(UroToday.com) The 2022 IKCS North American annual meeting featured a session on multidisciplinary team approaches to rare subtypes, including a presentation by Dr. Srinivas Viswanathan discussing translocation type subtypes of renal cell carcinoma (RCC). Dr. Viswanathan notes that translocation RCC is an aggressive type of non-clear cell RCC, representing ~1-5% of all RCCs. It is primarily characterized by gene fusions (translocations) involving a member of the MiT/TFE transcription factor family, which is usually TFE3 or TFEB. It is also now recognized as a distinct subtype of RCC by the World Health Organization.
Wild type MiT/TFE proteins come from the family of 4 bHLH/LZ transcription factors, including TFE3, TFEB, MITF, and TFEC. They bind to promoters of lysosomal biogenesis and autophagy genes, with localization/activity being regulated by nutrient status. Oncogenic MiT/TFE rearrangements are most often involving TFE3 (rarer: TFEB, MITF), with the fusion partner usually being an RNA-binding protein. TFEB amplifications also occur and are molecularly/clinically distinct, making up ~2-5% of adult and 30-40% of pediatric kidney cancer:
The median age of translocation RCC is ~40 years of age (for both TFE3 and TFEB entities), representing ~15% of RCCs amongst young adults. The female to male predominance is ~2:1 and is associated with prior exposure to chemotherapy, representing a secondary malignancy. Lymph node metastases predominate for translocation RCC and the incidence may be underestimated due to morphological overlap with other RCC subtypes. Translocation RCC can mimic other common subtypes of RCC given their wide histologic spectrum with many different architectural and cytologic features possible, most commonly papillary architecture with epithelioid clear cells and abundant psammoma bodies. This histology stains PAX8+, CK7-, and CK20-, in addition to melanocyte markers potentially being positive (Melan-A and HMB45), and cathepsin K being positive in ~50% of cases. Immunohistochemistry for TFE3 protein can detect overexpressed nuclear TFE3 fusion, but the positive predictive value is poor; the caveat is that there can be false positives from detection of native TFE3 and detection is highly fixation dependent. Break-apart FISH is highly sensitive and specific, with the caveat that split signals can be very close in cases of fusions rising via intrachromosomal inversion:
Next generation sequencing can effectively detect TFE3 or TFEB fusions, however the caveat is that TFE3/B is not always included in targeted panels. Genomically, there are few alterations in translocation RCCs aside from the MiT/TFE fusion, with TFE3 being the most often involved in fusion. Importantly, activation of the NRF2 pathway is a defining feature with TGFb, MET, and metabolic/proliferative signaling representing other downstream pathways.
With regards to outcomes and treatment patterns in translocation RCC, Dr. Viswanathan’s group retrospectively assessed metastatic RCC patients from the Dana-Farber/Harvard Cancer Center, identifying 734 patients with clear cell RCC, 97 patients with papillary RCC, 23 patients with chromophobe RCC, and 19 patients with translocation RCC [1]. Patients with translocation RCC were identified on the basis of positive TFE3 FISH or strongly positive TFE3 immunohistochemistry when FISH was not available. Among this cohort, translocation RCC patients had significantly worse outcomes than did patients with the other major histologies of RCC:
Among 52 patients in a multicenter retrospective analysis of translocation RCC patients treated with cabozantinib, Thouvenin et al. [2] found that the proportion of patients who achieved an objective response was 17.3%, including 2 complete responses and 7 partial responses. For 26 (50%) patients, stable disease was the best response, and with a median follow-up of 25.1 months (IQR 12.6-39), the median PFS was 6.8 months (95%CI 4.6-16.3) and median OS was 18.3 months (95%CI 17.0-30.6):
Multicenter retrospective studies assessing outcomes of translocation RCC patients treated with immune checkpoint inhibitors suggest that the response rate is ~15-17%, disease control rate is ~29-30%, and median PFS for patients during their first immune checkpoint inhibitor treatment is ~2.5 months. Extracting from prospective trials, the combination of cabozantinib + nivolumab (n = 2 translocation RCCs) resulted in 1 of 2 objective responses, the combination of atezolizumab + bevacizumab (n = 5 translocation RCCs) resulted in 1 of 5 objective responses, and the combination of pembrolizumab + lenvatinib (n = 5 translocation RCCs) resulted in 3 of 5 objective responses.
Dr. Viswanathan concluded his presentation discussing translocation type subtypes of RCC with the following take home messages:
- Translocation RCC can be frequently misdiagnosed as other subtypes of RCC, thus accurate diagnosis requires clinical suspicion and molecular testing
- There is no clear treatment guideline tailored to the biology of this subtype and molecularly targeted therapies for translocation RCC remain a major unmet medical need
Presented by: Srinivas R. Viswanathan, MD, PhD, Dana-Farber Cancer Institute, Boston, MA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 International Kidney Cancer Symposium (IKCS) North America, November 4-5, Austin, Texas, USA
References:
- Bakouny Z, Sadagopan A, Ravi P, et al. Integrative clinical and molecular characterization of translocation renal cell carcinoma. Cell Rep. 2022;38(1):110190.
- Thouvenin J, Alhalabi O, Carlo M, et al. Efficacy of cabozantinib in Metastatic MiT family translocation renal cell carcinomas. Oncologist 2022 Aug 18;158.