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3 pages, 179 KiB

Open AccessEditorial

Special Issue “Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer”

by Ranjit Manchanda

Cancers 2022, 14(2), 319; https://doi.org/10.3390/cancers14020319 - 10 Jan 2022

Cited by 2 | Viewed by 2361

Abstract

Over the last decade there have been significant advances and developments in our understanding of factors affecting women’s cancer risk, our ability to identify individuals at increased risk and risk stratify populations, as well as implement and evaluate strategies for screening and prevention [...] Read more.

Over the last decade there have been significant advances and developments in our understanding of factors affecting women’s cancer risk, our ability to identify individuals at increased risk and risk stratify populations, as well as implement and evaluate strategies for screening and prevention [...] Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

Research

Jump to: Editorial, Review

17 pages, 303 KiB

Open AccessArticle

Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study

by Dhivya Chandrasekaran, Monika Sobocan, Oleg Blyuss, Rowan E. Miller, Olivia Evans, Shanthini M. Crusz, Tina Mills-Baldock, Li Sun, Rory F. L. Hammond, Faiza Gaba, Lucy A. Jenkins, Munaza Ahmed, Ajith Kumar, Arjun Jeyarajah, Alexandra C. Lawrence, Elly Brockbank, Saurabh Phadnis, Mary Quigley, Fatima El Khouly, Rekha Wuntakal, Asma Faruqi, Giorgia Trevisan, Laura Casey, George J. Burghel, Helene Schlecht, Michael Bulman, Philip Smith, Naomi L. Bowers, Rosa Legood, Michelle Lockley, Andrew Wallace, Naveena Singh, D. Gareth Evans and Ranjit Manchanda Show full author list Hide full author list

Cancers 2021, 13(17), 4344; https://doi.org/10.3390/cancers13174344 - 27 Aug 2021

Cited by 33 | Viewed by 3996

Abstract

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled [...] Read more.

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p < 0.001). The median age was 54 (IQR = 51–62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51–71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

15 pages, 561 KiB

Open AccessArticle

The Relationship between Body Mass Index and Mammographic Density during a Premenopausal Weight Loss Intervention Study

by Emma C. Atakpa, Adam R. Brentnall, Susan Astley, Jack Cuzick, D. Gareth Evans, Ruth M. L. Warren, Anthony Howell and Michelle Harvie

Cancers 2021, 13(13), 3245; https://doi.org/10.3390/cancers13133245 - 29 Jun 2021

Cited by 6 | Viewed by 2191

Abstract

We evaluated the association between short-term change in body mass index (BMI) and breast density during a 1 year weight-loss intervention (Manchester, UK). We included 65 premenopausal women (35–45 years, ≥7 kg adult weight gain, family history of breast cancer). BMI and breast [...] Read more.

We evaluated the association between short-term change in body mass index (BMI) and breast density during a 1 year weight-loss intervention (Manchester, UK). We included 65 premenopausal women (35–45 years, ≥7 kg adult weight gain, family history of breast cancer). BMI and breast density (semi-automated area-based, automated volume-based) were measured at baseline, 1 year, and 2 years after study entry (1 year post intervention). Cross-sectional (between-women) and short-term change (within-women) associations between BMI and breast density were measured using repeated-measures correlation coefficients and multivariable linear mixed models. BMI was positively correlated with dense volume between-women (r = 0.41, 95%CI: 0.17, 0.61), but less so within-women (r = 0.08, 95%CI: −0.16, 0.28). There was little association with dense area (between-women r = −0.12, 95%CI: −0.38, 0.16; within-women r = 0.01, 95%CI: −0.24, 0.25). BMI and breast fat were positively correlated (volume: between r = 0.77, 95%CI: 0.69, 0.84, within r = 0.58, 95%CI: 0.36, 0.75; area: between r = 0.74, 95%CI: 0.63, 0.82, within r = 0.45, 95%CI: 0.23, 0.63). Multivariable models reported similar associations. Exploratory analysis suggested associations between BMI gain from 20 years and density measures (standard deviation change per +5 kg/m² BMI: dense area: +0.61 (95%CI: 0.12, 1.09); fat volume: −0.31 (95%CI: −0.62, 0.00)). Short-term BMI change is likely to be positively associated with breast fat, but we found little association with dense tissue, although power was limited by small sample size. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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15 pages, 493 KiB

Open AccessArticle

Is Breast Cancer Risk Associated with Menopausal Hormone Therapy Modified by Current or Early Adulthood BMI or Age of First Pregnancy?

by Eleni Leventea, Elaine F. Harkness, Adam R. Brentnall, Anthony Howell, D. Gareth Evans and Michelle Harvie

Cancers 2021, 13(11), 2710; https://doi.org/10.3390/cancers13112710 - 31 May 2021

Cited by 3 | Viewed by 3265

Abstract

Menopausal hormone therapy (MHT) has an attenuated effect on breast cancer (BC) risk amongst heavier women, but there are few data on a potential interaction with early adulthood body mass index (at age 20 years) and age of first pregnancy. We studied 56,489 [...] Read more.

Menopausal hormone therapy (MHT) has an attenuated effect on breast cancer (BC) risk amongst heavier women, but there are few data on a potential interaction with early adulthood body mass index (at age 20 years) and age of first pregnancy. We studied 56,489 women recruited to the PROCAS (Predicting Risk of Cancer at Screening) study in Manchester UK, 2009-15. Cox regression models estimated the effect of reported MHT use at entry on breast cancer (BC) risk, and potential interactions with a. self-reported current body mass index (BMI), b. BMI aged 20 and c. First pregnancy >30 years or nulliparity compared with first pregnancy <30 years. Analysis was adjusted for age, height, family history, age of menarche and menopause, menopausal status, oophorectomy, ethnicity, self-reported exercise and alcohol. With median follow up of 8 years, 1663 breast cancers occurred. BC risk was elevated amongst current users of combined MHT compared to never users (Hazard ratioHR 1.64, 95% CI 1.32–2.03), risk was higher than for oestrogen only users (HR 1.03, 95% CI 0.79–1.34). Risk of current MHT was attenuated by current BMI (interaction HR 0.80, 95% CI 0.65–0.99) per 5 unit increase in BMI. There was little evidence of an interaction between MHT use, breast cancer risk and early and current BMI or with age of first pregnancy. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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16 pages, 2285 KiB

Open AccessArticle

Tumor Signature Analysis Implicates Hereditary Cancer Genes in Endometrial Cancer Development

by Olga Kondrashova, Jannah Shamsani, Tracy A. O’Mara, Felicity Newell, Amy E. McCart Reed, Sunil R. Lakhani, Judy Kirk, John V. Pearson, Nicola Waddell and Amanda B. Spurdle

Cancers 2021, 13(8), 1762; https://doi.org/10.3390/cancers13081762 - 7 Apr 2021

Cited by 6 | Viewed by 3335

Abstract

Risk of endometrial cancer (EC) is increased ~2-fold for women with a family history of cancer, partly due to inherited pathogenic variants in mismatch repair (MMR) genes. We explored the role of additional genes as explanation for familial EC presentation by investigating germline [...] Read more.

Risk of endometrial cancer (EC) is increased ~2-fold for women with a family history of cancer, partly due to inherited pathogenic variants in mismatch repair (MMR) genes. We explored the role of additional genes as explanation for familial EC presentation by investigating germline and EC tumor sequence data from The Cancer Genome Atlas (n = 539; 308 European ancestry), and germline data from 33 suspected familial European ancestry EC patients demonstrating immunohistochemistry-detected tumor MMR proficiency. Germline variants in MMR and 26 other known/candidate EC risk genes were annotated for pathogenicity in the two EC datasets, and also for European ancestry individuals from gnomAD as a population reference set (n = 59,095). Ancestry-matched case–control comparisons of germline variant frequency and/or sequence data from suspected familial EC cases highlighted ATM, PALB2, RAD51C, MUTYH and NBN as candidates for large-scale risk association studies. Tumor mutational signature analysis identified a microsatellite-high signature for all cases with a germline pathogenic MMR gene variant. Signature analysis also indicated that germline loss-of-function variants in homologous recombination (BRCA1, PALB2, RAD51C) or base excision (NTHL1, MUTYH) repair genes can contribute to EC development in some individuals with germline variants in these genes. These findings have implications for expanded therapeutic options for EC cases. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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13 pages, 971 KiB

Open AccessArticle

Performance Characteristics of the Ultrasound Strategy during Incidence Screening in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

by Jatinderpal Kalsi, Aleksandra Gentry-Maharaj, Andy Ryan, Naveena Singh, Matthew Burnell, Susan Massingham, Sophia Apostolidou, Aarti Sharma, Karin Williamson, Mourad Seif, Tim Mould, Robert Woolas, Stephen Dobbs, Simon Leeson, Lesley Fallowfield, Steven J. Skates, Mahesh Parmar, Stuart Campbell, Ian Jacobs, Alistair McGuire and Usha Menon Show full author list Hide full author list

Cancers 2021, 13(4), 858; https://doi.org/10.3390/cancers13040858 - 18 Feb 2021

Cited by 6 | Viewed by 6620

Abstract

Randomised controlled trials of ovarian cancer (OC) screening have not yet demonstrated an impact on disease mortality. Meanwhile, the screening data from clinical trials represents a rich resource to understand the performance of modalities used. We report here on incidence screening in the [...] Read more.

Randomised controlled trials of ovarian cancer (OC) screening have not yet demonstrated an impact on disease mortality. Meanwhile, the screening data from clinical trials represents a rich resource to understand the performance of modalities used. We report here on incidence screening in the ultrasound arm of UKCTOCS. 44,799 of the 50,639 women who were randomised to annual screening with transvaginal ultrasound attended annual incidence screening between 28 April 2002 and 31 December 2011. Transvaginal ultrasound was used both as the first and the second line test. Participants were followed up through electronic health record linkage and postal questionnaires. Out of 280,534 annual incidence screens, 960 women underwent screen-positive surgery. 113 had ovarian/tubal cancer (80 invasive epithelial). Of the screen-detected invasive epithelial cancers, 37.5% (95% CI: 26.9–49.0) were Stage I/II. An additional 52 (50 invasive epithelial) were diagnosed within one year of their last screen. Of the 50 interval epithelial cancers, 6.0% (95% CI: 1.3–16.5) were Stage I/II. For detection of all ovarian/tubal cancers diagnosed within one year of screen, the sensitivity, specificity, and positive predictive values were 68.5% (95% CI: 60.8–75.5), 99.7% (95% CI: 99.7–99.7), and 11.8% (95% CI: 9.8–14) respectively. When the analysis was restricted to invasive epithelial cancers, sensitivity, specificity and positive predictive values were 61.5% (95% CI: 52.6–69.9); 99.7% (95% CI: 99.7–99.7) and 8.3% (95% CI: 6.7–10.3), with 12 surgeries per screen positive. The low sensitivity coupled with the advanced stage of interval cancers suggests that ultrasound scanning as the first line test might not be suitable for population screening for ovarian cancer. Trial registration: ISRCTN22488978. Registered on 6 April 2000. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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23 pages, 10340 KiB

Open AccessArticle

Metabolomic Biomarkers for the Detection of Obesity-Driven Endometrial Cancer

by Kelechi Njoku, Amy E. Campbell, Bethany Geary, Michelle L. MacKintosh, Abigail E. Derbyshire, Sarah J. Kitson, Vanitha N. Sivalingam, Andrew Pierce, Anthony D. Whetton and Emma J. Crosbie

Cancers 2021, 13(4), 718; https://doi.org/10.3390/cancers13040718 - 10 Feb 2021

Cited by 21 | Viewed by 4897

Abstract

Endometrial cancer is the most common malignancy of the female genital tract and a major cause of morbidity and mortality in women. Early detection is key to ensuring good outcomes but a lack of minimally invasive screening tools is a significant barrier. Most [...] Read more.

Endometrial cancer is the most common malignancy of the female genital tract and a major cause of morbidity and mortality in women. Early detection is key to ensuring good outcomes but a lack of minimally invasive screening tools is a significant barrier. Most endometrial cancers are obesity-driven and develop in the context of severe metabolomic dysfunction. Blood-derived metabolites may therefore provide clinically relevant biomarkers for endometrial cancer detection. In this study, we analysed plasma samples of women with body mass index (BMI) ≥ 30 kg/m² and endometrioid endometrial cancer (cases, n = 67) or histologically normal endometrium (controls, n = 69), using a mass spectrometry-based metabolomics approach. Eighty percent of the samples were randomly selected to serve as a training set and the remaining 20% were used to qualify test performance. Robust predictive models (AUC > 0.9) for endometrial cancer detection based on artificial intelligence algorithms were developed and validated. Phospholipids were of significance as biomarkers of endometrial cancer, with sphingolipids (sphingomyelins) discriminatory in post-menopausal women. An algorithm combining the top ten performing metabolites showed 92.6% prediction accuracy (AUC of 0.95) for endometrial cancer detection. These results suggest that a simple blood test could enable the early detection of endometrial cancer and provide the basis for a minimally invasive screening tool for women with a BMI ≥ 30 kg/m². Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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19 pages, 2156 KiB

Open AccessArticle

Aberrant Dyskerin Expression Is Related to Proliferation and Poor Survival in Endometrial Cancer

by Rafah Alnafakh, Gabriele Saretzki, Angela Midgley, James Flynn, Areege M. Kamal, Lucy Dobson, Purushothaman Natarajan, Helen Stringfellow, Pierre Martin-Hirsch, Shandya B. DeCruze, Sarah E. Coupland and Dharani K. Hapangama

Cancers 2021, 13(2), 273; https://doi.org/10.3390/cancers13020273 - 13 Jan 2021

Cited by 10 | Viewed by 3371

Abstract

Dyskerin is a core-component of the telomerase holo-enzyme, which elongates telomeres. Telomerase is involved in endometrial epithelial cell proliferation. Most endometrial cancers (ECs) have high telomerase activity; however, dyskerin expression in human healthy endometrium or in endometrial pathologies has not been investigated yet. [...] Read more.

Dyskerin is a core-component of the telomerase holo-enzyme, which elongates telomeres. Telomerase is involved in endometrial epithelial cell proliferation. Most endometrial cancers (ECs) have high telomerase activity; however, dyskerin expression in human healthy endometrium or in endometrial pathologies has not been investigated yet. We aimed to examine the expression, prognostic relevance, and functional role of dyskerin in human EC. Endometrial samples from a cohort of 175 women were examined with immunohistochemistry, immunoblotting, and qPCR. The EC cells were transfected with Myc-DDK-DKC1 plasmid and the effect of dyskerin overexpression on EC cell proliferation was assessed by flow cytometry. Human endometrium expresses dyskerin (DKC1) and dyskerin protein levels are significantly reduced in ECs when compared with healthy postmenopausal endometrium. Low dyskerin immunoscores were potentially associated with worse outcomes, suggesting a possible prognostic relevance. Cancer Genome Atlas (TCGA) ECs dataset (n = 589) was also interrogated. The TCGA dataset further confirmed changes in DKC1 expression in EC with prognostic significance. Transient dyskerin overexpression had a negative effect on EC cell proliferation. Our data demonstrates a role for dyskerin in normal endometrium for the first time and confirms aberrant expression with possible prognostic relevance in EC. Interventions aimed at modulating dyskerin levels may provide novel therapeutic options in EC. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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19 pages, 673 KiB

Open AccessArticle

Long-Term Evaluation of Women Referred to a Breast Cancer Family History Clinic (Manchester UK 1987–2020)

by Anthony Howell, Ashu Gandhi, Sacha Howell, Mary Wilson, Anthony Maxwell, Susan Astley, Michelle Harvie, Mary Pegington, Lester Barr, Andrew Baildam, Elaine Harkness, Penelope Hopwood, Julie Wisely, Andrea Wilding, Rosemary Greenhalgh, Jenny Affen, Andrew Maurice, Sally Cole, Julia Wiseman, Fiona Lalloo, David P. French and D. Gareth Evans Show full author list Hide full author list

Cancers 2020, 12(12), 3697; https://doi.org/10.3390/cancers12123697 - 9 Dec 2020

Cited by 11 | Viewed by 4011

Abstract

Clinics for women concerned about their family history of breast cancer are widely established. A Family History Clinic was set-up in Manchester, UK, in 1987 in a Breast Unit serving a population of 1.8 million. In this review, we report the outcome of [...] Read more.

Clinics for women concerned about their family history of breast cancer are widely established. A Family History Clinic was set-up in Manchester, UK, in 1987 in a Breast Unit serving a population of 1.8 million. In this review, we report the outcome of risk assessment, screening and prevention strategies in the clinic and propose future approaches. Between 1987–2020, 14,311 women were referred, of whom 6.4% were from known gene families, 38.2% were at high risk (≥30% lifetime risk), 37.7% at moderate risk (17–29%), and 17.7% at an average/population risk who were discharged. A total of 4168 (29.1%) women were eligible for genetic testing and 736 carried pathogenic variants, predominantly in BRCA1 and BRCA2 but also other genes (5.1% of direct referrals). All women at high or moderate risk were offered annual mammographic screening between ages 30 and 40 years old: 646 cancers were detected in women at high and moderate risk (5.5%) with a detection rate of 5 per 1000 screens. Incident breast cancers were largely of good prognosis and resulted in a predicted survival advantage. All high/moderate-risk women were offered lifestyle prevention advice and 14–27% entered various lifestyle studies. From 1992–2003, women were offered entry into IBIS-I (tamoxifen) and IBIS-II (anastrozole) trials (12.5% of invitees joined). The NICE guidelines ratified the use of tamoxifen and raloxifene (2013) and subsequently anastrozole (2017) for prevention; 10.8% women took up the offer of such treatment between 2013–2020. Since 1994, 7164 eligible women at ≥25% lifetime risk of breast cancer were offered a discussion of risk-reducing breast surgery and 451 (6.2%) had surgery. New approaches in all aspects of the service are needed to build on these results. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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21 pages, 1143 KiB

Open AccessArticle

Women’s Intentions to Engage in Risk-Reducing Behaviours after Receiving Personal Ovarian Cancer Risk Information: An Experimental Survey Study

by Ailish Gallagher, Jo Waller, Ranjit Manchanda, Ian Jacobs and Saskia Sanderson

Cancers 2020, 12(12), 3543; https://doi.org/10.3390/cancers12123543 - 27 Nov 2020

Cited by 5 | Viewed by 3303

Abstract

Risk stratification using genetic and/or other types of information could identify women at increased ovarian cancer risk. The aim of this study was to examine women’s potential reactions to ovarian cancer risk stratification. A total of 1017 women aged 45–75 years took part [...] Read more.

Risk stratification using genetic and/or other types of information could identify women at increased ovarian cancer risk. The aim of this study was to examine women’s potential reactions to ovarian cancer risk stratification. A total of 1017 women aged 45–75 years took part in an online experimental survey. Women were randomly assigned to one of three experimental conditions describing hypothetical personal results from ovarian cancer risk stratification, and asked to imagine they had received one of three results: (a) 5% lifetime risk due to single nucleotide polymorphisms (SNPs) and lifestyle factors; (b) 10% lifetime risk due to SNPs and lifestyle factors; (c) 10% lifetime risk due to a single rare mutation in a gene. Results: 83% of women indicated interest in having ovarian cancer risk assessment. After receiving their hypothetical risk estimates, 29% of women stated they would have risk-reducing surgery. Choosing risk-reducing surgery over other behavioural responses was associated with having higher surgery self-efficacy and perceived response-efficacy, but not with perceptions of disease threat, i.e., perceived risk or severity, or with experimental condition. A substantial proportion of women age 45–75 years may be open to the idea of surgery to reduce risk of ovarian cancer, even if their absolute lifetime risk is only increased to as little as 5 or 10%. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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12 pages, 548 KiB

Open AccessArticle

Multi-Marker Longitudinal Algorithms Incorporating HE4 and CA125 in Ovarian Cancer Screening of Postmenopausal Women

by Aleksandra Gentry-Maharaj, Oleg Blyuss, Andy Ryan, Matthew Burnell, Chloe Karpinskyj, Richard Gunu, Jatinderpal K. Kalsi, Anne Dawnay, Ines P. Marino, Ranjit Manchanda, Karen Lu, Wei-Lei Yang, John F. Timms, Max Parmar, Steven J. Skates, Robert C. Bast, Jr., Ian J. Jacobs, Alexey Zaikin and Usha Menon

Cancers 2020, 12(7), 1931; https://doi.org/10.3390/cancers12071931 - 17 Jul 2020

Cited by 18 | Viewed by 4512

Abstract

Longitudinal CA125 algorithms are the current basis of ovarian cancer screening. We report on longitudinal algorithms incorporating multiple markers. In the multimodal arm of United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), 50,640 postmenopausal women underwent annual screening using a serum CA125 [...] Read more.

Longitudinal CA125 algorithms are the current basis of ovarian cancer screening. We report on longitudinal algorithms incorporating multiple markers. In the multimodal arm of United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), 50,640 postmenopausal women underwent annual screening using a serum CA125 longitudinal algorithm. Women (cases) with invasive tubo-ovarian cancer (WHO 2014) following outcome review with stored annual serum samples donated in the 5 years preceding diagnosis were matched 1:1 to controls (no invasive tubo-ovarian cancer) in terms of the number of annual samples and age at randomisation. Blinded samples were assayed for serum human epididymis protein 4 (HE4), CA72-4 and anti-TP53 autoantibodies. Multimarker method of mean trends (MMT) longitudinal algorithms were developed using the assay results and trial CA125 values on the training set and evaluated in the blinded validation set. The study set comprised of 1363 (2–5 per woman) serial samples from 179 cases and 181 controls. In the validation set, area under the curve (AUC) and sensitivity of longitudinal CA125-MMT algorithm were 0.911 (0.871–0.952) and 90.5% (82.5–98.6%). None of the longitudinal multi-marker algorithms (CA125-HE4, CA125-HE4-CA72-4, CA125-HE4-CA72-4-anti-TP53) performed better or improved on lead-time. Our population study suggests that longitudinal HE4, CA72-4, anti-TP53 autoantibodies adds little value to longitudinal serum CA125 as a first-line test in ovarian cancer screening of postmenopausal women. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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38 pages, 5596 KiB

Open AccessArticle

Economic Evaluation of Population-Based BRCA1/BRCA2 Mutation Testing across Multiple Countries and Health Systems

by Ranjit Manchanda, Li Sun, Shreeya Patel, Olivia Evans, Janneke Wilschut, Ana Carolina De Freitas Lopes, Faiza Gaba, Adam Brentnall, Stephen Duffy, Bin Cui, Patricia Coelho De Soarez, Zakir Husain, John Hopper, Zia Sadique, Asima Mukhopadhyay, Li Yang, Johannes Berkhof and Rosa Legood

Cancers 2020, 12(7), 1929; https://doi.org/10.3390/cancers12071929 - 17 Jul 2020

Cited by 51 | Viewed by 13707

Abstract

Clinical criteria/Family history-based BRCA testing misses a large proportion of BRCA carriers who can benefit from screening/prevention. We estimate the cost-effectiveness of population-based BRCA testing in general population women across different countries/health systems. A Markov model comparing the lifetime costs and effects of [...] Read more.

Clinical criteria/Family history-based BRCA testing misses a large proportion of BRCA carriers who can benefit from screening/prevention. We estimate the cost-effectiveness of population-based BRCA testing in general population women across different countries/health systems. A Markov model comparing the lifetime costs and effects of BRCA1/BRCA2 testing all general population women ≥30 years compared with clinical criteria/FH-based testing. Separate analyses are undertaken for the UK/USA/Netherlands (high-income countries/HIC), China/Brazil (upper–middle income countries/UMIC) and India (low–middle income countries/LMIC) using both health system/payer and societal perspectives. BRCA carriers undergo appropriate screening/prevention interventions to reduce breast cancer (BC) and ovarian cancer (OC) risk. Outcomes include OC, BC, and additional heart disease deaths and incremental cost-effectiveness ratio (ICER)/quality-adjusted life year (QALY). Probabilistic/one-way sensitivity analyses evaluate model uncertainty. For the base case, from a societal perspective, we found that population-based BRCA testing is cost-saving in HIC (UK-ICER = $−5639/QALY; USA-ICER = $−4018/QALY; Netherlands-ICER = $−11,433/QALY), and it appears cost-effective in UMIC (China-ICER = $18,066/QALY; Brazil-ICER = $13,579/QALY), but it is not cost-effective in LMIC (India-ICER = $23,031/QALY). From a payer perspective, population-based BRCA testing is highly cost-effective in HIC (UK-ICER = $21,191/QALY, USA-ICER = $16,552/QALY, Netherlands-ICER = $25,215/QALY), and it is cost-effective in UMIC (China-ICER = $23,485/QALY, Brazil−ICER = $20,995/QALY), but it is not cost-effective in LMIC (India-ICER = $32,217/QALY). BRCA testing costs below $172/test (ICER = $19,685/QALY), which makes it cost-effective (from a societal perspective) for LMIC/India. Population-based BRCA testing can prevent an additional 2319 to 2666 BC and 327 to 449 OC cases per million women than the current clinical strategy. Findings suggest that population-based BRCA testing for countries evaluated is extremely cost-effective across HIC/UMIC health systems, is cost-saving for HIC health systems from a societal perspective, and can prevent tens of thousands more BC/OC cases. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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21 pages, 591 KiB

Open AccessArticle

Population Study of Ovarian Cancer Risk Prediction for Targeted Screening and Prevention

by Faiza Gaba, Oleg Blyuss, Xinting Liu, Shivam Goyal, Nishant Lahoti, Dhivya Chandrasekaran, Margarida Kurzer, Jatinderpal Kalsi, Saskia Sanderson, Anne Lanceley, Munaza Ahmed, Lucy Side, Aleksandra Gentry-Maharaj, Yvonne Wallis, Andrew Wallace, Jo Waller, Craig Luccarini, Xin Yang, Joe Dennis, Alison Dunning, Andrew Lee, Antonis C. Antoniou, Rosa Legood, Usha Menon, Ian Jacobs and Ranjit Manchanda Show full author list Hide full author list

Cancers 2020, 12(5), 1241; https://doi.org/10.3390/cancers12051241 - 15 May 2020

Cited by 27 | Viewed by 6053

Abstract

Unselected population-based personalised ovarian cancer (OC) risk assessment combining genetic/epidemiology/hormonal data has not previously been undertaken. We aimed to perform a feasibility study of OC risk stratification of general population women using a personalised OC risk tool followed by risk management. Volunteers were [...] Read more.

Unselected population-based personalised ovarian cancer (OC) risk assessment combining genetic/epidemiology/hormonal data has not previously been undertaken. We aimed to perform a feasibility study of OC risk stratification of general population women using a personalised OC risk tool followed by risk management. Volunteers were recruited through London primary care networks. Inclusion criteria: women ≥18 years. Exclusion criteria: prior ovarian/tubal/peritoneal cancer, previous genetic testing for OC genes. Participants accessed an online/web-based decision aid along with optional telephone helpline use. Consenting individuals completed risk assessment and underwent genetic testing (BRCA1/BRCA2/RAD51C/RAD51D/BRIP1, OC susceptibility single-nucleotide polymorphisms). A validated OC risk prediction algorithm provided a personalised OC risk estimate using genetic/lifestyle/hormonal OC risk factors. Population genetic testing (PGT)/OC risk stratification uptake/acceptability, satisfaction, decision aid/telephone helpline use, psychological health and quality of life were assessed using validated/customised questionnaires over six months. Linear-mixed models/contrast tests analysed impact on study outcomes. Main outcomes: feasibility/acceptability, uptake, decision aid/telephone helpline use, satisfaction/regret, and impact on psychological health/quality of life. In total, 123 volunteers (mean age = 48.5 (SD = 15.4) years) used the decision aid, 105 (85%) consented. None fulfilled NHS genetic testing clinical criteria. OC risk stratification revealed 1/103 at ≥10% (high), 0/103 at ≥5%–<10% (intermediate), and 100/103 at <5% (low) lifetime OC risk. Decision aid satisfaction was 92.2%. The telephone helpline use rate was 13% and the questionnaire response rate at six months was 75%. Contrast tests indicated that overall depression (p = 0.30), anxiety (p = 0.10), quality-of-life (p = 0.99), and distress (p = 0.25) levels did not jointly change, while OC worry (p = 0.021) and general cancer risk perception (p = 0.015) decreased over six months. In total, 85.5–98.7% were satisfied with their decision. Findings suggest population-based personalised OC risk stratification is feasible and acceptable, has high satisfaction, reduces cancer worry/risk perception, and does not negatively impact psychological health/quality of life. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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21 pages, 4091 KiB

Open AccessArticle

High Galectin-7 and Low Galectin-8 Expression and the Combination of both are Negative Prognosticators for Breast Cancer Patients

by Anna Trebo, Nina Ditsch, Christina Kuhn, Helene Hildegard Heidegger, Christine Zeder-Goess, Thomas Kolben, Bastian Czogalla, Elisa Schmoeckel, Sven Mahner, Udo Jeschke and Anna Hester

Cancers 2020, 12(4), 953; https://doi.org/10.3390/cancers12040953 - 12 Apr 2020

Cited by 16 | Viewed by 2874

Abstract

Galectins are commonly overexpressed in cancer cells and their expression pattern is often associated with the aggressiveness and metastatic phenotype of the tumor. This study investigates the prognostic influence of the expression of galectin-7 (Gal-7) and galectin-8 (Gal-8) in tumor cell cytoplasm, nucleus [...] Read more.

Galectins are commonly overexpressed in cancer cells and their expression pattern is often associated with the aggressiveness and metastatic phenotype of the tumor. This study investigates the prognostic influence of the expression of galectin-7 (Gal-7) and galectin-8 (Gal-8) in tumor cell cytoplasm, nucleus and on surrounding immune cells. Primary breast cancer tissue of 235 patients was analyzed for the expression of Gal-7 and Gal-8 and correlated with clinical and pathological data and the outcome. To identify immune cell subpopulations, immunofluorescence double staining was performed. Significant correlations of Gal-7 expression in the cytoplasm with HER2-status, PR status, patient age and grading, and of Gal-8 expression in the cytoplasm with HER2-status and patient age and of both galectins between each other were found. A high Gal-7 expression in the cytoplasm was a significant independent prognosticator for an impaired progression free survival (PFS) (p = 0.017) and distant disease-free survival (DDFS) (p = 0.030). Gal-7 was also expressed by tumor-infiltrating macrophages. High Gal-8 expression in the cytoplasm was associated with a significantly improved overall survival (OS) (p = 0.032). Clinical outcome in patients showing both high Gal-7 and with low Gal-8 expression was very poor. Further understanding of the role of galectins in the regulation and interaction of tumor cells and macrophages is essential for finding new therapeutic targets. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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Review

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21 pages, 756 KiB

Open AccessReview

Identifying Ovarian Cancer in Symptomatic Women: A Systematic Review of Clinical Tools

by Garth Funston, Victoria Hardy, Gary Abel, Emma J. Crosbie, Jon Emery, Willie Hamilton and Fiona M. Walter

Cancers 2020, 12(12), 3686; https://doi.org/10.3390/cancers12123686 - 8 Dec 2020

Cited by 14 | Viewed by 4767

Abstract

In the absence of effective ovarian cancer screening programs, most women are diagnosed following the onset of symptoms. Symptom-based tools, including symptom checklists and risk prediction models, have been developed to aid detection. The aim of this systematic review was to identify and [...] Read more.

In the absence of effective ovarian cancer screening programs, most women are diagnosed following the onset of symptoms. Symptom-based tools, including symptom checklists and risk prediction models, have been developed to aid detection. The aim of this systematic review was to identify and compare the diagnostic performance of these tools. We searched MEDLINE, EMBASE and Cochrane CENTRAL, without language restriction, for relevant studies published between 1 January 2000 and 3 March 2020. We identified 1625 unique records and included 16 studies, evaluating 21 distinct tools in a range of settings. Fourteen tools included only symptoms; seven also included risk factors or blood tests. Four tools were externally validated—the Goff Symptom Index (sensitivity: 56.9–83.3%; specificity: 48.3–98.9%), a modified Goff Symptom Index (sensitivity: 71.6%; specificity: 88.5%), the Society of Gynaecologic Oncologists consensus criteria (sensitivity: 65.3–71.5%; specificity: 82.9–93.9%) and the QCancer Ovarian model (10% risk threshold—sensitivity: 64.1%; specificity: 90.1%). Study heterogeneity precluded meta-analysis. Given the moderate accuracy of several tools on external validation, they could be of use in helping to select women for ovarian cancer investigations. However, further research is needed to assess the impact of these tools on the timely detection of ovarian cancer and on patient survival. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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23 pages, 708 KiB

Open AccessReview

Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

by Marina Pavanello, Isaac HY Chan, Amir Ariff, Paul DP Pharoah, Simon A. Gayther and Susan J. Ramus

Cancers 2020, 12(10), 3046; https://doi.org/10.3390/cancers12103046 - 19 Oct 2020

Cited by 26 | Viewed by 5101

Abstract

A family history of ovarian or breast cancer is the strongest risk factor for epithelial ovarian cancer (EOC). Germline deleterious variants in the BRCA1 and BRCA2 genes confer EOC risks by age 80, of 44% and 17% respectively. The mismatch repair genes, particularly [...] Read more.

A family history of ovarian or breast cancer is the strongest risk factor for epithelial ovarian cancer (EOC). Germline deleterious variants in the BRCA1 and BRCA2 genes confer EOC risks by age 80, of 44% and 17% respectively. The mismatch repair genes, particularly MSH2 and MSH6, are also EOC susceptibility genes. Several other DNA repair genes, BRIP1, RAD51C, RAD51D, and PALB2, have been identified as moderate risk EOC genes. EOC has five main histotypes; high-grade serous (HGS), low-grade serous (LGS), clear cell (CCC), endometrioid (END), and mucinous (MUC). This review examines the current understanding of the contribution of rare genetic variants to EOC, focussing on providing frequency data for each histotype. We provide an overview of frequency and risk for pathogenic variants in the known susceptibility genes as well as other proposed genes. We also describe the progress to-date to understand the role of missense variants and the different breast and ovarian cancer risks for each gene. Identification of susceptibility genes have clinical impact by reducing disease-associated mortality through improving risk prediction, with the possibility of prevention strategies, and developing new targeted treatments and these clinical implications are also discussed. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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16 pages, 3099 KiB

Open AccessReview

Worldwide Review and Meta-Analysis of Cohort Studies Measuring the Effect of Mammography Screening Programmes on Incidence-Based Breast Cancer Mortality

by Amanda Dibden, Judith Offman, Stephen W. Duffy and Rhian Gabe

Cancers 2020, 12(4), 976; https://doi.org/10.3390/cancers12040976 - 15 Apr 2020

Cited by 92 | Viewed by 9501

Abstract

In 2012, the Euroscreen project published a review of incidence-based mortality evaluations of breast cancer screening programmes. In this paper, we update this review to October 2019 and expand its scope from Europe to worldwide. We carried out a systematic review of incidence-based [...] Read more.

In 2012, the Euroscreen project published a review of incidence-based mortality evaluations of breast cancer screening programmes. In this paper, we update this review to October 2019 and expand its scope from Europe to worldwide. We carried out a systematic review of incidence-based mortality studies of breast cancer screening programmes, and a meta-analysis of the estimated effects of both invitation to screening and attendance at screening, with adjustment for self-selection bias, on incidence-based mortality from breast cancer. We found 27 valid studies. The results of the meta-analysis showed a significant 22% reduction in breast cancer mortality with invitation to screening, with a relative risk of 0.78 (95% CI 0.75–0.82), and a significant 33% reduction with actual attendance at screening (RR 0.67, 95% CI 0.61–0.75). Breast cancer screening in the routine healthcare setting continues to confer a substantial reduction in mortality from breast cancer. Full article

(This article belongs to the Special Issue Gynaecological Cancers Risk: Breast Cancer, Ovarian Cancer and Endometrial Cancer)

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