Association of Stromal Tumor-Infiltrating Lymphocytes With Recurrence-Free Survival in the N9831 Adjuvant Trial in Patients With Early-Stage HER2-Positive Breast Cancer

Abstract

Importance Tumor-infiltrating lymphocytes at diagnosis are reported to be prognostic in triple-negative breast cancer. Objective Here we evaluate the association of stromal tumor infiltrating lymphocytes (STILs) with recurrence-free survival (RFS) in N9831 HER2-positive patients treated with chemotherapy or chemotherapy plus trastuzumab. Design H&E tumor slides from patients on N9831 Arm A (standard AC→T chemotherapy) and Arm C (concurrent chemotherapy with trastuzumab) were assessed for STILs. STILs were quantitated in deciles and ≥60% STILs was used for the pre-specified categorical cutoff. The association between STILs and recurrence-free survival (RFS) was evaluated with Cox models. Setting Academic medical center Participants Tumor specimens from patients with early stage HER2+ breast cancer. Intervention(s) for clinical trials or exposure(s) for observational studies None. Main outcome measures Stromal tumor infiltrating lymphocytes (STILs) and their association with relapse-free survival. Results 489 pts from Arm A and 456 pts from Arm C were assessed with a median follow-up of 4.4 years. The 10 year Kaplan-Meier estimates for RFS in Arm A were 90.9% and 64.5% for patients with high STILs and low STILs, respectively (HR 0.23; 95%CI: 0.073 to 0.73; p=0.013). The 10 year estimates for RFS in Arm C were 80.0% and 80.1% for patients with high STILs and low STILs, respectively (HR 1.26; 95%CI: 0.5 to 3.2; p=0.63). The test for interaction between trastuzumab treatment and STILS status was statistically significant (p=0.026). In a multivariable analysis, STILs status remained significantly associated with RFS in Arm A and not significantly associated in Arm C (interaction p=0.042). Conclusions and relevance The analysis of N9831 patients found that STILs were prognostically associated with RFS in patients treated with chemotherapy alone, but not prognostically associated with RFS in patients treated with chemotherapy plus trastuzumab. High STILS were predictive of lack of trastuzumab benefit in contrast to a previously reported association between increased STILs and increased trastuzumab benefit in HER2 positive patients. Trial Registration Trial registration information: Clinicaltrials.gov, NCT00005970, https://clinicaltrials.gov/show/NCT00005970

CD8+ tumor infiltrating lymphocytes strongly correlate with molecular subtype and clinico-pathological characteristics in breast cancer patients from Sudan

“…To the best of our knowledge, this is the first study to correlate the role of TIL subtypes with clinico-pathological characteristics in BC patients from Sudan. Several studies have highlighted the importance of CD8 + TIL with patients' overall survival and response to treatment in particular in patients with Triple Negative BC and HER2/neu positive BC [11,18,19,35,36]. In our study, the small number of patients in luminal B breast cancer type renders the comparison difficult, nevertheless, CD8 + TILs were significantly higher in HER2/neu positive BC, which is comparable to state of the art studies in MENA countries and worldwide [16,36].…”

“…However, recent findings have shown that patients with early stage HER2/neu positive BC and high TILs do not require anti-HER2 therapy [19], this finding may be significant for our group of patients in economically challenged societies where anti-HER2 treatment (such as trustazumab) is neither subsidized nor available [17,18,21].…”

“…Such discoveries may add to the development of novel immune related targets of therapy that can be used in combination with established therapies including chemotherapy and ionizing radiation. Indeed in both adjuvant and untreated breast cancer patient cohorts, transcriptomic studies of CD8+ TIL and its immunogenic signature in both HER2/neu positive and TNBC patients have been verified as positive prognosticators of patient survival [18][19][20][21]33]. Ionizing radiation has been found to be a powerful immune modulator of T cells present in BC.…”

“…While in in situ carcinoma, antibody producing B-lymphocytes appear to play a significant role in cancer development, chronic B lymphocytic presence appears to encourage invasion and metastasis [12]. CD8 immune tumor infiltrate has been reported to be a good prognostic indicator in multiple invasive solid tumors including colorectal carcinoma, melanoma, and breast carcinoma [13][14][15][16][17][18][19]. In BC, CD8 T-cell infiltration also correlates with having a smaller tumor size, lymph node negativity, lower histologic grade and recurrence-free survival.…”

The Effect of Immunology on Surgical Outcome: an Observational Hypothesis

“…Breast cancer has a more favorable prognosis among several other major solid tumors such as lung, colon, ovarian, stomach and liver (www.sser.cancer.gov). It is not coincidental that concomitant anti-tumor immunity is also more prominent in breast cancer [29][30][31][32]. Biopsy and surgery tumor samples from breast cancer patients consistently indicated heightened immune responses characterized by presence of large numbers of T cells that coincide with destruction of tumor structure and inhibition of tumor replication (our unpublished observation and [33].…”