scholarly journals Nationwide evaluation of mutation-tailored anti-EGFR therapy selection in patients with colorectal cancer in daily clinical practice

2021 ◽  
pp. jclinpath-2021-207865
Author(s):  
Elisabeth M P Steeghs ◽  
Geraldine R Vink ◽  
Marloes A G Elferink ◽  
Quirinus J M Voorham ◽  
Hans Gelderblom ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Gene ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Therapy Resistance ◽  
Mutation Testing ◽  
Treatment Line ◽  
Netherlands Cancer Registry ◽  
Stage Iv Disease ◽  
Next Generation Sequencing Ngs

For a nationwide real-word data study on the application of predictive mutation testing of patients with colorectal cancer (CRC) for anti-epidermal growth factor receptor (EGFR) therapy stratification, pathology data were collected from the Dutch Pathology Registry from October 2017 until June 2019 (N=4060) and linked with the Netherlands Cancer Registry. Mutation testing rates increased from 24% at diagnosis of stage IV disease to 60% after 20–23 months of follow-up (p<0.001). Application of anti-EGFR therapy in KRAS/NRAS wild-type patients was mainly observed from the third treatment line onwards (65% vs 17% in first/second treatment line (p<0.001)). The national average KRAS/NRAS/BRAF mutation rate was 63.9%, being similar for next-generation sequencing (NGS)-based approaches and single gene tests (64.4% vs 61.2%, p=ns). NGS-based approaches detected more additional potential biomarkers, for example, ERBB2 amplifications (p<0.05). Therefore, single gene tests are suitable to stratify patients with mCRC for anti-EGFR therapy, but NGS is superior enabling upfront identification of therapy resistance or facilitate enrolment into clinical trials.

scholarly journals A Case Report of Primary Resistance to EGFR TKI in Lung Adenocarcinoma Due to Coexisting MET Exon 14 Skipping Mutation with Excellent Response to Combination of Gefitinib and Capmatinib

2021 ◽  
Author(s):  
Nirmal Vivek Raut ◽  
Siddharth Srivastava ◽  
Guarav Dilip Gangwani ◽  
Heena Sajid Ali
Keyword(s):  
Kinase Inhibitors ◽  
Single Gene ◽  
Growth Factor Receptor ◽  
Nonsmall Cell Lung Cancer ◽  
Primary Resistance ◽  
Gene Testing ◽  
Comprehensive Genomic Profiling ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Next Generation Sequencing Ngs ◽  
Egfr Tki

AbstractTreatment of nonsmall cell lung cancer (NSCLC) carrying an epidermal growth factor receptor (EGFR) mutation depends on EGFR tyrosine kinase inhibitors (TKIs). However, all patients treated with EGFR TKI eventually develop progressive disease. Approximately, 20% of patients do not respond to EGFR TKIs, which is defined as primary resistance. The prognosis of these patients is similar to NSCLC with nondriver mutations. We report a case of a patient with EGFR exon 21 mutation who rapidly progressed in 15 days on Gefitinib. Next-generation sequencing (NGS) showed a MET exon 14 skip mutation coexisting with EGFR exon 21 mutation, causing primary resistance to EGFR TKI. Based on NGS reports, a treatment combining Gefitinib and Capmatinib, a MET inhibitor, induced a rapid response in the patient, which was sustained at the end of 8 months. This clearly emphasizes the need for comprehensive genomic profiling using NGS over single gene testing.

Long-term maintenance capecitabine and celecoxib improved clinical outcomes by targeting colorectal cancer micrometastasis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14513-14513
Author(s):  
M. Zhang ◽  
S. Curley ◽  
C. Ng ◽  
B. Kurland ◽  
S. Krishnan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stage Iv ◽  
Complete Response ◽  
Kaplan Meier ◽  
Stage Iv Disease ◽  
Disease Site ◽  
Colorectal Cancer Patients

14513 Background: Role of mainteance therapy after achieving complete response (CR) remain undefined for patients with metasatic colorectal cancer. We studied prognostic and treatment factors including maintenance capecitabine and celecoxib (XCEL) in all 19 unresectable metastatic colorectal cancer patients (pts) who had CR from the prior XCEL study. Methods: Event charts are used to summarize the timeline of the various treatments. Kaplan-Meier survival estimates and univariate log-rank tests were used to evaluate RFS and OS as time from CR. Prognostic and treatment factors included: tumor size, metastasis number (9 solitary disease), site (13 being extrahepatic), stage on diagnosis (stage II versus III/IV), disease free interval prior to stage IV disease, surgery (5 R0, 3 R1–2 resections), lactate dehydrogenase levels, first-line irinotecan chemotherapy, radiation (9 pts ≥ 45 Gy, 3 Pts < 45 Gy), and maintenance XCEL (duration 0–50.3 months). Results: Nine of 19 patients experienced recurrence (median 13 months after CR), and 4 died during the follow-up period (median 31 months after CR). The 2-year RFS for the unresected and R1–2 resected patients was 71% versus 20% for the R0 resected patients (p = 0.07). This paradoxical RFS pattern corresponded to a RFS advantage for maintenance XCEL (p = 0.002), but not any other prognostic or treatment factors. All relapses occurred in situ following discontinuation of XCEL except for the surgical cases. Patients undergoing maintenance XCEL also benefited in OS (p = 0.04). The median OS from XCEL and from onset of metastasis reached 51.9 months (95% CI, 45 months- not reached [NR]) and 73.3 months (95% CI, NR-NR months) respectively. Conclusions: Maintenance XCEL targets colorectal micrometastases and produces a paradoxical RFS and OS advantage among the high-risk unresected/R1–2 resected patients than R0 resected patients. Prospective studies are warranted to validate roles of maintenance XCEL in the treatment of colorectal micrometastases. No significant financial relationships to disclose.

Role of surgical resection among chemotherapy-treated patients with colorectal cancer stage IV disease: A survival analysis.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 3564-3564 ◽  
Author(s):  
B. S. Lin ◽  
A. Ziogas ◽  
T. E. Seery ◽  
M. J. Stamos ◽  
J. A. Zell
Keyword(s):  
Colorectal Cancer ◽  
Survival Analysis ◽  
Surgical Resection ◽  
Stage Iv ◽  
Cancer Stage ◽  
Stage Iv Disease

Treatment monitoring of metastatic colorectal cancer by quantification and genotyping of mutated KRAS in circulating cell-free DNA.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15037-e15037 ◽  
Author(s):  
Thomas Seufferlein ◽  
Daniel Schwerdel ◽  
Hanna Welz ◽  
Ralf Marienfeld ◽  
Stefan A. Schmidt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mutational Analysis ◽  
Early Stage ◽  
Therapy Monitoring ◽  
Stage Iv ◽  
Therapy Resistance ◽  
Disease Monitoring ◽  
Liquid Biopsies ◽  
Kras Mutations ◽  
Non Invasive

e15037 Background: Treatment of stage IV colorectal cancer (mCRC) has made substantial progress over the last years but therapy monitoring still is in its early stage. A facile, non-invasive, repeatable assessment of the mutational state of a given tumor even during treatment could constitute a desirable biomarker for therapy stratification and disease monitoring. "Liquid biopsies" analyzing circulating free and circulating tumor DNA (cfDNA/ctDNA) from patients’ blood have been proposed as a a simple, non-invasive method that could fulfil this requirement. Methods: 27 patients with histologically confirmed mCRC were enrolled into a treatment surveillance cohort. For the analysis of concordance between tumor tissue DNA and cfDNA we analyzed 40 tissue and blood pairs from therapy naïve patients regarding their KRAS mutation status. The course of cfDNA values combined with targeted genotyping of KRAS mutations were assessed during several palliative chemotherapeutic regimens. cfDNA data were correlated with clinical parameters to establish its prognostic and predictive value. Results: Baseline cfDNA levels allow to significantly differentiate mCRC from healthy controls (14.23 ± 6.33 ng/ml vs. 2.60 ± 1.59 ng/ml; p < 0.0001). cfDNA values at baseline in therapy naïve patients correlate well with tumor burden (p < 0.05) and CEA levels (p < 0.05). cfDNA values significantly increased upon disease progression during 1st (p < 0.01) and 2nd line (p < 0.05) treatment, enabling a non-invasive disease monitoring approach. Moreover, there was a significant correlation between the cfDNA levels upon treatment and progression-free survival (p < 0.05). In addition, our data show that KRAS genotyping of cfDNA under therapy is feasible (80% blood-tissue concordance) and might benefit the patient due to early detection of therapy resistance. Conclusions: Repetitive quantitative and mutational analysis of cfDNA is likely to complement current diagnostic standards in stage IV CRC over the whole continuum of treatment.

scholarly journals Immune Resistance and EGFR Antagonists in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1089 ◽  
Author(s):  
Giordano ◽  
Remo ◽  
Porras ◽  
Pancione
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Therapy Resistance ◽  
Cell Interaction ◽  
Molecular Alterations ◽  
Immune Resistance ◽  
Epidermal Growth ◽  
Mechanistic Basis

: Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy in patients with RAS wild type metastatic colorectal cancer (mCRC) has revolutionized the treatment of CRC, but with less results than initially envisaged. In recent years, the discovery of multiple pathways leading to the escape from anti-EGFR therapy has revealed an enormous complexity and heterogeneity of human CRC due to the intrinsic genomic instability and immune/cancer cell interaction. Therefore, understanding the mechanistic basis of acquired resistance to targeted therapies represents a major challenge to improve the clinical outcomes of patients with CRC. The latest findings strongly suggest that complex molecular alterations coupled with changes of the immune tumor microenvironment may substantially contribute to the clinical efficacy of EGFR antagonist. In this review, we discuss the most recent findings that contribute to both primary and acquired anti-EGFR therapy resistance. In addition, we analyze how strategies aiming to enhance the favorable effects in the tumor microenvironment may contribute to overcome resistance to EGFR therapies.

Incidence of peripheral neuropathy in patients with colorectal cancer receiving oxaliplatin alone vs. radiation therapy and oxaliplatin.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18281-e18281
Author(s):  
Matthew Blake Lockwood ◽  
Krishna Prasad Joshi ◽  
James Mobley ◽  
Suneetha Sampath ◽  
Eric R Siegel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Radiation Therapy ◽  
Peripheral Neuropathy ◽  
Stage Iv ◽  
Sensory Neuropathy ◽  
Chi Square ◽  
Stage Iv Disease ◽  
Nerve Fibrosis ◽  
Colorectal Cancer Patients

e18281 Background: Peripheral sensory neuropathy (PN) is a known dose limiting toxicity of oxaliplatin, used to treat patients with colorectal cancer. Patients with rectal cancer receive radiation therapy (RT) in addition to oxaliplatin in adjuvant setting. Pelvic radiation causes plexopathy due to demyelination, ischemia due to blood-vessel injury, and nerve fibrosis. To assess if RT increases the incidence of peripheral neuropathy, we conducted an analysis of patients with colorectal cancer treated with oxaliplatin alone vs. oxaliplatin and radiation. Methods: A retrospective analysis of subjects with stages II, III, and IV rectal (R) and colon (C) cancer from 2005 to 2014 was conducted. Only subjects receiving O with or without RT were included. The incidence of PN was compared for increase in subjects receiving both O and RT compared to O alone via one-sided chi-square tests at 5% alpha, both overall and after subgrouping by stage. Results: Out of 261 subjects analyzed, 158 met the study’s criteria. There were 97 C (all received only O) and 61 R (10 received only O; 51 received O+RT). PN occurred in 37% (19/51) of subjects receiving O+RT compared to 22% (24/107) receiving only O ( P= 0.025). In Stage II-III disease, PN occurred at nearly equal rates of 36% (14/39) in subjects receiving O+RT and 33% (16/46) in subjects receiving O only ( P= 0.457). However, in Stage IV disease, PN occurred in 42% (5/12) of subjects receiving O+RT compared to 13% (8/61) of subjects receiving only O ( P= 0.009). Conclusions: In our study, the incidence of PN was higher in subjects receiving both RT and O compared to O alone. Although our study did not show higher PN in stages II and III disease, patients with rectal cancer may have residual neurotoxicity from previous radiation and the subsequent exposure to oxaliplatin may be contributing to the cumulative toxicity. [Table: see text]

The impact of colorectal cancer screening on incidence and stage IV disease in the Netherlands.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3531-3531
Author(s):  
Myrtle F Krul ◽  
Marloes AG Elferink ◽  
Niels FM Kok ◽  
Evelien Dekker ◽  
Iris Lansdorp-Vogelaar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
The Netherlands ◽  
Local Treatment ◽  
Stage Iv ◽  
Stage I ◽  
Crc Screening ◽  
Stage Distribution ◽  
Incidence And Mortality ◽  
Stage Iv Disease ◽  
The Impact

3531 Background: Population-based screening for colorectal cancer (CRC) aims to decrease incidence and mortality due to precancerous polyp removal, early detection and early treatment of CRC. In the Netherlands, phased introduction of a biennial fecal immunochemical hemoglobin test started in 2014 for individuals aged 55-75. This evaluation of the national data focuses on the initial effect of CRC screening on incidence and stage distribution and the impact on stage IV disease. Methods: All CRC patients diagnosed in the Netherlands between 2009 and 2018 were selected from the Netherlands Cancer Registry (NCR). Patients were linked to the Dutch national pathology registry (PALGA) to identify screen-detected tumors. Results: The NCR identified 137,717 CRC patients between 2009 and 2018. The incidence within screening age (55-75 yr) of all CRC stages showed an initial peak after introduction of screening in 2014, followed by a continuous decrease for all stages. CRC incidence outside the screening age did not show these explicit changes between 2009 and 2018. In 2018, the incidence of stage IV CRC within screening age was lower than the level at the start of the screening program. Stage distribution within screening age shifted towards earlier stages in the screening period (2014-2018) compared to the period before screening (2009-2012) (stage I: 31% vs. 18%, stage II: 22% vs. 26%, stage III: 29% vs. 31%, Stage IV: 18% vs. 25%, respectively). In the period 2014-2018 and within screening age, the ratio of screen-detected and symptom-detected tumors was highest in stage I (47%:53%) and lowest in stage IV (9%:91%). Screen-detected compared to symptom-detected stage IV patients diagnosed in the period 2014-2018 and within screening age had more frequently single organ metastases (74.5% vs 57.4%, p < 0.001), higher resection rate of the primary tumor (57.5% vs. 41.3%; p < 0.001) and higher local treatment rate of metastases (40.0% vs. 23.4% p < 0.001). The median overall survival of screen-detected stage IV patients was significantly longer than that of symptom-detected stage IV patients (31.0 months (95% CI: 27.7 – 34.3) vs. 15.0 months (95% CI: 14.5 – 15.5), p < 0.001). Conclusions: The initial results of the introduction of CRC screening in the Netherlands showed a favorable trend on CRC incidence and stage distribution. Screen-detected patients with stage IV disease had less extensive disease, resulting in better treatment options and improved survival.

scholarly journals Toxicity with small molecule and immunotherapy combinations in non-small cell lung cancer

2020 ◽  
Author(s):  
H. Adderley ◽  
F. H. Blackhall ◽  
C. R. Lindsay
Keyword(s):  
Small Molecule ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Stage Iii ◽  
Driver Mutations ◽  
Anaplastic Lymphoma ◽  
Significant Toxicity ◽  
Stage Iv Disease

Abstract Treatment stratification in stage IV NSCLC is guided by identification of oncogene driver mutations. Actionable mutations with current licenced therapeutic agents include epidermal growth factor receptor (EGFR), rearrangements of anaplastic lymphoma kinase (ALK), ROS-1 and BRAF V600. Alongside progress with small molecule therapy, developments in immune checkpoint inhibitors (CPIs) have transformed the landscape of stage III and stage IV NSCLC. The success of CPIs has led to evaluation with small molecule therapy in both concurrent and sequential settings. In this review we summarise recent results of combination CPIs and tyrosine kinase inhibitors (TKIs) in stage IV NSCLC, detailing significant toxicity and its potential mechanisms with both concurrent and sequential approaches. As more therapeutic targets are being discovered it is becoming increasingly important for clinicians to correctly sequence therapy for delivery of safe and effective treatment. In addition to stage IV disease we suggest that comprehensive molecular profiling of key NSCLC drivers, particularly in stage III disease, will help to inform optimal treatment sequencing and minimise potential toxicity.

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