La clinica

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Novità nel campo della

genetica medica: la clinica

Valentina Guarneri

DiSCOG, Università di Padova

Istituto Oncologico Veneto IRCCS

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2

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Why perform BRCA1/2 test in ovarian cancer patients?

• Prognostic importance/prediction of tumor behaviour

• Impact on patient treatment

- Platinum sensitivity

- Sensitivity to intraperitoneal chemotherapy - Sensitivity to other chemotherapy

- Pegylated liposomal doxorubicin - Trabectedin

- PARP inhibition

• Identification of unaffected mutation carriers

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Bolton, JAMA 2012

Impact of BRCA1/2 germline mutations on survival

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Kaye SB, et al. J Clin Oncol 2012

BRCA status and response to chemotherapy

• 42% platinum resistant; 58% partially platinum sensitive

Monk , et al. Ann Oncol 2015

• OVA-301 phase III study in recurrent ovarian cancer

• PLD +/- trabectedin

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Olaparib 400mg bid

Placebo bid 1:1

Platinum-sensitive high-grade serous ovarian cancer (>6m response to prior platinum)

>2 previous platinum-containing regimens

Relapse Platinum-based

Chemotherapy

> 6 months

Platinum-based Chemotherapy

<8 weeks

Primary endopoint: PFS

Secondary endpoints: TTP (recist+CA125) OS

ORR

Safety, QoL

Ledermann J et al. N Engl J Med 2012;366:1382–92

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Ledermann J et al. Lancet Oncol 2014

22% mBRCA 14% BRCA neg 63% BRCA unknown

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Ledermann J et al. Lancet Oncol 2014

Progression-free Survival in BRCAm

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Cancers associated with BRCA genes

mutations

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• Today the focus of BRCA testing is generally on risk

assessment and the potential for preventive interventions

• Ovarian cancer patients have different priorities from genetic testing

• A formal pre-test genetic counselling is maybe not necessary providing:

• Expert genetic for result interpretation

• Genetic counselling availability (post-test or pre-test if patients require additional discussion)

• Specific genetic counselling for family members

Adapting genetic counselling to the new paradigm

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Adapting genetic counselling to the new paradigm

• Therapeutic decisions are impacted by BRCA mutation status

• Some women will be adversely affected discussing the implication of BRCA testing at the time of cancer diagnosis.

• However, not having BRCA status takes away choice

• It’s our role to identify those people who are struggling, and providing them with additional support

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Recent recommendations for genetic testing for OC

Australian national guidelines (July 2013):

Women ≤70 years of age with ovarian cancer can receive genetic testing for BRCA 1/2 mutations regardless of family history

NCCN (National Comprehensive Cancer Network) (V2, February 2014):

Epithelial ovarian cancer at any age

SGO (Society of Gynecologic Oncology) (March 2014):

Women diagnosed with epithelial ovarian, tubal, and peritoneal cancers should be considered for genetic counseling and

testing, even in the absence of a family history Europe: No standardised guidelines, vary by country

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Genetic Basis of Breast

Cancer

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Homologous recombinant deficiency and BRCAness

• Patients with BRCA1

^m

or BRCA2

^m

tumors are extremely sensitive to PARPi and

platinum salts

• Are there groups of patients with TNBC without BRCA1

^m

or BRCA2

^m

who have

similarly targetable biology and how to we

find them?

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Tutt A, SABCS 2014

TNT: Carboplatin vs Docetaxel as 1

^st

line

for TNBC

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Tutt A, SABCS 2014

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ABRAZO phase 2 trial

N=140 metastatic/

locally advanced BC

pts

gBRCA1/2 mut

Cohort assignme

nt based on prior

CT

Cohort 1 n=70 Previous response to

platinum- containing

regimen

Cohort 2 n=70

• >2 prior CT for ABC

• No prior platinum

regimen

Talazoparib 1mg PO QD until PD or

discontinuation per protocol

Primary objective: ORR

Secondary objectives: CBR, DOR, PFS, OS

2-stage design: at least 5 responses per cohort in the

first 70 pts enrolled (35+35) to allow enrollment of 140 pts

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Phase III trials examining PARP inhibitors in HER2-neg BRCA1/2 carriers with Breast

Cancer

R

Potent PARP inhibitor at MTD as

continuous exposure

Physician Choice within SOC options

Capecitabine or

Vinorelbine or Eribulin

or

Gemcitabine

gBRCA1 / BRCA2 Carriers

Advanced

anthracycline taxane resistant breast cancer

Primary endpoint

PFS

Olaparib – OLYMPIAD - NCT02000622

Talazoparib (BMN 673)

– EMBRACA - NCT01945775

Niraparib – EORTC / BIG BRAVO Trial

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Adjuvant olaparib in breast cancer patients with gBRCA mutations at high risk of recurrence

N=1,320

• Study to start recruiting patients with TNBC; plan to add ER/PR+ patients once data available from PK/PD interactions (expected Mid 2014)

• Primary endpoint: IDFS (invasive disease-free survival; STEEP approach)

• HR=0.7 (CV=0.81), 90% power, 5% significance level, approx 330 events required

• Assumes consistent treatment effect (HR=0.7) across patient groups

• N=1320 (25% maturity), assuming 4 years recruitment, IDFS analysis estimated approx. 5.5–

6 years from FSI Post-neoadjuvant gBRCA TNBC

Non pCR patients Assumptions:

- Control arm 3-year EFS ~ 60%C

Post-adjuvant gBRCA TNBC Node positive or N0 with T>2 cm

Assumptions:

- Control arm 3-year EFS ~ 77%C

12 mos Olaparib

300mg bd _DDF

S, OS 12 mos Placebo

IDFS 1:1 R

OlympiA

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pCR Rates by Treatment and According to <br />HR Deficiency Status (ypT0 ypN0)

Presented By Gunter Von Minckwitz at 2015 ASCO Annual Meeting

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