Efficacy of deescalated chemotherapy according to PAM50 subtypes, immune and proliferation genes in triple‐negative early breast cancer: Primary translational analysis of the WSG‐ADAPT‐TN trial

Abstract

In the neoadjuvant WSG‐ADAPT‐TN trial, 12‐week nab‐paclitaxel + carboplatin (nab‐pac/carbo) was highly effective and superior to nab‐paclitaxel + gemcitabine (nab‐pac/gem) in triple‐negative breast cancer regarding pathological complete response (pCR). Predictive markers for deescalated taxane/carbo use in TNBC need to be identified. Patients received 4 × nab‐pac 125 mg/m2 (plus carbo AUC2 or gem 1,000 mg/m2 d1,8 q21). Expression of 119 genes and PAM50 scores by nCounter were available in 306/336 pretherapeutic samples. Interim survival analysis was planned after 36 months median follow‐up. Basal‐like (83.3%) compared to other subtypes was positively associated with pCR (38% vs. 20%, p = 0.015), as was lower HER2 score (p < 0.001). Proliferation biomarkers were positively associated with pCR, that is, PAM50 proliferation, ROR scores (all p < 0.004), higher Ki‐67 (IHC; p < 0.001). For nab‐pac/carbo, expression of immunological (CD8, PD1 and PFDL1) genes and proliferation markers (proliferation and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3 and TYMS) were positively associated with pCR (p < 0.05 for all). For nab‐pac/gem, angiogenesis genes were negatively associated with pCR (ANGPTL4: p = 0.05; FGFR4: p = 0.02; VEGFA: p = 0.03). pCR after 12 weeks was strongly associated with favorable outcome (3y event‐free survival: 92% vs. 71%, p < 0.001). In early TNBC, basal‐like subtype, higher Ki‐67 (IHC) and lower HER2 score were, associated with chemosensitivity. Chemoresistance pathways differed between the two taxane based combinations. Combination of proliferation/immune markers and PAM50 subtype could allow patient selection for further deescalated chemotherapy and/or immune treatment approaches.

Neoadjuvant Treatment for Triple Negative Breast Cancer: Recent Progresses and Challenges

“…When patients were treated with carboplatin AUC2 with nab-paclitaxel 125 mg/m 2 on day 1 and 8 for four three-week cycles, the pCR rate was 44.9 (N = 154). The expression of immunological genes (CD8, PD-L1), basal-like mRNA expression profile, and high Ki-67 were associated with pCR in a multi-variate model (p < 0.05) [127]. All three trials are consistent with a favorable toxicity profile and high efficacy using carboplatin and taxane based anthracyclin-free regimen.…”

Identification of candidate mediators of chemoresponse in breast cancer through therapy-driven selection of somatic variants

“…Two of the genes that were validated in the METABRIC data have previously been reported as mediators of breast cancer chemotherapy response. ABL1, a non-receptor tyrosine kinase, has been implicated in response to DNA-damaging chemotherapeutics in tissue culture [28], while high expression of the centrosomal protein CENPF has been associated with good chemoresponses in breast cancers [29]. Of the other validated genes, only one has previously been associated with cytotoxic chemotherapy response in other cancers: somatic variants in SYNE1, which codes for a nuclear envelope-associated protein [30], correlated with poor response to induction chemotherapy in head and neck cancer [31].…”

Neoadjuvant Immune-Checkpoint Blockade in Triple-Negative Breast Cancer: Current Evidence and Literature-Based Meta-Analysis of Randomized Trials

“…Gaining knowledge concerning such mechanisms may help to identify novel targets and efficaciously enlarge the therapeutic armamentarium currently available to TNBC patients [3][4][5].…”