Multi-institutional analysis of incidence and risks for late-onset immune toxicity in breast cancer - PubMed (original) (raw)
doi: 10.1038/s41523-025-00849-1.
Samantha Fisch 3, Carolyne Face 3, Kelly Blum 3, Madhuri Chengappa 4, Saliha Chaudhry 4, Alexis LeVee 5, Nikita V Baclig 6, Andrew Soliman 6, Laura A Huppert 3, Zoe Quandt 7, Laura Quintal 3, Dame Idossa 4, Michelle Melisko 3, A Jo Chien 3, Mi-Ok Kim 3, Joanne Mortimer 5, Kelly McCann 6, Anne Blaes 4, Hope S Rugo 8 9
Affiliations
- PMID: 41339346
- PMCID: PMC12714743
- DOI: 10.1038/s41523-025-00849-1
Multi-institutional analysis of incidence and risks for late-onset immune toxicity in breast cancer
Saya Jacob et al. NPJ Breast Cancer. 2025.
Abstract
Immune checkpoint inhibitors (ICI) improve survival in triple-negative breast cancer (TNBC) but cause late-onset toxicity, with unknown incidence in breast cancer. This retrospective study included 700 patients (61%, n = 424 early-stage; 39%, n = 276 metastatic; 77% TNBC) from four NCI-designated centers treated with ICI between 2014-2021. Chart review identified immune toxicities, defined as ICI-related, as noted by the oncology provider or steroid-treated. 61% (n = 430) had toxicity: 37% (n = 257) early (≤90 days after ICI start), 34% (n = 240) delayed (>90 days), 10% (n = 67) both. Of the delayed, 144 (60%) were on-treatment, 56 (23%) off-treatment, 40 (17%) both. Twenty-two (9.2%) had off-treatment toxicity >1 year post-ICI. Median onset: 138 days (range 90-1380) on-treatment; 76 days (21-1144) off-treatment. Risk increased with more ICI cycles, especially >4 (early OR 1.104; metastatic OR 1.06; p < 0.0001) and higher baseline eosinophils (OR 3.46, p = 0.0484). Metastatic disease (OR 0.18, p < 0.0001) and early toxicity (OR 0.53, p = 0.0008) reduced risk. Findings support the need for high clinical suspicion for late toxicity.
© 2025. The Author(s).
Conflict of interest statement
Competing interests: The authors declare no competing interests.
Figures
Fig. 1. Definitions of toxicity groups.
Delayed toxicity was defined as any toxicity with onset occurring at least 90 days after the start of immune checkpoint inhibitors. Early toxicity was any toxicity with onset occurring prior to 90 days after the start of the immune checkpoint inhibitor. Delayed toxicity was divided into two subgroups: on-treatment toxicity and off-treatment toxicity, which was defined as a toxicity occurring 21 days after the last dose of ICI.
Fig. 2. Incidence of toxicity.
A total of 700 patients with breast cancer undergoing treatment with immune checkpoint inhibitors were identified across 4 NCI-designated cancer centers with stage and subtype information outlined above. Patients within the box represent those who had an immune-related toxicity at any time point and are further categorized as those having early toxicity depicted within the blue circle with blue text, delayed toxicity depicted in the orange circle with orange text, or both. Stage and subtype information are outlined for both early and delayed toxicity. Patients within the subgroups of on and off treatment delayed toxicity are outlined in the orange box. TNBC triple negative breast cancer, HR+ hormone receptor positive, HER2+ human epidermal growth factor receptor 2, irAE immune related adverse event, pts patients.
Fig. 3. Median time to onset of delayed toxicities.
The median time to onset of delayed toxicities, both on and off treatment, is depicted above for both groups overall, as well as the most common types of toxicity. Text within the bars represents the numerical value of the median time to onset. The error bars extending to the right depict the range in days, with the upper limit of the range written to the right of the error bars. Orange bars depict median time to onset since the start of immune checkpoint inhibitors for those with on-treatment delayed toxicity. The blue bar depicts time to onset from the end of immune checkpoint inhibitor treatment, specifically for those toxicities occurring off treatment. AI Adrenal insufficiency.
Fig. 4. Types of delayed toxicity.
Bar graph depicting specific subtypes of delayed toxicity as outlined by the x-axis. The Y axis depicts the number of patients. Toxicities of any grade are depicted in the blue bars. Toxicities of grade 3 or greater are depicted in the orange bars. Numbers above each bar represent the absolute value of patients experiencing that toxicity. The percentage of total delayed toxicities is listed to the right of each absolute value. Those toxicities representing less than 5% of all delayed toxicities are depicted with an asterisk. Specific “other” toxicities are outlined in Table 2. AI Adrenal insufficiency.
Fig. 5. Risk factors for developing delayed toxicity.
Multi-variable analysis controlled for institution of treatment and metastatic vs early-stage disease was performed with results outlined above. The y-axis outlines specific clinical risk factors evaluated, and the x-axis depicts odds ratios additionally adjusted for the rest of the candidate risk factors included in the multivariable analysis. Each plot depicts point estimates of specific odds ratios with error bars depicting confidence intervals. Absolute values of odds ratios, confidence intervals and _p_-values are shown to the right of each plot. Plots in red indicate those that show a statistically significant result, while those in black are not significant. CI confidence intervals, No number, HR+ hormone receptor positive, BMI body mass index.
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