A phase III non-inferiority randomised ShortHER study was a multicentric trial conducted in Italy that enrolled patients with ERBB2-positive breast cancer. Patients received 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Tumour samples were evaluated for tumour-infiltrating lymphocytes (TILs). In 10-year follow-up analysis, the study team reported a strong independent association of TILs with overall survival (OS) for patients with ERBB2-positive early breast cancer treated with adjuvant chemotherapy and trastuzumab.
Patients with TILs 20% or higher, who de-escalated trastuzumab duration and chemotherapy dose, were not exposed to an excess risk of distant relapse or death. Validation is needed to confirm that patients with high TILs can safely undergo treatment de-escalation according to Dr. Vittoria Dieci of the Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova in Padova, Italy and colleagues, who published the findings on 13 February 2025 in the JAMA Oncology.
While the primary disease-free survival (DFS) analysis did not allow for the non-inferiority of the short treatment duration, the recently published 10-year OS update of ShortHER showed quite superimposable outcomes for the 2 arms, especially for patients with no or limited nodal involvement.
The study team previously reported on the possible prognostic role of TILs in ShortHER at a median follow-up of 6 years, showing a positive, independent association between TIL density and distant DFS (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.59-0.89). The study team observed a statistically significant interaction between TIL levels at a 20% or higher cut-off and treatment arm, as patients with low TILs showed a statistically significant benefit from the longer treatment (HR 1.75; 95% CI 1.09-2.80), whereas those with high TILs had an excellent prognosis regardless of treatment duration, with even numerically better outcome in the short arm (HR 0.23; 95% CI 0.05-1.09).
The authors wrote that their previous analysis added to a growing body of evidence supporting the prognostic value of TILs in ERBB2-positive breast cancer in both the neoadjuvant and adjuvant setting, where TILs are strongly associated with surrogate endpoints such as increased rates of pathological complete responses and reduced risk of relapse. However, no single study has demonstrated an association between TILs and OS, the most important survival endpoint in the early setting.
In the latest manuscript published in the JAMA Oncology, the authors presented the updated analysis of the possible prognostic role of TILs in the ShortHER study and assessed the impact of this biomarker on survival outcomes, including OS, at a long-term follow-up. Patients were evaluated at a median follow-up of 9 years, and data were analyzed from February 2023 to August 2024.
Patients were randomised to receive four cycles of anthracycline-based chemotherapy followed by 4 courses of taxanes combined with trastuzumab for 1 year (long treatment) or 3 courses of taxanes combined with trastuzumab for 9 weeks followed by reduced-dose anthracycline-based chemotherapy for 3 courses (short treatment). The association of TILs with distant DFS and OS was assessed with Cox models.
Of 1253 patients enrolled in the study, 866 women (median [interquartile range] age, 56 years) had evaluable TILs. In Cox models with relevant factors, each 5% TIL increment was associated with improved distant DFS (HR 0.87; 95% CI 0.80-0.95; p = 0.001) and OS (HR 0.89; 95% CI 0.81-0.98; p = 0.01). The 10-year OS rate was 91.3% for patients with TILs 20% or higher, 93.3% for patients with TILs 30% or higher, and 98.1% for patients with TILs 50% or higher, resulting higher versus lower TIL counterparts.
Patients with TILs lower than 20% showed a better outcome with the long versus short treatment (10-year distant DFS 88.7% versus 81.0%), whereas patients with TILs 20% or higher showed the opposite (10-year distant DFS 87.1% versus 92.2%; p for interaction = 0.01). Similarly, patients with TILs 20% or higher had a 10-year OS rate of 89.3% in the long treatment arm versus 93.1% in the short treatment arm (HR 0.36; 95% CI 0.10-1.36); patients with TILs lower than 20% had a 10-year OS rate of 91.3% in the long treatment arm versus 86.9% in the short treatment arm (HR 1.36; 95% CI 0.82-2.23; p for interaction = 0.06).
The authors concluded that this updated analysis provides the first evidence of an independent effect of TILs on OS in patients with ERBB2-positive early breast cancer treated with adjuvant chemotherapy and trastuzumab. Moreover, the study data suggest that patients with high TILs at the 20% or higher cut-off who de-escalate trastuzumab duration and chemotherapy dose are, at least, not exposed to an excess risk of death. These findings support the integration of immune-related features into prognostic tools for ERBB2-positive early breast cancer, moving toward personalised treatment strategies beyond clinical-pathological features.
This work was supported by grants from the Agenzia Italiana del Farmaco, the Italian Association for Cancer Research, funding from the University of Padova’s Department of Surgery, Oncology and Gastroenterology, and the Veneto Institute of Oncology.
Reference
Dieci MV, Bisagni G, Bartolini S, et al. Tumor-Infiltrating Lymphocytes and Survival Outcomes in Early ERBB2-Positive Breast Cancer 10-Year Analysis of the ShortHER Randomized Clinical Trial. JAMA Oncology; Published online 13 February 2025. doi:10.1001/jamaoncol.2024.6872