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Clinical Trial for NEWLY DIAGNOSED–Surgery Now or Later with an Immune Therapy Option

Kidney cancer patients are stunned by their diagnosis, anxious to make a treatment decision, and  simply not know what to expect.  If you are struggling with the issue of surgery to remove the tumor/kidney or to start with a med, you need to read this.  Deb Maskens, Kidney Cancer Patient and Patient Advocate, our guest writer is a valued member of our disease community and currently serves on the Renal Task Force for the National Cancer Institute.  A series of links below will also be helpful.  (My extra comments will be in italics, like this. )Welcome aboard, Deb! 

Clinical Trial Opportunity for Newly Diagnosed (Non Metastatic) Kidney Cancer

As a community of kidney cancer patients, we  hear from newly diagnosed patients  looking for treatment options. This is written for those patients, and for patient advocates who help patients navigate through their treatment decisions.

The challenge: this clinical trial is available at many locations across the U.S. and Canada, but patients must ask about it BEFORE they have a nephrectomy. Their own doctors may be unaware of the trial and how to work with the trial centres.  In many places, patients get booked for surgery prior to learning about this option.  That would be too late for a trial like this–it gives a drug therapy before the surgery for a brief period.  (In one of the t wo arms, there is medication before the surgery.)

Why Might Patients Consider this Trial?

For years, the standard of care for early stage kidney cancer has been to remove the tumour surgically, sometimes with the entire kidney–either a partial or full nephrectomy. That was the end of treatment and the beginning of surveillance to watch for any signs of recurrence.  (And early stage tumors can be quite large–up to 7cm or about 2 3/4″.)

Now we hope to prevent a recurrence of disease. Since advanced or metastatic kidney cancer is still incurable for the vast majority of patients, this is a worthy goal. With preventive or ‘adjuvant’ treatments, maybe we can stop the disease before it gets to the lungs, liver, bones — to those places where it begins to threaten our lives.  Other cancers use this approach and offer patients a real chance to avoid recurrence.

Adjuvant – and Perhaps One Step Better to Neo-Adjuvant

We’ve seen trials for “Adjuvant” (or preventative) therapy which hope to prevent recurrence (treatments given immediately after nephrectomy). But one trial goes one step better – it’s for “Neo-Adjuvant” (before nephrectomy) as well as Adjuvant (after).

Patients may want to rush to surgery to “get it out”. In reality, those tumours have generally been  growing slowly, undetected for many years. Kidney cancer surgery is rarely an emergency. There is usually time for a second opinion and to check out any newer approaches.

Here’s the thought: given that the tumour cells have gone undetected and tolerated by the immune system for so long, can put those millions of cells to work and make them “show their calling cards” to our immune system before we take them out?

Combining Neo-Adjuvant and Adjuvant Treatment – PROSPER-RCC

The Phase 3 clinical trial called PROSPER-RCC (NCT03055013) is  for patients whose tumors are 7cm (2 ¾”) and larger in size, but not spread beyond the kidney area.  These patients are at greater risk of spread of the cancer than those with Stage I or with smaller tumors.

Based on earlier studies, nivolumab (Optivo) is now approved for advanced kidney cancer. This is a trial to test whether there is a benefit when nivolumab is given immediately before and after a nephrectomy when tumor cells might have spread outside the kidney but are too small (microscopic) to see on scans.  (Typically a patient without spread of disease would not be treated, but monitored.)

The Rationale for PROSPER-RCC: Why It Might Be Helpful

Here’s what I’ve learned:

  • Checkpoint inhibitor treatments with PD-1 blocking drugs like nivolumab seem to work best when the immune system may be being turned off by this cellular growth pathway. Cancer is deceptively clever and some tumours can express a protein, PD-L1. This protein can turn off our immune cell responses that recognize and fight the cancer.  There was a hint of this  with some positive data that indicates that these drugs work best in patients whose tumors were “PD-L1 positive”.  (PD means Programmed Death and PD-L Programmed Death Ligand or connector.  Death to the cells, and the signalling loop that hinders the immune response.)
  • In theory, when the kidney tumour is in place, there are millions of cancer cells. All of those tumour cells send off multiple negative signals to the immune system to stop it from working. However, if a checkpoint inhibitor was used and stopped those blocking signals, the immune system would have a big wake-up call – e.g., lots of targets with which to build an army of T cells. In theory, these newly educated T cells would later turn into memory cells. (If the body can maintain these memory cells, they would continue to fight any return of disease.)This is much like what happens when we are exposed to certain bacteria or viruses. Once we get exposed to the bug, we don’t usually get it again. Our immune cells have learned (“immunity”) how to kill it more quickly the next time before it turns into a full blown cold. Similarly, if these anti-RCC immune cells ever see one of these tumor cells anywhere in our bodies again, they would know to attack and kill them even if there is no drug in the patient and has not been for some time.
  • Surgery is still the main treatment to control early stage kidney cancer. But it will also remove the majority of targets (PD-L1) that the checkpoint drug uses to rev up the immune system. Giving the checkpoint inhibitor before surgery may maximize/optimize the drug’s ability to wake up the immune system and build that T cell army.
  • So the surgery is important. But let’s assume a few cells might be still circulating and have gone undetected for some time. They could still show up later on a scan as an enlarged lymph node or spot somewhere. A boost of the same checkpoint inhibitor right after the surgery could then be used to remind the immune system to continue to look for those cells and kill/eliminate them when they are small. In theory, the immune system will remember what the past “trouble” was: “Hey, haven’t I seen you before?”

From what I understand, this theory worked well in mice. The checkpoint inhibitors worked better if the primary tumour was there to help provide “a target” to activate the immune system first before the tumor was removed.  While we’re not mice, this  makes sense, no?

Trial Design: What Really Happens to the Patient in the Trial

PROSPER-RCC will place patients randomly into two groups:

  • Group One gets two infusions of nivolumab before surgery (at about 28 days and 14 days before surgery). Following that nephrectomy, the patient will receive more infusions of nivolumab. This is for 9 months post-surgery altogether, with 12 more doses.
  • Group Two gets the usual standard of care: upfront nephrectomy, partial or radical nephrectomy, and will be followed by close observation at an expert centre.
  • Two arms/groups:  BLUE arm with surgery  and monitoring by the trial team, the standard of care; the RED arm with  medication before to surgery, followed by more after the surgery.

It is important to note that no patient on this trial receives any intravenous placebo/inactive treatment. Every patient is treated.  Each patient will have either the experimental treatment or the standard of care.  All are under close observation at the trial centre. This trial has been designed and discussed with patient advocates and is supported by the NCI.

For More Information

Patient-friendly explanation herehttp://www.10forio.info/clinical-trials/prosper-rcc

For contact information at over 100 trial sites, dig a bit in the site below:

https://clinicaltrials.gov/ct2/show/NCT03055013

or call the office of the Principal Investigator, Dr. Lauren Harshman, at: 617-632-2429

Deb’s Disclaimer:

As a patient and advocate for kidney cancer patients, I have been delving into the world of clinical trials and trying to understand as much as I can. I’m not a scientist, but I am a patient with this disease, so I bring that lens, along with some abilities to translate science into understandable terms. As a volunteer, I have no financial interest in this trial or any specific medications. @DebMaskensKCC; dmaskens@rogers.com

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Genetic Differences in Kidney Cancer? So What or What’s UP?

A few years back, I attended a kidney cancer conference with a highly eminent kidney cancer doctor.  He opened his talk by saying he was no longer treating kidney cancer!  The room was stunned, patients already wondering where to go for the next appointment when he finished his statement. “From now on, I will be treating cancers of the kidney.”

Not a small distinction, and a great way to confuse the patient and the newly diagnosed, but is critical.

Just because some growth lands in the kidney, that growth is not the same person to person, and even not from kidney to kidney in one person. In the link below, CURE magazine, May 5, 2017,  interviews Dr. Marston Linehan who expands upon the history and future of this work, which I have used as the basis for this report.  This research started in the 1980s, when doctors and researchers noted that some families were at greater risk l to develop some growths and tumor, some of which ‘landed’ in the kidney.  The early work defined that disease, Von Hippel Lindau hereditary cancer syndrome as to its genesis–an inherited mutational tendency in the VHL gene.

http://www.curetoday.com/articles/expert-stresses-significance-of-genetic-differences-in-kidney-cancer

This research started in the 1980s, when doctors and researchers noted that some families were at greater risk l to develop some growths and tumor, some of which ‘landed’ in the kidney.  The early work defined that disease, Von Hippel Lindau hereditary cancer syndrome as to its genesis–an inherited mutational tendency in the VHL gene.  Given that clue, patients with kidney cancer but from this inherited tendency, most often had mutations in that same gene.  These were ‘sporadic’, out of the blue mutations, but that opened the door to treatment improvements.  About 90% of patients with the more common clear cell kidney cancer have a mutation in the VHL gene–but not due to any inherited tendency.  Much work has been done for these patients and less for those with the rarer cancers of the kidney.

AND…there are more inherited kidney cancers which also enlightened research.  One is PRCC, Papillary Renal Cell Carcinoma, defined in the 1990s.  The gene that drove this kidney cancer was MET, wh0se mutations make those patients “highly likely to develop bilateral, multifocal, Type I papillary kidney cancer,” per Dr. Marston Linehan of the National Cancer Institute.

Research is being done for these people, as well as those who are affected by the similar disease which is NOT inherited. There disease also comes from sporadic mutations, these from the same MET gene.  This work is critical, as the generally available treatments are not as effective with the rare RCCs.

Still another and challenging rare kidney cancer is HLRCC, or hereditary leiomyomatosis with renal cell carcinoma. Linehan says it is not uncommon, and can make the patient vulnerable to develop leiomyomas–particular kinds of growths–and an aggressive form of Type 2 papillary kidney cancer.  Quite different genes make this happen, which can be referred to as Krebs cyle enzyme mutation cancers.  Obviously, still quite different that the garden-variety clear cell RCC (ccRCC) and requiring quite a different approach as to treatment.

Though there are currently studies underway to find more appropriate therapies for these rarer forms of RCC, some with combinations of agents that have been developed earlier in the decade, and with agents that were not originally envisioned to be used with kidney cancer–oops, cancers of the kidney.

If you don’t really know the pathology of your tumor and its genetic drive, you don’t have a complete diagnosis.  And if you relatively young for kidney cancer, the 46 and under group, this is time to discuss it with your kidney cancer cancer of the kidney specialist.

PS According to Linehan, there are at least 13 different types of inherited kidney cancers, and at least 16 known genes that can cause cancer in the kidneys…lots to learn and to discuss with your doctors!

 

 

 

 

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New “NEWS!” for Non-Clear Cell re NIVO or NOT? Limited data or a light along the way?

With the headline, “Nivolumab Shows a Substantial Objective Response Rate in Refractory Non-Clear-Cell Renal Cell Carcinoma”, the article should be welcome to all of those in the  in the non clear cell RCC world.  Clear cell  is the most common, the garden variety of renal cell carcinoma.  This is welcome news, as the non clear cell patients get very little attention from the research world. Though the patient with nccRCC might interpret this as, “Good news! Now that they know what to do for me!” , it is just not the case.  Rarely is the news all that good or all that simple.

Let’s back up here and lay the groundwork.  Clear cellRCC, or ccRCC is the most common of about 10 RCCs.  They all land in the kidney, but can vary widely. ccRCC may be about 65% to 85% of the cases of kidney cancer,  with the rarer non-ccRCCs making up the rest.  Maybe 15-35% of the RCCs are considered rare, with the most common Papillary Type I, Papillary Type II, chromophobe, clear cell papillary, collecting duct/Bellini’s, medullary,  translocational (not to be confused with transitional, etc, etc.) and to make it still more confusing, unclassified RCC. But when the most common is described as either 65% of the whole or 85% percent, you have to question if there is clarity in that category!

Clinical trials for RCC have usually only included patients who had clear cell. The reasons are simple; it is the biggest group, the patients can be more readily found, and that is the largest group in need of the medications.  But the patients with nccRCC are really also terribly underserved.    Back in the day, none of us had many options beyond surgery, so little distinction was made.  The prognosis was grim all around, once the cancer had spread.

But the new world of precision medicine, in its name alone, reminds us that the meds need to be developed more precisely, that they be given to the right patients at the right time.  The general crap shoot or “wild-ass guessing”, as a friend says, still remains.  The latest (not necessarily greatest) group of meds are the newish immune therapies.  You have seen their ads, no doubt.

One of those is Opdivo or nivolumab, its research name.  It tries to unblock some of the inhibiting mechanisms that prevent the immune system from doing its job, but it has been tested in trials only with clear cell patients.  BUT,  that does not mean that only clear cell patients are being prescribed the meds–this, thanks to the slightly wild west of the US medical system, that can truly go beyond the FDA approved medication guidelines.

This study, which will be formally presented at ASCO in June, 2017 was announced with the headline above, “Nivolumab Shows a Substantial Objective Response Rate in Refractory Non-Clear-Cell Renal Cell Carcinoma”.  The researchers are NOT in charge of the headlines, so we must dig deeper and see what this study really means to the patients with nccRCC

I tried to sort out what it means–or does not mean. My quick review is that it does not give a great deal of clarity to the majority of those nccRCC patients. A more complete report may improve upon this.  Based on this link, I offer the following:

http://www.practiceupdate.com/news/16132/67/10?elsca1=

“I am always concerned that these new study reports are characterized carefully. They are always more complex and incomplete than I would like. A patient in a forum says this tells of  ‘good’ responses, and especially so for the non clear cell group, but s does ‘good’ really mean generally a benefit to those rarer nccRCCs? Until a fuller report emerges, I can only note the following:

There were 23 patients, from three centers, with a median age of 59. Surprisingly 30% were African -American. This may tell us that there are more African-Americans with the rarer non-clear cell RCCs, or  could reflect the local population of the three centers.  Only 23 patients and with a mix of diseases will never meet the statistically critical requirements to reach the level of excellent evidence–but it may be all we have at this point.

All 23 had non-clear cell, but nearly half had ‘unclassified’ RCC, quite a high rate.  Usually that is considered to represent between 1 to 4% of renal tumors. Most of the rest were papillary, but they generally make up the largest percentage of nccRCCs. No distinction is made here between Papillary Type I or Type II, which are really quite different diseases. Papillary Type I and II are the most common of the uncommon, non clear cell RCCs, and are readily distinguished from each other.  This would be valuable info, and wonder if this was noted in the fuller report. 

Only 3 of 4 patients had nephrectomies before the trial treatment. Were 1 of 4 patients too sick to be given the standard of care of surgery or were their doctors unaware of that? How does this affect the study, and were the no nephrectomy patients from one center or with one subtype?   We do not know the reason for this high rate of no surgery, and at a time in which it is clear that the removal of the tumor is a great benefit to the patient, metastatic or not.

Two-thirds had metastatic disease at the time of diagnosis. Of the total 23, 74% had a prior treatment, mostly Sutent or Votrient. Of these patients with prior treatments, 26% had TWO such treatments.  Thus these patients had already received treatments that were not directly approved for their subtypes.  This is not too rare in the US, where we have greater leeway from our prescribing doctor than do patients elsewhere.  But how does this fit in with the relatively low rate of nephrectomies?

This report does not say how quickly they were treated, i.e., how long from initial diagnosis until treatment with Nivolumab?A patient with Papillary Type II found to have no metastatic disease at the time of diagnosis, but who received a nephrectomy, was monitored for a year or so, then went on one or more systemic therapy is quite different from the patient with an unclassified RCC,  metastatic at the time of diagnosis, not given a nephrectomy, though treated quickly with Nivolumab.  What can be learned when there are such wide variations in just 23 patients that would be helpful to the Papillary Type 1 patient?

The follow up period was a median of 6.5 months, which seems very short, especially when the median Progression Free Survival of the responders was 4.2 months. The median OS is not given. That certainly may reflect an ongoing study situation, or a failure to provide a longer period of follow up.

As to objective response, 6 of  the 21 evaluable patients (29%) had a Partial Response, which would likely be a 30% reduction in metastases. Another 4(19%) had Stable Disease. Two of the 23 patients died, but not from the treatment. (Assume that had to be due to the disease, but certainly indicates that for nearly 10% of the patients, this was not at all effective.)

When the final analysis was done, nine patients were still receiving Nivo. Newly recruited patients might still be in treatment at that time, but those recruited earlier may have gone out of the trial at the same time.  It is important to not that Nivolumab treatments were stopped in three patients due to intolerance, and six more had postponed treatment, i.e., 9 of the 23.

Certainly we need to find meds which create responses for nccRCC patients. However,  I am concerned we draw any certain conclusions from this study.  Indeed, it is “good” to know that the treatment was tolerable for the majority of the participants, but not so good to read that 6 of the 21 patients had to postpone treatment, and three were removed from treatment due to intolerable/toxic side effects.  We also do not know which subtypes seem to have shown responses, which would have been qutie easy to report.  Did the group with Papillary Type II do generally better that the majority “unclassified” group?  No answer from this stury report. And in the back of my head, I keep wondering why in the world there were so many unclassified patients in this small study?  Was there a standard pathology review, or could these patients been misdiagnosed by one pathologist. Typically there is a single pathologist which can standardize the reporting.  Were all these patients properly diagnosed?

Just wishing there were greater clarity and hoping to get a fuller report, post ASCO.

Without a doubt, the ‘good’ that comes from this sort of report begins with the recognition that the nccRCC group is underserved by the research community> They probably have the poorest outcomes, rarely have a clear diagnosis, and must wait for the ever popular “further research is warranted.”  But all must be aware that these very small observational studies must be reviewed very carefully for what they show or do not show.  Again, one to watch at ASCO, but not enough to make a major change in treatment for any one with a non clear cell RCC.

PS.  Does your doctor know that there are at least four subtypes of clear cell–the big ‘common’ group–which have clearly different survival patterns?  Thought so.

 

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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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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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Filed under Ablation & Radiation, Basics, Genomics & Genes, Making a Plan, Newly Diagnosed, Rarer RCC Cancers, Surgery, Uncategorized

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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