Introduction
Breast cancer is the most common type of cancer and the second leading cause of death in women. Approximately one in eight women will develop breast cancer in their lifetime. The treatment of breast cancer requires a multidisciplinary approach and often includes a surgical, medical, and radiation oncologist. An extensive network of subspecialists is also needed, including pathologist, radiologist, physiatrist, physical therapist, occupational therapist, and pain management and palliative care physicians. Also, integrative services such as massage therapy and acupuncture are increasingly being utilized. Herein we will discuss the systemic treatment of breast cancer.
Clinical Presentation and Diagnostic Workup
The majority of breast cancers are diagnosed with mammogram. Over 90% of breast cancers are detected mammographically. Only about 10% of patients present with a palpable breast mass, overlying skin breakdown, redness, nipple retraction, and/or discharge. Patients who have an abnormal screening mammogram undergo further diagnostic workup with a mammogram showing additional views and/or limited breast ultrasound. This information is used to determine if a biopsy of a concerning area is needed. A clinically suspicious mass is always biopsied. Once a tissue biopsy is obtained, it is reviewed by a pathologist to determine if it is cancer. After a diagnosis of breast cancer is made, it is important to determine the receptor status in order to assess the prognosis and plan the treatment. Additional images such as a magnetic resonance imaging might be needed to evaluate the extent of the disease. Only patients with signs or symptoms of systemic involvement, large tumors (≥5 cm), and/or multiple lymph nodes (≥3) require further staging with either a computed tomography (CT) of the chest–abdomen–pelvis and a bone scan or a positron emission tomography–CT. Head imaging is done if patients have concerning neurological symptoms. Patients diagnosed with metastatic cancer undergo routine scans and tumor markers to assess the response to therapy. Patients with metastatic breast cancer (MBC) present with symptoms such as fatigue, weight loss, changes in lab chemistries, new and persistent pain, or new masses. Common sites of breast cancer metastasis are lungs, bones, liver, and brain.
Nonmetastatic Versus Metastatic Breast Cancer
Breast cancer is a heterogeneous disease. Systemic treatment refers to medications that work throughout the body, eliminating cancer cells. The treatment options include endocrine therapies (ETs), chemotherapy, and targeted therapies. Clinical trials should always be considered. Fortunately, there have been some meaningful improvements in survival due to the increasing availability of more effective systemic therapies.
The treatment options are based on the tumor type, receptor status, and extent or burden of disease. Patient’s baseline functional status and comorbidities are also considered. The treatment differs widely in patients with nonmetastatic versus MBC. In patients with non-MBC the goal of treatment is curative. Systemic therapy can be given either before (neoadjuvant) or after (adjuvant) surgery. For large tumors and tumors with positive lymph nodes, neoadjuvant systemic therapy is often preferred. One of the benefits of administering neoadjuvant chemotherapy is that it can downstage the tumor, permitting a less extensive surgery. In addition, it allows for the evaluation of the effectiveness of the systemic therapy, and in the case of a suboptimal response, it gives the opportunity for additional treatment after surgery. An Early Breast Cancer Trialist Collaborative Group (EBCTCG) metaanalysis of long-term outcomes of neoadjuvant versus adjuvant chemotherapy showed that neoadjuvant chemotherapy was associated with more breast-conserving therapy and similar rates of distant recurrence and overall survival. The effectiveness of neoadjuvant therapy can be determined by assessing the complete pathologic response (pCR) that is defined as the absence of residual invasive cancer after neoadjuvant therapy. It has been used as a surrogate end point in many clinical trials. Patients who achieve a pCR have better disease-free survival and overall survival when compared to patients who have residual disease.
The approach to the treatment of MBC differs from that of non-MBC because the goal of therapy is usually not curative. The goal of treatment is palliative and to extend life. However, a large focus is also placed on maintaining an acceptable quality of life and improving symptoms. The role of surgery and radiation is usually reserved for palliation of distressing symptoms. Systemic therapies are typically given sequentially to minimize toxicity. However, there are times when combination therapies are administered.
Systemic Treatment by Receptor Status
Depending on the receptor status, tumors can be categorized as hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) positive or triple negative.
Hormone Receptor–Positive Breast Cancer
The majority of breast cancers have estrogen and/or progesterone receptors. ET is the mainstay treatment, but chemotherapy can be given in a subset of patients.
Nonmetastatic
Adjuvant endocrine therapy is recommended for the majority of patients with HR-positive breast cancer and is administered after completing chemotherapy in patients who require it. ET is typically given for 5–10 years. Since HR-positive tumors grow with estrogen the aim is to decrease the estrogen levels and/or the estrogen activity. In premenopausal women, estrogen is primarily produced by the ovaries. In these women, estrogen can be depleted by ET alone or by using a combination therapy of ovarian function suppression (OFS) or ovarian ablation with ET. Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely used drug. It blocks the ER and decreases the activity of estrogen in the breasts. In young patients and/or patients with high risk of recurrence, the combination of OFS with an aromatase inhibitor (AI) or tamoxifen has shown a decrease in the risk of recurrence with a trade-off of more side effects. OFS is done either surgically by removing the ovaries with an oophorectomy or chemically using luteinizing hormone-releasing hormone agonists and antagonists.
When the ovaries stop making estrogen, a woman enters menopause. In postmenopausal women, low levels of estrogen are still being made by conversion of adrenal precursors, testosterone, and androstenedione through aromatase activity in the body. AIs are used to block this production of estrogen in postmenopausal women. For postmenopausal women, AIs are the preferred treatment. They include letrozole, anastrozole, and exemestane. All of them have shown to improve outcomes when compared to tamoxifen in the adjuvant setting.
In general, patients with tumors of ≤1 cm do not require chemotherapy. Genomic testing to assess the benefit of chemotherapy should be considered in patients who have small tumors (≤5 cm) and three or less positive lymph nodes. The 21-gene expression assay (Oncotype DX) categorizes patients in three risk groups: low, intermediate, and high. Patients in the low-risk group are not offered chemotherapy, whereas patient in the high-risk group receive chemotherapy. The intermediate group was studied in the TAILORx trial. This study randomized patients with an intermediate score to chemotherapy versus no chemotherapy. The study only included patients with HR-positive and HER2-negative breast cancer who had negative lymph nodes and T1 (≤2 cm) or T2 (≤5 cm) tumors. This trial showed that ET alone was noninferior to the addition of chemotherapy. Another genomic test that is widely used is the 70-gene signature test (MammaPrint). The MINDACT study demonstrated that the 70-gene signature test can be used to determine which patients benefit from adjuvant chemotherapy. They included patients with early node-negative disease or with one to three positive lymph nodes. Based on these results, chemotherapy is only offered to patients with high recurrence scores. Patients with large tumors and/or with multiple positive lymph nodes do not need to have genomic testing and receive chemotherapy upfront. The chemotherapy options are discussed in the triple negative section.
Metastatic
Patients with HR-positive MBC can be treated with ET only or in combination with targeted agents. Typically, ET is the first choice for the treatment of HR-positive MBC, unless a more rapid response is needed due to a patient’s symptoms or tumor burden. The choice of therapy depends on the degree of HR positivity, the use and timing of previous therapies, and the HER2 status. The use of ET alone or in combination with targeted agents is used to reduce cancer burden and cancer-related symptoms. These therapies have different side effects when compared to chemotherapy.
HR-positive MBC therapy is targeted at depleting estrogen. In premenopausal women, OFS is recommended. The ET used in the combination with OS can be tamoxifen or AIs. The first choice is usually OFS in combination with an AI. If ET is given alone in premenopausal women, then tamoxifen is typically used.
AIs should be offered as part of the first-line therapy in postmenopausal women. As discussed before, there are three different AIs: letrozole, anastrozole, and exemestane. Since the clinical activity, side effects and toxicities of these medications are nearly identical, they can be used interchangeably.
Since the approval of the cyclin-dependent kinase (CDK) 4/6 inhibitors, their combination with ET is the preferred first-line endocrine treatment for MBC. CDK 4/6 inhibitors are targeted therapies that block cell growth by stopping the progression from G1 to S phase. CDK 4/6 inhibitors are typically used as first-line therapy, but they can also be used in subsequent lines of treatment. Currently, there are three approved CDK 4/6 inhibitors for MBC treatment: palbociclib, ribociclib, and abemaciclib. They all have progression-free survival (PFS) benefit. Ribociclib and Abemaciclib have also shown an overall survival benefit.
Fulvestrant, a selective ER degrader is another option. It can be given alone or in combination with a CDK 4/6 inhibitor or with alpelisib, a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) inhibitor. In order to receive alpelisib, tumors must have a PIK3CA mutation and should have progressed after treatment with an AI. This combination has shown to improve PFS when compared with single-agent fulvestrant.
Everolimus can be given in combination with an AI. Everolimus inhibits the mammalian target of rapamycin pathway. The combination of everolimus with an AI has a PFS benefit when used after progression on ET.
In BRCA-associated breast cancer with prior exposure to chemotherapy, the polyadenosinediphosphate-ribose polymerase (PARP) inhibitors, olaparib and talazoparib can be used after ET.
The presence of new metastatic lesions, worsening symptoms, or clinical deterioration is a sign concerning for disease progression. After progression on ET or a targeted therapy a decision is made to either proceed with another line of ET, with or without a targeted agent, or with chemotherapy. The patient’s tolerance of therapy, the duration of response, and the extent of disease are all factored into the decision-making process. Most patients are given two or three lines of ET therapy, with or without targeted agents, before receiving chemotherapy. Chemotherapy is typically given as single-agent sequential therapy. The goal of therapy is to stabilize or reduce disease with the fewest side effects, and therapy is continued until the patient develops significant side effects or disease progression occurs.
Toxicities
Endocrine Therapy
Common side effects of tamoxifen include, but are not limited to, hot flashes, amenorrhea, decreased sex drive, vaginal dryness, and fatigue. Hot flashes can be managed with the use of medications such as venlafaxine or less commonly oxybutynin. Vaginal dryness can improve with the use of vaginal lubricants. Cancer and cancer therapy-related fatigue can be distressing for patients, and at times, it may be difficult to treat. This type of fatigue is persistent, and it affects the individual physically, emotionally, and cognitively, and it is not proportionally related to recent activity. It is recommended to first look for underlying medical causes for fatigue such as hypothyroidism, electrolyte imbalances, deconditioning, cardiac dysfunction, depression, anxiety, poor nutrition, or anemia as well as to evaluate the patient for obstructive sleep apnea or poor sleep hygiene. A nonpharmacologic approach may include yoga, massage therapy, cognitive behavioral therapy, and supportive therapies such as group therapy or counseling. The use of psychostimulants such as methylphenidate remains investigational. There is also an increased risk of thrombosis, stroke, cataracts and uterine hyperplasia, and uterine cancer due to the effects of tamoxifen in the uterus.
The side effects of AIs include, but are not limited to, fatigue, hot flashes, arthralgias, and decreased bone mineral density. AIs can lead to the loss of bone over time. Patients are encouraged to take vitamin D and calcium supplements. In the setting of osteopenia or osteoporosis, bisphosphonates or denosumab are used. The addition of ovarian suppression to ET has shown to increase the rate of adverse events, especially musculoskeletal symptoms, decreased bone density, dyspareunia, and vaginal dryness. Common side effects with fulvestrant include injection site pain, musculoskeletal symptoms, and fatigue.
Targeted Therapy
CDK 4/6 inhibitors : The common side effects are neutropenia, anemia, thrombocytopenia, fatigue, and nausea. Diarrhea is seen with abemaciclib.
Everolimus : The side effects include, but are not limited to, hyperglycemia, stomatitis, pneumonitis, and risk of infection.
Alpelisib : Common side effects include hyperglycemia, sometimes requiring involvement of an endocrinologist, lymphopenia, anemia, nausea, rash, interstitial pneumonitis, and headaches.
Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer
Approximately 20% of breast cancers have HER2 amplification. Prior to HER2-targeted therapy, the prognosis was dismal. HER2-directed therapy greatly changed the outcomes in this patient population.
Nonmetastatic
Trastuzumab is a monoclonal antibody directed against the HER2 receptor. The combination of trastuzumab with different chemotherapy backbones has shown to improve both disease-free survival and overall survival in the adjuvant setting. Most studies have shown that 1 year of trastuzumab is the optimal length of therapy.
In patients with small tumors (≤2 cm) and negative lymph nodes, the combination of trastuzumab with single-agent paclitaxel given weekly for 12 weeks in the adjuvant setting is appropriate. This is based on a phase 2 single-arm study that showed a 7-year disease-free survival of 93%.
For patients with tumors larger than 2 cm and/or positive lymph nodes, neoadjuvant therapy is often preferred. Pertuzumab is a newer monoclonal antibody that binds to a different domain of the HER2 receptor that has been studied in combination with trastuzumab and different chemotherapy regimens. In the neoadjuvant setting, it improved the rate of pCR, whereas in the adjuvant setting it showed a small but statistically significant improvement in invasive disease-free survival (IDFS), especially in patients with positive lymph nodes.
Neratinib is an oral tyrosine kinase inhibitor that was studied in the ExteNET trial. The addition of neratinib for 1 year, after completing a year of adjuvant trastuzumab, showed a statistically significant improvement in IDFS. A prespecified subgroup analysis suggested that the benefit was greater in patients with HR-positive disease.
Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate of trastuzumab with the cytotoxic agent DM1 that is approved for the adjuvant treatment of HER2-positive disease in patients who do not achieve a pathologic complete response after neoadjuvant therapy. This approval was based on the results of the Katherine trial.
Metastatic
The combination of a taxane with trastuzumab and pertuzumab is the preferred first-line therapy for metastatic HER2-positive breast cancer. The pivotal trial that led to the approval of trastuzumab in 2001 showed a significant improvement of PFS and overall survival when it was added to chemotherapy in patients with metastatic HER2-positive breast cancer. The addition of pertuzumab is supported by the results of the Cleopatra trial. Chemotherapy is continued for 4–6 months or to the time of maximal response, and then HER2-targeted therapy is continued until progression.
The preferred second-line agent is the antibody–drug conjugate T-DM1. It has shown to improve PFS and overall survival. The treatment beyond second line often includes some form of HER2-directed therapy, in combination with chemotherapy. Lapatinib, an oral tyrosine kinase inhibitor, can be used in this setting.
In patients with HER2-positive and HR-positive breast cancer, ET is usually added in combination with HER2-directed therapy once chemotherapy is completed.
Toxicities
Trastuzumab is associated with the increased risk of heart failure. Patients need to be monitored with routine echocardiograms while receiving trastuzumab. The incidence is higher in patients who receive anthracycline-based chemotherapy. Other side effects include infusion reactions and pulmonary toxicity. The addition of pertuzumab to trastuzumab-containing regimens increases the incidence of diarrhea and rash.
In the Katherine trial, more patients in the T-DM1 arm had neuropathy, thrombocytopenia, and pneumonitis when compared to trastuzumab. Diarrhea is a common side effect of lapatinib and neratinib. For this reason, antidiarrheal prophylaxis is often given with these medications.
Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) lacks the expression of the ER, progesterone receptor, and HER2 receptor. TNBC is a very aggressive subtype of breast cancer. Chemotherapy is the mainstay treatment for TNBC.
Nonmetastatic
Chemotherapy is indicated for any tumor that is greater than 0.5 cm. Depending on the size of the tumor and the presence of lymph nodes, chemotherapy is given either prior to surgery (neoadjuvant) or after surgery (adjuvant).
There are a number of chemotherapy regimens that are active in breast cancer. The most widely used regimens include anthracyclines, alkylators, and taxanes. The preferred regimen is dose-dense adriamycin with cyclophosphamide followed by paclitaxel (dd AC-T). Other regimens include the combination of cyclophosphamide, methotrexate and fluorouracil or the combination of docetaxel with cyclophosphamide.
The addition of taxanes is supported by many randomized trials. A metaanalysis of 13 trials, including 22,903 patients, showed that the addition of taxanes to an anthracycline-based regimen improved both disease-free survival and overall survival. The benefit was independent of HR status.
A metaanalysis of three adjuvant trials, including 4242 women, showed that the addition of anthracyclines to a taxane-based regimen improved IDFS in patients with high-risk breast cancer. The 4-year IDFS was 90.7% for the anthracycline-containing regimen and 88.2% for the nonanthracycline-containing regimen. Exploratory analysis suggested that the benefit of adding anthracyclines was greater in patients with HR-negative breast cancer and in women with positive lymph nodes.
Finally, shortening the interval between treatments (dose-dense regimens) has shown to improve disease-free survival and breast cancer mortality.
The addition of carboplatin in the neoadjuvant setting has shown to improve the rates of pathologic complete response, but this has not translated into improvement in overall survival and is not widely used.
In patients who received neoadjuvant chemotherapy and do not achieve a pathologic complete response, adjuvant capecitabine has shown to improve outcomes in patients with TNBC.
Metastatic
Chemotherapy is the mainstay treatment for TNBC and is used first line with or without immunotherapy.
For patients who have programmed cell death-ligand 1 (PD-L1), positive immune cells in their tumor, the combination of atezolizumab with paclitaxel protein bound (nab-paclitaxel) as first-line treatment has shown to improve outcomes when compared with chemotherapy.
For patients who lack PD-L1 positive immune cells and do not have progressive visceral disease, single-agent sequential chemotherapy is the preferred option. Combination chemotherapy can be considered in patients with progressive visceral disease who need a prompt response. The patient’s preferences and overall health status are always taken into consideration when deciding on treatment. Common chemotherapy treatments are taxanes, anthracyclines, vinorelbine, gemcitabine, eribulin, and capecitabine. In individuals with BRCA mutations, carboplatin may be considered.
Poly (ADP-ribose) polymerase (PARP) inhibitors are an option for patients with germ line BRCA1 or BRCA2 mutations and MBC. Talazoparib and olaparib have shown to improve outcomes when compared to standard chemotherapy and are approved for patients with locally advanced or metastatic breast cancer with a BRCA1 or BRCA2 mutation who were treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting.
Toxicities
Chemotherapy
Chemotherapy is associated with many toxicities. Many patients will have fatigue, nausea, vomiting, mucositis, and alopecia. Cytopenias are not uncommon. Prophylactic growth factor support is needed in some adjuvant and neoadjuvant regimens to decrease the risk of febrile neutropenia.
Depending on the type of chemotherapy and the risk of emesis, patients receive prophylactic medications. Some of the premedications include steroids, olanzapine, and neurokinin 1 receptor (NKR1) antagonists such as aprepitant and selective type three 5-hydroxytryptamine (5-HT3) receptor antagonists such as ondansetron or palonosetron. Patients may require additional medications to control the nausea and vomit after chemotherapy. Antiemetics such as ondansetron and prochlorperazine are often given. Anticipatory nausea and vomiting can be triggered by strong smells, taste, or emotions and may not have a direct relationship with the timing of chemotherapy. This can be controlled with cognitive behavioral therapy, acupuncture, or with anxiolytic medications such as lorazepam.
Anthracyclines are associated with cardiotoxicity. Prior to initiation of anthracyclines, patients need to have a baseline echocardiogram. Anthracyclines have also been associated with secondary acute myeloid leukemia and myelodysplastic syndrome. Taxanes can cause anaphylaxis, and patients need premedication with steroids and antihistamines prior to starting the infusion. Patients need to be monitored for peripheral neuropathy and fluid retention.
Atezolizumab
In patients receiving immunotherapy, it is important to monitor immune-mediated reactions such as pneumonitis, thyroiditis, and hepatitis.
PARP Inhibitors
The two approved PARP inhibitors for breast cancer are olaparib and talazoparib. Talazoparib is associated with more fatigue, nausea, and anemia when compared with chemotherapy. Anemia, requiring transfusion, is more frequent with olaparib than in patients receiving chemotherapy.
Conclusion
When treating breast cancer, it is always important to maximize efficacy and minimize toxicity. Patient’s preferences should always guide the therapy that is given. The systemic treatment differs based on the stage of the disease (metastatic vs nonmetastatic) and the receptor status. Great advances have been made in the systemic treatment of breast cancer, and the outcomes have improved significantly with the discovery of new therapies. Unfortunately, there are still many patients that recur and die from the disease despite systemic therapy. For this reason, many clinical trials are evaluating new drugs and different combinations with the ultimate goal of reducing breast cancer mortality.
Patient Resources
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American Cancer Society: https://www.cancer.org/cancer/breast-cancer.html
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American Society of Clinical Oncology (ASCO): https://www.cancer.net/sites/cancer.net/files/asco_answers_guide_breast.pdf
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Clinical Trials: https://clinicaltrials.gov
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NCCN guidelines for patients: https://www.nccn.org/patients/guidelines/breast-invasive/index.html
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References
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