TK, Fay AP, Rini B, Thorner AR, de Velasco G, et al. Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin Cancer Res 2016;22:2445-52.  Back to cited text no. 3
Uchida K, Miyao N, Masumori N, Takahashi A, Oda T, Yanase M, et al. Recurrence of renal cell carcinoma more than 5 years after nephrectomy. Int J Urol 2002;9:19-23.  Back to cited text no. 4
Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008;8:592-603.  Back to cited text no. 5
Wan X, Helman LJ. The biology behind mTOR inhibition in sarcoma. Oncologist 2007;12:1007-18.  Back to cited text no. 6
Humar R, Kiefer FN, Berns H, Resink TJ, Battegay EJ. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 2002;16:771-80.  Back to cited text no. 7


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  [Table 1]

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