Carriers Of Pathogenic Variants Research Articles

Abstract PO4-08-04: Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer

Abstract Introduction: While outcomes are similar following breast-conserving surgery (BCS) or mastectomy among patients with sporadic breast cancer, data are still controversial for germline BRCA pathogenic variant carriers. We previously compared outcome following BCS between BRCA pathogenic variant carriers and non-carriers, and reported higher ipsilateral breast recurrence and comparable prognosis in the carriers. The purpose of this current study was to compare outcomes among BRCA pathogenic variant carriers undergoing BCS versus mastectomy in long-term follow-up period. Methods: Women with a BRCA pathogenic variant and a stage 0-III breast cancer who underwent definitive surgery from 1987–2021 were retrospectively identified from institutional database. Factors including clinicopathologic information and treatment characteristics were identified. Subsequent local recurrence, regional recurrence, distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) rates were compared between BCS and mastectomy using Kaplan-Meier method and log-rank test. The chi-square test and t-test were used to compare patient characteristics between the two groups. Results: A total of 232 BRCA mutation carriers with 257 cancers including 25 patients with synchronous bilateral breast cancer were identified. Surgical treatment included BCS for 82 cancers and mastectomy for 175 cancers including nipple-sparing mastectomy for 51 cancers. Patient age at surgery and cancer stage did not statistically differ between BCS and mastectomy groups. Comparing to patients choosing mastectomy, patients who underwent BCS were less likely to be aware of their genetic status before surgery and were more likely to receive radiation therapy (p < 0.001). Contralateral risk reducing mastectomy was performed in 22.5% (18/80) in the BCS group and 48.7% (74/152) in the mastectomy group (p < 0.001) concurrently or at any time after the first definitive surgery. Risk reducing salpingo-oophorectomy was performed in 40% (32/80) in the BCS group and 49% (75/152) in the mastectomy group (p = 0.17). At 7.5 years median follow-up, local recurrence rate was statistically higher in the BCS group than in the mastectomy group (20.0% in BSC vs. 4.6% in mastectomy, p = 0.043). In patients who underwent nipple-sparing mastectomy, 4.0% (2/51) had local subcutaneous recurrence and no nipple-areolar recurrence was observed. Median duration from the first definitive surgery to ipsilateral local recurrence was 10.0 years in the BCS group and 2.3 years in the mastectomy group. Regional lymph node recurrence (11.2% in BCS vs. 6.4% in mastectomy, p = 0.62), distant recurrence (13.7% vs. 9.2%, p = 0.84), CBC (15.0% vs. 8.6%, p = 0.70), BCSS (88.8% vs. 94.1%, p = 0.65) and OS (87.5% vs. 94.1%, p = 0.49) rates did not statistically differ between two groups. Conclusions: With 7.5 years median follow-up, higher local recurrence rate was observed in BCS than in mastectomy among BRCA pathogenic variant carriers. Our results found no statistical difference between BCS and mastectomy in regional recurrence, distant recurrence, CBC, and prognosis, indicating relatively higher risk in BCS. While BCS could be an option for BRCA pathogenic variant carriers willing to continue high-risk breast surveillance, shared decision making should be carefully performed based on the long-term local recurrence risk. Citation Format: Kumiko Kida, Junko Takei, Misato Suzuki, Megumi Okawa, Sakurako Kazama, Sakiko Kondo, Michiko Yamanaka, Atsushi Yoshida. Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-08-04.

Abstract PO5-08-05: Breast Cancer in PMS2 related Lynch Syndrome: evidence of a possible association?

Abstract Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. LS is associated with increased risk of colorectal, and endometrial cancers but breast cancer risk is uncertain, with some studies suggesting MSH6 and PMS2 PVs may have a higher risk for breast cancer. Our study outlines the incidence and clinical characteristics of breast cancer in PMS2-related LS identified at a large academic center. Methods: Patients with PMS2 PVs identified between July 2009 and May 2023 were selected from a database at the Nancy and James Grosfeld Cancer Genetic Center at Beaumont Health. Data on demographics, genetic testing, cancer types, and breast cancer characteristics were retrospectively analyzed. Results: A total of 108 patients from 74 families were found to carry a pathogenic or likely pathogenic variant in PMS2, of whom the majority were female (75%) and Caucasian (85%). The median age at genetic testing was 52y (19 to 95y). The most common variant was c.137G > T (p.Ser46Ile), seen in 15 of 74 (20%) families. Forty-seven patients (46%) had a personal history of cancer, with a median age at diagnosis of 58y. Of these forty-seven patients, sixteen (34%) had multiple malignancies, including one patient with six separate cancers. The most common malignancies were breast (19; 40%), colon (16; 34%), followed by uterine cancer (7), pancreas (4), and prostate (3). The median age at breast cancer diagnosis was 53y, with a range of 41-78y. The most common histopathology was invasive ductal carcinoma (54%), followed by DCIS (31%), and invasive lobular carcinoma (15%). The majority of patients had breast tumors with stage 0 or 1 (75%), grade 2 (63%), ER-positive (92%), PR positive (67%), and HER2-negative (88%). One patient had triple-negative breast cancer. Sixty-seven percent of breast cancers were less than two centimeters, and 92% were lymph node-negative. Fifty-nine percent received radiation therapy and 53% received chemotherapy. Conclusion: Our study outlines the incidence and clinical characteristics of breast cancer in PMS2-related LS. Breast cancer was the most common malignancy in our cohort of PMS2 PV carriers, accounting for 40% of all cancers, supporting a possible association between PMS2 and breast cancer. The majority of PMS2-related breast cancers were invasive ductal type, early stage, intermediate grade, and hormone receptor-positive. Further studies with larger diverse cohorts of patients with LS are needed to better characterize a possible association in order to provide tailored breast cancer screening and management guidelines for this population. Citation Format: Ujjwal Karki, Tara Rangarajan, Dana Zakalik. Breast Cancer in PMS2 related Lynch Syndrome: evidence of a possible association? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-05.

Germline Pathogenic Variants in Patients With Pancreatic and Periampullary Cancers.

Inherited cancer susceptibility is often not suspected in the absence of a significant cancer family history. Pathogenic germline variants in pancreatic cancer are well-studied, and routine genetic testing is recommended in the guidelines. However, data on rare periampullary cancers other than pancreatic cancer are insufficient. We compared the prevalence of germline susceptibility variants in patients with pancreatic cancer and nonpancreatic periampullary cancers. Six hundred and eight patients who had undergone pancreaticoduodenal resection at a tertiary referral hospital were studied, including 213 with pancreatic ductal adenocarcinoma, 172 with ampullary cancer, 154 with distal common bile duct cancer, and 69 with duodenal adenocarcinoma. Twenty cancer susceptibility and candidate susceptibility genes were sequenced, and variant interpretation was assessed by interrogating ClinVar and PubMed. Pathogenic or likely pathogenic, moderate- to high-penetrant germline variants were identified in 46 patients (7.7%), including a similar percentage of patients with pancreatic (8.5%) and nonpancreatic periampullary cancer (7.1%). Low-penetrant variants were identified in an additional 11 patients (1.8%). Eighty-nine percent of the moderate- to high-penetrant variants involved the major cancer susceptibility genes BRCA2, ATM, BRCA1, CDKN2A, MSH2/MLH1, and PALB2; the remaining 11% involved other cancer susceptibility genes such as BRIP1, BAP1, and MSH6. Almost all pathogenic variant carriers had a family history of cancer. Patients with pancreatic and nonpancreatic periampullary cancer have a similar prevalence of pathogenic cancer susceptibility variants. Germline susceptibility testing should be considered for patients with any periampullary cancer.

Description of the Two-Dimensional Layer-Specific Strain Echocardiography Phenotype of Arrhythmogenic Left Ventricular Cardiomyopathy

Arrhythmogenic left ventricular cardiomyopathy (ALVC) is characterized by fibrofatty myocardial replacement demonstrated on cardiac magnetic resonance by late gadolinium enhancement (LGE) mainly involving the subepicardium. The aims of this study were to describe the layer-specific strain (LSS) echocardiography phenotype of ALVC and to compare it with LGE features. All consecutive ALVC pathogenic genetic variant carriers and noncarrier relatives were separated into four prespecified groups (overt ALVC [group 1], isolated LGE [group 2], pathogenic genetic variant carrier without ALVC phenotype [group 3], and no genetic variant carrier [group 4]) and studied accordingly using cardiac magnetic resonance and LSS echocardiography. Eighty-five individuals were included. Endocardial global longitudinal strain (GLS)-epicardial GLS (GLSepi) gradient was altered predominantly in group 1, illustrating transmural strain alteration in overt ALVC (3.8±1.1 in group 1, 4.3±2.2 in group 2, 5.2±1.2 in group 3, and 5.4±1.6 in group 4; P=.0017), whereas GLSepi was impaired predominantly in group 2 (endocardial GLS and GLSepi were 15.0±4.1% and 11.2±3.3%, respectively, in group 1; 20.5±2.8% and 16.2±5.5% in group 2; 23.4±3.3% and 18.2±2.7% in group 3; and 24.6±2.8% and 19.2±1.9% in group 4; P<.0001 for all). GLSepi was able to detect subepicardial LGE in genetic variant carriers without overt ALVC with an area under curve of 0.84 (95% CI, 0.73-0.95). However, segmental epicardial and endocardial strain behaved similarly and showed comparable diagnostic values for segmental LGE detection (areas under the curve, 0.72; [95% CI, 0.69-0.76] and 0.73 [95% CI, 0.70-0.76], respectively, P=.40). LSS alteration in ALVC progresses from the epicardium to the endocardium along with disease severity. Irrespective of LSS analysis, which did not provide incremental diagnostic value for the detection and localization of LGE, strain echocardiography was shown to be a potential surrogate marker of LGE, including in apparently healthy individuals with isolated LV fibrosis.

Deciphering the clinical spectrum of gastric disease in patients with juvenile polyposis syndrome

Juvenile polyposis syndrome (JPS) is a rare hereditary autosomal dominant cancer-predisposition syndrome caused by germline pathogenic variants (PVs) located in SMAD4 or BMPR1A genes. Accurate clinical and endoscopic data regarding the evolution of gastric lesions remain sparse. Clinical, endoscopic, genetic, and pathologic data from patients with SMAD4 or BMPR1A PVs included between 2007 and 2020 in the French network on rare digestive polyposis (RENAPOL [French National Polyposis Register]) database were prospectively collected to address uncertainties regarding gastric involvement. Thirty-six patients were included: 25 (69.5%) had SMAD4 PVs, and 11 had BMPR1A PVs. For SMAD4 PV carriers, median age at inclusion was 43.0 years (range, 10-78 years). At baseline EGD, 22 (88%) of 25 patients exhibited at least 1 gastric juvenile polyp, and 5 (20%) of 25 had macroscopic signs of inflammatory gastritis. Early gastric disease was mostly located under the cardia, then progressed to the gastric antrum and body. During a mean follow-up period of 55.0 months, 12 of 25 patients had gastric disease progression (ie, new juvenile polyps [91.6%], diffuse gastric involvement [41.6%], inflammatory flat progression [25%]). Among 62 biopsies, low-grade dysplasia was observed in 5 (7.5%) samples from 2 patients. Nine carriers (36%) underwent gastrectomy (mean age, 47.2 years) due to diffuse gastric involvement or worsening clinical symptoms. Gastric adenocarcinoma (T1) was found in 1 gastrectomy specimen. Among the 11 patients with BMPR1A PVs, 2 had gastric hamartomatomas at baseline EGD, none with dysplasia or symptoms. Gastric involvement in JPS seems to be progressive over a lifetime, initiates in the cardia area, and mostly involves SMAD4 PV carriers.

The Added Value of Blood Glucose Monitoring in High-Risk Individuals Undergoing Pancreatic Cancer Surveillance.

The study aimed to investigate the added value of blood glucose monitoring in high-risk individuals (HRIs) participating in pancreatic cancer surveillance. High-risk individuals with a CDKN2A/p16 germline pathogenic variant participating in pancreatic cancer surveillance were included in this study. Multivariable logistic regression was performed to assess the relationship between new-onset diabetes (NOD) and pancreatic ductal adenocarcinoma (PDAC). To quantify the diagnostic performance of NOD as a marker for PDAC, receiver operating characteristic curve with area under the curve was computed. In total, 220 HRIs were included between 2000 and 2019. Median age was 61 (interquartile range. 53-71) years and 62.7% of participants were female. During the study period, 26 (11.8%) HRIs developed NOD, of whom 5 (19.2%) later developed PDAC. The other 23 (82.1%) PDAC cases remained NOD-free. Multivariable analysis showed no statistically significant relationship between NOD and PDAC (odds ratio, 1.21; 95% confidence interval, 0.39-3.78) and 4 of 5 PDAC cases seemed to have NOD within 3 months before diagnosis. Furthermore, NOD did not differentiate between HRIs with and without PDAC (area under the curve, 0.54; 95% confidence interval, 0.46-0.61). In this study, we found no added value for longitudinal glucose monitoring in CDKN2A pathogenic variant carriers participating in an imaging-based pancreatic cancer surveillance program.

Genetic Landscape and Clinical Features of Hyperphenylalaninemia in North Ossetia-Alania: High Frequency of P281L and P211T Genetic Variants in the PAH Gene.

This study, conducted in the Republic of North Ossetia-Alania (RNOA), aimed to explore the genetic landscape of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) in the Ossetian population using data from newborn screening (NBS). Through comprehensive molecular genetic analysis of 29 patients with HPA from diverse ethnic backgrounds, two major genetic variants in the PAH gene, P281L and P211T, were identified, constituting 50% of all detected pathogenic alleles in Ossetian patients. Remarkably, these variants exhibited an exceptionally high frequency in the Ossetian population, surpassing global prevalence rates. This study unveiled a notable prevalence of mild forms of HPA (78%), underscoring the importance of genetic counseling for carriers of pathogenic variants in the PAH gene. Moreover, the findings emphasized the necessity for ongoing monitoring of patients with mild forms, as they may lack significant symptoms for diagnosis, potentially impacting offspring. Overall, this research offers valuable insights into the genetic landscape of HPA and PKU in the Ossetian population.

Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer

RAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival. To characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status. This retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023. Clinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test. A total of 9507 index patients were reviewed, and 91 patients (1.0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86.7%) were women and 181 (55.8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c.1026+5_1026+7del (11 of 56 [19.6%]) and c.709C>T (9 of 56 [16.1%]) in RAD51C and c.694C>T (20 of 35 [57.1%]) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55.2% (16 of 29) and 61.1% (11 of 18) for RAD51C, respectively, and 66.7% (6 of 9) and 90.0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD. In this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor-positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate-ribose] polymerase) inhibitors.

Screening for dilated cardiomyopathy in immediate family members: to whom, how, when (and where).

Dilated cardiomyopathy (DCM) is defined by the presence of left ventricular dilation and systolic dysfunction in the absence of coronary artery disease, valvular disease, congenital heart disease, or altered haemodynamic conditions. Dilated cardiomyopathy can recognize multiple aetiologies, including infectious processes, effect of toxic substances, immunological mechanisms, and genetic causes. In recent years, many genes coding for proteins involved in the structure and function of the cardiomyocytes have been associated with the development of DCM, making the identification of familial forms increasingly frequent. At the same time, an ever-increasing use of cardiac magnetic resonance imaging has made it possible to identify early morpho-functional alterations in subjects with initial forms of the disease, or carriers of pathogenic genetic variants. The increasingly in-depth understanding of the genetic and molecular mechanisms operating in DCM has also favoured the development of new therapeutic strategies including drugs with molecular targets and gene therapies. In this panorama, screening of family members of patients affected by DCM represents an important tool for early diagnosis, treatment, and prognostic stratification. In relation to its clinical relevance and its complexity, it is important that family screening and follow-up of identified patients are carried out in units dedicated to the treatment and study of cardiomyopathies.

Abstract P70: HIGH-THROUGHPUT IMAGING-BASED PHENOTYPIC PROFILING OF IMMUNE CELLS FROM BRCA2 VARIANT CARRIERS AND NON-CARRIERS

Abstract Mutated germline alleles in the DNA damage repair (DDR) genes BRCA1/2 are major risk factors for breast and ovarian cancers. Recent studies have found that BRCA1-mutant tumors tend to have higher abundance of immune cells within the tumor microenvironment, but much better response was observed from the BRCA2-mutant tumors when given immune-checkpoint inhibitors, suggesting possible functional and phenotypic effects of germline BRCA2 mutations on the immune cells. However, most existing studies focus on investigating the genomic instability and phenotypes of hereditary mutations in breast and ovarian cancer cells. Thus, the impact of these mutations on immune cells’ phenotypes and functions remains largely unknown. Here, we report a study of immune cells with and without BRCA2 mutations using High-throughput Imaging-based Phenotypic Profiling (HIPP), which can identify changes in cellular morphology and protein subcellular localization patterns that are not obvious from other traditional functional assays. We performed HIPP on immune cells from nine BRCA2 pathogenic variant carriers and eight non-carriers. Automatic quantification of ~200 phenotypic features from each single cell revealed that CD8+ T cells from BRCA2 variant carriers have distinct and quantifiable changes in their morphological features (such as cytoskeleton structures) and immunological features (such as Granzyme B expressions). Moreover, we found that BRCA2-mutant CD8+ T cells proliferate faster than normal CD8+ T cells. Our results suggest that BRCA2 mutations affect the functions and phenotypes of immune cells. Some of these phenotypic features and markers may be used to classify BRCA2 variants and predict the pathogenicity of variants of uncertain significance (VUS). Our study provides new insight into the immune phenotyping of cancer patients at individual level and may help to stratify patients, leading to the development of more effective therapeutic strategies. This method can potentially extend to other germline variants and overcome the challenge of VUS interpretation in clinical management. Citation Format: Guorui Zhong, Oscar Fu, Claresta Yeo, Siao Ting Chong, Sock Hoai Chan, Joanne Ngeow, Lit-Hsin Loo. HIGH-THROUGHPUT IMAGING-BASED PHENOTYPIC PROFILING OF IMMUNE CELLS FROM BRCA2 VARIANT CARRIERS AND NON-CARRIERS [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P70.

Uptake of screening and risk-reducing recommendations among women with hereditary breast and ovarian cancer syndrome due to pathogenic BRCA1/2 variants evaluated at a large urban comprehensive cancer center.

Carriers of pathogenic variants in BRCA1/2 have an elevated lifetime cancer risk warranting high-risk screening and risk-reducing procedures for early detection and prevention. We report on prevention practices among women with pathogenic BRCA variants in order to document follow through with NCCN recommendations and to identify barriers to guideline-recommended care. Our cohort included women who had genetic testing through a cancer genetic clinic and completed a 54-item questionnaire to measure socio-demographics, medical history, rates of cancer screening and risk-reducing surgery, disclosure of test results, and cancer worry. Outcomes included rates of completion of risk-reducing salpingo-oophorectomy (RRSO), risk-reducing mastectomy (RRM), and NCCN risk-reducing and age-dependent screening guidelines (version 3.2019). Multivariable logistic regression analyses were used to evaluate potential predictors of these outcomes. Of 129 evaluable women with pathogenic BRCA1/2 variants, 95 (74%) underwent RRSO and 77 (60%) had RRM, respectively, and 107 (83%) were considered adherent to NCCN guidelines. Women with a history of breast or ovarian cancer were more likely to have RRM (OR = 4.38; 95% CI 1.80-11.51; p = 0.002). Increasing age was associated with an increased likelihood of RRSO (OR = 1.05; 95% CI 1.01-1.09; p = 0.019) and decreased likelihood for RRM (OR = 0.95; 95% CI 0.92-0.99; p = 0.013). Women who had RRM were 3 times more likely to undergo RRSO (OR = 2.81; 95% CI 1.10-7.44; p = 0.025). Women who had genetic testing after June 2013 were less likely to have RRM than those tested before June 2013 (OR = 0.42; 95% CI 0.18-0.95; p = 0.040. None of the other measured factors were associated with rates of RRSO, RRM or follow through with NCCN recommendations. There was near universal (127/129) reported disclosure of genetic test results to family members, resulting in the discovery of a median of 1 relative with a pathogenic variant (range = 0-8). An evaluation of follow up practice in a cohort of women with pathogenic variants in BRCA1/2 revealed high rates of reported completion of screening and surgical risk-reducing recommendations. Educational efforts should continue to reinforce the importance of follow-through with guideline recommended care among this high-risk group.

Understanding familial risk of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is the result of an accumulation of sequential genetic alterations. These genetic alterations can either be inherited, such as pathogenic germline variants that are associated with an increased risk of cancer, or acquired, such as somatic mutations that occur during the lifetime of an individual. Understanding the genetic basis of inherited risk of PDAC is essential to advancing patient care and outcomes through improved clinical surveillance, early detection initiatives, and targeted therapies. In this review we discuss factors associated with an increased risk of PDAC, the prevalence of genetic variants associated with an increased risk in patients with PDAC, estimates of PDAC risk in carriers of pathogenic germline variants in genes associated with an increased risk of PDAC. The role of common variants in pancreatic cancer risk will also be discussed.

Outcomes of SDHB Pathogenic Variant Carriers.

Carriers of germline pathogenic variants (PVs) in succinate dehydrogenase type B (SDHB) are at increased risk of developing pheochromocytomas and paragangliomas (PPGLs). Understanding their outcomes can guide recommendations for risk assessment and early detection. We performed a systematic review and meta-analysis of the following outcomes in SDHB PV carriers: age-specific risk of developing tumors, metastatic progression, second primary tumor development, and mortality. PubMed, MEDLINE, and EMBASE were searched. Sixteen studies met the inclusion criteria and were sorted into 4 outcome categories: age-specific penetrance, metastatic disease, risk of second tumor, and mortality. We assessed heterogeneity and performed a meta-analysis across studies using a random-effects model with the DerSimonian and Laird method. Penetrance of PPGLs for nonproband/nonindex SDHB PV carriers by age 20 was 4% (95% CI, 3%-6%), 11% (95% CI, 8%-15%) by age 40, 24% (95% CI, 19%-31%) by age 60%, and 35% (95% CI, 25%-47%) by age 80. The overall risk of metastatic disease for nonproband/nonindex carriers with PPGLs was 9% (95%, CI 5%-16%) per lifetime. In all affected cases (combining both proband/index and nonproband/nonindex carriers with tumors), the risk of a second tumor was 24% (95% CI, 18%-31%) and all-cause 5-year mortality was 18% (95% CI, 6%-40%). Penetrance for PPGLs in SDHB PV carriers increases linearly with age. Affected carriers are at risk of developing and dying of metastatic disease, or of developing second tumors. Lifelong surveillance is appropriate.

Evaluating homologous recombination activity in tissues to predict the risk of hereditary breast and ovarian cancer and olaparib sensitivity.

Homologous recombination (HR) repairs DNA damage including DNA double-stranded breaks and alterations in HR-related genes results in HR deficiency. Germline alteration of HR-related genes, such as BRCA1 and BRCA2, causes hereditary breast and ovarian cancer (HBOC). Cancer cells with HR deficiency are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents. Thus, accurately evaluating HR activity is useful for diagnosing HBOC and predicting the therapeutic effects of anti-cancer agents. Previously, we developed an assay for site-specific HR activity (ASHRA) that can quantitatively evaluate HR activity and detect moderate HR deficiency. HR activity in cells measured by ASHRA correlates with sensitivity to the PARP inhibitor, olaparib. In this study, we applied ASHRA to lymphoblastoid cells and xenograft tumor tissues, which simulate peripheral blood lymphocytes and tumor tissues, respectively, as clinically available samples. We showed that ASHRA could be used to detect HR deficiency in lymphoblastoid cells derived from a BRCA1 pathogenic variant carrier. Furthermore, ASHRA could quantitatively measure the HR activity in xenograft tumor tissues with HR activity that was gradually suppressed by inducible BRCA1 knockdown. The HR activity of xenograft tumor tissues quantitatively correlated with the effect of olaparib. Our data suggest that ASHRA could be a useful assay for diagnosing HBOC and predicting the efficacy of PARP inhibitors.

Safety of the Breast Cancer Adjuvant Radiotherapy in Ataxia-Telangiectasia Mutated Variant Carriers.

The Ataxia-Telangiectasia Mutated (ATM) gene is implicated in DNA double-strand break repair. Controversies in clinical radiosensitivity remain known for monoallelic carriers of the ATM pathogenic variant (PV). An evaluation of the single-nucleotide polymorphism (SNP) rs1801516 (G-A) showed different results regarding late subcutaneous fibrosis after breast radiation therapy (RT). The main objective of this study was to evaluate acute and late toxicities in carriers of a rare ATM PV or predicted PV and in carriers of minor allele A of rs1801516 facing breast RT. Fifty women with localized breast cancer treated with adjuvant RT between 2000 and 2014 at Institut Curie were selected. Acute and late toxicities in carriers of a rare PV or predicted PV (n= 9), in noncarriers (n = 41) and in carriers of SNP rs1801516 (G-A) (n = 8), were examined. The median age at diagnosis was 53 years old and 82% of patients had an invasive ductal carcinoma and 84% were at clinical stage I-IIB. With a median follow-up of 13 years, no significant difference between carriers and noncarriers was found for acute toxicities (p > 0.05). The same results were observed for late toxicities without an effect from the rs1801516 genotype on toxicities. No significant difference in acute or late toxicities was observed between rare ATM variant carriers and noncarriers after breast RT for localized breast cancer.

Population-based BRCA germline mutation screening in the Han Chinese identifies individuals at risk of BRCA mutation-related cancer: experience from a clinical diagnostic center from greater Shanghai area

BackgroundDeleterious BRCA1/2 (BRCA) mutation raises the risk for BRCA mutation-related malignancies, including breast, ovarian, prostate, and pancreatic cancer. Germline variation of BRCA exhibits substantial ethnical diversity. However, there is limited research on the Chinese Han population, constraining the development of strategies for BRCA mutation screening in this large ethnic group.MethodsWe profile the BRCA mutational spectrum, including single nucleotide variation, insertion/deletion, and large genomic rearrangements in 2,080 apparently healthy Chinese Han individuals and 522 patients with BRCA mutation-related cancer, to determine the BRCA genetic background of the Chinese Han population, especially of the East Han. Incident cancer events were monitored in 1,005 participants from the healthy group, comprising 11 BRCA pathogenic/likely pathogenic (PLP) variant carriers and 994 PLP-free individuals, including 3 LGR carriers.ResultsHealthy Chinese Han individuals demonstrated a distinct BRCA mutational spectrum compared to cancer patients, with a 0.53% (1 in 189) prevalence of pathogenic/likely pathogenic (PLP) variant, alongside a 3 in 2,080 occurrence of LGR. BRCA1 c. 5470_5477del demonstrated high prevalence (0.44%) in the North Han Chinese and penetrance for breast cancer. None of the 3 LGR carriers developed cancer during the follow-up. We calculated a relative risk of 135.55 (95% CI 25.07 to 732.88) for the development of BRCA mutation-related cancers in the BRCA PLP variant carriers (mean age 42.91 years, median follow-up 10 months) compared to PLP-free individuals (mean age 48.47 years, median follow-up 16 months).ConclusionThe unique BRCA mutational profile in the Chinese Han highlights the potential for standardized population-based BRCA variant screening to enhance BRCA mutation-related cancer prevention and treatment.

Uptake of Risk-Reducing Measures, Cascade Testing, and Related Challenges Among Carriers of Breast Cancer-Associated Germline Pathogenic Variants in Mexico.

Genetic cancer risk assessment (GCRA) provides pathogenic variant (PV) carriers with the invaluable opportunity to undertake timely cancer risk-reducing (RR) measures and initiate cascade testing (CT). This study describes the uptake of these strategies and the related barriers among breast cancer-associated germline PV carriers in Mexico. Carriers who were at least 6 months after disclosure of genetic test results at two GCRA referral centers were invited to answer a survey assessing sociodemographic characteristics, awareness of their carrier status and its implications, uptake of RR measures according to international guidelines by PV, CT initiation, and associated challenges. Of the eligible carriers, 246/384 (64%) answered the survey (median age: 44 years). Most were female (88%), married/in domestic partnership (66%), and had personal breast/ovarian cancer history (61%). PVs included BRCA1/2 (75%), CHEK2 (10%), PALB2 (5%), ATM (5%), NF1 (2%), RAD51C (2%), PTEN (1%), and TP53 (1%). Most (87%) participants were aware of their carrier status. When recommended, 37% underwent RR bilateral mastectomy, 48% RR oophorectomy, 70% annual mammogram, and 20% breast magnetic resonance imaging. Challenges hindering the uptake of RR measures included financial limitations (67%), lack of recommendation by their physician (35%), and fear (24%). Nearly all (98%) claimed sharing their results with their relatives. CT was initiated in 63% of families and was associated with carriers being married/in domestic partnership (P = .04) and believing GCRA was useful (P < .001). Despite the resource-constrained setting, relevant rates of RR measures and CT were observed. Targeted interventions to reduce out-of-pocket expenses and improve patient-physician communication and patients' understanding on carrier status are warranted to enhance the overall benefit of GCRA and ultimately improve the provision of patient-centered care to both carriers and their at-risk relatives.

Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants

In young-onset breast cancer (YOBC), a diagnosis within 5 to 10 years of childbirth is associated with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with BC at younger ages, but the impact of childbirth on mortality is unknown. To determine whether time between most recent childbirth and BC diagnosis is associated with mortality among patients with YOBC and germline BRCA1/2 PVs. This prospective cohort study included women with germline BRCA1/2 PVs diagnosed with stage I to III BC at age 45 years or younger between 1950 and 2021 in the United Kingdom, who were followed up until November 2021. Data were analyzed from December 3, 2021, to November 29, 2023. Time between most recent childbirth and subsequent BC diagnosis, with recent childbirth defined as 0 to less than 10 years, further delineated to 0 to less than 5 years and 5 to less than 10 years. The primary outcome was all-cause mortality, censored at 20 years after YOBC diagnosis. Mortality of nulliparous women was compared with the recent post partum groups and the 10 or more years post partum group. Cox proportional hazards regression analyses were adjusted for age, tumor stage, and further stratified by tumor estrogen receptor (ER) and BRCA gene status. Among 903 women with BRCA PVs (mean [SD] age at diagnosis, 34.7 [6.1] years; mean [SD] follow-up, 10.8 [9.8] years), 419 received a BC diagnosis 0 to less than 10 years after childbirth, including 228 women diagnosed less than 5 years after childbirth and 191 women diagnosed 5 to less than 10 years after childbirth. Increased all-cause mortality was observed in women diagnosed within 5 to less than 10 years post partum (hazard ratio [HR], 1.56 [95% CI, 1.05-2.30]) compared with nulliparous women and women diagnosed 10 or more years after childbirth, suggesting a transient duration of postpartum risk. Risk of mortality was greater for women with ER-positive BC in the less than 5 years post partum group (HR, 2.35 [95% CI, 1.02-5.42]) and ER-negative BC in the 5 to less than 10 years post partum group (HR, 3.12 [95% CI, 1.22-7.97]) compared with the nulliparous group. Delineated by BRCA1 or BRCA2, mortality in the 5 to less than 10 years post partum group was significantly increased, but only for BRCA1 carriers (HR, 2.03 [95% CI, 1.15-3.58]). These findings suggest that YOBC with germline BRCA PVs was associated with increased risk for all-cause mortality if diagnosed within 10 years after last childbirth, with risk highest for ER-positive BC diagnosed less than 5 years post partum, and for ER-negative BC diagnosed 5 to less than 10 years post partum. BRCA1 carriers were at highest risk for poor prognosis when diagnosed at 5 to less than 10 years post partum. No such associations were observed for BRCA2 carriers. These results should inform genetic counseling, prevention, and treatment strategies for BRCA PV carriers.

A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency.

Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis is often hampered by the identification of mismatch repair (MMR) variants of unknown significance and difficulties in PMS2 analysis, the most frequently mutated gene in CMMRD. We present the validation of a robust functional tool for CMMRD diagnosis and the characterization of microsatellite instability (MSI) patterns in blood and tumors. The highly sensitive assessment of MSI (hs-MSI) was tested on a blinded cohort of 66 blood samples and 24 CMMRD tumor samples. Hs-MSI scores were compared with low-pass genomic instability scores (LOGIC/MMRDness). The correlation of hs-MSI scores in blood with age of cancer onset and the distribution of insertion-deletion (indel) variants in microsatellites were analyzed in a series of 169 individuals (n = 68 CMMRD, n = 124 non-CMMRD). Hs-MSI achieved high accuracy in the identification of CMMRD in blood (sensitivity 98.5% and specificity 100%) and detected MSI in CMMRD-associated tumors. Hs-MSI had a strong positive correlation with whole low-pass genomic instability LOGIC scores (r = 0.89, P = 2.2e-15 in blood and r = 0.82, P = 7e-3 in tumors). Indel distribution identified PMS2 pathogenic variant (PV) carriers from other biallelic MMR gene PV carriers with an accuracy of 0.997. Higher hs-MSI scores correlated with younger age at diagnosis of the first tumor (r = -0.43, P = 0.011). Our study confirms the accuracy of the hs-MSI assay as ancillary testing for CMMRD diagnosis, which can also characterize MSI patterns in CMMRD-associated cancers. Hs-MSI is a powerful tool to pinpoint PMS2 as the affected germline gene and thus potentially personalize cancer risk.

Abstract 7321: Second primary cancer risks following breast cancer in BRCA1/2 pathogenic variant carriers

Abstract Background: Second primary cancer (SPC) risk estimates in breast cancer (BC) survivors carrying germline BRCA1/2 pathogenic variants (PVs) remain uncertain. We estimated relative and absolute SPC risks following BC in BRCA1/2 PV carriers using genetic testing laboratory data in England, linked for the first time to population-scale electronic health records data from the National Disease Registration Service and Hospital Episode Statistics. Material and methods: The cohort contained 27,154 women diagnosed with primary BC and tested for germline BRCA1/2 PVs between 1995-2019. Follow-up began at the latest of the genetic test dates and one year following the BC diagnosis and continued until the first SPC diagnosis, death, migration, relevant surgery, and the end of 2020, whichever came first. We estimated overall and site-specific standardized incidence ratios (SIRs) by comparing observed and expected SPC counts, with expected counts calculated using incidences for the general English population accounting for calendar year, SPC site, age, and gender. We stratified the SIRs by age, estrogen-receptor status, and cancer site. We further assessed associations using Cox regression adjusted for age at BC diagnosis and estrogen-receptor status of the first BC, and estimated 10-year absolute SPC risks with Kaplan-Meier analysis. Results: There were 1909 BRCA1 (138 with SPCs) and 1926 BRCA2 (101 with SPCs) PV carriers, with mean follow-up lengths of 4.2 and 4.4y and median follow-up lengths of 3.4 and 3.6y. In BRCA1 PV carriers, there were elevated contralateral BC (SIR:15.3, 95%CI:11.5-19.8), ovarian (SIR:43.3, 95%CI:30.9-58.9), non-breast and non-ovarian combined (SIR:2.23, 95%CI:1.63-2.98), colorectal (SIR:4.72, 95%CI:2.58-7.92) and uterine (SIR:3.42, 95%CI:1.25-7.44) SPC risks. In BRCA2 PV carriers, there were increased contralateral BC (SIR:7.53, 95%CI:5.33-10.3), ovarian (SIR:16.5, 95%CI:10.1-25.5), non-breast and non-ovarian (SIR:1.72, 95%CI:1.27-2.27) and pancreatic (SIR:6.57, 95%CI:2.63-13.5) SPC risks. Consistently, when we compared BC survivors carrying a BRCA1 PV to BC survivors without a PV in either gene, they were at elevated contralateral BC (HR:3.94, 95%CI:2.91-5.33), ovarian (HR:35.7, 95%CI:21.3-60.0), non-breast and non-ovarian (HR:1.53, 95%CI:1.11-2.12) and colorectal (HR:2.95, 95%CI:1.56-5.55) SPC risks, whereas BRCA2 PV carriers were at increased contralateral BC (HR:2.59, 95%CI:1.83-3.65), ovarian (HR:12.3, 95%CI:6.93-21.9) and pancreatic (HR:5.32, 95%CI:2.30-12.3) SPC risks. We estimated 10-year cumulative contralateral BC, ovarian, and non-breast and non-ovarian SPC risks of 15%, 6.3%, and 7.8% in BRCA1 PV carriers and 12%, 2.9%, and 6.2% in BRCA2 PV carriers. Conclusions: Cancer risks were increased, at combined and specific sites, following BC in BRCA1/2 PV carriers. These findings could aid the clinical management of BC survivors carrying BRCA1/2 PVs. Citation Format: Isaac Allen, Hend Hassan, Yvonne Walburga, Catherine Huntley, Lucy Loong, Tameera Rahman, Beth Torr, Andrew Bacon, Craig Knott, Sophie Jose, Sally Vernon, Margreet Lüchtenborg, Joanna Pethick, Francesco Santaniello, Shilpi Goel, Sophie Allen, Katrina Lavelle, Fiona McRonald, Diana M. Eccles, Eva Morris, Steven Hardy, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou. Second primary cancer risks following breast cancer in BRCA1/2 pathogenic variant carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7321.