Page 74 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

Serbian Association for Cancer Research SDIRSACR

Discussion
The OlympiA trial demonstrated that one year of adjuvant olaparib can significantly reduce the risk of recurrence
and help prevent progression to metastatic disease in patients with high-risk early breast cancer who carry germline
BRCA1 or BRCA2 pathogenic variants. This treatment was associated with high adherence rates and primarily low-
grade toxicity.
As awareness grows regarding the impact of germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants on
treatment decisions, an increasing number of these variants are being identified in patients with early breast cancer.
The development of PARP inhibitors (PARPi) for BRCA1/2-associated cancers represents a major advancement in cancer
therapy. The hope is that by identifying which tumors are most likely to develop resistance to PARPi and understanding
the key mechanisms to prevent or reverse such resistance, whether through new therapies or novel combinations—
treatment outcomes will improve.
Timing may be crucial, as evidenced by the OlympiA trial in BRCA-associated breast cancer and by first-line maintenance
therapy in ovarian cancer. Ongoing studies are also exploring neoadjuvant approaches. Furthermore, improving assays
for detecting homologous recombination deficiency (HRD) and deepening our understanding of predictors of PARPi
response beyond just germline and somatic pathogenic variants are essential steps toward expanding the patient
population that can benefit from these therapeutic strategies.

References:

1. Effect of screening and adjuvant therapy on mortality from breast cancer. Berry DA, Cronin KA, Plevritis SK, Fryback
DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ, Cancer Intervention and Surveillance
Modeling Network (CISNET) Collaborators, N Engl J Med. 2005;353(17):1784.
2. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. 2017. Risks of breast, ovarian, and contralateral breast cancer for
BRCA1 and BRCA2 mutation carriers. JAMA 317(23):2402–16
3. Li S, Silvestri V, Leslie G, et al. 2022. Cancer risks associated with BRCA1 and BRCA2 pathogenic variants. J. Clin.
Oncol. 40(14):1529–41
4. Farmer H, McCabe H, Lord CJ, et al. 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic
strategy. Nature 434(7035):917–21
5. Bryant HE, Schultz N, Thomas HD, et al. 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-
ribose) polymerase. Nature 434(7035):913–17
6. Fong PC, Boss DS, Yap TA, et al. 2009. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation
carriers. N. Engl. J. Med. 361(2):123–34
7. Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, Gelber RD, de Azambuja E, Fielding A, Balmaña J,
Domchek SM, Gelmon KA, Hollingsworth SJ, Korde LA, Linderholm B, Bandos H, Senkus E, Suga JM, Shao Z, Pippas
AW, Nowecki Z, Huzarski T, Ganz PA, Lucas PC, Baker N, Loibl S, McConnell R, Piccart M, Schmutzler R, Steger GG,
Costantino JP, Arahmani A, Wolmark N, McFadden E, Karantza V, Lakhani SR, Yothers G, Campbell C, Geyer CE Jr,
OlympiA Clinical Trial Steering Committee and Investigators, N Engl J Med. 2021;384(25):2394. Epub 2021 Jun 3.
8. Geyer CE Jr, Garber JE, Gelber RD, Yothers G, Taboada M, Ross L, Rastogi P, Cui K, Arahmani A, Aktan G, Armstrong
AC, Arnedos M, Balmaña J, Bergh J, Bliss J, Delaloge S, Domchek SM, Eisen A, Elsafy F, Fein LE, Fielding A, Ford JM,
Friedman S, Gelmon KA, Gianni L, Gnant M, Hollingsworth SJ, Im SA, Jager A, JóhannssonÓÞ, Lakhani SR, Janni W,
Linderholm B, Liu TW, Loman N, Korde L, Loibl S, Lucas PC, MarméF, Martinez de Dueñas E, McConnell R, Phillips
KA, Piccart M, Rossi G, Schmutzler R, Senkus E, Shao Z, Sharma P, Singer CF,ŠpanićT, Stickeler E, Toi M, Traina TA,
Viale G, Zoppoli G, Park YH, Yerushalmi R, Yang H, Pang D, Jung KH, Mailliez A, Fan Z, Tennevet I, Zhang J, Nagy T,
Sonke GS, Sun Q, Parton M, Colleoni MA, Schmidt M, Brufsky AM, Razaq W, Kaufman B, Cameron D, Campbell C,
Tutt ANJ, OlympiA Clinical Trial Steering Committee and Investigators, Ann Oncol. 2022;33(12):1250. Epub 2022
Oct 10.

59