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Clear Cell RCC: Not as Clear as It Used to Be!

We struggle to understand what to do about our kidney cancer, but first must  exactly WHICH kidney cancer we have. Frankly, even the doctors are never too sure, and outcomes for patients with the “same” cancer varied widely.  No ready explanation was available, in those bad old days.

Treatment decisions were easy, but not effective for most, when every kidney cancer patient was treated the same.  Patients had surgery and were sent home. Those with smaller tumors, under about 2 inches, had little or no follow up.  Those with larger tumors might be monitored more frequently. Mets might emerge, and maybe more surgery would follow, but no meds were available until 1992 when high dose interleukin was approved.

Patients who presented with metastatic disease were not even offered surgery, being told that there no value to removing the primary!  An ongoing “controversy” was whether there was value in a nephrectomy when mets were found.  Too bad, so sad. (If your doctor is telling you that last bit, you need a new doctor. Now.)

Then came the recognition that there were different kidney cancers, variants and subtypes, all based on the look under the microscope.  Conventional kidney cancer became known at clear cell, and a mix of new subtypes were named.  We now hear of clear cell, papillary type I and type II, chromophobe and more.  Sarcomatoid RCC can arise from any of these types, confusing things and reflecting a more aggressive course for the patient.  Most are sporadic, out of the blue, but others have an inherited component.  Again, making things trickier yet!

Ironically, the trials in the late 80s of high dose interleukin which led to the first FDA-approved treatment, included all the above types. The relatively low response rate in this trial may have been due to the rarer RCC types, unlikely to respond.  This minimized the use of HD IL2, perhaps to the detriment of many patients. The targeted therapy studies often excluded the rarer types, hoping to boost response in a more limited group.  Few trials really test agents appropriate for the non-clear cell types, so the guessing game for them is really the norm.

With that background, there was still wide variation in the outcomes for clear cell RCC patients.  Some patients with small tumors, found at an early stage, can have very poor response to treatment.  Many such patients have long-term survival, easily over 10 years, while others who “seem” similar, succumb to their disease quickly.

Why is this the case?  Short term survival vs long term survival, aggressive appearance of mets vs slow-growing, good response to treatment vs minimal response?  Why would the same disease be so different?

Easy answer.  It is not the same disease.  Clear cell RCC, that so-called conventional type, maybe 75% of all the kidney cancers, is not really one disease. Clear cell may be subdivided into four separate types, each with its own survival pattern–and all due to its early genetic drivers. Researchers have been able to sort out the genes, compare the mutations, deficient or over-expressed, and find them in tumors of patients who were treated and followed over many years.

Just as there is no magic bullet, no one medicine that fixes everything, there also seems to be no one poison bullet.  It is not just one thing that goes wrong, one nasty gene breaking the DNA rules, but a combination.  And there will be more combinations.  This is like the typical disaster stories, where it is not just one thing that goes wrong, but a series of events and changes.  Each one of the series might not create a problem, but in combination and with the right timing, there is a perfect storm–the very aggressive tumor.

Without getting too technical, clear cell RCCs can have a mix of genes that mutate.  Recent studies have shown that two genes in particular, BAP1 and PBRM1 can either be sufficient (or competent or positive) or they can be deficient in their expression.  There are four possible combinations, positive for both genes BAP1 + and PBRM1+, negative for both genes BAP1- and PBRM-, and combinations with the BAP1+ and PBRM-, and the reverse, BAP- and PBRM+.

Why does this matter for the study patients? All of them had localized disease at the time they were diagnosed and all were clear cell patients of similar age.  BAP1 was mutated/inactivated/deficient in about 15% of these patients, and that mutation was associated with high nuclear grade, or a more aggressive type of tumor.

About 50% of clear cell patients had the PBRM1- tumors. Others had a mix of one gene positive and the other negative. Mutations of BAP1- and PBRM1- were rarely found together, but that combination predicted poor survival, in one study of just 2.1 years.   Having just the BAP1- had an overall survival of 4.6 years median, while the deficiency of PBRM1 (-) had an overall survival of 10.6 years.

This shows that clear cell RCC is really not one disease type, but four.  Most importantly for patients is the knowledge that these varying mutations may respond to different medications.  Also, these mutational differences can be seen in immunohistochemical or pathology tests, which can give greater guidance to treating physicians.

Coming soon is another lectures by Dr. Brugarolas, so watch this space.

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Filed under Genomics & Genes, Lectures from Experts, RCC Basics

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

Oligometastases?! Patients Changing the Rules

Kidney cancer is the focus here, but I can’t resist writing about the empowered and determined lung cancer patients who changed the rules–the NCCN guidelines–in treating their  cancer.  With this, there is  support for treatment for their newly established metastases which was previously lacking.  Translation for the patient was, “It’s come back, so just go home. End of story.”

What does this mean for kidney cancer patients, or for others?  For that matter what does “oligometastases” mean anyway?

” Oligometastases are defined as 1–5 distant metastases that can be treated by local therapy to achieve long-term survival or cure.”

Earlier, some doctors felt that there was no reason to treat a patient who was initially diagnosed with metastatic disease.  If the cancer had already metastasized, nothing that could be done, not even the removal of the primary tumor.  Oddly enough, patients often got no treatment and the self-fulfilling prophecy worked again.

We kidney cancer patients know better. (My 10cm tumor and the lungs full of mets would have NOT been treated by many doctors.)  Removal of the primary tumor can have real benefit, even when there is no treatment for the metastases.

Similarly, the emergence of mets post-surgery was also seen as a “game over” by many doctors.  The “got it all” surgery that was welcome news was suddenly a forgotten phrase. How many sad visits a year or two after of misplaced confidence? Kidney cancer will come back far too often, suddenly emerging near the old tumor or in some of the favored spots.  With kidney cancer, that is the lungs, bones, adrenal gland and the brain.

These new mets, generally in the area of the primary, are those oligomets.  Hard enough to say, and harder yet to be told that the docs will do nothing–because the guidelines say it is not worth it.  That was the situation for non-small cell lung cancer patients with new mets.

But these cancer patients were NOT having that kind of non-help!

They gathered all the data, showed the value of going after these mets and convinced the NCCN to make significant changes in their guidelines.  Now doctors and the insurance people cannot deny these treatments on the basis of these guidelines.

Patients helping patients, patients helping doctors, patients helping create better guidelines, patients living longer…might be a trend we can emulate.

LITTLE BACKGROUND:

Keep in mind that most doctors and insurance companies want to use treatment guidelines based on some acceptable medical standards.  One guideline comes from the National Comprehensive Cancer Network.  This establishes the working rules for what kind of treatment or monitoring is thought appropriate for any stage of cancer.  For example, the treatment for a Stage I tumor is quite different from that of a Stage IV tumor.  There are guidelines for shifting to new medications, and for monitoring of primary tumors or mets after surgery.

Since kidney cancer most often metastasizes to the lung, I monitor some of their sites, and was thrilled to see this.  Power to the patients, people!

http://www.curetoday.com/community/tori-tomalia/2015/03/empowered-patients-change-national-cancer-guidelines

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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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Filed under Clinical Trials, FDA Meds & Trials, Guidelines, Medications, Targeted Therapies, Uncategorized, Your Role

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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