Association Between ABCB1 Genetic Variants and Persistent Chemotherapy-Induced Alopecia in Women With Breast Cancer

Abstract

IMPORTANCE Persistent chemotherapy-induced alopecia (pCIA) has been recently described in patients with breast cancer and in its most severe form occurs in up to 10% of these patients. Genetic risk factors associated with pCIA have not been adequately explored.OBJECTIVE To identify genetic variants associated with pCIA. DESIGN, SETTING, AND PARTICIPANTSIn this genetic association study, 215 women with breast cancer treated with docetaxel-based chemotherapy with a follow-up of 1.5 to 10 years after the end of the treatment were recruited retrospectively through 3 hospital oncology units across Spain between 2005 and 2018. Severe pCIA was defined as lack of scalp hair recovery (Common Terminology Criteria for Adverse Events, version 3.0, grade 2) 18 months or more after the end of treatment. Patients with grade 2 pCIA were selected as cases, and those with no sign of residual alopecia 12 months after the end of docetaxel treatment were selected as controls. A genome-wide association study in a discovery phase was conducted, and logistic regression was used to identify variants associated with the risk to develop this adverse effect. The validity of the association was addressed through a replication phase. EXPOSURES Docetaxel-based chemotherapy.MAIN OUTCOMES AND MEASURES Genotypes of single-nucleotide variants associated with pCIA. RESULTSIn total, 215 women with breast cancer (median age, 51.6 years; interquartile range, 44-60 years) were recruited (173 patients for the discovery phase and 42 patients for the replication phase). In the discovery phase, ABCB1 genetic variants were associated with risk to develop pCIA. In particular, single-nucleotide variation rs1202179, a regulatory variant located in an enhancer element that interacts with the ABCB1 promoter, was associated with the occurrence of pCIA. This finding was validated in the replication cohort (combined odds ratio, 4.05; 95% CI, ). This variant is associated with ABCB1 mRNA expression, and the risk allele was associated with decreased ABCB1 expression levels (P = 1.64 × 10 −20 ).CONCLUSIONS AND RELEVANCE This is the first study, to our knowledge, that identifies an association between a regulatory variant in the ABCB1 gene and the occurrence of pCIA in patients with breast cancer who were treated with docetaxel-based therapies. This finding suggests an important insight into the biological mechanisms underlying pCIA and opens the opportunity to explore personalized treatment of these patients.

Clinicopathologic Characteristics and Response to Treatment of Persistent Chemotherapy-Induced Alopecia in Breast Cancer Survivors

“…3,6,8,10,14,18,26 Although, to our knowledge, HFSC damage has not yet been documented in pCIA samples, normal human HFs cultured ex vivo with docetaxel or paclitaxel show massive mitotic defects and apoptosis in not only bulb matrix keratinocytes but also in bulge stem cells that express keratin 15, suggesting that taxanes have the potential to inflict HFSC damage. 28 Furthermore, a recent genetic association study identified a variant located in the ABCB1 gene in patients with persistent alopecia after docetaxel-based chemotherapy for breast cancer. 29 The ABCB1 gene, which is expressed in human HFSCs, 30 encodes the membrane transporter P-glycoprotein, also known as multidrug resistance protein 1, which mediates the efflux of anticancer drugs and other xenobiotics from cells.…”

Cancer-Related Alopecia: From Etiologies to Global Management

“…Furthermore, pCIA also exhibits modifications in hair quality: indeed, it has been estimated that up to 75% of patients with pCIA still had hair thinning at 3 years post-chemotherapy [ 30 ]. Notably, an association has recently been shown between a regulatory portion of the ABCB1 gene and pCIA in patients with BC treated with taxane-based chemotherapy [ 31 ]. Specific attention should be given after bone marrow transplant pCIA in pediatric oncology, where a frequency of ≈20% has been reported [ 32 ].…”

Pharmacogenetics of Breast Cancer Treatments: A Sub-Saharan Africa Perspective

“…There is some evidence of a possible effect of ABCB1 rs1045642 (3435C>T) on docetaxel plasma levels 156 and toxicity, 157 , 158 and of rs1202179 (287-4740G>A) on chemotherapy-induced alopecia. 159 Although there are no association studies conducted in African cohorts, some of the variants of interest are found in African populations ( Table 14 ).…”