In the HERA trial, the 2-year follow-up report revealed that adjuvant treatment with trastuzumab for 1 year lowered risk of death by 34% as compared to the observation group, which corresponded to an absolute overall survival benefit of 2.7% at 36 months with a statistically significant difference. However, after a median follow-up of 4 years, the absolute benefit in overall survival declined to 1.6% at 48 months and statistical significance was not observed between the two groups. Some investigators argued that crossover to trastuzumab of patients originally allocated to the observation arm might disrupt and bias the intention-to-treat comparison between the 1-year trastuzumab and observation arms, but others took issue with this line of thought since the findings from the PACS 04 and FinHer studies revealed that adjuvant trastuzumab did not affect overall survival despite the lack of crossover. KPT330 Selinexor Secondly, many oncologists reported frequent central nervous system metastasis during trastuzumab therapy in several clinical trials, which has raised burning concerns over the association of trastuzumab use with the development of CNS recurrence. Thirdly, there is growing attention toward how to optimize the combination of trastuzumab with adjuvant chemotherapy. Updated results of the NCCTG N9831 study demonstrated a strong trend for an absolute benefit in DFS of 4.4% at 5 years with concomitant trastuzumab relative to sequential administration. Although this did not cross the boundary for statistical significance, investigators recommended incorporation of adjuvant trastuzumab concurrent with the taxane portion of chemotherapy. Nevertheless, currently SQ109 available data are still not adequate to judge which schedule is superior in efficacy, prompting further investigation for additional evidence. Last but not least, relevant analyses from several large randomized clinical trials have been much updated recently, which makes it obliged to obtain the timely insight into a paradigm shift in how we deal with HER2-positive breast cancer patients in the adjuvant setting.