What is all the essential information in breast cancer?

Essential Information in Breast Cancer

Epidemiology and Incidence

Breast cancer is the most common malignancy in women worldwide, with an estimated age-adjusted annual incidence of 88.4/100,000 in Europe and remains the leading cause of cancer-related deaths in European women despite declining mortality rates. 1

• Approximately 12% of women in the United States will be diagnosed with breast cancer over their lifetime, with more than 250,000 new cases diagnosed annually 2
• The incidence is increasing due to mammographic screening, aging population, postmenopausal hormone replacement therapy, Western-style diet, obesity, and consumption of alcohol and tobacco 1
• About 25% of breast cancers occur before age 50, with less than 5% occurring before age 35 1
• Ten-year survival exceeds 70% in most European regions, with 89% survival for local disease and 62% for regional disease 1

Screening and Early Detection

Mammography screening in the 50-70 year age group reduces breast cancer mortality and should be the primary screening modality. 1

• For women with familial breast cancer (with or without proven BRCA mutations), annual screening with MRI combined with mammography is recommended 1
• Women with BRCA mutations should be offered annual MRI screening in addition to mammography 3
• Imaging includes bilateral mammography and ultrasound of the breast and regional lymph nodes 1
• MRI is not routinely recommended but should be considered for: familial breast cancer with BRCA mutations, breast implants, lobular cancers, suspicion of multifocality/multicentricity, large discrepancies between conventional imaging and clinical examination, and before/during neoadjuvant chemotherapy 1

Diagnosis and Pathological Assessment

Diagnosis must be based on core needle biopsy obtained by ultrasound or stereotactic guidance, with pathological confirmation mandatory before treatment. 1

• Diagnosis and treatment should be carried out in specialized "breast units" with multidisciplinary teams including surgeon, radiation oncologist, medical oncologist, radiologist, pathologist, and breast nurse—all specialized in breast cancer 1
• Complete personal and family medical history is essential, including evaluation of menopausal status, physical examination, full blood count, liver and renal function tests, alkaline phosphatase and calcium levels 1
• A marker (surgical clip, carbon) should be placed into the tumor at biopsy to ensure surgical resection of the correct site 1

Required Pathological Elements

The pathological report must include histological type, grade, ER status, and for invasive cancer: PgR status, HER2 status, and a proliferation measure such as Ki67. 1, 3

• Estrogen/progesterone receptor tests are essential biomarkers that must be evaluated 3
• HER2/neu testing is required for invasive breast cancers, determined via immunohistochemistry (IHC) or in situ hybridization techniques 3
• Tumors should be grouped into surrogate intrinsic subtypes defined by routine histology and IHC data for prognostication and treatment decision making 1
• If ER/PgR and HER2 are negative in the biopsy specimen, retesting in the surgical specimen is advisable to account for tumor heterogeneity 1

Molecular Subtypes and Pathophysiology

Breast cancer is classified into three major subtypes based on molecular markers: hormone receptor positive/HER2 negative (70%), HER2 positive (15-20%), and triple-negative (15%). 2

• Approximately 85-90% of invasive breast carcinomas are ductal in origin, while the remainder arise from lobular tissue 4
• The disease develops through stepwise progression from hyperplasia to atypical hyperplasia, in situ carcinoma, and ultimately invasive carcinoma 4
• Molecular subtypes based on mRNA gene expression include Luminal A, Luminal B, HER2-enriched, and basal-like 5

Genetic Risk Factors

BRCA1 and BRCA2 genetic analysis is recommended for risk assessment in individuals with strong family history of breast/ovarian cancer. 3

• TP53 mutations (Li-Fraumeni Syndrome) confer up to 25% risk of breast cancer by age 74 4
• PTEN mutations (Cowden Syndrome) can confer up to 85% lifetime risk 4
• CDH1 mutations increase lobular breast cancer risk by approximately 39% 4
• Moderate-penetrance genes including CHEK2, ATM, PALB2, and BRIP1 contribute to risk through DNA repair mechanism disruption 4

Staging and Risk Assessment

Lymph nodes should be assessed by clinical examination and ultrasound, supplemented by ultrasound-guided fine needle aspiration or core biopsy of suspicious lymph nodes. 1

• Routine staging evaluations are directed at locoregional disease, as asymptomatic distant metastases are very rare in early breast cancer and patients do not benefit from comprehensive laboratory and radiological staging 1
• Postoperative pathological assessment should include: number, location and maximum diameter of tumor(s), histological type and grade, vascular and lymphovascular invasion, biomarker analysis, evaluation of resection margins, total number of removed and positive lymph nodes, and extent of metastases in lymph nodes 1

Recurrence Patterns and Follow-up

The annual hazard of recurrence peaks in the second year after diagnosis but remains at 2-5% in years 5-20, with relapse potentially occurring more than 20 years after initial diagnosis, particularly in ER/PgR-positive disease. 1

• Patients with node-positive disease have higher annual hazards of recurrence than node-negative cancers 1
• In the first few years, ER-negative cancers have higher recurrence risk, but 5-8 years after diagnosis, their annual hazard drops below ER-positive tumors 1

Follow-up Schedule

Regular visits every 3-4 months in the first 2 years, every 6 months from years 3-5, and annually thereafter are recommended. 1

• Every visit should include thorough history, eliciting of symptoms, and physical examination 1
• Annual ipsilateral (after breast-conserving therapy) and/or contralateral mammography with ultrasound is recommended 1
• MRI may be indicated for young patients, especially with dense breast tissue and genetic or familial predispositions 1

Treatment by Subtype

Hormone Receptor-Positive/HER2-Negative (70% of cases)

Patients with hormone receptor-positive tumors receive endocrine therapy for 5-10 years, with a minority also receiving chemotherapy. 2

• Endocrine therapy is essential for ER-positive early breast cancer 1
• For advanced disease, endocrine therapy with targeted agents such as CDK4/6 inhibitors and PI3K inhibitors is used 6
• Median overall survival for metastatic disease is approximately 5 years 2

HER2-Positive (15-20% of cases)

Patients with HER2-positive tumors receive HER2-targeted antibody or small-molecule inhibitor therapy combined with chemotherapy. 2

• Preoperative or neoadjuvant therapy, including targeted drugs, has become standard of care for most early-stage HER2-positive breast cancer 6
• Anti-HER2 targeted therapy is used for HER2-positive metastatic disease 6
• Stage I HER2-positive tumors have 94-99% 5-year breast cancer-specific survival 2

Trastuzumab (HER2-Targeted Therapy)

Trastuzumab can result in serious cardiomyopathy, with left ventricular ejection fraction decline requiring cardiac monitoring before and during treatment. 7

• Most common adverse reactions include fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia 7
• Serious pulmonary toxicity can occur, including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, and pulmonary fibrosis 7
• Exacerbation of chemotherapy-induced neutropenia is more common when combined with myelosuppressive chemotherapy 7
• Extending adjuvant treatment beyond one year is not recommended due to increased asymptomatic cardiac dysfunction (8.1% vs 4.6%) and higher rates of Grade 3+ adverse reactions 7

Triple-Negative (15% of cases)

Patients with triple-negative tumors receive chemotherapy alone, with emerging immunotherapy options for part of triple-negative disease. 2, 6

• Triple-negative breast cancer is more likely to recur than other subtypes, with 85% 5-year breast cancer-specific survival for stage I tumors 2
• Median overall survival for metastatic triple-negative breast cancer is approximately 1 year 2
• Preoperative therapy has become standard for most early-stage triple-negative breast cancer, followed by risk-adapted post-surgical strategies 6

Capecitabine (Chemotherapy)

Capecitabine is used for metastatic breast cancer that has spread to other parts of the body, either with docetaxel or after failure of paclitaxel and anthracycline-containing medicines. 8

• Capecitabine increases the effect of blood thinners such as warfarin; more frequent monitoring of blood clotting is required with dose adjustment of the blood thinner as needed 8
• Most common side effects include diarrhea, nausea, vomiting, mouth/throat sores (stomatitis), stomach pain, upset stomach, constipation, loss of appetite, and dehydration (more common in patients age 80 and older) 8
• Contraindicated in patients who are nursing, allergic to 5-fluorouracil or capecitabine, or lack the enzyme DPD (dihydropyrimidine dehydrogenase) 8
• Usually taken for 14 days followed by a 7-day rest period for a 21-day cycle, within 30 minutes after meals (breakfast and dinner) 8

Local Therapy

Breast conservation (wide local excision and radiotherapy) is the local treatment of choice in the majority of cases, provided clear resection margins can be achieved. 1

• Local therapy for all patients with nonmetastatic breast cancer consists of surgical resection, with consideration of postoperative radiation if lumpectomy is performed 2
• Whole breast radiotherapy after breast-conserving surgery for DCIS decreases the risk of local recurrence with survival equal to that after mastectomy 1
• Risk-reducing surgery with prophylactic bilateral mastectomy and reconstruction may be offered to women with very high risk, such as those with previous chest wall irradiation for lymphoma or carrying BRCA1 or BRCA2 gene mutations 1

Advanced/Metastatic Disease

Metastatic breast cancer with distant metastases is currently considered incurable, with treatment goals focused on prolonging life and palliating symptoms. 6

• Systemic therapies are determined by subtype: endocrine therapy with targeted agents for hormone receptor-positive disease, anti-HER2 therapy for HER2-positive disease, PARP inhibitors for BRCA1/2 mutation carriers, and immunotherapy for part of triple-negative disease 6
• Median overall survival varies significantly by subtype: approximately 1 year for triple-negative vs approximately 5 years for hormone receptor-positive and HER2-positive subtypes 2

Lifestyle and Supportive Care

Regular exercise provides functional and psychological benefits, possibly reduces the risk of recurrence, and should be recommended to all suitable patients after treatment. 1

• Weight gain and obesity likely adversely affect prognosis; nutritional counseling should be recommended as part of survivor care for all obese patients 1
• Hormone replacement therapy (HRT) increases the risk of recurrence and should be discouraged 1
• Patients should have unlimited access to specialized rehabilitation facilities to decrease physical, psychological, and social sequelae of treatment 1
• Main aims of physiotherapy include prevention and treatment of lymphedema, assuring full range of movements of arm and shoulder, and prevention/correction of postural defects resulting from mastectomy 1

Common Pitfalls

Failing to reassess receptor status in metastatic disease, which may differ from the primary tumor, is a common pitfall. 3

• Relying solely on one risk assessment model without considering its limitations should be avoided 3
• Not accounting for the increased effect of blood thinners when prescribing capecitabine can lead to serious bleeding complications 8
• Extending trastuzumab adjuvant treatment beyond one year increases cardiac toxicity without additional benefit 7
• Failing to place a marker in the tumor at biopsy can result in incorrect surgical resection site 1