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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 3  |  Page : 619-624

The importance of stromal and intratumoral tumor lymphocyte infiltration for pathologic complete response in patients with locally advanced breast cancer


1 Department of Medical Oncology, School of Medicine, Akdeniz University, Konyaalti, Antalya 07070, Turkey
2 Department of Pathology, School of Medicine, Akdeniz University, Konyaalti, Antalya 07070, Turkey

Date of Web Publication12-Jun-2018

Correspondence Address:
Dr. Melek Karakurt Eryilmaz
Department of Medical Oncology, School of Medicine, Akdeniz University, Konyaalti, Antalya, 07070
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.174550

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 > Abstract 


Objective: Increased tumor-infiltrating lymphocytes (TILs) in breast carcinoma tissues is an independent predictive factor for pathologic complete response (pCR). The increased intratumoral and stromal TILs (sTILs) in breast cancer (BC) have significant prognostic effects. In this study, we evaluated whether pCR rates to neoadjuvant chemotherapy (NACT) are higher in tumors with increased number of TILs in the pretreatment biopsy.
Materials and Methods: We retrospectively evaluated the number of TILs in intratumoral TILs (iTILs) and sTILs compartments from pretreatment full-face hematoxylin and eosin-stained sections of 62 patients with locally advanced BC (LABC) who received NACT. The capacity of sTILs and iTILs in predicting pCR to NACT in LABC analyzed using receiver operating characteristic (ROC) curve analysis.
Results: According to ROC curve analysis, the optimum sTILs and iTILs cut-off points (the number of positive cells per square millimeter of tissue) for patients with LABC patients with pCR (+) were 19 (area under the curve (AUC): 0.668, 95% confidence interval [CI] [0.501–0.835],P = 0.064) and 4 (AUC: 0.786, 95%CI [0.666–0.907],P = 0.002), respectively. Of the 62 patients, 26 had sTILs >19 and 25 had iTILs >4. The patients were divided into two according to percent of sTILs (sTILs >19 and sTILs ≤19 groups) and iTILs (iTILs >4 and iTILs ≤4 groups). Both sTILs >19 and iTILs >4 patients were associated with development higher pCR. While pCR was significantly higher in iTILs >4 patients (P = 0.002), it was not significantly in sTILs >19 patients (P = 0.107).
Conclusions: There is significantly an association between pCR and increased number of intratumoral TILs (>4 cells/mm 2 of tissue) in BC who received NACT.

Keywords: Breast cancer, neoadjuvant chemotherapy, pathologic complete response, tumor-infiltrating lymphocytes


How to cite this article:
Eryilmaz MK, Mutlu H, Ünal B, Salim DK, Musri FY, Coşkun H&. The importance of stromal and intratumoral tumor lymphocyte infiltration for pathologic complete response in patients with locally advanced breast cancer. J Can Res Ther 2018;14:619-24

How to cite this URL:
Eryilmaz MK, Mutlu H, Ünal B, Salim DK, Musri FY, Coşkun H&. The importance of stromal and intratumoral tumor lymphocyte infiltration for pathologic complete response in patients with locally advanced breast cancer. J Can Res Ther [serial online] 2018 [cited 2020 Jul 9];14:619-24. Available from: http://www.cancerjournal.net/text.asp?2018/14/3/619/174550




 > Introduction Top


Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths.[1] Locally advanced BC (LABC) includes a subset of patients with clinical Stage IIB disease (T3N0) and patients with Stage IIIA–IIIC disease. Most patients with LABC are treated with neoadjuvant systemic therapy. The aim of treatment is to reduce tumor before surgery and make it suitable for breast conservation. Neoadjuvant therapy also allows early evaluation of the effectiveness of systemic therapy. The absence of invasive disease in the breast and axilla (pT0 pN0 or pT0/is pN0) for patients treated with neoadjuvant chemotherapy (NACT) is referred to as pathologic complete response (pCR). Patients who achieved pCR following NACT for BC have significantly better disease-free survival (DFS) and overall survival (OS).[2],[3]

Adaptive and innate immune responses play an important role in immune response to the tumor, their role is to control the growth and recurrence of human tumors. The presence of tumor-infiltrating lymphocytes (TILs) in cancer tissues such as prostate, renal-cell, esophageal, ovarian, and colorectal carcinomas has been shown to associated with improved outcome.[4],[5],[6],[7],[8]

In this study, we retrospectively evaluated whether pCR rates to NACT are higher in tumors with increased number of TILs in the pretreatment biopsy.


 > Materials and Methods Top


Study patients

The current study included a sample of 62 patients with LABC, who received NACT between January 2000 and December 2014 at our hospital, retrospectively. The patients who preoperatively have any chronic disease or diagnosed by biopsy of the lymph nodes were excluded from the evaluation. The age, menopausal status, performance status, tumor and nodal stage, histological type, the presence of lymphovascular invasion (LVI), grade, estrogen, progesterone and human epidermal growth factor receptor 2 (HER2) status were recorded into the Statistical Package for the Social Sciences version 16.0 (SPSS 16.0, SPSS Inc., Chicago, IL, USA) from the medical archives retrospectively.

Pathologic assessment

All samples were collected from the surgical specimen at baseline. The surgical specimens were obtained by core needle biopsy and excisional biopsy of primary breast tumor. Four-micrometer-thick tissue sections from the surgical specimens fixed in 10% formalin and embedded in paraffin were reviewed, and representative tissue blocks were selected. Slides were immunostained with hematoxylin and eosin. Histopathologic analysis of the percentage of TILs was performed on full-face hematoxylin and eosinstained sections. Each patient case was evaluated by a pathologist. We evaluated the percentage of stromal as well as intratumoral TILs (iTILs) separately. iTILs was defined as the percentage of mononuclear cells within the epithelium of the invasive tumor cell nests. Stromal TILs (sTILs) was defined as the percentage of tumor stroma area that contains a lymphocytic infiltrate without direct contact to tumor cells. In each case, positive cells were counted at ×400 magnification in 10 systematically selected fields of vision, and their mean number was obtained by averaging the number of positive cells per square millimeter of tissue.

Statistical analyses

To determine the properties of patients with LABC according to sTILs and iTILs, frequency analysis, two independent samples t-test, and Chi-square tests were performed. The capacity of sTILs and iTILs in predicting pCR (breast and axillary) to NACT in patients with BC was analyzed by using receiver operating characteristic (ROC) curve analysis. Optimal cut-off values were determined. While evaluating the area under the curve (AUC), a 5% Type-I error level was used to accept a statistically significant predictive value of the test variables. Statistical analysis was performed by using SPSS software version 16.0. A P < 0.05 was considered significant.


 > Results Top


A total of 62 were retrospectively evaluated for TILs. According to ROC curve analysis, the optimum sTILs and iTILs cut-off points (the number of positive cells per square millimeter of tissue) for patients with LABC patients with pCR (+) were 19 (AUC: 0.668, 95% confidence interval [CI] [0.501–0.835], P = 0.064) and 4 (AUC: 0.786, 95% CI [0.666–0.907], P = 0.002), respectively [Figure 1]. Of the 62 patients, 26 had sTILs >19 and 25 had iTILs >4.
Figure 1: Receiver operating characteristic analysis

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When we evaluated the patients with LABC as two groups according to sTILs (sTILs >19 and sTILs ≤19), there was no difference between sTILs >19 and sTILs ≤19 groups regarding the menopausal status, performance status, histological type, grade, LVI positivity, clinical T and clinical N stage (P = 0.288, P = 0.605, P = 0.246, P = 0.058, P = 0.344, P = 0.395, P = 0.480, respectively). sTILs ≤19 patients were significantly younger than sTILs >19 patients. The mean age was 46 ± 10, 7 and 51, 9 ± 11, 7 for groups with sTILs ≤19 and sTILs >19, respectively (P = 0.036) [Table 1]. The ratio of estrogen receptor (ER) positivity and progesterone receptor (PR) positivity were respectively also more higher in sTILs ≤19 but statistically not significant (P = 0.105, P = 0.232, respectively). In contrast, HER2 positivity was significantly more higher at sTILs >19 (P = 0.017) [Table 1].
Table 1: Prognostic factors according to the stromal lymphocyte infiltration

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When we evaluated the patients with LABC as two groups according to sTILs (iTILs >4 and iTILs ≤4 groups), there was no difference between iTILs >4 and iTILs ≤4 groups regarding the mean age, menopausal status, performance status, histological type, grade, LVI positivity, clinical T and clinical N stage (P = 0.184, P = 0.840, P = 0.688, P = 0.512, P = 0.125, P = 0.083, P = 0.638, P = 0.204, respectively). ER and PR positivity were more higher in iTILs ≤4 group but statistically not significant (P = 0.069, P = 0.331, respectively). Whereas, HER2-positivity was significantly more higher in iTILs >4 group (67% vs. 41% for iTILs >4 and iTILs ≤4 groups, respectively, P = 0.030) [Table 2].
Table 2: Prognostic factors according to the intratumoral lymhocyte infiltration

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Both sTILs >19 and iTILs >4 patients were associated with development higher pCR. While pCR was significantly higher in iTILs >4 patients (P = 0.002), it was not significantly in sTILs >19 patients (P = 0.107) [Table 3] and [Table 4].
Table 3: Stromal lymphocyte infiltration and breast and axillary complete response

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Table 4: Intratumoral lymphocyte infiltration and breast and axillary complete response

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 > Discussion Top


In this retrospective study, we found that the number of positive cells per square millimeter of tissue iTILs rather than sTILs was linked to pCR.

pCR is the most significant prognostic factor in BC patients who treated with NACT. Patients who achieved a pCR have significant improvements in event-free survival (EFS) and OS compared with patients with residual invasive disease.[9] The association between pCR and long-term outcomes is strongest in patients with triple negative BC and in those with HER2 positive, hormone receptor (HR) negative tumors who received HER2-directed agent such as trastuzumab. In contrast, ER positive, HER2 negative BCs rarely achieve pCR to NACT.[3],[10] However, pCR is greater in BC who has Grade 3, higher Ki-67 expression, invasive ductal carcinoma subtype, and smaller size tumors.[11],[12],[13],[14] Taxan addition to an anthracycline-containing regimen is associated with increased pCR.[15],[16]

In addition to the factors mentioned above, increased TILs is also an independent predictive factor for pCR in BC.[17],[18],[19] In previous studies has been found that higher levels of TILs were associated with pCR in patients with both ER negative, HER2 positive and ER negative, HER2 negative tumors.[20] However, the percentage of both intratumoral and stromal lymphocytes infiltration is an independent predictive marker for higher pCR rate to NACT.

The presence of TILs varies depending on the subtype of BC. Increased TILs has been reported to be associated with ductal histology, high grade, the absence of HR expression, the presence of vascular invasion and high expression of the proliferation antigen, Ki-67.[21] In the breast ınternational group 02–98 study, TILs (both sTILs and iTILs) was significantly associated with ductal histology, high histologic grade, HR negativity, and high Ki-67 expression. There was no significant association with age, menopausal status, increasing lymph node involvement, and tumor size. However, TILs were significantly higher in the ER negative/HER2 negative and HER2 positive BC compared with the ER positive/HER2 negative BC.[18] In our study, we found that patients with sTIL ≤19 were younger than patients with sTIL >19, however these younger patients had lower pCR rates. Subgroup analysis showed no relationship was found between menopausal status, performance status, histological type, grade, LVI positivity, clinical T or N stage, ER or PR positivity with either sTILs or iTILs. HER2 positivity were significantly high in patients with sTIL >19 and iTIL >4.

In a meta-analysis on the relationship between TILs and BC; 17 studies were analyzed. Total TILs were not associated with tumor grade, HR or HER-2 status but the relationship of tumor size, lymph node status, and Ki-67 expression were not analyzed in this meta-analysis. They found that programmed death-1 (PD-1) positive TILs were related to high tumor grade, big tumor size, positive lymph node, negative HR and HER2 status. However, high-TILs were also associated with elevated pCR rate to NACT for HR positive, HER2 positive, and HER2 negative BC except for HR negative subtype. In this meta-analysis, iTILs and sTILs were associated with better DFS and OS whereas DFS was statistically significant, OS was not statistically significant. In subgroup analysis, both PD-1 (+) TILs and the forkhead box protein 3 (FOXP3) (+) TILs predicted poor OS, while BC with high level of CD8 (+) TILs showed a favorable DFS.[22]

The presence of sTILs and iTILs in ER negative tumors is independently associated with a reduced relative risk of death from BC, iTILs is also associated with ER positive HER2 positive subgroup a reduction in BC-specific mortality.[19],[23] Also, higher levels of sTIL in triple negative (i.e., ER negative, PR negative, and HER2 negative) BC are significantly associated with decreased distant recurrence rates and death.[24],[25] In a meta-analysis including 2987 triple negative BC patients, rich TILs were associated with 30%, 22%, and 34% reduction in the risk of recurrence, distant recurrence, and death.[26]

A 30% threshold for sTILs in HER2 positive BC significantly predicted pCR to trastuzumab-based NACT in both HR positive and HR negative tumors.[27] In a study evaluating the prognostic and predictive value of TILs in adjuvant BC, high TILs (iTILs and/or sTILs ≥50%) in both triple negative BC and HER2 positive BC were strong prognostic factors for OS but a significant relationship between TILs and anthracycline treatment have not been demonstrated.[28] Similar results were found in the secondary analysis of the NeoALTTO Trial. The presence of TILs was an independent, positive, prognostic marker in HER2 positive early BC treated with neoadjuvant anti-HER2 agents (trastuzumab, lapatinib, or the combination) and chemotherapy for both pCR and EFS.[29] In the recently published N9831 study evaluating the association between recurrence-free survival (RFS) and sTILs in HER2 positive BC treated with chemotherapy or chemotherapy plus trastuzumab, the presence of high sTILs was associated with improved RFS in patients treated with chemotherapy alone but there was no relationship in patients treated with chemotherapy plus trastuzumab, in contrast to previously reported NeoALTTO Trial.[30] For this reason, based on the current findings, the effect of TILs in mediating the response to adjuvant trastuzumab is unclear. Despite the controversy regarding the role of TILs in response to HER2-targeted therapy, previous studies have suggested that increased TILs is a predictive marker of trastuzumab response.[25]

The most commonly tested markers for TILs subset in BC are CD3+, CD4+, CD8+ and FOXP3+. TILs subsets play a different role in predicting response to NACT. Higher level of CD4+ and CD8+ TILs are associated with better clinical outcome. In contrast, the abundance of FOXP3 expressing regulatory T lymphocyte (Tregs) in the tumor bed of BC patients are significantly associated with poor clinical outcome.[31],[32] The major role for the immune system is to recognize and eliminate cells undergoing carcinogenesis. Cancerous cells often express aberrant peptides, leading to a cellular adaptive immune response. These peptides are presented on the surface of cells by HLA molecules for binding by T-cell receptors on the surface of T-lymphocytes. CD8+ cytotoxic T lymphocytes (CTLs), a major component of the adaptive immune system, directly kill tumor cells by producing interferon gamma. CD4+ T helper lymphocytes (Th) activate humoral immunity, CTLs, eosinophils by secreting various cytokines. A CD4+ Treg subset suppresses CTLs. FOXP3 that a transcription factor expressing Tregs have been described as putative mediators of immune tolerance, and thus facilitators of tumor growth.

The prognostic significance of FOXP3+ TILs in patients with BC remains controversial. In a meta-analysis of 13 published studies including 3251 BC patients, the detection of higher TILs predicted higher pCR rates in triple negative, HER2 positive BC, but not in ER positive patients. Furthermore, higher levels of CD8+ and FOXP3+ T lymphocytes in pretreatment biopsy predicted better pathological response to NACT but higher levels of FOXP3+ T lymphocytes infiltration in posttreatment breast tissue predicted a lower pCR rate in univariate and multivariate analysis.[33] In another meta-analysis of 17 studies including 8277 BC patients, the incidence of FOXP3+ TILs was significantly higher in the lymph node positive, high tumor grade, ER positive, PR positive, HER2 positive, and triple negative group. High FOXP3+ TILs group were significantly associated with a poor OS and TILs decreased RFS.[34]

The major limitation of our study was a retrospective design. Also, immunohistochemical analysis for CD3+, CD4+, CD8+, and FOXP3+ to determine TILs subset can not be performed.


 > Conclusion Top


There are an association between pCR and TILs in BC who received NACT. According to our results, increased number of iTILs (>4 cells/mm 2 of tissue) was significantly associated with higher pCR in patients with LABC. The patients with LABC who had increased number of sTILs (>19 cells/mm 2 of tissue) were more higher pCR but statistically not significant. We believe that the number of TILs in patients with LABC is a strong predictive factor for pCR according to our results and literature information and may suggest that TILs (especially the number of iTILs) can be used to decide NACT in patients with early BC for example >2 cm, nod negative, ER- and PR-negative, HER2 positive disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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