The first question a patient often asks their FP after receiving a diagnosis of breast cancer (BC) is “What will my treatment be?” This article will help FPs answer this complex question by reviewing multimodal therapy for BC, which is contingent on molecular subtype and stage (Figure 1).1
Overview of breast cancer therapies: Range of multimodal breast cancer therapies are displayed. Patients start at the top of the cascade and depending on molecular subtype, stage, and preferences, may receive some or all of these treatments, typically in the order they are shown. The approximate duration of each treatment is shown in the arrows.
Pathology
Initial pathology reports for BC will have both pathologic and immunohistochemical information, including the following2:
Cell type: Ductal carcinoma is the most common cell type, followed by lobular carcinoma; however, other rarer cell types are possible.
Grade: This measures disease aggressivity, ranging from well-differentiated (grade 1) to poorly differentiated (grade 3).
Estrogen receptor (ER)–progesterone receptor (PR) test status: This test indicates sensitivity to estrogen and progesterone and is predictive of response to endocrine therapy.
Human epidermal growth factor receptor 2 (HER2) (also known as erb-b2 receptor tyrosine kinase 2 [ERBB2]) gene status: This measures the overamplification of HER2. Overexpression of this transmembrane receptor in BC causes uncontrolled cell growth and replication.1
Four discrete molecular subtypes of BC are recognized on the basis of an ER-PR test and HER2 status: luminal A (ER-positive, PR-positive, HER2-negative); luminal B (ER-positive, PR-positive or PR-negative, HER2-positive or HER2-negative); HER2 (ER-negative or PR-negative, HER2-positive); and triple-negative (ER-negative or PR-negative, HER2-negative).3,4 Each subtype informs a specific treatment regimen and is predictive of disease recurrence and mortality rate.5
Surgery
Surgery is often the first step in the treatment of early-stage BCs. However, locally advanced cancers or triple-negative and HER2 BCs may be treated with preoperative chemotherapy.2,6 Neoadjuvant chemotherapy can downstage disease, allowing for less aggressive surgery of the breast or axilla, and it can guide additional adjuvant systemic treatment options depending on the patient’s response to preoperative chemotherapy.
Surgical options include lumpectomy or mastectomy with or without reconstruction (which may be immediate or delayed). Lumpectomy in addition to radiation therapy is equivalent to mastectomy and is preferred when tumours are less than 5 cm in diameter, clear margins can be obtained, and there are no contraindications to subsequent radiation therapy.7 Patients with clinically positive axillary nodes (≥3 nodes) that are confirmed by biopsy will have axillary dissection, while those who have clinically negative axillary nodes will have sentinel node biopsy. In the latter technique, a radioactive tracer is infiltrated into the tumour, mapping the lymphatic drainage to the sentinel nodes, which are then removed. If cancer is present in the sentinel nodes, completion axillary lymph node dissection may be performed. Use of sentinel node biopsy has been shown to substantially decrease postoperative shoulder morbidity and lymphedema.8
Chemotherapy and immunotherapy
The decision to administer chemotherapy is based on careful review of the benefits and toxicities of treatments, as well as patient comorbidities and preferences. Generally, chemotherapy is indicated for tumours that are lymph node–positive or for tumours greater than 0.5 cm to 1 cm in diameter that are lymph node–negative but have unfavourable prognostic factors (eg, high grade, ER-negative or PR-negative, HER2-positive).1 In postmenopausal women with ER-positive, PR-positive, and HER2-negative BC with negative or minimal lymph node involvement (1 to 3 nodes), genomic testing of the tumour can generate a recurrence risk score to help guide treatment. The recurrence score can identify those patients who would benefit mainly from endocrine therapy and those in whom chemotherapy can safely be omitted.9
Chemotherapy, if required, starts within 8 to 12 weeks of surgery. Preferred chemotherapy regimens include doxorubicin and cyclophosphamide followed by paclitaxel for 16 to 20 weeks or docetaxel and cyclophosphamide for 12 weeks.1 Family physicians should be aware that doxorubicin, an anthracycline, may cause decreased ejection fraction many years after treatment, and both doxorubicin and cyclophosphamide can be associated with secondary blood cancers.10 Patients with triple-negative or HER2-positive BC who have residual disease at time of surgery despite neoadjuvant chemotherapy may be treated with further chemotherapy postoperatively: capecitabine for triple-negative BC or trastuzumab-emtansine for HER2-positive disease.11
Immunotherapy is now used in the treatment of triple-negative BCs and shows substantial improvements in event-free survival. It is given neoadjuvantly with chemotherapy in stage II and III triple-negative cancers and in metastatic triple-negative BCs with high expression of programmed cell death 1 ligand 1.12
Targeted therapy
Patients with HER2 BC are candidates for trastuzumab, a monoclonal antibody that blocks the HER2 receptor. Trastuzumab reduces the risk of recurrence by half and the mortality rate by one-third.13 Decreased ejection fraction is seen in up to 5% of patients taking trastuzumab.1 It is given every 3 weeks for up to 1 year and is started upon completion of anthracycline chemotherapy so as not to compound cardiotoxicity. Pertuzumab is a monoclonal antibody also targeting the HER2 receptor and can be taken alongside trastuzumab in patients with high-risk disease.1
Radiation therapy
Adjuvant radiation therapy after lumpectomy reduces the risk of local recurrence in the breast.14 Radiation may be delivered to either the whole or partial breast, depending on patient and tumour characteristics. Typical treatment regimens involve 3 weeks of daily radiation (Monday to Friday) up to a dose of 40 Gy in 15 fractions.15 Moreover, a recent study has provided evidence for ultrahypofractionation radiotherapy with only 5 treatments (eg, 26 Gy in 5 daily fractions or 28.5 Gy in 5 weekly fractions).15 Women with high-risk cancers (age <50, high grade, positive margins) are considered for an additional radiation boost to the tumour bed. In those with lymph node–positive BC, regional nodal irradiation should also be considered.16 Chest wall radiation is indicated following mastectomy for those with lymph node–positive disease and multiple risk factors of chest wall recurrence. There is evidence to consider omitting radiation after lumpectomy in women who are 70 years or older with early stage, ER-positive BC who are being treated with endocrine therapy.17 Patients who have surgery and radiation to the breast and axilla are at risk of developing lymphedema.
Bisphosphonates
Bisphosphonates can decrease in-bone recurrence and BC mortality in postmenopausal woman with high-risk cancers. Treatment regimens include parenteral formulations such as zoledronic acid given every 6 months for 2 to 3 years or daily oral clodronate for 2 to 3 years. Administration should start within a year of diagnosis or within 18 months of surgery.18 Patients should avoid invasive dental procedures while taking this therapy due to the risk of osteonecrosis of the jaw.
Endocrine therapy
Much like HER2 receptors, ERs and PRs work to increase cell replication (Figure 2). Estrogen activity can be minimized by blocking receptors directly (eg, with tamoxifen, a selective ER modulator); lowering circulating levels of estrogen with aromatase inhibitors (AIs) (eg, letrozole, anastrozole, exemestane); or centrally inhibiting with gonadotropin-releasing hormone agonists (eg, goserelin).19 Cyclin-dependent kinases are enzymes involved in the control of cell cycle regulation. Cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibitors (eg, palbociclib, ribociclib, abemaciclib), when used in conjunction with endocrine therapy, act as molecular brakes to slow or stop cell division.20
Endocrine therapies’ mechanisms of action on breast cancer tumour cell
Endocrine therapy is the treatment standard of care for ER-positive and PR-positive BC. Tamoxifen reduces BC mortality by about 30%; while 5 years of AIs reduce the 10-year BC mortality rate by 15% compared with 5 years of tamoxifen.21 Although AIs are more effective than tamoxifen, they cannot be used in premenopausal woman because resultant decreased circulating levels of estrogen will stimulate ovarian production of estrogen. The addition of abemaciclib to either tamoxifen or an AI for 2 years has been approved in the adjuvant setting for high-risk ER-positive, HER2-negative BC.22
Women are offered varying endocrine regimens and durations of treatment based on menopausal status and BC risk (Box 1).1 Endocrine therapy should be continued for at least 5 years, and women with high-risk disease gain a survival benefit by extending therapy to 7 to 10 years.1 Treatment for more than 7 years does not have further mortality benefit but may decrease the incidence of new BCs. Adherence to endocrine therapy is only about 70%, primarily due to vasomotor and other side effects (Box 2).23 Family physicians should be aware of the risk of endometrial cancer in patients taking tamoxifen and the potential for osteoporosis in women taking AIs.
Endocrine therapy regimens
Premenopausal (duration of treatment: 5-10 years)
Tamoxifen
Tamoxifen plus ovarian suppression*
AI plus ovarian suppression*
Postmenopausal (duration of treatment: 5-10 years)
Tamoxifen
AI
Tamoxifen followed by AI
AI followed by tamoxifen
AI—aromatase inhibitor.
*Includes gonadotropin-releasing hormone agonists, ablation, or oophorectomy.
Data from the National Comprehensive Cancer Network.1
Potential side effects of endocrine therapies
Tamoxifen
Venous thromboembolic disease
Endometrial cancer
Vaginal dryness
Vasomotor symptoms
Aromatase inhibitors
Myalgias and-or arthralgias
Osteoporosis
Hyperlipidemia
Vasomotor symptoms
Data from Cella and Fallowfield.23
Metastatic disease
Median survival with metastatic BC is 3 to 5 years depending on molecular subtype.24 Treatment for patients with metastatic disease is essentially continuous, with patients remaining on a specific therapy until there is evidence of disease progression or intolerance, at which point a new line of therapy begins. Patients progress through “lines” of therapy until they decide not to continue treatment or until they are no longer well enough to receive further treatment. Regardless of tumour pathology, patients with bone metastases should receive bisphosphonate or receptor activator of nuclear factor–B ligand inhibitor therapy to prevent skeletal-related events such as hypercalcemia and pathologic fractures.1
Cyclin-dependent kinase 4 or cyclin-dependent kinase 6 inhibitors in combination with AIs or fulvestrant (an estrogen down-regulator [Figure 2]) is first-line therapy for ER-positive, PR-positive disease in postmenopausal or premenopausal patients with ovarian suppression. Treatment yields an average progression-free survival of 20.2 months, with neutropenia and leukopenia as common side effects.25 Upon progression, patients can be treated sequentially with available endocrine therapies while the cancer remains endocrine responsive. Oral endocrine therapies are favoured as initial treatments due to their tolerability and ease of administration; however, in cases where there is visceral disease needing rapid response, chemotherapy is used preferentially.1
In patients with triple-negative BC, the primary treatment is chemotherapy, although immunotherapy can also be used. First-line treatment for HER2-positive disease involves chemotherapy and HER2-targeted therapies. Newer treatments are evolving rapidly and antibody-drug conjugates, such as trastuzumab-deruxtecan, are poised to play a larger role in the treatment of metastatic disease.26 There are also specific targeted therapies available for patients who have BRCA mutations.1
Conclusion
Adjuvant and metastatic therapies for BC are varied and highly dependent on molecular subtype. Adjuvant therapy for BC is involved and complex, lasting up to 10 years. Recent developments in the treatment of metastatic BC have greatly improved prognosis with manageable toxicity and good quality of life. With insights provided in this article, FPs will be better positioned to answer questions their patients may have about BC and can support them during and after BC treatment.
Footnotes
Competing interests
None declared
This article is eligible for Mainpro+ certified Self-Learning credits. To earn credits, go to https://www.cfp.ca and click on the Mainpro+ link.
La traduction en français de cet article se trouve à https://www.cfp.ca dans la table des matières du numéro de juillet 2023 à la page e149.
- Copyright © 2023 the College of Family Physicians of Canada