Clinical Characteristics and Outcomes of TFE3-Rearranged/TFEB-Altered Renal Cell Carcinoma with Systemic Therapies, Including Tyrosine Kinase Inhibitors or Immune Checkpoint Inhibitors: An Observational Study

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J Urol Oncol. 2024;22(1):59-67

Publication date (electronic) : 2024 March 31

doi : https://doi.org/10.22465/juo.234600660033

Joohyun Hong¹, Ghee Young Kwon², Minyong Kang³, Seong Il Seo³, Se Hoon Park^,4

¹Division of Hematology-Oncology, Department of Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea

²Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

³Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

⁴Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Corresponding author: Se Hoon Park Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnaum-gu, Seoul 06351, Korea Email: hematoma@skku.edu

Received 2023 November 21; Revised 2024 February 16; Accepted 2024 February 19.

Abstract

INTRODUCTION

In 2020, there were more than 430,000 new cases of kidney cancer globally and 179,000 deaths globally [1]. Smoking, obesity, and hypertension are established risk factors for renal cell carcinoma (RCC), which is a heterogeneous disease comprised of several histological subtypes with different genetic and clinicopathological characteristics. Among the histologic subtypes of RCC, clear cell carcinoma is the most common, accounting for 75% to 90% of total kidney cancers [2]. The remaining 20% include non-clear cell RCCs, such as papillary, chromophobe, and other rare subtypes. A single patient with RCC can sometimes harbor more than one subtype.

The benefits of vascular endothelial growth factor receptor (VEGFR)-targeted therapies for advanced RCC have long been known in palliative settings. Although the therapeutic options for advanced RCC have expanded in recent years to include immune checkpoint inhibitors (ICIs), such as pembrolizumab and nivolumab, VEGFR-targeted tyrosine kinase inhibitors (TKIs) remain the backbone of most current treatment guidelines [3-6]. However, novel therapeutic strategies have primarily focused on clear cell RCC, and few studies have evaluated ICIs in non-clear cell RCC.

In the latest (2022) World Health Organization (WHO) Classification of Urinary and Male Genital Tumors, rare subtypes of RCC were newly categorized according to their molecular features [7]. Most notably, the 2022 WHO classification introduced a new category of molecularlydefined renal tumors in addition to a morphology-based classification of renal tumors.

Microphthalmia transcription factor family (MiTF) translocation RCC was first described as an Xp11 translocation RCC by the WHO classification in 2004 [2]. Xp11 translocation RCC is characterized by chromosomal translocations involving the TFE3 transcription factor gene located at the chromosome Xp11.2 locus. The fusions include PRCC, ASPL, and SFPQ/PSF as partner genes [8,9]. Meanwhile, t(6;11) translocation RCC is characterized by fusion between TFEB on chromosome 6p21.2 and Alpha/MALAT1 on chromosome 11q13 [10]. Because of the rarity of t(6;11) translocation RCC, and because it was believed that translocation RCCs with TFE3 or TFEB rearrangements share clinical and histopathological features, these tumors were previously grouped as MiTF/TFE translocation RCC [11,12]. However, as described above, TFE3-rearranged RCC and TFEB-altered RCC were separated into 2 distinct molecularlydefined subtypes in the 2022 WHO classification. MiTF/TFE translocation RCC represents up to 40% of all pediatric and adolescent RCCs and 1% to 4% of adult RCCs [13]. Due to the morphological overlap with more common subtypes, the frequency of translocation RCC in adults is probably underestimated in the absence of specific molecular studies [14].

Although more than a decade has passed since MiTF/TFE translocation RCC was recognized, effective therapies for these tumors represent an unmet medical need. Radical or nephron-sparing nephrectomy is considered for localized tumors, but there are few studies of systemic therapies in advanced settings. The available treatment options have all been based on the extrapolation of data from studies conducted almost exclusively in more common types of RCC. Due to the lack of a full understanding of molecular carcinogenesis, as well as the rarity of the disease, there have only been retrospective studies on VEGFR-targeted agents, mammalian target of rapamycin (mTOR) inhibitors, and ICIs [15-19].

Considering the difficulties in conducting a prospective study, we designed the present study to describe clinical and histopathological characteristics of patients with MiTF/TFE translocation RCC. We also investigated the clinical outcomes of existing systemic therapies.

MATERIALS AND METHODS

This was a single-center, retrospective study. Patients with MiTF/TFE translocation RCC were identified through an electronic medical record search of the patient database for the period between January 2004 and September 2021 in Samsung Medical Center (Seoul, Korea). We identified 32 eligible patients among a total of 37 patients diagnosed with MiTF/TFE translocation RCC, and 9 of those patients who were treated with systemic therapies were included in the present retrospective study (Fig. 1). Eligibility criteria were adult patients (20 years or older) with MiTF/TFE translocation RCC diagnosed by a dedicated genitourinary pathologist utilizing immunohistochemistry (IHC) and/or fluorescent in situ hybridization (FISH) and treatment with at least one dose of TKIs or ICIs.

Fig. 1.

Flowchart of patient inclusion. TFE3, transcription factor E3; TFEB, transcription factor EB.

The medical records of the patients were reviewed, and information on patient death was obtained from census data. The demographic, histological, and clinical characteristics of patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. The data cutoff date was July 2022. Targeted sequencing of primary tumors using TruSight Oncology 500 (Illumina, San Diego, CA, USA) was performed in 6 of the 9 eligible patients. Tumor samples from 3 patients who were lost to follow-up were not available for targeted sequencing.

We collected tumor samples from archival tissues obtained from surgery. Genomic DNA was extracted and the DNA quality and quantity were assessed in a similar manner to a previous study [20]. DNA libraries were prepared using the hybrid capture-based TruSight Oncology 500 Library Preparation Kit (Illumina) following the manufacturer’s instructions. Because this study was retrospective in nature, matched normal tissues were not available. The tumor mutational burden, microsatellite instability calls, germline variants, and called variants were generated and filtered in a similar manner to another study [21].

Because the sample was small, the endpoints of the present study were mainly descriptive in nature. Data were collected on patients’ baseline characteristics, including sex, age, International Metastatic RCC Database Consortium (IMDC) risk score, performance status, American Joint Committee on Cancer TNM stage, and metastatic sites, as well as primary treatment were collected. In addition, indices for clinical outcomes such as types of therapy, clinical responses, and survival status were also collected. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Statistical analyses were performed with R for Windows v4.2.0 software (R Core Team, Vienna, Austria; http://www.Rproject.org).

RESULTS

1. Demographic and Clinical Characteristics of Patients

As described in the Methods section, 32 patients diagnosed with MiTF/TFE translocation RCC between January 2004 and September 2021 were eligible for this study (Table 1). Their median age was 45.5 years (range, 20–67 years). Histologically, 26 patients (81.3%) had TFE3-rearranged RCC and only 1 patient (3.1%) had TFEB-altered RCC. The others (15.6%) were morphologically diagnosed with MiTF/TFE translocation RCC. Except for 5 patients (15.6%) whose electronic medical records were not available, curative or cytoreductive nephrectomy was performed in all 27 patients (84.4%), and 4 patients (12.6%) were diagnosed with metastatic disease at the time of initial diagnosis. Nine patients (28.1%) were treated with systemic therapy with TKIs, 2 (6.3%) of whom received simultaneous TKI and ICI treatment.

Table 1.

Baseline characteristics of 32 patients with MiTF/TFE translocation renal cell carcinoma

2. Patients Treated With TKIs or ICIs

All 9 MiTF/TFE translocation RCC patients treated with TKIs had TFE3-translocation RCC, with 8 patients having positive IHC staining for TFE3. The baseline characteristics before TKI or ICI administration are shown in Table 2. Five patients were men and 4were women. The median patient age was 47 years. Among the 9 patients, 4 were IMDC intermediate-risk, 3 were favorable-risk, and the other 2 were poor-risk before TKI or ICI administration. Five patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, and the other 4 patients had an ECOG performance status of 1. Eight patients had distant metastases before TKI or ICI administration, and only 1 patient exhibited a complete response (CR) after left radical nephrectomy with lymph node dissection. This patient underwent adjuvant TKI treatment for more than 10 regional lymph node metastases in surgical specimens, which indicated a high risk of relapse. Regarding metastasis sites before TKI or ICI administration, 4 patients had distant lymph node metastasis to the mediastinal or supraclavicular lymph nodes. There were also liver, lung, bone, soft tissue, and peritoneal seeding metastases. All 9 patients underwent nephrectomy with curative or cytoreductive intent. Among them, 7 underwent curative or cytoreductive nephrectomy, radiofrequency ablation, or metastasectomy before TKI administration. The other 2 underwent interim cytoreductive nephrectomy while receiving TKIs in combination with ICIs because of partial response (PR) to treatment.

Table 2.

Histological and clinical characteristics^* of 9 patients treated with systemic therapy (TKI or ICI)

3. Efficacy of TKIs and ICIs

Treatment with TKIs and ICIs and the resulting clinical outcomes are shown in Table 3. Among 9 patients, 6 were treated with sunitinib, 2 with axitinib and pembrolizumab, and the remaining patient received pazopanib as the first TKI exposure. Eight patients were treated with systemic therapy in a palliative setting, and 1 patient was treated with a TKI as adjuvant therapy. Seven received their first TKI or ICI exposure as first-line therapy, while the other 2 patients received their first TKI exposure as second-line treatment after an mTOR inhibitor or bevacizumab with interferon-α. The response to systemic therapy (TKI or ICI) and the duration of response were variable, ranging from CR to progressive disease (Fig. 2). Five of the 9 patients achieved an overall response to the TKI or ICI to which they were first exposed, with 4 exhibiting CR and 1 showing PR. Excluding 1 patient who was treated with TKI in the adjuvant setting, the overall response rate in 8 metastatic patients was 50% and the CR rate was 37.5%. During the median follow-up of 29 months, the median PFS was 21 months, the median OS was not reached, and 2 deaths occurred (Table 4, Fig. 3). The median PFS was not reached and 5 months for the CR group (3 patients) and non-CR group (5 patients), respectively (p=0.041). The median OS was not reached and 29 months for the CR group and non-CR group, respectively (p=0.32).

Table 3.

Treatment and clinical outcomes of 9 patients treated with systemic therapy (TKI or ICI)

Fig. 2.

Duration of clinical benefits. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

Table 4.

Clinical outcomes of systemic therapy (TKI or ICI)

Fig. 3.

Kaplan-Meier curves for progression-free survival (PFS) (A) and overall survival (OS) (B).

4. Tumor Mutational Profiles With Targeted Sequencing

Tumor samples from 6 of the 9 patients were available for targeted sequencing analysis with TruSight Oncology 500 (Illumina). The top 10 mutated genes among the 221 genes were FAT1, FANCA, SPTA1, ANKRD26, GEN1, NUTM1, ALK, FGFR4, MSH3, and EML4 (Fig. 4A). Each of these mutations existed in all 6 samples. While missense mutations were most common, there were also in-frame deletions and insertions, nonsense mutations, frameshift deletions and insertions, and splice site mutations (Fig. 4B).

Fig. 4.

Tumor mutational profiles based on targeted sequencing. The top 10 mutated genes (A) and variant classification (B).

DISCUSSION

Until recently, MiTF/TFE translocation RCC was defined as kidney cancers harboring gene fusions involving members of the MiT family of transcription factors, including TFE3 and TFEB. Subsequently, the latest WHO classification (2022) separated TFE3-rearranged RCC and TFEB-altered RCC as 2 distinct molecularly-defined entities. These entities may overlap with each other and with other RCC subtype morphologies [22]. These overlapping morphological features may lead to misdiagnosis if specific IHC analyses are missing.

TFE3-rearranged RCC comprises 20%–75% of RCCs in children and 1%–4% of adult RCCs, with a median age of onset of 33 years [23]. As explained above, the incidence of TFE3-rearranged RCC in adults may be underestimated due to their morphological overlap with more common RCC subtypes such as papillary and clear cell carcinoma. Similar to other RCC subtypes, one-third of all TFE3-rearranged RCC patients are asymptomatic and often incidentally diagnosed. TFEB-altered RCC is a much rarer subtype, accounting for only 0.02% of all kidney tumors and comprising 6p21.1 translocated RCC and 6p21.1 amplified RCC [23]. The t(6;11) translocation fuses the gene for TFEB, located on chromosome 6, resulting in overexpression of TFEB. As a TFE3-rearranged tumor, TFEB-altered RCC does not have distinctive microscopic findings. Clinically, most cases with TFE3-rearranged and TFEB-altered RCCs are found incidentally, with median PFS and OS of 72 and 198 months, respectively [24]. Retrospective studies have shown that age and T stage at presentation and the presence of metastases were associated with aggressive behavior [24,25].

In metastatic settings, although no consensus exists regarding the optimal systemic therapy for TFE3-rearranged/TFEB-altered RCC, clinicians often extrapolate from treatment guidelines for clear cell RCC. The juvenile RCC network reported a series of 11 patients treated with sunitinib in the first-line setting, with a median PFS of 8.2 months [17]. Choueiri et al. [16] reported another series of 15 adult patients with metastatic Xp11 translocation RCC who received sunitinib, with 3 responders (20%) and a median PFS of 7.1 months. Subsequently, several attempts have been made to explore the efficacy of systemic therapies in patients with non-clear cell disease [26-28]. In these prospective studies, although sunitinib appeared to have clinically meaningful activity in non-clear cell RCC, each study included a diverse mix of histologic subtypes and no information was available on the clinical benefits for each distinct subtype. Although our small sample size poses a limitation for evaluating the efficacy of firstexposure systemic therapy of TKI and ICI, the median PFS in 9 patients with metastatic TFE3-rearranged RCC was 21 months.

There is no consensus regarding predictive factors for choosing the best systemic therapy for an individual patient. Interestingly, activation of the NRF2 pathway, which has recently been identified as a hallmark of TFE3-rearranged RCC, was previously shown to be associated with resistance to VEGFR-targeted TKIs [29]. Moreover, MiTF/TFE translocation RCCs are known to harbor strong expression of MET. Cabozantinib, a TKI with activity against VEGFR-2 and MET, has been evaluated in patients with clear cell RCC and, more recently, in patients with MiTF/TFE translocation RCC [30-32]. In 2 retrospective studies of patients with TFE3-rearranged/TFEB-altered RCC treated with cabozantinib, the promising disease control rates of 63%–82% suggest a therapeutic role for this TKI [31,32]. Prospective and larger studies are warranted to confirm these results. In addition to MET, PD-L1 expression by tumor cells and tumor-infiltrating mononuclear cells was reported in 30% and 90% of TFE3-rearranged/TFEB-altered RCC cases, respectively, suggesting that ICIs may be beneficial in these populations [33]. In addition, programmed cell death ligand 1 (PD-L1) expression in MiTF/TFE translocation RCC has been reported to be associated with a poor prognosis [34,35]. Boilève et al. [15] reported the efficacy of ICIs in 24 MiTF/TFE translocation RCC patients, with a response rate of 17% and median PFS of 2.5 months. They also reported that mutations in bromodomain-containing genes (PBRM1 and BRD8) might be associated with clinical benefit for ICIs, consistent with a previous report on clear cell RCC [36]. In parallel with advancement of the standard of care for metastatic clear cell RCC, several combinations involving ICIs and TKIs are being investigated in non-clear cell RCC, including TFE3-rearranged/TFEB-altered RCC [3,4].

The small number of patients and retrospective nature are limitations of the present study. Four of 9 patients were diagnosed less than 2 years before the data search, which indicates that MiTF/TFE translocation RCC was diagnosed recently. This might have been due to greater clinical alertness to this rare disease, and vigorous suspicion might have led to a larger number of diagnoses. In addition, all 9 patients were diagnosed with TFE3-rearranged RCC rather than TFEB-altered RCC, and FISH was not performed routinely for diagnosis. This might be due to the much lower prevalence of TFEB-altered RCC than TFE3-rearranged RCC or the frequency of misdiagnosis of TFEB-altered RCC as conventional RCC or TFE3-rearranged RCC. In addition to IHC for several markers, performing FISH for TFE3 or TFEB gene rearrangements or gene sequencing for identifying gene amplification can help differentiate diagnoses. In addition, TKI treatment was not uniform among patients, although 6 of 9 patients were treated with sunitinib. The absence of normal samples for comparison is another limitation of our analysis of mutational profiles. Whole genome sequencing or whole exome sequencing might give more information. Moreover, the small number of tumor samples analyzed was insufficient to draw solid conclusions.

CONCLUSION

Despite these limitations, we demonstrated the efficacy of TKI or ICI treatment for MiTF/TFE translocation RCC, a rare disease. With the further development of novel TKIs in combination with ICIs in other RCCs—mainly the clear cell type—these treatments could be expanded to MiTF/TFE translocation RCC. Further studies evaluating the efficacy of this therapeutic strategy and identifying predictive markers for treatment are warranted.

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