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Cancer Mutations and Immunotherapy Drugs

Picture, if you will, a laundromat.  One of the washing machines is messed up; it stops in mid-wash cycle, and leaves your clothes all wet and soapy.  Which one is it?  From the outside, they all look the same.  If nobody tells the repair guy which one is broken, how’s he going to know which one to fix?

The immune system’s great warrior cells, called T cells, face a similar predicament with some types of cancer, including prostate cancer – because the cancerous cells don’t look that different from normal cells.  If the T cells could speak, they might say, “What am I, psychic?  How am I supposed to know which ones I’m supposed to kill?”  Hard to believe, but many cancer cells aren’t considerate enough to advertise their presence to the immune cells that would gladly kill them!   From cancer’s standpoint, this is a win.

But some cancers, to the immune system, stick out like the proverbial sore thumb.  They look sketchy.  This makes it a lot easier for the T cells to notice them.  Why do some cancers look like the enemy invaders they are?  Genetic mutations.  Our cells copy DNA constantly, to make new cells.  Sometimes, our little genetic copiers make mistakes.  They make typos, and sometimes, despite our genetic army of very good spell-checkers and quality-control experts, these typos don’t get caught.

When one of these spell-checker genes, called a DNA mismatch repair gene, is defective, these mistakes start to add up over time.  With each mutation, the cancer cell looks just a little bit different.  The rate of these mutations can be estimated by looking at their results: microsatellite alterations.  These are genetic error messages, short bits of repeated DNA. 

Cancer cells that have a lot of mutations – as estimated by the number of altered microsatellites — are much easier for the immune system to see.  These pieces of DNA are biomarkers, and a pathologist looking at the cancer under the microscope, would say these multi-mutated cancer cells are “microsatellite instability-high,” or MSI-H.

In colon cancer, for example, the presence of MSI-H is so important, and so common, that knowing this biomarker status is the key to determining treatment:  in MSI-H patients with several forms of cancer, certain immunotherapy drugs are much more likely to work than they are in other patients.

What about prostate cancer?  Only an estimated 3 to 4 percent of men with prostate cancer have MSI-H, mismatch repair-deficient (dMMR) cancer.  But for those men, knowing that they are in this subgroup of patients could make a huge difference in their treatment and prognosis.

“We used to put everyone with advanced prostate cancer in the same category,” says PCF Young Investigator Wassim Abida, M.D., Ph.D., medical oncologist at Memorial Sloan Kettering Cancer Center.   The thinking was, “if it’s cancer that is sensitive to hormones, then everyone gets the same androgen deprivation therapy (ADT).  Then, if that doesn’t work, everyone gets the same chemo.  But now we’re starting to understand the biology of the disease, the mutations in DNA that can drive the prostate cancer to grow.  And based on that, we can develop selected treatments for different groups of patients, depending on what the biology of their particular cancer is.  Now we need to know:  how is person A’s disease different from person B’s disease, and how can we use that knowledge to treat them differently?”

There are several important points of interest about these subgroups, or phenotypes of cancer:  One is that, in terms of treatment, the particular gene may matter more than the organ it happens to affect.  For example, a man with prostate cancer who has the same mutated gene as a person with colon cancer, or melanoma, or breast cancer, or another type of cancer, may have more in common with that person than with another man who has prostate cancer, but who has a different genetic mutation.

Also, “even though we can identify patients with MSI-H cancer, not all of them respond to immunotherapy,” says Abida.  “And some who do respond eventually have progression and growth of their disease, and we don’t know why,” although he and colleagues are working hard to find answers.   Another key point:  MSI can develop as the cancer evolves, which means that it may not be present in a man’s initial needle biopsy for prostate cancer – but it could be found in a biopsy of a metastatic tumor.  One day, it might be found by looking at circulating tumor cells in the blood, but that technology is not quite ready yet.

Abida recently was lead author of a large study published in JAMA Oncology, looking at the prevalence of MSI in prostate cancer and its response to pembrolizumab, an immunotherapy drug called a “checkpoint inhibitor.”  In the study, Memorial Sloan Kettering investigators did “molecular profiling” on biopsied tumors from more than a thousand patients with prostate cancer.  Of 1,033 patients, just slightly over 3 percent (32) had “MSI-H/dMMR” prostate cancer.  Eleven of these men, who had castration-resistant prostate cancer, received pembrolizumab; of these, six had a greater than 50 percent drop in their PSA levels, and four men had radiographic responses – on images, their cancer appeared significantly smaller.   “Five of these six responders were still on therapy for as long as 89 weeks,” when the study was written.

So, although just about 3 percent of men were in this MSI-H/dMMR subgroup, some of them responded to a checkpoint-inhibitor, and some of them responded exceptionally well.  “This is our future,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation.  “Precision diagnosis and precision treatment.  One single form of treatment may not ever work for all men with metastatic prostate cancer.  But if we can’t help 100 percent of men with one treatment, we can find multiple treatments that each work for smaller groups of patients.  These exceptional responders are the key to helping us understand how.”

Janet Worthington
Janet Farrar Worthington is an award-winning science writer and has written and edited numerous health publications and contributed to several other medical books. In addition to writing on medicine, Janet also writes about her family, her former life on a farm in Virginia, her desire to own more chickens, and whichever dog is eyeing the dinner dish.