Abstract
Abstract
Background: Our group has previously reported (SABCS 2012, abstract 1081) a 2-fold higher pathologic complete response (pCR) rate in TNBC treated with panitumumab+FEC100 (47%) than with the standard therapy alone. However, in a half of the patients (pts) a residual tumor (RT) was detected. Having in mind the detrimental impact of resistant TNBC on patient outcome, we have investigated the tumor tissue factors that might have been important in development of resistance to this treatment.
Methods: 40 TNBC pts, treated with 8 cycles the anti-EGFR antibody panitumumab combined with FEC 100 for the first 4 and with docetaxel only for the last 4 cycles, were eligible. All pts underwent breast surgery after the neoadjuvant chemotherapy (NACT) completion. Formalin-fixed, paraffin-embedded tumor samples were collected before and after NACT for biomarker analysis. EGFR, HER3, IGF-1R, MET and the number of FOXP3+ or CD8+ tumor-infiltrating lymphocytes (TIL) were evaluated by immunohistochemistry (IHC). Expression of the kinases was graded semi-quantitatively (histoscores).
Results: Out of 40 treated pts, 21 demonstrated a RT (53%, according to the Chevallier classification, PMID 8338056). The IHC data were available for 17 pts. Since high EGFR expression was important for pCR achievement in this study (SABC 2012), we first investigated the expressions of EGFR, HER3 and MET in the RT. The results are presented in Table 1.
Table 1post-NACT RTn = 17EGFR down or flatEGFR up143HER3 upHER3 flatHER3 upHER3 flat8512MET upMET down or flatMET upMET down or flatMET upMET down or flatMET upMET down or flat17220120
Overall, among the 9 cases (cs) with increased post-NACT HER3 expression (HER3 up), only 1 had increased MET (MET up), while among the 7 cs with no change in HER3 post-CTNA (HER3 flat), 4 had MET expression increased.
Interestingly, although the pre-NACT IGF-1R expression was a strong predictor of pCR (p = 0.028, SABCS 2012), no significant changes in this kinase expression were observed in the RT, compared to the pre-NACT levels. Most RT had low IGF-1R scores (<100). The only 2 RT in which IGF-1R was increased post-CTNA were small groups of tumor cells either in breast or in the nodes, heavily surrounded by lymphocytes.
The density of TIL post-NACT correlated principally with the% of tumor mass (TM) reduction. Among the 7 pts with average reduction of 20%, there was only 1 cs with a good InSitu Immune Response (ISIR: dense TIL, with CD8+/FOXP3+ > 1.2). On the contrary, among the 9 pts with average TM reduction of 90%, 8 demonstrated a good ISIR.
Conclusion: The results indicate that HER3 and MET play significant roles in development of TNBC resistance to the anti-EGFR agents. Those molecules seem to drive 2 different resistance pathways in TNBC, as it has been shown in other malignancies. As several anti-HER3 or anti-MET drugs are nowadays available, we find very important investigating the expression of HER3 and MET in each TNBC pt pre- and post-NACT, in order to rapidly detect and combat the resistance. The ISIR-stimulating agents may bring an additional therapeutic benefit to those patients.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-07.