Prognostic significance of stroma tumorinfiltrating lymphocytes according to molecular subtypes of breast cancer

Transcription

1 Prognostic significance of stroma tumorinfiltrating lymphocytes according to molecular subtypes of breast cancer Hee Jung Kwon, Nuri Jang, Min Hui Park, Young Kyung Bae Department of Pathology, Yeungnam University College of Medicine

2 The authors declare that there is no conflict of interest.

3 Backgroud Tumor infiltrating lymphocytes (TILs) Indicator of immune microenvironment in cancer tissues Prognostic factor and predictor of therapeutic efficacy

4 Aim of this study 1. To investigate whether stromal TILs (stils) which is measured in routine clinical practice is prognostic in breast cancer 2. To find valid cutoffs for TILs that represent clinical significance

5 Material & Methods Invasive breast carcinoma samples (n=1489) Patients who underwent surgical resection between postoperative follow-up: months (median, 117 months) Adjuvant chemotherapy Chemotherapy type Regimen Number of cases None Anthracyclines FEC AC 274 FAC 130 Others 5-FU CMF 94 Taxol, taxotere, furtulon, xeloda 30 Total

6 Material & Methods Measurement of TILs one representative whole section H&E slide Inside the borders of invasive tumor Only stromal TILs (lymphocytes and plasma cells) Percentage of stromal TILs over the analyzed stromal area (1%, 5%, 10%, 20%, 30%...) Average TILs (not hotspots) International TILs Working Group 2014 (Ann Oncol 2014; 26: 259) + Average

7 Material & Methods Molecular subtypes St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 Ann. Oncol. 2013; 24: Subtype Definition No. of cases Luminal A ER+/PR+/HER2 /Ki-67 20% 424 Luminal B, HER2-negative Luminal B, HER2-positive ER+/HER2 /Ki-67>20% or ER+/HER2 /PR or low ER+/HER2+/any Ki-67/any PR HER2-positive ER /PR /HER Triple-negative ER /PR /HER2 308 Unknown 12 Total

8 Results Representative cases showing variable density of TILs 1% 10% 40% 70%

9 Results Distribution of cases according to % stromal TILs TILs high (n=427, 28.7%) Mean: 9.85% Median: 5% ROC curve: 5% (AUC=0.598; 95% CI, ; p<0.001)

10 Results Correlations between TILs and clinicopathological parameters Parameter Total cases TILs (n=1489) (%) Low (%) (n = 1062) High (%) (n = 427) P-value Age < (65.5) 697 (65.6) 278 (65.1) (34.5) 365 (34.4) 149 (34.9) Tumor size cm 787 (52.9) 591 (55.6) 196 (45.9) >2 cm 702 (47.1) 471 (44.4) 231 (54.1) LN metastasis Absent 809 (54.4) 571 (53.9) 238 (55.7) Present 677 (45.6) 488 (46.1) 189 (44.3) LVI Absent 737 (49.5) 514 (48.4) 223 (52.2) Present 752 (50.5) 548 (51.6) 204 (47.8) Histological grade < and (47.2) 613 (57.7) 90 (21.1) (52.8) 449 (42.3) 337 (78.9) Estrogen receptor <0.001 Negative 476 (32.0) 219 (20.6) 257 (60.2) Positive 1013 (68.0) 843 (79.4) 170 (39.8) Progesterone receptor <0.001 Negative 615 (41.3) 330 (31.1) 285 (66.7) Positive 874 (58.7) 732 (68.9) 142 (33.3) HER2 <0.001 Negative 1207 (81.1) 908 (85.5) 299 (70.0) Positive 282 (18.9) 154 (14.5) 128 (30.0) Ki-67 labeling index < % 621 (41.7) 540 (50.9) 81 (19.0) >20% 867 (58.3) 521 (49.1) 346 (81.0)

11 Results TILs according to molecular subtypes Comparison of TILs between two different molecular subtypes Lum A Lum B (HER2-) HER2+ TNBC Lum A Lum B (HER2-) p=0.147* HER2+ p<0.001* p<0.001* TNBC p<0.001* p<0.001* p<0.001* *P value by one-way ANOVA

12 Results TILs according to adjuvant chemotherapy Comparison of TILs between two different treatment groups No CTx Anthracycline Nonanthracycli ne No CTx p<0.001* Anthracycline Nonanthracycli ne p=0.024 p=0.270 *P value by one-way ANOVA

13 Results: Survival analysis in all patients (n=1489) High TILs (n=427) High TILs (n=427) Low TILs (n=1062) Low TILs (n=1062) p=0.09 p<0.001

14 Results: Survival analysis in all patients (n=1489) Multivariate analysis for DFS TILs, 10% p<0.001 Tumor size, >2 cm p=0.016 LN metastasis LVI p=0.001 p<0.001 Histologic grade, 3 ER positivity PR positivity HER2 positivity Ki-67, >20% Adjuvant CTx -anthracyclines Adjuvant CTx -non-anthracyclines * * * * * p=0.001 * favorable unfavorable Hazard ratio (range, 95% confidence interval) for recurrence/metastasis * p>0.05

15 Results: Survival analysis according to adjuvant chemotherapy in all patients (n=1489) Low TILs group (n=1062) High TILs group (n=427) No chemotherapy (n=175) Non-anthracycline (n=191) Anthracycline (n=696) Anthracycline (n=328) Non-anthracycline (n=66) No chemotherapy (n=33) p<0.001 p=0.222

16 Results: subgroup analysis No chemotherapy (n=208) Anthracyclines (n=1024) Non-anthracyclines (n=257) Low TILs (n=175) High TILs (n=33) High TILs (n=328) Low TILs (n=696) Low TILs (n=191) High TILs (n=66) p=0.293 p=0.012 p=0.873 Low TILs (n=175) High TILs (n=328) High TILs (n=66) High TILs (n=33) Low TILs (n=696) Low TILs (n=191) p=0.02 p<0.001 p=0.158

17 Results: Survival analysis in anthracycline group (n=1014) Luminal A Luminal B (HER2-) HER2+ Triple-negative High TILs (n=22) High TILs (n=59) High TILs (n=106) High TILs (n=137) Low TILs (n=220) Low TILs (n=254) Low TILs (n=122) Low TILs (n=94) p=0.519 p=0.012 p=0.064 p=0.063 p=0.394 p=0.002 p=0.007 p=0.031

18 Multivariate analysis for DFS Luminal B (HER2-) subtype TILs, 10% p=0.003 Tumor size, >2 cm Histologic grade, 3 p=0.009 p=0.002 HER2+ subtype TILs, 10% p=0.011 LVI p=0.045 Triple-negative subtype TILs, 10% p=0.034 LVI p<0.001 Hazard ratio (range, 95% confidence interval) for recurrence/metastasis

19 Conclusion High TILs ( 10%) was significantly associated with large tumor size (>2cm), histologic grade 3, negative hormone receptors, positive HER2 status and high Ki-67 (>20%) Prognostic significance of TILs was associated with adjuvant treatment and molecular subtypes High TILs was predictive of better OS and DFS in patients who received adjuvant anthracyclines in univariate and multivariate analyses High TILs was an independent marker for favorable DFS in patients with luminal B (HER2-), HER2+, and TNBC in univariate and multivariate analyses High TILs could be a useful marker to predict therapeutic effect of anthracyclines in luminal B, as well as HER2-positive and triple-negative subtypes of breast cancer