Negative prognostic impact of higher residual disease-TILs after anti-HER2+ neoadjuvant therapy

To date, the prognostic role of tumour-infiltrating lymphocytes on residual disease (RD-TILS) after neoadjuvant treatment (NAT) is still not clear. In this setting, an Italian study now reported on an independent negative prognostic impact of higher RD-TILs after NAT in HER2+ breast cancer patients. Additionally, a new composite prognostic score based on residual cancer burden (RCB) and RD-TILS (RCB+TIL) was developed, which was significantly associated with overall survival.

The achievement of pathologic complete response (pCR) represents a positive prognostic biomarker in patients with early stage of breast cancer (BC) undergoing neoadjuvant treatment (NAT). However, patients who do not achieve pCR and have residual disease (RD) represent a very heterogeneous subgroup of patients. Therefore, the identification of additional biomarkers capable of improving the prognostic ability is crucial for these patients. Within this frame, residual cancer burden (RCB) has proved to provide additional prognostic value, while the investigation of the prognostic role of tumour-infiltrating lymphocytes (TILs) on residual disease (RD-TILS) has provided conflicting data. While a positive prognostic role of RD-TILS has been consistently reported for triple-negative breast cancer, in HER2+ BC, a prognostic impact of RD-TILs in both directions (positive and negative) has been reported. This study aimed to deepen the prognostic role of RD-TILS in HER2+BC, and to assess the feasibility of combining the prognostic information of RCB and RD-TILS into a composite score (RCB+TIL).

Study design

This study focused on stage I-III HER2+ BC patients treated with anti-HER2+chemotherapy-based NAT at three Italian centres (n= 295). RCB and stromal RD-TILS were evaluated on post-NAT samples of patients failing to achieve pCR. RCB was evaluated both as a continuous and a categorical variable (class I-III). TILS were evaluated according to the recommendations by the International Working group of Immune Biomarkers, and were categorised into low vs. high RD-TILS (<15% and ≥15%), according to the Harrel’s c-index.  A composite prognostic model was calculated from the sum of the estimated coefficients of RD-TILs and RCB at the bivariate logistic model for OS.

Results

Of the 295 patients that were included, 195 had RD at surgery, of which 70% expressed the hormone-receptor (HR+). RCB and RD-TILs were available for 180 and 159 patients. The pathological assessment of RD revealed that most patients belonged to RCB class II (62.2%) and had low levels of RD-TILs (82.4%). Interestingly, RD-TILs were significantly associated with HR status, as HR- patients were much more likely to have high levels of RD-TILs (p= 0.012). No other significant associations between RD-TILs and other clinical pathological features and treatment were found. The separate evaluation of the prognostic value of RCB and RD-TILs confirmed the significant association between these parameters and OS, both when considered as a continuous and categorical value. Patients with high levels of RD-TILs experienced significantly poorer outcomes vs. low RD-TILs (6-year OS rates of 67.9% vs. 83.7%, p= 0.028). Subsequently, the RCB+TIL composite score was developed, which was significantly associated with OS, both when considered as a continuous score and when categorised as tertiles.  The prognostic performance of this score (C-index 0.73) was numerically higher than that of RCB (0.68, p= 0.080) and significantly higher than that of RD-TILS (0.58, p= 0.007). Exploratory analysis focused on the group of patients with a matched evaluation of baseline TILs and RD-TILs. Although overall TILs levels did not significantly differ from baseline to RD, almost all patients with high levels post-NAT TILs showed some increase from baseline, in the vast majority converting from low baseline TILs to high TILs on RD.

Conclusions

This study reported an independent negative prognostic impact of higher RD-TILs after anti-HER2+ chemotherapy-based NAT in patients failing to achieve a pCR. “Our results suggest that the immune microenvironment of residual disease, after exposure to chemotherapy and anti-HER2-targeted therapy, promotes the growth of cancer cells rather than fighting against them, and this phenomenon seems to profoundly affect the natural history of the disease”. The new composite prognostic score based on RCB+TIL demonstrated to be significantly associated with OS, outperforming the prognostic performance of RD-TILs alone (significantly) and the RCB index (numerically).

Reference

Miglietta F, Ragazzi M, Fernandes B, et al. A composite prognostic model for overall survival (OS) based on residual cancer burden (RCB) and tumor-infiltrating lymphocytes (TILs) on residual disease (RCB+TIL) in HER2+ breast cancer patients treated with neoadjuvant therapy: a multicenter study. Presented at EBCC 2022; Abstract PPT-147.