Well, this is something. My last diary said that we’ve been chipping away at cancer’s secrets, and we can expect new successes based on new knowledge we keep gathering. Then, literally days later, along comes a trial in which another highly targeted (but different) treatment completely annihilates every single case of cancer in its wake. I swear I had no idea this was going to happen!
On June 5, the New England Journal of Medicine reported a Phase 2 rectal cancer trial in which each and every patient (14 of them) recovered one hundred percent. No more detectable cancer. No followup chemo necessary. No surgical removal of rectum. No colostomy bags. No disfigurement. No clinically significant complications. Cancer simply gone for everybody. Buh-bye!
Author Dr. Luis A. Diaz Jr., of Memorial Sloan Kettering Cancer Center, said ...
… he knew of no other study in which a treatment completely obliterated a cancer in every patient. “I believe this is the first time this has happened in the history of cancer.”
Dr. Alan P. Venook, a colorectal cancer specialist at the University of California, San Francisco, who was not involved with the study, said he also thought this was a first.
A complete remission in every single patient is “unheard of,” he said.
Usually when someone asks, “Wanna see some endoscopy scans?”, a polite no-thanks is in order, but in this case, well … you might want to see this.
This particular type of rectal cancer occurs commonly in patients with a genetic disorder called mismatch repair deficiency, for which people can fortunately be tested. We humans have some complex machinery to spot and fix mistakes in the replication of our DNA shortly after they happen.
Let’s say a mistake gets made in the replication of DNA as a cell divides. The bases across from each other on your two DNA strands are supposed to be A-T or G-C, but (very rarely) you get an error, say a G-T pair. Just one mistake like that can set the wheels in motion for a disease like cancer, so it’s important that the cell catch this and fix it.
Here’s a simple figure that conveys the basic idea of how DNA mismatch repair gets started. Three proteins called MutS, MutL, and PCNA team up to find the mismatch and snip the offending DNA strand (the one with the mistake on it):
After Yellow Guy tells Blue Guy which strand to snip, Blue and Green Guys clear out. Yellow Guy then recruits a Pac-Man-like enzyme (EXO1) that chews off some of the new DNA strand, including the mistake. Then Yellow Guy calls up DNA polymerase δ to come down and fill in the chewed-up part. The entire process is shown in a less-cartoonish way here:
But some people inherit genetic defects in this machinery, so it has a harder time correcting mistakes. These people are much more prone to certain kinds of cancer, colorectal being right up at the top of the list.
One tricky thing the immune system has to deal with is knowing how to attack cancer cells but leave normal cells alone. T cells can find markers on the surfaces of cancerous cells that indicate they should be attacked, but there is also a brake on this action that prevents it from being too strong, lest normal cells be attacked. Both tumor cells and normal cells have a surface marker called PD-L1 whose function seems to be letting the T cell know (by shaking hands with the T cell’s own PD-1 surface protein) that this is a friendly native cell and thus the T cell should hold off its attack. So the T cell can get a mixed message from a cancer cell and thus may not attack very effectively.
But if we are able to administer an antibody that blocks this little handshake by hooking up with either PD-1 or PD-L1, we disrupt the “call off the dogs” signal. Anti-PD-1 antibodies are the more practical of the two because it makes more sense to treat just the T cells, not every cell in the whole body. And that’s exactly what happened in this study.
These kinds of antibodies had been tried with some modest success generally in 2017 on patients with metastatic cancers of the mismatch-repair-deficiency type, so the approach was tried again with these types of cancers at an earlier stage. Patients with locally advanced rectal cancer (but not yet metastatic) tend to respond very poorly to chemotherapy, so they seemed like good candidates. The drug was dostarlimab, a PD-1 inhibitor. In November 2020, JAMA Oncology reported that dostarlimab had given a 42% response rate (13% total remission) in patients with endothelial cancer who had already undergone chemotherapy.
But if this approach worked at an earlier stage, the thought process going into the trial was that maybe some of these patients could be spared at least some chemo. Patient No. 1 in this study:
Sascha Roth was in her late 30s and feeling great. Then she noticed some bleeding when she used the bathroom. She went to see a gastroenterologist, who diagnosed her with rectal cancer. Her doctor, she recalled, “was as shocked as I was.”
It certainly turned her life upside-down. She hadn’t yet had chemotherapy, so she was eligible for the trial, and she entered. Good choice, Sascha.
Not expecting a complete response to dostarlimab, Ms. Roth had planned to move to New York for radiation, chemotherapy and possibly surgery after the trial ended. To preserve her fertility after the expected radiation treatment, she had her ovaries removed and put back under her ribs.
But you saw the endoscope pictures above. Stunningly, after the trial, her cancer had disappeared entirely, and so had everyone else’s. Talk about a special group of new friends!
But they got a surprise: No further treatment was necessary.
“There were a lot of happy tears,” said Dr. Andrea Cercek, an oncologist at Memorial Sloan Kettering Cancer Center and a co-author of the paper, which was presented Sunday at the annual meeting of the American Society of Clinical Oncology.
Two years later, not one patient in the trial has detectable cancer.