PDF(Pubmed)
Abstract：
Breast cancer (BC) is the most prevalent malignancy affecting women worldwide, including Portugal. While the majority of BC cases are sporadic, hereditary forms account for 5-10% of cases. The most common inherited mutations associated with BC are germline mutations in the BReast CAncer (BRCA) 1/2 gene (gBRCA1/2). They are found in approximately 5-6% of BC patients and are inherited in an autosomal dominant manner, primarily affecting younger women. Pathogenic variants within BRCA1/2 genes elevate the risk of both breast and ovarian cancers and give rise to distinct clinical phenotypes. BRCA proteins play a key role in maintaining genome integrity by facilitating the repair of double-strand breaks through the homologous recombination (HR) pathway. Therefore, any mutation that impairs the function of BRCA proteins can result in the accumulation of DNA damage, genomic instability, and potentially contribute to cancer development and progression. Testing for gBRCA1/2 status is relevant for treatment planning, as it can provide insights into the likely response to therapy involving platinum-based chemotherapy and poly[adenosine diphosphate (ADP)-ribose] polymerase inhibitors (PARPi). The aim of this review was to investigate the impact of HR deficiency in BC, focusing on BRCA mutations and their impact on the modulation of responses to platinum and PARPi therapy, and to share the experience of Unidade Local de Saúde Santa Maria in the management of metastatic BC patients with DNA damage targeted therapy, including those with the Portuguese c.156_157insAlu BRCA2 founder mutation.
摘要：
乳腺癌（BC）是影响全球女性最普遍的恶性肿瘤，包括葡萄牙。虽然大多数BC病例是零星的，遗传形式占病例的5-10%。与BC相关的最常见的遗传突变是BreastCAncer(BRCA)1/2基因(gBRCA1/2)中的种系突变。它们在大约5-6％的BC患者中发现，并且以常染色体显性遗传。主要影响年轻女性。BRCA1/2基因中的致病变异会增加乳腺癌和卵巢癌的风险，并产生不同的临床表型。BRCA蛋白通过同源重组（HR）途径促进双链断裂的修复，在维持基因组完整性中起关键作用。因此,任何损害BRCA蛋白功能的突变都会导致DNA损伤的积累，基因组不稳定性，并可能导致癌症的发展和进展。gBRCA1/2状态的检测与治疗计划有关，因为它可以提供对铂类化疗和聚[二磷酸腺苷(ADP)-核糖]聚合酶抑制剂(PARPi)治疗的可能反应的见解。这篇综述的目的是调查HR缺乏对BC的影响，关注BRCA突变及其对铂和PARPi治疗反应调节的影响，并分享UnidadeLocaldeSaúdeSantaMaria在接受DNA损伤靶向治疗的转移性BC患者的管理经验，包括那些与葡萄牙c.156_157insAluBRCA2创始人突变。
