Category Archives: Medical Conferences

Classifying Kidney Cancer by Its Biology; Good Looks Won’t Do It Anymore

Looks don’t matter in kidney cancer as much as they used to, as more information comes to us about the molecular or biological nature of the diseases which fall under the “kidney cancer” umbrella.  Can those important biological differences be seen in the pathology laboratory? Must we rely on next generation sequencing to determine which of the subtypes we might have?

Recent work by Dr. James Brugarolas and colleagues is reassuring.  Even as they found  new subtypes of clear cell renal cell carcinoma, they have also determined that these differences can be seen the pathology lab.

Why is this important?  So-called similar tumors may behave in quite different and more aggressive ways, so this is vital to understand the threat of recurrence from a very small tumor.  The affects monitoring and eventually will be helpful in drug selection.

An interview at the 13th International Kidney Cancer Symposium   October 2014

https://www.youtube.com/watch?v=tCoLwClv0tw

Cut and paste the above youtube address into your browser to be able to hear the lecture, while following along below.  The questions are in bold face.

Dr. James Brugarolas Discusses Biologically Classifying Kidney Cancer

“What we have learned with the development of next generation sequencing (NGS) is that no two tumors are the same. Every tumor has different mutations. Mutations are the drivers of tumor biology. With the advances of next generation sequencing, we have been able to identify and group different subtypes of kidney cancer, according to their mutation status.

Specifically, my laboratory discovered that the BAP1 gene is inactivated in 15% of clear-cell renal cell carcinomas. We found that BAP1 mutations are associated with high nuclear grade. That let us to hypothesize that patients who had BAP1 deficient tumors are going to have more aggressive tumors.

Furthermore, we found that mutations in BAP1 tended to anti-correlate with mutations in the second gene discovered by the Sanger Institute, by Michael Estrada and Andrew Futreal, the polybromo1 gene, PBRM1.

That led us to a classification that about 50% of the patients with clear-cell renal cell carcinoma will have PBRM1 deficient tumors and 15% of patients will have BAP1 deficient tumors. A small percentage of patients will have tumors that are deficient for both genes.

In a very productive collaboration we have had with Mayo Clinic, with Rick Joseph and Alex Parker, we’ve been able to determine that these different subtypes are associated with very different outcomes in patients. Patients that have tumors which are competent (not deficient) for both BAP1 and PBRM1 have excellent survival, whereas the cancer specific survival (CSS) is very poor in patients that have tumors that are deficient for both BAP1 and PBRM1. BAP1 deficient tumors have a somewhat intermediate survival phenotype, and the PBRM1 deficient tumors are similar to tumors that are competent for both BAP1 and PBRM1.

So we think for the first time, we’ve able to identify subtypes of clear-cell renal cell carcinoma that are likely to inform therapy in the future.

There is a gap between the discovery of the gene, to the determination of the clinical implications and subsequently to the therapeutic developments. That is because the therapeutic developments are going to emerge from the biologic understanding which we don’t have yet.

   How can improved classification of kidney cancer subtypes improve clinical trial design?

 That’s actually a very good question. So, what has traditionally happened is that a trial may be performed and one may find a group of patients–sometimes small, sometimes larger–that appear to do well with that agent. But if the group of patients is small, the trial is considered to be negative and the drug is abandoned. And I would say the problem is not that the drug did not have activity, it is that we were not able to identify the group of patients who appeared to benefit from that agent.

So the classification that we have developed and the identification of these different subtypes will pave the way to be able to do correlations. So then, when a clinical trial is executed when it is able to characterize better those subsets of patients that may benefit from the agent. For instance, as I was alluding to before, the BAP1 gene is inactivated in 15% of the tumors. It is possible that one of the drugs which has been tried in kidney cancer could have activity against that tumor. But there could never be a trial in that is positive that is being active in a small percentage of the patients, in 15% of the patients.

By identifying meaningful biological subtypes, we hope to deconvolute kidney cancer. It probably makes sense in trials going forward to do prespecified analysis of these genes that we now define as different biological subtypes–to be able to get at the question whether a particular treatment is having greater affect in one biological subtype versus the other. It is possible that it may not be that not all the PBRM1 deficient tumors that benefit, that are inhibited by a particular agent, there are other mutations. But it’s the beginning that which will lead us to identify those biomarkers and patients who are most resistant to a particular treatment.

 What is the significance of improved disease classification for kidney cancer patients?

 That is also an excellent question. These are discoveries that we and others have made over the last two or three years. The implications clinically have begun to be unraveled. It’s going to take significant effort and investment in research for us to go forward. We need to understand how loss of these genes, how mutations in BAP1 and PBRM1, are affecting processes inside the cancer cell, leading to kidney cancer development.

And in particular, we need to understand how BAP1, which is associated with most aggressive type of kidney cancer, is inducing that process. How is it that loss of the BAP1 gene makes the tumor be so aggressive? It’s only once we are able to elucidate the signaling pathways, that we will be able to identify targets for therapeutic invention.

On the other hand, we already know that for patients with localized disease, their prognosis is influenced biology of the tumor. I was alluding to this before, those patients who have removal of a tumor, localized to the kidney who deficient for BAP1 and PBRM1, they have a very high likelihood of recurrence in a short period of time. Those patients whose tumors are wild type for PBRM1 and BAP1 can do very well. (Wild type here means that the two genes are competent, or not deficient.)

Importantly, from the important view of translating these findings to the clinic, we have been able to develop assays, immunohistochemistry assays which are routinely performed in tumor samples at most institutions. (This is done in pathology labs).That allows us to very quickly determine whether we are dealing with the wild type tumor, BAP1 tumor, PBRM1 deficient tumor, or one that is deficient for both.

(Transcribed from the above YouTube video by Peggy Zuckerman. Any mistakes are mine alone, but hope this is helpful in understanding this approach to using gene sequencing in kidney cancer.

May 16, 2015)

 

 

 

 

 

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Filed under Genomics & Genes, Lectures from Experts, Medical Conferences, Rarer RCC Cancers, RCC Basics

Locally Advanced RCC /Kidney Cancer; Dr. Chris Wood; Budd-Chiari Syndrome & Nodal Disease; Part 3/4

Dr. Chris Wood; MD Anderson Cancer Center

KCA Patient Conference; April 14, 2010

Surgical Management of Locally Advanced Renal Cell Carcinoma Part 3 of 4

Budd-Chiari Syndrome & Nodal Disease

One  devastating complications of venous tumor thrombi  is  the Budd-Chiari Syndome.   The thrombus gets so big that it plugs up the vein, plugs up venous outflow from the liver. Patients present with abdominal pain, ascites, i.e., fluid in the abdomen, edema of lower extremities, enlarged liver, and their liver function tests are all abnormal.

If we take these patients to the operating room, the mortality rate is about 80%.  Because of this we no longer take these patients to the OR  Instead we will embolize the tumor, cutting off flow of the blood to the tumor.  For those patients that regress, we will take them to surgery and they do well.

It is not a very common presentation; we had six patients, two of whom were without evidence of disease after 3 years, using this approach.

NODAL DISEASE

There is a study where patients with localized RCC were randomized to either node dissection or not– to look to see if node dissection improved outcome. This trial showed that patients who had no dissection did no better than those who did not have node dissection.  Many will use this in urology community to say that patients who have kidney cancer do not need to undergo node dissection in the absence of metastatic disease.

In a more recent update on this, again, those patients who had a node dissection did no better than those with a node dissection.

But one thing about this trial that troubles me and many in the urologic community is the significant percentage of patients who had very low stage disease.  So it gets to the discussion of risk. If you study what you are doing in a low risk population where the frequency of the percent of expected adverse event is so small, you will never see a difference.  The problem with this trial is that they need to focus on more advanced stage disease to see if node dissection really makes a difference with kidney cancer.

The group at Mayo did some very elegant studies which showed us where the positive nodes are.  So now we go in and do a node dissection on a patient with locally advanced tumor, and we have a very defined area where we know the highest likelihood of metastatic disease is to occur.  If we took out all the nodes, the complications would be enormous.  We now are directed in where we go looking for nodes and remove them in that fashion.

Side 37 : The group at UCLA did a retrospective study and noted that if you did not have enlarged nodes, it did not matter if you took them out or not. Again, like the EORTC trial, but critics of this argue that it presents low stage disease.  But one of the interesting things that did notice that in the patients with positive nodes, that if you took those nodes out they did significantly better.  Indicating, even in the absence of systemic treatment, surgery could influence the biology of the tumor.

Slide 38

The group from Mayo identified features that predicted for positive nodes.  These include high nuclear grade, the presence of sarcomatoid histology, large tumors or more advanced tumors, or the presence of tumor necrosis.

38a They assessed the primary tumor when it came out of the patient, and if there were 2 or 3 of these features, the risk of having nodal disease was significantly high that they triggered a node dissection.  Now  they use this prospectively to see if this does let us give better outcomes. This may give us the ability to predict who likely has positive nodes and therefore should undergo a node dissection.

Slide 39 This was a study that was done some years back, but it intrigued me. In patients that had even met and positive nodes, for example, mets to the lungs and positive nodes.  Those patients do significantly worse in their prognosis than those without positive nodes.  This suggests some adverse biology that is associated with positive node involved. 

They also noted that if they could just dissect those nodes, again even in the presence of metastatic disease, they did significantly better than those whose nodes were left in place.

This is a study out of UCLA which shows that patients with metastatic disease do worse in the presence of positive nodes.

Slide 41a We recently looked at our experience (MDACC) with patients with metastatic RCC and positive nodes, limited to clear cell histology.  We had 55 with positive nodes compared to 322 who did not.  What we noted that those who present with positive nodes do worse than if they do not have them.

Slide 41b But you can see that if they undergo lymph node dissection, even in setting of metastatic disease, they did significantly better, almost a doubling of their survival as patients who did not.

Cytoreductive Surgery Prior to Systemic Therapy for Metastatic RCC

Slide 41c If patients do present with positive nodes, we aggressively resect them, as it significantly impacts on their ability to get treatment. So nowadays, when patients present for cytoreductive nephrectomies, if they have positive nodes, we aggressively resect them, as it significantly impacts their outcome, and their ability to go and get treatment.

 Role of Aggressive Surgical Resection in Patients with Positive Nodes in the Absence of Distant Metastases

 What about those patients that don’t have metastatic disease but just positive nodes. How do those patients do? We recently looked at our series of patients with positive nodes in the absence of distant metastases, and wanted to asses what factors predicted what affected outcome.

Slide 41d

Out of 3201 nephrectomies, we identified 2521 who did not have metastatic disease, and of those 68 had positive nodes.  Surprisingly, we found,  that in positive nodes–that the tumor has left the kidney and metastasized–and surgical patients still do pretty well.

Slide 42: There overall survival rate at five years is 37%.  You might say, that is pretty low, but that is with surgery alone.  But disease specific survival is 39% at five years.

slide44: But when disease recurs, it generally recurs early, at within the first year, but more than a third recur greater than a year out.

Slide 44a:  And when patients do recur after this surgery, they usually recur in multiple places with metastatic disease.

Slide45

We wanted to look at factors that predicted for outcomes in these patients.  So these are these are the demographics, (editor’s note; the video does not include these charts and slide, which are from the original, unedited video) the vast majority had good performance status, they had local disease, confined to the primary tumor and the overwhelming majority had clinically positive disease. This was not microscopic disease, rather big nodes you can see on CT scans.

What we noted, interestingly, in terms as predictors of overall survival those patients with papillary histology had a significantly better outcome, than those with clear cell histology. Those with only one node had a significantly better outcome than those with more than one mode.

When we looked at time to recurrence, again, papillary histology seemed to be a predictor of who would do well.  So patients with papillary histology and positive node involvement, we will aggressively resect them.

Slide 45: The multi-variate analysis  predicts for overall survival, and  papillary histology, the number of nodes positive involved,  the presence of sarcomatoid features and status all predicted outcome.

Regards of the time to recurrence, only the number of nodes involved and tumor grade were predictive of outcome in these patients.

(Slides are variations of the same information.)

Secondary Treatments

What about adjuvant therapy in these patients?  I already told you that adjuvant therapy doesn’t work. In this particular group, 5 got adjuvant ttreatment and in those 4 patients, it recurred.  The important thing is that 85% of these patients had good performance status at three months. What does this say?  It means we can do an aggressive surgical resection and patients bounce back very quickly. If they need to go on to get additional treatment, even after this very large surgery.

So these are the feature that predict outcome; papillary histology, number of nodes, sarcomatoid features and ECOG performance status.

I will continue with “Adjacent Organ Invasion” in the next part of the lecture.

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Kidney Cancer Conference and the Latest Thinking

In April of 2012, the KCA held a patient conference at MD Anderson Cancer Center, which gathers about 75 patients and caregivers to hear internationally-respected experts about kidney cancer. I attended the conference and had the opportunity to meet with my “Friends on Account of Kidney Cancer”, all of joined by our experience with kidney cancer.  We had never seen one another, had to send pix to make sure we could find one another, and greeted each other as long-lost friends.

To make these lectures more meaningful, I have edited each one, after countless hours of review and correction, adding the slides to the lectures and recreating them to make them more easy to email and share.  Several friends through my patient connections have read them and found them useful, and I hope you will as well. 

The first lecture is by Dr. Jose Karam of MD Anderson, and is presented in its edited form in the next post.  Other similar posts will follow until all the lectures are available.  With the ASCO conference going on, you will see mention of trials now being published presented at ASCO.  These lectures will give you some skills to assess that information , which is now hitting the airways, with the usual lack of perspective and background which we need to understand these new findings.

Looking for comments, as always.

PeggyRCC

 

 

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