CYP2D6 genotype linked to tamoxifen discontinuation and prognosis, not efficacy, in breast cancer
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Increasing tamoxifen dosage did not lead to a higher rate of 6-month PFS among patients with hormone receptor-positive metastatic breast cancer who have CYP2D6-variant alleles, according to results of a randomized phase 2 study.
Further, after receiving a standard tamoxifen dose, poor and ultrarapid CYP2D6 metabolizers had a worse breast cancer prognosis than normal metabolizers, results of a separate prospective-retrospective study showed.
The findings of both studies, published in Journal of Clinical Oncology, suggest that the CYP2D6 genotype, which causes different exposure of the metabolite endoxifen, cannot solely explain variations in tamoxifen efficacy. Patients should be dosed individually, researchers noted.
“Adjuvant tamoxifen therapy reduces breast cancer mortality by 31%. However, tamoxifen effectiveness [varies] widely between individuals,” Wei He, PhD, clinical investigator in the department of medical epidemiology and biostatistics at Karolinska Institutet in Stockholm, and colleagues wrote. “Early evidence has shown that poor CYP2D6 metabolism could predict worse clinical outcomes among patients with breast cancer who are treated with tamoxifen. Several studies have confirmed and some have contradicted this observation.”
CYP2D6 genotype-guided dosing
In the open-label, prospective TARGET-1 study, Kenji Tamura, MD, PhD, oncologist at National Cancer Center Hospital in Japan, and colleagues sought to determine whether tamoxifen dosing guided by CYP2D6 genotype could impact clinical outcomes among 184 patients with hormone receptor-positive metastatic breast cancer.
Researchers performed individual CYP2D6 genotyping and randomly assigned 136 patients who were heterozygous or homozygous for variant alleles of decreased or no function to the standard 20 mg daily dose of tamoxifen (n = 66; median age, 61 years) or an increased dose of 40 mg daily (n = 70; median age, 59 years). Forty-eight patients (median age, 62 years) who were homozygous for wild-type alleles received the 20 mg daily dose.
The PFS rate at 6 months served as the primary endpoint. Secondary endpoints included PFS and correlation of Z-endoxifen concentration with clinical outcomes.
Results showed no significant difference in 6-month PFS rates between those randomly assigned the increased vs. standard dose (67.6% vs. 66.7%).
Serum trough concentration of Z-endoxifen, however, appeared higher in the increased-dose group compared with the standard-dose group (median, 89.2 nM vs. 51.1 nM; P < .0001) and with patients homozygous for wild-type alleles (median, 72 nM; P = .045).
Researchers observed no differences in Z-endoxifen concentrations between patients with disease progression and those with no progression at 6 months.
“The effect of CYP2D6 genotypes on endoxifen exposure indicates that CYP2D6 is the key enzyme for generating endoxifen in metabolic activation of tamoxifen,” Tamura and colleagues wrote. “In contrast, little impact of not only CYP2D6 genotypes but also endoxifen exposure on PFS at 6 months suggests that CYP2D6 genotype-guided dosing of tamoxifen is not likely to improve clinical outcomes. Furthermore, avoiding inhibitors of CYP2D6 would not be necessary, because endoxifen exposure was not clearly correlated with tamoxifen efficacy.”
Metabolizer status, prognosis
He and colleagues used the Swedish Prescribed Drug Register and self-reported questionnaires to study the relationship of CYP2D6 genotype, discontinuation of tamoxifen and prognosis among 1,309 patients with stage I to stage III breast cancer (median age at diagnosis, 58.1 years) who received tamoxifen.
The researchers performed CYP2D6 genotyping and categorized patients as poor (n = 113), intermediate (n = 503), normal (n = 645) or ultrarapid (n = 48) CYP2D6 metabolizers.
Researchers used Cox regression analysis to evaluate possible associations between metabolizer status and tamoxifen discontinuation and prognosis for breast cancer.
Results showed 6-month tamoxifen discontinuation rates of 7.1% for poor, 7.6% for intermediate, 6.7% for normal and 18.8% for ultrarapid CYP2D6 metabolizers.
Researchers observed a U-shaped association between CYP2D6 metabolizer status and breast cancer-specific mortality, with adjusted HRs of 2.59 (95% CI, 1.01-6.67) in the poor group, 1.48 (95% CI, 0.72-3.05) in the intermediate group, 1 (reference) in the normal group and 4.52 (95% CI, 1.42-14.37) in the ultrarapid group.
“Our findings thus strengthen the need to revisit the current guideline that recommends patients with breast cancer use a standard dose of tamoxifen regardless of their metabolizer status,” He and colleagues wrote. “It could be that CYP2D6 genotype-guided tamoxifen dose adjustment, in combination with concentration monitoring of tamoxifen metabolites, will maximize tamoxifen efficacy while maintaining patients’ quality of life and adherence to therapy.”
Implementing CYP2D6 as a biomarker
The results of these studies suggest that CYP2D6 genotype should not be used to guide endocrine therapy in women with ER-positive early or metastatic breast cancer, Daniel F. Hayes, MD, Stuart B. Padnos professor of breast cancer research and co-director of the breast oncology program at University of Michigan Comprehensive Cancer Center, and James M. Rae, PhD, Thomas H. Simpson collegiate professor of cancer research and associate professor of pharmacology at University of Michigan, Ann Arbor, wrote in an accompanying editorial.
“Any tumor biomarker test should be introduced into clinical practice only when it is shown with high levels of evidence to have clinical utility,” Hayes and Rae wrote. “The confounding results of the [study by He and colleagues] are insufficient to be a conclusive validation of the hypothesis. The prospective nature of the [study by Tamura and colleagues] provides more high-level evidence that CYP2D6 status does not affect the efficacy of tamoxifen in patients with ER-positive breast cancer.” – John DeRosier
Disclosures: Tamura reports research funding from Daiichi Sankyo, Eli Lilly and Pfizer. He reports no relevant financial disclosures. Please see the studies for all other authors’ relevant financial disclosures. Hayes reports stock and other ownership interests in Inbiomotion and OncoImmune; consultant/advisory roles with Agendia, Cellworks, Cepheid, CVS Caremark Breast Cancer Expert Panel, Epic Sciences, Freenome and Salutogenic Innovations; royalties from licensed technology for breast cancer diagnosis and treatment; and research funding to his institution from AstraZeneca, Eli Lilly, Menarini Silicon Biosystems, Merrimack Pharmaceuticals, Pfizer and Puma Biotechnology. Rae reports no relevant financial disclosures.
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