Breast Cancer: Risk and Genetic Counseling

Breast Cancer Risk Assessment and Genetic Counseling

• This is a communication process used to inform and prepare patients for genetic test results, along with the related medical management.

Overview of Breast Cancer Risk Assessment Tools

• Aims to educate on the available tools to assess breast cancer risk.
• Aims to educate on the available tools to predict the likelihood of a positive genetic test result.
• Aims to identify the strengths and weaknesses of these tools across various patient scenarios.
• Aims to integrate the use of these tools with clinical guidelines with the use of genetic counseling.

Case example

• A 40-year-old woman with a family history of breast and ovarian cancer had a mass identified in her right breast via a baseline mammogram.
• An image-guided biopsy later revealed a fibroadenoma.
• The patient had menarche at age 10.
• The patient is Gravida 2 Para 2, with her age at first pregnancy being 29.
• The patient is currently premenopausal.
• The patient has a height of 1.62 meters and a weight of 73.5 kilograms
• The patient's breast density is heterogeneously dense.
• The patient consumes 1-2 alcoholic drinks per week.
• The patient's mother was diagnosed with breast cancer at age 45 and died at age 50.
• The patient's maternal grandmother was diagnosed with ovarian cancer at age 60 and died at age 61.

Likelihood of Gene Mutation (BRCA1, BRCA2, etc.)

• The goal is to assess what the probability a patient carries a BRCA1, BRCA2, or other gene mutation.

Hereditary Breast Cancer Clues

• 3 or more individuals with cancer (breast, ovarian, pancreas, prostate, melanoma)
• 2 or more primary cancers in the same person, including bilateral breast cancer
• 1 individual with less common cancer, such as:
  • Male breast cancer
  • Triple-negative breast cancer
  • Cancer that occurs under the age of 50.
  • Ovarian, pancreas and metastatic prostate cancers

Family History Factors to Consider

• Penetrance and expressivity should be taken into account.
• Inheritance patterns need to be considered.
• Family size, structure, and number of women in the family is relevant.
• Reliability of the reported family history should be assessed.
• Modifiers, like risk-reducing surgeries, can influence risk.
• Ashkenazi Jewish ancestry can be a factor.
• Look for other hereditary syndrome features, like Cowden syndrome, autosomal recessive phenotypes, and Fanconi anemia.

Tools for Assessing Likelihood of Breast Cancer Susceptibility Gene Mutation

• Guidelines:
• NCCN (National Comprehensive Cancer Network)
• Insurance specific guidelines exist
• Laboratory prevalence data is utilized.
• Software and Online Tools, such as:
• CaGene (BRCAPro)
• PENN II (Couch)
• CanRisk (BOADICEA)
• Tyrer-Cusick (IBIS)
• Manchester
• Family History Assessment Tool (FHAT)
• PTEN risk calculator

Reasons to Calculate Probability of Gene Mutation

• Guidelines may not encompass all family members' situations.
• Situations don't fully meet guidelines but still warrant consideration for genetic testing.
• Important for risk management in patients with a strong family history who decline genetic testing. An affected or unaffected individual who otherwise does not meet the criteria above but has a >5% probability of a BRCA1/2 pathogenic variant based on prior probability models (eg, Tyrer-Cuzick, BRCAPro, CanRisk).
• Helps to offer reassurance in cases of low likelihood of gene mutation.

Laboratory Gene Prevalence Data

• It helps assess the likelihood of a positive genetic test using real-world data, like Myriad data.
• The Myriad data consists of older data with high risk family histories, and BRCA1&2 findings only
• This data is based on internal testing data, thus having biases due to testing criteria, which may or may not apply to specific patients

Penn II Risk Model

• Developed based on families with multiple affected close relatives.
• It may not be accurate for others outside of the target population.
• Includes pancreatic, prostate, and male breast cancer risks.
• Considers only one lineage at a time.
• Assesses only for BRCA1 and BRCA2 risks
• Provides both individual and family estimates.

Breast Cancer Risk Categories

• Familial Breast Cancer:
• Shared environment/lifestyle
• Polygenic risk factors
• Low-moderate risk genes
• Other familial factors
• Multiple occurrences of common cancer

Elevated Breast Cancer Risk Categories

• The chance of an average woman in the US developing breast cancer in her lifetime is 12.9% which is 1 in 8.
• Near population risk has less than 17% lifetime risk from age 20 with less than 3% risk between ages 40 and 50.
• Moderate risk has 17% or greater but less than 30% lifetime risk from age 20 with 3% or greater to 8% risk between ages 40 and 50.
• High risk as 30% or greater lifetime risk from age 20, with greater than 8% risk between ages 40 and 50.

Reasons to Assess Breast Cancer Risk and Risk Assessment Tools

• MRI screening with >20% lifetime breast cancer risk.
• Chemoprevention is indicated if there is a 5-year breast cancer risk of 1.7% or higher, or for women with hyperplasia or lobular carcinoma in situ between 35-39 with a 5 year absolute risk of 3% or higher.
• Reassurance is provided in many women who overestimate their risk

Tools for Risk assessment

• GAIL (Breast Cancer Risk Assessment Tool)
• Tyrer-Cuzick (IBIS)
• CanRisk (BOADICEA)
• BRCAPro (CaGene)
• Others

Gail Model

• This is a tool utilized to assess 5-year breast cancer risk in women aged 35-74 in order to determine if they meet guidelines for chemoprevention.
• Quick and easy to use and has expanded to include categories for non-European women while having its limitations.
• Risk factors include 1st degree relatives with breast cancer, prior breast biopsies, reproductive history (menarche, 1st childbirth), and BRCA1/2 results.
• Paternal history, breast cancer in SDR (second-degree relatives), TDR (third-degree relatives), and the age of diagnosis of breast cancer are not included.
• Should not be used to determine breast MRI eligibility, history of LCIS (lobular carcinoma in situ), or if it doesn't capture relevant family history.

Tyrer-Cuzick (IBIS)

• This is a tool utilized to assess breast cancer risk for MRI screening.
• Fairly quick and easy to use in order to provide 10 year and lifetime risks.
• Risk Factors include 1st, 2nd & 3rd degree relatives with breast & ovarian cancer, male breast cancer, women who have NOT had cancer, prior breast biopsies, breast density, BMI, reproductive history such as menarche, 1st childbirth, menopause, HRT, and BRCA results for patient and family
• Other cancers & cousins with ovarian cancer and other genes besides BRCA1/2 are not included.

CanRisk

• This incorporates the new version of BOADICEA v6 to analyze breast and ovarian cancer for the risk of disease incidence and carrier estimation algorithm.
• Used to calculate both cancer risk and likelihood of gene mutation in cases that need a personal family history that other tools don't capture.
• It benefits from calculating contralateral breast cancer or both breast & ovarian cancer risk (5, 10, lifetime).
• It benefits from calculate the likelihood of carrying mutations in 8 genes and contains patient friendly pictograms for education
• Risk factors include family history of breast, ovarian, pancreas, and prostate cancers, prior breast biopsies, density, BMI, alcohol use, breast tumor pathology, history of reproductive & endometriosis, tubal ligation, oophorectomy, genetic testing results (beyond just BRCA), and the ability to include polygenic/SNP info.
• Some limitations are its more time consuming, and the data it uses stemming from a white cohort.

BRCAPro

• Assesses the likelihood of multiple hereditary symptoms at once, like HBOC, Lynch, and FAMMM.
• Assesses the risk of several cancers at once, like breast, ovarian, uterine, colon, melanoma, and pancreas.
• Provides GAIL and Claus assessments, separates ethnicity by lineage, and can save patient data.
• Utilizes a family Hx of breast & ovarian cancers to calculate risk, and takes into account if the patient has history of breast pathology, mastectomy and oophorectomy, and genetic testing results.
• Important to note the tool needs to be installed and updated frequently.
• Additionally it has a hormonal history used only with the GAIL assessment.
• It tends to underestimate breast cancer risk.
• It uses data from white cohorts.

Summary of Breast Cancer Risk (Case Example)

• Gail - 1.2% (0.6%) 5 yr risk, Lifetime is 20.4% (12.4%)-age 90, Lifetime w/ Neg GT is 20.4%
• Tyrer-Cuzick - N/A 5 yr risk, Lifetime is 4.3% (1.6%), 25.1% (10.8%)-age 85, Lifetime w/ Neg GT is 23.3
• CanRisk - 1.1% (0.7%) 5 yr risk, Lifetime is 2.9% (1.6%), 20.7% (12.1%)-age 80, Lifetime w/ Neg GT is 18.5%
• BRCAPRO - 0.9% 5 yr risk, Lifetime is 13.5%-age 85, Lifetime w/ Neg GT is 11%

Genetic Testing Assessment (Example Case)

• Myriad & Ambry tables/tools:
  • M is 7.2% (BRCA1&2)
  • A is 8.2% (breast/ovarian panel)
  • A: is 11.9% (pan cancer panel)
• PENN II is 7% BRCA1&2 (13% for family)
• BRCAPRO: 3.9% (BRCA1&2)
• CanRisk: 6% (8 genes)
• NCCN: Meets guidelines for genetic testing (breast cancer 45 and SDR ovarian ca)

Risk Tools in Practice

• May be helpful for pre-and post-test genetic counseling
• May not be necessary for all patients, though used most often in those with a negative genetic test (or no test indicated)
• Each patient case does not require the use of every tool.
• Which tool fits patient history best & clinical workflow
• More than one tool can help provide risk range.
• Risk assessment is dynamic, thus needing updates regarding age or risk factor changes
• Some tools are integrated into pedigree software (like canrisk) or EHR.
• Risk discussions can foster dialogue regarding risk perception, patient goals, and psychosocial concerns.

Take Home Pearls

• Breast cancer risk is multifactorial and dynamic over time
• There are multiple tools to assess breast cancer risk and the likelihood of a pathogenic variant, each with strengths and limitations.
• Identifying women at increased breast risk helps target individualized intervention for early detection and risk reduction