Demystifying breast cancer

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.

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

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Figure 2.

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.

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