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Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas.

ABSTRACT: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC).HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3-4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used.Overall, 17% of EACs were HER2 positive (i.e., IHC3(+) or IHC2(+) with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio ?2) and expression (? = 0.83). HER2 positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barrett's esophagus (BE). EACs with BE had higher odds of HER2 positivity than EACs without BE, independent of pathologic features [OR = 1.8 (95% CI: 1.1-2.8), P = 0.014]. Among all cases, HER2 positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (P(interaction) = 0.0047). In EACs with BE, HER2 positivity was significantly associated with improved DSS [HR = 0.54 (95% CI: 0.35-0.84), P = 0.0065] and overall survival (P = 0.0022) independent of pathologic features, but was not prognostic among EACs without BE.HER2 positivity was shown in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2 positive and, within this subgroup, HER2 positivity was independently associated with improved survival.

SUBMITTER: Yoon HH

PROVIDER: S-EPMC3261584 | biostudies-other | 2012 Jan

REPOSITORIES: biostudies-other

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Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas.

Yoon Harry H HH Shi Qian Q Sukov William R WR Wiktor Anne E AE Khan Maliha M Sattler Christopher A CA Grothey Axel A Wu Tsung-Teh TT Diasio Robert B RB Jenkins Robert B RB Sinicrope Frank A FA

Clinical cancer research : an official journal of the American Association for Cancer Research 20120101 2

<h4>Purpose</h4>We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC).<h4>Experimental design</h4>HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3-4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesoph ...[more]

PMID: 22252257

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Project description:Importance:There has been significant recent interest in understanding the utility of quantitative imaging to delineate breast cancer intrinsic biological factors and therapeutic response. No clinically accepted biomarkers are as yet available for estimation of response to human epidermal growth factor receptor 2 (currently known as ERBB2, but referred to as HER2 in this study)-targeted therapy in breast cancer. Objective:To determine whether imaging signatures on clinical breast magnetic resonance imaging (MRI) could noninvasively characterize HER2-positive tumor biological factors and estimate response to HER2-targeted neoadjuvant therapy. Design, Setting, and Participants:In a retrospective diagnostic study encompassing 209 patients with breast cancer, textural imaging features extracted within the tumor and annular peritumoral tissue regions on MRI were examined as a means to identify increasingly granular breast cancer subgroups relevant to therapeutic approach and response. First, among a cohort of 117 patients who received an MRI prior to neoadjuvant chemotherapy (NAC) at a single institution from April 27, 2012, through September 4, 2015, imaging features that distinguished HER2+ tumors from other receptor subtypes were identified. Next, among a cohort of 42 patients with HER2+ breast cancers with available MRI and RNaseq data accumulated from a multicenter, preoperative clinical trial (BrUOG 211B), a signature of the response-associated HER2-enriched (HER2-E) molecular subtype within HER2+ tumors (n?=?42) was identified. The association of this signature with pathologic complete response was explored in 2 patient cohorts from different institutions, where all patients received HER2-targeted NAC (n?=?28, n?=?50). Finally, the association between significant peritumoral features and lymphocyte distribution was explored in patients within the BrUOG 211B trial who had corresponding biopsy hematoxylin-eosin-stained slide images. Data analysis was conducted from January 15, 2017, to February 14, 2019. Main Outcomes and Measures:Evaluation of imaging signatures by the area under the receiver operating characteristic curve (AUC) in identifying HER2+ molecular subtypes and distinguishing pathologic complete response (ypT0/is) to NAC with HER2-targeting. Results:In the 209 patients included (mean [SD] age, 51.1 [11.7] years), features from the peritumoral regions better discriminated HER2-E tumors (maximum AUC, 0.85; 95% CI, 0.79-0.90; 9-12 mm from the tumor) compared with intratumoral features (AUC, 0.76; 95% CI, 0.69-0.84). A classifier combining peritumoral and intratumoral features identified the HER2-E subtype (AUC, 0.89; 95% CI, 0.84-0.93) and was significantly associated with response to HER2-targeted therapy in both validation cohorts (AUC, 0.80; 95% CI, 0.61-0.98 and AUC, 0.69; 95% CI, 0.53-0.84). Features from the 0- to 3-mm peritumoral region were significantly associated with the density of tumor-infiltrating lymphocytes (R2?=?0.57; 95% CI, 0.39-0.75; P?=?.002). Conclusions and Relevance:A combination of peritumoral and intratumoral characteristics appears to identify intrinsic molecular subtypes of HER2+ breast cancers from imaging, offering insights into immune response within the peritumoral environment and suggesting potential benefit for treatment guidance.

Project description:BackgroundIdentification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy.MethodsA research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated.ResultsA total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01).ConclusionsCombining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.

Dataset Information

Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas.

Publications

Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas.

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