Pathogenic Germline Mutations Research Articles

The best linear unbiased prediction (BLUP) method as a tool to estimate the lifetime risk of pancreatic ductal adenocarcinoma in high-risk individuals with no known pathogenic germline variants.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the Western world. The number of diagnosed cases and the mortality rate are almost equal as the majority of patients present with advanced disease at diagnosis. Between 4 and 10% of pancreatic cancer cases have an apparent hereditary background, known as hereditary pancreatic cancer (HPC) and familial pancreatic cancer (FPC), when the genetic basis is unknown. Surveillance of high-risk individuals (HRI) from these families by imaging aims to detect PDAC at an early stage to improve prognosis. However, the genetic basis is unknown in the majority of HRIs, with only around 10-13% of families carrying known pathogenic germline mutations. The aim of this study was to assess an individual's genetic cancer risk based on sex and personal and family history of cancer. The Best Linear Unbiased Prediction (BLUP) methodology was used to estimate an individual's predicted risk of developing cancer during their lifetime. The model uses different demographic factors in order to estimate heritability. A reliable estimation of heritability for pancreatic cancer of 0.27 on the liability scale, and 0.07 at the observed data scale as obtained, which is different from zero, indicating a polygenic inheritance pattern of PDAC. BLUP was able to correctly discriminate PDAC cases from healthy individuals and those with other cancer types. Thus, providing an additional tool to assess PDAC risk HRI with an assumed genetic predisposition in the absence of known pathogenic germline mutations.

A case series of non-small cell lung cancer patients with EGFR or HER2 exon 20 insertion in Li Fraumeni syndrome.

Germline pathogenic mutations in TP53 gene are associated with a cancer predisposition syndrome known as Li Fraumeni syndrome. Albeit infrequently, non-small cell lung cancer, especially as oncogene-addicted disease, may be diagnosed in young patients with Li Fraumeni syndrome. We report three cases of patients affected by Li Fraumeni syndrome who developed non-small cell lung cancer with EGFR or HER2 exon 20 insertions. The first patient suffered from liposarcoma and, then, brain metastases from HER2-mutated non-small cell lung cancer: after stereotactic radiotherapy, he benefited from enrollment in a clinical trial with a HER2-targeted therapy. The second young patient was a female with personal history of rhabdomyosarcoma, diagnosed with brain metastases from EGFR-mutated non-small cell lung cancer: enrollment in a clinical trial led to a temporary clinical benefit. The last case was a female diagnosed with breast carcinoma, ovarian granulosa cell tumor and advanced EGFR-mutated non-small cell lung cancer at a young age. Young patients affected by oncogene-addicted non-small cell lung cancer and with a positive familial cancer history should be referred for an accurate genetic counselling to look for Li Fraumeni syndrome. The underlying molecular connection between TP53 and HER family receptor tyrosine kinases remains unclear, but an extensive molecular characterization of tumors from patients with Li Fraumeni syndrome should always be performed, to offer patients a personalized therapeutic approach.

Cascade genetic testing: an underutilized pathway to equitable cancer care?

The Precision Medicine Initiative was launched upon the potential of genomic information to tailor medical care. Cascade genetic testing represents a powerful application of precision medicine and involves the process of familial diffusion or the "cascade" of genomic risk information. When an individual (proband) is found to carry a cancer-associated germline pathogenic mutation, the information should be cascaded or shared with at-risk relatives. First degree relatives have a 50% likelihood of carrying the same cancer-associated mutation. This process of cascade testing offers at-risk relatives the opportunity for genetic testing and, for those who also carry the cancer-associated mutation, genetically targeted primary disease prevention through intensive cancer surveillance, chemoprevention and risk-reducing surgery, reducing morbidity and preventing mortality. Cascade testing has been designated by the Centers for Disease Control and Prevention as a Tier 1 genomic application for hereditary breast and ovarian cancer. In this manuscript we describe a cascade genetic testing and in particular focus on its potential to provide necessary care to medically underserved and vulnerable populations.

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.

Asymptomatic endometrial cancer with Lynch syndrome; in a woman with primary infertility-A case report and literature review.

Lynch syndrome, also called hereditary non-polyposis colorectal cancer, is an autosomal dominant disorder characterized by germline pathogenic mutations in DNA mismatch repair genes-resulting in increased susceptibility to colorectal, endometrial, and other tumors. This case report presents an incidental finding of endometrial cancer with Lynch syndrome during investigation for primary infertility. A 34-year-old woman presented to the fertility clinic with unexplained primary infertility. Investigations showed possible endometrial polyp, 13 × 11 mm in size. Hysteroscopic polypectomy and endometrial biopsy revealed complex endometrial hyperplasia amounting to endometroid adenocarcinoma. The case was discussed at the West of Scotland Gynecology-Oncology MDT meeting-management options including fertility-sparing treatment or radical surgery were presented to the patient and she opted for the latter. A total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed with pathology results consistent with well-differentiated endometroid adenocarcinoma Stage 1A. Peritoneal washings showed no malignant cells. Genetic testing confirmed a diagnosis of Lynch syndrome. On further questioning, it was revealed that the patient had a strong family history of colon cancer but had not previously met the criteria for genetic testing. She was referred to colorectal surgeons and underwent colonoscopy. This showed no abnormality; she was therefore scheduled for 2-yearly colonoscopic surveillance.

Abstract PO5-23-05: The Impact of Bi-Annual Diagnostic Imaging on Detecting Ipsilateral Breast Recurrence in Patients Undergoing Breast Conserving Surgery for Breast Cancer

Abstract Introduction: Breast conserving surgery (BCS) represents the preferred option for surgical treatment for a majority of patients with early-stage breast cancer who are eligible for this approach. When compared with mastectomy approaches, BCS provides patients with equivalent survival while preserving the affected breast. It is necessary to achieve clear surgical margins as positive lumpectomy margins are associated with an increased risk for ipsilateral breast tumor recurrence. With advances in imaging techniques, as well as effective systemic therapy and contemporary radiation therapy, local recurrence after BCS has decreased and overall survival for patients has improved. Retrospective studies have quantified the recurrence rate in unifocal breast cancer as 8 - 15% at 20 years. The NCCN recommends annual mammography at least 6 months after post-lumpectomy radiation therapy, but there is little data regarding more frequent surveillance after lumpectomy in the early post-operative setting. The purpose of this study was to evaluate the impact of short interval surveillance mammography on the detection of early in-breast recurrence in patients undergoing BCS. Methods: Our IRB-approved Breast Cancer Database was queried for patients enrolled from 11/2009 to 6/2023 who underwent breast conservation surgery for a diagnosis of in situ or invasive breast cancer in this retrospective analysis. Per our institutional protocol, patients were recommended to undergo diagnostic mammography of the treated breast(s) every 6 months for 2 years after BCS. After the initial 2 year period, bilateral mammography was performed annually in the absence of other indications. Additional supplemental imaging such as breast ultrasound and MRI were performed at physician discretion and based on patient risk and breast density. Variables of interest included the presence of pathogenic germline mutations, family history of breast cancer, and disease characteristics. Our primary endpoint was ipsilateral breast tumor recurrence. Results: Of 2491 patients who underwent breast conservation surgery for in situ or invasive breast cancer, 191 (7.7%) developed recurrent disease, including ipsilateral and contralateral recurrence, and distant disease, in the study period. A total of 83 (3.2%) patients developed ipsilateral breast recurrence during the entire study period. Of those, 19 (22.9%) were detected within the first two years after surgery. Six of the 19 patients (31.6%) had their recurrences detected on yearly diagnostic mammography while 6 (31.6%) patients had their recurrences detected on interval 6-month unilateral diagnostic imaging. In both groups, 5/6 recurrences were invasive disease after an original diagnosis of invasive cancer, and the remaining patient had recurrent DCIS. The remaining 7/19 patients (36.8%) had their ipsilateral recurrences detected on palpation or other diagnostic imaging. In this group as well, there was one case of recurrent DCIS, with the remaining 6 cases representing recurrent invasive cancer. Of the 19 patients with ipsilateral recurrences, none had pathogenic germline mutations. 4 of the 19 patients (21%) had positive margins after their initial lumpectomy surgery with re- excisions required to achieve clear margins. Conclusion: Interval diagnostic surveillance imaging every 6 months after breast conserving surgery identified almost one-third of the ipsilateral breast tumor recurrences that occurred within the first 2 years after surgery in our population. While our numbers are small, the relationship of re-excision lumpectomy surgery to subsequent risk for local recurrence has been described by others, and bears further study. Particularly in view of our observation that the majority of in-breast recurrences were invasive, our data supports the practice of more frequent imaging follow up in the first 2 years after breast conserving surgery. Citation Format: Pabel Miah, Laura Fiedler, Anthony Baez, Athanasios Sevdalis, Alyssa Marmer, Charles DiMaggio, Linda Pak, Richard Shapiro, Karen Hiotis, Deborah Axelrod, Amber Guth, Freya Schnabel. The Impact of Bi-Annual Diagnostic Imaging on Detecting Ipsilateral Breast Recurrence in Patients Undergoing Breast Conserving Surgery for Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-23-05.

Abstract PO5-08-09: Li Fraumeni Syndrome in Breast Cancer Patients of Ceará/Brazil: correlations of genotype - fenotype

Abstract Introduction: Li Fraumeni Syndrome (LFS) is a rare condition determined by germline mutation of TP53 gene. LFS has penetrance near 100% with a broad spectrum of malignances such as breast, lung, sarcomas, choroid plexus, adrenocortical carcinomas, gliomas, leukemia and other starting from early childhood. Breast cancer is the most frequent cancer type of adults with LFS, followed by soft tissue sarcomas. Individuals with LFS has an aggressive prognosis of multiple neoplasms lifetime. In Brazil the most described variant of TP53 is c.1010G >A; p.R337H (the Brazilian variant). This variant affects predominantly individuals of South and Southeastern regions. Usually presents with the same spectrum of tumor of other variants however R337H presents lower penetrance, higher frequency of adrenocortical carcinomas, later onset of tumors. Ceará is a northeastern state of Brazil highly miscegenated distinct from populations of South where predominates European colonization. At Ceará originals there are no description of R337H. The present study describes Clinical and tumoral caractheristics of breast cancer patients with LFS of Cancer Reference Center of Ceará. Methods: from 2018 to 2021 breast cancer patients admitted in Instituto do Câncer do Ceará-ICC filling NCCN criteria for hereditary breast cancer were screened for germline variants. After assigned consent it was offer NGS germline genetic panel of 33 genes and clinical and pathologic data were recorded. Results: 460 BC patients were recruited, of them 6 had germline pathogenic mutation of TP53. Table 1 list these women and their variants. The mean age of the first tumor was 30 years (range 18-44), only one patient had no knowledge of familiar history (HF) of child and adults cancer, all the other listed HF of early onset of breast cancer, lung cancer, osteosarcoma, rabdomyosarcoma, GBM and gastrointestinal cancers. One had bilateral metachronic breast cancer, 3 of them had HER2 positive tumor, 1 had a metaplasic TNBC, and 1 had a Luminal B tumor. 2 variants were not found at populational database (a exons 2-10 microdeletion and a c.637C >T variant). About half of relatives recruited for genetic test confirmed to the carriers and 3 of them developed neoplasms (GBM and breast cancer). Two patient had early recurrence (one of them had a third tumor of ovarian – carcinosarcoma) and died at age of 30 and 39 years old. Conclusion: The Northeast of Brazil has a distint clinical and genetic pattern of LFS from the South. No R337H variant were found in our population. We identified different variants in all patients with LFS. The BC subtype more commom was HER2 positive. The bias of our study is the original objective that evolved determination of prevalence of hereditary breast and ovarian cancer. Based on these results we are now recruiting exclusively cancer patients with clinical criteria for LFS. Table 1 - LFS patients caractheristics Citation Format: Rosane Sant' Ana, Isabelle Joyce Fernandes, Maria Claudia Luciano, Maria Julia Bezerra, Flavio Bitencourt, Clarissa Albuquerquye, Paulo Goberlanio Silva, José Fernando De Moura, Francisca Fernanda Oliveira. Li Fraumeni Syndrome in Breast Cancer Patients of Ceará/Brazil: correlations of genotype - fenotype [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 PO5-08-09.

Abstract PO1-20-01: A Prospective Single-Arm Pilot Interventional Trial to Assess Individual Breast Cancer Risk Prior to Gender-Affirming Chest Masculinization Surgery

Abstract Background: The number of individuals who identify as transgender and/or gender-diverse (TGD) is steadily increasing and the number of individuals seeking chest masculinization surgery, commonly called “top-surgery,” is also increasing. In persons assigned female at birth, top surgery removes most breast tissue to allow the chest to appear masculine. However, top surgery is not equivalent to oncologic risk-reducing mastectomies (RRM), which aim to remove all breast tissue to reduce future breast cancer (BC) risk. While top surgery has significant psychological and health benefits, its impact on future BC risk is unclear, especially for those individuals who are at high-risk for future BC development (defined as ≥17% by international consensus guidelines) and/or have a pathogenic germline mutation for BC. The aims of this study are to 1) determine the percentage of TGD persons assigned female at birth who are considering undergoing top surgery and are at elevated BC risk using validated risk models, 2) determine the percentage of TGD persons at elevated BC risk who choose to undergo RRM as part of top surgery, and 3) assess and compare self-perceived BC risk compared to calculated risk. Methods: A single-institution prospective single-arm pilot study is currently underway from March 2023 through January 2024. Individuals assigned female at birth, who are age ≥18 years, and considering undergoing top surgery, but have not yet undergone top surgery, are eligible to enroll (goal accrual N=35). Participants are being actively recruited form our institution’s Comprehensive LGBTQIA+ Inclusion Health Clinic and Plastic Surgery Clinic. Consented participants undergo a personalized BC risk assessment the validated IBIS and Gail (for those ≥35 years old) BC risk models. Those with an average lifetime BC risk (< 17%) are recommended to continue top surgery as planned/no intervention, participants with a moderate lifetime BC risk (17-30%) are counseled they may consider RRM as part of their top surgery operation given that sparse data exists in this space, while those with a high lifetime BC risk ( >30% or pathogenic germline variant) are counseled on the potential benefits of RRM. Participants with a family history suggestive of a hereditary cancer syndrome meet with a certified Genetics counselor for consideration of genetic testing, per NCCN guidelines. Results: We anticipate reporting 1) general demographic description of the cohort, 2) the percentage who have an elevated lifetime BC risk and/or a pathogenic genetic mutation, 3) the percentage of those with an elevated risk who choose to undergo RRM as part of top surgery, and 4) report the differences between self-perceived vs calculated lifetime BC risk. Conclusion: Our findings will inform TGD persons and surgeons on the utility of a personalized BC risk assessment prior to top surgery to assist in surgical decision-making, report the accuracy of self-perceived BC risk in TGD persons, and potentially change the standard pre-operative evaluation for TGD persons considering top surgery to include a formal BC risk assessment to ensure high-risk individuals have the option to undergo RRM to appropriately reduce their future BC risk. Citation Format: Chandler Cortina, Anna Purdy, Samantha Stachowiak, Kristen Klement, Sarah Sasor, Kate Krucoff, Andrew Petroll, Kevin Robertson, Annie Lakatos, Erin Doren. A Prospective Single-Arm Pilot Interventional Trial to Assess Individual Breast Cancer Risk Prior to Gender-Affirming Chest Masculinization Surgery [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 PO1-20-01.

Abstract PO1-09-02: Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to patients

Abstract Background: For newly diagnosed breast cancer (BC) patients, identification of pathogenic germline mutations in hereditary breast cancer (HBC) genes can inform clinical management and risk mitigation strategies and identify patients who would benefit from targeted therapy and clinical trials. Offering germline testing based on NCCN or other guidelines fails to identify all patients with germline HBC gene mutations, potentially with adverse consequences for patients and their families. As an integral part of the study, we have explored the acceptance of universal testing among patients and clinicians. Methods: This is the largest Australian multi-centre prospective study exploring the prevalence of hereditary pathogenic variants in the Australian BC population. 650 newly diagnosed consecutive, consented patients with non-metastatic breast cancer or high-grade DCIS were recruited from May 2020 to March 2023 in 2 phases. Phase 1 (n=157) offered a combination of germline and somatic sequencing. Germline testing was performed by whole genome sequencing on DNA from blood or saliva, and the data analyzed for actionable HBC gene mutations, including large genomic rearrangements. Germline variants were interrogated for pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51B, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, CDH1, PTEN, STK11, TP53 and NTHL1.Tumour sequencing will be reported separately. Phase 2 (n=493) included germline exome sequencing with no somatic sequencing. The objectives were to assess the additional actionable HBC gene mutations identified by universal testing compared to algorithmic based (MANCHESTER and BOADICEA scores) and NCCN guidelines, the clinical impact of this identification and the prevalence of germline mutations in the general BC population. A 3-generation pedigree was constructed for every patient for accurate estimation of NCCN, MANCHESTER, and BOADICEA scores. Phase 1 patients completed surveys of perceptions of universal testing, psychological distress and cancer-specific worry pre- and post-testing. Results: 50 carriers of actionable germline mutations were identified: (7.7%). BRCA1 (n=10), BRCA2 (n=12), PALB2 (n=7), CHEK2 (n=10), ATM (n=4), PMS2 (n=2), MSH6 (n=1), RAD51C (n=2), and BARD1 (n=3). One carrier had both PALB2 and CHEK2 mutations. Updated NCCN guidelines (2023 version) identified 44/50 pathogenic germline variant carriers (88%). The BOADICEA and MANCHESTER scores only identified 22 carriers (44%). Immediate clinical management changed due to the discovery of HBC gene in 40/50 (80%). Among 105 participants, cancer-specific distress declined from pre- to post-testing. Anxiety, stress and depression did not change. 90/103 participants agreed that genetic testing should be routine, 100/104 reported their decision to undergo testing as correct. All (n=25) BC clinicians reported that genetic test results were helpful for important treatment decisions and none that testing was distressing to patients. Conclusion: HBC gene mutation prevalence was 7.7%. Universal germline HBC gene testing is the best method for detecting carriers. Current testing guidelines would have missed HBC genes which would have impacted clinical management. Updated NCCN guidelines were sensitive in the detection of HBC gene mutation, but more than half of HBC gene mutations were missed by Australian standards. Discovery of HBC gene mutations led to changed management in most cases. Universal testing is highly acceptable to clinicians and patients who reported no adverse impact on psychological distress or cancer-specific worry and no decision regret. Germline mutations identified and their impact on management Citation Format: Dilanka De Silva, Lesley Stafford, Anita Skandarajah, Michelle Sinclair, Lisa Devereux, Kirsten Hogg, Maira Kentwell, Allan Park, luxi Lal, Magnus Zethoven, Madawa Jayawardena, Fiona Chan, Paul James, Geoffrey Lindeman, Ian Campbell, Bruce Mann. Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to 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 PO1-09-02.

A Modular Trial of Androgen Signaling Inhibitor Combinations Testing a Risk-Adapted Strategy in Patients with Metastatic Castration-Resistant Prostate Cancer.

To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers (mCRPC). In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone and apalutamide (AAPA; Module 1), then allocated to Modules 2 or 3 based on Satisfactory (≥50% PSA decline from baseline and <5 CTC/7.5 mL) versus Unsatisfactory status. Men in the former were randomized to continue AAPA alone (Module 2A) or with ipilimumab (Module 2B). Men in the latter had carboplatin+cabazitaxel added to AAPA (Module 3). Optional baseline biopsies were subject to correlative studies. Median overall survival (from allocation) was 46.4 (95% CI 39.2, 68.2), 41.4 (95% CI 33.3, 49.9) and 18.7 (95% CI 14.3, 26.3) months in Modules 2A (n=64), 2B (n=64) and 3 (n=59) respectively. Toxicities were within expectations. Of 192 eligible patients, 154 (80.2%) underwent pre-treatment metastatic biopsies. The aggressive variant prostate cancer molecular profile (defects in ≥2 of p53, RB1, and PTEN) was associated with Unsatisfactory status. Exploratory analyses suggested SPP1+ and IGFBP2+ macrophages, druggable myeloid cell markers, and germline pathogenic mutations were enriched in the Unsatisfactory group. Adding ipilimumab to AAPA did not improve outcomes in men with androgen responsive mCRPC. Despite the addition of carboplatin+cabazitaxel, men in the Unsatisfactory group had shortened survivals. Adaptive designs can enrich for biologically and clinically relevant disease subgroups, to contribute to the development of marker-informed, risk-adapted therapy strategies in men with prostate cancer.

Clinical features of patients with metastatic pheochromocytoma/paraganglioma

Objective: To analyze the clinical features of patients with metastatic pheochromocytoma/paraganglioma (PPGL). Methods: A follow-up study. The clinical data of 250 patients with metastatic PPGL treated at Peking Union Medical College Hospital from January 2018 to August 2023 were retrospectively analyzed, including 124 males and 126 females. The clinical features and treatment status of patients with metastatic PPGL were summarized and analyzed. Kaplan-Meier survival curve was used to evaluate patients' prognosis. Results: The age of onset, age of diagnosis, and age of tumor metastasis in patients with metastatic PPGL were (33.1±14.2) years, (35.4±15.2) years, and (40.7±15.3) years, respectively. Metastasis occurred in 26.4%(66/250) of patients at the time of initial diagnosis. Among patients without metastases at the time of initial diagnosis, the time from primary tumor resection to metastasis[M(Q1, Q3)] was 5.0 (3.0, 9.0) years, among which 20.1%(37/184) of patients had metastases more than 10 years after surgery. Most patients showed increased 24-hour urinary norepinephrine and plasma normetanephrine, accounting for 78.2%(176/225) and 78.7%(85/108), respectively. 42.3%(69/163) of patients had increased neuron specific enolase (NSE)levels. Germline mutations were screened in 201 patients, of which 55.2%(111/201) had germline pathogenic mutations. In patients with gene mutations, 76.5%(85/111) had SDHB mutations. 52.0%(130/250) of metastatic PPGL patients had primary sites outside the adrenal gland, with the Ki-67 index of 5% (3%, 8%). There were 85.6%(214/250) patients had multisystem metastasis, with bone metastasis being the most common site of metastasis, accounting for 60.8%(152/250). In terms of treatment, 32.8%(75/229) of patients underwent two treatment regimens and 8.7%(20/229) of patients underwent three treatment regimens. Most patients had a good prognosis, with a 5-year and 10-year survival rate of 88.0% and 84.0%, respectively. However, some patients had rapid disease progression, and as of August 2023, 30 patients died, and the time from diagnosis to death in deceased patients was 2.0 (1.0, 4.0) years. Conclusions: Patients with metastatic PPGL have a high rate of germline mutations, especially those with SDHB mutations. The metastatic PPGL is usually multisystem metastasis with the characteristics of mostly paraganglioma, large lesion diameter and high Ki-67 index.

Immunohistochemical findings and clinicopathological features of breast cancers with pathogenic germline mutations in Non-BRCA genes

Deleterious germline mutations in multiple genes confer an increased breast cancer (BC) risk. Immunohistochemical (IHC) expression of protein products of mutated high-risk genes has not been investigated in BC. We hypothesized that pathogenic mutations may lead to an abnormal IHC expression pattern in the tumor cells. BCs with deleterious germline mutations in CHEK2, ATM, PALB2 &PTEN were identified. Immunohistochemistry was performed using Dako staining platform on formalin fixed paraffin embedded tumor tissue. Primary antibodies for PALB2 (ab202970), ATM [2C1(1A10)}, CHK2 (EPR4325), and PTEN (138G6) proteins were used for BCs with respective deleterious mutations. IHC expression was assessed in tumor and adjacent benign breast tissue. Total 27 BCs with 10 CHEK2, 9 ATM, 6 PALB2 & 2 PTEN deleterious germline mutations were identified. IHC staining was performed on 8 CHEK2, 7 ATM, 6 PALB2 & 2 PTEN cases. Abnormal CHEK2 IHC staining was identified in 7/8(88%) BCs. Three distinct CHK2 IHC patterns were noted: 1) Strong diffuse nuclear positivity (5 BC), 2) Null-pattern (2 BC), & 3) Normal breast–like staining in 1 BC Four of 5 (80%) strong CHK2 staining BC had missense CHEK2 mutations. Null-pattern was present with a missense & a frameshift mutation. Normal breast-like CHEK2 IHC staining pattern was present in 1 BC with CHEK2 frameshift mutation. Loss of nuclear/cytoplasmic PTEN IHC expression was noted in 2 in-situ carcinomas. Abnormal PTEN and CHK2 IHC were present in atypical ductal hyperplasia and flat epithelial atypia. ATM and PALB2 IHC expression patterns were similar in tumor cells and benign breast epithelium: mild to moderate intensity nuclear and cytoplasmic staining. We report abnormal CHEK2 IHC expression in 88% of BCs with pathogenic CHEK2 mutations. With PTEN and CHEK2 pathogenic mutations, abnormal IHC patterns are seen in early atypical proliferative lesions. IHC may be applied to identify CHEK2 &PTEN mutated BCs and precursor lesions.

Abstract 1757: Pan-cancer analysis identifies signatures of HRD-positivity in germline BRCA1/2 mutated non-BRCA associated cancers

Abstract Introduction: BRCA-associated cancers (breast, ovarian, pancreas, and prostate) with germline pathogenic mutations in BRCA1/2 (gBRCA1/2) are associated with homologous recombination deficiency (HRD) and benefit from platinum/PARPi. However, the role of gBRCA1/2 in non-BRCA assoc. cancers is poorly understood. HRD tumors present with ‘genomic scars’ that can be quantified in tumor profiling (“HRD-sum” score). We reasoned that the HRD-sum score together with germline mutation status (including loss of wild-type) is a strong correlate of HRD-positivity. Leveraging 42,448 prospectively sequenced patients across 63 cancer types, we sought to characterize the prevalence of the HRD-positivity in non-BRCA-assoc. cancers. Methods: Allele-specific copy number data was inferred using FACETS. HRD-sum was calculated as a sum of the numbers of telomeric imbalances, large-scale transitions and genome-wide losses of heterozygosity. Calculating each score was iteratively optimized to improve detection of the scars using MSK-IMPACT targeted sequencing data using patient-matched WES data from 1841 tumors as reference. Germline mutations were identified by a clinically validated pipeline and annotated for pathogenicity using ClinVar. After excluding low quality tumors, 27,375 patients were retained for analysis. “HRD-positive” tumors are those with gBRCA1/2 mutations, loss of wild type, and an HRD-sum score &amp;gt;=42. Results: Expectedly, gBRCA1/2 mutations were more frequent in BRCA-assoc. cancers (7.2%, 558 of 7,737 patients) compared to non-BRCA-assoc. cancers (2.6%, 500 of 19,638) (p=5e-60). Among non-BRCA-assoc. cancers, gBRCA1/2 were most common in esophagogastric (3.9%), lung (3%), hepatobiliary (2.9%), and bladder (2.8%) cancers. Although biallelic loss in gBRCA1/2 patients was sig. higher in BRCA-assoc. cancers (80% vs. 37% in non-BRCA-assoc.), several cancer types showed high rates of loss of wild-type including gBRCA1 tumors in hepatobiliary (5/5) and endometrial (10/11) cancers. HRD-sum scores in all gBRCA1/2 biallelic tumors were sig. higher (median 58) compared to monoallelic (26) or wild-type (25) tumors. Notably, the non-BRCA assoc. cancers with biallelic gBRCA1/2 harbored higher HRD-sum scores compared to monoallelic (median 51 vs. 22, p&amp;lt;0.0001). These include cancer types such as endometrial (64 vs. 37, p= 0.0014) and esophagogastric (62 vs. 45, p=0.0017). In all, 68% of gBRCA1/2 patients in BRCA-assoc. cancers showed HRD-positivity. Interestingly, 18% (91/500) of gBRCA1/2 patients in non-BRCA-assoc. cancers also showed HRD-positivity. These included 52% of esophagogastric, 28% of lung, and 22% of bladder cancer patients with gBRCA1/2. Conclusion: Using a robust measure to detect HRD scars from MSK-IMPACT panel data, we demonstrate evidence for BRCA-mediated tumorigenesis in an expanded spectrum of cancers with potential therapeutic relevance. Citation Format: Daniel M. Muldoon, Miika Mehine, Samuel Tischfield, A. Rose Brannon, Marc Ladanyi, Zsofia K. Stadler, David B. Solit, Alexander Drilon, Michael F. Berger, Yonina Murciano-Goroff, Chaitanya Bandlamudi. Pan-cancer analysis identifies signatures of HRD-positivity in germline BRCA1/2 mutated non-BRCA associated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1757.

Whole-Genome Sequencing Analysis of Male Breast Cancer Unveils Novel Structural Events and Potential Therapeutic Targets

The molecular characterization of male breast cancer (MaBC) has received limited attention in research, mostly because of its low incidence rate, accounting for only 0.5% to 1% of all reported cases of breast cancer each year. Managing MaBC presents significant challenges, with most treatment protocols being adapted from those developed for female breast cancer. Utilizing whole-genome sequencing (WGS) and state-of-the-art analyses, the genomic features of 10 MaBC cases (n = 10) were delineated and correlated with clinical and histopathologic characteristics. Using fluorescence in situ hybridization, an additional cohort of 18 patients was interrogated to supplement WGS findings. The genomic landscape of MaBC uncovered significant genetic alterations that could influence diagnosis and treatment. We found common somatic mutations in key driver genes, such as FAT1, GATA3, SMARCA4, and ARID2. Our study also mapped out structural variants that impact cancer-associated genes, such as ARID1A, ESR1, GATA3, NTRK1, and NF1. Using a WGS-based classifier, homologous recombination deficiency (HRD) was identified in 2 cases, both presenting with deleterious variants in BRCA2. Noteworthy was the observation of FGFR1 amplification in 21% of cases. Altogether, we identified at least 1 potential therapeutic target in 8 of the 10 cases, including high tumor mutational burden, FGFR1 amplification, and HRD. Our study is the first WGS characterization of MaBC, which uncovered potentially relevant variants, including structural events in cancer genes, HRD signatures, and germline pathogenic mutations. Our results demonstrate unique genetic markers and potential treatment targets in MaBC, thereby underlining the necessity of tailoring treatment strategies for this understudied patient population. These WGS-based findings add to the growing knowledge of MaBC genomics and highlight the need to expand research on this type of cancer.

Natural History of Germline BRCA1 Mutated and BRCA Wild-type Triple-negative Breast Cancer.

In germline BRCA1 mutated and BRCA wild-type patients, TNBC shows a branching evolutionary pattern of mutations with a single founding clone, are polyclonal throughout their disease course, and have widespread copy-number aberrations. This evolutionary pattern may be associated with treatment resistance or sensitivity and could be therapeutically exploited.

A311 EFFICACY OF PANCREATIC CANCER SCREENING IN HIGH RISK INDIVIDUALS

Abstract Background Pancreatic cancer (PC) is the 11th most prevalent cancer in Canada with about 6900 new cases in 2021. Due to late diagnosis, it is the 4th largest cause of cancer related mortality in Canada. Despite advances in diagnosis and treatment over the past decade, the 5-year survival remains ampersand:003C10%, making pancreatic cancer one of the most lethal malignancies worldwide. However, if detected early, the 5-year survival increases to 80%. The incidence of pancreatic cancer remains low. Therefore, the International Cancer of the Pancreas Screening (CAPS) consortium do not recommend screening everyone. Selective screening in high-risk individuals may be effective in early detection and treatment of pancreatic cancer. Aims 1. To determine the characteristics of patients undergoing PC screening at a single tertiary care center in Vancouver. 2. To determine the frequency of disease progression and outcomes in patients diagnosed with high-risk lesions during screening. Methods Retrospective chart review was performed for patients who were screened between January 1, 2005 to June 30, 2023. As per consensus from the CAPS Consortium, patients with at least 2 close relatives with PC, and those with predisposing genetic mutations screened using endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) were included in the study. Clinical data, such as age, tobacco use, genetic risk, endoscopic findings, and outcomes, such as disease progression, were collected. Statistical analysis was performed using Rstudio and Microsoft Excel. Results 73 patients were included, with 42 included due to pathogenic germline mutations, and 31 with familial pancreatic cancer. Most were female (52, 71.2%). Median age in the study was 54 years (range 24-74 years) at initial screening. 66 patients (90.4%) received an EUS and 7 patients (9.6%) received MRI for initial screening. At the time of initial screening. 74.6% of patients had a normal pancreas. 6 patients (8.2%) were found to have neoplastic lesions, e.g. ampulloma, neuroendocrine tumour or adenocarcinoma at initial screening and referred for surgery. In the median follow up time of 67.9 months (range 0-168.1 months), 6 patients were noted to have disease progression, 4 of which had increase in cyst size without any other worrisome features. 2 patients had progression to malignancy. 1 of those patients received chemotherapy and surgical resection and remains alive; the other patient was lost of follow up due to geographical move. Conclusions Pancreatic cancer screening in high risk individuals is effective in early detection and treatment. Given lower incidence of pancreatic cancer, we likely need additional patient enrolment to observe a significant improvement in patient outcomes. Funding Agencies None

Germline mutations in patients with metastatic prostate cancer: A prospective cohort study in South Korea (KCSG GU20-19).

193 Background: Several clinical guidelines recommend screening for hereditary prostate cancer in high-risk groups for metastatic prostate cancer. However, despite the recent increase in the diagnosis of prostate cancer in Korea, genetic testing for hereditary prostate cancer is not being performed, making it impossible to know the frequency of hereditary prostate cancer. This study aimed to determine the prevalence of germline mutations in unselected Korean patients with metastatic prostate cancer. Methods: Between July 2021 and December 2022, metastatic prostate cancer patients were enrolled prospectively, without any specific selection based on age or family history. Germline mutation analysis was performed on DNA from blood via next generation sequencing using SOLIDaccuTestTM DNA HRD (NgeneBio, Korea). Results: A total of 301 patients were enrolled and the prevalence of germline mutation was analyzed. At diagnosis, the median age was 67 (46-91 years old), and the median PSA was 150 ng/mL (3.07-5000). 250 patients had a Gleason score of 8 or higher. 36 patients (12.0 %) carried a pathogenic (14/301, 4.6 %)/likely pathogenic (22/301, 7.3 %) variant in a germline mutation. Of these patients, 11 patients (3.65 %) had BRCA2 mutations. ATM (6/301, 1.99 %) was the second most frequently mutated gene, followed by FH (4/301, 1.33 %), FANCA, FANCD2, MRE11, SLFN11, SMO (0.66 % of each, 2/301), BLM, CHEK2, ERBB3, MAP2K1, and VHL (0.33 % of each, 1/301). Further analysis will be conducted to evaluate the impact of germline mutations on somatic mutation results, treatment patterns, and clinical outcomes. Conclusions: The prevalence of pathogenic germline mutations among unselected Korean patients with metastatic prostate cancer was 12.0 %. Germline mutation prevalence in this cohort was comparable to previous reported results. This study provides the framework for the development of preventive and treatment strategies based on hereditary genetic factors for prostate cancer in the Korean population. [Table: see text]

Abstract C104: Dual primary pancreas cancers – Related or independent lesions?

Abstract Background: Not infrequently, an apparent second pancreas ductal adenocarcinoma (PDAC) is identified either synchronously or metachronously. To date, it remains unclear whether these individual PDACs represent intrapancreatic metastases or a new primary PDAC. Here, we sought to understand the clinicogenomic features of this patient population to provide insights on the underlying biology and management implications. Methods: Memorial Sloan Kettering Cancer Center (MSK) institutional databases were searched for patients with two PDAC diagnoses and at least one pancreatic resection or patients who had undergone completion/total pancreatectomy and then manually curated. Detailed demographic and clinical information were abstracted from the medical record. Metachronous patients excluded if previous surgical margin positive for invasive or pre-invasive carcinoma. All patients were either consented to MSK IMPACT for somatic and germline sequencing (N=16), were approved for de-identified genomic analyses by IRB (N=3), or were excluded from genomic analysis (N=2). KRAS wild-type (WT) tumors were interrogated for targetable fusions with Archer FusionPlex solid tumor panel. Results: N=21 patients (pts) identified, N=6 synchronous, N=15 metachronous. Mean age at diagnosis of first PDAC (PDAC1): 67.1y (51.2–79.1y). PDAC risk factors: 52% (10/19) smoking history, 15% (2/13) with first degree relative with PDAC, 85% (11/13) with first degree relative with any malignancy, and 40% (8/20) with history of premalignant pancreas lesion. N=2 pts with pathogenic germline mutation in ATM. By morphology, 80% (4/5) of synchronous and 65% (11/17) of asynchronous lesions indistinguishable. Two lesions, both metachronous, demonstrated divergent histology while remaining cases demonstrated focal differences. Genomically, 40% (10/25) samples with mKRAS G12V, G12R (16%), G12D (12%), Q61H (8%), G12C (4%); 20% KRAS WT. Of available paired tumor samples, 71% (5/7) with identical KRAS alleles and additional driver mutations. N= 1 pt with different KRAS alleles also had divergent TP53 alleles and CDKN2A/B loss occur in metachronous lesions 14 m apart. N=1 pt with KRAS WT tumor had an actionable fusion involving FGFR2. For metachronous lesions, median interval PDAC1 to PDAC2: 5.1 y (1.1 – 15.2 y). At median follow-up of 7.2 y (0.2 – 15.4 y) from PDAC1, 90% (19/21) have undergone completion/total pancreatectomy and N=16 (76%) alive with 5-year survival rate of 93% (14/15). Conclusions: The clinical, pathologic, and genomic data strongly suggest that two PDAC, independent of disease interval, most often represent the same phylogenetic entity. KRAS allele variant adjudication was the single most important discriminator and was in concordance with other driver oncogenes. Pathogenic germline variants were rare and limited to gATM; notably no gBRCA/PALB2. Acknowledging the highly selected nature of this cohort, solitary intrapancreatic metastases demonstrate a more favorable biology and these patients may benefit from personalized management approaches beyond traditional paradigms. Citation Format: Joshua D. Schoenfeld, Hulya Sahan-Ozkan, Nadeem Bilani, Michael I. D'Angelica, William R. Jarnagin, Jeffrey Drebin, Diane Reidy-Lagunes, Alice C. Wei, Sree B. Chalasani, Anna M. Varghese, Fiyinfolu Balogun, Wungki Park, Kenneth H. Yu, Olca Basturk, Eileen M. O'Reilly. Dual primary pancreas cancers – Related or independent lesions? [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C104.

The structure of TRAF7 coiled-coil trimer provides insight into its function in zebrafish embryonic development.

TRAF7 serves as a crucial intracellular adaptor and E3 ubiquitin ligase involved in signal transduction pathways, contributing to immune responses, tumor progression, and embryonic development. Somatic mutations within the coiled-coil (CC) domain and WD40 repeat domain of TRAF7 could cause brain tumors, while germline pathogenic mutations contribute to severe developmental abnormalities. However, the precise molecular mechanism underlying TRAF7 involvement in embryonic development remains unclear. In this study, we employed zebrafish as an in-vivo model system. TRAF7 knockdown caused defects in zebrafish embryonic development. We determined the crystal structure of TRAF7 CC domain at 3.3Å resolution and found that the CC region trimerization was essential for TRAF7 functionality during zebrafish embryonic development. Additionally, disease-causing mutations in TRAF7 CC region could impair the trimer formation, consequently impacting early embryonic development of zebrafish. Therefore, our study sheds light on the molecular mechanism of TRAF7 CC trimer formation and its pivotal role in embryonic development.

Real-world prevalence of homologous recombination repair mutations in advanced prostate cancer: an analysis of two clinico-genomic databases.

Homologous recombination repair mutation (HRRm) status may guide risk-stratification and treatment decisions, including polyadenosine diphosphate-ribose polymerase inhibitor use, in advanced prostate cancer. Although HRRm prevalence has been reported in single-institution studies or clinical trials, real-world HRRm prevalence in diverse populations is unknown. We describe HRRm in the clinical setting using two real-world clinicogenomic databases: the Flatiron Health and Foundation Medicine, Inc. Clinico-Genomic Database (CGDB), a national electronic health record-derived database, and the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE). This cross-sectional analysis included 3757 individuals diagnosed with prostate cancer who had next generation sequencing (NGS) as standard of care. The CGDB included men with advanced/metastatic prostate cancer and genetic data included both germline and somatic pathogenic mutations. The GENIE analysis included men with prostate cancer whose received NGS as standard of care, but the data were filtered to include somatic mutations only. Due to key differences among databases, direct comparisons were not possible. Overall prevalence of HRRm was calculated and stratified by demographic and clinical characteristics. HRRm prevalence (combined germline and somatic) in CGDB (n = 487) was 24.6% (95% CI 20.9-28.7%), with no major differences across demographic and disease characteristic subgroups. HRRm prevalence (somatic) in GENIE (n = 3270) was 11.0% (95% CI 10.0-12.1%), which varied between 9.5% and 18.4% across treatment centers. Approximately one-quarter of patients with advanced/metastatic prostate cancer in the CGDB had germline and/or somatic HRRm, which is consistent with clinical trials such as the PROfound study that used a similar NGS platform and algorithm to define HRRm. In the GENIE database, HRRm prevalence varied by treatment center or NGS platform. More research is needed to understand real-world HRRm prevalence variations.