We struggle to understand what to do about our kidney cancer, but first must exactly WHICH kidney cancer we have. Frankly, even the doctors are never too sure, and outcomes for patients with the “same” cancer varied widely. No ready explanation was available, in those bad old days.
Treatment decisions were easy, but not effective for most, when every kidney cancer patient was treated the same. Patients had surgery and were sent home. Those with smaller tumors, under about 2 inches, had little or no follow up. Those with larger tumors might be monitored more frequently. Mets might emerge, and maybe more surgery would follow, but no meds were available until 1992 when high dose interleukin was approved.
Patients who presented with metastatic disease were not even offered surgery, being told that there no value to removing the primary! An ongoing “controversy” was whether there was value in a nephrectomy when mets were found. Too bad, so sad. (If your doctor is telling you that last bit, you need a new doctor. Now.)
Then came the recognition that there were different kidney cancers, variants and subtypes, all based on the look under the microscope. Conventional kidney cancer became known at clear cell, and a mix of new subtypes were named. We now hear of clear cell, papillary type I and type II, chromophobe and more. Sarcomatoid RCC can arise from any of these types, confusing things and reflecting a more aggressive course for the patient. Most are sporadic, out of the blue, but others have an inherited component. Again, making things trickier yet!
Ironically, the trials in the late 80s of high dose interleukin which led to the first FDA-approved treatment, included all the above types. The relatively low response rate in this trial may have been due to the rarer RCC types, unlikely to respond. This minimized the use of HD IL2, perhaps to the detriment of many patients. The targeted therapy studies often excluded the rarer types, hoping to boost response in a more limited group. Few trials really test agents appropriate for the non-clear cell types, so the guessing game for them is really the norm.
With that background, there was still wide variation in the outcomes for clear cell RCC patients. Some patients with small tumors, found at an early stage, can have very poor response to treatment. Many such patients have long-term survival, easily over 10 years, while others who “seem” similar, succumb to their disease quickly.
Why is this the case? Short term survival vs long term survival, aggressive appearance of mets vs slow-growing, good response to treatment vs minimal response? Why would the same disease be so different?
Easy answer. It is not the same disease. Clear cell RCC, that so-called conventional type, maybe 75% of all the kidney cancers, is not really one disease. Clear cell may be subdivided into four separate types, each with its own survival pattern–and all due to its early genetic drivers. Researchers have been able to sort out the genes, compare the mutations, deficient or over-expressed, and find them in tumors of patients who were treated and followed over many years.
Just as there is no magic bullet, no one medicine that fixes everything, there also seems to be no one poison bullet. It is not just one thing that goes wrong, one nasty gene breaking the DNA rules, but a combination. And there will be more combinations. This is like the typical disaster stories, where it is not just one thing that goes wrong, but a series of events and changes. Each one of the series might not create a problem, but in combination and with the right timing, there is a perfect storm–the very aggressive tumor.
Without getting too technical, clear cell RCCs can have a mix of genes that mutate. Recent studies have shown that two genes in particular, BAP1 and PBRM1 can either be sufficient (or competent or positive) or they can be deficient in their expression. There are four possible combinations, positive for both genes BAP1 + and PBRM1+, negative for both genes BAP1- and PBRM-, and combinations with the BAP1+ and PBRM-, and the reverse, BAP- and PBRM+.
Why does this matter for the study patients? All of them had localized disease at the time they were diagnosed and all were clear cell patients of similar age. BAP1 was mutated/inactivated/deficient in about 15% of these patients, and that mutation was associated with high nuclear grade, or a more aggressive type of tumor.
About 50% of clear cell patients had the PBRM1- tumors. Others had a mix of one gene positive and the other negative. Mutations of BAP1- and PBRM1- were rarely found together, but that combination predicted poor survival, in one study of just 2.1 years. Having just the BAP1- had an overall survival of 4.6 years median, while the deficiency of PBRM1 (-) had an overall survival of 10.6 years.
This shows that clear cell RCC is really not one disease type, but four. Most importantly for patients is the knowledge that these varying mutations may respond to different medications. Also, these mutational differences can be seen in immunohistochemical or pathology tests, which can give greater guidance to treating physicians.
Coming soon is another lectures by Dr. Brugarolas, so watch this space.