Impact of neoadjuvant single or dual HER2 inhibition and chemotherapy backbone upon pathological complete response in operable and locally advanced breast cancer: Sensitivity analysis of randomized trials

The role of the dual HER2 inhibition, and the best chemotherapy backbone for neoadjuvant chemotherapy still represent an issue for clinical practice. A literature-based meta-analysis exploring single versus dual HER2 inhibition in terms of pathological complete response (pCR, breast plus axilla) rate and testing the interaction according to the chemotherapy (anthracyclines-taxanes or taxanes) was conducted. In addition, an event-based pooled analysis by extracting activity and safety events and deriving 95% confidence intervals (CI) was accomplished. Fourteen trials (4149 patients) were identified, with 6 trials (1820 patients) included in the meta-analysis and 31 arms (14 trials, 3580 patients) in the event-based pooled analysis. The dual HER2 inhibition significantly improves pCR rate, in the range of 16-19%, regardless of the chemotherapy backbone (relative risk 1.37, 95% CI 1.23-1.53, p<0.0001); pCR was significantly higher in the hormonal receptor negative population, regardless of the HER2 inhibition and type of chemotherapy. pCR and the rate of breast conserving surgery was higher when anthracyclines were added to taxanes, regardless of the HER2 inhibition. Severe neutropenia was higher with the addition of anthracyclines to taxanes, with an absolute difference of 19.7%, despite no differences in febrile neutropenia. While no significant differences according to the HER2 inhibition were found in terms of cardiotoxicity, a slightly difference for grade 3-4 (1.2%) against the addition of anthracyclines was calculated. The dual HER2 inhibition for the neoadjuvant treatment of HER2-positive breast cancer significantly increases pCR; the combination of anthracyclines, taxanes and anti-Her2 agents should be currently considered the standard of care.