Background: Inflammatory breast cancer (IBC) is rare but aggressive, characterized by the rapid onset of diffuse skin erythema, edema, tenderness, induration, and fast metastasis. Both hormone receptor positive (HR+) and human epidermal receptor 2 positive (HER2+) are associated with inferior response after neoadjuvant systemic therapy (NAST) compared to non-IBC. Despite multimodal treatment approaches, the 3-year overall survival rate for stage III IBC remains low at approximately 74%, around 10% lower than the 83% for non-IBC.
Objectives: To evaluate whether the addition of neratinib, an irreversible pan-ErbB receptor small molecule tyrosine kinase inhibitor, improves the rate of pathological complete response in both HER2+ and HR+/HER2- IBC in neoadjuvant therapy, and to assess safety and explore biomarkers associated with response.
Design: This is a phase I/II (HER2+; cohort 1) and II (HR+/HER2-; cohort II trial conducted at a single center.
Methods: Pathological response was assessed using the pathological complete response (pCR) and residual cancer burden (RCB) criteria as the primary efficacy endpoint. Safety and biomarkers were assessed.
Results: In cohort 1, dose-limiting toxicities were Grade 2/3 diarrhea. Among the 10 evaluable patients from cohort 1 who underwent surgery, 5 achieved pCR (50%); in the intention-to-treat population of all 14 patients (counting drop-outs as nonresponders), the pCR rate was 36%. In cohort 2, 16 patients were enrolled, and 1 (6%) achieved pCR. Common adverse events (AEs) included Grade 2 alopecia, Grade 2/3 diarrhea, anemia, nausea, and neutropenia. High toxicity led to early closure of accrual. The median event-free survival in cohort 2 was 27.5 months, and was not reached for cohort 1 by data cutoff. Biomarker analysis showed that good responders (pCR + RCB-I) in both cohorts exhibited upregulation of immune-activating pathways, including interferon signaling and cytotoxic T-cell markers. By contrast, poor responders (RCB-II + RCB-III) showed immune-suppressive features, increased angiogenesis, proliferation, and anti-apoptotic gene expression.
Conclusion: The addition of neratinib to neoadjuvant therapy showed potential in improving the pCR rate in HER2+ IBC (36% in this study) but not in HR+/HER2- (6%), though high toxicity was a major limiting factor. Further research is needed to optimize the balance between efficacy and safety. Biomarker analysis uncovered interesting new hypothesis-generating data warranting future study in IBC.
Trial registration: ClinicalTrials.gov NCT03101748.
Keywords: HER2+ breast cancer; hormone receptor-positive breast cancer; inflammatory breast cancer; neoadjuvant therapy; pan-HER inhibitor.
Neratinib for inflammatory breast cancer patients Inflammatory breast cancer (IBC) is a rare and aggressive type of breast cancer. It spreads quickly, causing redness, swelling, and a pitted appearance of the skin on more than two-thirds of the breast. IBC is hard to treat, and even with combined treatments like chemotherapy, surgery, and radiation, the survival rate is much lower than for other breast cancers. This study aimed to find out if adding a drug called neratinib to the usual treatment could improve outcomes for IBC patients. Neratinib inhibits specific proteins like HER2 and EGFR that help cancer grow, potentially making it a valuable addition to the treatment plan. We tested the safety and efficacy of neratinib combined with standard IBC treatment. We monitored side effects and measured how well the cancer responded using pCR and RCB criteria. In one group (Cohort 1), the main side effects were moderate to severe diarrhea, hair loss, nausea, anemia, fatigue, low potassium, and low white blood cell counts. Once the dose of neratinib was determined, 14 participants were enrolled in phase II and 5 (36%) achieved pCR. If we only count participants who went through surgery, the pCR was 50%. In another group (Cohort 2), out of 16 participants, only 1 (6%) had pCR. The addition of neratinib to standard treatment showed some promise in helping patients with IBC, especially in the HER2-positive subgroup, yet due to the high number of side effects we stopped adding new patients. More research is needed to find a balance between benefits and risks, and future studies may be warranted to improve the response while mitigating side effects.
© The Author(s), 2025.