We found statistically significant association between p HER

We found statistically significant association between p95-HER2 levels and hormone receptor status, Ki-67 3CAI and metastatic regions (p = 0.004, <0.001 & 0.034 respectively). Kocar et al. [21] found no statistically significant relation between p95-HER2 levels and grade, hormone receptor status, or metastatic regions. The lymph node status was not significantly associated with p95-HER2 levels in this study. In contrast, Christianson et al. [22] found a higher proportion of positive node in patients expressing p95-HER2 (p = 0.032) and expression of p95-HER2 was not significantly associated with tumor size or hormone receptor status. Also, Molina et al. [15] reported that node-positive patients had higher rates of p95-HER2 expression than node-negative ones. Recently, Duchnowska et al. [26] studied the quantitative expression levels of HER2, HER3 and p95-HER2 in 189 HER2-positive advanced BC patients who progressed on trastuzumab and received second-line therapy of combined lapatinib plus capecitabine and found that the best outcomes as regard OS of lapatinib therapy was recorded in patients with moderate overexpression of HER2 accompanied with high p95-HER2 expression. The following reports can explain our results, as p95-HER2 lacks the ECD of the receptor making it more aggressive phenotype. Also, p95-HER2 expression in the primary BC was associated with higher incidence of lymph node metastasis [13], [22], [27] and considered as an independent prognostic factor associated with a poor clinical outcome [19]. Duchnowska et al. [20] reported that metastatic BC patients with expression of p95-HER2 were associated with a significantly decreased OS and PFS compared to patients with low p95-HER2 expression. Scaltriti et al. [3] found that out of 46 metastatic BC patients previously treated with trastuzumab, only 11.1% of patients expressing p95-HER2 had a partial response to trastuzumab, whereas complete response was achieved in 51.4% of patients expressing full-length HER2 (p = 0.029). Sáez et al. [10] investigated the prognostic role of p95-HER2 expression in 483 HER2-positive BC patients and found that p95-HER2 expression was associated with shorter DFS. Sperinde et al. [19] found a shorter PFS and OS among the group of BC patients presented with expression of p95-HER2 and suggested that the expression of p95-HER2 might be predictive of trastuzumab resistance. Kocar et al. [21] reported that the median PFS was 11.16 months versus 12.37 months (p > 0.05) and the median OS was 27.66 months versus 24.02 months for p95-HER2 positive and p95-HER2 negative BC patients respectively (p > 0.05). Finally, Kallergi et al. [24] found that the OS of metastatic BC patients with p95-HER2-positive circulating tumor cells was significantly decreased (p = 0.03). As regard the other prognostic factors, tumor grade, T stage, and Ki-67 expression significantly affected the time to metastases. Duchnowska et al. [20] reported that hormone receptor positive was significanly affected both OS and PFS rates. Sáez et al. [10] found that the age, lymph nodes, disease stage and ER status were significanly affected DFS. Resistance to targeted therapy represents the major challenge in the treatment of BC. Combination of different molecules targeting different levels of signaling pathways could prove to be a promising treatment keeping in mind the specific molecular profiling particularly for metastatic relapses [28]. Combined lapatinib and trastuzumab were successfully used for the treatment of metastatic BC that overexpresses HER2 [1]. Also, combined pertuzumab and trastuzumab was used for the treatment of HER2 positive metastatic BC and showed a statistically significant increase in OS [29]. The trastuzumab/lapatinib/hormonal therapy combination has proven to be effective in cases of hormonal receptor positive and overexpressed HER2 protein BC like the luminal B/HER2 enriched type [28]. On the other hand, combined lapatinib and trastuzumab were not successful as adjuvant treatment of BC that overexpresses HER2 as reported by Piccart-Gebhart et al. [30] in a randomized phase III trial that included 8381 HER2 positive BC patients treated with combined trastuzumab plus lapatinib. They found that the combined treatment did not significantly improve DFS compared with trastuzumab alone and moreover the combined therapy added more toxicity and they concluded that, one year of adjuvant trastuzumab remains standard of care of those patients.