MET and PTEN gene copy numbers and Ki-67 protein expression associate with pathologic complete response in ERBB2-positive breast carcinoma patients treated with neoadjuvant trastuzumab-based therapy

Abstract

BackgroundPathologic complete response (pCR) after neoadjuvant chemotherapy for breast cancer is associated with improved prognosis in aggressive tumor subtypes, including ERBB2- positive tumors. Recent adoption of pCR as a surrogate endpoint for clinical trials in early stage breast cancer in the neoadjuvant setting highlights the need for biomarkers that, alone or in combination, help predict the likelihood of response to treatment.MethodsBiopsy specimens from 29 patients with invasive ductal carcinoma treated with trastuzumab-based therapy prior to definitive resection and pathologic staging were evaluated by dual color bright field in situ hybridization (dual ISH) using probes for MET, TOP2A, PTEN, and PIK3CA genes, each paired with centromeric probes to their respective chromosomes (chromosomes 7, 17, 10, and 3). Ki-67 expression was assessed by immunohistochemistry (IHC). Various parameters describing copy number alterations were evaluated for each gene and centromere probe to identify the optimal parameters for clinical relevance. Combinations of ISH parameters and IHC expression for Ki-67 were also evaluated.ResultsOf the four genes and their respective chromosomes evaluated by ISH, two gene copy number parameters provided statistically significant associations with pCR: MET gain or loss relative to chromosome 7 (AUC = 0.791, sensitivity = 92 % and specificity = 67 % at optimal cutoff, p = 0.0032) and gain of PTEN (AUC = 0.674, sensitivity = 38 % and specificity = 100 % at optimal cutoff, p = 0.039). Ki-67 expression was also found to associate significantly with pCR (AUC = 0.726, sensitivity = 100 % and specificity = 42 % at optimal cutoff, p = 0.0098). Combining gain or loss of MET relative to chromosome 7 with Ki-67 expression further improved the association with pCR (AUC = 0.847, sensitivity = 92 % and specificity = 83 % at optimal cutoffs, p = 0.0006).ConclusionsAn immunogenotypic signature of low complexity comprising MET relative copy number and Ki-67 expression generated by dual ISH and IHC may help predict pCR in ERBB2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab. These findings require validation in additional patient cohorts.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2743-x) contains supplementary material, which is available to authorized users.

P53 and Ki-67 as prognostic markers in triple-negative breast cancer patients

“…The usage of Ki-67 as a prognostic marker in breast cancer has been widely studied, high Ki-67 expression has been demonstrated to be correlated with larger tumor size, higher histological grade, lymph node involvement, shorter DFS and OS in breast cancer [ 28 , 29 ]. Moreover, it was reported a positive association between Ki-67 expression and tumor response to neoadjuvant chemotherapy [ 30 , 31 ]. However, only a few groups have studied it in the triple negative subgroup [ 32 – 34 ].…”

Progression inference for somatic mutations in cancer

“…PBAM-based results for invasive breast carcinoma shown in Figure 4 illustrate that mutations in TP53, PIK3CA, and GATA3, and upregulation of ERBB2 were the main driver events observed in the data [33] , [47] , [48] , [37] , [38] , [51] , [52] . The events which followed TP53 mutations were comprised of a mixture of deletions, amplifications, downregulation and upregulation, with few mutational events, which include PTEN deletions [40] , [49] , PIK3CA amplifications [38] , [50] , downregulation of ERBB2 [51] , [52] , PTEN [51] , [44] , AKT1 [55] , [56] , TP53 [53] , [54] , ARID1A [57] , [58] , and CTCF [59] , [60] and upregulation of TP53 [53] , [54] , AKT1 [55] , [56] , PIK3CA [61] , [62] , and ARID1A [57] , [58] . Secondary events following mutations in PIK3CA included upregulation of PTEN [41] , [44] , RUNX1 [45] , [46] , and mutations in PTEN [40] , [41] , ERBB2 [42] , [43] and CDH1 [39] .…”