Cancer In Carriers Research Articles

Clinicopathologic Features of Breast Tumors in Germline TP53 Variant-Associated Li-Fraumeni Syndrome.

We present one of the largest cohorts of TP53-pathogenic germline variants (PGVs) associated with patients with Li-Fraumeni syndrome (n = 82) with breast tumors (19 to 76y; median age: 35). Most had missense variants (77%), followed by large gene rearrangements (LGRs; 12%), truncating (6%), and splice-site (5%) variants. Twenty-one unique germline missense variants were found, with hotspots at codons 175, 181, 245, 248, 273, 334, and 337. Of 100 total breast tumors, 63% were invasive (mostly ductal), 30% pure ductal carcinoma in situ, 4% fibroepithelial lesions, and 3% with unknown histology. Unlike BRCA-associated tumors, approximately half of the breast cancers exhibited HER2-positivity, of which ~50% showed estrogen receptor coexpression. Pathology slides were available for review for 61 tumors (44 patients), and no significant correlation between the type of TP53 PGVs and histologic features was noted. High p53 immunohistochemistry expression (>50%) was seen in 67% of tumors tested (mostly missense variant). Null pattern (<1% cells) was seen in 2 (LGR and splicing variants carriers). Surprisingly, 2 tumors from patients with an LGR and 1 tumor from a patient with a truncating variant showed p53 overexpression (>50%). The subset of patients with the Brazilian p.R337H variant presented at a higher age than those with non-p.R337H variant (46 vs 35y) though statistically insignificant (P = 0.071) due to an imbalance in the sample size, and were uniquely negative for HER2-overexpressing tumors. To conclude, breast cancer in carriers of TP53 PGVs has some unique clinicopathological features that suggest differential mechanisms of tumor formation. p53 immunohistochemistry cannot be used as a surrogate marker to identify germline TP53-mutated breast cancers.

Pathogenic variants in cancer susceptibility genes predispose to Ductal Carcinoma In situ of the breast.

To determine the relationship between germline pathogenic variants (PVs) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS). Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls, and between DCIS and infiltrating ductal carcinoma (IDC) cases from a clinical-testing cohort (n=9,887), a population-based cohort (n=3,876) and the UK Biobank (n=2421). The risk of contralateral breast cancer for DCIS cases with PVs was estimated in the population-based cohort. Germline PVs were observed in 6.5% and 4.6% of women with DCIS in the clinical-testing and population-based cohorts, respectively. BRCA1, BRCA2, and PALB2 PVs frequencies were significantly lower among women with DCIS than IDC (clinical cohort: 2.8% vs. 5.7%; population-based cohort: 1.7% vs. 3.7%), whereas the PV frequencies for ATM and CHEK2 were similar. ATM, BRCA1, BRCA2, CHEK2, and PALB2 PVs were significantly associated with an increased risk of DCIS (OR>2.0), but only BRCA2 PVs were associated with high-risk (OR>4) in both cohorts. The cumulative incidence of contralateral breast cancer among carriers of PVs in high penetrance genes with DCIS was 23% over 15 years. The enrichment of PVs in ATM, BRCA1, BRCA2, CHEK2 and PALB2 among women with DCIS suggests that multigene panel testing may be appropriate for women with DCIS. Elevated risks of contralateral breast cancer in carriers of PVs in high penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.

PMS2 mutation spectra in Norway and risk of cancer for carriers of pathogenic variants

BackgroundIn Norway, we have offered testing of PMS2 since 2006, and have a large national cohort of carriers. The aim of this study was to describe all PMS2 variants identified, and to describe frequency, spectrum and penetrance of cancers in carriers of class 4/5 variants.MethodsAll detected PMS2 variants were collected from the diagnostic laboratories and reclassified according to ACMG criteria and gene specific guidelines. Data on variant, gender, cancer diagnosis, age at diagnosis, and age at last known follow-up was collected on all carriers of class 4/5 variants from electronic patient records. The Kaplan-Meier algorithm was used to calculate cumulative risk of any cancer, colorectal cancer and endometrial cancer.ResultsIn total, 220 different PMS2 variants were detected. Twenty nine class 4/5 variants were identified in 482 carriers. The most common pathogenic variant was the founder mutation c.989-1G > T, detected in 204 patients from 58 families. Eighty seven out of 482 (18.0%) had been diagnosed with colorectal cancer, 10 of these (11.8%) before 40 years. Cumulative risk at 70 years in our cohort was 34.7% for colorectal cancer and 26.1% for endometrial cancer.ConclusionsAfter 15 years of genetic testing, 29 different class 4/5 variants have been detected in Norway. Almost half of Norwegian PMS2 carriers have the founder variant 989-1G > T. Penetrance of colorectal cancer in our cohort was moderate but variable, as 11.5% of those diagnosed were younger than 40 years.

Mutant p53 reactivation restricts the protumorigenic consequences of wild type p53 loss of heterozygosity in Li-Fraumeni syndrome patient-derived fibroblasts

The p53 tumor suppressor, encoded by the TP53 gene, serves as a major barrier against malignant transformation. Patients with Li-Fraumeni syndrome (LFS) inherit a mutated TP53 allele from one parent and a wild-type TP53 allele from the other. Subsequently, the wild-type allele is lost and only the mutant TP53 allele remains. This process, which is termed loss of heterozygosity (LOH), results in only mutant p53 protein expression. We used primary dermal fibroblasts from LFS patients carrying the hotspot p53 gain-of-function pathogenic variant, R248Q to study the LOH process and characterize alterations in various pathways before and after LOH. We previously described the derivation of mutant p53 reactivating peptides, designated pCAPs (p53 Conformation Activating Peptides). In this study, we tested the effect of lead peptide pCAP-250 on LOH and on its associated cellular changes. We report that treatment of LFS fibroblasts with pCAP-250 prevents the accumulation of mutant p53 protein, inhibits LOH, and alleviates its cellular consequences. Furthermore, prolonged treatment with pCAP-250 significantly reduces DNA damage and restores long-term genomic stability. pCAPs may thus be contemplated as a potential preventive treatment to prevent or delay early onset cancer in carriers of mutant p53.

Abstract PO5-08-04: Characteristics of breast cancer in carriers of pathogenic variant in ATM in a large academic health center

Abstract Background: Pathogenic variants (PVs) in ATM are associated with an increased risk of breast, pancreas, and other cancers. The clinical and pathological characteristics of ATM-associated breast cancers have not been well defined. Methods: Patients who underwent multigene panel testing between December 2012 and May 2023 and were identified to harbor ATM PVs were included in the study. We analyzed demographics, germline findings, histopathology, genomic recurrence score, and management of ATM PV carriers with breast cancer. Results: A total of 222 individuals were identified to have PVs in ATM, of whom 184 (83%) were female. The majority were Caucasian (n = 179, 81%) and of those, 22 (12%) had Ashkenazi Jewish ancestry. The median age at genetic testing was 52y, with a range of 20-90y. A total of 111 patients (50%) had a personal cancer diagnosis, the most common of which was breast cancer (n = 70; 63%). The median age at breast cancer diagnosis was 53y, with a range of 25-84y. The most common histopathology was invasive ductal carcinoma (74%), followed by DCIS (21%), and invasive lobular carcinoma (5%). The majority of patients had breast tumors with stage 2 or 3 (78%), grade 2 or 3 (92%), ER and/or PR positive (92%) and HER2 negative (70%). One patient had triple-negative breast cancer. Forty-four percent of breast cancers were less than two centimeters, 23% were lymph node-positive, and 29% had lymphovascular invasion. Thirty-eight percent of patients underwent bilateral mastectomy, 54% received radiation therapy, 40% received adjuvant chemotherapy, 24% received neoadjuvant chemotherapy, and 70% received hormonal therapy. Of the 15 breast cancers with known 21-gene recurrence scores, 47% were intermediate (11-26), 33% were high (&amp;gt;=26) and 20% were low (&amp;lt; =10). Other notable cancers observed were pancreas (n = 9), colorectal (n = 6), prostate (n = 5), uterine (n = 4), melanoma (n = 4), and thyroid (n = 4). Conclusion: Our study outlines the clinical and pathological characteristics of ATM-associated breast cancer in a large academic center. The majority of breast cancers were invasive ductal type, early stage, intermediate or high grade, and hormone receptor-positive with an intermediate or high recurrence score. Despite the early stage, a significant proportion of patients underwent bilateral mastectomy. Further studies are needed to better elucidate the unique characteristics of breast cancer in ATM PV carriers in order to provide tailored management guidelines for this population. Citation Format: Ujjwal Karki, Tara Rangarajan, Dana Zakalik. Characteristics of breast cancer in carriers of pathogenic variant in ATM in a large academic health center [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 PO5-08-04.

Abstract PS10-04: The Landscape of Somatic Genetic Alterations in Breast Cancers from Carriers of Germline Pathogenic Variants in DNA-repair Genes

Abstract Background: Hereditary breast cancer in carriers of germline pathogenic or likely pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 have unique clinicopathological characteristics compared to sporadic breast cancer. However, very little is known about the underlying differences in somatic genetic alterations between hereditary and sporadic breast cancer. Methods: The study included 7,533 individuals with breast cancer subjected to Tempus xT tumor-normal matched sequencing (596-648 genes). The frequencies of the somatic genetic alterations in each gene were compared separately between tumors arising in individuals with incidental germline PVs (gATM, gBRCA1, gBRCA2, gCHEK2, gPALB2) and sporadic breast tumors. Sporadic tumors were identified as individuals with no detected incidental germline PVs in these 5 genes. Comparisons were made by either Pearson’s Chi-squared or Fisher’s exact test, with false discovery rate (FDR) correction for multiple testing. Breast cancer subtype was determined based on the record of IHC positivity for ER, PR, or HER2. Detection of ERBB2 (HER2) gene amplifications via DNA sequencing was also used to classify samples as HER2+ in the absence of available IHC data. Results: The median age at breast cancer diagnosis for the cohort was 56 years. More than two-thirds of the patients were White (73%) while 14% identified as Black or African American. The overall frequency of incidental germline PVs in each gene was 0.8% for gATM, 1.4% for gBRCA1, 2.1% for gBRCA2, 1.0% for CHEK2, and 0.7% for PALB2. A total of 3,648 (48.4%) tumors were ER+/PR+/HER2-, 1,297 (17.2%) were triple-negative (TNBC), 841 (11.2%) were HER2+ and 1,747 (23.2%) could not be classified due to missing ER, PR or HER2 status, or absence of detected ERBB2 amplifications. Among ER+/PR+/HER2- breast cancers, compared to sporadic tumors, ESR1 mutations were significantly enriched in gATM carriers (33% vs. 11%, q-value 0.05), TP53 alterations were significantly enriched in gBRCA1 PV carriers (69% vs. 30%, q-value &amp;lt; 0.001) but depleted in gATM (12% vs. 30%, q-value 0.4) and gCHEK2 PV carriers (5.4% vs. 30%, q-value 0.06), and PIK3CA (14% vs. 35%, q-value 0.001) and CCND1 (3.4% vs. 17%, q-value 0.02) alterations were significantly lower in gBRCA2 PV carriers. Among TNBC, TP53 alterations were also significantly higher in gBRCA1 PV carriers compared to sporadic tumors (96% vs. 69%, q-value 0.004). In HER2+ breast cancers, ERBB2 alterations were observed in approximately two-thirds of the tumors, and a significant difference was not observed between incidental hereditary and sporadic tumors. Among ER+/PR+/HER2- tumors, although not statistically significant, the frequency of ESR1 (3.1% vs. 11%, q-value &amp;gt;0.9), PIK3CA (12% vs. 35%, q-value 0.2) alterations were lower in incidental gBRCA1 versus sporadic tumors, FGFR1 alterations were lower in incidental gBRCA1 (6.2% vs. 13%, q-value &amp;gt;0.9) and incidental gBRCA2 (3.4% vs. 13%, q-value 0.13) but enriched in incidental gATM (33% vs. 13%, q-value 0.05). Conclusions: The observed differences in the frequencies of CCND1, ESR1, PIK3CA, TP53, and other key genetic alterations between incidental hereditary and sporadic breast cancer highlight the unique tumor biology of breast cancer in germline PV carriers and have significant implications for understanding tumorigenesis and identifying therapeutic strategies for the management of hereditary breast cancer. Citation Format: Minxuan Huang, Melissa Stoppler. The Landscape of Somatic Genetic Alterations in Breast Cancers from Carriers of Germline Pathogenic Variants in DNA-repair Genes [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 PS10-04.

Screening Mammography for Males With Elevated Breast Cancer Risk, Mutation Carriers, and Gynecomastia

IntroductionThe recommendations for annual mammography for male carriers with gynecomastia are controversial. This study investigated the potential link between gynecomastia and breast cancer in male carriers. Patients and MethodsThe database of a tertiary medical center was retrospectively searched for all male patients who underwent at least 1 digital mammography study from 2016 to 2023. Known carriers of a pathogenic variant in a high-risk breast-cancer gene were identified. Patients were stratified by carrier status, diagnosis of breast cancer, and diagnosis of gynecomastia. Data on demographics, hormone profile, and pathology results were compared. ResultsThe cohort included 446 men of whom 82 were known carriers. Gynecomastia was diagnosed by mammography in 251 patients: 239/364 noncarriers (66%) and 12/82 carriers (15%) (P < .0001). Breast cancer was found in 21/364 noncarriers (6%) and 6/82 carriers (7%) (P < .6), and in 10/251 patients with gynecomastia (4%) and 17/193 (9%) without gynecomastia (P < .05). Among patients without gynecomastia, the number of breast cancer cases was similar in carriers and noncarriers (P = .3). Among patients with gynecomastia, the rate of breast cancer was higher in carriers (P < .08). On logistic regression analysis, the effect of gynecomastia on carriers was significant (P = .02). The odds ratio for a breast cancer diagnosis was 5.8 in the presence of gynecomastia (95% CI, 1.1-31, P < .04) and 0.52 in the absence of gynecomastia (95% CI, 0.2-1.7, P < .3). ConclusionGynecomastia may be associated with an increased risk of breast cancer in carriers. Larger studies are needed to determine whether and when to screen male carriers.

HAP1 cell utilization for accurate interpretation of germline BAP1 variants

Aims/Purpose: Pathogenic germline variants in BRCA1‐Associated Protein 1 (BAP1) gene cause a rare, dominant, life‐threatening tumour predisposition syndrome (BAP1‐TPDS). It increases risk for atypical cutaneous Spitz tumours and for several index cancers: uveal melanoma, malignant mesothelioma, cutaneous melanoma, clear cell renal cell carcinoma, and basal cell carcinoma. Because about 50% of variants in the public database CLINVAR are of unknown significance (VUS) and accurate interpretation of variants is crucial for screening cancer in carriers, improved tools for genomic BAP1 variant interpretation are needed. We aimed to create a mammalian cell based tool for this purpose.Methods: Four pathogenic BAP1 variants (c.67 + 1G &gt; T, c.281A &gt; G, c.680G &gt; A, and c.1780_1781insT) and one VUS (c.1526C &gt; T) were edited into the genome of near haploid HAP1 cells with CRISPR‐Cas9 and assayed for BAP1 expression and cell fitness. Proliferation and cell adhesion was quantified using xCelligence real‐time cell analysis system.Results: BAP1 loss reduces growth of HAP1 cells, which we exploited as phenotypic readout for pathogenicity of inserted variants. Three BAP1‐TPDS history‐associated variants c.67 + 1G &gt; T, c.281A &gt; G, and c.1780_1781insT reduced HAP1 adhesion and proliferation roughly by 70–80% whereas the c.680G &gt; A missense variant, identified in a patient with UM without BAP1‐TPDS family history, reduced proliferation by 50%. VUS c.1526C &gt; T behaved similarly to wild type.Conclusions: Qualitatively, the results of our in vitro tool for BAP1 variant interpretation agree with previous studies, validating the tool. The validated system has potential for scaling up for simultaneous analysis of multiple variants. Quantitatively, it might have potential for predicting higher or lower risk in family members.

Reduced Diversity of HLA Class I Alleles May Contribute to the Early Manifestation of Breast Cancer in Carriers of the BRCA1 Mutation

Reduced Diversity of HLA Class I Alleles May Contribute to the Early Manifestation of Breast Cancer in Carriers of the BRCA1 Mutation

Metachronous colorectal cancer risk according to Lynch syndrome pathogenic variant after extensive versus partial colectomy in the Netherlands: a retrospective cohort study

Extensive colectomy (subtotal or total colectomy) is often advised for carriers of Lynch syndrome with colorectal cancer. However, the risk of metachronous colorectal cancer might differ by Lynch syndrome variant, meaning that partial colectomy, which has better functional outcomes, might be adequate for some patients with low-risk variants. We aimed to assess the risk of metachronous colorectal cancer after partial colectomy and extensive colectomy in carriers of Lynch syndrome with different pathogenic variants. For this retrospective cohort study, carriers of Lynch syndrome with colorectal cancer in the Netherlands were identified by linkage of the Dutch Foundation for the Detection of Hereditary Tumors (StOET) database and the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) database. Data on demographics, Lynch syndrome variants, colorectal cancers, surgery types, mortality, and surveillance colonoscopies were extracted. Data on colorectal cancer and surveillance colonoscopies were updated until Feb 28, 2022. Data on survival status was updated until Feb 7, 2022. MLH1, MSH2, and EPCAM were classified as high-risk variants and MSH6 and PMS2 as low-risk variants. Patients for whom the type of surgery was unknown were excluded. Cox regression time-to-event analyses were done to assess the risk of metachronous colorectal cancer in four subgroups based on pathogenic variant (high-risk vs low-risk variants) and the extent of surgery (extensive colectomy vs partial colectomy). Sex, age at the time of primary colorectal cancer, primary colorectal cancer stage, performance of surveillance colonoscopies, adherence to the surveillance guidelines, and time period of primary colorectal cancer diagnosis were added to the model as possible confounders. Metachronous colorectal cancer was defined as colorectal cancer diagnosed more than 6 months after the primary colorectal cancer. Patients were censored at time of death or assembly of the database. Of 1908 carriers of Lynch syndrome registered in StOET, 532 with a history of colorectal cancer were identified after linkage with PALGA. Five carriers were excluded because of an unknown surgery type, leaving 527 in our sample (mean age at primary colorectal cancer 48·7 years [SD 12·1]; 274 [52%] male and 253 [48%] female). 121 (23%) patients developed metachronous colorectal cancer (median time from primary colorectal cancer to metachronous colorectal cancer 11·0 years [IQR 2·1-17·8]). Metachronous colorectal cancer occurred in 12 (12%) of 97 patients with high-risk variants and extensive colectomy, in 85 (32%) of 267 patients with high-risk variants and partial colectomy, in zero (0%) of 11 patients with low-risk variants and extensive colectomy, and in 24 (16%) of 152 patients with low-risk variants and partial colectomy. Partial colectomy was associated with a higher risk of metachronous colorectal cancer than extensive colectomy in the high-risk variant group (hazard ratio 1·97, 95% CI 1·04-3·73; p=0·039). The risk of metachronous colorectal cancer did not differ between carriers of low-risk variants who had partial colectomy and those of high-risk variants who had extensive colectomy (1·14, 0·55-2·36; p=0·72). The risk of metachronous colorectal cancer after partial colectomy in carriers of low-risk variants is similar to the risk after extensive colectomy in carriers of high-risk variants. This finding suggests that partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colorectal cancer in carriers of low-risk Lynch syndrome variants. None.

Germline EGFR Mutations and Familial Lung Cancer.

The genomic underpinnings of inherited lung cancer risk are poorly understood. This prospective study characterized the clinical phenotype of patients and families with germline EGFR pathogenic variants (PVs). The Investigating Hereditary Risk from T790M study (ClinicalTrials.gov identifier: NCT01754025) enrolled patients with lung cancer whose tumor profiling harbored possible germline EGFR PVs and their relatives, either in person or remotely, providing germline testing and follow-up. A total of 141 participants were enrolled over a 5-year period, 100 (71%) remotely. Based upon previous genotyping, 116 participants from 59 kindreds were tested for EGFR T790M, demonstrating a pattern of Mendelian inheritance with variable lung cancer penetrance. In confirmed or obligate carriers of a germline EGFR PV from 39 different kindreds, 50/91 (55%) were affected with lung cancer with 34/65 (52%) diagnosed by age 60 years. Somatic testing of lung cancers in carriers revealed that 35 of 37 (95%) had an EGFR driver comutation. Among 36 germline carriers without a cancer diagnosis, 15 had computed tomography (CT) imaging and nine had lung nodules, including a 28-year-old with >10 lung nodules. Given geographic enrichment of germline EGFR T790M in the southeast United States, genome-wide haplotyping of 46 germline carriers was performed and identified a 4.1-Mb haplotype shared by 41 (89%), estimated to originate 223-279 years ago. To our knowledge, this is the first prospective description of familial EGFR-mutant lung cancer, identifying a recent founder germline EGFR T790M variant enriched in the Southeast United States. The high prevalence of EGFR-driver lung adenocarcinomas and lung nodules in germline carriers supports effort to identify affected patients and family members for investigation of CT-based screening for these high-risk individuals.

Abstract P1-09-03: Impact of BRCA1/2 pathogenic variants on ipsilateral breast tumor recurrence and prognosis following breast-conserving surgery

Abstract Background The risk of ipsilateral breast tumor recurrence (IBTR) and the prognostic outcome of breast-conserving surgery (BCS) for germline BRCA1/2 pathogenic variant (BRCA1/2+) carriers remain controversial. We examined differences in IBTR and prognosis between BRCA1/2+ carriers and non-carriers following BCS for breast cancer. Methods Clinical and pathological data were collected by retrospectively reviewing charts of consecutive patients with stage 0-III breast cancer who underwent genetic testing for germline BRCA1/2 and BCS between 1996 and 2020. Patients with variants of breast cancer-associated genes other than BRCA1/2 were excluded. We compared the incidence of IBTR and prognosis, including overall survival (OS), breast cancer-specific survival (BCSS), and distant recurrence-free survival (DRFS), between BRCA1/2+ carriers and non-carriers. Results We analyzed 551 patients (587 breasts with cancer), including 30 BRCA1+ carriers (32 breasts) and 31 BRCA2+ carriers (32 breasts). The median follow-up was 5.8 years (7.2 and 5.3 years for carriers and non-carriers, respectively). The median age at breast cancer diagnosis was 43 and 46 years for carriers and non-carriers, respectively, indicating younger onset of cancer in carriers (age ≤ 40 years; 46.9% for carriers vs. 27.5% for non-carriers, p = 0.001). In carriers, breast cancer more frequently expressed estrogen receptor-negative (56.2% for BRCA1+ carriers and 15.6% for BRCA2+ carriers vs. 22.0% for non-carriers, p = 0.013), progesterone receptor-negative (62.5% for BRCA1+ carriers and 31.3% for BRCA2+ carriers vs. 29.5%, p = 0.005), nuclear grade III (45.3% for carriers vs. 29.5% for non-carriers, p = 0.010), or a higher Ki-67 index (Ki-67 index &amp;gt; 20) (89.5% vs. 61.8%, p = 0.001) than non-carriers. Moreover, carriers underwent chemotherapy more frequently than non-carriers (62.5% vs. 42.4%, p = 0.002). Cancer stage, tumor size, HER2 status, presence of lymphovascular invasion, and the rate of positive or close surgical margins did not statistically differ between the examined groups. No statistical differences were detected in the number of patients who underwent whole-breast radiotherapy following BCS: 59 breasts in carriers and 503 in non-carriers (92.2% vs. 96.4%). During follow-up, we noted that 9 breasts of BRCA1/2+ carriers (5 [15.6%] for BRCA1+ and 4 [12.5%] for BRCA2+) and 35 breasts (6.7%) of non-carriers developed IBTR (p = 0.035). In an analysis excluding patients who did not undergo radiotherapy, the rate of IBTR remained significantly higher in BRCA1/2+ carriers (p = 0.034) than that in non-carriers. The median time to IBTR was 10.2 years in carriers (10.2 years for BRCA1+ and 8.5 years for BRCA2+) and 3.5 years in non-carriers. Carriers were more likely than non-carriers to exhibit distinct subtypes of recurrent tumors in the ipsilateral breast (66.7% for carriers vs. 19.4% for non-carriers, p = 0.006), occurring in a different quadrant from the primary tumor (50.0% vs. 27.3%, p = 0.215). No significant differences in OS (p = 0.068), BCSS (p = 0.109), or DRFS (p = 0.359) were noted between carriers and non-carriers. Conclusion BRCA1/2+ carriers exhibited a higher risk of IBTR after BCS and a longer time to IBTR than non-carriers. One limitation of the present study is a longer follow-up period for carriers than for non-carriers, as carriers typically underwent long-term observation at our institution; hence, further data accumulation is warranted for validating these findings. Subtypes and quadrants of IBTR were frequently distinct in carriers, indicating the increased incidence of new primary breast cancer. Although the prognosis did not differ between carriers and non-carriers, our results suggest the necessity for long-term intensive breast surveillance of BRCA1/2+ carriers after BCS. Citation Format: Sakiko Kondo, Kumiko Kida, Misato Suzuki, Chika Fukano, Atsushi Yoshida, Naoki Hayashi, Junko Takei, Michiko Yamanaka, Hideko Yamauchi. Impact of BRCA1/2 pathogenic variants on ipsilateral breast tumor recurrence and prognosis following breast-conserving surgery [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-09-03.

Genetically engineered mouse models for hereditary cancer syndromes.

Advances in molecular diagnostics have led to improved diagnosis and molecular understanding of hereditary cancers in the clinic. Improving the management, treatment, and potential prevention of cancers in carriers of predisposing mutations requires preclinical experimental models that reflect the key pathogenic features of the specific syndrome associated with the mutations. Numerous genetically engineered mouse (GEM) models of hereditary cancer have been developed. In this review, we describe the models of Lynch syndrome and hereditary breast and ovarian cancer syndrome, the two most common hereditary cancer predisposition syndromes. We focus on Lynch syndrome models as illustrative of the potential for using mouse models to devise improved approaches to prevention of cancer in a high-risk population. GEM models are an invaluable tool for hereditary cancer models. Here, we review GEM models for some hereditary cancers and their potential use in cancer prevention studies.

Two germline mutations can serve as genetic susceptibility screening makers for a lung adenocarcinoma family.

Lung cancer is the most common form of cancer and the leading cause of cancer death. For familial lung cancer, identification of causing genetic factors is essential for prevention and control of non-lung cancer in carriers. We studied two generations of a family with suspected inherited lung cancer susceptibility. Four individuals in this family had lung adenocarcinoma. To identify the gene(s) that cause the lung cancer in this pedigree, we extracted DNA from the peripheral blood of four cancer individuals and blood from three cancer-free family members as the control and performed whole-genome sequencing. Our filtering strategy includes, assessment of allele frequency, functional affection on amino acids, mutation accumulation, phased blocks and evolution analysis towards the alterations. We identified two possible mutations, including PLEKHM2 (D134N) and MCC (R448Q) in all affected family members but did not found in the control group. Then, we performed a genetic susceptibility screening for 10 non-lung cancer relatives and found two individuals with PLEKHM2 (D134N) mutation, two with MCC (R448Q) mutation and one carrying both mutations. 3 carriers performed LDCT scan and 2 of them carried MCC (R448Q) also had ground-glass opacity (GGO) lesion in their lung. Our data suggested that WGS together with our filtering strategy was successful in identifying PLEKHM2 (D134N) and MCC (R448Q) as the possible driver mutations in this family. Genetic susceptibility screening of non-lung cancer carriers will be a useful approach to prevent and control lung cancer in families with high-risk for the disease.

Variable number tandem repeats (VNTRs) as modifiers of breast cancer risk in carriers of BRCA1 185delAG.

Despite substantial efforts in identifying both rare and common variants affecting disease risk, in the majority of diseases, a large proportion of unexplained genetic risk remains. We propose that variable number tandem repeats (VNTRs) may explain a proportion of the missing genetic risk. Herein, in a pilot study with a retrospective cohort design, we tested whether VNTRs are causal modifiers of breast cancer risk in 347 female carriers of the BRCA1 185delAG pathogenic variant, an important group given their high risk of developing breast cancer. We performed targeted-capture to sequence VNTRs, called genotypes with adVNTR, tested the association of VNTRs and breast cancer risk using Cox regression models, and estimated the effect size using a retrospective likelihood approach. Of 303 VNTRs that passed quality control checks, 4 VNTRs were significantly associated with risk to develop breast cancer at false discovery rate [FDR] < 0.05 and an additional 4 VNTRs had FDR < 0.25. After determining the specific risk alleles, there was a significantly earlier age at diagnosis of breast cancer in carriers of the risk alleles compared to those without the risk alleles for seven of eight VNTRs. One example is a VNTR in exon 2 of LINC01973 with a per-allele hazard ratio of 1.58 (1.07-2.33) and 5.28 (2.79-9.99) for the homozygous risk-allele genotype. Results from this first systematic study of VNTRs demonstrate that VNTRs may explain a proportion of the unexplained genetic risk for breast cancer.

Tumor immune microenvironment and apoptotic markers in breast cancer patients carrying &lt;I&gt;BRCA1&lt;/I&gt; gene mutations

Background. It is suggested that defects in BRCA1 / 2 genes contribute to a high mutational load and high immunogenicity, which modulates immune microenvironment. At the same time, it was shown that BRCA1 / 2-associated breast cancer tumors do not belong to the category of immunoactive ones. These tumors have low expression of immune response genes and exhibit an immunosuppressive type of microenvironment. This indicates the need of antitumor immune response modulation and maintaining of the optimal balance of tumor CD4/CD8 T-lymphocytes ratio. In addition, there is evidence of the additional evaluation of TP53 mutation in these tumors and disruption of the cell death process, which can also be a factor of resistance to therapy, including PARP inhibitors, and serve as a therapeutic target.Materials and methods. The prospective study included 20 patients with BRCA1-associated breast cancer. BRCA1 / 2 mutations (BRCA1 185delAG, 4153delA, 5382insC, 3819delGTAAA, 3875delGTCT, 300T&gt;G, 2080delA, BRCA2 6174delT) were detected in by real-time polymerase chain reaction. Immunohistochemical study was performed on paraffin embedded tissue blocks by an automated method on a ThermoScentific immunohistotainer using monoclonal antibodies. The expression of markers of tumor-infiltrating CD4+ and CD8+ T-lymphocytes, markers of macrophages (CD68, CD163), apoptosis (Bcl-2, p53), cell adhesion markers (E-cadherin, β-catenin) in breast cancer in carriers of BRCA1 mutations was assessed.Results. High CD4/CD8 ratio, which characterizes immunosuppressive microenvironment, occurred in 75 % of cases. BRCA1 5382insC mutation is associated with high level of CD4+ TILs (p˂0.05), G2 is associated with a low CD4/CD8 ratio (p = 0.039) and a high level of CD163 (p = 0.02, AUC = 0.739); T1 correlates with high levels of CD8+ TILs (p = 0.038) and high levels of CD163 (p = 0.033). High Ki-67 is associated with a lack of Bcl-2 expression (p = 0.04) and a low level of E-cadherin (p = 0.02). Negative expression of Bcl-2 occurred in 75 % of cases. High level of p53 expression has been described as the main type of expression in these tumors, suggesting a combination of TB53 and BRCA1 mutations and a violation of cell death mechanism of in these tumors.Conclusion. Breast cancer tumors of patients with hereditary mutations in BRCA1 gene demonstrate immunosuppressive type of microenvironment and a violation of the cell death mechanism. The main directions of future therapy of these tumors may include tumor immune microenvironment modification and activation of cell death mechanisms.

1346P Diagnosis of early-stage cancers in carriers of BRCA1/2 pathogenetic variants: Two years of activity of the multidisciplinary team for hereditary cancers

Carriers of BRCA1/2 pathogenetic variants are at increased risk of developing breast, tube/ovarian and other typical cancers of the hereditary spectrum. Secondary and primary prevention are the main strategies for the management of at-risk subjects. Intensified surveillance allows to identify early-stage cancers. Risk-reducing mastectomy and salpingo-oophorectomy decrease the incidence of primary cancers, the latter also decreases mortality.

Lessons from the Failure to Complete a Trial of Denosumab in Women With a Pathogenic BRCA1/2 Variant Scheduling Risk-Reducing Salpingo-Oophorectomy.

Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO with the goal of collecting valuable data on the biologic effects of denosumab on gynecologic tissue. The study was terminated early due to the inability to accrue participants. Challenges which impacted the conduct of this study included a study design with highly selective eligibility criteria and requirements and the COVID-19 pandemic. It is critical to reflect on these issues to enhance the successful completion of future prevention studies in individuals with hereditary cancer syndromes.

ASO Visual Abstract: Incidence of Occult Breast Cancer in Carriers of BRCA1/2 and Other High-Penetrance Pathogenic Variants Undergoing Prophylactic Mastectomy-When is Sentinel Lymph Node Biopsy Indicated?

ASO Visual Abstract: Incidence of Occult Breast Cancer in Carriers of BRCA1/2 and Other High-Penetrance Pathogenic Variants Undergoing Prophylactic Mastectomy-When is Sentinel Lymph Node Biopsy Indicated?

Territorial manifestation features of multiple primary malignant neoplasms in carriers of germline mutations in the BRCA 1 gene in Republic of Bashkortostan.

e22523 Background: Recent advances in the diagnostic and therapeutic fields of oncology have increased the life expectancy of cancer patients, and therefore carriers of germline mutations, who are at high risk of developing a malignant neoplasm, also have a higher risk of developing a second synchronous or metachronous malignant tumor. The aim of this work is to study the features of the development of primary multiple malignant neoplasms in patients with germline mutations in the repair genes. Methods: Among all treated in the Republican Clinical Oncological Dispensary patients germline mutations in the repair genes were detected in 225 persons. Mutations were determined by polymerase chain reaction (PCR). The material of the study was a sample of venous blood taken from a patient on an empty stomach. A diagnostic panel was used to detect the most common mutations in Russia in the BRCA1 (5382insC, 4153delA, 300T &gt; G, 185delAG, 2080delA, 3819delGTAAA) and BRCA2 (6174delT) genes. In the absence of a mutation, the study was carried out by the next generation sequencing (NGS) method. Results: After a molecular genetic study from 2014 to 2021, we determined the spectrum of germline mutations in residents of the Republic of Bashkortostan: BRCA 1 - c.5266dupC, c.3143delG, c.5161C &gt; T, c.5382 insC, c.3819delGTAAA, c. 300T &gt; G, c.5136G &gt; A, 185delAG, 4153delA, 2080delA; BRCA 2 - c.6621_6622del, p.39-1_39delGA, c.961_962insAA. Among carriers of germinal mutations, primary multiple cancer was registered in 14.6% (33/225) of patients with mutations in the BRCA 1 genes. The following mutations were identified in patients with primary multiple malignant neoplasms: c.5382 insC and c.3819delGTAAA in the BRCA gene 1. The first primary breast cancer was registered in 10.6% (24/225) of patients, ovarian cancer in 1.8% (4/225), gastric cancer in 0.4% (1/225), primary multiple synchronous breast and ovarian cancer in 1.8% (4/225). In carriers of germinal mutations, manifestations of the first primary cancer were observed at the age of 29 to 60 years. The manifestation of the second primary cancer was registered in 2-18 years after the manifestation of the first primary cancer. Twenty-two patients subsequently developed a second primary breast cancer and 11 patients developed ovarian cancer. Also, 6 patients had a manifestation of the third primary cancer of the breast, ovaries or stomach in 8-26 years after the manifestation of the second primary cancer. Conclusions: Primary multiple cancer in carriers of germline mutations in the Republic of Bashkortostan was observed in 14.6% (33/225) of patients with mutations in the BRCA 1 genes. The period of manifestation of a secondary malignant tumor ranged from 2 to 18 years. This study plays an important role in the process of optimizing screening for multiple primary malignant neoplasms for carriers of germline mutations.