Background: Baseline TIL density and T-cell clonality predict pathological complete response (pCR) to neoadjuvant (NA) trastuzumab (TRAS). Preclinical data suggests that a major mechanism of TRAS is enhancement of antibody-dependent cytoxicity (ADCC) and T-cell mediated tumor kill and that the combination of TRAS with pertuzumab (PERT) may enhance ADCC. This study quantifies both TIL density and T-cell clonality in both pre and post-NA samples from patients receiving NA TRAS +/- PERT.
Methods: Sequential subjects treated with NA docetaxel, carboplatin and TRAS +/- PERT were identified and pre-treatment (n=39) and post-treatment specimens (n=44, 36 pairs of pre and post-treatment; 19 with pCR) were sequenced using the ImmunoSEQ platform (Adaptive Bioscience, Seattle, WA). T-cell density and dominant T-cell clonality were measured by TCR sequencing and then associated with pCR using a two-tailed Mann-Whitney U test comparing patients with pCR versus those without. Paired values were compared using the sign test to evaluate change in pre and post-treatment T-cell density and clonality. TIL density was performed using standard IHC methodology.
Results: There was a trend towards increased T-cell clonality after treatment (p=0.08). T-cell clonality post-treatment was significantly increased compared to pre-treatment in those samples where post-treatment tumor was available (p=0.01). There was no difference in T-cell clonality between pre- and post-treatment in normal tissue from pts achieving a pCR (p=1.00). There was no difference in post-treatment T cell clonality when treated with TRAS vs. TRAS + PERT (p=0.19). No differences in the % of pretreatment TILs or T-cell clonality were seen in those who obtained a pCR vs. those who did not (p=0.39 and p=0.85). In addition, no differences in T-cell clonality were seen based on ER status in either pre-treatment or post-treatment samples (p=0.40/0.48)
Conclusions: After treatment with TRAS +/- PERT, there was an increase in T-cell clonality suggesting an enhanced immune response as a mechanism of action for HER2 targeting antibodies. This analysis is currently limited by a small sample size and high rate of pCR. We plan to include additional paired samples which may help to better demonstrate the increased immune response that occurs with HER-2 targeting antibodies.
Citation Format: Howie LJ, Marcom PK, Topping DL, Force J, Emerson R, Bhavsar NA, Abbott SE, Parks M, Robins HS, Blackwell KL. T-cell clonality increases after neoadjuvant treatment with trastuzumab and pertuzumab. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-16.