Background Tumour-infiltrating lymphocytes (TILs) are established biomarkers of breast cancer immunogenicity and prognosis. Reproductive events induce durable immunological remodelling of the breast, but whether TIL levels at diagnosis reflect the immunological imprint of these events remains unclear. Materials and methods We included women diagnosed with invasive breast cancer between 1978 and 2012 in the Energy Balance and Breast Cancer Aspects throughout Life study, a substudy of the population-based Tromsø Study (Norway). Prediagnostic host factors were obtained. TILs were scored on an ordinal scale (1-4). Associations between host factors and the TIL score were analysed using ordinal logistic regression with interaction terms for hormone receptor (HR) status. Breast cancer-specific mortality was evaluated using Kaplan–Meier methods and Cox regression. Results A total of 425 women were included [median age at diagnosis 56.0 years, 360 (87.6%) parous], of whom 84 (19.8%) had HR-negative tumours. Among HR-negative cases, parity [odds ratio (OR) 10.14, 95% confidence interval (CI) 1.97-52.22], longer breastfeeding duration [OR 1.87 per standard deviation (SD), 95% CI 1.10-3.17], and higher age at first birth (OR 1.79 per SD, 95% CI 1.06-3.01) were associated with higher TIL scores, whereas higher mean arterial pressure (OR 0.59 per SD, 95% CI 0.41-0.86) was inversely associated. Significant interactions with HR status were observed for parity and breastfeeding duration. No associations were observed in HR-positive tumours. High-TIL levels (scores 3-4 versus 1-2) were associated with lower breast cancer-specific mortality in HR-negative tumours (adjusted hazard ratio 0.32, 95% CI 0.14-0.72) but not in HR-positive disease (hazard ratio 0.98, 95% CI 0.58-1.68; Pinteraction = 0.023). Conclusions These findings suggest that reproductive history and timing may shape the tumour immune microenvironment over the life course. If confirmed in larger studies, TILs may represent an intermediate phenotype linking upstream host characteristics to downstream clinical outcomes in breast cancer.
Background Invasive lobular carcinoma (ILC) is known to exhibit distinct metastatic patterns compared with carcinoma of no special type (NST); however, little is known about its specific propensity for central nervous system (CNS) and leptomeningeal (LM) involvement, particularly in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative subtype. Patients and methods We leveraged a multicenter study of 1710 patients with advanced breast cancer (BC). We recorded site of first metastatic recurrence and occurrence/type of the first CNS event. The study endpoints were CNS-free survival, LM-free survival, and post-LM survival. The risk of LM as the first CNS event across histological types was evaluated using a competing-risk framework. Results Among 1587 patients with known tumor histology, 15.5% had ILC. Within the ER-positive/HER2-negative BC cohort (n = 669), 31.5% of patients developed a CNS event. ILC and NST were associated with similar metastatic CNS-free survival [hazard ratio (HR) 1.30, 95% confidence interval (CI) 0.95-1.77, P = 0.095]. In contrast, metastatic LM-free survival was significantly and independently shorter in ILC versus NST (multivariate analysis of LM events without concurrent brain metastases, adjusted HR 4.94, 95% CI 1.57-15.83, P = 0.006). Consistently, Fine-Gray competing-risk analysis confirmed a significantly higher risk of LM involvement as the first CNS event for ILC versus NST (adjusted subdistribution hazard ratio 5.07, 95% CI 1.57-16.41, P = 0.007). Among patients with ER-positive/HER2-negative BC and LM disease, ILC was associated with worse post-LM survival compared with NST (HR 2.79, 95% CI 1.03-4.17, P = 0.040). In patients with ILC presenting with extracranial metastatic disease, we observed similar LM-free survival between those treated with cyclin-dependent kinase 4 and 6 inhibitors and those who were not (P = 0.286). Conclusions In patients with ER-positive/HER2-negative advanced BC, ILC was independently associated with a higher cumulative incidence of LM as the first CNS event than NST. Patients with ILC who developed LM also experienced poorer post-LM survival. These findings highlight the need for heightened clinical awareness and support prospective studies evaluating earlier LM detection in this population.
Aim Whether intensity-modulated proton therapy (IMPT) offers measurable clinical benefits over intensity-modulated radiotherapy (IMRT) for oropharyngeal cancer remains debated. Methods We pooled data from two phase III randomized trials and one matched cohort study comparing IMPT with IMRT and analyzed disease-control, survival, acute toxicity, and nutritional outcomes. Results The hazard ratio for locoregional recurrence was 1.37 [95% confidence interval (CI) 0.56-3.36, I2 = 0%]; for progression-free survival, 0.90 (95% CI 0.61-1.33, I2 = 0%); and for overall survival, 0.79 (95% CI 0.32-1.98, I2 = 47%). Acute grade 3 dysphagia occurred in 24% of patients receiving IMPT, compared with 40.9% receiving IMRT [risk ratio (RR) 0.65, 95% CI 0.51-0.84, I2 = 0%]. Grade 3 xerostomia or oral/pharyngeal dryness occurred in 19.9% and 32.5%, respectively (RR 0.72, 95% CI 0.54-0.95, I2 = 0%). Exploratory nutritional outcomes showed no definitive benefit, including 12-month gastrostomy dependence (RR 0.32, 95% CI 0.08-1.28, I2 = 0%), weight loss ≥20% (RR 1.05, 95% CI 0.12-9.38, I2 = 85.7%), and composite nutritional endpoints (RR 0.92, 95% CI 0.12-7.07, I2 = 87.7%). Conclusions IMPT’s primary advantage is reducing acute toxicity, not improving efficacy.
