Bariatric Surgery and Cancer Risk; Obesity and Type 1 Diabetes

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include a new treatment for rectal cancer, using circulating DNA to guide colorectal cancer treatment, type 1 diabetes and obesity, and obesity and cancer.

Program notes:

0:40 Bariatric surgery and cancer risk

1:40 Followed for 6 years

2:41 Longer-term follow-up needed

3:22 Obesity and type 1 diabetes in late adolescence

4:22 Increased two- to three-fold

5:22 Gut microbiota involved

6:02 Management of colorectal cancer with circulating DNA

7:02 If DNA is circulating, continue treatment

8:02 Personalized approach to medicine

8:35 Rectal adenocarcinoma

9:35 100% remission

10:35 Weeks to months complete disappearance

11:53 End

Transcript:

Elizabeth Tracey: 100% remission for some people with rectal cancer.

Rick Lange, MD: Using a liquid biopsy to determine how to treat colon cancer.

Elizabeth: A disturbing rise in type 1 diabetes.

Rick: Can bariatric surgery decrease the risk of cancer?

Elizabeth: That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso, where I’m also dean of the Paul L. Foster School of Medicine.

Elizabeth: Rick, no COVID this week. I’m not sure how to behave. All right, so I’ll make a choice. Why don’t we turn right to JAMA, this notion of bariatric surgery and cancer risk?

Rick: We’ve talked before about the medical consequences of obesity and its association with type 2 diabetes, cardiovascular disease, and liver disease as well. Many of our listeners may not be aware that there are actually a number of cancers that are also associated with obesity. In fact, about 13 different cancers are thought to be obesity-related.

If you substantially reduce weight in someone that’s obese, can you actually decrease the risk of those subsequent cancers? Now, the most effective way we have of decreasing weight substantially is bariatric surgery.

What these investigators attempted to do was they used a matched cohort study of adult patients with a body mass index [BMI] of more than 35, who underwent bariatric surgery at a U.S. health system between 2004 and 2017. They matched them with five other patients who were obese that did not undergo bariatric surgery.

All in all, this is about 30,000 patients in this study — about 5,000 of whom had bariatric surgery — and they followed them for just a mean of 6 years. The average age was about 46. About 77% of these were female.

What they noticed first of all is 6 years in follow-up the difference in body weight, which was about a 50-pound difference, the incidence of cancer related to obesity went down approximately 30%, an incidence rate of three events per 1,000 person years in those that had the surgery versus 4.6 events in those that did not have surgery.

What about cancer-related mortality? Even that was down substantially. There was about a 40% decrease in the cumulative incidence of cancer-related mortality at 10 years in those that had bariatric surgery. This is, I think, pretty strong evidence that the bariatric surgery compared with no surgery is associated with a significantly lower incidence of obesity-related cancer and cancer-related mortality.

Elizabeth: Well, it makes a lot of sense, of course. We know that obesity is related to inflammation and inflammation is related to cancer. I mean, these things are inextricably linked. I guess one thing I would really love to see, of course — and we will see this — is going to be the longer-term follow-up.

Rick: Right. The remarkable thing to me is that this was evident at a relatively short period of follow-up. These are 46-year-olds, not many of which have cancers. The incidence goes up as the population ages.

Elizabeth: A lot of really compelling reasons to employ bariatric surgery, of course, and I would not be me without saying prevention would be way better than having to do something like this in order to reduce the risks of all kinds of diseases and conditions.

Rick: There is no doubt about that. But now since about 40% of the U.S. population is obese, these are issues that we have to address — not just related to obesity itself, but the subsequent consequences and complications such as cancer.

Elizabeth: Since we’re talking about obesity, let’s go to Diabetologia. This is taking a look at increased BMI and risk for developing type 1 diabetes in late adolescence. This association they took a look at is really adolescence. As we’re both aware — and I’m sure many of our listeners are aware — all kids, let’s call them, in Israel have to sign up for a medical evaluation in preparation for a mandatory military conscription.

They looked at the data from these folks from January 1996 to December 2016 and they also looked at this incidence of type 1 diabetes. They had 777 cases of diabetes among all of these folks, and basically what they found is that with increasing BMI there was an increased risk for the development of type 1 diabetes in this whole cohort. This adjusted risk for developing type 1 diabetes in adulthood increased approximately two- to three-fold in adolescents with obesity compared with those who had optimal BMI.

They also took a look at autoantibodies against the islet cells in the pancreas and found that these are part of this type 1 diabetes diagnosis. I think this is just really disturbing.

Rick: I do too. I want you to talk a little bit about what you think the reason for this is, because one usually thinks about type 1 diabetes and the formation of autoantibodies as being a genetic predisposition, and certainly there is one. This suggests that environmental or social behaviors also influence the risk of type 1 diabetes and, as you mentioned, this was obesity in adolescence and type 1 diabetes in adults.

Elizabeth: The hypothesis that these authors put forward really has a lot to do with just inflammation and the same thing that we were talking about before. There is also growing evidence of a link between obesity and various autoimmune conditions. Of course, we have thought for a long time that type 1 diabetes is an autoimmune condition.

Finally, they point to something that we are all pointing to right now, so I don’t know whether this is fashion or what. But they also think that there might be a modulation of the gut microbiota that might have something to do with the development of this condition.

Rick: That change in the microbiota has been associated with obesity. When you think of obesity as just being a weight gain and not often do we think of it being a chronic inflammatory condition that predisposes to a number of things. You had mentioned cancer already and now type 1 diabetes.

But those fat cells, the adipocytes, are actually involved with regulating inflammation and immune response in individuals. As you said, the microbiota is also playing an important role as well. We may talk a little bit more about that when we talk about colon cancer and rectal cancer, so let me lead off with colon cancer.

Elizabeth: Works for me and that’s in the New England Journal of Medicine.

Rick: This is looking at circulating tumor DNA as guiding therapy for colon cancer. Now, this circulating tumor DNA is, what I call a liquid biopsy that is drawing blood and looking for DNA that was present in the tumor that is now circulating in the blood. It gives us insight into the genetic characteristics of the tumor, but more importantly even if it’s there.

For colon cancer, the mainstay of therapy is removal of the colon cancer. But what I’m going to call the intermediate stage, stage two colon cancer, its removal and then treating with chemotherapy afterwards, what’s called neoadjuvant therapy, hoping to get rid of any residual disease. Well, you don’t know if there is any residual, what I’m going to call micrometastatic disease, and so you end up exposing a lot of people to neoadjuvant chemotherapy that may not even need it.

Can we use the circulating DNA to decide who needs this extra therapy after surgery has been done and if the circulating tumor DNA is not there, we don’t do it? That’s exactly how this study was designed. It took 455 patients with stage II colon cancer. They did the surgery and then 4 to 7 weeks after surgery they measured the circulating tumor DNA.

In half the group, they based the decision of whether to proceed with chemotherapy based upon that. If there wasn’t any circulating DNA, they didn’t give chemotherapy. If there was, they did. The other group they just treated routinely with the extra chemotherapy.

What they found out is when they follow these individuals, if you use the circulating tumor DNA strategy the results were just as good as if you just gave everybody chemotherapy. There was 93.5% of individuals that did not have recurrence after 3 years in the circulating tumor DNA strategy versus 92.4% in those that just got chemotherapy.

Using the circulating tumor DNA of the liquid biopsy, they only give chemotherapy to half the individuals. We’re using this liquid biopsy to guide therapy, getting results that are just as good, and we are avoiding chemotherapy when it doesn’t look like there is any residual disease after the surgery.

Elizabeth: I love this. I think this is just so great. It points to so many things that I’m fond of, this personalized approach to medicine, the avoidance of treatments that do not help and have a high potential for harm. To me, it sounds like a strategy that ought to be employed across the board.

Rick: I’m sure this is a strategy that we’ll be looking at in other tumor types. This really helps because with this particular stage II colon cancer there is really controversy about how best to treat it. It’s a win-win. Now, we’ll need to follow these patients for longer right now, being able to detect residual disease, which is what we want to do because that’s what we want to cure.

Elizabeth: Staying in the New England Journal of Medicine, let’s take a look at rectal adenocarcinoma. Just a little bit of background with this, it turns out that they are routinely treated with surgery, radiation therapy, and chemotherapy. However, some of them have a particular feature, which is that they have this mismatch repair-deficient colorectal cancer, so called the PD-1/programmed death-1 blockade. That’s what they are looking at.

In the study, they only report 12 patients, but actually in the New York Times today [June 5, at the time of the podcast] they are reporting follow-up on [18] patients. The crazy thing is that they used this single-agent called dostarlimab, an anti-PD-1 monoclonal antibody, and they administered it in these folks every 3 weeks for 6 months in patients with this mismatch repair-deficient stage II or III rectal adenocarcinoma. 100% of these patients — that’s just hard to even say that with any degree of seriousness — responded and had a complete clinical response, no evidence of tumor, using MRI, PET, and actual visualization and clinical exam. This is impressive — 6 months of follow-up; we need to keep looking at this, but boy is this amazing.

Rick: It is, and these are individual that had advanced rectal cancer. Elizabeth, as you mentioned, the current therapy in distant times was surgical removal. It carries a lot of complications associated with it and oftentimes the diverting colostomy.

People are now investing in what’s called non-operative therapy — ie., you give chemotherapy and radiation therapy, and if you get rid of it, you hold off on doing surgery. If there is any residual tumor, then in fact you might proceed to surgery.

The tumors that you mentioned that are deficient in this DNA mismatch-repair enzymes, it’s only about 5% to 10% of rectal cancers. But they are the ones that don’t usually respond to typical chemotherapy. To have this particular agent be able to administer and within weeks to months the tumor completely disappears for advanced rectal cancer, this is really pretty amazing.

We need to follow these individuals for a long period of time. These are individuals primarily who have just been followed for a little over 12 months. But when you look at the pictures, it’s pretty amazing.

Elizabeth: It’s incredible that the editorialist cites the fact that there was a PD-1 inhibitor that was used before, pembrolizumab, that’s been out there for a while and only 55% of patients treated with this for mismatch repair-deficient, metastatic colorectal cancer were alive without cancer progression at 12 months. This particular agent in this indication sounds like an advance.

Rick: Is it a different, better agent? Or is it just a different patient population? You mentioned before that the gut microbiome plays an important role in a lot of things and apparently in response to PD-1 inhibitors it plays a significant role as well. We need to expand that patient population to see if, in fact, it’s as effective as it appears in this initial group.

Elizabeth: Good news, however.

That’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: I’m Rick Lange. Y’all listen up and make healthy choices.