Abstract P4-04-14: Prediction of treatment responses to neoadjuvant chemotherapy in triple-negative breast cancer by analysis of immune checkpoint protein expression
Authors: Asano Y , Kashiwagi S , Goto W , Morisaki T , Noda S , Takashima T , Onoda N , Hirakawa K 
Published: May 2016

Purpose: "Avoiding immune destruction" has recently been established as one of the hallmarks of cancer. The programmed cell death (PD)-1/programmed cell death-ligand (PD-L) 1 pathway is also an important immunosuppression mechanism that allows cancer cells to escape host immunity. The effect of the tumor immune environment not only on immunotherapy effectiveness, but also on conventional anti-tumor therapy effectiveness and prognosis, has recently been demonstrated. Thus, improvement of the tumor immune environment is important. In other words, the tumor immune environment plays a role in the anti-tumor effects of conventional anti-tumor drugs. Moreover, immune checkpoint proteins such as PD-1, PD-L1, and PD-L2 may play an important role in improving the tumor immune environment. Given this background, the clinical significance of immune checkpoint protein expression was investigated in patients receiving neoadjuvant chemotherapy (NAC) for breast cancer using conventional anti-cancer drugs, and whether this would be useful as a marker to predict treatment response was evaluated.

Experimental Design: A total of 177 patients with resectable early-stage breast cancer were treated with NAC. All patients received a standardized protocol of NAC consisting of four courses of FEC100 (500 mg/m2 fluorouracil, 100 mg/m2 epirubicin, and 500 mg/m2 cyclophosphamide) every 3 weeks, followed by 12 courses of 80 mg/m2 paclitaxel administered weekly. Forty-five patients had HER2-positive breast cancer and were additionally administered weekly (2 mg/kg) or tri-weekly (6 mg/kg) trastuzumab during paclitaxel treatment. ER, PR, HER2, Ki67, PD-L1, PDL-2 and PD-1 status were assessed by immunohistochemistry on core needle biopsy specimens.

Results: There were 37 (20.9%) patients with high PD-1 expression, 42 (23.7%) patients had high PD-L1 expression, and 52 (29.4%) patients had high PD-L2 expression. The patients with high PD-1 and PD-L1 expressions had a significantly higher rate of triple-negative breast cancer (TNBC) (p=0.041) (p&lt;0.001). Univariate analysis showed that PD-1 and PD-L1 expressions were associated with significantly shorter DFS (p=0.008, HR=2.752) (p=0.002, HR=3.194). However, although multivariate analysis showed that lymph node metastases were an independent poor prognostic factor (p=0.046, HR=4.330), PD-1 and PD-L1 expressions were not independent prognostic factors (p=0.492, HR=1.415) (p=0.084, HR=2.613). In TNBC, patients with high PD-1 and PD-L1 expressions had significantly higher rates of non-pCR (p=0.003) (p&lt;0.001). Univariate analysis showed that PD-1 and PD-L1 expressions also significantly shortened disease free survival in TNBC (p=0.048, HR=3.318) (p=0.007, HR=8.375). However, multivariate analysis found that only PD-L1 expression was an independent prognostic factor (p=0.041, HR=9.479).

Conclusions: PD-1 and PD-L1 expressions may be useful as biomarkers to predict treatment responses to NAC in breast cancer. Above all, PD-L1 expression may also be useful as biomarkers for more effective chemotherapy in TNBC.

Citation Format: Asano Y, Kashiwagi S, Goto W, Morisaki T, Noda S, Takashima T, Onoda N, Hirakawa K. Prediction of treatment responses to neoadjuvant chemotherapy in triple-negative breast cancer by analysis of immune checkpoint protein expression. [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 P4-04-14.