In the Spanish Breast Cancer Research Group (GEICAM)/2006-03 Core-Basal phase II clinical trial, even though none of the clinicopathologic variables or gene signatures evaluated were identified as significant predictors of pCR, there was a strong correlation between high histological grade and cytotoxic effects of NAC, which is consistent with the results of the present study. Recent subgroup analyses of NAC clinical trials have reported a relationship between the histologic grade and therapeutic sensitivity to pCR in TNBC. Tumors were considered intratumoral stromal TIL-dominant if the intratumoral stromal TILs outnumbered the peritumoral TILs, and peritumoral TIL-dominant if the peritumoral TILs outnumbered the intratumoral stromal TILs. The relative proportions of peritumoral TIL and stromal TIL were determined. Additionally, we defined "peritumoral TIL" as the lymphocytes surrounding the peripheral border of the tumors as shown in Figure 2A. Intratumoral stromal TIL was defined as lymphocytes in the stroma between tumor cells without direct contact with the malignant cells according to the international TILs working group. Based on this categorization, the four subgroups were further dichotomized into low TIL (none or mild) and high TIL (moderate or severe) groups. This percentage was further divided into four categories as follows: none, no infiltration of lymphocytes mild, 60% for lymphocytic infiltration ( Figure 1). The percentage of the area occupied by the TILs over the total intratumoral stromal area was estimated. The histological grade of the CNB specimen was determined before the administration of the cytotoxic agent according to the Nottingham grading system. The histological variables that were evaluated to determine the significant predictors of chemotherapeutic response using the CNB specimens were the histological grade of the CNB specimens, the percentage of the area occupied by the tumor infiltrating lymphocytes (TILs), retraction artifact status, small-cell like feature status, level of tumor necrosis, and clear cytoplasm status.
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