(UroToday.com) The 2022 IKCS North American annual meeting featured a session on multidisciplinary team approaches to rare subtypes, including a presentation by Dr. Pavlos Msaouel discussing renal medullary cancer. Renal medullary cancer is extremely aggressive and found predominantly in young African Americans with sickle cell trait or other sickle hemoglobinopathies. Additionally, it is more common in men (70%), is three times more likely to be found in the right kidney (~75% of cases), and is defined by loss of the SMARCB1 (INI1) protein. Dr. Msaouel notes this is a rare entity, but in the MD Anderson Cancer Center experience, it is estimated that there are 3-5 follow-up renal medullary cancer patients weekly and 2-3 new renal medullary cancer patients per month.
Work from Dr. Msaouel’s group suggests that high-intensity, but not moderate intensity, exercise may aggravate RBC sickling in the renal medulla of individuals with sickle cell trait.1 As follows shows skeletal muscle surface area (red) in individuals with metastatic renal medullary cancer versus control patients with other metastatic genitourinary malignancies matched by age and biological sex:
With regards to treatment, these tumors have no response to anti-VEGF TKIs (ie. sunitinib, axitinib, cabozantinib, lenvatinib) or mTOR inhibitors (ie. everolimus, temsirolimus). As such, platinum-based cytotoxic chemotherapy is the preferred first-line therapy. Carboplatin + paclitaxel has shown durable complete responses in 2/22 patients (9%) with metastatic renal medullary cancer, with 1 patient currently disease free 7 years and the other 4 years from initial diagnosis. There are several renal medullary cancer specific clinical trials:
- NCT03587662: targeting replication and proteotoxic stress (this trial has completed enrollment with n = 30 patients)
- NCT03274258: nivolumab + ipilimumab, which was stopped for futility at 10 patients
- NCT02396208: relatlimab + nivolumab, which is ongoing
Dr. Msaouel notes that there is a distinct lack of anti-PD-1 +/- CTLA-4 efficacy in renal medullary cancer as highlighted by the following two case studies:
Dr. Msaouel highlighted that work from his group has previously shown that renal medullary cancer harbors dysfunctional CD8+ T cells, representing an “exhausted” T cell phenotype with LAG-3 upregulation:2
Renal medullary cancer often aggressively recurs while patients are still recovering from radical nephrectomy, thus upfront chemotherapy is recommended for most patients, including those with localized disease. The exception to this recommendation is for those with isolated tumors <= 4 cm in greatest dimension and confined to the kidney. Cytoreductive radical nephrectomy should be considered if feasible based on response to systemic therapy, performance status, and surgical evaluation. On the basis of recent advances in the diagnosis, management, and clinical trial development for renal medullary cancer, a panel of experts met in October 2017 and developed updated consensus recommendations to inform clinicians, researchers, and patients.3 After safety and dosing information has been established in adults, phase II and III trials enrolling patients with renal medullary cancer should allow patients aged 12 years and older to be accrued. Patients with the very rare unclassified renal cell carcinoma with medullary phenotype variant should also be included in renal medullary cancer trials. As follows is the consensus recommendations for the management for renal medullary cancer and renal cell carcinoma, unclassified with medullary phenotype.
Work presented at this meeting from Dr. Blum suggests that CA-125 can be used to monitor disease response in 60-70% of patients with renal medullary cancer. Salvage therapies include gemcitabine + doxorubicin, which demonstrates activity in platinum refractory renal medullary cancer. Additionally, erlotinib + bevacizumab is clinically active post-cytotoxic chemotherapy and proteasome inhibition. Furthermore, EGFR inhibition, but not VEGF inhibition is a viable therapeutic target for renal medullary cancer. With regards to metastasis directed therapy, the hypothesis is that SMARCB1 loss, leads to an early fitness peak, followed by a clonal sweep, leading to monophyletic metastatic seeding, and progressing metastases serve as dissemination foci acting as independent tumors:2
When considering radiation therapy for renal medullary cancer, Dr. Msaouel notes that we must be aware of local failure and use wider radiation fields when possible. In part due to upregulation of replication stress, renal medullary cancer appears to be more radiation sensitive than typical clear cell RCC. As a rule of thumb: use wider fields and lower radiation therapy doses for renal medullary cancer versus clear cell RCC.
Dr. Msaouel concluded his presentation discussing renal medullary cancer with the following take home messages:
- Renal medullary carcinoma responds to cytotoxic chemotherapy but not to anti-angiogenic tyrosine kinase inhibitors or conventional immune checkpoint blockade
- Upfront platinum-based chemotherapy is recommended for most patients with renal medullary carcinoma, including those with localized disease
Presented by: Pavlos Msaouel, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, TX
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:
- Shapiro DD, Soeung M, Perelli L, et al. Association of High-Intensity Exercise with Renal Medullary Carcinoma in Individuals with Sickle Cell Trait: Clinical Observations and Experimental Animal Studies. Cancer (Basel). 2021 Nov 30;13(23):6022.
- Msaouel P, Malouf GG, Su X, et al. Comprehensive molecular characterization identifies distinct genomic and immune hallmarks of renal medullary carcinoma. Cancer Cell. 2020 May 11;37(5):720-734.
- Msaouel P, Hong AL, Mullen EA, et al. Updated Recommendations on the Diagnosis, Management, and Clinical Trial Eligibility Criteria for Patients with Renal Medullary Carcinoma. Clin Genitourin Cancer. 2019 Feb;17(1):1-6.