Background: Expression of p95HER2, a truncated form of HER2 lacking the extracellular domain, has been associated with resistance to trastuzumab (T)-based therapy in metastatic breast cancer patients. Conversely, high levels of HER2 have been correlated with increased clinical benefit from anti-HER2 therapy in the neoadjuvant setting. In this work we correlated the expression of p95HER2 and HER2 with pathological complete response (pCR) following T, lapatinib (L) or the combination of both agents (T+L) with paclitaxel. Methods: p95HER2 and HER2 were quantified by VeraTag® and HERmark® (Monogram Biosciences), respectively, in primary tumors of 455 patients enrolled in the phase III neoadjuvant study NeoALTTO (Baselga J. et al. Lancet, 2012). The relationship of pCR status to p95HER2 and HER2 was studied using logistic regression models, which accounted for stratification factors and treatment. Unless specified, p95HER2 and HER2 were included as log terms. Results: p95HER2 was measurable in 283 cases (62%) and HER2 in 327 cases (72%). A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) where quantification of both markers was available. Increased HER2 was strongly associated with increased pCR rate in patients treated with the combination of T+L (OR 5.09, 95%CI 2.27-11.44; p<0.01), with a trend observed also in the L-only arm (OR 1.88, 95% CI 0.96-3.70; p = 0.067). Overall, patients with tumors that were HER2-positive (>17.8 RF/mm2) by HERmark had a higher pCR rate than those that were HER2-negative by HERmark (39% vs. 11%, respectively; p<0.001). Increasing p95HER2 levels did not predict for pCR in the L or T+L arms and showed weak evidence (p = 0.073) of an increase in pCR in the T arm. In an unplanned analysis, we examined the odds of achieving response to anti-HER2 therapy in patients with HER2 levels above and below the median (100 RF/mm2, HER2 entered as a binary covariate). HER2 levels above the median predicted a higher response rate to T (OR 3.6, 95% CI 1.2-11; p<0.05) and, more significantly, to T+L (OR 6.01, 95% CI 2.51-14.4; p<0.001). In particular, patients treated with T+L had a higher probability to achieve pCR compared to T alone when HER2 was above the median (T+L = 73% pCR vs. T = 43% pCR, p<0.01; OR 3.74, 95% CI 1.57-8.90), but not when HER2 was below the median (T+L = 29% pCR vs. T = 19% pCR, p>0.2; OR 1.84, 95% CI 0.74-4.55). When tumors were divided in hormone receptor (HR)-positive and HR-negative groups, total levels of HER2 still predicted response to T or T+L. Conclusions: Increasing HER2 protein expression correlated with increased benefit of adding L to T compared to T alone. In tumors above the median of HER2 expression, the levels of HER2 predicted for response to both T and T+L. Our interpretation is that, in the neoadjuvant setting, the association between p95HER2 expression and response to anti-HER2 therapy is likely a consequence of the correlation between p95HER2 and total HER2 levels. HER2 expression seems to be a stronger predictor of pCR than p95HER2 for response to T, L and especially, T+L. Future studies to understand the impact of p95HER2 and HER2 expression on disease-free and overall survival following anti-HER2 therapy are warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-42.
#708 Background: A subgroup of HER2 overexpressing tumors also express p95HER2, a truncated fragment of the HER2 receptor that lacks the extracellular domain and retains kinase activity. Tumors expressing p95HER2 have a worse clinical outcome and are resistant to trastuzumab therapy (Scaltriti M. et al, JNCI 2007). The hypothesis that lapatinib, a small molecule inhibitor that targets the intracellular kinase domain of EGFR and HER2, would be active in these tumors was tested by correlating p95HER2 expression with clinical response to lapatinib in EGF20009, a lapatinib monotherapy study
 Methods: Archival tumor blocks were obtained from patients (pts) participating in study EGF20009. In this study, pts with untreated locally advanced or metastatic HER2 amplified breast tumors either received lapatinib 1500mg daily or 500mg BID (H.L. Gomez et al, J Clin Oncol 2008). Pre-treatment samples were analyzed for p95HER2 expression by immunofluorescence using 2 antibodies against HER2, binding to the intracellular and extracellular domain, respectively, plus a pan-cytokeratin antibody. Tumors were scored as p95HER2 positive (p95HER2+) [if any cytoplasmic staining was detected with the intracellular HER2 antibody and this staining co-localized with the pan-cytokeratin antibody], negative (p95HER2-) [no intracellular HER2 cytoplasmic staining) or non-evaluable (N/E) [no cytokeratin or HER2 staining by immunofluorescence]. The presence of p95HER2 was then correlated with response rate (RR), stable disease for over 100 days (SD) and progression-free survival (PFS) to lapatinib. A Cox-proportional hazards model was used to compare the groups. In order to correlate the presence of p95HER2 with HER2 extracellular domain in the serum, a quantitative determination of the 105 kD ECD level in serum (Oncogene Science HER2/neu Microtiter ELISA) has also been performed.
 Results: 68/105 tumors were evaluable for p95HER2 expression. Fourteen were p95HER2+ (20.5%) and 54 were p95HER2- (79.5%). The observed percentage of p95HER2+ tumors is concordant with published reports. Among the 14 pts with p95HER2+ tumors, 7 responded (RR: 50%) and 1 had SD for > 100 days for an overall clinical benefit rate of 57% (RR+SD). In the p95HER2- population (N=54), 24 pts responded (RR: 44.4%) and 16 pts had SD >100 days for an overall clinical benefit rate of 56% (RR+SD). PFS was similar in both groups, with a median PFS of 24 wks in pts with p95HER2+ and p95HER2- tumors (p=0.97, HR 1.1). These findings compare with the median PFS of 20.7 wks for the entire population in the trial (N=138pts). Further correlation of p95 status and HER2 ECD status of the tumors will be presented.
 Conclusion: These data demonstrate that lapatinib has similar activity in pts with p95HER2+ or p95HER2-, HER2 amplified breast tumors. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 708.
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