title: A nested cohort study of 6,248 early breast cancer patients treated in neoadjuvant and adjuvant chemotherapy trials investigating the prognostic value of chemotherapy-related toxicities.
abstract: BACKGROUND
  The relationship between chemotherapy-related toxicities and prognosis is unclear. Previous studies have examined the association of myelosuppression parameters or neuropathy with survival and reported conflicting results. This study aims to investigate 13 common chemotherapy toxicities and their association with relapse-free survival and breast cancer-specific survival.
  
  
  METHODS
  Chemotherapy-related toxicities were collected prospectively for 6,248 women with early-stage breast cancer from four randomised controlled trials (NEAT; BR9601; tAnGo; Neo-tAnGo). Cox proportional-hazards modelling was used to analyse the association between chemotherapy-related toxicities and both breast cancer-specific survival and relapse-free survival. Models included important prognostic factors and stratified by variables violating the proportional hazards assumption.
  
  
  RESULTS
  Multivariable analysis identified severe neutropenia (grades ≥3) as an independent predictor of relapse-free survival (hazard ratio (HR) = 0.86; 95% confidence interval (CI), 0.76-0.97; P = 0.02). A similar trend was seen for breast cancer-specific survival (HR = 0.87; 95% CI, 0.75-1.01; P = 0.06). Normal/low BMI patients experienced more severe neutropenia (P = 0.008) than patients with higher BMI. Patients with fatigue (grades ≥3) showed a trend towards reduced survival (breast cancer-specific survival: HR = 1.17; 95% CI, 0.99-1.37; P = 0.06). In the NEAT/BR9601 sub-group analysis by treatment component, this effect was statistically significant (HR = 1.61; 95% CI, 1.13-2.30; P = 0.009).
  
  
  CONCLUSIONS
  This large study shows a significant association between chemotherapy-induced neutropenia and increased survival. It also identifies a strong relationship between low/normal BMI and increased incidence of severe neutropenia. It provides evidence to support the development of neutropenia-adapted clinical trials to investigate optimal dose calculation and its impact on clinical outcome. This is important in populations where obesity may lead to sub-optimal chemotherapy doses.
authors.affiliation: Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. ja344@medschl.cam.ac.uk.|NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. ja344@medschl.cam.ac.uk.|Strangeways Research Laboratory, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK. ja344@medschl.cam.ac.uk.|Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. ja344@medschl.cam.ac.uk.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Abraham
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. l.hiller@warwick.ac.uk.
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
authors.affiliation: Strangeways Research Laboratory, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK. ld429@medschl.cam.ac.uk.
authors.forename: Leila
authors.initials: L
authors.lastname: Dorling
authors.affiliation: Department of Oncology, Cambridge Cancer Trials Centre, Box 279 (S4), Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. anne-laure.vallier@addenbrookes.nhs.uk.|Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. anne-laure.vallier@addenbrookes.nhs.uk.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Vallier
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. j.a.dunn@warwick.ac.uk.
authors.forename: Janet
authors.initials: J
authors.lastname: Dunn
authors.affiliation: Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. s.j.bowden@bham.ac.uk.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bowden
authors.affiliation: Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. susan.ingle@addenbrookes.nhs.uk.|NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. susan.ingle@addenbrookes.nhs.uk.|Department of Oncology, Cambridge Cancer Trials Centre, Box 279 (S4), Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. susan.ingle@addenbrookes.nhs.uk.
authors.forename: Susan
authors.initials: S
authors.lastname: Ingle
authors.affiliation: Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. linda.jones@addenbrookes.nhs.uk.|NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. linda.jones@addenbrookes.nhs.uk.|Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. linda.jones@addenbrookes.nhs.uk.
authors.forename: Linda
authors.initials: L
authors.lastname: Jones
authors.affiliation: Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. richard.hardy@addenbrookes.nhs.uk.|NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. richard.hardy@addenbrookes.nhs.uk.|Department of Oncology, Cambridge Cancer Trials Centre, Box 279 (S4), Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. richard.hardy@addenbrookes.nhs.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Hardy
authors.affiliation: Level 4, Leeds Institute of Cancer and Pathology and Leeds Experimental Cancer Medical Centre, St James Institute of Oncology, Beckett Street, Leeds, LS9 7TF, UK. c.j.twelves@leeds.ac.uk.
authors.forename: Christopher
authors.initials: C
authors.lastname: Twelves
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. christopher.poole@warwick.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Poole
authors.affiliation: Strangeways Research Laboratory, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK. pp10001@medschl.cam.ac.uk.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. carlos.caldas@cruk.cam.ac.uk.|NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. carlos.caldas@cruk.cam.ac.uk.|Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. carlos.caldas@cruk.cam.ac.uk.|Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK. carlos.caldas@cruk.cam.ac.uk.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. hme22@cam.ac.uk.|NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. hme22@cam.ac.uk.|Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. hme22@cam.ac.uk.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Earl
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016022:Case-Control Studies; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects* / Q000379:methods; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D011379:Prognosis
chemical_list: D000970:Antineoplastic Agents