Familial Adenamotus Polyposis and new advances in potential chemoprevention

Jennifer Fijor, ARNP - CGA-IGC Communications Committee member

Familial adenomatous polyposis (FAP) is one of the well-known hereditary cancer syndromes, caused by an autosomal dominant pathologic germline variant in the APC gene.¹ If left untreated, there is nearly a 100% risk of colorectal cancer (CRC). Initial presentation is hundreds to thousands of adenomatous polyps during colonoscopy. FAP makes up approximately 0.5% of CRC cases and occurs in approximately 1/8,500 people, equally amongst females and males.¹ Not only is there a propensity to grow polyps in the colon, but in the rest of the gastrointestinal tract as well, including duodenal/periampullary, small intestine, gastric, and pancreatic cancers, in addition to other cancers such as hepatoblastoma, medulloblastoma, and papillary thyroid cancer.¹

Desmoid tumors are also a major concern and carry the highest extracolonic mortality risk.¹ There are additional extra-intestinal manifestations as well such as congenital hypertrophy of the retinal pigment epithelium (CHRPE), dermoid cysts, osteomas, dental abnormalities, benign cutaneous lesions, and adrenal masses.¹ While a vast majority of cases are passed down genetically, approximately 30% do not have a family history, arising from de novo germline mutations or mosaicism.¹ During FAP awareness week it is important to recognize how far we have come.

One of the most exciting developments in FAP management right now is the emerging data on potential chemoprevention. This may be the closest we have come to an FDA-approved medication for FAP chemoprevention, something this population has not had. A recently completed phase II trial evaluated eRapa (encapsulated rapamycin) in FAP patients.²

During this study 30 FAP patients were given eRapa in 3 different dosing schedules. The first cohort was eRapa 0.5 mg every other day, the second was daily every other week, and the third was daily.² Of the 30, only 2 dropped out due to toxicity concerns. The drug was generally safe and tolerable, with side effects most pronounced in the daily continuous dosing group.² What I found most interesting is that intermittent dosing seemed to perform best.

At 6 months the every-other-day cohort seemed to be the strongest at reducing colorectal and duodenal polyp burden, while the daily every-other-week cohort seemed to do best at the 12-month mark for overall polyp burden.² The largest reduction in colonic and duodenal polyp burden was observed in the first cohort, though most results did not reach statistical significance.² Given this data, the 0.5 mg daily every-other-week schedule was selected for an upcoming phase III trial.²

That said, there are some limitations to this study. Keep in mind that given the rarity of FAP (1/8,500 people),¹ study designs are much more difficult to accomplish the large, placebo-controlled studies we are used to. At this time, while the data is compelling, it doesn't reach statistical significance.² Without a basis for comparison it is difficult to attribute which portion is due to the medication versus natural polyp fluctuation or the overall impact of adherence to surveillance polypectomy. Not to mention 12 months is still a short window given the lifelong condition.²

Phase III has the burden of proof — the data will truly be put to the test. The phase III study will evaluate the 0.5 mg daily every-other-week schedule in a larger placebo-controlled FAP population with longer follow-up.² If the phase III trial delivers, this could represent the first FDA-approved medical option for FAP — a meaningful shift in how we manage a condition that has historically been defined almost entirely by surgical intervention.

FAP is a lifelong condition that requires lifelong vigilance. For patients and families, that means consistent surveillance, undergoing procedures/surgeries, knowing your family history, and connecting with a provider who specializes in hereditary cancer syndromes. The science is moving, but like any rare disease, it is slow. The goal has always been to give patients more options and more time. We are not there yet, but we are closer than we have ever been.

References

1. Joo JE, Viana-Errasti J, Buchanan DD, Valle L. Genetics, genomics and clinical features of adenomatous polyposis. PMCID: PMC12003455. PMID: 40237887.

2. Broderick JC, Samadder NJ, Stoffel E, Fang JC, Stanich PP, Wise P, Wright R, Clifton T, Peoples G, Burke CA. Phase II Trial of Encapsulated Rapamycin to Reduce Polyp Burden Associated with Familial Adenomatous Polyposis. Clin Cancer Res. 2025. https://doi.org/10.1158/1078-0432.CCR-25-4126

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Interested in learning more about chemoprevention in patients with FAP?

Watch CGA-IGC’s joint webinar with the American College of Gastroenterology, “Chemoprevention in Hereditary Cancer Syndromes: FAP and Lynch Syndrome,” featuring Pooja Dharwadkar, MD, and Katharina Germansky, MD.

In this session, Dr. Dharwadkar provides an overview of FAP, including current approaches to management and surveillance, as well as the role, evidence, and emerging trends in chemoprevention.

Visit cgaigc.com/webinars to learn more. CGA-IGC members can log in to the member portal to watch the full webinar.

In the meantime, read the accompanying webinar blog post written by CGA-IGC Communications Committee member Ophir Gilad, MD, HERE.