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Pharmacogenomic Assessment of Patients with Colorectal Cancer and Potential Treatments.

ABSTRACT: Evolving intensiveness of colorectal cancer (CRC) treatment, including chemotherapeutics and targeted agents associations, in adjuvant and metastatic CRC (MCRC) settings, increased overall survival (OS) with individual variability of toxicity. Pharmacogenomic guidelines recommended pre-treatment identification of at-risk patients suggesting dose adjustment of fluoropyrimidines based on dihydropyrimidine dehydrogenase (DPYD), and irinotecan on UDP glucuronosyl-transferase 1 family polypeptide A1 (UGT1A1) genetic variants, but they are poorly applied in clinical practice. This review highlighted clinically validated pharmacogenetic markers, to underline the need of their implementation in the multidisciplinary molecular board for individual CRC patients in clinical practice. Five clinically relevant DPYD variants with different prevalence impair enzymatic effectiveness and significantly increase toxicity: c.1236 G>A (c.1129-5923 C>G, HapB3), 4.1-4.8%; c.1679 T>G (DPYD*13), c.1905+1G>A (DPYD*2A), c.2846 A>T, c.2194 A>T (DPYD*6) 1% each. c.1679T>G and c.1905+1G>A are most deleterious on DPD effectiveness, moderately reduced in c.1236/HapB3 and c.2846A>T. Cumulatively, these variants explain approximately half of the estimated 10-15% fluoropyrimidine-related gastrointestinal and hematological toxicities due to DPD. Prevalent UGT1A1 gene [TA]7TAA promoter allelic variant UGT1A1*28, characterized by an extra TA repeat, is associated with low transcriptional and reduced enzymatic effectiveness, decreased SN38 active irinotecan metabolite glucuronidation, vs wild-type UGT1A1*1 [A(TA)6TAA]. Homozygote UGT1A1*28 alleles patients are exposed to higher hematological and gastrointestinal toxicities, even more than heterozygote, at >150 mg/m2 dose. Dose reduction is recommended for homozygote variant. Wild-type UGT1A1*28 alleles patients could tolerate increased doses, potentially affecting favorable outcomes. Implementation of up-front evaluation of the five validated DPYD variants and UGT1A1*28 in the multidisciplinary molecular tumor board, also including CRC genetic characterization, addresses potential treatments with fluoropyrimidines and irinotecan associations at proper doses and schedules, particularly for early CRC, MCRC patients fit for intensive regimens or unfit for conventional regimens, requiring treatment modulations, and also for patients who experience severe, unexpected toxicities. Integration of individual evaluation of toxicity syndromes (TS), specifically limiting TS (LTS), an innovative indicator of toxicity burden in individual patients, may be useful to better evaluate relationships between pharmacogenomic analyses with safety profiles and clinical outcomes.

SUBMITTER: Bruera G

PROVIDER: S-EPMC7678498 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Pharmacogenomic Assessment of Patients with Colorectal Cancer and Potential Treatments.

Bruera Gemma G Ricevuto Enrico E

Pharmacogenomics and personalized medicine 20201116

Evolving intensiveness of colorectal cancer (CRC) treatment, including chemotherapeutics and targeted agents associations, in adjuvant and metastatic CRC (MCRC) settings, increased overall survival (OS) with individual variability of toxicity. Pharmacogenomic guidelines recommended pre-treatment identification of at-risk patients suggesting dose adjustment of fluoropyrimidines based on dihydropyrimidine dehydrogenase (DPYD), and irinotecan on UDP glucuronosyl-transferase 1 family polypeptide A1 ...[more]

PMID: 33235483

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Project description:BackgroundObservational studies suggest that loss of skeletal muscle mass (SMM) is associated with chemotherapy-related toxicity, poor quality of life, and poor survival in metastatic colorectal cancer (mCRC) patients. Little is known about the evolution of SMM during palliative systemic therapy. We investigated changes in SMM during various consecutive palliative systemic treatment regimens using repeated abdominal computed tomography scans of mCRC patients who participated in the randomized phase 3 CAIRO3 study.MethodsIn the CAIRO3 study, mCRC patients with stable disease or better after 6 cycles of first-line treatment with capecitabine + oxaliplatin + bevacizumab (CAPOX-B) were randomized between maintenance treatment with capecitabine + bevacizumab (CAP-B) or observation. Upon first disease progression, in both groups, CAPOX-B or other treatment was reintroduced until the second disease progression, which was the primary study endpoint. We analysed 1355 computed tomography scans of 450 (81%) CAIRO3 patients (64 ± 9.0 years, CAP-B n = 223; observation n = 227) for SMM at four time points (i.e. prior to the start of pre-randomization initial treatment, at randomization, and at first and at second disease progression) using the Slice-o-matic software and single slice evaluation at the lumbar 3 level. By using accepted and widely used formulas, whole body SMM was calculated. A linear mixed effects model, adjusted for relevant confounders, was used to assess SMM changes for the total group and within and between study arms.ResultsDuring 6 cycles of initial treatment with CAPOX-B prior to randomization, SMM decreased significantly in all patients [CAP-B arm: -0.53 kg (95% CI -1.12; -0.07) and observation arm: -0.85 kg (-1.45; -0.25)]. After randomization, SMM recovered during CAP-B treatment by 1.32 kg (0.73; 1.90) and observation by 1.20 kg (0.63; 1.78) (median time from randomization to first disease progression 8.6 and 4.1 months for CAP-B arm and observation arm, respectively). After first progression and during reintroduction treatment with CAPOX-B or other treatment, SMM again decreased significantly and comparable in both arms, CAP-B: -2.71 kg (-3.37; -2.03), and observation: -2.01 kg (-2.64; -1.41) (median time from first progression until second progression CAP-B arm: 4.7 months and observation arm: 6.6 months).ConclusionsThis longitudinal study provides a unique insight in SMM changes in mCRC patients during palliative systemic treatment regimens, including observation. Our data show that muscle loss is reversible and may be influenced by the intensity of systemic regimens. Although studies have shown prognostic capacity for SMM, the effects of subsequent changes in SMM are unknown and may be clues for new future therapeutic interventions.

Project description:For the treatment of patients with cancer to be successful and well-tolerated, the complications and side effects of the disease and its treatment must be treated and limited as far as possible. Summarized recommendations based on the constantly increasing evidence in the area of supportive care must be defined, standardized, and communicated.We systematically reviewed the literature on the topics of anemia, neutropenia, nausea/vomiting, diarrhea, oral mucositis, skin toxicity, and peripheral neurotoxicity induced by cancer treatment, as well as osseous complications, extravasation, and side effects of radiotherapy. Recommendations were approved in a moderated, formalized consensus procedure.In patients suffering from chemotherapy-induced anemia, the administration of agents that stimulate erythropoiesis can be considered. This can potentially improve these patients' quality of life and lessen the frequency of blood transfusions, but it can also lead to thromboembolic complications and arterial hypertension. If only a single individual risk factor is present in a patient whose risk of febrile neutropenia is estimated at 10-20%, there is no obligatory indication for the administration of granulocyte-colony stimulating factor. Antiemetic treatment before carboplatin is given can consist of a neurokinin-1 receptor antagonist along with a setron and dexamethasone. Duloxetine is recommended for the treatment of neuropathic pain. Sensorimotor training is effective in the treatment of chemotherapy-induced peripheral neuropathy and can already be given at the same time as the chemotherapy. Women with bony metastases of breast cancer who have been taking zoledronate at four-week intervals for a year should take it at 12-week intervals from then onward in order to lessen the likelihood of osseus complications. There is no evidence for any effective prophylactic treatment of chemotherapy-induced diarrhea.Supportive measures are an integral component of all oncological treatments. More research is needed to determine how side effects can be lessened and prevented.

Dataset Information

Pharmacogenomic Assessment of Patients with Colorectal Cancer and Potential Treatments.

Publications

Pharmacogenomic Assessment of Patients with Colorectal Cancer and Potential Treatments.

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