Citations

Abstract Background: Pathogenic variants (PVs) in PALB2 are known to confer high-to-moderate risk for breast cancer. However, breast cancer risk estimates for PALB2 PVs for different populations are not well defined and associations with other cancers are still unclear. Using data from a large clinical genetic testing cohort we have established cancer-specific risks associated with PALB2 PVs. Methods: We analyzed the associations of PALB2 PVs with breast, ovarian, prostate, and pancreatic cancers in individuals tested at Ambry Genetics. Cancer-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated by comparing PV carrier frequencies in cancer cases to population controls from AllofUs matched by sex and adjusting for age and genetic ancestry and gnomAD v4.1 matched by sex and adjusting for ancestry. Two-sided p-values are reported. Results: Of 1,119,667 individuals tested, 357,109 had breast cancer, 37,468 ovarian cancer, 22,112 pancreatic cancer and 32,738 prostate cancer. PALB2 PVs were observed in 0.79% of breast cancer cases, 0.30% of ovarian cancer cases, 0.78% of pancreatic cancer cases, and 0.47% of prostate cancer cases, with mean age at diagnosis of 54.2 years for breast, 60.1 years for ovarian, 62.8 years for pancreatic and 66.7 years for prostate. Whereas only 2.4% of breast cancer cases with PVs had a personal history of ovarian or pancreatic, 13.4% of ovarian cases and 33.3% of pancreatic cases had a history of breast cancer. Analysis of PV types found that frameshift PVs accounted for 50% of PVs, nonsense for 30%, canonical splice sites for 5% and copy number variants for 8-9% of cases in all cancer types. Among 10,077 individuals with multiple primary cancers, PALB2 PVs were detected in 0.65% of cases, with the highest frequencies observed in combinations of breast and pancreatic cancer (1.87%) and pancreatic and prostate cancer (0.79%). To refine estimates of risks for breast cancer, association studies were performed separately with GnomAD v4.1 and AllofUs controls. PALB2 PVs were consistently associated with high risks of breast cancer with lower 95%CI above 4 (GnomADv.4.1 OR=6.85, 95%CI=5.94-7.96, p=3.05x10-145; AllofUs OR=5.65, 95%CI=4.83-6.65, p=2.54x10-155). This was significantly different and increased over breast cancer risk estimates from the CARRIERS and BRIDGES population-based studies (OR=4.67, 95%CI=3.73-5.85, p=3.95x10-27) and the UK Biobank population-based study (OR=3.87, 95%CI=3.09-4.83, p=4.62x10-27). Similarly, high risks of pancreatic cancer were confirmed (GnomADv.4.1 OR=5.14, 95%CI=4.15-6.32, p=3.38x10-52; AllofUs OR=5.59, 95%CI=3.92-7.85, p=2.78x10-18). Importantly, associations between PALB2 PVs and moderate risks of both ovarian cancer (GnomADv.4.1 OR=2.68, 95%CI=2.11-3.40, p=5.94x10-16; AllofUs OR=2.15, 95%CI=1.62-2.85, p=2.97x10-7) and prostate cancer (enriched for aggressive disease) (GnomADv.4.1 OR=2.45, 95%CI=2.01-2.97, p=1.52x10-19) were observed. Conclusions: This large-scale study provides robust estimates of PALB2 PV prevalence and associated cancer risks in a U.S. clinical genetic testing population. The findings provide refined risk estimates for breast and pancreatic cancers but also establish that PALB2 PVs confer increased risk for ovarian and prostate cancers. These results help clarify ongoing uncertainty, particularly for ovarian and prostate cancer, and highlight the importance of PALB2 in broader hereditary cancer risk assessment and multigene panel testing. Citation Format: Y. Y. Tan, C. Hu, H. Huang, N. J. Boddicker, W. Chen, M. Kaul, T. J. Rao, A. N. Monteiro, T. Pesaran, R. Karam, S. M. Domchek, S. Yadav, M. E. Richardson, F. J. Couch. Cancer-specific risks associated with germline PALB2 pathogenic variants from a large clinical genetic testing cohort [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF5-01.

Abstract Background & Aims Pregnancy can be a complex and risk-filled event for women with inflammatory bowel disease (IBD). High-quality studies in this population are lacking, with limited data on medications approved to treat IBD during pregnancy. For patients, limited knowledge surrounding pregnancy impacts pregnancy rates, medication adherence, and outcomes. Limited provider knowledge leads to highly varied practices in care affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike. The Global Consensus Consortium is a group of 39 IBD and content experts and 7 patient advocates from 6 continents who convened to review and assess current data and come to an agreement on best practices based on these data. Methods The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) process was used when sufficient published data were available and the RAND (Research and Development) process in those instances where expert opinion was needed to guide consistent practice. Recommendations were informed by the guiding principle that maternal health best supports infant health. Results The topics were divided into ten categories with 34 GRADE recommendations and 35 consensus statements. Conclusions Overall, the goal of the group was to provide data-driven and practical guidance to improve the care of women with IBD around the globe based on the best available research.

Abstract Background Children with inflammatory bowel disease (IBD) may have diminished serologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and increased risk for subsequent severe coronavirus disease 2019 (COVID-19) infection. We sought to describe outcomes among those who developed SARS-CoV-2 infection following vaccination, characterize SARS-CoV-2 antibodies 1 year post-vaccination, and identify factors associated with durable serologic response. Methods We recruited children with IBD who received ≥2 doses of SARS-CoV-2 vaccine and prospectively collected data on (1) demographics, IBD characteristics, and therapy and (2) SARS-CoV-2 vaccination, testing, and infection symptoms. Serum was obtained for measurement of anti-receptor-binding domain IgG antibodies following a 2-part immunization at 12 and 52 weeks. Results We enrolled 298 participants (mean age 11.9 ± 3.82, 50% female, 67% Crohn’s disease). Symptomatic COVID-19 infection after vaccination occurred in half of the participants, although only 2 (1%) required hospitalization. Anti-tumor necrosis factor alpha (TNF-α) was associated with higher likelihood of symptomatic COVID-19 infection, with an adjusted hazard ratio of 2.7 (95% CI, 1.5-5.0; P = .001). Nearly all participants (99%) had detectable antibody at Week 52. Children aged 1-5 years had lower 52-week antibody level compared to older children (P = .04), as did those on anti-TNF-α therapy (P = .007) and those who received only 2 vaccine doses prior to Week 52 (P < .001). Conclusions SARS-CoV-2 vaccination provides lasting serologic response and protection against severe COVID-19 for most children with IBD, despite the use of lower vaccine doses in younger children and wide-ranging classes of immunosuppressive therapies.

INTRODUCTION: Children with inflammatory bowel disease (IBD) may respond differently to COVID-19 immunization as compared with healthy children or adults with IBD. Those younger than 12 years receive a lower vaccine dose than adults. We sought to describe the safety and humoral immune response to COVID-19 vaccine in children with IBD. METHODS: We recruited children with IBD, ages 5–17 years, who received ≥ 2 doses of the BNT162b2 vaccine by a direct-to-patient outreach and at select sites. Patient demographics, IBD characteristics, medication use, and vaccine adverse events were collected. A subset of participants had quantitative measurement of anti-receptor binding domain IgG antibodies after 2-part immunization. RESULTS: Our study population included 280 participants. Only 1 participant required an ED visit or hospitalization because of an adverse event. Of 99 participants who underwent anti-receptor binding domain IgG antibody measurement, 98 had a detectable antibody, with a mean antibody level of 43.0 μg/mL (SD 67) and a median of 22 μg/mL (interquartile range 12–38). In adjusted analyses, older age ( P = 0.028) and antitumor necrosis factor monotherapy compared with immunomodulators alone ( P = 0.005) were associated with a decreased antibody level. Antibody response in patients treated with antitumor necrosis factor combination vs monotherapy was numerically lower but not significant. DISCUSSION: Humoral immune response to COVID-19 immunization in children with IBD was robust, despite a high proportion of this pediatric cohort being treated with immunosuppressive agents. Severe vaccine-related AEs were rare. Overall, these findings provide a high level of reassurance that pediatric patients with IBD respond well and safely to SARS-CoV-2 vaccination.

Lay SummaryWe demonstrate low rates of breakthrough coronavirus disease 2019 (COVID-19) infection and mild course of illness following severe acute respiratory syndrome coronavirus 2 vaccination in a large cohort of inflammatory bowel disease patients. Residence in southern United States and lower median anti-receptor binding antibody level were associated with development of COVID-19.