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NCCN Flash Updates: NCCN Guidelines Updated for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. These NCCN Guidelines^® are currently available as Version 1.2025.

Link directly to the Updates section of the NCCN Guidelines: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic

Global Updates

• References updated throughout the guideline.

EVAL-A (1 of 11)

• 2nd bullet, 1st sub-bullet added: For principles of genetic testing for patients with cancer (active diagnoses and previous history) when testing is performed outside of specialty genetics setting, see EVAL-A 10 of 11.

EVAL-A (2 of 11)

• Prior to genetic testing, the following should be taken into consideration:
  • 4th bullet revised from "Testing for unaffected family members when no affected member is available should be considered. Significant limitations of interpreting test results should be discussed." to "While testing an affected family member is most informative, it is also appropriate to test unaffected family members who meet testing criteria. Limitations of interpreting negative test results in unaffected individuals should be discussed."

EVAL-A (3 of 11)

• Choice of multigene testing
  • 4th bullet revised by adding: For individuals of Ashkenazi Jewish descent, complete gene panel analysis including specific AJ founder mutations should be considered based on family history; testing limited to AJ founder testing may be appropriate for families segregating known mutations, or in population screening in which a negative test is followed by more complete testing depending on personal and/or family history.

EVAL-A (5 of 11)

• 2nd bullet, 4th sub-bullet revised by adding: For these reasons, ctDNA should not be used, outside of the clinical trial setting, to replace well-established methods of cancer screening (eg, mammography).

EVAL-A (10 of 11)

• New page added: Principles of genetic testing for patients with cancer (active diagnoses and previous history) when testing is performed outside of specialty genetics setting

CRIT-2

• Testing Criteria for High-Penetrance Breast Cancer Susceptibility Genes
  • Header revised: SpecificallyGenes such as... (Also for CRIT-4, CRIT-5)
  • Personal history of breast cancer.. bullet revised: Lobular breast cancer with personal or family history of diffuse gastric cancer (NCCN Guidelines for Gastric Cancer)
  • Family history section revised:
    • Family history of cancer criteria: unaffected; or affected but does not meet above criteria
      • Individuals affected with breast cancer (not meeting testing criteria listed above) or
      • Individual unaffected with breast cancer with a first- or second-degree blood relative meeting any of the criteria listed above (except unaffected individuals whose relatives meet criteria only for systemic therapy decision-making).
      • Individuals affected or unaffected with breast cancer who otherwise do not meet the criteria above but have a probability >5% of a BRCA1/2 P/LP variant based on prior probability models (eg, Tyrer-Cuzick, BRCAPro, CanRisk)

CRIT-2A

• Footnote n revised: Consideration of the limitations of unknown or limited family structure is indicated in those aged ≥51 years. See EVAL-A.

CRIT-3

• Testing Criteria for High-Penetrance Breast Cancer Susceptibility Genes
  • Testing may be considered in the following scenarios
    • 1st bullet revised: Personal history of breast cancer <60 y ≤65 y not meeting any of the above criteria may approach a 2.5% probability of having a P/LP variant, based on recent data.
      • Footnote s revised: Kurian A, et al. JAMA 2020;323:995-997 Bedrosian I, et. al. J Clin Oncol 2024;42:584-604.
      • Corresponding footnote t added: Testing includes breast cancer genes plus other inherited cancer genes consistent with family phenotype.
    • 3rd bullet clarified from, "Individuals affected or unaffected with breast cancer who otherwise do not meet any of the above criteria (CRIT-2) but with a 2.5%–5% probability of BRCA1/2 P/LP variant based on prior probability models..." to "Individuals (unaffected; or affected but does not meet above criteria [CRIT-2]) with a 2.5%-5% probability of BRCA1/2 P/LP variant based on prior probability models..."
    • 4th bullet added: Personal history of malignant phyllodes tumors. Corresponding footnote u added: See Discussion.
  • There is a low probability...1st bullet revised: Female diagnosed with breast cancer at age >60 y>65 y,...

CRIT-4

• Testing Criteria for Ovarian Cancer Susceptibility Genes
  • Footnote x, last sentence revised: Examples include an association between sex-cord tumors with annular tubules and PJS or Sertoli-Leydig tumors, DICER1-related disorders, andsmall cell carcinoma of the ovary and hypercalcemic type with SMARCA4.

CRIT-6

• Testing Criteria for Prostate Cancer Susceptibility Genes
  • Header revised: SpecificallyGenes such as... and TP53)
  • Family history section revised:
    • Family history of cancer criteria: unaffected; or affected but does not meet criteria above
      • An affected (not meeting testing criteria listed above) or unaffected Individual with a first-degree blood relative meeting any of the criteria listed above (except unaffected individuals whose relatives meet criteria only for systemic therapy decision-making)

CRIT-8A

• Testing Diagnostic Criteria for Cowden Syndrome (CS)/PTEN Hamartoma Tumor Syndrome (PHTS)
  • Major and Minor Criteria clarified as diagnostic criteria and updated to be consistent with Pilarski R, et al. J Natl Cancer Inst 2013;105:1607-1616.
  • Footnote * revised from, "Other cancers associated with PTEN but not in the testing criteria include: colorectal, kidney cancer, and melanoma" to "Melanoma is also associated with PTEN but is not included in the testing criteria."

GENE-1

• Genetic Testing, No known familial P/LP variant revised: Germline multigene panel testing or if unaffected, attempt, if possible, to test family member with highest likelihood of a P/ LP variant before testing an unaffected family memberWhile testing an affected family member is most informative, it is also appropriate to test unaffected family members who meet testing criteria.

GENE-A (1 of 11)

• ATM
  • Primary Breast Cancer
    • Absolute risk revised from 20%–30% to 21%–24%
  • Other Cancer Risks: Colorectal cancer added.
  • Comments section revised: ...See Discussion for information regarding the c.7271T>G variant, which is associated with greater risk of breast cancer. ATM missense c.7271T>G variant is a higher penetrance allele (60% by age 80 y; Goldgar DE, et al. Breast Cancer Res 2011;13:R73) (Hall MJ, et al. Cancer Prev Res (Phila). 2021;14:433-440; Southey MC, et al. J Med Genet 2016;53:800-811).

GENE-A (2 of 11)

• BRCA1
  • Primary Breast Cancer
    • Absolute risk revised from >60% to 60%–72%
  • Comments section revised by adding: The risk for breast cancer appears to be lower for the BRCA1 R1699Q variant (24% by age 70 y) (Spurdle AB, et al. J Med Genet 2012;49:525-532). Screening should be individualized based on personal and family history.
• BRCA2
  • Primary Breast Cancer
    • Absolute risk revised from >60% to 55%–69%

GENE-A (3 of 11)

• CDH1
  • Primary Breast Cancer
    • Absolute risk revised from 41%–60% to 37%–55%
  • Comments section revised by removing: There is controversy over how to manage gastric cancer risk in individuals with CDH1 P/LP variants in the absence of a family history of gastric cancer. However, one small study found that >50% of such individuals had gastric cancer identified at the time of risk-reducing total gastrectomy (Jacobs MF, et al. Gastroenterology 2019;157:87-96), and penetrance for lifetime risk is increased with a positive family history of HDGC (Roberts ME, et al. JAMA Oncol 2019;5:1325-1331).

GENE-A (4 of 11)

• CDKN2A
  • Comments section, 1st sentence revised: Comprehensive skin examination by a dermatologist, supplemented with total body photography and dermoscopy is recommended biannuallyevery 6 mo for individuals
• CHEK2
  • Primary Breast Cancer
    • Absolute risk revised from 20%–49% to 23%–27%
  • Other Cancer Risks
    • Colorectal cancer removed.
  • Comment revised: ... The risks for most missense variants are unclear but for some P/LP variants, such as IIe157Thr, the risk for breast cancer appears to be lower. Additional cancer risk management based on this variant (IIe157Thr) is not recommended. There is emerging evidence that not all missense P/LP variants are low penetrance. For some P/LP variants, such as IIe157Thr and Ser428Phe, the risk for breast cancer appears to be lower. Additional cancer risk management based on these variants (IIe157Thr) is not recommended. Management should be based on best estimates of cancer risk for the specific P/LP variant and family history. There are some data to indicate females with biallelic CHEK2 P/LP variantshave a higher risk for invasive breast cancer, are more likely to be diagnosed at ≤50 years, and are more likely to have multiple primary breast cancers. However, lifetime risk estimates are difficult to quantify due to small study sizes. Therefore taking personal and family history into account to advise on cancer risk management is appropriate.

GENE-A (6 of 11)

• PALB2
  • Primary Breast Cancer
    • Absolute risk revised from 41%–60% to 32%–53%

GENE-A (7 of 11)

• RAD51C and RAD51D
  • Primary Breast Cancer
    • Absolute risk revised from 17%–30% to ~20%
    • Management, added sub-bullet: Risk reduction: Evidence insufficient for risk-reducing mastectomy (RRM); manage based on family history

GENE-A (9 of 11)

• Footnote b revised: Screening and risk-reduction management for breast and ovarian cancer is extrapolated from BRCA1/2 data based on risk levels.
• Footnote f added: Breast awareness starting at age 18 years. Clinical breast exam, every 6–12 months, starting at age 25 years or 5–10 years before the earliest known breast cancer in the family (whichever comes first). Age >75 years, management should be considered on an individual basis.

GENE-B

• Bullet added above table: Biallelic P/LP variants in some genes, included on gene panels, may be associated with rare autosomal recessive conditions, such as FA or CMMRD. For these genes, consideration should be given to carrier testing the partner for P/LP variants in the same gene if it would inform reproductive decision-making and/or risk assessment and management.

 

 

BRCA Pathogenic/Likely Pathogenic Variant-Positive Management

BRCA-A (2 of 5)

• Ovarian/Fallopian Tube/Peritoneal/Uterine Cancers
  • Surgical risk reduction with bilateral salpingo-oophorectomy, 4th bullet added: If serous tubal intraepithelial carcinoma (STIC lesion) is found, further consultation with a gynecologist oncologist is recommended.

 

Pancreatic Cancer Screening

PANC-A (1 of 2)

• 1st bullet, #2 revised: A family history of exocrine pancreatic cancer in ≥1 first-degree and ≥1 second-degree relatives from the same side of the family, even in the absence of a known P/LP germline variant (many centers would enroll individuals with one affected first-degree relative and one second-degree relative)
• Screening table revised:
  • Consider pancreatic cancer screening (preferably in the setting of a longitudinal study) for the following:
  • 3rd bullet added: Individuals with P/LP germline variants in ATM or BRCA2 - Beginning at age 50 years (or 10 years younger than the earliest exocrine pancreatic cancer diagnosis in the family, whichever is earlier).
  • 4th bullet: ATM and BRCA2 removed from first column and added to second column.

 

Li-Fraumeni syndrome

LIFR-A (3 of 6)

• Table 1: Workup and Management Depending on Etiology of TP53 Mutation Found on Genetic Testing extensively revised.

LIFR-A (4 of 6)

• Other cancer risks
  • 7th bullet added: For pancreatic cancer screening recommendations, see PANC-A.

 

Breast, Ovary, Uterine, and Prostate Cancer Risk Reduction Strategies for Transgender, Non-Binary and Gender Diverse People with Hereditary Cancer Syndromes

TNBGD-2

• Uterine cancer, 1st bullet revised: There are several PVs associated with an increased risk for uterine cancer, including BRCA1 (serous endometrioid type), PTEN and LS genes.

 

Summary of Genes and/or Syndromes Included/Mentioned in Other NCCN Guidelines

SUMM

• Revisions made throughout.

 

 

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