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Jack Cuzick

Publications and source records attributed to Jack Cuzick.

At least 37 records · Page 2Linked to original sources
PubMed2006

Human papillomavirus testing and liquid-based cytology in primary screening of women younger than 35 years: results at recruitment for a randomised controlled trial.

BACKGROUND: Testing for human papillomavirus (HPV) DNA is more sensitive but less specific than cytological analysis. Loss in specificity is most relevant in women younger than 35 years because of increased HPV prevalence. We aimed to compare conventional screening with an experimental strategy in women aged 25-34 years, and investigate the effect of different criteria of referral to define the best methods of HPV screening. METHODS: Women were randomly assigned to the conventional procedure (standard cytology, with referral to colposcopy if cytology showed atypical squamous cells of undetermined significance or more [ASCUS+]) or an experimental procedure (liquid-based cytology and testing for high-risk HPV types, with referral to colposcopy with ASCUS+ cytology). Women positive for HPV (cutoff > or = 1 pg/mL) but with normal cytology were retested after 1 year. The main endpoint was the presence of cervical intraepithelial neoplasia at grade 2 or more (CIN2+) in reviewed histology. The main analysis was by intention to screen. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN81678807. FINDINGS: We randomly assigned 5808 women aged 25-34 years to the conventional group and 6002 to the experimental group. The experimental procedure was significantly more sensitive than the conventional procedure (55 vs 33 CIN2+ lesions detected; relative sensitivity 1.61 [95% CI 1.05-2.48]), but had a lower positive predictive value (PPV; relative PPV 0.55 [0.37-0.82]). HPV testing (> or = 1 pg/mL) with cytology triage was also more sensitive than conventional cytology (relative sensitivity 1.58 [1.03-2.44], relative PPV 0.78 [0.52-1.16]). Relative PPV could be improved, with minimum loss in sensitivity, by use of a 2 pg/mL cutoff for HPV testing. Compared with conventional cytology, liquid-based cytology had a relative sensitivity of 1.32 (0.84-2.06), relative PPV 0.58 [0.38-0.89]). INTERPRETATION: HPV testing alone with cytology triage could be a feasible alternative to conventional cytology for screening women younger than 35 years. Follow-up will provide data on possible overdiagnosis and on the feasibility of extended intervals.

Adult↗
PubMed2006

Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer.

BACKGROUND: Over the past few years, data have been published concerning the relative efficacy and safety profiles of tamoxifen and the aromatase inhibitors (AIs) in the adjuvant therapy setting for women with early hormone receptor-positive breast cancer. Recently, debate has centred around trials which have studied primary tamoxifen and AI therapy, switching and sequencing strategies and extended adjuvant therapy. METHODS: Here, a group of 24 breast cancer experts review efficacy and safety data from the recent major trials investigating tamoxifen and the third-generation AIs in postmenopausal women, which have challenged the perception of tamoxifen as optimum adjuvant endocrine therapy. Data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, Breast International Group (BIG) 1-98 study, National Cancer Institute of Canada MA 17 trial, Intergroup Exemestane Study (IES), Italian Tamoxifen Anastrozole (ITA) trial, Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8 and Arimidex-Nolvadex (ARNO) 95 are considered to provide a rational interpretation of the impact of these data on current practice, and to highlight areas where further investigation is needed. CONCLUSION: We can be confident that AIs represent superior adjuvant endocrine treatment to tamoxifen in postmenopausal women, either as initial therapy or as an alternative for women who have started adjuvant therapy with tamoxifen. However, there remain issues regarding the best way to use AIs, such as the optimal length of AI treatment and how a sequence of tamoxifen followed by an AI compares with AI monotherapy; these will require further data to resolve.

Antineoplastic Agents, Hormonal↗
PubMed2006

Effect of an aromatase inhibitor on bmd and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230).

UNLABELLED: Aromatase inhibitors reduce estrogen levels in postmenopausal women with breast cancer. Residual estrogen is an important determinant of bone turnover. Adjuvant anastrozole was associated with significant BMD loss and increased bone remodeling, whereas tamoxifen reduced bone marker levels. INTRODUCTION: In the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial after a median follow-up of 68 months, a significant improvement in disease-free survival was observed with anastrozole treatment (hazard ratio [HR], 0.87; 95% CI, 0.78-0.97; p = 0.01). Anastrozole was also associated with tolerability benefits compared with tamoxifen, but with higher fracture rates. The HR of anastrozole compared with tamoxifen after 60 months of treatment was 1.49 (95% CI, 1.25-1.77). MATERIALS AND METHODS: This prospectively designed subprotocol (n = 308) of ATAC assessed changes in BMD and bone turnover markers in postmenopausal women with invasive primary breast cancer receiving anastrozole 1 mg/day, tamoxifen 20 mg/day, or combination treatment with both agents for 5 years. Patients with osteoporosis were excluded (osteopenia permitted at the investigators discretion). Lumbar spine and total hip BMD was assessed at baseline and after 1 and 2 years; bone turnover markers (serum C-telopeptide, urinary N-telopeptide [NTX], free deoxypyridinoline, serum procollagen type-1 N-propeptide, bone alkaline phosphatase [ALP]) were assessed at baseline and after 3, 6, and 12 months. Results were expressed as median percentage change. RESULTS: After 2 years of anastrozole treatment, BMD was lost at lumbar spine (median 4.1% loss) and total hip (median 3.9% loss) sites; increases of 2.2% and 1.2%, respectively, were observed with tamoxifen. After 1 year of anastrozole treatment, increased bone remodeling was observed (NTX, +15%; 95% CI, 3-25%; bone ALP, +20%; 95% CI, 14-25%); decreased bone remodeling was observed with tamoxifen (NTX, -52%; 95% CI, -62% to -33%; bone ALP, -16%; 95% CI, -24% to -11%). CONCLUSIONS: Anastrozole is associated with significant BMD loss and a small increase in bone turnover, whereas tamoxifen (and the combination) is associated with increased BMD and decreased remodeling. These data may explain the increased fracture risk observed with anastrozole treatment in the ATAC trial. The impact of anastrozole on bone should be weighed against its overall superior efficacy and tolerability as observed in the main ATAC trial.

Aged↗
PubMed2005

Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status: an hypothesis-generating study.

PURPOSE: Arimidex, tamoxifen alone, or in combination (ATAC) trial of anastrozole (Arimidex) versus tamoxifen or a combination of the two in 9,366 postmenopausal patients with primary breast cancer found a significant improvement in disease-free survival and time to recurrence (TTR) for anastrozole compared with tamoxifen, that was restricted to patients with hormone receptor-positive (ie, estrogen receptor-positive [ER+] and/or progesterone receptor-positive [PgR+]) disease, the target population for these therapies. We retrospectively tested the hypothesis that this benefit might differ according to PgR status. PATIENTS AND METHODS: TTR was compared between the three treatment groups for subgroups defined by ER and PgR status using Cox's proportional hazards model, with and without adjustment for baseline variables. RESULTS: The unadjusted hazard ratio (HR) for anastrozole versus tamoxifen for TTR was 0.74 (95% CI, 0.64 to 0.87) for women with either ER+ or PgR+ tumors. In the ER+/PgR+ subgroup (n = 3,834) the HR was 0.84 (95% CI, 0.69 to 1.02) compared with 0.43 (95% CI, 0.31 to 0.61) in the ER+/PgR-negative (PgR-) subgroup (n = 880). In the adjusted model the HRs were 0.83 and 0.45, respectively. CONCLUSION: Time to recurrence was longer for anastrozole- than tamoxifen-treated patients in both ER+/PgR+ and ER+/PgR- subgroups, but the benefit was substantially greater in the PgR- subgroup. As this was an "exploratory" analysis, this effect should be considered as hypothesis generating and assessed prospectively in other trials comparing the adjuvant use of an aromatase inhibitor with tamoxifen.

Anastrozole↗
PubMed2005

Early stopping of clinical trials.

Early stopping of clinical trials in favour of a new treatment creates ethical and scientific difficulties, which are different from those associated with early stopping due to toxicity or futility. Two major breast cancer trials have recently taken such a decision, and the problem is relevant for several ongoing trials. Here we argue that such a decision should be taken with the utmost gravity and should be based on a clear overall clinical benefit for the new treatment, and not as an automatic response to crossing a predefined threshold. Predefined rules can be used to trigger a debate within the Independent Data Monitoring and Safety Committee (IDMC) about early stopping, but the IDMC should retain the responsibility of assessing overall clinical benefit in making its recommendation.

Breast Neoplasms↗
PubMed2005

A multicentre epidemiological study on sunbed use and cutaneous melanoma in Europe.

A large European case-control study investigated the association between sunbed use and cutaneous melanoma in an adult population aged between 18 and 49 years. Between 1999 and 2001 sun and sunbed exposure was recorded in 597 newly diagnosed melanoma cases and 622 controls in Belgium, France, The Netherlands, Sweden and the UK. Fifty three percent of cases and 57% of controls ever used sunbeds. The overall adjusted odds ratio (OR) associated with ever sunbed use was 0.90 (95% CI: 0.71-1.14). There was a South-to-North gradient with high prevalence of sunbed exposure in Northern Europe and lower prevalence in the South (prevalence of use in France 20%, OR: 1.19 (0.68-2.07) compared to Sweden, prevalence 83%, relative risk 0.62 (0.26-1.46)). Dose and lag-time between first exposure to sunbeds and time of study were not associated with melanoma risk, neither were sunbathing and sunburns (adjusted OR for mean number of weeks spent in sunny climates >14 years: 1.12 (0.88-1.43); adjusted OR for any sunburn >14 years: 1.16 (0.9-1.45)). Host factors such as numbers of naevi and skin type were the strongest risk indicators for melanoma. Public health campaigns have improved knowledge regarding risk of UV-radiation for skin cancers and this may have led to recall and selection biases in both cases and controls in this study. Sunbed exposure has become increasingly prevalent over the last 20 years, especially in Northern Europe but the full impact of this exposure on skin cancers may not become apparent for many years.

Adult↗
PubMed2005

Vascular effects of aromatase inhibitors: data from clinical trials.

Aromatase inhibitors (AIs) are becoming the endocrine treatment of first choice for postmenopausal women with hormone receptor-positive breast cancer and are under investigation for use in breast cancer prevention. AIs reduce circulating estrogen to barely detectable concentrations. It is possible that such a low concentration will be deleterious to the vascular system since estrogen receptors are known to be in the cell walls of blood vessels and estrogen is thought to be important in maintaining blood vessel integrity. Because most women who present with primary breast cancer are cured by surgery and systemic therapy and the major cause of female death is vascular disease, it is particularly important to investigate the vascular side effects of AIs in current breast cancer adjuvant and prevention trials. In order to set the vascular toxicities of AIs reported in the current adjuvant trials into context, here we compare them with the toxicities seen during treatment with hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs). Clinical trial evidence indicates that HRT increases risk of coronary heart disease (CHD) whereas SERMs and AIs (to date) appear to be neutral. Cerebrovascular disease and venous thromboembotic events are increased by HRT and SERMs but appear to be unaffected by treatment with AIs. Cognitive function is also considered here since it may also have a vascular component and is potentially a serious potential side effect/benefit of AIs. Recent studies indicate that HRT has a small detrimental effect on cognitive function and is associated with a doubling of the incidence of dementia. A comprehensive study of the SERM, raloxifene, on cognitive function showed no significant effect. There are no definitive reported studies investigating tamoxifen and none for AIs on cognitive function, although there is one in progress in the context of the IBIS II prevention trial which compares anastrozole to placebo in women at high risk. At present concerns about deleterious vascular side effects are confined to HRT and SERMs. However, we have few long-term data using AIs for the treatment and prevention of breast cancer.

Antineoplastic Agents, Hormonal↗
PubMed2005

Anastrozole.

Recent trials have indicated that the aromatase inhibitors (anastrozole, letrozole, exemestane) are more effective than tamoxifen, the standard adjuvant treatment for estrogen receptor-positive breast cancer, both in adjuvant and first-line advanced settings. This paper reviews the mode of action and the main clinical trials done with anastrozole, the only aromatase inhibitor currently licensed for use in the adjuvant setting in estrogen receptor-positive tumors. Results from studies using anastrozole as a first-line treatment in advanced disease strongly suggest that this drug should now be considered as an alternative first-line therapy to tamoxifen in postmenopausal women with estrogen receptor-positive advanced breast cancer. As a second-line treatment in tamoxifen failures, anastrozole has shown a better survival rate and a better side-effect profile than megestrol acetate. Similarly, the use of anastrozole in the adjuvant setting has shown a significantly prolonged disease-free survival time and improved tolerability compared to tamoxifen in postmenopausal breast cancer survivors.

Anastrozole↗
PubMed2004

Quality of life of postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial.

PURPOSE: To determine the quality of life (QoL) of women participating in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial during the first 2 years of treatment. PATIENTS AND METHODS: A total of 1,021 women were enrolled onto the QoL subprotocol. All had completed primary treatment (surgery +/- radiotherapy +/- chemotherapy) and were to receive 5 years of adjuvant treatment with anastrozole (n = 335), tamoxifen (n = 347), or a combination (n = 339) of both. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) plus endocrine subscale (ES) at baseline and 3, 6, 12, 18, and 24 months, or until disease recurrence. The primary end point was the FACT-B Trial Outcome Index (TOI). The secondary end point was the ES total score. Analyses of individual endocrine symptoms were also explored. RESULTS: Questionnaire completion approximated 85% of assessments available for analysis. Overall QoL for all groups improved from baseline during the 2-year period. There were no significant differences in TOI or ES scores across treatment groups. Endocrine symptoms increased between baseline and 3 months for all groups and stabilized thereafter. There were some small differences in side effect profiles. Compared with patients receiving tamoxifen only, patients receiving anastrozole only reported significantly fewer cold sweats and vaginal discharge, yet more vaginal dryness, painful intercourse, and loss of sexual interest. CONCLUSION: Two years of treatment with anastrozole, tamoxifen, or the combination had a similar overall QoL impact, showing gradual improvement over time. Endocrine-related symptoms for all three arms worsened initially and recovered partially during 2 years. The different symptoms experienced may assist in decision making about treatment and supportive care needs.

Anastrozole↗
PubMed2004

Breast surgery in the 'Arimidex, Tamoxifen Alone or in Combination' (ATAC) trial: American women are more likely than women from the United Kingdom to undergo mastectomy.

BACKGROUND: Various factors affect patients' decisions regarding whether to undergo surgery for the treatment of early-stage breast carcinoma. The 'Arimidex, Tamoxifen Alone or in Combination' (ATAC) trial, the largest multinational randomized trial of adjuvant therapy for patients with operable breast carcinoma to date, offers the opportunity to investigate whether nationality is one such factor. METHODS: After receiving primary therapy for early-stage breast carcinoma, 9,366 women (from a total of 21 countries) were randomized to receive anastrozole, tamoxifen, or anastrozole plus tamoxifen for 5 years. In the current study, mastectomy and breast conservation rates were compared among participating countries. The possibility that variations from country to country could be explained by inequalities in terms of pathologic, clinical, and hospital-related correlates of surgical choice was explored first on univariate analysis and then on multivariate logistic analysis. RESULTS: National mastectomy rates ranged from 20% to 97%; 51% of the 2,222 enrollees from the United States had undergone mastectomy, compared with 42% of the 3228 enrollees from the United Kingdom (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.28-1.60; P < 0.001). On univariate analysis, larger tumor size, positive lymph node status, higher tumor grade, older age, and adjuvant chemotherapy use were found to be correlated with mastectomy use. In contrast, positive hormone receptor status, increased body weight, and enrollment at a center that had more than 40 enrollees were found to be associated with breast conservation. The same correlates were identified on multivariate logistic analysis (P < 0.05), except that the number of enrollees at a patient's treatment center no longer possessed predictive value. After correction for these correlated factors, residence in the United States (compared with residence in the United Kingdom) remained an independent predictor of mastectomy use (OR, 1.44; 95% CI, 1.26-1.64; P < 0.001). CONCLUSIONS: American women enrolled in the ATAC trial were more likely to undergo aggressive surgery compared with their counterparts from the United Kingdom. More generally, nationality was found to be an independent determinant of surgical choice in the current study.

Age Factors↗
PubMed2004

Tamoxifen and breast density in women at increased risk of breast cancer.

BACKGROUND: Although mammographic breast density is associated with the risk of breast cancer and is influenced by hormone levels, the effects of tamoxifen on breast density in healthy women and whether tamoxifen-induced density changes are associated with breast cancer risk are unclear. We investigated mammographic breast density in healthy women with an increased risk of breast cancer at baseline and during 54 months of tamoxifen treatment. METHODS: Mammograms were reviewed from 818 breast cancer-free women (388 in the tamoxifen group and 430 in the placebo group) at high risk for breast cancer, from the International Breast Cancer Intervention Study I, a trial of tamoxifen for breast cancer prevention. Breast density measurements, at baseline and during treatment, were obtained at 12- to 18-month intervals. Multivariable analysis was used to assess associations with breast density. All statistical tests were two-sided. RESULTS: Breast density at baseline was similar in placebo (42.6%, 95% confidence interval [CI] = 39.6% to 45.6%) and tamoxifen (41.9%, 95% CI = 38.8% to 45.0%) groups. The main determinants of breast density at baseline were age, menopausal status, body mass index, and previous atypical hyperplasia. A greater density reduction in the tamoxifen group (7.9%, 95% CI = 6.9% to 8.9%) than in the placebo group (3.5%, 95% CI = 2.7% to 4.3%) was apparent within 18 months of treatment (P<.001); the reduction in density continued until 54 months of treatment. After 54 months of tamoxifen treatment, breast density was 28.2% (decrease from baseline = 13.7%, 95% CI = 12.3% to 15.1%; P<.001) in the tamoxifen group and 35.3% (decrease from baseline = 7.3%, 95% CI = 6.1% to 8.4%; P<.001) in the placebo group. The tamoxifen-associated density reduction was apparent in all subgroups, but there was a statistically significant interaction with age. In women aged 45 years or younger at entry, the net reduction with tamoxifen was 13.4% (95% CI = 8.6% to 18.1%), whereas in women older than 55 years, it was 1.1% (95% CI = -3.0% to 5.1%). CONCLUSION: Tamoxifen treatment was associated with reduction in breast density, most of which occurred during the first 18 months of treatment.

Adult↗
PubMed2004

A breast cancer prediction model incorporating familial and personal risk factors.

Many factors determine a woman's risk of breast cancer. Some of them are genetic and relate to family history, others are based on personal factors such as reproductive history and medical history. While many papers have concentrated on subsets of these risk factors, no papers have incorporated personal risk factors with a detailed genetic analysis. There is a need to combine these factors to provide a better overall determinant of risk. The discovery of the BRCA1 and BRCA2 genes has explained some of the genetic determinants of breast cancer risk, but these genes alone do not explain all of the familial aggregation of breast cancer. We have developed a model incorporating the BRCA genes, a low penetrance gene and personal risk factors. For an individual woman her family history is used in conjuction with Bayes theorem to iteratively produce the likelihood of her carrying any genes predisposing to breast cancer, which in turn affects her likelihood of developing breast cancer. This risk was further refined based on the woman's personal history. The model has been incorporated into a computer program that gives a personalised risk estimate.

Adult↗