Longitudinal evaluation of health-related quality of life in Chinese patients with early-stage HER2-positive breast cancer undergoing neratinib extended adjuvant therapy: a real-world prospective cohort study.

Background: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is a well-established extended adjuvant therapy for early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer. However, its clinical application is often constrained by the high incidence of treatment-related diarrhea. This study sought to assess the dynamic changes in health-related quality of life (HRQoL) and the tolerability of neratinib, with a particular focus on dose escalation strategies and anti-diarrheal prophylaxis, within a real-world Chinese patient cohort. Methods: This single-center, prospective observational study included 31 female patients diagnosed with stage I-III HER2-positive breast cancer who initiated neratinib therapy following the completion of trastuzumab-based adjuvant treatment between October 2022 and January 2024. Patients were administered either non-dose-escalation group (240 mg/day) or dose-escalation group (120 mg/160 mg daily during Week 1, 160 mg/200 mg daily during Week 2, and 240 mg daily from Week 3 onward). Diarrhea management was conducted using prophylactic or on-demand loperamide. HRQoL was evaluated longitudinally through the EQ-5D-5L (health utility index and EQ visual analog scale [EQ VAS]) and Functional Assessment of Chronic Illness Therapy-Diarrhea (FACIT-D) questionnaires at predefined time points: baseline (D1), D30, D60, D90, D180, and D360. Diarrhea severity was graded according to Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0) criteria. Statistical analyses encompassed descriptive statistics and Wilcoxon signed-rank tests. Results: The median age of the patients was 48 years (range: 37-65 years), with 58.1% and 41.9% classified as pathological stage II and III, respectively. A total of 64 diarrhea events were recorded (grade 1, 48.4%; grade 2, 50.0%; grade 3, 1.6%), with no grade 4 events or fatalities. Permanent discontinuation of treatment due to diarrhea occurred in 16.1% of patients, 23.5% in the dose-escalation group vs. 7.1% in the non-dose-escalation group. HRQoL temporarily declined during the early treatment phase, as evidenced by a reduction in the EQ-5D-5L health utility index from 0.96 ± 0.07 at baseline to 0.89 ± 0.15 at D30 (p=0.011) and a decrease in the EQ VAS score from 89.94 ± 9.92 to 84.16 ± 12.64 at D30 (p=0.018). However, HRQoL demonstrated progressive recovery from D90 onward, with scores surpassing baseline levels by D180 (EQ-5D-5L utility index: 0.96 ± 0.07; EQ VAS: 89.92 ± 7.74) and D360 (utility index: 0.97 ± 0.06; EQ VAS: 92.84 ± 7.19). The FACIT-D score showed an initial improvement (baseline: 58.81 ± 7.95 vs. D30: 66.90 ± 11.39, p=0.002), followed by stabilization at baseline levels from D180 onward. Notably, no disease recurrence or distant metastasis was observed in patients who completed the treatment. Conclusions: Neratinib-associated HRQoL impairment is transient, with initial declines primarily due to diarrhea, which typically resolves within 3-6 months of treatment. With the implementation of appropriate supportive measures, such as loperamide prophylaxis and dose modifications, the majority of patients experience sustained HRQoL recovery, and even improvement, over a 12-month period.