وصف
HRD (Homologous Recombination Deficiency) evaluation plays a crucial role in assessing the genetic characteristics and treatment strategies for various types of cancers. In breast cancer, it helps identify patients with DNA repair defects that may benefit from targeted therapies. In ovarian cancer aids in determining the potential responsiveness to PARP inhibitors, a class of drugs used in DNA repair-deficient tumors. In prostate cancer, it assists in identifying patients who may respond well to certain DNA-damaging agents or PARP inhibitors. Understanding HRD status in pancreatic cancer helps in identifying patients with defects in DNA repair pathways, which may influence treatment decisions. In lung cancer allows for the identification of patients who may benefit from DNA damage response-targeted therapies.
ملخص
- The discussion begins with a real-world patient scenario involving confusion over which genetic test to order for breast cancer, highlighting the evolution of BRCA testing to include HRR gene mutation panels and HRD tests. The lack of Indian companies offering HRD tests until recently, with Myriad Genetics' MyChoice CDx being the primary option, is emphasized. The importance of tumor-agnostic biomarkers and the shift away from organ-specific biomarkers like EGFR in lung cancer is discussed, noting that biomarkers are increasingly found across multiple cancer types due to shared oncogenesis mechanisms.
- The role of DNA damage response (DDR) in cancer evolution is highlighted, suggesting genetics plays a more significant role than the commonly cited 20% environmental impact, with the environment's role diminishing. The discussion advocates moving beyond traditional BRCA1 and BRCA2 testing to include full gene coverage that is relevant to diverse populations, particularly Indian women, for whom Caucasian-focused studies may not be applicable. BRCA testing's expanded application to ovarian, pancreatic, and prostate cancers beyond just breast cancer is mentioned.
- The mechanism of action of PARP inhibitors, crucial in DNA repair, is explained. These inhibitors exploit synthetic lethality, creating a situation where cancer cells, already damaged, cannot survive additional stress from PARP inhibition. Several PARP inhibitor drugs, including olaparib (Lynparza), niraparib, rucaparib, and talazoparib, are discussed. The need to update guidelines on HRR and HRD testing, initially approved in 2016-2017, is stressed, given the advancements and studies since then.
- HRR and HRD tests are differentiated, with HRR focusing on mechanisms of DNA damage response and HRD directly assessing DNA damage. The human body's constant exposure to radiation and toxins, leading to DNA damage, is described, emphasizing the evolutionary development of DNA repair mechanisms. The different DNA damage repair pathways are explained, including nucleotide excision repair, base excision repair, and mismatch repair, highlighting the roles of proteins like p53, XRCC1, and ATM in these pathways.
- The complexity of the DNA repair process is likened to an orchestra, requiring multiple proteins to communicate and repair damage. Homologous recombination repair, using a healthy DNA strand as a template, is contrasted with non-homologous end joining, which can lead to more problems. HRR tests analyze 10-15 genes, and while increasing genes does not necessarily improve accuracy, the focus is on genes essential for identifying and recruiting repair mechanisms for DNA damage. HRR mutation gene panels indicate potential HR failure, while HRD tests directly identify DNA damage.
- HRD tests, typically more expensive, are performed using Next Generation Sequencing or long-read technologies. Clinical guidelines differ between HRR and HRD tests for different cancer types. Somatic and germline mutations in ovarian cancer patients, and the growing emphasis on germline mutation testing, is addressed. The biomarkers developed by Myriad Genetics, including Loss of Heterozygosity (LOH), Telomeric Allelic Imbalance (TAI), and Large-Scale State Transitions (LST), are described.
- Genomic stability scores are generated using machine learning, taking into account BRCA mutations and promoter methylation. Methylation acts as an epigenetic regulator, typically silencing DNA, including promoters, resulting in similar effects as mutations. A key takeaway is that patients with wild-type BRCA in regular testing may still benefit from PARP inhibitor therapy if promoter methylation is present. Several companies offering these tests, including Myriad Genetics, Caris Molecular Intelligence, Foundation Medicine, and Tempus, are mentioned.
- The HRR gene panel typically includes BRCA1/2, ATM, BAP1, PALB2, and RAD51C, among others. The ATM protein was discovered in a disease called Ataxia-Telangiectasia Mutated. Minimum gene lists are given for affordable testing solutions, highlighting the roles of FANconi anemia complex proteins, and cell cycle checkpoints in DNA repair. Different clinical trials involving PARP inhibitors, as well as key information relating to trial populations and findings, are compared.
نموذج شهادة
حول المتحدثين
الدكتور شيباتشاكرافارثي كانان
بريسيجن أونكولوجي، المؤسس والرئيس التنفيذي لشركة أونكوفينوميكس، حيدر أباد
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