Questions Over Promise of Personalized Cancer Medicine

Pam Harrison

September 29, 2016

The promise of personalized cancer medicine is still a long way off, and it's questionable whether any personalized approach will ever benefit patients to any significant degree, say two researchers writing in a "sounding board" article published online September 29 in the New England Journal of Medicine.

"Patients love the idea that they have a specific mutation in their tumour and that if they have their cancer gene sequenced, there will be a specific and effective drug that targets their mutation," coauthor Ian Tannock, MD, PhD, Princess Margaret Cancer Center and the University of Toronto, Ontario, Canada, told Medscape Medical News in an email.

"In addition, I think cancer institutes know that it is attractive to patients and many of their fund raising efforts support it," he added.

"But in our opinion, personalized medicine is unlikely to ever deliver highly effective therapies," Dr Tannock said.

In the commentary that he cowrote with John Hickman, DSc, AGON-Paris, France, the pair write: "There should be a clear message to patients that personalized cancer medicine has not led to gains in survival or its quality and is an appropriate strategy only within well-designed clinical trials."

Different Signaling Pathways

As Dr Tannock and Dr Hickman acknowledge, an increasing number of drugs that target different signaling pathways are becoming available.

However, they point out that most of these targeted agents only partially inhibit signaling pathways.

"With the possible exception of immune-checkpoint inhibitors, cancer cells have an almost universal capacity to develop resistance to a single molecular targeted agent by means of upregulation of the partially inhibited pathway, mutation of the target, or activation of alternative pathways," they explain.

Dr Tannock and Dr Hickman also emphasize that many molecular targeted agents are too toxic to be used in combination with other agents, so combining different agents to provide more complete inhibition of different pathways, even if the cost of such an approach could be justified, is usually not feasible.

Furthermore, some mutations may be present in all sampled cancer cells and are clonal markers of the cancer, but other mutations are specific to subclones that are generated during tumor growth and spread.

"Sensitive genetic characterization of individual cancer cells indicates that intratumor heterogeneity is present early in cancer development and that subclones are selected by cancer treatment," they add.

Even if an effective agent does exist that matches the molecular analysis of a single biopsy, "it is likely to have limited benefit because molecular pathways that are active in other parts of the tumor will lead to tumor growth from different clones of tumor cells," Dr Tannock and Dr Hickman write.

Thus, intratumor heterogeneity is an unassailable limitation to the central concept of personalized medicine, they emphasize, and not one that is easily overcome.

Extremely Limited

So far, clinical evidence supporting the efficacy of the use of targeted drugs that are matched to the genetic sequence of a patient's tumor has been extremely limited.

Outcomes from various published series that do exist have been "discouraging," Dr Tannock and Dr Hickman note.

Although enthusiasts for personalized medicine point out that molecular techniques characterizing tumors will likely improve and that new therapies will emerge, "we suggest that inherent limitations of molecular targeted agents, as well as the Darwinian evolution of tumors leading to intratumor heterogeneity, will limit this improvement," the authors suggest.

Then there is the cost of personalized cancer medicines. As Dr Tannock and Dr Hickman point out, the price tag that accompanies new targeted agents has little to do with their clinical effectiveness, raising doubts about their real value in the practice of precision oncology.

Although some medications, such as imatinib (Gleevac, Novartis) and trastuzumab (Herceptin, Roche), have proven to be cost-effective despite exorbitant up-front costs, "the development and marketing of expensive drugs with marginal effectiveness diverts resources from the development of more effective therapies," Dr Tannock and Dr Hickman worry.

This concern is compounded by the fact that most cancer institutions are committed to undertaking independent research without cooperating with each other. As a result, discoveries are likely to be duplicated and valuable resources wasted as a result, the authors assert.

"The concept of personalized medicine is so appealing that seemingly only curmudgeons could criticize it," Dr Tannock and Dr Hickman conclude. They are not saying that the approach should be abandoned; rather, they suggest that personalized medicine should be evaluated "in a small number of well-designed collaborative programs, with research programs that recognize and combat the limitations we have described."

Potential Futility

Dr Tannock and Dr Hickman are not alone in voicing their concerns about the potential futility of personalized medicine, at least as it pertains to cancer therapy.

In another opinion piece published online September 7 in Nature, Vinay Prasad, MD, assistant professor of medicine, Oregon Health and Science University, Portland, writes that to date, few patients have benefited from precision oncology.

For example, the MD Anderson Cancer Center in Houston, Texas, has invited some 2600 patients into their sequencing program. So far, slightly more than 6% of them have received treatment targeting their mutations.

"Similarly, the Molecular Analysis for Therapy Choice (NCI-MATCH) trial at the US National Cancer Institute has enrolled 795 people who have relapsed solid tumours and lymphoma, but as of May 2016, it had only been able to pair 2% of patients with a targeted therapy," Dr Prasad writes.

Furthermore, receiving some sort of targeted agent is no guarantee of benefit, he notes.

Dr Prasad highlights the results recently reported in JAMA Oncology that show that only 30% of patients with a variety of types of relapsed cancer treated with agents selected on the basis of biological markers responded at all, and the median progression-free survival rate in this group overall was 5.7 months.

"Multiplying the percentage of patients receiving targeted therapies by this response rate, I estimate that precision oncology will benefit around 1.5% of patients with relapsed and refractory solid tumours," Dr Prasad writes.

As for isolated reports of patients who apparently did spectacularly well when given a targeted agent, Dr Prasad and a colleague identified only 32 such instances of these so-called "super-responders" in their review of the medical literature.

"Indeed, we found several cases in which the 'exceptional' responder had already experienced exceptional responses to conventional chemotherapy before their supposedly miraculous response to precision oncology," Dr Prasad observes.

"It is hard to avoid the unsettling conclusion that such cases do not reflect the success of precision oncology, but rather the selective reporting of individuals who were always likely to do well."

Dr Prasad agrees with Dr Tannock and Dr Hickman that the concept of precision oncology is "inspirational."

"What doctor or patient would not want to harness genetics to tailor a therapy to an individual?" he asks.

But, like Dr Tannock and Dr Hickman, Dr Prasad maintains that "precision oncology remains a hypothesis in need of verification" and that at best, "we may expect short-lived responses in a tiny fraction of patients, with the inevitable toxicity of targeted therapies and inflated cost that this approach guarantees."

N Engl J Med. Published online September 29, 2016. Abstract

Nature. Published online September 7, 2016. Full text

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