A total of 252 patients with T1-2N0M0 TNBC were identified across UT Southwestern Medical Center (n = 211) and Parkland Health (n = 41) (Fig. 1). The overall cohort comprised Stage I (n = 154), Stage II with tumor size < 3 cm (n = 61), and node-negative Stage II with tumor size > 3 cm disease (n = 37). Subsequent analyses focused on a predefined “small TNBC” cohort consisting of Stage I and Stage II, < 3 cm tumors (n = 215). The small TNBC cohort comprised 182 UTSW (84.7%) and 33 Parkland patients (15.3%). Baseline demographics and pathological variables were typical of TNBC (82.5% grade 3 histology; 89.3% ductal histology; Table 1). NAT was administered in 70.6% of patients, surgery in 98.8%, adjuvant therapy in 60.3%, and adjuvant radiation in 42.1%. KEYNOTE-522 was the most common NAT regimen overall (60.1% of NAT-treated patients). With a median follow-up of 2.6 years, recurrence occurred in 18 patients (7.1%) and death in 11 patients (4.4%). Collectively, this represented a contemporary, real-world TNBC cohort treated during the immunotherapy era.

The small TNBC cohort included 154 Stage I and 61 node-negative Stage II, < 3 cm patients. Demographic characteristics were largely similar between groups (Table 2). Median age did not significantly differ between Stage I and Stage II, < 3 cm disease, nor did menopausal status, hypertension, hyperlipidemia, diabetes, or BRCA mutation prevalence. Median BMI was higher in Stage II, < 3 cm patients (30.3 vs. 27.3 kg/m², p = 0.016). Histopathologic features were also broadly similar between groups, although grade 3 histology was more common in Stage II, < 3 cm tumors (93.4% vs. 74.7%, p = 0.0013).

Despite largely similar demographic and pathological metrics, treatment patterns differed substantially between Stage groups (Table 2). NAT was more frequently utilized in node-negative Stage II, < 3 cm disease compared with Stage I disease (85.2% vs. 61.0%, p = 0.0006). NAT regimen distributions also differed significantly (p = 0.0070), primarily driven by greater KEYNOTE-522 utilization in node-negative Stage II, < 3 cm patients (75.0% vs. 45.7%, adjusted p = 0.0052). Surgical approach distributions were similar between groups (p = 0.56), although surgery rates were slightly lower in node-negative Stage II, < 3 cm disease due to disease progression precluding surgery (n = 2) and patient refusal (n = 1). Adjuvant treatment distributions also differed significantly (p = 0.0001), with node-negative Stage II, < 3 cm patients more frequently receiving adjuvant pembrolizumab, while Stage I patients more commonly received non-pembrolizumab adjuvant approaches. Adjuvant radiation utilization was similar between groups (43.5% vs. 42.6%, p = 0.48). Despite greater neoadjuvant treatment intensity for node-negative Stage II, < 3 cm disease, recurrence (6.5% vs. 3.3%, p = 0.52) and mortality rates (1.9% vs. 6.6%, p = 0.10) were not significantly different between groups (Stage II T<3 cm, N0 vs. Stage 1, respectively).

Among NAT-treated small TNBC patients (n = 146), KEYNOTE-522 was the predominant regimen (56.2%), followed by CT + P (16.4%), AC/T (13.7%), and other NAT regimens (13.7%) (Table 3). Overall pCR for the small TNBC NAT cohort was 51.3% (75/146), with similar pCR rates between Stage I and node-negative Stage II, < 3 cm tumors (51.1% vs. 51.9%, p = 0.92). Regimen-specific pCR rates within the combined small TNBC cohort were 52.4% for KEYNOTE-522, 45.8% for CT + P, 50.0% for AC/T, and 55.0% for other NAT regimens. No NAT regimen demonstrated significantly different pCR rates within the small TNBC (p = 0.93), Stage I (p = 0.62), or node-negative Stage II, < 3 cm (p = 0.16) cohorts. No statistically significant differences in pCR between Stage I and Stage II, < 3 cm N0 disease were observed for any individual NAT regimen, including AC/T (47.1% vs. 66.7%, p = 0.99), CT + P (55.6% vs. 16.7%, p = 0.17), KEYNOTE-522 (51.2% vs. 53.8%, p = 0.81), or other NAT regimens (50.0% vs. 75.0%, p = 0.59). KEYNOTE-522 did not demonstrate significantly different pCR rates from AC/T (p = 0.84), CT + P (p = 0.57), or non-KEYNOTE-522 NAT (p = 0.77) within the small TNBC cohort. Similarly, no significant differences were observed within the Stage I group compared with AC/T (p = 0.77), CT + P (p = 0.75), or non-KEYNOTE-522 NAT (p = 0.99). While KEYNOTE-522 was the most frequently used regimen, substantial heterogeneity in NAT administration practice was observed. Beyond the four principal treatment groups, 10 additional NAT regimens were identified within the cohort (Supplementary Table 1).

Median follow-up for the overall small TNBC cohort was 2.6 years (range 1.8–3.5) without significant difference between Stage groups. Kaplan–Meier analyses demonstrated significant differences in EFS and RFS across NAT regimens (EFS p = 0.0025; RFS p = 0.0066), primarily driven by poorer outcomes in the CT + P subgroup (Fig. 2A). However, these findings should be interpreted cautiously as EFS did not significantly differ between NAT and non-NAT approaches within the small TNBC cohort (p = 0.16; Fig. 2B) and as NAT-treated Stage I versus Stage II T < 3 cm N0 patients demonstrated similar EFS (p = 0.86; Fig. 2C). Within KEYNOTE-treated patients, EFS also did not significantly differ by Stage subgroup (p = 0.057; Fig. 2D). Taken together, small TNBCs had overall similar survival outcomes despite varying treatment strategies.

Survival of Small TNBC Cohort. Kaplan-Meier (KM) curves of event-free survival (EFS) of the small TNBC cohort (Stage I and Stage II, tumor < 3 cm). EFS calculated from date of diagnosis and compared via log-rank testing. A) KM curve comparing EFS for the most common neoadjuvant therapies (NAT). B) KM curve comparing EFS between any NAT and “No NAT”, which comprised adjuvant only, surgery only, radiation only, or no treatment. C) KM curve comparing EFS for any NAT between Stage groups. D) KM curve comparing EFS for KEYNOTE-522 between Stage groups