July 2020: Tumor mutational burden and immune gene expression in GeparNuevo trial

Recent results of the neoadjuvant randomized phase II GeparNuevo (GBG 89) study suggested that the addition of durvalumab to anthracycline/taxane-based neoadjuvant chemotherapy for treatment of triple-negative breast cancer (TNBC) increased the rate of pathological complete response (pCR), mainly in the subgroup of patients treated with durvalumab alone prior to start of chemotherapy (Loibl S et al. 2019). The predictive value of tumor mutational burden (TMB), alone or in combination with immune gene expression profile (GEP), for response to neoadjuvant therapy in early TNBC is currently not known, neither for combining immune-checkpoint blockade (ICB) with chemotherapy nor conventional chemotherapy alone. Therefore, this study aimed to investigate TMB and immune GEP parameters in pre-treatment samples of TNBC from the neoadjuvant ICB trial GeparNuevo.

For the TMB calculation, whole exome sequencing (WES) was conducted on fresh-frozen pre-therapeutic core biopsies and patient-matched blood samples with an Illumina HiSeq 4000. RNA sequencing was performed on formalin-fixed paraffin-embedded tissue using a HTG EdgeSeq instrument and a predefined immune GEP was evaluated. WES and RNA-Seq were available for 149 and 159 patients, respectively, with both data available for 136 patients. Median TMB was 1.52 mut/Mb (range 0.02-7.65) and was significantly higher in patients with pCR (median with pCR 1.87 vs. 1.39 without pCR; p=0.005). In multivariate analysis, odds ratios for pCR (ypT0 ypN0) per mut/Mb were 2.06 (95%CI 1.33-3.20, p=0.001) among all patients, 1.77 (95%CI 1.00-3.13, p=0.049) in the durvalumab arm, and 2.82 (95%CI 1.21-6.54, p=0.016) in the placebo arm, respectively. The continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. When patients were stratified in subgroups based on the upper tertile of TMB and median GEP, a pCR rate of 82% (95%CI 60%-95%) was observed in the subgroup with both high TMB and GEP, in contrast to only 28% (95%CI 16%-43%) in the subgroup with both low TMB and GEP.

In conclusions, this study showed for the first time that TMB and immune GEP add independent value for pCR prediction both for ICB and for chemotherapy. These results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.

Karn T, Denkert C, Weber KE, et al. Tumor mutational burden and immune infiltration as independent predictors of response to neoadjuvant immune checkpoint inhibition in early TNBC in GeparNuevo. Ann Oncol. 2020;S0923-7534(20)39836-7. doi:10.1016/j.annonc.2020.05.015

• Link in PubMed

• Full paper freely available until October at https://authors.elsevier.com/a/1bbP63I2OQUvyV