Table 2.

Clinical scenarios

Scenario 1. What to do when the disease progresses after a second-line of trastuzumab containing-regimen?

Background: There is a substantial lack of evidence on what to do beyond a second-line trastuzumab-containing regimen. However, the clinical trial TH3RESA showed promising results with T-DM1. In this setting, T-DM1 provided a significant improvement in PFS (HR=0.53, 95% CI 0.42–0.66) with a better safety profile than the physician's choice treatment in patients with mBC treated with at least 2 previous lines of anti-HER2 therapy [34]. In addition, the combination of trastuzumab and lapatinib has been shown to improve OS in heavily pretreated patients with disease progression after adjuvant or metastatic treatment [29, 35].

Recommendation: HER2-positive mBC with progression of disease after 2 or more previous HER2-targeted therapies can be treated with T-DM1 or dual HER2 blockade. Whenever T-DM1 is available and was not given in previous lines, it seems to be the best treatment option in almost all settings. Only when lapatinib is a particularly attractive option (e.g. if there are brain metastases; see Scenario 4) may the dual HER2 blockade be more promising than T-DM1.

Scenario 2. When to consider clinical resistance to anti-HER2 therapy?

Background: This scenario refers to the concept of a clinical resistance to anti-HER2 rather than a molecular resistance to anti-HER2 described elsewhere [36]. It is based on the clinical experience of the group of experts in situations where there is lack of clinical benefit.

Recommendation: Patients with mBC meeting the 3 following criteria can be considered to possess clinical resistance to anti-HER2: At least 3 consecutive lines of anti-HER2 therapy

At least 1 dual anti-HER2 targeted therapy

Progression of the disease after the first assessment of tumor during fourth- or later-line treatment

Scenario 3. When to re-treat with trastuzumab after lapatinib-containing regimen?

Background: Re-treatment with trastuzumab after disease progression during lapatinib-containing therapy has been shown to provide a clinical benefit of 47% [37]. Even after exposure to T-DM1, re-treatment with trastuzumab appears to have a potential benefit [38].

Recommendation: For those patients with mBC and progression of the disease after a lapatinib-containing second-line regimen, re-treatment with trastuzumab can be considered based on the following criteria:

T-DM1 (if available, and not given in previous lines) may have priority over the others Dual HER2 blockade

Added to chemotherapy

Scenario 4. What to do in patients with brain metastases concerning anti-HER2 therapy?

Background: Anti-HER2 therapies have limited potential to cross the blood-brain barrier, and the available evidence is not strong enough to recommend treatment for these patients [39]. ASCO practice guidelines suggest the continuation of HER2-targeted therapy for patients who receive standard therapy for the treatment of brain metastases (surgical and/or radiotherapy) and whose systemic disease is progressive at the time of brain metastasis diagnosis [19]. For systemic therapy, lapatinib may be a potential option in this setting, although the evidence so far is rather exploratory [40]. Recently, the drug penetration of capecitabine and lapatinib uptake in resected brain metastases from women with metastatic breast cancer has been reported in a case-series study [41]. Therefore, the combination of lapatinib and capecitabine may be considered in this setting [19].

Recommendation: For patients with mBC and brain metastases with progression of disease after anti-HER2 therapy, the combination of lapatinib and chemotherapy may be a good option after best local treatment.

Scenario 5. When to continue trastuzumab after a complete response?

Background: If there is evidence supporting the use of trastuzumab beyond the progression of disease [22, 42], it is recommended to continue with trastuzumab while there is a clinical benefit [14].

Recommendation: After a complete response with an anti-HER2-containing therapy, anti-HER2 therapy can be continued until the progression of disease, unacceptable toxicity or patient decision, in the absence of evidence to discontinue anti-HER2 earlier.

Patients’ preferences should be discussed to make a patient-physician shared decision.

T-DM1 = trastuzumab emtansine, PFS = progression-free survival, HR = hazard ratio, CI = confidence interval, mBC = metastatic breast cancer, HER2 = human epidermal growth factor receptor 2, OS = overall survival, ASCO = American Society of Clinical Oncology.