The most important breakthrough in kidney-cancer biology was the identification of the Von Hippel-Lindau (VHL) gene in patients presenting with hereditary multifocal clear cell renal cell carcinomas (CCRCCs). Dr. Linehan explained the key genetic-linkage experiments performed to locate the disease gene to the short arm of chromosome 3. In 1993, the seminal paper linking the VHL mutation to hereditary CCRCC was published, and the next step was to assess whether the same mutated gene was seen in patient with sporadic CCRCC. In a study reported in 1994, the VHL gene was found to have mutated in over 90% of sporadic CCRCCs. Over the following years, the VHL pathway was further elucidated, and key functions of the VHL protein were established along with potential pathways for tumorigenesis. The key factor of kidney-cancer formation was the upregulation of the HIF-α protein, which causes the upregulation of several angiogenic pathways (vascular endothelial growth factor and platelet-derived growth factor). Several targeted therapies have been developed to block several of these pathways, which have the changed the treatment landscape for metastatic RCC.
Dr. Linehan also discussed some clinical pearls in the treatment of patients with multifocal hereditary CCRCC, advocating for enucleation partial nephrectomy to optimize parenchymal preservation, given the high local recurrence rate in this patient group. He also favored active surveillance in this group, with the trigger for excision being mass growth past 3 cm. Dr. Linehan also emphasized the safety of this method, with no patients, to date, progressing to metastatic disease following this algorithm.
With regardto nonclear cell kidney cancer, he commented on the discovery of hereditary papillary RCC (HPRCC). This disease is highly penetrant, with linkage genetic analysis leading to identifying the disease gene to be located in chromosome 7, more specifically in the MET oncogene. The MET oncogene is a tyrosine kinase protein that is activated in HPRCC and forms numerous papillary renal tumors. A tyrosine kinase inhibitor was the clear next step in his patients’ treatment. A phase-II clinical study at the National Institutes of Health, patients with HPRCC started on foretinib, a vascular endothelial growth factor receptor and MET inhibitor, showing significant regression of renal lesions and avoiding surgical excision in a large number of patients.
A more aggressive form of hereditary papillary kidney cancer that was unrelated to the MET mutation was also identified at the National Institutes of Health. Further work led to discovering two genetic translocations as the cause of this hereditary syndrome, which developed into the activation of the TFE3 and TEFB pathways. More recently, a new mutation—MiTF—has been associated with this aggressive form of hereditary papillary syndrome. On review of data from The Cancer Genome Atlas, three mutations are associated with approximately 2% of all tumors, but they were noted to be applicable to 20% to 45% of renal tumors in children and young adults. Given the aggressive nature of this tumor, Dr. Linehan did not advocate for active surveillance in such patients.
He ended his talk by concentrating on the most aggressive form of kidney cancer that he had faced so far in his career. The tumor was of papillary type 2 histology and associated with cutaneous leiomyomas and uterine fibroids, now referred to as hereditary leiomyomatosis RCC. Metastatic presentation has been common in these patients, even with small renal masses, so active surveillance is highly discouraged in this particular population. The tumor was also highly infiltrative to the adjacent parenchyma, requiring wide excision. Dr. Linehan advocated for these masses to be treated via open partial nephrectomy, with careful attention given at surgical margins. Genetic evaluation of these tumors identified the mutation in the fumarate hydratase gene located in chromosome 1. Further study into the diseased pathway showed an independent activation of the HIF pathway, leading to renal cancer tumorigenesis. Downstream blockade of the HIF pathway with bevacizumab plus erlotinib has shown encouraging results in patients with metastatic disease. Dr. Linehan finally noted that future treatment of these hereditary disorders, most likely in the form of chronic low-toxicity targeted therapy, would prevent the local and distant progressions of this renal neoplasm.
Presenter: W. Marston Linehan, MD, National Cancer Institute at the National Institutes of Health
Written By: Andres F. Correa, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center
at the 2017 Genitourinary Cancers Symposium - February 16 - 18, 2017 – Orlando, Florida USA