scholarly journals Precision Medicine for the Management of Therapy Refractory Colorectal Cancer

2020 ◽  
Vol 10 (4) ◽  
pp. 272
Author(s):  
Hossein Taghizadeh ◽  
Robert M. Mader ◽  
Leonhard Müllauer ◽  
Friedrich Erhart ◽  
Alexandra Kautzky-Willer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Precision Medicine ◽  
Targeted Therapies ◽  
Targeted Treatment ◽  
Treatment Recommendation ◽  
Molecularly Targeted Therapy ◽  
Time To Treatment Failure ◽  
Heavily Pretreated ◽  
Recommended Therapy ◽  
Generation Sequencing

In this analysis, we examined the efficacy, feasibility, and limitations of molecular-based targeted therapies in heavily pretreated metastatic colorectal cancer (mCRC) patients after failure of all standard treatments. In this single-center, real-world retrospective analysis of our platform for precision medicine, we mapped the molecular profiles of 60 mCRC patients. Tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite instability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after consensus discussion. In total, we detected 166 mutations in 53 patients. The five most frequently found mutations were TP53, KRAS, APC, PIK3CA, and PTEN. In 28 cases (47% of all patients), a molecularly targeted therapy could be recommended. Eventually, 12 patients (20%) received the recommended therapy. Six patients (10%) had a clinical benefit. The median time to treatment failure was 3.1 months. Our study demonstrates the feasibility and applicability of using targeted therapies in daily clinical practice for heavily pretreated mCRC patients. This could be used as a targeted treatment option in half of the patients.

scholarly journals Genetic Heterogeneity in Colorectal Cancer and its Clinical Implications

2015 ◽  
Vol 28 (3) ◽  
pp. 370 ◽  
Author(s):  
Rui Barranha ◽  
José Luís Costa ◽  
Fátima Carneiro ◽  
José Carlos Machado
Keyword(s):  
Colorectal Cancer ◽  
Next Generation Sequencing ◽  
Genetic Heterogeneity ◽  
Targeted Therapies ◽  
Poor Prognosis ◽  
Genetic Diagnosis ◽  
Influence Factors ◽  
Clinical Implications ◽  
Generation Sequencing ◽  
Colorectal Tumours

<p>Despite the recent advances in the development of complementary diagnostic exams and modern targeted therapies, colorectal cancer remains a major cause of morbidity and mortality worldwide. In this context, a lot of research has been conducted in the last years to find new markers of poor prognosis. The existence of a complex tumour architecture formed by multiple subclones genetically heterogeneous has been increasingly considered in recent studies as an element of particular importance. This feature seems to influence factors as relevant as the representativeness of tumour biopsies for genetic diagnosis and the efficacy of targeted therapies.<br />There is growing evidence suggesting a relation between genetic heterogeneity and the patients’ prognosis. The widespread use of next-generation sequencing techniques will allow a better understanding of the true degree of genetic heterogeneity in colorectal tumours, its causes and impact on the course of the disease. In this review we intend to analyse the recent findings related to the genetic heterogeneity of colorectal cancer, as well as its major clinical implications.</p>

scholarly journals Applied precision medicine in metastatic pancreatic ductal adenocarcinoma

2020 ◽  
Vol 12 ◽  
pp. 175883592093861 ◽  
Author(s):  
Hossein Taghizadeh ◽  
Leonhard Müllauer ◽  
Robert M. Mader ◽  
Martin Schindl ◽  
Gerald W. Prager
Keyword(s):  
Precision Medicine ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Mtor Inhibitor ◽  
Ductal Adenocarcinoma ◽  
Clinical Routine ◽  
Dismal Prognosis ◽  
Frequent Mutations ◽  
Recommended Therapy ◽  
Generation Sequencing

Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) bears a dismal prognosis due to the limited activity of systemic chemotherapy. In our platform for precision medicine, we aim to offer molecular-guided treatments to patients without further standard therapy options. Methods: In this single center, real-world retrospective analysis of our platform, we describe the molecular-based therapy approaches used in all 50 patients diagnosed with therapy-refractory mPDAC. A molecular portrait of the tumor specimens was created by next-generation sequencing, immunohistochemistry (IHC), microsatellite instability (MSI) testing, and fluorescence in situ hybridization. Results: In total, we detected 123 mutations in 50 patients. The five most frequent mutations were KRAS ( n = 40; 80%), TP53 ( n = 29; 58%), CDKN2A ( n = 8; 16%), SMAD4 ( n = 4; 8%), and NOTCH1 ( n = 4; 8%), which together accounted for 40.2% of all mutations. Two patients had gene fusions, namely, TBL1XR1–PIK3CA and EIF3E–RSPO2. IHC detected expression of EGFR, phosphorylated mTOR, and PTEN in 36 (72%), 33 (66%), and 17 patients (34%), respectively. For 14 (28%) of the 50 patients, a targeted therapy was suggested based on the identified molecular targets. The recommended treatments included the mTOR inhibitor everolimus ( n = 3), pembrolizumab ( n = 3), palbociclib ( n = 2), nintedanib ( n = 2), and cetuximab, crizotinib, tamoxifen, and the combination of lapatinib and trastuzumab, in one patient each. Finally, five patients received the recommended therapy. Four patients died due to disease progression before radiological assessment. One patient was treated with nintedanib and achieved stable disease for 6 months. Conclusion: Based on our observations, precision medicine approaches are feasible and implementable in clinical routine and may provide molecular-based therapy recommendations for mPDAC.

scholarly journals Tumor-Agnostic Biomarkers: Heed Caution, and Why Cell of Origin Still Matters

Onco ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 95-100
Author(s):  
Aaron C. Tan
Keyword(s):  
Colorectal Cancer ◽  
Cancer Therapy ◽  
Precision Medicine ◽  
Targeted Therapies ◽  
Braf V600e ◽  
Egfr Mutations ◽  
Cell Of Origin ◽  
Tumor Origin ◽  
Tissue Of Origin ◽  
Exon 19

Since the very beginnings of cancer therapy with chemotherapy, tumors have been treated according to the organ or tissue of origin. The advent of precision medicine however, has recently led to growing promise for tumor-agnostic biomarkers for targeted therapies and immunotherapies, such as NTRK fusions. Despite this, prominent examples such as BRAF V600E mutations in melanoma compared to colorectal cancer, in which the site of tumor origin dramatically influences the efficacy of targeted therapies, heeds caution against disregarding the importance of cell of origin. Indeed, another illustrative example, is the almost complete absence outside of cancers originating from the lung of the classical activating EGFR mutations—exon 19 deletions and exon 21 L858R mutations. Consequently, an understanding of lineage dependency and lineage-survival oncogenes may still offer significant mechanistic insights into the malignant transformation of tumors to ultimately identify further therapeutic vulnerabilities.

Novel and Emerging Targeted Therapies of Colorectal Cancer

2015 ◽  
Vol 10 (4) ◽  
pp. 279-298 ◽  
Author(s):  
Niklas Finnberg ◽  
Prashanth Gokare ◽  
Wafik El-Deiry
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapies

scholarly journals Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3296
Author(s):  
Ioannis Chanias ◽  
Kristina Stojkov ◽  
Gregor Stehle ◽  
Michael Daskalakis ◽  
Helena Simeunovic ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Myelodysplastic Syndromes ◽  
Clonal Evolution ◽  
Driver Mutations ◽  
Future Perspectives ◽  
Hematopoietic Stem ◽  
Secondary Acute Myeloid Leukemia ◽  
Stem And Progenitor Cells ◽  
Unfit Patients ◽  
Generation Sequencing

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

scholarly journals Colorectal Cancer Biomarkers in the Era of Personalized Medicine

2019 ◽  
Vol 9 (1) ◽  
pp. 3 ◽  
Author(s):  
Jai Patel ◽  
Mei Fong ◽  
Megan Jagosky
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Therapy Response ◽  
Dose Intensity ◽  
Cancer Biomarkers ◽  
Clinical Implications ◽  
Test Results ◽  
First Line ◽  
Genomic Markers ◽  
Generation Sequencing

The 5-year survival probability for patients with metastatic colorectal cancer has not drastically changed over the last several years, nor has the backbone chemotherapy in first-line disease. Nevertheless, newer targeted therapies and immunotherapies have been approved primarily in the refractory setting, which appears to benefit a small proportion of patients. Until recently, rat sarcoma (RAS) mutations remained the only genomic biomarker to assist with therapy selection in metastatic colorectal cancer. Next generation sequencing has unveiled many more potentially powerful predictive genomic markers of therapy response. Importantly, there are also clinical and physiologic predictive or prognostic biomarkers, such as tumor sidedness. Variations in germline pharmacogenomic biomarkers have demonstrated usefulness in determining response or risk of toxicity, which can be critical in defining dose intensity. This review outlines such biomarkers and summarizes their clinical implications on the treatment of colorectal cancer. It is critical that clinicians understand which biomarkers are clinically validated for use in practice and how to act on such test results.

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