• 6/8/2007
  • London, England
  • staff
  • Economist.com

Drugs directed at precise molecular targets are helping cancer patients live longer. They have yet, however, to fulfil all expectations.

Researchers have been promising a revolution in cancer treatment for a long time. More effective and less toxic drugs are expected to replace old-fashioned chemotherapies. The approach is called targeted molecular medicine and the idea is to substitute the blunderbuss of chemotherapy with the sharp-shooting of a chemical that interrupts a single molecular pathway—one that is crucial for the survival of cancer cells, but not normal cells.

The problem is that this pathway will vary from cancer to cancer. You therefore have to find out which pathway is crucial in a cancer before you can make the drug. And once armed with the drug, you have to devise tests that reveal what type of cancer someone has, in order to find out whether the drug will work in his case. Even then, there is no guarantee it will work well—as three large clinical trials unveiled at this week’s meeting of the American Society of Clinical Oncology, in Chicago, sadly demonstrate.

It is not that any of the trials failed, exactly: all added weeks or months to the lives of those taking the new therapies. It is rather that physicians were hoping for years of extra life. There are useful lessons to be learned from these trials. Unfortunately, the main one is that molecular medicine is harder than it looks.

The tumours treated in the three trials were head-and-neck cancer, liver cancer and kidney cancer. One relied on drugs intended to block the growth of the tumour itself. In the other two cases the idea was to block the growth of blood vessels into the cancer. Without these extra vessels, a cancer cannot grow. That reduces both the threat from the primary tumour and the risk that it will metastasise, spreading secondary tumours around a patient’s body.

The head-and-neck trial was conducted by Jan Vermorken of the University of Antwerp. Dr Vermorken did not abandon standard chemotherapy completely. He did, however, combine it with Erbitux, an antibody that binds to and thus disables a protein that promotes the proliferation and growth of cells. The 222 patients treated with Erbitux and chemotherapy survived for an average of 40 weeks. The 220 treated with chemotherapy alone lived for 30 weeks. Viewed positively, this ten-week increase in survival is the first improvement in prognosis for those with head-and-neck cancer that has been seen for 25 years. On the other hand, it is hardly a cure.

Josep Llovet of the Mount Sinai School of Medicine in New York had a similar outcome with sorafenib, an agent aimed at a protein that promotes blood-vessel growth. His patients had advanced liver cancer, which is untreatable. Like Erbitux, sorafenib works. Indeed, it prolongs life by almost exactly the same amount of time as the head-and-neck treatment—from 32 weeks for those in the control group, who were given a placebo, to 43 weeks for those receiving the drug. This is a big advance, given that 100 previous trials of other potential drugs had failed completely. But again, it is not a cure.

The new approach did a bit better against kidney cancer. Avastin, another blood-vessel-growth blocker, increased average survival from 22 weeks to 42 weeks when it was added to the standard treatment by Bernard Escudier of the Gustave-Roussy Institute, in Paris. But that was still not what had been hoped for.
Off target

David Gandara of the University of California, Davis, is looking for ways to improve the strength of these drugs. Part of the problem, he thinks, is that although the drugs on trial have been designed to attack particular targets, none of the trials was based on selecting patients whose tumours were known to be producing the target proteins. Although tumours are classified anatomically (eg, head-and-neck, liver, kidney), these tissues can become tumorous in many ways, only some of which will be susceptible to a particular drug. If the pathway attacked by that drug is not active in a patient, the drug is unlikely to curb his tumour’s growth.

In fairness to the researchers, the trials were conducted this way because quick, reliable tests to identify the molecular nature of these cancers do not exist. For the drugs to be deployed to greatest effect, such tests would need to be developed.

But there is another, deeper, problem. Even when a drug’s mechanism looks obvious, it sometimes is not. Erbitux, for example, binds to a cell-surface protein called epidermal growth-factor receptor (EGFR). This controls growth and survival pathways in cells. Many types of tumour produce far more EGFR than normal cells do, and one effect of that is to stimulate the proliferation of tumour cells. Researchers thought this meant the receptor would be central to the survival of those cancer cells, but that has not consistently been so.

Erbitux slows the progression of colorectal cancer, but the drug’s activity does not correlate with expression of EGFR in such tumours. Its activity does, however, correlate with EGFR expression in lung cancer, according to data presented at the conference by Roy Herbst of the M.D. Anderson Cancer Centre in Texas. The cause of this contradiction is mysterious.

Even when the level of a molecule seems to predict a drug’s success, a test may prove unreliable. One of the biggest success stories of targeted therapy is a drug called Herceptin. This dramatically reduces the risk of relapse in breast-cancer patients whose tumours make a protein called Her2/neu, and only those women whose tumours produce this protein will respond to the drug.

That was proved two years ago, when three large trials showed Herceptin’s value in treating early-stage Her2-positive breast cancer. However, recent re-tests of tissue taken at the time, and reported at the meeting, suggested that 10% of the tests which were originally positive for Her2/neu appeared negative on re-testing.

That is surprising, as many of these women responded to therapy. Nor is there any question over Herceptin’s specificity—that is now well established. What is called into question is the reliability of the test. If a woman is denied treatment on the grounds that she could not possibly benefit, the basis of that denial had better be rock-solid. For the moment, the suggestion is that those who test negative should get a second opinion. But it all goes to show that what looks clean and simple in theory can be very complicated in practice.