Pathogenic Variants In BRCA2 Research Articles

Clinical Outcomes for BRCA Pathogenic Variant Carriers With Breast Cancer Undergoing Breast Conservation

Although most women with BRCA-associated breast cancer choose bilateral mastectomy, current guidelines support breast-conserving therapy as an option. As the indications for genetic testing expand and targeted therapies emerge, understanding the outcomes of breast-conserving therapy in the population of patients choosing breast conservation is important. To describe the clinical outcomes of women with BRCA-associated breast cancer who were treated with breast-conserving therapy, including the risks of ipsilateral and contralateral cancer events and bilateral mastectomy-free survival. This cohort study conducted at a single-institution academic national comprehensive cancer center included 172 women identified from a prospectively maintained database who had pathogenic BRCA1/2 variants and were treated with breast-conserving therapy from January 1, 1977, to December 31, 2021. Clinical and pathologic characteristics for patients with BRCA1 and BRCA2 were compared, and estimates of overall survival, bilateral mastectomy-free survival, distant disease-free survival, risk of ipsilateral breast cancer, and risk of contralateral cancer were computed. The cohort included 172 women (mean [SD] age, 47.1 [11.7] years), with 42 (24.4%) receiving a diagnosis of breast cancer prior to 40 years of age. Compared with BRCA2 variant carriers (80 [46.5%]), women with BRCA1 variants (92 [53.5%]) were younger at breast cancer diagnosis and tended to have more advanced tumors, which were more likely to be hormone receptor negative and higher grade. At a median follow-up of 11.8 years (IQR, 5.7-18.2 years), estimates of 10-year survival and risk were: overall survival, 88.5% (95% CI, 83.1%-94.2%); bilateral mastectomy-free survival, 70.7% (95% CI, 63.3%-78.9%); risk of an ipsilateral breast cancer event, 12.2% (95% CI, 5.8%-18.2%); and risk of contralateral cancer, 21.3% (95% CI, 13.3%-28.6%). Risks continued to increase after 10 years of follow-up. In this cohort study, although women with breast cancer and pathogenic BRCA1/2 variants treated with breast-conserving therapy had above-average risks of ipsilateral and contralateral breast cancer events, most did not have another cancer event and remained bilateral mastectomy free. These findings may be useful for informing patients with BRCA variants choosing breast conservation.

Featuring BRCA1 and BRCA2 germline mutational landscape from Asturias (North Spain).

The singular BRCA1/2 mutational landscape of Asturias is updated 10 years after the first study. We analyzed BRCA1 and BRCA2 pathogenic variants in 1653 index cases. In total, 238 families were identified to carry a pathogenic variant, 163 families in BRCA1 and 75 families in BRCA2. This yielded a prevalence rate of 14.4%. Seven recurrent variants were found accounting for 55% of the cases. Among them, three are widely distributed (BRCA1 c.211A>G, c.470_471del and c.3331_3334del) and four had been reported as novel in Asturias: two in BRCA1 (c.1674del and c.2901_2902dup) and two in BRCA2 (c.2095C>T and c.4040_4035delinsC). A common haplotype was established for all recurrent variants indicating a shared ancestral origin. Three splicing analyses are shown: BRCA1:c.5152+3A>C and BRCA1:c.5333-3T>G that lead to skipping of exon 18, and 22 respectively, and BRCA1:c.5278-1G>T giving rise to two transcripts, one lacking exon 21 (p.Ille1760Glyfs*60) and one lacking the first 8 nucleotides of exon 21 (p.Phe1761Asnfs*14), supporting pathogenicity for these variants.

Subset of retinoblastoma tumours is associated with BRCA1/2 mutations

BackgroundWe investigated the potential association between pathogenic BRCA1/2 variants and retinoblastoma pathogenicity.MethodsIn this single-centre, retrospective case series, we performed hereditary cancer panel tests using blood samples for patients with retinoblastoma...

Impact of hormone receptor status and tumor subtypes of breast cancer in young BRCA carriers

Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes. This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]. From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype). In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.

LGG-24. PEDIATRIC GANGLIOGLIOMA WITH GERMLINE BRCA2 MUTATION

Abstract BACKGROUND BRCA1 and BRCA2 are genes associated with breast and ovarian cancer development in adults. Their influence on brain tumor formation is less understood. METHODS Retrospective review RESULTS An 11 year-old girl was diagnosed with ganglioglioma after presenting with seizures. Tumor sequencing revealed three mutations: a PDAP1-BRAF fusion, a BRAF-HIP1 non-canonical fusion, and a pathogenic BRCA2 variant D252*fs. Upon further review, a family history of breast cancer in the grandmother and several great-aunts was identified, and genetic testing confirmed this mutation to be germline. We then conducted an institutional review and identified a second pediatric low-grade glioma (pilocytic astrocytoma) patient with a pathogenic mutation in BRCA2 (T3085Fs*26) in addition to a BRAF-KIAA1549 fusion; the family declined germline BRCA2 testing. BRCA1/2 knockout models have demonstrated that both genes play a role in brain development. Concurrent BRCA2 and TP53 loss triggers formation of early onset murine medulloblastoma, a finding not observed with TP53 loss alone. In human patients, heterozygous and biallelic mutations in BRCA2 were identified as risk factors for medulloblastoma development in a recent integrative genomic analysis. Retrospective review CONCLUSION We report two cases of BRCA2 mutation in pediatric low-grade gliomas, one of which was confirmed to be germline. While somatic variants of BRCA2 have been reported in both high- and low-grade glioma, their role in these tumors has not been established to date. The BRCA2 tumor predisposition syndrome increases the risk of some types of brain tumors such as medulloblastoma, although the risk remains low compared to the risk of developing breast or ovarian cancer later in life. More evidence is required to determine whether BRCA2 germline mutations can similarly increase the risk of glioma formation.

(112) SEXUAL HEALTH AFTER RISK REDUCING SALPINGO-OOPHERECTOMY FOR BRCA PATIENTS

Abstract Introduction There is no study assessing the changes in sexual health after risk reducing oopherectomy in premenopausal women. Objective Objective: To evaluate the effect of risk-reducing salpingo-oophorectomy (RRSO) on change in sexual function in women aged 34-50 years with pathogenic variants in BRCA1 or BRCA2 (BRCA1/2). Methods Methods: The PROSper (Prospective Research of Outcomes after Salpingo-oophorectomy) study is a prospective cohort of women aged 34-50 years with BRCA1 or two germline pathogenic variants that compares health outcomes after RRSO to a non-RRSO control group with ovarian conservation. Women aged 34-50 years, who were planning either RRSO or ovarian conservation, were enrolled for 3 years of follow-up. Sexual Function was measured using the Sexual Health Outcomes in Women (SHOW-Q) a validated survey tool that measures sexual desire, frequency, satisfaction, orgasm, and discomfort specifically in patients with a history of a pelvic condition, including oophorectomy. Differences in sexual function between the RRSO and non-RRSO groups, were determined by using mixed effects multivariable linear regression models. Results Results: Of 100 PROSper participants, all completed SHOW Q. At baseline patients who had undergone RRSO before enrollment had lower SHOW-Q scores (71 vs 64). Across all 60 months of the study the SHOW-Q scores remained persistently lower in those undergoing RRSO raging from 6-13 points across the time studied (p &amp;lt;0.05) controlling for age, depression, partner, menopausal symptoms and hormone therapy Conclusions Conclusion: Women with pathogenic variants in BRCA1/2 who undergo RRSO before the age of 50 years have greater effects on sexual function than those that do not. The detrimental effect of rRRSO is not otherwise explained by hormone therapy, depression or menopausal symptoms. This information should be incorporated into counseling and post op management to consider options to improve sexual health post surgery Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: sprout pharma.

Information needs of women with BRCA mutations regarding cancer risk management and decision-making

PurposeProviding women who have tested positive for a pathogenic variant in BRCA1 or BRCA 2 relevant information can help them to make informed decisions about managing their cancer risk. However, there is a lack of targeted informational support for BRCA positive women specific to the Irish context. The objective of this study is to identify the information needs of women diagnosed with a pathogenic variant in BRCA1 or BRCA 2 regarding cancer risk management and decision-making. MethodsThis is a descriptive qualitative study. Participants were recruited using purposive sampling and included women with a pathogenic variant in BRCA1 or BRCA2 without a history of breast or ovarian cancer. Two focus groups were held with women (n = 16) to enable them to generate ideas and understanding of their shared information needs. In addition, ten individual interviews were conducted to capture the additional perspectives of health care and relevant policy stakeholders. Interviews were analysed using inductive coding (Braun and Clarke, 2006), with NVivo software (Qsr international, 1999). ResultsThree main themes were identified, Cancer Risk Management, Receiving Information, and Implications to Health and Wellbeing. BRCA-positive women expressed a need for information about managing their cancer risk. They were particularly concerned with managing the impact of cancer risk-reducing interventions on their psychological and physical health, wellbeing, and family life. Many women felt they had to advocate for themselves to get treatment and receive information. Participants expressed a need for a comprehensive informational resource where all relevant information related to BRCA risk management could be accessed at a single location. ConclusionThis study suggests that women diagnosed with a pathogenic variant in BRCA1 or BRCA2 in Ireland need more accessible information about managing their cancer risk, and the impact of a BRCA diagnosis on their family, health and wellbeing. These results will be used to identify relevant content for developing an informational decision aid for Irish women.

Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers

BackgroundNo 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...

Breast cancer after ovarian cancer in BRCA1 and BRCA2 pathogenic variant heterozygotes: Lower rates for 5 years post chemotherapy

PurposeThe identification of germline BRCA1/BRCA2 pathogenic variants (PV) infer high remaining lifetime breast/ovarian cancer risks, but there is paucity of studies assessing breast cancer risk after ovarian cancer diagnosis. MethodsWe reviewed the history of breast cancer in 895 PV heterozygotes (BRCA1 = 541). Cumulative annual breast cancer incidence was assessed at 2, 5, 10, and >10 years after ovarian cancer diagnosis date. ResultsBreast cancer annual rates were evaluated in 701 assessable women with no breast cancer at ovarian diagnosis (BRCA1 = 425). Incidence was lower at 2 years (1.18%) and 2 to 5 years (1.13%) but rose thereafter for BRCA1 with incidence post 10 years in excess of 4% annually. Breast cancer pathology in BRCA1 PV heterozygotes showed less high-grade triple-negative breast cancer and more lower-grade hormone-receptor-positive cancer than women with no prior ovarian cancer. In the prospective cohort from ovarian cancer diagnosis, <4% of all deaths were caused by breast cancer, although 50% of deaths in women with breast cancer after ovarian cancer diagnosis were due to breast cancer. ConclusionWomen can be reassured that incidence of breast cancer after ovarian cancer diagnosis is relatively low. It appears likely that this effect is due to platinum-based chemotherapy. Nonetheless women need to be aware that incidence increases thereafter, especially after 10 years.

Interaction of BRCA1 vs BRCA2 pathogenic variants with primary tumor location in pancreatic cancer.

e16326 Background: BRCA1/2 germline or somatic pathogenic variants (PVs) are found in 5-10% of pancreatic adenocarcinoma (PDAC) patients. Recent data suggest that BRCA2 PVs may be associated with increased overall survival (OS) compared to BRCA1 PVs after adjusting for treatment and clinical characteristics. Additionally, pancreatic tail PDAC was found to harbor PVs in BRCA1/2 more frequently compared to PDAC within the pancreatic head (HOP). We hypothesized that tumor location in patients with BRCA1 and BRCA2 PVs would associate with overall survival and somatic mutation profile. Methods: We conducted a retrospective cohort study using a database of patients with PDAC and BRCA1/2 PVs at an academic center. Demographic and clinical data were compared by Fisher’s exact test. OS was measured using date of death or last follow-up and compared by Cox proportional hazards regression adjusting for treatment with platinum-based chemotherapy and curative-intent surgical resection. Cases with available next generation somatic sequencing were reviewed. Results: There were no significant differences in age, sex, stage at diagnosis, ECOG status at diagnosis, tumor location, treatments, or sites of metastasis between patients with BRCA1 vs BRCA2 PVs. In the overall cohort, we observed no significant difference in OS between patients with BRCA1 vs BRCA2 (17.0 vs 20.2 months). However, survival analysis stratified by tumor location demonstrated that BRCA1 patients with HOP tumors had significantly worse OS compared to BRCA2 patients with HOP tumors (13.1 vs 25.7 months, p = 0.014) and had a significantly higher rate of TP53 mutations (100% vs 50%, p = 0.032). No significant differences in OS or rates of TP53 mutations were observed in the body/tail of the pancreas. Conclusions: These results suggest that there may be differences in rates of somatic variants between BRCA1- and BRCA2-related HOP PDAC and suggest an interaction between BRCA1/2 tumor biology and anatomical location. [Table: see text]

Incidental Serous Tubal Intraepithelial Carcinoma Finding in a Nepalese Patient Undergoing Opportunistic Salpingectomy and the Discovery of a BRCA1 Pathogenic Variant

BACKGROUND: Serous tubal intraepithelial carcinoma lesions are the precursor to high-grade serous ovarian carcinomas, which have the highest mortality rate among gynecologic malignancies. In women diagnosed with high-grade serous ovarian carcinoma, 20% of the carcinomas are found to be secondary to hereditary causes, with the majority being associated with germline pathogenic variants in BRCA1 and BRCA2 genes. Patients with a pathogenic variant are at high risk for developing high-grade serous ovarian carcinoma, so it is recommended that they undergo risk-reducing salpingo-oophorectomy in their 30s–40s. Opportunistic salpingectomy is the only ovarian cancer prevention method available for patients at average risk. Although serous tubal intraepithelial carcinoma lesions are rare in women at average risk, studies quote incidental serous tubal intraepithelial carcinoma lesion findings in 1–7% of patients undergoing opportunistic salpingectomy. CASE: A 38-year-old woman, gravida 2 para 2, of Nepalese ethnicity had an incidental finding of a serous tubal intraepithelial carcinoma lesion at the time of opportunistic salpingectomy for permanent sterilization at cesarean delivery. The serous tubal intraepithelial carcinoma lesion was found with representative sampling of the fallopian tubes because the patient was considered to be at average risk for ovarian cancer. This method is much less sensitive than the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) protocol, which is used with women known to be at high risk. This ultimately led to discovery of a BRCA1 mutation in the patient. CONCLUSION: The SEE-FIM protocol is used to identify serous tubal intraepithelial carcinoma lesions, but it is not routinely used on fallopian tubes of patients at average risk. Using the SEE-FIM protocol would lead to fewer missed serous tubal intraepithelial carcinoma lesions, but it is unclear how much extra cost and effort would be required to implement this protocol. There are knowledge gaps when it comes to understudied populations and hereditary breast and ovarian cancer gene prevalence. Studies show that current BRCA prediction models underestimate hereditary breast and ovarian cancer gene prevalence in Asian populations. Diagnosing serous tubal intraepithelial carcinoma lesions in understudied populations could lead to the discovery of a hereditary breast and ovarian cancer pathogenic variant that the patient may not have discovered until after a cancer diagnosis. Identification of a serous tubal intraepithelial carcinoma in a patient at average risk should lead to a referral for genetic counseling and screening.

Novel Cancer Prevention Strategies in Individuals With Hereditary Cancer Syndromes: Focus on BRCA1, BRCA2, and Lynch Syndrome.

Germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes confer elevated risks of breast, ovarian, and other cancers. Lynch syndrome (LS) is associated with increased risks of multiple cancer types including colorectal and uterine cancers. Current cancer risk mitigation strategies have focused on pharmacologic risk reduction, enhanced surveillance, and preventive surgeries. While these approaches can be effective, they stand to be improved on because of either limited efficacy or undesirable impact on quality of life. The current review summarizes ongoing investigational efforts in cancer risk prevention strategies for patients with germline PVs in BRCA1, BRCA2, or LS-associated genes. These efforts span radiation, surgery, and pharmacology including vaccine strategies. Understanding the molecular events involved in the premalignant to malignant transformation in high-risk individuals may ultimately contribute significantly to novel prevention strategies.

Impact of hormone receptor status and tumor subtypes on clinical behavior and outcomes of breast cancer in young BRCA carriers.

504 Background: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer (BC). Among young patients harboring germline BRCA1or BRCA2 (BRCA) pathogenic variants (PVs), most of the tumors arising in BRCA2carriers express hormone receptors, while most BC cases in BRCA1 carriers do not; however, limited evidence exists on the impact of hormone receptor status on clinical behavior and outcomes in young patients harboring BRCA PVs. Methods: This is an international, multicenter, hospital-based, retrospective cohort study including young patients (≤40 years) diagnosed with invasive BC between January 2000 and December 2020, harboring germline PVs in BRCA genes. Our analysis investigates the impact of hormone receptor status on clinical behavior and outcomes of BC. The type and pattern of recurrence and survival outcomes (disease-free survival [DFS], BC specific survival [BCSS] and overall survival [OS]) were first investigated according to hormone receptors expression (positive vs. negative), and then according to BC subtype (luminal A-like vs. luminal B-like vs. triple-negative vs. HER2-positive BC). Results: From 78 centers worldwide, 4,709 BRCA carriers were included in this analysis, of whom 2,143 (45.5%) had hormone receptor-positive and 2,566 (54.5%) hormone receptor-negative BC. Patients with hormone receptor-positive BC were more likely to harbor BRCA2 PVs while less frequently had grade 3 tumors and nodal involvement. Median follow-up was 7.88 (IQR 4.47-12.61) years. The rate of distant recurrences was higher in patients with hormone receptor-positive BC (13.1% vs. 9.6%, p&lt;.001), while the rate of second primary BC was lower (9.1% vs. 14.7%, p&lt;.001) when compared to patients with hormone receptor-negative disease. The 8-years DFS was 65.8% in patients with hormone receptor-positive and 63.4% in those with hormone receptor-negative BC. No differences in terms of OS nor BCSS were observed. The hazard ratio of hormone receptor-positive vs. negative disease changed over time for DFS, BCSS, and OS (p&lt;.05 for interactions of hormone receptor status and survival time). Among the 4,363 patients eligible for subtypes analysis, 612 had luminal A-like, 1,038 luminal B-like, 2,373 triple-negative and 340 HER2-positive BC. Patients with Luminal A-like BC had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-years DFS: 60.8% in luminal A-like vs. 63.5% in triple-negative vs. 65.5% in HER2-positive and 69.7% in luminal B-like subtype). Conclusions: In young BRCAPVs carriers with early BC, hormone receptor status did not appear to be a positive prognostic factor. The differences in pattern of recurrence and second primary BC among hormone receptor-positive vs. negative disease warrants consideration in counseling patients on treatment, follow-up strategies and indication for risk-reducing surgery.

Clinical behavior of breast cancer in young BRCA carriers and prognostic impact of the timing of genetic testing: Results from an international cohort study.

10503 Background: Germline BRCA testing is recommended in all patients (pts) diagnosed with breast cancer (BC) at a young age (40 years or younger). Limited evidence exists regarding clinical behavior of BC in young BRCA1and BRCA2 carriers or the impact of the timing of genetic testing (before or at diagnosis) on tumor characteristics and pts outcomes. Methods: This was an international, multicenter, hospital-based, retrospective cohort study including pts harboring germline pathogenic variants (PVs) in BRCA1or BRCA2 and diagnosed with stage I-III invasive BC at 40 years or younger between January 2000 and December 2020 (NCT03673306). Baseline pt, tumor, and treatment characteristics, as well as survival outcomes (disease-free survival [DFS] and overall survival [OS]) were compared between BRCA1and BRCA2carriers. A further comparison was performed between pts who underwent genetic testing before (i.e. any time up to 2 months prior to BC diagnosis) or at (i.e. between 2 months prior and up to 6 months after diagnosis) BC diagnosis. Results: From 78 centers worldwide, 4,752 pts were included, of whom 3069 harbored BRCA1and 1683 BRCA2 PVs. Compared to BRCA2carriers, BRCA1 carriers were significantly younger, had more grade 3 tumors, less nodal involvement, lobular histology, hormone receptor and HER2 positivity, and received chemotherapy more frequently and endocrine therapy less frequently. Median follow-up was 7.8 years (range 4.4-12.6 years). Second primary BCs (13.7% vs. 9.3%) and non-breast new primary malignancies (4.5% vs. 3.0%) were significantly more frequent among BRCA1 carriers, while distant recurrences were less frequent (9.7% vs. 13.6%). No differences in DFS or OS were observed between BRCA1 and BRCA2 carriers. However, BRCA1 carriers had worse DFS and OS in the first 5 years due to a peak in DFS events in the first 2 years while BRCA2 carriers had a constant risk of recurrence over time and worse OS after year 9. Compared to pts tested for BRCA at BC diagnosis (n = 1671), those tested before BC diagnosis (n = 411) had significantly smaller tumors (T1: 61.3% vs 32.4%) and less nodal involvement (N0: 65.9% vs 50.8%). 8-year DFS and OS in patients tested before and at BC diagnosis were 73% vs 70% (HR 1.25; 95% CI 0.99-1.58) and 91% vs 87% (HR 1.65; 95% CI 1.08-2.52), respectively. Conclusions: In this global study of young BRCA carriers, different pts, tumor, and treatment characteristics, as well as pattern and risk of DFS/OS events over time were observed between BRCA1and BRCA2. Identification of carrying a BRCA PV in healthy individuals led to earlier BC diagnosis and improved OS. These findings highlight the importance of conducting efforts to identify women at risk for carrying a BRCA1or BRCA2PV to offer them genetic counseling and testing to inform not only prevention, but tailored earlier detection, treatment and follow-up strategies once diagnosed.

Clinical features of breast cancer in Ashkenazi Jewish carriers of the two founder BRCA1 pathogenic variants.

e12557 Background: Germline pathogenic variants (PVs) in BRCA1 and BRCA2 are the most common cause of hereditary breast and ovarian cancer. Carriers have a significantly elevated risk of developing breast cancer (BC) and ovarian cancer (OC) compared to the general female population. Two prevalent PVs in Ashkenazi Jews (AJ) in the BRCA1 gene are 185delAG and 5382insC. This study aims to compare clinical features of disease between the PV carrier groups. Methods: Data was collected retrospectively on 282 BC patients who were carriers of 5382insC or 185delAG, treated in Hadassah and Shaare Zedek Medical Centers between the years 1978 and 2021. Data collected included features such as age at disease onset, staging at diagnosis, additional malignancies or recurrence of disease, pathological features such as hormone receptor status and HER2 status (tumor subtype), and treatments. Disease characteristics and outcomes were compared. Results: There were 207 carriers of the 185delAG PV, while 75 carried the 5382insC PV. Amongst carriers of 185delAG, vs. 5382InsC, 58.1% vs. 35.8% (p&lt;0.01) had triple negative BC (TNBC), while 28.2% vs. 52.6% (p&lt;0.01) had hormone positive BC, respectively (Table). There was no significant difference in disease-free or overall survival, even after adjusting for age, stage and other potential confounders. Although it appeared that 5382insC carriers suffered a higher rate of OC (14% vs. 9.6%), and that 185delAG had a higher rate of non-OC malignancies (8.2% vs. 4%), these differences did not reach statistical significance. Conclusions: Our study suggests that 5382insC and 185delAG differ in their patterns of disease. Despite the lower rates of TNBC, 5382insC carriers had similar survival to 185delAG carriers. This could suggest that the hormone receptor positive disease amongst 5382InsC carriers had a less favorable course of disease, with a similar outcome as in those with TNBC. Further studies are warranted to better understand this pattern of disease aggression. [Table: see text]

Digenic Inheritance of Mutations in Homologous Recombination Genes in Cancer Patients.

BRCA1, BRCA2, ATM, and CHEK2 are known cancer predisposition genes (CPGs), but tumor risk in patients with simultaneous pathogenic variants (PVs) in CPGs remains largely unknown. In this study, we describe six patients from five families with multiple cancers who coinherited a combination of PVs in these genes. PVs were identified using NGS DNA sequencing and were confirmed by Sanger. Families 1, 2, and 3 presented PVs in BRCA2 and ATM, family 4 in BRCA2 and BRCA1, and family 5 in BRCA2 and CHEK2. PVs were identified using NGS DNA sequencing and were confirmed by Sanger. The first family included patients with kidney, prostate, and breast cancer, in addition to pancreatic adenocarcinomas. In the second family, a female had breast cancer, while a male from the third family had prostate, gastric, and pancreatic cancer. The fourth family included a male with pancreatic cancer, and the fifth family a female with breast cancer. The early age of diagnosis and the development of multiple cancers in the reported patients indicate a very high risk of cancer in double-heterozygous patients associated with PVs in HR-related CPGs. Therefore, in families with patients who differ from other family members in terms of phenotype, age of diagnosis, or type of cancer, the cascade testing needs to include the study of other CPGs.

HRD-negative high-grade carcinoma of the ovary in &lt;i&gt;BRCA2&lt;/i&gt; pathogenic variant carrier

Background. Homologous recombination deficiency (HRD) is a valuable molecular marker for predicting response to platinum agents and poly(ADP-ribose)-polymerase (PARP) inhibitors. Germline and somatic alterations in the BRCA1 and BRCA2 genes are the major cause of HRD in ovarian cancer. However, in some cases, tumors arising in carriers of BRCA1 or BRCA2 pathogenic variants do not lose the normal copy of the corresponding gene and are not deficient for homologous recombination. Aim of the study was to present a case of high-grade ovarian carcinoma without HRD phenotype developed in a BRCA2 mutation carrier. Case report. A 48-year-old woman was diagnosed with multiple primaries: HER2-positive high-grade ovarian cancer and colorectal adenocarcinoma. analysis of the coding BRCA1/BRCA2 sequences revealed the germline BRCA2 c.658_659delgt [rs80359604] pathogenic variant. Given the unusual histological features, namely the absence of serous or endometrioid markers and high HER2 expression, we performed additional molecular analysis of the metastatic lesions in the lymph nodes. In all samples, the pattern of chromosomal instability did not match the HRD profile and there was loss of the mutant copy of the BRCA2 gene. Therefore, this tumor lacked the BRCAness phenotype. Conclusion. Tumors arising in HRR gene mutation carriers require additional molecular analysis for a comprehensive assessment of HRD.

Dynamic change of cancer genome profiling in metachronous bilateral breast cancer with BRCA pathogenic variant.

A 61-year-old woman with BRCA2 pathogenic variant had been treated for 20years and showed dynamic changes in the genomic profile of her metachronous bilateral breast cancer and metastases. She underwent right breast conservation surgery at age 42-Genome 1, lung metastasis and left axillary lymph node metastasis at age 51, partial excision under local anesthesia for left breast cancer at age 53-Genome 2, left axillary lymph node dissection was added 6month later-Genome 3. Then, olaparib was administered, and subsequently, left mastectomy was performed for the recurrence of left breast cancer at age 59-Genome 4. Genomic profile of the tumor was analyzed at four points (Genome 1-3 were analyzed by in house breast cancer panel, and Genome 4 was analyzed by Foundation One CDx). Two interesting findings emerged from these analyses. First, the genomic profile revealed that the left axillary lymph node metastasis, considered histologically from right breast cancer, was a metastasis from the left breast cancer. The second finding is that as the disease progressed, mutation profile became more diverse. The profile of the left breast cancer removed after olaparib and other treatments showed reversion mutation of BRCA2 and was diagnosed as tumor mutation burden high. Subsequent response to pembrolizumab was favorable.

Targeted sequencing for hereditary breast and ovarian cancer in BRCA1/2-negative families reveals complex genetic architecture and phenocopies

Approximately 20% of breast cancer cases are attributed to increased family risk; yet variation in BRCA1/2 can only explain 20-25% of cases. Historically, only single gene or single variant testing were common in at-risk family members, and further sequencing studies were rarely offered after negative results. In this study, we applied an efficient and inexpensive targeted sequencing approach to provide molecular diagnoses in 245 human samples representing 134 BRCA mutation negative (BRCAX) hereditary breast and ovarian cancer (HBOC) families recruited from 1973-2019 by Dr. Henry Lynch. Sequencing identified 391 variants, which were functionally annotated and ranked based on their predicted clinical impact. Known pathogenic CHEK2 breast cancer variants were identified in five BRCAX families in this study. While BRCAX was an inclusion criterion for this study, we still identified a pathogenic BRCA2 variant (p.Met192ValfsTer13) in one family. A portion of BRCAX families could be explained by other hereditary cancer syndromes that increase HBOC risk: Li-Fraumeni Syndrome (gene: TP53) and Lynch Syndrome (gene: MSH6). Interestingly, many families carried additional Variants of Undetermined Significance (VOUSs) that may further modify phenotypes of syndromic family members. Ten families carried more than one potential VOUS suggesting the presence of complex multi-variant families. Overall, nine BRCAX HBOC families in our study may be explained by known likely-pathogenic/pathogenic variants, and six families carried potential VOUSs, which require further functional testing. To address this, we developed a functional assay where we successfully re-classified one family’s PMS2 VOUS as benign.

High Frequency of BRCA2 c.5576_5579del Carriers in Kakogawa, Japan.

Certain germline pathogenic variants (PVs), known as founder mutations, have been frequently observed in specific regions and ethnic groups. In Japan, several pathogenic variants of BRCA1/2 have been identified as founder mutations, with their distribution varying across different regions. This retrospective study aimed to further investigate the detailed distribution and correlation between genotype and clinical features among breast cancer patients. This study was conducted at Kobe University Hospital and three collaborating institutions. It included breast cancer patients who underwent BRCA1/2 genetic testing between July 1, 2018, and March 31, 2021, and were found to have germline PVs. Clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2 c.5576_5579del and those with other PVs. Additionally, the detection rate of BRCA2 c.5576_5579del was compared with that observed in a previous report. A total of 38 breast cancer patients were included; PVs in BRCA1 and BRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2 c.5576_5579del carriers. BRCA2 c.5576_5579del carriers were more likely to develop triple negative breast cancers among all BRCA2 PV carriers. BRCA2 c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital. BRCA2 c.5576_5579del was detected with a particularly high frequency in Hyogo Prefecture, especially in Kakogawa city. In the future, a survey of the distribution of the BRCA2 c.5576_5579del carriers may provide more clarity regarding their localization.