What are the treatment options for breast cancer?

Treatment Options for Breast Cancer

Breast cancer treatment is determined by disease stage and molecular subtype, with a multimodal approach combining surgery, radiation, systemic therapy (chemotherapy, endocrine therapy, and/or targeted agents), tailored to hormone receptor (ER/PR) status, HER2 status, and nodal involvement. 1, 2

Initial Evaluation and Molecular Characterization

Before initiating treatment, comprehensive staging and tumor characterization are mandatory 2:

• Tumor assessment must include: histological type and grade, ER and PR status by immunohistochemistry, HER2 status, and proliferation markers (Ki67) 2
• Staging workup includes: physical examination, complete blood counts, routine chemistry, bilateral mammography with ultrasound of breasts and axillae 2
• For higher-risk disease: chest X-ray or CT, abdominal ultrasound or CT scan, and bone scan are required 2
• Genetic testing: BRCA1/2 testing should be offered to high-risk patients 2

Treatment by Disease Stage

Early-Stage Non-Metastatic Disease (Stages 0-III)

Surgical Management

For tumors amenable to breast conservation, breast-conserving surgery with radiation therapy is the standard approach 3, 1, 2:

• Breast-conserving surgery plus radiation provides equivalent survival to mastectomy when complete excision with good cosmetic results is achievable 4, 5
• Modified radical mastectomy is standard for larger tumors or multifocal disease 2
• Sentinel lymph node biopsy is the preferred method for axillary staging in clinically node-negative patients 1, 2
• Immediate reconstruction can be considered but must not compromise delivery of appropriate locoregional or systemic treatment 3, 2

Radiation Therapy

After breast-conserving surgery, breast radiotherapy is mandatory using a minimum dose of 50 Gy in 25 fractions 3:

• Breast irradiation significantly reduces local recurrence risk irrespective of initial disease stage 3
• Boost to tumor bed should be administered routinely in women under 50 years old, even when margins are clear 3
• Post-mastectomy chest wall radiotherapy is indicated when ≥4 positive lymph nodes are present 3, 2
• Regional nodal irradiation: infra- and supraclavicular lymph nodes should be irradiated when axillary lymph node involvement is present 3
• Internal mammary lymph node irradiation is indicated in all cases of axillary lymph node involvement and when the tumor is medial or central 3
• Women aged 70+ with ER-positive, clinically node-negative early breast cancer may omit radiation after lumpectomy if receiving endocrine therapy 2

Neoadjuvant (Preoperative) Therapy

Neoadjuvant therapy is standard for locally advanced breast cancer and allows for tumor downstaging 1, 2:

• Neoadjuvant chemotherapy is an option in operable breast cancer where first-line breast-conserving surgery is not possible, in the absence of multifocal lesions 3
• Compared with adjuvant therapy: neoadjuvant therapy has no effect on survival but avoids mastectomy in more than 50% of women 3
• After neoadjuvant chemotherapy: locoregional treatment should be performed in the same manner as first-line locoregional treatment 3

Systemic Therapy by Molecular Subtype

Hormone Receptor-Positive/HER2-Negative Disease

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

Node-Positive Disease

• Premenopausal women: standard treatment is chemotherapy and tamoxifen 3
• Postmenopausal women: standard treatment is tamoxifen, with tamoxifen plus chemotherapy as an option 3
• Tamoxifen duration: 5-10 years for ER-positive or unknown receptor status tumors 2, 6

Node-Negative Disease with Risk Factors

• Premenopausal women with ER-positive tumors: standard is chemotherapy and tamoxifen 3
• Premenopausal women with ER-negative tumors: standard is chemotherapy 3
• Postmenopausal women with ER-positive tumors: standard is tamoxifen, with tamoxifen plus chemotherapy as an option 3
• Postmenopausal women with ER-negative tumors: chemotherapy is an option 3

Node-Negative Disease without Risk Factors

• Standard: no adjuvant medical treatment 3
• Option: tamoxifen if ER-positive 3

Chemotherapy Regimens

Anthracycline-containing polychemotherapy is more efficacious than CMF (cyclophosphamide, methotrexate, fluorouracil) 3:

• Preferred regimens: dose-dense AC followed by paclitaxel (doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² every 14 days × 4 cycles, followed by paclitaxel 175 mg/m² every 14 days × 4 cycles) 7
• Alternative preferred: AC followed by weekly paclitaxel (doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² every 21 days × 4 cycles, followed by paclitaxel 80 mg/m² weekly × 12 weeks) 7
• When anthracyclines contraindicated: TC × 4 cycles offers improved disease-free survival and overall survival with lower cardiac toxicity risk 7
• Optimal number of cycles: four to six cycles 3
• Chemotherapy should be started promptly after surgery 3

HER2-Positive Disease

Trastuzumab is mandatory for adjuvant treatment of node-positive or high-risk node-negative HER2-positive disease 2, 8:

• Patient selection: based on HER2 protein overexpression or HER2 gene amplification using FDA-approved companion diagnostic tests 8
• Cardiac monitoring: assess left ventricular ejection fraction (LVEF) prior to initiation and at regular intervals during treatment 8
• Preferred regimens for HER2-positive disease: AC followed by paclitaxel plus concurrent trastuzumab, or TCH (docetaxel + carboplatin + trastuzumab) 7
• Trastuzumab duration: 1 year 7
• Post-mastectomy chest wall radiotherapy is indicated when ≥4 positive lymph nodes are present 2

Triple-Negative Breast Cancer

Chemotherapy is the primary and only systemic treatment option for triple-negative disease 2, 9:

• Standard chemotherapy regimens: anthracycline-taxane sequential regimens as described above 7
• Immunotherapy: should be considered if PD-L1 positive 2
• Prognosis: 85% 5-year breast cancer-specific survival for stage I triple-negative tumors vs 94%-99% for hormone receptor-positive and HER2-positive 9

Treatment for Metastatic Breast Cancer (Stage IV)

The primary treatment goal is palliation, maintaining or improving quality of life, and possibly extending survival—cure is not currently achievable 2, 9:

General Principles

• Sequential single-agent chemotherapy provides equivalent survival with better quality of life compared to combination chemotherapy for most patients 1, 2
• Median overall survival: approximately 1 year for metastatic triple-negative breast cancer vs approximately 5 years for hormone receptor-positive and HER2-positive subtypes 9

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
• CDK4/6 inhibitors combined with endocrine therapy have shown significant progression-free survival benefits 2

HER2-Positive Metastatic Disease

• First-line therapy: trastuzumab with vinorelbine or a taxane 2, 8
• Dual HER2 blockade: trastuzumab and pertuzumab can be combined with docetaxel, weekly paclitaxel, vinorelbine, or nab-paclitaxel 2
• Single-agent trastuzumab: indicated for patients who have received one or more chemotherapy regimens for metastatic disease 8

Triple-Negative Metastatic Disease

• 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

Management of Recurrent Disease

Local Recurrence After Breast-Conserving Treatment

Local recurrence should be treated with surgery, with simple total mastectomy as the standard treatment 3:

• Radiotherapy should not be considered except in specific cases 3
• Immediate reconstruction can be considered 3
• If oestrogen receptors are present: additional hormone therapy is recommended 3
• Breast-conserving surgery can only be considered if the patient refuses mastectomy or if mastectomy is technically impossible, but patients should be informed of the high risk of recurrent disease 3

Uncontrolled, Isolated Local Recurrence

• There is no standard treatment 3
• Chemotherapy can be considered, followed if possible by radiotherapy 3
• Chemotherapy is appropriate for an inflammatory recurrence 3
• Radiotherapy can be considered if there are contraindications for chemotherapy 3

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 2
• Routine follow-up should be continued after 10 years, with timing adjusted based on risk of local recurrence 2
• Evaluation of response to therapy should occur every 2-4 months for endocrine therapy or after 2-4 cycles of chemotherapy 2

Supportive Care and Quality of Life

Psychological and social support should be provided routinely to help patients and their families 3:

• Dietary advice should be provided routinely to avoid weight gain 3
• Sexual problems should be evaluated and treated 3
• Contraception and family planning advice should be discussed individually 3
• Hormone replacement treatment for postmenopausal symptoms should not be prescribed after treatment for breast cancer, except in specific cases 3
• Patient rehabilitation groups can contribute to psychosocial support 3

Critical Pitfalls and Caveats

Adjuvant therapy must never replace optimal locoregional treatment—both are essential components 1, 2:

• Incomplete pathology reporting significantly impacts treatment decisions—standardized reporting of all molecular markers is essential 2
• For multifocal lesions: nonsurgical treatment is not indicated and mastectomy should be the local treatment 2
• Immediate breast reconstruction should not compromise delivery of appropriate adjuvant therapy 1, 2
• After axillary dissection: radiotherapy to the axilla should be avoided as much as possible because of the increased risk of locoregional complications 3
• Cardiac monitoring is essential when cumulative anthracycline doses approach doxorubicin 450-550 mg/m² or epirubicin 800-1000 mg/m² 7
• Pregnancy status must be verified in females of reproductive potential prior to initiation of trastuzumab, as exposure during pregnancy can result in oligohydramnios and fetal harm 8