With the advent of poly‐ADP‐ribose polymerase inhibitor (PARPi) therapies, the focus of genetic testing for breast, ovarian, and other cancers has shifted from risk management to treatment ...decision‐making in high‐resource settings. Due to the shortage of genetic counselors worldwide, alternative ways of delivering genetic counseling have been explored, including training nongenetics healthcare professionals (NGHPs) to provide genetic counseling. However, little is known about the feasibility of adopting such models in healthcare settings with insufficient specialists, where population health literacy is low and where access to new therapies may be limited. In this study, we evaluated the attitudes, considerations, and self‐efficacy of oncologists, breast surgeons, and general surgeons in mainstreaming breast cancer genetic counseling in Malaysia, a middle‐income Asian country with a universal healthcare system. We developed a 32‐item survey via a modified Delphi method, which was then distributed via a purposive and network sampling approach. While 77% of respondents expressed interest in providing breast cancer genetic counseling, 85% preferred to refer patients directly to genetic services for genetic counseling and testing. The main considerations for mainstreaming were the cost of genetic testing and PARPi therapy, as well as the availability of support from genetics professionals. Respondents reported a lack of confidence in communicating genetic risk, particularly to patients with poor health literacy, and in the clinical management of patients with variants of uncertain significance. Our results highlight the urgent need to train more NGHPs in providing genetic counseling and testing in low‐to‐middle income countries, and suggest that the mainstay for genetic counseling in this setting may be for risk management rather than access to PARPi therapy.
Aim
A large proportion of cancer patients are at high risk for chemotherapy‐induced nausea and vomiting (CINV), but the choice of anti‐emetics for CINV in Malaysia is limited.
Methods
This was a ...real‐world study of a fixed‐dose combination of netupitant and palonosetron (NEPA) to inhibit CINV in adult patients receiving moderately (MEC) or highly emetogenic chemotherapy (HEC) for solid/hematological malignancies at eight Malaysian centers. Each HEC/MEC cycle received one dose of NEPA + dexamethasone for CINV prevention. Complete response (no emesis, no rescue medication) (CR), no more than mild nausea (severity score ≤ 2.5), and complete control (CR) (no more than mild nausea) during the acute (0–24 h), delayed (25–120 h), and overall (0–120 h) phases post‐chemotherapy were measured. Treatment‐related adverse events (AEs) were recorded.
Results
During March 2016–April 2018 (NMRR‐17‐3286‐38282), NEPA + dexamethasone was administered to 54 patients (77.8% solid, 22.2% hematological malignancies). Note that 59.3% received HEC, while 40.7% received MEC regimen. During the overall phase of the first cycle, the majority had CR (77.8%), no more than mild nausea (74.1%), and complete control (61.1%). Seventeen patients received two consecutive cycles at any point of chemotherapy cycles. During the overall phases across two consecutive cycles, all patients achieved CR, and the majority reported no more than mild nausea and complete control. No grades 3–4 AEs were reported.
Conclusions
NEPA had sustained efficacy and tolerability at first administration and across two cycles of MEC/HEC for CINV prevention.
The fixed combination of netupitant and palonosetron (NEPA) provided sustained efficacy and tolerability across two cycles of moderately or highly emetogenic chemotherapy for chemotherapy‐induced nausea and vomiting prevention in adult patients with solid or hematological malignancies.
This study aimed to identify candidate proteins which may serve as potential biological markers for cervical cancer using 2D-DIGE. Serum samples of controls, patients with cervical intraepithelial ...neoplasia grade 3 (CIN 3), squamous cell carcinoma of early (SCC I and II) and late (SCC III and IV) stage were subjected to 2D-DIGE. Differentially expressed spots were identified by tandem mass spectrometry. Validation of candidate proteins in serum and tissue samples were then performed by ELISA and immunohistochemistry (IHC) analysis respectively. A total of 20 differentially expressed proteins were identified. These proteins were found to play key roles in the apoptosis pathway, complement system, various types of transportation such as hormones, fatty acids, lipid, vitamin E and drug transportation, coagulation cascade, regulation of iron and immunologic response. Based on their functional relevancy to the progression of various cancers, 4 proteins namely the complement factor H, CD5-like antigen, gelsolin and ceruloplasmin were chosen for further validation using ELISA. Biological network analysis showed that ceruloplasmin and gelsolin are closely interacted with the oncogene NF-κb. These two proteins were further validated using the IHC. Gelsolin and ceruloplasmin may serve as potential predictive biomarkers for the progression of high grade lesions.
Nonhematologic adverse events (AEs) of docetaxel constitute an extra burden in the treatment of cancer patients. Therefore, we investigated the association of genetic polymorphisms and AEs. A total ...of 110 Malaysian breast cancer patients were enrolled in the present study. Rash, fatigue, nausea, and oral mucositis were associated with gene polymorphisms, which can be used as predictive biomarkers for docetaxel nonhematologic AEs.
Nonhematologic adverse events (AEs) of docetaxel constitute an extra burden in the treatment of cancer patients and necessitate either a dose reduction or an outright switch of docetaxel for other regimens. These AEs are frequently associated with genetic polymorphisms of genes encoding for proteins involved docetaxel disposition. Therefore, we investigated that association in Malaysian breast cancer patients.
A total of 110 Malaysian breast cancer patients were enrolled in the present study, and their blood samples were investigated for different single nucleotide polymorphisms using polymerase chain reaction restriction fragment length polymorphism. AEs were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0.
Fatigue, nausea, oral mucositis, and vomiting were the most common nonhematologic AEs. Rash was associated with heterozygous and mutant genotypes of ABCB1 3435C>T (P < .05). Moreover, patients carrying the GG genotype of ABCB1 2677G>A/T reported more fatigue than those carrying the heterozygous genotype GA (P < .05). The presence of ABCB1 3435-T, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-G alleles was significantly associated with nausea and oral mucositis. The coexistence of ABCB1 3435-C, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-A was significantly associated with vomiting (P < .05).
The prevalence of nonhematologic AEs in breast cancer patients treated with docetaxel has been relatively high. The variant allele of ABCB1 3435C>T polymorphism could be a potential predictive biomarker of docetaxel-induced rash, and homozygous wild-type ABCB1 2677G>A/T might predict for a greater risk of fatigue. In addition, the concurrent presence of specific alleles could be predictive of vomiting, nausea, and oral mucositis.
•Discussion on molecular testing for targeted therapy of advanced NSCLC in Malaysia.•Recommendations for molecular testing in metastatic non-small cell lung cancer.•Testing algorithms in the first ...line setting and upon disease progression.
In the recent years, increased understanding of the molecular profiles of non-small cell lung cancer (NSCLC) has allowed for targeted treatment of actionable genetic mutations. The management of NSCLC now requires multiple molecular tests to guide the treatment strategy. In the light of this, there is a need to establish a molecular testing consensus statement for advanced NSCLC patients in Malaysia. This Malaysian consensus statement was developed by a panel of experts, chaired by a pathologist and composed of three other pathologists, four respiratory physicians and three oncologists. It reflects currently available scientific data and adaptations of recommendations from international guidelines to the local landscape. Expert recommendations on different aspects of molecular testing agreed upon by the panel are provided as structured discussions. These recommendations address the appropriate patients and samples to be tested, as well as when and how these tests should be performed. The algorithms for molecular testing in metastatic NSCLC, in the first line setting and upon disease progression beyond first line therapy, were developed.
Context: Rash and oral mucositis are major non-haematological adverse events (AEs) of docetaxel, in addition to fatigue, nausea, vomiting and diarrhoea, which restrict the use of the drug in cancer ...therapy. Alpha-1-acid glycoprotein (AAG) is an acute phase reactant glycoprotein and is a primary carrier of docetaxel in the blood. Docetaxel has extensive binding (>98%) to plasma proteins such as AAG, lipoproteins and albumin.
Objective: To study the association between plasma AAG level and non-haematological AEs of docetaxel in Malaysian breast cancer patients of three major ethnic groups (Malays, Chinese and Indians).
Materials and methods: One hundred and twenty Malaysian breast cancer patients receiving docetaxel as single agent chemotherapy were investigated for AAG plasma level using enzyme-linked immunosorbent assay technique. Toxicity assessment was determined using Common Terminology Criteria of Adverse Events v4.0. The association between AAG and toxicity were then established.
Results: There was interethnic variation of plasma AAG level; it was 182 ± 85 mg/dl in Chinese, 237 ± 94 mg/dl in Malays and 240 ± 83 mg/dl in Indians. It was found that low plasma levels of AAG were significantly associated with oral mucositis and rash.
Conclusions: This study proposes plasma AAG as a potential predictive biomarker of docetaxel non-haematological AEs namely oral mucositis and rash.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important ...roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.
Abstract
Docetaxel is an antitubulin chemotherapeutic agent approved for the treatment of breast, lung, ovarian and non-hormonal dependent prostate cancers. However, the success of this drug is ...limited by adverse effects (AEs), the severity of which ranged from tolerable to life threatening. Tapering the dose or diverting to another regimen would limit the use of docetaxel. Single nucleotide polymorphisms (SNPs) of genes encoding for enzymes and proteins involved in the metabolism and transport of docetaxel can cause accumulation of the drug and consequent AEs. Hence, we embarked on a study to investigate the association between SNPs of ABCB1, SLCO1B3 and CYP3A5 genes with docetaxel AEs in Malaysian breast cancer patients. Seventy five breast cancer patients receiving docetaxel as single agent chemotherapy in the adjuvant and metastatic settings were enrolled in this study. They were recruited from University Malaya Medical Centre and Universiti Kebangsaan Malaysia Medical Centre. The doses given were 90-100 mg/m2 in adjuvant setting and 75 mg/m2 in metastatic setting. The SNPs (CYP3A5 6986AG, ABCB1 3435CT and SLCO1B3 334TG) were analyzed using PCR-RFLP technique followed by DNA sequencing of selected samples. AEs were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The SNPs were correlated with AEs using Chi-square and Fisher's exact tests. The patients aged 53.7±9.4 years consisted of three main ethnic groups (Chinese 37 (49%), Malays 32 (43%) and Indians 6 (8%). The most commonly reported AEs were fatigue (55%), nausea (40%), and mucositis (35%). There was a significant association of vomiting with race (p<0.05), where Indians significantly developed vomiting. The presence of ABCB1 3435CT (heterozygous) was significantly associated with rash (p<0.05). Simultaneous presence of SLCO1B3 334GG (mutant) and CYP3A5 6986GG (mutant) was found to have significantly protected the patients from developing mucositis. Although CYP3A5 6986AG polymorphism alone was not significantly associated with mucositis, presence of CYP3A5 6986AA (wild type) and ABCB1 3435TT (mutant) had a significant association with mucositis (p<0.05). On the contrary, patients exhibiting CYP3A5 6986AG (heterozygous) and ABCB1 3435TT (mutant) did not develop mucositis (p<0.05). In conclusion, the SNPs of CYP3A5 6986AG, ABCB1 3435CT and SLCO1B3 334TG had significant influence on the development of docetaxel AEs. Simultaneous interaction between SLCO1B3 334GG (mutant) and CYP3A5 6986GG (mutant); CYP3A5 6986AA (wild type) and ABCB1 3435TT (mutant); CYP3A5 6986AG (heterozygous) and ABCB1 3435TT (mutant) appeared to be significant factors determining whether or not specific AE develops. The SNPs-AEs association provides a great avenue for potential application of biomarkers to personalize treatment to reduce AEs of docetaxel. We would like to thank the Malaysian Ministry of Higher Education (MOHE) and University Malaya for supporting this project through FRGS (04-04-10-848FR) and HIR (UM.C/625/1/HIR) grants, respectively.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A210.
Citation Format: Rafid Salim Jabir, Gwo Fuang Ho, Muhammad Azrif bin Ahmad Annuar, Johnson Stanslas. Single nucleotide polymorphisms of ABCB1, SLCO1B3, and CYP3A5: Potential biomarkers of docetaxel adverse effects in Malaysian breast cancer patients. abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A210.
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