Association of serum sex steroid receptor bioactivity and sex steroid hormones with breast cancer risk in postmenopausal women

Postmenopausal women with elevated serum sex steroids have an increased risk of breast cancer. Most of this risk is believed to be exerted through binding of the sex steroids to their receptors. For the first time, we investigate the association of estrogen receptor (ER) and androgen receptor (AR) serum bioactivity (SB) in addition to hormone levels in samples from women with breast cancer collected before diagnosis. Two hundred postmenopausal women participating in the UK Collaborative Trial of Ovarian Cancer Screening who developed ER-positive breast cancer 0.6-5 years after sample donation were identified and matched to 400 controls. ER and AR bioassays were used to measure ERα, ERβ, and AR SB. Androgen and estrogen levels were measured with immunoassays. Subjects were classified according to quintiles of the respective marker among controls and the associations between SB and hormones with breast cancer risk were determined by logistic regression analysis. ERα and ERβ SB were significantly higher before diagnosis compared with controls, while estrogens showed no difference. Women had a twofold increased breast cancer risk if ERα SB (odds ratio (OR), 2.114; 95% confidence interval (CI), 1.050-4.425; P=0.040) was in the top quintile >2 years before diagnosis or estrone (OR, 2.205; 95% CI, 1.104-4.586; P=0.029) was in the top quintile <2 years before diagnosis. AR showed no significant association with breast cancer while androstenedione (OR, 3.187; 95% CI, 1.738-6.044; P=0.0003) and testosterone (OR, 2.145; 95% CI, 1.256-3.712; P=0.006) were significantly higher compared with controls and showed a strong association with an almost threefold increased breast cancer risk independent of time to diagnosis. This study provides further evidence on the association of androgens and estrogens with breast cancer. In addition, it reports that high ER but not AR SB is associated with increased breast risk >2 years before diagnosis.     

Placental pathology of recurrent spontaneous abortion: the role of histopathological examination of products of conception in routine clinical practice: a mini review

BACKGROUND: Histopathological examination of products of conception from miscarriages is part of routine clinical practice. The extent of additional clinically relevant information provided by this investigation in the setting of recurrent spontaneous abortion remains uncertain. METHODS: Review of the literature was performed to identify studies reporting on findings of histological examination of routinely obtained products of conception in the setting of recurrent spontaneous abortion. The initial search identified 312 potential references, but 300 were excluded on further examination due to lack of data on specific histopathological findings in routine products of conception specimens from patients with recurrent spontaneous abortion. The 12 included studies indicated that such examination may identify hydatidiform moles, villous dysmorphic features suggesting fetal aneuploidy, chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition and impaired trophoblast invasion. However, in most cases, morphological assessment cannot reliably determine the cause of the miscarriage or distinguish recurrent from sporadic miscarriage. Studies reporting on the use of additional immunohistochemical methods do not currently provide additional clinically useful diagnostic or prognostic information. CONCLUSION: Routine histological examination of products of conception in the setting of recurrent spontaneous abortion can provide important clinical information in a minority of cases.     

HOXA methylation in normal endometrium from premenopausal women is associated with the presence of ovarian cancer: A proof of principle study

DNA methylation of polycomb group target (PCGT) genes is an early step in carcinogenesis and could potentially be assayed to determine cancer risk prediction. To assess whether methylation changes in PCGT genes in normal tissue is able to predict the presence of cancer, we studied HOXA gene methylation in normal endometrium from premenopausal ovarian cancer patients and age‐matched healthy controls without ovarian cancer. DNA methylation of HOXA9 and HOXA11 genes in normal endometrium was associated with ovarian cancer in an initial test set and this was subsequently confirmed in independent validation sample sets. The overall risk of ovarian cancer was increased 12.3‐fold by high HOXA9 methylation for all stages, and 14.8‐fold for early stage ovarian cancers, independent of age, phase of the menstrual cycle and histology of the cancer. The results of this proof of principle study demonstrate the potential to detect ovarian cancer via analysis of normal endometrial cells and provide insight into the possible contribution of this novel approach in ovarian cancer risk prediction and prevention. © 2009 UICC     

Histological confirmation of breast cancer registration and self-reporting in England and Wales: a cohort study within the UK Collaborative Trial of Ovarian Cancer Screening

Background:

In research studies, accurate information of cancer diagnosis is crucial. In women with breast cancer (BC), we compare cancer registration (CR) in England/Wales and self-reporting with independent confirmation.

Methods:

In the UK Collaborative Trial of Ovarian Cancer Screening, notification of BC diagnosed between randomisation and 31 December 2009 was obtained through (1) CR (17 October 2011) and (2) self-reporting using postal-questionnaire. Breast cancer was confirmed using a detailed questionnaire (BC questionnaire BCQ) completed by the treating clinician (gold standard). Apparent sensitivity and positive-predictive value of CR/self-reporting vs BCQ were calculated.

Results:

Of 1065 women with possible BC notification, diagnosis was confirmed in 932 (87.5%). A total of 3.1% (28 out of 918) of BC CR and 12.4% (128 out of 1032) of women with self-reported BC only had in-situ carcinoma on BCQ. Another 4.6% (43 out of 932) of BCQ-confirmed cancer did not have a BC registration, and 3.6% (34 out of 932) did not self-report BC. Apparent sensitivity of CR and self-reporting vs BCQ were 95.4 and 96.4%, respectively. Positive-predictive value of self-reporting (87.1%) was significantly lower than that of CR (96.8%). Women aged<65 were more likely to over report in-situ carcinoma as BC. Overall, 73 (6.8%) women would have been misclassified/missed if CR, and 167 (15.6%) if self-reporting data alone was used.

Conclusion:

This study confirms the reliability of BC registration in England/Wales and highlights the fact that 1 in 10 women self-reporting BC might only have in-situ breast carcinoma.     

Autoantibodies to MUC1 glycopeptides cannot be used as a screening assay for early detection of breast,ovarian, lung or pancreatic cancer

Background:

Autoantibodies have been detected in sera before diagnosis of cancer leading to interest in their potential as screening/early detection biomarkers. As we have found autoantibodies to MUC1 glycopeptides to be elevated in early-stage breast cancer patients, in this study we analysed these autoantibodies in large population cohorts of sera taken before cancer diagnosis.

Methods:

Serum samples from women who subsequently developed breast cancer, and aged-matched controls, were identified from UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and Guernsey serum banks to formed discovery and validation sets. These were screened on a microarray platform of 60mer MUC1 glycopeptides and recombinant MUC1 containing 16 tandem repeats. Additional case–control sets comprised of women who subsequently developed ovarian, pancreatic and lung cancer were also screened on the arrays.

Results:

In the discovery (273 cases, 273 controls) and the two validation sets (UKCTOCS 426 cases, 426 controls; Guernsey 303 cases and 606 controls), no differences were found in autoantibody reactivity to MUC1 tandem repeat peptide or glycoforms between cases and controls. Furthermore, no differences were observed between ovarian, pancreatic and lung cancer cases and controls.

Conclusion:

This robust, validated study shows autoantibodies to MUC1 peptide or glycopeptides cannot be used for breast, ovarian, lung or pancreatic cancer screening. This has significant implications for research on the use of MUC1 in cancer detection.     

Early detection of cancer in the general population: a blinded case–control study of p53 autoantibodies in colorectal cancer

Background:

Recent reports from cancer screening trials in high-risk populations suggest that autoantibodies can be detected before clinical diagnosis. However, there is minimal data on the role of autoantibody signatures in cancer screening in the general population.

Methods:

Informative p53 peptides were identified in sera from patients with colorectal cancer using an autoantibody microarray with 15-mer overlapping peptides covering the complete p53 sequence. The selected peptides were evaluated in a blinded case–control study using stored serum from the multimodal arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening where women gave annual blood samples. Cases were postmenopausal women who developed colorectal cancer following recruitment, with 2 or more serum samples preceding diagnosis. Controls were age-matched women with no history of cancer.

Results:

The 50 640 women randomised to the multimodal group were followed up for a median of 6.8 (inter-quartile range 5.9–8.4) years. Colorectal cancer notification was received in 101 women with serial samples of whom 97 (297 samples) had given consent for secondary studies. They were matched 1 : 1 with 97 controls (296 serial samples). The four most informative peptides identified 25.8% of colorectal cancer patients with a specificity of 95%. The median lead time was 1.4 (range 0.12–3.8) years before clinical diagnosis.

Conclusion:

Our findings suggest that in the general population, autoantibody signatures are detectable during preclinical disease and may be of value in cancer screening. In colorectal cancer screening in particular, where the current need is to improve compliance, it suggests that p53 autoantibodies may contribute towards risk stratification.     

DNA methylation of polycomb group target genes in cores taken from breast cancer centre and periphery

We previously demonstrated that methylation of neugogenic differentiation 1 (NEUROD1) gene, a polycomb group target (PCGT) gene is a predictor of response to neoadjuvant chemotherapy in breast cancer. Here, we address the question whether NEUROD1 methylation provides clinical information independent from its expression level, and whether PCGT methylation is homogeneous in breast cancer. We examined: (1) NEUROD1 methylation and mRNA expression in 9 breast cancer cell lines and 63 tumour specimens, (2) DNA methylation in a training set of 55 PCGT genes taken from the centre (TUC) and periphery (TUP) of 15 breast cancer specimens, and compared this with 22 non neoplastic controls, and finally, (3) validated statistically significant genes in an independent set of 20 cases versus 18 controls. 8/9 cell lines demonstrated NEUROD1 methylation, whereas, there was only one cell-line that showed NEUROD1 expression. There was no association between methylation and expression in breast tumour specimens, with only 14% exhibiting NEUROD1 expression. Of the 55 PCGT genes analysed, 24% (13/55) were shown to be cancer specific (p < 0.05) with a receiver-operating-characteristic (ROC) area-under-the-curve (AUC) of >0.7 (range 0.71–0.95). DNA methylation accurately predicted the presence of cancer in both TUC and TUP. DNA methylation of PCGT genes predicts the presence of breast cancer and is not subject to tumour heterogeneity. Further work will reveal if methylation of PCGT genes will serve as a robust means for the clinical detection and assessment of breast cancer.     

Protein Z: A putative novel biomarker for early detection of ovarian cancer

Ovarian cancer (OC) has the highest mortality of all gynaecological cancers. Early diagnosis offers an approach to achieving better outcomes. We conducted a blinded‐evaluation of prospectively collected preclinical serum from participants in the multimodal group of the United Kingdom Collaborative Trial of Ovarian Cancer Screening. Using isobaric tags (iTRAQ) we identified 90 proteins differentially expressed between OC cases and controls. A second targeted mass spectrometry analysis of twenty of these candidates identified Protein Z as a potential early detection biomarker for OC. This was further validated by ELISA analysis in 482 serial serum samples, from 80 individuals, 49 OC cases and 31 controls, spanning up to 7 years prior to diagnosis. Protein Z was significantly down‐regulated up to 2 years pre‐diagnosis (p = 0.000000411) in 8 of 19 Type I patients whilst in 5 Type II individuals, it was significantly up‐regulated up to 4 years before diagnosis (p = 0.01). ROC curve analysis for CA‐125 and CA‐125 combined with Protein Z showed a statistically significant (p= 0.00033) increase in the AUC from 77 to 81% for Type I and a statistically significant (p= 0.00003) increase in the AUC from 76 to 82% for Type II. Protein Z is a novel independent early detection biomarker for Type I and Type II ovarian cancer; which can discriminate between both types. Protein Z also adds to CA‐125 and potentially the Risk of Ovarian Cancer algorithm in the detection of both subtypes.     

Diagnostic routes and time intervals for ovarian cancer in nine international jurisdictions; findings from the International Cancer Benchmarking Partnership (ICBP)

Background International Cancer Benchmarking Partnership Module 4 reports the first international comparison of ovarian cancer (OC) diagnosis routes and intervals (symptom onset to treatment start), which may inform previously reported variations in survival and stage.Methods Data were collated from 1110 newly diagnosed OC patients aged >40 surveyed between 2013 and 2015 across five countries (51–272 per jurisdiction), their primary-care physicians (PCPs) and cancer treatment specialists, supplement by treatment records or clinical databases. Diagnosis routes and time interval differences using quantile regression with reference to Denmark (largest survey response) were calculated.Results There were no significant jurisdictional differences in the proportion diagnosed with symptoms on the Goff Symptom Index (53%; P = 0.179) or National Institute for Health and Care Excellence NG12 guidelines (62%; P = 0.946). Though the main diagnosis route consistently involved primary-care presentation (63–86%; P = 0.068), onward urgent referral rates varied significantly (29–79%; P < 0.001). In most jurisdictions, diagnostic intervals were generally shorter and other intervals, in particular, treatment longer compared to Denmark.Conclusion This study highlights key intervals in the diagnostic pathway where improvements could be made. It provides the opportunity to consider the systems and approaches across different jurisdictions that might allow for more timely ovarian cancer diagnosis and treatment.Subject terms: Cancer, Health services