(UroToday.com) The 2022 IKCS North American annual meeting featured a session on multidisciplinary team approaches to rare subtypes, including a presentation by Dr. David Braun discussing collecting duct, sarcomatoid, and rhabdoid subtypes of renal cell carcinoma (RCC). Differentiation can occur in the setting of clear cell or variant histologies, leading to sarcomatoid and rhabdoid histology. Sarcomatoid is made of malignant spindle cells and rhabdoid is composed of large epithelioid cells resembling rhabdomyoblasts:
Sarcomatoid and rhabdoid histologies occur in 10-15% of RCCs and can co-occur in the same tumor or be independent. Moreover, these aggressive histologies can represent <10% to >90% of the tumor and are associated with aggressive behavior. Previous work from Dr. Braun’s group has demonstrated that sarcomatoid and rhabdoid histologies have distinctive genomic features [1]. BAP1 and NF2 somatic alterations were significantly and consistently enriched in sarcomatoid and rhabdoid histologies compared to non-sarcomatoid and rhabdoid histology RCC, whereas KDM5C somatic alterations were significantly less frequent in sarcomatoid and rhabdoid histologies compared to non-sarcomatoid and rhabdoid histologies:
Additionally, Dr. Braun’s group found that 12 gene sets were upregulated in sarcomatoid and rhabdoid histologies compared to non-sarcomatoid and rhabdoid histologies RCC in the two cohorts independently, including cell cycle programs, genes regulated by MYC, and apoptosis programs:
High MYC expression significantly correlated with worse clinical outcomes in both the subset of patients with sarcomatoid and rhabdoid histologies in the anti-PD-1 (nivolumab) arm of the CheckMate cohort as well as the subgroup of stage IV sarcomatoid and rhabdoid histologies RCC patients in TCGA independently. Additionally, patients with non-sarcomatoid and rhabdoid histologies RCC, and MYC scores similar to those of sarcomatoid and rhabdoid histologies RCC had significantly worse outcomes in both the TCGA and CheckMate PD-1 cohorts:
Sarcomatoid and rhabdoid histologies have a “favorable” inflamed tumor-immune microenvironment, whereby CD8+ T cell infiltration, CD8+/CD4+ T cell ratio, activated/resting NK cell ratio, M1 macrophages, M1/M2 macrophage ratio, as well as the Th1 score were all significantly increased in sarcomatoid and rhabdoid histologies RCC in both cohorts independently:
Furthermore, the increased expression of tumor cell PD-L1 in sarcomatoid and rhabdoid histologies RCC tumors and the responsiveness of these tumors to PD-1 inhibitor monotherapy appeared to be independent of CD274 gene amplification.
Finally, Dr. Braun’s group showed that sarcomatoid and rhabdoid histologies respond best to immune-checkpoint inhibitor therapy in two independent cohorts:
Previous work from Tannir and colleagues assessing 139 patients with sarcomatoid RCC in CheckMate 214 [2] showed that median OS favored nivolumab + ipilimumab (NR, 95% CI 25.2- NE) versus sunitinib (14.2 months, 95% CI 9.3-22.9; HR 0.45, 95% CI, 0.3-0.7):
PFS benefits with nivolumab + ipilimumab were similarly observed (median 26.5 vs. 5.1 months; HR 0.54, 95% CI 0.33-0.86):
To summarize his discussion of sarcomatoid and rhabdoid histologies, Dr. Braun noted that these entities can occur with any underling histology and are historically associated with poor prognosis. Sarcomatoid and rhabdoid histologies have altered genetics, gene expression, and tumor microenvironment, and the definitive reason for the immune-checkpoint inhibitor responsiveness remains unknown. Immune checkpoint inhibitor therapy is the standard of care for advanced sarcomatoid and rhabdoid histologies, and nivolumab + ipilimumab is a reasonable choice given the high complete response rate and long follow-up.
Collecting duct carcinoma is also known as Bellini Duct carcinoma and is very rare, making up <1% of kidney tumors. These are more common in men (70%), with a high incidence in African Americans (23% of all cases). The clinical presentation is represented by a highly aggressive phenotype, frequently metastatic, and with a median overall survival of <1 year. Recurrently altered genes for collecting duct carcinoma include NF2, SMARCB1, and CDKN2A. Interestingly, the gene expression profiling is more comparable to upper tract urothelial carcinoma than RCC. With regards to treatment, there is no consensus, therefore multidisciplinary care is encouraged even in metastatic disease. Cytotoxic chemotherapy has activity in these patients with a phase II trial (n = 23) of gemcitabine + cisplatin or carboplatin reporting 1 complete response, 5 partial responses, and an objective response rate of 26%. The median PFS was 7.1 months and median overall survival was 10.5 months.
Dr. Braun concluded his presentation discussing collecting duct, sarcomatoid, and rhabdoid subtypes of RCC with the following take home messages:
- Anti-PD-1 based therapy is the standard of care for first-line management of advanced RCC with sarcomatoid and rhabdoid features
- Clinical trials should be considered for all patients with collecting duct carcinoma. Among standard of care, cytotoxic chemotherapy (gemcitabine + platinum) can be used
Presented by: David Braun, MD, PhD, Yale School of Medicine, New Haven, CT
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, Braun DA, Shukla SA, et al. Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma. Nat Commun 202112:808.
- Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin Cancer Res. 2021;27(1):78-86.