Counseling genetici e tumori ereditari per selezionare la
terapia più efficace:
BRCA e inibitori di PARP nel carcinoma della mammella
Dott.ssa Elena Maccaroni, MD, PhD Clinica Oncologica
AOU Ospedali Riuniti di Ancona
Hereditary breast cancer
Tumori ereditari della mammella e dell’ovaio: BRCA1 e BRCA2
• portatori della mutazione germinale BRCA1/2 nella popolazione generale:
1/500 –1000
• Eterogeneità genetica e allelica:
➢ ampio spettro mutazionale
➢ mutazioni disperse nei 24 esoni di BRCA1 e 27 esoni di BRCA2
Larsen MJ et al. PLoS One. 2013 May 21;8(5):e64268
Caratteristiche dei tumori mammari BRCAmut
• Known mutation in at least one blood relative
• Breast cancer diagnosis ≤35 years
• Familial clustering of BR and/or OV cancers
• Triple-negative breast cancer diagnosis ≤ 60 years
• Male breast cancer
• Ovarian cancer, especially papillary serous (except mucinous histology and borderline tumours)
• Per guidelines
̵ Pancreatic and related malignancies in the family
̵ Castrate-resistant prostate cancer
̵ Results of tumor (somatic) genetic analysis
̵ Not yet finalized on guidelines
Criteri di selezione al test genetico BRCA
What is the function of BRCA 1 and BRCA 2 ?
• Tumor suppressor genes involved in DNA repair
• Autosomally transmitted (chromosomes 17 and 13)
• When mutated: higher incidence of hereditary breast and ovarian cancer (HBOC syndrome)
HOMOLOGOUS
RECOMBINATION
PARP-inibitori e letalità sintetica
Mechanism of action of PARP inhibition.Abbreviations: BER, base excision repair; DSB, double strand break; PARPi, PARP inhibitor; SSB, single strand break.
Lyons TG et al. J Natl Compr Canc Netw 2018;16(9):1150–1156
Timeline of PARP inhibitor clinical milestones. Abbreviations: ATM, ataxia-telangiectasia mutated; EMA, European Medicines Agency; gBRCA, germline BRCA; mBRCA, BRCA mutated; TNBC, triple-negative breast cancer.
Lyons TG et al. J Natl Compr Canc Netw 2018;16(9):1150–1156
Phase III trials with PARP-Inhibitors
in BRCAmut breast cancer pts
OlympiAD trial: Olaparib
Robson et al. N Engl J Med. 2017; 377:523-533
Robson et al. N Engl J Med. 2017; 377:523-533
EMBRACA trial: Talazoparib
Open Questions
• Chi sottoporre a test genetico BRCA?
• Chi trattare? (solo le pazienti con tumore triplo negativo? Solo le pazienti con gBRCAmut)?
• Quale linea di trattamento?
• Combinazioni con la chemioterapia?
• PARP-inibitori come terapia di mantenimento dopo chemioterapia?
• PARP-inibitori vs Platino?
• Combinazioni con altri farmaci (checkpoint inhibitors, CDK4/6 inhibitors?)
• Studi clinici nei carcinomi mammari in stadio precoce?
Open Questions
• Quale linea di trattamento?
Open Questions
• Quale linea di trattamento?
Open Questions
• Combinazioni con la chemioterapia?
• Combinazioni con la chemioterapia?
Open Questions
• Combinazioni con la chemioterapia?
Open Questions
• Combinazioni con altri farmaci (checkpoint inhibitors, CDK4/6 inhibitors?)
Conclusioni
PARP-inhibitors showed a significant clinical benefit in phase III studies in patients with gBRCAm BC
Olaparib was the first PARPi to demonstrate superior efficacy compared with standard chemotherapy in patients with gBRCA-mutated advanced breast cancer Talazoparib is more efficient in HR+ gBRCAm patients and a trend for OS advantage was seen
Further studies are required to determine optimal sequencing with other therapies (eg, platinum compounds, hormonal therapies)
Ongoing studies are investigating PARP inhibitors in the neoadjuvant and adjuvant
adjuvant setting
Combinations with other agents, such as immunotherapy, are promising and under investigation
