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Z Kemp,1 JA Ledermann1,21Department of Oncology, University College London Hospitals, 2University College London Cancer Institute, University College London, London, United KingdomAbstract: Despite the high response rate to first-line treatment of advanced ovarian cancer, the vast majority of patients relapse. Maximal debulking surgery and chemotherapy with a platinum doublet have remained the standard of care for many years and new approaches are imperative. Recent clinical trials have given grounds for hope. Neoadjuvant chemotherapy, intraperitoneal delivery, and dose-dense strategies have all shown promising results, as has the targeting of angiogenesis. A greater understanding of the molecular landscape of ovarian cancer is helping to identify new treatment options. In this review, we will highlight the key trials and recent progress in these areas.Keywords: ovarian cancer, first-line therapy, neoadjuvant, intraperitoneal, dose-dense, angiogenesis

Background: Genetic testing to identify germline high-risk pathogenic variants in breast cancer susceptibility genes is increasingly part of the breast cancer diagnostic pathway. Novel patient-centred pathways may offer opportunity to expand capacity and reduce turnaround time., Methods: We recruited 1140 women with unselected breast cancer to undergo germline genetic testing through the BRCA-DIRECT pathway (which includes a digital platform, postal saliva sampling and a genetic counsellor telephone helpline). Ahead of consenting to the test, participants were randomised to receive information about genetic testing digitally (569/1140, 49.9%) or via a pre-test genetic counselling consultation (571/1140, 50.1%)., Results: 1001 (87.8%) participants progressed to receive their pre-test information and consented to testing. The primary outcome, uptake of genetic testing, was higher amongst participants randomised to receive digital information compared with those randomised to a pre-test genetic counselling consultation (90.8% (95% CI: 88.5% to 93.1%) vs 84.7% (95% CI: 81.8% to 87.6%), p = 0.002, adjusted for participant age and site). Non-inferiority was observed in relation to patient knowledge, anxiety, and satisfaction., Conclusions: Findings demonstrate that standardised, digital information offers a non-inferior alternative to conventional genetic counselling, and an end-to-end patient-centred, digital pathway (supported by genetic counselling hotline) could feasibly be implemented into breast oncology settings., Clinical Trial Registration: The study is registered with, and protocol available on, ClinicalTrials.gov (NCT04842799)., (© 2024. The Author(s).)

Background: No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of BRCA1/2 PV carriers ascertained through clinical genetic centres., Methods: We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 BRCA1 and 1365 BRCA2 PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 SNPs and family history information., Results: The full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95% CI: 0.92 to 1.24) and in quintiles of predicted risk. Discrimination was maximised when all risk factors were considered (Harrell's C-index=0.70, 95% CI: 0.67 to 0.74; area under the curve=0.79, 95% CI: 0.76 to 0.82). The model performance was similar when evaluated separately in BRCA1 or BRCA2 PV carriers. The full model identified 5.8%, 12.9% and 24.0% of BRCA1/2 PV carriers with 5-year breast cancer risks of <1.65%, <3% and <5%, respectively, risk thresholds commonly used for different management and risk-reduction options., Conclusion: BOADICEA may be used to aid personalised cancer risk management and decision-making for BRCA1 and BRCA2 PV carriers. It is implemented in the free-access CanRisk tool (https://www.canrisk.org/)., Competing Interests: Competing interests: ACA and DFE are named creators of the BOADICEA model which has been licensed by Cambridge Enterprise (University of Cambridge). All the other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Low-profile suture passers have been introduced to facilitate thoracolumbar fascia closure in minimally invasive spine (MIS) surgery. The purpose of this study was to evaluate the closure time of a modern suture passer to a conventional curved need for MIS fascia closure in a cadaveric model., Methods: Six clinicians specializing in orthopedic spine surgery were recruited for the study and randomly assigned 1 cadaveric torso. Subcutaneous tissue was resected at L4-L5, replicating MIS surgery, followed by placement of a 60×18-mm or 100×18-mm tubular retractor for access. Clinicians were required to close the fascia with three unknotted, simple interrupted sutures using a swaged curved needle or suture passer (Spine Scorpion™, Arthrex, Inc., Naples, FL). The completion time was recorded, starting immediately before suturing and ending after the last pass. A time cutoff of 10 min was implemented in consideration of reasonable operating room time, and the number of achieved suture passes (of 6) were recorded. Clinicians were asked to qualitatively grade ease of use in relation to prior fascial closure experience per a 0-5 scale, where 0 is impossible and 5 is easiest., Results: The mean change in fascial closure completion time (Δ) was significantly reduced with the Spine Scorpion compared to the curved needle with the 60×18-mm retractor (Δ=5.80 min; 95% CI, 2.92-8.67 min; p=.004) and 100 × 18-mm retractor (Δ=5.28 min; 95% CI, 2.76-7.80 min; p=.003). Full closure was achieved within the time limit for all trials of the Spine Scorpion, while the standard needle achieved full closure in 67% (4 of 6) and 50% (3 of 6) of trials with the 60 × 18-mm and 100×18-mm retractors, respectively. Median ease-of-use scores with the 60×18-mm and 100×18-mm retractors, respectively, were 4.5 (range, 4-5) and 4.5 (range, 3-5) for the Spine Scorpion, and both 1.0 (range, 1-2) for the curved needle., Conclusion: Results from this laboratory investigation using a suture passer for thoracolumbar fascia closure show a significant reduction in closure time and completion of the procedure compared to a conventional curved needle., Competing Interests: One or more authors declare potential competing financial interests or personal relations as specified on required ICMJE-NASSJ Disclosure Forms., (© 2024 The Author(s).)

Purpose: The interim analysis of the phase IIIb LUCY trial demonstrated the clinical effectiveness of olaparib in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC), with median progression-free survival (PFS) of 8.11 months, which was similar to that in the olaparib arm of the phase III OlympiAD trial (7.03 months). This prespecified analysis provides final overall survival (OS) and safety data., Methods: The open-label, single-arm LUCY trial of olaparib (300 mg, twice daily) enrolled adults with gBRCAm or somatic BRCA-mutated (sBRCAm), HER2-negative mBC. Patients had previously received a taxane or anthracycline for neoadjuvant/adjuvant or metastatic disease and up to two lines of chemotherapy for mBC., Results: Of 563 patients screened, 256 (gBRCAm, n = 253; sBRCAm, n = 3) were enrolled. In the gBRCAm cohort, median investigator-assessed PFS (primary endpoint) was 8.18 months and median OS was 24.94 months. Olaparib was clinically effective in all prespecified subgroups: hormone receptor status, previous chemotherapy for mBC, previous platinum-based chemotherapy (including by line of therapy), and previous cyclin-dependent kinase 4/6 inhibitor use. The most frequent treatment-emergent adverse events (TEAEs) were nausea (55.3%) and anemia (39.2%). Few patients (6.3%) discontinued olaparib owing to a TEAE. No deaths associated with AEs occurred during the study treatment or 30-day follow-up., Conclusion: The LUCY patient population reflects a real-world population in line with the licensed indication of olaparib in mBC. These findings support the clinical effectiveness and safety of olaparib in patients with gBRCAm, HER2-negative mBC., Clinical Trial Registration: Clinical trials registration number: NCT03286842., (© 2023. The Author(s).)

Aim: The UK National Institute for Health and Care Excellence guideline DG27 recommends universal testing for Lynch syndrome (LS) in all newly diagnosed colorectal cancer (CRC) patients. However, DG27 guideline implementation varies significantly by geography. This quality improvement project (QIP) was developed to measure variation and deliver an effective diagnostic pathway from diagnosis of CRC to diagnosis of LS within the RM Partners (RMP) West London cancer alliance., Method: RM Partners includes a population of 4 million people and incorporates nine CRC multidisciplinary teams (MDTs), overseen by a Pathway Group, and three regional genetic services, managing approximately 1500 new CRC cases annually. A responsible LS champion was nominated within each MDT. A regional project manager and nurse practitioner were appointed to support the LS champions, to develop online training packages and patient consultation workshops. MDTs were supported to develop an 'in-house' mainstreaming service to offer genetic testing in their routine oncology clinics. Baseline data were collected through completion of the LS pathway audit of the testing pathway in 30 consecutive CRC patients from each CRC MDT, with measurement of each step of the testing pathway. Areas for improvement in each MDT were identified, delivered by the local champion and supported by the project team., Results: Overall, QIP measurables improved following the intervention. The Wilcoxon signed rank test revealed significant differences with strong effect sizes on the percentile of CRC cases undergoing mismatch repair (MMR) testing in endoscopic biopsies (p = 0.008), further testing with either methylation or BRAF V600E (p = 0/03) and in effective referral for genetic testing (from 10% to 74%; p = 0.02). During the QIP new mainstreaming services were developed, alongside the implementation of systematic and robust testing pathways. These pathways were tailored to the needs of each CRC team to ensure that patients with a diagnosis of CRC had access to testing for LS. Online training packages were produced which remain freely accessible for CRC teams across the UK., Conclusion: The LS project was completed by April 2022. We have implemented a systematic approach with workforce transformation to facilitate identification and 'mainstreamed' genetic diagnosis of LS. This work has contributed to the development of a National LS Transformation Project in England which recommends local leadership within cancer teams to ensure delivery of diagnosis of LS and integration of genomics into clinical practice., (© 2023 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Background: Germline pathogenic variants mutations) in the BRCA1 and BRCA2 genes cause an increased risk of breast cancer and ovarian cancer. Mainstream cancer genetic testing (MCG) was introduced for breast cancer patients in our unit in 2013. Non-geneticist clinicians have been trained to offer genetic testing during initial treatment planning. We assessed the impact of timely test results on surgical decision-making., Methods: Women who had undergone mainstream genetic testing for breast cancer between September 2013 and September 2018 were identified from a prospective database. Surgical data were collected retrospectively., Results: 580 eligible women had mainstream genetic testing. For 474 this was their first breast cancer diagnosis. The median age was 46 years (interquartile range (IQR) 38-57). The indications were: age ≤45 years for 233 (49%); triple negative disease for 192 women (40.5%); bilateral breast cancer age <60 for 39 (8%) and other for 72 (14%) women. The median time for test initiation to result was 18 days (IQR 15-21). 302 (64% received results before surgery. 88% of those found to have a BRCA mutation before surgery opted for bilateral mastectomy (compared to 5% with BRCA wild type). An additional 106 patients had a new diagnosis on a background of previous treatment. Of these all with a pathogenic variant chose bilateral mastectomy., Conclusion: Timely BRCA gene testing influences surgeons' and patients' choice of surgery. It reassures women with a negative result and allows those with a positive result to take an active decision about the management of their future risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Genomics is rapidly changing treatment paradigms for cancers, obligating oncologists to have good genomics knowledge. Through this survey, we aimed to assess the current understanding of cancer genomics among UK oncologists., Methods: We conducted a web-based nation-wide self-assessment survey of the cancer genomics knowledge of UK clinical and medical oncology trainees and consultants., Results: In total, 150 oncologists (81 consultants and 69 trainees) responded, representing 10% of UK oncologists.Formal training in genomics had not been received by 38.7% of oncologists and 92.7% identified a need for additional genomics training.In total, 71.3% self-reported to have good knowledge of defining somatic and germline mutations, falling to 35.3% for understanding principles of gene expression and regulation. Knowledge of cancer-predisposing syndromes was highest for Lynch syndrome (40.7% good knowledge) and lowest for multiple endocrine neoplasia (14.0% good knowledge).Overall, 49.0% of respondents had consented patients for germline testing, but 80.7% reported a lack of training in genetic counselling., Conclusion: Large knowledge gaps have been identified through this survey, highlighting the need for incorporation of improved formal training in cancer genomics for consultants and trainees, with an aim to equip oncologists for advances in clinical practice and to take up genetic mainstreaming confidently., (© Royal College of Physicians 2023. All rights reserved.)

Background: Germline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing., Methods: We designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing of BRCA1/BRCA2/PALB2 (BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway)., Results: Uptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with <5% of patients contacting the genetics specialist hotline. All progression criteria established for continuation of the study were met., Conclusion: Pilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses., Trial Registration Number: ISRCTN87845055., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers., (© 2022. The Author(s).)

Background For patients with early breast cancer, knowledge of germline BRCA1 / 2 status increasingly influences management as well as informing future cancer risk for patients and their families. As access to germline testing expands, it is important that this benefit is extended to survivors as well as to the newly diagnosed. Methods In collaboration with our breast unit colleagues and by embedding a Senior Genetic Counsellor in the virtual multidisciplinary meeting, we identified patients suitable for genetics review 5 years after their breast cancer diagnosis. Results Between May 2015 and December 2018, 2044 patients were discussed, of whom 769 patients were identified for notes review by Genetics. Of these, 275 had already undergone testing and 47 had confirmed germline pathogenic variants in BRCA1 / 2 A further 463 were recommended for referral. One hundred and eighty patients were subsequently offered testing with 161 accepting (161/180, 89%). Nine patients were found to harbour pathogenic variants in either BRCA1 or BRCA2 (9/161, 6%). Of the initial 2044 patients reviewed, 2.7% (56/2044) are now known to carry germline pathogenic variants. Conclusion The survivorship setting provides an opportunity for genetic review underpinned by collaborative working between cancer specialists and the genetics team., Competing Interests: Competing interests: AG received honoraria from Astra Zeneca and Roche paid to the institution and personal fees from Tesaro. ZK received honoraria for education talks from Astra Zeneca and Tesaro (paid to institution) and Lilly (personal fees)., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Suzette DelalogeConsulting or Advisory Role: AstraZeneca Research Funding: AstraZeneca (Inst), Pfizer (Inst), Roche (Inst), Genentech (Inst), Puma (Inst), Lilly (Inst), Novartis (Inst), Sanofi (Inst) Travel, Accommodations, Expenses: Pfizer, AstraZeneca, RocheGaia SchiavonEmployment: AstraZeneca Stock and Other Ownership Interests: AstraZenecaMagali Lacroix-TrikiLeadership: MyPL Stock and Other Ownership Interests: MyPL Honoraria: Myriad Genetics, Genomic Health Consulting or Advisory Role: Roche Travel, Accommodations, Expenses: AgendiaT. Hedley CarrEmployment: AstraZeneca Stock and Other Ownership Interests: AstraZenecaIwanka KozarewaEmployment: AstraZeneca Stock and Other Ownership Interests: AstraZenecaZoe KempHonoraria: Lilly Honoraria: AstraZenecaNicholas TurnerConsulting or Advisory Role: Roche, Novartis, AstraZeneca, Pfizer, Bicycle Therapeutics, Bristol-Myers Squibb, Merck Sharp & Dohme, Tesaro, Lilly Research Funding: Pfizer (Inst), Roche (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), Bio-Rad (Inst), Guardant Health (Inst)Fabrice AndréResearch Funding: AstraZeneca (Inst), Novartis (Inst), Pfizer (Inst), Lilly (Inst), Roche (Inst), Daiichi (Inst) Travel, Accommodations, Expenses: Novartis, Roche, GlaxoSmithKline, AstraZeneca No other potential conflicts of interest were reported.

Importance: Increasing BRCA1 and BRCA2 (collectively termed herein as BRCA) gene testing is required to improve cancer management and prevent BRCA-related cancers., Objective: To evaluate mainstream genetic testing using cancer-based criteria in patients with cancer., Design, Setting, and Participants: A quality improvement study and cost-effectiveness analysis of different BRCA testing selection criteria and access procedures to evaluate feasibility, acceptability, and mutation detection performance was conducted at the Royal Marsden National Health Service Foundation Trust as part of the Mainstreaming Cancer Genetics (MCG) Programme. Participants included 1184 patients with cancer who were undergoing genetic testing between September 1, 2013, and February 28, 2017., Main Outcomes and Measures: Mutation rates, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios were the primary outcomes., Results: Of the 1184 patients (1158 women [97.8%]) meeting simple cancer-based criteria, 117 had a BRCA mutation (9.9%). The mutation rate was similar in retrospective United Kingdom (10.2% [235 of 2294]) and prospective Malaysian (9.7% [103 of 1061]) breast cancer studies. If traditional family history criteria had been used, more than 50% of the mutation-positive individuals would have been missed. Of the 117 mutation-positive individuals, 115 people (98.3%) attended their genetics appointment and cascade to relatives is underway in all appropriate families (85 of 85). Combining with the equivalent ovarian cancer study provides 5 simple cancer-based criteria for BRCA testing with a 10% mutation rate: (1) ovarian cancer; (2) breast cancer diagnosed when patients are 45 years or younger; (3) 2 primary breast cancers, both diagnosed when patients are 60 years or younger; (4) triple-negative breast cancer; and (5) male breast cancer. A sixth criterion-breast cancer plus a parent, sibling, or child with any of the other criteria-can be added to address family history. Criteria 1 through 5 are considered the MCG criteria, and criteria 1 through 6 are considered the MCGplus criteria. Testing using MCG or MCGplus criteria is cost-effective with cost-effectiveness ratios of $1330 per discounted QALYs and $1225 per discounted QALYs, respectively, and appears to lead to cancer and mortality reductions (MCG: 804 cancers, 161 deaths; MCGplus: 1020 cancers, 204 deaths per year over 50 years). Use of MCG or MCGplus criteria might allow detection of all BRCA mutations in patients with breast cancer in the United Kingdom through testing one-third of patients. Feedback questionnaires from 259 patients and 23 cancer team members (12 oncologists, 8 surgeons, and 3 nurse specialists) showed acceptability of the process with 100% of patients pleased they had genetic testing and 100% of cancer team members confident to approve patients for genetic testing. Use of MCGplus criteria also appeared to be time and resource efficient, requiring 95% fewer genetic consultations than the traditional process., Conclusions and Relevance: This study suggests that mainstream testing using simple, cancer-based criteria might be able to efficiently deliver consistent, cost-effective, patient-centered BRCA testing.

Background: Since April 2013, the UK's National Health Service Breast Screening Programme (NHSBSP) centers have been obliged to provide services for women at the highest risk of breast cancer, including those carrying highly penetrant single gene mutations (BRCA1, BRCA2, TP53). Since then, such individuals previously undergoing surveillance in the Royal Marsden Hospital were referred to their local NHSBSP centers. We aimed to assess patient experience of surveillance provided by local NHSBSP services at 1 and 3 years after repatriation., Patients and Methods: High-risk gene mutation carriers referred to the NHSBSP for breast cancer surveillance were identified from a departmental database in the Cancer Genetics Unit and invited to complete questionnaires about their experience of surveillance under this new pathway, first in 2014 and again in 2016., Results: Three hundred forty-six individuals were invited to participate in 2014, of whom 182 responded (53%). A total of 464 patients were invited in 2016, of whom 246 (53%) completed the second questionnaire. Ninety-four percent of patients with residual breast tissue received some screening at the first (n = 161) and second (n = 185) time points. Ninety-one percent of patients (n = 146) received at least recommended surveillance in the year preceding the initial survey, a proportion decreasing slightly by the second time point (n = 164, 87%). Seventeen percent of individuals required additional diagnostic investigations, with cancers detected in 2%. These proportions remained stable between surveys., Conclusion: Repatriation of high-risk individuals from Royal Marsden Hospital to NHSBSP centers has been successfully accomplished. Most individuals received appropriate recommended annual surveillance. Further improvements are required to ensure equal and timely provision of recommended surveillance., (Copyright © 2017 Elsevier Inc. All rights reserved.)