***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: PURPOSE Immune checkpoint inhibition has been demonstrated to be an effective anticancer strategy . Several lines of evidence support the study of immunotherapy in triple-negative breast cancer ( TNBC ) . We assessed the safety and antitumor activity of the programmed cell death protein 1 ( PD-1 ) inhibitor pembrolizumab in patients with advanced TNBC . METHODS KEYNOTE-012 ( Clinical Trials.gov identifier : NCT01848834 ) was a multicenter , nonr and omized phase Ib trial of single-agent pembrolizumab given intravenously at 10 mg/kg every 2 weeks to patients with advanced PD-L1-positive ( expression in stroma or ≥ 1 % of tumor cells by immunohistochemistry ) TNBC , gastric cancer , urothelial cancer , and head and neck cancer . This report focuses on the TNBC cohort . RESULTS Among 111 patients with TNBC whose tumor sample s were screened for PD-L1 expression , 58.6 % had PD-L1-positive tumors . Thirty-two women ( median age , 50.5 years ; range , 29 to 72 years ) were enrolled and assessed for safety and antitumor activity . The median number of doses administered was five ( range , 1 to 36 doses ) . Common toxicities were mild and similar to those observed in other tumor cohorts ( eg , arthralgia , fatigue , myalgia , and nausea ) , and included five ( 15.6 % ) patients with grade ≥ 3 toxicity and one treatment-related death . Among the 27 patients who were evaluable for antitumor activity , the overall response rate was 18.5 % , the median time to response was 17.9 weeks ( range , 7.3 to 32.4 weeks ) , and the median duration of response was not yet reached ( range , 15.0 to ≥ 47.3 weeks ) . CONCLUSION This phase Ib study describes preliminary evidence of clinical activity and a potentially acceptable safety profile of pembrolizumab given every 2 weeks to patients with heavily pretreated , advanced TNBC . A single-agent phase II study examining a 200-mg dose given once every 3 weeks ( Clinical Trials.gov identifier : NCT02447003 ) is ongoing PURPOSE Pre clinical data suggest a contribution of the immune system to chemotherapy response . In this study , we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy . METHODS We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies ( GeparDuo , n = 218 , training cohort ; and GeparTrio , n = 840 , validation cohort ) . Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed , paraffin-embedded tumor sample s. Results In a multivariate regression analysis including all known predictive clinicopathologic factors , the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response ( pCR ) in both cohorts ( training cohort : P = .012 ; validation cohort : P = .001 ) . Lymphocyte-predominant breast cancer responded , with pCR rates of 42 % ( training cohort ) and 40 % ( validation cohort ) . In contrast , those tumors without any infiltrating lymphocytes had pCR rates of 3 % ( training cohort ) and 7 % ( validation cohort ) . The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate , and logistic regression showed a significant association of the T-cell-related markers CD3D and CXCL9 with pCR . CONCLUSION The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy Breast carcinomas are often infiltrated by inflammatory cells , particularly macrophages and T lymphocytes , but the significance of these cells remains unclear . One possible role of these inflammatory cells is that they represent a cell-mediated immune response against the carcinoma . CD8(+ ) lymphocytes are a known crucial component of cell-mediated immunity . The purpose of this study was to explore the prognostic value of tumor-infiltrating CD8(+ ) cytotoxic lymphocytes in breast cancer .  Tumor-infiltrating CD8(+ ) lymphocytes were assessed by immunohistochemical staining of tissue microarray cores from 1,334 unselected breast tumors from patients with long-term follow-up . The number of CD8(+ ) T cells was counted in tumor nests ( intratumoral ) , in stroma adjacent to tumor cells , and in stroma distant to tumor cells , and their relationship with clinical outcome was determined . The total number of CD8(+ ) cells was positively correlated with tumor grade ( r(s ) = 0.20 ; P < .001 ) and inversely correlated with patient 's age at diagnosis , estrogen receptor-alpha ( ER-α ) , and progesterone receptor ( PgR ) expression ( Mann-Whitney U test , P < .001 ) . The total patient cohort was r and omly divided into two separate training and validation sets before performing univariate survival analysis . Total number and distant stromal CD8(+ ) lymphocytes were associated with better patient survival ( P = .041 and P < .001 , respectively ) in the training set . In multivariate analysis , total CD8(+ ) T-cell count was an independent prognostic factor in both training and validation sets . These results suggest that tumor-infiltrating CD8(+ ) T lymphocytes have antitumor activity as judged by their favorable effect on patients ' survival and could potentially be exploited in the treatment of breast cancer BACKGROUND We have previously shown the prognostic importance of tumor-infiltrating  lymphocytes ( TILs ) in newly diagnosed triple-negative breast cancer ( TNBC ) using tumor sample s from a large clinical trial cohort . In this study , we aim ed to vali date these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease ( HER2 + ) . PATIENTS AND METHODS A prospect ive-retrospective study was conducted using sample s from the FinHER adjuvant , phase III trial that enrolled 1010 early-stage BC patients , 778 of whom were HER2-nonamplified . Those with HER2 + disease ( n = 232 ) were r and omized to 9 weeks of trastuzumab or no trastuzumab in addition to chemotherapy . Two pathologists independently quantified stromal TILs in 935 ( 92.6 % ) available slides . The primary end point of distant disease-free survival ( DDFS ) and interactions with trastuzumab  were studied in Cox regression models . RESULTS Confirming our previous findings , in TNBC ( n = 134 ) each 10 % increase in TILs was significantly associated with decreased distant recurrence in TNBC ; for DDFS the hazard ratio adjusted for clinicopathological factors : 0.77 ; 95 % confidence interval ( CI ) 0.61 - 0.98 , P = 0.02 . In HER2 + BC ( n = 209 ) , each 10 % increase in lymphocytic infiltration was significantly associated with decreased distant recurrence in patients r and omized to the trastuzumab arm ( DDFS P interaction = 0.025 ) . CONCLUSIONS Higher levels of TILs present at diagnosis were significantly associated with decreased distant recurrence rates in primary TNBC . These results confirm our previous data and further support that TILs should be considered as a robust prognostic factor in this BC subtype . We also report for the first time an association between higher levels of TILs and increased  trastuzumab  benefit in HER2 + disease . Further research into why some TN and HER2 + BCs can or can not generate a host antitumor immune response and how trastuzumab can favorably alter the immune microenvironment is warranted PURPOSE Previous pre clinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy ( CT ) ; however , clinical relevance has yet to be established in breast cancer ( BC ) . We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case , anthracycline-only CT-in  selected BC subtypes . PATIENTS AND METHODS We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC sample s from the BIG 02 - 98 adjuvant phase III trial comparing anthracycline-only CT ( doxorubicin followed by cyclophosphamide , methotrexate , and fluorouracil [ CMF ] or doxorubicin plus cyclophosphamide followed by CMF ) versus CT combining doxorubicin and docetaxel ( doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF ) . Readings were independently performed by two pathologists . Disease-free survival ( DFS ) , overall survival ( OS ) , and interaction with type of CT associations were studied . Median follow-up was 8 years . RESULTS There was no significant prognostic association in the global nor estrogen receptor ( ER ) -positive/human epidermal growth factor receptor 2 ( HER2 ) -negative population . However , each 10 % increase in intratumoral and stromal lymphocytic infiltrations was associated with 17 % and 15 % reduced risk of relapse ( adjusted P = .1 and P = .025 ) , respectively , and 27 % and 17 % reduced risk of death in ER-negative/HER2-negative BC regardless of CT type ( adjusted P = .035 and P = .023 ) , respectively . In HER2-positive BC , there was a significant interaction between increasing stromal lymphocytic infiltration ( 10 % increments ) and benefit with anthracycline-only CT ( DFS , interaction P = .042 ; OS , P = .018 ) . CONCLUSION In node-positive , ER-negative/HER2-negative BC , increasing lymphocytic infiltration was associated with excellent prognosis . Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted . Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes PURPOSE Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy . To investigate the immunogenicity of human epidermal growth factor receptor 2 ( HER2 ) -positive and triple-negative ( TN ) breast cancers ( BCs ) , we evaluated tumor-infiltrating lymphocytes ( TILs ) and immunologically relevant genes in the neoadjuvant GeparSixto trial . PATIENTS AND METHODS GeparSixto investigated the effect of adding carboplatin ( Cb ) to an anthracycline-plus-taxane combination ( PM ) on pathologic complete response ( pCR ) . A total of 580 tumors were evaluated before r and om assignment for stromal TILs and lymphocyte-predominant BC ( LPBC ) . mRNA expression of immune-activating ( CXCL9 , CCL5 , CD8A , CD80 , CXCL13 , IGKC , CD21 ) as well as immunosuppressive factors ( IDO1 , PD-1 , PD-L1 , CTLA4 , FOXP3 ) was measured in 481 tumors . RESULTS Increased levels of stromal TILs predicted pCR in univariable ( P < .001 ) and multivariable analyses ( P < .001 ) . pCR rate was 59.9 % in LPBC and 33.8 % for non-LPBC ( P < .001 ) . pCR rates ≥ 75 % were observed in patients with LPBC tumors treated with PMCb , with a significant test for interaction with therapy in the complete ( P = .002 ) and HER2-positive ( P = .006 ) , but not the TNBC , cohorts . Hierarchic clustering of mRNA markers revealed three immune subtypes with different pCR rates ( P < .001 ) . All 12 immune mRNA markers were predictive for increased pCR . The highest odds ratios ( ORs ) were observed for PD-L1 ( OR , 1.57 ; 95 % CI , 1.34 to 1.86 ; P < .001 ) and CCL5 ( OR , 1.41 ; 95 % CI , 1.23 to 1.62 ; P < .001 ) . CONCLUSION Immunologic factors were highly significant predictors of therapy response in the GeparSixto trial , particularly in patients treated with Cb . After further st and ardization , they could be included in histopathologic assessment of BC 
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RESULTS We find that whilst factors such as TILs and certain subgroups of TILs ( e.g. , CD8 + and regulator T-cells ) have been extensively research ed , none of these markers are currently applicable to routine clinical practice .
Also , TNBC differs from other types of breast cancer with regards to cellular composition of the immune infiltrate and PD-L1 expression , and the prognostic significance of these .
Immune-related factors have the potential as both prognostic and predictive biomarkers for new treatments targeting the immune system in breast cancer .