2026· Oncology Research· pp. 1-10· 0 citations· 89 references
TL;DR
This narrative review aims to present the major hereditary cancer syndromes associated with an increased breast cancer risk, and to highlight the evidence-based genotype-specific screening and treatment protocols.
Abstract
: Breast cancer remains the most prevalent malignancy worldwide, ranking second in terms of cancer-related mortality. While exposure to modifiable risk factors, variations in screening efficacy, and inaccessibility to early-stage diagnosis contrast, an increased focus has been directed toward the study of its genetic profiles; particularly those attributed to germline pathogenic variants. This narrative review aims to present the major hereditary cancer syndromes associated with an increased breast cancer risk, and to highlight the evidence-based genotype-specific screening and treatment protocols. We examined current published literature and synthesized evidence from randomized controlled trials, observational studies and current clinical guidelines. The significance of genetic testing in breast cancer extends beyond prognostic, diagnostic and risk-assessment utility, with major contributions in therapeutic decision-making. Well-defined criteria for genetic testing are established, encompassing age, familial clustering of cancer, or tumor subtype. The most prevalent hereditary cancer syndrome is the Hereditary Breast and Ovarian Cancer (HBOC) syndrome, driven by mutations in the BRCA1 , BRCA2, and PALB2 genes, while other syndromes, less prevalent but with an increased risk of breast cancer development, like Li-Fraumeni syndrome and Peutz-Jeghers syndrome, arise from mutations in tumor suppressor genes. Despite the contrast in penetrance and risk profiles between the two categories, surveillance should be initiated at early ages, across all syndromes. The therapeutic approach is based on PARP (poly-(adenosine diphosphate–ribose) polymerase (PARP)) inhibitors for BRCA1/2 and PALB2 carriers, while in cases with TP53 mutations, radiotherapy is contraindicated, due to the risk of radiation-induced secondary malignancies. Germline pathogenic variant testing in high-penetrance susceptibility genes serves as the cornerstone of personalized, risk-stratified breast cancer management, enabling prevention, surveillance, and case-specific therapeutic decision-making. The broader integration of multigene panel testing and genetic counselling into routine cancer care remains a fundamental step toward optimizing outcomes across hereditary breast cancer syndromes.
Evidence shows that the interaction between genetic predisposition and environmental factors is a key determinant of breast carcinogenesis, underscoring the importance of understanding the underlying molecular mechanisms to improve prevention and care strategies.
Ana Paula Borges da Silva, Taynara de Almeida Campos, Juliano Rodrigues Coimbra et al.· Brazilian Journal of Health...· 0 citations
IMPORTANCE
Patients diagnosed with breast cancer (BCa) are at increased risk of multiple common diseases; however, the spectrum of these diseases and the contribution of inherited genetic susceptibility remain incompletely characterized.
METHODS
We evaluated 15 common diseases and tested their associations with BCa exposure and disease-specific polygenic risk scores (PRS) in the UK Biobank (UKB; N = 254,736). Analyses were performed using cause-specific Cox proportional hazards models within a full-cohort framework, with time-updated BCa status, delayed entry at study recruitment, and age as the underlying time scale.
RESULTS
After recruitment, incident BCa was diagnosed in 11,386 women (4.47%), including 2,742 (24.08%) with metastatic BCa. Patients with BCa had an increased risk of nine diseases spanning cardiovascular, metabolic, and neuropsychiatric domains (P<0.003, Bonferroni-corrected). Elevated risks were generally observed among patients with both early staged and advanced BCa. Inherited susceptibility further stratified disease risk, with the highest risks observed among patients with BCa with elevated disease-specific PRS. For example, compared with women without BCa, the hazard ratio (HR; 95% CI) for osteoporosis was 2.33 (2.15-2.52) among women with any BCa, 2.38 (2.18-2.59) among those with non-metastatic BCa, and 2.12 (1.78-2.54) among those with metastatic BCa; the HR was 4.48 (3.99-5.02) among patients with BCa in the highest quartile of osteoporosis-specific PRS (all P<0.001). In contrast, BCa was not significantly associated with risk of coronary artery disease.
CONCLUSION
BCa and inherited genetic susceptibility jointly contribute to increased risk of multiple common diseases, supporting the integration of genetic risk stratification into survivorship care.
Annabelle Ashworth, Zhu-Qing Shi, Huy Tran et al.· JNCI Cancer Spectrum· 0 citations
The genome-wide and phenome-wide analyses provide new insights into the genetic susceptibility and causes for EOBC, highlighting the age-decreasing breast cancer risk gradient for common genetic variants and potential roles of neurocognitive pathways in EOBC susceptibility.
S. Peng, V. E. Jackson, K. Alpen et al.· medRxiv· 0 citations
Cancer predisposition syndromes (CPS), arising from germline pathogenic variants in cancer predisposition genes (CPGs), are increasingly recognized as major contributors to pediatric and adult malignancies. Recent genomic advances have significantly enhanced the diagnosis, surveillance, and management of CPS, providing a unique framework for cancer prevention and interception of pre-malignant lesions. Increased utilization of comprehensive germline and tumor-normal sequencing has improved diagnostic precision, allowing early identification of at-risk individuals, including those with and without a family history of cancer. Integration of genome and long-read sequencing technologies further increases diagnostic yield by detecting structural and noncoding variants. Early diagnosis strategies, such as newborn screening, have demonstrated clinical utility and cost-effectiveness in population studies, such as the TP53 R337H variant newborn screening in Brazil. Evidence-based surveillance protocols, supported by outcome data, have led to earlier tumor detection and improved survival. Novel 'liquid biopsy' approaches offer minimally invasive tools for surveillance, with the potential to detect malignancies prior to radiologic findings. Beyond early detection, emerging strategies aim to intercept tumor development. Medical prevention strategies such as metformin in Li-Fraumeni syndrome and aspirin in Lynch syndrome show promise in modifying cancer risk. Immunoprevention, particularly neoantigen-targeted vaccines in mismatch repair-deficient tumors, is an evolving frontier with preliminary evidence of immunogenicity and safety. Together, these advances represent a paradigm shift in CPS management, offering a model for precision cancer prevention. Continued international collaboration, longitudinal studies, and health economic evaluations will be critical to translating these innovations into clinical and public health practice.
Yiming Wang, D. Malkin, Steven M. Lipkin· International Journal of Can...· 0 citations
Ovarian cancer remains one of the leading causes of cancer-related mortality among women because of its asymptomatic early course, delayed diagnosis, and frequent presentation at advanced stages. Germline and somatic mutations in the BRCA1 and BRCA2 genes significantly increase the risk of ovarian cancer by impairing homologous recombination DNA repair, resulting in genomic instability. Beyond their role in carcinogenesis, BRCA mutations have become important prognostic and predictive biomarkers, influencing treatment response and clinical outcomes. This review summarizes current evidence regarding the impact of BRCA1/2 status on prognosis and therapeutic strategies in ovarian cancer.
A literature review was conducted using the PubMed and Scopus databases. English-language articles published between 2016 and 2026 were identified using combinations of the keywords
ovarian cancer
,
BRCA1
,
BRCA2
,
PARP inhibitors
,
homologous recombination deficiency
, and
treatment
. Original studies, systematic reviews, meta-analyses, and relevant clinical trials were included.
The available evidence demonstrates that patients carrying BRCA1 or BRCA2 mutations generally experience improved progression-free survival and, in many studies, prolonged overall survival compared with non-carriers. This survival advantage is largely attributed to increased sensitivity to platinum-based chemotherapy and the efficacy of PARP inhibitors, which exploit synthetic lethality in homologous recombination-deficient tumors. The literature also emphasizes the importance of universal BRCA testing to optimize treatment selection, identify candidates for maintenance PARP inhibitor therapy, and facilitate genetic counseling. In addition, emerging mechanisms of resistance to PARP inhibitors remain a significant therapeutic challenge.
BRCA1/2 mutation status is a key biomarker in the management of ovarian cancer, supporting personalized treatment strategies and improving patient outcomes. Further research is needed to identify novel predictive biomarkers, overcome therapeutic resistance, and develop more effective targeted therapies.
Weronika Pawul, Paulina Opoka, Agata Dusza et al.· Frontiers in Oncology· 0 citations
PURPOSE
Quantitative assessment of the risk of inherited cancer susceptibility should reflect the growing number of well-documented gene-cancer associations beyond single syndromes, to increase efficiency when identifying candidates for genetic testing and early detection.
METHODS
We validate Fam3PRO, a computationally efficient Mendelian risk prediction methodology and platform that supports constructing models with an arbitrary number of genes and cancers, on three independent multi-ethnic panel cohorts. Fam3PRO was trained using population-level parameters from existing literature for 21 genes and 17 cancers.
RESULTS
Fam3PRO provides discrimination and calibration comparable to the widely-adopted syndrome-specific models BRCAPRO and MMRpro, for genes associated with Breast-Ovarian and Lynch syndromes. Furthermore, when assessing the probability of being heterozygous for at least one pathogenic variant in any of the 21 genes, Fam3PRO has a discrimination of 0.64 (95% C.I. 0.62-0.67) and a calibration (observed divided by expected) of 1.13 (95% C.I. 1.05-1.22) in the combined cohort. At probability thresholds of 2.5% and 5%, Fam3PRO identifies more individuals at high risk of being heterozygous for pathogenic variants in any of the 21 genes than BRCAPRO and MMRpro.
CONCLUSION
Fam3PRO provides a validated approach for familial risk stratification across a broad spectrum of cancer types, including estimates of carrier probabilities and future cancer risk.
Jane W. Liang, Gregory E. Idos, C. Hong et al.· Genetics in Medicine· 0 citations
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