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.

4 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.

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