Renal Cell Carcinoma and Novel Therapies

Robert Alter, MD: We’re going to start off talking about the biology of renal cell carcinoma [RCC]. As we know, the most common histology for renal cell carcinoma is clear cell renal carcinoma. We’re going to talk about clear cell carcinoma since that is the most common disease that we see, the biology of which has evolved from our understanding dating back from the 1980s. There is increasing awareness of the complexity of clear cell renal cell carcinoma, which has multiple molecular profiles, each with unique biologic properties.

Sporadic clear cell renal cell carcinoma is associated with the loss of function and alterations of the VHL gene, which is characterized by neoangiogenesis and up-regulation of the hypoxia inducible factor [HIF].Wild-type VHL protein functions as a ubiquitous ligase participating in the upregulation of HIF in patients bearing HIF alterations. The resulting high levels of HIF result in upregulation of vascular endothelial growth factor, which activates VEGFR, which triggers the PI3K/Akt signaling cascade.

Downstream mTOR is activated and leads to the transcription of a variety of tumor promoting factors, resulting in increasing cellular migration and angiogenesis. It has been found that several drivers of tumor progression, including VEGFR and other transmembrane receptors, may potentially drive metastases including AXL and MET. These studies led to a therapeutic development of anti-VEGF and anti-mTOR agents in the treatment of clear cell renal cell carcinoma.

Improved understanding of T-cell biology has defined the role of immune checkpoints []in curbing immune responses to prevent autoimmunity while simultaneously allowing tumor growth escape. This led to the development of immune checkpoint inhibitors designed to remove the brakes of immune activation against tumors.

Robert Motzer, MD: Renal cell carcinoma is a malignancy that primarily affects individuals aged in their 40s and up. It is more common in men than women. The most well recognized risk factor for renal cell carcinoma is tobacco use. Renal cell carcinoma is comprised of a number of different malignancies. The most common of these is called clear cell carcinoma, which comprises between 70% and 80% of diagnosed kidney tumors. There’s a spectrum of other malignancies that arise from the kidney, and these are generally referred to as non–clear cell renal cell carcinoma, with the most common variance being papillary RCC or chromophobe tumors.

The initial presentation has most often been a hematuria that’s either observed by the patient, reported to the physician, or picked up by routine urinalysis. Other common presenting signs or symptoms are flank pain, or either an abdominal or flank mass. Historically, a triad of hematuria, flank mass, and abdominal pain were considered classic for renal cell carcinoma. However, because of our improvements in medical imaging and screening for various conditions, now the most common way this tumor is noticed is as an incidental finding on a radiograph that’s performed for some other reason.

The classic method of diagnosis has been to do ultrasounds to assess people with signs and symptoms of gall bladder disease, or sonograms or CT scans to investigate trauma or any other signs or symptoms. Nowadays, up to 60% of people who are diagnosed with kidney cancer will be diagnosed based on this so-called incidental finding. As a result of this new pattern of diagnosis, the tumors are often noticed at a lower stage and when they’re smaller, and are more amenable to surgical resection and cure. However, surgery remains the mainstay of therapy for kidney cancer and the only curative therapy. Still, a fair number of patients either present with metastasis, or about 30% will relapse following a nephrectomy, and all those patients will eventually require systemic therapy.

Transcript edited for clarity.