What to Do with Hundreds or Thousands of Intestinal Polyps? | FAP (Familial Adenomatous Polyposis) Lecture | Ge Sai, Peking University Cancer Hospital

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We are honored to have Dr. Ge Sai from the Department of Gastrointestinal Oncology at Peking University Cancer Hospital to explain the rare disease FAP (Familial Adenomatous Polyposis).

FAP is primarily caused by germline mutations in the APC gene. Some FAP patients also develop DT (desmoid tumors). The lecture covers FAP treatment options and the importance of preventing colorectal cancer.

FAP is an autosomal dominant genetic disorder. Without preventive surgery or close endoscopic polyp removal, about 10% of patients develop colorectal cancer around age 30. If left untreated for life, the cancer risk is nearly 100%.

Additionally, the meeting discussed medications for desmoid tumor patients, such as sorafenib, anlotinib, and liposomal doxorubicin, as well as progress on upcoming clinical trials for new drugs.

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Article Summary | Dongzi
Proofreading | Zhouzhou

Editorial Director | Xianning

Conference Date: March 31, 2024

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Xiao Han

We are very pleased today to welcome Dr. Ge Sai from the Department of Gastrointestinal Oncology at Peking University Cancer Hospital. Dr. Ge has interacted frequently with our group and participated in many patient education sessions, previously discussing adverse reaction management and genetic testing. Now, let's hand the floor over to Dr. Ge.

Ge Sai

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I am very glad to have this opportunity today.

When reviewing the latest developments in FAP, progress has generally been slow.

The most significant progress over the past year relates to desmoid tumors associated with FAP. Actually, it's not just FAP-related; it's the Phase III clinical trial results for Notch inhibitors in desmoid tumors overall. This has certainly raised academic attention to the treatment of this type of sarcoma.

Today, I will mainly cover three areas, which I believe are frequently asked and highly concerning to everyone:

First, information related to FAP;

Second, desmoid tumors associated with FAP;

Third, why genetic sequencing is necessary, how FAP and polyps are treated, how DT (desmoid tumors) are treated, and the clinical trials we plan to conduct.

01 Diagnosis and Risks of FAP (Familial Adenomatous Polyposis)

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FAP (Familial Adenomatous Polyposis) is an autosomal dominant genetic disorder. Initially, FAP was defined as having over 100 adenomatous polyps throughout the entire intestine, typically with a relatively young onset age.

Without preventive surgical resection or close endoscopic polyp removal, about 10% of patients develop colorectal cancer around age 30. If left untreated for life, the risk of developing cancer is nearly 100%.

FAP is primarily caused by germline mutations in the APC gene. The global prevalence is 2 to 3 per 100,000, with a 1:1 male-to-female ratio. Among all colorectal cancer patients, 1 in 100 has FAP.

It is important to note that not all FAP patients have a family history. Approximately 25%-30% are the first in their family to be diagnosed (proband), possibly due to spontaneous mutations in parental sperm or eggs.

Currently, we classify FAP into three types:

Type 1: Classic - Over 100 adenomatous polyps throughout the intestine;

Type 2: Attenuated - 20 to 100 adenomatous polyps. Therefore, if there are more than 20 polyps, we should consider an FAP diagnosis. The lifetime risk of colorectal cancer for attenuated and classic types is 80% and nearly 100%, respectively;

Type 3: Severe/Profuse - Over 1,000 polyps throughout the intestine. Since APC germline mutations are autosomal dominant, each child of a patient has a 50% chance of inheriting the mutation, regardless of gender.

02 Genetic Testing and Disease Classification for FAP Patients

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Why should FAP patients undergo genetic testing?

The vast majority of adenomas in FAP patients do not become cancerous; only a small fraction progress to cancer. However, because the denominator (number of polyps) is so large, the overall probability of tumor development increases significantly.

As early Nordic studies have shown, different gene mutation sites correlate with the number of polyps. Let's first look at how to interpret your genetic sequencing report to identify your specific mutation site.

For example, in the report above, a "p." prefix indicates an amino acid change, while "c." indicates a nucleotide change. Looking at the amino acid change, this patient's mutation is at position 1114. Previous reports clearly state that mutations at the two ends of the APC gene tend to cause the attenuated phenotype. Mutations between positions 1250 and 1465 are likely to cause the most severe type (over 1,000 polyps), while other sites typically cause the classic type (over 100 polyps).

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This chart shows our statistical analysis of globally uploaded APC mutation sites and their corresponding polyp counts. The bottom section represents the most severe type, severe FAP (over 1,000 polyps), where you can see position 1309.

First, I want to note that positions 1062 and 1309 are the two most common mutation sites among all FAP patients. You can see that 1309 is also common in the classic type, but very rare in the attenuated type. It is highly prevalent in the most severe type. Position 1062 is very common in the classic type (100 to 1,000 polyps).

If the mutation is before position 400, especially at position 141, there is a high probability of attenuated FAP.

If a colonoscopy has already confirmed adenomatous polyposis (dozens, hundreds, or thousands of polyps), you already know your type without genetic testing.

However, if we look ahead to a child who has not yet biologically manifested the disease, deciding whether to choose aggressive surgery or delay treatment and observe is closely related to the genetic mutation site. Therefore, we need to pay attention to this: mutations before position 400 likely indicate the attenuated type, while mutations further downstream, especially at 1309, likely indicate a severe type.

03 Risk Assessment for Desmoid Tumors

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On another note, why is proactive genetic testing important? Because we recognize that the second leading cause of death in FAP is the development of desmoid tumors, typically appearing an average of 2 to 3 years after surgery.

I must emphasize one point: not all FAP patients will develop desmoid tumors, so please do not panic. It is incorrect to avoid surgery due to the fear of postoperative DT. Surgery remains the primary treatment for FAP patients, especially those with the profuse polyp type. This principle must not be overturned.

Unfortunately, about 10%-20% of FAP patients do develop desmoid tumors. Among these, half may experience slow growth or even spontaneous regression. This concept is crucial to understand.

Therefore, for classic FAP-associated DT, as mentioned earlier regarding mutation sites, mutations occurring after position 1400 significantly increase the risk of familial DT or intra-abdominal DT post-surgery. You can see that most FAP patients in our group with DT have mutations after position 1400, such as 1404 or 1444.

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This chart is based on our actual data, where each number corresponds to a mutation site. The triangles indicate patients who developed desmoid tumors. While DT can occur at any mutation site, clinical data shows that for Chinese patients, the risk becomes more severe, faster-growing, and requires intervention for mutations after position 1062. Mutations before 1062 tend to grow slowly and may even regress spontaneously.

Therefore, for patients with mutations after position 1400 who have not yet developed colorectal cancer at initial diagnosis, I personally strongly recommend delaying surgery as much as possible rather than opting for immediate bowel resection upon discovery.

04 Decision-Making for Rectal Polyp Surgery and Postoperative Management

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I reiterate that preventive surgery to avoid colorectal cancer is the primary approach for FAP patients.

Unfortunately, there is no precise guideline on exactly when different patients should undergo preventive total colectomy. It is understandable that this surgery causes significant trauma, and every patient feels anxious before choosing it. I completely understand.

In short, the timing of surgery should be neither too early nor too late. It must occur before cancer develops, but should be delayed as much as possible. This is the current principle for surgical timing.

However, in Nordic countries like the Netherlands, all patients aged 18 to 20 undergo surgery, regardless of attenuated or classic type. Their database, with follow-ups up to age 90, confirms that most FAP patients who undergo preventive surgery in their youth have unaffected overall survival.

If patients wish to delay surgery, several factors must be considered:

First, your specific FAP type. For example, if you only have 20-30 polyps, removing the entire colon is unreasonable.

Second, the current state of your polyps. If pathology shows low-grade dysplasia, high-grade dysplasia, or cancer has already appeared, do not hesitate; total colectomy is absolutely necessary.

This involves whether to preserve the rectum, which directly impacts quality of life. Preservation depends on polyp distribution and whether rectal polyps can be controlled via regular endoscopic removal. For example, if polyps are densely concentrated in the left colon, do not preserve the rectum.

If polyps are mostly in the right colon with few in the rectum, preservation can be considered. Of course, doctors will advise that preserving the rectum requires regular colonoscopies of the remaining segment. If issues arise, a second surgery may be needed.

Third, the risk of desmoid tumors is highest for mutations after position 1400. There is a high probability of developing DT within two years post-surgery. The cause of death may not be colorectal cancer but DT. We must be highly vigilant. However, I must state that patients with the 1400 mutation represent a minority (less than 10%) of all FAP patients, so there is no need for excessive panic. The proportion of DT is not that high.

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Current clear evidence comes from the 2015 American College of Gastroenterology guidelines, which specify when surgery is mandatory: confirmed or highly suspected cancer requires immediate surgery.

Alternatively, if high-grade dysplasia is present, surgery is recommended soon. If only low-grade dysplasia is found, observation and waiting are acceptable.

Second, if symptoms appear, such as recurrent intestinal bleeding, or many large polyps (>5mm) cannot be cleared endoscopically, or if you previously removed 30-40 polyps annually but suddenly need to remove 200-300 in one year, this indicates a significant change and rapid polyp increase. Prompt evaluation and surgery are necessary.

Third, for younger patients (under 18) with fewer polyps, or families where other FAP patients developed cancer at a later age without severe mutation phenotypes, surgery can be delayed. During this period, a colonoscopy must be performed at least annually.

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Additionally, the International Society for Gastrointestinal Hereditary Tumours provides detailed guidelines.

Reading this chart from bottom to top: if there are over 1,000 polyps, or they have merged together, endoscopic removal alone is ineffective. If cancer is already present, surgery must be scheduled promptly.

For 500 to 1,000 polyps, endoscopic control is possible, but colonoscopies may be needed every six months. If such frequent monitoring is undesirable, surgery should be considered.

Moving up to Stage 2 (200-500 polyps), with fewer than ten polyps larger than 1cm, polypectomy is preferred, with a follow-up colonoscopy within a year.

Stage 1 (20-100 polyps), mostly small (<5mm) with none >1cm, requires a follow-up colonoscopy within a year. For these patients, total colectomy is generally not needed in our view, though some guidelines suggest otherwise.

Thus, the chart clearly addresses many patient concerns. The decision on when to operate depends on individual circumstances, choosing the appropriate timing and method to optimize treatment outcomes.

05 Medication Guidelines for the Rare Disease FAP

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Oral medication options are a major concern for many patients. Do sulindac, celecoxib, or aspirin actually help? Current data shows:

First, sulindac 150mg twice daily. Its main side effects are gastrointestinal, and some cannot tolerate it. It controls colorectal polyps best for about six months, but polyps quickly regrow after stopping. It seems ineffective for duodenal polyps.

Second, celecoxib (Celebrex). It has fewer gastrointestinal side effects. However, it must be clearly understood that celecoxib poses cardiac risks. It is not recommended for patients over 40. For children aged 12-14 with healthy hearts, celecoxib is safe and effective, as supported by US reports for pediatric polyp suppression. However, long-term use in adults, especially over 40, is dangerous for the heart and not recommended. Additionally, most oral drugs share the issue of rapid polyp regrowth upon discontinuation.

Third, aspirin, which is currently our first choice. Clinical studies in FAP have used aspirin doses from 100mg to 600mg once daily. Japanese reports indicate that close endoscopic monitoring combined with oral aspirin helps manage intestinal polyps. Aspirin is safe enough for lifelong use, even in the elderly. Therefore, the dose depends on tolerance; if 200mg causes discomfort or GI issues, do not force a higher dose. Long-term aspirin use carries a risk of GI bleeding. We acknowledge all treatments have risks, but aspirin remains the safest long-term option among these drugs.

Finally, the combination of erlotinib and sulindac. Dosages are listed below: sulindac 150mg twice daily, erlotinib 75mg once daily. Erlotinib is an anti-tumor drug, but this combination's Phase II trial was terminated early due to exceptional efficacy. It effectively suppresses both colorectal and small intestinal polyps. Currently, only a few Chinese centers occasionally recommend this combination. It is successful, with a treatment duration of six months. If a patient cannot tolerate aspirin or sulindac, or is an adult unsuitable for celecoxib, this combination is a viable alternative.

Currently, guidelines do not recommend sulindac or celecoxib.

06 Extra-colorectal Manifestations and Screening for FAP Patients

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Extra-colorectal manifestations:

First, specific eye fundus findings. If you are worried your young child (even under 10) carries the FAP gene, a fundus exam is inexpensive (around 20 RMB) and ophthalmologists are familiar with it. If CHRPE (congenital hypertrophy of the retinal pigment epithelium) is diagnosed, the child is highly likely an FAP carrier. Other signs include nasopharyngeal angiofibromas and dental abnormalities. Many of our patients have dental issues; if a child has 40 teeth after losing baby teeth, it is definitely abnormal.

Second, prevention of thyroid, gastric, and duodenal cancers. Many patients report numerous stomach polyps, which is normal.

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Starting at age 25, regular thyroid ultrasounds and gastroscopies are required. Here, I will emphasize monitoring for gastric and duodenal cancers.

Most FAP patients have many stomach polyps. Small ones usually don't need intervention, but large ones should be removed per your endoscopist's advice.

The most critical purpose of gastroscopy is to check for duodenal polyps. Duodenal polyps are highly significant and dangerous. Their removal often requires experienced centers, preferably higher-tier hospitals. Patients ask when duodenal polyps warrant surgery or preventive bowel resection, as duodenal surgery is more extensive.

Internationally, there is a clear scoring system for this.

Stage 4 scores 9 to 12 points; surgical evaluation for possible resection is needed every 3-6 months. What does a score of 9 mean? We consider not just polyp count, but size, histological type, and presence of severe dysplasia. If your score is high (9 points) with severe dysplasia, numerous and large duodenal polyps, do not hesitate; surgery is necessary because duodenal malignancies have a very poor prognosis and progress rapidly. This is why we recommend early gastroscopy to regularly remove small duodenal polyps.

07 Standardized Diagnosis and Treatment of DT (Desmoid Tumors)

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About 10%-20% of FAP patients develop desmoid tumors within 2-3 years post-surgery, with a higher incidence in women. The significant abdominal trauma from surgery is a clear trigger for DT development.

Desmoid tumors can encase adjacent structures, causing bowel obstruction, ischemia, or wound complications. Some patients experience obstruction or perforation without prior intervention, which is a major challenge in FAP management.

Surgery is definitely not the first choice for DT. Clear data supports this, and prior radiotherapy, microwave, or cryotherapy lack strong evidence of efficacy. Therefore, medical therapy is now the primary approach. I emphasize the standardized treatment chart for desmoid tumors.

Most sporadic desmoid tumors are caused by CTNNB1 mutations, whereas FAP-associated DTs are mostly driven by APC mutations.

FAP-related DTs tend to be more malignant, located intra-abdominally, significantly impacting survival, thus requiring more aggressive treatment.

Regardless of the type, upon DT diagnosis:

First, perform a biopsy to confirm whether it is a tumor or a desmoid tumor;

Second, actively monitor. Follow up within 1-2 years, as some grow slowly or regress spontaneously, reducing the need for aggressive treatment.

Current principles dictate that after initial diagnosis, follow-up CT or MRI every 3-6 months is acceptable. If two scans within a year show growth exceeding 20%, we consider it rapid growth, and treatment is necessary.

For cases already affecting kidney function (e.g., hydronephrosis) or causing symptoms, earlier and more aggressive treatment may be required.

Only one type warrants surgery as a first choice: small desmoid tumors on the abdominal wall. For other locations, whether extremities or intra-abdominal, surgery is not preferred; clear medical drug therapy is the standard.

08 Medication Guidelines for DT and Our Upcoming Clinical Trials

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The medication guidelines were updated in 2023. The first recommendation is Nirogacestat (a Notch inhibitor). Unfortunately, it is not yet available in China, though Shanghai may have a clinical trial.

The second drug is sorafenib, an anti-angiogenic agent studied earlier.

Clinically, we find that sorafenib, anlotinib, famitinib, and regorafenib have similar effects as multi-target TKIs with anti-angiogenic properties. Any can be chosen.

Anlotinib has extensive experience from Prof. Li Shu's team, shows good tolerability, and can be covered by insurance under sarcoma indications.

Therefore, we currently highly recommend anlotinib. Drugs like imatinib or pazopanib, though guideline-recommended, show poor efficacy and are not chosen.

The third option is the chemotherapy drug liposomal doxorubicin. It shows relatively high efficacy, especially for intra-abdominal tumors. Upon DT diagnosis, seek specialized hospitals (like ours or Prof. Li Shu's center) familiar with this disease.

I also want to report on a clinical trial we conducted with strong support from our group, testing famitinib for FAP-related DT. All 12 cases have been observed, and the manuscript will be completed and submitted this month.

Among the 12 patients, results were excellent: 7 achieved PR (partial response) with significant and sustained tumor shrinkage. I also learned much from these cases, discovering that perforation is a severe issue inherent to the disease itself, not necessarily drug-induced. The tumor may adhere to the bowel, leading to perforation, which can cause rapid health decline and even indirect death.

We are actively collaborating with radiology to see if CT can predict perforation events earlier. Unfortunately, one of the 12 patients, who was responding well, developed duodenal cancer mid-treatment and passed away due to rapid progression. This reminds us CP (FAP) patients that regular gastroscopy to remove duodenal polyps is crucial.

Of course, consistent with reports on XX inhibitors, we clearly observed that intra-abdominal DTs are significantly more sensitive to drugs than those in extremities or the abdominal wall. Although intra-abdominal DTs are more malignant and severely impact life and survival, they respond better to medication, which is very encouraging.

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Next, we plan to launch a clinical trial for a new drug. I have actively coordinated with Prof. Shen for support, and ethical approval is underway.

This drug is safer. In Phase I trials with 20 patients, it caused almost no side effects. It is a bispecific antibody targeting CD39 and TGF-β.

Our planned trial will not be limited to FAP-related DT; all desmoid tumor patients can enroll. We will perform CD39 molecular staining to check for high expression.

Currently, about one-third of DT patients show strong expression. We will initially explore clinical use in this subgroup.

I look forward to this drug providing more treatment options for all desmoid tumor patients, which is our goal.

Finally, with more new drug research underway, I am very confident about improving survival and prognosis for this disease.

Thank you all!

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Xiao Han

Thank you, Dr. Ge Sai, for the wonderful and detailed lecture lasting over an hour!

We learned a lot. Many questions raised by the group were answered as Dr. Ge progressed through the lecture. Please review the replay, as some scoring charts require comprehensive evaluation to decide on surgery.

Someone asked which hospital is best for duodenal polyp removal. I recommend major domestic endoscopy centers, such as Zhongshan or Changhai in Shanghai, or Friendship, Peking Union, Peking University Third Hospital, and 301 in Beijing. Generally, every major tertiary hospital has at least one skilled endoscopy expert for complex cases. Find that expert.

Our FAP group administrator is a young patient who underwent total colectomy with a permanent stoma and developed secondary desmoid tumors. He still works at a high intensity. Whenever he visits Beijing or I go to Shanghai, we meet. He often shares food photos in the group, showing a remarkably resilient and optimistic attitude toward life.

Today's lecture was very thorough. FAP group members, especially newcomers, should review Dr. Ge Sai's presentation, clarify the key points, and apply what is useful to your situation.

Extended supplement: FAP treatment mind map organized by the FAP administrator: