Significato clinico di BRCA in ovarian cancer
Sandro Pignata
Department of Urology and Gynecology National Cancer Institute of Naples Italy
Carcinoma ovarico
4800 nuovi casi nel 2015 in Italia
3251 decessi nel 2012
80 % III e IV stadi 20 % I e II stadi
Maschi Femmine
Età Età
Rango 0-49 50-69 70+ 0-49 50-69 70+
1° Polmone
(15%) Polmone (30%) Polmone (27%) Mammella (29%) Mammella (23%) Mammella (16%)
2° Sistema nervoso centrale (9%)
Colon-retto (10%)
Colon-retto
(10%) Polmone (9%) Polmone (14%) Colon-retto (12%)
3° Colon-retto (8%) Fegato
(8%) Prostata (8%) Colon-retto (7%) Colon-retto (10%) Polmone (11%)
4° Leucemie (7%) Pancreas (6%) Fegato (7%)
Ovaio (6%)
Pancreas (7%)
Pancreas (7%)
5° Stomaco
(6%) Stomaco (6%) Stomaco (6%)
Sistema nervoso centrale
(6%)
Ovaio (7%)
Stomaco (6%)
70000 donne all’anno muoiono di cancro in Italia
ogni anno
Perché questa malattia è così letale?
E’ impossibile la diagnosi precoce (eccetto che nelle pazienti BRCA mutate)
I numerosi trattamenti disponibili hanno
ritardato la progressione ma non migliorato la sopravvivenza
I farmaci biologici sono arrivati con ritardo a causa di una biologia estremamente
complessa
HRD
TGA -The Cancer Genome Atlas Network Research. Nature.
2011;474(7353):609-615.
BRCA mutations : 17% germinal
3% somatic
Ben David Y et al. JCO 2002;20:463-6 by American Society of Clinical Oncology
Survival in BRCA1/2 carriers
0 20 40 60 80 1.0
0.9 0-8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Cum Survival
TIME (months)
Carriers
Non- carriers
Adapted from: Jemal et al. CA Cancer J Clin 2009
Mortality per 100,000 women
1993 1995 1997 2013 2015 Year
20
15
10
5
0
Platinum +
anthracycline Platinum/taxane therapy
Front line
Come è cambiata la storia naturale del carcinoma ovarico negli ultimi 20 anni
Io ho iniziato qui
Platinum/taxane Beva therapy
•OC III stadio nel 1995
•Carbo-paclitaxel
•Recidiva nel1999
•4 linee di chemio
•Deceduta nel 2003
Valore
per le pazienti
Maria 58 anni
La madre Elena 37 anni
La figlia
•OC stadio IV nel 2011
•Carbo-paclitaxel
• Attualmente in recidiva platino sensibile alla terza linea di CT
Author | 00 Month Year
12 Set area descriptor | Sub level 1
Studio svedese di popolazione
Malander S, et al. Eur J Cancer 2004;40(3):422‒428.
Invasive epithelial ovarian cancer patients (N=161) BRCA mutations: 13/161 (8%)
Serous 65%
BRCA mutations 7.6%
Endometrioid 14%
BRCA mutations 13.0%
Mucinous 10%
BRCA mutations 0%
Clear cell 5%
BRCA mutations 12.5%
Papillary, SSPC 5%
BRCA mutations 14.2%
Unspecified
BRCA mutations 0%
The majority of tumours were serous and among these, 7.6% had BRCA mutations
30% of women had a family history of breast
and/or ovarian cancer
Unico dato in Italia viene dal MITO15: 30 % delle pazienti con profilo BRCAness è mutato
BRCA status and age at diagnosis in sporadic ovarian cancer: Florida study
115
0 10 20 30 40 50 60
≤40 years 41-50 years 50-60 years >60 years BRCA1 BRCA2 Total BRCA positive
1. Pal T et al. Cancer 2005;104:2807‒16
2. Harvey A et al. AM J Hum Genet 2001;68:700‒10
Canadian study2
18% of women diagnosed 40-50 years had BRCA mutations (4.2% for women <40years)
Average age of BRCA1 positive cases = 51.2 years Average age of BRCA2 positive cases = 57.5 years
Percentage of patients
Author | 00 Month Year
16 Set area descriptor | Sub level 1
• Interim OS analysis (38% maturity): HR=0.94; 95% CI, 0.63–1.39; P=0.75
0 0.6 0.8 0.9
0 0.1 0.2 0.3 0.4 0.5 0.7 1.0
3 6 9 12 15 18
Probability of progression-free survival
Time from randomization (months)
Primary analysis (58% maturity; n=154/265) PFS HR=0.35 (95% CI, 0.25–0.49) P<0.00001
Randomized treatment*
Placebo (n=129)
Olaparib 400 mg bd monotherapy (n=136)
Study 19: Olaparib maintenance therapy in platinum- sensitive relapsed ovarian cancer
Ledermann J et al. N Engl J Med 2012;366:1382–1392
PFS by BRCA mutation status
0
Time from randomization (months)
0 1.0
Proportion of patients progression-free
3 6 9 12 15
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
• 82% reduction in risk of disease progression or death with olaparib
Olaparib BRCAm Placebo BRCAm
Number at risk Olaparib BRCAm Placebo BRCAm
74 59 33 14 4 0
62 35 13 2 0 0
BRCAm (n=136) Olaparib Placebo Events: total pts (%) 26:74 (35.1) 46:62 (74.2) Median PFS, months 11.2 4.3
HR=0.18 95% CI (0.11, 0.31);
P<0.00001
Ledermann JA et al . J Clin Oncol 2013;31(15S); abstr 5505
Updated OS in BRCA mutation positive patients
0
Time from randomization (months)
0
48 1.0
Proportion of patients alive
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Number at risk
62 62 58 52 50 46 39 36 33 29 29 27 21 12 4 Placebo BRCAm
74 71 69 67 65 62 57 54 50 48 39 36 26 12 7 Olaparib BRCAm
Randomized treatment Placebo BRCAm Olaparib BCRAm
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
BRCAm (n=136) Olaparib Placebo Deaths: total pts (%) 37:74 (50.0) 34:62 (54.8)
Median OS, months 34.9 31.9
HR=0.74 95% CI (0.46, 1.19)
P=0.208
• 14/62 (22.6%) placebo patients switched to a PARP inhibitor
Ledermann J et al . J Clin Oncol 31, 2013 (suppl; abstr 5505)
Study 19: Time to second subsequent therapy
0
Time from randomisation (months)
0 1.0
Proportion of patients receiving study treatment or first subsequent therapy
10 20 30 40
Olaparib BRCAm
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
Placebo BRCAm
Number at risk Olaparib BRCAm Placebo BRCAm
74 62
5 15 25 35 45
70 60
65 46
50 31
38 21
33 18
30 11
23 9
9 2
0 0
BRCAm (n=136) Olaparib Placebo Events: total pts (%) 42:74 (57%) 49:62 (79%) Median TSST, months 23.8 15.2
HR=0.44
95% CI: 0.29, 0.67;
p<0.00013
Ledermann J et al. Lancet Oncol 2014
A uso esclusivo Medical Affairs – riservato – non promozionale
AstraZeneca raccomanda l'uso dei propri prodotti secondo il Riassunto delle Caratteristiche di prodotto
Duration of treatment and tolerability
Ledermann JA et al . J Clin Oncol 2013;31(15S); abstr 5505/ ASCO 2013 oral presentation
Study 19: Dose adjustments, discontinuations and treatment duration
Ledermann, J et al. J Clin Oncol 2011;29;A5003
Olaparib 400 mg bid
(n=136)
Placebo (n=128) Discontinuations due to AEs, n (%) 3 (2) 1 (1) Dose interruptions due to AEs, n (%) 38 (27.9) 11 (8.6) Dose reductions due to AEs, n (%) 31 (22.8) 6 (4.7)
Median treatment duration, days 206.5 141
AEs, adverse events
Ledermann J et al. N Engl J Med 2012;366:1382–92
A uso esclusivo Medical Affairs – riservato – non promozionale
AstraZeneca raccomanda l'uso dei propri prodotti secondo il Riassunto delle Caratteristiche di prodotto
QoL in patients with a BRCAm
FACT-O domain Olaparib Placebo
TOI improved, n (%) 16/64 (25.0) 10/53 (18.9) OR, 1.37
95% CI 0.56–3.46, P=0.49
TOI, Trial Outcome Index; FACT-O, functional assessment of cancer therapy for ovarian cancer; FOSI, FACT-O Symptom Index
Odds ratio (OR) >1 favours olaparib
• In patients with a BRCAm:
– No statistically significant differences were observed in improvement rates or time to worsening of TOI, FOSI and Total FACT-O
– A numerically higher proportion of patients reported
improvements in TOI, FOSI and Total FACT-O following treatment with olaparib vs placebo
Ledermann JA et al . ASCO 2013 (oral presentation)
Solo 1
Carbo-taxolo
Placebo
Olaparib
Studio multicentrico di Fase III, randomizzato, in doppio cieco,
controllato con placebo, per valutare il trattamento di mantenimento con Olaparib in monoterapia dopo una prima linea di chemioterapia
a base di platino in pazienti con carcinoma ovarico in stadio avanzato (stadio FIGO III-IV) e mutazione del gene BRCA
PAOLA1
Platine, Avastin and OLAparib in 1
stline of advanced high grade epithelial ovarian, fallopian tube, or
primary peritoneal cancer
28
Randomized, Double-blind, Phase III Trial of olaparib vs. placebo in combination with bevacizumab in women following first-line chemotherapy plus bevacizumab for advanced high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer
An International Randomised Trial of Cediranib and Olaparib Maintenance in Patients with Relapsed Platinum Sensitive Ovarian Cancer Proposal from the NCRI Clinical Studies Group
GCIG Melbourne, Nov 2014
PARP Inhibitors
• Olaparib
• Niriparib
• Rucaparib
PARP Inhibition in HRD deficient
61 % response rate in platinum sensitive BRCA mut
32 % response rate in High LOH 8% response rate in Low LOH
Ariel 3
• I PARP inibitori hanno la doppia potenzialità di dare beneficio al paziente e di migliorare il SSN
• BRCA è stato sottovalutato anche da noi oncologi, il sistema sanitario non è stato costruito adeguatamente e non è pronto
• La identificazione dei familiari mutati è l’unico modo di impattare sulla mortalità
Opportunità e sfida
• Abbiamo scritto le raccomandazioni
AIOM, forse le più avanzate in Europa
• Le regioni si devono adeguare
• Sanger o NGS?
• In alcune regioni non vi è accesso al test o non è rimborsato
Opportunità e sfida
La conoscenza del BRCA status è importante anche per altre
scelte terapeutiche
Efficacy of platinum based therapy in BMOC
Response rate Comment Author
First line 87%-96%
(n= 105)
•71% (p=0.002) in sporadic OC
•No difference
between BRCA1 and BRCA2
Venken et al1 Tan et al2
Recurrent
2nd- 3° line 65-100%
(n=67) Mostly platinum
sensitive
Only one cohort of 10 pts had primary platinum resistant disease with 8 reponders (80%)
Alsop et al 3 Tan et al 2
1. Venken et al Ann Onc2011 2. Tan et al Jco 2008 3. Alsop et al JCO2012
Platinum based therapy more active in BRCA mutated than in sporadic patients
Efficacy of Pegylated liposomal doxorubicin (PLD)- based treatment in BMOC
Response rate (RECIST or Ca125)
Median PFS
(months) Comment Author
68%
(n= 40) 15.8 mo
•PLD plus platinum in 22
•Mostly platinum sensistive (31)
•RR for PD/platinum in NH of 49%;
mPFS of 8 mo (p=0.009)
Safra et al1
56%
(n= 23) 6.3 mo
•Single agent PLD
•RR for PD/platinum in NH of 19%;
mPFS of 4 mo (p=0.004)
•Non correlation with platinum sensitivity
Adams et al2
39%
(n=33) 7.1 mo
• Single agent PLD
• Patients had 0-12 months of PFI
• Part of randomized trial vs olaparib wich had a RR of 59% and mPFS of 8.8 mo
Kaye et al3
1. Safra et al Mol Canc Ther 2011 2. Adams et al Gyn Onc 2011 3. Kaye et al J Clin Oncol 2012
• Trabectedin is a minor groove DNA binding agent derived from marine organism
Schöffski, et al. Eur J Cancer 2011
Efficacy of Trabectedin-based treatment in BMOC
Trabectedin
PFS and OS by BRCA1 Genotypes in Treatment Groups
BRCA1mut BRCA1wt
BRCA1-mutated
patients treated with T+PLD showed longer PFS and OS compared to PLD.
XPG-mutated patients treated with T+PLD had shorter PFS compared to XPG-wildtype.
BRCA1mut may predict improved outcome to T+PLD treatment
XPG mut was associated to less RR, PFS and OS. Possible biomarker of poor outcome in this patients
Monk et al. Gynecologic Oncology 133 (2014) Abs 99
Efficacy of trabectedin-based
treatment in BMOC
Cosa resta da fare?
Maria non sapeva di essere mutata.
Elena lo ha saputo
Nuovi modelli di counseling?
Author | 00 Month Year
42 Set area descriptor | Sub level 1
