Adrià López-Fernández

Purpose Breast cancer risk varies widely among women with a pathogenic variant (PV) in a breast cancer susceptibility gene; however, follow-up and prevention strategies are often homogeneous. Polygenic risk scores (PRS) may refine risk stratification. We evaluated changes in breast cancer risk categories and clinical actionability after incorporating PRS into classical risk factors in unaffected carriers. Methods This nationwide multicenter study conducted across Spain included unaffected women carrying a germline PV in a breast cancer susceptibility gene. Ten-year and lifetime breast cancer risk categories were estimated using the BOADICEA model before and after incorporation of the PRISMA-268 PRS. Risk categories were defined according to the NICE thresholds. The primary outcome was change in breast cancer risk category and clinical actionability. Results Among 1,205 women, 577 were non- BRCA1/2 carriers and 628 were BRCA1/2 carriers. PRS incorporation resulted in lifetime-risk reclassification in 31% of non- BRCA1/2 carriers compared with 12% of BRCA1/2 carriers. After PRS integration, 29%, 35%, and 36% of non- BRCA1/2 carriers were classified as having average, moderate, and high lifetime breast cancer risk, respectively. At age 30 years, 61% of non- BRCA1/2/PALB2 carriers would be eligible to initiate breast cancer surveillance. Conclusions Incorporating PRS into multifactorial breast cancer risk assessment significantly modifies risk stratification, particularly among non- BRCA1/2/PALB2 carriers, and provides clinically relevant information to guide personalized prevention and screening strategies.

Genetic testing for cancer susceptibility underpins precision cancer prevention and care. Gaps in the healthcare providers’ genetic literacy and an ambiguous lexicon for variant description may hinder proper delivery and clinical application of consistently trustworthy test results. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) international consortium supports controlled terminology and recommends a framework for reporting germline variants in cancer susceptibility genes, using breast cancer as an exemplar. Moving forward towards terminological coherence across disciplines and borders, the ENIGMA Clinical Working Group launched a multinational effort to release consortium-approved translations of the published recommendations. The herein reported Vocabulary Translation Project offered an opportunity to reappraise and align the reference text to the recent BRCA1 and BRCA2 specifications to the American College of Medical Genetics and Genomics/Association for Molecular Pathology rules by the ENIGMA Variant Curation Expert Panel and to highlight country-specific differences in breast cancer risk assessment and management. The updated recommendations and their 20 translations are now provided as easy to handle documents, covering 11 of the most widely spoken languages in the world. They will contribute to minimised erroneous inferences, more informed decision-making, improved health outcomes and equity in the use of genetic testing for cancer predisposition and in translational oncology.

Effective breast cancer (BC) screening relies on shared decision‐making and clear communication to help patients understand their risk and choose strategies aligned with that risk. The CanRisk tool was used to estimate BC risk in healthy women with a familial history of BC and the absence of a pathogenic variant in BC genes. Results were disclosed to patients using different formats, and data were collected to analyze the association between patient characteristics and risk communication preferences. Participants preferred their risk explained by percentages (59%) over fractions (15%), icon arrays (13%) or risk groups (13%) and 10‐year risk estimation was favored to remaining lifetime risk (71% vs. 22%). Participants highlighted the use of positive and negative formats and comparison with the population's risk formats, and line graphic (61%) was selected over numerical table or a color‐graph (19% each). However, participants with lower numeracy preferred color graphics (OR: 1.42; 95% CI 1.15–1.77 p = 0.001). The use of percentages, line graphics, and 10‐year risk formats are highly accepted for healthy participants with a family history of BC, although adaptation may be needed for those with lower numeracy skills.

Background: Estimating breast cancer risk involves quantifying genetic and non-genetic factors. This supports health interventions and risk communication to ensure adherence to screening recommendations. This study evaluated the change in risk estimation when incorporating breast density and polygenic risk score (PRS) into the baseline cancer risk assessment and compared the efficacy of 2 risk-assessment delivery models. Methods: This 2-step study included 663 healthy women with a family history of breast cancer in which no pathogenic variants were identified. First, breast density and PRS were added to the baseline risk assessment for all participants. A randomized intervention study compared 2 delivery models (in-person vs pre-recorded video) for risk assessment in women at moderate or average risk. All tests were 2-sided. Results: Breast density and PRS reclassified the risk group into 33% of the participants, with only 5% reclassified as high-risk. After disclosure of their estimated multifactorial risk, 65% of women aligned their risk perception with their estimated risk, compared to 47% at baseline (P < .05). No statistically significant differences were found in the primary endpoint cancer worry, mean = 10.2 (SD = 3.1) vs 10.1 (2.7), between delivery models. In-person delivery had slightly better psychological outcomes (excluding the primary outcome) and higher satisfaction, though few participants in the video group sought in-person clarification. Conclusions: Incorporating breast density and PRS into risk assessments led to substantial reclassification, with 1 in 5 women facing de-escalated surveillance. Personalized assessments improve objective perceptions alignment. A model using a pre-recorded video-based model matches in-person delivery for moderate and average-risk women and is scalable for population-level implementation.

The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.

Clinical and familial factors predict psychological distress after genetic testing for cancer susceptibility. However, the contribution of an individual's psychological background to such distress is unclear. This study aims to analyze the psychological impact of genetic testing and to identify the profile of individuals at higher risk. This is a longitudinal multicenter study of individuals undergoing genetic testing for cancer susceptibility. Demographic, clinical, genetic, familial, and psychological (personality types, cancer worry) characteristics were assessed by validated questionnaires the day of genetic testing. Distress, uncertainty, and positive experience perception (MICRA scale) were evaluated at the results disclosure visit, and 3 and 12 months afterwards. Multivariate analysis was performed. A total of 714 individuals were included. A high neuroticism score, high baseline cancer worry, and a positive genetic test result were independently associated with higher psychological impact (p‐value < 0.05). The highest risk profile (10% of the cohort) included women with high level of neuroticism and a positive result. Uncertainty was mainly associated with a high level of neuroticism, regardless of the genetic test result. A holistic approach to personalized germline genetic counseling should include the assessment of personality dimensions.

Background/Objectives: Exome sequencing may identify pathogenic variants unrelated with the purpose of the analysis. We investigated the frequency of secondary and incidental findings (SF/IF) in cancer susceptibility genes (CSG), their clinical actionability and the psychological impact in individuals with an SF/IF (cases) compared with individuals tested due to their cancer history (controls). Methods: This study analysed 533 exomes ordered for non-cancer conditions. Medical records were reviewed for clinical actionability of SF/IF. Psychological impact was analysed using the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale and compared between cases and controls with a propensity score weighting method. Results: The frequency of SF/IF in CSG was 2.1% (95% CI 1.1% to 3.8%): three BRCA2, three PMS2, two SDHB, and one each in BRCA1, MLH1 and RAD51C. Among the relatives, 18 were carriers. Twenty enrolled for surveillance, and a neoplasm was diagnosed in 20%: three paragangliomas and one breast cancer. Cases presented higher MICRA mean scores than controls (21.3 vs 16.2 in MICRA total score, 6.3 vs 4.2 in the distress subscale, and 8.3 vs 6.6 in the uncertainty subscale; all p<0.001). Conclusion: SF/IF in CSG were identified in 2.1% of patients. Despite a numerically higher psychological impact, the identification of SF/IF allowed early detection and cancer prevention in families without cancer history.