What are the treatment options for breast cancer?

Treatment Options for Breast Cancer

Breast cancer treatment is determined by disease stage, molecular subtype (hormone receptor, HER2, and triple-negative status), and menopausal status, with a multimodal approach combining surgery, radiation, systemic therapy (endocrine therapy, chemotherapy, and/or targeted agents), tailored to these specific tumor characteristics. 1, 2

Initial Evaluation Required Before Treatment

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

• Tumor characterization must include: histological type and grade, estrogen receptor (ER) and progesterone receptor (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 counseling and BRCA1/2 testing should be offered to high-risk patients 2
• Cardiac assessment: evaluate left ventricular ejection fraction (LVEF) prior to treatment initiation, particularly if anthracyclines or trastuzumab are planned 3

Treatment by Disease Stage

Early-Stage Non-Metastatic Breast Cancer

Surgical Options

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

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

Radiation Therapy

After breast-conserving surgery, breast radiotherapy must always be performed, using a minimum dose of 50 Gy in 25 fractions 4:

• Breast irradiation after breast-conserving surgery significantly reduces the risk of local recurrence regardless of initial disease stage 4
• In women under 50 years old, a boost should be administered routinely to the tumor bed even when margins are clear 4
• Post-mastectomy chest wall radiotherapy is indicated when ≥4 positive lymph nodes are present 2, 3
• Irradiation of internal mammary lymph nodes is indicated in all cases of axillary lymph node involvement and when the tumor is medial or central 4
• Irradiation of infra- and supraclavicular lymph nodes is indicated in the presence of axillary lymph node involvement 4
• 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 4
• Compared with adjuvant therapy, neoadjuvant therapy has no effect on survival but has been shown to avoid mastectomy in more than 50% of women 4
• After neoadjuvant chemotherapy, locoregional treatment should be performed in the same manner as first-line locoregional treatment 4

Treatment 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:

For Premenopausal Women (Node-Positive or High-Risk Node-Negative):

• Standard: chemotherapy and tamoxifen 4
• Options: chemotherapy and ovarian ablation ± tamoxifen, or ovarian suppression ± tamoxifen (without chemotherapy) 4

For Postmenopausal Women (Node-Positive):

• If ER-positive: tamoxifen is standard 4
• Option: tamoxifen plus chemotherapy 4
• If ER-negative or unknown: chemotherapy is standard 4

For Node-Negative Disease with Risk Factors:

• Premenopausal, ER-positive: chemotherapy and tamoxifen is standard 4
• Postmenopausal, ER-positive: tamoxifen is standard, with tamoxifen plus chemotherapy as an option 4
• ER-negative or unknown: chemotherapy is standard 4

For Node-Negative Disease without Risk Factors:

• If ER-positive: tamoxifen is standard 4
• If ER-negative or unknown: no adjuvant treatment is standard 4

Tamoxifen should be given for 5-10 years 2, 5:

• Tamoxifen lowers the chance of getting breast cancer by 44% in high-risk women (from 7 in 1,000 to 4 in 1,000 per year) 5
• In women with DCIS, tamoxifen lowers the chance of invasive breast cancer by 43% (from 17 in 1,000 to 10 in 1,000 per year) 5
• Important caveat: tamoxifen doubles the risk of endometrial cancer (from 1 in 1,000 to 2 in 1,000 per year) and increases the risk of uterine sarcoma 5

HER2-Positive Disease

Trastuzumab is mandatory for adjuvant treatment of node-positive or high-risk node-negative HER2-positive disease 1, 2, 3:

• For adjuvant treatment: trastuzumab is indicated as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, or as part of a regimen with docetaxel and carboplatin, or as a single agent following multi-modality anthracycline-based therapy 3
• Critical monitoring: assess LVEF prior to initiation and at regular intervals during treatment, as trastuzumab can result in subclinical and clinical cardiac failure 3
• Discontinue trastuzumab in patients receiving adjuvant therapy with clinically significant decrease in left ventricular function 3
• For metastatic disease: trastuzumab in combination with paclitaxel for first-line treatment, or as a single agent for patients who have received one or more chemotherapy regimens 3
• Dual HER2 blockade with trastuzumab and pertuzumab can be combined with docetaxel, weekly paclitaxel, vinorelbine, or nab-paclitaxel 2

Triple-Negative Breast Cancer

Chemotherapy is the primary and only systemic treatment option for triple-negative disease 1, 2:

• Anthracycline-containing polychemotherapy is currently the most commonly used regimen and is more efficacious than CMF (cyclophosphamide, methotrexate, and 5-FU) 4
• Doxorubicin, epirubicin, 5-FU, cyclophosphamide, and methotrexate used in combination every 3-4 weeks, with a maximum of six cycles, is the reference treatment 4
• Chemotherapy should be started promptly 4
• Immunotherapy should be considered if PD-L1 positive 2

Treatment for Metastatic Breast Cancer

The primary treatment goal for metastatic breast cancer is palliation, with the aim of maintaining or improving quality of life and possibly extending survival—cure is not currently achievable 1, 2:

General Principles

• For most patients, sequential single-agent chemotherapy provides equivalent survival with better quality of life compared to combination chemotherapy 1, 2
• Systemic treatment options include chemotherapy, biological agents (trastuzumab, bevacizumab, lapatinib) 1

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

• 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

Triple-Negative Metastatic Disease

• There are no specific chemotherapy recommendations different from other HER2-negative disease 2
• For previously treated patients with anthracyclines with/without taxanes, 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, and the standard treatment is a simple total mastectomy 4:

• Radiotherapy should not be considered except in specific cases 4
• Immediate reconstruction can be considered 4
• If oestrogen receptors are present, additional hormone therapy is recommended 4
• 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 4

Uncontrolled, Isolated Local Recurrence

• There is no standard treatment 4
• Chemotherapy can be considered, followed if possible by radiotherapy 4
• Chemotherapy is appropriate for an inflammatory recurrence 4
• Radiotherapy can be considered if there are contraindications for chemotherapy 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
• Evaluation of response to therapy should occur 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 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
• After axillary dissection, radiotherapy to the axilla should be avoided as much as possible because of the increased risk of locoregional complications 4
• Hormone replacement treatment for postmenopausal symptoms should not be prescribed after treatment for breast cancer, except in specific cases 4
• Psychological support may be required at some stage during management, and social support should be provided routinely to help patients and their families 4
• Sexual problems should be evaluated and treated, and contraception and family planning advice should be discussed individually 4