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Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Denkert Carsten,von Minckwitz Gunter,Darb-Esfahani Silvia,Lederer Bianca,Heppner Barbara I,Weber Karsten E,Budczies Jan,Huober Jens,Klauschen Frederick,Furlanetto Jenny,Schmitt Wolfgang D,Blohmer Jens-Uwe,Karn Thomas,Pfitzner Berit M,Kümmel Sherko,Engels Knut,Schneeweiss Andreas,Hartmann Arndt,Noske Aurelia,Fasching Peter A,Jackisch Christian,van Mackelenbergh Marion,Sinn Peter,Schem Christian,Hanusch Claus,Untch Michael,Loibl Sibylle The Lancet. Oncology BACKGROUND:Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal-HER2-negative breast cancer. METHODS:Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0-10% immune cells in stromal tissue within the tumour), intermediate (11-59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts. FINDINGS:In the luminal-HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0·0001 for each subtype, χ test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio [HR] 0·93 [95% CI 0·87-0·98], p=0·011) and HER2-positive breast cancer (0·94 [0·89-0·99], p=0·017), but not in luminal-HER2-negative tumours (1·02 [0·96-1·09], p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 [0·86-0·99], p=0·032), but had no association in HER2-positive breast cancer (0·94 [0·86-1·02], p=0·11), and was associated with shorter overall survival in luminal-HER2-negative tumours (1·10 [1·02-1·19], p=0·011). INTERPRETATION:Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal-HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted. FUNDING:Deutsche Krebshilfe and European Commission. 10.1016/S1470-2045(17)30904-X
Relationship between serum HER2 extracellular domain levels, tissue HER2 expression, and clinico-pathological parameters in early stage breast cancer. Ma Li,Yang Hong-ying,Han Xiao-hong,Li Jia,Wang Fang,Zhang Chun-ling,Yao Jia-rui,Shi Yuan-kai Chinese medical journal BACKGROUND:Measurement of human epidermal growth factor receptor 2 (HER2) protein in the serum of metastatic breast cancer patients has previously been reported, but there are no consistent data to support the clinical utility of serum HER2 extracellular domain for patients with early stage breast cancer. We aimed to evaluate the correlation between serum extracellular domain levels and tissue HER2 expression, and analyzed their relationship with clinico-pathological parameters in patients with early stage disease. METHODS:A prospective study was conducted on 232 breast cancer patients with stage I-III prior to treatment. Preoperative serum samples were measured by enzyme-linked immunosorbent assay. Tissue HER2 status was analyzed by immunohistochemistry and fluorescence in situ hybridization assays. RESULTS:The median serum extracellular domain concentration was 6.8 ng/ml. The best diagnostic cut-off value was 7.4 ng/ml, with 62.9% sensitivity and 85.3% specificity. High serum extracellular domain levels were reported in 89 patients (38.3%), and HER2-positive expression was observed in 77 patients (33.2%). Multivariate analysis showed that elevated serum extracellular domain correlated with postmenopausal status (P < 0.001), high histological grade (P < 0.001), negativity of both estrogen (P = 0.012) and progesterone receptors (P < 0.001), and high levels of carcinoembryonic antigen 153 (P = 0.048). CONCLUSIONS:We recommend that 7.4 ng/ml should be used as the cut-off value when evaluating serum extracellular domain levels in early stage of breast cancer. Patients with high serum extracellular domain levels have a certain clinico-pathological characteristics, may provide a basis for clinical practice.
High serum HER2 extracellular domain levels: correlation with a worse disease-free survival and overall survival in primary operable breast cancer patients. Kong Yanan,Dai Shuqin,Xie Xinhua,Xiao Xiangsheng,Lv Ning,Guo Jiaoli,Li Laisheng,Jia Weihua,Zhang Yin,Liu Wanli,Wei Weidong,Xie Xiaoming Journal of cancer research and clinical oncology PURPOSE:High serum human epidermal growth factors receptor-2 (HER2) extracellular domain (ECD) has been identified as an independent prognostic indicator of poor prognosis in metastatic breast cancer. However, its prognostic value in primary operable breast cancer was still controversial. We aim to investigate the correlation between serum HER2 ECD levels and tissue HER2 status, the association between serum HER2 ECD levels and clinicopathological characteristics, and their impacts on disease-free survival (DFS) and overall survival (OS) in primary operable breast cancer. METHODS:Two hundred and fifty-two primary operable breast cancer patients pretreated from 2002 to 2009 in Sun Yat-Sen University Cancer Center were enrolled in this study. Serum HER2 ECD was measured by chemiluminescent assay, and tissue HER2 status was accessed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) assay. RESULTS:There was a significant correlation between serum HER2 ECD levels and HER2 tissue status (P < 0.001, R = 0.36). High serum HER2 ECD levels (≥15 ng/mL) were significantly associated with age (≥35 years) (P = 0.028), postmenopausal status (P < 0.001), stage III (P < 0.001), tumor size (≥2 cm) (P < 0.001), lymph node involvement (P < 0.001), negative estrogen receptor (P = 0.005), and progesterone receptor status (P = 0.001). Multivariate analysis showed that high serum HER2 ECD level was an independent prognostic factor of worse DFS (P = 0.014) and OS (P = 0.014) in primary operable breast cancer patients. CONCLUSION:Serum HER2 ECD level can reflect tissue HER2 status and can be an independent prognostic indicator for primary operable breast cancer patients. 10.1007/s00432-011-1095-9
The Significance of Serum HER2 Levels at Diagnosis on Intrinsic Subtype-Specific Outcome of Operable Breast Cancer Patients. Lee Moo Hyun,Jung So-Youn,Kang Sun Hee,Song Eun Jin,Park In Hae,Kong Sun-Young,Kwon Young Mee,Lee Keun Seok,Kang Han-Sung,Lee Eun Sook PloS one PURPOSE:This study evaluated the association of serum HER2 (sHER2) levels at diagnosis with clinicopathologic parameters and disease free survival (DFS) in operable breast cancer patients according to intrinsic subtype. METHODS:The sHER2 levels were measured using a chemiluminescence immunoassay. The HER2 status in all tumor tissues was determined by immunohistochemistry, and confirmed in equivocal cases by fluorescence in situ. RESULTS:There were 436 consecutive stage I-III breast cancer patients with sHER2 result at diagnosis between Nov 2004 and Dec 2011. High sHER2 levels (≥ 15 ng/ml) were reported in 52 patients (11.9%) and HER2 overexpression in tumor tissue was observed in 111 patients (25.5%). High sHER2 levels were associated significantly with advanced stage (P < 0.001), mastectomy (P = 0.012), neoadjuvant chemotherapy (P < 0.001), anti-HER2 therapy (P < 0.001) and hormone therapy (P = 0.022). The patients with high sHER2 levels had a worse DFS (P < 0.001). In multivariate analysis, high sHER2 levels were associated significantly with worse DFS (HR = 2.25, 95% CI 1.27-3.99, P = 0.005). High sHER2 levels were associated with worse DFS in the HR+/HER2-, HR+/HER2+ and HR-/HER2+ subtypes (P = 0.043, 0.003 and 0.041, respectively). CONCLUSIONS:These results show that the sHER2 level at diagnosis is a useful prognostic factor in patients with operable breast cancer, especially in the HR+/HER2-, HR+/HER2+ and HR-/HER2+ subtypes. 10.1371/journal.pone.0163370