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.

Prognostic Significance of Angiogenesis and Ki-67, p53, and p21 Expression: A Population-Based Endometrial Carcinoma Study

1999 ◽  
Vol 17 (5) ◽  
pp. 1382-1382 ◽  
Author(s):  
Helga B. Salvesen ◽  
Ole Erik Iversen ◽  
Lars A. Akslen
Keyword(s):  
High Risk ◽  
Endometrial Carcinoma ◽  
Cox Regression ◽  
Figo Stage ◽  
Population Based ◽  
Prognostic Impact ◽  
Histologic Type ◽  
Ki 67 ◽  
Cox Regression Analysis

PURPOSE: For endometrial carcinoma patients, there is a need for improved identification of high-risk groups that may benefit from postoperative adjuvant therapy. We therefore studied the prognostic impact of markers for cell proliferation, cell-cycle regulation, and angiogenesis among endometrial carcinoma patients in a population-based setting. PATIENTS AND METHODS: All patients diagnosed with endometrial carcinoma between 1981 and 1985 in Hordaland County, Norway, were studied. The median follow-up for the survivors was 11.5 years (range, 8 to 15 years), with no patient lost because of insufficient follow-up information. Paraffin-embedded tumor tissue, available in 96% of the cases (n = 142), was studied immunohistochemically for microvessel density (MVD) and expression of Ki-67, p53, and p21 proteins. We used the hot spot method for calculation of MVD, and expression of Ki-67 and p21 protein, because this approach may increase the probability of detecting small aggressive clones of possible prognostic relevance. The importance of these tumor markers was investigated in univariate survival analyses and Cox regression analysis. RESULTS: The majority of traditional clinicopathologic variables was significantly associated with the tumor biomarkers. Age, International Federation of Gynecology and Obstetrics (FIGO) stage, histologic type, histologic grade, MVD, as well as Ki-67, p53, and p21 protein expression, all significantly influenced survival in univariate analyses (P ≤ .05). In the Cox regression analysis, age, FIGO stage, MVD, Ki-67 expression, and p53 expression were the only variables with independent prognostic impact (P ≤ .05), whereas histologic type, histologic grade, and p21 expression had no independent influence. A group of high-risk patients with more than one unfavorable marker was identified. CONCLUSION: In addition to age and FIGO stage, MVD, Ki-67, and p53 protein expression showed an independent prognostic impact. Thus, information derived from routine histologic specimens identified a subgroup of high-risk endometrial carcinoma patients in this population-based study.

Single nucleotide polymorphisms (SNPs) in COL4A2, PPP1R17, and ARHGAPP44 and prognostic value in metastatic colorectal cancer (mCRC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 720-720
Author(s):  
Amanda Rose Townsend ◽  
Rebecca Asher ◽  
Timothy Jay Price ◽  
Chee Khoon Lee ◽  
Hilary Dorward ◽  
...  
Keyword(s):  
Treatment Response ◽  
Regression Models ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Nucleotide Polymorphisms ◽  
Significant Difference

720 Background: Our previous study has identified COL4A2, PPP1R17 and ARHGAP44 SNPs using whole exome sequencing with potential prognostic significance (Townsend et al. ASCO GI 2017). COL4A2 encodes a subunit of type IV collagen, the C-terminal of which is an inhibitor of angiogenesis. We assessed prognostic impact of these variants in patients from the phase III MAX study (capecitabine +/- bevacizumab (+/- mitomycin C)). An analysis of predictive effect on bevacizumab was also undertaken. Methods: DNA was extracted from archival macrodissected formalin fixed paraffin embedded tumor tissue and genotyped using Agena Bioscience MassARRAY system (AGRF). Univariate association of variant group (WT versus mutation (MT)) with progression free survival (PFS) and overall survival (OS) was assessed using Kaplan-Meier curves and Cox regression models. Logistic regression models were used to assess association with response rate (RR). A cox regression model with treatment, variant status and their interaction investigated if variants were predictive of bevacizumab effect. Results: Of the available 145 of 471 (31%) patients in the MAX study, 25 (17%) had COL4A2 MT, 29 (20%) PPP1R17 MT, 14 (10%) ARHGAP44 MT. Patient demographics were comparable across treatment groups and outcomes similar to whole study population. On univariate analysis median PFS was numerically longer for WT vs MT in all 3 variants, but these differences were not significant (COL4A2 WT 8.4m v MT 6.0m, p=0.09; PPP1R17 WT 7.8m v MT 7.5m, p=0.76; ARHGAP44 WT 8.2m v MT 6.5m, p=0.86). There was also no significant association between variant type and OS. Multivariate analysis for COL4A2 MT v WT showed no significant difference in PFS or OS (HR 1.42; 95% CI 0.91-2.22, p=0.13 and HR 1.33; 95% CI 0.85-2.1, p=0.21). There was no association between treatment response and variant status. Variant status was not predictive of bevazicumab efficacy for treatment response, PFS or OS. Conclusions: There was no significant prognostic or predictive impact of novel gene variants in patients treated with bevacizumab. This may be due to small numbers of MT variants in this study and further studies in larger populations may be useful.

scholarly journals Prognostic impact of proliferation-associated factors MIB1 (Ki-67) and S-phase in node-negative breast cancer

1997 ◽  
Vol 75 (10) ◽  
pp. 1525-1533 ◽  
Author(s):  
P Dettmar ◽  
N Harbeck ◽  
C Thomssen ◽  
L Pache ◽  
P Ziffer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Associated Factors ◽  
S Phase ◽  
Prognostic Impact ◽  
Ki 67 ◽  
Node Negative ◽  
Node Negative Breast Cancer

Ki-67 is a Luminal B marker that identifies a high-risk subgroup in hormone receptor positive and node negative breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10521-10521
Author(s):  
M. Cheang ◽  
D. Voduc ◽  
S. Leung ◽  
D. Turbin ◽  
P. S. Bernard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Poor Prognosis ◽  
Cox Regression ◽  
Breast Cancers ◽  
Ki 67 ◽  
Node Negative ◽  
Luminal B ◽  
Poor Outcome ◽  
Hormone Receptor Positive

10521 Background: Gene expression profiling studies have revealed prognostically significant intrinsic breast cancer subtypes, designated Luminal A, Luminal B, Basal and Her2. Expression of ER and associated genes characterizes the luminal breast cancers. The Lum B subgroup is associated with poor outcome, but we lack immunohistochemical (IHC) markers to distinguish Lum A and Lum B subgroups. MKI67 is one gene known to be highly expressed in Lum B tumors, encoding the Ki-67 protein, a robust marker of cell proliferation. In this study, we perform IHC analysis of Ki-67 in a large breast cancer tissue microarray. Methods: Our patient cohort consists of 2222 consecutive cases of invasive breast cancer referred to the BC Cancer Agency from 1986 to 1992. Archival paraffin tissue blocks were used to construct a tissue microarray that was then stained for Ki-67 using a commercially available mouse monoclonal antibody. Ki-67 staining was scored quantitatively by automated image analysis and a tumor was positive if the percent positive nuclei was >30%’ Results: Of the 2,222 patients, there are 1,437 Luminal tumors as defined by IHC (ER or PR positive). As Her2 positive status is an established marker of poor prognosis, we excluded these tumors from our analysis. Of the remaining tumors, 9% were Ki-67 positive when using a ki-67 cut off of 30% positive nuclei. In survival analysis of patients ER/PR positive and Her2 negative, we found that Ki-67 identifies a population with poor prognosis (10-yr BCSS 60% vs. 80%). In a multivariate Cox regression we found that Ki-67 is independently prognostic. We repeated Cox regression analysis including only node negative patients and again found that Ki-67 is an independent predictor of poor outcome. Conclusions: Ki-67 has prognostic significance on multivariate survival analysis. Hormone receptor positive and node negative status is typically associated with a favorable outcome for breast cancer. However, Ki-67 is able to identify a small, but clinically significant subgroup with a particularly poor outcome. Defining the Luminal B subtype as (ER or PR) positive and (HER2 or Ki-67) positive, results in a subgroup that contains 18% of hormone receptor positive breast cancers with 10-yr BCSS of 61%. No significant financial relationships to disclose.

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 Comparative frequency and prognostic impact of myocardial injury in hospitalized patients with COVID-19 and Influenza

2021 ◽  
Author(s):  
Luigi Biasco ◽  
Catherine Klersy ◽  
Giulia S Beretta ◽  
Marco Valgimigli ◽  
Amabile Valotta ◽  
...  
Keyword(s):  
Regression Models ◽  
Influenza A ◽  
Myocardial Injury ◽  
Cox Regression ◽  
Absolute Risk ◽  
Hospitalized Patients ◽  
Viral Diseases ◽  
Admission Diagnosis ◽  
Prognostic Impact ◽  
Risk Of Death

Abstract Aims Myocardial injury (MINJ) in Coronavirus disease 2019 (COVID-19) identifies individuals at high mortality risk but its clinical relevance is less well established for Influenza and no comparative analyses evaluating frequency and clinical implications of MINJ among hospitalized patients with Influenza or COVID-19 are available. Methods and Results Hospitalized adults with laboratory confirmed Influenza A or B or COVID-19 underwent highly-sensitive cardiac T Troponin (hs-cTnT) measurement at admission in four regional hospitals in Canton Ticino, Switzerland. MINJ was defined as hs-cTnT &gt;14 ng/L. Clinical, laboratory and outcome data were retrospectively collected. The primary outcome was mortality up to 28 days. Cox regression models were used to assess correlations between admission diagnosis, myocardial injury and mortality. Clinical correlates of MINJ in both viral diseases were also identified. MINJ occurred in 94 (65.5%) out of 145 patients hospitalized for Influenza and 216 (47.8%) out of 452 patients hospitalized for COVID-19. Advanced age and renal impairment were factors associated with myocardial injury in both diseases. At 28 days, 7 (4.8%) deaths occurred among Influenza and 76 deaths (16.8%) among COVID-19 patients with a hazard ratio (HR) of 3.69 (95%-CI 1.70-8.00). Adjusted Cox regression models showed admission diagnosis of COVID-19 [HR:6.41 (95%-CI 4.05-10.14)] and MINJ [HR:8.01 (95%-CI 4.64-13.82)] to be associated with mortality. Conclusions Myocardial injury is frequent among both viral diseases and increases the risk of death in both COVID-19 and Influenza. The absolute risk of death is considerably higher in patients admitted for COVID-19 as compared with Influenza.

scholarly journals T1 Bladder Cancer: Comparison of the Prognostic Impact of Two Substaging Systems on Disease Recurrence and Progression and Suggestion of a Novel Nomogram

2021 ◽  
Vol 8 ◽  
Author(s):  
Anastasios D. Asimakopoulos ◽  
Gaia Colalillo ◽  
Rossana Telesca ◽  
Alessandro Mauriello ◽  
Roberto Miano ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Lamina Propria ◽  
Regression Models ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Disease Recurrence ◽  
Prognostic Impact ◽  
Free Survival ◽  
Prognostic Accuracy ◽  
Significant Difference

Background: The T1 substaging of bladder cancer (BCa) potentially impacts disease progression. The objective of the study was to compare the prognostic accuracy of two substaging systems on the recurrence and progression of primary pathologic T1 (pT1) BCa and to test a nomogram based on pT1 substaging for predicting recurrence-free survival (RFS) and progression-free survival (PFS).Methods: The medical records of 204 patients affected by pT1 BCa were retrospectively reviewed. Substaging was defined according to the depth of lamina propria invasion in T1a−c and the extension of the lamina propria invasion to T1-microinvasive (T1m) or T1-extensive (T1e). Uni- and multivariable Cox regression models evaluated the independent variables correlated with recurrence and progression. The predictive accuracies of the two substaging systems were compared by Harrell's C index. Multivariate Cox regression models for the RFS and PFS were also depicted by a nomogram.Results: The 5-year RFS was 47.5% with a significant difference between T1c and T1a (p = 0.02) and between T1e and T1m (p &lt; 0.001). The 5-year PFS was 75.9% with a significant difference between T1c and T1a (p = 0.011) and between T1e and T1m (p &lt; 0.001). Model T1m−e showed a higher predictive power than T1a−c for predicting RFS and PFS. In the univariate and multivariate model subcategory T1e, the diameter, location, and number of tumors were confirmed as factors influencing recurrence and progression after adjusting for the other variables. The nomogram incorporating the T1m−e model showed a satisfactory agreement between model predictions at 5 years and actual observations.Conclusions: Substaging is significantly associated with RFS and PFS for patients affected by T1 BCa and should be included in innovative prognostic nomograms.

scholarly journals Unmarried or less-educated patients with mantle cell lymphoma are less likely to undergo a transplant, leading to lower survival

2021 ◽  
Vol 5 (6) ◽  
pp. 1638-1647
Author(s):  
Ingrid Glimelius ◽  
Karin E. Smedby ◽  
Alexandra Albertsson-Lindblad ◽  
Michael J. Crowther ◽  
Sandra Eloranta ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Regression Models ◽  
Hematopoietic Cell Transplantation ◽  
Cox Regression ◽  
Cell Lymphoma ◽  
Prognostic Impact ◽  
Never Married ◽  
Logistic Regression Models ◽  
Mantle Cell ◽  
All Cause Mortality

Abstract It is unknown how many mantle cell lymphoma (MCL) patients undergo consolidation with autologous hematopoietic cell transplantation (AHCT), and the reasons governing the decision, are also unknown. The prognostic impact of omitting AHCT is also understudied. We identified all MCL patients diagnosed from 2000 to 2014, aged 18 to 65 years, in the Swedish Lymphoma Register. Odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models were used to compare the likelihood of AHCT within 18 months of diagnosis. All-cause mortality was compared between patients treated with/without AHCT using hazard ratios (HRs) and 95% CIs estimated from Cox regression models. Probabilities of being in each of the following states: alive without AHCT, alive with AHCT, dead before AHCT, and dead after AHCT, were estimated over time from an illness-death model. Among 369 patients, 148 (40%) were not treated with AHCT within 18 months. Compared with married patients, never married and divorced patients had lower likelihood of undergoing AHCT, as had patients with lower educational level, and comorbid patients. Receiving AHCT was associated with reduced all-cause mortality (HR = 0.58, 95% CI: 0.40-0.85). Transplantation-related mortality was low (2%). MCL patients not receiving an AHCT had an increased mortality rate, and furthermore, an undue concern about performing an AHCT in certain societal groups was seen. Improvements in supportive functions potentially increasing the likelihood of tolerating an AHCT and introduction of more tolerable treatments for these groups are needed.

scholarly journals Prognostic Significance of Focal Adhesion Kinase in Node-Negative Breast Cancer

Breast Care ◽  
2017 ◽  
Vol 12 (5) ◽  
pp. 329-333 ◽  
Author(s):  
Katrin Almstedt ◽  
Isabel Sicking ◽  
Marco J. Battista ◽  
Shangou Huangfu ◽  
Anne-Sophie Heimes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cox Regression ◽  
Prognostic Impact ◽  
Free Survival ◽  
Node Negative ◽  
Cox Regression Analysis ◽  
Luminal B ◽  
Prognostic Relevance

Background: Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays an important role as a mediator of cell migration, invasion, proliferation and survival. Conflicting results for the prognostic role of FAK in breast cancer (BC) prompted us to determine its impact. Methods: Patients with node-negative BC entered this retrospective study. FAK expression was determined by immunohistochemistry (n = 335). The prognostic impact of FAK was examined with Cox regression analyses and Kaplan-Meier estimation in the whole cohort as well as in different molecular subtypes. Results: 151 (45.1%) had a FAK-positive BC. In univariate analyses, FAK expression showed a significant impact for shorter disease-free survival (DFS) (hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, p = 0.030) but not for metastasis-free survival and overall survival. Significant prognostic relevance for DFS (HR 1.76, 95% CI 1.05-2.97, p = 0.033) was observed in particular in estrogen receptor-positive HER2-negative BC patients, most notably in luminal B-like tumors (HR 2.32, CI 1.20-4.48, p = 0.012). However, FAK lost its prognostic impact in multivariate Cox regression analysis. Conclusion: FAK was associated with impaired DFS in univariate analysis. Prognostic relevance for DFS was most pronounced in luminal B-like BC. However, FAK expression was not associated with an independent impact on survival for BC in multivariate analysis.

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