La scelta terapeutica nel carcinoma ovarico avanzato...

La scelta terapeutica nel carcinoma ovarico avanzato guidata da istotipo e

caratteristiche biomolecolari: novità e prospettive future

Dr.ssa Lorena Incorvaia

Tutor Roberto Sabbatini

Azienda Ospedaliera Universitaria Policlinco

«P.Giaccone» Palermo

Ovarian Cancer: setting the scene

5 Y survival <25% for stage III/IV

Minimal improvement in ovarian cancer mortality rates – no new front-line

therapy for >20 years

Cisplatin

Cisplatin

Paclitaxel

Carboplatin

Paclitaxel

Platinum Paclitaxel

Bevacizumab

0

5

10

15

20

25

30

1990 1993 1998 2013

DFS

Survie depuis rechute

Survie globale

Survival from recurrence

Overall survival

The overall survival increase in ovarian cancer is mainly due

to the treatment of recurrent disease

Primary Treatment

Cytoreductive surgery + platinum based

Carboplatin-Paclitaxel PFS = 16-23 m

OS = 31-65 m

Intraperitoneal

Chemotherapy

PFS = + 5.5 m

OS = + 15 m

Weekly Carboplatin-

Paclitaxel

PFS = + 10.8 m

Carboplatin-Paclitaxel +

bevacizumab

PFS = + 4 m

First line treatment options

in advanced ovarian cancer at present

Karam A, et al. Annals of oncology 2017

Recurrence very common: multiple ralapses

75% of patients responde to first line platinum-based chemotherapy

70% of them experience recurrences within 24 months

The platinum free interval dogma

Refractory

Resistent

Partially sensitive

Fully sensitive

Relapsed ovarian cancer categories

Choise of treatment: What did we know?

Epithelial ovarian tumors: from singular to plural

Choise of treatment: What do we know today?

The backstage….

Epithelial Ovarian cancer is not a unique disease

Epithelial ovarian

tumors

Impact of histological subtype

Prognostic impact of separating HGSOC and LGSOC

Histology more important?

Refractory

Resistent

Partially sensitive

Fully sensitive

Relapsed ovarian cancer categories


Treatment guidance by histologic type

WHO 2014 diagnostic criteria

Low grade serous cancer

- Young age at diagnosis

- Chemoresistance

- Prolonged overall survival

- May arise de novo or following

diagnosis of serous borderline

tumor

- Aberrations within the MAP

kinase signaling pathway

Farley et al. Lancet Oncol 2013 Friday et al. Cancer Res 2008

Ras

MEK

ERK

Other substrates

Frequent mutations in SBTs and low-grade

serous carcinomas

Raf

MAPK

P P

P

P P

P P

MAPK Elk

SA

P Target

genes

Nucleus

Y Growth factor

SBT: serous borderline tumour

• Selumetinib, trametinib

– Potent

– Selective

– Orally available

– Non-ATP competitive inhibitor of

the mitogen-activated protein kinase

(MAPK), MEK-1/2

Recurrent or persistent

low-grade serous

carcinomas of the ovary,

fallopian tube or

primary peritoneum

MEK162

CT

(liposomal doxorubicin,

Paclitaxel

or topotecan)

MILO Study

Hormonal Maintenance Therapy for Women with Low-Grade Serous

Carcinoma of the

Ovary or Peritoneum

David M. Gershenson, MD

• High frequency of ER and PR expression in LGSC

Wong et al. Int J Gynecol Pathol 2007

• Hormonal therapy for recurrent LGSC associated with ORR = 9%, SD = 66%,

median PFS = 7.4 mo

Gershenson et al. Gynecol Oncol 2012

• LGSC similar to luminal breast cancer: Worse prognosis for women age < 35 y

Gershenson et al. J Clin Oncol 2015

Rationale

Stage II-

IV

LGSC

Primary

Cytoreductive

Surgery

Platinum-

Based Chemotherapy

Surveillance

N = 134

Hormonal Maintenance

Therapy

N = 70


ASCO 2016

Hormonal Maintenance Therapy for Women with Low-Grade Serous

Carcinoma of the

Ovary or Peritoneum

Group Median

PFS (mo)

95% CI P-

Value

SURV

(n = 121) 29.9 24.5, 35.2

< .001

HMT

(n = 27) 81.1 55.2, 106.9

ALL

(N = 148) 33.0 28.4, 37.7

p<.001

Results: PFS in Patients NED at Completion of

Chemotherapy


ASCO 2016

Results: OS in Patients NED at Completion of

Chemotherapy

Group Median

OS (mo)

95% CI P-

Value

SURV

(n = 121) 106.8 72.8, 140.7

.04

HMT

(n = 27) 191.3 93.5, 289.1

ALL

(N = 148) 115.7 86.5, 144.9


ASCO 2016


From singular to plural

Molecular profile

Epithelial Ovarian cancer: Molecular profiling

Epithelial ovarian

tumors

What did we know? What do we know today?

Family history OC/BC

Age at diagnosis

BRCA1/BRCA2

Germline Mutations

BRCA mutation is not

correlate to age and

family history

Beyond gBRCA1/BRCA2:

Not only germline mutations: somatic!

Not only BRCA: “HRD phenotype”

BRCA testing

prognostic and predictive value:

BIOMARKER!

Molecular Profiling of High-Grade Serous Ovarian Cancer

Surveillance

program

Prophylactic

surgery

• Approximately 35%-40% of BRCA 1-2 mutation carriers do not have a

family history of cancer

BRCA mutation is not correlated to age and family history

• At least 25% of BRCA 1-2 mutation carriers are >60 yrs old

Available evidence

Median Age BRCA 1/2

Yrs

BRCA 1 +

Yrs

BRCA 2 +

Yrs

Alsop et al. 60 53 60

Soegaard et al. 61 49

Risch et al. 56 51 57

Malander et al. 59 57

Song et al. 59 52 57

Age is not a good predictor of BRCA mutation

BRCA Mutation Carriers

Who Lack a Family History (%)

Walsh et al. 27

Soegaard et al. 54

Malander et al. 8

Risch et al. 37

Alsop et al. 44

Song et al. 39

Family history is not a good predictor of BRCA mutation

BRCA mutation is not correlated to histotype

Alsop K, et al. J Clin Oncol 2012; 30: 2654–63.

BRCA mutation in 14.1% of the studied population

16.6% of serous histotype

22.6% of high grade serous subtype

Available evidence

6.3% of clear cell subtype

8.4% of endometrioid subtype

Total population

(%)

Serous (%)

Endometrioid (%)

Clear Cell (%)

Mucinous (%)

Alsop et al.

14.1 16.6 8.4 6.3 NA

Risch et al.

13.2 18.0 7.1 7.1 0

Soegaard et al.

5.8 5.4 5.4 9.1 0

Jacobi et al.

13.9 10.8 0 0 0

Malander et al.

8 7.6 13.0 12.5 0

Soergaard M. et al., Clin Cancer Rev. 2008; Risch HA et al., JNCI 2006; Alsop K et al., JCO 2012 Malander S. et al., EJC, 2004; Jacobi CE et al., Genet Med, 2007

Available evidence

Histotype is not a good predictor of BRCA mutation



Age at diagnosis

BRCA1/BRCA2

Surveillance

program

Prophylactic

surgery



family history

Beyond BRCA1/BRCA2:

“Beyond HR repair genes”

“HRD phenotype”

BRCA test: prognostic and

predictive value:

BIOMARKER!

1. Prognostic

Patients with BRCA mutated ovarian cancer show a significantly more

favourable prognosis

BRCA: impact of germline mutations

Bolton KL, et al. JAMA. 2012;307(4):382-390. Zhong Q et al. Clin Cancer Res. 2014;21(1):211-220.

5-year survival:

•BRCA1 – 44%

•BRCA2 – 61%

•No mutation – 25%



Pts with gBRCA mutations have a longer survival than in

women with sporadic ovarian cancer

1. Prognostic

BRCA: impact on patient therapy

2. Predictive

Improved survival in

BRCA-mutated ovarian

cancer patients treated

with Intraperitoneal

cisplatin and paclitaxel

Lesnock JL, Br J Cancer, 2013


2. Predictive


2. Predictive

Trabectedin in patients with BRCA-mutated and BRCAness

phenotype Advanced Ovarian Cancer (AOC): Phase II Prospective

MITO-15 Study


2. Predictive

Analysis of OV-301 according to BRCA status

Monk BJ Ann Oncol 2015

Study 19: OLAPARIB. PFS by BRCAm status

0

Time from randomization (months)

0

1.0

Pro

po

rtio

n o

f p

atie

nts

pro

gre

ssio

n-

fre

e

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


2. Predictive

SOLO-1, -2, -3

Randomized phase III studies of Olaparib in OC

No. at risk

Olaparib Placebo

196 99

182 70

156 37

134 22

118 18

104 17

89 14

82 12

32 7

29 6

3 0

2 0

0 0

100

90

80

70

60

50

40

30

20

10

0

Pro

gres

sio

n-f

ree

surv

ival

(%

)

Months since randomization

0 3 6 9 12 15 18 21 24 27 30 33 36

19.1

Olaparib

Placebo

5.5

Olaparib

(n=196)

Placebo

(n=99)

Events (%) 107 (54.6) 80 (80.8)

Median PFS, months 19.1 5.5

HR 0.30

95% CI 0.22 to 0.41

P<0.0001

Median follow-up was 22.1 months in the olaparib group and 22.2 months for placebo

Presented by Pujade-Lauraine at SGO 2017 annual meeting

SOLO 2, PFS by investigator assessment

Abbreviations: MMR, mismatch repair; BER, base excision repair; NHEJ, nonhomologous end-

joining; HRR, homologous recombination repair; NER, nucleotide excision repair; TLJ, translesional

joining.

Major interactive pathways involved in DNA damage and repair

Functioning PARP1

Single-strand break

PARP1

Repaired DNA

Mutation in BRCA1 or

BRCA2 gene

Cell death

PARP

1

PARP-inhibitor

No DNA repair

Single-strand break

Collapsed replication

fork

Double-strand break

No homologous recombination

No repair

PARPi-sensitive

PARP inhibitor and tumor selective synthetic lethality

PARP1

Incorvaia et Al, Oncotarget 2016

Age and family history are not sufficient

criteria for BRCA testing

Histologic type (except mucinous) is not a

sufficient criterio for BRCA testing

Key points

BRCA is predictive of PARP-inhibitor

sensitivity

BRCA testing for all women with epitelial ovarian cancer, regardless of age,

histologic type and family history



Age at diagnosis

BRCA1/BRCA2

Surveillance

program

Early

diagnosis

Prophylactic

surgery

Tumor risk

reduction



family history

Beyond BRCA1/BRCA2:

“Beyond HR repair genes”

“HRD phenotype”

BRCA test: prognostic and predictive

value

Beyond germline BRCA1/2 mutations

Not only germline mutations Not only BRCA mutations

HR gene mutations are not restricted to

BRCA

Sensitivity to DNA repair inhibitors?

BRCA-like signature

Beyond BRCA: “HRD phenotype”

BRCA germline

mutation

BRCA somatic

mutation

HR mutation,

non-BRCA

Parp-inhibitor trials for sporadic, BRCA WT, ovarian cancer:

Do we have one?

Rucaparib,

Ariel 3 trial

Niraparib,

NOVA trial

2 Randomised maintenance trials following platinum-based chemotherapy in

BRCAm and BRCAwt

gBRCAmut

Non-gBRCAmut

gBRCAmut

BRCA-like

Biomarker negative

Homologous Recombination Deficiency (HRD) Assay

Do we have one?

ARIEL 2, ASCO 2015

Biomarker

negative

gBRCAmut

BRCA-like

ORR

80%

ORR

29%

ORR

10%

Rucaparib,

Ariel 2 trial

McNeish IA, et al. J Clin Oncol. 2015;


Do we have one?

• Loss of heterozygosity (LOH)

• Telomeric allelic imbalance (TAI)

• Large-scale state transitions (LST)

HRD score is sum of LOH + TAI + LST scores

- Presented evidence of correlation between HRD score and in

vitro/in vivo response to niraparib in 106 tumor samples

Thus:

- Two assays under further evaluation, as key elements in 2 randomized

maintenance trials, with niraparib and rucaparib in sporadic and BRCAm-

associated ovarian cancer

Developed HRD score in the NOVA trial incorporating 3 components:


Do we have another?

Haluska P et al, NCI/EORTC/AACR 2014 (Eur J Cancer. 2014)

gBRCAmut Non-gBRCAmut

Non-gBRCAmut cohort, HRDpos group

NOVA trial, Niraparib PFS

Mirza MR et al. N Engl J Med. 2016

Germline

BRCA1/BRCA2 “HRD phenotype”

Olaparib

Niraparib

Rucaparib

….....

Molecular Profiling of High-Grade Serous Ovarian Cancer

Refractory

Resistent

Partially sensitive

Fully sensitive


Molecular biology more important?

Identifying the HR Deficiency Signature

Identifying the subset of BRCA-like tumors, which respond to HRR-

directed therapy

OC and HR: How the debate is evolving?

Need for Biomarkers!

Panel testing: Which molecular alterations most important?

Sensitivity to targeted therapy? Clinically relevant?

Heterogeneity! How can we account for heterogeneity and dynamic changes that

occur in response to a given targeted therapy?

Tumor Heterogeneity

BRCA2

BRCA1

RAD51

BRIP

EMSY

FANCF

TP53

CHECK2

ATM

ATR

BRCA1/2

ATM/

ATR

BRCA1/2

Tp53

ATM/

ATR

ATM/

ATR

ATM/

ATR ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR ATM/

ATR ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR

BRCA1/2

BRCA1/2

BRCA1/2

BRCA1/2

BRCA1/2

BRCA1/2

Tp53

Tp53

Tp53 Tp53

Tp53

Tp53 Tp53

Tp53

Tp53

Tp53

Tp53

Tp53

Tp53 Tp53

Tp53

Tp53

Beltrame L et al., Ann Oncol 2015

BRCA1/2

ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR ATM/

ATR

ATM/

ATR

ATM/

ATR ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR ATM/

ATR ATM/

ATR

ATM/

ATR

ATM/

ATR ATM/

ATR

ATM/

ATR

BRCA1/2

BRCA1/2

BRCA1/2

BRCA1/2

BRCA1/2

Tp53

Tp53

Tp53

Tp53

Tp53

ATM/

ATR

AF=1%-

20%

AF=20%-

50%

AF=50%-

100%

Non HGS-EOC HGS-EOC

Inter-patients Heterogeneity

BRCA2

BRCA1

RAD51

BRIP

EMSY

FANCF

TP53

CHECK2

ATM

ATR

BRCA1/2

Tp53

BRCA1/2

BRCA1/2

BRCA1/2

BRCA1/2

BRCA1/2

Tp53

Tp53 Tp53

Tp53

Tp53

Tp53

Tp53

Tp53 Tp53

ATM/

ATR

ATM/

ATR

BRCA1/2

BRCA1/2

Tp53

Tp53

AF=1%-20% AF=20%-50% AF=50%-100%

BRCA1/2

BRCA1/2

BRCA1/2

BRCA1/2

BRCA1/2

BRCA1/2

Tp53

Tp53 Tp53

ATM/

ATR

ATM/

ATR

BRCA1/2

BRCA1/2 Tp53

HGS-EOC Non- HGS-EOC

Spatial and Temporal Heterogeneity

Where to go next?

Until we identify actionable target, the severe genomic

instability found across HGSOC remains the fulcrum

HRD

Synthetic Lethality

iPARP

Leverage

DNA damage

response

(DDR)

New opportunities…..

Clinical Synthetic Lethality

Targeting the molecular and

microenvironmental

characteristics of tumor

Endogenous tumor factors

HRD

TP53

Cell cycle regulation

Exogenous tumor factors

Hypoxia

Immune activation

Glucose metabolism

Chemical

synthetic

lethality

Contextual

synthetic

lethality

+

Hypoxia

Hypoxia downregulates

key genes in the

homologous-

recomination and

mismatch-repair pathway

(RAD 51, RAD 52,

BRCA, MSH2, and

MSH6)

Hypoxia is presumed to be generated locally by angiogenesis

inhibitors

Leveraging hypoxia to induce HRD-like environment

Leverage

DNA damage

response

(DDR)

Testing the hypothesis: PARPi + VEGFRi


microenvironmental



HRD

TP53



Hypoxia

Immune activation

Glucose metabolism

Chemical

synthetic

lethality

Contextual

synthetic

lethality

+

Olaparib + Cediranib

Olaparib + Cediranib signifcantly increased PFS in patients

without BRCA mutation

Sinergy between hypoxia and inhibition of DNA

repair

Poster 5535 ASCO 2017

Leverage

DNA damage

response

(DDR)




microenvironmental



HRD

TP53



Hypoxia

Immune activation

Glucose metabolism

Chemical

synthetic

lethality

Contextual

synthetic

lethality

+

Targeting cell cycle to inhibit DDR

Cell cycle checkpoint abrogation:

CHK1/2 inhibitor

Cell cycle checkpoint abrogation:

Wee-1 inhibitor (AZ1775)

Wee-1i + Carboplatin/paclitaxel in TP 53 mut

HGSOC

Oza and colleagues ASCO 2015

In combination con carboplatin, promosing activity in “platinum-

resistant” disease with p53 mutations.

Leverage

DNA damage

response

(DDR)




microenvironmental



HRD

TP53



Hypoxia

Immune activation

Glucose metabolism

Chemical

synthetic

lethality

Contextual

synthetic

lethality

+

Ovarian Cancer

Immunogenic

T cell infiltration

affect outcome

Anti PD1/PDL1

-ORR 15%

-Very rarely long lasting responses

Other Studies

-Disis et Al, Avelumab: ORR 9.7%

-Brahmer et al, Nivolumab: 17 pts, 1 PR, 2 SD

Leverage

DNA damage

response

(DDR)

Testing the hypothesis: PARPi + Immunotherapy


microenvironmental



HRD

TP53



Hypoxia

Immune activation

Glucose metabolism

Chemical

synthetic

lethality

Contextual

synthetic

lethality

+

Why combine DDR inhibitors + immunotherapy

• HGSOC has intermediate mutational load with high genomic instability,

causing neoantigen production

• Inhibition of DDR pathways would be expected to propagate DNA damage and

thus increase neoantigen potential

Promising start!

J-m Lee et al, JCO 2017

On going Clinical Trials

The range of

DNA

opportunities

Combine with

other DNA

repair targets

Cell cycle

dysregulation

Epigenetic

generation of

HRD

Hypoxia

Immunotherapy

combinations

?

?

?

?

? ?

?

?

Navigating the new information….

Options likely will increase in tandem with our

understanding as long as we keep asking relevant

questions….

Is it possible to prospectively profile tumors to guide therapy choice?

Individualized Medicine in Ovarian Cncer: Are we there yet?

OC is a tumor where new knowledge has changed the landscape

Treatment according to histotype and molecular definitions is the future!

Antiangiogenic agents and parp inhibitors are changing the natual history

of ovarian cancer disease.

Understanding DNA repair and DDR continues to evolve and offers

opportunities for therapeutic intervention, leveraging clinical synthetic

lethality

Defining combination therapies with the optimal potential to be synthetic

lethal

Further defining biomarkers, beyond BRCA, to more effectively select

patients for individualized medicine in ovarian cancer

Conclusions

Thanks!

La scelta terapeutica nel carcinoma ovarico avanzato...

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