Category Archives: Uncategorized

Kidney Tumors & Diagnosis? Size Matters–Big Surprise

Kidney cancer is generally a very silent disease. It is sneaky, hides out for years, and is often assumed to be something else.  In my case, my doctor essentially decided I was just a menopausal women with the ever-popular “stress” as a an extra.  The stress of carrying about a 10 cm tumor and wasting away  was probably part of it.

That slow diagnosis, often delayed for years is far too typical.  Only the greater use of CT scans has been significant in finding kidney cancer at an early stage. And just what is early or small? Looking for a cracked rib, or the dislocated shoulder has often revealed kidney cancer, and in the case of the shoulder, lung mets.  And then the hunt is on!  By the time this diagnosis is made, nearly 30-40% of kidney cancer is already metastatic.

The ‘classic triad’ of symptoms, are 1) blood in the urine, 2) flank pain, and 3) palpable mass in the abdomen. There are doctors who will consider kidney cancer only when the patient has these three symptoms, but that happens in fewer than 10% of patients.  The cancer has to be pretty far along to be found this way.  Meeting a pair of new doctors who were aware of my kidney cancer, they were obviously bewildered to hear that I had had none of the these symptoms.  “But those are the usual symptoms,” one said.  Maybe ‘classical’, but not ‘usual’.  Unfortunately that expectation is a barrier to good diagnosis.

Beyond the diagnosis and the staging of the disease is the pretty obvious question of what to do next. (Staging: another of those words used one way in English, and quite another in medicine No wonder we are confused.)  Getting treatment is derived from that ‘staging’.  To be told your cancer is at Stage I seems the only  bright spot of a cancer diagnosis,  but not so reassuring with kidney cancer.  The  “SMALL” Stage I kidney tumor is one which is confined to the kidney (good news) and is 7 centimeters or less.  Maybe Europeans react with the required, “Yipes!”, but few Americans would until they know that this is almost 3 inches in size!

Ain’t so small in my world, or in my kidney!, or anywhere else. In my previously-naive patient world, I thought a ‘small’ tumor was the size of a pea, or maybe a peanut.  In any case, these so-called small tumor are Stage I, of four Stages.  Don’t even ask about Stage V.  Calling a near-three inch tumor small reflects the history of many very large tumors being found in the early days.  Even in 1997 there was discussion about whether a 5cm (2 inch) tumor should be the ‘small’, and in the 1987 system, it had to be 2.5cm to be small, ie, about one inch a T1 stage.  I do not understand why this basic staging was so dramatically changed, but it may well be that there were so few truly small tumors found in this early CT era.

In any case, we now have a system which lumps all tumors 7 cm or smaller into TI category, re-divided into T1a if under 4cm, and T1b, up to 7cms.  This minimizes the sense of risk that comes with these larger Stage I tumors, despite clear evidence of much greater risk at about as they grow.  That shift to a more aggressive tumor, capable of having metastatic potential, seems to start just over 1 inch, about 2.8cm.  There is a measurable increase in risk of about 62% at this size, so waiting around for a mass to be palpable (ie, it can be felt) puts us all at risk.  And of course, that metastatic potential has likely started even earlier, prepping the body to accept new cancer in new locations.

Thus, the absolute need to monitor patients who have had large ‘small’ tumors far more carefully and for a longer time.  The reality is that even truly small tumors have the ability to start the metastatic process.  Tiny and invisible even to a CT, they can grow unnoticed for several years.  There is no magic ‘five years/safe at home’ for kidney cancer patients, sad to say.

So, if your doctor tells you not to worry, that he got it all, that it was small, that there is no need for further monitoring, you might just find another doctor who keeps up with the kidney cancer literature.  If you got this far with this post, you may be ahead of your doctor.

Re the above risk stats, seehttp://www.cancertherapyadvisor.com/renal-cell-carcinoma/renal-cell-carcinoma-larger-tumors-high-grade-pathology/article/415189/

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Filed under Guidelines, Newly Diagnosed, Patient Engagement, Patient Resources, RCC Basics, Uncategorized, Your Role

Immune Therapies: Headlines, Hype or Hope?

Recent headlines called a new medication, Nivolumab, both a miracle or breakthrough and more.  Is it hype or hope?Why is it so hard to sort out the reality?

Let’s go through the facts from the New England Journal of Medicine and ignore the headlines. First, its being  in the NEJM is important, as it has passed review by other researchers.  (Sadly missing in too many ‘breakthroughs”).

The new med, Nivolumab was compared against Everolimus, a second-line treatment. Therefore Evero is thought to be of lesser effectiveness than the first line meds.  Second-line meds are generally used when others meds quit helping or their side effects are too hard. Automatically NOT the miracle cure, but another option when first-line treatments fail.

Should Nivo have been compared to the first-line meds?  Being better in the first-line would be bigger deal, but we need more approved meds. Second-line treatments usually are easier to ‘beat’, as the new med must be better or less toxic.  Again, more likely to be approved!

PATIENT CHARACTERISTICS

The study had 821 patients 24 countries, half using Nivo and half Evero. Patients were similar, 90% having had a nephrectomy, removing the tumor and some or all the kidney. Then the cancer spread, making metastases, (mets, for short). These patients had 1-3 treatments, first-line drugs like Sutent, a targeted therapy, and a few had used cytokines or even chemotherapy.  Having had an mTOR inhibitor like Everolimus was not acceptable. Most had lung mets (67%), followed by liver(12%) and then bone mets (18%). Most with 2 or more sites of mets.

To enter the trial, the patient had to have had disease progression after their last treatment, within six months of enrolling in the trial. No doubt, some patients had greater disease progression than others, but had relatively good performance status, not completely bed-ridden or unable to function.

The median time from initial diagnosis of kidney cancer at any stage to entering the trial was 31 months;  half had been diagnosed less than 31 months ago, and half more than 31 months before the trial. That range of time from diagnosis to trial was 1 to 392 months. That means that for some patients, they went a long time either fighting the disease since diagnosis, having a later recurrence, being treated, yet having disease progression years after the intial diagnosis.  At least one person was diagnosed 392 months earlier. This is a good reminder to patients who have been told, “I got it all”. This darn stuff can return, so having a plan B is important. Again, the previous treatment failed and these patients got directed into this trial.

GENERAL RESULTS

Median Overall Survival (OS) is a measured when one-half of the total number in the group dies. Median OS for Nivo was 25 months with some patients still surviving at time of report, beyond the 25 months. For Evero, OS was 19.6 months, some of who were also likely surviving, as well.  The OS of 25 months was clearly better with the Nivo group by this analysis. Nevertheless, half of all the 821 patients total died while on this trial from progressive disease.  Of  183 of the 410 Nivo patients, 183 has died by 25 months, and 215 of the 411 Evero patients had died at 19.6 months. 

 

There is no report of ongoing response here, but many went on to other meds, as explained below. 

Median Progression Free Survival (PFS), measurable growth of disease,  was 4.6 months for Nivo, 4.4 months for Evero.  The median shows that half of each group, roughly 200 each had return of disease in less than 5 months!  Again, these trial patients were pretty sick or at risk. All had been treated earlier, and had to stop previous treatments due to recurrence of disease. However, this shows a pretty quick return of disease or new growth from the base CT scan for nearly  65-70% of all patients.

One subgroup did a bit better than the 4 1/2 months median PFS.  At six months after the start of treatment, there was a special subgroup was noted,  about 1/3 of those patients–145 pts (35%) with Nivo, and 129 (31%) with Evero. Obviously they did not die or have Progressive Disease until after six months.  The Nivo group had eventually had a median PFS of 15.6months, and the Evero group, 11.7 months.  Their success pushed the median OS higher, especially for the Nivo group.

Obviously, there were some patients with far more aggressive disease in both groups, some dying before six months, and others not progressing to more disease until after six months.  In contrast, nearly 1/3 of all the patients had PFS of 12-15 months, and much longer OS. What is the common characteristic in the most successful two groups in both arms of treatment?  Not answered by this trial report.

The duration of treatment was longer with Nivo, and likely easier to tolerate. Since Nivo was given by IV every two weeks, the doses were most consistently received. Even so, 51% of them had dose delays, but no per dose reductions.  Those people were seen by the medical team every two weeks.

The Evero group took oral meds, and 66% had dose delays or interruptions with 26% with at least one dose reduction. This would indicate that these meds could be hard to take, or perhaps lacking the same interaction with their medical team.  Of course the Evero patients may have underreported how much of the medication they actually took!

However, the reported types of side effects were generally similar, but the more severe grade 3 and 4s effects in the Evero group.There were 2 treatment related deaths in the Ever group, none in the Nivo group.

POST PROGRESSIVE DISEASE

Even after the disease did progress, about half of  patients in both groups stayed with their meds–despite ‘failing’, the researchers hopes that would continue to benefit, perhaps slowing the disease.  In a local clinic setting or with a less experienced docs, their meds might have been stopped or changed. Afterall, those meds were no longer “working” and  mets are growing. This approach is significant to consider, especially after multiple treatments.  (The decision to keep giving a medication or increasing its dosage where tolerable is causing some changes in treatment in a number of the targeted therapies.)

Perhaps because of being in a trial or getting care than was more expert than most, one-half of  patients chose to keep on the trial meds.  Others crossed over to the med in the other arm or returned to existing non-trial meds. In some countries, there were likely fewer choices than in the US.  There are no real stats as to survival for those on those who stopped taking the meds. It is reported that indicate that 55% of the surviving Nivo group and surviving 63% of the Evero group went on to other agents. About one-quarter of the Nivo group shifted to  the Evero. Of the Nivo group, 36% shifted to axitinib.

Sadly, as per the chart in the New England Journal of Medicine, all these patients had died by 30-33 months post enrollment.  However, it is again not clear what was effect, if any on that period from the non-trial drugs.  Of the 227 who stopped Nivo for any reason, nearly half shifted to Evero. Of those who stopped Evero, 140 went to Axitinib.

DURABLE RESPONSES?  HOW LONG? FOR HOW MANY?

The writers of the study say that there was a higher number of objective responses with Nivo vs Everolimus, and that many (of the Nivo group) “were durable”.  There is no definition of ‘durable’.  My question is “What equals durable?”.  We patients really want a cure, but are very grateful for anything that pushes the cancer back, slows it, stops in from growing any further. Nevertheless, we do want those responses to last.  The clearest reference to durable responses is a note that 32 of the Nivo patients and 6 of the Evero patients had a response that lasted more than 12 months.  But in an unexplained statement, the median duration of treatment was just 5.5 months for the Nivo patients, 3.7 for the Evero group.  It seems that there was not an extension available, or that the patients moved on to a different treatment or passed away.

CONCLUSIONS AND EDITORIALIZING AGAIN

It seems that Nivo is more helpful for some patients than others in this group previously been treated with other TKIs. This is NOT A SILVER BULLET.  There would be greater value to know more about the molecular nature of  the tumors of the responding and the non-responding patients.  We desperately need to know for whom any of these drugs is likely to be more effective.  The headlines that don’t discuss that challenge underserve us, as does the design of the trial that does not elicit the more nuanced, genomic data that could be forthcoming!

We all know that headline claims are more wonderful  than the reality.  The story of RCC medication development is that of more and more help in a difficult disease, making mixed progress, while the other researchers find out that RCC is really many diseases.  Clear cell is probably better defined as being made up of four types, Papillary Type 1 and Type 2 being further divided into three Type 2, then there is chromophobe, clear cell papillary and the really odd versions of RCC.  I known this, and so do you.  But why don’t the researchers incorporate those definitions and monitor the patients with those various subtypes as they go forward?

Good luck to all of us.

 

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Filed under Clinical Trials, genomics, Genomics & Genes, Immune Therapies Old & New, Newly Diagnosed, Patient Activism, Therapies, Uncategorized

We hear of “patient engagement” as a topic, but it can be misused in a self-serving way! For some hospitals, it comes in the form of a survey that asks your opinion of the newly-remodeled lobby, but never asks if you were properly treated while in the hospital.  That is my least favorite and most cynical use of ‘patient engagement’ efforts.

We patients must be engaged, especially needed in this cancer world.  But that is a huge challenge when we have not be taught by experience or the medical world to do so.  Just how does the nervous or bewildered patient do that when the problem is confusing or terrifying?

Starting with what we know about ourselves and knowing HOW to explain it is obvious, but not easy.  Just how to do that?

See what doctors are learning, as in the following short article.  There is a link to a Patient ToolKit  http://www.patient-experience.org/PDFs/Patient_Toolkit_v4A_Fillable-Format.aspx developed by others who work with me to improve diagnosis.  This is available for anyone to use, can be filled in online or printed out as needed.

Simply, it helps the patient organize his symptoms, concerns and history in a way that MIGHT be more acceptable to the doctor.  It can remind you well ahead of the appointment what to do so that the appointment is more useful and efficient.

Your ideas gratefully requested.

http://www.patient-experience.org/Resources/Blogs/DM-Blog/Blogs/July-2015-(1)/Engaging-Patients-Before-You-Even-See-Them-Tools-t.aspx

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by | July 30, 2015 · 9:58 am

Genetics of RCC: Paving the Way for the Next Generation of Therapies

This lecture is the most important I have heard this year.  Dr. Brugarolas provides us significant data to explain by RCC cancers behave so differently.  This data will affect how we name our cancers, and how we treat them.  Take this lecture in bits, as it is complex.  You might want to start with a companion interview, entitled “Classifying RCC by Its Biology: Good Looks Won’t Do It Anymore.”

James Brugarolas, MD, PhD.

Kidney Cancer Program Leader Associate Professor of Internal Medicine & Developmental Biology; University of Texas Southwestern Medical Center

http://www.chemotherapyfoundationsymposium.org/mobile/player.php?id=476

“Welcome to everyone and I thank the organizers for their kind invitation. I’m going to talk to you today about the genetics of kidney cancer and how I believe the paving the way for the next generation therapies. (There are no significant disclosures.)

Brug 1 What is the Problem

What is the problem? This is a problem that we are well aware of some nowadays. We’re using one drug for all patients with kidney cancer. You may imagine that these are all patients with metastatic renal cell carcinoma. But it is a heterogeneous population. Some have the red tumor, some of them the green tumor, and the drug may work with a subset of patients, but it may not work for another subset of patients.

The paradigm we should be evolving to is a paradigm where patients with different tumors should be treated with different drugs.
BRUG 2 Kidney Cancer subtypes
In the context of renal neoplasms , as you are well aware, we have kidney cancer with clear-cell carcinoma which accounts for the vast majority (75%) of that, and that’s going to be the focus of the first part of the talk.

BRUG 2 EDITSCapture
The work from the Sanger Institute by Andy Futeral and Michael Stratton led to the identification of mutations in the polybromo1 gene. Polybromo1, like VHL, the most commonly mutated gene in clear cell renal cell carcinoma, is a two hit tumor suppressor gene. That means both copies are mutated in tumors. They identified through truncating mutation in approximately 41% of clear-cell RCC. PolyBromo1 encodes BAF 180, which is a component of a nucleosome modeling complex which may regulate, among other processes, transcription.

BRUG 3BAP1 loss defiens new class of RCCCapture
Work from my laboratory led to the discovery of another gene mutated in RCC, the BAP1 gene. Like the BPRM1 and VHL, BAP1 is a two-hit tumor suppressor gene, but it is mutated in only about 15% of sporadic clear-cell RCC. This work was done focusing on tumors that were of high grade. Indeed, we found there was a correlation between BAP1 loss and high grade, and also activation of the mTOR1 pathway. BAP1 encodes a nuclear deubiquitinase. Of greatest interest, were mutations in BAP1 and BPMR1, we found, are largely mutually exclusive. This is shown this more detailed the next slide

BRUG 4Mutation in BAP1 ^ PBMR1 mut exclu
What you are seeing here are 176 tumors, each in a row. These are tumors that have a deletion in PBMR1, these are tumors with the insertion, this with a point mutation. All the tumors in blue are tumors that have a mutation. As you can see most of the tumors, we see with PBRM1 mutations do not have mutations in BAP1. (in last column) Here you have some tumors with mutations in BAP1, and we only identified three tumors that had mutations in both genes. The probability of having mutations in both was statistically significant. Based on the individual mutation probability, we would have expected 13 tumors to have both genes. Only three were found, suggesting that BAP1 and BPRM1 mutations are largely mutually exclusive.

BRUG 5BAP1 & PBRM1 meta anal

We went on to performing a meta-analysis. This is looking at data from that Beijing Genome Institute, at Memorial Sloan-Kettering and this from the TCGA. As you can see, even though the numbers are small, the numbers of tumors with mutations in both BAP1 and PBRM1 was reduced, compared to the expected number of tumors based on the individual mutation frequency, and the p value was statistically significant.

BRUG 6BAP1 & PBRM1 gene signature
I’m going to go through these and not spend much time, but suffice it to say that that we found that these tumors that have had mutations in BAP1 have a characteristic gene expression signature, and the tumors that have mutations in PBRM1 also have a characteristic gene expression signature. These gene expression signatures do not overlap. These are tumors that have different tumor patterns and different biology.

BRUG 7 BAP1 & PBRM1 ex  diff SMALL
We think this establishes a foundation for the first molecular genetic classification clear-cell RCC. In our series 55% have mutations in PBRM1, and 15% of the tumors have BAP1, and 3% have mutations in both.

We also observed that there is a statistically significant correlation between mutations in BAP1 and high grade, and mutations in PBRM1 are low-grade.

BRUG 8Fdn Mole Gene sign ccRCC

So that led us to propose the following model. This is a model based on the fact that very interestingly, VHL, BAP1, and PBRM1 are all located on chromosome 3. In fact, the short-arm of chromosome 3, and this is an area that is deleted in the majority of patients with von Hippel-Lindau-associated renal cell carcinoma, as well as in the majority of sporadic renal cell carcinoma, depicted here (pie chart) in blue. You can imagine that with a single deletion, the kidney cell is losing, in fact, four copies or one copy of these four different tumor suppressor genes, the BAP1, PBRM1 and VHL.
BRUG 10 VHL mutat high low grade diff
We have proposed the following model. We believe that renal cell carcinoma, and this is consistent with Gerlinger and colleagues, that it begins with an intergenic mutation in the VHL gene. And this is followed by loss of 3p, with a concomitant loss of one copy of all of these tumor suppressor genes. We then think that a mutation in PBRM1 leads to the loss of PBRM1 function, which is a two-hit tumor suppressor gene and low-grade tumors, whereas the mutation in BAP1 is associated with the development of high grade tumors.

REFER to ABOVE PIE CHART re High and Low Grades
This model also predicts that patients with BAP1 and PBRM1 deficient tumor have different outcomes. So we simply took those patients whose tumors we had analyzed and asked what happens to their outcomes.

BRUG 9  BAP1 & PBRM1 on chromo 3p VHL

BRUG 12 BAP1 & PBRM1 diff outcomes

As you can see here, we found that patients with PBRM1 deficient tumors had a significant better Overall Survival than those who had BAP1 in their tumors, which had a Hazard Ratio for that of 2.7.

We did a similar analysis with the TCGA cohort, and we found essentially the same result in the same hazard ratio of 2.8, indicating that BAP1 mutant tumors are associated with worse outcomes. This data has now been reproduced by Hakimi and James Ying at Memorial Sloan Kettering, as well as the TCGA with their own analysis and our colleagues in Japan and Tim Eisen.

BRUG 12 Limit of Sequencing
There are some limitations of sequencing. We all like next generation sequencing, but it has some limitations. First, it focuses on DNA. Second it uses pooled material. Thirdly, it has reduced sensitivity which is a consequence of contamination by normal cells. In addition, a negative result does not guarantee that it is normal function. There is poor discrimination of subclonal mutations in different cell populations, and as a consequence of using poor material, we cannot tell whether these mutations are found in the same cells or different cells. Typically, it involves fresh frozen samples which are reduced in numbers, and consequently has limited power for doing some analysis.
Interestingly enough, immunohistochemistry (IHC), which we’ve use for a long time is a lot more precise. This is because actually you get information at the cellular level, and you get information about the protein. I mentioned to you that BAP1 is a two-hit tumor suppressor gene, which basically means when it gets mutated, you lose both copies.BRUG 14 dev of BAP1 IHC test

As you can see here–this is the same series showed before. These are here in blue the tumors that had mutations, in the second column, you can see blue and brown, the results by immunohistochemistry. That is done by IHC. And BPA1 is a nuclear protein, as you can see in these beautiful nuclear staining.

The bottom line is the majority of tumors that had mutations had lost BAP1. There were two tumors with point mutations where we were able to detect the protein. But there were three additional tumors we could not detect protein, but where there was no protein. If there is no protein, there cannot be functioning.

With the rest of the tumors, with one exception, were all positive. So compared to mutation analysis, in fact, there is positive predictive value is better and the negative predictive value is pretty similar.

Brug 14
We have used this immunohistochemisty test in conjunction with the Mayo Clinic, looking at their registry with over 1300 with localized ccRCC. As you can see, looking here with people with specific RCC survival, patients with RCC tumors that have BAP1 positive tumors have significantly better survival outcomes than those who have BAP1 negative tumors, again with a Hazard Ratio of approximately 3.

BRUG 16Evalu of PBRM1 by IHC cohort
Now in the same cohort we looked at BPRM1, which like BAP1 in a two-hit tumor suppressor gene, and we find no significant differences.
(The following slide in presented in two parts for ease of following the lecture.)
Importantly, this test allows us to identify tumors that are simultaneously mutated for BAP1 and PBRM1. This is important.

BRUG 17a IHC ids tumors Upper

Upper half of slide. These images of pathology slides

I am going to show you look at this tumor over here (upper left path slide) you can see that the tumor cells, there are some that have brown nuclei, but these are the endothelial and the stromal cells (along the edge of the white). The tumor cells are negative for BAP1.
This is the immunohistochemistry (upper right path slide) for PBRM1, where we find the same thing, the tumor cells are negative for PBRM1.

Lower half of slideBRUG 17b IHC PathSLIDE

Now (below left path slide) compare these tumors with these below. You can see here that the tumor cells positive for BAP1 in this area (the upper right portion of the path slide indicated) and they are negative (in the lower left of the lower left path slide.), where you can see specific nuclei which look blue over there.

Now if you look at the parallel section (Lower right path slide) you can see the area that was BAP1 positive (left hand side) is actually also PBRM1 negative, and the area which was BAP1 negative is actually PBRM2 positive. So what you have over here (in the upper slides as above) is a tumor which has lost BAP1 and PBRM1 in the same tumor region, the same cells. The tumor has lost BAP1 and PBRM1 in independent regions. Obviously these tumors will be acting differently and the tumor we are most interested in is this tumor type (in the upper left image).

BRUG 18 IHC BAP1 & PBRM1 ids 4 sutypes ccRCC
You have seen in our immunohistochemistry test, and we believe we can separate clear cell renal cell carcinoma into four different molecular subtypes. This is looking at Mayo registries where the patients with best outcomes are those whose tumors are well-typed for PBRM1 and BAP1. Then you have patients that have tumors which are deficient for for PBRM1, patients that have tumors that are deficient for BAP1, and patients whose tumors are deficient for both. As you can see the Hazard Ratio is 1.3, 3.2 and 5.2, respectively. As I mentioned to you at the outset, that these tumors are under represented and indeed in this very large cohort, we found a very large significant under representation with 1.8% of the tumors being double mutant, compared to 5.3% (which would been expected) with a very highly significant p value, again indicating there is mutual exclusivity–for reasons we do not yet understand.

BRUG 19 Nomogr vs Biology
Importantly BAP1 and PBMR1 do not predict outcomes independently of SSIGN, which is the nomogram created by the Mayo Clinic, which is based on Stage, SIze, Grade, and Necrosis. This is the SSIGN nomogram; this is the independent validation. You can see the curves separate beautifully, depending upon the score.

BRUG 20 Nomo vs Bio ANIMACapture
Now another question I submit to you. Should nomograms trump biology? In other words, if they live the same, “What do I care?” That has been the traditionally the thinking in the clinic. But look at these animals. A bullfrog and a grizzly bear also live about 30 years. However, they’re very different. The same is true for cottonmouth, a beaver or hummingbird or a newt. So even though they live the same, they are actually quite different!

We should be probing deeper and in fact, they should be dealt with differently!

BRUG 21ccRCC per genes
I believe that clear-cell renal cell carcinomas are in fact divided for at least four different subtypes. There are tumors that are both wild type for both BAP1 and PBRM1, tumors that are PBRM1 deficient, tumors that are BAP1 deficient, and tumors that are deficient for both. In the future were going to see different treatments for different tumor types.

BRUG 22 Conclusions

These two genes define for distinct subtypes, which I just went over and you have the Hazard Ratios and p-values. These two tumors are not only associated with different outcomes, but they are also associated with different activations on the mTOR1 pathway and gene expression. Finally we identify mutations in BAP1 which define a novel clear-cell renal cell carcinoma syndrom e. I have forty seconds left!

BRUG 23 nnRCC graphic

I will go through these very quickly. Suffice it to say, we have done molecular genetic analysis in non-clear-cell renal cell carcinoma, papillary, chromophobe, oncocytomas, This is now in press in Nature Genetics.
We found that papillary clear-cell carcinoma have more mutations than clear cell carcinoma, whereas chromophobe and oncocytomas have significantly lower mutation burdens, which is depicted there.

BRUG 24 Intr gen analy subtype RCC

These are some genes we found overrepresented– five seconds! You can see the copy number alterations, gene expressions. Anyway, these papers will be coming out next week.

BRUG 25 Associates

Finally, to acknowledge people who did the work in my laboratory, Pena-Llopis. We have had a close collaboration with the people at Mayo Clinic, and also the group at Genentech, and we work very closely with our surgeon and Payal Kapur, our pathologist.”

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Younger Patients & Kidney Cancer: Your Genes or Your Luck?

Once you reach a ‘certain’ age, you are horrified, but not surprised to get a cancer diagnosis, or hear about it in a loved one.  That same cancer in a young person is even more horrifying, we instinctively know.

Most kidney cancers (and there are more types than we previously knew) are found in people in their 60s and 70s.  Bad enough, but a cancer called by the same name and found in a younger person is often a very different cancer, with a very different prognosis.

Some new research recognizes that special attention should be paid to those RCCs found in patients 46 years of age and younger.  Why is this?

The quick answer is that this may represent a more aggressive kidney cancer and/or be of a familial or hereditary nature.  That important distinction has researchers strongly recommending that young patients be referred for genetic testing.  This can explain those special risks and create more appropriate treatment plans, and alert other family members as to special monitoring. Critically it may change the approach to any removal of the kidney and/or tumor.

Typically a small renal mass might be monitored or removed by either surgery or some laser ablation.  If removed, the tumor can be assessed by a pathologist–a look under the microscope.Without a prior biopsy, the ablated tumor will not be examined, and no genetic testing can be done.

BIG HOWEVER HERE: even with a good pathology report, that may tell only what that tumor looks like–not what pushed it to grow, i.e., the genetic drivers. And those genes don’t go away with the tumor, so the risk remains that more tumors will grow, maybe in the second kidney, or in the partially removed kidney.  Plus the rest that can happen with cancer…

An 75 year old whose small renal mass is removed will likely function well with one kidney.  That same tumor  in a 35 year old creates another challenge.  If that tumor is driven by familial genes–not just by sheer bad luck–more tumors on the other kidney may be in the works.  A partial nephrectomy   must be considered. The risk of more tumors emerging in that kidney AND the other kidney is high.  The younger patient needs decades of good kidney functioning, but those decades carry the risk of the emergence of more mets.

What else should trigger a genetic testing?

Quick answer: anything that doesn’t look like the senior  citizen with a single tumor in one kidney.  More officially below:

Early onset of kidney cancer is 46 years or less.

Bilateral (two-sided) or Multifocal (many locations) kidney tumors

Family history of kidney cancer, 1 or more close relative, 2 or more in more distant relatives

Kidney cancer with either a mix of other tumor types roughly related to kidney cancer or with lung cysts or pneumothorax (air leaking out of lung into chest cavity)

Personal or family history of kidney cancer syndromes.

The above list is from Yale  School of Medicine, Professor Brian Shuch, who work includes dealing with heredity forms of kidney cancer.

More small renal masses found at an earlier age in more patients, as our imaging techniques improve and more CTs scans are done. Not all will be hereditary, and many will be sporadic or out-of-the-blue kidney cancers.  Those are likely due to the sheer chance. Things go wrong as trillions of cells divide and make DNA mistakes along the way. Years of environmental damage may overwhelm the body’s ability to correct those DNA mistakes–i.e., the immune system gets overwhelmed, tricked, tired, etc.

Kidney cancer found at an early age or with the bilateral/multifocal tumors simply must be tested as to it genetic origins.  This gives information critical to protect the rest of the kidney(s) and to participate in treatment that is more helpful.  Finding an effective treatment will still be a challenge, but proper treatment requires knowing exactly which kidney cancer you have.  From there, a real plan can be developed.

Just as I remind all readers to work with an experienced RCC oncologist–not just a surgeon and/or urologist (sorry guys, we need a team)–those who fall into this early and hereditary renal cell carcinoma category must also work with super specialists.

The person to contact at NIH is genetic counselor Lindsay Middelton at (301) 402-7911. She is with the National Cancer Institute’s Urologic Oncology Branch.  An introductory link is below to the NCI and two other rare kidney cancer organizations.

http://www.cancer.gov/cancertopics/causes-prevention/genetics/genetic-testing-fact-sheet

Birt-Hogg-Dubé syndrome:
http://www.bhdsyndrome.org/for-families/what-is-bhd/

Other syndromes causing kidney cancer:
http://www.bhdsyndrome.org/for-families/kidney/other-causes-of-hereditary-kidney-cancer/

 

 

 

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Recurrence? Is There an App for That–or a Medicine?

Being diagnosed with kidney cancer is a stunner.  Facing surgery and endless, oft unanswered questions changes your life.  Patients with small tumors, easily removed, are often told not to worry about it coming back.  Of course, there is ALWAYS the possibility that even small “I got it all tumors” can recur.  Sadly, the current guidelines fail to catch about 30% of recurrences, using the 2013, 2014 guidelines.  These guidelines were from an earlier era, where there were fewer small tumors found, so there was data lacking on long-term follow-up.

We patients ask? “Why not just take the meds that the patients with metastatic disease do?  Wouldn’t that prevent it from coming back?  If it works to fight the mets, why wouldn’t it prevent new ones from getting a foothold? “

Why not use the meds that they use now against metastatic disease? Why wouldn’t that work?  Have they tested that idea?

In February of 2015, a study was released which comparing patient response to 1) sunitinib (Sutent),2) sorafenib (Nexavar), or 3) placebo (no real medicine).  This  three-arm study included 1,943 patients who had locally advanced clear cell and non-clear cell histology RCCs. They were thought to be at high-risk for recurrence of their cancer, and might benefit from “adjuvant” therapy.  The researchers hoped that they would see a 25% improvement in time to recurrence of disease with the meds vs no meds.. That would means that the typical 5.8 years median Disease Free Survival (DFS) would go to 7.7 years.

Sadly, there was no benefit to taking the active drugs compared to the placebo.  More sad is that the patients had side effects associated with the drug, referred to as “adverse events”. In fact, many dropped out of the active agent arms into the placebo arm, certainly knowing that the med they were taking were anti-cancer meds.  Those “adverse events”, severe fatigue, hypertension or hand-foot reactions, were observed in those taking the active agents and rarely in the placebo patients.

The median time on the drugs was 8 months.  That means half the patients  were on drugs more than 8 months and half were on the drugs less than 8 months.  Even those patients starting with lower doses of the drugs fared worse than the placebo group.

Despite taking the medications and enduring the side effects, the recurrence was about the same.   With medication or without, these patients, as groups, did the same.  Those taking the meds had Disease Free Survival of 5.6 or 5.7 years, similar to those not taking any real meds.  There was no real added benefit to these patients.  Certainly the quality of the life was affected by the side effects, and the constant reminder of the spectre of more cancer.

What can patients learn from this study?

The fear of recurrence is real. After all, the expected time until the disease progressed (love using that term for cancer!), was about 5 1/2 years.  These patients were carefully monitored with CTs on a regular basis, which caught their recurrences as soon as possible. Had they not been in this trial, it is reasonable to expect that many would not have received those scans and not know of the recurrence as it happened.

The reality is that the typical patient may or may not continue to be monitored. Even those who passed the 5 1/2 year mark without recurrence may not realize that RCC can come back.  Again, 30% of recurrences in small, non-metastatic disease are not caught.  One can assume that the higher risk group in this trial would also be at risk for that level of recurrence.

Take-home message: At present, nothing has been shown to prevent recurrence of this locally advanced disease. Even the non-metastatic small tumors that have sent out invisible “wanna-be mets”, and no one can yet guess who is at the most risk.

The best approach is to monitor yourself and your general health and to demand CT scans, especially in the lungs, where metastatic RCC is most likely to start.  That does NOT mean an x-ray, as those mets would have to be about 1/4″ in order to be seen.  My own lung mets were under that size when first found, but there were hundreds of them, and they grew quickly.  Not visible on an x-ray, but growing every day.

Despite the disappointing study above, the ASSURE study, more clinical trials are recruiting patients for similar studies using drugs that have already been shown to be less active than those in the ASSURE study.  I would be cautious in getting into such a trial, and would spend my energies seeing that my monitoring is extended at least until 10 years past my surgery–even with those “got it all” primary tumors.

 

 

 

 

 

 

 

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Molecular Pathways–A Mess or a Network?

Trying to explain in a patient- and Peggybrain-friendly way how molecular pathways which go awry and lead to cancer, I kept reading about enzymes and antagonists.  With these various genes with their cloning, overexpressions, mutations, and amplifications, and their antagonizing one another into action or inaction,  now I antagonized!   Go slow on this, marvel at the body’s complexity and remember there is no magic bullet to end cancer.  Sorry to all, especially to the newly diagnosed, but this is true.

Molecular Pathways—Or a Network?

The complexity of the dynamic molecular pathways that are essential to our very beings cannot be understated. Researchers are beginning to understand these signaling systems.and no wonder. In a dynamic dance, push cells to divide, to move and to die off, all  to support the human organism. When those actions become aberrant,  tiny changes can be life-threatening.

“Pathway” is used to explain these interactions in the molecular processing, but it evokes a linear image, direct and orderly. Each chemical reaction may seem to be a stepping stone on that path of cell growth. Missing a step or shifting into another pathway may impact the information sent to the nucleus of the cell.  Missteps in this process can lead to unwanted growth, or the path being interrupted completely. But  a molecular pathway is anything but simple and predictable.

Pathways may better be described as a string of knots to be loosened or tightened—or both. Each knot is a point where molecular changes may be triggered by chance interactions from outside that string. Those many pathways with their overlapping functions are wadded together, in an intricate spider web.  These tangled paths add efficiency as they can create “work-arounds” as needed, supporting the required needs of the system. All such pathways lead, directly or indirectly to the nucleus of cells, and to some function of the cell or larger system.

As those actions cascade down that string, from one knot to the next, they are influenced by other actions and reactions, and can trigger other pathway cascades. The aberrant or misdirected impulses can trigger unintended growth signals, or fail to stop the appropriate death of unnecessary cells (apoptosis=cell death). If something goes wrong, the exquisite and swift balancing act can shift to support a cancer cell. Once that cell has been created, it may evade the inhibiting signals,  subvert other processes, create its own support structure and to move to other parts of the body.  This may lead to metastases or spread of a cancer to a new site.

One large and complex pathway which can give rise to sporadic tumors and to genetic syndromes is that of the PI3K (phosphoinositide 3-kinase) pathway. Most often it is referred to as the PI3K/AKT/mTOR pathway, a reminder of its wide  span of action. It is an especially involved pathway, as per the long name! Studied since the 1980s, the PI3K pathway plays a key role in essential cellular functions. It is fundamentally involved in development of the embryo, and is one of the most commonly activated signaling pathways in cancer.

Mutations can be found in the inherited gene (germline mutations) or sporadically (somatically) as a part of normal growth, aging or environmental causes.  Germline mutations make some people more likely to develop a certain cancer, while other people get a similar cancer by sheer chance.  By studying germline mutations, researchers gain insight into the sporadic mutation versions of many cancers.  Since the PI3K pathway is so fundamental in growth, there is great need to target of this pathway to find relief from the cancer-inducing signals.

Relationship to Receptor Tyrosine Kinases

The PI3K pathway is linked to the large class of Receptor Tyrosine Kinases, (RTKs), and its activation can lead to a wide variety of cancers. The type of those alterations–whether mutations (changes) or amplifications (duplications)—gives rise to different cancers. For example, a mutation of PIK3CA on this pathway is found in 27% of breast cancers, and 17% of urinary tract cancers. Amplifications of that same gene is found in different rates in several lung cancers. Related PIK3CA is found in 53% of squamous cell cancer and just 12% of adenocarcinomas, while the mutation of PIK3CB is expressed in 80% of bladder cancers, and only 5% of breast cancers.

 Activation of Pathway

 As PI3K becomes activated, whether from PTEN or other growth factors, it subsequently will activate AKT (Protein Kinase B) and then mTOR (mammalian Target of Rapamycin. All play a role in cell proliferation and apoptosis (natural cell death), so any over activation can lead to excessive growth or loss of  natural inhibitors. Once cells no longer function under the normal restrictions, they recruit additional growth factors, override immune responses, and proliferate.

 Tumor Suppressor PTEN and PI3K

A tumor suppressor PTEN (phosphastase and tensin homolog) can be found on this pathway. This protein is encoded by a gene which is frequently mutated in many cancers. Loss of  this tumor suppression activity happens in about 70% of prostate cancers. Coupled with the other alterations in PI3K and its downstream AKT (protein kinase B), the loss of this suppressor can lead to the development, not only of many cancers, but other disorders. Germline (or inherited) mutations in PTEN play a role in, some non-malignant tumors and related syndromes, and possibly some autism spectrum disorders.

Should the PTEN gene mutate and its tumor suppression be limited, changes are triggered along the PI3K pathway. Those mutations can occur in many of the steps along the pathway to the nucleus of the cell. One misstep–an amplification or a mutation–can lead to more such missteps. With those variations, the resulting tumors will have varying incidence of that mutation. An amplification of one element will be found more frequently in certain lung cancers, and rarely in a prostate cancer. Bladder cancer may show overexpression of a related element in 89% of the time, while never exhibit another type of mutation.

All of the elements in this PI3K pathway can contribute to cell proliferation, to cell survival and motility (ability to move) and to angiogenesis (blood vessel development). Agents to target this missteps along the path have been developed, Some act to inhibit in the PI3K subpath, others in the AKT subpath, and several in the mTOR(mammalian target of Rapamycin). These agents are prescribed for cancers as  varied as the steps along the pathway.

 Therapeutic Agents in Use and Development

 The mTOR family of inhibitors includes Temsirolimus (Torisel) and Everolimus (Afinitor), approved for some renal cell, breast and pancreatic cancers. Many others are in development and in trials for a mix of blood and soft tissue tumors.

Upstream from mTOR is the PI3K pathway, so both can be targeted. Currently under study is an inhibitor of the AKT pathway, Perifosine, for the treatment of colorectal cancer and multiple myeloma, in combination with other drugs. Similar drugs are under investigation as they may overcome resistance developed to other drugs.

 Genetic Analysis and Treatment Approaches

Multiple genetic alterations these pathways can be found in the tumors or blood of cancer patients. Those alterations may trigger more changes in the primary tumor as it grows. That first kidney tumor can continue to change, following the initial mutation in the first few cancer cells. Billions of cells mutate, evade the immune system response, and respond to the new molecular actions. Thus,  new and different cell types may be created. A primary may exhibit certain characteristics, and its metastatic tumors may be quite different. Some tumors may respond to a treatment and nearby tumors will not, as each may have developed in response to different molecular interactions in the same pathway.

It is vital to have a thorough analysis of the tumor’s  from several places in the tumor, as well as from any metastases. Only with this can therapeutic agents be chosen to counter the cancer/those cancers. Pathologists may find several different types of cells in one tumor, and in the same tumor find still other unique cells from another tumor sample. The impact of molecular analysis will certainly change treatment, but it must begin with a very sophisticated and thorough gathering of the cellular material deemed to be cancer.

 

 

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Biopsies for Tumor Identification–Is the Biopsy Dangerous?

For years, doctors have debated one another about what to do with little kidney masses, i.e., “small renal masses or SRMs” in doctor-talk. Patients hear this debate only when it applies to them, or if there is some hysterical headline about tumor cells escaping the tumor because a biopsy was taken. What is the reality, and what value does this have to the patient?

First of all, most large tumors/masses on the kidney are found by CT or other imaging. In the kidney tumor world, large can mean

For years, doctors have debated one another about what to do with little kidney masses, i.e., “small renal masses or SRMs” in doctor-talk. Patients hear this debate only when it applies to them, or if there is some hysterical headline about tumor cells escaping the tumor because a biopsy was taken. What is the reality, and what value does this have to the patient?

First of all, most large tumors/masses on the kidney are found by CT or other imaging. In the kidney tumor world, large can mean anything over 3 to 4 centimeters in size. Taking out my inch ruler with its handy centimeter imprint, I see that is just over an inch to about 1 1/2″ in size. Might be the size of a walnut to so–still doesn’t belong there, nor sound too insignificant to me!

Nevertheless, that is a Small Renal Mass, and is not even considered for treatment by some doctors. Our newer and more frequent imaging can find tumors of this size, long before they would be felt by a patient. They may or may not ever grow much larger, or do so very slowly. In fact, about 25% of these SRMs are not cancerous. Rather reassuring, except for the obvious conclusion that 75% of them are indeed cancerous! Size doesn’t matter in this case! Add to that the possibility of that benign mass may continue to grow and mutate/change over time. Its benign character may not remain benign.

Some 10% of these masses may subtypes of RCC which rarely grow,and imaging cannot determine that. The patient may be too old or ill for surgery at the time of discovery. A rush to surgery may not be appropriate but can a biopsy answer some questions–and is that dangerous?

Some have raised a concern that inserting a needle into the mass to get cells to examine is inherently dangerous, and could release cancer cells into the body, especially along the track of the needle. Of course, any mass large enough to be seen is likely already sending out cells in the course of its growth. The chances of any such cell becoming an established tumor is incredibly small, but every metastasis got started from some ambitious and lucky cell landing on a fertile spot in the body.

The reality is that there have been very few cases of obvious tumor seeding along the needle path, as a biopsy is taken. And these biopsies can be very helpful in determining whether or not the mass is cancerous. Thus a biopsy should not be avoided, if there is a question as to the nature of the biopsy or if surgery is considered inherently dangerous.

But does the biopsy give all the answers? Unfortunately, it does not, and especially since the typical biopsy will not differentiate between certain of the newly-discovered subtypes of clear cell renal cell. In short, some clear cell tumors may be destined to be more aggressive, while others may be very slow-growing. This can be analyzed only by a molecular review of the cells, which is not done typically. Thus, even a biopsy–now thought to be far safer than in earlier years–may not provide a solid guideline for the next treatment. Getting the molecular analysis, as described in a previous blog about ccA and ccB variants of clear cell RCC, will become essential for patients in the near future. Or so I fervently hope.

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Help Save Research Data; Your Signature Needed

This is a call to sign and save research data that may disappear and not be used for any purposes, which could impact not only current patients, but others who may be affected by this research.  We as cancer patients are aware of the value of other research suddenly being valuable to us. Having been diagnosed with a potentially fatal aneurysm (all OK now), I jumped at the chance to help.  Please do sign onto this petition. The link is below.

After 10 years of gathering data and tissue samples, this ongoing study has been canceled. All the work will simply be lost. The study is the major hope for people with potentially deadly connective tissue syndromes including fibromuscular dysplasia, Ehlers-Danlos syndrome, aneurysms, Marfans, and Stickler syndrome. We have communities at Smart Patients for FMD and EDS, but they don’t have enough people to carry this petition. Only a few hundred more signatures are needed. Help keep hope alive. Please sign the petition. Please share this petition with your own community and your friends elsewhere, just as been done at my favorite site, https://www.smartpatients.com

It could save lives. http://www.change.org/petitions/nih-keep-hope-alive-and-restore-lifesaving-study?share_id=QHpGZOagay&utm_campaign=signature_receipt&utm_medium=email&utm_source=share_petition

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Early Stage RCC: We Caught it Early. I Was Lucky; –Maybe Not So!

One of the warnings about kidney cancer is that it is sneaky. Researchers call it aggressive and insidious in nature, as there is a 20-40% recurrence rate for clinically localized disease, i.e, small, hasn’t spread, not to worry, etc. There are many patients who feel reassured by the doctor, generally a surgeon, that “we got it all”, and that there was no need for additional follow up.  No CT scans, no blood tests, no nothing. 

Most patients are pretty grateful until RCC lives up to its sneaky reputation and makes a surprise return.  Since the return is indeed sneaky, is it also sporadic?  Is there a way to know which of those patients might need far closer monitoring, or should all of these patients have multiple CT scans or just wait until there is a return.  Most early tumors are found incidentally, while checking on something else. That “lucky” patient with a RCC diagnosis may be part of the group which will never have another problem again, or part of the  20-40% who gets “lucky” again.  That return of disease can also be silent, with the patient at an advanced stage and in far worse shape than the first time around.  What to do?  CT scans have their disadvantages, and living under a cloud is pretty hard, and getting RCC again beyond discouraging.

Those nameless researchers, for whom I say prayers of thanks often, have a new tool to determine which early RCC tumors are naturally more aggressive.  With this info, patients can be monitored more closely, while the others can live with greater confidence.  We’ve been hearing about BRCA genes in breast cancer, thanks to the attention-getting Angelina Jolie. Now we are learning about a related protein in RCC.  The expression of this protein helps refine the risks of the early stage RCC patient.

Now it gets a bit technical,but it is important to understand the science here to understand its impact.  he expression or lack of expression of some genes can impact prognosis, or clinical expectations, in cancer patients.  In clear cell RCC, not the rare variants,such as papillary or others, the  lowered or negative (or lack of) expression of BAP1 may signal a cancer that is naturally more aggressive than others.  BAP1, also called BRCA1 associated protein-1, is an enzyme which plays a role in cell development, can be mutated or changed in breast and lung cancers, which has been recognized for some time.  Recently the Mayo Clinic released a report which indicates that the lack of BAP1 in early stage RCC was associated with greater risk of death for those patients.  This is important stuff.

How do they know this?  The researchers can detect that expression in tumors.  They compared its presence with the outcomes of patients described above.  They used 1,479 tumors from patients with nephrectomies for localized ccRCC.  This is a very large sample, something important in any trial or research of this nature.  They were able to test 98% of the samples provided, and found 10.5% were negative for BAP1, 84.8% were BAP1 positive, and the balance were unclear.  After 8.3 years of following patients (Notice how long it can take to get GOOD data.), 1,092 patients were alive, and 252 had ccRCC specific death.  Those patients who had BAP1-negative tumors were at a threefold increase risk of death compared to those with BAP1-positive tumors.

Thus, the researcher advocate using BAP1 staining, or analyses, post surgery, to monitor those patients at greater risk of recurrence and death from this subset of ccRCC patients who are likely at greater risk.

All the nagging that kidney cancer patients do to one another to be monitored, despite having had small tumor which was supposedly completely excised is not as effective as it should be.  Neither is the “Don’t worry, we got it all” attitude that too often impedes a proper monitoring.  This new tool is more objective and should be part of the post ccRCC surgery monitoring.

Just to stir up extra trouble, there may be a case for getting a biopsy to use for this testing, when the small, incidentally found tumor is “slated to be ablated”.  Would a biopsy be appropriate, in order to see the level of this protein and the aggressiveness of the tumor?  Stay tuned.

http://www.cancernetwork.com/news/bap1-independent-marker-outcomes-low-risk-rcc?GUID=D8B6CC05-B375-4A91-92DB-5FF37C469CDF&rememberme=1&ts=15012014

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