UKCRC Accredited Trials Unit
Cancer Prevention Trials Unit

Epidemiolgy and Statistics

The Epidemiology, Mathematics and Statistics group is involved in clinical trials and epidemiology and as such its work is essentially collaborative. Currently, the major areas of interest are cancers of the breast, uterine cervix, prostate and colorectum. In these areas there are activities encompassing prevention studies, screening studies, treatment comparisons, prognostic factors for survival, and aetiological studies of risk factors for developing the disease. Screening, early detection and disease prevention form a focus for much of this work. The analysis of data from these projects often requires the development of new mathematical and statistical techniques, and the group has an active interest in the development of new methodology.

Breast

The IBIS research programme has been investigating breast cancer chemoprevention since 1985. The IBIS-I trial which commenced in 1992 studied the use of tamoxifen among a group of 7145 pre- and postmenopausal women aged 35 to 70 with an increased risk of developing breast cancer. These women were largely recruited from UK and Australian centres, although there was much interest from other European groups. The updated analysis of the IBIS-I data was published earlier this year [1] and indicates that tamoxifen can reduce breast cancer incidence by about one third. The prophylactic effect of tamoxifen was fairly constant over the entire follow-up period after 10 years of randomisation. This is supported by an overview of all breast cancer prevention trials [2], where it is clear that tamoxifen reduces ER positive breast cancer by about one-half, but has no effect on ER negative cancers. These data have also contributed to a heightened awareness of the increased risk of thromboembolic events associated with the use of tamoxifen. A recent report examines genetic and other factors which might identify women at high risk of VTEs [3].

The group is also the statistical centre for four mammographic screening trials (Swedish Two-County, Gothenburg, the UK Frequency Trial, and the CADET trial of computer aided detection), and several service screening evaluation projects, including the FH01 study of mammographic surveillance services in young women with a family history of breast cancer. Results include a confirmation of the reduction in breast cancer mortality associated with screening in the service setting [4], and that this is achieved mainly through diagnosis if small invasive rather than in situ cancers [5]. Related research on mammographic density indicates that radiologically dense tissue is a strong marker for risk of breast cancer, has a complex multivariate relationship with other breast cancer risk factors, and is reduced by treatment with tamoxifen [6] [7].

HPV and Cervix

The group has a wide-ranging programme looking at the prevention of cervical cancer. This ranges from evaluation of service screening to the study of molecular markers that could potentially be used in screening, and from the introduction of an effective cervical screening programme in developing countries [Almonte et al Int J Ca 2007] to the study of cofactors that influence progression in HPV positive women. Over the last five years, we have continued to evaluate programmatic screening through analysis of trends [8] and through a population based case-control study [9] and we are now modeling the natural history of cervical neoplasia using data both from our UK based case-control study and from 2.5 million women screened in Taiwan.

In 1999, we published an influential systematic review of the role of HPV testing in cervical screening [10]. More recently, we published a meta analysis of all European and North American studies that directly compared cytology to HPV testing.[Cuzick et al Int J Ca 2006] In 2006, Jack Cuzick co-edited a special edition of Vaccine looking at the whole area of HPV vaccination and cervical screening. This is already considered to be a seminal publication.

We have carried out two important trials of HPV testing in screening. In 1999, we published the first HPV screening study in older women, where screening is most needed [11]. We have recently completed a long term follow-up of women in that study to determine the length of protection afforded by a negative HPV test. This was followed by a multi-centre randomised trial looking at the role of HPV testing both as a primary test and in the management of women with low-grade cytological abnormalities [12]. Our laboratory has been at the forefront of evaluating hybrid capture technology and the development of a multiplex type-specific PCR assay [13]. In collaboration with the Hammersmith and St. Mary’s Hospitals, we have been carrying out a study looking at different markers for cervical disease. The study is comparing the sensitivity and specificity of cytology, HPV testing, p16, PCNA, HPV mRNA and related markers available in a liquid based sample in the diagnosis of cervical intraepithelial neoplasia.

We have been studying the possible use of self-collected samples for HPV testing and analysing women's views on HPV testing [14] [15] [16] [17] [18] [19].  The results suggest that women find the idea acceptable and the self-test easy to perform. Clearly, this has potential and we are now looking into further studies, in different groups of women.

We are one of four centres in the UK recruiting into an international HPV vaccine trial, which has recruited 18,000 women 15-25 years of age for a four-year period. We are also the principal UK centre (of six) in a trial of 5,400 women aged over 26 for a three year period

Colorectal

In conjunction with the St Mark’s Hospital Colorectal Cancer Unit and the Health Behavioural Unit at UCL, a large multi-centre screening trial of once-in-a-lifetime sigmoidoscopy to reduce the incidence of distal bowel cancer is being undertaken. Screening is complete and a report on the baseline result of over 40,000 flexible sigmoidoscopies has been published [20]. Currently we are monitoring for subsequent cancers with the first results expected 2008-2009. Several additional studies are attached to this trial to study the question of acceptability, methods of achieving high compliance, diet, pathology and a range of other questions.

To examine whether population based flexible sigmoidoscopy screening could be performed by nurse endoscopists, a demonstration study funded by the Department of Health is currently underway in north-west London.

Prostate

A large study of the natural history of prostate cancer identified almost two and a half thousand men diagnosed with clinically localised disease, in the UK, between 1990 and 1996. This resulted in an improved prognostic classification for local progression and death from prostate cancer based on measurements of prostate specific antigen (PSA) and Gleason score [21] [22] [23] and identified a need for further biomarkers. Diagnostic biopsy specimens from those diagnosed by TURP have been assembled in a tissue micro array and probed with a variety of candidate biomarkers, in a continuing search for new markers with prognostic value that will lead to an improvement in the management and treatment of a disease which now kills 10,000 British men, a year. Initial results have been very successful [24] and future clinical trials will establish the value of these new biomarkers

References

  1. Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H; Holli K, Howell A (2007). Long-Term Results of Tamoxifen Prophylaxis for Breast Cancer – 96-Month Follow-up of the Randomized IBIS-I Trial. JNCI  99: 272-282.
  2. Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S and Boyle P (2003).   Overview of the main outcomes in breast cancer prevention trials.  Lancet, 361:  296-300.
  3. Duggan C, Marriott K, Edwards R, Cuzick J (2003). Inherited and acquired risk factors for venous thromboembolic disease among women taking tamoxifen to prevent breast cancer. JCO, 21(19):3588-93.
  4. Tabár L, Dean PB (2003). Mammography and breast cancer: the new era. Int J Gynaecol Obstet.,82(3):319-26.
  5. Duffy SW, Tabar L, Vitak B, Day NE, Smith RA, Chen HH, Yen MF (2003). The relative contributions of screen-detected in situ and invasive breast carcinomas in reducing mortality from the disease. Eur J Cancer, 39(12):1755-60.
  6. Duffy SW, Jakes RW, Ng FC, Gao F (2004). Interaction of dense breast patterns with other breast cancer risk factors in a case-control study. Br J Cancer, 2004 Jul 19;91(2):233-6.
  7. Cuzick J, Warwick J, Pinney E, Warren RML, Duffy SW (2004). Tamoxifen and breast density in women at increased risk of breast cancer. J Natl Cancer Inst, 96: 621-628.
  8. Sasieni PD (2000). Human papillomavirus screening and cervical cancer prevention. J Am Med Womens Assoc, 55(4):216-9.
  9. Sasieni P, Adams J, Cuzick J (2003). Benefit of cervical screening at different ages: evidence from the UK audit of screening histories. Br J Cancer, 89(1):88-93.
  10. Cuzick J, Sasieni P, Davies P, Adams J, Normand C, Frater A, van Ballegooijen M, van den Akker, E (1999).  A systematic review of the role of human papillomavirus testing within a cervical screening programme.  Health Technology Assessment, 3: No. 14.
  11. Cuzick J, Beverley E, Ho L, Terry G, Sapper H, Mielzynska I, Lorincz A, Chan W-K, Krausz T & Soutter P (1999).  HPV testing in primary screening of older women.  Br J Cancer, 81: 554-558.
  12. Cuzick J, Szarewski A, Cubie H, Hulman G, Kitchener H, Luesley D, McGoogan E, Menon U, Terry G, Edwards R, Brooks C, Desai M, Gie C, Ho L, Jacobs I, Pickles C, Sasieni P. (2003) Management of women who test positive for high risk types of human papillomavirus: The HART study.  Lancet; 362:1871-76 
  13. Terry G, Ho L, Londesborough P, Cuzick J, Mielzynska-Lohnas I, Lorincz A (2001). Detection of high-risk HPV types by the hybrid capture 2 test. J Med Virol, 65(1):155-62.
  14. McCaffery K, Forrest S, Waller J, Desai M, Szarewski A, Wardle J. (2003) Attitudes towards HPV testing: a qualitative study of beliefs among Indian, Pakistani, African Caribbean and white British women in the UK.  Br J Cancer; 88: 42-46
  15. Waller J, McCaffery K, Forrest S, Szarewski A, Cadman L, Wardle J. (2003) Awareness of human papilloma virus (HPV) among women attending a well-woman clinic. Sex Transm Infect;79:320–322
  16. Forrest S , McCaffery K, Waller J, Desai M, Szarewski A, Cadman L, Wardle J. (2004) Attitudes to Self-Sampling for HPV among Indian, Pakistani, African-Caribbean and white British Women in Manchester.   J Med Screening 11:85–88
  17. McCaffery K, Waller J, Forrest S, Cadman L, Szarewski A, Wardle J. (2004) Testing positive for Human Papillomavirus in routine cervical screening: examination of psychosocial impact.  BJOG; 111: 1437-43
  18. Waller J, McCaffery K, Szarewski A, Cadman L, Austin J, Wardle J.  (2006) Acceptability of unsupervised HPV testing by self-sampling using only written instructions. J Med Screening; 13 (4): 208-213
  19. Szarewski A, Cadman L, Mallett S, Austin J, Londesborough P, Waller J, Wardle J, Altman DG, Cuzick J. (2007) HPV Testing by Self-sampling:  Assessment of Accuracy in an Unsupervised Clinical Setting. J Med Screening; 14: :34 –42
  20. UK Flexible Sigmoidoscopy Screening Trial Investigators (2002). Single flexible sigmoidoscopy screening to prevent colorectal cancer: baseline findings of a UK multicentre randomised trial. Lancet, 359(9314):1291-300.
  21. Cuzick J, Fisher G, Kattan MW, Berney D, Oliver T, Foster CS, Møller H, Reuter V, Fearn P, Eastham J, Scardino P; and the Transatlantic Prostate Group (2006). Long-term outcome among men with conservatively treated localised prostate cancer. Br J Cancer, 95(9):1186-94
  22. Berney DM, Fisher G, Kattan MW, Oliver RT, Møller H, Fearn P, Eastham J, Scardino P, Cuzick J, Reuter VE, Foster CS (2007). Pitfalls in the diagnosis of prostatic cancer: retrospective review of 1791 cases with clinical outcome. Histopathology, 51(4):452-457.
  23. Eastham JA, Kattan MW, Fearn P, Fisher G, Berney DM, Oliver T, Foster CS, M? H, Reuter V, Cuzick J, Scardino P (2007). Local Progression among Men with Conservatively Treated Localized Prostate Cancer: Results from the Transatlantic Prostate Group. Eur Urol., 2007 May 30 (ahead of print).
  24. Attard G, Clark J, Ambroisine L, Fisher G, Kovacs G, Flohr P, Berney D, Foster CS, Fletcher A, Gerald WL, Moller H, Reuter V, De Bono JS, Scardino P, Cuzick J, Cooper CS (2007). Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene, 2007 Jul 16 (ahead of print).

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