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BRCA genes

BRCA1 Mutations and Breast Cancer

Prevalence and Inheritance:

  • Up to 5% of breast cancers are caused by germline mutations in BRCA1 and BRCA2.
  • These mutations are inherited in an autosomal dominant fashion with varying degrees of penetrance.

BRCA1 Gene Details:

  • Located on chromosome arm 17q.
  • Spans approximately 100 kilobases (kb) of DNA.
  • Contains 22 coding exons for 1863 amino acids.
  • Function: BRCA1, along with BRCA2, functions as a tumor-suppressor gene, requiring the loss of both alleles for cancer initiation.
  • Role: Involved in transcription, cell-cycle control, and DNA damage repair pathways.

Mutations and Cancer Risk:

  • Over 500 sequence variations in BRCA1 have been identified.
  • Germline mutations in BRCA1 contribute to 45% of hereditary breast cancers and at least 80% of hereditary ovarian cancers.
  • Lifetime Risk:
    • Up to 85% for developing breast cancer.
    • Up to 40% for developing ovarian cancer.
    • The average lifetime risk is reported to be between 60% and 70%.
  • Inheritance: Approximately 50% of children of carriers inherit the trait.

Clinical Features of BRCA1-Associated Breast Cancers:

  • Typically invasive ductal carcinomas, poorly differentiated.
  • Hormone Receptor Status: Majority are hormone receptor-negative.
  • Triple-Negative Phenotype: Commonly exhibit ER-negative, PR-negative, and HER2-negative or basal phenotype.
  • Distinguishing Features:
    • Early age of onset compared to sporadic cases.
    • Higher prevalence of bilateral breast cancer.
    • Association with ovarian cancer and possibly colon and prostate cancers.

Founder Mutations:

  • Two most common BRCA1 mutations: 185delAG and 5382insC.
    • Account for 10% of all BRCA1 mutations.
    • Occur at a 10-fold higher frequency in the Ashkenazi Jewish population than in non-Jewish Caucasians.
  • Carrier Frequency:
    • 185delAG mutation has a 1% carrier frequency in the Ashkenazi Jewish population.
    • Along with 5382insC, these mutations account for almost all BRCA1 mutations in this population.
  • Early-Onset Breast Cancer:
    • 20% of Jewish women who develop breast cancer before age 40 carry the 185delAG mutation.
  • Founder Mutations in Other Populations:
    • Identified in Dutch, Polish, Finnish, and Russian populations, among others.

BRCA2 Mutations and Breast Cancer

Gene Location and Structure:

  • Location: BRCA2 is located on chromosome arm 13q.
  • Genomic Region: Spans approximately 70 kb of DNA.
  • Coding Region: Contains 26 coding exons within an 11.2-kb region.
  • Protein: Encodes a protein of 3418 amino acids.

Function:

  • No Homology: The BRCA2 gene bears no homology to any previously described gene, and the protein contains no previously defined functional domains.
  • Postulated Role: Involved in DNA damage response pathways, similar to BRCA1.
  • Expression: BRCA2 mRNA is highly expressed in the late G1 and S phases of the cell cycle, with protein regulation kinetics similar to BRCA1, suggesting coregulation.

Mutational Spectrum:

  • >250 mutations have been identified in BRCA2, although its spectrum is not as well established as BRCA1.

Cancer Risk:

  • Breast Cancer:
    • The risk for BRCA2 mutation carriers is close to 85%.
    • BRCA2-associated breast cancers are typically invasive ductal carcinomas, more likely to be well differentiated and to express hormone receptors compared to BRCA1-associated breast cancers.
  • Ovarian Cancer:
    • Lifetime risk is estimated to be close to 20%, lower than BRCA1.
  • Male Breast Cancer:
    • Men with BRCA2 mutations have a 6% risk of developing breast cancer, representing a 100-fold increase over the general male population.

Inheritance and Penetrance:

  • Autosomal Dominant Trait: BRCA2-related breast cancer susceptibility has high penetrance.
  • Inheritance: Approximately 50% of children of carriers inherit the trait.

Distinguishing Clinical Features:

  • Early Age of Onset: Compared with sporadic cases.
  • Higher Prevalence of Bilateral Breast Cancer.
  • Associated Cancers:
    • Ovarian, colon, prostate, pancreatic, gallbladder, bile duct, stomach cancers, and melanoma.

Founder Mutations:

  • 6174delT:
    • Found in Ashkenazi Jews with a prevalence of 1.2%.
    • Accounts for 60% of ovarian cancer and 30% of early-onset breast cancer among Ashkenazi women.
  • 999del5:
    • Observed in Icelandic and Finnish populations.
  • 3036delACAA:
    • Found in several Spanish families.

Identification of BRCA Mutation Carriers

Four-Step Process:

  1. Obtaining a Complete, Multigenerational Family History:
    • A thorough and accurate family history is essential, assessing both maternal and paternal sides, as 50% of women with a BRCA mutation may inherit it from their fathers.
  2. Assessing the Appropriateness of Genetic Testing:
    • Determine if the individual is an appropriate candidate for genetic testing.
    • Evaluate whether genetic testing will be informative for personal and clinical decision-making.
  3. Counseling the Patient:
    • Genetic testing should be offered in conjunction with patient education and counseling, including referral to a genetic counselor.
  4. Interpreting the Results of Testing:
    • Proper interpretation of the results is crucial for guiding clinical decisions.

Considerations for Genetic Testing:

  • Referral to Genetic Counseling:
    • Use statistically based models like the Manchester scoring system and BODICEA to determine the probability of carrying a BRCA mutation and to guide referral to a specialist genetic clinic.
  • Hereditary Risk Indicators:
    • Ashkenazi Jewish heritage.
    • First-degree relative with breast cancer before age 50.
    • History of ovarian cancer at any age in the patient or first- or second-degree relative.
    • Breast and ovarian cancer in the same individual.
    • Two or more first- or second-degree relatives with breast cancer at any age.
    • Patient or relative with bilateral breast cancer.
    • Male breast cancer in a relative at any age.

Lower Threshold for Testing:

  • Genetic testing is more readily considered for individuals who are members of ethnic groups with increased mutation prevalence.

Cancer Prevention for BRCA Mutation Carriers

Risk Management Strategies:

  1. Risk-Reducing Mastectomy and Reconstruction:
    • Reduces the likelihood of developing breast cancer but does not eliminate all breast tissue, so some risk remains.
  2. Risk-Reducing Salpingo-Oophorectomy:
    • Reduces the risk of ovarian cancer and breast cancer when performed in premenopausal BRCA mutation carriers.
  3. Intensive Surveillance for Breast and Ovarian Cancer:
    • Breast Cancer Surveillance:
      • Clinical breast examination every 6 months.
      • Mammography every 12 months starting at age 25 years.
      • Annual MRI screening is recommended for women with a 20% to 25% or greater lifetime risk, known BRCA mutations, or specific syndromes (e.g., Li-Fraumeni, Cowden).
      • MRI is more sensitive for detecting breast cancer in younger women with dense breasts, but it may lead to more false-positive events and subsequent interventions.
    • Ovarian Cancer Surveillance:
      • Yearly transvaginal ultrasound, timed to avoid ovulation.
      • Annual measurement of serum cancer antigen 125 levels starting at age 25 years.
  4. Chemoprevention:
    • Tamoxifen:
      • Effective in reducing the incidence of estrogen receptor-positive tumors in high-risk women, particularly BRCA2 mutation carriers.
      • Limited efficacy in BRCA1 mutation carriers, as most BRCA1-associated breast cancers are hormone receptor-negative.

Hormone Replacement Therapy:

  • Postmenopausal BRCA Mutation Carriers:
    • It may be advisable to avoid hormone replacement therapy due to the lack of data on its effect on the penetrance of BRCA mutations.

Ovarian Cancer Risk and Prevention:

  • Risk: Ranges from 20% to 40% in BRCA1 and BRCA2 mutation carriers, which is 10 times higher than in the general population.
  • Salpingo-Oophorectomy:
    • Consider bilateral risk-reducing salpingo-oophorectomy between ages 35 and 40 years after childbearing is complete.
    • Discuss hormone replacement therapy with the patient at the time of oophorectomy.

Screening Recommendations:

  • American Cancer Society Recommendations:
    • Annual MRI for women with a 20% to 25% or greater lifetime risk.
    • Includes women with known BRCA1 or BRCA2 mutations, those with a first-degree relative with these mutations, and women with specific syndromes or a family history of these syndromes.

Efficacy of Tamoxifen:

  • NSABP P1 Trial Findings:
    • 49% reduction in overall breast cancer incidence in high-risk women.
    • 69% reduction in estrogen receptor-positive tumors.
    • 62% reduction in breast cancer incidence in BRCA2 carriers.
    • No reduction in breast cancer incidence in BRCA1 carriers aged 35 years or older.

PALB2 and Other High-Risk Genes for Breast Cancer

PALB2:

  • Role: PALB2 (partner and localizer of BRCA2) allows nuclear localization of BRCA2 and provides a scaffold for the BRCA1–PALB2–BRCA2 complex.
  • Breast Cancer Risk:
    • Analysis suggests that the risk for PALB2 mutation carriers is as high as that for BRCA2 mutation carriers.
    • Absolute Risk by Age 70:
      • 33% (95% CI, 25–44) for those with no family history of breast cancer.
      • 58% (95% CI, 50–66) for those with two or more first-degree relatives with breast cancer by age 50.
    • The risk for female PALB2 mutation carriers is five to nine times higher compared to the general population.
  • Screening and Management:
    • Suggested screening includes mammogram and MRI starting at age 30.
    • Consideration of risk-reducing mastectomy.
    • Ovarian Cancer Risk: Insufficient evidence regarding risk and management.

Other Hereditary Syndromes Associated with Breast Cancer:

  • Cowden Disease (PTEN mutations):
    • Associated with cancers of the thyroid, GI tract, and benign skin and subcutaneous nodules.
  • Li-Fraumeni Syndrome (TP53 mutations):
    • Associated with sarcomas, lymphomas, and adrenocortical tumors.
  • Hereditary Diffuse Gastric Cancer Syndrome (CDH1 mutations):
    • Associated with diffuse gastric cancer and lobular breast cancers.
  • Syndromes of Breast and Melanoma:
    • Increased risk of both breast cancer and melanoma.

Panel Testing:

  • With the discovery of additional genes related to breast cancer susceptibility, panel testing is now available for a number of genes in addition to BRCA1 and BRCA2.
  • Interpretation of Results:
    • Complex and best conducted with the assistance of a genetic counselor.

Breast Cancer Risk Assessment Models

Lifetime Risk of Breast Cancer

  • Average lifetime risk for U.S. women: 12%
  • Age-specific lifetime risks:
    • Age 50: 11%
    • Age 70: 7%

Key Risk Factors

  • Risk factors interact, making evaluation of combinations challenging.
  • Major risk factors include:
    • Age
    • Age at menarche
    • Age at first live birth
    • Number of breast biopsy specimens
    • History of atypical hyperplasia
    • Number of first-degree relatives with breast cancer

Most Widely Used Models

1. Gail Model

  • Developed from: Breast Cancer Detection Demonstration Project (mammography screening, 1970s).
  • Predicts: Cumulative breast cancer risk across decades of life.
  • Input factors:
    • Age
    • Age at menarche
    • Age at first live birth
    • Number of breast biopsies
    • History of atypical hyperplasia
    • Number of first-degree relatives with breast cancer
  • Output: 5-year and lifetime risk.
  • Modifications:
    • Adjusted for African American and Asian/Pacific Islander women.
    • Revised model includes body weight and mammographic density, but excludes age at menarche.

2. Claus Model

  • Developed from: Cancer and Steroid Hormone Study (case-control study).
  • Focuses on: Family history of breast cancer, prevalence of high-penetrance breast cancer genes.
  • Incorporates:
    • First- and second-degree relatives' breast cancer history
    • Relatives' age at diagnosis
  • Excludes: Other risk factors like diet, contraceptives, or radiation exposure.

Other Risk Assessment Models

1. BRCAPRO Model

  • Mendelian model focused on BRCA1 and BRCA2 gene mutations.
  • Input: Detailed family history of breast and ovarian cancer.
  • Output:
    • Probability of carrying a mutation.
    • Risk of developing breast or ovarian cancer based on age-specific incidence curves.

2. Tyrer-Cuzick Model

  • Combines: Family history with personal risk factors.
  • Input factors:
    • Age at menarche
    • Parity
    • Age at first live birth
    • Age at menopause
    • History of atypical hyperplasia or LCIS
    • Height and body mass index (BMI)
  • Output: Adjusted risk based on mutation probability and personal factors.

Key Points

  • Risk models do not account for mutations in BRCA1 or BRCA2 except the BRCAPRO and Tyrer-Cuzick models.
  • Use of these models helps assess individual risk and guide management options for breast cancer prevention.

Risk Management in Breast Cancer Prevention

Key Medical Decisions Affected by Breast Cancer Risk

  • Postmenopausal hormone replacement therapy (HRT): When and whether to use HRT.
  • Mammography and MRI screening: Deciding the appropriate age to begin.
  • Tamoxifen use: When to initiate for breast cancer prevention.
  • Prophylactic mastectomy: Considering surgery to prevent breast cancer.

Postmenopausal Hormone Replacement Therapy (HRT)

  • Widely prescribed in the 1980s and 1990s for managing estrogen deficiency symptoms:
    • Vasomotor symptoms: Hot flashes, night sweats, sleep deprivation.
    • Osteoporosis and cognitive changes.
  • Previously believed to reduce coronary artery disease risk.

HRT Regimens

  • Combined estrogen + progesterone: Standard for women with an intact uterus (prevents uterine cancer from unopposed estrogen).
  • Estrogen alone: Used for women post-hysterectomy.

Key Findings from Studies on HRT

1. Women's Health Initiative (WHI) Study (2002)

  • Findings:
    • Breast cancer risk increased 3 to 4 times after >4 years of use.
    • No significant reduction in coronary artery or cerebrovascular risks.

2. Collaborative Group on Hormonal Factors in Breast Cancer

  • Combined data from studies on 52,705 women with breast cancer and 108,411 women without breast cancer.
  • Increased breast cancer risk with every use of estrogen replacement therapy.
  • Current users faced higher risk than past users.
  • Risk increased with the duration of hormone use.

3. WHI Study by Cheblowski et al

  • Estrogen + progesterone further increased the incidence of breast cancer.

4. Million Women Study

  • Confirmed findings of WHI, showing substantially higher risk for combined estrogen + progesterone replacement therapy compared to other types of HRT.

Summary

  • Breast cancer risk increases with duration and current use of HRT, particularly with combined estrogen + progesterone.
  • Decisions regarding HRT, screening, and preventive measures like tamoxifen or prophylactic mastectomy must account for individual breast cancer risk based on factors such as duration of HRT and personal/family history.

Breast Cancer Screening

Effectiveness of Mammography

  • Routine mammography in women aged ≥50 years reduces breast cancer mortality by 25%.
  • Screening comes at an acceptable economic cost.

Controversy Over Screening Recommendations

Organizations with Differing Guidelines:

  • U.S. Preventive Services Task Force (USPSTF)
  • American Cancer Society (ACS)
  • National Comprehensive Cancer Network (NCCN)

High-Risk Women Defined as Those With:

  • Personal history of breast cancer.
  • History of chest radiation at a young age.
  • Confirmed or suspected genetic mutations that increase breast cancer risk.

Screening Guidelines

USPSTF:

  • Biennial mammography for women aged 50 to 74 years.
  • Applies to asymptomatic women aged ≥40 years who do not have:
    • Preexisting breast cancer.
    • History of high-risk breast lesions or genetic mutations.

ACS (2015 Guidelines):

  • Average-risk women:
    • Begin annual screening at age 45.
    • Women aged 45 to 54: Annual screening.
    • Women aged 55 and older: Biennial screening or continue annual screening.
    • Women aged 40 to 44: Have the option to begin annual screening.
    • Continue screening as long as health is good and life expectancy is ≥10 years.
  • No clinical breast exams recommended for screening.

NCCN:

  • Annual mammography starting at ≥40 years.
  • Annual clinical breast exams and breast awareness.

Screening in the UK

  • Independent expert panel reviewed the benefits and harms of screening.
  • 20% reduction in breast cancer mortality for women >50 years of age.
  • 11% overdiagnosis in screened women, but benefits outweigh harms.

Challenges in Screening Women Aged <50 Years

  1. Greater breast density: Mammography has reduced sensitivity.
  2. More false positives: Results in unnecessary biopsies.
  3. Lower incidence of breast cancer: Fewer young women benefit.

Higher Risk in Younger Women

  • Family history: Women aged 40 to 49 with a family history of breast cancer are three times more likely to have an abnormal mammography finding that is cancer.

Mammographic Breast Density

  • Breast density is an independent risk factor for breast cancer.
  • Incorporating breast density into risk models improves accuracy but faces challenges in consistent reporting.

Ultrasonography in Dense Breasts

  • Ultrasound can detect additional cancers in women with dense breasts, but no evidence shows it reduces mortality.

MRI for Breast Cancer Screening

  • ACS recommends MRI for women with a 20% to 25% lifetime risk, based on:

    • Family history or BRCA mutation.
    • Radiation to the chest between ages 10 to 30.
    • History of Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome.
    • First-degree relatives with one of these syndromes.

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Benefits and Limitations of MRI:

  • MRI is highly sensitive and not affected by breast tissue density.
  • Moderate specificity leads to more false positives and increased need for biopsies.

Summary

  • Biennial mammography is recommended for women aged 50-74 years.
  • MRI screening is for those at high genetic risk or with a significant family history.

Chemoprevention in Breast Cancer

Tamoxifen: The First Chemopreventive Drug

  • Tamoxifen, a selective estrogen receptor modulator (SERM), was the first drug shown to reduce breast cancer incidence in healthy women.
  • Four prospective studies evaluated tamoxifen vs. placebo in reducing invasive breast cancer for high-risk women.

Key Study: Breast Cancer Prevention Trial (NSABP P-01)

  • Participants: >13,000 women with a 5-year Gail risk ≥1.66% or LCIS.
  • Results:
    • 49% reduction in breast cancer incidence after 4 years in the tamoxifen group.
    • Effect limited to ER-positive breast cancers; no effect on ER-negative tumors.

Other Tamoxifen Trials:

  • Royal Marsden Hospital, Italian Tamoxifen Prevention Trial, and IBIS-I all confirmed a reduction in ER-positive breast cancers.
  • Adverse effects:
    • Increased risk of endometrial cancer, thromboembolic events (DVT, PE), cataracts, and vasomotor disturbances.

Tamoxifen Recommendations

  • Candidates:
    • Women with a Gail risk ≥1.66%, age 35-59, over 60, or diagnosed with LCIS or atypical hyperplasia.
  • Increased Risks:
    • DVT: 1.6x higher.
    • Pulmonary emboli: 3x higher.
    • Endometrial cancer: 2.5x higher.
    • Cataract surgery: 2x more frequent.

Gail Model for Risk-Benefit Ratio:

  • Used to assess the net risk-benefit of tamoxifen for individual patients based on their breast cancer risk and comorbidities.

Raloxifene vs. Tamoxifen: STAR Trial (P-2)

  • Study Design: 19,747 postmenopausal women randomized to tamoxifen or raloxifene.
  • Results:
    • Both drugs were similarly effective in reducing breast cancer risk.
    • Raloxifene had a more favorable side effect profile.
    • At follow-up, raloxifene retained 76% of tamoxifen's efficacy with fewer risks, particularly a lower risk of endometrial cancer.
    • Raloxifene did not reduce LCIS and DCIS as tamoxifen did.

Aromatase Inhibitors (AIs)

  • More effective than tamoxifen in reducing contralateral breast cancers in postmenopausal women receiving AIs for adjuvant treatment.

Key Studies:

  • MAP.3 Trial:
    • Participants: 4560 postmenopausal women.
    • Intervention: Exemestane 25 mg daily vs. placebo for 5 years.
    • Results:
      • 65% reduction in invasive breast cancer.
      • Increased arthritis and hot flashes in the exemestane group.
  • IBIS II Trial:
    • Participants: 3864 postmenopausal women.
    • Intervention: Anastrozole (nonsteroidal AI) vs. placebo.
    • Results:
      • 50% reduction in invasive breast cancer after 5 years.
      • No adverse cognitive effects reported.

Recommendations for Chemoprevention

  • Tamoxifen: Recommended for premenopausal and postmenopausal women at high risk.
  • Raloxifene or Exemestane: Considered for postmenopausal women at increased risk.
  • Discussion with Patients:
    • Risk assessment and discussion of the potential risks and benefits of each chemopreventive agent are essential.

Summary

  • Tamoxifen effectively reduces ER-positive breast cancer risk but increases risks for certain adverse events (endometrial cancer, thromboembolism).
  • Raloxifene offers similar protection with fewer side effects in postmenopausal women.
  • Aromatase inhibitors (exemestane, anastrozole) are highly effective in postmenopausal women but have different side effects, particularly affecting joints and causing hot flashes.

Risk-Reducing Surgery in High-Risk Breast Cancer Patients

Prophylactic Mastectomy

  • Effectiveness:
    • Reduces breast cancer risk by >90% in women at high risk.
    • Impact on long-term quality of life is not well-quantified.

BRCA Mutation Carriers

  • Study findings:
    • Prophylactic mastectomy adds:
      • Almost 3 years of life for women with a 40% lifetime risk.
      • >5 years of life for women with an 85% lifetime risk.
  • Domchek et al. Study:
    • Risk-reducing mastectomy effectively prevents breast cancer in BRCA1 and BRCA2 mutation carriers.
    • Risk-reducing salpingo-oophorectomy:
      • Reduces the incidence of ovarian and breast cancer in BRCA mutation carriers.
      • Lowers breast cancer-specific mortality, ovarian cancer-specific mortality, and all-cause mortality.

Outcomes and Considerations

  • Bilateral prophylactic mastectomy:
    • Shows dramatic reductions in breast cancer incidence even in women without BRCA mutations.
    • Survival benefit is not well-supported by data.

Patient Satisfaction

  • Most patients are satisfied with their decision for risk-reducing surgery.
  • Dissatisfaction primarily stems from cosmetic outcomes, especially due to reconstructive issues.

Summary

  • Prophylactic mastectomy is highly effective in reducing breast cancer risk, especially in BRCA mutation carriers.
  • Risk-reducing salpingo-oophorectomy offers additional benefits in lowering cancer incidence and improving survival.
  • Cosmetic outcomes and patient satisfaction should be considered in decision-making.