Riding High on MSI - Charles Ryan

If you treat mCRPC you need to know about mismatch repair. I don’t say this often, but it could be a matter of life or death. And that is not an exaggeration.

Ok, now that I have your attention, let’s talk about the science, the clinical care and the implications for the field.

But first, a brief case. Consider my patient Arnold (not his real name). He is a 68-year old man who underwent radical prostatectomy in 2011. (Gleason 5+4 with Invasion into bilateral seminal vesicles, +LVI, +PNI, +extensive extraprostatic extension), followed by a brief course of ADT and salvage radiation a year after that. He experienced a rise in his PSA about 3 years later. A Sodium Fluoride PET Scan (we don’t do those anymore BTW…. more on that later) showed evidence of moderate volume metastatic disease. Given our enthusiasm for the newly released CHAARTED data at the time, I started him on ADT and offered him docetaxel, which he readily accepted. He tolerated it reasonably well and finished all 6 cycles, but within another year the psa was rising. Abiraterone and enzalutamide both proved ineffective, he was essentially primarily resistant to both. This was all within about 3 years of starting the ADT. A clinical trial of a novel agent with promise in prostate cancer proved to be only toxic and his PSA kept climbing.

In early 2016 I sent a guardant 360 cell free DNA test and it showed a pik3ca mutation, among some other relatively unimportant findings. This prompted enrollment in a clinical trial of a targeted agent that proved to be unsuccessful. His PSA was rising (now at about 150 ng/dL) and he had new bone metastases. In late 2017 I sent his RP tissue sample, which showed both a pathogenic ATM mutation and a mutation in MSH2.

I nearly fell out of my chair when reading the results. MSH2 mutation! an MSI high patient! I called him right away to come in to the office to talk and started him on Pembrolizumab (a PD-1 inhibitor) the next week. We drew a baseline PSA prior to the first dose of Pembrolizumab- it was 175 ng/dL. Three weeks later, at the start of cycle 2, the PSA was down to 20 ng/dL and by cycle #4 it was undetectable. His pain is gone, his appetite is better, he is gaining weight and spent the Christmas holiday in Europe. 

It’s a good story. It is rare, but not an extreme outlier. About 2% of prostate cancer patients have this mutation – but it may be a bit higher if we enrich for mCRPC and treatment refractory status like in Arnold’s case. I’m sure I’ve had many similar patients over the years but did not recognize this MSI high status, nor did I have an agent to offer them if I had discovered it. 

He is alive today because I sequenced his tumor. Most importantly, he may be alive one year from now, or even two, because I sequenced his tumor.

So lets break down what is going on here biologically.

  1. MSH2. The MSH2 protein is also known as the mismatch repair (MMR) protein, the gene that encodes it is called MSH2. The primary function of MSH2 is DNA repair (e.g. repair of mismatches). MSH2 mutations are the cause of hereditary nonpolyposis colorectal cancer (HNPCC) otherwise known as the Lynch Syndrome. We have known about Lynch syndrome for a long time, but mostly in the context of colorectal cancer.
  2. ATM – this is another DNA repair gene, and the fact that he has mutations in both of these may be partly, but not wholly, responsible for this response. ATM mutation alone, without the MSH2 mutation may have prompted me to treat him with a Parp inhibitor on a clinical trial.
  3. Microsatellite Instability (MSI or MSI High) is the result of mutations of MSH2 and MMR ( this can also result from mutations of a related gene MLH1 as well). A microsatellite is a short sequence 2-4 nucleotides of DNA that result from impaired repair of DNA ( they are sometimes called STR – for short tandem repeats). Think of the cell as a film editing room with a drunk editor, microsatellites are the snippets of film (DNA) that fall to the floor as he cuts randomly and doesn’t splice film together. Pathologists have known about MSI since the 1970’s and a variety of testing methodologies exist via PCR and Immunohistochemistry.
  4. A result of all of this erroneously cut DNA are the random production of peptides-  or small protein fragments. 
  5. These protein fragments are recognized by the immune system as ‘not self’ and the immune system seeks to attack the cells producing them.
  6. However, cancer cells typically have mechanisms of immune escape, one of which is activation of PD-1 on T cells. 
  7. That’s were the therapy choice comes in. In May 2017 the FDA approved Pembrolizumab (PD-1 inhibitor) for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment. Note that no specific cancer is mentioned. This is the first approval by the FDA of a treatment that is organ of origin agnostic. It is also independent of the level of PD-L1 expression.
Things look good for my patient Arnold. Many questions remain about his case. The big one is how long should I continue the Pembrolizumab? A recent paper in the Journal of Clinical Oncology showed that in melanoma patients who have had Pembrolizumab for 6 months and achieved a complete response were about 90% likely to stay in a complete response over the next year or more if the Pembrolizumab was discontinued. 

So I don’t think it is an exaggeration, in this case, to say that this testing and this therapy are the difference between life and death. Coming from an oncologist, that is saying a lot.

Written By: Charles J. Ryan, MD

References:
1. Le et al PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20
2. Research, Center for Drug Evaluation and. "Approved Drugs - FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication". www.fda.gov. Retrieved 2017- 05-24.
3. Robert C, Ribas A, Hamid O, Daud A, Wolchok JD, Joshua AM, Hwu WJ, Weber JS, Gangadhar TC, Joseph RW, Dronca R, Patnaik A, Zarour H, Kefford R, Hersey P, Zhang J, Anderson    J, Diede SJ, Ebbinghaus S, Hodi FS. Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma.J Clin Oncol. 2017 Dec 28:JCO2017756270 

Further Related Content:
Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade






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