What is the etiology, pathogenesis, clinical features, and management of breast cancer in adult women, particularly those over 50 with a family history of breast cancer?

Breast Cancer: Comprehensive Overview

Epidemiology and Incidence

Breast cancer is the most common malignancy in women worldwide, with an estimated age-adjusted annual incidence of 94.2 per 100,000 in Europe and over 192,000 new cases annually in the United States. 1

• The incidence increases with age, showing a steep age gradient: approximately 25% of cases occur before age 50, and less than 5% before age 35 1
• The 10-year probability of developing invasive breast cancer is 0.4% for women aged 30-39,1.5% for ages 40-49,2.8% for ages 50-59, and 3.6% for ages 60-69 1
• Breast cancer is the second leading cause of cancer-related death in women, though mortality rates have decreased in recent years due to improved treatment and earlier detection 1
• The 5-year prevalence in Europe was 1,814,572 cases in 2012, increasing due to both rising incidence and improved survival 1

Etiology and Risk Factors

Non-Modifiable Risk Factors

The most significant non-modifiable risk factors include female gender, increasing age, genetic predisposition (particularly BRCA1/2 mutations), and family history of breast cancer. 1

• Genetic predisposition: BRCA1 and BRCA2 mutations confer substantially increased lifetime risk; women with these mutations should be referred for genetic counseling 1
• Family history: Having a first-degree relative with breast cancer increases risk, especially if both a mother and sister had early-onset disease 1, 2
• Reproductive factors: Early menarche, late menopause, nulliparity, late age at first full-term pregnancy (after age 30), and low parity all increase risk 1, 2
• Race and ethnicity: White women have higher incidence after age 45; Ashkenazi Jewish ancestry carries increased genetic risk 1

Modifiable Risk Factors

• Hormonal exposure: Prolonged exposure to endogenous and exogenous estrogens, including prolonged hormone replacement therapy 1
• Lifestyle factors: Western-style diet, obesity (particularly in postmenopausal women), and alcohol consumption 1, 2
• Radiation exposure: Previous therapeutic chest wall irradiation, particularly at young ages 1
• Benign breast disease: Biopsy-confirmed atypical hyperplasia significantly increases risk 1

Pathogenesis

Breast cancer develops through progressive accumulation of genetic and epigenetic alterations in breast epithelial cells, leading to uncontrolled proliferation and invasion. 3

• Proliferative abnormalities are limited to lobular and ductal epithelium, progressing through hyperplasia → atypical hyperplasia → in situ carcinoma → invasive carcinoma 1
• Approximately 85-90% of invasive carcinomas are ductal in origin 1
• Molecular heterogeneity is substantial, with tumors classified by mRNA gene expression into subtypes: Luminal A, Luminal B, HER2-enriched, and basal-like 3, 4
• Key molecular alterations include activation of HER2, hormone receptor expression (ER/PR), PIK3CA mutations, and BRCA1/2 mutations 3

Clinical Features

Presentation

Most breast cancers present as a palpable breast mass, though screening mammography increasingly detects pre-clinical disease. 1

• Clinical examination should include bimanual palpation of breasts and assessment of locoregional lymph nodes 1
• Symptoms may include breast mass, skin changes, nipple discharge, nipple retraction, or axillary lymphadenopathy 1
• Inflammatory breast cancer presents with skin erythema, edema (peau d'orange), and warmth 1

Diagnostic Workup

Diagnosis requires triple assessment: clinical examination, radiological imaging (bilateral mammography and ultrasound), and pathological confirmation via core needle biopsy. 1

Imaging Modalities

• Mammography: Sensitivity ranges from 77-95% for cancers detected in the first year, but only 56-86% for cancers over two years; sensitivity is lower in women under 50, those with dense breasts, or on hormone replacement therapy 1
• Ultrasound: Essential for evaluating palpable masses and axillary lymph nodes 1
• MRI: Not routine but indicated for diagnostic challenges in dense breasts, young women, BRCA mutation carriers, occult primary with positive axillary nodes, or suspected multifocal disease 1

Pathological Assessment

Core needle biopsy must provide histologic type, grade, and determination of ER, PR, and HER2 status. 1

• Estrogen receptor (ER) and progesterone receptor (PR) status by immunohistochemistry 1
• HER2 status by IHC or FISH/CISH testing 1
• Ki-67 proliferation index 3
• Histologic grade and type 1

Staging

Staging includes clinical TNM assessment, with additional investigations for locally advanced disease or suspected metastases. 1

• Patient assessment: complete medical and family history, physical examination, performance status, complete blood count, liver and renal function, alkaline phosphatase, calcium 1
• Menopausal status determination (measure serum estradiol and FSH if uncertain) 1
• For locally advanced disease or neoadjuvant therapy candidates: chest X-ray, abdominal ultrasound, and bone scintigraphy to exclude metastatic disease 1

Management

Screening and Early Detection

Biennial mammography screening for women aged 50-69 years provides the greatest mortality reduction benefit (approximately 20% relative reduction). 1

• Screening every 12-33 months has demonstrated effectiveness; for women ≥50 years, little evidence supports annual over biennial mammography 1
• For women aged 40-49, evidence for screening benefit is limited and controversial 1
• Women with genetic predisposition (BRCA mutations) should receive annual MRI plus mammography starting at age 25 1, 5
• Clinical breast examination every 6-12 months for high-risk women; sensitivity ranges 40-69%, specificity 86-99% 1

High-Risk Women Management

Women at high risk (≥1.67% 5-year risk by Gail Model or >20% lifetime risk) require enhanced surveillance and should consider risk-reduction strategies. 1, 6

• Clinical breast examinations every 6-12 months and annual mammography 1
• Annual breast MRI for women with >20% lifetime risk based on family history models 1
• Tamoxifen 20 mg daily for 5 years reduces breast cancer incidence by 44% in high-risk women (86 cases on tamoxifen vs. 156 on placebo; RR=0.56,95% CI: 0.43-0.72) 6
• Genetic counseling and testing for women meeting NCCN criteria: early-onset breast cancer (≤50 years), two breast primaries, breast and ovarian cancer, male breast cancer, known family BRCA mutation, or Ashkenazi Jewish ancestry 1, 5

Surgical Management

For early-stage breast cancer, surgical options include breast-conserving surgery (lumpectomy) with radiation or total mastectomy. 1

Axillary Management

• Sentinel lymph node biopsy is standard for clinically node-negative disease 1
• In women ≥65 years with no palpable axillary nodes, particularly favorable tumors, and when adjuvant therapy selection is unaffected, axillary lymph node dissection or sentinel node biopsy may be omitted 1
• Women not undergoing axillary assessment have increased risk of ipsilateral lymph node recurrence, especially without standard adjuvant systemic therapy 1

Radiation Therapy

Radiation therapy following breast-conserving surgery is standard for most patients to reduce local recurrence. 1

• In women ≥70 years with stage I, ER-positive breast cancer, negative margins, and planned 5 years of endocrine therapy, radiation may be omitted (local recurrence 4% vs. 1% at 5 years, 10% vs. 2% at 10 years, but no difference in overall survival or distant metastases) 1
• Advanced radiation techniques with normal tissue sparing are important for all patients, particularly older adults 1

Systemic Therapy

Endocrine Therapy

For ER-positive early breast cancer, endocrine therapy for 5-10 years is essential. 1, 3

• Tamoxifen 20 mg daily is indicated for adjuvant treatment of node-positive and node-negative breast cancer 6
• Patients whose tumors are ER-positive are more likely to benefit from tamoxifen 6
• Primary endocrine therapy without surgery should be reserved only for patients who are not surgical candidates with predicted life expectancy <5 years 1

Neoadjuvant/Preoperative Therapy

Neoadjuvant therapy has become standard for most early-stage HER2-positive and triple-negative breast cancer, followed by risk-adapted post-surgical strategies. 3

• Allows for tumor downstaging and assessment of treatment response 3
• Additional staging investigations (chest X-ray, abdominal ultrasound, bone scan) should be performed before neoadjuvant therapy 1

Advanced Disease

For metastatic breast cancer, systemic therapy is palliative and includes endocrine therapy with targeted agents for hormone receptor-positive disease, anti-HER2 therapy for HER2-positive disease, PARP inhibitors for BRCA mutation carriers, and immunotherapy for select triple-negative disease. 3

• CDK4/6 inhibitors combined with endocrine therapy for hormone receptor-positive disease 3
• PI3K inhibitors for PIK3CA-mutated tumors 3
• Poly(ADP-ribose) polymerase (PARP) inhibitors for BRCA1/2 mutation carriers 3

Special Considerations for Older Adults (≥65 years)

Older women often receive less aggressive treatment despite similar benefit from standard therapies when adequate supportive care is provided; biologic age should guide treatment decisions, not chronologic age alone. 1

• Older adults with breast cancer enrolled in cooperative trials derive similar disease-free survival and overall survival benefits from adjuvant chemotherapy as younger patients 1
• Women >75 years receive less aggressive treatment and have higher mortality from early-stage breast cancer than younger women 1
• Treatment decisions should consider comorbidities and life expectancy; women with conditions limiting life expectancy are unlikely to benefit from screening or aggressive treatment 1

Ductal Carcinoma In Situ (DCIS)

Following breast surgery and radiation for DCIS, tamoxifen 20 mg daily reduces the risk of invasive breast cancer. 6

• Tamoxifen decreased incidence of small ER-positive tumors but did not alter incidence of ER-negative or larger tumors 6

Common Pitfalls and Caveats

• Do not assume all breast cancers are ER-positive: Approximately 15-20% are triple-negative, requiring different treatment approaches 1, 3
• Family history assessment must include both maternal and paternal sides: This is commonly overlooked in risk assessment 5
• Screening mammography carries risks: False-positive rate of 3-6% on initial screening; positive predictive value increases with age (2-4% ages 40-49,7-19% ages ≥60) 1
• Tamoxifen for risk reduction has significant adverse effects: Increased risk of endometrial cancer (RR=2.48), pulmonary embolism (RR=3.01), deep vein thrombosis (RR=1.59), stroke (RR=1.42), and cataracts (RR=1.51 for surgery) 6
• Young women (<40 years) have distinct tumor biology: More aggressive features, higher Ki-67, more hormone receptor-negative tumors, and worse prognosis despite similar stage 7
• Insufficient data exist for tamoxifen effectiveness in BRCA mutation carriers for risk reduction 6