When you are suddenly thrust into the medical world, unwillingly and without any kind of road map, you are surrounded by poorly marked turns, meaningless abbreviations and the sudden shift in the dialect. The Wellness Center is usually about having lost one’s “wellness”, a word used only in the medical world, and not by real people.
Pressed to make decisions that may change your life, for the better or worse, you can be confused by those clever new words, some from the marketing people (see above) and others from the clinical side. It is critical to understand how familiar words get reworked to explain new concepts. Such explanations rarely reach patients, who are numbed and deafened after a shocking diagnosis. And in the medical “new-speak”, those same patients may be told that this is the time in which they must take charge of their health, and make wise decisions quickly and correctly. I find this a cynical and self-serving approach, as rarely is any real education offered in the language of the patient.
In kidney cancer, we have been blessed with new drugs these past eight years, but have no clear way to determine which of these agents might be of benefit to any of us. On top of the shock of diagnosis, the patient is thrust into a guessing game. Even the doctor is forced to play along, and often neither party knows the rules or the chances to win. The doctor may recognize the vocabulary used in this new guessing game, but the patient does not. Words which have meaning in day to day life don’t work the same. Even some of the goals of the game are unclear to the patient. Wait! You probably think that being cured is the goal. you
For example, we patients think that “progress” is good, but that is not true in cancer. Progression is the goal of the cancer, so Progression Free Survival (PFS) measures the time between treatment and when the cancer is on the visible move again. The word “visible” is important here, as that is a reminder that cancer does not just start at a size or style to match the sensitivity of imaging. X Rays cannot see things as small as a CT scan can. Bone scans see bone mets better than other scans and so on.
In reading clinical trials, you will encounter “durable” to explain how long a median PFS can be. It may be described as remarkably durable, but in the pre-patient world, we would think that is pushing into years and years. In reality is may be 15- 18 months. We happily grasp at any more months than the non-treatment reality may be, but be aware of your and your doctor’s expectations in durability.
“Durable response” is surely what we want, but that is not translated to a cure, which might be the patient’s interpretation. When you hear that, do ask for clarification, “How long does that response last? What do you mean by ‘durable’? What do we do after the duration of response comes to a stop?”
Having a firm grasp of this term and all others is an absolute necessity, and even if that is hard–in the real sense–it will be worth it to you. You will have greater understanding of the treatments, the disease process, and a bit more sense of where you are.
More on these topics later, but do track the language, and remember than you still speak the old language. At the very least, be ready to question anything that has that new dialect sound to it!
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.
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 immunemonoclonal 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.
“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.
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.
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.
Why should you care about genomic research? Simple; it could save your life! Want to know EXACTLY which type of cancer you have, and how to choose the best treatment? New hope comes from this research which really examines the nature of the cells that make up your cancer. Pretty important stuff.
Genomic research is bringing improvements to care, and points up the need to be aware of this new knowledge–and if your own doctor is keeping up with that type of data. At a 2012 Conference sponsored by the The Oncology Journal, Dr. Kimrym Rathmell spoke in regard the genomic knowledge that is leading to improved care for kidney cancer patients. Maybe the most critical lecture of late.
Dr. Rathmell begins after introductory remarks; Complete access on YouTube via this link:
First, kidney cancer, like pancreatic cancer, has been on the rise. This is a somewhat dated slide, dating back to the 70s. We have seen a steady increase in this cancer. Although it was originally characterized as a rare tumor type, it is not really anymore.This talk will focus on one subtype of kidney cancer, that is, clear cell histology renal cell carcinoma. This is a histology slide showing why it is called clear cytoplasm
This tumor is characterized by particular mutation. That is the Von Hippel Landau gene, coordinate the loss of 3p, (a chromosome) where VHL is housed. We see these in mutations and loss of 3p which house other tumor suppressors as well, in up to 90% of these tumors. Based on this strong correlation between clear cell renal cell carcinoma and the VHL mutation, a tumor type. is a very distinct paradigm in which VHL loss causes upregulation of hypoxia inducible factors (HIF). These tumors are characterized by loss of high loss of these HIF factors. These are transcription factors that normally allow cells to respond to low levels of oxygen by turning on a repertoire of genes that allow them to bring in new blood vessels, to shift their metabolic properties, to migrate away, to promote survival, and to de-differentiate. That is a perfect storm for kidney cancer, in some respects.
Targeted Agents in Use
Because this cancer has highly nonresponsive to typical chemotherapy, there’s much effort in recent years to develop targeted agents. These targeted agents to date all focus on this well-known pathway in clear cell type renal cell carcinoma. Most of the agents focus far down on this pathway, including that of receptors of VEGF and PDGF. They are tyrosine kinase inhibitors, effective at reducing the tumor angiogenic profile and can be quite effective at reducing the bulk of these diseases. Other drugs similarly target this pathway, for example, targeting features of the tumor that enable HIF to be stabilized such as that in the mTOR pathways. Temsirolimus and Everolimus are approved for use. There are in-developments drugs for targeting MET, which is another mutation that can occur in this cancer, similarly increases HIF levels.
But the reality of treating kidney cancer is that the available drugs that we have do not produce complete responses. We only work in the arena of minimal response and partial response. The extent of response that a patient gets is unpredictable. The duration is also unpredictable and the toxicity is also unpredictable. For drugs we expect them to be effective on average 1 to 2 years, this is chronic therapy, very expensive, and it’s dominated by effects that are substantially detrimental to quality-of-life—fatigue, rash, diarrhea, as well as laboratory abnormalities that indicate damage to the liver or elevations of glucose and cholesterol.
PART I: Clear Cell Renal Cell Carcinoma, Molecular and Genetic Contributions to
INTER–Tumoral Heterogeneity.
With that, I will talk about various molecular probes that we use to understand some of the diversity or the heterogeneity of these tumors across the clear cell renal cell carcinoma spectrum. Before I really dive into clear cell renal cell carcinoma, I need to point out that there are other histologies with this tumor as well. So when we say kidney cancer, we’re talking about a big spectrum. Clear cell renal cell carcinoma, we are talking about those tied to Von Hippel Lindau disease and loss of 3p and it is about 70% of all cases we encounter in cancers of the kidney. But there are also other types. Papillary type renal carcinoma, chromophobe, benign tumor—oncocytoma, a translocation form and some very rare. With these types of tumors we have very little in terms of knowledge of how to treat these patients. Their genetics are highly distinct from clear cell renal cell carcinoma. So someday in the future, we will understand not only how to treat not only our clear cell carcinoma patients, but how to use effective molecular information to target these cancers as well.
Clear cell carcinoma is well know to be molecularly heterogeneous for some time. This is a gene expression profile. We’ve already seen heat maps from several of these other talks, looking at gene expression profiles. And as you can see the gene expression profiles across a large selection of tumors here, suggests there are great areas of variability–at least two and as many as five groups, based upon gene expression purely.
Pattern Recognition Profile to Find Subtypes
Our group undertook at the time developing a pattern recognition profile which is now fairly routine use. To try to see with a more robust computational strategy what subtypes we could really identify, that we could really pen down and understand with genetic profiles. 8aWe found two. For lack of better knowledge, we are calling clear cell A and clear cell B, ccA and ccB. These are very distinct biologically, and when we look at these tumors in terms of their outcome, they also have significant prognostic relevance–with the ccA tumors in this original cohort having a median survival of 103 months, compared to the 24 months for ccB tumors.
The TCGA which is been discussed here in many of the previous talks is a great source of validation. We assigned these tumors to clear cell A and cc B groups subtypes, validating our previous results with the clear cell A tumors having much better survival profile than those ccB tumors.
This classification scheme, which is based 120-130 gene signatures classified robust subdivisions of clear cell type renal cell can be applied with a small number of genes on individual tumors and is independently associated disease-specific overall survival, making it a valuable prognostic biomarker.
PART II: Rare Variant Groups
We use these profile tools to understand the rare variants. This is still in the clear cell renal cell carcinoma arena, but when we took a very large group of compiled tumors; this was a meta-analysis of 500 tumors, all histologically defined as clear cell type renal cell carcinoma, and we applied our expression pattern recognition algorithm. We asked for two groups and we found two and they correlated with our ccA and ccB, but when we ask for three groups, we can find a small group that now filters out. Now that we have power in numbers to identify what we called Cluster 3. What is in Cluster 3?
Cluster 3, as we’ve said, is histologically defined as clear cell renal cell carcinomas. But we look to the genetic expression profiles, it’s very different, particularly with regard to metabolic properties. We see upregulation of genes that are involved in mitochondrial regulation and oxidative phosphorylation, suggesting a striking difference in the way these tumors likely regulate metabolism.
In addition, and now these are tumors that we can not go back and genotype for VHL mutation, for loss of chromosome 3p, but the loss VHL regulation leads to characteristic changes in the gene expression profile. So when we use the gene expression changes to predict whether these tumors have an intact VHL or a mutant type VHL. The wild type VHLS signature shown here is shown in purple. You can see that these purple tumors, the wild type VHL tumors all tightly cluster with Cluster 3. These are probably not clear cell renal cell carcinomas although many, pathologists call them that. So we pulled them all out so, asking, “DO they look a little bit different?” My graduate student, who did this work, came right away and said “There’s something funky about these clear cell tumors that we call Cluster 3.”
As you can see, these are clear cell A and a clear cell B tumors, but they all have the clear cytoplasm and really, what we are seeing, is that they are not distinct histologically, although they are very different molecularly. And as I have shown, they have a very different prognostic outcome. The Cluster 3 tumors; although the cells themselves might have clear cell cytoplasm that gave them the clear cell histology designation, they have a very different pattern of organization—with a papillary type of feature. So what we think it would be identified as is a new rare variant of clear cell renal cell carcinoma.
Simultaneously another group of pathologists identified, that the pathologists call clear cell papillary carcinoma. That suggests that we need to take a very great care as we treat these patients. What we have is clear cell type renal cell carcinoma, most of which are VHL-mutated, and we do have clear cell A and clear cell B. These are the tumors we should be treating with the drugs with identified, based on the effect of the pathway that is activated by loss of VHL. But clear cell papillary renal cell carcinomas probably won’t react very well, as they are VHL-wild type. Just like papillary renal cell carcinomas don’t react well either.
To summarize this section, clear cell renal carcinoma can be separated into ccA and ccB groups, based on transcript profiling, but further clustering can identify highly biologically dissimilar subtypes within the clear cell group, and that subtyping can convey a biological distinction which is a valuable tool for prognostic evaluation, and a likely cause of poor responses to some therapy.
Part III; Using Clinical Trials to Understand Biological Relationships to Response to Therapy
As my title indicated, we also refer to clinical trials to help us understand renal cell carcinoma a bit more. A clinical trial we completed some years ago, LCCC0603, was in neoadjuvant trial that looked at the treatment of renal tumors with sorafenib. Patients were identified as having renal tumor and underwent CT scans for basic size, description and PET scan, and then were treated with sorafenib. It is the first generation VEGF receptor tyrosine kinase inhibitor for 4 to 8 weeks, and then underwent post treatment CT scan, PET scan and a nephrectomy. We are going to look at radiographic indicators of response, rather than molecular indicators.
Waterfall Graph with Response at 30% as goal
First standard RECIST criteria do show that we do see partial responses. Again, there were no complete responses. Many had subpartial or minimal or some partial responses. Their tumors shrank, but most did not meet the standard criteria of 30% decrease in one longest size. Some tumors actually grew.
Now what we realized as we looked at these tumors, is that we probably need new ways to describe response. The standard RECIST criterion response is just based on longest diameter and measuring this in comparison, after treatment..
I will use this patient is an example. (References I and J, in the lowest row). Here is a pretreatment; we have a very large renal tumor. Post treatment, the tumor was still large, but it measures slightly larger than it had been before. But if you look at this tumor, it is very different. The central area of this tumor is now very dark, indicating necrosis—is what we think. But we took these tumors out, we could confirm that these dark areas were indeed necrotic. So we developed a new way to try to quantify the area of the tumor that is actually killed in response with this treatment.
Similarly we were doing PET scans on these patients, and we were doing this because we’re trying to understand how the metabolic properties of these tumors might indicate how these tumors were likely to respond to this treatment. We see, and have known, that are some tumors which are very dim on FTG PET. This is a tumor; (Smallest of upper images) you can see that here is very visible on the PET scan. It doesn’t take up any FTG. So this tumor has the metabolic profile that is not dependent upon uptake of glucose. Others; this tumor (Smallest of lower picture), for example, have regional areas that are can be very high in terms of FTG uptake. When we looked at these tumors, we discovered first that non-clear histology tumors were much more likely to have high levels of FTG uptake. So, metabolically active tumors more likely in the (correction) non-clear cell group, probably the papillary, the chromophobes and the papillary clear cell types, than the clear cell group. Secondly. we discovered that the correlation between FTG uptake and response looked somewhat different than we might have expected. We might have expected the most metabolically active tumors would be those that would response better to anti-angiogenic agent. But the opposite was true. The best are those that had very low levels of uptake FTG uptake. We are still trying to understand exactly what that means. Certainly that means that those clear cell tumors are the ones more like to respond, activity, what we have known, but those are the ones with the lower level FTG activity. But we continue to try the metabolic properties of the tumors that make theme different more likely to respond.
That leads to our next clinical trial. This is now ongoing. This is LCCC1028. It is a neoadjuvent clinical trial using the newest generation—well, they are coming out so fast that it’s the not the newest, but the next to newest VEGF receptor tyrosine kinase inhibitor. They are now getting PET scans and a biopsy to confirm in fact that they would be clear cell renal cell carcinoma, and also to allow us to do molecular studies that directly measure their metabolic activity and other effects. They’re being treated for eight weeks with another CT scan, undergoing nephrectomy. We will then be able to look at clear cell variant histology. They will all be clear cell going in, but there may be variants included–as well as looking at their VHL mutation and their other mutational status, their transcript profile, in particular the clear cell A and clear cell B group and other protein expression signatures.
This, of course, is known for all tumors, but if you sample in multiple different places, the histology will look different and in effect, the grade can look different depending on where you are sample.
What does that mean molecularly? Well, a group at the Sanger Center published on a small number of tumors. When they sequenced these tumors, they found while there are some mutations that are ubiquitous, meaning the mutation is found in all samples across the primary tumor and the metastatic tumors, that there are mutations that are private. There are mutations that are common only among the primary tumors and there are mutations that are common only in the metastases, and there are a lot mutations that are unique to the individual sample. This makes a whole new level of complication as we moved toward personalized therapy, in particular therapy that is based on biopsy metrics.
This group also looked at our clear cell A and B subtypes. And what they saw, when they looked at six samples from the primary tumors, was that in five of those samples, the gene signature indicated that these would be clear cell B type tumors. So depending on your glass half-full/glass half empty: The glass half full version of this, that five out of six times, they would pick that the patient would have poor outcomes. This patient has metastatic disease, so it fact, that is true. The glass half empty would be that one out of six times, he would pick wrong. This patient would have been indicated to have clear cell type A tumor, and you might have predicted that this patient would do well, when in fact that would be wrong. So what helps us understand the limitation of this test. It also gives us the opportunity to understand a little bit more about these tumors.
(Footnote reads: BRIC Funded Grants LCCC1213) So for the future, a trial (LCCC1213) that we have really just initiated is uniting some of these imaging observations we have made with genetics.
We are taking in patients. This is patient number one. Patient number two just has his MRI last week. and doing an MR in coordination with the PET scan so we can get the detailed look at these patients’ tissue perfusions, vascularity and the density of these tumors, as well as regional areas at the FTG uptake and sample according to the map that is created by the imaging, as well as samples that are collected, based on what we see grossly in the tumor. Here you can see a sample that we collected from a tumor region that is highly distinct from the mostly more pale yellow regions of tumor.
This is just begun, so I cannot tell how well were going to get to correlate the gene expression and genetic underpinnings, and what we see in the tumor and what we see in the MR / PET. But it will help us to move forward.
To summarize are multiple ways for RCC to diverge. The subsets can enrich tumor sets for clinical and genetic features, and a multiplatform approach that with genetics, molecular biology and imaging techniques will give us man ways to tackle a surprisingly very heterogeneous disease.
Once a patient can stop asking why cancer happened to him/her, the next question is the fundamental version of the many questions that the researchers ask– “What is cancer really? and “Why can’t they just stop it?”.
The scary part of cancer is that it seems so insidious. Cut it out. Burn it out. Zap or freeze it out. Why doesn’t that work, at least for the solid tumors? Getting rid of the blood cancers, like leukemia and lymphomas seem more difficult, less obvious, but it was really the cases of leukemia which first responded to treatments.
Without going into volumes of discussion about cell and molecular biology (you are safe from that with me), just understand that cells go wild, left to their own with the family checkbook, an endless liquor cabinet, permanent pizza delivery, car keys, disguises, blind neighbors, a fancy cloning machine, and the police on strike. You get the picture. Now a more formal explanation.
Cells are supposed to do their respective duties and then die. That process is called apoptosis. You know that your scabs don’t keeping growing, but cancer cells lose the “time to die” signal.
Foreign bodies are supposed to be cleared by the immune system, and what is more foreign that cancer? However, cancer cells manage to evade immune destruction. And while doing that, they can also evade the growth suppressors, the immune brakes which would otherwise slow and prevent excess growth.
While cutting the brake lines to growth, they can also change the regulating signals for growth (think scars and healing), so those signals all left in permanent “ON” position. No brakes and an open throttle with a very full tank of fuel. To top that, they reprogram the nutrition or energy metabolism to keep the fuel of growth alive.
Liking the growth, the cancer cells override signals that naturally limit the times a cell can divide, creating endless replication instead. With the endless replication, the chances for mistakes, or genetic mutations increase, which can mean changes from the original cancer cells. Sheesh, not only alien cells, but aliens cells making alien-er cells!
To keep tumors growing, cancer cells send out signals to create blood vessels or angiogenesis when tumors outgrowth the local nutrient sources. Running out of room for all these many cells, billions and billions, the cells break down the lining of blood vessels and the lymphatic system to search out new locations, spreading and metastasizing away from the original cancer. Quite naturally, they also provide support to those tumors through inflammation-related factors, mimicking the way that the immune system responds to any injury.
Since a healthy being grows, fights off infections, responds to an allergy or heals after an injury, usually with little support, those healthy responses are amazingly efficient and interactive. Complex cellular, molecular and chemical actions are occurring all the time, and with aging, some genetic dispositions, the harmful things we ingest or do to ourselves, it is no wonder that a few things go on without our noticing it. But when those few things are not noticed by the immune system, slipping into a growth phase, a cancer can begin.
Estimates of the numbers of cells in the human body are calculated from 10 trillion to 100 trillion, so if the occasional cell goes rogue, what’s the problem? When all things are working well, there will be no problem. But when the tiniest cancer is visible with a CT scan, perhaps 1/8 inch, it will have millions of cells. Not all tiny cancer tumors are dangerous. Not all become aggressive. Digging around to cut out a tiny tumor creates plenty of opportunity for infection, for expense and emotional anguish. But does that mean that a “Cancer!” has been prevented. Or would the person and his natural immune system have lived in complete tranquility with his cancer until the end of his days?
Probably the most talked about studies at the June 2013 ASCO in Chicago swirled around the newly released trials about PD-1 (Programmed Death-1) and similar. “What the heck is this all about, and why should I care?”, you may be asking. This is important as it shifts attention back to the original immune therapies that kept me alive (and many others) when there was nothing else to offer any hope in the olden days of the 1990s.
Though a number of targeted therapies have since emerged, and you have been hearing about them, there is new interest in the earlier and modestly successful immune therapies. I confess a fondness for anything described as an immune therapy, as I am alive–which I would NOT have been–without the first FDA approved agent against kidney cancer, high dose interleukin 2, brand name Proleukin.
The first new agents in the 2005+, the anti-angiogenesis drugs (not easy to pronounce,much less to understand) brought new hope to metastatic RCC patients. With the late diagnoses of many kidney cancer patients, we desperately needed hope. For about 14 years, HD Il2 (high dose interleukin 2) was the only game in town. Nothing else existed, so any patient lucky enough to hear about it, and not actively discouraged by the very “realistic” doctors, probably considered it. This is a hospital-based agent which revs up the immune system, so the immune system would go after the metastatic disease, at least for some number of months or years. That is why I am alive. Nothing else was offered and nothing else was available. Nine years!
Since that time the anti-angiogenesis drugs–translation: those that fight against (anti..) the creation (genesis) of angio (think blood vessels) drugs were approved. Think Sutent (sunitinib) and Avastin (bevacizumab) and others,. They have been the weapon of choice for oncologists and patients. Why is that? Though these drugs rarely offer more than some pushing back of the drug, decidedly welcome, they have rarely given more than some slowing or relief from the metastases, and always with some side effects.
For us old-timers, who faced only death, whether by efficient means or by surgical cut-and-pastes as holding actions, this was a tremendous breakthrough. For these options, even if only holding actions versus mop-up operations, we were grateful. We who had nothing previously were slightly scornful of those who complained about the side effects, as we were grateful to be around to have such effects. The Stage IV sufferer in 2004 knew too well that Stage V was a damn unpleasant journey and without a return ticket.
Now we have become greedy again, wanting more than the “stability” or “some shrinkage”, which I applaud. We want success and life, not holding actions. High dose interleukin 2 continues to offer that success to patients, but no one can predict which patients and which conditions that might be likely.
Bless those researchers who continued to wonder why kidney cancer and melanoma (and maybe non-small cell lung cancer) respond to some sorts of immune therapies, and what happens to make that happen and not happen. Those fine people have come to understand that the immune response which is revved up by HD IL2 has a complex set of “calls and responses” which either let loose the dogs of war/and immune responses, or fail to do so.
Most people understand that the body tries to protect itself from assaults, whether by poison ivy, bronchitis or cancer. The immune system responds, gives the body aches, pains, fevers, chills, etc. Think of flu and how rotten you can feel. Think also of old diseases like Black Death which stimulated the immune system so violently that it was the strong and healthy with good immune systems that succumbed to the immune response, dying with lungs filled with immune reactions and fluids. Only those with weakened systems and slower responses managed to live through the symptoms.
Obviously the body’s immune response needs a moderation, and not one that saves the village by killing it. All of this leads to an explanation of the newest immune therapies, now in clinical trials in RCC. You may hear about PD-1 and CTLA-1 trials, and how they may be helpful in kidney cancer, melanoma, and now in non-small cell lung cancer.
To understand all of this, it is helpful to think of a system of checks and balances, perhaps in an electrical or computer communication system. Just as every electrical impulse might be appropriate, it could also do damage by overwhelming the system, burning it out, or failing to meet the requirements to be able to answer a “send me” signal. So it is with the latest research on immune therapies with the PD or Programmed Death agents.
Keep in mind that the immune response is typically used against infections, and not generally against cancer. I assume that we cavemen needed more protection evolution-wise against infections and less so against the ravages of cancer, which seems to result from getting older and getting overwhelmed by changes/mutations in the body. (Not always, I know, but that is a discussion for later.)
T cells are supposed to react to a number of infections and such, and trigger an immune response to fight back against the “aliens”, such as cancer and ragweed. Just right amount of fight, and the body recovers. Too little, and you have the devastation of the Black Death, an over-the-top immune response.
The immune system is supposed to respond to handle the natural threats to the body, but not over react and set the system on fire metaphorically. It had built in checks in balances, as do normal cells. We see this everyday when our normal growing hair cells decide to stop growing and the hair fall out. Chemo patients struggle with the balance of killing all cells, with the faster-growing cancer cells being killed off first.
New agents have been developed that interfere with a signaling system that puts the T cells, the protective/fighter cells into action against cancer cell. This naturally happens, but the nasty cancer cells try to evade that process by interfering with that process. Not letting the body protect itself, by disguising itself as the evil twin, equally eager to live, as the good twin, the healthy cell, cancer interferes with Programmed Death. More next time…
And as Mae West said, “I like a man who takes his time.”…
If anyone can find a cancer event exciting, it is the ASCO annual meeting, at which thousands of oncologists present their studies and learn from one another. In the kidney cancer world, the “buzz” has been about “programmed death”–for the cancer cells, which we all prefer over that of our healthy cells.
This is a transcribed lecture, fairly short, to explain the immune therapies that may add to those weapons against RCC. Dr. Wolchok clarifies how this happens, with the agents interfering with the “Shields Up!” commands that protect the cell from what should be their programmed deaths. With appreciation to all researchers.
Peggy–Nine years of life free of cancer, thanks to the original immune therapy, HD IL2
ASCO Daily News June 6, 2013
Dr. Jedd D. Wolchok, MD PhD of Sloan Kettering Memorial Cancer Center
We now recognize that there are several pathways that constrain T Cells and the immune system from achieving a state of full and persistent activation.
One of those pathways is called the CTLA4 pathway and there was a medicine approved call Ipilumimab last year, that blocks CTLA4 for treatment of melanoma. There is another pathway, the PD 1 pathway which usually constrains the immune system in a different way. And PD 1 is also present on T cells in the immune system and it binds to a family of ligands, one of which is known as PD-L1 or PDL ligand 1.
In the ever-expanding a list of ways in which cancers try to evade the immune system, cancers have learned to express this PDL-1 ligand on their surface. By doing so, they actually cause the death of T cells that come close enough to them or PDL-1 to bind to PD-1 on the T cell surface. This ability of cancer cells to express PD L1 on their surface allows them to defend themselves against T cells that the body is trying to educate to see the cancer and to defend itself.
So the PD-1 pathway is active across multiple disease sites. Some of the earliest work done with anti-bodies that block the PD -1 pathway used an anti-body called Nivolumab. Nivolumab was used in a phase 1 clinical trial that was presented at ASCO last year, and additional data will be presented this year.
The data last year showed that the antibody Nivolumab blocks PD -1, and that it can cause regressions in melanoma, in kidney cancer and importantly, really, non-small cell lung cancer. It is not traditionally recognized that as a cancer amenable to immune intervention. But when you people talk about cancers that responsive to immunotherapy, melanoma and renal cell carcinoma come to mind.
Now I think with the data generated first with Nivolumab and now with another PD-1 blocking antibody called Lambrolizumab(MK-3475), these anti-bodies which block the PD -1 pathway are demonstrating activity outside the “usual suspects”, melanoma and kidney cancer.
This ability to affect multiple different cancer types is important, as it shows that immunotherapy is not a treatment for one particular kind of cancer,. It is a treatment that primarily targets the patient, Then it is the patient’s immune system that goes out and treats the cancer.
One of the most important characteristics of immunotherapy is its ability to induce durable and certainly there are many different types of anticancer medications which can cause a tumor to reduce in size, but the challenge has been and continues to be, how to get disease to regress and stay regressed. Tumors, because of their genetic instability, can find pathways to become resistant to these interventions such as chemotherapy or targeted pathway inhibitions.
Immunotherapy really falls into a different category. Again, it is not targeting the tumor itself. It is targeting the patient’s immune system. It is causing the patient’s immune system to respond to certain parts of the tumor cells that the immune system finds interesting and then to control.
We know that the immune system has the ability to remember, through to a population of cells called memory cells. Because the immune system is really a dynamic organ that cannot only sculpt itself around changes in the cancer, but also can remember what it has been exposed to in the past, we believe that durability is in fact a hallmark of response to immunotherapy. The first medicine to show us this in a meaningful way was a drug called interleukin two which was really actually developed now over 25 years ago and has led to the cure of some patients with melanoma and kidney cancer. That medicine is a hormone that causes the growth and differentiation of T-cells and patients who have a complete response to IL-2 and remain in complete response for at least two years don’t ever seem to recur with 10 or more years of follow-up.
We definitely need to learn more about the PD-1 pathway we specifically need to know whether it’s absolutely required for a tumor cell to express PDL-1 that on that surface to benefit from PD-1 or PD L-1blockade. It would be ideal, in fact, if a predictive biomarker that could identify the precise patient population who would benefit from that intervention. However, I think that is not going to be a simple as predictive biomarkers been for some of the targeted therapies, where it is mutation-present or –absent. Here PDL-1 is not just important when it was expressed on the tumors, but PDL-1 plays a role by its presence on antigen-presenting cells. So, in its normal physiologic role, the PD -1 pathway actually involves interactions between T cells and antigen presenting cells and by blocking cells–even if the cells doesn’t express PDL-1–one could imagine that a patient could benefit, perhaps not as likely as if the tumor expressed PD L1.
When I was diagnosed with kidney cancer in 2004, with a tumor that had pushed my kidney toward my belly button, and had filled my lungs with tiny white dots foretelling my death, I had one FDA-approved treatment offered me. It was that or nothing. And by nothing, I mean the big, metaphysical NOTHING. There was no way to nip and tuck away at my lungs to remove the tumors. It would have been like trying to salvage a sponge by cutting away the black fungus that grew throughout its nooks and crannies.
Systemic disease sounded more hideous than distant metastases. The one treatment–high dose interleukin 2–was already about 12 years old, and nothing better had come along. The rate of benefit was low, and many hospitals didn’t even bother to offer it. That is still the case today, with fewer than 90% of kidney cancer patients (and our melanoma counterparts) are told about it. Desperate patients whose disease could not be chopped out were the candidates, and I was one of them.
This was an immune therapy, described to rev up one’s immune system, just as happens when you catch a cold or have an infection. It’s pretty obvious that this worked for me, not just to keep be alive while fighting the diseases incursions. I am free of cancer, though I get a CT scan every six months, a search and destroy-if-we-find-anything mission. so far so good, and I may even be cured.
Me, seven –TEN–had to edit it, as I keep living– years after HD IL2 and healthy
No one yet understands why I responded to high dose interleukin, but this old and disrespected therapy has been the silent reminder of the possibility of turning cancer off in the body. New studies are emerging to support this approach.
Just days ago in Chicago, researchers presented information on related immune therapies that offer benefit to some patients, spotlighting HD IL2 and using immune response to conquer cancer. Not just to contain or to making cancer chronic, which is laudable in itself, but to conquer it. Why has it taken so long to use the success of HD IL2 as a beacon to light the way to increased study?
Some say that finding out that HD IL2 worked was plain lucky, but that does not carry the appreciation for the effort that went into it. Brilliant researchers led the way, but desperate patients of 25 years ago, having no options and fiercely determined to make sense of the devastation of this disease, entered clinical trials, With tremendous risks, no guarantees, and no fall back plans, some died. Others lived a few more months than expected, which equaled success at that grim time. Some lived without disease, their cancer conquered and vanquished. Brave and selfless people, to be admired.
Some new research on the dynamic signaling process that characterizes the growth of cancer has been emerging of late. Cancer grows by evading the immune system, sneaking under that exquisite alarm and response process, turning off chemical triggers that should remain on to block its growth. Learning more about that intricate system, a call-and-response process that is just now being understood has brought about agents to support the immune system.
Not just killing cancer cells faster than the health cells are killed–quick version of chemotherapy–these new agents interfere in the cancer growth. Whether the research will show that response is durable and lasting, as with some HD IL2 patients, is yet to be seen. But my hope is that this type of research will reinvigorate the interest in using the immune system to return many more patients to health, as was done for me.
PS A new lecture by Dr. Jedd D. Wolchok–blessedly short, though well-explained will be posted shortly. PD-1 Pathway. Watch for it. Also Dr. Sumanta Pal of the City of Hope, my own doctor, discusses ongoing use and sequencing of targeted therapies, both from 2013 June ASCO
QED
Me,