Paziente con carcinoma mammario metastatico triplo negativo e mutazione germinale BRCA

Caso clinico

Paziente con carcinoma

mammario metastatico triplo negativo e mutazione germinale

BRCA

Grazia Vernaci

Università degli Studi di Padova Istituto Oncologico Veneto IRCCS

grazia.vernaci@iov.veneto.it Tutor: Giusy Ricciardi

Università degli Studi di Messina

 No familiar history for breast/ovarian cancer

 Never smoker, no comorbidities

 2009, April (52 years): right lumpectomy +SNB for ductal invasive carcinoma G3, ER 0%, PgR 0%, HER2 0, MIB1 43% (pTNM: pT1c N0)

E.B. 61 years

E₉₀C x 4  Paclitaxel qw x 12  RT

2017, May: Cough with haemoptysis  c/a CT scan:

Parenchymal lung mass (Ø 6 cm) with single mediastinal adenopathy

Trans-thoracic needle-biopsy: poorly differentiated cells of carcinoma consistent with metastasis of TNBC

iDFS: 8 yrs

To recap…

 Female, 61 yrs, no familiar history of breast/ovarian cancer

 2009 (52 yrs): 1^st diagnosis of TNBC

 2017: lung mass + single mediastinal adenopathy

 Since 2015: extension of genetic counseling indication to TNBC pts < 60 yrs irrespectively of familiar history

Indication for BRCA test: BRCA2 mutation

Treatment for mTNBC

 mTNBC pts often received A-T as neo/adjuvant treatment

 Frequent visceral involvement

 Poor survival from the onset of mBC

 Limited options available with limited efficacy

1

line treatment for BRCA mut mTNBC

 Capecitabine +/- vinorelbine

 Taxane-based

 Platinum-based combination

TNT phase III trial for TN metastatic BC Trial design

Tutt A. et al., Nat Med. 2018 May, 24

TNT phase III trial for TN metastatic BC

Tutt A. et al., Nat Med. 2018 May, 24

Objective Response – BRCA 1/2 status PFS– BRCA 1/2 status

End Points

• Primary – PFS (central)

• Secondary – ORR, OS, DCR, DOR, Safety Stratification

• Disease free interval ≤ 1 year vs > 1 year

• Prior taxane neo/adjuvant therapy (Ph 3 only)

First Line TNMBC

nab-Paclitaxel + Gemcitabine

N = 60

Gemcitabine + Carboplatin

N = 60

RANDOMIZE

nab-Paclitaxel + Carboplatin

N = 60

nab-Paclitaxel arm selected by combination of efficacy + safety

Winner of the 2 nab-Paclitaxel arms

N = 275

Gemcitabine + Carboplatin

N = 275

RANDOMIZE

Phase 2 Phase 3

Ph2 Patients will not be included in Ph3

analysis

End Points

• Primary – PFS (investigator)

• Secondary – ORR, % of patients initiating cycle 6, OS, Safety

Abraxane 125mg/m2,

Gemcitabine 1000mg/m2 D1,8 q21d Carboplatin AUC2

N = 730 subjects (Phase 2 = 180 (240) ; Phase 3 = 550), 150 sites

tnAcity - Study Design

Due to the changing treatment landscape, this study was stopped after the phase 2 portion was concluded

Yardley DA et al., Ann Oncol. 2018 Jun 6

tnAcity: results

nab-P/C nab-P/G G/C

Median PFS, months 8.3 5.5 6.0

HR (95% CI) P value

– –

.59 (.38 - .92) 0.02^a

.58 (.37 - .90) 0.02^a

12-month PFS rate, % 30 13 11

a Compared with nab-P/C.

Yardley DA et al., Ann Oncol. 2018 Jun 6

nab-P/C nab-P/G G/C

Median OS, months 16.8 12.1 12.6

HR (95% CI) P value

– –

.73 (.47 - 1.13) .16^a

.80 (.52 - 1.22) .29^a

a Compared with nab-P/C.

2017, Sept: PR 2018, Jan: PR 2018, April: PR

2017, June:

Carboplatin AUC2 + Nab-

P start

2017, Sept:

Carboplatin reduction due to tox

2018, Jan:

Last CT dose (12 courses)

2017, May: baseline

To be continued…

BRCA mut mTNBC: how long should 1st line be continued?

 Continue with dose reduction

 Stop therapy and tight follow up

 Maintenance therapy (?)

 Capecitabine +/- vinorelbine

 Eribulin

 PARP inhibitor

BRCAmut mTNBC: 2

line after platinum-

taxane combination

Olaparib showed a significant benefit

over TPC

HER2-ve mBC

• Previous A and/orT (adj or mBC)

• <1 prior CT for mBC

• HR+: > 1 prior ET (adj or mBC)

LUCY (expanded access) – Study Design

Multi-Center, Single Arm, Interventional Study

+ve

-ve

gBRCAm N=250

Wild Type

Not included in outcomes analysis

Olaparib 300mg BD

Physician defined Progression

Clinical outcomes:

• PFS (physician defined)

• OS

• Safety

Target Accrual N=250

Completion date: April 29, 2020