Treatment Response, Tumor Infiltrating Lymphocytes and Clinical Outcomes in Inflammatory Breast Cancer-Treated with Neoadjuvant Systemic Therapy

Abstract

Inflammatory breast cancer (IBC) is a rare (1%-5%), aggressive form of breast cancer, accounting for approximately 10% of breast cancer mortality. In the localized setting, standard of care is neoadjuvant chemotherapy (NACT) ± anti-HER2 therapy, followed by surgery. Here we investigated associations between clinicopathologic variables, stromal tumor-infiltrating lymphocytes (sTIL), and pathologic complete response (pCR), and the prognostic value of pCR. We included 494 localized patients with IBC treated with NACT from October 1996 to October 2021 in eight European hospitals. Standard clinicopathologic variables were collected and central pathologic review was performed, including sTIL. Associations were assessed using Firth logistic regression models. Cox regressions were used to evaluate the role of pCR and residual cancer burden (RCB) on disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS). Distribution according to receptor status was as follows: 26.4% estrogen receptor negative (ER-)/HER2-; 22.0% ER-/HER2+; 37.4% ER+/HER2-, and 14.1% ER+/HER2+. Overall pCR rate was 26.3%, being highest in the HER2+ groups (45.9% for ER-/HER2+ and 42.9% for ER+/HER2+). sTILs were low (median: 5.3%), being highest in the ER-/HER2- group (median: 10%). High tumor grade, ER negativity, HER2 positivity, higher sTILs, and taxane-based NACT were significantly associated with pCR. pCR was associated with improved DFS, DRFS, and OS in multivariable analyses. RCB score in patients not achieving pCR was independently associated with survival. In conclusion, sTILs were low in IBC, but were predictive of pCR. Both pCR and RCB have an independent prognostic role in IBC treated with NACT.

Significance: IBC is a rare, but very aggressive type of breast cancer. The prognostic role of pCR after systemic therapy and the predictive value of sTILs for pCR are well established in the general breast cancer population; however, only limited information is available in IBC. We assembled the largest retrospective IBC series so far and demonstrated that sTIL is predictive of pCR. We emphasize that reaching pCR remains of utmost importance in IBC.

FIGURE 1

sTIL scoring and its association with clinicopathological features in all patients. A, Distribution of sTIL (continuous) in the entire cohort and in subtypes. B, Distribution of sTIL (category) in the entire cohort and in subtypes. C, Forest plots showing the association of sTIL (continuous) and sTIL (categorical) with standard clinicopathologic variables evaluated by regression analyses in all patients.

FIGURE 2

Association of pCR with clinicopathologic features and treatment in all patients. A–C, Forest plots showing the association of pCR with standard clinicopathologic and treatment variables (A), with sTILs (continuous %; B), and with sTILs (categorical; C) evaluated by regression analyses in all patients.

FIGURE 3

Association of RCB with clinicopathologic features and treatment in all patients. A–C, Forest plots showing the association of RCB, either as RCB class or continuous RCB score, with standard clinicopathologic and treatment variables (A), with sTILs (continuous %; B), and with sTILs (categorical; C) evaluated by regression analyses in all patients. Analyses were performed on the subset of patients diagnosed and treated at UZ Leuven, Belgium.

FIGURE 4

Association of pCR with DFS. A, Kaplan–Meier curves of DFS according to pCR. B, Forest plots showing the association of pCR and standard clinicopathologic and treatment variables with DFS quantified by Cox regression.

FIGURE 5

Association of pCR with OS. A, Kaplan–Meier curves of OS according to pCR. B, Forest plots showing the association of pCR and standard clinicopathologic and treatment variables with OS quantified by Cox regression.