Human skin biomarkers and his relation with the response to treatment to tyrosine kinase inhibitors in advanced EGFR mutated lung adenocarcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21544-e21544
Author(s):  
Jeronimo Rafael Rafael Rodriguez Cid ◽  
Anahi Castañeda-Zárraga ◽  
Rodrigo Rodrigo Flores-Mariñelarena ◽  
María Elisa Vega-Memije ◽  
Valeria Michelle Fernández Garibay ◽  
...  
Keyword(s):  
Stratum Corneum ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Free Survival ◽  
A Value ◽  
Number Of Layers ◽  
Adequate Response ◽  
Skin Biopsies ◽  
Egfr Mutated

e21544 Background: A relationship between EGFR signaling pathway expression in skin and the use of targeted cancer therapies has been consistently demonstrated. Nonetheless, consistent evidence to support the use of skin biopsies as a surrogate for therapeutic evaluation. Methods: The present study is a prospective single-blind analysis of skin biopsies of patients with confirmed advanced EGFR mutated lung adenocarcinoma. Immunohistochemistry was performed with EGFR, p27, Ki67, STAT3, and MAPK, as well as an H&E histopathological analysis, looking for their relationship with the response to treatment with tyrosine kinase inhibitors. ROC curve analysis was used to determine the cutoff value for each biomarker selected dichotomizing the response to treatment as mentioned in the tissue samples section (adequate response or no response). Kaplan Meier analysis for progression-free survival was performed. Results: From the 35 biopsies obtained, 21 (60%) of the patients were women and 14 (40%) men; the mean age of participants was 60.6±11.7 years. Twelve patients (34.3%) were at the pre-treatment group, 12 (34.3%) had an adequate response to treatment and 11 (31.4%) were at the no response to treatment group. The median progression-free survival was 9 months. The next biomarkers were significantly related to an adequate response to treatment by using a bivariate correlation test: EGFR (p = 0.025), Ki67 (p = 0.015), STAT3 (p = 0.017), stratum corneum thickness (p = 0.039) and the number of layers of the stratum corneum(p = 0.041). A better median of progression-free survival was obtained on those with a value above of the cutoff preestablished of EGFR (21 months versus 7 months, 95% CI 0-46 versus 4.23-9.77, p = 0.025) and number of layers of the stratum corneum (21 months versus 8 months, 95% CI 0-43.81 versus 6.72-9.28, p = 0.030), however, for p27 a better median of progression-free survival was shown in those with a value below the cutoff before mentioned (21 months versus 8 months, 95% CI 8.17-33.83 versus 6.87-9.13, p = 0.031). Conclusions: We found a relationship between EGFR, Ki67, STAT3, stratum corneum, number of layers of stratum corneum, with the response to treatment, and better progression-free survival for high expression EGFR, number of layers of the stratum corneum and low expression for p27. The present study should incite to perform a further investigation to validate these markers as potential prognostic and predictive factors.

scholarly journals Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 434 ◽  
Author(s):  
Ming-Ju Tsai ◽  
Jen-Yu Hung ◽  
Mei-Hsuan Lee ◽  
Chia-Yu Kuo ◽  
Yu-Chen Tsai ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
First Line ◽  
Free Survival ◽  
Younger Patients ◽  
Epidermal Growth

Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) “a single sensitizing uncommon mutation”, 7 (12%) “multiple sensitizing mutations”, 5 (9%) “a sensitizing mutation and a resistant uncommon mutation”, and 18 (32%) “other resistant uncommon mutations”. No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings.

scholarly journals Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas

1997 ◽  
Vol 2 (3) ◽  
pp. E1
Author(s):  
Roger J. Packer ◽  
Joanne Ater ◽  
Jeffrey Allen ◽  
Peter Phillips ◽  
Russell Geyer ◽  
...  
Keyword(s):  
Objective Response ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Low Grade ◽  
Significant Prognostic Factor ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Low Grade Gliomas ◽  
Response To Chemotherapy

The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided. There has been increased interest in the use of chemotherapy for young children, but little information concerning the long-term efficacy of such treatment. Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed, progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy. The patients were followed for a median of 30 months from diagnosis, with 31 patients followed for more than 3 years. Fifty-eight children had diencephalic tumors, 12 had brainstem gliomas, and three had diffuse leptomeningeal gliomas. Forty-four (56%) of 78 patients showed an objective response to treatment. Progression-free survival rates were 75 ± 6% at 2 years and 68 ± 7% at 3 years. There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year, progression-free survival 79 ± 11% vs. 75 ± 6%, respectively). The histological subtype of the tumor, its location, and its maximum response to chemotherapy did not have an impact on the duration of disease control. The only significant prognostic factor was age: children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 ± 7% compared with a rate of 39 ± 21% in older children (p < 0.01). Treatment with carboplatin and vincristine is effective, especially in younger children, in controlling newly diagnosed progressive low-grade gliomas.

scholarly journals Evaluation of Histopathological Changes in Control Biopsies Which Taken 48 Sessions after NBUVB Phototherapy for Early-Stage Mycosis Fungoides

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Ebru Zemheri ◽  
Seyma Ozkanli ◽  
Ilkin Zindanci ◽  
Serkan Senol ◽  
Ozge Akbulak ◽  
...  
Keyword(s):  
Stratum Corneum ◽  
Early Stage ◽  
Response To Treatment ◽  
Epidermal Thickness ◽  
Dermal Fibrosis ◽  
Narrowband Uvb ◽  
Before And After ◽  
Histomorphological Changes ◽  
Skin Biopsies ◽  
Perivascular Infiltration

Background.There are not many studies investigating histomorphological changes in 48 sessions in patients with early-stage MF after narrowband UVB (NBUVB) treatment. Our purpose is to evaluate histological features of phototherapy after 48 sessions and determine which parameters are more reliable for controlling skin biopsies.Methods.Biopsies of 32 patients with early stage of MF, who were treated with NBUVB phototherapy, were histologically evaluated before and after the treatments, including epidermotropism, stratum corneum, epidermal thickness, dermal infiltration, papillary dermal fibrosis, vascular alterations, and other dermal changes. We discuss the histomorphological effects of NBUVB phototherapy on skin biopsies by comparing the responders with nonresponders, with before and after the treatment.Results.9 patients (28%) did not give any response to treatment. Alleviation in epidermotropism, increases in parakeratosis and normal keratosis, perivascular infiltration, and melanophages, decrease in the lichenoid/patchy lichenoid infiltration pattern after the treatment was statistically significant. Comparing by response, normalization of stratum corneum and epidermis, orthohyperkeratosis, decrease in linearly arranged cells, the lichenoid/patchy lichenoid infiltration, the loss of inflammation were statistically significant in responders group.Conclusion.We detected a significant decrease in linearly arranged cells after phototherapy, indicating that it is an “important diagnostic parameter" in evaluation of therapeutic response.

scholarly journals Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis

BMJ ◽  
2019 ◽  
pp. l5460 ◽  
Author(s):  
Yi Zhao ◽  
Jingting Liu ◽  
Xiuyu Cai ◽  
Zhenkui Pan ◽  
Jun Liu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Meta Analysis ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Combination Treatments ◽  
Exon 19 Deletion ◽  
Egfr Mutated

AbstractObjectiveTo compare the efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC).DesignSystematic review and network meta-analysis.Data sourcesPubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and several international conference databases, from inception to 20 May 2019.Eligibility criteria for selecting studiesPublished and unpublished randomised controlled trials comparing two or more treatments in the first line setting for patients with advanced EGFR mutated NSCLC were included in a bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: progression free survival, overall survival, objective response rate, and adverse events of grade 3 or higher.Results18 eligible trials involved 4628 patients and 12 treatments: EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed based chemotherapy, pemetrexed free chemotherapy, and combination treatments (afatinib plus cetuximab, erlotinib plus bevacizumab, gefitinib plus pemetrexed based chemotherapy, and gefitinib plus pemetrexed). Consistent with gefitinib plus pemetrexed based chemotherapy (hazard ratio 0.95, 95% credible interval 0.72 to 1.24), osimertinib showed the most favourable progression free survival, with significant differences versus dacomitinib (0.74, 0.55 to 1.00), afatinib (0.52, 0.40 to 0.68), erlotinib (0.48, 0.40 to 0.57), gefitinib (0.44, 0.37 to 0.52), icotinib (0.39, 0.24 to 0.62), pemetrexed based chemotherapy (0.24, 0.17 to 0.33), pemetrexed free chemotherapy (0.16, 0.13 to 0.20), afatinib plus cetuximab (0.44, 0.28 to 0.71), and gefitinib plus pemetrexed (0.65, 0.46 to 0.92). Osimertinib and gefitinib plus pemetrexed based chemotherapy were also consistent (0.94, 0.66 to 1.35) in providing the best overall survival benefit. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab, which caused the most adverse events of grade 3 or higher. Different toxicity spectrums were revealed for individual EGFR-TKIs. Subgroup analyses by the two most common EGFR mutation types indicated that osimertinib was associated with the best progression free survival in patients with the exon 19 deletion, and gefitinib plus pemetrexed based chemotherapy was associated with the best progression free survival in patients with the Leu858Arg mutation.ConclusionsThese results indicate that osimertinib and gefitinib plus pemetrexed based chemotherapy were associated with the best progression free survival and overall survival benefits for patients with advanced EGFR mutated NSCLC, compared with other first line treatments. The treatments resulting in the best progression free survival for patients with the exon 19 deletion and Leu858Arg mutations were osimertinib and gefitinib plus pemetrexed based chemotherapy, respectively.Systematic review registrationPROSPERO CRD42018111954.

scholarly journals More than a Decade of Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors: What We Have Learned and What the Future Holds

2015 ◽  
Vol 10s3 ◽  
pp. BMI.S22436 ◽  
Author(s):  
Maria Vergoulidou
Keyword(s):  
Tyrosine Kinase ◽  
Small Molecules ◽  
Solid Tumors ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Free Survival ◽  
Free Treatment

The use of tyrosine kinase inhibitors (TKIs) in the treatment of solid tumors is the expected standard of care for many types of tumors. Since the description of signal transduction pathways, followed by the development of small molecules designed to inhibit those pathways, there has been significant improvement not only in progression-free survival and overall survival but also in aiming toward chemotherapy-free treatment of solid tumors to maximize quality of life. This article reviews available TKIs and discusses toxicity, dosing, and resistance.

Immunologic Recovery after Autologous Transplant in Multiple Myeloma and Progression Free Survival

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4444-4444
Author(s):  
Fernanda Maria Rodrigues Trigo-Miranda ◽  
Rui Cordeiro Bergantim ◽  
Ricardo Moreira Pinto ◽  
Patricia Guimarães ◽  
Jose E. Guimaraes
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Cell Transplant ◽  
Haematopoietic Progenitor Cell ◽  
Free Survival ◽  
Post Transplant ◽  
Historical Comparison ◽  
Significant Difference

Abstract Several factors influencing disease progression and survival have been identified in multiple myeloma (MM). We analysed a series of 49 consecutive patients with MM that underwent autologous haematopoietic progenitor cell transplant (HPCT) in one center regarding the following variables: use of G-CSF for haematopoietic recovery post-transplant; recovery of normal IgM levels at day +100 post-transplant; levels of lymphocytes namely of the CD4+ and CD8+ subsets also at day +100. Before 2006, all patients had G-CSF starting 24 hours after the cell infusion until neutrophil &gt; 500×10^9/L in two consecutive days; in the years 2006–2008, no G-CSF was given to transplanted patients. A historical comparison was done and at the time of this study no significant difference in progression free survival (Kaplan-Meyer analysis), was detected between the two groups, possibly due to the shorter follow-up of the “no G-CSF” (n=19) group; nevertheless median progression free survival (PFS) in the “G-CSF” group was 12 months while median PFS was not attained in the “no G-CSF” group (median follow-up = 7 months). Post transplant IgM levels were also determined in 39 patients. Eighteen patients recovered normal IgM levels at day +100 (46.8 %) and 21 (53.8 %) did not. Comparison of Kaplan-Meyer curves for the two groups did not show any statistically significant difference but there is a sharp difference between median PFS of the “low IgM” (10 months) and the “normal IgM” (27 months) groups. CD4/CD8 ratio was determined in 18 patients at day +100. The ratio varied between 0 and 0.63 (median – 0.305). No correlation was found between post-transplant IgM recovery and CD4/CD8 ratio. In conclusion, in our series of MM patients treated with autologous HPCT we could not find a definite relationship between immunologic recovery and response to treatment although there is a trend to a better outlook of the patients which recover normal IgM levels. It is also uncertain whether use of G-CSF in the post-transplant period would have any effect on disease behaviour.

Mutational Status of the TP53 Gene as a Predictor of Response and Survival in CLL Patients with and without 17p Deletion

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 784-784 ◽  
Author(s):  
David Gonzalez ◽  
Pilar Martinez ◽  
Rachel Wade ◽  
Sarah Lorna Hockley ◽  
Vasantha Brito-Babapulle ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Tp53 Gene ◽  
Response To Treatment ◽  
Prognostic Indicators ◽  
Free Survival ◽  
Tp53 Mutations ◽  
Cd38 Expression ◽  
Mutational Status ◽  
The Uk ◽  
Tp53 Mutational Status

Abstract Background: Deletion of 17p in chronic lymphocytic leukaemia (CLL) is associated with resistance to conventional therapy and a poor clinical outcome. Though TP53 mutations have been described in some of these cases, the extent to which they occur in CLL patients and their clinical implications remain unclear. We investigated the prognostic value of TP53 mutations in the clinical course of CLL patients. Methods: We analysed 529 CLL samples from the UK LRF CLL4 clinical trial (Chlorambucil vs Fludarabine±Cyclophosphamide) for the presence of TP53 mutations and their association with response to treatment, progression-free survival (PFS) and overall survival (OS). We also investigated the correlation between TP53 mutations and other well-known prognostic indicators in CLL including stage, chromosomal aberrations, VH mutational status and CD38 and ZAP-70 expression. Results: Mutations of TP53 were found in 44 of 529 patients overall (8.3%). TP53 mutations were present in 26 out of 32 (81%) patients with 17p deletion in >20% of cells (p<0.0001). TP53 mutations were also present at lower frequencies in samples with no 17p deletion (13/446; 2.9%) or with <20% of cells with 17p deletion (4/47; 8.5%). Overall response rates were significantly better in patients without TP53 mutations compared to those with mutations (82% vs 34%; p<0.0001), including complete or nodular partial responses in 42% of patients without TP53 patients compared to only 10% of patients with mutations (p<0.0001). TP53 mutations were associated with significantly poorer OS; 36% (95% CI 22–51) at 3 years versus 79% (95% CI 75–83) for patients without mutations, p<0.00001 (Figure 1a). Similarly, PFS was significantly shorter for patients with TP53 mutations (3 year PFS: 9% [95% CI: 1–18]) compared to those without (34% [95% CI 30–38], p<0.00001; Figure 1b). CLL patients with TP53 haploinsufficiency -either TP53 mutation or >20% of 17p deletion- define a subgroup with intermediate prognosis (3 year OS: 52% [95% CI 32–73]) compared to those with neither (80% [95% CI 76–83]) or both (23% [95% CI 7–39]) (p(trend)<0.00001, Figure 2). There was no significant association between TP53 mutations and age, stage, VH mutations, CD38 expression, ZAP-70 expression or any other chromosomal abnormality other than 17p deletion. Conclusions: Our data shows that TP53 mutations are associated with a poor outcome in CLL patients regardless of the deletion of 17p. Furthermore, the clinical significance of 17p deletion seems to be tightly linked to the presence of mutations in the remaining TP53 allele, and these patients with no wild-type TP53 genes have the lowest OS and PFS rates. Finally, the group of CLL patients with TP53 haploinsufficiency (either by mutation or deletion in >20% of the cells) presents an intermediate prognosis and will be further investigated. Fig 1a - OS by TP53 mutational status Fig 1a -. OS by TP53 mutational status Fig 1b - PFS by TP53 mutational status Fig 1b -. PFS by TP53 mutational status Fig 2 - OS by TP53 mutational status and/or 17p deletion Fig 2 -. OS by TP53 mutational status and/or 17p deletion

Correlation of hypothyroidism with survival in metastatic renal cancer patients treated with sorafenib or sunitinib.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 379-379
Author(s):  
L. Riesenbeck ◽  
S. Bierer ◽  
I. Hoffmeister ◽  
T. Koepke ◽  
L. Hertle ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Prognostic Markers ◽  
Progression Free Survival ◽  
Response To Therapy ◽  
Metastatic Renal Cancer ◽  
Free Survival ◽  
Normal Limits ◽  
Serum T3 ◽  
Univariate Analyses ◽  
Serum Tsh

379 Background: To investigate prognostic markers in patients with metastatic renal cell carcinoma (mRCC) undergoing treatment with the tyrosine kinase inhibitors (TKIs) sorafenib (So) or sunitinib (Su). Methods: Eighty-three patients with mRCC, who were treated at our institution between 2006 and 2009, were evaluated prospectively. Clinical and laboratory parameters were investigated, as well as, treatment-related adverse events. Subclinical hypothyroidism was characterized by serum TSH above the upper limit of normal and both total triiodtyronine (T3) and thyroxine (T4) within normal limits. Clinical hypothyroidism was defined as low serum T3 and T4 together with elevated TSH. Results: Thirty-one (37.3%) patients received So, and 52 (62.7%) were treated with Su. In univariate analyses, a poor ECOG status was associated with an unfavorable progression-free survival (PFS) (p<0.0001); similarly high risk MSKCC criteria correlated with a worse PFS (p=0.003). Furthermore, response to therapy was a surrogate parameter (p<0.0001). Twenty-one of 66 (31.8%) patients developed hypothyroidism during treatment, which was associated with a positive prognosis (p=0.032). In multivariate analyses, only the ECOG status (ECOG 0/1 vs. ECOG 2, p=0.018) and hypothyroidism (p=0.01) were independent prognostic parameters. Conclusions: The development of hypothyroidism during treatment might be useful as a clinical predictor of PFS for mRCC patients undergoing treatment with targeted agents. No significant financial relationships to disclose.

The combination of intravenous bevacizumab and metronomic oral cyclophosphamide for recurrent platinum-resistant ovarian cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5039-5039
Author(s):  
Emma L. Barber ◽  
Nikki Lynn Neubauer ◽  
Emese Zsiros ◽  
Julian C. Schink
Keyword(s):  
Overall Survival ◽  
Ovarian Carcinoma ◽  
Single Agent ◽  
Progression Free Survival ◽  
Complete Response ◽  
Response To Treatment ◽  
Ca 125 ◽  
Oral Cyclophosphamide ◽  
Free Survival ◽  
Platinum Resistant

5039 Background: This study was undertaken to determine the progression free survival and overall survival in heavily pre-treated patients with recurrent ovarian carcinoma treated with bevacizumab and metronomic oral cyclophosphamide. Methods: An IRB-approved retrospective review was performed for all patients with recurrent ovarian, fallopian tube or primary peritoneal carcinomas treated with intravenous bevacizumab 10mg/kg every 14 days and oral cyclophosphamide 50mg daily between January 2006 and December 2010. Response to treatment was determined by change in disease status according to RECIST criteria and/or CA-125 levels. Results: Sixty-six eligible patients were identified with a median age of 58 years. Fifty-five patients (83%) originally had optimal cytoreduction and all were platinum resistant. Median time from diagnosis to beginning bevacizumab and cyclophosphamide was 36 months. Median number of prior chemotherapy treatments was 7.5 (range 3-16). Eight patients (12.1%) had side effects which required discontinuing bevacizumab and cyclophosphamide, most common were hypertension, proteinuria, and fatigue. There was one bowel perforation (1.5%). A complete response was noted in 7 patients (10.6%), partial response was seen in 21 patients (31.8%) with an overall response rate of 42.4%. Fifteen patients (22.7%) had stable disease and 23 (34.8%) had disease progression. Median progression free survival (PFS) for responders was 5 months (range 2-14) and 11 months (range 4-14) for those with a complete response. Median overall survival (OS) from start of bevacizumab and cyclophosphamide for responders was 20 months (range 2-56) and 9 months (range 1-51) for nonresponders. Conclusions: Bevacizumab and cyclophosphamide is an effective, well-tolerated chemotherapy regimen in heavily pre-treated patients with recurrent ovarian carcinoma which significantly improves PFS and OS in responders. Response rates were significantly better than the rates we have reported in this same group of patients receiving topotecan (22%) or liposomal doxorubicin (25%) and were superior to reported rates for single agent bevacizumab (18%) in patients with only 2-3 prior regimens.

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