Adverse prognostic impact of heterogeneous HER2 gene amplification in patients with esophageal adenocarcinoma (EAC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4009-4009
Author(s):  
Harry H. Yoon ◽  
Qian Shi ◽  
William R. Sukov ◽  
Christopher A. Sattler ◽  
Anne E. Wiktor ◽  
...  
Keyword(s):  
Genetic Heterogeneity ◽  
Multivariable Analysis ◽  
Chromosome 17 ◽  
Prognostic Impact ◽  
Her2 Amplification ◽  
Her2 Gene ◽  
Digestive Cancer ◽  
Cox Models ◽  
Her2 Heterogeneity ◽  
Risk Of Cancer

4009 Background: HER2 expression in upper digestive cancer is reported to be heterogeneous, which substantially affects interpretation of HER2 positivity in the clinic. Yet the frequency and prognostic impact of HER2 genetic heterogeneity and polysomy 17 (poly17) are unknown in EAC. Methods: HER2 amplification (fluorescence in situ hybridization) and protein expression were examined in untreated surgical EAC specimens (N = 661) at Mayo Clinic. HER2 genetic heterogeneity was defined per ASCO/CAP as amplification (HER2/CEP17 ratio ≥ 2) in 5-50% of cancer cells; poly17 refers to ≥ 3 copies of chromosome 17. Most tumors were T3-4 (68%) or lymph node (LN)-positive (73%). Cox models were used to assess disease-specific (DSS) and overall survival (OS). Results: HER2 amplification was detected in 117 of 661 EACs (18%), of which 20 (17%) showed HER2 heterogeneity. HER2 heterogeneous tumors had a significantly higher frequency of poly17 and high tumor grade. HER2 heterogeneity by amplification vs expression were correlated. Since heterogeneity was limited to HER2-amplified tumors, survival analysis was stratified by amplification status. In multivariable analysis, only HER2 heterogeneity and metastatic LN number were prognostic (Table). Conclusions: Among HER2 amplified EACs, 17% show HER2 heterogeneity, which is associated with increased poly17 and independently predicts 2-fold higher risk of cancer-specific death. Among HER2-nonamplified cases, poly17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and evaluation of benefit from HER2 targeted therapy. [Table: see text]

scholarly journals Adverse Prognostic Impact of Intratumor HeterogeneousHER2Gene Amplification in Patients With Esophageal Adenocarcinoma

2012 ◽  
Vol 30 (32) ◽  
pp. 3932-3938 ◽  
Author(s):  
Harry H. Yoon ◽  
Qian Shi ◽  
William R. Sukov ◽  
Mark A. Lewis ◽  
Christopher A. Sattler ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Esophageal Adenocarcinoma ◽  
Gene Amplification ◽  
Prognostic Impact ◽  
Her2 Amplification ◽  
Her2 Gene ◽  
Cox Models ◽  
Node Number ◽  
Polysomy 17 ◽  
Her2 Heterogeneity

PurposeThere is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. We determined the frequency and prognostic impact of heterogeneous HER2 gene amplification and polysomy 17 in patients with esophageal adenocarcinoma (EAC).Patients and MethodsHER2 amplification (by fluorescence in situ hybridization) was examined in surgical EAC specimens (n = 675). HER2 heterogeneity was defined according to consensus guidelines as gene amplification (HER2/CEP17 ratio ≥ 2.0) in more than 5% but less than 50% of cancer cells. No patient received neoadjuvant or HER2-targeted therapy. Cox models were used to assess disease-specific survival (DSS) and overall survival (OS).ResultsOverall, 117 EACs (17%) demonstrated HER2 amplification, of which 20 (17%) showed HER2 heterogeneity. All HER2-heterogeneous tumors were amplified. Among HER2-amplified tumors, heterogeneous tumors had significantly higher frequency of poor histologic grade and polysomy 17. In multivariable models that included number of metastatic lymph nodes, grade, tumor stage, and polysomy 17, only HER2 heterogeneity and node number were prognostic among HER2-amplified tumors, with heterogeneity showing worse DSS (hazard ratio, 2.04; 95% CI, 1.09 to 3.79; P = .025) and OS (P = .026). Among HER2-nonamplified EACs, polysomy 17 was independently associated with worse DSS (P = .012) and OS (P = .023).ConclusionAmong HER2-amplified EACs, 17% show HER2 heterogeneity, which independently predicts for worse cancer-specific death. Among HER2-nonamplified EACs, polysomy 17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and determination of benefit from HER2-targeted therapy.

scholarly journals The Prognostic Impact of HER2 Genetic and Protein Expression in Pancreatic Carcinoma—HER2 Protein and Gene in Pancreatic Cancer

Diagnostics ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 653
Author(s):  
Song-Hee Han ◽  
Ki Hyun Ryu ◽  
Ah-Young Kwon
Keyword(s):  
Protein Expression ◽  
Genetic Heterogeneity ◽  
Growth Factor Receptor ◽  
Ductal Adenocarcinoma ◽  
Prognostic Impact ◽  
Her2 Expression ◽  
Her2 Protein ◽  
Epidermal Growth ◽  
Her2 Heterogeneity

Pancreatic ductal adenocarcinoma (PDAC) is a lethal and clinically heterogeneous disease with a limited benefit from human epidermal growth factor receptor 2 (HER2)-targeted therapy. Recently, some studies have addressed the antitumoral effect of novel anti-HER2 drugs in HER2 low-expressing tumors. However, there have been few studies on the significance of low HER2 expression and genetic heterogeneity in PDAC. Using immunohistochemistry and dual-color silver-enhanced in situ hybridization based on the Trastuzumab for a gastric cancer scoring scheme, we evaluated HER2 protein expression, gene amplification, and genetic heterogeneity in three groups (HER2-neg, HER2-low, HER2-pos) of 55 patients. Among the 55 cases, 41.8% (23/55) showed HER2 expression of any intensity. HER2 amplification independent of HER2 expression was 25.5% (14/55). Patients in both these groups had a shorter overall survival than did patients in the HER2-neg group. HER2 genetic heterogeneity was identified in 37 (70.9%) of the 55 cases, mainly in HER2-neg and HER2-low groups. HER2 genetic heterogeneity significantly correlated with worse survival in the HER2-low and HER2-neg groups of PDAC. These findings support the hypothesis that low-level HER2 expression and heterogeneity have significant clinical implications in PDAC. HER2 heterogeneity might indicate the best strategies of combination therapies to prevent the development of subdominant clones with resistance potential.

Adverse prognostic impact of intratumor heterogeneous HER2 gene amplification in patients with breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 617-617
Author(s):  
Carmen Criscitiello ◽  
Giuseppe Viale ◽  
Davide Disalvatore ◽  
Vincenzo Bagnardi ◽  
Luca Fumagalli ◽  
...  
Keyword(s):  
Regression Models ◽  
Cox Regression ◽  
Intratumoral Heterogeneity ◽  
Chromosome 17 ◽  
Prognostic Impact ◽  
Her2 Gene ◽  
Ki 67 ◽  
Node Negative ◽  
Risk Of Recurrence ◽  
Her2 Positivity

617 Background: There is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. Only patients (pts) with HER2 positivity - defined as 3+ by IHC or FISH amplified defined as a HER2 gene to chromosome 17 (HER2/CEP17) ratio ≥ 2.0 - are eligible to receive trastuzumab treatment. Limited information is available on the prognosis of pts with HER2 2+ or FISH test with a HER2/CEP17 ratio < 2.0. Methods: We retrospectively analyzed data from 455 consecutive early BC pts with HER 2+ and HER2/CEP17 ratio < 2.0 who underwent surgery after 2007. The association between HER2/CEP17 ratio and other known prognostic factors was evaluated with multivariable linear regression models. The role of HER2/CEP17 ratio on recurrence free survival was assessed with multivariable Cox regression models. Results: Fifty-one percent of the evaluated pts were node negative, 51% were postmenopausal, 93% had ER positive BC and 85% had Ki-67 ≥14%. The mean HER2/CEP17 ratio was 1.27 (SD=0.3). A significant positive relationship between HER2/CEP17 ratio and Ki-67 was observed (p<0.01). During a median follow-up time of 2.7 years, 40 recurrences were observed (15 locoregional events and 25 distant metastases). Overall, the association between HER2/CEP17 and the risk of recurrence was not significant. From subgroup analysis, a significant interaction between HER2/CEP17 ratio and nodal involvement emerged (p=0.02). Among pts with node-negative disease, pts with HER2/CEP17 ratio ≥1.27 were at higher risk of recurrence with respect to pts with HER2/CEP17 ratio < 1.27 (adjusted HR 4.0, 95% CI 1.01-15.9). Conclusions: Among pts with BC and HER2 intratumoral heterogeneity, HER2/CEP17 ratio ≥1.27 could have a strong prognostic role in node negative HER2 2+ BC, thus suggesting potential future therapeutic approaches in this setting of pts.

CD3+ tumor-infiltrating lymphocytes (TILs) as prognostic in patients (pts) with stage II colon cancer (CC) not treated with adjuvant chemotherapy (ADJ).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 167-167
Author(s):  
Edoardo Francini ◽  
Fang-Shu Ou ◽  
Stefano Lazzi ◽  
Roberto Petrioli ◽  
Andrea Giovanni Multari ◽  
...  
Keyword(s):  
Clinical Decision Making ◽  
Multivariable Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Clinical Decision ◽  
Stage Ii ◽  
Prognostic Impact ◽  
Curative Surgery ◽  
Cox Models ◽  
Risk Of Death ◽  
The Impact

167 Background: Previous studies have reported high TILs are a favorable prognostic factor in stage II CC. However, whether the impact of TILs on overall survival (OS) differs among pts who did or did not receive ADJ is still to be determined. We assessed the prognostic value of CD3+ TILs in pts with stage II CC according to whether they received ADJ or not (no-ADJ). Methods: Pts treated with curative surgery for stage II CC (2002-2013) were identified through the Santa Maria alle Scotte Hospital database. CD3+ TILs at the invasive front, center of tumor, and stroma, were determined by immunohistochemistry and manually quantified as the rate of TILs/total tissue areas. High TILs (H-TILs) was defined as > 20%. Pts were classified as high or low TILs (L-TILs) and ADJ or no-ADJ. Cox models were used to assess OS with hazard ratio estimates (95% CI). Results: Of the 678 pts included (356 deaths), 137 (20%) received ADJ while 541 (80%) did not. ADJ comprised fluoropyrimidine +/- oxaliplatin. Median follow-up was 8.5 years. The distributions of the 4 groups were: 16% (L-TIL/ADJ), 64% (L-TIL/no-ADJ), 5% (H-TIL/ADJ), 15% (H-TIL/no-ADJ). Compared to H-TILs/no-ADJ, ADJ pts had a significantly longer OS (P < .0001) regardless of the TILS rate while L-TILs/no ADJ had significantly shorter OS and higher risk of death (HR = 1.41; 95% CI, 1.06-1.88; P < .0001) [See table]. On multivariable analysis, adjusting for perforation, obstruction, T-stage, grade, < 12 lymph nodes resected, lymphovascular and perineural invasion, the adverse prognostic impact of L-TILs (vs H-TILs) in no-ADJ pts was confirmed (HR = 1.36; 95% CI 1.02, 1.82; P = .0373). Conclusions: Low CD3+ TILs rate was independently associated with shorter OS in stage II CC pts who did not receive ADJ, but was not prognostic among pts who had ADJ. These data suggest a potentially different impact of TILs in chemo-treated vs -untreated stage II CC which could affect clinical decision making. [Table: see text]

Use of FoxP3+ and cytotoxic CD8+ T lymphocytes to identify a patient subgroup with a favorable prognosis similar to colon cancers with deficient DNA mismatch (dMMR) repair.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 460-460
Author(s):  
Harry H. Yoon ◽  
Jared M Orrock ◽  
Nathan R. Foster ◽  
Daniel J. Sargent ◽  
Thomas C. Smyrk ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Cox Models ◽  
Dna Mismatch ◽  
Colon Cancers ◽  
Resected Stage ◽  
Prognostic Data

460 Background: The immune response has emerged as a strong prognostic factor in colon cancer. Whereas CD8+ T cells mediate antitumor response, regulatory T cells expressing FoxP3+ can antagonize this effect, though prognostic data conflict. These markers have yet to be analyzed with MMR status, which is important since dMMR tumors show enhanced immune response. Methods: CD8+ and FoxP3+ density were analyzed by immunohistochemistry (IHC) in resected stage II and III colon carcinomas (N = 216) from participants in phase III adjuvant 5-fluorouracil-based trials. High vs low immune density was dichotomized at the median. MMR status, determined by IHC or analysis of microsatellite instability, was categorized as dMMR (12%) or proficient MMR (pMMR). Cox models, stratified by study, were adjusted for age, stage, grade and, where noted, MMR. Results: The association of FoxP3+ density with overall survival (OS) differed by CD8+ density (P for interaction = .040). By multivariable analysis, FoxP3+high was significantly associated with improved OS in CD8+low tumors (hazard ratio 0.43 [95% confidence interval 0.19 – 0.95]; P = .030], but not in CD8+high tumors (P = .91). Results were consistent after MMR adjustment. We then determined their prognostic impact in the larger pMMR subset (N = 119). Tumors with high FoxP3+ were associated with improved OS in cases with low, but not high, CD8+ density ( Table ). These patients (FoxP3+high, CD8+low) had similar 5-year OS rates as 107 dMMR cases from parent studies (89% vs 80%; P = .74), despite having distinct clinicopathologic features. Conclusions: The prognostic impact of FoxP3+ T cells depends on CD8+, indicating the importance of analyzing both in combination. High FoxP3+ exerts a paradoxically favorable survival impact, but only when CD8+ is low. Survival in pMMR tumors with high FoxP3+ and low CD8+ was similar to that of dMMR tumors, indicating that a favorable pMMR subset can be identified. [Table: see text]

Genetic Heterogeneity in HER2 Testing in Breast Cancer: Panel Summary and Guidelines

2009 ◽  
Vol 133 (4) ◽  
pp. 611-612 ◽  
Author(s):  
Gail H. Vance ◽  
Todd S. Barry ◽  
Kenneth J. Bloom ◽  
Patrick L. Fitzgibbons ◽  
David G. Hicks ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Amplification ◽  
Practice Guidelines ◽  
Genetic Heterogeneity ◽  
Her2 Amplification ◽  
Her2 Gene ◽  
Her2 Testing ◽  
Her2 Gene Amplification ◽  
Gene Status ◽  
Panel Summary

Abstract Context.—Intratumoral heterogeneity of HER2 gene amplification has been well documented and represents subclonal diversity within the tumor. The reported incidence of intratumor HER2 amplification genetic heterogeneity ranges in the literature from approximately 5% to 30%. The presence of HER2 genetic heterogeneity may increase subjectivity in HER2 interpretation by the pathologist. Objectives.—To define HER2 genetic heterogeneity and to provide practice guidelines for examining and reporting breast tumors with genetic heterogeneity for improvement of HER2 testing in breast cancer. Design.—We convened an expert panel to discuss HER2 gene amplification testing by fluorescence in situ hybridization. Components addressed included a definition of HER2 amplification heterogeneity, practice guidelines for examination of the tissue, and reporting criteria for this analysis. Results.—Genetic heterogeneity for amplification of HER2 gene status in invasive breast cancer is defined and guidelines established for assessing and reporting HER2 results in these cases. These guidelines are additive to and expand those published in 2007 by the American Society of Clinical Oncology and the College of American Pathologists. Conclusion.—Standardized methods for analysis will improve the accuracy and consistency of interpretation of HER2 gene amplification status in breast cancer.

scholarly journals HER2 Heterogeneity in Gastric Cancer: A Comparative Study, Using Two Commercial Antibodies

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Catalin Bogdan Satala ◽  
Ioan Jung ◽  
Raluca Ioana Stefan-van Staden ◽  
Zsolt Kovacs ◽  
Calin Molnar ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Growth Factor Receptor ◽  
Fish Analysis ◽  
Her2 Amplification ◽  
Her2 Gene ◽  
Gene Encoding ◽  
Gold Standard Method ◽  
Negative Prognostic Factor ◽  
Significant Difference ◽  
Her2 Heterogeneity

Background. Although amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) is used as an indicator for response to trastuzumab, the reported response rate is low, and few patients with gastric cancer (GC) benefit from this individualized therapy. The aim of this study was to examine the expression of c-erbB-2 oncoprotein (HER2), in GC samples, using two commercial immunohistochemical (IHC) antibodies, and to validate the results by checking HER2 gene amplification by fluorescence in situ hybridization (FISH). Methods. We assessed the IHC expression of HER2 using the polyclonal antibody from Dako and CB11 clone from Leica, in 93 consecutive cases of GC samples. In all of the cases, FISH analysis was also performed using the BOND-MAX platform. Results. No significant difference was observed between the two HER2 antibodies. Of the 93 cases, 22.58% demonstrated at least focal and 1+ HER2 positivity. Seven cases (7.53%) exhibited 3+ expression, and another 7 carcinomas (7.53%) were equivocal (2+). HER2 amplification was seen in 11 cases (11.83%), 10 of which were differentiated adenocarcinomas. In 5 of the cases, 2–5 sections were examined, which proved the extremely high intratumorally/intraglandular heterogeneity. FISH heterogeneity was higher in cases with only 2+ positivity on IHC assessment, compared with those showing at least one small focus of 3+ overexpression. HER2 amplification proved to be an independent negative prognostic factor. Conclusions. Due to the highly heterogeneous aspect of GC, at least 3-4 slides should be assessed by IHC, before considering a tumor to be HER2-negative. In cases with small 3+ foci representing less than 5% of tumor and in equivocal (2+) cases, FISH analysis remains the gold standard method.

Assessment of HER2 gene status in breast carcinomas with polysomy of chromosome 17

Cancer ◽  
2010 ◽  
Vol 117 (1) ◽  
pp. 48-53 ◽  
Author(s):  
Semir Vranic ◽  
Bryan Teruya ◽  
Susan Repertinger ◽  
Pamela Ulmer ◽  
Jill Hagenkord ◽  
...  
Keyword(s):  
Chromosome 17 ◽  
Breast Carcinomas ◽  
Her2 Gene ◽  
Gene Status

scholarly journals Detection of HER2 Amplification in Breast Carcinomas: Comparison of Multiplex Ligation-Dependent Probe Amplification (MLPA) and Fluorescence In Situ Hybridization (FISH) combined with Automated Spot Counting

2006 ◽  
Vol 28 (4) ◽  
pp. 151-159
Author(s):  
Elna Moerland ◽  
Rens L. H. P. M. van Hezik ◽  
Toine C. J. M. van der Aa ◽  
Mike W. P. M. van Beek ◽  
Adriaan J. C. van den Brule
Keyword(s):  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Gene Amplification ◽  
Her2 Status ◽  
Her2 Amplification ◽  
Breast Carcinomas ◽  
Her2 Gene ◽  
Her2 Gene Amplification ◽  
Dependent Probe

In this study the detection of HER2 gene amplification was evaluated using Fluorescence In Situ Hybridization (FISH; PathVysion) in comparison with Multiplex Ligation-dependent Probe Amplification (MLPA), a PCR based technique. These two methods were evaluated on a series of 46 formalin fixed paraffin embedded breast carcinomas, previously tested for protein overexpression by HercepTest (grouped into Hercep 1+, 2+ and 3+). HER2 gene amplification (ratio ≥ 2.0) by FISH was found in 9/10, 10/30 and 0/6 in IHC 3+, 2+ and 1+/0 cases, respectively. Digitalized automated spot counting performed with recently developed CW4000 CytoFISH software was 100% concordant with manual FISH scoring. Using MLPA 18/46 samples showed a clear HER2 amplification. Comparing MLPA and IHC showed the same results as for FISH and IHC. All but one FISH positive cases (18/19) were confirmed by MLPA for the presence of the gene amplification. The overall concordance of detection of Her2 gene amplification by FISH and MLPA was 98% (45/46). Furthermore, both the level of amplification and equivocal results correlated well between both methods. In conclusion, MLPA is a reliable and reproducible technique and can be used as an either alternative or additional test to determine HER2 status in breast carcinomas.

scholarly journals Remdesivir Use in Patients Requiring Mechanical Ventilation due to COVID-19

2020 ◽  
Vol 7 (11) ◽  
Author(s):  
Giuseppe Lapadula ◽  
Davide Paolo Bernasconi ◽  
Giacomo Bellani ◽  
Alessandro Soria ◽  
Roberto Rona ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Hospital Discharge ◽  
Multivariable Analysis ◽  
Competing Risk ◽  
Lower Mortality ◽  
Hospital Death ◽  
Related Factors ◽  
Cox Models ◽  
Treatment Groups ◽  
Reduction Of Mortality

Abstract Background Remdesivir has been associated with accelerated recovery of severe coronavirus disease 2019 (COVID-19). However, whether it is also beneficial in patients requiring mechanical ventilation is uncertain. Methods All consecutive intensive care unit (ICU) patients requiring mechanical ventilation due to COVID-19 were enrolled. Univariate and multivariable Cox models were used to explore the possible association between in-hospital death or hospital discharge, considered competing-risk events, and baseline or treatment-related factors, including the use of remdesivir. The rate of extubation and the number of ventilator-free days were also calculated and compared between treatment groups. Results One hundred thirteen patients requiring mechanical ventilation were observed for a median of 31 days of follow-up; 32% died, 69% were extubated, and 66% were discharged alive from the hospital. Among 33 treated with remdesivir (RDV), lower mortality (15.2% vs 38.8%) and higher rates of extubation (88% vs 60%), ventilator-free days (median [interquartile range], 11 [0–16] vs 5 [0–14.5]), and hospital discharge (85% vs 59%) were observed. Using multivariable analysis, RDV was significantly associated with hospital discharge (hazard ratio [HR], 2.25; 95% CI, 1.27–3.97; P = .005) and with a nonsignificantly lower mortality (HR, 0.73; 95% CI, 0.26–2.1; P = .560). RDV was also independently associated with extubation (HR, 2.10; 95% CI, 1.19–3.73; P = .011), which was considered a competing risk to death in the ICU in an additional survival model. Conclusions In our cohort of mechanically ventilated patients, RDV was not associated with a significant reduction of mortality, but it was consistently associated with shorter duration of mechanical ventilation and higher probability of hospital discharge, independent of other risk factors.

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