Recent Advances in Our Knowledge of mCRC Tumor Biology and Genetics: A Focus on Targeted Therapy Development

Gmeiner, William H.

doi:10.2147/ott.s242224

Cited by 12 publications

(10 citation statements)

References 90 publications

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“…Treatment of metastatic CRC (mCRC) also continues to rely heavily on FP-based chemotherapy regimens ( 8 ). However, the use of FPs for mCRC is evolving with refined implementation based on biomarker-based stratification to deliver optimal treatment.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, FPs remain among the most effective drugs for treating GI malignancies, including colorectal cancer (CRC) (1.8 million), gastric (1 million), and pancreatic cancer (n=460,000) ( 7 ). Personalized medicine is advancing FP use in two ways: (I) Identifying the patient population for whom FPs constitute the preferred chemotherapeutic option and treating these patients with optimized regimens that include FPs ( 8 ); and (II) Identifying patient population for whom standard FP dosing poses a known pre-determined risk of serious toxicities, or even death, and either modifying FP dose or treating these patients with alternative drugs. The implementation of a personalized medicine approach to FP treatment has already contributed to a decline in mortality due to CRC, and these approaches are likely to become more widespread and applicable to treatment of other malignancies.…”

Section: Introductionmentioning

confidence: 99%

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A narrative review of genetic factors affecting fluoropyrimidine toxicity

Gmeiner¹

2021

Precis Cancer Med

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Objective: Our objective is to document progress in developing personalized therapy with fluoropyrimidine drugs (FPs) to improve outcomes for cancer patients and to identify areas requiring further investigation. Background: FPs including 5-fluorouracil (5-FU), are among the most widely used drugs for treating colorectal cancer (CRC) and other gastrointestinal (GI) malignancies. While FPs confer a survival benefit for CRC patients, serious systemic toxicities, including neutropenia, occur in ~30% of patients with lethality in 0.5–1% of patients. While serious systemic toxicities may occur in any patient, patients with polymorphisms in DPYD , which encodes the rate-limiting enzyme for pyrimidine degradation are at very high risk. Other genetic factors affecting risk for 5-FU toxicity, including miR-27a, are under investigation. Methods: Literature used to inform the text of this article was selected from PubMed.gov from the National Library of Medicine while regulatory documents were identified via Google search. Conclusions: Clinical studies to date have validated four DPYD polymorphisms ( DPYD *2A, DPYD *13, c.2846A>T, HapB3) associated with serious toxicities in patients treated with 5-FU. Genetic screening for these is being implemented in the Netherlands and the UK and has been shown to be a cost-effective way to improve outcomes. Factors other than DPYD polymorphisms (e.g., miR-27a, TYMS , ENOSF1, p53) also affect 5-FU toxicity. Functional testing for deficient pyrimidine catabolism {defined as [U] >16 ng/mL or [UH2]:[U] <10} is being implemented in France and has demonstrated utility in identifying patients with elevated risk for 5-FU toxicity. Therapeutic drug monitoring (TDM) from plasma levels of 5-FU during first cycle treatment also is being used to improve outcomes and pharmacokinetic-based dosing is being used to increase the percent of patients within optimal area under the curve (AUC) (18–28 mg*h/L) values. Patients maintained in the optimal AUC range experienced significantly reduced systemic toxicities. As understanding the genetic basis for increased risk of 5-FU toxicity becomes more refined, the development of functional-based methods to optimize treatment is likely to become more widespread.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A narrative review of genetic factors affecting fluoropyrimidine toxicity

Gmeiner¹

2021

Precis Cancer Med

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“…Colorectal cancer is one major causes of cancer deaths, despite the advances in the management of patients with operable stage I-III cancers. Regarding metastatic CRC, the 5-year survival rate is between 13.8 and 14.7% for stage IV CRC patients [ 21 ]. Therefore, new treatments that could increase survival rate should be considered by health care decision makers as indispensable.…”

Section: Discussionmentioning

confidence: 99%

“…It is important to note that comparison of mutation and line with the corresponding weighted average cannot contribute to a holistic approach regarding patients’ needs per mutation and line. As mCRC is a heterogeneous disease each mutation presents diverse clinical challenges and physicians have different treatment options available in order to improve patients’ OS and PFS [ 21 ]. For example, BRAF V600E accounts for more than 90% of BRAF mutations in CRC [ 26 ] and a new targeted therapy, currently approved for 2nd line, for this mutation has been recently introduced in the Greek market (encorafenib plus cetuximab).…”

Section: Discussionmentioning

confidence: 99%

Treatment pathways and associated costs of metastatic colorectal cancer in Greece

Sougklakos

Athanasiadis

Boukovinas³

et al. 2022

Cost Eff Resour Alloc

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Objectives Colorectal cancer (CRC) is the second leading cause of cancer in Europe, with 1.931.590 people newly diagnosed in 2020. The purpose of this study is the investigation of treatment options and healthcare resource metastatic CRC (mCRC) in Greece. Methods This study is based on the information collected in November 2020 by an expert panel comprising of 6 medical oncologists from major public and private centers around Greece. A 3-round survey was undertaken, according to Delphi method. The treatment phases studied were: pre-progression; disease progression and terminal care. Pharmaceutical costs and resource utilization data were considered from the perspective of the Greek National Services Organization (EOPYY). RESULTS: Experts agreed that the anticipated prevalence of RAS mutation in mCRC is 47% (30% RAS/BRAF WT Left, 17% RAS/BRAF WT Right); 8% BRAF while, MSI-H/dMMR are found in 5% of mCRC tumors. Based on mutational status, 74.8% of patients receive biological targeted therapies in combination with fluoropyrimidine/based combination chemotherapy, as 1st line treatment, and 25.2% combination chemotherapy alone. At 2nd line, 58.6% of patients receive biological targeted therapies in combination with chemotherapy, 25.4% immunotherapy, 11% combination chemotherapy and 5% biological targeted therapies. At 3rd line 56% of patients receive combination chemotherapy, 28% biological targeted therapies, 10% biological targeted therapies in combination with chemotherapy and 6% immunotherapy. The weighted annual cost (pharmaceuticals and resource use cost) in 1st line per mCRC patient was calculated at €28,407, in 2nd line €33,568, in 3rd line €25,550. The annual cost beyond 3rd line per patient regardless mutation was €19,501 per mCRC patient. Conclusions mCRC is a societal challenge for healthcare systems as the treatment is more prolonged but expand patients’ survival. Thus, reimbursement decisions should be based not just on the cost of the treatment, but on the magnitude of the benefit of its treatment on patients’ survival and quality of life.

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“…Novel research focuses on the use of genetic mutations, not only as biomarkers but also as treatment targets [ 26 ]. Attention is also paid to epigenetics.…”

Section: Genetic Mutations In Crcmentioning

confidence: 99%

Resectable Colorectal Cancer: Current Perceptions on the Correlation of Recurrence Risk, Microbiota and Detection of Genetic Mutations in Liquid Biopsies

Koulouris

Tsagkaris

Messaritakis

et al. 2021

Cancers

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Metastatic colorectal cancer (mCRC) remains a highly lethal malignancy, although considerable progress has resulted from molecular alterations in guiding optimal use of available treatments. CRC recurrence remains a great barrier in the disease management. Hence, the spotlight turns to newly mapped fields concerning recurrence risk factors in patients with resectable CRC with a focus on genetic mutations, microbiota remodeling and liquid biopsies. There is an urgent need for novel biomarkers to address disease recurrence since specific genetic signatures can identify a higher or lower recurrence risk (RR) and, thus, be used both as biomarkers and treatment targets. To a large extent, CRC is mediated by the immune and inflammatory interplay of microbiota, through intestinal dysbiosis. Clarification of these mechanisms will yield new opportunities, leading not only to the appropriate stratification policies, but also to more precise, personalized monitoring and treatment navigation. Under this perspective, early detection of post-operative CRC recurrence is of utmost importance. Ongoing trials, focusing on circulating tumor cells (CTCs) and, even more, circulating tumor DNA (ctDNA), seem to pave the way to a promising, minimally invasive but accurate and life-saving monitoring, not only supporting personalized treatment but favoring patients’ quality of life, as well.

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Recent Advances in Our Knowledge of mCRC Tumor Biology and Genetics: A Focus on Targeted Therapy Development

Cited by 12 publications

References 90 publications

A narrative review of genetic factors affecting fluoropyrimidine toxicity

A narrative review of genetic factors affecting fluoropyrimidine toxicity

Treatment pathways and associated costs of metastatic colorectal cancer in Greece

Resectable Colorectal Cancer: Current Perceptions on the Correlation of Recurrence Risk, Microbiota and Detection of Genetic Mutations in Liquid Biopsies

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