CHEK2 Mutations Research Articles

8576 Genomic and Transcriptomic Characterization of Pediatric Thyroid Cancers

Abstract Disclosure: J.C. Ricarte-Filho: None. E.R. Reichenberger: None. K. Hinkle: None. A.R. Isaza: None. A.J. Bauer: None. A.T. Franco: None. Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer in both pediatric and adult populations. Recent genomic profiling of papillary thyroid cancers, including that of the Cancer Genome Atlas, has uncovered the genetic alterations and molecular mechanisms driving thyroid cancer. However, these studies were primarily focused on adult patients. Despite their favorable prognosis, pediatric PTCs have higher rates of metastasis and recurrence than adult PTCs, but the molecular characterization of these tumors have been comparatively lacking. Methods: Here we explore the genomic and transcriptomic landscape of pediatric PTCs from 126 patients, including 107 primary tumors and 19 lymph node metastases (non-paired) using whole-exome sequencing and RNA sequencing. Thirteen primary tumors also had a paired lymph node metastasis analyzed. Results: We found driver alterations in 113 of 126 (90%) of the PTCs investigated, including the identification of a novel receptor tyrosine kinase (RTK) fusion not previously reported in thyroid cancer. Genetic drivers were predominantly kinase fusions (48%), most commonly fusions of RET (22%), NTRK3 (10%), ALK (5%) and NTRK1 (5%). The most common point mutations were BRAF p.V600E (21%), NRAS p.Q61R/K (9%) and hotspot mutations in DICER1 (4%). We found genetic alterations in 12 of the 13 paired lymph node metastasis. In all 12 cases the metastatic tissue harbored the same alterations found in the primary tumor. Eight out of 12 cases had fusions (3 RET, 3 NTRK3 and 2 NTRK1), and the additional 4 cases had point mutations (3 BRAFV600E and 1 TSHRM543T). Fourteen patients (11%) had widely invasive disease with lateral lymph node and distant metastases (N1bM1). Most of these N1bM1 tumors (13/14; 93%) were driven by RTK fusions (5 NTRK3, 3 RET, 3 NTRK1 and 2 ALK). The one case lacking a kinase fusion had a CHEK2 mutation. Conclusion: Our genomic and transcriptomic analysis allowed the detection of driver alterations in ∼90% of the cases, reducing the so-called “dark matter” in our cohort. Our data support that kinase fusions are associated with metastatic disease in pediatric PTC. Patients with RET/NTRK/ALK fusions have worse outcomes than those with BRAF p.V600E mutation and RAS-like alterations (NRAS, DICER1, non-V600 BRAF, PTEN). By using the transcriptional profiling generated in this study, we are currently investigating the molecular mechanisms underlying the metastatic behavior of pediatric PTCs harboring oncogenic fusions, including changes in MAPK transcriptional output, differentiation score and recruitment of signaling pathways potentially associated with the metastatic behavior of these tumors. Presentation: 6/3/2024

B-191 Genomic Profile of Circulating Tumor DNA in Advanced Lung Cancer: Comparison with Tissue DNA

Abstract Background The most common cancer in Korea is thyroid cancer, followed by lung cancer, and the most common cancer in men is lung cancer. The cancer with the highest mortality rate is lung cancer. Recently, the precision medical approach is becoming a major treatment strategy for lung cancer. For precision medical approach, the usefulness of next-generation sequencing (NGS) analysis targeting circulating tumor DNA (ctDNA) is being emphasized. Therefore, in this study, NGS analysis was performed on blood and tissues of advanced lung cancer patients to compare and analyze genetic mutation patterns to confirm the usefulness of ctDNA NGS assay. Methods A total of 101 patients with advanced lung cancer (stage 3 or 4) were recruited, and ctDNA NGS assays were performed on their plasma using a Pan100 panel (Dxome). Tissues from primary lung cancer, metastatic lymph nodes, or metastatic organs of 22 patients were analyzed using ONCOaccuPanel (NGeneBio). All variants were classified into four tiers based on the level of clinical significance, according to the standards and guidelines established by the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. Results In the ctDNA NGS assay of 101 patients, 70 (69.3%) harbored 154 tier 1 or 2 variants. Mutations in TP53 (45, 29.2%) and EGFR (23, 14.9%) were the most frequently detected, followed by mutations in RB1, CHEK2, ATM, JAK2, ATR, DNMT3A, and KRAS. Among the 22 patients whose tissue was examined, tier 1 or 2 variants were detected in both the plasma and tissue of 14 patients and only in the tissue of six patients. All genes for these variants were targeted using both methods. Identical variants were detected in the plasma and tissue of six of the 14 patients, and discordant results were observed in the remaining eight patients. Twenty copy number variations were detected in 13 of the 101 patients, with copy number gain of EGFR being the most common (6, 30%). Fusion genes were detected in five of the 101 patients, two of which were not detected in the tissue. Overall, 74 (73.3%) of the 101 patients had positive ctDNA NGS assay results. Conclusions Although the NGS assay with ctDNA is less sensitive than that with tissue DNA, some genetic alterations are detected only in ctDNA NGS assays; therefore, it is useful to apply the ctDNA NGS assay as a complement.

Abstract PR-04: Phase 2 Trial Testing The PARP Inhibitor Niraparib In Patients With Advanced Pancreatic Cancer with Pathogenic Variants In BRCA 1, BRCA2, PALB2, ATM and CHEK2

Abstract Background: Poly-(adenosine diphosphate ribose) polymerase (PARP) inhibitors have demonstrated efficacy in patients with platinum-sensitive pancreatic cancer who harbor germline BRCA 1/2 pathogenic variants (PVs). Whether PARP inhibitors are effective in a broader population of pancreatic cancer patients is still under investigation. Methods: This was a multicenter, single arm, open-label phase II trial (NCT03601923) investigating the use of the PARP inhibitor niraparib in patients with advanced pancreatic cancer. Eligible patients were required to have germline or somatic mutations in BRCA1, BRCA2, PALB2, ATM and/or CHEK2. Prior treatment with PARP inhibitors and prior progression on a platinum chemotherapy were not allowed, though patients could be included if they had progression on non-platinum based therapy. Patients were treated with weight-adjusted niraparib (200 mg or 300 mg) once daily on a 28-day cycle. The primary endpoint was 6-month progression free survival (PFS) rate (binary). Secondary endpoints were PFS, overall survival (OS), objective response rate (ORR) by RECIST v1.1, and safety. Serial plasma samples were collected for circulating tumor DNA analyses. Results: Thirty-two patients (10 females [31%]; median age 67) were evaluable for the primary endpoint. Patients had a germline or somatic alteration in one or more of the following genes: ATM (n=14), BRCA2 (n=10), PALB2 (n=3), CHEK2 (n=4), or BRCA1 (n=2). There were 10 patients who received niraparib as maintenance therapy and 12 patients whose tumors previously progressed on a non-platinum-based chemotherapy. The 6-month PFS rate was 25% (90% CI: 13-41), rejecting the null hypothesis of a 17% 6-month PFS rate. The median PFS for the entire population was 2.0 months (90% CI: 1.7-3.7) and median OS was 10.2 months (90% CI: 8.2-13.2). The objective response rate was 14% (90% CI: 5-30%); 2 patients had a complete response, 2 patients had a partial response. Patients who never previously progressed on chemotherapy had a significantly longer median PFS (p=0.02) and OS (p=0.003) than patients who previously progressed on chemotherapy. Three patients with biallelic inactivation of ATM, who never progressed on prior lines of chemotherapy, were on niraparib for over 1 year (range 1 – 4 years). Reversion mutations restoring the reading frame in BRCA2 were identified in cell-free DNA in 3 patients with BRCA2 pathogenic frameshift variants. Additional putative resistance mutations in other DNA repair genes were identified and will be reported. Conclusions: Niraparib demonstrated a promising 6-month PFS rate and provided clinically meaningful benefit in patients with pancreatic cancer. The observation of prolonged benefit of three patients with biallelic ATM inactivation warrants further investigation. Acknowledgment: Funding for this study was provided by GSK. GSK was provided the opportunity to review a preliminary version of this abstract for factual accuracy. The authors are solely responsible for final content and interpretation. Citation Format: Brandon M. Huffman, Jett Crowdis, Matthew B. Yurgelun, Nora Horick, Yvonne Li, Huy Nguyen, Kalindi Parmar, Bose S. Kochupurakkal, Andrea Enzinger, Marios Giannakis, Nadine McCleary, Kimmie Ng, Anuj K. Patel, Kimberly J. Perez, Douglas A. Rubinson, Benjamin L. Schlechter, Harshabad Singh, Helen Lam, Kaitlyn Ramsey, Elizabeth Andrews, Leigh Culnane, Andrea Bullock, Ahmed Rattani, Jeffrey Clark, Mary Linton Peters, Brian M. Wolpin, Alan D. D'Andrea, Geoffrey I. Shapiro, Andrew J. Aguirre, James M. Cleary. Phase 2 Trial Testing The PARP Inhibitor Niraparib In Patients With Advanced Pancreatic Cancer with Pathogenic Variants In BRCA 1, BRCA2, PALB2, ATM and CHEK2 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-04.

Real-world data analysis of next-generation sequencing and corresponding clinical characteristics in thyroid tumor.

Next-generation sequencing (NGS) is of great benefit to clinical practice in terms of identifying genetic alterations. This study aims to clarify the gene background and its influence on thyroid tumors in the Chinese population. NGS data and corresponding clinicopathological features (sex, age, tumor size, extrathyroidal invasion, metastasis, multifocality, and TNM stage) were collected and analyzed retrospectively from 2844 individual thyroid tumor samples from July 2021 to August 2022. Among the cohort, 2337 (82%) cases possess genetic alterations, including BRAF (71%), RAS (4%), RET/PTC (4%), TERT (3%), RET (2.2%), and TP53 (1.4%). Diagnostic sensitivity before surgery can be significantly increased from 0.76 to 0.91 when cytology is supplemented by NGS. Our results show that BRAF-positive papillary thyroid cancer (PTC) patients tend to have older age, smaller tumor size, less vascular invasion, more frequent tumor multifocality, and a significantly higher cervical lymph node metastatic rate. Mutation at RET gene codons 918 and 634 is strongly correlated with medullary thyroid cancer. However, it did not display more invasive clinical characteristics. TERT-positive patients are more likely to have older age, and have larger tumor size, more tumor invasiveness, and more advanced TNM stage, indicating a poor prognosis. Patients with TERT, RET/PTC1, and CHEK2 mutations are more susceptible to lateral lymph node metastasis. In conclusion, NGS can be a useful tool that provides practical gene evidence in the process of diagnosis and treatment in thyroid tumors.

CHEK2 mutation causes manifestations similar to Lynch syndrome and Li-Fraumeni syndrome

CHEK2 mutation causes manifestations similar to Lynch syndrome and Li-Fraumeni syndrome

Real-world data on the prevalence of BRCA1/2 and HRR gene mutations in patients with primary and metastatic castration resistant prostate cancer

PurposeThis study seeks to contribute real-world data on the prevalence of BRCA1/2 and HRR gene mutations in prostate cancer.MethodsWe compiled sequencing data of 197 cases of primary and metastatic prostate cancer, in which HRR mutation analysis was performed upon clinical request within the last 5 years. All cases were analyzed using a targeted NGS BRCAness multigene panel, including 8 HRR genes (ATM, BRCA1, BRCA2, CDK12, CHEK2, FANCA, HDAC2, PALB2).ResultsOur findings reveal a prevalence of potentially targetable mutations based on FDA criteria of 20.8%, which is comparable to the literature. However, the frequency of targetable BRCA2 mutations within our cohort was lower than reported for mCRPC and ATM and CHEK2 mutations were more prevalent instead. Thus, while 20.8% (n = 38) of the cases meet the criteria for olaparib treatment per FDA approval, only 4.9% (n = 9) align with the eligibility criteria according to the EMA approval.ConclusionThis study offers valuable real-world insights into the landscape of BRCA1/2 and HRR gene mutations and the practical clinical management of HRR gene testing in prostate cancer, contributing to a better understanding of patient eligibility for PARPi treatment.

Comprehensive analysis of the functional impact of single nucleotide variants of human CHEK2.

Loss of function mutations in the checkpoint kinase gene CHEK2 are associated with increased risk of breast and other cancers. Most of the 3,188 unique amino acid changes that can result from non-synonymous single nucleotide variants (SNVs) of CHEK2, however, have not been tested for their impact on the function of the CHEK2-enocded protein (CHK2). One successful approach to testing the function of variants has been to test for their ability to complement mutations in the yeast ortholog of CHEK2, RAD53. This approach has been used to provide functional information on over 100 CHEK2 SNVs and the results align with functional assays in human cells and known pathogenicity. Here we tested all but two of the 4,887 possible SNVs in the CHEK2 open reading frame for their ability to complement RAD53 mutants using a high throughput technique of deep mutational scanning (DMS). Among the non-synonymous changes, 770 were damaging to protein function while 2,417 were tolerated. The results correlate well with previous structure and function data and provide a first or additional functional assay for all the variants of uncertain significance identified in clinical databases. Combined, this approach can be used to help predict the pathogenicity of CHEK2 variants of uncertain significance that are found in susceptibility screening and could be applied to other cancer risk genes.

False-Positive Circulating Tumor DNA Results Do Not Explain Lack of Efficacy for PARP Inhibitors in Patients With Castration-Resistant Prostate Cancer Harboring ATM and CHEK2 Mutations.

False-positive ctDNA results do not explain lack of efficacy for PARPi in patients with ATMm and CHEK2m CRPC.

Untapped Potential of Poly(ADP-Ribose) Polymerase Inhibitors: Lessons Learned From the Real-World Clinical Homologous Recombination Repair Mutation Testing.

Testing for homologous recombination deficiency (HRD) mutations is pivotal to assess individual risk, to proact preventive measures in healthy carriers and to tailor treatments for cancer patients. Increasing prominence of poly(ADP-ribose) polymerase (PARP) inhibitors with remarkable impact on molecular-selected patient survival across diverse nosologies, ingrains testing for BRCA genes and beyond in clinical practice. Nevertheless, testing strategies remain a question of debate. While several pathogenic BRCA1/2 gene variants have been described as founder pathogenic mutations frequently found in patients from Russia, other homologous recombination repair (HRR) genes have not been sufficiently explored. In this study, we present real-world data of routine HRR gene testing in Russia. We evaluated clinical and sequencing data from cancer patients who had germline/somatic next-generation sequencing (NGS) HRR gene testing in Russia (BRCA1/2/ATM/CHEK2, or 15 HRR genes). The primary objectives of this study were to evaluate the frequency of BRCA1/2 and non-BRCA gene mutations in real-world unselected patients from Russia, and to determine whether testing beyond BRCA1/2 is feasible. Data of 2,032 patients were collected from February 2021 to February 2023. Most had breast (n = 715, 35.2%), ovarian (n = 259, 12.7%), pancreatic (n = 85, 4.2%), or prostate cancer (n = 58, 2.9%). We observed 586 variants of uncertain significance (VUS) and 372 deleterious variants (DVs) across 487 patients, with 17.6% HRR-mutation positivity. HRR testing identified 120 (11.8%) BRCA1/2-positive, and 172 (16.9%) HRR-positive patients. With 51 DVs identified in 242 formalin-fixed paraffin-embedded (FFPE), testing for variant origin clarification was required in one case (0.4%). Most BRCA1/2 germline variants were DV (121 DVs, 26 VUS); in non-BRCA1/2 genes, VUS were ubiquitous (53 DVs, 132 VUS). In silico prediction identified additional 4.9% HRR and 1.2% BRCA1/2/ATM/CHEK2 mutation patients. Our study represents one of the first reports about the incidence of DV and VUS in HRR genes, including genes beyond BRCA1/2, identified in cancer patients from Russia, assessed by NGS. In silico predictions of the observed HRR gene variants suggest that non-BRCA gene testing is likely to result in higher frequency of patients who are candidates for PARP inhibitor therapy. Continuing sequencing efforts should clarify interpretation of frequently observed non-BRCA VUS.

Double Heterozygosity for Germline Mutations in Chinese Breast Cancer Patients.

Double pathogenic mutations occurring in an individual are considered a rare event. The introduction of a multiple-gene panel at Hong Kong Hereditary Breast Cancer Family Registry has allowed the identification of pathogenic variants in multiple genes, providing more information on clinical management and surveillance to the proband and their family members. Breast cancer patients who are double heterozygous (DH) for different hereditary breast and ovarian cancer syndrome (HBCO)-related genes were identified from a cohort of 3649 Chinese patients. Nine patients (0.25%) were observed to have germline DH mutations in ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MSH6, PALB2, and TP53. Three probands were diagnosed with unilateral breast cancer, two patients were diagnosed with bilateral breast cancer, and four patients had multiple primary cancers. The median age for breast cancer diagnosis was an early age of 36 years. Chinese DH carriers did not show worse phenotypes or have a significantly downhill clinical presentation. However, seven out of nine (77.8%) of our DH carriers harbored a BRCA1 mutation, and four of them (44.4%) developed bilateral breast cancer, suggesting Chinese DH individuals may have a higher chance of having bilateral breast cancer than other populations (p = 0.0237).

Gastrointestinal Polyps and Polyposis in Individuals Harboring Germline CHEK2 Mutations.

Checkpoint kinase 2 is a tumor suppressor gene in the deoxyribonucleic acid damage checkpoint system that may be mutated in several cancers. Patients with germline checkpoint kinase 2 mutations and multiple colon polyps were noted during routine care, and genetic testing is recommended for patients with as few as 10 lifetime polyps. This study assessed whether checkpoint kinase 2 is associated with attenuated or oligopolyposis and characterized the gastrointestinal clinicopathologic profile. Retrospective observational study. Records from patients harboring germline checkpoint kinase 2 mutations from 1999-2020 were reviewed. A total of 45 patients with germline checkpoint kinase 2 mutations with endoscopic examinations. Description of clinicopathologic variables. Twenty-five of 45 patients had polyps: 3 with only upper gastrointestinal polyps, 17 with only lower gastrointestinal polyps and 5 with both upper and lower gastrointestinal polyps. The most common germline checkpoint kinase 2 mutations in patients with polyps were p.S428F (n = 10), p.I157T (n = 4) and p.T476M (n = 2), with other mutations present in 1 patient each. Among patients with lower gastrointestinal polyps, 9 had adenomas, 6 had serrated polyps, 1 had an inflammatory polyp and 6 had both adenomatous and serrated polyps. Three patients (p.I157T, n = 2; p.R117G, n = 1) had >10 adenomas, and 1 (p.G259fs) had 18 serrated polyps. Five patients (11.1%) developed colorectal adenocarcinoma, including 2 with >10 adenomas. Five patients with p.S428F (50%) exclusively had right- sided adenomas. Single-center descriptive study. Germline checkpoint kinase 2 mutations should be considered in patients with polyposis. The preponderance of right- sided adenomas in patients with p.S428F mutations suggests the importance of right-sided colonoscopy in these patients. See Video Abstract.

Rethinking the use of germline CHEK2 mutation as a marker for PARP inhibitor sensitivity.

Rethinking the use of germline CHEK2 mutation as a marker for PARP inhibitor sensitivity.

TRIUMPH: phase II trial of rucaparib monotherapy in patients with metastatic hormone-sensitive prostate cancer harboring germline homologous recombination repair gene mutations.

The activity of PARP inhibitors (PARPi) in patients with homologous recombination repair (HRR) mutations and metastatic castration-resistant prostate cancer has been established. We hypothesized that the benefit of PARPi can be maintained in the absence of androgen deprivation therapy (ADT) in an HRR-mutated population. We report the results of a phase II clinical trial of rucaparib monotherapy in patients with metastatic hormone-sensitive prostate cancer (mHSPC). This was a multi-center, single-arm phase II trial (NCT03413995) for patients with asymptomatic, mHSPC. Patients were required to have a pathogenic germline mutation in an HRR gene for eligibility. All patients received rucaparib 600 mg by mouth twice daily, without androgen deprivation. The primary endpoint was a confirmed PSA50 response rate. Twelve patients were enrolled, 7 with a BRCA1/2 mutation and 5 with a CHEK2 mutation. The confirmed PSA50 response rate to rucaparib was 41.7% (N = 5/12, 95% CI: 15.2-72.3%, one-sided P = .81 against the 50% null), which did not meet the pre-specified efficacy boundary to enroll additional patients. In patients with measurable disease, the objective response rate was 60% (N = 3/5), all with a BRCA2 mutation. The median radiographic progression-free survival on rucaparib was estimated at 12.0 months (95% CI: 8.0-NR months). The majority of adverse events were grade ≤2, and expected. Rucaparib can induce clinical responses in a biomarker-selected metastatic prostate cancer population without concurrent ADT. However, the pre-specified efficacy threshold was not met, and enrolment was truncated. Although durable responses were observed in a subset of patients, further study of PARPi treatment without ADT in mHSPC is unlikely to change clinical practice.

Early-onset appendiceal adenocarcinoma (EOAA): 10-year experience from a single center.

4178 Background: The incidence of early-onset (age <50) gastrointestinal cancers, including early onset Appendiceal Adenocarcinoma (EOAA) is on the rise, however reported data on etiology, treatment, and outcomes is scarce. Here we present outcomes for EOAA patients treated at a single high-volume center. Methods: Records of patients (pts) with EOAA were reviewed. Clinicopathological and genomic data were abstracted. Pts aged 18 - 49 years at diagnosis with Appendiceal Adenocarcinoma (AA) seen at UCMC between 2013 - 2023 were included. The primary outcome of Overall survival (OS) was analyzed using univariable Cox proportional hazards regression analysis. Results: 116/492 (23.6%) appendix cancer pts seen at UCMC had early-onset disease. 45 pts met eligibility (Table). 10/20 (50%) pts with localized disease had recurrence after hemicolectomy (median recurrence free survival = 41.6 months; 95% CI, 34.3 – NR; follow-up = 46.42 months). 22/44 (50%) pts had mucinous AA, 21 (47.7%) goblet cell AA, and 1 (2.33%) had poorly differentiated AA. In 35 pts with metastatic/recurrent disease, mOS was 35.93 months (95% CI, 28.4 – NR). Lymphovascular (LVI) or perineural invasion (PNI) (HR, 6.41; 95% CI, 2.10 – 19.59, p = 0.001), lymph nodes metastasis (HR, 13.11; 95% CI, 3.53 – 48.68; p < 0.001), and grade 3 disease (vs. grade 1; HR, 5.28; 95% CI, 1.43 – 19.51, p = 0.01) were prognostic for worse OS in univariable analysis. Cytoreductive surgery (CRS), irrespective of completeness, was associated with improved OS (HR = 0.21; 95% CI, 0.09 – 0.53; p < 0.001). Next Generation Sequencing results were available in 20 cases: KRAS (n = 10, 50%), TP53(n = 7, 35%), GNAS (n = 6, 30%), SMAD4 (n = 4, 20%), and MYC (n = 3, 15%) were frequently altered. Alterations with potential therapeutic targets were seen in 12/20 (60%) cases. 10 pts had germline testing with 2 (20%) pathogenic alterations detected: SDHA(H447Mfs*23) and CHEK2 (T367Mfs*15). The pt with CHEK2 mutation had AA as the only malignancy, was the youngest (age 26.17) and passed away 17.26 months after diagnosis. Conclusions: A considerable number of patients with AA may have early-onset disease. A median OS of about 3 years in this young and vulnerable patient population is alarming. As in late-onset disease, EOAA is often incidentally diagnosed. LVI or PNI may be associated with poorer outcomes and deserve additional consideration for risk stratification. Many patients have targetable genomic alterations and should be included in clinical trials where current enrollment is often unsatisfactory for AA. Germline mutation testing in patients with EOAA should be widely implemented. [Table: see text]

Analysis of the occurrence of germline mutations BRCA1\2, PALB2, CHEK2, NBN in patients with pancreatic malignancies. Single-center cohort non-randomized retrospective study

Objective. To analyze the frequency of carriage of BRCA1\2, PALB2, CHEK2, NBN mutations in patients with malignant neoplasms of pancreas. Materials and methods. The single-center cohort non-randomized retrospective study is based on the data of 82 patients who were examined and treated in Russian Research Center of Radiology and Surgical Technologies named after academician A.M. Granov from 2020 to 2022. Patients with confirmed ductal adenocarcinoma of pancreas were included into the study group. Screening of mutations in exons 2,10, 18, 19 of BRCA1 gene and exon 11 of BRCA2 gene was performed in these patients. In addition, oncological family histories were studied. Results. Analysis of medical documentation data showed that 18 (22 %) patients with pancreatic cancer had a hereditary oncological history. In this cohort of patients, 5 (28 %) had relatives with pancreatic cancer, 9 (50 %) had a family history of ovarian cancer, 2 (11 %) female relatives of patients in the study group were diagnosed with breast cancer before the age of 50, also 2 (11 %) patients had a history of more than 2 relatives who suffered from breast cancer and / or prostate cancer. When evaluating the results of revealing the mutations in the entire study group (82 patients), BRCA1 (c.5266dupC) was revealed in 8 patients (9.7 %), PALB-2 (c.1592delT) – in 2 patients (2.4 %), mutations CHEK2, NBN and BRCA2 were not diagnosed in any patient. 5 (6 %) patients who were BRCA1 mutation carriers and one patient with an established PALB2 mutation, according to the analysis of case histories, had no oncological history. None of the patients in the study group was a carrier of the BRCA2, CHEK2 and NBN mutations. Conclusions. Some patients with pancreatic cancer are carriers of germline mutations. Considering our data on the trend of association between germline mutations and pancreatic cancer, we can make an assumption about the prospect of using this indicator as one of the markers for early detection of pancreatic cancer not only in patients with hereditary risk factors for neoplasia, but also in patients without cancer anamnesis. To obtain the results, further observation of patients in the study group and randomized multicenter studies are required.

Mutation characteristics of cancer susceptibility genes in Chinese ovarian cancer patients.

The association between mutations in susceptibility genes and the occurrence of ovarian cancer has been extensively studied. Previous research has primarily concentrated on genes involved in the homologous recombination repair pathway, particularly BRCA1 and BRCA2. However, a wider range of genes related to the DNA damage response pathways has not been fully explored. To investigate the mutation characteristics of cancer susceptibility genes in the Chinese ovarian cancer population and the associations between gene mutations and clinical data, this study initially gathered a total of 1171 Chinese ovarian cancer samples and compiled a dataset of germline mutations in 171 genes. In this study, it was determined that MC1R and PRKDC were high-frequency ovarian cancer susceptibility genes in the Chinese population, exhibiting notable distinctions from those in European and American populations; moreover high-frequency mutation genes, such as MC1R: c.359T>C and PRKDC: c.10681T>A, typically had high-frequency mutation sites. Furthermore, we identified c.8187G>T as a characteristic mutation of BRCA2 in the Chinese population, and the CHEK2 mutation was significantly associated with the early onset of ovarian cancer, while the CDH1 and FAM175A mutations were more prevalent in Northeast China. Additionally, Fanconi anemia pathway-related genes were significantly associated with ovarian carcinogenesis. In summary, this research provided fundamental data support for the optimization of ovarian cancer gene screening policies and the determination of treatment, and contributed to the precise intervention and management of patients.

Outcomes of a universal germline screening program in a community urology practice.

The role of germline genetic testing in urologic oncology has expanded in recent years. However, implementation of genetic testing in community practices remains a challenge, often due to limited access to qualified genetics trained providers. In this study, we report outcomes of a universal germline screening program in a community urology practice. Between November 2021 and September 2022, all patients referred for urology clinic visits at Frederick Health (Frederick, MD, USA) were provided an online genetics screening questionnaire prior to the visit. Responses were compared against National Comprehensive Cancer Network (NCCN) criteria for germline testing. Those who met criteria were provided educational materials at the end of the questionnaire, and then counseled by a trained urologic oncologist (HC) in the clinic or referred to a genetic counselor prior to testing. Testing was performed with a 36-gene pan-cancer panel (CancerNext) or a 14-gene targeted prostate cancer panel (ProstateNext), with or without additional RNA analysis (RNAinsight) (Ambry Genetics, CA, USA). Demographic and clinical parameters, as well as genetic testing results, were retrospectively collected under IRB approval. In the study period, 765 patients were seen over 1370 clinic visits. Of these, 505 patients (66.0%) completed the screening questionnaire. The majority were completed via email (54.5%) with the remainder (45.5%) via text message. Of the patients who completed screening, 125/505 (24.7%) met NCCN criteria for germline testing. 58/125 patients (46.4%) who met criteria underwent germline testing, of whom 5/58 (8.6%) had distinct pathogenic mutations identified. These included actionable mutations in BRCA1, BRCA2, and CHEK2, as well as an additional pathogenic mutation in NBN. Variants of unknown significance were identified in 8/58 patients (13.8%) in 11 total genes. Challenges to implementation of this program included meeting institutional requirements for genetic testing consent, facilitating specimen collection in clinic, and integration of results into the electronic health record. Genetic risk assessment for high-risk individuals is feasible as part of a universal screening program in a community urology practice. Approximately 8% of tested patients were found to have pathogenic germline mutations, which is consistent with contemporary tertiary referral cohorts.

Abstract PO1-08-06: Clinical-molecular correlation in breast cancer with pathogenic variants in CHEK2. Is there a relationship with HER2+ breast cancer?

Abstract Background: The CHEK2 gene codes for checkpoint protein Kinase 2 (CHK2), an effector in the ATM-CHK2-p53 DNA damage repair pathway in double-stranded DNA breaks. Initially, germline pathogenic variants were associated with moderate risk for breast carcinoma, but later studies linked alterations in the gene to other types of cancer. The aim of our study was to establish a clinical-molecular correlation of profiles of patients carrying pathogenic variants and variants of uncertain significance (VUS) in CHEK2 with a diagnosis of breast carcinoma, in patients treated in our hospital. And to describe whether the pathogenic variant c.1100del present different clinical or immunohistochemical characteristics than the rest, also considering the particularity of being an island population. Methodology: We have collected data from genetic studies performed in patients from our hospital, covering a population of 580,000 inhabitants, in Santa Cruz de Tenerife ( Canary Islands, Spain), between 2017 and 2023.Out of 952 patients with suspected hereditary cancer, 81 had CHEK2 mutations. In patients with CHEK2 mutations and breast cancer we established three groups for clinical molecular analysis: 1) pathogenic variant c.1100del, 2) other pathogenic variants and 3) VUS, to be correlated with age, histology, ER, PR, Ki, grade (G), HER2, second tumour or recurrence, subtype, HER2 low, aggressive clinic, neuropathy, haematological and digestive toxicity. The germline genetic study performed covered 77 genes related to hereditary cancer using the SureSelect HS library preparation kit (Agilent Technologies). The classification of the variants identified was performed according to the American College of Medical Genetics (ACMG) criteria. Results: In the 952 genetic studies performed, 8.5% of cases had CHEK2 mutations, 2.62% were related to breast carcinoma (N=26) of which 54% had the pathogenic variant “c.1100del”, 16% “other” pathogenic variants and 30% VUS. The mean age at diagnosis was 42 years, being lower than 38 years in pathogenic variants other than c.1100del. Histologically, infiltrating ductal carcinoma (85%) and mucinous carcinomas (12%), ER+ (93%), PR+ (77%), HER 2+ (31%), HER2 low (44%), G2-3 (84%) and Ki >15% (70%) were predominant. Second diagnoses were tumour or recurrence in 40%, being higher in the group of pathogenic variants other than c.1100del (50%), and showing aggressive clinical course in 26%. The predominant subtype was luminal B (50%), HER2+ (31%), luminal A (12 %) and triple negative (7%), although in the cluster analysis patients with pathogenic variant c.1100del HER2+ were higher (38%) and luminal B (38%), while in pathogenic variants other than c.1100del and VUS the luminal subtype was predominant (75%). Chemotherapy toxicity: neuropathy (35%), haematological and digestive toxicity (50%). Conclusion: Our results are consistent with other reported series, being related with all breast carcinoma subtypes, mainly luminal B and HER2+ and with triple negative at a lesser extend. Considering HER2 low patients were about 75% of patients with CHEK2 mutations, a molecular mechanism that correlates a truncating mutation in CHK2 and HER2 overexpression can be hypothesized. In the cluster analysis, HER2+ (38%), and luminal B (38%) subtypes predominate in patients with pathogenic variant c.1100del, while in pathogenic variants other than c.1100del and VUS the luminal B subtype predominates (75%), as well as recurrence or second tumours in 50% of cases. On the other hand, considering that this is an island population, the possible effect of geographical isolation and the resulting inbreeding in the past, these facts do not seem to elicit differences comparing to the rest of the continental population, although the increase in pathogenic variants in CHEK2 were observed in patients from the small island of La Gomera. The relationship between CHEK2 and HER2 in breast cancer is an area of active research. Relative frequency in groups of CHEK2 variants Relative frequency in CHEK2 “ pathogenic variants c.1100 del (53%)”, “other”pathogenic variants no c.1100 del (15 %)" and VUS (30%). Relative frequency of breast cancer subtypes according to CHEK2 variants. HER2+: 30,8%. Luminal A: 11,5% . Luminal B: 50%. Triple negative: 7,7% . Histology, ER, PR, Ki, HER2 and HER2 low Histology , infiltrating ductal carcinoma (84%), ER+ (92%), PR (77%), Ki >15% (70%), HER2+ (31%), HER2 low (45%) Citation Format: Natalia Pérez-Rodríguez, Carol Prieto-Morin, Maria del Carmen Maeso, Lina Pérez-Mendez. Clinical-molecular correlation in breast cancer with pathogenic variants in CHEK2. Is there a relationship with HER2+ 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 PO1-08-06.

Abstract PO5-09-04: Oncotype DX Breast Recurrence Score® analysis in early-stage breast cancer associated with CHEK2, ATM and PALB2 germline pathogenic variants

Abstract Background: The 21-gene assay (Oncotype DX Recurrence Score, RS) is the only clinically validated assay to determine the prognosis in hormone-positive, HER2-negative breast cancer (BC) patients treated with endocrine therapy alone by predicting locoregional and distant recurrence. Outcomes of Oncotype RS in BRCA-associated BC has been studied previously, but the results of RS analysis in BC patients with the other BC susceptibility genes have not been documented. This study evaluates the clinical and pathological characteristics of BC patients with ATM, CHEK2 and PALB2 germline pathogenic variants (PV). Methods: Patients with invasive hormone-positive, HER2-negative BC who have had Oncotype DX Breast Recurrence Score® testing and who underwent genetic testing in the Breast Medical Oncology and the Breast Clinical Cancer Genetics Clinic at the University of Texas MD Anderson Cancer Center (MDACC) were identified from the prospectively maintained research database. Clinical and tumor characteristics were analyzed using descriptive statistics. Results: Between 1996 and June 2023, 5652 patients with Oncotype RS were included in this analysis. Amongst those 828 BC patients had genetic testing and 81 patients were found to have a pathogenic variant: 17 patients with a CHEK2 mutation, 10 patients with an ATM mutation, and 18 patients with a PALB2 mutation. Among patients with CHEK2 PV, median Oncotype RS was 17 (5–32) overall, 21 (13–32) for patients age < 50, and 14.5 (5–28) for patients age ≥50 (p= 0.2). Among patients with ATM PV, median RS was 16.5 (3–54) overall, 25 (10–54) for patients age < 50, and 14.5 (3–29) for patients age ≥50 (p= 0.19). Among patients with PALB2 PV, median RS was 26.5 (15–40) overall, 20 (15–40) for patients age < 50, and 31 (26–37) for patients age ≥50 (p= 0.012). Further patient and tumor characteristics are shown in Table 1. Conclusion: This is a single-institutional cohort of hormone-positive, HER2-negative BC patients who had Oncotype RS and who underwent genetic testing. Further analysis on clinical and tumor pathological characteristics and long-term outcome is ongoing. Table1. Patient and tumor characteristics Citation Format: Fatma Akkoc Mustafayev, Angelica Gutierrez Barrera, Diane Liu, Banu Arun. Oncotype DX Breast Recurrence Score® analysis in early-stage breast cancer associated with CHEK2, ATM and PALB2 germline pathogenic variants [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 PO5-09-04.

Abstract PO5-23-06: Predictive Factors for Reconstructive Method and Outcomes in Mutation-Positive Breast Cancer Patients

Abstract Background: BRCA1 and BRCA2 mutations significantly increase the risk of breast cancer, and prophylactic mastectomy reduces the risk by around 90% in these patients. Previous studies have explored predictors of mastectomy type in high-risk genetic mutation patients, but further characterization is needed. This study aims to identify factors associated with resection and reconstruction methods and predictors of postoperative complications in mutation-positive (M+) patients. Methods: A multicenter retrospective cohort study included patients with a genetic predisposition for breast cancer undergoing breast surgery, seen between January 2016 and October 2022. Patient demographics, comorbidities, oncologic history, operative details, and postoperative outcomes were collected. Descriptive statistics and multivariate logistic regression were performed. Results: Among the 176 patients analyzed, 75 (42.6%) had BRCA1, 71 (40.3%) had BRCA2, 11 (6.3%) had PALB2, and 8 (4.5%) had CHEK2 mutations. Mean age and body mass index (BMI) were 41.0±17 years and 24.9±6.9 kg/m2, respectively. Among patients with prior breast reconstruction (n=86, 48.9%), augmentation mammoplasty (n=31, 17.6%) was the most common procedure, followed by oncologic resection (n=21, 11.9%) and reduction mammoplasty (n=15, 8.5%). Nipple-sparing mastectomy (NSM) (n=107, 60.8%) was the most frequent surgical approach, followed by skin-sparing mastectomy (SSM) (n=43, 24.4%), simple mastectomy (n=14, 8.0%), lumpectomy (n=4, 2.3%), and radical mastectomy (n=4, 2.3%). Tissue expander (n=77, 43.8%) was the most common reconstruction method. By a median follow-up duration of 23.9 months, 66 (37.5%) of patients experienced postsurgical complications. Operative complications recorded within 30 days included seroma (n=9, 5.1%), hematoma (n=8, 4.5%), cellulitis (n=10, 5.7%), dehiscence (n=13, 7.4%), surgical site infection (n=11, 6.3%), and delayed wound healing (DWH) (n=24, 13.6%). Other long-term complications included mastectomy flap necrosis (n=22, 12.5%), total reconstructive failure (n=9, 5.1%), red breast syndrome (n=2, 1.1%), and capsular contracture (n=12, 6.8%). The choice of autologous breast reconstruction was correlated with younger age (OR 0.81, 95% CI: 0.69-0.95, p = 0.012) and Hispanic or Latino race (OR 0.01, 95% CI: 0.001-0.25, p=0.007). BMI was significantly correlated with incidence of hematoma (OR 1.17, 95% CI: 1.02-1.33, p=0.024), DWH (OR=1.1, 95% CI: 1.01-1.20, p=0.030), and dehiscence (OR 1.25, 95% CI: 1.09-1.43, p=0.001). Choice of autologous reconstruction was positively correlated with DWH (OR 8.86, 95% CI: 2.25-34.86, p=0.002) and dehiscence (OR 18.24, 95% CI: 2.58-129.158, p=0.004). Conclusion: In this macroscopic study, the most common breast reconstruction method for M+ patients was tissue expander-based. However, only autologous reconstruction was found to have positive correlates, specifically younger age and Hispanic or Latino origin. Younger patients may pursue this method given less concern for short term complications, which are historically increased in autologous reconstruction. Minority distrust of foreign medical material implantation may play a role in Hispanic or Latino choice. Additionally, autologous reconstruction and BMI were associated with certain postoperative complications, particularly dehiscence, DWH, and hematoma, results consistent with general breast cancer surgery cohorts. This study helps better characterize the M+ population and contributes insight into the resection and reconstructive choice in this patient population. Citation Format: Shrayus Sortur, Jaytin Gupta, Christian Lava, Lauren Berger, Varsha Harish, Zoya Khan, Daisy Spoer, Lindy Rosal, Ian Greenwalt, Lucy De La Cruz, David Song, Kenneth Fan. Predictive Factors for Reconstructive Method and Outcomes in Mutation-Positive Breast Cancer Patients [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 PO5-23-06.