Study: Resistant starch may help prevent some cancers in people with Lynch syndrome

IN-DEPTH REVIEW OF RESEARCH

Study background

Dietary fiber is part of plant-derived foods that cannot be completely broken down in the digestive system. Many studies have looked at whether dietary fiber can lower the risk of colorectal cancer in the general population. Generally, dietary fiber has been shown to lower the risk of colorectal cancer, but this protective effect is lost when other dietary factors are considered. So the effect of dietary fiber is unclear. Aside from colorectal cancer, a higher intake of dietary fiber can lower the incidence of heart disease, liver cancer and generally lower the risk of death from cancer.

While increasing the amount of dietary fiber has been linked to reduced risks of colorectal cancer and some non-colorectal cancers, the part of dietary fiber responsible for this improvement is unknown. Dietary fiber includes insoluble fiber that is undigested, while soluble fiber which is partially digested in the large intestine. Although resistant starch is not a fiber—it is a type of starch—it is often considered to be a component of dietary fiber.

Little is known about how resistant starch may prevent colorectal cancer and non-colorectal cancers in people with Lynch syndrome. This study looked at the effect of resistant starch and the risk of colorectal and non-colorectal cancers in people with Lynch syndrome.

This study reports on some of the data from the Colorectal Adenoma/Carcinoma Prevention Program 2 (CAPP2) study, a first-of-its-kind effort that was designed to test whether daily aspirin and/or daily resistant starch prevents colorectal cancer in people with Lynch syndrome.

Researchers of this study wanted to know

There are limited options to lower the risk of non-colorectal cancers such as cancers in the upper gastrointestinal (GI) tract in people with Lynch syndrome. Researchers of this study wanted to know whether incorporating resistant starch into the diet of Lynch syndrome patients would lower their risk of colorectal and non-colorectal Lynch syndrome-associated cancers.

Populations looked at in this study

The participants were people who were over age 25 and with Lynch syndrome. Participants had an inherited mutation in MLH1, MSH2 and/or MSH6 (people with PMS2 or EPCAM mutations were not included in this study) or were members of a high-risk family according to the Amsterdam diagnostic criteria for Lynch syndrome. This is a set of diagnostic criteria used by doctors to diagnose Lynch syndrome in individuals who have not had genetic testing.

Participants included people from Northern Europe, the United Kingdom, Australia and Hong Kong, Southern Europe (the Iberian Peninsula and Italy), South Africa and the Americas. 

Participants who had previously been cured of Lynch syndrome cancer and still had their colon were also eligible. Colonoscopy and clearance of any found polyps were prerequisites within three months of study recruitment. Patients diagnosed with bowel cancer were excluded for a year if their tumor was Duke stage A (cancer only in the mucosa or cell lining of an organ such as the stomach), two years if their tumor was stage B (cancer that has advanced to the outer layer of cells of the stomach but not to the lymph nodes) and five years if their tumor was stage C (positive lymph nodes) or D (metastatic).

Study design

This was a double-blind study. To ensure that neither participants nor researchers knew who was getting resistant starch, cornstarch (an inactive alternative to resistant starch) was used as a placebo.

Participation included a colonoscopy at study entry and exit after two years, in addition to routine screenings. Participants were treated daily for two years with 30 grams of resistant starch (called Novelose) or placebo (cornstarch taken in two separate doses). After two years, participants had the option to continue for two more years. After that, some participants consented to have a follow-up of 10 years or more, up to 20 years.

Participants were placed randomly (via computer) into one of 2 treatment groups:

• Resistant starch: 463 participants
• Placebo (cornstarch): 455 participants

 At the end of treatment and through long-term follow-up, researchers gathered information on whether participants were diagnosed with colorectal cancer or other Lynch syndrome-associated non-colorectal cancers.

Study findings

The analyses presented below presents data for  the entire CAPP2 cohort at 10 years as well as at 20 years for participants in England, Finland and Wales. Information on cancer diagnoses was obtained from national cancer or clinical registries.

The aspirin results from this study, presented previously, have already changed the standard of care for people with Lynch syndrome in the United Kingdom (UK). Based on the results of the study, the National Institute for Health and Care Excellence (NICE) in the UK now recommends that people with Lynch syndrome take daily aspirin for more than two years to prevent colorectal cancer. Read more in our XRAY review here.

Colorectal Cancer Outcomes

• 52 participants developed colorectal cancer in the resistant starch group; 53 participants developed colorectal cancer in the placebo group
• Analysis showed no effect of resistant starch on colorectal cancer incidence.

Non-Colorectal Cancer Lynch syndrome cancer outcomes

• There were 27 non-colorectal cancers in the resistant starch group and 48 in the placebo group.
• Resistant starch was found to have a significant protective effect for multiple, non-colorectal, Lynch syndrome-associated primary cancers.
  • This effect was especially strong for cancers of the upper gastrointestinal (GI) tract, including stomach, duodenal, bile duct and pancreatic cancers.
    • The resistant starch group developed 5 upper GI cancers; the placebo group developed 21.

Non-colorectal Lynch Syndrome cancer outcomes by treatment group

All Lynch syndrome Cancer Outcomes

• Resistant starch was not protective when all Lynch syndrome cancers (colorectum, endometrium, prostate, ovary, kidney/ureter, stomach, bladder, small intestine, pancreas, bile duct and brain) were looked at together.
• Resistant starch was protective in patients who had multiple primary Lynch syndrome-associated cancers.
• Resistant starch slightly prevented Lynch syndrome-associated cancers at 10 years, but this was most evident at the 20-year follow-up.

Non-Lynch syndrome cancer outcomes

• During follow-up, 45 non-Lynch syndrome-associated cancers were diagnosed in patients taking resistant starch; 44 non-Lynch syndrome-associated cancers were diagnosed in patients taking a placebo.
• Resistant starch did not affect the risk of non-Lynch syndrome cancers.

The researchers were surprised when the trend of reduced colorectal cancer risk that was shown in participants who had daily resistant starch in previous studies did not occur in this study.

Strengths and limitations

Strengths

• Participants were followed for up to 20 years, meaning that the long-term treatment effect on cancer risk would be more apparent.
• The randomization of participants and study design strengthened the study, making the results more trustworthy.
• The study focused on people with Lynch syndrome, meaning that the results should be relevant for most people with Lynch syndrome. Although no participants had a PMS2 or EPCAM mutation, the effect of resistant starch on people with Lynch syndrome who have these mutations is unknown.
• Researchers tracked many different cancer types for which people with Lynch syndrome have a high risk.

Limitations

• The numbers of non-colorectal cancer cases were too small to make conclusions for a specific site.
• The estimated dose of resistant starch was 13.2 grams compared to the habitual intake of 4.2 grams per day in Europe. This larger amount caused considerable bloating in participants.
• The consistency between databases and registries is generally too low to confirm cancer diagnoses.
• Researchers did not show why resistant starch lowers the risk of upper GI cancers.
• The number of study participants was small; therefore it is difficult to make a strong conclusion.
• Researchers did not perform compliance testing for all of the participants to verify whether they took the required doses of resistant starch.
• In studies involving diet, the foods that participants eat or don’t eat cannot be controlled. This could affect the study results. Randomizing the study helps to limit this somewhat.
• Researchers made no mention of other patient characteristics such as family history, race, BMI, exercise level and diet history.
• The study did not address variations in dietary patterns in Eastern vs Western countries.

Context

Many studies have looked at whether dietary fiber can lower the risk of colorectal cancer in the general population. Generally, dietary fiber has been shown to lower this risk, but this protective effect may be lost due to other dietary factors. Aside from colorectal cancer, a higher intake of dietary fiber can lower the incidence of heart disease, liver cancer and lower the risk of death from cancer more generally.

Population-based studies that assess how dietary fiber may lower the risk of upper GI cancers are lacking. Studies that have been done show that higher dietary fiber may lower the risk of stomach and pancreatic cancers. A Japanese study also showed that higher amounts of dietary fiber may lower the risk of lower bile duct cancer. In another study, researchers saw that higher dietary fiber was associated with reduced intrahepatic (a network of small tubes that carry bile inside the liver to the duct) bile duct cancer. This data is promising but limited.

Resistant starch and dietary fiber may lower cancer risk by slowing cell growth in parts of the colon and changing the expression of genes that block cancer growth. Many different types of bacteria in our gut consume resistant starch. These bacteria produce substances that stop cancer cell growth and kill cancer cells after they consume resistant starch. These substances can also affect the immune system, which plays a large role in the development of cancer.

Conclusions

For people with Lynch syndrome, resistant starch does not alter colorectal cancer risk, but it does lower the risk of non-colorectal Lynch syndrome-associated cancers, especially upper GI cancers. Since screening, diagnosis and management of these cancers are difficult, this finding could lead to a change in the standard of care for people with Lynch syndrome to help reduce their risk for upper GI cancers. It is important to continue to study this association with more people with Lynch syndrome as well as the general population to determine whether resistant starch and dietary fiber reduce the risk of GI cancers in the broader non-hereditary cancer population.

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posted 10/17/22