scholarly journals HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alison E. Smith ◽  
Emanuela Ferraro ◽  
Anton Safonov ◽  
Cristina Bernado Morales ◽  
Enrique J. Arenas Lahuerta ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Therapy Resistance ◽  
Breast Cancers ◽  
Free Survival ◽  
Activating Mutations ◽  
Metastatic Setting ◽  
Driver Pathway ◽  
Somatic Alterations ◽  
Erk Inhibition

AbstractInhibition of HER2 in HER2-amplified breast cancer has been remarkably successful clinically, as demonstrated by the efficacy of HER-kinase inhibitors and HER2-antibody treatments. Whilst resistance to HER2 inhibition is common in the metastatic setting, the specific programs downstream of HER2 driving resistance are not established. Through genomic profiling of 733 HER2-amplified breast cancers, we identify enrichment of somatic alterations that promote MEK/ERK signaling in metastatic tumors with shortened progression-free survival on anti-HER2 therapy. These mutations, including NF1 loss and ERBB2 activating mutations, are sufficient to mediate resistance to FDA-approved HER2 kinase inhibitors including tucatinib and neratinib. Moreover, resistant tumors lose AKT dependence while undergoing a dramatic sensitization to MEK/ERK inhibition. Mechanistically, this driver pathway switch is a result of MEK-dependent activation of CDK2 kinase. These results establish genetic activation of MAPK as a recurrent mechanism of anti-HER2 therapy resistance that may be effectively combated with MEK/ERK inhibitors.

Outcomes in Latin American NSCLC patients harboring wild-type or activating mutations of EGFR (CLICaP Registry).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18114-e18114
Author(s):  
Andres Felipe Cardona Zorrilla ◽  
Oscar Arrieta ◽  
Guillermo Federico Bramuglia ◽  
Alma Delia Campos-Parra ◽  
Henry Alberto Becerra Ramirez ◽  
...  
Keyword(s):  
Latin American ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Progression Free Survival ◽  
Wild Type ◽  
Free Survival ◽  
Treatment Groups ◽  
Activating Mutations ◽  
Activating Egfr Mutation ◽  
Nsclc Patients

e18114 Background: Previous exploratory analysis of EGFR status in tumor samples from five LATAM countries suggested that frequency of mutations lies between that of Asian and Caucasian populations and therefore support the genetic heterogeneity of NSCLC around the world. Methods: We analyzed the EGFR sequence of tumor samples from advanced stage NSCLC patients previously participated in the CLICaP registry. We compared the outcomes (overall and progression free survival) of 175 patients (from Argentina, Colombia and México) with an activating EGFR mutation with 414 subjects without this condition. Results: Mutations were more frequent in women (57,1%), in patients who had never smoked (67,4%), and in those with adenocarcinomas (89,4%) (P<0,002 for all comparisons). The mutations were deletions in exon 19 (58,3%) and L858R (36%). Median progression-free survival and overall survival for 175 patients who received tyrosine-kinase inhibitors (TKIs) were 13-mo (95%CI 11,2-14,8) months and 36-mo (95%CI 25,4-46,5), respectively. TKIs produced higher response rates (used as first or second line therapy) in the EGFR mutation-positive patients (70,8% vs. 29,2%; P<0,001), as well as improved PFS (13,0 vs. 3,0; P<0,001). OS is significantly different between treatment groups (36 vs. 14; P<0,001). Conclusions: The analysis of a large comparative registry of Latin-American EGFR mutated and wild type patients confirms the results of individual clinical trials previously published.

scholarly journals Phase II Trial of Cetuximab With or Without Paclitaxel in Patients With Advanced Urothelial Tract Carcinoma

2012 ◽  
Vol 30 (28) ◽  
pp. 3545-3551 ◽  
Author(s):  
Yu-Ning Wong ◽  
Samuel Litwin ◽  
David Vaughn ◽  
Seth Cohen ◽  
Elizabeth R. Plimack ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Single Agent ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
Free Survival ◽  
Metastatic Urothelial Cancer ◽  
Metastatic Setting ◽  
Previously Treated ◽  
Grade 3

Purpose The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. Patients and Methods Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m2 with or without paclitaxel 80 mg/m2 per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. Results We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). Conclusion Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.

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.

Comparative Analysis of Durable Responses on Immune Checkpoint Inhibitors Versus Other Systemic Therapies: A Pooled Analysis of Phase III Trials

2019 ◽  
pp. 1-10 ◽  
Author(s):  
Elvire Pons-Tostivint ◽  
Aurélien Latouche ◽  
Pauline Vaflard ◽  
Francesco Ricci ◽  
Delphine Loirat ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Durable Response ◽  
Free Survival ◽  
Drug Classes ◽  
Metastatic Setting ◽  
The Mean

PURPOSE Immune checkpoint inhibitors (ICIs) have been demonstrated to improve overall survival (OS) in several tumor types. Durable responses have been reported with these agents in patients with melanoma and lung cancer. We aimed to quantify the proportion of patients who experience durable responses on ICIs and to compare it with other drug classes. PATIENTS AND METHODS We retrieved published phase III randomized trials that included at least one ICI arm in the recurrent and/or metastatic setting. A durable response to treatment was defined as a progression-free survival that exceeded three times the median progression-free survival of the whole population. The proportion of patients who experienced an OS that exceeded two times the median OS of the whole patient population also was estimated. RESULTS Nineteen studies involving 11,640 patients treated in 42 treatment arms (26 ICI and 16 non-ICI arms) were included. The mean proportion of patients who experienced a durable response was 2.3 times higher in those treated with an ICI compared with those treated in the control arms (25% v 11%). Durable responses were more frequent in patients treated with anti–PD-1/PD-L1 agents than in patients treated with anti–CTLA-4 agents (28% v 18%). The mean proportion of patients who had an OS that exceeded two times the median OS was also higher in those treated with ICIs than in those treated in the control arms (30% v 23%). In multivariable analysis, the effects of treatment with anti–PD-1/PD-L1 agents and of first-line treatment were statistically associated with a higher mean proportion of durable responses. CONCLUSION Durable responses were more frequent in patients treated with ICIs, although they also occurred in patients treated with other drug classes.

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.

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.

Sequential TKI treatments for iodine-refractory differentiated thyroid carcinomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6092-6092
Author(s):  
Christelle de la Fouchardiere ◽  
Marie-Helene Massicotte ◽  
Isabelle Borget ◽  
Maryse Brassard ◽  
Mederic Claude-Desroches ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Specific Treatment ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Off Label ◽  
Line Therapy ◽  
Number Of Patients ◽  
Third Line Therapy ◽  
Third Line

6092 Background: Tyrosine kinase inhibitors (TKI) are currently used to treat patients with advanced iodine-refractory differentiated thyroid cancers (DTC) but none has been approved by the FDA or the EMA until now. Sometimes, patients are treated with off-label TKI when a clinical trial is not available or in second- and third-line therapy. Methods: We hereby report the efficacy of “off-label” sorafenib and sunitinib treatments as first-, second- and third-line therapy in metastatic DTC patients from the French TUTHYREF (TUmeurs THYroïdiennes REFractaires) network. Primary endpoints were progression free survival (PFS) and tumor response according to sequential TKI treatment. Secondary endpoint was organ-specific metastatic site analysis. Results: 45 patients with advanced iodine-refractory DTC treated with off-label TKI were included in this study (26 men, mean age: 62 years). 22 had papillary, 10 had follicular and 13 had poorly DTC. 24/45 patients were treated with two and 3/45 with three lines of TKIs. Sorafenib was the most frequently used (57%) followed by sunitinib (21.5%) and vandetanib (21.5%). Partial response (PR) rate was of 29% in the 21 patients who received first-line sorafenib therapy whereas PR was observed in 57% of the 7 first-line sunitinib patients. There was no PR with second- (n=24) and third-line (n=3) treatments. However, median progression free survival (PFS) was similar in second- as compared to first-line sorafenib or sunitinib treatment (6.7 vs. 7.6 months, HR 0.85 (95CI 0.45-1.61) p=0.6). Liver metastases were the most responsive to treatment (n=7; mean of -30%), followed by lung (n=57; mean of -19%) and lymph node (n=43; mean of -13%) metastases. Bone (n=14) and pleural (n=9) lesions were the most refractory to treatment (mean of -1% and -5%, respectively). Conclusions: Due to the small number of patients, we could not recommend a specific treatment sequence (sorafenib then sunitinib) over another (sunitinib then sorafenib). But TKI therapy appears to be beneficial in refractory DTC patients even in second- and third-line therapy, with similar PFS and stable disease as best response. Bone and pleural metastases were the most refractory and liver lesions the most responsive to treatment.

Comparison of allogeneic stem cell transplantations in chronic myeloid leukemia before and after the era of tyrosine kinase inhibitors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7038-7038
Author(s):  
Muhit Ozcan ◽  
Bengi Ozturk ◽  
Mehmet Ozen ◽  
Pervin Topcuoglu ◽  
Mutlu Arat ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Donor Lymphocyte Infusion ◽  
First Year ◽  
Free Survival ◽  
New Era ◽  
Blastic Phase ◽  
Before And After

7038 Background: In this retrospective study we aimed to evaluate the rates and the clinical outcomes of allo-HSCT in CML following the advent of TKIs. Methods: We compared the transplantations (Txs) performed prior to 2002 (old era), the first year of TKIs, with the Txs during and after 2002 (new era). Results: Between 1989 and 2012 inour Tx unit a total of 189 allo-HSCTs were performed in 185 CML patients (second Tx for 4 patients). The ratio of Tx for CML among the whole Tx group decreased from 40 % to 12 % after 2002. The ratio also dropped to less than 5 % after 2008 and increased again to 15% in 2012. Time from diagnosis to Tx was longer in the old era than in the new era (9.2 months vs 15.4 months, p<.0001). The ratio of patients with advanced disease (accelerated or blastic phase) was higher in the new era. Although the progression free survival (PFS) was shorter in the new era than in the old era (median 13.8 months vs 37.1 months, p=0.09), overall survival, Tx outcomes and survival curves did not change. Conclusions: AlloHSCT rates sharply decreased after the TKIs, but a slight increase in recent years have been observed compatible with the TKI’s failure in years. Despite the fact that patients who underwent allo HSCT in the new era had more challenging disease biologically, overall survival was not affected possibly due to post-Tx interventions such as use of TKI alone or with donor lymphocyte infusion. [Table: see text]

Treatment of nonresectable and metastatic gastrointestinal stromal tumors: Experience with the use of tyrosine kinase inhibitors in a third-level hospital in Mexico city.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 224-224
Author(s):  
Abdel Karim Dip Borunda ◽  
Alejandro J. Silva
Keyword(s):  
Overall Survival ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Gastrointestinal Stromal Tumors ◽  
Poor Prognosis ◽  
Kinase Inhibitors ◽  
Systemic Treatment ◽  
Progression Free Survival ◽  
Free Survival ◽  
Stromal Tumors

224 Background: Stromal tumors of the digestive tract are uncommon malignant diseases, and are subclassified as leiomyosarcomas and gastrointestinal stromal tumors (GIST) depending on the molecular expression of CD117 (KIT). GISTs represent 1% of malignant tumors affecting this anatomical site. Located diseases are reasonably well controlled by surgical resection and several criteria define the need for adjuvant therapy. In the case of metastatic disease a poor prognosis has been reported with systemic treatment based on chemotherapy. Recently, significant advances have been shown since Tyrosine – kinase inhibitors were introduced, with median overall survival close to 5 years. Unfortunately in Mexico, even though the therapy has been long used there are no published data of the experience in the treatment of these tumors. Methods: We used an electronic data base to obtain clinical, radiological and histological data of patients diagnosed with GIST and treated in the oncological center of the Mexican Institute of Social Security, patients were subclassified by stage, symptoms at diagnosis as well as the initial and subsequent systemic treatment. Finally we made an analysis for progression free survival and overall survival identifying prognostic factors. Results: We obtained information of 71 patients with metastatic, nonresectable or recurrent GIST, treated with a TKI, we observed a predominant relation for women (60.4%), with median age of 58 years. Stage at diagnosis was predominantly metastatic (46.5%) most frequently affected sites were lung, liver and retroperitoneum. Median progression free survival was 23.6m and overall survival was 81.3 months. All patients were initially treated with imatinib at a dose of 400mg per day. Treatment was well tolerated in most cases. Conclusions: Metastatic GIST evaluated in our center shows a different affection in gender and age, our population shows a different response to TKI’s, than reported in other series with superior overall survival, Poor prognosis is associated with lung affection. Biological studies will be started for the molecular evaluation of these tumors.

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