What are the management options for individuals with familial cancer syndromes?

Management of Familial Cancer Syndromes

Individuals with familial cancer syndromes require a systematic approach centered on comprehensive family history collection, genetic testing with counseling, syndrome-specific surveillance protocols, and risk-reducing interventions tailored to their specific mutation. 1

Initial Assessment and Identification

Collect a detailed three-generation pedigree at the first oncology visit, documenting all cancer types, ages at diagnosis, and both maternal and paternal lineages. 1 This family history serves as the cornerstone for identifying the 5-10% of cancers attributable to hereditary cancer predisposition syndromes. 1

Key red flags warranting further evaluation include: 1, 2

• Early age of cancer onset (particularly <45-50 years for breast cancer)
• Multiple affected family members across generations
• Multiple primary cancers in a single individual
• Bilateral or multifocal disease
• Rare cancer types (male breast cancer, adrenocortical carcinoma)
• Specific ethnic backgrounds (Ashkenazi Jewish ancestry with breast/ovarian/pancreatic cancer)

Genetic Testing Strategy

Tumor Testing First for Colorectal Cancer

For all patients with colorectal cancer, perform tumor testing for DNA mismatch repair (MMR) deficiency using immunohistochemistry and/or microsatellite instability testing. 1 This universal screening approach identifies Lynch syndrome candidates more effectively than relying solely on clinical criteria.

If MLH1/PMS2 loss is detected, first test for BRAF V600E mutation or MLH1 promoter methylation to exclude sporadic cases before proceeding to germline testing. 1 If other MMR proteins are absent (MSH2, MSH6, PMS2), proceed directly to germline testing for the corresponding genes. 1

Multigene Panel Testing

Use multigene panel testing when multiple genes could explain the clinical presentation, as this approach is more cost-effective and comprehensive than sequential single-gene testing. 1, 3 The NCCN recognizes that panels can identify mutations in genes beyond those initially suspected, though interpretation of variants of uncertain significance remains challenging. 1, 3

Critical caveat: Over 70% of familial breast cancer cases remain genetically unexplained despite comprehensive testing. 3 A negative genetic test does not exclude hereditary risk when family history remains compelling. 3

Syndrome-Specific Management

Lynch Syndrome

Initiate colonoscopy surveillance every 1-2 years beginning at age 20-25 years (or 2-5 years before the youngest family diagnosis if earlier). 1 Lynch syndrome carriers face 52-82% lifetime colorectal cancer risk versus 5.5% in the general population, with most cancers occurring in the proximal colon. 1

For women with Lynch syndrome: 1

• Annual endometrial sampling and transvaginal ultrasound starting at age 30-35 years (16-60% lifetime endometrial cancer risk)
• Consider prophylactic hysterectomy and bilateral salpingo-oophorectomy after childbearing is complete
• Upper endoscopy every 3-5 years starting at age 30-35 years for gastric cancer surveillance

Important distinction: MSH6 and PMS2 mutations confer 10-22% colorectal cancer risk by age 70, while MLH1 and MSH2 mutations carry significantly higher risks. 1 However, all confirmed Lynch syndrome patients should follow intensive surveillance protocols. 1

BRCA1/BRCA2-Associated Breast and Ovarian Cancer

For BRCA mutation carriers, implement the following surveillance: 1

• Annual breast MRI and mammography starting at age 25-30 years
• Clinical breast examination every 6-12 months starting at age 25 years
• Risk-reducing bilateral mastectomy reduces breast cancer risk by approximately 90%
• Risk-reducing bilateral salpingo-oophorectomy at age 35-40 years (or upon completion of childbearing) reduces ovarian cancer risk by 80-90% and breast cancer risk by approximately 50%

BRCA status directly influences acute treatment decisions: BRCA-positive patients may benefit from more extensive surgical resection (bilateral mastectomy vs. lumpectomy) given their 40-60% risk of contralateral breast cancer. 1

High-Penetrance Syndromes Beyond BRCA

TP53 mutations (Li-Fraumeni Syndrome): 3

• Annual whole-body MRI starting in childhood
• Brain MRI annually starting at age 18 years
• Breast MRI annually starting at age 20-25 years (up to 25% breast cancer risk by age 74)
• Avoid radiation therapy when possible due to increased secondary malignancy risk

PTEN mutations (Cowden Syndrome): 1, 3

• Annual mammography and breast MRI starting at age 30-35 years (up to 85% lifetime breast cancer risk)
• Annual thyroid ultrasound starting at diagnosis
• Colonoscopy every 5 years starting at age 35 years
• Annual endometrial sampling starting at age 35 years

CDH1 mutations (Hereditary Diffuse Gastric Cancer): 3

• Prophylactic total gastrectomy is recommended given the high penetrance and poor prognosis of diffuse gastric cancer
• Annual breast MRI and mammography starting at age 30 years (39% lifetime lobular breast cancer risk)

Familial Adenomatous Polyposis (FAP)

Begin annual flexible sigmoidoscopy or colonoscopy at age 10-12 years for classic FAP. 1 Once adenomas develop, prophylactic colectomy is indicated, typically performed in late teens to early twenties. 1

For attenuated FAP (AFAP): Begin colonoscopy at age 18-20 years and repeat every 1-2 years. 1

Family Member Testing and Counseling

When a pathogenic mutation is identified, offer predictive testing to all first-degree relatives (or more distant relatives if first-degree relatives are unavailable or decline testing). 1 This cascade testing allows for precise risk stratification and targeted interventions.

Provide pre- and post-test genetic counseling to ensure informed decision-making and address psychosocial implications. 4, 5 Some individuals elect not to undergo testing; these individuals should continue enhanced surveillance based on family history. 1

Management When Testing is Negative but Family History Remains Concerning

Do not falsely reassure patients based on negative genetic testing alone when strong family history persists. 3 Current testing identifies causative mutations in less than 30% of hereditary breast cancer cases. 3

For these patients: 3

• Refer to cancer genetics specialist for comprehensive risk assessment
• Implement enhanced surveillance protocols based on calculated lifetime risk from family history
• Update family history annually as new cancer events may alter risk assessment
• Consider repeat genetic testing as new genes are discovered and testing methods improve
• Document complete three-generation pedigree including all cancer types and ages at diagnosis

Critical pitfall: Small family size or predominance of male relatives can mask hereditary predisposition, leading to underestimation of risk. 3

Survivorship and Long-Term Management

Tailor survivorship plans to incorporate surveillance for second primary malignancies based on the specific syndrome. 1 For example, Lynch syndrome patients who develop colorectal cancer face a 40% risk of second primary colorectal cancer within 7 years. 1

Reassess family history and genetic testing options at regular intervals throughout the long-term oncologist-patient relationship, as the field of hereditary cancer predisposition advances rapidly. 1 Newly defined cancer susceptibility genes and improved testing methods may provide opportunities for more precise risk assessment. 1