Abstract
Abstract
Background: EGFR overexpression is one of the hallmarks of the “basal-like” TNBC definition by immunohistochemistry (IHC) (Nielsen, 2004). In a phase II neoadjuvant clinical trial targeting EGFR in TNBC, we investigated various biomarkers to better identify an EGFR-sensitive population for potential further regimen development.
Methods: Sixty patients (pts) with stage II-IIIA TNBC were prospectively included. Systemic treatment (ST) consisted of the anti-EGFR antibody panitumumab combined with FEC 100, followed by 4 cycles of docetaxel. All pts underwent surgery after 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 ST for biologic studies. Germinal BRCA1 mutations, and EGFR, KRAS, BRAF and PI3KCA somatic mutations were analyzed by NGS. 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) were evaluated by IHC. Biopsies and surgical samples were analysed using Affimetrix arrays.
Results : By univariate analysis, high CD8+ TILs was response-predictive (pCR rates: CD8 TILs: 84% high vs 10% low; p=3.4.10−6). Tumor FOXP3 expression and high FOXP3 TILs tended to be predictive (pCR rates: tumor FOXP3: 77% positive vs 36% negative, p=0.07; FOXP3 TILs: 66% high vs 37% low, p= 0.08). High IGF-1R expressors responded better than low expressors (80% vs 33%, respectively, p=0.028).
As could be expected, a positive correlation between tumor FOXP3 expression and FOXP3 TILs was found (p = 2.7.10−4, r = 0.56). Surprisingly, a positive correlation was found between FOXP3 TILs and CD8+ TILs (p = 2.10−5, r = 0.59) and between tumor FOXP3 and CD8+ TILs (p = 6.3.10−3, r = 0.43).
Comparison of EGFR, IGF-1R and Her3 in biopsies versus surgical samples showed reduced EGFR levels in non-responders (p = 0.037), while Her3 (p = 0.049) and IGF-1R (p = 0.08) increased.
Sequencing revealed BRCA1 mutations in 10% of pts. No difference of response (pCR) was observed between mutated patients and others (p=0.91). Somatic mutations of PI3K were observed in 6 pts. No mutations were observed in BRAF, KRAS, or EGFR. Analysis of Affymetrix arrays for gene expression is underway and will be presented.
Conclusions : Interestingly, the CD8+ TIL count seems to predict the response to panitumumab. Tumor FOXP3 expression and high FOXP3 TILs also tended to be predictive. Tumor levels of IGF-1R seem to play a determinant role in TNBC response to anti-EGFR antibodies, in concordance with our observations in a head-and-neck cancer cohort (Clin Canc Res 2012). Confirmatory and mechanistic studies of those biomarkers are warranted.
Citation Format: 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, Nassera Chalabi, Yves-Jean Bignon, Philippe Chollet, Jean-Marc Nabholtz. Response to the anti-EGFR antibody panitumumab combined with standard neoadjuvant chemotherapy in triple negative breast cancer (TNBC): the immune and IGFR pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4669. doi:10.1158/1538-7445.AM2013-4669