Optimizing systemic treatment in HER2-positive early breast cancer

Imaging can be used to evaluate the tumor response during and after neoadjuvant therapy with possibilities for response-based treatment adaptations. Positron emission tomography combined with computed tomography (PET/CT) with use of radiolabeled fluor-18-deoxyglucose (18F-FDG) can visualize glucose metabolism in the primary breast tumor and lymph node metastases. In HER2-positive breast cancer the metabolic response of the primary breast tumor during treatment predicts pathologic complete response in breast and axilla poorly and may improve by the addition of the metabolic response of the axilla. Achieving a radiologic complete response of the breast on contrast-enhanced magnetic resonance imaging (MRI) after trastuzumab-based neoadjuvant chemotherapy corresponds to a pathologic complete response of the breast in 73% of cases. The agreement between the radiologic and pathologic complete response is especially good in hormone-receptor-negative tumors.

Patients with small node-negative HER2-positive tumors have a worse outcome compared to HER2-negative tumors but uncertainty remained whether their outcome improves by trastuzumab-based chemotherapy.
Trastuzumab-based chemotherapy improves overall and breast-cancer-specific survival in patients with stage I disease, without heterogeneity of the treatment effect according to tumor size or hormone-receptor status. Therefore, systemic therapy can be considered in all patients with HER2-positive breast cancer, but the benefit should be weighed against the potential side effects.

Since the introduction of the highly effective HER2-directed antibody trastuzumab the search for equally effective anthracycline-free regimens started due to the overlap in cardiotoxic effects of trastuzumab and anthracyclines. The value of anthracyclines is especially unknown in the era of dual HER2-blockade.
An anthracycline-free neoadjuvant regimen consisting of weekly paclitaxel, carboplatin and trastuzumab is highly effective in patients with stage II-III HER2-positive breast cancer with a pathologic complete response rate of 43%. In the presence of dual HER2-blockade with trastuzumab plus pertuzumab, a paclitaxel-carboplatin regimen has similar efficacy as an anthracycline-containing regimen (pathologic complete response rate of 68% versus 67%, respectively), but a more favorable hematological toxicity and cardiotoxicity profile. An anthracycline-free regimen is therefore an excellent alternative for an anthracycline-containing regimen in the presence of HER2-blockade. Given the good prognosis of most patients with HER2-positive early breast cancer with currently available therapies, future studies should focus on selective treatment de-escalation to reduce toxicity while maintaining efficacy. Imaging with subsequent response-based treatment adaptations may be used for this purpose.