Importanza del test genetico nel carcinoma mammario ed ovarico

(1)

Lorena Incorvaia

Azienda Ospedaliera Universitaria Policlinco «P.Giaccone» Palermo

UOC Oncologia Medica

(2)

The range of DNA

opportunities

Ovarian Cancer Breast Cancer

Prognostic Predictive

Preventive

(3)

(4)

Refractory Resistent

Partially sensitive Fully sensitive

Relapsed ovarian cancer categories

Ovarian Cancer: setting the scene

 No new front-line therapy for >20 years

 Choise of treatment: The platinum free interval dogma

No predictive factors!

(5)

Family history OC/BC Age at diagnosis BRCA1/BRCA2 Germline Mutations

BRCA mutation is not associate 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!

Surveillance program Prophylactic

surgery

(6)

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

BRCA mutation: 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

(7)

Epithelial ovarian tumors: from singular to plural

The backstage….

(8)

Epithelial Ovarian cancer is not a unique disease

Epithelial ovarian tumors

(9)

(10)

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

Epithelial ovarian tumors

(11)

(%) (%)

^(%)

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

Histotype is not a good predictor of BRCA mutation

(12)

What did we know? What do we know today?

BRCA mutation is not correlate to age and

family history

BRCA testing

BIOMARKER!

Ovarian Cancer: Genetic Testing

surgery

(13)

Patients with BRCA mutated ovarian cancer show a significantly more favourable prognosis

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%

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

(14)

Pts with gBRCA mutations have a longer survival than in women with sporadic ovarian cancer

1. Prognostic

(15)

Improved survival in BRCA-mutated ovarian

cancer patients treated with Intraperitoneal cisplatin and paclitaxel

Lesnock JL, Br J Cancer, 2013

(16)

BRCA: impact on patient therapy

2. Predictive

(17)

Trabectedin in patients with BRCA-mutated and BRCAness phenotype Advanced Ovarian Cancer (AOC): Phase II Prospective

MITO-15 Study

(18)

BRCA: impact on patient therapy 2. Predictive

Analysis of OV-301 according to BRCA status

Monk BJ Ann Oncol 2015

(19)

Study 19: OLAPARIB. PFS by BRCAm 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

(20)

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

Progression-free survival (%)

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

(21)

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

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

(22)

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

(23)

Histologic type (except mucinous) is not a sufficient criterio for BRCA testing

BRCA is predictive of PARP-inhibitor sensitivity

Genetic Testing: Predictive!

(24)

What did we know? What do we know today?

BRCA mutation is not correlate to age and

family history

BRCA testing

BIOMARKER!

Ovarian Cancer: Genetic Testing

surgery

(25)

(26)

Sensitivity to DNA repair inhibitors?

BRCA-like signature

Beyond BRCA: “HRD phenotype”

BRCA germline mutation BRCA somatic

mutation HR mutation,

non-BRCA

(27)

Rucaparib, Ariel 3 trial

Niraparib, NOVA trial

BRCAm and BRCAwt

gBRCAmut

Non-gBRCAmut gBRCAmut

BRCA-like

Biomarker negative

(28)

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

Homologous Recombination Deficiency (HRD) Assay Do we have one?

Rucaparib, Ariel 2 trial

(29)

ARIEL

2, ASCO 2015 Biomarker

negative gBRCAmut

BRCA-like

ORR 80%

ORR 29%

ORR 10%

Rucaparib, Ariel 2 trial

(30)

• 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:

Homologous Recombination Deficiency (HRD) Assay Do we have another?

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

(31)

gBRCAmut Non-gBRCAmut

Non-gBRCAmut cohort, HRDpos group

Mirza MR et al. N Engl J Med. 2016

(32)

Germline

BRCA1/BRCA2 “HRD phenotype”

Olaparib Niraparib Rucaparib

…...

OC and HR: How the debate is evolving?

Identifying the HR Deficiency Signature

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

Need for Biomarkers!

(33)

Analyzing “BIG” data…

Norquist BM, et al. JAMA Oncol. 2015

18% carried a germline mutation:

– 15% in BRCA1 or BRCA2 – 3% in BRIP1, RAD51C,

RAD51D, PALB2, BARD1 – 0.4% in a MMR gene

2. What is the clinical utility of non-BRCA genes?

3. Who should order and

interpret the findings of panel testing? Clinically relevant?

1. Which genes?

(34)

Tumor Heterogeneity!

How can we account for heterogeneity and dynamic changes that occur in response to a given targeted therapy?

OC and HR: How the debate is evolving?

(35)

BRCA2 BRCA1 RAD51 BRIP EMSY FANCF TP53 CHECK2 ATM ATR

BRCA1/2 Tp53

BRCA1/2 BRCA1/2

BRCA1/2

BRCA1/2 Tp53

Tp53 Tp53

Tp53

Tp53 Tp53 ATM/

ATR

ATM/

ATR

BRCA1/2

Tp53

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

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

Beltrame L et al., Ann Oncol 2015

(36)

Until we identify actionable target, the severe genomic instability found across HGSOC remains the fulcrum

Where to go next?

(37)

HRD

iPARP

(38)

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

+

(39)

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

(40)

Testing the hypothesis: PARPi + VEGFRi

Targeting the molecular and microenvironmental characteristics of tumor

Endogenous tumor factors HRD

TP53

Cell cycle regulation

Exogenous tumor factors Hypoxia

Immune activation Glucose metabolism

lethality

+

(41)

 Olaparib + Cediranib signifcantly increased PFS in patients without BRCA mutation

Sinergy between hypoxia and inhibition of DNA repair

Poster 5535 ASCO 2017

(42)

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

lethality

+

(43)

Immunogenic

T cell infiltration

affect outcome

(44)

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

(45)

Targeting the molecular and microenvironmental characteristics of tumor

Endogenous tumor factors HRD

TP53

Cell cycle regulation

Exogenous tumor factors Hypoxia

Immune activation Glucose metabolism

lethality

+

(46)

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

(47)

The range of DNA

opportunities

Combine with other DNA repair targets

Cell cycle dysregulation Epigenetic

generation of HRD

Hypoxia

Immunotherapy combinations

(48)

The range of DNA

opportunities

Ovarian Cancer Breast Cancer

Prognostic Predictive

Preventive

(49)

1.Wide range of cancer genes can operate (upto90)

Balko Cancer Discovery 2014

2.Different subtypes have different genomic features

3.Extensive heterogeneity

(50)

Do mutations predict response?

(51)

Overall population:

No difference

gBRCA: Carboplatin superior to docetaxel

Tutt A SABCS 2016

(52)

Platinum sensitivity not associated with higher HRD scores in mTNBC

But BRCA mutation and methylation in primary

show very different relationships with platinum

response measured in metastatic disease

Tutt A IMPAKT 2017

(53)

Polyak K, Garber J. Nat Med. 2011

(54)

Olaparib versus physicians’ choice:

The phase III OLYMPIAD study in advanced gBRCA carriers

(55)

 Estimation of the lifetime risk of cancer in an individual and/or her family

 Identification of individuals at sufficient risk to consider enhanced screening or prevention strategies

 Provide prognostic information about standard therapy

 Offers opportunities for therapeutic intervention: predictive information

about response to specific therapies

(56)

Improve understanding of tumor biology:

-Spectrum of mutations becoming clearer

-Need to consider beyond the «singol gene» vision: beyond mutations, to gene expression, pathway activation, tumor microenvironment, cooperation between mutation, tumor heterogeneity.

-Need to understand clinical utility of other mutations and the evolution of tumors under treatment stress

Potential benefits of genomic testing

Conclusions

(57)