Expression Analysis of α5 Integrin Subunit Reveals Its Upregulation as a Negative Prognostic Biomarker for Glioblastoma

Integrin α5β1 was suggested to be involved in glioblastoma (GBM) aggressiveness and treatment resistance through preclinical studies and genomic analysis in patients. However, further protein expression data are still required to confirm this hypothesis. In the present study, we investigated by immunofluorescence the expression of integrin α5 and its prognostic impact in a glioblastoma series of patients scheduled to undergo the Stupp protocol as first-line treatment for GBM. The integrin α5 protein expression level was estimated in each tumor by the mean fluorescence intensity (MFI) and allowed us to identify two subpopulations showing either a high or low expression level. The distribution of patients in both subpopulations was not significantly different according to age, gender, recursive partitioning analysis (RPA) prognostic score, molecular markers or surgical and medical treatment. A high integrin α5 protein expression level was associated with a high risk of recurrence (HR = 1.696, 95% CI 1.031–2.792, p = 0.0377) and reduced overall survival (OS), even more significant in patients who completed the Stupp protocol (median OS: 15.6 vs. 22.8 months; HR = 2.324; 95% CI 1.168–4.621, p = 0.0162). In multivariate analysis, a high integrin α5 protein expression level was confirmed as an independent prognostic factor in the subpopulation of patients who completed the temozolomide-based first-line treatment for predicting OS over age, extent of surgery, RPA score and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (p = 0.029). In summary, for the first time, our study validates that a high integrin α5 protein expression level is associated with poor prognosis in GBM and confirms its potential as a therapeutic target implicated in the Stupp protocol resistance.

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P14.122 Integrin α5 is a poor prognostic factor in patients with glioblastoma treated by the Stupp protocol

Neuro-Oncology ◽

10.1093/neuonc/noz126.357 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii97-iii97

Author(s):

N Etienne-Selloum ◽

J Prades ◽

D Bello Roufai ◽

F El Azumi ◽

M Boone ◽

...

Keyword(s):

Protein Expression ◽

Survival Data ◽

Poor Prognosis ◽

Univariate Analysis ◽

Expression Level ◽

Rank Test ◽

Protein Expression Level ◽

Poor Prognostic Factor ◽

Integrin Α5 ◽

Stupp Protocol

Abstract BACKGROUND Integrin α5β1 was suggested to be involved in glioblastoma (GBM) aggressiveness through preclinical studies and genomic analysis of several cohorts of patients. However, protein expression data are still missing to confirm this hypothesis. Our aim was to investigate the prognostic value of integrin α5 protein expression level in GBM. MATERIAL AND METHODS We retrospectively determined the protein expression level of integrin α5 using immunochemistry in tumors from patients treated in 6 French centers. Paraffin sections of GBM were labeled by immunofluorescence and analyzed by confocal microscopy. The corresponding clinical and survival data have been identified and analyzed. The primary end-point was overall survival (OS). RESULTS Out of 297 patients newly diagnosed with GBM between 2006 and 2013, 152 met the inclusion criteria (scheduled for initial treatment with the Stupp protocol, age > 18 years) and 95 tumor samples were suitable for immunohistochemical analysis. The median age is 58 years, (64 men, 34 women). Most of patients received macroscopic (43%) or partial (36%) surgery. In univariate analysis using the Log Rank test, high integrin α5 expression level was associated with poor prognosis (PFS: hazard ratio (HR) = 1,696, p=0,0355; OS: HR=1,598, p = 0,0508). Corresponding median OS were 15,6 versus 19,2 months. Similarly, OS was significantly reduced with age (> 60 years), lower resection degree, higher RPA (recursive partitioning analysis) score and non-methylated MGMT (O-6-methylguanine-DNA methyltransferase) promoter. In the subgroup of patients who received the full initial protocol (temozolomide treatment together with radiotherapy and later as adjuvant treatment; n=58) mean OS was strongly reduced when integrin α5 expression level was high (15,6 versus 22,8 months, p=0,0162) suggesting an impact of integrin signaling on temozolomide response in GBM. CONCLUSION Our study validates for the first time that the high protein level expression of α5 integrin is associated with poor prognosis in GBM. It also confirms its potential as a therapeutic target and its likely role in resistance to temozolomide as previously shown in preclinical study.

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Lactate Dehydrogenase (LDH) Response to First-Line Treatment Predicts Survival in Metastatic Breast Cancer: First Clues for A Cost-Effective and Dynamic Biomarker

Cancers ◽

10.3390/cancers11091243 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1243 ◽

Cited By ~ 9

Author(s):

Giacomo Pelizzari ◽

Debora Basile ◽

Silvia Zago ◽

Camilla Lisanti ◽

Michele Bartoletti ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Lactate Dehydrogenase ◽

Prognostic Factor ◽

Metastatic Breast ◽

Prognostic Impact ◽

Line Treatment ◽

First Line ◽

Cox Regression Analysis ◽

First Line Treatment

Background: Elevated plasmatic lactate dehydrogenase (LDH) levels are associated with worse prognosis in various malignancies, including metastatic breast cancer (MBC). Nevertheless, no data are available on the prognostic role of LDH as a dynamic biomarker during first-line treatment in unselected MBC. Methods: We reviewed data of 392 women with MBC to evaluate the association between LDH variation after 12 weeks of first-line treatment and survival. The prognostic impact was tested by multivariate Cox regression analysis. Results: Plasmatic LDH was confirmed as an independent prognostic factor in MBC. Patients who maintained elevated LDH levels after 12 weeks of first-line treatment experienced worse progression-free survival (PFS, HR 2.88, 95% CI: 1.40–5.89, p = 0.0038) and overall survival (OS, HR 2.61, 95% CI 1.16–5.86, p = 0.02) compared to patients with stable normal LDH levels, even after adjustment for other prognostic factors. Notably, LDH low-to-high variation emerged as an unfavorable prognostic factor for PFS (HR 3.96, 95% CI 2.00–7.82, p = 0.0001). Conclusions: Plasmatic LDH and its variation during first-line treatment predict PFS and OS in MBC, providing independent prognostic information. It would be worthwhile to prospectively evaluate the association between LDH variation and therapeutic benefit in MBC, and explore how it may affect treatment strategies.

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Prognostic Impact of Her2, Egfr, and C-Met Status on Overall Survival of Advanced Gastric Cancer Patients Treated with Standard Chemotherapy Without Trastuzumab in a First-Line Treatment: a Japanese Multicenter Collaborative Retrospective Study

Annals of Oncology ◽

10.1093/annonc/mdu334.11 ◽

2014 ◽

Vol 25 ◽

pp. iv214

Author(s):

E. Shinozaki ◽

N. Fuse ◽

Y. Kuboki ◽

T. Kuwata ◽

T. Nishina ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Retrospective Study ◽

Cancer Patients ◽

Prognostic Impact ◽

Line Treatment ◽

First Line ◽

Standard Chemotherapy ◽

Gastric Cancer Patients ◽

First Line Treatment

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Prognostic impact of human epidermal growth factor-2 (HER2) status on overall survival (OS) of advanced gastric cancer (AGC) patients (pts) treated with standard chemotherapy without trastuzumab as a first-line treatment: A Japanese multicenter collaborative retrospective study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4075 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4075-4075

Author(s):

Tomohiro Nishina ◽

Nozomu Fuse ◽

Takeshi Kuwata ◽

Shigenori Kadowaki ◽

Eiji Shinozaki ◽

...

Keyword(s):

Performance Status ◽

Gastroesophageal Junction ◽

Her2 Status ◽

Prognostic Impact ◽

Line Treatment ◽

First Line ◽

Standard Chemotherapy ◽

Ecog Performance Status ◽

Significant Difference ◽

First Line Treatment

4075 Background: The prognostic impact of HER2 status on OS of AGC pts treated with standard chemotherapy without trastuzumab for first-line treatment remains controversial. This study investigated whether HER2 status is an independent prognostic factor for AGC pts. Methods: Formalin-fixed paraffin-embedded tumor samples from 293 eligible pts were examined for HER2 by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). Eligible criteria included: 1) histologically confirmed gastric or gastroesophageal junction adenocarcinoma, 2) unresectable or recurrent cancer, 3) treated with S-1 plus cisplatin as first-line chemotherapy, 4) age: ≥20, 5) ECOG performance status score: 0-2 and 6) with archived tumor sample. HER2+ was defined as IHC 3+ or IHC 2+/FISH+. Results: Of 293 pts, 43 (15%) were HER2+. Baseline pt characteristics between HER2+ and HER2- pts were significantly different by histology (intestinal/diffuse, 65%/35% vs. 39%/61%; p=0.001), measurable disease by RECIST v1.0 (91% vs. 69%; p=0.003), No. of metastatic sites (≥2, 72% vs. 46%; p=0.003) and presence of liver metastasis (56% vs. 31%; p=0.003). After median follow-up time of 48.9 months with 270 (92%) death events, there was no significant difference in OS between HER2+ and HER2- pts (median, 11.7 vs. 13.7 months; hazard ratio [HR] 1.11, 95% CI 0.79–1.55; log rank p=0.550). After adjusting other prognostic factors with Cox hazard model, HER2+ was still not prognostic for OS (HR 0.890, 95% CI 0.627–1.262, p=0.513). Conclusions: HER2 status has no significant prognostic impact on OS of AGC pts treated with S-1 plus cisplatin without trastuzumab as a first-line treatment.

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Cost–effectiveness analysis of nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced NSCLC

Immunotherapy ◽

10.2217/imt-2020-0112 ◽

2020 ◽

Vol 12 (14) ◽

pp. 1067-1075

Author(s):

Jiahao Li ◽

Tiantian Zhang ◽

Yongmei Xu ◽

Peiyao Lu ◽

Jiaxin Zhu ◽

...

Keyword(s):

Cost Effectiveness ◽

Advanced Nsclc ◽

Expression Level ◽

Line Treatment ◽

First Line ◽

Programmed Death Ligand 1 ◽

Payer Perspective ◽

Programmed Death ◽

The Cost ◽

First Line Treatment

Aim: To evaluate the cost–effectiveness of nivolumab plus ipilimumab (NI) in the first-line treatment of patients with advanced non-small-cell lung cancer from a US-payer perspective. Materials & methods: We developed a Markov model to evaluate the cost and effectiveness of NI versus chemotherapy as first-line treatment of NSCLC. Quality-adjusted life-years (QALYs) and incremental cost–effectiveness ratios (ICERs) were estimated. Results: NI provided an additional 0.715 QALYs compared with chemotherapy in all population. The corresponding ICER of NI was $180,307 per QALY gained. However, the ICER decreased to $143,434 per QALY in the programmed death ligand 1 expression level <1% population. Conclusion: From a US-payer perspective, NI is estimated to be cost-effective in the first-line setting for advanced NSCLC patients with programmed death ligand 1 expression level <1%.

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Differential impact of tumor suppressor gene (TP53, PTEN, RB1) alterations and treatment outcomes in metastatic, hormone-sensitive prostate cancer

Prostate Cancer and Prostatic Diseases ◽

10.1038/s41391-021-00430-4 ◽

2021 ◽

Author(s):

Miguel Gonzalez Velez ◽

Heidi E. Kosiorek ◽

Jan B. Egan ◽

Andrea L. McNatty ◽

Irbaz B. Riaz ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Suppressor ◽

Cox Regression ◽

Multivariable Analysis ◽

Rank Test ◽

Prognostic Impact ◽

Line Treatment ◽

First Line ◽

Hormone Sensitive ◽

First Line Treatment

Abstract Background Altered tumor suppressor genes (TSG-alt) in prostate cancer are associated with worse outcomes. The prognostic value of TSG-alt in metastatic, hormone-sensitive prostate cancer (M1-HSPC) is unknown. We evaluated the effects of TSG-alt on outcomes in M1-HSPC and their prognostic impact by first-line treatment. Methods We retrospectively identified patients with M1-HSPC at our institution treated with first-line androgen deprivation therapy plus docetaxel (ADT + D) or abiraterone acetate (ADT + A). TSG-alt was defined as any alteration in one or more TSG. The main outcomes were Kaplan–Meier-estimated progression-free survival (PFS) and overall survival, analyzed with the log-rank test. Clinical characteristics were compared with the χ2 test and Kruskal–Wallis rank sum test. Cox regression was used for univariate and multivariable analyses. Results We identified 97 patients with M1-HSPC: 48 (49%) with ADT + A and 49 (51%) with ADT + D. Of 96 patients with data available, 33 (34%) had 1 TSG-alt, 16 (17%) had 2 TSG-alt, and 2 (2%) had 3 TSG-alt. The most common alterations were in TP53 (36%) and PTEN (31%); 6% had RB1 alterations. Median PFS was 13.1 (95% CI, 10.3–26.0) months for patients with normal TSGs (TSG-normal) vs. 7.8 (95% CI, 5.8–10.5) months for TSG-alt (P = 0.005). Median PFS was lower for patients with TSG-alt vs TSG-normal for those with ADT + A (TSG-alt: 8.0 [95% CI, 5.8–13.8] months vs. TSG-normal: 23.2 [95% CI, 13.1–not estimated] months), but not with ADT + D (TSG-alt: 7.8 [95% CI, 5.7–12.9] months vs. TSG-normal: 9.5 [95% CI, 4.8–24.7] months). On multivariable analysis, only TSG-alt predicted worse PFS (hazard ratio, 2.37; 95% CI, 1.42–3.96; P < 0.001). Conclusions The presence of TSG-alt outperforms clinical criteria for predicting early progression during first-line treatment of M1-HSPC. ADT + A was less effective in patients with than without TSG-alt. Confirmation of these findings may establish the need for inclusion of molecular stratification in treatment algorithms.

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