Extended panel testing in ovarian cancer reveals BRIP1 as the third most important predisposition gene.

PURPOSE: The prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain. METHODS: An observational study reporting the detection rate of germline PVs in HRR and LS genes in all OC cases tested in the North West Genomic Laboratory Hub between September 1996 and May 2024. Effect sizes are reported using odds ratios (ORs) and 95% confidence intervals (95% CI) for unselected cases tested between April 2021 and May 2024 versus 50703 controls from the Breast Cancer Risk after Diagnostic Gene Sequencing study. RESULTS: 2934 women were tested for BRCA1/2 and 433 (14.8%) had a PV. In up to 1572 women tested for PVs in non-BRCA1/2 HRR genes, detection rates were PALB2=0.8%, BRIP1=1.1%, RAD51C=0.4% and RAD51D=0.4%. In 940 unselected cases, BRIP1 (OR=8.7, 95% CI 4.6-15.8) was the third commonest OC predisposition gene followed by RAD51C (OR=8.3, 95% CI 3.1-23.1), RAD51D (OR=6.5, 95% CI 2.1-19.7) and PALB2 (OR=3.9, 95% CI 1.5-10.3). No PVs in LS genes were detected in unselected cases. CONCLUSIONS: Panel testing in OC resulted in a detection rate of 2-3% for germline PVs in non-BRCA1/2 HRR genes, with the largest contributor being BRIP1. Screening for LS in unselected cases of OC is unnecessary.

Optimization of polygenic risk scores in BRCA1/2 pathogenic variant heterozygotes in epithelial ovarian cancer.

PURPOSE: A third of familial epithelial ovarian cancer (EOC) is explained by BRCA1/2 pathogenic variants. Polygenic risk scores (PRSs) for BRCA1/2 heterozygotes associated with EOC have been created, but impact of combination with clinical and hormonal risk factors is unclear. METHODS: We genotyped 300 cases and 355 controls and constructed modified PRSs based on those validated by Barnes et al. Model discrimination and EOC risk was assessed by area under the curve (AUC) values and difference between lowest and highest quintile odds ratios (ORs). We investigated model optimization using logistic regression to combine models with clinical and hormonal data. RESULTS: Unadjusted AUC values ranged from 0.526 to 0.551 with 2.2- to 2.3-fold increase in OR between lowest and highest quintiles (BRCA1 heterozygotes) and 0.574 to 0.585 AUC values with a 6.3- to 7.7-fold increase (BRCA2 heterozygotes). The optimized model (parity, age at menarche, menopause, and first full-term pregnancy) estimated AUC values of 0.872 to 0.876 and 21- to 23-fold increase in OR (BRCA1 heterozygotes) and AUC values of 0.857 to 0.867 and 40- to 41-fold increase (BRCA2 heterozygotes). CONCLUSION: The combination of PRS with age, family history, and hormonal factors significantly improved the EOC risk discrimination ability. However, the contribution of the PRS was small. Larger prospective studies are needed to assess if combined-PRS models could provide information to inform risk-reducing decisions.

BRCA1/2 in non-mucinous epithelial ovarian cancer: tumour with or without germline testing?

National guidelines recommend testing all cases of non-mucinous epithelial ovarian cancer (NMEOC) for germline (blood) and somatic (tumour) BRCA1/2 pathogenic variants (PVs). We performed paired germline and somatic BRCA1/2 testing in consecutive cases of NMEOC (n = 388) to validate guidelines. Thirty-four somatic BRCA1/2 (sBRCA) PVs (9.7%) were detected in 350 cases with germline BRCA1/2 (gBRCA) wild-type. All sBRCA PVs were detected in non-familial cases. By analysing our regional germline BRCA1/2 database there were 92/1114 (8.3%) gBRCA PVs detected in non-familial cases (only 3% ≥70 years old) and 245/641 (38.2%) in familial cases. Germline non-familial cases were dominated by BRCA2 in older women (8/271 ≥ 70 years old, all BRCA2). The ratio of sBRCA-to-gBRCA was ≤1.0 in women aged <70 years old, compared to 5.2 in women aged ≥70 years old (P = 0.005). The likelihood of missed germline BRCA1/2 PVs (copy-number variants missed on most somatic assays) by testing only tumour DNA was 0.4% in women aged ≥70 years old. We recommend reflex tumour BRCA1/2 testing in all NMEOC cases, and that gBRCA testing is not required for women aged ≥70 years old with no identifiable tumour BRCA1/2 PV and/or family history of breast, ovarian, prostate and/or pancreatic cancer.

High detection rate from genetic testing in BRCA-negative women with familial epithelial ovarian cancer.

PURPOSE: Epithelial ovarian cancer (EOC) is associated with pathogenic variants (PVs) in homologous recombination and/or mismatch repair genes. We aimed to review the testing of women with familial EOC at our center. METHODS: Women with familial EOC (≥2 EOC in family, including index case) referred to our center between 1993 and 2021 were included. Genetic testing (BRCA/Lynch syndrome screening, exome sequencing, panel testing, 100,000 Genome Project, and NIHR BioResource genome sequencing) and clinical demographic, diagnosis, and survival data were reviewed. RESULTS: Of 277, 128 (46.2%) women were BRCA heterozygotes (BRCA1: 89, BRCA2: 39). The detection rate in BRCA-negative women was 21.8%; the most commonly affected gene was BRIP1 (5.9%). The non-BRCA detection rate was significantly higher in families with 2 affected members with EOC only (22.4%) than the families with ≥3 (11.1%) affected members (odds ratio = 9.9, 95% CI = 1.6-105.2, P = .0075). Overall, 112 different PVs in 12 homologous recombination/mismatch repair genes were detected in 150 of 277 (54.2%) unrelated women. CONCLUSION: This is the largest report of women with familial EOC undergoing wider testing to date. One-fifth of BRCA-negative women were heterozygous for a PV in a potentially actionable gene. Wider genetic testing of women with familial EOC is essential to optimize their treatment and prevention of disease in family members.

Dominant-negative pathogenic variant BRIP1 c.1045G>C is a high-risk allele for non-mucinous epithelial ovarian cancer: A case-control study.

BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case-control study of 3767 cases and 2043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3-444.2; P = 0.0001). The risk was highest for women with EOC (OR = 140.8; 95% CI 23.5-1723.0; P < 0.0001) and lower for BC (OR = 11.1; 95% CI 1.2-106.5; P = 0.1588). BRIP1 c.2392C>T was associated with smaller risks for BC/EOC (OR = 5.4; 95%CI 2.4-12.7; P = 0.0003), EOC (OR = 5.9; 95% CI 1.3-23.0; p = 0.0550) and BC (OR = 5.3; 95%CI 2.3-12.9; P = 0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant-negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant-negative missense variants may confer higher risks than their loss-of-function counterparts.

Specialist oncological surgery for removal of the ovaries and fallopian tubes in BRCA1 and BRCA2 pathogenic variant carriers may reduce primary peritoneal cancer risk to very low levels.

Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is highly effective for the prevention of high-grade serous ovarian cancer (HGSOC) in BRCA1/2 pathogenic variant carriers (PVCs), but does not completely eliminate future risk of primary peritoneal cancer (PPC). The requirement to completely remove fallopian tubes at RRBSO and carefully exclude occult cancer/serous tubal intraepithelial carcinoma (STIC) lesions may not have been appreciated historically. We calculated rates of HGSOC and PPC in confirmed BRCA1/2 PVCs registered on the regional database in those who did (cases) and did not (controls) undergo RRBSO after genetic testing. Expected annual rates of ovarian/peritoneal cancer were 1% for BRCA1 ≥ 35 years and 0.5% for BRCA2 ≥ 45 years. Follow-up before 35/45 years was "risk free" and lead time excluded RRBSO <35 years and <45 years for BRCA1 and BRCA2, respectively. Women were followed from personal mutation report (controls) or RRBSO (cases) to death, ovarian/peritoneal cancer or last follow-up, whichever was sooner. In total, 891 cases (BRCA1 = 468, BRCA2 = 423) and 1302 controls had follow-up ≥35 years (BRCA1 = 736) and ≥45 years (BRCA2 = 566), respectively, over a total of 7261.1 risk eligible years (mean = 8.15 years). Twenty-one occult ovarian cancers were found at RRBSO (2.4%), 16 at stage 1. Post RRBSO, 56.97 ovarian/peritoneal cancers were expected but only 3 were observed (HR = 0.053; 95% CI = 0.013-0.14), with combined Kaplan-Meier analysis HR = 0.029 (95% CI = 0.009-0.100, P < .001). Risk reduction was greater in specialist (HR = 0.03; 95% CI = 0.001-0.13) compared to non-specialist centres (HR = 0.11; 95% CI = 0.02-0.37) (P = .07). In controls, 23.35 ovarian/peritoneal cancers were expected with 32 observed (HR = 1.37; 95% CI = 0.95-1.91). RRBSO <35/<45 years reduces the risk of ovarian/peritoneal cancer by 95% in BRCA1/2 PVCs and may be greater in specialist centres.

Epithelial ovarian cancer risk: A review of the current genetic landscape.

Ovarian cancer is the fourth most common cause of cancer-related death in women in the developed world, and one of the most heritable cancers. One of the most significant risk factors for epithelial ovarian cancer (EOC) is a family history of breast and/or ovarian cancer. Combined risk factors can be used in models to stratify risk of EOC, and aid in decisions regarding risk-reduction strategies. Germline pathogenic variants in EOC susceptibility genes including those involved in homologous recombination and mismatch repair pathways are present in approximately 22% to 25% of EOC. These genes are associated with an estimated lifetime risk of EOC of 13% to 60% for BRCA1 variants and 10% to 25% for BRCA2 variants, with lower risks associated with remaining genes. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) thought to explain an additional 6.4% of the familial risk of ovarian cancer, with 34 susceptibility loci identified to date. However, an unknown proportion of the genetic component of EOC risk remains unexplained. This review comprises an overview of individual genes and SNPs suspected to contribute to risk of EOC, and discusses use of a polygenic risk score to predict individual cancer risk more accurately.

Prevalence of germline pathogenic BRCA1/2 variants in sequential epithelial ovarian cancer cases.

INTRODUCTION: Poly(ADP-ribose) polymerase inhibitors significantly improve progression-free survival in platinum-sensitive high-grade serous and endometrioid ovarian carcinoma, with greatest benefits observed in women with a pathogenic BRCA1/2 variant. Consequently, the demand for germline BRCA1/2 testing in ovarian cancer has increased substantially, leading to the screening of unselected populations of patients. We aimed to determine the prevalence of pathogenic germline BRCA1/2 variants in women diagnosed with epithelial ovarian cancer, categorised according to the established risk factors for hereditary breast and ovarian cancer syndrome and the Manchester BRCA Score, to inform risk stratification. METHODS: A cohort of sequential epithelial ovarian cancer cases recruited between June 2013 and September 2018 underwent germline BRCA1/2 testing by next-generation sequencing and multiplex ligation-dependent probe amplification. RESULTS: Five hundred and fifty-seven patients were screened. Of these, 18% had inherited a pathogenic BRCA1/2 variant. The prevalence of pathogenic BRCA1/2 variants was >10% in women diagnosed with ovarian cancer earlier than 60 years of age (21%) and those diagnosed later than 60 years of age with a family history of breast and/or ovarian cancer (17%) or a medical history of breast cancer (34%). The prevalence of pathogenic BRCA1/2 variants was also >10% in women with a Manchester BRCA Score of ≥15 points (14%). DISCUSSION: Our study suggests that age at diagnosis, family history of breast and/or ovarian cancer, medical history of breast cancer or a Manchester BRCA Score of ≥15 points are associated with a >10% prevalence of germline pathogenic BRCA1/2 variants in epithelial ovarian cancer.

Adjuvant chemotherapy and outcomes in patients with nodal and resection margin-negative pancreatic ductal adenocarcinoma: A systematic review and meta-analysis.

Adjuvant chemotherapy (AC) following pancreatic carcinoma (PC) resection improves overall survival (OS). A systematic review identified 10 phase-2/3 studies investigating AC in 3644 patients looking at the influence of nodal and resection status. AC significantly improved disease free survival, OS and 5-year odds of death risk. There was greater survival benefit in patients PS 0 and with body/tail tumors. There was a nonsignificant effect in N - /N + patients on OS and no difference between R0/R1 patients.

Everolimus in the treatment of neuroendocrine tumors of the respiratory and gastroenteropancreatic systems.

Neuroendocrine tumors (NETs) are a rare diverse group of malignancies occurring most commonly in the gastroenteropancreatic system and the lungs. The incidence of NETs is increasing worldwide; median survival for patients with metastatic NETs is 5-65 months. A growing body of evidence shows survival benefit in patients with advanced NETs (gastroenteropancreatic and lung) treated with mTOR inhibitor everolimus, with improvement in survival being demonstrated in the clinical trial and real-world setting. Everolimus has been shown to have a manageable safety profile, with the most common adverse events being stomatitis, rash, diarrhea, fatigue and infections. Due to the rarity of the condition, there are challenges in conducting clinical trials in these patients. Further research is required to clarify the role of adjuvant therapy, treatment sequencing and the use of multimodality treatments.

Cross-cultural adaptation of the PROFFIT Instrument to measure financial toxicity in people living with cancer within a UK population.

BACKGROUND: This study aimed to develop a British version of the Patient Reported Outcomes for Fighting Financial Toxicity of Cancer (PROFFIT): originally designed to measure financial toxicity in cancer for an Italian universal healthcare system. The instrument was carefully evaluated for crosscultural equivalence, face validity and practicality. METHODS: A systematic approach to cross-cultural adaptation was used, including forward translation, synthesis, backward translation, consolidation of translations with an expert committee, and cognitive interviews. As part of the cognitive interview process, 18 cancer patients completed a structured interview of 60-90 min in length. RESULTS: The translated and modified PROFFIT questionnaire demonstrated good psycho-linguistic properties, including high compliance (only one item was revised for clarity), high retrieval from memory, high decision-making processes, and high response processes. CONCLUSION: PROFFIT has been found to be functional and adaptable in a new social environment. The tool may be useful for tailoring interventions to address and measure financial hardships within the cancer population, which appear to be a current challenge for public health. POLICY SUMMARY: Even in universal healthcare systems, financial toxicity due to the increase in outof-pocket expenses poses a significant problem. The FT phenomenon warrants proper attention in the United Kingdom since it may negatively impact financial well-being, quality of life, psychosocial health, and treatment adherence.

Is Reflex Germline BRCA1/2 Testing Necessary in Women Diagnosed with Non-Mucinous High-Grade Epithelial Ovarian Cancer Aged 80 Years or Older?

Women diagnosed with non-mucinous high-grade epithelial ovarian cancer (EOC) in England are often reflex-tested for germline and tumour BRCA1/2 variants. The value of germline BRCA1/2 testing in women diagnosed aged ≥80 is questionable. We performed an observational study of all women diagnosed with non-mucinous high-grade EOC who underwent germline and tumour BRCA1/2 testing by the North West of England Genomic Laboratory Hub. A subgroup of women also underwent germline testing using a panel of homologous recombination repair (HRR) genes and/or tumour testing for homologous recombination deficiency (HRD) using Myriad's myChoice® companion diagnostic. Seven-hundred-two patients successfully underwent both germline and tumour BRCA1/2 testing. Of these, 48 were diagnosed with non-mucinous high-grade EOC aged ≥80. In this age group, somatic BRCA1/2 pathogenic/likely pathogenic variants (PV/LPVs) were detected nine times more often than germline BRCA1/2 PV/LPVs. The only germline PV reported in a patient aged ≥80 was detected in germline and tumour DNA (BRCA2 c.4478_4481del). No patient aged ≥80 had a germline PV/LPVs in a non-BRCA1/2 HRR gene. Thirty-eight percent of patients aged ≥80 had a tumour positive for HRD. Our data suggest that tumour BRCA1/2 and HRD testing is adequate for patients diagnosed with non-mucinous high-grade EOC aged ≥80, with germline BRCA1/2 testing reserved for women with a tumour BRCA1/2 PV/LPVs.

Predicting the likelihood of a BRCA1/2 pathogenic variant being somatic by testing only tumour DNA in non-mucinous high-grade epithelial ovarian cancer.

AIMS: Clinical guidelines recommend testing both germline and tumour DNA for BRCA1/2 pathogenic variants (PVs) in non-mucinous high-grade epithelial ovarian cancer (NMEOC). In this study, we show that some tumour BRCA1/2 PVs are highly likely to be somatic based on certain clinical and variant characteristics, meaning it may not be necessary to test all NMEOC cases for germline BRCA1/2 PVs. METHODS: An observational study that included all tumour BRCA1/2 PVs detected in cases of NMEOC in the Northwest of England between July 2017 and February 2022. All tumour BRCA1/2 PVs were compared with PVs recorded in a prospectively gathered pan-cancer germline BRCA1/2 (gBRCA) testing database for the same geographical region (gBRCA1 PVs=910 and gBRCA2 PVs=922). Tumour BRCA1/2 PVs were categorised as common (≥1%), uncommon (<1%) or absent from the germline database. RESULTS: One hundred and thirteen tumour BRCA1/2 PVs were detected in 111 NMEOC cases. There were 69 germline and 44 somatic variants. The mean age at diagnosis for gBRCA and somatic BRCA1/2 (sBRCA) PVs was 56.9 and 68.5 years, respectively (Student's t-test p<0.0001). All sBRCA PVs were detected in non-familial cases. All tumour BRCA1/2 PVs with a variant allele frequency (VAF) <35% in non-familial cases were somatic variants. Eighty-one per cent of germline-tumour BRCA1/2 PVs were present (common=31, uncommon=25) in the gBRCA testing database, while 89% of somatic-tumour BRCA1/2 PVs were absent (n=39). CONCLUSIONS: We predict the likelihood of a tumour BRCA1/2 PV being somatic is 99.8% in non-familial cases of NMEOC diagnosed aged ≥75, where the VAF is ≤30% and there is no regional germline commonality.

Mainstreaming germline BRCA1/2 testing in non-mucinous epithelial ovarian cancer in the North West of England.

Poly(ADP-ribose) polymerase (PARP) inhibitors improve survival in BRCA-mutant high-grade serous ovarian carcinoma. As a result, germline and somatic BRCA1/2 testing has become standard practice in women diagnosed with ovarian cancer. We outline changes in testing and detection rates of germline BRCA1/2 pathogenic variants (PVs) in cases of non-mucinous epithelial ovarian cancer diagnosed during three eras, spanning 12 years, within the North West of England, and compare the uptake of cascade testing in families identified by oncology-led mainstreaming versus regional genetics clinics. Eras included: Period 1 (20% risk threshold for testing): between January 2007 and May 2013; Period 2 (10% risk threshold for testing): between June 2013 and October 2017 and; Period 3 (mainstream testing): between November 2017 and November 2019. A total of 1081 women underwent germline BRCA1/2 testing between January 2007 and November 2019 and 222 (20.5%) were found to have a PV. The monthly testing rate increased by 3.3-fold and 2.5-fold between Periods 1-2 and Periods 2-3, respectively. A similar incidence of germline BRCA1/2 PVs were detected in Period 2 (17.2%) and Period 3 (18.5%). Uptake of cascade testing from first-degree relatives was significantly lower in those women undergoing mainstream testing compared with those tested in regional genetics clinics (31.6% versus 47.3%, P = 0.038). Mainstream testing allows timely detection of germline BRCA1/2 status to select patients for PARP inhibitors, but shortfalls in the uptake of cascade testing in first-degree relatives requires optimisation to broaden benefits within families.

Balancing the Economics and Ethics of Personalised Oncology.

The cost of personalised medicine in oncology is increasing. The varied and contrasting priorities of the pharmaceutical industry, local and national governments, international medical community, and patients need to be reviewed and balanced. In addition to the economic and political standpoints on this issue, the ethical considerations from physicians' viewpoints need to be considered to optimise cancer patients' care. In this paper we discuss the way research and development (R&D) of these drugs is carried out and reimbursed, and how this needs to change. We describe frameworks assessing the value of these treatments which been developed. Physicians need to develop their knowledge and understanding of these issues to best meet their dual responsibilities of advocating for their patients and promoting public health.