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.Grant sponsor: Cancer Research UK; Grant number: C570/A16491; Grant sponsor: Medical Research Council; Grant number: MR/ K02700X/

Creating and Validating an Algorithm to Measure AIDS Mortality in the Adult Population using Verbal Autopsy

BACKGROUND: Vital registration and cause of death reporting is incomplete in the countries in which the HIV epidemic is most severe. A reliable tool that is independent of HIV status is needed for measuring the frequency of AIDS deaths and ultimately the impact of antiretroviral therapy on mortality. METHODS AND FINDINGS: A verbal autopsy questionnaire was administered to caregivers of 381 adults of known HIV status who died between 1998 and 2003 in Manicaland, eastern Zimbabwe. Individuals who were HIV positive and did not die in an accident or during childbirth (74%; n = 282) were considered to have died of AIDS in the gold standard. Verbal autopsies were randomly allocated to a training dataset (n = 279) to generate classification criteria or a test dataset (n = 102) to verify criteria. A rule-based algorithm created to minimise false positives had a specificity of 66% and a sensitivity of 76%. Eight predictors (weight loss, wasting, jaundice, herpes zoster, presence of abscesses or sores, oral candidiasis, acute respiratory tract infections, and vaginal tumours) were included in the algorithm. In the test dataset of verbal autopsies, 69% of deaths were correctly classified as AIDS/non-AIDS, and it was not necessary to invoke a differential diagnosis of tuberculosis. Presence of any one of these criteria gave a post-test probability of AIDS death of 0.84. CONCLUSIONS: Analysis of verbal autopsy data in this rural Zimbabwean population revealed a distinct pattern of signs and symptoms associated with AIDS mortality. Using these signs and symptoms, demographic surveillance data on AIDS deaths may allow for the estimation of AIDS mortality and even HIV prevalence

Risk factors for ovarian cancer by histological phenotype in the Million Women Study

There is growing evidence that the different histological types of ovarian cancer have diverse origins. Many high-grade serous tumours (the most common type) are hypothesised to arise from the fallopian tubes, while endometrioid and clear cell tumours are hypothesised to develop from endometriosis, and the origins of mucinous tumours are uncertain. If these hypotheses are true, then the population-level risk factors for the ovarian cancer histotypes should likewise vary â but few epidemiological studies have sufficient cases to explore this. This thesis investigates the association between ovarian cancer and various exposures (including tubal ligation and reproductive factors), in a cohort of 1.3 million women, with 8,000 incident ovarian cancers. Participants completed a questionnaire at recruitment, and were followed up for routinely collected information on cancers and deaths using national registries. Cox proportional hazards models were used to estimate adjusted relative risks of ovarian cancer in women by different exposures. Tubal ligation was associated with reduced risks of cancers of the ovary, and also of the peritoneum and fallopian tube; parity and breastfeeding were also associated with reduced risks of ovarian cancer. These associations with ovarian cancer were highly heterogeneous between the different histological tumour types, consistent with hypotheses of their distinct origins. In particular, risks of endometrioid and clear cell tumours were substantially reduced amongst women with tubal ligation, but substantially increased amongst nulliparous women. For high-grade serous carcinomas, there was a smaller but significant reduction in risk with tubal ligation, and no significant association with parity. I also describe some methodological studies I set up for future tissue-based work: developing techniques in image analysis, and a pilot study of obtaining linked pathology reports and tissue samples. The population-level associations demonstrated by histotype are largely consistent with the new hypotheses of the different origins of ovarian cancer histotypes.</p

Angiogenesis inhibitors for the treatment of epithelial ovarian cancer

Background: Many women, and other females, with epithelial ovarian cancer (EOC) develop resistance to conventional chemotherapy drugs. Drugs that inhibit angiogenesis (development of new blood vessels), essential for tumour growth, control cancer growth by denying blood supply to tumour nodules. Objectives: To compare the effectiveness and toxicities of angiogenesis inhibitors for treatment of epithelial ovarian cancer (EOC). Search methods: We identified randomised controlled trials (RCTs) by searching CENTRAL, MEDLINE and Embase (from 1990 to 30 September 2022). We searched clinical trials registers and contacted investigators of completed and ongoing trials for further information. Selection criteria: RCTs comparing angiogenesis inhibitors with standard chemotherapy, other types of anti‐cancer treatment, other angiogenesis inhibitors with or without other treatments, or placebo/no treatment in a maintenance setting, in women with EOC.  Data collection and analysis: We used standard methodological procedures expected by Cochrane. Our outcomes were overall survival (OS), progression‐free survival (PFS), quality of life (QoL), adverse events (grade 3 and above) and hypertension (grade 2 and above). Main results: We identified 50 studies (14,836 participants) for inclusion (including five studies from the previous version of this review): 13 solely in females with newly‐diagnosed EOC and 37 in females with recurrent EOC (nine studies in platinum‐sensitive EOC; 19 in platinum‐resistant EOC; nine with studies with mixed or unclear platinum sensitivity). The main results are presented below.  Newly‐diagnosed EOCBevacizumab, a monoclonal antibody that binds vascular endothelial growth factor (VEGF), given with chemotherapy and continued as maintenance, likely results in little to no difference in OS compared to chemotherapy alone (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.88 to 1.07; 2 studies, 2776 participants; moderate‐certainty evidence). Evidence is very uncertain for PFS (HR 0.82, 95% CI 0.64 to 1.05; 2 studies, 2746 participants; very low‐certainty evidence), although the combination results in a slight reduction in global QoL (mean difference (MD) ‐6.4, 95% CI ‐8.86 to ‐3.94; 1 study, 890 participants; high‐certainty evidence). The combination likely increases any adverse event (grade ≥ 3) (risk ratio (RR) 1.16, 95% CI 1.07 to 1.26; 1 study, 1485 participants; moderate‐certainty evidence) and may result in a large increase in hypertension (grade ≥ 2) (RR 4.27, 95% CI 3.25 to 5.60; 2 studies, 2707 participants; low‐certainty evidence). Tyrosine kinase inhibitors (TKIs) to block VEGF receptors (VEGF‐R), given with chemotherapy and continued as maintenance, likely result in little to no difference in OS (HR 0.99, 95% CI 0.84 to 1.17; 2 studies, 1451 participants; moderate‐certainty evidence) and likely increase PFS slightly (HR 0.88, 95% CI 0.77 to 1.00; 2 studies, 2466 participants; moderate‐certainty evidence). The combination likely reduces QoL slightly (MD ‐1.86, 95% CI ‐3.46 to ‐0.26; 1 study, 1340 participants; moderate‐certainty evidence), but it increases any adverse event (grade ≥ 3) slightly (RR 1.31, 95% CI 1.11 to 1.55; 1 study, 188 participants; moderate‐certainty evidence) and may result in a large increase in hypertension (grade ≥ 3) (RR 6.49, 95% CI 2.02 to 20.87; 1 study, 1352 participants; low‐certainty evidence).  Recurrent EOC (platinum‐sensitive)Moderate‐certainty evidence from three studies (with 1564 participants) indicates that bevacizumab with chemotherapy, and continued as maintenance, likely results in little to no difference in OS (HR 0.90, 95% CI 0.79 to 1.02), but likely improves PFS (HR 0.56, 95% CI 0.50 to 0.63) compared to chemotherapy alone. The combination may result in little to no difference in QoL (MD 0.8, 95% CI ‐2.11 to 3.71; 1 study, 486 participants; low‐certainty evidence), but it increases the rate of any adverse event (grade ≥ 3) slightly (RR 1.11, 1.07 to 1.16; 3 studies, 1538 participants; high‐certainty evidence). Hypertension (grade ≥ 3) was more common in arms with bevacizumab (RR 5.82, 95% CI 3.84 to 8.83; 3 studies, 1538 participants).  TKIs with chemotherapy may result in little to no difference in OS (HR 0.86, 95% CI 0.67 to 1.11; 1 study, 282 participants; low‐certainty evidence), likely increase PFS (HR 0.56, 95% CI 0.44 to 0.72; 1 study, 282 participants; moderate‐certainty evidence), and may have little to no effect on QoL (MD 6.1, 95% CI ‐0.96 to 13.16; 1 study, 146 participants; low‐certainty evidence). Hypertension (grade ≥ 3) was more common with TKIs (RR 3.32, 95% CI 1.21 to 9.10). Recurrent EOC (platinum‐resistant)Bevacizumab with chemotherapy and continued as maintenance increases OS (HR 0.73, 95% CI 0.61 to 0.88; 5 studies, 778 participants; high‐certainty evidence) and likely results in a large increase in PFS (HR 0.49, 95% CI 0.42 to 0.58; 5 studies, 778 participants; moderate‐certainty evidence). The combination may result in a large increase in hypertension (grade ≥ 2) (RR 3.11, 95% CI 1.83 to 5.27; 2 studies, 436 participants; low‐certainty evidence). The rate of bowel fistula/perforation (grade ≥ 2) may be slightly higher with bevacizumab (RR 6.89, 95% CI 0.86 to 55.09; 2 studies, 436 participants). Evidence from eight studies suggest TKIs with chemotherapy likely result in little to no difference in OS (HR 0.85, 95% CI 0.68 to 1.08; 940 participants; moderate‐certainty evidence), with low‐certainty evidence that it may increase PFS (HR 0.70, 95% CI 0.55 to 0.89; 940 participants), and may result in little to no meaningful difference in QoL (MD ranged from ‐0.19 at 6 weeks to ‐3.40 at 4 months). The combination increases any adverse event (grade ≥ 3) slightly (RR 1.23, 95% CI 1.02 to 1.49; 3 studies, 402 participants; high‐certainty evidence). The effect on bowel fistula/perforation rates is uncertain (RR 2.74, 95% CI 0.77 to 9.75; 5 studies, 557 participants; very low‐certainty evidence). Authors' conclusions Bevacizumab likely improves both OS and PFS in platinum‐resistant relapsed EOC. In platinum‐sensitive relapsed disease, bevacizumab and TKIs probably improve PFS, but may or may not improve OS. The results for TKIs in platinum‐resistant relapsed EOC are similar. The effects on OS or PFS in newly‐diagnosed EOC are less certain, with a decrease in QoL and increase in adverse events. Overall adverse events and QoL data were more variably reported than were PFS data. There appears to be a role for anti‐angiogenesis treatment, but given the additional treatment burden and economic costs of maintenance treatments, benefits and risks of anti‐angiogenesis treatments should be carefully considered.

Ovarian cancer survival by stage, histotype, and pre-diagnostic lifestyle factors, in the prospective UK Million Women Study

Background Ovarian cancer is the fifth leading cause of cancer mortality in UK women. Ovarian cancer survival varies by disease stage at diagnosis, but evidence is mixed on the effect of tumour histological type (histotype) and other factors. Methods 1.3 million UK women completed a detailed health questionnaire in 1996–2001 and were followed for incident cancers and deaths via linkage to national databases. Using Cox regression models, we estimated adjusted relative risks (RRs) of death from ovarian cancer, by stage at diagnosis, tumour histotype, and 16 other personal characteristics of the women. Results During 17.7 years’ average follow-up, 13,222 women were diagnosed with ovarian cancer, and 8697 of them died from the disease. Stage at diagnosis was a major determinant of survival (stage IV vs I, RR=10.54, 95% CI: 9.16–12.13). Histotype remained a significant predictor after adjustment for stage and other factors, but associations varied over the follow-up period. Histotype-specific survival was worse for high-grade than low-grade tumours. Survival appeared worse with older age at diagnosis (per 5 years: RR=1.19, 95% CI: 1.15–1.22), higher BMI (per 5-unit increase: RR=1.06, 95% CI: 1.02–1.11), and smoking (current vs never: RR=1.17, 95% CI: 1.07–1.27), but there was little association with 13 other pre-diagnostic reproductive, anthropometric, and lifestyle factors. Conclusion Stage at diagnosis is a strong predictor of ovarian cancer survival, but tumour histotype and grade remain predictors of survival even after adjustment for stage and other factors, contributing further evidence of biological dissimilarity between the ovarian cancer histotypes. Obesity and smoking represent potentially-modifiable determinants of survival, but the stronger association with stage suggests that improving earlier diagnosis would have a greater impact on increasing ovarian cancer survival

Histological subtypes of ovarian cancer associated with parity and breastfeeding in the prospective Million Women Study

Ovarian cancer risk is known to be reduced amongst women who have had children, but reported associations with breastfeeding are varied. Few studies have had sufficient power to explore reliably these associations by tumour histotype. In a prospective study of 1.1 million UK women, 8719 developed ovarian cancer during follow-up. Cox regression yielded adjusted relative risks (RRs) overall and by tumour histotype amongst women with different childbearing patterns. Nulliparous women had a 24% greater ovarian cancer risk than women with one child, with significant heterogeneity by histotype (p = 0.01). There was no significant increase in serous tumours, a modest increase in mucinous tumours, but a substantial increase in endometrioid (RR = 1.49, 95% CI: 1.18-1.89) and clear-cell tumours (RR = 1.68, 1.29-2.20). Among parous women, each additional birth was associated with an overall 6% reduction in ovarian cancer risk; this association also varied by histotype (p = 0.0006), with the largest reduction in risk for clear-cell tumours (RR per birth = 0.75, 0.65-0.85, p < 0.001) and weak, if any, effect for endometrioid, high-grade serous, or mucinous tumours. We found little association with age at first or last birth. There was about a 10% risk reduction per 12-months breastfeeding (RR = 0.89, 0.84-0.94, p < 0.001), with no significant heterogeneity by histotype, but statistical power was limited. In this large prospective study, ovarian cancer risk associated with parity varied substantially by tumour histotype. Nulliparity was associated with a substantially greater overall risk than expected from the effect of a single birth, especially for clear cell and endometrioid tumours, perhaps suggesting that infertility is associated with these histotypes