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Статті в журналах з теми "EGFR / ErbB-1 / HER1":
1
Elster, Naomi, Sinead Toomey, Yue Fan, Mattia Cremona, Clare Morgan, Karolina Weiner Gorzel, Una Bhreathnach, et al. "Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer." Therapeutic Advances in Medical Oncology 10 (January 1, 2018): 175883591877829. http://dx.doi.org/10.1177/1758835918778297.
Анотація:
Background: Somatic mutations in the ERBB genes (epidermal growth factor receptor: EGFR, ERBB2, ERBB3, ERBB4) promote oncogenesis and lapatinib resistance in metastatic HER2+ (human epidermal growth factor-like receptor 2) breast cancer in vitro. Our study aimed to determine the frequency of mutations in four genes: EGFR, ERBB2, ERBB3 and ERBB4 and to investigate whether these mutations affect cellular behaviour and therapy response in vitro and outcomes after adjuvant trastuzumab-based therapy in clinical samples. Methods: We performed Agena MassArray analysis of 227 HER2+ breast cancer samples to identify the type and frequency of ERBB family mutations. Of these, two mutations, the somatic mutations ERBB4-V721I and ERBB4-S303F, were stably transfected into HCC1954 (PIK3CA mutant), HCC1569 (PIK3CA wildtype) and BT474 (PIK3CA mutant, ER positive) HER2+ breast cancer cell lines for functional in vitro experiments. Results: A total of 12 somatic, likely deleterious mutations in the kinase and furin-like domains of the ERBB genes (3 EGFR, 1 ERBB2, 3 ERBB3, 5 ERBB4) were identified in 7% of HER2+ breast cancers, with ERBB4 the most frequently mutated gene. The ERBB4-V721I kinase domain mutation significantly increased 3D-colony formation in 3/3 cell lines, whereas ERBB4-S303F did not increase growth rate or 3D colony formation in vitro. ERBB4-V721I sensitized HCC1569 cells (PIK3CA wildtype) to the pan class I PI3K inhibitor copanlisib but increased resistance to the pan-HER family inhibitor afatinib. The combinations of copanlisib with trastuzumab, lapatinib, or afatinib remained synergistic regardless of ERBB4-V721I or ERBB4-S303F mutation status. Conclusions: ERBB gene family mutations, which are present in 7% of our HER2+ breast cancer cohort, may have the potential to alter cellular behaviour and the efficacy of HER- and PI3K-inhibition.
2
Erben, Philipp, Felix Wezel, Ralph Wirtz, Thomas Martini, Doron Stein, Cleo-Aaron Weis, Arndt Hartmann, and Christian Bolenz. "Bedeutung der ERBB-Rezeptorfamilie beim Urothelkarzinom der Harnblase: mRNA-Expression und prognostische Relevanz." Aktuelle Urologie 48, no. 04 (July 27, 2017): 356–62. http://dx.doi.org/10.1055/s-0043-110403.
Анотація:
Zusammenfassung Hintergrund Es sind widersprüchliche Ergebnisse zur (Über)-Expression der Epidermalen Wachstumsfaktoren (ERBB1 – 4) Rezeptoren beim Urothelkarzinom der Harnblase (UCB) beschrieben. EGFR (ERBB1) und HER2 (ERBB2) stellen interessante und bereits bei anderen Entitäten etablierte therapeutische Zielstrukturen dar. Wir untersuchten die Expression von ERBB 1 – 4 auf mRNA-Ebene. Material und Methoden 94 Patienten (w = 22; m = 72; medianes Alter: 66,5 (39 – 88) wurden retrospektiv analysiert. In Zystektomiepräparaten wurde die Expression der ERBB-Familie (ERBB1 – 4) auf RNA-Ebene nach Extraktion aus Formalin-fixiertem und Paraffin-eingebettetem Gewebe bestimmt. Die Genexpression wurde mittels Partitionstest, univariable und multivariable Regressionsanalysen in Assoziation mit histopathologischen Parametern, dem rezidivfreien (RFS) und krebsspezifischen Überleben (CSS) untersucht. Das mediane Follow up betrug 28,2 Monate (0,6 – 139). Ergebnisse Unter Verwendung des für das CSS etablierten Cut off Levels wurde eine Überexpression bei 18 % (ERBB3), 39 % (EGFR), 34 % (HER2, ERBB2), und 30 % (ERBB4) der Patienten beobachtet. In der univariablen Analyse zeigten eine hohe HER2 – (ERBB2-) Expression (p = 0,014), ein höheres pT-Stadium (p = 0,012), ein positiver pN-Status (p = 0,0002) und eine hohe ERBB4-Expression (p = 0,012) eine signifikante Assoziation mit dem RFS. Eine niedrige HER2 – (ERBB2-) Expression (p = 0,042) und ein pN0-Status (p = 0,0003) waren signifikant mit einem längeren CSS assoziiert. Ein positiver pN-Status (p = 0,0011) und eine hohe ERBB4-Expression (p = 0,0073) waren unabhängige Prognosefaktoren für ein reduziertes RFS. Ein positiver pN-Status (p = 0,0016) war ein unabhängiger Prognosefaktor für ein reduziertes CSS. Schlussfolgerungen Eine hohe HER2-Expression ist mit einem reduzierten krankheitsspezifischen Überleben bei Patienten mit UCB nach radikaler Zystektomie assoziiert, zeigte jedoch keinen unabhängigen Prognosewert. Weitere Studien müssen klären, welche Patienten von einer zielgerichteten Therapie gegen HER2 (ERBB2) profitieren könnten.
3
Hullmann, Grace, and Michael A. Azfer. "Immunogenic properties of outer membrane protein of Acinetobacter baumannii that loaded on chitosan nanoparticles." American Journal of BioMedicine 5, no. 1 (February 11, 2017): 32–44. http://dx.doi.org/10.18081/2333-5106/017-32-44.
Анотація:
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands. The identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR. The most common adverse effect of EGFR inhibitors, found in more than 90% of patients, is a papulopustular rash and in 10% to 15% of patients the effects can be serious and require treatment. While the risk of neutropenic fever toxicity has only recently been recognized. A total of 279 patients were enrolled in the present study. Progression-free survival (PFS) and overall survival (OS) of patients with a lowh grade of neutropnic fever were significantly longer than those with a high grade of neutropnic fever (median PFS: 3.6 months vs 8.4 months, P<0.001; median OS: 7.6 months vs 17.1 months, P=0.006, respectively).
4
Shen, Wang, Jeffrey Bacha, Dennis Brown, Sarath Kanekal, Neil Sankar, ZhenZhong Wang, Harry Pedersen, et al. "THER-01. PRECLINICAL DEVELOPMENT OF EO1001, A NOVEL IRREVERSIBLE BRAIN PENETRATING PAN-ErbB INHIBITOR." Neuro-Oncology Advances 1, Supplement_1 (August 2019): i10—i11. http://dx.doi.org/10.1093/noajnl/vdz014.044.
Анотація:
Abstract Dysregulation of ErbB-mediated signaling is observed in up to 90% of solid tumors. ErbB family cross-talk is implicated in the development of resistance and metastasis, including CNS metastases. Inhibition of multiple ErbB receptors may result in improved patient outcomes. EO1001 is a novel, patented, oral, brain-penetrating, irreversible pan-ErbB inhibitor targeting EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4). METHODS: (1) In vitro testing. EO1001 demonstrates high specificity for the ErbB family of receptors with excellent, balanced equipotent activity against EGFR, HER2 and HER4 (0.4 to 7.4 nM). EO1001 inhibits signaling downstream of wild type EGFR, mutant EGFR (T790M, L858R and d746-750) and HER2. (2) PK and toxicity. In rodent studies in vivo, EO1001 exhibited a half-life of 16–20 hours. EO1001 rapidly enters the CNS and penetrates tumor tissue at higher concentrations relative to plasma. Safety of EO1001 was evaluated by repeat-dosing studies in SD rats and beagle dogs. Toxicities typical of the ErbB inhibitor class, including gastro-intestinal effects, weight loss and decreased activity were observed at higher dose groups in both species. Mortality was observed in SD rats at higher dose groups. (3) In vivo efficacy studies. EO1001 was studied following oral administration in several erbB-positive mouse xenograft models including N87 (Her2+), H1975 (EGFR/T790M), GBM12 (EGFR+), GBM39 (EGVRvIII+). Following oral administration, treatment with EO1001 resulted in a statistically significant improvement in outcomes compared to positive and negative controls in both CNS and systemic tumor models. EO1001 was well-tolerated with no gastrointestinal side effects observed at efficacious doses in these models. CONCLUSION: Based on research to date, EO1001 has the potential to be a best-in-class CNS-penetrating pan-ErbB inhibitor with a safety and pharmacokinetic profile amenable for use as a single agent and in combination with other agents. EO1001 is poised to enter phase 1-2a clinical testing in the second-half of 2019.
5
Ma, Fei, Qiao Li, Xiuwen Guan, Shanshan Chen, Zongbi Yi, Bo Lan, Puyuan Xing, et al. "Safety, efficacy, and biomarker analysis of pyrotinib in combination with capecitabine in HER2-positive metastatic breast cancer patients: A phase I clinical trial." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 1035. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1035.
Анотація:
1035 Background: Cross-signaling in the ErbB family is an important mechanism in Trastuzumab resistance. Pyrotinib is an irreversible pan-ErbB inhibitor targeting EGFR/HER1, HER2 and HER4, which may offer the potential for improved efficacy to block HER2 signaling in trastuzumab-resistant breast cancer. This phase I study assessed the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics, antitumor activity and predictive biomarkers of pyrotinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer (MBC). Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1000mg/m2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected predose on day 1 and day 14 of treatment. Next-generation sequencing (NGS) was performed on circulating tumor DNA (ctDNA) to probe for predictive biomarkers of this combination. Results: A total of 28 patients were enrolled. All 28 (100%) patients experienced at least one treatment-related Adverse Events (AE), which were predominantly grade 1 or 2. Grade 3 treatment-related AE occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. Three (10.7%) patients discontinued capecitabine administration due to AEs. The overall response rate (ORR) was 78.6% (95% CI: 59.0% to 91.7%), and the disease control rate (complete response+ partial response+ stable disease) was 96.4% (95% CI: 81.7% to 99.9%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0 to 26.2 months). ORR was 70.6% (12/17) in trastuzumab-pretreated patients and 90.9% (10/11) in trastuzumab-naive patients. NGS analysis of all genetic alterations of HER2 bypass signaling pathway, PI3K/Akt/mTOR pathway and TP53 in baseline blood samples suggested that concomitant (two or more) genetic alterations were significantly associated with poorer PFS compared to none or one genetic alteration (median, 15.8 vs. 26.2 months, p = 0.006). Conclusions: Pyrotinib in combination with capecitabine are well-tolerated and demonstrate promising antitumor activity in HER2-positive MBC patients. Clinical trial information: NCT02361112.
6
Choudhury, Noura, Alexa Campanile, Tatjana Antic, James Lloyd Wade, Walter Michael Stadler, Yusuke Nakamura, and Peter H. O'Donnell. "Afatinib activity in platinum-refractory metastatic urothelial carcinoma (UC) patients with ErbB alterations: Results of a phase II trial." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 459. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.459.
Анотація:
459 Background: Metastatic UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable therapeutic targets. We studied whether afatinib, an oral, irreversible Erb family blocker, has activity in UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance.The primary endpoint was 3-mo progression-free survival (PFS3) using a Simon two-stage design, with the trial proceeding to stage II if ≥ 30% pts in stage I had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman) of available archival tumor tissue. Results: The initial enrollment goal of 23 ptswas met: 18 M/5 F, median age 67 (36-82), ECOG 0 in 26%/1 in 74%, Hb < 10 g/dl in 17%, liver metastases in 30%, median time from prior chemotherapy = 3.6 mo. No unexpected toxicities were observed; 2 pts required dose-reduction (grade 3 fatigue, grade 3 rash). 5/23 pts (21.7%) had PFS3 (1 partial response (PR), 4 stable disease). Notably, 5/7 pts (71.4%) with ErbB molecular alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 4.6 (ongoing) and 3.9 (ongoing) mo respectively) while 0/16 without alterations reached PFS3 (p < 0.001, Fisher’s exact). The 2 pts with alterations (both HER2 amplified) who did not reach PFS3 had liver metastases. All 3 pts with ErbB3 somatic mutations were responders. One pt with both HER2 amplification and R103G ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. Average time to progression/discontinuation was 4.9 mo in pts with molecular alterations vs 1.7 mo for pts without alterations (p = 0.03). Conclusions: Afatinib demonstrates significant activity in platinum-refractory UC pts with HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. A follow-on phase II study of afatinib in marker-selected refractory UC pts is underway. Clinical trial information: NCT02122172.
7
Choudhury, Noura, Alexa Campanile, James Lloyd Wade, Tatjana Antic, Walter Michael Stadler, Yusuke Nakamura, and Peter H. O'Donnell. "Association of HER2 and ErbB3 molecular alterations with afatinib sensitivity in platinum-refractory metastatic urothelial carcinoma (UC) in a phase II trial." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 312. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.312.
Анотація:
312 Background: Platinum-refractory UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable targets for novel therapies. We aimed to investigate whether afatinib, an oral, irreversible Erb family blocker, has clinical benefit in metastatic UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC who received ≤1 chemotherapy in the metastatic setting received afatinib 40 mg/day continuously until disease progression or intolerable toxicity.Primary endpoint was 3-month progression-free survival (PFS3), with drug deemed promising if ≥42% pts had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman). Results: 15 ptshave enrolled: median age 66 (44-78), 11 M/4 F, ECOG PS 0 in 20%, PS 1 in 80%, Hb<10 g/dl in 20%, liver metastases in 13%, median time from prior chemotherapy=4.4 mo. Rash (73%), diarrhea (33%), and fatigue (13%) were the most common drug-related toxicities; 1 pt required dose-reduction (grade 3 fatigue). 3/14 pts (21%) had PFS3 (1 partial response (PR), 2 stable disease); 1 pt has not reached 3 mo on therapy. All 3 responders had molecular alterations in Erb genes: 1 pt with 4 copies of HER2 achieved PR and responded for 6.9 mo; 1 pt with Gly284Arg ErbB3 mutation responded for 7 mo; and 1 pt with 73 copies of HER2 and Arg103Gly ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. None of the 10 non-responders had alterations in these four genes. Time to progression/discontinuation was 8.1 mo in pts with molecular alterations vs. 1.8 for pts without alterations (p=0.02). Conclusions: Afatinib demonstrates activity in platinum-refractory UC, with all responders bearing HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. These data support ongoing testing of afatinib as a potential therapy for refractory UC in marker-selected pts. Clinical trial information: NCT02122172.
8
Janjigian, Yelena Yuriy, David Ilson, David Paul Kelsen, Mark Schattner, Adriana Heguy, and Efsevia Vakiani. "A phase II study of afatinib (BIBW 2992) in patients with advanced HER2-positive trastuzumab-refractory esophagogastric cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS4144. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps4144.
Анотація:
TPS4144 Background: Trastuzumab, approved by the FDA, has been the standard of care for patients (pts) with HER2-positive esophagogastric cancer. Acquired and de novo resistance to trastuzumab is an important clinical issue. Afatinib, an oral irreversible inhibitor of the ErbB-family of tyrosine kinase receptors, EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), in combination with cetuximab, demonstrated a 40% partial response (PR) rate, with clinical benefit in >90% in lung cancer patients with acquired resistance to erlotinib. (Janjigian Y. ASCO 2011). MSKCC data in a HER2-positive NCI-N87 gastric cancer xenograft showed that while trastuzumab alone was minimally effective, single-agent afatinib resulted in near complete tumor regression by inducing apoptosis and downregulation of HER2, p-HER2, EGFR, p-EGFR with minimal additive benefit of trastuzumab. In light of these data and the efficacy of afatinib in patients with trastuzumab-refractory breast cancer, we designed a phase II study to determine if afatinib will benefit patients with trastuzumab-refractory HER2-positive esophagogastric cancer. We hypothesize that simultaneous inhibition of ErbBB receptor family components with afatinib will overcome trastuzumab resistance. Molecular bases of trastuzumab resistance will be examined. Methods: Pts with metastatic HER2-positive (IHC 3+ or FISH >2.0) esophagogastric cancer with disease progression on a trastuzumab-containing regimen will receive afatinib 40 mg once daily. Primary endpoint RECIST 1.1 response (SD+CR+PR) at 4 months, with imaging every 8 wks. 13 pts will be enrolled in the 1st stage and if ≥1 responses are observed, additional 14 ps (total of 27) will be treated. An initial biopsy prior to the start of therapy, a second biopsy after 1 wk of afatinib, analysis of archival pre-trastuzumab tissue and blood sample for matched normal DNA control are mandated. Changes in signaling following afatinib therapy will provide insight into response heterogeneity. Degree of target inhibition will be correlated with responses. Archival baseline (pre-trastuzumab) and pre-afatinib tissue will be assessed for abnormalities in pathways implicated in trastuzumab resistance.
9
Schuler, Martin H., David Planchard, James Chih-Hsin Yang, Joo-Hang Kim, Filippo De Marinis, Yuh-Min Chen, Caicun Zhou, et al. "Interim analysis of afatinib monotherapy in patients with metastatic NSCLC progressing after chemotherapy and erlotinib/gefitinib (E/G) in a trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy following progression on afatinib monotherapy." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 7557. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.7557.
Анотація:
7557 Background: The benefit of sustained ErbB family blockade in NSCLC patients with acquired resistance (AR) to EGFR TKIs is unknown. We investigated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC, who had failed chemotherapy and E/G. Methods: This was a Phase III, randomized, open-label, multi-center trial. Patients with pathologically confirmed Stage IIIB/IV metastatic NSCLC after ≥1 line of chemotherapy who failed E/G received oral afatinib 50 mg until disease progression (Part A). After progression, patients with clinical benefit (≥12 wks) were eligible to continue afatinib 40 mg plus paclitaxel or receive investigator’s choice chemotherapy (Part B). Primary endpoint for Part A was PFS (RECIST 1.1; CT scan every 6 wks). Available tumor samples were collected for central EGFR mutation testing; local mutation data were also collected. An interim analysis of Part A, assessing afatinib monotherapy, is reported. Results: Part A enrolled April 2010 through to May 2011; 1154 patients received afatinib monotherapy. The majority had adenocarcinoma (85%), 57% were female, 43% were Asian, 54% were never smokers. Best response to prior E/G was CR (2%), PR (31%), SD (42%) and PD (20%). Median PFS for afatinib was 3.3 mths; 88 patients (8%) achieved an objective tumor response, 648 (56%) had SD. For EGFR mutation positive patients (n=49, centrally confirmed), PFS was 4.2 vs. 2.6 mths for EGFR mutation negative patients (n=35). When applying clinical enrichment criteria for AR, PFS was 4.2 mths for those with enrichment (n=597) vs. 2.8 mths for those without (n= 557; logrank test p<0.0001). The most common grade 3/4 adverse events were diarrhea (17%) and rash/acne (11%). In Part A, 99 patients remain on treatment. Conclusions: Afatinib monotherapy provided a clinically meaningful benefit in this large, treatment-refractory NSCLC trial, similar to LUX-Lung 1. Those clinically enriched for AR to EGFR TKIs achieved prolonged disease control upon continued ErbB blockade.
10
Choudhury, Noura J., Alexa Campanile, Tatjana Antic, Kai Lee Yap, Carrie A. Fitzpatrick, James L. Wade, Theodore Karrison, Walter M. Stadler, Yusuke Nakamura, and Peter H. O’Donnell. "Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma in Patients With ERBB Alterations." Journal of Clinical Oncology 34, no. 18 (June 20, 2016): 2165–71. http://dx.doi.org/10.1200/jco.2015.66.3047.
Анотація:
Purpose Somatic mutations and copy number variation in the ERBB family are frequent in urothelial carcinoma (UC) and may represent viable therapeutic targets. We studied whether afatinib (an oral, irreversible inhibitor of the ErbB family) has activity in UC and if specific ERBB molecular alterations are associated with clinical response. Patients and Methods In this phase II trial, patients with metastatic platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance. The primary end point was 3-month progression-free survival (PFS3). Prespecified tumor analysis for alterations in EGFR, HER2, ERBB3, and ERBB4 was conducted. Results The first-stage enrollment goal of 23 patients was met. Patient demographic data included: 78% male, median age 67 years (range, 36 to 82 years), hemoglobin < 10 g/dL in 17%, liver metastases in 30%, median time from prior chemotherapy of 3.6 months, and Eastern Cooperative Oncology Group performance status ≤ 1 in 100%. No unexpected toxicities were observed; two patients required dose reduction for grade 3 fatigue and rash. Overall, five of 23 patients (21.7%) met PFS3 (two partial response, three stable disease). Notably, among the 21 tumors analyzed, five of six patients (83.3%) with HER2 and/or ERBB3 alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 6.3, and 5.0 months, respectively) versus none of 15 patients without alterations ( P < .001). Three of four patients with HER2 amplification and three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) met PFS3. One patient with both HER2 amplification and ERBB3 mutation never progressed on therapy, but treatment was discontinued after 10.3 months as a result of depressed ejection fraction. The median time to progression/discontinuation was 6.6 months in patients with HER2/ERBB3 alterations versus 1.4 months in patients without alterations ( P < .001). Conclusion Afatinib demonstrated significant activity in patients with platinum-refractory UC with HER2 or ERBB3 alterations. The potential contribution of ERBB3 to afatinib sensitivity is novel. Afatinib deserves further investigation in molecularly selected UC.
Дисертації з теми "EGFR / ErbB-1 / HER1":
1
Blancafort, Jorquera Adriana. "Fatty acid synthase expression and inhibition in cancer." Doctoral thesis, Universitat de Girona, 2016. http://hdl.handle.net/10803/671774.
Анотація:
In this thesis,the association of FASN (fatty acid synthase) expression with clinicopathological and anthropometric characteristics in breast cancer patients is studied to find out FASN role as a prognostic in early stage breast cancer.
We also study the expression of FASN and its implication (alone or in combination with EGFR/HER/ErbB pathway inhibition) in cellular and animal models (xenografts and patient derived xenografts) or HER1+/FASN+ lung cancer and HER2+/FASN+ breast cancer.
Finally, we have developed pre-clinical models of HER2+ breast cancer resistant to anti-HER2 therapies(trastuzumab and lapatinib), to study expression of FASN and other proteins involved in resistance, and, in vivo, the anti-tumoral efficacy of FASN inhibitors, alone or in combination.
As a general conclusion, FASN is described as a new possible anti-tumoral target (alone or in combination) for future pre-clinical and clinical studies in FASN-positive tumor modelsEn aquesta tesi s’estudia la relació entre l’expressió de FASN (sintasa d'àcids grassos) i les característiques clinicopatològiques i antropomètriques en pacients amb càncer de mama, per esbrinar el paper de FASN com a pronòstic de càncer de mama d’estadis primerencs. També s'estudia l’expressió de FASN i la seva inhibició (sola o en combinació amb la inhibició de la ruta EGFR/HER/ErbB) en models cel·lulars i animals (xenografts i ortoxenopatients) de càncer de pulmó HER1+/FASN+, i en càncer de mama HER2+/FASN+. Finalment, s’han desenvolupat models pre-clínics de càncer de mama HER2+ resistents a teràpies anti-HER2 (trastuzumab i lapatinib) per estudiar l’expressió de FASN i altres proteïnes involucrades en la resistència i també, l’eficàcia anti-tumoral in vivo dels inhibidors de FASN, sols o en combinació. Com a conclusió, es descriu FASN com a possible nova diana anti-tumoral (sola o en combinació) per futurs estudis pre-clínics i clínics en models tumorals FASN+
Doctorat en Ciències Experimentals i Sostenibilitat
2
Bernardes, Vanessa de Fatima. "Receptores C-ERBB-1 (EGFR) e C-ERBB-2 (HER-2) em carcinoma de células escamosas de Boca." Universidade Federal de Minas Gerais, 2010. http://hdl.handle.net/1843/BUOS-8GXLJS.
Анотація:
O carcinoma de células escamosas de boca (CCEB) é a neoplasia maligna mais frequente da região bucomaxilofacial. Receptores c-erbB e seus ligantes estão envolvidos na patogênese e progressão do CCEB, entretanto, estudos detalhados que avaliem a expressão destas proteínas em relação ao comportamento tumoral não foram ainda adequadamente explorados. O objetivo deste estudo foi avaliar o papel dos receptores EGFR e Her-2 no CCEB e sua associação com MMP-2/-9, VEGF-A/-C e EGF. Foram mensurados níveis salivares de EGFR, Her-2 e EGF em indivíduos com CCEB, antes e após o tratamento cirúrgico, comparando-se a indivíduos clinicamente saudáveis. Os dados foram analisados nos softwares SPSS 17.0 e GraphPad Prism 5, adotando-se nível de significância p < 0,05. A amostra total compreendeu 72 casos de CCEB em que foi investigada a expressão imunoistoquímica de EGFR, Her-2, VEGF-A/-C, MMP-2/-9 e EGF, sendo realizadas a técnica de CISH para amplificação gênica de EGFR em 50 casos e dosagem por ELISA dos níveis salivares de EGFR, Her-2 e EGF em 46 casos e 46 controles. Observou-se positividade para EGFR e Her-2 em 43 (59,7%) e 1 (1,4%) casos de CCEB respectivamente. Observou-se associação entre a imunoexpressão para VEGF-C e para EGF (p < 0,05). Não houve associação entre a imunoexpressão das proteínas estudadas e dados clinicopatológicos como idade, sexo, hábitos tabagista e etilista do indivíduo, tamanho, envolvimento linfonodal e localização da neoplasia. Observou-se amplificação em 3 (6%) casos de CCEB, estando a maioria (94%) das lesões não amplificada para EGFR. EGFR e Her-2 apresentaram níveis salivares elevados após a remoção cirúrgica quando comparados ao CCEB e controle, enquanto níveis salivares de EGF foram baixos no CCEB em relação ao controle (p < 0,05). Ainda que positivo em 59,7% dos casos avaliados, EGFR não apresentou associação com VEGF, MMPs, níveis salivares ou amplificação gênica. Her-2 não apresentou expressão significativa em CCEB. Por outro lado, baixos níveis de EGF na saliva parecem relacionar-se à presença do carcinoma de células escamosas de boca.
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Cirne, Lima Fernando Krebs. "Expressão imunohistoquímica de Her-2/Neu-CerbB-2 e EGFR na mucosa gástrica de pacientes portadores de adenocarcinoma de estômago." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2006. http://hdl.handle.net/10183/7802.
Анотація:
O câncer gástrico é ainda hoje um dos tumores sólidos mais comuns , sendo a segunda causa mais freqüente de morte por doença maligna no mundo. Apesar do aprimoramento da técnica cirúrgica e da utilização de tratamentos multimodais, o câncer gástrico, em geral, ainda permanece com um mau prognóstico. Na maioria dos países a doença é freqüentemente diagnosticada após ter invadido a camada muscular própria do órgão, estágio no qual a sobrevida média em cinco anos é inferior a 20%. Como a maioria dos tumores humanos, o câncer gástrico é uma doença multifatorial, que se desenvolve em indivíduos geneticamente suscetíveis expostos a agentes carcinogênicos externos. Ultimamente, diversos oncogenes e genes supressores tumorais vêm sendo estudados na tentativa de esclarecer detalhadamente a carcinogênese gástrica. Her-2/Neu ou CerbB-2 e EGFR são oncogenes da família Her ou erb de receptores de fatores de crescimento. Ambos têm se mostrado com expressão aumentada em diversas neoplasias e possuem anticorpos monoclonais específicos como potencial forma de tratamento adjuvante. Em relação ao câncer gástrico, as prevalências destes oncogenes são bastante variáveis na literatura. O objetivo deste estudo foi determinar as prevalências de Her-2/Neu e EGFR na mucosa gástrica de pacientes com adenocarcinoma de estômago. Foram estudados 37 casos com avaliação de expressão imunohistoquímica de Her-2/neu e EGFR em amostras teciduais fixadas em formalina e armazenadas em parafina. Dois casos demonstraram expressão aumentada de Her-2/Neu, correspondendo a 5,4%. Nenhum caso demonstrou aumento da expressão de EGFR. Os autores concluem que a ausência da expressão do EGFR na amostra estaria mais relacionada a uma dificuldade encontrada de trabalhar com o anticorpo do que a real ausência de expressão do oncogene no câncer gástrico. Também sugerem que, apesar da baixa prevalência do Her-2/Neu na amostra, e devido à pouca resposta dos tumores gástricos às terapias hoje disponíveis, os anticorpos monoclonais específicos anti-Her deveriam ser futuramente testados nos indivíduos Her positivos, em ensaios clínicos randomizados.