day 298 – Personalized Cancer Therapy – from Innovation to Implementation

Last week I attended a great cancer conference, the WIN Symposium which this year was titled “Personalized Cancer Therapy – from Innovation to Implementation”.

This conference has brought together some of the best thinkers and doers in cancer these past few years in Paris in July. The focus of the WIN Consortium, the parent organization of the symposium, is to collaborate on clinical trials that will usher in the era of personalized therapy for cancer. The first trial from the group is called WINTHER and uses biomarkers to stratify patients with metastatic cancer. I should disclose that I am an elected member of the WIN Consortium’s Directorate  and that my employer, MD Anderson Cancer Center is a founding member institution.

The dream of this group, and of course many others is that one day an in depth molecular analysis of an individual’s tumor will allow the oncologist to select a cocktail of drugs that selectively kill the cancer, leading to a cure with little side effects. No more chemo broadsides or radiation burns. I have to say that this year the dream still seems very remote.

What we learned about the actual clinical impact of personalized medicine so far is not all that encouraging. There are clearly some examples of remarkable success, but it is proving to be very transient. Front and center currently is the BRAF story in melanoma, which has rightfully caused a lot of excitement, but recent data show that many patients experience tumor recurrence, and that the recurrent tumors have become resistant to Vemurafenib. The sad story is that these patients are dying at the same time they would have without the BRAF inhibitor. Admittedly they have more of that time without high tumor burden. As Dr. Lex Eggermont of Institute Gustave Roussy, who summed up this field at the symposium, said: BRAF inhibitors have been a scientific success but not a clinical one.

More fundamentally, for most cancers we still lack the necessary combination of well defined molecular defect that drives the tumor and corresponding drug. At the symposium, we learned a lot about the complexity of cancers, perhaps best summed up by the statement from MSKCC’s Dr. Levi Garraway when he said that there is a long tail in cancer, and that when considered at the level of mutations, all tumors are rare. In other words, your breast cancer and mine may look the same, have the same grade and may be treated with the same therapy today, but if we looked under the hood at the molecular abnormalities they could be quite different. The key mutations might be different enough so that a personalized therapy that is effective against your cancer wouldn’t work well against mine. That is a huge problem both from the point of view of clinical research and from drug development. The more fragmented the patient population, the more different therapy combinations will be needed. It’s a bit daunting.

To complete the story further, Dr. Nicholas Navin shared recent insights from looking at the mutations in individual breast cancer cells. Bottom line is that while there are many mutations that the cells share, there are also quite a few that are only present in some cells. This may well explain why targeted therapies work transiently – there may already be a few cancer cells that have resistance mutations, or lack the mutation that conveys susceptibility to the drug at the time the treatment is administered. These cells survive the treatment, and come back as the recurrent tumor.

On the plus side, the technological advances we heard about, both in assessing molecular changes with ever more precision and sophistication and using ever smaller amounts of tissue, is promising as it will allow us to hone in on the tumor cells. In parallel the informatics are evolving rapidly to help us manage the large data and get it to the clinical decision makers in the appropriate format. There are still many hurdles to overcome in all these areas, but academic and commercial entities are engaged, and progress is being made. Groups like the WIN Consortium can make important contributions to this fight. In my next post, I will also describe how you, the cancer patient, can make an essential contribution.