Use of neoadjuvant therapy in BC treatment has increased substantially in China in recent years. Dual HER2-targeted trastuzumab–pertuzumab (HP)–based regimens are the standard neoadjuvant approach for HER2+ eBC, with reported pCR rates of >60 percent. [Int J Cancer 2020;147:3049-3058; Oncotarget 2017;8:75864-75873; Chinese Journal of Practical Surgery 2024;1:98-102; CBCS guideline; Lancet Oncol 2018;19:1630-1640]
“Neoadjuvant therapy is a powerful tool in the curative era, however, nearly 20 percent of patients still face risk of recurrence within 5 years after neoadjuvant treatment,” said Zhang. [Gland Surg 2021;10:3211-3221]
Postoperative treatment approaches in non-pCR patients
Patients with HER2+ BC who do not achieve pCR after neoadjuvant therapy have substantially higher recurrence risk. The phase III KATHERINE study demonstrated that ado‑trastuzumab emtansine (T-DM1) reduced recurrence risk by 46 percent in non-pCR patients. [Lancet 2014;384:164-172; Loibl S, et al, SABCS 2023, abstract GS03-12]
“Accordingly, the Chinese Breast Cancer Society [CBCS] guideline, which is the cornerstone of our decision-making, recommends adjuvant T-DM1 in case of residual disease after surgery, irrespective of hormone-receptor status,” explained Zhang. (Table) [CBCS guideline; J Zhang, 2026]
“The CBCS guideline integrates evidence levels, expert consensus and real-world accessibility, and is framed around intended treatment goals and local clinical needs rather than being solely indication-driven as in some international guidelines, such as the National Comprehensive Cancer Network’s [NCCN],” Zhang noted.
Despite T-DM1, about 20 percent of non-pCR patients experienced recurrence within 7 years, indicating an unmet need in this high-risk group. Central nervous system (CNS) recurrence poses an additional challenge: In KATHERINE, among non‑pCR patients with distant metastases, the proportion with CNS metastases was 23.7 percent with trastuzumab vs 47.6 percent with T‑DM1. In addition, T-DM1 is associated with adverse events (AEs) leading to dose reductions, interruptions or discontinuation, with thrombocytopenia-related AEs particularly prevalent among Asian patients. [Loibl S, et al, SABCS 2023, abstract GS03-12; Ann Oncol 2021;32:1005-1014]
“Even in HER2+ eBC patients treated with trastuzumab or dual HER2-targeted therapy, distant metastasis and CNS recurrence remain clinically relevant. The risk is higher among neoadjuvant non-pCR patients,” Zhang emphasized. Consequently, the CBCS guideline includes sequential neratinib as an important adjuvant option for selected high-risk patients. (Table) [Postgrad Med J 2019;95:155-161; CBCS guideline]
Extended adjuvant therapy with neratinib
Neratinib is an oral, irreversible pan-HER tyrosine kinase inhibitor (TKI) that covalently binds the intracellular tyrosine-kinase domain of HER1, HER2 and HER4, offering a mechanism to overcome trastuzumab resistance. [Clin Drug Investig 2019;39:221-229]
Survival benefit in non-pCR patients
In the phase III ExteNET study (n=1,334), among non-pCR patients who initiated neratinib ≤1 year of trastuzumab-based therapy, neratinib produced a 5-year absolute invasive disease–free survival (DFS) benefit of 7.4 percent vs placebo (hazard ratio [HR], 0.60; 95 percent confidence interval [CI], 0.33–1.07; p=0.086). Although not statistically significant, the result is clinically notable in this high-risk subgroup. Long-term data showed an 8-year overall survival (OS) benefit with neratinib (HR, 0.47; 95 percent CI, 0.23–0.92; p=0.031), with an absolute 8-year OS benefit of 9.1 percent. [Clin Breast Cancer 2021;21:80-91.e7]
Efficacy against CNS metastases
As a small-molecule TKI, neratinib more readily penetrates the blood-brain barrier than large monoclonal antibodies (eg, trastuzumab and pertuzumab) or antibody–drug conjugates (eg, T-DM1), which may contribute to its CNS activity. [Oncologist 2021;26:e1327-e1338]
Neratinib was associated with a 59 percent reduction in 5-year risk of brain metastasis (HR, 0.41; 95 percent CI, 0.18–0.85). Its 5-year CNS DFS rate was 98.4 percent. “Notably, neratinib is currently the only approved adjuvant therapy in HER2+ eBC to show a signal towards preventing CNS recurrence,” Zhang remarked. [Clin Breast Cancer 2021;21:80-91.e7]
Neratinib for high-risk patients with pCR
A systematic review of 54 randomized anti-HER2 neoadjuvant trials (n=32,611) found only a weak correlation between pCR rates and improvements in DFS and OS. “While pCR remains a strong favourable prognostic marker, it is not a complete surrogate for long-term outcomes. Achieving pCR does not eliminate relapse risk,” Zhang highlighted. “A real-world retrospective cohort study reported recurrence of around 10 percent among HER2+ patients with pCR – higher than in HER-negative disease. Therefore, we need to identify which patients with pCR remain at risk.” [BMJ 2021:375:e066381; Eur J Surg Oncol 2019;45:2289-2294]
Pooled analyses of neoadjuvant trials (n=3,160) indicate that baseline clinical characteristics, such as high tumour burden (cT3/T4) and nodal positivity (cN+), are independent adverse prognostic factors even when pCR is achieved. “Thus, the CBCS guideline suggests that patients who achieve pCR, but had baseline cT3/4 disease or cN+ status, should be considered for additional intensification with neratinib – reflecting a shift from decisions based solely on pathological response to those incorporating initial clinical risk,” noted Zhang. [Breast Cancer Res 2019;21:60; Breast Care (Basel) 2021;16:664-676]
Safety of neratinib
Diarrhoea is the most common AE with neratinib (any grade, 93.6 percent; grade ≥3, 37 percent). “Diarrhoea is the main practical challenge. Grade ≥3 events can lead to dose reductions and discontinuation, affecting adherence. Mitigation strategies include step-by-step dose escalation, routine prophylactic loperamide and dietary advice [eg, low-fat and low-fibre diets]. For refractory diarrhoea, additional antidiarrhoeals or traditional Chinese medicine may help,” shared Zhang. “Local experience suggests that with prophylactic measures, more than two-thirds of patients can complete a 1-year course of neratinib.” [Nerlynx Hong Kong Prescribing Information; J Zhang, 2026]
Patient-centred treatment decisions
The ASKHER2 patient survey (n=622) found that almost all HER2+ BC patients wish to be involved in treatment decisions. Critically, 68.5 percent were willing to undergo further treatment to reduce relapse risk even if the absolute risk reduction was <50 percent. “Patients are motivated by the prospect of cure and are open to extended adjuvant therapy to improve recurrence-free probability,” Zhang commented. “Proactive patient education on expectations and safety, along with clear discussion of risks and benefits, can improve adherence and outcomes.” [Breast 2025:81:104456]
Emerging treatments and future role of neratinib
Trastuzumab deruxtecan (T‑DXd) is under investigation in the post‑neoadjuvant setting for HER2+ eBC and has shown superior invasive DFS vs T‑DM1 in high‑risk patients in early reports. However, discontinuation rates due to drug‑related AEs were similar to T‑DM1, and no clear reduction in CNS metastases has been demonstrated. Whether T-DXd will reshape existing treatment standards requires careful assessment of risks and benefits. [N Engl J Med 2026;394:845-857]
The small-molecule TKI neratinib has pharmacologic properties that reduce brain metastasis and reverse T-DXd resistance. How to best integrate neratinib if T-DXd is adopted in eBC therapy requires further study. [Nat Cancer 2025;6:1202-1222]