by | July 17, 2014 · 11:00 pm

Adaptive Immunity in Cancer Immunology & Therapeutics–My Summary

I was dying ten years ago. My kidney cancer had moved into my lungs, threatening to choke me to death.The tumor and kidney were gone, but 100s of tiny lung metastases were growing. Lucky to get an FDA-approved immune therapy, high dose interleukin 2, my own immune system was revved up so as to destroy the cancer. Thus, I am intrigued by all things about the immune system and cancer research. “Adaptive immunity in cancer immunology and therapeutics”is one of the most comprehensive explanation of the tumor cell/immune system interactions–that I can somewhat(!) understand.

http://ecancer.org/journal/8/full/441-adaptive-immunity-in-cancer-immunology-and-therapeutics.php

My summary is below, a more patient-friendly version. Don’t hesitate to take on the original, via the link! It is just the kind of article to take to your doctor to discuss immune response meds/treatments. It begins with the “abstract”, a summary of the information to follow.

Abstract: The vast genetic alterations characteristic of tumours produce a number of tumour antigens that enable the immune system to differentiate tumour cells from normal cells. Counter to this, tumour cells have developed mechanisms by which to evade host immunity in their constant quest for growth and survival. Tumour-associated antigens (TAAs) are one of the fundamental triggers of the immune response. They are important because they activate, via major histocompatibility complex (MHC), the T cell response, an important line of defense against tumourigenesis. However, the persistence of tumours despite host immunity implies that tumour cells develop immune avoidance. An example of this is the up-regulation of inhibitory immune monoclonal antibodies in clinical practice have been developed to target tumour-specific antigens. More recently there has been research in the down-regulation of immune checkpoint proteins as a way of increasing anti-tumour immunity.”

Immune Responses in Tumors—A Quick Summary by Peg

Since cancer cells are genetically different from normal cells, they also produce different substances—antigens—which can make them more noticeable to the immune system. Any antigen will generate a response from the immune system—think how the body reacts to an infection, an insect sting or a splinter.
Antigens trigger the immune system into action, keeping abnormal cells from taking over the system—most of the time. To grow, tumor cells develop inhibitory responses to limit or down-regulate those immune responses. An over-active immune response can be problem, well-known to those with severe allergies or auto-immune diseases like lupus. Keeping the proper balance is the norm for the immune system, despite ongoing external and internal changes

Using knowledge of these interactions to support the immune system, researchers have develop agent/medications. These are intended to strengthen the beneficial responses, and to prevent the tumors from suppressing or down-regulating those desired responses. Some monoclonal antibodies can effectively target these tumor-specific antigens and trigger tumor death or inhibit such growth. Some of these new agents include bevacizumab (Avastin), rituximab (Rituxin), alemtuzumab (Campath or Lemtrada), bortezomib (Velcade), denosumab (Xgeva) and trastuzumab (Herceptin), among many others, and for a variety of cancers.

Be aware that these agents may be called by the brand name, as Sutent, or the scientific name, as sunitinib, and may have several brand names for different cancers. Just another new challenge to all of us newbies.

Tumors exist with a system of structures, various types of cells and with a chemical signaling process. These shifts away from the normal cells and organs produce tumor antigens. The immune system notices the antigens and works to destroy the foreign cells. Then the tumors shift to counter the immune response in an endless signaling battle. It is a dynamic “fail-safe” system, with multiple checks and balances, work-around pathways, evasive signaling, and constant testing to maintain itself. When this system does fail, a tumor can be established and move to different sites.

Solid tumors have a tumor core, a margin that is invading into a healthy structure–blood vessels or layers of an organ–and lymphoid components. This can vary patient to patient, despite the seeming similarity of tumors, and vary from one metastatic tumor site to another. Inside the tumor will be the immune-cell types–macrophages, dendritic cells, natural killer (NK) cells, mast cells, B cell, and T cells. Different immune cells can be found in different parts of the tumor, and the variation and the density of these cells may play a role in clinical response. It may be that this reflects the robust nature of the natural response to the tumor invasion, or reflect that the system is being overwhelmed by the tumor. Others think that the infiltration of immune cells can be utilized the support of the treatments given to the patient.
The linked journal article goes into detail as to the various types of responses, including adaptive immunity, immune editing and immune evasion. In summary, there are numerous approaches to limit tumor growth within the complex system of antigens and immune responses.
As immune cells infiltrate a tumor, that infiltration can be measured. What is the meaning of a higher or lower level of immune cell infiltration? The following paragraph sums up the challenge of using tumor infiltration as a marker of prognosis or treatment response.
It is a commonly held belief that infiltration of immune cells into tumor tissues and direct physical contact between tumor cells and infiltrated immune cells is associated with physical destruction of the tumor cells. That can reduce the tumor burden, and improve prognosis. An increasing number of studies, however, have suggested that aberrant infiltration of immune cells into tumor or normal tissues may promote tumor progression, invasion, and metastasis. Neither the primary reason for these contradictory observations, nor the mechanism for the reported diverse impact of tumor-infiltrating immune cells has been elucidated, making it difficult to judge the clinical implications of infiltration of immune cells within tumor tissues. J Cancer 2013; 4(1):84-95. doi:10.7150/jca.5482

Tumor Infiltrating Immune Cells—a Good Sign or Not?

If the immune system is at work, immune cells infiltrate the tumor to work directly against the tumor cells, is the tumor destroyed? Does the body naturally destroy the tumor? Does the patient benefit from medical treatments which support the immune system? Unfortunately, the presence of the tumor-infiltrating cells can mean very different things, with a better prognosis in one type of cancer, and a poorer prognosis in another.

Monoclonal antibodies can target antigens in blood cancers and solid tumors. In blood cancers, antibodies counter several cluster of differentiation (CD) markers, and in solid tumors, growth factors such as EGFR (epidermal growth factor receptor) or angiogenesis factors, such as vascular endothelial growth factor (VEGF). The mechanisms of action can lead to direct cell death, or simply impede its growth or inhibit checks on the immune response.

Normal cells are naturally programmed to die, but cancer cells do not “follow the program”. When certain proteins on the surface of cells bind with one another, the expected immune response is inhibited. These anti-PD-1 (anti-Programmed Death-1) proteins bind with other proteins, the binders or ligands, PD-L1 and PD-L2. Studies indicated these agents can help the immune system, with some disease stabilization or tumor shrinkage. Recent trials show some response by 20-25% of patients, some of whom had failed previous treatments. Some responses lasted more than a year. In a few cases, some responses were lasted for a period after stopping the medications. Newer trials will likely combine several of these therapies. This is not without risk, as some had severe side effects, and several patients  died from such side effects.

Nevertheless, the earlier successes with this approach and the increased knowledge of the various immune responses to be targeted will continue, especially in combination studies. This work will have impact on existing immune therapies, as does the more integrated approach to cancer treatment.

I welcome any comments and corrections, and remind you that I am a patient, and am not a medical professional. My goal is to help educate other patients to receive the best understanding of their illness and best possible treatment.

Peggy Zuckerman

peggyzuckerman@gmail.com

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by | July 16, 2014 · 2:00 am

Gene Sequencing? What is it? Does it Matter? (* *YES***)

We hear about gene sequencing and personalized medicine, and yet few of us really understand what that means. All of this, despite the hype! We also hear about targeted therapy. As a minimum that should mean that doctors are targeting the tumor for destruction, but is not that easy.  As usual.

The University of North Carolina researchers have done critical reviews of clear cell kidney cancer. They questioned why there is such wide variation in the aggressiveness of clear cell RCC (ccRCC). Almost all ccRCC looks alike under the microscope, the usual “pathology” report, but tumors don’t behave the same. Some are shockingly aggressive in their growth, even the small ones.  They metastasize quickly, and break the surgeon’s “got it all” prediction.  The overall survival (OS–the longer, the better!) is wildly different, despite the similarity.

If this is the same kind of cancer, why does it behave so differently?

The obvious answer is that these tumors are not really the same biologically. That can be shown by an inside look at the tumor’s DNA and patient’s normal kidney DNA. This is what gene sequencing can do, i.e., help define what differences exist in the tumor cell. This is essential in “targeting” the treatment to the tumor. You have to see the recognize what IS the target to hit it with the right treatment.

This linked YouTube lecture below helps explain these new terms. It gives me appreciation for the challenge faced by researchers, clinicians and patients in getting proper treatment.  And nobody cares as much as we patients!

Dr. Kimryn Rathmell and colleagues at U of NC created a test which can differentiate the more aggressive form of clear cell kidney cancer from a less aggressive form.  Should one monitor a smallish tumor, monitor a patient more closely after surgery, or just assume everything is fine and dandy?  These tests help in that decision.  (PS Don’t forget that a “small” Stage 1 kidney cancer tumor can be the size of a golf ball.  “Regular” size Stage 1 tumor can be the size of a nice tomato.  Small, indeed.)

We’ve learned it isn’t just “cancer”. It’s not just “kidney cancer”. It’s not even just just “clear cell” or “papillary” or “chromophobe”! Instead it is a molecularly defined cancer which has taken up residence in one’s kidney. Different drivers, some more aggressive than others–big surprise.  Different strokes for different folks, and different targets for different testy genes in our tumors!

https://www.youtube.com/watch?v=Y9HumO20GKc A transcription can be found in “Genetic Sequencing for Dummies and Me”

 

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by | July 15, 2014 · 8:30 pm

Biopsies for Tumor Identification–Is the Biopsy Dangerous?

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

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

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

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

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

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

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

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

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

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by | May 30, 2014 · 10:05 pm

Treatments for Metastatic RCC? Does Timing Matter? Who Is On First?

“Now what?” may be the first coherent question a newly diagnosed cancer patient asks.  Maybe the smarter version of that is “What–when and why?” And your doctor had better have a good answer, as to the treatment, the when and the why.

We cancer patients usually get surgery “first”, even when the disease has spread.  Primary surgical strike and then a clean-up operation, in the ‘war on cancer’ parlance, we think–when we can think. “But which is the best and first clean-up approach?” we must ask. “What works the best? What can I take with my other health problems? Where does surgery or radiation fit in this scheme? What does the doctor favor and why? Where do I get this treatment? And then what?”

Treatments and their sequence are often chosen with little reliance or clarity as to the data. But some light was shed today at ASCO (American Society of Clinical Oncology). It released a comparison of the sequencing of High Dose Interleukin2 (HD IL2) and of targeted therapies for metastatic RCC.  Which should come first?

It shouldn’t be a high-stakes  gamble to choose a medication, as no one can guarantee any results–with any of the meds. You take a chance with any drug, so which do you start wi We may be closer to a logical approach in sequencing these drugs. Sequencing of these highly different medications has measurable effect on overall survival (OS)—and to patients’ lives.  That sequencing is critical and certainly can extend life, even when treatments fail, as they so often do.

A retrospective study  of 97 US patients who received HD IL2, before or after a targeted therapy was just presented at ASCO. These patients were followed for a median duration 37 months–half more than 37 months, half fewer than 37 months. Of that group, 22% had either a partial (14%) or complete (8%) response to HD IL2. (No specifics as to what was a “partial” response, perhaps a 30% shrinkage of the total tumor burden). In addition, another 24% of patients had Stable Disease(SD). Thus, nearly half of these patients benefited from having had HD IL2.

Stable disease is better than progressive disease, as any patient knows, though it was rarely measured in older trials. Though we patients really want a cure, we do want to be around for the next treatment, to have a surgery or ablation to remove the “stable” tumor, or to try another medication.

Of these 97 patients, 82 received HD IL2 before any targeted therapy. Another 15 patients had HD IL2 following a TKI therapy. That timing made an important difference. HD IL2 followed by the TKI, showed a median Overall Survival (OS) of 61.8 months. The OS of those with the TKI before the HD IL2 was 48 months.  A median, not an average, so half lived longer, half lived shorter than the quoted medians.

A pre-2006 NCI (National Cancer Institute) series showed a 19 month median survival for HD IL2 alone, and a similar 19 months for the use of targeted therapy alone. Using the two in sequence dramatically improved OS, especially when HD IL2 was first line of treatment.  Obviously things have improved, though it can be very difficult to compare older trial data, as so many variables are different–including the type of RCC the patients had as they entered the trials.

Several points can be made from this study. First, no therapy should be examined only as to Complete or Partial Response. Stable Disease also adds to Overall Stability.  To stop the tumor from growing, even if for a period of time, is valuable to patients and can prep them for the next anticipated treatment.  Sure beats tumor growth!

Second, therapies should be chosen to maximize their impact on the overall survival of the patient. Some patients will naturally be precluded (or delayed) from surgery, or taking one drug due to existing co-morbidities, due to heart disease or liver damage. For those post-op patients, likely to tolerate the side effects of HD IL2, it should be given in a first-line setting.

The most critical variables that impact patients are the recommendations and expectations of the physician. Most patients are not even told about HD IL2 treatment, or it is dismissed casually as “not for you”.  Others are told to wait until more mets emerge, with some weird theory that waiting for more trouble is a good thing!  Many nephrectomy patients are not monitored post-operatively, despite the risk of mets. This is surely an indicator of the lack of knowledge by urologists. Still others are told that the disease has spread, and that nothing can be done–also untrue.

The rarity of RCC and its variants leaves most physicians unaware of all options in the field, and how to any one might suit for a particular patient.  Most oncologists to whom patients are referred, have little or no experience treatmenting for RCC, or may not access to academic centers for support until it is too late. Even the pathology of the primary tumor and later metastases may be questionable, adding to the challenge of care.

With the dramatic changes in the RCC field, this is to be expected—but not tolerated. The patient may have to provide his physician with the data that can extend or save his life, which is a sad but realistic commentary on the field today.

 

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by | February 24, 2014 · 1:09 am

Hereditary Kidney Cancer–Confusing but Critical!

Hereditary RCC: Genetic or Familial RCC

 

Most people are not surprised that there is no ONE thing called cancer. Tumors in all the organs or invasive cells in the blood or bones are referred to as cancer, but start when cells go wrong, whatever the cause.  As soon as you are told you cancer, whatever it, the quest begins to find out exactly which cancer it is.  With kidney cancer, or its more melodious name, renal cell carcinoma, there seem to be endless variations on what may be called kidney or renal cancer.  To treat it requires a very careful analysis of what is really is, starting with the pathology of the tumor when it is biopsied.  With kidney cancer that biopsy is usually done after surgery for the tumor. That biopsy will describe the shapes and type of cell in the tumor, which can be mix of types.  And then the real work begins.

A recent article in “European Urology” reviewed the mix of HEREDITARY renal cancers, those that arise due to one’s background. More common are the “sporadic” kidney cancer that could arise out of the blue or in response to some environmental toxin. There are ten Heredity Renal Cancers, or HRCs.  My goal is to alert the reader to the possibility that his cancer might be one of these. This would affect treatment, and may suggest the need to test family members.

If you have kidney cancer or RCC, you may be familiar with “clear cell” or “papillary” to refine the description of the cells in the tumors.  This may not be the whole story, as those HRCs—the hereditary kinds—may manifest a mix of ways, including as clear cell or papillary histology.

The most common HRC is Von Hippel-Lindau (VHL) disease, with both benign or malignant tumors.  RCC can be found in a 24-34% of VHL patients, appearing at mean age 39 years (far younger than non-heredity RCC), and often with multiple tumors and in both kidneys.  Cysts which appear not to be malignant must be watched–they have the potential to become malignant over time. Generally they are managed based on the size of the largest of these lesions.  Clear cell RCC is the one VHL-related subtype.

Hereditary papillary renal carcinoma (HPRC) is rarer, and typically occurs later in life.  Papillary tumors are the only phenotype with HPRC, and patients often develop numerous tiny tumors, 1000 or more.  These tumors are considered type 1 papillary renal cell carcinoma (pRCC) with a low nuclear grade, monitored with CT scans, and some do metastasize, though this is rare.  The MET gene is implicated in the growth of these tumors.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is newly identified as a HRC. Rarely do patients develop RCC, but are susceptible to developing multiple leiomylomas, which are generally benign.  When there is early onset of HLRCC, then RCC is found in about 20% of those patients.  These tumors can be aggressive, and about 2/3 display a papillary pattern.  Such tumors tend to be hyper-vascular.

Birt-Hogg-Dube (BHD) syndrome is quite rare, about 1 in 200,000 people, and thereby likely under diagnosed.  This raises the risk of developing kidney tumors, which occurs in 25-35% of BHD patients, and at mean age of 50. These tumors have varying histologic subtypes, generally chromophobe RCC or hybrid variants.  And there can be variants in the same tumor or within the kidney.  There is a risk of metastases, though rare. The characteristic skin lesions of BHD syndrome are not malignant.

Even more rare is Tuberous Sclerosis Complex (TSC), which can manifest itself in renal lesions, cysts and occasionally, RCC, the latter at a young, average age 28.  Neurologic complications can accompany this syndrome.

SDHB-associated paraganglioma/phaeochromoytoma is another heredity condition which may give rise to a mix of renal tumor, including clear cell RCC, chromophobe RCC and oncocytomas, i.e., a mix of histologically different types.

An HRCmay be suspected in patients with a family or individual history of renal tumors, in the instance of both kidney having tumors, or one kidney having multiple tumors or in early-onset renal tumor, i.e., under 50 years of age.

Clinical diagnosis can be further refined by genetic testing, and thorough review by an experienced uropathologist is fundamental to the diagnosis.  First consideration would be a VHL analysis and genetic analysis of SDHB and FLCN genes, as warranted.  Patients with type 1 papillaryRCC should be considered for MET analysis.  The presence of clinical symptoms related to any of the syndromes will guide the gene screening.  Testing on family members may well be warranted.

With these cancers, it is possible to have multiple lesions and affect both kidneys. Thus, treatment should preserve renal function and control the risk for metastases. Use of ablation to retain maximum renal function may be preferable to partial nephrectomies, for example.

Though these heredity renal cancers arise in a different manner than the more common sporadic RCC, the study of the molecular pathways provide some insight into new therapies for those patients as well.  Thanks always to those researchers who help in this struggle for information, as that is essential to provide treatments.

Peggy—Based on the European Urology 2010.

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by | February 7, 2014 · 12:15 am

Molecular Marker for RCC/ Papillary RCC. Molecular

One of the many challenges in fighting kidney cancer is knowing where it all got started.  This research indicates that a gene gone astray, the MET gene, is part of the problem from some patients.  It is this type of study that will change the treatment for us, as there will be greater clarity as to the “target” to be reached by “agents of change”.  (Nothing political intended, but seems to work here!)  Especially of interest to patients who have the variant of papillary RCC, about 10% of us.

 MET Variant as a Prognostic Marker in Clear Cell Renal Cell Carcinoma

 Dr. Ari Hakimi of Memorial Sloan-Kettering Cancer Ctr.,New York USA

ASCO GU Congress 2014

eCancer reporter Peter Goodwin’s questions are in italics. Where I was not certain of the lecture, I added a (?) to show that. Link below to the actual lecture.

Ari, you have been looking at prognosis or prognostic features, or actually, molecular features of renal cell carcinoma. Can you tell me what you were doing in the study you’ve just been talking about?

There was a great paper that was published by the people at Harvard and Lancet (?) Oncology last year. It found for the first time a prognostic marker that was associated with poor survival in kidney cancer, a molecular marker. This was a variant, a normal variant in the gene, the MET gene. In that study they had several hypotheses they generated from that study, but they didn’t really have enough genetic data to try to figure out what was going on here with this variant in the genes. So what we did was, we took that same concept, that same variant, in the Cancer Genome Atlas Study, which has both patient information and then a host of genomic information. We tried to validate their finding and explore the biology of that marker.

It sounds like a needle in the haystack but you’ve but you become quite familiar with this variant called RS11762213. What you know about it so far?

 We know about that it is a variant in the MET oncogene, a very important gene in a lots of different cancers, particularly in papillary renal cell cancer. It’s a gene not thought to be very important in clear cell renal cell carcinoma, but we found that it is, and we explored the variant in an exonic region of the gene–meaning the coding region of the gene.  Because the variant is in a coding region of the gene, we thought it might be more than just a prognostic marker. It might also have some biological implications.

Biological implications?  What sort of biological implications?

 We think the marker may be; we figured out through computational methods, exploring the TCGene data(?) that it might be in the region of enhancement,  meaning the variant leads to higher activation of the MET oncogene.  In turn, this might explain why these patients have a poorer outcome.  It might also have potential therapeutic implications.

So what have you found so far then, about the level of additional risk if you happen to have this variant gene?

Great question.  We took about 270 patients from the cohort who had available information.  We genotyped them, meaning we determined what percentage of these patients had the risk variant, which is about 10 %, consistent with prior studies.  We showed that when these patients had that risk, in addition to the current prognostic features, they had about a 3-4 fold increased risk of cancer-specific death, or tumor recurrence after surgery.

That’s really quite powerful!  Am I right that there wasn’t any clear kind of molecular feature to give you some help in the past?

Until this study, which was published last year, there were really only tumor features and patient features that were associated with poor survival in kidney cancer. This is the first study that really showed, that they published last year, to show in two different cohorts that had a molecular feature that added to the prognostic models.  We showed, augmented their findings, that if you took the best current prognostic models and stratified patients, added to that model, meaning it improved the predictive accuracy of even the best post-surgical models that are out there.

You are looking actually disease mechanisms–mechanisms of cancer production. You established prognosis, but what about predicting response to therapy?

That’s a great question. Our goal now– that we’ve established that this is a valid biomarker, truly multiple cohorts now showing this marker can stratify patients for aggressive behavior, we can now explore—hopefully–whether this has therapeutic implications because it is in a gene that is a known cancer gene.  Because there are multiple drugs that target this gene, and because we think that this variant that is activating this gene, it stands to reason that an inhibitor for these patients with this variant might work. These patients might have another option.

So theoretically a new drug which is an inhibitor for this variant might work.  What about existing cancer drugs? Do you have any ideas about if any these do influence that variant?

We don’t know yet. We are trying to find it in cell lines, meaning cell lines that are derived from tumors that are used in the lab, to see MET inhibitors that currently exist and are in phase I or II trials in kidney cancer could potentially be used against patients against this variant. That could be a very powerful tool, and a kind of the precision medicine that were looking for.

This is an amazing achievement, actually going through the Cancer Genome Atlas to find information like this, information about expression. In the realm of the everyday cancer doctor with patients to treat today, tomorrow, what you think the doctor should take home from this development?

The exciting thing about this is to genotype the patient, that is to determine that this patient carries this risk variant, is something you can detect from the patient’s blood or even a swab from the cheek. It’s a very inexpensive. It costs about $10-$70 to get this information for a patient. You can have what is called a liquid biopsy, meaning you need any tissue. You can get it from their own normal cells, because this is germline variant. You can find out this information very affordably and very quickly to determine risk for these patients. Obviously, if we are able to show that it has implications for therapy, that as a whole opens a whole new avenue.

How much hope to have that this it will be possible to manipulate this gene expression by using this kind of drug to target this?

I think that the data there is quite strong for other types of cancers. We know that other genes that are overexpressed or mutated in activated fashion respond quite well to inhibitors. This exists in multiple cancer types, lung cancer, breast cancer, for example. It stands to reason that this would work as well in kidney cancer, and the hope would be that this variant would be actually an activating factor and that we could use that also.

We’re also hearing, and especially at this GU meeting here in San Francisco, about the heterogeneity of the tumors. In fact, you may have tracked down one particular cause of cancer, but there’s another five going to rear their ugly heads at the same time. What you make of that?

 Well, that’s definitely a major factor, particularly in kidney cancer, where heterogeneity was really first described in the clinical setting two years ago in the New England Journal. What the nice thing is about this variant is, is that it is germline. It exists in every cell. Thus heterogeneity does not exist in this situation. The variant is present in all cells, including the tumor cells. So if our data does hold up, and it is a therapeutic target, it will not be affected by tumor heterogeneity.

Give me a message to take home for the community cancer doctor very briefly..

The messages that we have truly validated this important finding that was published last year and we truly believe that this is a new prognostic marker and adds to the existing prognostic markers.  Time will tell if it will actually help guide treatment of metastatic disease and really change the paradigm for kidney cancer.

Thank you very much.

 http://ecancer.org/video/2663/met-variant-as-a-prognostic-marker-in-clear-cell-renal-cell-carcinoma.php

 

 

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by | February 4, 2014 · 12:58 am

Help Save Research Data; Your Signature Needed

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

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

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

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Video

Morgan’s Morning Rant in the Hospital–“Treat Me Like a Person”

This young woman–aged 15–has just ‘explained’ in clear and articulate terms why it is so hard to get both well and respect in a hospital. Must it be this way?  Though it is referred to as a “rant”, that is not really the case–it is an indictment of the lack of respect for patients found too often in the health system.

Morgan has some serious health challenges, and has had to learn to advocate for herself to work to get better.  But the concerns she raises are typical for most patients, and the lack of coordination of care, and the lack of communication of care is huge barrier to getting well.  As do most of us, she understands that the failure to let her sleep is a barrier to that care.  And the further failure to let her wake up and be a part of her own care, communication symptoms, asking questions, is far too common.

I congratulate Morgan and her family for sharing this very important reminder.

 

 

 

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by | January 23, 2014 · 12:04 am
by | January 15, 2014 · 9:37 pm

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

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

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

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

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

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

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

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

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

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

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by | January 14, 2014 · 9:52 pm

Radiation for RCC? What Really Works?

Is kidney cancer really so resistant to radiation?  Many studies indicate that kidney cancer is far more resistant to radiation therapy than many other cancers. RCC just doesn’t behave as other cancers do, so the most knowledgeable doctors use radiation very carefully.  The typical wider damage that comes with general radiation is not balanced by a good response in RCC.  To be effective, a more specialized radiation is needed.

One of my most knowledge SmartPatients/friend has provided important information about radiation and RCC. The following is a link to  videos, and is followed by advice to a fellow patient trying to understand her options.  SBRT is Stereotactic Body Radiation Therapy, and not at all the same as general radiation, as is explained..

“For right now let me sort of define whats important about SBRT and why it works on RCC. SBRT is all about high daily dose needed for radioresistant cancers.

What is important is the high daily dose for RCC used in SBRT. For example, an SBRT plan for a lung met will use 3 fractions x 15 Gy/day or 5 fractions x 10 Gy/day. Fields will be very conformal to the tumor (but usually not by using shaped fields)

Forget shaped. Conformal small fields–yes.

An IMRT (Intensity-modulated radiation therapy) or shaped conventional plan might use 25 fractions x 10 Gy/day.

And to give daily doses of 15 Gy you need excellent imaging and mechanical capability that not every machine has.

Does it matter? Yes! The recurrence rate for RCC is much higher with low daily doses. The SBRT dose regimes will give about 90% local control (meaning that met never comes back-if you get cancer, it is a new spot.) Standard dose regimes give more like 60% long term local control.

SBRT typically uses dose modulation(which may or may not involve shaping beams ) to control where dose goes.

MLC or block shaped beam IMRT IMRT/IGRT-all use shaped beams but are not SBRT.

Cyberknife and Gammaknife, for example, use no beam shaping-they use hundreds of tiny identical circular pencil beams to build dose covering the tumor.

ANALOGY: Let’s say you have a huge thistle in your lawn. And you have a cup of Roundup. You can go outside 3 days in a row and put 1/3 of a cup on it. Or you can go out every other day for a month and put a spoonful on it. You are more likely to kill it for good with the first method. We want a quick thorough cell kill.”

This SmartPatient does not mince words.  We all want a quick through cell kill, which may bring a met under control permanently.  Not mentioned in this article, is that the body can also have an immune response in the area of the radiation, and deliver a burst of its own cancer-fighting proteins to the area.  This can have an additional effect in countering those super-tiny mets that may be invisible, or just trying to establish themselves in the neighborhood.

Just as there are a range of antibiotics, and we know that the choice of each is dependent up the infection, its location, and the individual’s system, so it is with radiation therapy.  Properly chosen, delivered correctly and to the exact place, with an understanding of the person’s disease, it may be a very effective tool to fight RCC, and not just clear cell.

 

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