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 OncologicaAOU 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 ovariancancer (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 patientswith gBRCAm BC

Olaparib was the first PARPi to demonstrate superior efficacy compared withstandard chemotherapy in patients with gBRCA-mutated advanced breast cancer

Talazoparib is more efficient in HR+ gBRCAm patients and a trend for OSadvantage was seen

Further studies are required to determine optimal sequencing with othertherapies (eg, platinum compounds, hormonal therapies)

Ongoing studies are investigating PARP inhibitors in the neoadjuvant andadjuvant

adjuvantsetting

Combinations with other agents, such as immunotherapy, are promising andunder investigation