Germline Mutations In High Risk Research Articles

Non-sclerosing (T-cell) and sclerosing (B-cell) lymphocytic lobulitis in diagnostic breast biopsies: Clinical, imaging, and pathologic features

Lymphocytic lobulitis (LL) is characterized by prominent lymphocytic infiltrates centered on lobules. Sclerosing lymphocytic lobulitis (SCLL) associated with diabetes mellitus (DM) or autoimmune disease (AI) was the first type to be described. Subsequently, non-sclerosing LL (NSCLL) was reported as an incidental finding in prophylactic mastectomies due to high risk germline mutations or a family history of breast cancer. The two types of LL were distinguished by stromal features and a predominant population of B-cells in the former and T-cells in the latter. In this study, 8 cases of NSCLL detected clinically or by screening were compared to 44 cases of SCLL. One case of NSCLL presented as a palpable mass, 2 as masses on screening, and 5 as MRI enhancement. In contrast, 80% of SCLL cases presented as palpable masses. Half the cases of NSCLL were associated with a BRCA1 or 2 mutation compared to 1 case of SCLL (2%). Three additional cases of NSCLL were associated with a strong family and/or personal history of breast cancer. Almost half (52%) of SCLL cases were associated with DM or AI, but only 25% of NSCLL. Immunoperoxidase studies confirmed a predominance of T-cells in NSCLL and B-cells in SCLL associated with DM or AI. It is important for pathologists to be aware of this new observation that NSCLL can be detected as a palpable mass or an imaging finding in diagnostic biopsies, as its presence can be indicative of a significant risk for breast cancer.

Clinical Significance of Background Parenchymal Enhancement in Breast Cancer Risk Stratification.

Background parenchymal enhancement (BPE) is an established breast cancer risk factor. However, the relationship between BPE levels and breast cancer risk stratification remains unclear. To evaluate the clinical relationship between BPE levels and breast cancer risk with covariate adjustments for age, ethnicity, and hormonal status. Retrospective. 954 screening breast MRI datasets representing 721 women divided into four cohorts: women with pathogenic germline breast cancer (BRCA) mutations (Group 1, N = 211), women with non-BRCA germline mutations (Group 2, N = 60), women without high-risk germline mutations but with a lifetime breast cancer risk of ≥20% using the Tyrer-Cuzick model (Group 3, N = 362), and women with <20% lifetime risk (Group 4, N = 88). 3 T/axial non-fat-saturated T1, short tau inversion recovery, fat-saturated pre-contrast, and post-contrast T1-weighted images. Data on age, body mass index, ethnicity, menopausal status, genetic predisposition, and hormonal therapy use were collected. BPE levels were evaluated by two breast fellowship-trained radiologists independently in accordance with BI-RADS, with a third breast fellowship-trained radiologist resolving any discordance. Propensity score matching (PSM) was utilized to adjust covariates, including age, ethnicity, menopausal status, hormonal treatments, and prior bilateral oophorectomy. The Mann-Whitney U test, chi-squared test, and univariate and multiple logistic regression analysis were performed, with an odds ratio (OR) and corresponding 95% confidence interval. Weighted Kappa statistic was used to assess inter-reader variation. A P value <0.05 indicated a significant result. In the assessment of BPE, there was substantial agreement between the two interpreting radiologists (κ = 0.74). Patient demographics were not significantly different between patient groups after PSM. The BPE of Group 1 was significantly lower than that of Group 4 and Group 3 among premenopausal women. In estimating the BPE level, the OR of gene mutations was 0.35. Adjusting for potential confounders, the BPE level of premenopausal women with BRCA mutations was significantly lower than that of non-high-risk women. 3 TECHNICAL EFFICACY: Stage 3.

Prevention over screening for ovarian cancer in patients with high-risk germline mutations: Misinterpreting the findings of ALDO

In November 2022, the findings of the Avoiding Late Diagnosis of Ovarian cancer (ALDO) study were published. Subsequent media coverage suggested that investigators had found a safe alternative to risk-reducing bilateral salpingoophorectomy (rrBSO) in patients with pathogenic BRCA1 and BRCA2 germline mutations who chose to decline or defer risk-reducing surgery. Unfortunately, this media coverage was largely misleading. Specifically, in the ALDO trial, 4 of 6 patients found to have ovarian cancer by the ALDO screening methodology were diagnosed with advanced-stage disease. The primary endpoint of the ALDO study was the rate of complete surgical cytoreduction, rather than stage at diagnosis or overall survival, which is an inappropriate surrogate for benefit in a population at risk of ovarian cancer.The ALDO trial again demonstrates that screening women at high-risk of ovarian cancer should not be considered a safe alternative to risk-reducing surgery, and can lead to false reassurance and the development of preventable cases of ovarian cancer. While we should continue to investigate new screening options, future efforts should largely focus on why patients decline rrBSO in the first place and how we can pivot our efforts to better address concerns related to rrBSO, including sequelae of surgical menopause. Furthermore, as we continue to understand the role of the fallopian tube in the epithelial ovarian cancer (EOC) disease process, we must identify the role of salpingectomy alone in prevention of EOC.

The role of prophylactic prostatectomy as a primary prevention strategy in high-risk germline mutation carriers.

Men with high-risk germline mutations are at significantly higher risk of developing and dying from prostate cancer. Current screening and treatment paradigms may lead to missed opportunities for cure. Herein we review the current literature on prevention, screening and treatment of these carriers and explore the potential role of prophylactic prostatectomy in primary prevention of prostate cancer mortality. Prostate-specific antigen (PSA)-based screening has demonstrated marginal benefits in prostate cancer (PCa) survival and uncertainty remains on its true benefit among high-risk carriers. Recent results indicate that PCa in BRCA 2 carriers occurs at a higher incidence, younger age and progresses more rapidly compared with noncarriers. An intensified screening protocol of MRI and PSA in young carriers demonstrated how using PSA values alone may be insufficient. Current evidence indicates that high-risk carriers have worse survival outcomes after undergoing radical treatment for screening detected disease when compared with noncarriers. Prophylactic prostatectomy within the context of a clinical trial is a reasonable primary prevention option for discussion with high-risk carriers, especially BRCA2 carriers during the shared decision-making process. Limitations exist in the current strategies of early PSA screening followed by radical treatment in this group.

Risk reducing surgeries among mutation carriers treated at a safety NET hopsital breast cancer clinic.

e12583 Background: For women with certain high risk germline mutations, preventive surgical procedures (PSP) have been shown to reduce the risk of cancer. Uptake of these PSP, however, is highly variable among the population at risk. Rate of contralateral mastectomies is reported to be lower among African American (AA) and Asian women compared to Whites. Low socioeconomic status (SES) is reported to impact decision making concerning PSP, but the data remains scant due to associated low healthcare access. Our comprehensive cancer center is notable for providing state of the art care at a public safety net hospital, Harris Health System (HHS), where the population is &gt; 80% racial and ethnic minorities, 60% uninsured and predominantly of low SES. Patients who meet the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing are provided with the opportunity for counseling and testing. We therefore evaluated the likelihood of PSP among our patients with known germline mutations. Methods: We performed a retrospective chart review of a prospectively maintained database of patients who were offered genetic counseling and testing at HHS. We included patients diagnosed with high-risk mutations in BRCA1, BRCA2, PALB2, ATMand CHEK2 between 10/1/2009-09/30/2019 . We abstracted data on date of birth, race and ethnicity, history of breast cancer, breast cancer subtype, family history of breast or ovarian cancers. We collected data on whether the patients had undergone any PSP: bilateral or contralateral mastectomy, salpingectomy, or BSO. We used descriptive statistics to compare patient profiles in each mutation category. We performed univariate and multivariate logistic regression to evaluate whether differences in race, ethnicity, family history of breast or ovarian cancer, or personal history of breast cancer contributed to the likelihood of undergoing PSP. Results: Our dataset identified a total of 202 patients who had a pathogenic mutation in one of the genes above. This included 108 BRCA1, 57 BRCA2, 26 PALB2, 8 ATM and 4 CHEK2 mutation carriers. Sixty-one percent of the mutation carries identified as Hispanic, 18% as AA, 10% as White and 3% as Asian, 31% of the population never had a history of breast cancer. Sixty-three percent of the patients underwent at least one PSP. The results of the regression analysis identified personal history of breast cancer as the only predictor of undergoing PSP, OR 2.77, p = 0.002, which remained significant on the multivariate analysis with OR 4.4, p &lt; 0.001. There were no statically significant findings with regards to race, ethnicity or family history of breast or ovarian cancers. Conclusions: Among our population racially diverse patients with low SES, history of breast cancer significantly increases the likelihood of opting to have prophylactic PSP. We will use this information to tailor our approach towards patient education and future quality improvement projects.

Clinical Management of Prostate Cancer in High-Risk Genetic Mutation Carriers.

Simple SummaryMen with certain genetic differences are at much higher risks of developing metastatic and lethal prostate cancer. With the recent introduction of a new class of medications specifically targeted to these gene repair pathways (PARP inhibitors), it is critical to review the state of the literature surrounding the management of men with prostate cancer who have these genetic differences. We review the existing literature to address common clinical questions pertaining to this population. There is an urgent need for further research regarding clinical management in these scenarios as patients are increasingly seeking out genetic testing and consulting healthcare professionals for guidance.Background: Prostate cancer is a leading cause of death. Approximately one in eight men who are diagnosed with prostate cancer will die of it. Since there is a large difference in mortality between low- and high-risk prostate cancers, it is critical to identify individuals who are at high-risk for disease progression and death. Germline genetic differences are increasingly recognized as contributing to risk of lethal prostate cancer. The objective of this paper is to review prostate cancer management options for men with high-risk germline mutations. Methods: We performed a review of the literature to identify articles regarding management of prostate cancer in individuals with high-risk germline genetic mutations. Results: We identified numerous publications regarding the management of prostate cancer among high-risk germline carriers, but the overall quality of the evidence is low. Conclusions: We performed a review of the literature and compiled clinical considerations for the management of individuals with high-risk germline mutations when they develop prostate cancer. The quality of the evidence is low, and there is an immediate need for further research and the development of consensus guidelines to guide clinical practice for these individuals.

Prophylactic In Vivo Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models.

Population-wide testing for cancer-associated mutations has established that more than one-fifth of ovarian and breast carcinomas are associated with inherited risk. Salpingo-oophorectomy and/or mastectomy are currently the only effective options offered to women with high-risk germline mutations. Our goal here is to develop a long-lasting approach that provides immunoprophylaxis for mutation carriers. Our approach leverages the fact that at early stages, tumors recruit hematopoietic stem/progenitor cells (HSPC) from the bone marrow and differentiate them into tumor-supporting cells. We developed a technically simple technology to genetically modify HSPCs in vivo. The technology involves HSPC mobilization and intravenous injection of an integrating HDAd5/35++ vector. In vivo HSPC transduction with a GFP-expressing vector and subsequent implantation of syngeneic tumor cells showed >80% GFP marking in tumor-infiltrating leukocytes. To control expression of transgenes, we developed a miRNA regulation system that is activated only when HSPCs are recruited to and differentiated by the tumor. We tested our approach using the immune checkpoint inhibitor anti-PD-L1-γ1 as an effector gene. In in vivo HSPC-transduced mice with implanted mouse mammary carcinoma (MMC) tumors, after initial tumor growth, tumors regressed and did not recur. Conventional treatment with an anti-PD-L1 mAb had no significant antitumor effect, indicating that early, self-activating expression of anti-PD-L1-γ1 can overcome the immunosuppressive environment in MMC tumors. The efficacy and safety of this approach was further validated in an ovarian cancer model with typical germline mutations (ID8 p53-/- brca2-/-), both in a prophylactic and therapeutic setting. This HSPC gene therapy approach has potential for clinical translation. SIGNIFICANCE: Considering the limited prophylactic options that are currently offered to women with high-risk germ-line mutations, the in vivo HSPC gene therapy approach is a promising strategy that addresses a major medical problem.

Pancreatic cancer screening in high-risk individuals with germline genetic mutations

Pancreatic cancer (PC) is a deadly disease that is most commonly diagnosed at an incurable stage. Different high-risk genetic variants and cancer syndromes increase the lifetime risk of developing PC. This study aims to assess the yield of initial PC screening in patients with high-risk germline mutations. Asymptomatic adults underwent PC screening by EUS, magnetic resonance imaging, or CT during a 10-year period and were retrospectively identified. High-risk individuals were defined as carrying germline mutations in BRCA1, BRCA2, p53 (Li-Fraumeni), STK11 (Peutz-Jeghers), MSH2 (Lynch), ATM (ataxia-telangiectasia), or APC (familial adenomatous polyposis). Patients without germline mutations were excluded. In total, 86 patients met the study criteria. The median age was 48.5 years (interquartile range, 40-58), 79.1% (68) were women, and 43.0% (37) had a family history of PC. The genetic mutations were BRCA2 (50,58.1%), BRCA1 (14, 16.3%), p53 (12, 14.0%), STK11 (5, 5.8%), MSH2 (3, 3.5%), ATM (1, 1.2%), and APC (1,1.2%). Screening detected a pancreatic abnormality (PA) in 26.7% (23/86), including cysts (11, 47.8%), hyperechoic strands and foci (10, 43.5%), and mild pancreatic duct dilation (2, 8.7%). Patients older than 60 years were more likely to have a PA detected (P= .043). EUS detected more PAs than magnetic resonance imaging or CT. Nocases of PC were diagnosed by screening or during follow-up (median, 29.8 months; interquartile range, 21.7-43.5). Unless indicated otherwise by family or personal history, PC screening under the age of 50 is low yield. Linear EUS may be the preferred modality for initial PC screening.

Correlational study on mitochondrial DNA mutations as potential risk factors in breast cancer.

The presented study performed an mtDNA genome-wide association analysis to screen the peripheral blood of breast cancer patients for high-risk germline mutations. Unlike previous studies, which have used breast tissue in analyzing somatic mutations, we looked for germline mutations in our study, since they are better predictors of breast cancer in high-risk groups, facilitate early, non-invasive diagnoses of breast cancer and may provide a broader spectrum of therapeutic options. The data comprised 22 samples of healthy group and 83 samples from breast cancer patients. The sequencing data showed 170 mtDNA mutations in the healthy group and 393 mtDNA mutations in the disease group. Of these, 283 mtDNA mutations (88 in the healthy group and 232 in the disease group) had never been reported in the literature. Moreover, correlation analysis indicated there was a significant difference in 32 mtDNA mutations. According to our relative risk analysis of these 32 mtDNA mutations, 27 of the total had odds ratio values (ORs) of less than 1, meaning that these mutations have a potentially protective role to play in breast cancer. The remaining 5 mtDNA mutations, RNR2-2463 indelA, COX1-6296 C>A, COX1-6298 indelT, ATP6-8860 A>G, and ND5-13327 indelA, whose ORs were 8.050, 4.464, 4.464, 5.254 and 4.853, respectively, were regarded as risk factors of increased breast cancer. The five mutations identified here may serve as novel indicators of breast cancer and may have future therapeutic applications. In addition, the use of peripheral blood samples was procedurally simple and could be applied as a non-invasive diagnostic technique.

Cancer population genetics and tumour prevention: an unfulfilled paradigm

The molecular approach to cancer has identified specific abnormalities that contribute to malignant pathogenesis in an aetiological manner and define individuals who are at higher risk for specific malignancies. Studies of cancer distribution in families suggest that 15–20% of all malignancies may have a significant germ line hereditable mutation that directly or indirectly contributes to tumour development. Additionally, the identification of many genetically-determined polymorphisms that regulate carcinogen metabolism indicate that their assessment may contribute to selecting individuals for preventive surveillance or intervention as well. Locating individuals in the population who have moderate to high risk germ line mutations in critical oncogenic regulatory genes and assessing a panel of polymorphisms that underlie a significant attributable risk for cancer development may allow the recruitment of individuals at high risk for a particular malignancy and, therefore, represent good candidates for either directed organ surveillance and/or chemoprevention trials.