title: The Relationship between Common Genetic Markers of Breast Cancer Risk and Chemotherapy-Induced Toxicity: A Case-Control Study.
abstract: Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores (adjusted p-value = 0.06). Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy (adjusted p-value = 0.48). These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment.
authors.affiliation: Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom.
authors.forename: Leila
authors.identifier: http://orcid.org/0000-0003-1214-8080
authors.initials: L
authors.lastname: Dorling
authors.affiliation: Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Kar
authors.affiliation: Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom.|Department of Electron Microscopy/Molecular Pathology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Michailidou
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Coventry, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
authors.affiliation: Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Cambridge, United Kingdom.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Vallier
authors.affiliation: Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Cambridge, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Ingle
authors.affiliation: Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Cambridge, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Hardy
authors.affiliation: Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bowden
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Coventry, United Kingdom.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Dunn
authors.affiliation: Leeds Institute of Cancer and Pathology and Leeds Experimental Cancer Medical Centre, Leeds, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Twelves
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Coventry, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Poole
authors.affiliation: Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Cambridge, United Kingdom.|Cambridge Experimental Cancer Medicine Centre, Cambridge, United Kingdom.|Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, United Kingdom.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Cambridge, United Kingdom.|Cambridge Experimental Cancer Medicine Centre, Cambridge, United Kingdom.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Earl
authors.affiliation: Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom.|Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Cambridge, United Kingdom.|Cambridge Experimental Cancer Medicine Centre, Cambridge, United Kingdom.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Abraham
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D000071185:Pharmacogenomic Testing; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor