Prediction of Response to the Anti-EGFR Antibody Panitumumab Combined with Standard Neoadjuvant Chemotherapy in Triple Negative Breast Cancer (TNBC): The Immune and IGFR Pathways
Frederique Penault-Llorca, Catherine Abrial, Marie-Melanie Dauplat, Maud Privat, Nancy Uhrhammer, Alexis Desrichard, Yannick Bidet, Nina Radosevic-Robin, Anne Cayre, Cecile Aube, Fabrice Kwiatkowski, Yves-Jean Bignon, Philippe Chollet, Jean-Marc Nabholtz. Centre Jean Perrin and EA 4677 ERTICa University of Auvergne, Clermont-Ferrand, France
Background: EGFR overexpression is one of the hallmarks of the “basal-like” TNBC definition by immunohistochemistry (IHC) (Nielsen, 2004). A phase II neoadjuvant clinical trial targeting EGFR in TNBC was conducted in our institution. We investigated various biomarkers in order to better identify an EGFR-sensitive population for potential further regimen development.
Design: Sixty patients (pts) with stage II-IIIA TNBC were prospectively included. The systemic treatment (ST) consisted of panitumumab combined with FEC 100, followed by 4 cycles of docetaxel. All pts underwent surgery after the ST completion. Patient characteristics: median tumor size: 40 mm [20-120]; invasive ductal carcinoma: 96.7%; SBR grade III: 71.7%; complete pathological response (pCR) rate: 46.8% (Chevallier's classification). Paraffin-embedded and frozen tumor samples were collected before and after the ST for biologic studies. Germinal BRCA1 mutations, FC-gamma receptor polymorphism and EGFR, KRAS, BRAF and PI3KCA somatic mutations were analyzed by NGS. Biomarkers evaluated by IHC were: EGFR, IGF-1R, MET, cytokeratins 5/6 and 8/18, PTEN, P-cadherin, ALDH1, Ki-67, p53, tumoral FOXP3 expression and the number of FOXP3+ or CD8+ tumor-infiltrating lymphocytes (TILs).
Results: By univariate analysis, high CD8+ TILs and tumor FOXP3-positivity were response-predictive (pCR rates: CD8 TILs: 84% high vs 16% low; FOXP3: 80% high vs 30% low; p=0.000004). Similarly, high IGF-1R expressors responded better than the low ones (67% vs 28%, respectively, p=0.012). In multivariate analysis, only CD8+ TIL count remained significant (p=0.0002). Sequencing revealed BRCA1 mutations in 10% of pts. Somatic mutations of PI3K were observed in 6 pts. No mutations were observed in BRAF, KRAS, or EGFR, although numerous EGFR SNPs were found.
Conclusions: Interestingly, the CD8+ TIL count and tumor FOXP3 expression seem to predict the response to panitumumab. The IGF-1R tumor levels seem to play a determinant role in TNBC response to anti-EGFR antibodies, which is in concordance with our recent observations in a head-and-neck cancer cohort (Clin Canc Res 2012). Confirmatory and mechanistic studies of those biomarkers are warranted.
Tuesday, March 5, 2013 11:30 AM
Proffered Papers: Section B, Tuesday Morning