Wednesday, June 7, 2017

A Big Advance in Cancer Care

One May 23 a very significant event took place in the history of cancer treatment. The FDA approved use of an existing drug for first line treatment of cancers based purely on specific DNA changes in the tumor, regardless of the body site of the tumor.

This is a first for the FDA. All previous cancer drug approvals have been for cancer originating in specific body site such as colon, breast, lung, etc.

This is a long post, but I want to describe the context so you can understand the significance of this event.

After the human genome was sequenced at the beginning of the 21st century, cancer researchers began to discover that some DNA changes were common in cancers originating in the same site: for example, a particular DNA mutation in the gene called BRAF is common in colon cancers. Drugs - called targeted therapies - were developed to kill cells with that specific mutation. Similar targeted therapies were developed for other mutations, which had common occurrence in other tumor sites.

Targeted therapies were a great advance and they are still being developed. But most of them produce drug resistance. The drug kills the cells at which it is aimed, but the tumor evolves. Yes, just like Darwin described: other cells in the tumor do not carry the targeted mutation and are thus more adapted to their environment and outcompete the targeted cells. The drug stops working and the tumor grows again: cancer recurrence.

In a separate thread, cancer researchers have wondered since the 1960s why the immune system doesn't attack tumors. One core answer to that question is provided by Siddhartha Mukherjee in "The Emperor of All Maladies": cancer is us. It is not a foreign substance or organism in the body, it is our own cells that have sustained DNA damage and lost control over their growth and division. Thus the immune system does not generally recognize cancer cells as foreign.

The immune system is incredibly complex. But knowing the human genome and being able to use that knowledge as a scaffold has allowed researchers to gain much more understanding of adaptive immune cell function; specifically the proteins on the surface of T cells and B cells, the core components of the adaptive immune system.

The most significant discovery in this realm so far was that some tumors could "hide" from the immune system by manufacturing a specific protein (PD-L1). Drug companies were able to make drugs that target that protein, unmasking the tumor cells and "releasing the brakes" on the immune system so that it would attack the tumor.

Results have been spectacular. It is not an exaggeration to say that this has been the single most significant impact on cancer care in decades. Cancers that were death sentences before these drugs, such as the first approved cancer type, metastatic melanoma, suddenly were treatable and some patients cancers disappeared completely (e.g. Jimmy Carter).

This class of drug is called immunotherapy for obvious reasons.

Unfortunately, these drugs don't work for all tumors. They currently produce a partial or complete response in about 30-40% of the cancers in which they are most used. So the obvious question is: why? And can we tell ahead of time which patients will benefit?

One of the drugs (pembrolizumab, marketed by Merck in the US as Keytruda) uses a biomarker to try to determine a patient's likely response. A biomarker is just a biological factor you can measure. Simple examples are weight or blood type. A more complex one (to measure) is amount of PD-L1 produced by a tumor. Pembrolizumab was believed to work in patients with "high" PD-L1 expression and was approved by the FDA for patients with that biomarker - in specific cancers.

[Full disclosure: I used to be employed by Merck but I have no current financial interest]

But more recent research has shown that what might really tell us which patients will respond to immunotherapies is how many mutations they have in their tumor cells' DNA. DNA is the template for proteins; DNA mutations can result in changes in the proteins produced. The theory is that the more mutations a cell has, the more changes are likely to occur in the proteins the cell has on its surface. And the more protein changes on the cell surface, the more likely the immune system will recognize the cell as "bad" and kill it.

As I've described in previous posts and above, cancer is a disease of the DNA. Accumulated mutations eventually activate an oncogene, causing cells to lose control over growth and division, or mutations disable a tumor suppressor gene, leading to the same problem.

Cells have multiple mechanisms to repair DNA damage and do so on a regular basis. But if you end up with mutations in the repair mechanisms, you're in trouble. One of these mechanism is mismatch repair. Loss of the mismatch repair mechanism can lead to one specific type of hypermutation called microsatellite instability.

These two characteristics of tumor DNA lead to high tumor mutational load. Remember that a high number of mutations seems to increase the likelihood that a tumor will respond to immunotherapy.

And now we're back at the the recent FDA approval. It says:

Keytruda (pembrolizumab) is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with certain chemotherapy drugs.

The most important part is that it is approved for any solid tumor that has these DNA characteristics, regardless of the body site in which the tumor arose.

[You may not be used to the term solid tumor. It means what it sounds like: a cohesive mass of cancer cells in a mass. Liquid tumors includes such cancers as leukemias and lymphomas in which the cancer cells are distributed through the body in blood, bone marrow or the lymphatic system.]

People like myself who work in cancer genomics have long "known" that a day would come when we would treat cancers by their molecular (DNA) characteristics instead of their site of origin.

This FDA approval represents the first milestone in that transition.

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