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Advances in Inherited Breast and Ovarian Cancer and Its Imaging

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (15 July 2023) | Viewed by 16997

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Special Issue Editors

Prof. Dr. Gareth Evans

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Guest Editor

Division of Evolution & Genomic Sciences, the University of Manchester, Manchester, United Kingdom
Interests: BRCA1; BRCA2; breast and ovarian screening and prevention; PALB2; TP53
Special Issues, Collections and Topics in MDPI journals

Dr. Emma Woodward

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Guest Editor

Manchester University NHS Foundation Trust, Manchester, United Kingdom
Interests: BRCA1; BRCA2; breast and ovarian screening and prevention; PALB2; TP53; hereditary renal cancer; hereditary thyroid cancer

Prof. Dr. Judy Garber

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Guest Editor

Dana-Farber Cancer Institute and Medicine at Harvard Medical School, MA 02115, USA
Interests: BRCA1; BRCA2; breast and ovarian screening and prevention; PALB2; TP53

Special Issue Information

Dear Colleagues,

It is our pleasure to announce the launch of a new Special Issue in Cancers on the topic of “Advances in Inherited Breast and Ovarian Cancer and Its Imaging”. As the title suggests, we are interested in articles that reflect the sea change in inherited breast and ovarian cancer, specifically in the last 2–3 years. Some of the topics of interest include:

Emergence of genes now established as causative in both cancers, e.g., RAD51C and RAD51D;
Contribution of genes other than BRCA1 and BRCA2;
Emergence of clinical utility of polygenic risk scores;
Emergence of new preventive agents such as anti-progestins and RANKLi;
Updates on MRI screening;
Updates on ovarian screening.

We look forward to receiving your submissions.

Prof. Dr. Gareth Evans
Dr. Emma Woodward
Prof. Dr. Judy Garber
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

BRCA1
BRCA2
PALB2
RAD51C
RAD51D
BRIP1
MRI screening
polygenic risk scores
chemoprevention

Published Papers (7 papers)

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Research

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10 pages, 252 KiB

Open AccessArticle

Real-World Concordance between Germline and Tumour BRCA1/2 Status in Epithelial Ovarian Cancer

by Robert D. Morgan, George J. Burghel, Helene Schlecht, Andrew R. Clamp, Jurjees Hasan, Claire L. Mitchell, Zena Salih, Joseph Shaw, Sudha Desai, Gordon C. Jayson, Emma R. Woodward and D. Gareth R. Evans

Cancers 2024, 16(1), 177; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16010177 - 29 Dec 2023

Viewed by 594

Abstract

Patients diagnosed with epithelial ovarian cancer may undergo reflex tumour BRCA1/2 testing followed by germline BRCA1/2 testing in patients with a positive tumour test result. This testing model relies on tumour BRCA1/2 tests being able to detect all types of pathogenic variant. We analysed germline and tumour BRCA1/2 test results from patients treated for epithelial ovarian cancer at our specialist oncological referral centre. Tumour BRCA1/2 testing was performed using the next-generation sequencing (NGS)-based myChoice^® companion diagnostic (CDx; Myriad Genetics, Inc.). Germline BRCA1/2 testing was performed in the North West Genomic Laboratory Hub using NGS and multiplex ligation-dependent probe amplification. Between 11 April 2021 and 11 October 2023, 382 patients were successfully tested for tumour BRCA1 and BRCA2 variants. Of these, 367 (96.1%) patients were tested for germline BRCA1/2 variants. In those patients who underwent tumour and germline testing, 15.3% (56/367) had a BRCA1/2 pathogenic variant (36 germline and 20 somatic). All germline BRCA1/2 pathogenic small sequencing variants were detected in tumour DNA. By contrast, 3 out of 8 germline BRCA1/2 pathogenic large rearrangements were not reported in tumour DNA. The overall concordance of germline BRCA1/2 pathogenic variants detected in germline and tumour DNA was clinically acceptable at 91.7% (33/36). The myChoice^® CDx was able to detect most germline BRCA1/2 pathogenic variants in tumour DNA, although a proportion of pathogenic large rearrangements were not reported. If Myriad’s myChoice^® CDx is used for tumour BRCA1/2 testing, our data supports a testing strategy of germline and tumour BRCA1/2 testing in all patients diagnosed with epithelial ovarian cancer aged < 79 years old, with germline BRCA1/2 testing only necessary for patients aged ≥ 80 years old with a tumour BRCA1/2 pathogenic variant. Full article

(This article belongs to the Special Issue Advances in Inherited Breast and Ovarian Cancer and Its Imaging)

14 pages, 753 KiB

Open AccessArticle

Satisfaction with Long-Term Aesthetic and 10 Years Oncologic Outcome following Risk-Reducing Mastectomy and Implant-Based Breast Reconstruction with or without Nipple Preservation

by Rachel Louise O’Connell, Marios Konstantinos Tasoulis, Evguenia Hristova, Victoria Teoh, Ana Agusti, Ann Ward, Catherine Montgomery, Kabir Mohammed, Janet Self, Jennifer E. Rusby and Gerald Gui

Cancers 2022, 14(15), 3607; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14153607 - 24 Jul 2022

Cited by 3 | Viewed by 1899

Abstract

Incidence of bilateral risk-reducing mastectomies (RRMs) is increasing. The aim of this study was to compare satisfaction, aesthetic and oncological outcomes in women undergoing RRM with implant-based reconstruction comparing nipple-sparing mastectomy (NSM) with skin-sparing mastectomy (SSM) (sacrificing the nipple +/− nipple reconstruction). Women who had undergone bilateral RRM between 1997 and 2016 were invited. Aesthetic outcome and nipple symmetry were evaluated using standardized anthropometric measurements. The oncological outcome was assessed at last documented follow up. Ninety-three women (186 breasts) participated, 60 (64.5%) had NSM, 33 (35.5%) SSM. Median time between surgery and participation was 98.4 months (IQR: 61.7–133.9). Of the women, 23/33 (69.7%) who had SSM underwent nipple reconstruction. Nipple projection was shorter in the reconstructed SSM group than the maintained NSM group (p < 0.001). There was no significant difference in overall symmetry (p = 0.670), satisfaction regarding nipple preservation (p = 0.257) or overall nipple satisfaction (p = 0.074). There were no diagnoses of breast cancer at a median follow up of 129 months (IQR: 65–160.6). Women who undergo nipple-sparing RRM maintain long-term nipple symmetry. Nipple projection was less maintained after nipple reconstruction. Although satisfaction with the nipples was higher in the NSM group, this did not reach statistical significance. No breast cancers developed after RRM with long-term follow up. Full article

(This article belongs to the Special Issue Advances in Inherited Breast and Ovarian Cancer and Its Imaging)

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9 pages, 386 KiB

Open AccessArticle

Risk of Second Primary Thyroid Cancer in Women with Breast Cancer

by Monika Cieszyńska, Wojciech Kluźniak, Dominika Wokołorczyk, Cezary Cybulski, Tomasz Huzarski, Jacek Gronwald, Michał Falco, Tadeusz Dębniak, Anna Jakubowska, Róża Derkacz, Wojciech Marciniak, Marcin Lener, Karolina Woronko, Dominika Mocarz, Piotr Baszuk, Marta Bryśkiewicz, Steven A. Narod and Jan Lubiński

Cancers 2022, 14(4), 957; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14040957 - 15 Feb 2022

Cited by 5 | Viewed by 2353

Abstract

The goal of this study was to estimate the risk of thyroid cancer following breast cancer and to identify therapeutic and genetic risk factors for the development of thyroid cancer after breast cancer. We followed 10,832 breast cancer patients for a mean of 14 years for new cases of thyroid cancer. All women were genotyped for three Polish founder mutations in BRCA1 (C61G, 4153delA, 5382insC) and four mutations in CHEK2 (1100delC, IVS2 + 1G/A, del5395, I157T). Information was collected on chemotherapy, radiotherapy, hormonal therapies, and oophorectomy. Of the 10,832 women, 53 (0.49%) developed a second primary thyroid cancer. Based on Polish population statistics, the expected number was 12.4 (SIR = 4.3). The ten-year risk of developing thyroid cancer was higher in women who carried a CHEK2 mutation (1.5%) than in women who carried no mutation (0.9%). The age-adjusted hazard ratio for developing thyroid cancer was 1.89 (0.46–7.79; p = 0.38) for those with a CHEK2 protein-truncating mutation and 2.75 (1.29–5.85; p = 0.009) for those with a CHEK2 missense mutation. Full article

(This article belongs to the Special Issue Advances in Inherited Breast and Ovarian Cancer and Its Imaging)

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12 pages, 1113 KiB

Open AccessArticle

Whole-Body MRI Surveillance—Baseline Findings in the Swedish Multicentre Hereditary TP53-Related Cancer Syndrome Study (SWEP53)

by Meis Omran, Emma Tham, Yvonne Brandberg, Håkan Ahlström, Claudia Lundgren, Ylva Paulsson-Karlsson, Ekaterina Kuchinskaya, Gustav Silander, Anna Rosén, Fredrik Persson, Henrik Leonhardt, Marie Stenmark-Askmalm, Johanna Berg, Danielle van Westen, Svetlana Bajalica-Lagercrantz, Lennart Blomqvist and on behalf of the Swedish Clinical TP53 Study Group (SweClinTP53)

Cancers 2022, 14(2), 380; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020380 - 13 Jan 2022

Cited by 5 | Viewed by 2404

Abstract

A surveillance strategy of the heritable TP53-related cancer syndrome (hTP53rc), commonly referred to as the Li–Fraumeni syndrome (LFS), is studied in a prospective observational nationwide multi-centre study in Sweden (SWEP53). The aim of this sub-study is to evaluate whole-body MRI (WB-MRI) regarding the rate of malignant, indeterminate, and benign imaging findings and the associated further workup generated by the baseline examination. Individuals with hTP53rc were enrolled in a surveillance program including annual whole-body MRI (WB-MRI), brain-MRI, and in female carriers, dedicated breast MRI. A total of 68 adults ≥18 years old have been enrolled to date. Of these, 61 fulfilled the inclusion criteria for the baseline MRI scan. In total, 42 showed a normal scan, while 19 (31%) needed further workup, of whom three individuals (3/19 = 16%) were diagnosed with asymptomatic malignant tumours (thyroid cancer, disseminated upper GI cancer, and liver metastasis from a previous breast cancer). Forty-three participants were women, of whom 21 had performed risk-reducing mastectomy prior to inclusion. The remaining were monitored with breast MRI, and no breast tumours were detected on baseline MRI. WB-MRI has the potential to identify asymptomatic tumours in individuals with hTP53rc syndrome. The challenge is to adequately and efficiently investigate all indeterminate findings. Thus, a multidisciplinary team should be considered in surveillance programs for individuals with hTP53rc syndrome. Full article

(This article belongs to the Special Issue Advances in Inherited Breast and Ovarian Cancer and Its Imaging)

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15 pages, 589 KiB

Open AccessArticle

Gene Panel Testing for Breast Cancer Reveals Differential Effect of Prior BRCA1/2 Probability

by D. Gareth Evans, Elke M. van Veen, Emma R. Woodward, Elaine F. Harkness, Jamie M. Ellingford, Naomi L. Bowers, Andrew J. Wallace, Sacha J. Howell, Anthony Howell, Fiona Lalloo, William G. Newman and Miriam J. Smith

Cancers 2021, 13(16), 4154; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164154 - 18 Aug 2021

Cited by 5 | Viewed by 2386

Abstract

Whilst panel testing of an extended group of genes including BRCA1/2 is commonplace, these studies have not been subdivided by histiotype or by a priori BRCA1/2 probability. Patients with a breast cancer diagnosis undergoing extended panel testing were assessed for frequency of actionable variants in breast cancer genes other than BRCA1/2 by histiotype and Manchester score (MS) to reflect a priori BRCA1/2 likelihood. Rates were adjusted by prior testing for BRCA1/2 in an extended series. 95/1398 (6.3%) who underwent panel testing were found to be positive for actionable non-BRCA1/2 breast/ovarian cancer genes (ATM, BARD1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53). As expected, PALB2, CHEK2 and ATM were predominant with 80-(5.3%). The highest rate occurred in Grade-3 ER+/HER2− breast cancers-(9.6%). Rates of non-BRCA actionable genes was fairly constant over all likelihoods of BRCA1/2 but adjusted rates were three times higher with MS < 9 (BRCA1/2 = 1.5%, other = 4.7%), but was only 1.6% compared to 79.3% with MS ≥ 40. Although rates of detection of non-BRCA actionable genes are relatively constant across BRCA1/2 likelihoods this disguises an overall adjusted low frequency in high-likelihood families which have been heavily pre-tested for BRCA1/2. Any loss of detection sensitivity for BRCA1/2 actionable variants in breast cancer panels should lead to bespoke BRCA1/2 testing being conducted first. Full article

(This article belongs to the Special Issue Advances in Inherited Breast and Ovarian Cancer and Its Imaging)

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10 pages, 910 KiB

Open AccessArticle

Blood Arsenic Levels as a Marker of Breast Cancer Risk among BRCA1 Carriers

by Wojciech Marciniak, Tomáš Matoušek, Susan Domchek, Angelo Paradiso, Margherita Patruno, Arvids Irmejs, Irita Roderte, Róża Derkacz, Piotr Baszuk, Magdalena Kuświk, Cezary Cybulski, Tomasz Huzarski, Jacek Gronwald, Tadeusz Dębniak, Michał Falco, Marcin R. Lener, Anna Jakubowska, Katherine Pullella, Joanne Kotsopoulos, Steven Narod and Jan Lubiński Show full author list Hide full author list

Cancers 2021, 13(13), 3345; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133345 - 03 Jul 2021

Cited by 6 | Viewed by 3500

Abstract

An important group of breast cancers is those associated with inherited susceptibility. In women, several predisposing mutations in genes involved in DNA repair have been discovered. Women with a germline pathogenic variant in BRCA1 have a lifetime cancer risk of 70%. As part of a larger prospective study on heavy metals, our aim was to investigate if blood arsenic levels are associated with breast cancer risk among women with inherited BRCA1 mutations. A total of 1084 participants with pathogenic variants in BRCA1 were enrolled in this study. Subjects were followed from 2011 to 2020 (mean follow-up time: 3.75 years). During that time, 90 cancers were diagnosed, including 67 breast and 10 ovarian cancers. The group was stratified into two categories (lower and higher blood As levels), divided at the median (<0.85 µg/L and ≥0.85 µg/L) As level among all unaffected participants. Cox proportional hazards models were used to model the association between As levels and cancer incidence. A high blood As level (≥0.85 µg/L) was associated with a significantly increased risk of developing breast cancer (HR = 2.05; 95%CI: 1.18–3.56; p = 0.01) and of any cancer (HR = 1.73; 95%CI: 1.09–2.74; p = 0.02). These findings suggest a possible role of environmental arsenic in the development of cancers among women with germline pathogenic variants in BRCA1. Full article

(This article belongs to the Special Issue Advances in Inherited Breast and Ovarian Cancer and Its Imaging)

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10 pages, 1792 KiB

Open AccessProtocol

Personalised Risk Prediction in Hereditary Breast and Ovarian Cancer: A Protocol for a Multi-Centre Randomised Controlled Trial

by Stephanie Archer, Nichola Fennell, Ellen Colvin, Rozelle Laquindanum, Meredith Mills, Romy Dennis, Francisca Stutzin Donoso, Rochelle Gold, Alice Fan, Kate Downes, James Ford, Antonis C. Antoniou, Allison W. Kurian, D. Gareth Evans and Marc Tischkowitz

Cancers 2022, 14(11), 2716; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112716 - 31 May 2022

Cited by 8 | Viewed by 2702

Abstract

Women who test positive for an inherited pathogenic/likely pathogenic gene variant in BRCA1, BRCA2, PALB2, CHEK2 and ATM are at an increased risk of developing certain types of cancer—specifically breast (all) and epithelial ovarian cancer (only BRCA1, BRCA2, PALB2). Women receive broad cancer risk figures that are not personalised (e.g., 44–63% lifetime risk of breast cancer for those with PALB2). Broad, non-personalised risk estimates may be problematic for women when they are considering how to manage their risk. Multifactorial-risk-prediction tools have the potential to deliver personalised risk estimates. These may be useful in the patient’s decision-making process and impact uptake of risk-management options. This randomised control trial (registration number to follow), based in genetic centres in the UK and US, will randomise participants on a 1:1 basis to either receive conventional cancer risk estimates, as per routine clinical practice, or to receive a personalised risk estimate. This personalised risk estimate will be calculated using the CanRisk risk prediction tool, which combines the patient’s genetic result, family history and polygenic risk score (PRS), along with hormonal and lifestyle factors. Women’s decision-making around risk management will be monitored using questionnaires, completed at baseline (pre-appointment) and follow-up (one, three and twelve months after receiving their risk assessment). The primary outcome for this study is the type and timing of risk management options (surveillance, chemoprevention, surgery) taken up over the course of the study (i.e., 12 months). The type of risk-management options planned to be taken up in the future (i.e., beyond the end of the study) and the potential impact of personalised risk estimates on women’s psychosocial health will be collected as secondary-outcome measures. This study will also assess the acceptability, feasibility and cost-effectiveness of using personalised risk estimates in clinical care. Full article

(This article belongs to the Special Issue Advances in Inherited Breast and Ovarian Cancer and Its Imaging)

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