Discussion
tumor, TILs, breast cancer, cancer, already-discussed, tumors
TUMOR, INFILTRATION, HER2-POSITIVE BREAST CANCER, BREAST CANCER, ADVERSE EVENTS, CANCER, DISEASE, RESIDUAL CANCER, TUMORS
HER2-positive breast cancer represents a heterogeneous entity, as shown by PAM50 molecular subtypesWhile pCR achievement is a strong prognostic factor in HER2-positive breast cancers after neoadjuvant therapyOther predictive/prognostic models have been developed in early-stage HER2-positive breast cancer. For example, a combined score of TILs and tumor cellularity (CelTIL) measured at week 2 after starting neoadjuvant anti-HER2 therapy (without chemotherapy) provided predictive information in the PAMELA studyBy characterizing the gene expression profiles of the prognostic groups, we showed an enrichment for immune-related processes in the group presenting good prognosis after either pCR or RD, leading us to hypothesize that tumors presenting an active immune response at baseline present biological similarities beyond HER2/estrogen receptor pathways activation.As we are moving toward optimizing treatment strategies, we may argue that the lack of pCR in patients with baseline favorable clinical/immune features may not necessarily require treatment escalation approaches in all patients. In the seminal trial KATHERINE, post-operative trastuzumab emtansine (T-DM1) showed remarkable benefit compared to trastuzumab in patients with RD at surgery; however, more adverse events were also observedThe role of B cell infiltration and clonal diversity in modulating the immune response in cancer has been described by several worksIn light of all these aspects, our model could be prospectively tested in studies designed to evaluate approaches involving the use of immunotherapy-based regimens and/or de-escalation/shorter duration of post-operative treatments in low risk patients with an excellent prognosis, as well as alternative therapeutic strategies in those with poor outcome.Our study presented several challenges and limitations. In addition to the already-discussed differences in terms of patient populations, the NeoALTTO and the CALGB 40601 trials had some differences in study design, namely in the timing of the start of neoadjuvant paclitaxel and in the post-operative treatments (details in the METHODS). We standardized the survival outcome measure (EFS) used for our analyses across the two trials; however, neither NeoALTTO nor CALGB 40601 were powered to detect survival benefits. Moreover, these trials evaluated lapatinib, which is not currently adopted in early-stage HER2-positive breast cancer. Therefore, validating these findings in cohorts receiving standard treatment regimens (e.g., pertuzumab in combination with trastuzumab) would be extremely valuable.Characterizing the BCR and TCR repertoires from bulk RNA sequencing data represents a challenge in itselfIn addition, more reliable cutoffs may need to be defined for the HER2-EveNT score. Moreover, the inclusion of the residual cancer burden, given its prognostic value in patients with RDDespite these considerations, findings from NeoALTTO were confirmed in CALGB 40601, suggesting the robustness of the results, which first and foremost provide the rationale for interrogating more extensively the role of B cells in this disease.In conclusion, we demonstrated the heterogeneity of BCR repertoire measures and immune response within HER2-positive breast cancer and the potential of BCR diversity as a prognostic biomarker. Our model identified a group of patients with immune-enriched tumors who may be eligible for treatment de-escalation approaches, even after RD, and highlighted the importance of integrating clinicopathological characteristics, treatment response information, and immune-related features to define the clinical risk in the neoadjuvant setting. Further validation of our findings and exploration of the role of BCR/TCR repertoire measures in HER2-positive as well as other breast cancer subtypes is warranted.