UKIBCS

Queen Mary's University, London, UK

Specific research roles and achievements.
Jack Cuzick is internationally recognised for his leadership and major role in creating and developing the field of chemoprevention of breast cancer and methodologies for estimating breast cancer risk. He has also transformed cervical cancer screening and prevention. His research provided evidence for the use of flexible sigmoidoscopy to detect lower bowel cancer, and the potential of aspirin to reduce colon cancer.

Jack Cuzick’s foundational work on chemoprevention and therapy of breast cancer.
In 1985 he made the seminal observation that tamoxifen reduced recurrence of breast cancer and also prevents the occurrence of new contralateral tumours. Shortly after this initial observation, Professor Cuzick published a detailed rationale for the prophylactic use of tamoxifen, in which the choice of a high-risk population, potential benefits and side effects were clearly enunciated. This provided a scientific basis and justification for the four large tamoxifen chemoprevention trials, which have now been completed, and his overview paper has provided unambiguous evidence for tamoxifen’s ability to prevent breast cancer.

He has gone on the lead 3 major trials is this area: IBIS-I has shown that 5 years of tamoxifen can reduce new breast cancers in high risk women by 30=40% for at least 20 years, IBIS-II has shown that anastrozole can reduce new cancers by 50% in postmenopausal women for at least 11 years, and the ATAC adjuvant trial was first to show that anastrozole was more effective that tamoxifen in preventing recurrence and new contralateral tumours over 10 years.

Professor Cuzick has also made valuable contributions to assessing the risk of developing breast cancer, which is essential if prevention is to be target to high-risk individuals. His risk model (known as the Tyrer-Cuzick model) is widely used in family history clinics to assess risk and determine the most appropriate screening interval and modality.

Enhancing the targeting of breast cancer prevention

Jack Cuzick, Kim Chu, Brian Keevil, Adam R Brentnall, Anthony Howell, Nicholas Zdenkowski, Bernardo Bonanni, Sibylle Loibl, Kaija Holli, D. Gareth Evans, Steve Cummings, Mitch Dowsett on behalf of IBIS-II collaborators

Background. An increased breast cancer risk associated with high serum levels of both oestradiol and testosterone is well established in postmenopausal women. However very little is known about the impact of these hormones on response to endocrine therapy in either the preventive or adjuvant setting. The role of baseline serum oestradiol on the effectiveness of the SERMs tamoxifen and raloxifene has been studied in the prevention setting in two different trials, with differing results, but there haven’t been any studies on aromatase inhibitors.

Methods. We studied the effect of oestradiol, testosterone and SHBG measured at trial entry on the development of breast cancer in the IBIS-II prevention trial, which compared anastrozole to placebo in 3864 high risk postmenopausal women. The primary analysis was a case-control study of the impact of the baseline oestradiol/SHBG ratio on the effectiveness of anastrozole for cancer prevention.

Findings. Cases were reduced by 49% in the anastrozole arm, matching the findings for the whole trial. There was a clear trend of increasing risk with increasing E2/SHBG level in the placebo arm (P = 0.0033), but not in the anastrozole arm (P= 0.60). There was a large 55% reduction in cancer incidence with anastrozole in quartiles 2-4 (P =1.91x10^-5), but only a small, non-significant 18% reduction in the lowest quartile.

Interpretation. The benefit of anastrozole may be much less when oestradiol levels are low, and may not justify the side effects. This study also indicates a larger treatment effect for higher E2/SHBG levels, which could make this an even more attractive option for women with normal or high levels. These results also raise the question of whether serum hormones should be measured more routinely and integrated into risk models and treatment decisions, including the need for more (or less) screening.