Metastatik Meme Kanserinde BRCA1/2 ve PALB2 İlişkili Tümörler
Özet
BRCA1/2 ve PALB2 genlerinde meydana gelen patojenik mutasyonlar, homolog rekombinasyon aracılı DNA onarım mekanizmasında bozulmalara yol açarak genetik instabiliteye neden olur ve meme kanseri başta olmak üzere birçok kanser türünün gelişiminde önemli rol oynar. Bu mutasyonları taşıyan metastatik HER2-negatif meme kanseri hastalarında, poli(ADP-riboz) polimeraz (PARP) inhibitör tedavilerinin etkili olduğu gösterilmiştir. EMBRACA ve OlympiAD çalışmaları, talazoparib ve olaparib gibi PARP inhibitörlerinin etkinliğini ortaya koymuş, bu ajanların progresyonsuz sağkalım da anlamlı iyileşmeler sağladığını göstermiştir. Bununla birlikte, genel sağkalım üzerindeki etkileri değişkenlik göstermekte ve hasta alt gruplarına göre farklılık arz etmektedir. Bu ajanların en sık görülen yan etkileri arasında hematolojik toksisiteler yer almakta, ancak genel olarak standart kemoterapiye göre daha iyi tolere edilmektedir. Bu derlemede, BRCA1/2 ve PALB2 mutasyonları taşıyan metastatik meme kanseri hastalarında PARP inhibitörlerinin rolü, etkinlikleri, yan etki profilleri ve tedavi stratejileri ele alınmaktadır. Gelecekte yapılacak çalışmalar, bu ajanların uzun dönem etkinliği, kombinasyon tedavileri ve kişiselleştirilmiş tedavi yaklaşımlarında daha fazla bilgi sağlayacaktır.
Referanslar
Jiang Q, Greenberg RA. Deciphering the BRCA1 Tumor Suppressor Network. J Biol Chem 2015;290:17724-32
Gorodetska I, Kozeretska I, Dubrovska A. BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance. J Cancer 2019;10:2109-27
Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science 2017;355:1152-8
Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 2008;26:3785-90
Couch FJ, Shimelis H, Hu C, Hart SN, Polley EC, Na J, et al. Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer. JAMA Oncol 2017;3:1190-6
Tung N, Lin NU, Kidd J, Allen BA, Singh N, Wenstrup RJ, et al. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. J Clin Oncol 2016;34:1460-8
Kurian AW, Ward KC, Howlader N, Deapen D, Hamilton AS, Mariotto A, et al. Genetic Testing and Results in a Population-Based Cohort of Breast Cancer Patients and Ovarian Cancer Patients. J Clin Oncol 2019;37:1305-15
Mehrgou A, Akouchekian M. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Iran 2016;30:369
LaDuca H, Polley EC, Yussuf A, Hoang L, Gutierrez S, Hart SN, et al. A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Genet Med 2020;22:407-15
Kurian AW, Bernhisel R, Larson K, Caswell-Jin JL, Shadyab AH, Ochs-Balcom H, et al. Prevalence of Pathogenic Variants in Cancer Susceptibility Genes Among Women With Postmenopausal Breast Cancer. Jama 2020;323:995-7
Tischkowitz M, Balmaña J, Foulkes WD, James P, Ngeow J, Schmutzler R, et al. Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2021;23:1416-23
Pylkäs K, Erkko H, Nikkilä J, Sólyom S, Winqvist R. Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families. BMC Cancer 2008;8:146
Yang X, Leslie G, Doroszuk A, Schneider S, Allen J, Decker B, et al. Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families. J Clin Oncol 2020;38:674-85
Tew WP, Lacchetti C, Ellis A, Maxian K, Banerjee S, Bookman M, et al. PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline. J Clin Oncol 2020;38:3468-93
Eskiler GG. Talazoparib to treat BRCA-positive breast cancer. Drugs Today 2019;55:459-67
Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017;377:523-33
Dieras V, Han H, Kaufman B, Wildiers H, Friedlander M, Ayoub J-P, et al. Phase III study of veliparib with carboplatin and paclitaxel in HER2-negative advanced/metastatic gBRCA-associated breast cancer. Annals of Oncology 2019;30:v857-v8
Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med 2018;379:753-63
Litton JK, Hurvitz SA, Mina LA, Rugo HS, Lee KH, Gonçalves A, et al. Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann Oncol 2020;31:1526-35
Ettl J, Quek RGW, Lee KH, Rugo HS, Hurvitz S, Gonçalves A, et al. Quality of life with talazoparib versus physician's choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: patient-reported outcomes from the EMBRACA phase III trial. Ann Oncol 2018;29:1939-47
Robson ME, Tung N, Conte P, Im SA, Senkus E, Xu B, et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 2019;30:558-66
Gelmon KA, Fasching PA, Couch FJ, Balmaña J, Delaloge S, Labidi-Galy I, et al. Clinical effectiveness of olaparib monotherapy in germline BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: phase IIIb LUCY interim analysis. Eur J Cancer 2021;152:68-77
Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, et al. TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. J Clin Oncol 2020;38:4274-82
