When should a breast panel, including genetic testing for BRCA1 (Breast Cancer Gene 1) and BRCA2 (Breast Cancer Gene 2), be performed for a patient with a complex papillary lesion, particularly those with a family history of breast cancer or other risk factors?

When to Perform Genetic Testing for Complex Papillary Breast Lesions

Genetic testing with a breast cancer panel (BRCA1/BRCA2 and other genes) should be offered to patients with complex papillary lesions who meet standard hereditary breast cancer testing criteria, not based on the papillary histology itself. The papillary architecture is a pathologic descriptor that does not independently trigger genetic testing indications 1.

Key Testing Criteria for Patients with Complex Papillary Lesions

Age-Based Indications

• Offer BRCA1/BRCA2 testing if diagnosed before age 50 years, regardless of family history 1
• Consider testing for triple-negative papillary lesions diagnosed before age 60 years 1
• Test patients age 65 years or younger who meet NCCN criteria, as they have a 9.0% likelihood of carrying pathogenic variants in breast cancer predisposition genes 2

Family History Triggers

• Strong family history: Two or more close (first- or second-degree) relatives with breast, ovarian, pancreatic, or high-grade/metastatic prostate cancer 1
• Early-onset family history: Breast cancer before age 50 in a first-degree relative 1
• Multiple cancer types: Family history of both breast and ovarian cancer 1
• Male breast cancer: Any male relative with breast cancer 1
• Second breast cancer: Personal history of contralateral breast cancer 1

Ancestry and Tumor Subtype

• Ashkenazi Jewish ancestry with any breast cancer diagnosis warrants testing, as BRCA mutation prevalence is 1/50 in this population versus 1/500-1/1,000 in the general population 1
• Triple-negative subtype of any papillary lesion diagnosed before age 60 years 1

Expanded Panel Testing Beyond BRCA1/BRCA2

When offering BRCA1/BRCA2 testing, simultaneously test for other cancer predisposition genes tailored to personal and family history 1. This approach is critical because:

• Among BRCA1/2-negative patients with breast cancer diagnosed before age 40, 11% carry deleterious variants in other genes (PALB2, TP53, CHEK2, ATM, PTEN, STK11, CDH1) 1
• High-penetrance genes beyond BRCA1/2 inform surgical decisions, medical therapy eligibility, and second primary cancer risks 2
• Multigene panels increase detection rates from 87% sensitivity for BRCA1/2 alone to >90% for nine predisposition genes when using expanded age criteria 1

Recommended Panel Composition

The panel should include at minimum 1:

• High-penetrance genes: BRCA1, BRCA2, TP53, PTEN, STK11, CDH1
• Moderate-penetrance genes: ATM, CHEK2, PALB2, BRIP1
• Additional genes based on family history: Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM) if family history includes colon or endometrial cancer 1

Clinical Implications of Testing

Treatment Impact

• PARP inhibitor eligibility: BRCA1/2 carriers with high-risk, HER2-negative early-stage breast cancer benefit from adjuvant olaparib, improving 3-year invasive disease-free survival from 77.1% to 85.9% 2
• Surgical planning: BRCA1/2 pathogenic variants increase risk of synchronous or metachronous breast cancer, particularly in premenopausal patients, informing decisions about bilateral mastectomy versus breast-conserving surgery 1, 2

Risk Management

• Contralateral breast cancer risk: BRCA1 carriers have 65% cumulative risk by age 70; BRCA2 carriers have 45% risk 1
• Ovarian cancer prevention: Risk-reducing salpingo-oophorectomy is recommended at appropriate age for BRCA1/2 carriers (48.3% lifetime ovarian cancer risk for BRCA1, 20.0% for BRCA2) 3, 2
• Pancreatic cancer screening: Consider for BRCA1/2 or PALB2 carriers with family history of pancreatic cancer, starting at age 50 or 10 years before earliest family diagnosis 1

Family Cascade Testing

Identifying pathogenic variants enables cascade testing for at-risk relatives, allowing family members to pursue surveillance and risk-reduction strategies before cancer develops 2, 4. Each first-degree relative has a 50% chance of carrying the same mutation 1.

Common Pitfalls to Avoid

• Do not delay testing until after surgical treatment is complete if the patient is a candidate for bilateral mastectomy, as BRCA status may influence surgical decision-making 1, 2
• Do not restrict testing to only BRCA1/2 when broader panel testing is indicated, as this misses 11% of actionable mutations 1
• Do not assume older age (>65 years) excludes testing benefit if the patient has triple-negative disease, suggestive family history, or is a PARP inhibitor candidate 1, 2
• Do not test for low-penetrance SNPs or pancreatitis genes (PRSS1, SPINK1) without specific clinical indications, as these are not part of standard breast cancer genetic evaluation 1