Abstract P6-09-09: Evaluation of tumor infiltrating lymphocytes (TILs) and their association with homologous recombination deficiency and BRCA1/2 mutation status in triple-negative breast cancer (TNBC): A pooled analysis
Authors: Telli ML , Badve S , Vinayak S , Silver DP , Isakoff SJ , Kaklamani VG , Gradishar WJ , Stearns V , Connolly RM , Ford JM , Adams S , Garber JE , Evans B , Timms K , Wenstrup R , Richardson AL 
Published: March 2017

Background: TNBC patients with homologous recombination (HR) deficient tumors have significantly higher pathologic complete response (pCR, ypT0/is ypN0) rates when treated with platinum-based chemotherapy. TILs are prognostic and predictive of chemotherapy benefit in TNBC. Interestingly, recent data suggests that HR deficient TNBCs and BRCA1/2 mutant ovarian cancers may be enriched for immune cell infiltration. Thus, we performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HR deficiency status and tumor BRCA1/2 mutation status.

Methods: 166 patients with TNBC and known HR deficiency status from the following clinical trials were available for analysis: PrECOG 0105 (N=72), NCT00580333 (N=32), NCT01372579 (N=26), TBCRC 008 (N=18) and NCT00148694 (N=18). Neoadjuvant chemotherapy regimens included 1) carboplatin, gemcitabine, iniparib, 2) cisplatin with or without bevacizumab 3) carboplatin, eribulin, 4) carboplatin, nab-paclitaxel, with or without vorinostat. HR deficiency status was defined as a high HRD score (42 or higher) and/or presence of a BRCA1/2 tumor mutation (tBRCA). Digitized pre-treatment core biopsy H&E sections were reviewed and scored by two blinded expert breast cancer pathologists using the international TIL working group guidelines. The density (%) of both intratumoral TILs (iTILs) and stromal TILs (sTILs) was recorded by deciles (n=122 thus far, additional cases to be included in final analysis).

Results: Among 122 patients, pCR was achieved in 36 patients (29.5%) and 71 tumors (58.2%) were HR deficient. In total, 24 patients (19.7%) patients had a deleterious BRCA1/2 mutation. Among all tumors, iTIL and sTIL median densities were 0% (range 0-20) and 10% (range 0-80), respectively, and were not statistically different in HR deficient versus non-deficient tumors (iTIL p=0.746; sTIL p=0.159). The same absent association was observed for tBRCA mutation status (iTIL p=0.607; sTIL p=0.315) and binary HRD score (iTIL p=0.879; sTIL p=0.364). Updated results with additional cases scored for TILs will be reported at time of presentation. Additional analyses assessing the relationship between TILs and pCR/residual cancer burden adjusting for HRD status and other clinical variables will also be included at the time of presentation.

Conclusion: Several previous studies have reported that TILs are significantly associated with response to standard chemotherapy regimens when given in the neoadjuvant setting. Measures of genomic instability and DNA repair deficiency, including HRD, have been shown to be robust predictors of response to chemotherapy, including platinum containing regimens. It is unclear if TILs will be predictive in a similarly robust way for response to platinum-containing regimens. Results of this study suggest TIL density and HR deficiency status may be independent and non-overlapping. Final analysis including additional cases will be included in the final presentation.Background: TNBC patients with homologous recombination (HR) deficient tumors have significantly higher pathologic complete response (pCR, ypT0/is ypN0) rates when treated with platinum-based chemotherapy. TILs are prognostic and predictive of chemotherapy benefit in TNBC. Interestingly, recent data suggests that HR deficient TNBCs and BRCA1/2 mutant ovarian cancers may be enriched for immune cell infiltration. Thus, we performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HR deficiency status and tumor BRCA1/2 mutation status.

Methods: 166 patients with TNBC and known HR deficiency status from the following clinical trials were available for analysis: PrECOG 0105 (N=72), NCT00580333 (N=32), NCT01372579 (N=26), TBCRC 008 (N=18) and NCT00148694 (N=18). Neoadjuvant chemotherapy regimens included 1) carboplatin, gemcitabine, iniparib, 2) cisplatin with or without bevacizumab 3) carboplatin, eribulin, 4) carboplatin, nab-paclitaxel, with or without vorinostat. HR deficiency status was defined as a high HRD score (42 or higher) and/or presence of a BRCA1/2 tumor mutation (tBRCA). Digitized pre-treatment core biopsy H&E sections were reviewed and scored by two blinded expert breast cancer pathologists using the international TIL working group guidelines. The density (%) of both intratumoral TILs (iTILs) and stromal TILs (sTILs) was recorded by deciles (n=122 thus far, additional cases to be included in final analysis).

Results: Among 122 patients, pCR was achieved in 36 patients (29.5%) and 71 tumors (58.2%) were HR deficient. In total, 24 patients (19.7%) patients had a deleterious BRCA1/2 mutation. Among all tumors, iTIL and sTIL median densities were 0% (range 0-20) and 10% (range 0-80), respectively, and were not statistically different in HR deficient versus non-deficient tumors (iTIL p=0.746; sTIL p=0.159). The same absent association was observed for tBRCA mutation status (iTIL p=0.607; sTIL p=0.315) and binary HRD score (iTIL p=0.879; sTIL p=0.364). Updated results with additional cases scored for TILs will be reported at time of presentation. Additional analyses assessing the relationship between TILs and pCR/residual cancer burden adjusting for HRD status and other clinical variables will also be included at the time of presentation.

Conclusion: Several previous studies have reported that TILs are significantly associated with response to standard chemotherapy regimens when given in the neoadjuvant setting. Measures of genomic instability and DNA repair deficiency, including HRD, have been shown to be robust predictors of response to chemotherapy, including platinum containing regimens. It is unclear if TILs will be predictive in a similarly robust way for response to platinum-containing regimens. Results of this study suggest TIL density and HR deficiency status may be independent and non-overlapping. Final analysis including additional cases will be included in the final presentation.

Citation Format: Telli ML, Badve S, Vinayak S, Silver DP, Isakoff SJ, Kaklamani VG, Gradishar WJ, Stearns V, Connolly RM, Ford JM, Adams S, Garber JE, Evans B, Timms K, Wenstrup R, Richardson AL. Evaluation of tumor infiltrating lymphocytes (TILs) and their association with homologous recombination deficiency and BRCA1/2 mutation status in triple-negative breast cancer (TNBC): A pooled analysis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-09.