Most of the clinical trials of EGFR-targeting therapy in triple negative breast cancer (TNBC) were disappointing. Our team has conducted two neoadjuvant trials testing the activity of the anti-EGFR antibodies panitumumab and cetuximab combined with chemotherapy in locally advanced TNBC. We used pre-treatment samples and residual tumours (RT) at surgery to investigate the possible genomic determinants of disease recurrence.
Tumour tissues sampled before and after neoadjuvant therapy have been analysed by NGS using a targeted exome panel (MSK-IMPACT) of 410 cancer-related genes. The correlations between recurrences and genomic findings were analysed in a case-by-case fashion.
Interpretable data have been obtained for 15 patients (pts) that achieved pathological complete response (pCR) and for 33 that did not. Among the non-pCR pts, 5 presented early fatal metastatic recurrences (EFMR: 1year, < 2 years post-surgery). 23 pts with RT had no recurrences after 5 years post-surgery. Among the 15 pCR pts, only one presented a LNFR (solitary brain metastasis (SBM)). No obvious genomic pattern was predictive of recurrence. Each pts with EFMR had a set of anomalies which will be presented (Pt 1: FGFR2, MLL2, GLI1, RAF1 mutated (mut); Pt 2: no mutations, AKT1, TGFBR2 and TERT loss, SOX9 amplification (amp); Pt 3: KDM6A mut, PTEN loss, MYC amp; Pt 4: PTEN, PIK3CA, ERBB3, ARID1B mut, RAD21, NOTCH2, SOX9 amp; Pt 5: SETD2 mut, HIST2H3D, HIST2H3C, MCL1, EZH2 amp, MAP3K1 loss). Patient with pCR and SBM had BRCA1, MLL2, CDK12 and PPM1D mut, in the pre-therapy sample. In other non-pCR pts various genomic aberrations were detected, including 3 different activating mutations in PIK3CA in one single RT, as well as post-treatment appearance of HRAS G12S mut or PARP1 amp in the non-pCR pts.
This hypothesis-generating study is intended to capture the intrinsic inter-tumour heterogeneity associated with response to EGFR-targeting and chemotherapy in TNBC. These genomic data should be interpreted in the context of other tumour features such as histology, protein and gene expression, immune infiltrates.
Clinical trial identification
NCT00933517 and NCT00600249
Legal entity responsible for the study
Centre Jean Perrin
Breast Cancer Research Fund
All authors have declared no conflicts of interest.