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Cytochrome genotype affects outcome with tamoxifen
Newsdesk
Cytochrome genotype affects outcome with tamoxifen The cytochrome P450 CYP2D6 genotype of women with oestrogenreceptor-positive breast cancer might affect the risk of relapse after tamoxifen treatment, US researchers report (J Clin Oncol 2005; 23: 9312–18). Tamoxifen reduces the recurrence of oestrogen-receptor-positive breast cancer by about 50% a year, and mortality by about 33%, but the prediction of non-responders is not possible. However, some women produce types of the CYP2D6 cytochrome that metabolise the drug into endoxifen less efficiently. “Since the metabolites of tamoxifen are far more potent than the drug itself, it is possible that patients who do not metabolise it so well may fail to fully respond”, says Matthew Goetz (Mayo Clinic, Rochester, MN, USA). Goetz’s team defined the CYP2D6 and CYP3A5 genotypes of more than 220 women receiving adjuvant
tamoxifen treatment, and assessed their effect on relapse. The researchers found that those with the homozygous (CYP)2D6 (*4/*4) genotype had worse relapse-free survival and disease-free survival than did those who were homozygous for the wildtype allele or who were *4/wildtype heterozygous. “Though overall survival was not affected, women with [the (CYP)2D6 (*4/*4)] genotype are more likely to have a diseaserecurrence problem”, explains Goetz. Variations in CYP3A5 were not associated with any survival variable. Furthermore, Goetz’s team found that the (*4/*4) women did not have moderate to severe hot flushes—a known side-effect of tamoxifen. However, hot flushes might be a sign that the drug is working. Moreover, some new drugs that reduce tamoxifen-associated hot flushes are known CYP2D6 inhibitors. Therefore,
although these agents stop the flushes, they might also prevent tamoxifen’s therapeutic effect by substantially reducing the production of the active metabolite endoxifen. “Given that recent practice surveys suggest that upwards of 25% of tamoxifen-treated patients are receiving [such drugs] for the treatment of hot flushes, it is imperative that we determine quickly whether these or any others that inhibit the CYP2D6 system affect the risk of relapse”, says Goetz. “Identifying women most, or least, likely to benefit from tamoxifen will help people decide whether to use it”, comments Mike Clarke (Clinical Trial Service Unit, University of Oxford, UK). “This study provides a direction for new research into the drug’s metabolism.”
Adrian Burton
Recall bias in self-reporting of familial cancer Self-reported information on familial cancer is often biased, which can lead to inaccurate risk estimates. However self-reporting is usually preferred over medical records for analysis in retrospective case-control studies because it is easier and less costly to obtain. By comparing records from self-reported telephone questionnaires with those from national registries, researchers at the Karolinska Institute (Stockholm,
Telephone questionnaires prone to recall bias
112
Sweden) quantified recall bias from differential reporting of familial cancer between Swedish individuals with malignant lymphoma and controls (J Natl Cancer Inst 2006; 98: 61–68). Participants were obtained from the Swedish Multi-Generation Register, which links individuals to their firstdegree family members, and the Swedish Cancer Register, which records all new cancer diagnoses in Swedish residents. The use of these registers is important: “Few studies have the ability to evaluate recall bias, because they lack a gold standard source of validated data for comparison to self-reported data”, says author Ellen Chang (Northern California Cancer Center, CA, USA). A significantly higher sensitivity (true positive reports) but a lower specificity (true negative reports) of self-reported family history of cancer was seen in patients than in controls.
The results were generally unsurprising. “Patients are more likely to report previous cancer (whether accurate or not) in a family member, since they are likely to be more sensitive to familial cancer than individuals who themselves do not have cancer” explains Chang. Therefore, she urges caution in the interpretation of familial risk in observational studies based on self-reported data. Harvey Murff (Vanderbilt University, Nashville, TN, USA) praises the study’s findings and emphasises the importance of accurate familial information in cancer prevention, surveillance care, and genetic testing. “This important study by Chang and colleagues is the largest study to date to validate the reliability of both positive reports of family cancer histories as well as negative reports”, he concludes.
Vivien Chen http://oncology.thelancet.com Vol 7 February 2006
Cytochrome genotype affects outcome with tamoxifen The cytochrome P450 CYP2D6 genotype of women with oestrogenreceptor-positive breast cancer might affect the risk of relapse after tamoxifen treatment, US researchers report (J Clin Oncol 2005; 23: 9312–18). Tamoxifen reduces the recurrence of oestrogen-receptor-positive breast cancer by about 50% a year, and mortality by about 33%, but the prediction of non-responders is not possible. However, some women produce types of the CYP2D6 cytochrome that metabolise the drug into endoxifen less efficiently. “Since the metabolites of tamoxifen are far more potent than the drug itself, it is possible that patients who do not metabolise it so well may fail to fully respond”, says Matthew Goetz (Mayo Clinic, Rochester, MN, USA). Goetz’s team defined the CYP2D6 and CYP3A5 genotypes of more than 220 women receiving adjuvant
tamoxifen treatment, and assessed their effect on relapse. The researchers found that those with the homozygous (CYP)2D6 (*4/*4) genotype had worse relapse-free survival and disease-free survival than did those who were homozygous for the wildtype allele or who were *4/wildtype heterozygous. “Though overall survival was not affected, women with [the (CYP)2D6 (*4/*4)] genotype are more likely to have a diseaserecurrence problem”, explains Goetz. Variations in CYP3A5 were not associated with any survival variable. Furthermore, Goetz’s team found that the (*4/*4) women did not have moderate to severe hot flushes—a known side-effect of tamoxifen. However, hot flushes might be a sign that the drug is working. Moreover, some new drugs that reduce tamoxifen-associated hot flushes are known CYP2D6 inhibitors. Therefore,
although these agents stop the flushes, they might also prevent tamoxifen’s therapeutic effect by substantially reducing the production of the active metabolite endoxifen. “Given that recent practice surveys suggest that upwards of 25% of tamoxifen-treated patients are receiving [such drugs] for the treatment of hot flushes, it is imperative that we determine quickly whether these or any others that inhibit the CYP2D6 system affect the risk of relapse”, says Goetz. “Identifying women most, or least, likely to benefit from tamoxifen will help people decide whether to use it”, comments Mike Clarke (Clinical Trial Service Unit, University of Oxford, UK). “This study provides a direction for new research into the drug’s metabolism.”
Adrian Burton
Recall bias in self-reporting of familial cancer Self-reported information on familial cancer is often biased, which can lead to inaccurate risk estimates. However self-reporting is usually preferred over medical records for analysis in retrospective case-control studies because it is easier and less costly to obtain. By comparing records from self-reported telephone questionnaires with those from national registries, researchers at the Karolinska Institute (Stockholm,
Telephone questionnaires prone to recall bias
112
Sweden) quantified recall bias from differential reporting of familial cancer between Swedish individuals with malignant lymphoma and controls (J Natl Cancer Inst 2006; 98: 61–68). Participants were obtained from the Swedish Multi-Generation Register, which links individuals to their firstdegree family members, and the Swedish Cancer Register, which records all new cancer diagnoses in Swedish residents. The use of these registers is important: “Few studies have the ability to evaluate recall bias, because they lack a gold standard source of validated data for comparison to self-reported data”, says author Ellen Chang (Northern California Cancer Center, CA, USA). A significantly higher sensitivity (true positive reports) but a lower specificity (true negative reports) of self-reported family history of cancer was seen in patients than in controls.
The results were generally unsurprising. “Patients are more likely to report previous cancer (whether accurate or not) in a family member, since they are likely to be more sensitive to familial cancer than individuals who themselves do not have cancer” explains Chang. Therefore, she urges caution in the interpretation of familial risk in observational studies based on self-reported data. Harvey Murff (Vanderbilt University, Nashville, TN, USA) praises the study’s findings and emphasises the importance of accurate familial information in cancer prevention, surveillance care, and genetic testing. “This important study by Chang and colleagues is the largest study to date to validate the reliability of both positive reports of family cancer histories as well as negative reports”, he concludes.
Vivien Chen http://oncology.thelancet.com Vol 7 February 2006