Rorshach and biomarkers


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Psychology, or for that matter being able to read others’ personalities, has never been a strong suit for me. Neither was art – I still am at the stick figure stage when drawing. It turns out that Hermann Rorshach was probably good at both. The question of what you see when looking at an ink blot seems relevant to the current status of biomarkers in prostate (and others) cancer. On the one hand, some biomarkers are fabulous – for example the Philadelphia chromosome, described in 1959, was the first unique cancer marker that ultimately resulted in a specific targeted treatment, imatinib (Gleevec), dramatically improving survival for patients with chronic myelogenous leukemia. PSA, on the other hand (our “favorite”) is not so great, and as I previously noted, may give rise to the “PSA Clock” effect in which patients ruin their lives by clock watching. But, as we know, it is remarkably useful as a weather vane. When a prostate cancer patient is being followed on any sort of therapy, going down is good and going up is bad.

Thus, there have been thousands of articles attempting to either make PSA interpretation  better, or to replace it with more sensitive or more accurate predictors of prostate cancer behavior. I reviewed some of these, and the challenges here. Today, yet another article on a rather “simple” biomarker, PTEN loss, showed up among the >20 prostate related emails I receive each day. Writing in European Urology, a group of well-known prostate cancer investigators looked at immunohistochemistry (using special stains to highlight a protein in cells under a microscope slide) to evaluate loss of PTEN, a tumor suppressor gene, in prostatectomy specimens. This simple test (in this particular experiment) was as good as the commercial Prolaris test that evaluates a panel of genes related to how fast cells are dividing in predicting biochemical recurrence (PSA relapse) or prostate cancer specific mortality. With PTEN loss, the chances of having a biochemical relapse (rising PSA) or developing metastases or dying in a 10 year followup period were significantly greater than if you did not have PTEN loss. A simple, inexpensive test might replace a more complicated one.

Screen Shot 2018-10-23 at 8.55.02 AM

Here’s where Dr. Rorshach’s psychological construct comes into play at so many levels. If you are the scientist looking through the microscope, do you score a loss when there is only faint staining? Are you sure you are looking at a cancer cell and not a normal cell or  a stromal cell, or maybe even an immune cell? If you decide on giving a score to each cell, say “1+, 2+, or 3+” staining, how do you add all those up?  How many cells should you examine? All parts of the tumor, or only the most aggressive (Gleason pattern ≥ 4) And if you can figure all that out, can you teach your colleagues to look at the same specimen(s) and come up with the same answer? These are the challenges we face when we move a lab experiment into the clinic (and they are well recognized by the authors).

But…there is more! Look at the graphs. Obviously you would rather be on the upper curve with PTEN present, but how bad is it really? At 10 years, only ~10% of the men had developed metastases or died in this study. Recognize that these men were a cross section of patients, median age 59, median PSA 5.9, 64% Gleason 3+3 and another 23% Gleason 3+4 with pretty low a priori risk (did we need the PTEN test to tell us?). So the real issue is whether you would want anything different done to you if you were one of the few patients with Gleason 3+3 and PTEN loss, just because you have this new information? And what would that be?? Radiation? Hormone therapy? How much and how long? -all in the psychology of looking at those curves. Some men might want nothing more done, while others would want “the kitchen sink” thrown at them, even if they had relatively little (and unproven) to gain.

So, medicine remains as much an art as it is a science (with no offense to my mathematical statistical colleagues). As the father of American Internal Medicine, William Osler, told his students, “Common sense in matters medical is rare, and is usually in inverse ratio to the degree of education.”

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Money, Medicine, and Me


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In an article appearing on Medscape on September 13, a Reuters correspondent cited a recent study published in the Lancet looking at doctors who tweet. Although tweeting is a form of social media I have not embraced, I did participate in an attempt to study its use in the ASCO meetings in this article. However, the Medscape and Lancet articles did cause me to think about transparency in this blog.

I began blogging at the invitation of an internet company looking for physicians who would provide content they could use. When they were successful enough, they began using pharmaceutical advertising, and I left them, choosing to pay for my own web presence on wordpress.com. However, I now realize that I should also disclose my other relationships with pharmaceutical companies. In the Medscape article, there is a reference to a government website where you can look up the payments and transactions I have with pharmaceutical companies. What it does not reveal is the nature of those transactions which I will herewith share.

In doing drug development, pharmaceutical companies rely on [mostly] academic physicians to perform clinical trials. These activities may involve grants to study drugs in the laboratory, grants to their institutions to offset the cost of data managers, IRB costs, and reimbursement for travel to discuss the ongoing trial or its publication with other physician/researchers. In the past, I have had support in all of these categories, most notably (in terms of career influences) in the development of leuprolide, the first new drug approved for treating prostate cancer in many decades back in ~1985. It was an amazing opportunity for a young faculty member to treat the first patients in the world with a new drug, eventually present the findings to the FDA, publish the results, and then participate in teaching the medical community about its use.

Since then, the landscape of disclosure has changed for the better. Now when my colleagues and I give presentations or publish articles we sign disclosure agreements revealing which companies we consult for, and there are annual reporting requirements to our academic institutions. In my case, the current companies I have consulting relationships with include Janssen (abiraterone, apalutamide), Bayer (rogaratinib), and Seattle Genetics (enfortumab vedotin). I also have founded (and have ownership interests in) Aurora Oncology, ProTechSure, and Gonex/Cedus, three startup companies attempting to move drugs we have worked on in my laboratory to the clinic. None of these relationships involve giving promotional talks, using company slides in education, or advocating for the drugs on this blog or elsewhere. For the large commercial companies they involve insuring patient safety in ongoing trials as an independent monitor.

I have expressed my concerns about the rapid increase in medical costs for cancer care here and here. I do not have a solution for this intrinsically difficult challenge in our capitalistic system, and I realize that my own consulting and entrepreneurial activities ultimately add to those costs. Indeed, the costs of prostate cancer detection and treatment in men over 70 is 1.2 Billion dollars every 3 years. The newest targeted agents and immuno-oncology agents are phenomenally expensive, often in the $8-10,000/month range which can result in severe economic distress even for those patients who have co-pay supplemental insurance. Eventually, American medicine, with all of its amazing basic science and translational science (bench to bedside research) will need to find a balance between the profit motives that drive innovation and the altruistic care that medicine embodies in its most noble applications. What is an extra 3 months of life worth, and what toxicities (economic or clinical) are acceptable to pay for that? We need to have honest discussions as a society, and importantly, with our own families about these questions, especially when we are facing the diminishing benefits of aggressive/expensive care in terminal illnesses.

 

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A perfect death


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This week in which the country will come together to mourn the passing of a true American original, John McCain, it might be worth considering our (your) own mortality. Even as the ongoing progress toward controlling prostate cancer is underway, it remains clear that “something else” will get us. As an example, in a study I was privileged to lead among patients with high risk prostate cancer, other cancers (many of which were caused by our adjuvant mitoxantrone treatment) were as likely to lead to death and prostate cancer was the cause of dying only ~20% of the time

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As oncologists, we face the “end of life” issues more frequently than most physicians, and certainly deal with the reality of death more than folks in most other professions. I distinctly remember one lovely woman in her 50’s who was very open in discussing her wishes. She wanted to die while lying on her favorite beach in Florida watching the sunlight sparkling on the ocean – not an easy thing to arrange (and it didn’t happen). My own fantasy would be to have a lovely vacation in Hawaii (without this week’s rain) with my entire family, say my good-byes as I put them all on the plane, and stay over an extra day to pay for the hotel and be sure all of my financial affairs were up to date – then die of a heart attack on the way home the next day. Perfect. The airline would be carrying my carcass home for the mere cost of a coach seat and I wouldn’t even have to suffer that long in the crunched position with no leg room.

Short of these fantasies, however, I recently undertook an exercise that anyone could do and I herewith commend to you as well. My wife and I were lucky enough to score tickets to the London production of Hamilton last February. In it, there were two numbers that grabbed me by the heart. First was Washington’s “teach ’em how to say goodbye” song, “One Last Time”. As with John McCain’s final commentaries over the past few months, Hamilton’s farewell speech written for Washington was masterful (as is Lin-Manuel Miranda’s reprise).

But the song that most moved me to tears (and action) was “Who Lives, Who Dies, Who Tells Your Story”. After listening to it about a dozen times, I realized that we all have a story. It may not be as honest/noble as John McCain’s, or as consequential as Hamilton’s or Washington’s, but for some small group of your relatives or children or grandchildren, your story will have special meaning. If you don’t write it, your memories of your father, your grandfather, your family in general will die with you. In my case, I read a couple of autobiographies, self-published, from friends/acquaintances and decided that their stories were highly personal, and not terribly interesting. But when I started writing the story of my own grandfather and father, and my story, it was a joyful experience of reliving many happy memories, and a way of reconnecting with my first love affair, our children’s births, and the many blessings that have come my way. The result is not a literary masterpiece, but I am going to have it bound and give a copy to each of my kids to gather dust on their bookshelves.

In the arc of history, some things have not changed. “Our days may come to seventy years, or eighty, if our strength endures; yet the best of them are but trouble and sorrow, for they quickly pass, and we fly away.” (Psalm 90:10). Although trouble and sorrow are a part of life (and of dying), there can be real joy in pausing to appreciate all life has given you. Carpe diem!

 

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The Hits Just Keep on Coming


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I have a hiking companion who loves math, computers, and to a large extent, eugenics. He posits that we will eventually understand the human genome so well that we will be able to make all humans “smart” or “better” through genetic engineering. I argue back endlessly, with little success, that his definition of “smart” and “better” may not be shared  by everyone (he counters that these definitions will be left to the parents…) and that there will be unintended consequences of diving into our DNA with CRISPR/Cas9 technology.

The wonderful complexity of humankind is, of course, reflected in every single cell in our bodies and in all of our cancer cells as well. The debate over the number of synapses (or permutations) in our brains versus atoms (or stars etc.) in the observable universe is well beyond my comprehension. Unfortunately the “much simpler” question of how many things go wrong in cancer cells is also mind boggling. Hence, the phenomenal work of one of the West Coast Dream Team’s recent publications is not surprising. A reductionist view is shown in this diagram from their paper published last month:

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The scientific team, using funds from PCF, SU2C, and Movember (among others), did a whole genome analysis of metastatic tumor specimens from 101 men with castration resistant (hormone insensitive) prostate cancer. There is an excellent report on this work from the UCSF News Center here. Lest you believe that the results have resulted in an “aha moment” that will lead to “A prostate cancer cure”, you might do as I had to do and Google the word I had not heard of in the above figure, “chromothripsis“. Rather, the research leads to some very important insights that will doubtless contribute towards more effective therapy for 1000’s of patients eventually. By looking at the structural variants in the DNA that occurs outside of expressed genes, a much more complex picture of what drives castration resistant prostate cancer (CRPC) becomes evident. For example the androgen receptor (AR) is over-expressed in the majority of metastases and this study found a region of the “junk DNA” (non-coding for genes) that lies 66.94 million base pairs upstream of the AR that was amplified in 81% of the cases. This was 11% more common than the amplification of AR itself – an indication of how important the DNA controlling a gene like AR is, compared to the gene itself. So much for calling the DNA that doesn’t code for a protein “junk”!

A second example is the insight into patients who have alterations in a gene called CDK12 that may render them more sensitive to one of the “hottest” areas of cancer research, the use of checkpoint inhibitors of the PD-1 pathway I described in my last post.  This abnormality results in the cancer cells having an increased number of “neoantigens” (targets) for the immune system to attack as shown in this illustration from another recent exceptional paper.

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The ongoing research from the many scientific teams focused on prostate cancer is awe-inspiring when you consider the complexities involved in the two figures in this post alone. Even getting a complete picture from a single patient is impossible, given the genetic instability and the variable mutations found in different metastases. Remember, this team looked at the DNA from only one (or a few) of the many metastatic sites found in each patient. Other studies have shown lots of different mutations depending on which site is evaluated as I reviewed here.  In spite of all of this complexity, the ability to at least begin to understand what is going on “underneath the hood” is the way forward, and just as we can recognize Fords vs Chevys vs Toyotas, “brands” that emerge from such studies will lead to treatments that are more appropriate for certain classes of patients. As we have known for a very long time, the most common feature is the “gasoline” of testosterone, and how it fuels the amplified AR has remained an effective target for the newer drugs like abiraterone, enzalutamide, and apalutamide. Perhaps studies such as this one will lead to a way of kinking the hose upstream of the gasoline nozzle, or throwing sand (immunotherapy) into the engine itself. But… to admit that we will never understand it all (or design the “perfect human”) still seems an appropriate expression of humility to me.

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Human Sexuality and Prostate Cancer


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My first academic encounter with the field of human sexuality as a topic was a series of lectures by none other than William Masters and Virginia Johnson at Washington University in 1970. The sexual revolution afforded by birth control pills and the reactionary politics of the late 60’s have been well chronicled in many places but were fairly remote to someone like me who had been studying hard to achieve medical school admission and then trying to keep up with an exceptionally bright group of classmates. Never-the-less, as a prostate cancer specialist, I have been drawn into countless differing situations that impact individual patients and their sexuality issues. While discussing sexual function has become far easier than it was when Masters had the doors locked at the back of our lecture hall in order to show videos of the human sexual response to our class, it is still a delicate topic for most patients, and, I suspect, for most physicians.

Every patient I have encountered has a different history, sexual relationship, and level of interest in delving into the side effects of prostate cancer treatment. There are a few givens that every patient should understand, however. First, in my experience there are virtually no patients who don’t experience negative side effects of ANY prostate cancer treatment, although with active surveillance and focal treatment of a small cancer with a technique like cryotherapy or HIFU , many have minimal side effects (if they are lucky). Even these patients must deal with the psychological burden of being diagnosed with cancer and the possibility that further treatment may eventually be necessary.

A second observation is that even though for most of my patients, sexuality is a “couples experience”, only about half of the men have had a spouse or significant other with them during my initial consultation. In addition, the spouse/SO has her/his own issues regarding the sexual side effects their partner may experience. As a relatively common observation I have noted among heterosexual, married patients, the wife often expresses some version of the following statement: “I just want it out of [George/John/Billy] – we don’t care that much about the side effects…I just want him to be alive 10 years from now…” Often, George is sitting quietly in the patient chair looking somewhat forlorn after such a revelation/statement. There are many books etc. written about the highly variable but often differing interest in sexual relationships among aging couples.  I am certainly not an expert, just an observer, but I have pondered the larger meaning of these sentiments compared to the relatively intense emotions that some attach to, for example, breast reconstruction after a mastectomy for breast cancer. In any case, I think those men who have supportive SO’s who come to their doctor visits with them are fortunate and should express their appreciation to their partners. Sometimes these life challenges can be opportunities for growth in a relationship. Sometimes they are a disaster…

Most of the prostate cancer support groups, and the very large body of literature available on the internet and elsewhere, have sessions and chapters devoted to sexuality, recovery from treatment, and references to other resources. Examples include the ASCO patient website, and a similar one from the AUA. I have cared for a few men from the LGBT community and I was recently sent a book, Gay & Bisexual Men Living with Prostate Cancer,  that I scanned and seems to be a well written and fine resource for those men, but there are also a very large number of websites devoted to that community as well.

The bottom line for men with prostate cancer is that there will be sexual side effects, even if only emotional ones. The same could of course be said for aging itself. Whether one chooses to talk about it or “just deal with it” is an individual decision, and different for each man/couple and no doubt different for men of differing ages. In reality, as with the many competing causes of death/debilitation as we grow older, prostate cancer is but one of the many challenges we all will face. In this regard I rather enjoy this perspective from Willie Nelson:

“I have outlived my pecker.”
The Penis Poem–by Willie Nelson

My nookie days are over,
My pilot light is out.
What used to be my sex appeal,
Is now my water spout.
Time was when, on its own accord,
From my trousers it would spring.
But now I’ve got a full time job,
To find the f***in’ thing.
It used to be embarrassing,
The way it would behave.
For every single morning,
It would stand and watch me shave.
Now as old age approaches,
It sure gives me the blues.
To see it hang its little head,
And watch me tie my shoes!!?

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An Amateur Explanation of Immunotherapy


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For as long as I can remember, there has been lurking excitement regarding the possibility that our immune systems can find and destroy cancer cells. The history of well-documented spontaneous remissions goes back decades and is briefly reviewed here. I have personally never seen a spontaneous remission of cancer, although I have had patients who have done far better than anyone would have expected, suggesting that something must have slowed down their tumor progression.

In prostate cancer, one of the early hints that it might be possible to stimulate an immune attack on the disease came from the studies on Provenge (Sipuleucel-T). My colleagues and I placed several patients on the trials that led to approval of this “vaccine” by the FDA. These studies have continued to demonstrate improved survival of patients with metastatic disease who have failed hormone therapy, although the trials were all done before the availability of the newer ADT drugs abiraterone, enzalutamide, and apalutamide. On the other hand, in spite of the optimistic data we obtained in another vaccine trial on a product known as prostvac, the pivotal trial to prove efficacy failed. It is possible that the vaccine produced modest efficacy, but the signal was drowned out by treatment with the new ADT agents.

As anyone who watches the evening news or other TV-ad-saturated programs aimed at us seniors, other cancers – especially melanoma, lung, bladder, kidney and a few additional ones have been more “easily” treated with newer immune therapies known as check point inhibitors. The idea here is that our normal immune system has built in “braking systems”, the best studied and clinically utilized to date being the PD-1/PDL-1 mechanism. If we immunize you against, for example, measles – you want a vigorous immune response, but you don’t want your entire immune system to keep working on fighting measles. There are other threats it needs to be on guard against. Shutting down the T-cells that fight viruses and cancer involves the Programed Death receptor-1 on these T-cells with a specific protein, Programed Death receptor Ligand-1. Cancer cells can take advantage of initiating this same braking system by releasing their own PDL-1 that will kill the incoming tumor-fighting T-cell. This devious cancer mechanism to avoid our immune systems can be blocked by therapeutic antibodies directed against either the receptor or the PDL-1 ligand protein.

At the recent ASCO meeting, it was revealed that selected metastatic lung cancer patients who have an activated PD-1/PDL-1 braking system are now more effectively treated with pembrolizumab (Keytruda) than chemotherapy. It is emerging that the subgroup of patients who have tumors that are genetically highly unstable, (regardless of tumor type) with lots of mutations leading to abnormal proteins that can stimulate an immune response, may all benefit from PD-1/PDL-1 directed therapy. These patients, including prostate cancer patients can be identified by testing their tumors for microsatellite instability or mismatch repair deficiency. At a practical level, however, when and how to test prostate cancers for such biomarkers remains challenging. Last week at the ASCO annual meeting, Dr. De Bono from the UK reported results on treating patients with metastatic prostate cancer who had progressed on hormones and chemotherapy (docetaxel) with pembrolizumab. 17/163 patients had ≥30% shrinkage of their tumors, but overall results were disappointing with only 11% of patients having ≥50% decline in PSA. Testing for the presence of PDL-1 was not particularly predictive of which patient would benefit most. However, this way of treating prostate cancer will eventually lead to important progress in my opinion. Combining vaccines with the checkpoint inhibitors is currently being studied, and there are other checkpoint drugs and targets that are in development as well. Timing the checkpoint drugs with hormonal therapy or radiation therapy may also find optimal ways of stimulating an immune response. The field of immuno-oncology is an exciting new frontier and well worth keeping your eyes on.

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Here be Dragons


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There are times in everyone’s life when it is worth pausing to consider larger issues than the conditions you find yourself facing every day. Big issues like the meaning of life, how we got here, what happens after we leave…, have been the topics of philosophers and kings with far more eloquence than I have. Nevertheless, I am compelled to pay homage to one of the most influential philosopher-teachers in my own life today, because failing to do so would be an injustice to my feelings about him, and this blog is my sole “public forum”.

Donald Seldin was the Chief of Medicine at UT Southwestern Medical School, better known to most people as “Parkland Hospital”, the place they took Kennedy. I went there as an intern in 1972 and was privileged to be under his spell for the two years of my training that represent, for most physicians, the most intense interval in all of their preparation to become “a doctor”. Unless you have lived through your first night on call, wondering whether and how your medical school has prepared you to actually make decisions about another human being who has, by choice or by chance, placed their life in your hands, it is hard to put those feelings into words. “Here be Dragons” is a myth about maps relating to what early cartographers would put on maps when they reached the edge of the known world. I always found that phrase evocative when it comes to facing the unknown. For thousands of physicians who trained under Dr. Seldin, he became the pilot who helped you edge out onto that unknown sea called MEDICINE and gave you the confidence to succeed.

Dr. Seldin died at the age of 97 last week. His life and contributions have been extolled by many of his admirers. The shortest version I can find is this obituary from the New York Times. For a more extensive version, and to meet the man himself, you can watch this video. When I was in mid-career in the 1980’s, we took a sabbatical in Helsinki, Finland. It gave me time to think about the larger issues and to write to some of my mentors, thanking them for taking me on as a student and sharing their wisdom with me. Dr. Seldin was one of the men to whom I corresponded. As I recall, in the letter I referred to the pop song, “To Sir with Love” because at an emotional level, the phrase “How do you thank someone who has taken you from crayons to perfume?”  best captured how I felt about his tutelage. He wrote back to the effect that he “had no idea that he cast such a long shadow”, which was surely not true, but his modesty was just another facet of his remarkable personality.

So, if you are in any sort of a contemplative mood at some point this year, take a bit of time to write to one of your mentors or a family member. Thank them for what they mean to you. When they are gone (or when you are gone), that letter will be worth your time as an emotional bond as you sail on into the unknown. Godspeed Dr. Seldin!

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