Tag Archives: cancer research

Why can’t we cure this???


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A frustration for patients and physicians alike is the incurability of metastatic prostate cancer in spite of the great response that many/most patients have to initial hormonal treatment. As most readers of this blog know, almost all prostate cancer cells depend on stimulation from testosterone to grow and to get outside the prostate, moving to lymph nodes or bones (the most common place for metastases in pca). Testosterone is normally made by the testes and adrenal gland, circulates in the blood stream, and enters the cancer cells where it binds to the AR (androgen receptor). The AR then translocates to the nucleus where it binds to specific locations “upstream” from various genes (including PSA, and interestingly TMPRSS2 which has implications for COVID-19) leading to the gene being “activated”. Many of the activated genes lead to cell division and invasion that characterize/lead to metastases we detect with bone, CT, or PET scans.

Normally, the way we detect that cancer cells are “turned off” or dying is by the PSA falling. PSA in general is far more sensitive than scans, but it really tells us about the “big picture”, not what is going on with individual collections of metastatic cancer cells. Measuring PSA every 3 months is a very common way to monitor the response to drugs that stop testosterone synthesis (abiraterone – Zytiga) or block testosterone from binding to the AR (bicalutamide-Casodex, enzalutamide-Xtandi, apalutamide-Erleda, darolutamide-Nubeqa)

Although much more expensive, monitoring response by repeating scans can begin to answer the question posed for the title of this blog. Why doesn’t hormone therapy lead to cures? The reason lies in a single word, heterogeneity. As I reviewed previously, when we look at different sites of cancer metastases, the tumor deposits in one area may have a very different genetic mutation profile than those in a different area. I was very struck by how well this is illustrated in a recent article using quantitative PET scans. In patients treated with enzalutamide, the different sensitivity is graphic as shown in this figure from the article:

Compare PET1 taken at the start of treatment with enzalutamide to PET3 when disease was progressing indicated by a rising PSA. Green spots indicate partial or complete response to the antiandrogen while red ones are new or progressive locations. This is a graphic example of the result of tumors having genetic changes that make them more or less sensitive to the drug. Finding a combination of chemotherapy or hormone therapy that can attack all of the genetically different deposits is impossible at this time. However, the immune system may be able to keep up with all the changes in some patients, and this provides hope for the expanding trials of immunotherapy in prostate cancer you can find here. Glass half full or half empty? You choose!

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Prostate Theranostics


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Sometimes a great new word evokes curiosity, so I have used it to title this post and see if a few of you thought it would be worth looking at rather than sending to your “junk” email. You can’t find it in the dictionary, interestingly enough, but it’s related in derivation to Theranos, the bizarre company started by Elizabeth Holmes and if you haven’t read “Bad Blood” or seen the video you can find that story here:

For us prostate cancer followers, however, theranostics represent a “new” field in which the same/similar drugs can potentially be used for both diagnosis and therapy. There is a nice review of an ASCO educational presentation on the topic here. The main idea is that a radioisotope can be specifically directed to a target for either diagnosis or therapy. One of the oldest examples of this is radioiodine which is taken up by the thyroid gland. If you have thyroid cancer, the metastases will also take up the radioactive iodine and with nuclear medicine detectors you can see them, or if you inject even more, it will be “hot” enough to kill them.

223Ra is an isotope that seeks bone, just like calcium, and where there is more bone turnover/remodeling, more of it accumulates. As a drug, it was given the name Xofigo, and was approved for treating prostate cancer in men with bone dominant disease in 2013. It emits alpha particles, which are known as “high Linear Energy Transfer” radiation because they go only a very short distance before interacting with cancer cells and killing them. This is important since you would not want the radiation to kill the normal bone marrow cells that live in the same neighborhood. In the study leading to approval of 223Ra, men with symptomatic bone metastases and no visceral (e.g. liver or lung) metastases who received the isotope as a monthly injection for 6 months lived 14.9 months as compared to 11.3 months for placebo (P<0.001) and had fewer skeletal events and less bone pain. I always loved alpha emitters because I had the fun of making a cloud chamber for a science fair when I was in 6th grade. You might want to help a grandchild do that!

177Lutetium (177Lu) is an isotope that allows both diagnosis and therapy because it emits gamma radiation for detection, and high energy beta radiation that can kill cancer cells. When bound to PSMA (see these posts)

177Lu becomes a theranostic that shows considerable promise for treating prostate cancer. There are a number of completed trials of 177Lu-PSMA that have been summarized in this table:

For more details on 177Lu-PSMA treatment, this is an excellent recent review from the European Society of Radiology:

https://epos.myesr.org/poster/esr/ecr2020/C-00307

There are a number of ongoing trials of 177Lu-PSMA that you can find here.

Keep wearing your masks to protect your fellow prostate cancer groupies, be patriotic, and if you want to pay homage to one of the great scientists whose research led to these advances, look no farther than Radioactive, the recent Amazon Prime movie about Marie Curie. As one of the commentators on the trailer posted, “In a world full of Kardashian’s… be Madam Curie.”

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CAR-T and related immunotherapies


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One of your co-subscribers to this blog contacted me and asked if I would write a blog about CAR-T cells, and I have decided to include the closely related bi-specific antibody therapies. I am very intimidated by even attempting this, because the complexities of this field are daunting, so please do NOT show this post to your PhD immunologist cousin.

As most readers probably know, the immune system consists broadly of the “humoral” and “cellular” arms. When you get corona virus, (or any other virus) both arms are activated. Broadly speaking, your B-cells (lymphocytes that live in the lymph nodes and also circulate in your blood stream) make antibodies that attach to targets (“antigens” – in the case of corona virus, the spike protein you are tired of looking at on TV is the target antigen we hope a vaccine can be made from) and can inhibit the virus or can clear the antigen from your circulation. Antibodies consist of proteins (chains) that combine with each other and this is where things start getting VERY complex, but a single B-cell can make only one type of antibody (called a monoclonal antibody). Whether you know it or not, if you have an interest in prostate cancer, monoclonal antibody technology is “why you are here” – PSA detection was made possible by isolating a monoclonal antibody that would bind to Prostate Specific Antigen. But with modern recombinant DNA techniques, the chains that make up these antibodies can be combined in highly variable ways never found in nature. The history and complexity of the antibody story is illustrated here from this article. Screen Shot 2020-06-13 at 10.31.25 AM

The Y-shaped figure above is “an antibody” and the colored chains are the proteins in the antibody that can be extremely variable and give the antibody its ability to bind to any target. Note that the two arms of the antibody could be designed so that one arm would bind to one target and the other arm could bind to a different target. Voila! You could design one arm to bind to PSMA and another to a killer T-cell that would link a killer cell to your cancer cell.

Screen Shot 2020-06-13 at 10.42.33 AM

 This is the general idea behind an innovative cancer approach you may hear about called BiTE. In this figure, the working part of the tips of two “Y” antibodies have been linked and when injected into a patient, in theory the “killer” T-cell is forced to bind to the tumor cell via its “TAA” or tumor antigen. If you are a dedicated reader of this blog, you already are thinking about a great target antigen I previously introduced you to, PSMA

Now on to my VERY oversimplified description of CAR-T cells. The terminology refers to Chimeric Antigen Receptor – T cells. The science of these is related to the above description of antibodies in the following way: On the surface of the T-cells in your lymphocyte library is a completely different group of proteins that allow the T-cells to bind to and recognize antigens, much like the antibody system we discussed above. These proteins combine in chains on the surface of the cells to form “T-cell receptors”. Unlike the antibody system, their interactions with antigens are further modified by requiring recognition of “self”. Non “self” is why people who receive a kidney or heart transplant must receive drugs to suppress the immune system that will reject the transplant. Unfortunately cancer cells are mostly recognized as “self” so we don’t reject them. BUT… again using recombinant DNA technology, the T-cell receptors (TCR) can be re-designed so they DO recognize a tumor target, even though it is “self”. You can start with lazy, somewhat unresponsive T-cells that might be in the blood or even infiltrating a tumor, take them out, modify the receptor (dramatically as shown in the following figure), and force them to recognize a cancer, then re-infuse them into the patient like any blood transfusion.

Screen Shot 2020-06-13 at 11.02.34 AM

In the figure (taken from this article), the “antibody like” part of the receptor that controls “self” is CD3 and the “antibody like” part of the TCR receptor that binds to a tumor antigen or virus infected cell are the green proteins marked alpha and beta. The recombinant magic that is WAY beyond this blog is everything on the right. If you have the time and interest in really delving into CAR-T therapy for cancer, you really do have to read this article. But, for those who wonder “so why aren’t we doing this?”, the Cliff’s Notes answer is that (1) it is VERY expensive – each patient has to have his/her T-cells taken out and modified, expanded, then re-infused; (2) it has only worked well for blood cancers like leukemias so far; and (3) even though PSMA or some similar tumor target might be thought to be “tumor specific”, it turns out these targets are often expressed in low levels in places like your brain or lung. When the CAR-T cells begin attacking your normal tissues, you are in a world of hurt. If you have followed the COVID-19 story, you may have heard about the “cytokine storm” that is killing people by destroying their lungs. As you might imagine, combining these approaches with the other “hot” area of immunotherapy, the PD-1 inhibitors I have previously written about could make CAR-T treatment more effective but the toxicities even worse.

I hope this has been helpful and that your immunologist cousin or highly informed oncologist will forgive the effort to simplify a very promising but challenging field. I’m also grateful to the myriad of incredible researchers who have put this all together for us “cancer fighters” and their dedication is equally as worthy of honor as other warriors on front lines.

 

 

 

 

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COVID-19, ADT and Prostate Cancer


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Spoiler alert: As I start to write this, my intent is to delve into some basic science readers may find too detailed/complex and some speculation that has limited/no support and should NOT be taken as anything other than hypothesis generating. I fell in love with biology in about the 8th grade and with thinking about how to answer biology questions in medical school, so this is more self-indulgent writing rather than being written to inform.

Starting with the COVID-19 story, there have been so many excellent articles that if you haven’t read too many already, you can get a one minute overview from this video. Now for some more Screen Shot 2020-03-29 at 8.47.20 AMdetailed science. This figure from an excellent article in Science shows the real details of how the virus works and some of the drugs that might be useful in stopping or slowing it down at the cellular level. If you use your best “Where’s Waldo” approach, (and if you are an avid follower of prostate cancer biology) you may find a very familiar protein hiding in the membrane where the virus binds to the exterior of the cell, TMPRSS2. This protein is an enzyme in the family of serine proteases, proteins that can cut peptide bonds at the site of the amino acid serine. Trypsin is another example of this category of enzymes we use in the lab to release cells from petri dishes, and you use various enzymes every day in your dishwasher to digest proteins stuck to your dishes. As shown in the figure, TMPRSS2 plays a crucial role in the entry of the SARS-CoV-2 virus into the respiratory epithelial cells leading to COVID-19 disease.

I first heard of TMPRSS2 several years ago in a lecture at the PCF annual scientific meeting. Investigators at the University of Michigan found that in a large percentage of prostate cancer, the androgen response elements in DNA that control the expression of TMPRSS2 have become fused to an oncogene, ERG. Every gene in our DNA is controlled by “upstream” segments of DNA called promoters or enhancers that regulate the expression of the gene. In the case of prostate cancer the androgen receptor, AR, binds to testosterone (or DHT) and then the is translocated to the nucleus where it binds to DNA at the sites of androgen response elements, leading to transcription and expression of the “downstream” genes. A reasonable analogy is to think of testosterone flipping a light switch to “on” and the AR being the wire going to the light bulb, TMPRSS2, in our case. You are familiar with this if you know about drugs like Lupron, Zytiga, or Xtandi that block testosterone signaling in various ways. Although taking any of these drugs turns off many genes related to prostate cancer development and progression, one of these genes is clearly ERG (if you have the TMPRSS2:ERG fusion), and of course you probably turn down expression of TMPRSS2 in normal cells.

So what does this have to do with COVID-19? As you may have seen, men have approximately twice the mortality of women from infection with SARS-CoV-2. There are no doubt many possible reasons. Men smoke more. Men may not practice social distancing as much. Men have more heart disease. But what if one reason is that they express higher levels of TMPRSS2 in their respiratory epithelium? The exact mechanism of TMPRSS2 in the infection can be found in this article.  A cartoon from the article illustrates the several points in the viral infection cycle where TMPRSS2 (and other serine proteases) acts to facilitate the entry, replication and budding of the virion from a cell.

Screen Shot 2020-03-29 at 10.19.32 AM

The article discusses several drugs that are being investigated to inhibit TMPRSS2 that could hopefully be effective in fighting COVID-19. One of them, camostat (seen in the first figure in this post), is already scheduled to begin clinical trial at the end of this month.

However, there is already a very interesting global “clinical trial” underway if you have followed the above (and necessarily complex …sorry!) story about TMPRSS2. If ADT, familiar to all men with metastatic or high risk prostate cancer, turns down the expression not only of ERG and other oncogenic pathways, but also the expression of TMPRSS2, it might reduce the infection rate or morbidity/mortality from COVID-19. Looking at large global databases, it may be possible to see whether men with a diagnosis of both “prostate cancer” and “COVID-19”  can be extracted from the data, and then whether within this grouping, those men on ADT have a better outcome than those not on ADT. It would be complex, of course, since some of the men not on ADT might be on chemotherapy, or more sick in general, and thus more susceptible to dying from the infection. It might also be possible to see what the expression levels of TMPRSS2 in the pulmonary epithelium of men versus women are as a potential partial explanation of the differences in mortality. Finally, and this would be the most intriguing possibility of all, a clinical trial that combined some partially effective “drug X” from the list of drugs in the first figure with or without ADT could determine whether short term use of ADT could enhance the treatment. Proof that no one ever has a “unique” idea (and of the speed with which you can share ideas in today’s internet environment), in doing a minimal amount of literature research on this topic, I came across a preprint of a beautiful article looking at exactly the hypotheses I laid out above. It was submitted only 5 days ago! The authors have found very significant differences in the levels of expression of TMPRSS2 among adults using published databases and hypothesize that this could explain why some individuals may be more susceptible to bad outcomes. They also evaluate the potential of down regulation of the gene with ADT drugs like enzalutamide or estrogens and they conclude, “Together, these results identify existing drug compounds that can potentially be repurposed to transcriptionally inhibit TMPRSS2 expression, and suggest that the activation of estrogen pathways or inhibition of androgen pathways can be a promising modality for clinical intervention in SARS-CoV-2 infection.”

In summary, if you have prostate cancer and are on ADT, the well known side effects you put up with are unpleasant to say the least. But there is a “not-zero” possibility that your ADT is also protecting you. The best advice is still to practice social distancing, wash your hands, and be vigilant regarding your health, but maybe there is a silver lining in this story. I hope so, and there are already clinical and basic scientists exploring the hypotheses discussed above. Be well and my best wishes during these trying times!

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New findings from clinical trials 2020


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There are a number of ongoing trials or completed trials that represent attempts to develop new approaches to prostate cancer. I am sometimes asked what I know or think about them (often not as much as I would like) from various investment consultants, so I thought rather than respond to a recent list, I would just use it to explain the trials for readers of this blog. Perhaps when your friends ask you whether there is “anything new out there”, you can point them to some of these.

The PROFOUND, TALAPRO-1, TRITON-2 studies are all designed to evaluate the efficacy of small molecule drugs that inhibit “PARP” which stands for an enzyme (Poly ADP-ribose polymerase) that is involved in DNA repair. It turns out that patients who inherit a damaged/mutated version of any of several enzymes that help cells maintain their DNA integrity (BRCA1/2 being an example you may have heard of – when mutated it leads to the development of breast and ovarian cancers as well) are more likely to get prostate cancer, and often it is of the more aggressive variety. It is also a frequent condition of prostate cancer metastases in patients who no longer respond to hormone therapies (leuprolide, abiraterone, enzalutamide, etc). These patients appear to be uniquely sensitive to PARP inhibitors and several pharmaceutical companies are developing them. Olaparib and rucaparib received breakthrough designation from the FDA for accelerated development. In the PROfound trial, patients who had progressed on either enzalutamide (Xtandi) or abiraterone (Zytiga) were randomized to receive the “other” new hormonal agent or the PARP targeted drug olaparib (Lynparza). As reported by my friend/colleague Maha Hussain, the olaparib treated patients fared significantly better than the patients who received the “other hormone”. The take-home message from these trials is that we now have ways to look at the molecular underpinnings of resistant prostate cancer. If you have metastatic prostate cancer, ask your physician about the genomic tests that can be done to see if you might benefit from one of these new drugs.

In a somewhat similar design, the CARD trial evaluated treating patients who had had been treated with docetaxel (Taxotere) and then progressed while on enzalutamide or abiraterone with cabazitaxel (Jevtana) rather than the alternate hormone targeted drug. Chemotherapy with cabazitaxel was the better approach. This was similar to a previous trial called FIRSTANA that looked at alternatives of mitoxantrone or cabazitaxel in progressing docetaxel treated patients. The take-home message here is that chemotherapy with cabazitaxel may be a good choice if you don’t fit the PARP profile above, and studies have shown that cabazitaxel is preferred in terms of side effects compared to docetaxel.

Finally, I will comment on the VISION trial. PSMA stands for prostate specific membrane antigen and it is expressed on prostate cancer cells. It can be used to direct pet-scanning agents to metastatic cancer deposits and these scans are currently the most sensitive ones we have for detecting prostate cancer. These scans are available at several centers in the U.S. and are now routinely used in Europe. By linking a more radioactive isotope, Lu177 to the PSMA, you can also treat prostate cancer and early results in patients with progressive hormone refractory disease have been encouraging with more than half of patients responding. The VISION trial compares this approach with cabazitaxel to see which might be the best, but in the long run, it may be possible to use both agents, and potentially to use them even earlier before resistant disease has developed.

We have entered an era when there are numerous promising options for treatment, and the key is to get as many men  as possible to participate so we can finish the trials and get these new agents approved. We also have drugs like cabazitaxel that have been approved for some time and a better idea of when to use them. Working with a team that has the expertise to guide a patient and offer the right choices at the right time is essential for the best outcomes.

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Thanksgiving for an oncologist


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First, I want to thank those readers who generously helped me reach my goal of fundraising for the annual Movember effort to increase awareness and support research into prostate cancer and men’s health. If you are so inclined and want to make a last minute contribution, you may do so here: https://mobro.co/michaelglode?mc=1 My itchy, scraggly moustache is destined to come off tomorrow!

Second, it has been an incredible journey since my internship to watch the evolution of our understanding of cancer. In 1972, when my mother called to tell me (a young medical intern) she “had a little lump in her breast” – it turned out to be not-so-little, and she fought the disease for another 4 years before succumbing – we had little we could do other than surgery and in some cases radiation. Even adjuvant chemotherapy (the CMF treatment) had not been published yet. During the next decade, remarkable strides were made in finding new drugs, most notably cisplatin, that allowed cures of previously lethal diseases – especially testis cancer.

Then, while on sabbatical in Helsinki in 1986, I found an article to present at our journal club that I thought would revolutionize medicine. The PCR reaction opened the door to rapid DNA sequencing. When I returned to my lab in Denver, my PhD colleague, Ian Maxwell had already started to use the technique with his own jury-rigged thermal cycler, but it would be 3 or 4 more years until a medical student in his/her 3rd year clinical rotation would be able to tell me what PCR stood for. Recognizing there would be a generation of physicians who “missed out” on what would be the revolution, I was able to help start a catch-up course in Aspen, Molecular Biology in Clinical Oncology, that is still ongoing. As a “fly on the wall” I was able to listen to the world leaders in molecular oncology (including this year’s Nobel Prize winner, Bill Kaelin) describe their research that unlocked the mysteries of how cancer works. Fly-fishing with some of them on the Frying Pan was a bonus to be cherished!

As the cancer story unfolded, I was able to participate in many clinical trials, bringing new treatments that emerged to my patients. Thanks to the brilliant writing of Siddhartha Mukherjee, author of “The Emperor of all Maladies“, it became possible for my patients to begin to understand the nagging question, “how did this happen to me?” And now, this week, a brilliant article summarizing all we know about the genes and mutations that cause cancer has appeared in the New England Journal. I invite you to read that (it’s free online) if you want to join me in peering over the horizon to the future of cancer medicine. It is both overwhelming and humbling.

The privilege of living through the last half of the 20th century and into the 21st is one of the most amazing journeys one could ask of a human lifetime. As I ponder it, looking out on the snow I will get to ski on next week and enjoying my grandchildren and family, I am truly thankful to have been here. Happy Thanksgiving to all!

 

 

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Immuno-Fighting Cancer Like Wildfires


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I live in what is now known as the urban wildland interface west of Denver, the kind of area prone to the devastating fires that have been scorching California. Our firewise community efforts have taught us a lot about how a single windblown ember from miles away can destroy your house, and many of us have done a lot of mitigation. But, if the “big one” comes, our best hope is to grab the family albums and head down the hill.

Cancer can be very similar. If someone walks in with widespread disease, unless it is one of the highly treatable ones like testis cancer, flying over the patient with flame retardant (chemotherapy) may delay things for a while, but often the home is lost. The earliest realization of how to do better may have come from breast cancer. William Halstead realized in 1894 that putting out the fire effectively might include getting the surrounding “embers” (lymph nodes) at the time of removing the primary breast tumor (campfire in this analogy). A century later, it had become clear that in many instances the embers had spread too far for more radical surgical approaches, but that in some cases the embers could be extinguished (adjuvant chemotherapy) before the fire got out of control.

But what if the fire could be self-extinguishing? What if there was a boy scout at the campfire with a fire extinguisher? Better yet, what if you had smoke jumpers who could parachute in and help the boy by putting out the small fires elsewhere started by the embers? Immunotherapy offers just such hope. In the 1980’s we learned that giving high dose IL-2 to some patients with particularly sensitive tumors (kidney, melanoma) could produce cures in some cases. I liken this to sending in a group of non-specialist firemen/women in huge numbers to fight the forest fire doing the best they can.

Sending these individuals to more specialized training resulted in Provenge (sipuleucel-T), the first “vaccine” approved for treating any cancer, prostate being the target, and I was fortunate to participate in some of the first trials of this approach. But what was needed was both more effective equipment (in this case the PD-1 inhibitors that can “extinguish” the cancer’s ability to turn off the immune response) and more highly trained firefighters (potentially think of CAR-T cells) who have advanced skills, graduate degrees from a university, and can be deployed to go in search of the embers.

Now to torture this analogy just a bit further, let’s imagine that rather than sending the firefighters to universities for advanced generalized training, we could send them to CIA camps where they would receive the most specialized training possible right at the site where the fire started. In cancer, this may be the idea of using cryotherapy or irreversible electroporation to kill the local tumor, then injecting some cocktail of immune stimulatory molecules that enhance the body’s ability to create very effective T-cells that can go out as smoke jumpers looking for the embers (metastases), without the need for the university training outside the body (Sip-T or CAR-T).

Screen Shot 2019-11-11 at 8.13.35 AM

Already there are clinical trials underway with this technique that show promise. Gary Onik has demonstrated some remarkable responses in metastatic prostate cancer patients. Diwakar Davar just presented similarly exciting data in high risk melanoma patients who received intratumoral CMP-001 and systemic nivolumab before resection of the primary tumors. 62% of the patients had no tumor left in their surgical specimens! So  the cancer/firefighters are out there and although there will always be wildfires we simply can’t extinguish, the prospects for controlling them before or soon after they have spread have never looked better.

 

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[How to] Choose Your Own Adventure


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Back when Al Gore and I invented the internet (just kidding…but it does seem like a long time ago – before twitter, instagram, and all the rest), I had the privilege of helping my professional society create its first website, ASCO Online. As part of that effort, I wrote an introductory article to assist my colleagues in understanding what I felt lay in the future. In addition to trying to explain how browsers and the internet worked (as an amateur early adopter), I stated, “Oncologists will increasingly act as information guides rather than information resources for patients and their families with cancer.”

Herein, I will attempt to make that easier for you if you have a personal interest in prostate cancer. There are now more than 103 million “hits” in a google search for “prostate cancer”. Therefore, first understand your condition. If you are thinking about screening, put that in your search term, or read this article I selected for you.

Next, be familiar with the myriad of terms that have evolved to describe different situations (“states”, “stages”, “conditions” etc.) to describe the disease. “Localized” means you have prostate cancer that is felt to be (or even proven to be after surgery) confined to the prostate. If localized, is it high risk, intermediate risk, or low risk? Your physician should be able to help you understand this based on the Gleason score, pathology findings, and PSA, but there are now multiple molecular tests that can be done to help further characterize what has been found. There is an excellent article to help you understand these here. If you haven’t had surgery or radiation, and are just deciding what to do, some of these tests can be done on your biopsy. I once wrote a blog about the challenging decision of choosing a method of primary treatment that is still relevant here.

However to be really up to date, you may wish to look at the research going on for any of the more advanced prostate cancer conditions. For this, you should become familiar with and use the NIH website, Clinicaltrials.gov. To help you with this, I have done some preliminary searches for different conditions, but recognize that the terms you enter change what you see, so regard this as just a start. Pick your condition, and click on it and you will find some trials that are ongoing (I preselected “recruiting”) for some common situations. If you don’t see your situation, play with the search terms yourself.

High risk after surgery based on pathology
Rising PSA (biochemical failure) after surgery or radiation
Known metastatic disease (spread to bones or nodes on scans) never previously treated
Rising PSA or new metastases on scans while on hormone therapy

Now, taking the last example which gave links to 160 studies, you can narrow the search results by using the pull down menu on the search screen, starting with country. Note that limiting to the U.S. drops the available trials from 160 to 93. Adding the state, Colorado, drops it to 14 studies, etc. Maybe you have a relative in a certain city or state you could visit if a trial fits your situation. If you would like to look only at immunotherapy trials, try entering the term, “immunotherapy”.

Next, let’s go further into one trial. Let’s say we are interested in the NIH immunotherapy trial being conducted at the NCI. If you scroll down, you can see what will be involved:

Screen Shot 2019-10-05 at 12.48.14 PM

Next, since the devil is in the details, you need to know if you are eligible for this trial. Continue to scroll down to the Eligibility Criteria section. Here you find what clinical conditions you MUST have (Inclusion Criteria) or MUST NOT have (Exclusion Criteria).

At this point, you should understand how it would be almost impossible for your physician to stay up on all of the trials. YOU are now the “information guide” and if you are interested in whether a certain trial (or even an approach you have found that might be something you could do outside of a trial) could be useful in your case, you should make an appointment to speak with your doctor about the trial/approach. Recognize that this will probably take more time than your “usual visit” and notify the clinic you will want extra time to discuss this. Print out the relative parts of the trial so you can show it to her/him, and ideally have your meeting in an exam room with an internet-connected computer so you can search through details together. If there are questions, each trial has the phone number for a contact person (typically a research nurse), and since your physician may be able to answer questions you would have trouble finding in your record, this phone call is best made together from the exam room.

In our fast-moving, internet-enabled era of medicine, this is how I think medicine should be practiced. The shared burden of “keeping up” means the patient has to do his (no women have prostate cancer) or her (if you are a supportive spouse or similar) own research, help the doctor, and work on approaches as a team. Being respectful of the time involved is critical, but it CAN work. And it is much more rewarding than keeping up with tweet storms!! And if this is “not for you”, find a grandchild and choose some different adventures here. (disclaimer: I have never done this, but looks like it could be fun)

 

 

 

 

 

 

 

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What we see and what YOU get.


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Will Rogers is said to have stated, “When the Oakies left Oklahoma and moved to California, it raised the IQ of both states.” This story has given rise to the concept of the “Will Rogers phenomenon” in medicine that is very well explained in this essay. Basically, it provides a cautionary message when evaluating new therapies in cancer medicine, because if a new study has taken advantage of newer diagnostic techniques to eliminate some of the patients with higher risk (say those with metastases), then it could easily be that an improved result is not from the new therapy, but from the ability to throw out the higher risk patients from a study cohort.

We are certainly at risk of this now in prostate cancer. In the last 5-10 years, a number of more sensitive scans have been introduced that can reveal metastatic deposits previously missed by standard technetium-99m bone scans or CT scans. Most of these rely on the technology known as PET (positron emission tomography) scanning. The first clinical PET scans mostly utilized glucose to which a positron emitter, Fluorine-18, was attached. For bone metastases, it is easy to see how much more sensitive F-18 scans are as shown in this image: (Same patient – A. “Regular” Tc-99m bone scan  B. NaF-18 PET scan)

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Suppose you have a new treatment that is for patients “with 10 or fewer” bone metastases. If you are comparing the new treatment with one that was used in the past, and you now use the PET scan (on the right), this patient would not be eligible, whereas in the past (old scanning technique) he would have been. He clearly has a higher tumor burden than 10 metastases. Hence, he is now eliminated from the new study, and therefore the new study will automatically look better in terms of outcome than previous treatments. This is called “stage migration” or the “Will Rogers phenomenon”.

For “soft tissue” metastases (lymph nodes, liver, lung, etc.) the regular Fluorodeoxyglucose FDG-PET scans were approved decades ago for lung cancer, colon cancer, lymphomas and breast cancer but they never worked well for prostate cancer. A simplistic explanation may have to do with the different metabolism of prostate cancer which tends to utilize lipid rather than glucose for energy. (see our study here). Therefore researchers looked for other metabolites that would light up prostate cancer. Acetate and choline could be labelled with Carbon-11 and worked well. However, C-11 has a half life of only 20 minutes, so making the label in a cyclotron had to be done essentially in the room next door to the scanner and injected immediately into the patient. Another metabolite taken up by prostate cancer, an artificial amino acid (fluciclovine), could be labeled with F-18, worked well and has now been approved, called the Axumin scan.  Potentially even better will be the PSMA scan, now in research mode.

The net result of these new scans is to allow physicians to answer the frequent question patients ask, “Where is the PSA coming from?” The problem then becomes the title of this essay – What we see and what You get. There are numerous scenarios. For example, a patient who comes in with a very aggressive Gleason 9 cancer and a PSA of 12.3. Should we go immediately to a routine bone and CT scan, or just order an Axumin scan? And if we find 2 positive spots, one in a rib and the other in a lymph node, does that mean the patient can’t be cured?? Five years ago, we would have never known about the metastases and we would have operated or used radiation therapy in a curative attempt. Screen Shot 2019-04-09 at 9.56.43 PMWhat about the patient with a rising PSA 5 years after he had surgery. We do a PSMA scan and find a solitary node near the left iliac artery. Should we irradiate the node? What about operating and removing it – remember, it may not look any different from all the other nodes to the surgeon. Which one should he/she take out? And what is accomplished by these efforts? Should the PSA go down (yes if that’s the only metastasis) and what to do if it doesn’t go down. Are we playing “whack a node”? How many times do we go after spots that keep showing up, versus starting some sort of hormone therapy?

There is an excellent article addressing some of these questions written by my good friend Chris Sweeney and colleagues that you can read here. A summary quote from their article states, “Given the current limited understanding of how reliable these scans are in predicting the need for appropriate management change, data-driven guidelines and standardized consensus approaches are more critical than ever.” A review of some of the early attempts to treat a small number of metastases (called oligometastatic disease) has just appeared here. One example of a paper reporting interesting results is summarized as follows: “Of the retrospective reports, the largest includes 119 treatment‐naive patients who had ≤3 sites of oligorecurrence and received SBRT to all involved sites, with 92 of 119 (77%) undergoing pretreatment choline PET. The 3‐year distant PFS [progression free survival] rate of 31% and the 3‐year OS rate of 95% are favorable and suggest a subset of patients likely benefitted from aggressive local therapy; however, conclusions from these data are limited in the absence of a comparative control arm.”

Maybe we simply have to refer back to another quote from Will Rogers, “America is a nation that conceives many odd inventions for getting somewhere but it can think of nothing to do once it gets there.” Stay tuned…

 

 

 

 

 

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Filed under General Prostate Cancer Issues, Oligometastatic prostate cancer, Prostate cancer therapy, Targeted treatment

Black holes and genetic laws


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I just finished reading Stephen Hawking’s last book, Brief Answers to the Big Questions, which I found more accessible than A Brief History of Time, written more than 30 years ago. Hawking’s abilities to explain the very (for me) abstract concepts of how no information can flow out of black holes and that the amount in there is somehow directly related to the cross sectional area of the hole was satisfying. As a very math challenged individual, I’m also a fan of Heisenberg and the perplexing issue that in the quantum/wave world of particle physics, you just can’t be certain about position and momentum. Yet, there are certain laws, like the speed of light, that are never violated, at least in the universe we live in.

So what does this have to do with genetics and prostate (or other) cancers? Here is a law: A always pairs with T, and C always pairs with G. In our biologic universe, without this law, no life as we know it could exist (prions may be an exception, but that gets too far into the definition of “life”). Yet, just as with the uncertainty of Heisenberg, the base pairing in DNA/RNA is not completely inviolable. Mistakes are made…and this can result in cancer. Cancer is a genetic disease and for anyone who hasn’t read it, I still recommend you avail yourself of the incredibly well written book, The Emperor of All Maladies. In the short time since that book was written, the explosion in our understanding of how genetic errors and cancer are related has been difficult to keep up with. The Cancer Genome Atlas (clever name, eh?) is but one example, and its use by scientists skilled in math (ugh) continues to help classify cancers based on how their mutations drive them rather than just how they look under the microscope or which organ they started in. Here is the math and the results one such analysis has on predicting survival for stomach cancer:

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As you can see, the prognosis and potentially the treatment for one subtype of “stomach cancer” might be very different for one patient than for another. Bringing this technology to prostate cancer, we already know the mutational landscape is vast. For example, this article looked at 1,013 different prostate cancers and found 97 significantly mutated genes, including 70 not previously recognized, and many present in <3% of cases. There is hidden good news in this story, in that the same mutational uncertainties that can give rise to cancer (breaking the law of AT-CG) also allows our immune systems to react to the novel mutated proteins that cancers now display. For an interview from this week’s NEJM on gene editing, click here.

Keeping up with this world of laws, broken laws, and “black holes” will be a remarkable challenge for patients and oncologists alike. My final recommendation for reading about this is a terrific article you can find here by George Sledge, one of the outstanding leaders in our field. He notes that even the most skilled oncologist, paired with the smartest of patients, will be unable to keep up. But remember this, you can’t go faster than the speed of light. That’s the law!

 

 

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Filed under General Prostate Cancer Issues, Prostate cancer therapy, Targeted treatment