Kezia Gaitskell

Menopausal hormone use and ovarian cancer risk : individual participant meta-analysis of 52 epidemiological studies

Summary Background Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk. Methods Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. Findings During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31–1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29–1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40–1·66; p<0·0001) and endometrioid (1·42, 1·20–1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07–1·46, p=0·005). Interpretation The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users. Funding Medical Research Council, Cancer Research UK.BACKGROUND Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk. METHODS Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. FINDINGS During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31-1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29-1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40-1·66; p<0·0001) and endometrioid (1·42, 1·20-1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07-1·46, p=0·005). INTERPRETATION The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users. FUNDING Medical Research Council, Cancer Research UK.Gapstur, S. M.; Patel, A. V.; Banks, E.; Dal Maso, L.; Talamini, R.; Chetrit, A.; HirshYechezkel, G.; Lubin, F.; Sadetzki, S.; Beral, V.; Bull, D.; Cairns, B.; Crossley, B.; Gaitskell, K.; Goodill, A.; Green, J.; Hermon, C.; Key, T.; Moser, K.; Reeves, G.; Sitas, F.; Collins, R.; Peto, R.; Gonzalez, C. A.; Lee, N.; Marchbanks, P.; Ory, H. W.; Peterson, H. B.; Wingo, P. A.; Martin, N.; Silpisornkosol, S.; Theetranont, C.; Boosiri, B.; Chutivongse, S.; Jimakorn, P.; Virutamasen, P.; Wongsrichanalai, C.; Goodman, M. T.; Lidegaard, O.; Kjaer, S. K.; Morch, L. S.; Kjaer, S. K.; Tjonneland, A.; Byers, T.; Rohan, T.; Mosgaard, B.; Vessey, M.; Yeates, D.; Freudenheim, J. L.; Titus, L. J.

Derivation of new reference tables for human heart weights in light of increasing body mass index

As body weights and body mass indices have increased over time, we questioned the validity of correlating heart weight with body weight and whether tables from previous decades remain relevant. We investigated this by collecting details of heart weight, body weight, height, gender and age from 384 autopsy cases with no obvious heart or lung disease. Heart weights, body weights and heights showed a normal distribution for both genders. Heart weight correlated slightly better with body surface area than body weight and we present new reference charts derived from these data. The correlation between heart weight and body weight has changed little, despite increases in body weight and body mass index. As life expectancy is increasing, we investigated the effect of age on heart weight and demonstrated a small increase in heart weight relative to body surface area for both genders, in contrast to a previous study.

Tubal ligation and ovarian cancer risk in a large cohort: Substantial variation by histological type.

Histopathological and molecular studies suggest that different histological subtypes (histotypes) of ovarian cancer have different aetiologies. Few studies have been large enough to explore reliably the effect of tubal ligation (sterilization), which has been associated with a reduced overall risk of ovarian cancer, on different tumour histotypes. In a prospective study of 1.1 million UK women without prior cancer or bilateral oophorectomy, 8,035 ovarian cancers occurred during mean follow‐up of 13.8 years. Using a Cox proportional hazards model, we estimated adjusted relative risks of ovarian cancer associated with tubal ligation. Overall, there was substantial heterogeneity in tumour risk associated with tubal ligation for the four main histotypes, serous, endometrioid, mucinous and clear cell (heterogeneity: p < 0.0001). For serous tumours, the most common histotype (n = 3,515), risks differed significantly between high‐grade (RR: 0.77, 95% CI: 0.67–0.89) and low‐grade tumours (RR: 1.13, 95% CI: 0.89–1.42); heterogeneity: p = 0.007. Relative risks were almost halved for endometrioid (n = 690, RR: 0.54, 95% CI: 0.43–0.69) and clear cell tumours (n = 401, RR: 0.55, 95% CI: 0.39–0.77), but there was no association between tubal ligation and mucinous tumours (n = 836, RR: 0.99, 95% CI: 0.84–1.18). For the main tumour histotypes we found little variation of risk by timing of tubal ligation. The significant differences by tumour histotype are unlikely to be due to confounding and are consistent with hypotheses that high‐grade and low‐grade serous tumours have different origins, and that some endometrioid and clear cell tumours might arise from cells and/or carcinogens travelling through the fallopian tubes.

Serous tubal intraepithelial carcinomas associated with high‐grade serous ovarian carcinomas: a systematic review

Serous tubal intraepithelial carcinomas (STICs) have been documented in high‐grade serous ovarian carcinomas (HGSOCs). However, the rate of association between STICs and HGSOCs and, therefore, the fraction of HGSOCs that are likely to have originated from the fallopian tube (FT), has remained unclear.

Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies

Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40 kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p < 2−16), which was not found in patients without cancer (n = 108). Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n = 100), and common in BRCA1-BRCA2 mutation carriers (n = 71) who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease.

Tubal ligation and incidence of 26 site-specific cancers in the Million Women Study

Background:Tubal ligation is known to be associated with a reduction in ovarian cancer risk. Associations with breast, endometrial and cervical cancers have been suggested. We investigated associations for 26 site-specific cancers in a large UK cohort.Methods:Study participants completed a questionnaire on reproductive and lifestyle factors in 1996–2001, and were followed for cancer and death via national registries. Using Cox regression models, we estimated adjusted relative risks (RRs) for 26 site-specific cancers among women with vs without tubal ligation.Results:In 1 278 783 women without previous cancer, 167 430 incident cancers accrued during 13.8 years’ follow-up. Significantly reduced risks were found in women with tubal ligation for cancers of the ovary (RR=0.80, 95% CI: 0.76–0.85; P<0.001; n=8035), peritoneum (RR=0.81, 0.66–0.98; P=0.03; n=730), and fallopian tube (RR=0.60, 0.37–0.96; P=0.04; n=168). No significant associations were found for endometrial, breast, or cervical cancers.Conclusions:The reduced risks of ovarian, peritoneal and fallopian tube cancers are consistent with hypotheses of a common origin for many tumours at these sites, and with the suggestion that tubal ligation blocks cells, carcinogens or other agents from reaching the ovary, fallopian tubes and peritoneal cavity.

Heterogeneity of colorectal cancer risk by tumour characteristics: Large prospective study of UK women

Associations between behavioural and other personal factors and colorectal cancer risk have been reported to vary by tumour characteristics, but evidence is inconsistent. In a large UK‐based prospective study we examined associations of 14 postulated risk factors with colorectal cancer risk overall, and across three anatomical sites and four morphological subtypes. Among 1.3 million women, 18,518 incident colorectal cancers were identified during 13.8 (SD 3.4) years follow‐up via record linkage to national cancer registry data. Cox regression yielded adjusted relative risks. Statistical significance was assessed using correction for multiple testing. Overall, colorectal cancer risk was significantly associated with height, body mass index (BMI), smoking, alcohol intake, physical activity, parity and menopausal hormone therapy use. For smoking there was substantial heterogeneity across morphological types; relative risks around two or greater were seen in current smokers both for signet ring cell and for neuroendocrine tumours. Obese women were also at higher risk for signet ring cell tumours. For adenocarcinomas, the large majority of colorectal cancers in the cohort, all risk factor associations were weak. There was little or no heterogeneity in risk between tumours of the right colon, left colon and rectum for any of the 14 factors examined. These epidemiological findings complement an emerging picture from molecular studies of possible different developmental pathways for different tumour types.

Past cervical intraepithelial neoplasia grade 3, obesity, and earlier menopause are associated with an increased risk of vulval cancer in postmenopausal women.

Background:Vulval cancer predominantly affects postmenopausal women. A smaller proportion of vulval cancers, particularly at older ages, are now thought to be associated with human papillomavirus infection than previously reported, but other risk factors have not been well examined in prospective cohort studies.Methods:A total of 1.3 million women aged 49–65 years were followed for incident vulval cancer (ICD-10 C51). Adjusted Cox regression models were used to examine the relationship between reproductive and lifestyle factors and risk of vulval cancer.Results:There were 898 vulval cancers registered in the cohort over an average of 14 years of follow-up; 70% were squamous cell carcinomas. Past registration of cervical carcinoma in situ (RR 2.68; 95% CI 1.71–4.18; P<0.001), obesity (RR 1.71; 95% CI 1.44–2.04; P<0.0001), and menopause before the age of 50 years (RR 1.52; 95% CI 1.22–1.89; P<0.001) were associated with a significantly increased risk of subsequent vulval cancer.Conclusion:Past cervical pre-cancer, obesity, and earlier age at menopause are associated with an increased risk of vulval cancer at older ages.

Establishing an evidence base for frequency of monitoring glycated haemoglobin levels in patients with Type 2 diabetes: projections of effectiveness from a regression model.

Diabet. Med. 29, 266–271 (2012)

Personalised Medicine: The Promise, the Hype and the Pitfalls.

In engaging critically with personalised medicine and mapping pitfalls which mark its progress this project aims to stimulate conversations which deal intelligently with controversies for the sake of consensus. We aim to ask the ethical questions which will lead to the improvement of healthcare and we take an open-minded approach to finding answers to them over time. What is or should be meant by ‘personalised medicine’ is a major theme of this issue. It is a debate bound up with question of both values in the sense of ethical reflection and value in the sense of economic return. This editorial discusses and interrelates the articles of the issue under four headings: the promise and the hype of personalised medicine; the human person and the communication of risk; data sharing and participation; value, equity and power. A key intention throughout is to provoke discourse and debate, to identify aspirations which are more grounded in myth or hype than reality and to challenge them; and to identify focussed, practical questions which need further examination.