Treatment de-escalation safe in patients with ERBB2-positive early breast cancer and high TILs

De-escalation of chemotherapy dose and trastuzumab duration may not increase the risk of distant relapse or death in patients with ERBB2-positive (also referred to as HER2-positive) early breast cancer and tumour infiltrating lymphocyte (TIL) levels of ≥20 percent, according to a 10-year analysis of the phase III ShortHER trial.

The trial’s previous 6-year analysis showed a positive, independent association between TIL density and distant disease–free survival (DDFS). [Ann Oncol 2019;30:418-423] “However, to our knowledge, no single study has demonstrated an association between TILs and overall survival [OS], the most important survival endpoint in the early breast cancer setting,” wrote the researchers. [JAMA Oncol 2025;doi:10.1001/jamaoncol.2024.6872]

De-escalation safe in TIL ≥20 percent

In the 10-year follow-up analysis, 866 patients had evaluable TILs (median age, 56 years). Patients were treated with either four cycles of anthracycline-based chemotherapy followed by four courses of taxanes plus trastuzumab for 1 year (long arm; n=441), or three courses of taxanes plus trastuzumab for 9 weeks followed by three cycles of reduced-dose anthracycline-based chemotherapy (short arm; n=425). Data were analyzed between February 2023 and August 2024.

After a median follow-up of 9.02 years, patients with TILs <20 percent showed better 10-year DDFS with long vs short treatment (88.7 vs 81.0 percent; p=0.006), whereas patients with TILs ≥20 percent showed excellent 10-year DDFS irrespective of treatment arm (87.1 vs 92.2 percent; p=0.09).

OS rates at 10 years were numerically higher for patients with TILs ≥20 percent in the short vs long treatment arm (93.1 vs 89.3 percent; hazard ratio [HR], 0.36; 95 percent confidence interval [CI], 0.10–1.36; p=0.13), and those with TILs <20 percent in the long vs short treatment arm (91.3 vs 86.9 percent; HR, 1.36; 95 percent CI, 0.82–2.23; p=0.23).

“Patients with low TILs showed better outcomes with the standard long treatment, while patients with high TILs had an excellent prognosis regardless of treatment duration, with numerically improved outcomes in the short treatment arm,” summarized the researchers.

Higher TILs predict better OS

For every 5 percent increase in TILs, there was a 13 percent reduction in the risk of a DDFS event (HR, 0.87; 95 percent CI, 0.80–0.95; p=0.001) and an 11 percent reduction in the risk of death (HR, 0.89; 95 percent CI, 0.81–0.98; p=0.01).

The 10-year OS rate was 91.3 percent for patients with TILs ≥20 percent, 93.3 percent for TILs ≥30 percent, and 98.1 percent for TILs ≥50 percent.

“The question about optimal TIL cut-off remains open since there is no evidence of a natural cut-off that maximizes the possible prognostic potential of TILs in this study. TILs are associated with survival as a continuous variable,” commented the researchers. “Therefore, the higher the cut-off point, the higher the ability of the high-TIL definition to identify patients with an excellent outcome.”

TILs for personalized treatment

“[Our] findings suggest that TILs help identify patients who may be optimally treated with de-escalated treatment … [and] support the integration of immune-related features into prognostic tools for ERBB2-positive early breast cancer, moving toward personalized treatment strategies beyond clinical-pathological features,” commented the researchers.