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Study Suggests More People with Kidney Cancer Should Be Screened for Hereditary Cancer Genes

Source: Memorial Sloan Kettering - On Cancer
Date: 09/06/2018
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Kidney cancer, also called renal cell carcinoma (RCC), is a relatively common cancer. It’s diagnosed in nearly 65,000 people in the United States every year. Yet despite its frequency, very little is known about what causes it, beyond two broad factors linked to many common cancers: smoking and obesity.

That’s now starting to change for one advanced form of the disease, called non-clear cell RCC. Recent research from a collaborative team at Memorial Sloan Kettering found that more than 20% of people with this type of RCC have disease that is driven by inherited cancer mutations. Many of the types of mutations that were found indicated that the tumors might respond to targeted therapies that would not otherwise be prescribed for kidney cancer.

“These findings suggest that everyone with advanced non-clear cell RCC should be referred for genetic counseling,” says medical oncologist Robert Motzer, one of the authors of the study, published in July in JAMA Oncology. “Beyond a rare inherited condition called von Hippel-Lindau syndrome, as well as a few other uncommon disorders, we haven’t previously known that kidney cancer had this strong hereditary component.”

Non-clear cell RCC makes up about one-quarter of RCC cases. For clear cell RCC, the more common type, the study found that only about 2% of tumors were caused by inherited cancer genes. Before this study, the rate for all kidney cancers was expected to be about 5%.

A Surprising Finding about a Diverse Group of Cancers

Over the past decade, a number of targeted drugs and immunotherapies have changed the outlook for many people with clear cell RCC. Dr. Motzer and his team have led many of the clinical trials that have resulted in US Food and Drug Administration approval for these drugs, including sunitinib (Sutent®), sorafenib (Nexavar®), axitinib (Inlyta®), and nivolumab (Opdivo®). Thanks to these new drugs, even people with advanced kidney cancer can live for many years, often with very few side effects from their treatments.

Non-clear cell RCC has been a different story. Many of the drugs approved to treat clear cell RCC do not have the same efficacy against non-clear cell tumors. “Non-clear cell” is a catch-all term that applies to several types of cancer including papillary, chromophobe, and collecting-duct tumors.

In this current research, investigators looked at 254 people who had been treated for advanced RCC at MSK. Each person had undergone MSK-IMPACT™ testing to look for mutations in their cancer. As part of this test, both normal tissue and tumor cells are analyzed. This enables doctors to detect cancer-related mutations that someone may have inherited.

Unexpectedly, about 20% of people with non-clear cell RCC carried inherited mutations. The study found the most frequently inherited mutation in people with non-clear cell RCC was in a gene called CHEK2. Mutations in this gene have previously been connected to an increased risk of breast and colon cancer, but the link to RCC was not known. The researchers found mutations in other cancer-linked genes not previously known to play a role in kidney cancer as well.

The team also found several people with non-clear cell RCC who had inherited mutations in a gene called FH. Mutations in FH have already been linked to a condition called hereditary leiomyomatosis and renal cell cancer. But they were more common than what would have been expected in a group of people with RCC.

“Once we know that someone has one of these hereditary gene mutations, we can help make sure they get the right treatment,” says Maria Carlo, a clinical geneticist and medical oncologist on the Genitourinary Service and first author of the study. “In addition, we can offer them screening tests for other cancers that may be linked to the same mutation.”

Discoveries Lead to Changes in the Clinic

At the American Society of Clinical Oncology (ASCO) meeting in June, Dr. Carlo presented similar findings from people being treated for advanced bladder cancer at MSK. About 16% were found to have inherited mutations. Some of these mutations suggested that they might benefit from targeted therapies that are not usually given for bladder cancer.

Learning that someone has an inherited cancer gene has important implications for his or her close relatives as well. MSK’s genetic counselors are able to offer them genetic tests. If any of them are found to have the same mutation, they can participate in screening programs for cancer as well.

In fact, due in large part to the findings reported in the JAMA Oncology and ASCO studies, Dr. Carlo is now leading a Genitourinary Cancer Genetics Program within MSK’s Clinical Genetics Service. The program offers genetic testing and screening services to people with hereditary prostate, kidney, and bladder cancers and their families.

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Research Efforts Focus on Underactive Bladder, a Common but Poorly Understood Condition

Source: Brigham and Women's Hospital - On a Mission
Date: 12/06/2019
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Physicians have a good sense of the symptoms and causes of overactive bladder, and clear guidelines exist for diagnosis. Thanks to advertising for pharmaceuticals and other products, even many members of the general public are aware of this condition and know that treatments are available.

Underactive bladder (UAB), on the other hand, is a condition that is poorly understood and not well-studied. Currently, a clear definition of what constitutes UAB is lacking. Even most specialists don’t know how to recognize it. This dearth of information is the motivation behind a collaborative research investigation that has been ongoing for over two years. The effort aims to develop patient-reported outcome measures that can ultimately enable research and treatment for UAB.

“There are urodynamic parameters that we think are characteristic of this condition, but we really don’t know much about it,” said Michael O’Leary, MD, MPH, a senior urologic surgeon at the Brigham’s Division of Urology and one of the study’s principal investigators. “Once you have clear guidelines for what constitutes a particular condition, it makes the job of studying it much easier.”

Establishing Metrics to Characterize UAB

The initial goal of the collaboration is to generate a screening method for UAB based on symptoms and then to validate those questions based on what is already known about the condition. Accordingly, the investigators are aiming to develop a questionnaire for UAB that is similar to those established for conditions like erectile dysfunction and chronic pelvic pain syndrome. The project was begun in response to a request from the National Institute of Diabetes and Digestive and Kidney Diseases, which is funding the research.

“Our job is to better characterize UAB,” Dr. O’Leary said. “So the first thing we need to do is to find out what the patient experience is. Because this condition is symptom-driven, having a way to measure patient-reported outcomes will be valuable.”

Early results have identified a number of indicators that are shared with detrusor underactivity, a potential causal factor for UAB. The study so far has collected data on people aged 40 to 89, with the majority over age 70, and has included both men and women. Dr. O’Leary estimated that up to 20 percent of the elderly population may experience UAB, but noted that the condition is so understudied that its frequency is difficult to determine.

The prominent symptoms identified so far include frequent urination, decreased sensation, incontinence and frequently waking to urinate. The fact that many of these symptoms are similar to other bladder disorders makes diagnosis more challenging, the researchers said.

“The classic teaching is that you would expect underactive bladder to look like retention,” said the Brigham’s Elodi Dielubanza, MD, an associate surgeon and a co-investigator in the study. “In reality, when you encounter patients with UAB, it’s a lot more heterogeneous and nuanced. We currently have no way to understand what the expected patterns might be.

“The difficulty in this work is about trying to recognize something that is so poorly understood. We have to work backwards and start with the patient experience first.”

Identifying the Needs of an Undertreated Condition

This study involves researchers in urology and urogynecology at the Brigham and Massachusetts General Hospital. The New England Research Institute is providing expertise in epidemiology and data collection and management.

“Because this condition is not often diagnosed, currently it tends not to get treated,” Dr. O’Leary said. “Some patients who have a poorly contractile bladder may need to do self-catherization, but there is no standard treatment. The pharmaceutical industry is interested in potential development of new drugs. But before any treatments can be developed, we need to know much more about the underlying causes of this condition, in addition to having a way to measure any benefit that may come from treatments.”

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Using Motion-Capture Technology to Advance Ergonomic Studies of Ureteroscopy

Source: Brigham and Women's Hospital - On a Mission
Date: 01/22/2020
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Ureteroscopy is one of the most common procedures performed by urologists. Yet little is known about what optimizes the procedure’s success, especially in terms of how the urologist holds the ureteroscope and which hand and arm movements are most effective.

A study published in the Journal of Urology in 2018 looking at common gestures that surgeons used in performing robotic radical prostatectomy inspired Brigham and Women’s Hospital urologist Daniel Arthur Wollin, MD, to conduct similar research analyzing the ergonomics of ureteroscopy.

“You sometimes hear a particular person described as being a really good urological endoscopist, but it’s unclear what makes someone good at doing these procedures,” he said. “We don’t know whether it’s speed, consistency, form, economy of motion or particular tricks that they’ve taught themselves or picked up from others. We wanted to take a closer look.”

Using Technology to Monitor Movement

Dr. Wollin decided to use ureteroscopy simulators that are currently available for training purposes to study particular movements and how they correlate to various metrics of procedure success. He did this by labeling volunteers with tracking dots (the same kind that are employed in motion-capture animation) to monitor movements of the torso, head, pelvis, hands and wrists during simulated procedures.

He recruited 12 urologists to participate, six men and six women. Half were residents and half were attendings or fellows. Some had completed endourologic fellowships.

The participants completed 13 different timed tasks for the removal of kidney stones, and their movements were correlated with their procedure times and other measures of success.

“We know there’s a wide variety of skill levels in ureteroscopy. There are certain things that will take one urologist hours, and another person can do it in 20 minutes,” he said. “Many of these skills build up over time, but they may also be dependent on tricks that people are shown during their training. One of our goals is to determine whether there are ‘right’ ways to do certain procedures and, if so, how those things can be taught.”

Looking More Deeply at Cause and Effect

Dr. Wollin explained that it’s too early to make recommendations based on his studies. But he did offer a few observations. For example, the less a urologist moved their head and body around while performing a complex task, the faster they completed it. This correlation was not seen with simple tasks.

“People may have been moving around more because they were having trouble and needed to shift their bodies around and try a lot of different things,” he said. “Or they may have just been people who move around more in general, and those movements led to slower task times. We can’t yet differentiate between the two. But we can say that people who move less tended to do better.”

Dr. Wollin noted that companies that make ureteroscopes could be interested in his research. “This device was designed 30 or 40 years ago, and given the technology we have today, it’s unlikely it would be designed in the same way now,” he said. “We would like to be able to gather more data and conduct this research on a larger scale, maybe at a national or international conference. Theoretically, you could map everyone’s style while operating the scope and use that information to take a more in-depth look at how it connects to clinical outcomes.”