How close are we really to “precision medicine” for cancer care?

A newly published paper in the journal JCO Precision Oncology confirms what many of us may have suspected — that the practical application of somatic tissue testing to clinical decision-making was low prior to 2015 .

Tao et al., from Oregon Health and Science University (a group with recognized expertise in the treatment of men with late stage prostate cancer), report that, between 2012 and 2015, 59 of their patients with metastatic, castration-resistant prostate cancer (mCRPC) were given metastatic tissue biopsies, and that tissue from those biopsies then underwent genetic testing (“genotyping”) through the use of a 37-gene panel. In addition, tissue from 35 of those patients also underwent immunohistochemical testing for expression of the PTEN gene.

The authors go on to report that:

  • 46/59 patients with mCRPC (78.0 percent) had sufficient tissue for mutational testing.
  • 31/59 patients (52.5 percent) were found to have identifiable mutations.
  • 13/35 patients whose samples were tested by immunohistochemistry  showed loss of PTEN expression.
  • 2/59 patients were actually given treatment  based specifically on the results of the molecular tests.
  • 1/59 patients (i.e., just one of the two patients who were treated on the basis of their molecular test results) showed any sign of greater tumor control with this molecular -guided therapy than he had on his immediately preceding therapy.

In other words, the practical application of molecular testing to prostate cancer treatment at a major academic center with significant experience in the treatment of mCRPC between 2012 and 2015 was minimal and had little documented impact on patient care.

Now this could have started to change significantly in the 2.5 years since the end of 2015. We have better forms of genetic test that use much larger gene sequencing panels. We have ongoing clinical trials (such as the TAPUR trial) that have been designed very specifically to encourage genetic testing and the selection of drug therapy based on the results of such testing. Indeed, in the UK just the other day, the chief medical officer of the United Kingdom recommended (in her annual report) that

Genomic testing should become a normal part of … care [within the National Health Service], beginning with cancer patients and those with rare diseases …

However, we still have very little idea to what extent such genetic/genomic testing would have real practical value in the selection of appropriate drug therapy beyond some highly defined sets of patients with a few types of cancers.

As just a very recent example of the problem, it was initially thought that the BRCA1/2 mutation was a clear signal for ovarian cancer patients who would respond well to one of the relatively new PARP inhibitors. It has already turned out that, in at least one large Phase III trial, all groups of patients randomized to receive a PARP inhibitor as “maintenance therapy” after the patients had responded to platinum-based chemotherapy exhibited a progression-free survival benefit (compared to the patients randomized to treatment with a placebo), regardless of their genotype.

It is true that in this trial the patients with the BRCA1/2 mutation showed the greatest degree of benefit, but there was clear benefit across the entire “intent-to-treat” cohort. The real “best indicator” that the patients would respond to a PARP inhibitor appears to have been that they had already responded to platinum-based chemotherapy!

To paraphrase Tao et al., a second problem is that even if there are strong suggestions that a patient with genetic mutation AAA might respond to treatment with drug BBB, unless drug BBB is approved for the treatment of the specific form of cancer exhibited by a patient with mutation AAA, the patient may not be able to receive drug BBB because such therapy is “off-label” and not approved for use to treat that patient.

And to quote Tao et al., in detail

We are in a new era of cancer treatment, wherein molecular testing of tumors is commonplace. Our study provides important information on the need to not only have comprehensive molecular panels but also the complexities of implementing molecularly guided therapy. We will not truly be able to implement precision cancer care for patients through molecular testing until issues of access to drugs that target the identified abnormalities can be resolved.

25 Responses

  1. Just to give you another perspective on the gap between the rhetoric and routine clinical practice …

    MSKCC has made a big PR announcement about it’s new Precision Medicine Center. However, when I went to one of their oncologists not connected to that center for a second opinion about treatment options for my Gleason 9 (5 + 4) cancer, which has not responded to either surgery or salvage radiation treatment, he recommended ADT without even having reviewed my medical records.

    When I asked him how he could make that recommendation without at least reviewing my records, he said: “I don’t need to know anything else about your history. This is the protocol we follow.”

    Needless to say, that ended that consultation!

  2. My own advocacy experience suggests we should not turn patients away from genomic sequencing based on the cost of off-label treatments alone.

    Most of the “pharmas” have financial assistance programs to make these very expensive drugs available off label … notwithstanding they still may not be affordable to many. Additionally, the “pharmas” are often geared up to assist your medical team in making the case for their drug off label to insurers.

  3. Dear Rick:

    I don’t think anyone is suggesting that patients should be “turned away” from “genomic sequencing based on the cost of off-label treatments alone.” I think the point is that our ability to accurately use genomic testing to pick a drug that may or really is going to “work” based on genomic data is still very limited, and in my opinion such treatments are investigational and therefore much better done as part of a clinical trial like the TAPUR trial and some others.

    I will also state, however, that the ability of a drug company to advocate actively for a patient to get a drug off label outside of a clinical trial may place that company on very slippery ice because it can be argued that such advocacy is actually off-label promotional activity — which is illegal. When the treatment is being done in the context of a clinical trial, it is much easier for the companies to become involved (up to and including a willingness to provide free drug in some cases).

  4. As a side note, there is a clinical trial in Switzerland (NCT02311764) of carboplatin for men with mCRPC who have failed a taxane and an advanced hormonal therapy and who have DNA-repair defects. They aren’t comparing it to a PARP inhibitor, but it will be interesting to see if it gets a response. I suppose that carboplatin is a lot less expensive than olaparib. It would be nice if precision medicine didn’t have to mean expensive medicine.

  5. Mike – My point is not about obtaining drugs. It is only about accessing sequencing. We can discuss the pros and cons of pharma involvement and slippery slopes elsewhere! Pharma involvement should only supplement physician efforts to access personalized drugs.

  6. Allen … this article may be of interest to you. I know the second- and third-listed authors and have linked this research on several occasions.

  7. Rick:

    My point remains. I still think all of this is best done in the context of clinical trials so that everyone’s best interests are thoroughly protected.

  8. Thanks, Rick. I’ve talked to a few patients with the mixed adenocarcinoma/small-cell subtype who responded well to carboplatin + docetaxel, and found the toxicity tolerable. With the lytic bone mets, the imprecise biomarkers, and the low PSA, it is challenging to monitor effectiveness of therapies. I hope there will be an RCT with a cross-over design.

  9. Mike – just consider the patient in a far flung place who has no access to trials.

    AnCan recently educated the community doctor of a man in Piedmont, SC; eventually that man was sequenced and found to be receptive to a PARP inhibitor — although too late. Should that man — and many like him — have been forced to find an appropriate clinical trial?

    In a perfect world with ready access for all patients to trials, I agree with you. In an imperfect world, we have to make accommodations that may involve blemishes!

  10. Dear Rick:

    Any oncologist in America (however “far flung”) has very simple access to the TAPUR trial. It was carefully designed to make that possible!

  11. Sorry Mike – you don’t get it; if we are lucky community oncologists might think the TAPUR trial is about an animal.(sp.!!) .

    You and I are educated — they are not. We are doing the education — and I have heard this from other patient advocacy organizations too.

    You think in theory — I think in practice.

  12. Dear Rick:

    I am sorry but you are wrong. I am a member of the TAPUR case review team and I have been on calls that are largely from community oncologists seeking approval to enter their patients into TAPUR. This trial has been heavily promoted by ASCO to all of its members. It is not a trial of the type you are used to where you have to go to a specific site for treatment. Any community oncologist can enter a patient into this trial and treat that patient him- or herself. Since you are not a member of ASCO you don’t see most of the information or communication about this trial.

    You should also know that many of the applications to enter patients into these trials come with complete Foundation One reports on the patient’s genetic profiles and possible applicable forms of therapy.

  13. I am aware of TAPUR, Mike …. but truly concerned many ASCO members do not have it front and center on their radar.

    All too often, I hear from other advocacy organizations, not to mention patients, that their doctors need education.

    While I am sure ASCO’s intentions are good, I see and fear an ivory tower syndrome. How you want it to be is not how it is out there. My personal opinion is that those who think we can manage somatic sequencing and prescription of personalized medicines via clinical trials are living in that tower.

    Educating medical oncologists is a significant challenge Foundation Medicine has accepted — not to say ASCO has ignored it either. Nothing you can say here will convince me, or for that matter the hundreds of thousands of very sick cancer patients in the US, that clinical trials alone are going to provide them the service they need to access somatic sequencing and personalized meds!

  14. Mike – In my view, the points you make are . . . well, pointless, and even have the potential to harm some patients.

    To quote: “I think the point is that our ability to accurately use genomic testing to pick a drug that may or really is going to “work” based on genomic data is still very limited, and in my opinion such treatments are investigational and therefore much better done as part of a clinical trial like the TAPUR trial and some others.”

    I’m an advanced prostate cancer patient undergoing treatment with a PARP inhibitor based on a pathogenic mutation in BRCA2, after failing a number of other therapies. So far my treatment has been phenomenally successful — two years after beginning treatment, most mets have disappeared and I’m living a normal life despite being told by a clinician just before treatment began that I had a few months to live at best. My treatment is not within the context of a clinical trial, and my insurance company agreed to pay, without a fight — and after I turned 65 a few months ago, Medicare helped with the cost. None of the clinicians treating me knew about the drug I’m taking. I had to educate them, despite the fact I’m being treated at a major NCI-designated cancer center. I know, or know of, a number of other patients who have similar stories. Note also that I do not qualify for entry into many of the clinical trials for PARP inhibitors, for a variety of reasons. Granted, my BRCA mutation is a germline (inherited) mutation, but it’s in my tumor cells as well, and would also have been detected just by sequencing of my tumor cell DNA,

    It is likely that there are thousands of other men with prostate cancer who could similarly benefit from treatment with PARP inhibitors — and that’s just the guys with BRCA mutations! How many of them will read your words in this thread and think: “Oh well, there’s no point in getting tested” or who, if they are tested and test positive for a BRCA or other actionable mutations, will not understand that they may need to push their oncologist for treatment, or won’t bother to do so because they think their insurance won’t cover it?

    I will be blunt — some of these men will likely die earlier than they would if they had been tested and appropriately treated. This is the argument you should be making! Of course more work needs to be done by the urological oncology community before it can fully leverage the promise of therapies targeted at specific mutations! But why focus on this negative? I think you need to think this issue through more carefully and responsibly.

  15. Dear Dr. Burhans:

    You are entirely entitled to your opinion. I happen to have a different one. Differences of opinion are not uncommon in this increasingly complex world — and I certainly don’t claim I am necessarily “right”.

    I am delighted for you that your particular condition responded well to a PARP inhibitor, and I hope it continues to do so … but given the number of trials now ongoing or being initiated of PARP inhibition in the treatment of prostate cancer (BRCA1/2 germline and somatic subtypes included), I continue to hope that a large number of such patients are (a) appropriately genotyped and (b) actually treated in clinical trials. We have already learned some distinctly unexpected data as a consequence of such trials of PARP inhibitors in the management of ovarian cancers.

  16. I believe we have identified the common ground … that genomic testing whether germline or somatic, may identify potentially successful treatment protocols for some cancer patients, albeit a fairly small number of prostate cancer ones.

    The issue at debating is (1) how accessible is sequencing, (2) should access be provided commercially with heavy subsidization where necessary, or only via clinical trials, and (3) should patients who appear to have actionable mutations be encouraged to involve the pharmaceutical companies to obtain such drugs at an affordable price.

    The difference of opinion here is whether pharma involvement is a slippery slope liberally peppered with conflict of interest. And if discouraging pharma involvement and relying solely on clinical trials is a better approach.

    I would hope we encourage both avenues …. Why? A few, like Dr. Burhans, may benefit however they arrive at these protocols and whoever pays for their treatment. I have to agree with Dr. Burhans that as patient advocates and opinion leaders we have an obligation to encourage, not discourage, ALL avenues that lead to potential treatment.

  17. Dear Rick:

    Respectfully, I have never been “debating” the first three issues that you raise at all. Of course “genomic testing whether germline or somatic, may identify potentially successful treatment protocols for some cancer patients, albeit a fairly small number of prostate cancer ones.” I have never suggested otherwise, but please note my heavy emphasis on the word “may”.

    Furthermore, I have no opinion whatsoever on how an individual patient and his doctor and the insurance and pharmaceutical industries want to go about making specific drugs available to specific patients for whom those drugs may be appropriate (so long as it is legal and “transparent”). I have also never suggested that we should rely solely on clinical trials.

    All I have ever pointed out is that, in my opinion, clinical trials are the “best” way for this to be done because: (a) they lead to the accumulation of reliable data; (b) those data can then be made available to others and used for the appropriate education of patients and their physicians; (c) the provision of drugs for use off-label in clinical trials is protected by law and can often ensure that those drugs are available to patients at no cost (although that is not necessarily the case in the TAPUR trial).

    What I absolutely do encourage patients to do is to learn and become their own best advocates. Dr. Burhans is an excellent example of this. But he is also, for all sorts of reasons, an outlier (in terms of the nature of his cancer and the knowledge he has because of his scientific training and work). What I do not want to see is the average patient being given the misleading idea that if he goes and gets germline and somatic genotyping that: (a) it will necessarily give him and his doctor insight into the “right” way to treat any type of prostate cancer; (b) even if such genotyping does suggest therapy with a specific drug or biologic, it will necessarily be possible to get such a drug, be treated with it, and have it provide significant therapeutic benefit.

    This takes us back to what I wrote about above, which is what Tao et al. showed in their study. And that is all I was ever commenting on.

  18. Mike,

    If you’re referring to the “unexpected data” that you also referred to above as the “problem” that “the best indicator that the patients would respond to a PARP inhibitor appears to have been that they had already responded to platinum-based chemotherapy!” — your facts are wrong. This result is not unexpected. Inhibition of PARP leads to an increase in lethal DNA damage specifically to tumor cells that harbor mutations in BRCA and other genes, which also cause DNA damage — this is the basis for the efficacy of PARP inhibitors in the clinic. The basis for the improved response of patients with these mutations to cisplatin drugs is exactly the same — these drugs also cause DNA damage, the lethality of which is increased by the DNA-damaging effects of these mutations. In short, rather than being a “problem” as you have labeled it , this finding validates the general approach of treating patients who harbor these mutations in their tumors with drugs that damage DNA, which act synergistically with DNA damage caused by the mutations. The only difference is that PARP inhibitors provide a more directed approach to damaging DNA specifically in tumor cells, which does not cause as much collateral damage (and thus side effects) in normal cells compared to cisplatin drugs. In any case, it makes perfect sense that these tumors would respond better to cisplatin drugs compared to drugs that do not damage DNA.

    This isn’t my opinion — it’s the facts, and (as has been said very often in a different context lately), no one is entitled to their own set of facts. This is the last I will say on this topic in this thread — frankly, however, this discussion is discouraging and frustrating.

  19. In my mind, we should encourage all patients with advanced cancers, prostate cancer and otherwise, to discuss sequencing with their medical team through both commercial avenues and clinical trials … and subsequently, how best to obtain personalized medications, no matter how slim the chances they may find something actionable.

    I see no downside for the patient if a pharma advocates to an insurance company on their behalf based on valid independent medical recommendations. All too often recently, I have encountered the same slippery slope when it comes to doctors recommending trials to their patients — even at the most reputable institutions.

    My starting point and end point is that any discouragement is a disservice to our patient community … although I agree and always do point out that many patients may not find an actionable mutation!

    I hope we can agree Mike.

    PS: Purely as an anecdotal aside, the number of AnCan participants with actionable mutations appears to be well in excess 2%-3%!

  20. Mike,

    I posted my second comment before your latest post, so let me add very briefly — Tao et al. agree in their paper that their conclusions were limited by a number of factors, including the small number of actionable genes that were available earlier when they conducted their study. The situation now is quite different. For example, their study involved 37 genes, whereas FoundationOne (for example) now sequences up to 360 genes. It makes no sense to argue that a patient’s options for treatment are severely limited based on the small, 10-fold fewer number of genes involved in the Tao et al. study. Finally, it’s irrelevant that as a cancer scientist I have more access to information. I’m trying to get this information out to others who don’t have as much access — once they have it they can pursue exactly the same treatment. But they won’t if they’re being counseled that it’s pointless …

  21. Dear Dr. Burhans:

    When did I ever say anything about genotyping being “pointless”? You are making utterly inaccurate and misleading statements about things that I am pointing out.

    And Dear Rick:

    I am more than willing to encourage patients to discuss genotyping with their physicians — and in fact I would argue that if we could afford it this should probably be done at time of diagnosis for any man with a high-risk or metastatic form of prostate cancer. Why do you think I was so careful to include (above) the recent recommendation from the UK’s Chief Medical Officer? What is then done on the basis of the resulting data is an entirely separate issue.

  22. Mike …

    I don’t want to put words into Dr. B’s mouth, but can see how the statement:

    “However, we still have very little idea to what extent such genetic/genomic testing would have real practical value in the selection of appropriate drug therapy beyond some highly defined sets of patients with a few types of cancers.”

    … can lead readers to infer you are not supportive of genotyping, especially since there are many examples of genotyping having real practical value.

    As respected advocates, we all have to be aware that what we write may not be interpreted the way we we expect. Bill’s point, and mine, is to tread carefully so as not to deter genotyping.


  23. Dear Rick:

    I am regularly accused by people of writing things that they don’t like or agree with. And I almost invariably assist them by politely posting their comments on this web site. (I believe that there have been about 10 comments in the past 9 years that I did not post because they were either utterly delusional or they were a verbatim repeat of a comment I had previously posted.) However, I will continue to write, with great care, what I believe to be truth. The sentence you have picked out is true and entirely accurate. And, as you well know, not a single drug has been approved to date in the management of prostate cancer based on the germline or somatic genotype of a patient with prostate cancer. I expect one of the PARP inhibitors to break that particular barrier within the next 2 or 3 years.

    If someone chooses to “infer” that I am not supportive of genotyping on the basis of an accurate, single sentence out of the dozens of posts on this site that have dealt with the potential of genetic/genomic information on the treatment of prostate cancer that’s fine. I have a thick skin. However. as I have carefully pointed out, it is an inaccurate and inappropriate inference.

    It would have been just as reasonable for someone to infer that, because I had included the comment made by the CMO of the National Health Service in England, that I was in complete agreement with that particular perspective … but both you and Dr. Burhans chose to ignore that possible inference.

  24. Don’t shoot the messenger, Mike ….. just saying that your written word can easily be interpreted by educated readers to carry a message you do not intend – as you see!

    If I am reading you right, you have done a great job clarifying your position that you do support genomic sequencing by any channel possible, that for a few may lead to significant benefits.

  25. Dear Rick:

    I’m not “shooting the messenger”. I am merely observing that “interpretation” (as opposed to actually reading what is written) is a very dangerous game to play.

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