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NCCN Flash Updates: NCCN Guidelines Updated for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric. These NCCN Guidelines^® are currently available as Version 1.2024.

Link directly to the Updates section of the NCCN Guidelines: Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric

New

• Endometrial cancer recommendations included throughout.
• Hereditary Diffuse Gastric Cancer section added (see HGAST-1).

 

Global Changes

• References updated throughout the Guideline.

 

Principles of Cancer Risk Assessment and Counseling

EVAL-A 1 of 9

• Pre-test counseling column revised as follows:
  • 4th bullet modified: ...in a gene that does not currently explain the patient's personal or family history of cancer.

EVAL-A 2 of 9

• 5th bullet modified to include APC/MUTYH only testing.
• 6th bullet added: MGPT increases the likelihood of finding P/LP variants in genes; however, some genes do not have clear clinical significance actionability or result in a change in medical management.
• Footnote a added: Single-gene testing or testing that is not otherwise sufficient to address the personal and/or family history.

EVAL-A 5 of 9

• Page for "Tumor Genomic Testing: Potential Implications for Germline Testing" extensively revised.

EVAL-A 6 of 9

• Page for "Post-Germline Test Counseling" extensively revised.

EVAL-A 7 of 9

• Page for positive results added.

EVAL-A 8 of 9

• Page for negative results added.

EVAL-B 1 of 4

• Family History of Cancer and Expanded Pedigree, bullet 2
  • Sub-bullet 3 revised: Cancer site and type of cancer
  • Sub-bullet 8 revised: Suspected colon cancer/polyposis, endometrial cancer or gastric cancer syndromes...(eg, Muir-Torre syndrome, Turcot syndrome, PJS, JPS)
  • Sub-bullet 9 revised: All other inherited conditions and birth defects (eg, cleft lip and/or palate)
  • Sub-bullet 11: revised from "Genetic test results in family members" to "Documentation of prior germline test results for proband or family"
• Detailed Medical and Surgical History
  • Bullet 5 revised as follows:
    • For patients with prior polyps:
      • Pathology verification strongly encouraged
      • Polyps, including number, location and histology histologic type
    • For patients with prior cancer, sub-bullets added:
      • Pathology verification strongly encouraged
      • Hormone or oral contraceptive use
      • History of risk-reducing surgeries
• Directed Examination for Related Manifestations (if suspicion for a CRC/polyposis, endometrial, or gastric cancer syndrome)
  • Bullet 3, sub-bullet 1 revised: Eye (including retinal) examination

 

Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric

HRS-1

• Page significantly revised and title updated to "General Criteria for Testing and Genetic Evaluation for Hereditary Syndromes Associated with Colorectal, Endometrial, and Gastric Cancer" and includes two sections, "Testing is clinically indicated in the following scenarios" and "Genetic evaluation is clinically indicated in the following scenarios"

HRS-2

• Footnote l revised: Rare PVs associated with adenomatous polyposis include...and biallelic PVs in MLH3, MSH3, MBD4, and NTHL1.

HRS-3

• Header revised to add ... Colorectal or Endometrial Cancer and "or EC" added as appropriate.
• No or not tested pathway: Added "and/or"; removed "Utilize tumor and family history based criteria for evaluation of LS and."
• Footnote o added: For multidisciplinary treatment planning, many patients will require tumor-based testing; see the NCCN Treatment Guidelines.

HRS-A 1 of 3

• Pros column, 1st bullet, 2nd sub-bullet, 3rd sentence added: MGPT identified a PV in 9.2%–14% of patients with EC.
• Cons column:
  • 1st bullet revised: ...a germline MGPT result alone does not inform CRC or EC treatment...
    • Sub-bullet modified: ...in an LS-associated MMR gene, or in POLE/D1 is not sufficient to initiate immune checkpoint blockade therapy based on MSI-H status. because Tumor-based microsatellite instability (MSI) testing or immunohistochemistry (IHC) testing for expression of the MMR proteins, or a measure of tumor mutational burden are the gold standards for are required for determining eligibility for immune checkpoint blockade therapy based on presence of dMMR.
  • 5th bullet, sub-bullet 1, last sentence added: In the United States, 66,200 women are diagnosed with EC annually, and there are >600,000 EC survivors.
  • 5th bullet, sub-bullet 2, last sentence added: Tumor Registry data from 2013–2019 indicate that genetic testing rates among CRC and EC patients are 5%–6%.

HRS-A 2 of 3

• Test Selection section extensively revised.

 

Lynch Syndrome

LS-1

• Header added: Evaluation is indicated in the following scenarios
• 1st row added: Personal history of CRC or EC at any age
• 3rd row added: Personal history of a P/LP variant identified on tumor genomic testing that has clinical implications if also identified in the germline

LS-1A

• Footnote c added: Tumor mutational burden (TMB) can be used as surrogate to some degree for MSI, but there are causes of increased TMB other than dMMR.
• Footnote d added: This should prompt a careful evaluation of personal and family history of the individual to determine the yield of germline sequencing.
• Footnote e added: Mandelker D, et al. Ann Oncol 2019;30:1221-1231.

LS-A 2 of 10

• Bullet 2 revised: ...germline genetic testing (PV detection) or tumor testing...
• Bullet 3 added: Absence of MMR protein expression in both cancer and normal tissue may be suggestive of CMMRD.
• Footnote a added: Patients with constitutional MLH1 epimutation are a rare exception. Consider referral to individual with expertise in genetic testing for consideration of constitutional MLH1 methylation testing in patients with early-onset CRC (≤55 y), no BRAF V600E PV, loss of MLH1 on IHC, and no germline MLH1 P/ LP variant or >1 tumor with MLH1 promoter hypermethylation at any age. Hitchins MP, et al. J Natl Compr Canc Netw 2023;21:743-752.

LS-A 3 of 10

• Adenomas
  • Bullet 1 first sentence revised: IHC for MMR protein expression can also be performed...
  • Bullet 1, last sentence revised: If PMS2 and MLH1 protein expression are absent are missing, further tumor testing should be considered...

LS-A 7 of 10

• Additional Testing, last row revised: None, unless young age of onset or significant family history; then consider constitutional MLH1 epimutation testing...

 

Gene Specific Lynch Syndrome Cancer Risks And Surveillance/Prevention Strategies

LS-B 3 of 5 (Also for LS-C 3 of 5, LS-D 3 of 5, and LS-E 3 of 5)

• Footnote t, 2nd sentence revised from, "There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant patients despite potential risks" to "Daily low-dose (81 mg/d) aspirin use in pregnancy is considered safe and is associated with a low likelihood of serious maternal or fetal complications related to use."

LS-B 4 of 5

• Endometrial cancer surveillance
  • Bullet 3 revised by adding: For patients requiring a colorectal surgery such as for CRC resection, coordination with hysterectomy should be considered. Given the higher risks of early EC in MLH1, hysterectomy with bilateral salpingectomy may be considered starting at age 40 y with delayed bilateral oophorectomy starting at age 50 y.
• Ovarian cancer surveillance
  • Bullet 2 revised: For patients requiring a colorectal surgery such as for CRC resection, coordination with hysterectomy and oophorectomy should be considered. Given the higher risks of EC and ovarian cancer in MLH1, hysterectomy with bilateral salpingectomy may be considered starting at age 40 y, with delayed bilateral oophorectomy starting at age 50 y. As premature menopause due to oophorectomy can cause detriments to bone health, cardiovascular health, and generalized quality of life, estrogen replacement therapy should be considered. Estrogen replacement after premenopausal oophorectomy may be considered.
  • Bullet 3 revised: Data do not support routine ovarian cancer screening for LS. CA-125 and pelvic ultrasound are recommended for preoperative planning. Since there is no effective screening for ovarian cancer, patients should be educated on the symptoms that might be associated with the development of ovarian cancer, such as pelvic or abdominal pain, bloating, increased abdominal girth, difficulty eating, early satiety, or urinary frequency or urgency. Symptoms that persist for several weeks and are a change from a patient's baseline should prompt evaluation by their physician.
  • Bullet 4 added: Salpingectomy has been shown to reduce the risk of ovarian cancer in the general population and is an option for premenopausal patients with hereditary cancer risk who are not yet ready for oophorectomy. (Also for LS-C 4 of 5, LS-D 4 of 5 and LS-E 4 of 5)
  • Bullet 5 revised: Consider risk-reduction agents for endometrial and ovarian cancers, including oral contraceptive pills and progestin intrauterine systems discussing risks and benefits (see Discussion for details). (Also for LS-C 4 of 5, LS-D 4 of 5 and LS-E 4 of 5)
  • Bullet removed: Data do not support routine ovarian cancer screening for LS. Transvaginal ultrasound for ovarian cancer screening has not been shown to be sufficiently sensitive or specific to support a routine recommendation, but may be considered at the clinician’s discretion. Serum CA-125 is an additional ovarian screening test with caveats similar to transvaginal ultrasound.
• Gastric and small bowel cancer surveillance: (Also for LS-C 4 of 5, LS-D 4 of 5 and LS-E 4 of 5)
  • Bullet 1 revised: Upper GI surveillance with high-quality EGD...

 

MSH2 and EPCAM Lynch Syndrome: Surveillance/Prevention

LS-C 4 of 5

• Endometrial cancer surveillance
  • Bullet 3 revised by adding: For patients requiring a colorectal surgery such as for CRC resection, coordination with hysterectomy should be considered. Given the higher risks of early EC and ovarian cancer in MSH2, hysterectomy with BSO may be considered starting at age 40 y. As premature menopause due to oophorectomy can cause detriments to bone health, cardiovascular health, and generalized quality of life, estrogen replacement therapy should be considered.
• Ovarian cancer surveillance
  • Bullet 2 revised: For patients requiring a colorectal surgery such as for CRC resection, coordination with hysterectomy and oophorectomy should be considered. For patients requiring a colorectal surgery such as for CRC resection, coordination with hysterectomy should be considered. Given the higher risks of EC and ovarian cancer in MSH2, hysterectomy with BSO may be considered starting at age 40 y. As premature menopause due to oophorectomy can cause detriments to bone health, cardiovascular health, and generalized quality of life, estrogen replacement therapy should be considered. Estrogen replacement after premenopausal oophorectomy may be considered.
  • Footnote u added: Evidence for gynecologic cancer surveillance recommendations for individuals with a P/LP EPCAM variant are lacking.

 

MSH6 Lynch Syndrome: Surveillance/Prevention

LS-D 4 of 5

• Endometrial cancer surveillance
  • Bullet 3 revised by adding: For patients requiring a colorectal surgery such as for CRC resection, coordination with hysterectomy should be considered. Given the higher risks of EC in MSH6, hysterectomy with bilateral salpingectomy may be considered starting at age 40 y, with delayed bilateral oophorectomy starting at age 50 y
• Ovarian cancer surveillance
  • Bullet 2 revised: For patients requiring a colorectal surgery such as for CRC resection, coordination with hysterectomy and oophorectomy should be considered. Given the higher risks of EC and ovarian cancer in MSH6, hysterectomy with BSO may be considered starting at age 40 y, with delayed bilateral oophorectomy starting at age 50 y. As premature menopause due to oophorectomy can cause detriments to bone health, cardiovascular health, and generalized quality of life, estrogen replacement therapy should be considered. Estrogen replacement after premenopausal oophorectomy may be considered.

 

PMS2 Lynch Syndrome: Surveillance/Prevention

LS-E 4 of 5

• Endometrial cancer surveillance
  • Bullet 4 revised by adding: Given the higher risks of EC in PMS2, hysterectomy with BSO may be considered starting at age 50 y.
• Ovarian cancer surveillance
  • Bullet 3 revised: Hysterectomy with BSO may be considered starting at age 50 y. As premature menopause due to oophorectomy can cause detriments to bone health, cardiovascular health, and generalized quality of life, estrogen replacement therapy should be considered. Estrogen replacement after premenopausal oophorectomy may be considered.

LS-F

• Adenomas
  • Bullet revised: Complete endoscopic polypectomy with follow-up colonoscopy every 1–2 y for MSH2/MLH1 and every 1–3 y for PMS2/MSH6.

LS-G

• New table added: Surgical Options for Treating the Colon in Patients with LS

 

Adenomatous Polyposis

POLYP-1

• Testing Criteria
  • Sub-bullets moved from Consider testing to Recommend testing: Family history of polyposis and family unwilling/unable to have testing and Cribriform-morular variant of papillary thyroid cancer
  • Bullet 3 added: In individuals with any cancer with a P/LP APC variant identified on tumor-only genomic testing, germline testing should be considered for:
    • Those meeting one or more of the other adenomatous testing criterion above after reevaluation of personal and family history
    • Those diagnosed age <30 y with any cancer.
• Results
  • PV not identified, branch added: If individual has <10 adenomas

POLYP-1A

• Footnotes
  • Footnote a added: Also known as retinal pigment epithelium (RPE) hamartomas associated with FAP (RPEH-FAP).
  • Footnote c added: This should prompt a careful evaluation of personal and family history of the individual to determine the yield of germline sequencing. Somatic APC P/LP variants are common in many tumor types in absence of a germline P/LP variant.
  • Footnote d added: Mandelker D, et al. Ann Oncol 2019;30:1221-1231.

 

APC-Associated Polyposis

FAP/AFAP-1

• Classical FAP
  • Bullet 5 revised: ...hepatoblastoma, periampullary cancer, gastric cancer, duodenal/periampullary cancer
• Attenuated FAP
  • Bullet 5 revised: Upper GI findings, thyroid and duodenal/periampullary cancer risks are similar to classical FAP
• Footnote b revised: Genetic testing with MGPT is recommended to differentiate FAP, MAP, polyposis due to a mutation in a rare gene for which testing is available, and colonic polyposis of unknown etiology. MGPT is recommended to differentiate APC from MAP and other adenomatous polyposis syndromes and CPUE. See HRS-A for CRC/polyposis gene list and GENE-1 for surveillance recommendations.
• Footnote c revised: Individuals with > ≥100 polyps...

 

Familial Adenomatous Polyposis

FAP-2

• Surveillance
  • APC negative pathway revised: NCCN Guidelines for Colorectal Cancer Screening- Average risk (Also for AFAP-2)
  • Not tested, bullet 2: If genetic testing not completed, high-quality colonoscopy (preferred) or flexible sigmoidoscopy every 12 mo beginning at age 10–15 y.

FAP-A 1 of 3

• Sites updated:
  • Colorectal cancer (without colectomy)
  • Colon Rectal/Pouch cancer (post-colectomy)
• Footnote a added: There is one report showing increased pancreas cancer risk, but this study had significant limitations (Karstensen J, et al. Gastro 2023;165:573-581; see Discussion); whether pancreatic cancer risk is increased remains uncertain.

FAP-B

• Gastric cancer: Recommendations removed and bullet added: See FAP-D for follow-up of gastric findings.
• CNS cancer: There is currently no support for routine surveillance imaging. However, patients should be educated regarding signs and symptoms of neurologic cancer and the importance of prompt reporting of abnormal symptoms to their physicians.
• Intra-abdominal desmoids: If personal history of symptomatic desmoids, consider imaging with abdominal CT or MRI with and without contrast no less frequently than annually. Suggestive abdominal symptoms should prompt immediate abdominal imaging. Patients should be educated regarding signs and symptoms of intra-abdominal desmoids and the importance of prompt reporting of abdominal symptoms to their physicians. See NCCN Guidelines for Soft Tissue Sarcoma.
• Small bowel polyps and cancer: High-level evidence to support routine small bowel screening distal to the duodenum is lacking. However, may consider small bowel visualization (eg, capsule endoscopy or CT/MRI enterography), especially if advanced duodenal polyposis.

FAP-C 1 of 2

• Spigelman Score 9-12, surveillance revised: Expert surveillance every 3–6 mo and surgical consultation for consideration of duodenectomy.

FAP-D

• New section added: Gastric Findings and Management.

FAP-E

• Surgical Options for Treating the Colon and Rectum: Proctocolectomy with end ileostomy (PC/EI), Possible advantages, bullet 1 revised: Removes risk of CRC rectal cancer risk

 

MUTYH-Associated Polyposis

MAP-3

• Surveillance, No MUTYH PVs found pathway revised: NCCN Guidelines for Colorectal Cancer Screening- Average risk
• Footnote removed: There are no specific data available to determine screening recommendations for a patient with heterozygous MUTYH PV and a second-degree relative affected with CRC.

 

Colonic Adenomatous Polyposis of Unknown Etiology

CPUE-1

• Management/Surveillance, "including complete visualization of the ampulla of Vater" added to baseline upper endoscopy.
• Footnote b, 2nd sentence revised: and biallelic PVs in NTHL1, MUTYH, MBD4, MLH3, and MSH3 and 3rd sentence added. See HRS-A for CRC/polyposis gene list and GENE-1 for surveillance recommendations. (Also for CPUE-2)
• Footnote d added: Cap-assisted endoscopy may be adequate for visualization of the ampulla (Kallenberg F, et al. Endoscopy 2017;49:181-185).

 

Peutz-Jeghers Syndrome

PJS-1

• Indications for Genetic Testing for PJS
  • Bullet 2 added: STK11 P/LP variant detected by tumor genomic testing on any tumor type in the absence of germline analysis.
  • Bullet 2, sub-bullet added: This should prompt a careful evaluation of personal and family history of the individual to determine the yield of germline sequencing. Somatic STK11 P/LP variants are common in many tumor types in absence of germline P/LP variant.

PJS-3

• Breast (female), Screening Procedure and Interval
  • Bullet 2 revised: Clinical breast exam every 6–12 mo

 

Juvenile Polyposis Syndrome

JPS-1

• Indications for Genetic Testing for PJS
  • Bullet 2 added: BMPR1A or SMAD4 P/LP variants detected by tumor genomic testing on any tumor type in the absence of germline analysis.
  • Bullet 2, sub-bullet added: This should prompt a careful evaluation of personal and family history of the individual to determine the yield of germline sequencing.

JPS-2

• Footnote e revised: For consensus guidelines for the management and prevention of HHT-related symptoms and complications, see Faughnan M, et al. Ann Intern Med 2020;173:989-1001.

JPS-3

• Stomach
  • Patients column: separated SMAD4 and BMPR1A.
  • % Lifetime risk of BMPR1A changed to "Rare"
• Footnote f added: In a meta-analysis of 204 patients (Singh A, et al. Gastrointest Endosc 2023;97:407-414) with BMPR1A, only one patient with gastric cancer was identified.

 

Multigene Testing

GENE-3

• APC I1307K variant
  • Comments revised: In the Ashkenazi Jewish population in the United States, the APC c.3920T>A (p.I1307K) variant is reported in 6%–7% 11.5% of those diagnosed with CRC and 7.2% of those not diagnosed with CRC. (Abrahamson J, et al. Cancer Res 1998;58:2919-2922 Valle L, et al. J Med Genet 2023;60:1035-1043).

GENE-4

• APC promoter 1B/Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)
  • Colon Cancer, Management revised: Baseline colonoscopy at time of diagnosis first EGD to exclude colon polyposis, if not previously done.
  • Other Cancers, Management, bullet 2 revised: Consider risk-reducing total gastrectomy from third decade, annual gastroscopy EGD from age 15.

GENE-5

• BMPR1A
  • Other Cancers, Absolute Risk updated: Stomach cancer - up to 21% see comment
  • Comments, 2nd sentence added: In a meta-analysis of 204 patients (Singh A, et al. Gastrointest Endosc 2023;97:407-414.e1) with BMPR1A, only one patient with gastric cancer was identified. For management, see JPS-3.

GENE-6

• CHEK2
  • Colon Cancer
    • Estimated Absolute Risk revised from "5%–10%" to "No increased risk"
    • Management revised from "For probands with a personal history of CRC and one of these pathogenic variants: See surveillance recommendations for post-CRC resection: NCCN Guidelines for Colon Cancer and NCCN Guidelines for Rectal Cancer. For probands without a personal history of CRC, high-quality colonoscopy screening every 5 y, beginning at age 40 or 10 y prior to age of first-degree relative’CRC diagnosis when indicated." to "General population screening is appropriate for these individuals. For probands with a personal or first-degree family history of CRC or polyps: increased screening as per the relevant guidelines: NCCN Guidelines for Colon Cancer, NCCN Guidelines for Rectal Cancer, and NCCN Guidelines for Colorectal Cancer Screening."
    • Strength of Evidence revised from "Limited" to "Strong"
    • Comment removed: Heterogeneity in CRC risk may exist based on type of pathogenic CHEK2 variant (Han FF, et al. DNA Cell Biol 2013;32:329-335; Liu C, et al. Asian Pac J Cancer Prev 2012;13:2051-2055); some patients may elect for less aggressive screening based on shared decisionmaking. One model has suggested that earlier screening than the average-risk initiation may be justified for CHEK2 1100delC and I157T carriers based on reaching the same risk for CRC at an earlier age than observed among persons at average risk initiating screening at age 50 (Katona B, et al. Genet Med 2018;20:1324-1327).

GENE-9

• MUTYH/monoallelic pathogenic variant/heterozygote (carrier)
  • Colon Cancer, Management, bullet 2 revised: For probands with a personal or first-degree family history of CRC or polyps (not explained by MAP): increased screening as per the relevant guideline...

GENE-10

• NTHL1 biallelic pathogenic variants
  • Comments, added: Beck SH, et al. Fam Cancer 2022;21:453-462.

GENE-11

• POLD1/Polymerase proofreading-associated polyposis and POLE/Polymerase proofreading-associated polyposis
  • Colon Cancer
    • Management revised: Begin high-quality colonoscopy at age 25–30 y or 2–5 y prior to the earliest CRC in the family if it is diagnosed before age 25 y and repeat every 2–3 y if negative.
    • Strength of Evidence revised from "Limited" to "Strong"
  • Other cancers revised from "Unknown or insufficient evidence" to "See comment"
  • Comments extensively revised

GENE-12

• PTEN/PTEN hamartoma tumor syndrome
  • Estimated Absolute Risk revised from 11%–20% to 9%–20%.

GENE-13

• RPS20
  • Colon cancer, Management revised from "Evidence insufficient to provide specialized CRC screening recommendations; manage based on family history" to "Colonoscopy every 5 y beginning at age 20. If the patient had a hematopoietic cell transplant prior to age 20, colonoscopy is recommended to begin one year after transplant."
  • Comments extensively revised.

GENE-15

• Footnote k revised by adding: Breen KE, Katona BW, Catchings A, et al. An updated counseling framework for moderate-penetrance colorectal cancer susceptibility genes. Genet Med 2022;24:2587-2590.
• Footnote removed and added to HRS-A: The following genes and others are found on some genetic testing panels, but at present there is insufficient evidence to make any recommendations for specialized CRC screening for MBD4 and FOCAD.
• Footnote removed: Heterogeneity in CRC risk may exist based on type of pathogenic CHEK2 variant (Han F, Guo C, Liu L. The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol 2013;32:329-335; Liu C, Wang Q, Wang Y. The CHEK2 I157T variant and colorectal cancer susceptibility: a systematic review and meta-analysis. Asian Pac J Cancer Prev 2012;13:2051-2055; Xiang H, Geng X, Ge W, Li H. Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. Eur J Cancer 2011;47:2546-2551); some patients may elect for less aggressive screening based on shared decision-making. One model has suggested that earlier start of screening than average-risk initiation may be justified for CHEK2 1100delC and I157T carriers based on reaching the same risk for CRC at an earlier age than observed among persons at average risk initiating screening at age 50 (Katona BW, Yurgelun MB, Garber JE, et al. A counseling framework for moderate-penetrance colorectal cancer susceptibility genes. Genet Med 2018;20:1324-1327).

 

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