R2 김형오 / Pf. 김시영

 Recent results  Presence of extensive lymphocytic infiltration in early stage breast cancer  Good prognosis  High response rates to neoadjuvant chemotherapy  TIL(Tumor-infiltrating lymphocytes)  Shown to be a good prognostic indicator ▪ Only in highly proliferative breast tumor ▪ Not routine

 Recent concept  Cell death induced by chemotherapies can promote permanant antitumor immunity ▪ Anthracyclines, oxaliplatin, gemcitabine etc ▪ May be critical for long-lasting remission  BIG(Breast International Group) study  Extensive follow up  Randomized  Prospectively planned

 To examine the hypothesis  Increased lymphocytic infiltration would be associated with good prognosis  Benefit from immunogenic chemotherapy in selected breast cancer subtypes

 BIG  Multicenter, randomized, prospective, phase III  2887 patients, LN (+), 1998~2001 ▪ A1 : Sequential control ▪ CMF 3 cycle -> doxorubicin 75mg/m2, 4 cycles ▪ A2 : Concurrent control ▪ CMF 3 cycle -> Doxorubicin 60mg/m2 4 cycles + cyclophosphamide 600mg/m2 ▪ B : Sequential docetaxel ▪ CMF 3 cycle -> docetaxel 100mg/m2 -> doxorubicin 75mg/m2 ▪ C : Concurrent doxetaxel ▪ CMF 3 cycle -> docetaxel 75mg/m2 + doxorubicin 50mg/m2 -> 2009 samples analyzed(69.6%)

 Definitions  Intratumoral lymphocytic infiltration ▪ Percentage of mononuclear cells within the epithelium of the invasive tumor cell nests  Stromal lymphocytic infiltration ▪ Percentage of tumor stroma containing infiltrating lymphocytes  Disease free survival(DFS) ▪ Date of random assignment ~ 1 st relapse, 2 nd primary, death  Overall survival(OS) ▪ Date of random assignment ~ date of death with any cause  Lymphocyte predominant breast cancer ▪ >=50% infiltration of stromal or intratumoral lymphocytic infiltration

 Group subtypes  ER, HER2 ▪ ER negative / HER2 negative ▪ HER2 overexpressing ▪ ER positive / HER 2 negative

 TILs and pathologics association  TILs(stromal/intratumoral) were associated with ▪ Infiltrating ductal histology, (P<0.001, p=0.048) ▪ High histologic grade, (p<0.001, p<0.001) ▪ Hormone receptor negativity, (P<0.001, p<0.001) ▪ Not associated with age, menopausal state, increasing lymph node involvement, tumor size  Median percentage ▪ Infiltration of intratumoral lymphocytes : 2% ▪ Stromal lymphocytes : 10%

10% increment of infiltration stromal, 15% reduction of risk for recurrence or death (17% risk of death) intratumoral 17% reduction of risk for recurrence or death (27% risk of death)

HER2(+), anthracycline only HER2(+), anthracycline, docetaxel

 Increasing lymphocytic infiltration of the tumor and stroma  Associated with good prognosis  Only in ER(-)/HER2(-) subgroup  Interaction between increasing stromal infiltration and chemotherapy regimen was seen only in the HER2(+)  Strengths  Size,  Randomization,  Long-term follow-up,  Two independent pathologic assessment  Increasing lymphocytic infiltration is a strong prognostic factor for the ER(-)/HER2(-) BC subtype