Recently, in many large-scale prospective clinical trials, TILs have been proven to be useful as a prognostic factor  [6, 8, 9, 31]. These reports have suggested that TILs can be useful as clinical biomarkers, and today attempts to unify their evaluation methods are underway [3, 4]. According to the International Working Group, in the evaluation of TILs, the percentage of immunocytes within a tumor stroma should be measured at the border of the cancer infiltration region . However, there is not yet a standardized opinion regarding determination of the region within the tumor stroma. Therefore, we also paid attention to FF in regions that were within the tumor stroma and were surrounded by infiltrating tumor cells. Wide-ranging FF contribute to the tumor’s acquisition of a malignant condition due to the hypoxic environment within the tumor, and are related to prognosis and drug resistance [32–34]. In the present study, when we investigated TILs that exist within FF as FF-TILs in patients undergoing NAC, the high-FF-TIL group had a longer DFS period after NAC than did the low-FF-TIL group.
When studied by subtype, TILs have been considered useful as prediction markers for treatment effect in subtypes with high immunological action, such as TNBC and HER2BC [4, 8, 9, 31]. However, in HRBC, which has the highest frequency, there are few reports that show a clinical relationship with TILs. In the present study, FF-TILs have been proven useful as prognostic factors following NAC not only for TNBC and HER2BC, but also for HRBC. Furthermore, for non-HRBC, such as TNBC and HER2BC, it is thought that wide-ranging FF exist , and in the present study as well, for non-HRBC, we observed that FF-TILs were significantly high.
In the current study, a reason that outcome prediction was possible even for HRBC is the heterogeneity of TILs in the cancer microenvironment. ER, which is important for the occurrence and development of HRBC, is activated not just by estrogen but also by the signal cascade of a pathway via phosphorylation due to various growth factors, and the control of ER depends on the cancer microenvironment . However, there are reports that, in a hypoxic environment, expression of hormone receptors is weakened [36, 37]. That is, it is thought that, in an FF region, hormone receptors are weakened owing to the hypoxic environment; therefore, biomarkers for ER-negative cancers are useful. It is possible to dynamically understand the changes in the cancer microenvironment more precisely with FF-TILs than with the previous evaluation range of TILs; therefore, we believe it may be a better evaluation method.
In the present study, patients in the low-FF-TIL group experienced a high recurrence rate, and perhaps, depending on the subtype, adjuvant therapy should have been added. That is, in the selection of post-surgical adjuvant therapy for patients undergoing NAC, it is suggested that determination using FF-TILs can contribute to the choice of a proper treatment strategy.
However, the retrospective nature of this study is a limitation, and regarding adjuvant therapy after NAC, since there are differences among cases, and since it is difficult to evaluate FF with CNB specimens, it is necessary to obtain more tissue through the use of methods such as VAB during diagnoses. In the previous report, we classified FF long diameter 8 mm as positive / negative as cutoff. However, with this method, evaluable FFs are limited. In this study, we used FF as the convergent focal point of the fiber component surrounded by infiltrating tumor cells without using the cutoff value. That is, it was possible to evaluate FF even if the area was small. Therefore, the evaluation rate of FF is higher than the previous report. Even a minute specimen at CNB or VAB, in the method we used. Evaluation of FF becomes possible.