What are the treatment options for breast cancer?

Treatment of Breast Cancer

Breast cancer treatment is determined by disease stage and molecular subtype, with early-stage disease treated with curative intent using surgery (breast-conserving surgery with radiation or mastectomy) plus subtype-directed systemic therapy, while metastatic disease is treated palliatively with systemic therapy tailored to hormone receptor and HER2 status. 1, 2

Initial Diagnostic Workup and Staging

Before initiating treatment, comprehensive staging must be performed to determine disease extent and guide therapeutic decisions 1, 2:

• Mandatory tumor characterization includes histological type and grade, estrogen receptor (ER) and progesterone receptor (PR) status by immunohistochemistry, HER2 status, and proliferation markers (Ki67) 2, 3
• Baseline imaging should include bilateral mammography with ultrasound of breasts and axillae 2
• For higher-risk disease, additional staging includes chest imaging, abdominal imaging (ultrasound or CT), and bone scan 2
• Genetic counseling and BRCA1/2 testing should be offered to high-risk patients 2

Treatment Approach for Early-Stage (Non-Metastatic) Breast Cancer

Surgical Management

For tumors amenable to breast conservation, breast-conserving surgery with whole breast radiation therapy is the standard approach 1, 2:

• Breast-conserving surgery with radiation provides equivalent survival to mastectomy for appropriate candidates 1
• Modified radical mastectomy is indicated for larger tumors, multifocal disease, or patient preference 2
• Sentinel lymph node biopsy is the preferred method for axillary staging in clinically node-negative patients 2
• Immediate breast reconstruction should not compromise delivery of appropriate locoregional or systemic treatment 4, 2

Radiation Therapy

• Whole breast radiation is mandatory after breast-conserving surgery 2
• Post-mastectomy chest wall radiotherapy is indicated when ≥4 lymph nodes are positive or other high-risk features are present (primary tumors >5 cm, close or positive margins) 4, 2
• Women aged 70+ with ER-positive, clinically node-negative early breast cancer may omit radiation after lumpectomy if receiving endocrine therapy 2
• Recommended radiation dose is 45-50 Gy in fractions of 1.8-2.0 Gy, with boost doses of 10-16 Gy for high-risk patients (age <50 years with high-grade tumors) 4

Neoadjuvant (Preoperative) Therapy

• Neoadjuvant therapy is standard for locally advanced breast cancer and allows for tumor downstaging 1, 2
• Options include neoadjuvant chemotherapy, hormone therapy, or radiotherapy depending on tumor subtype 2
• Decisions regarding radiation therapy should be based on preoperative tumor characteristics irrespective of response to neoadjuvant therapy 4

Systemic Therapy by Molecular Subtype

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

Endocrine therapy is the cornerstone of treatment and must be administered for hormone receptor-positive tumors 1, 2:

• Tamoxifen is indicated for ER-positive tumors, given for 5-10 years 2, 5
• The optimal duration for adjuvant tamoxifen is 5 years at 20 mg daily 4
• Menopausal status assessment is critical for determining appropriate endocrine therapy selection (tamoxifen for premenopausal, aromatase inhibitors for postmenopausal) 4, 1
• In postmenopausal women, combination of chemotherapy with endocrine therapy significantly improves progression-free and overall survival 4
• Patients treated with tamoxifen should have regular gynecological clinical examinations 4

HER2-Positive Disease (15-20% of cases)

Trastuzumab is mandatory for adjuvant treatment of node-positive or high-risk node-negative HER2-positive disease 2, 6:

• Trastuzumab is indicated as part of a treatment regimen with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel 6
• Evaluate left ventricular ejection fraction (LVEF) prior to and during treatment with trastuzumab, as it can result in cardiomyopathy, with highest incidence when combined with anthracyclines 6
• Trastuzumab can be administered concurrently with radiation therapy if indicated 4
• For metastatic HER2-positive disease, trastuzumab combined with paclitaxel is indicated for first-line treatment 6

Triple-Negative Breast Cancer (15% of cases)

Chemotherapy is the primary and only systemic treatment option for triple-negative disease 2, 7:

• Triple-negative breast cancer has higher recurrence rates, with 85% 5-year breast cancer-specific survival for stage I disease compared to 94-99% for other subtypes 7
• Immunotherapy should be considered if PD-L1 positive 2
• Median overall survival for metastatic triple-negative breast cancer is approximately 1 year versus 5 years for other subtypes 7

Treatment Approach for Metastatic Breast Cancer

The primary treatment goal for metastatic breast cancer is palliation to maintain or improve quality of life and possibly extend survival—cure is not currently achievable 1, 8:

General Principles

• Sequential single-agent chemotherapy provides equivalent survival with better quality of life compared to combination chemotherapy for most patients 1, 2
• Treatment selection is based on hormone receptor and HER2 status 8
• Monitor patients frequently: every 2-3 months if on endocrine therapy and every 1-2 chemotherapy cycles 8

Hormone Receptor-Positive/HER2-Negative Metastatic Disease

• Endocrine therapy partnered with targeted agents (CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors) is preferred over chemotherapy 2
• Start with endocrine therapy unless biologically aggressive disease mandates rapid response 8
• Third-generation aromatase inhibitors are options for postmenopausal patients 8

HER2-Positive Metastatic Disease

• Trastuzumab with vinorelbine or a taxane is preferred for first-line therapy 2
• Dual HER2 blockade with trastuzumab and pertuzumab can be combined with docetaxel, weekly paclitaxel, vinorelbine, or nab-paclitaxel 2
• Avoid anthracyclines with trastuzumab due to cardiotoxicity risk 8

Triple-Negative Metastatic Disease

• There are no specific chemotherapy recommendations different from other HER2-negative disease 2
• For previously treated patients, carboplatin has shown comparable efficacy with more favorable toxicity profile compared to docetaxel 2

Special Considerations for Occult Primary Breast Cancer

For patients with axillary adenocarcinoma without identified primary breast lesion 4:

• Breast MRI and ultrasound are recommended for detection 4
• For MRI-positive disease, undergo ultrasound or MRI-guided biopsy and treat according to clinical stage 4
• For T0, N1, M0 disease, options include mastectomy plus axillary dissection OR axillary dissection plus whole-breast irradiation 4
• For T0, N2-N3, M0 disease, consider neoadjuvant chemotherapy followed by axillary dissection and mastectomy 4

Follow-Up Protocol

• History and physical examination every 3-6 months for 3 years, then every 6-12 months thereafter 2
• Annual mammography should be performed for at least 10 years, starting 6 months after treatment 1, 2
• Routine follow-up should be continued after 10 years, with timing adjusted based on risk of local recurrence 2
• For metastatic disease, evaluate response every 2-4 months for endocrine therapy or after 2-4 cycles of chemotherapy 2

Critical Pitfalls and Caveats

• Adjuvant therapy must never replace optimal locoregional treatment—both are essential components 4, 2
• Incomplete pathology reporting significantly impacts treatment decisions—standardized reporting of all molecular markers is essential 2
• For multifocal lesions, mastectomy should be the local treatment rather than nonsurgical approaches 2
• Verify pregnancy status in females of reproductive potential prior to initiating trastuzumab, as exposure during pregnancy can result in oligohydramnios and fetal harm 6
• Trastuzumab infusion reactions can be serious and fatal; monitor patients until symptoms completely resolve and discontinue for anaphylaxis or acute respiratory distress syndrome 6
• Tamoxifen doubles the risk of endometrial cancer (from 1 in 1,000 to 2 in 1,000 annually) in women who still have their uterus 5