1. Nalley, Catlin

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With ongoing advances and new therapeutic options, the treatment landscape of renal cell carcinoma has evolved significantly throughout the last several years. And this includes, as with other cancer types, a greater shift towards personalized medicine.


"Many of the treatment options that we have in renal cell carcinoma now are responsive to the genomic changes and underlying biological changes that we've identified over the years," said Sumanta "Monty" Pal, MD, medical oncologist and Co-Director of the Kidney Cancer Program at City of Hope. "For instance, this begins with a class of targeted therapies known as VEGF inhibitors.


"All of these drugs are predicated on the fact that many patients with kidney cancer have disruption in VHL," he noted. "This particular gene ultimately drives production of VEGF through various pathways and then results in a mechanism that we can target with pharmaceuticals."


"Renal cell carcinoma is one of the diseases in which the underlying biology has had significant impact on the drug development process," noted Chung-Han (Joe) Lee, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center who specializes in the treatment of kidney cancer.


"Historically speaking, we went through a long stretch of multiple negative clinical trials until we were able to develop drugs that specifically targeted mechanisms downstream of VHL," he explained. "Around 2006 is when we first started having targeted therapies that showed activity within clear cell kidney cancer."


Since then, there have been a number of large sequencing efforts, according to Lee, who noted that this has led to the identification of multiple mutations within kidney cancer that can provide prognostic information. As research efforts continue, more is being learned about the genomics of renal cell carcinoma and its impact on treatment and overall patient care.


Research Avenues

With an ongoing emphasis on personalized medicine and targeted therapies, there are a number of research avenues currently under investigation in the renal cell carcinoma space. One area Pal finds particularly exciting is minimal residual disease.


"This is a phenomenon in which we've identified that kidney cancer can be detected at very low levels," he told Oncology Times. "Work from Dr. Toni Choueiri at the Dana-Farber Cancer Institute has done a great deal to demonstrate that you can use things like methylation signatures to detect very low levels of circulating tumor DNA."


Pal and his group have also shown very similar principles in kidney cancer, as well as in the setting of more advanced disease, which he noted they have used to distinguish partial and complete responses to therapies.


"There are a lot of different applications of these technologies," he said. "But I think the focus is going to be towards liquid biopsy in the future-an easy way to access genomic data-as opposed to tissue biopsies, and something that can be done serially in the patient's time course as they go through therapy."


Researchers are also exploring the use of HIF2 inhibitors in kidney cancer. "HIF2 is a transcription factor that activates and leads to transcription of genes downstream of VHL loss," Lee said. "It is very exciting to have specific targeting of a transcription factor. Currently, HIF2 inhibitors are already approved for people with VHL disease, and ongoing studies are underway to determine whether they may also have activity in individuals with kidney cancer.


"Another area we have been looking at is using the degree of HLA diversity as a potential predictor for response to certain types of immunotherapies," he continued. "When we think about systemic therapies for kidney cancer, especially immunotherapies, it is this triad of the actual tumor in and of itself, the microenvironment, and the patient's immune system, and understanding how all of these pieces come together."


Other malignancies have demonstrated that if you quantify the amount of HLA diversity-which is hereditary-there seems to be an impact on sensitivity to immunotherapies, noted Lee. "This is something that is interesting and promising. And certainly requires more evaluation and investigation to demonstrate if this can be used to stratify patients."


Genomics in Clinical Care

There is an increasing role for genomic testing in the treatment of renal cell carcinoma, and it is important that clinicians are aware of how it can be used to potentially enhance their treatment plans for individual patients.


"I would suggest that it does have value in renal cell carcinoma because there are cases where you find a patient who may have a very targetable genomic alteration that you can exploit and that can really benefit their overarching clinical outcome," said Pal. "And so, we need to get the word out that genomic profiling is reasonable in this patient population, especially among those who have progressed on multiple therapies and testing may yield other options."


At the minimum, looking at a patient's genomic profile can provide prognostic information, according to Lee, who noted that there are certain patients with kidney cancer whose disease is expected to behave more aggressively based on their mutation profile. "Having access to that type of information will help the oncologist factor in how they want to potentially sequence treatments or what types of treatments they want to prioritize," he said.


As the role of genomics grows in clinical care, there are also challenges to be addressed. One of the biggest hurdles is the turnaround time for the data, according to Lee. "In order for clinical decision making to happen, we have to get this information in a timely fashion," he elaborated.


"When we think about genomic testing, we have to ask: How do we shorten that time from when we see the patient and when we actually receive the results?" he added. "That is a key logistic challenge that needs to be addressed, especially as this continues to become standard of care."


What Does the Future Hold?

Looking forward, Lee envisions a greater role for genomics in kidney cancer, especially as the cost and convenience of sequencing improves, as well as an increased ability to accurately guide treatment. With ongoing research and discovery, its uses will continue to expand. This includes, according to Lee, answering key questions, such as how to integrate genomics into some of the predictive nomograms that we have for recurrence of disease.


"Today, we have FDA-approved adjuvant immunotherapy for kidney cancer," Lee said. "And now, whenever we think about adjuvant treatment, as in any setting, it's a balance between the potential side effects and response as well as your risk of recurrence.


"The current way we handle risk of recurrence is mostly based off of clinical and histological factors, and we haven't integrated some of the genomic factors into those predictions," he added. "So, as we can get better estimates and understanding of how genomics impact that risk of recurrence, I believe that will also have a huge impact in the adjuvant space."


Overall, the role of genomics will, hopefully, be quite expansive in the future, concluded Pal. "I think we will see multiple applications of this technology, particularly as the number of targeted therapies that can respond to genomic profiling increases."


Catlin Nalley is a contributing writer.