Purpose: High levels of tumor-infiltrating lymphocytes (TILs) before neoadjuvant chemotherapy (NAC) are associated with higher pathological complete response (pCR) rates, and better survival in TNBC and HER2-positive breast cancers (BCs). We investigated the value of changes in TIL levels and final TIL levels after treatment, by evaluating lymphocyte infiltration before and after NAC in a real-life BC cohort. Patients and methods: We assessed stromal TIL levels in 716 pre- and post-treatment matched paired specimens, according to the guidelines of the international TIL working group. Results: Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases of residual disease (33.9% versus 20.3%, p=0.001), in luminal tumors and TNBCs, but not in HER2-positive BCs, (pInteraction =0.001). The association between pre-NAC TIL levels and pCR was non-linear in TNBCs (p=0.005). Mean TIL levels decreased during NAC (pre-NAC TILs: 24.1% versus post-NAC TILs: 13.0%, p<0.001). This decrease was strongly associated with high pCR rates, and TIL level variation was strongly inversely correlated with pre-NAC TIL levels (r=-0.80, p<0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a non-linear manner (p<0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in HER2-positive BCs (HR=1.04, CI [1.02-1.06], p=0.001), but not in luminal tumors or TNBCs (pInteraction =0.04). Conclusion: The associations of pre, post-NAC TIL levels with response to treatment and DFS differ between BC subtypes and may deviate from linearity. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, BC subtype, response to treatment and prognosis. Citation Format: Hamy A-S, Bonsang-Kitzis H, De Croze D, Laas E, Darrigues L, Topciu L, Menet E, Vincent-Salomon A, Lerebours F, Pierga J-Y, Brain E, Feron J-G, Benchimol G, Lam G-T, Laé M, Reyal F. Interaction between molecular subtype and stromal immune infiltration dynamics in breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-11-01.
Purpose : Lymphovascular invasion (LVI) is a poor prognosis factor in breast cancer (BC), but data on its value in the neoadjuvant setting is scarce. This study evaluates the relationships between post-NAC LVI and prognosis in BC. Methods: We identified 1197 patients with primary BC receiving NAC +/- trastuzumab between 2002 and 2011. Information on LVI in post-NAC surgical specimen was retrieved from review of medical charts. Univariate and multivariate analyses were performed to assess the association of clinical, pathological factors with disease free survival (DFS) and overall survival (OS) was assessed using a cox proportional hazard model. Results: On 1197 tumors, 528 were luminal (44.1%), 375 were triple negative breast cancer (TNBC) (31.3%) and 294 were HER2-positive (24.6%). On post-NAC surgical specimens, LVI was present in 302 (25.2%), absent in 531 (44.4%), and was not mentionned in 364 cases (30.4%). The presence of post-NAC LVI was associated with an impaired DFS (HR=2.17, 95 CI [1.65 - 2.86], p<0.001) and the magnitude of this impact varied by BC subtype (p-value for interaction=0.02), (luminal BC: HR=1.75, p=0.006; TNBC : HR=2.77, p<0.001 ; HER2-positive BC : HR=5.12, p<0.001). Table 1 Univariate analysis and multivariate analysis on DFS (whole population) Univariate Multivariate VariableClassHRClpHRCIpAge< 451 0.35 45-550.82[0.62 - 1.08] >550.87[0.64 - 1.19] Menopausal statuspremenopausal1.04[0.81 - 1.34]0.75 postmenopausal1 BMI class19-251 < 191.24[0.75 - 2.05]0.41 > 251.36[1.06 - 1.75]0.01 Tumor sizeT1-T21 T31.77[1.38 - 2.27]<0.011.77[ 1.32 - 2.38 ]<0.001Clinical nodal statusN01 N1-N2-N31.35[1.05 - 1.72]0.021.43[ 1.07 - 1.91 ]0.016HistologyDuctal1 Other1.24[0.87 - 1.78]0.24 GradeGrade I-II1 III1.24[0.87 - 1.78]0.07 Ki 67<201 >201.54[1.06 - 2.22]0.02 Mitotic index≤221 >221.18[0.9 - 1.53]0.23 DCIS componentno1 yes1.33[0.88 - 2.01]0.18 Pre-NAC LVIno1 yes1.35[0.88 - 2.01]0.09 ER statusnegative1 positive0.72[0.56 - 0.91]<0.01 PR statusnegative1 positive0.66[0.51 - 0.85]<0.01 HER2 statusnegative1 positive0.84[0.62 - 1.14]0.26 BC subtypeluminal1 TNBC1.53[1.17 - 2]<0.012.67[ 1.93 - 3.69 ]<0.001 HER20.99[0.72 - 1.38]0.971.25[ 0.82 - 1.88 ]0.299Post NAC parametersPost-NAC LVI (breast)no1 yes2.17[1.65 - 2.86]<0.012.3[ 1.72 - 3.08 ]<0.001pCRNo pCR1 pCR0,4[0.27 - 0.59]<0.01 Pathological nodal involvement0 1-31.48[1.11 - 1.97]<0.01 ≥4 N+3.13[2.34 - 4.19]<0.01 RCB class01 10.97[0.36 - 2.64]0.96 22.88[1.69 - 4.89]<0.01 35.21[3.01 - 9.02]<0.01 ER: oestrogene receptor PR: progesteron receptor RCB: residual cancer burden Post-NAC LVI was an independent predictor of poor DFS, that overwhelmed the prognostic impact of pathological complete response in all 3 BC subtypes. Post-NAC LVI was also an independent predictor of poor OS in the whole cohort and in all BC subtypes. Table 1 resumes univariate and multivariate analysis on DFS in whole population. Conclusion: Post-NAC LVI is a strong independent prognostic factor associated with poor DFS and OS, that (i) should be systematically mentioned in pathological reports following NAC and (ii) could be used to select high risk patients candidates to second line trials in the post-neoadjuvant window. Citation Format: Hamy-Petit A-S, Lam G-T, Laas E, Darrigues L, Balezeau T, Guerin J, Livartowski A, Sadacca B, Pierga J-Y, Vincent-Salomon A, Bidard F-C, Lerebours F, Brain E, Becette V, Rouzier R, Lae M, Reyal F. Lymphovascular invasion in breast carcinoma following neodjuvant chemotherapy is a strong prognosis factor [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-03-04.
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