INTRODUCTION — Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among females worldwide [1]. In the United States, up to 5 percent of women diagnosed with breast cancer have metastatic disease at the time of first presentation despite the gains in early detection. In addition, up to 30 percent of women with early-stage, non-metastatic breast cancer at diagnosis will develop distant metastatic disease [2]. Although metastatic breast cancer is unlikely to be cured, meaningful improvements in survival have been seen, coincident with the introduction of newer systemic therapies [3-5].
Available treatment options vary based on whether the tumor is hormone receptor positive (estrogen and/or progesterone receptor positive) and whether or not human epidermal growth factor receptor 2 (HER2) is overexpressed (ie, HER2 positive). The treatment of HER2-positive metastatic breast cancer is reviewed here. An overview of the approach to metastatic breast cancer, HER2 as a predictive marker, endocrine therapy for hormone receptor-positive metastatic breast cancer, chemotherapy for metastatic breast cancer, and breast cancer in men are reviewed separately. In addition, commonly used chemotherapy treatment regimens in the treatment of breast cancer are also compiled in a separate topic.
●(See "Overview of the approach to metastatic breast cancer".)
●(See "HER2 and predicting response to therapy in breast cancer".)
●(See "Breast cancer in men".)
●(See "Treatment protocols for breast cancer".)
RATIONALE FOR HER2-DIRECTED THERAPY AND AVAILABLE AGENTS — Approximately 20 percent of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein epidermal growth factor receptor (EGFR) with tyrosine kinase activity. Historically, overexpression of this receptor was associated with an increased risk of disease recurrence and an overall worse prognosis.
A high level of HER2 overexpression, as determined by either 3+ staining by immunohistochemistry for the HER2 protein or evidence of HER2 gene amplification by fluorescence in situ hybridization (FISH ratio ≥2.0 or HER2 copy number ≥6.0), is a strong predictive factor for sensitivity to HER2-targeted agents, and these criteria should be used to select patients for these drugs [6-8]. Patients without HER2 overexpression do not appear to benefit from these drugs [9,10]. Recommendations for assessing HER2 status, selection of patients, and HER2 status discordance between the primary tumor and metastases are presented separately. Of note, biopsy of tumor metastases and analysis for HER2 status is recommended. (See "HER2 and predicting response to therapy in breast cancer" and "Overview of the approach to metastatic breast cancer".)
Therapies that target HER2 have become important agents in the treatment of metastatic breast cancer and have altered the natural course of HER2-positive breast cancer [11]. Because the use of HER2-directed therapy improves survival for patients with HER2-positive metastatic breast cancer, we recommend that such patients receive HER2-directed therapy as first- and later-line treatment [12]. In a meta-analysis of seven randomized trials, involving 1497 patients with HER2-positive metastatic breast cancer, the addition of trastuzumab to treatment improved overall survival (hazard ratio 0.82, 95% CI 0.71-0.94) [12]. Trastuzumab extended time to death by between five and eight months. Although it also increased the risk of congestive heart failure (relative risk 3.49, 90% CI 1.88-6.47), cardiotoxicity was reversible with holding treatment.
Multiple HER2-directed agents are available for use in the treatment of HER2-positive breast cancer, either in the first-line or later-line setting:
●Trastuzumab – Trastuzumab is a monoclonal antibody that binds the extracellular domain of HER2. Information about prescribing trastuzumab, including available formulations, is discussed separately. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Prescribing information and formulations'.)
●Pertuzumab – Pertuzumab is a monoclonal antibody that binds the extracellular dimerization domain of HER2 and prevents it from binding to itself or to other members of the EGFR family. It is administered in combination with trastuzumab rather than as a single agent in the treatment of HER2-positive breast cancer. (See 'Trastuzumab plus pertuzumab plus a taxane' below.)
●Ado-trastuzumab emtansine (T-DM1) – Ado-trastuzumab emtansine (also commonly referred to as T-DM1) is an antibody-drug conjugate composed of trastuzumab, a thioether linker, and the antimicrotubule agent DM1. The HER2-directed antibody-drug conjugates incorporate a cytotoxic agent, and therefore chemotherapy is not added. (See 'Earlier line options' below.)
●Fam-trastuzumab deruxtecan (T-DXd) – T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. As with T-DM1, this conjugate incorporates a cytotoxic agent, and chemotherapy is not added. (See 'Fam-trastuzumab deruxtecan (preferred)' below.)
●Tucatinib – Tucatinib is an oral tyrosine kinase inhibitor that is selective for the kinase domain of HER2, with minimal inhibition of EGFR. It is used in combination with capecitabine and trastuzumab. (See 'Tucatinib, capecitabine, and trastuzumab' below.)
●Lapatinib – Lapatinib is a tyrosine kinase inhibitor against EGFR1 and HER2 that results in inhibition of signaling pathways downstream of HER2, used in combinations with trastuzumab or capecitabine. (See 'Lapatinib plus trastuzumab' below and 'Tyrosine kinase inhibitor plus capecitabine' below.)
●Neratinib – Neratinib is an irreversible pan-HER inhibitor, used in combination with capecitabine. (See 'Tyrosine kinase inhibitor plus capecitabine' below.)
●Margetuximab – Margetuximab is an Fc-engineered anti-HER2-receptor monoclonal antibody used in combination with chemotherapy. (See 'Margetuximab' below.)
PREVIOUSLY UNTREATED PATIENTS
Preferred option — While there is no ideal strategy for the management of patients with HER2-positive metastatic breast cancer, one reasonable approach stratifies patients by whether or not they were previously treated with trastuzumab in the adjuvant setting. For previously untreated patients, we suggest trastuzumab, pertuzumab, and a taxane (docetaxel or paclitaxel). This regimen improves clinical outcomes compared with trastuzumab plus docetaxel. For most patients receiving treatment with trastuzumab or pertuzumab, we administer the HER2-directed agent along with chemotherapy. (See 'Trastuzumab plus pertuzumab plus a taxane' below.)
However, patients with hormone receptor- and HER2-positive metastatic breast cancer may receive HER2-directed therapy in combination with endocrine therapy, especially if their disease is not rapidly progressive or symptomatic, or is not characterized by significant visceral involvement (ie, multiorgan metastases). For women with hormone receptor-positive, HER2-positive disease, endocrine plus HER2-directed therapy may offer a less toxic approach compared with HER2 treatment combined with chemotherapy. (See 'Special considerations for hormone receptor-positive disease' below.)
The approach to those with previous HER2-directed therapy in the adjuvant or neoadjuvant setting is discussed below. (See 'Patients who received (neo)adjuvant HER2-directed therapies' below.)
Trastuzumab plus pertuzumab plus a taxane — For patients with untreated HER2-positive metastatic breast cancer who did not receive adjuvant therapy at the time of the initial diagnosis, we administer trastuzumab plus pertuzumab in combination with a taxane (docetaxel or paclitaxel). In our practice, we often use weekly paclitaxel rather than docetaxel with this combination as a less toxic and better tolerated taxane. However, other taxanes are appropriate in this setting. Alternatives to this regimen, and particular considerations for those with hormone receptor-positive disease, are discussed below. (See 'Special considerations for hormone receptor-positive disease' below.)
The evidence to support the three-agent combination of trastuzumab plus pertuzumab and a taxane comes from the phase III CLEOPATRA trial, including 808 women with HER2-positive metastatic breast cancer who were treated with trastuzumab (8 mg/kg loading dose then 6 mg/kg intravenous [IV]) and docetaxel (75 mg/m2 IV) and then randomly assigned to treatment with pertuzumab (840 mg loading dose then 420 mg) or placebo [13,14]. Treatment was administered every three weeks and continued until disease progression or intolerable side effects. Approximately 10 percent of these patients had previously received trastuzumab in the adjuvant or neoadjuvant setting. At a median follow-up of 19 months, the addition of pertuzumab to docetaxel plus trastuzumab resulted in (see "Treatment protocols for breast cancer", section on 'THP (docetaxel, trastuzumab, and pertuzumab)'):
●Improvement in the overall response rate (ORR, 80 versus 69 percent).
●Improvement in progression-free survival (PFS) compared with placebo (median, 19 versus 12 months; hazard ratio [HR] 0.62, 95% CI 0.51-0.75).
At over eight years of follow-up, the addition of pertuzumab resulted in:
●Improvement in overall survival (OS) compared with placebo (median, 57 versus 41 months without pertuzumab; eight-year survival rates of 37 versus 23 percent without pertuzumab; HR for death 0.69, 95% CI 0.58-0.82) [15].
Trastuzumab, pertuzumab, and docetaxel is associated with higher rates of toxicity compared with trastuzumab and docetaxel [13]. These included higher rates of diarrhea (67 versus 46 percent), neutropenia (53 versus 50 percent), rash (34 versus 24 percent), mucosal inflammation (27 versus 20 percent), dry skin (10 versus 4 percent), and serious (grade 3/4) febrile neutropenia (14 versus 8 percent). However, there was no increase in the rate of left ventricular dysfunction, which was very low in both arms (1 versus 2 percent).
Although the CLEOPATRA trial described above used docetaxel, we consider other taxanes to be acceptable alternatives to docetaxel in combination with trastuzumab and pertuzumab. In the first reporting from the PERUSE study, among 1436 patients with advanced HER2-positive breast cancer, median PFS was comparable between docetaxel, paclitaxel, and nanoparticle albumin-bound paclitaxel (nabpaclitaxel; 20, 23, and 18 months, respectively) [16]. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (31 versus 16 percent), but less febrile neutropenia (1 versus 11 percent) and mucositis (14 versus 25 percent). A limitation in interpretation of these data, however, is that patients were not randomly assigned to different taxanes.
The addition of trastuzumab to chemotherapy has shown OS benefits in the adjuvant setting as well. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Benefits'.)
Formulations — Subcutaneous forms of trastuzumab as well as trastuzumab and pertuzumab have received approval by the US Food and Drug Administration based on similar pathologic complete response rates as the IV forms of these therapies when used with chemotherapy in the neoadjuvant setting [17-20]. Either formulation may be used in the metastatic setting. Further data are discussed elsewhere. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Formulations'.)
Alternatives
Options irrespective of hormone receptor status — For patients who are otherwise candidates for trastuzumab plus pertuzumab but are not appropriate candidates for a taxane for whatever reason, there are limited data to guide the choice of an alternative agent. Most often, we would use ado-trastuzumab emtansine (T-DM1); though if peripheral neuropathy is significant, single-agent trastuzumab or trastuzumab plus pertuzumab may be used. Additionally, treatments used for later-line treatment with less neurotoxicity could be considered. The choice of the appropriate treatment should be guided by patient and provider preferences. (See 'Patients who require second- or later-line treatment' below.)
●Ado-trastuzumab emtansine (T-DM1) – T-DM1 is an antibody-drug conjugate composed of trastuzumab, a thioether linker, and a microtubule inhibitor, DM1 [21]. Although this could be an alternative first-line treatment for patients unable to receive trastuzumab plus pertuzumab plus taxane, we typically utilize T-DM1 in later lines, if they have not received it in the post-neoadjuvant setting. (See 'Earlier line options' below.)
The role of T-DM1 as a first-line treatment of advanced or metastatic HER2-positive breast cancer was evaluated in the phase III MARIANNE trial [22]. This trial enrolled over 1000 women with progressive or recurrent locally advanced breast cancer or previously untreated metastatic breast cancer (provided they had at least a six-month treatment-free interval from neoadjuvant or adjuvant treatment). Patients were randomly assigned to trastuzumab plus a taxane (docetaxel or paclitaxel, arm 1), T-DM1 plus placebo (arm 2), or T-DM1 plus pertuzumab (arm 3).
•The median PFS for arms 1, 2, and 3 was 13.7, 14.1, and 15.2 months, respectively. There was no significant difference in PFS in arm 2 compared with arm 1 (HR 0.91, 97.5% CI 0.73-1.13), arm 3 compared with arm 1 (HR 0.87, 97.5% CI 0.69-1.08), or between arm 3 and arm 2 (HR 0.91, 97.5% CI 0.73-1.13).
•The ORR in the three arms was 68, 60, and 64 percent, respectively.
•Some toxicities, including neutropenia, neuropathy, and peripheral edema, were less frequently reported in the nontaxane arms. In particular, alopecia was numerically much less common in the nontaxane arms (60 percent with taxane versus 7 percent with T-DM1 and 9 percent with T-DM1 plus pertuzumab). Liver function test abnormalities and thrombocytopenia were more commonly reported in the T-DM1 arms.
●Single-agent trastuzumab, or trastuzumab plus pertuzumab – For patients who want to avoid cytotoxic chemotherapy, the administration of single-agent trastuzumab or trastuzumab plus pertuzumab may be reasonable, in particular if they do not have visceral disease and could tolerate some initial disease progression without survival consequence. Moreover, if a patient initiates single-agent trastuzumab or trastuzumab plus pertuzumab and progresses on therapy, we add chemotherapy to treatment rather than discontinue trastuzumab. Although this sequential treatment (trastuzumab alone followed by chemotherapy upon disease progression or vice versa) reduces the risk of initial treatment-related toxicity, available data cannot assure non-inferiority for OS from the sequential approach.
We are aware of three published trials randomizing patients to chemotherapy plus trastuzumab, or the sequence of trastuzumab followed by chemotherapy at disease progression [23-25]. The main characteristics and efficacy findings from these trials are summarized in the table (table 1). Together, these results suggest, but do not prove, that the sequential approach (antibody therapy followed by chemotherapy at progression) may not be inferior to the combination strategy. We therefore consider trastuzumab monotherapy or trastuzumab plus pertuzumab for select patients who desire to avoid chemotherapy or in whom cytotoxic therapy is contraindicated due to concurrent illness or comorbidity.
In situations where chemotherapy is not given, we prefer dual monoclonal antibody therapy with trastuzumab plus pertuzumab, based on improved outcomes with the addition of pertuzumab in the CLEOPATRA trial (with chemotherapy), in the phase II PERTAIN trial (with endocrine therapy), as well as improved complete pathologic response rate in the NEOSPHERE neoadjuvant trial. (See 'Trastuzumab plus pertuzumab plus a taxane' above and 'Special considerations for hormone receptor-positive disease' below and "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Addition of pertuzumab'.)
Special considerations for hormone receptor-positive disease — Women with hormone receptor-positive, HER2-positive breast cancer should receive HER2-directed therapy as a component of their first-line treatment plan. While most patients are treated in the first line with a HER2-directed agent plus chemotherapy, HER2-directed therapy in combination with endocrine therapy is an acceptable alternative for those whose disease is not rapidly progressive or symptomatic, or is not characterized by significant visceral involvement (ie, multiorgan metastases). For such women, endocrine plus HER2-directed therapy may offer a less toxic first-line approach compared with HER2 treatment combined with chemotherapy.
●For premenopausal women in whom HER2-directed therapy and endocrine therapy are appropriate, our typical approach is to offer ovarian suppression or ablation in combination with endocrine therapy and HER2-directed therapy. We prefer an aromatase inhibitor (AI) over tamoxifen as the endocrine agent in this setting.
●For postmenopausal women in whom HER2-directed therapy and endocrine therapy are appropriate, administration of HER2-directed therapy plus an AI is an effective treatment strategy.
Results of the randomized phase II PERTAIN study, in which 258 postmenopausal women were randomly assigned to first-line pertuzumab plus trastuzumab and an AI (anastrozole or letrozole) or trastuzumab plus an AI, suggest improved PFS with the three-drug combination (18.9 versus 15.8 months; HR 0.65, 95% CI 0.48-0.89) [26]. Grade 3 or higher adverse events were observed in 50 percent of patients receiving trastuzumab and pertuzumab versus 39 percent of those receiving trastuzumab alone. Although these results are arguably strong for a regimen excluding chemotherapy, it must be noted that one-half of women received induction therapy with a taxane for 18 to 24 weeks prior to the initiation of endocrine therapy.
PATIENTS WHO RECEIVED (NEO)ADJUVANT HER2-DIRECTED THERAPIES — In the case of disease relapse after adjuvant treatment, we choose first-line metastatic treatment based on what treatment exposure the patient has had and the treatment-free interval.
In view of the lack of consensus or high-quality data regarding the issue of a treatment-free interval, we base our decisions on an interval of six months to determine subsequent treatment, which is a definition used by the US Food and Drug Administration.
Treatment-free interval of six months or longer — For patients with a treatment-free interval of six months or longer, we administer a taxane plus trastuzumab and pertuzumab. These patients were included in the clinical trial that established the benefit of this combination in women with HER2-positive metastatic breast cancer. (See 'Trastuzumab plus pertuzumab plus a taxane' above.)
Note that, since ado-trastuzumab emtansine (T-DM1) is now used as adjuvant therapy if there is not a complete pathologic response to neoadjuvant taxane, trastuzumab, and pertuzumab, there may be patients presenting with a treatment-free interval of six months or longer who have also received T-DM1. For such patients as well, it is appropriate to return to taxane, trastuzumab, and pertuzumab for treatment, or to consider use of later-line therapies such as fam-trastuzumab deruxtecan. (See 'Trastuzumab plus pertuzumab plus a taxane' above.)
Treatment-free interval of less than six months
The majority of patients presenting with early-stage, HER2-positive breast cancer will be treated with trastuzumab, pertuzumab, and a taxane in the (neo)adjuvant setting, and those patients with residual disease will receive adjuvant T-DM1. For patients who relapse on treatment or within six months of completing adjuvant HER2-directed treatment, we will proceed with appropriate second- and later-line HER2-directed therapies. (See 'Patients who require second- or later-line treatment' below.)
MONITORING THERAPY AND DEFINITION OF TREATMENT FAILURE
●The continuous evaluation of patients during therapy (including timing of imaging and the selection of imaging modality) should be individualized according to patient preferences, disease-related factors (sites of disease, evaluability of disease by imaging or tumor markers, pace of disease progression), and clinical factors (renal function, iodinated contrast dye allergy, presence of uncontrolled diabetes). Careful assessment for response to treatment requires serial clinical examination, repeat laboratory evaluation (including tumor markers when initially elevated), and radiographic imaging. Further discussion on the monitoring of patients with metastatic breast cancer is covered separately. (See "Overview of the approach to metastatic breast cancer" and "Overview of the approach to metastatic breast cancer", section on 'Monitoring therapy'.)
●Treatment failure is determined for HER2-positive breast cancer as it is for HER2-negative breast cancer, and is discussed in more detail elsewhere. (See "Overview of the approach to metastatic breast cancer".)
●Patients on HER2-directed therapy require regular monitoring of cardiac function with echocardiogram or multigated acquisition scan. We typically follow the recommendations for cardiac monitoring presented in the drug label (every three months) for the first year of therapy, and if there has been no evidence of cardiac toxicity after a year of treatment, we decrease the frequency of monitoring to every six months for patients remaining on treatment. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)
DURATION OF TREATMENT
Optimal treatment duration of chemotherapy — For patients receiving a taxane, trastuzumab, and pertuzumab as their first-line treatment for metastatic disease, 5 to 10 percent of patients will have a complete radiologic response to this three-agent combination [7]. After achievement of best response to treatment (usually after 6 to 12 months of combined therapy), we will typically discontinue cytotoxic chemotherapy and continue trastuzumab (with or without pertuzumab therapy), although the optimal duration of trastuzumab treatment is also unknown. (See 'Optimal treatment duration of a HER2-directed agent' below.)
In patients whose tumors are also hormone receptor positive, we will add endocrine therapy to HER2-directed therapy following discontinuation of chemotherapy. A typical treatment approach upon discontinuation of chemotherapy would be to use an aromatase inhibitor (with ovarian suppression or ablation for women who are premenopausal) in combination with HER2-directed therapy. (See 'Special considerations for hormone receptor-positive disease' above.)
Further discussion on the duration of cytotoxic chemotherapy in the metastatic setting is discussed separately. (See "Treatment of endocrine therapy resistant/refractory hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Duration of treatment'.)
Optimal treatment duration of a HER2-directed agent — After achievement of best response to treatment (usually after 6 to 12 months of combined therapy) and for whom cytotoxic chemotherapy has been discontinued, the decision on whether and how long to continue HER2-directed therapy should be individualized because there are no prospective data to inform this issue.
Anti-HER2-directed therapy can be continued for years in such patients, and in our experience, decades, without disease progression. However, the same can be said for patients who discontinued treatment. While continuation of HER2-directed treatment can increase the risk of cumulative toxicity (especially cardiotoxicity), increase healthcare costs, and may be inconvenient, these considerations must be balanced by the potential benefit of treatment in delaying (or preventing) disease progression.
For those who experience progression at any point, we move to next-line therapy. (See 'Patients who require second- or later-line treatment' below.)
PATIENTS WHO REQUIRE SECOND- OR LATER-LINE TREATMENT — For patients with metastatic breast cancer who progress on HER2-directed therapy, we continue HER2-directed agents with subsequent regimens as needed, provided there is no evidence of clinically significant toxicity. The decision to continue HER2-directed treatment, and the choice of subsequent therapy, must be based on an individualized assessment of treatment-related toxicity, prior treatments, and patient preferences. (See 'Later line options/alternatives' below.)
Subsequent treatment with HER2-directed agents in the metastatic setting may be limited by a cardiomyopathy, potentially caused by cardiotoxicity induced by these agents. In these situations, cooperation between the oncologist and a cardiologist is advised to optimize management of the patient. In addition, antibody-drug conjugates such as fam-trastuzumab deruxtecan, and to a lesser extent ado-trastuzumab emtansine, may cause interstitial lung disease/pneumonitis, and should be used with caution in patients with significant underlying lung disease. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)
Earlier line options
Fam-trastuzumab deruxtecan (preferred) — Fam-trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor [27]. It is approved by the FDA for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen in the metastatic, or (neo)adjuvant setting and developed progression during or within six months of completing therapy [28].
A randomized trial comparing ado-trastuzumab emtansine (T-DM1) and T-DXd is discussed below. (See 'Rationale for T-DXd over T-DM1' below.)
In a single-arm phase II trial, among 112 patients with a median of six prior lines of treatment, the median duration of PFS with T-DXd was 16 months. The most common grade ≥3 adverse events included decreased neutrophil count (21 percent), anemia (9 percent), and nausea (8 percent). T-DXd was associated with interstitial lung disease in 14 percent of patients, including one patient who died from this complication. While on treatment, patients should be monitored for signs/symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. T-DXd should be permanently discontinued if grade 2 or higher interstitial lung disease/pneumonitis develops.
Ado-trastuzumab emtansine (alternative) — For patients who progress after trastuzumab and a taxane in the metastatic setting, with or without pertuzumab, T-DM1 is an alternative to fam-trastuzumab deruxtecan, provided they have not received it previously. This recommendation is based on randomized trial evidence showing benefit for T-DM1 over clinician's choice therapy. However, other appropriate strategies exist. (See 'Later line options/alternatives' below and 'Those with hormone receptor-positive disease' below and 'Rationale for T-DXd over T-DM1' below.)
●Comparison with clinician's choice of treatment – In the TH3RESA trial, 602 patients with unresectable, locally advanced, recurrent, or metastatic breast cancer were randomly assigned in a 2:1 ratio to treatment with T-DM1 or clinician's choice therapy [29,30]. All patients had progressed on at least two HER2-directed regimens (with progression on both trastuzumab- and lapatinib-containing regimens). Of those assigned to clinician's choice, the majority received trastuzumab plus chemotherapy (68 percent). Compared with treatment with clinician's choice, patients treated with T-DM1 had:
•An improvement in progression-free survival (PFS; median, 6.2 versus 3.3 months; hazard ratio [HR] 0.53, 95% CI 0.42-0.66). This improvement in PFS was seen in those patients treated with and in those treated without trastuzumab in the clinician's choice arm.
•An improvement in overall survival (OS; median, 22.7 versus 15.8 months; HR 0.68, 95% CI 0.54-0.85).
In addition, treatment with T-DM1 was not associated with an increased incidence of serious (grade 3/4) adverse events. Based on these data, T-DM1 should be administered in patients who progress on prior HER2-directed therapies.
●Comparison with lapatinib plus capecitabine – The EMILIA trial showed that T-DM1 improved survival outcomes compared with lapatinib plus capecitabine, after prior HER2-based treatment, without a significant risk of serious toxicity. This trial enrolled 978 patients with HER2-positive breast cancer previously treated with trastuzumab and a taxane (84 percent of whom had received trastuzumab in the metastatic setting), and randomly assigned them to treatment with T-DM1 (3.6 mg/kg intravenous [IV]) or the combination of capecitabine (1000 mg/m2 orally twice a day, days 1 to 14) plus lapatinib (1250 mg orally daily) with each regimen repeated every three weeks [31]. With a median duration of follow-up of 19 months, T-DM1 resulted in:
•An improvement in PFS compared with lapatinib plus capecitabine (median, 10 versus 6 months, respectively; HR 0.65, 95% CI 0.55-0.77).
•An improvement in OS (median, 31 versus 25 months; HR 0.68, 95% CI 0.55-0.85). A subsequent report of longer follow-up (>40 months) also showed improved survival with T-DM1, even in the presence of crossover treatment.
•A clinically significant improvement in the overall response rate (ORR; 44 versus 31 percent).
•A lower rate of serious (grade 3/4) toxicity overall (41 versus 57 percent), including diarrhea (2 versus 21 percent), palmar plantar erythrodysesthesia (0 versus 16 percent), and vomiting (0.8 versus 5 percent). The most common serious toxicities associated with T-DM1 were thrombocytopenia (13 versus 0.2 percent with capecitabine plus lapatinib) and elevated liver function enzymes: aspartate aminotransferase (AST) and alanine aminotransferase (ALT; 7 versus 2 percent, respectively).
•The incidence of left ventricular ejection fraction (LVEF) decline to less than 50 percent was low in both treatment arms (2 percent).
Of note, patients treated with T-DM1 in the EMILIA trial experienced an overall higher rate of bleeding compared with those treated with capecitabine plus lapatinib (30 versus 16 percent, respectively), though the rate of serious bleeding events was low in both arms (1.4 versus 0.8 percent). However, the etiology of bleeding is not entirely explained by other risk factors (eg, use of anticoagulants or concomitant thrombocytopenia). For example, in this trial, one patient who received T-DM1 experienced a grade 4 gastrointestinal bleeding event despite having a normal platelet count. Based on these findings, the US Food and Drug Administration (FDA) revised the label for T-DM1 in July 2014 to highlight this increased risk of bleeding with recommendations for careful follow-up for patients during treatment with T-DM1 [32].
●Comparison with fam-trastuzumab deruxtecan (T-DXd) – This is discussed below. (See 'Rationale for T-DXd over T-DM1' below.)
Rationale for T-DXd over T-DM1 — Given the strong advantage from T-DXd compared with ado-trastuzumab emtansine (T-DM1) in a randomized trial in the second-line setting, and expert guidelines [33-35], we suggest T-DXd after progression on a trastuzumab- and taxane-containing regimen for most patients, but recognize T-DM1 as an appropriate alternative. However, due to the risk of pulmonary toxicity with this agent, we also consider baseline pulmonary status when weighing the risks and benefits of this treatment and favor T-DM1 for those with significant pulmonary comorbidity.
In the phase III Destiny-Breast03 trial including 524 patients with HER2-positive metastatic breast cancer with progression on a trastuzumab- and taxane-containing regimen, median PFS was 28.8 months for T-DXd and 6.8 months for T-DM1 (HR 0.33, 95% CI 0.26-0.43) [35]. The T-DXd group experienced improved OS compared with the T-DM1 group (median OS not reached in either group, HR 0.64, 95% CI 0.47-0.87). Grade ≥3 adverse events occurred in 56 percent on T-DXd and 52 percent on T-DM1. Interstitial lung disease occurred in 15 percent of patients on T-DXd and 3 percent of those on T-DM1. Results among those with treated brain metastases are discussed elsewhere. (See "Brain metastases in breast cancer", section on 'HER2-positive disease'.)
Later line options/alternatives — For patients with HER2-positive metastatic breast cancer who experience disease progression following a trastuzumab-containing regimen, T-DXd, and T-DM1 in the metastatic setting, there are several other options available. Although there is no direct evidence supporting an optimal sequence of treatment, settings in which particular agents are favorable are presented.
Special approaches for those with hormone receptor-positive disease are discussed further below. (See 'Those with hormone receptor-positive disease' below.)
Tucatinib, capecitabine, and trastuzumab — Tucatinib is an oral tyrosine kinase inhibitor that is selective for the kinase domain of HER2, with minimal inhibition of epidermal growth factor receptor [36]. It is approved by the FDA for use in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens in the metastatic setting [37]. Given that it has shown efficacy among patients with brain metastases in a randomized trial, it is a particularly appealing later-line option for those with brain metastases from HER2-positive breast cancer. (See "Brain metastases in breast cancer", section on 'Tucatinib, capecitabine, and trastuzumab'.)
In a randomized trial including 480 heavily pretreated patients with HER2-positive metastatic breast cancer (median of four prior lines of therapy), the one-year PFS rate was 33 percent among patients receiving tucatinib-capecitabine-trastuzumab versus 12 percent among those receiving capecitabine-trastuzumab only (HR for disease progression or death 0.54, 95% CI 0.42-0.71), and the median duration of PFS was 7.8 and 5.6 months, respectively [36]. OS at two years was 45 percent in the tucatinib-combination group and 27 percent in the placebo-combination group (HR for death 0.66, 95% CI 0.50-0.88). Among patients with brain metastases, the one-year PFS rate among those receiving the capecitabine-trastuzumab combination with and without tucatinib was 25 versus 0 percent, respectively. Further details of results in this subset are found elsewhere. (See "Brain metastases in breast cancer", section on 'Tucatinib, capecitabine, and trastuzumab'.)
The most common grade ≥3 adverse events observed in the tucatinib-combination group versus the placebo-combination group were palmar-plantar erythrodysesthesia syndrome (13 versus 9 percent), diarrhea (13 versus 9 percent), elevations in ALT and AST levels (approximately 5 versus 0.5 percent for each), and fatigue (5 versus 4 percent).
Margetuximab — Margetuximab is an Fc-engineered anti-HER2-receptor monoclonal antibody that is FDA approved, in combination with chemotherapy, for treatment of metastatic HER2-positive breast cancer in patients who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease [38]. It has higher affinity for the Fc receptor CD16A than trastuzumab. However, as this is a relatively newer agent with only modest benefits over trastuzumab, and data have only been presented in abstract form, we reserve this agent as a later-line option, after agents discussed above are no longer effective or tolerated. The most common adverse drug reactions (>10 percent) with margetuximab plus chemotherapy include fatigue, gastrointestinal symptoms, headache, cough, dyspnea, infusion-related reactions, and palmar-plantar erythrodysesthesia. Additionally, left ventricular dysfunction can occur with margetuximab (1.9 percent). Cardiac monitoring is discussed elsewhere. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents", section on 'Margetuximab'.)
In the phase III SOPHIA trial, among 536 patients with disease progression after at least two lines of anti-HER2 therapy, the addition of margetuximab to chemotherapy prolonged PFS relative to trastuzumab plus chemotherapy (median PFS 5.8 versus 4.9 months; HR 0.76, 95% CI 0.59-0.98), with similar rates of OS [39]. Serious adverse events were comparable between the two groups.
Trastuzumab with cytotoxic agents — As an alternative to options described above, a reasonable strategy after progression on trastuzumab/pertuzumab chemotherapy regimens and T-DM1 is to resume trastuzumab with a different cytotoxic agent than was originally used.
Although the data are limited, continuation of HER2-directed agents is common practice and is supported by experts at UpToDate and guidelines, such as those published by the National Comprehensive Cancer Network [40] and the American Society of Clinical Oncology [41].
Despite the common practice of continuation of trastuzumab across multiple lines of treatment, there are only low-quality data to support this approach [23,42]. In one retrospective study that included 69 patients who were retreated with a trastuzumab-based strategy (typically incorporating chemotherapy) following disease progression on lapatinib, retreatment with a trastuzumab-based regimen was associated with an ORR of 31 percent with a median duration of response of eight months [43]. The median PFS and OS were 5 and 15 months, respectively. However, the lack of an appropriate control arm makes these results difficult to interpret.
Other tyrosine kinase inhibitor combinations — Several other tyrosine kinase inhibitor combinations are later-line options for patients who remain appropriate candidates for treatment, but there is no direct evidence supporting an optimal sequence of treatment.
Lapatinib plus trastuzumab — The combination of lapatinib and trastuzumab is an option for patients with HER2-positive metastatic breast cancer whose disease has progressed on trastuzumab, and is particularly attractive for patients who wish to avoid, or are not candidates for, chemotherapy.
In one trial, 296 patients, 51 percent of whom were hormone receptor negative, with disease progression following one or more prior trastuzumab-containing regimens were randomly assigned treatment with lapatinib alone or in combination with trastuzumab [44,45].
Compared with lapatinib alone, the combination of lapatinib and trastuzumab resulted in [45]:
●An improvement in PFS (median, 11 versus 8 weeks; HR 0.74, 95% CI 0.58-0.94)
●An improvement in OS (median, 14 versus 10 months; HR 0.74, 95% CI 0.57-0.97)
Of 148 patients in the lapatinib monotherapy arm, 77 patients crossed over to combination therapy [45]. With exclusion of the patients who crossed over from the analysis, a more pronounced benefit in OS was seen, favoring combination therapy (median, 14 versus 8 months; HR 0.65, 95% CI 0.46-0.94).
Additional evidence of efficacy of lapatinib plus trastuzumab has been documented in a hormone receptor-positive cohort. (See 'Those with hormone receptor-positive disease' below.)
Tyrosine kinase inhibitor plus capecitabine — Both lapatinib and neratinib have been studied in combination with the oral fluoropyrimidine chemotherapy capecitabine, and these combinations are appropriate later-line options for patients who remain candidates for treatment. A benefit is they allow avoidance of infusional therapy, since all involved drugs are administered orally. Another advantage is the theoretic diffusion across the blood-brain barrier, and possible activity against central nervous system metastases, although it is not clear this effect is established. (See "Brain metastases in breast cancer", section on 'Choosing between options'.)
Although both lapatinib and capecitabine are more effective than capecitabine alone, a prospective randomized clinical trial has demonstrated that neratinib is more effective than lapatinib when combined with capecitabine. We prefer to start with neratinib and capecitabine, but, if the gastrointestinal toxicity is intolerable in spite of appropriate conservative measure to treat it, it is reasonable to revert to lapatinib plus capecitabine to evaluate if that is better tolerated by the patient.
●Neratinib and capecitabine – Neratinib is approved by the FDA, in combination with capecitabine, for the treatment of adult patients with advanced HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting [46].
The FDA approval was based on results of the NALA trial. In this phase III trial, among 621 patients with metastatic HER2-positive breast cancer who had received two or more prior anti-HER2-based regimens in the metastatic setting, neratinib and capecitabine improved mean PFS relative to lapatinib with capecitabine (8.8 versus 6.6 months, respectively; HR 0.76, 95% CI 0.63-0.93), although OS results were similar (mean OS of 24 versus 22 months, respectively; HR 0.88, 95% CI 0.72-1.07) [47]. Diarrhea was the most frequent adverse event, with grade ≥3 diarrhea occurring in 24 percent of those receiving neratinib with capecitabine versus 13 percent receiving lapatinib with capecitabine.
A previously published phase II trial failed to demonstrate any difference between the neratinib monotherapy versus lapatinib combined with capecitabine [48].
●Lapatinib plus capecitabine – Lapatinib plus capecitabine is an option for patients who experience disease progression on trastuzumab, particularly if they prefer an orally administered regimen and do not tolerate neratinib. The use of this regimen among patients with brain metastases is discussed elsewhere. (See "Brain metastases in breast cancer", section on 'Alternatives or later-line options'.)
The systemic benefit of treatment was shown in a phase III trial of 399 patients randomly assigned to treatment with lapatinib (1250 mg once daily) plus capecitabine (1000 mg/m2 twice daily for 14 of every 21 days) or capecitabine alone (1250 mg/m2 twice daily) [49-51]. Compared with capecitabine, the combination of lapatinib plus capecitabine resulted in:
•A significant benefit in time to tumor progression (median, six versus four months).
•A trend towards an improvement in OS (median, 75 versus 65 weeks), which was not statistically significant.
Special considerations
Those who develop cardiomyopathy during treatment — Subsequent treatment with HER2-directed agents in the metastatic setting may be limited by a cardiomyopathy, potentially caused by cardiotoxicity induced by these agents. In these situations, cooperation between the oncologist and a cardiologist is advised to optimize management of the patient. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)
Those with hormone receptor-positive disease — In patients who have received trastuzumab, pertuzumab, and an aromatase inhibitor (AI) in the first line (as in the PERTAIN trial, above), it would be reasonable to discontinue pertuzumab and add lapatinib (with or without an alternative endocrine therapy) upon progression, provided that the disease is not rapidly progressive, symptomatic, or characterized by significant visceral involvement. This strategy would allow the further postponement of chemotherapy, for those who prefer to avoid it or are not appropriate candidates.
Management of hormone receptor-positive and HER2-positive metastatic disease without chemotherapy could conceivably include combinations of available endocrine therapies such as AIs, selective estrogen receptor down-regulators, or tamoxifen, with one or more of the approved HER2-targeted agents (including trastuzumab, pertuzumab, or lapatinib), and other targeted therapies (eg, an inhibitor of cyclin-dependent kinase 4/6 [CDK 4/6]), making the testing of each combination against the other impractical. Our practice is to determine which drugs the patient has already progressed on, and to adjust the combination of targeted therapies for disease control, keeping in mind that the one constant appears to be the benefit of continuing trastuzumab.
In the ALTERNATIVE trial, 355 postmenopausal women with HER2-positive, hormone receptor-positive metastatic breast cancer were randomly assigned to lapatinib plus trastuzumab plus an AI, lapatinib plus an AI, or trastuzumab plus an AI without chemotherapy [52]. All patients had received prior trastuzumab and prior endocrine therapy, either in the adjuvant or metastatic disease setting. PFS, the primary endpoint of the trial, was improved with the AI in combination with lapatinib plus trastuzumab, as compared with an AI plus trastuzumab without lapatinib (11 versus 5.6 months; HR 0.62, 95% CI 0.45-0.88). The ORR was also increased with the three-drug combination (31.7 versus 13.7 percent). OS data were immature in this initial report of the trial, and, therefore, it is uncertain whether the best strategy is to use the three-drug regimen (AI plus lapatinib plus trastuzumab) first; or whether it would be equally acceptable to first use an AI plus trastuzumab, and add lapatinib at the time of disease progression.
The incorporation of a CDK 4/6 inhibitor with endocrine and anti-HER2 therapy as a later-line option is supported by the phase II monarcHER trial. In this trial, 237 patients with unresectable locally advanced, recurrent, or metastatic disease who had previously received at least two lines of HER2-based therapy were randomly assigned to abemaciclib/fulvestrant/trastuzumab; abemaciclib/trastuzumab; or trastuzumab plus clinician's choice of standard-of-care single-agent chemotherapy [53]. At a median follow-up of 19 months, median PFS was 8.3 months in the abemaciclib/fulvestrant/trastuzumab group versus 5.7 in the other two groups (HR 0.67, 95% CI 0.45-1, in comparison with trastuzumab and chemotherapy). Overall response rates were 33 percent with abemaciclib/fulvestrant/trastuzumab, and 14 percent in each of the other arms. Differences in OS were not statistically significant, but results are still immature.
Approach to patients with HER2-low tumors — The approach to tumors that have low levels of HER2 expression are discussed elsewhere. (See "Overview of the approach to metastatic breast cancer", section on 'HER2-low tumors'.)
APPROACHES NOT TYPICALLY USED
Trastuzumab in combination with multiagent chemotherapy — We generally do not administer trastuzumab in combination with multiagent chemotherapy in the metastatic setting. Although this approach might improve response rates and progression-free survival (PFS), these gains are associated with an excess risk for toxicity [54-58]. Furthermore, no trials have demonstrated that this approach improves overall survival (OS). As an example, in one trial, 196 patients were randomly assigned treatment with trastuzumab plus either a combination regimen (paclitaxel and carboplatin) or single-agent paclitaxel [55]. Combination chemotherapy plus trastuzumab resulted in:
●A higher incidence of grade 3 and 4 hematologic toxicity.
●A higher objective response rate compared with trastuzumab plus paclitaxel (52 versus 36 percent).
●Longer PFS (median, 10.7 versus 7.1 months) but no statistically significant improvement in OS (median, 36 versus 32 months).
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)
SUMMARY AND RECOMMENDATIONS
●Introduction – Approximately 20 percent of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein epidermal growth factor receptor (EGFR) with tyrosine kinase activity.
●HER2 and predicting response to therapy – A high level of HER2 overexpression, as determined by either 3+ staining by immunohistochemistry (IHC) for the HER2 protein or evidence of HER2 gene amplification by fluorescence in situ hybridization (FISH ratio ≥2.0 or HER2 copy number ≥6.0), is a strong predictive factor for sensitivity to HER2-targeted agents, and these criteria should be used to select patients for these drugs. Patients without HER2 overexpression do not appear to benefit from these drugs. (See "HER2 and predicting response to therapy in breast cancer".)
●Rationale for HER2-directed therapy – For patients with metastatic HER2-positive breast cancer, we recommend that anti-HER2-directed therapy be included in the treatment regimen (Grade 1A). (See 'Rationale for HER2-directed therapy and available agents' above.)
●For patients with newly diagnosed metastatic disease – For patients with newly diagnosed metastatic disease, our approach is as follows:
•For patients who were not treated with trastuzumab previously (ie, in the adjuvant setting), we suggest the combination of trastuzumab, pertuzumab, plus a taxane (docetaxel or paclitaxel) rather than trastuzumab and a taxane alone (Grade 2B). (See 'Previously untreated patients' above.)
However, alternative strategies are acceptable:
-For patients who prefer not to proceed with a three-drug combination or are felt not to be good candidates for pertuzumab for whatever reason, trastuzumab plus a single-agent taxane (paclitaxel or docetaxel) is an appropriate regimen.
-For patients with hormone receptor- and HER2-positive metastatic breast cancer, HER2-directed therapy in combination with endocrine therapy is an acceptable alternative, especially if their disease is not rapidly progressive or symptomatic, or is not characterized by significant visceral involvement (ie, multiorgan metastases). For women with hormone receptor-positive, HER2-positive disease, endocrine plus HER2-directed therapy may offer a less toxic approach compared with HER2 treatment combined with chemotherapy. (See 'Special considerations for hormone receptor-positive disease' above.)
●Monitoring therapy – Careful assessment for response to treatment requires serial clinical examination, repeat lab evaluation (including tumor markers), and radiographic imaging. Patients on HER2-directed therapy require regular monitoring of cardiac function with echocardiogram or multigated acquisition scan. (See 'Monitoring therapy and definition of treatment failure' above and "Overview of the approach to metastatic breast cancer".)
●For patients requiring second- or later-line therapy – For patients who relapse after previous treatment with adjuvant trastuzumab, our approach takes into account the treatment-free interval:
•For patients who progress six months or longer after the completion of adjuvant therapy, we suggest trastuzumab plus pertuzumab in combination with a taxane (docetaxel or paclitaxel) rather than other agents (Grade 2C). (See 'Treatment-free interval of six months or longer' above and 'Trastuzumab plus pertuzumab plus a taxane' above.)
•For patients who progress during or within six months of adjuvant treatment, we suggest fam-trastuzumab deruxtecan (T-DXd) rather than trastuzumab-emtansine (Grade 2B), although we recognize that ado-trastuzumab emtansine (T-DM1) is a reasonable alternative. For those with baseline pulmonary comorbidity, T-DM1 is preferred. (See 'Rationale for T-DXd over T-DM1' above.)
For patients with HER2-positive metastatic breast cancer who experience disease progression following a trastuzumab-containing regimen and T-DM1 in the metastatic setting, options include T-DXd, continuation of trastuzumab with a different chemotherapy partner, tucatinib-capecitabine-trastuzumab, margetuximab, or a tyrosine kinase-based combination. The choice is often based on patient preference, prior toxicities, and drug availability. (See 'Patients who require second- or later-line treatment' above.)
