Medicina de precisión en cáncer de ovario: Determinación de BRCA germinal y somático

Dra. Cristina Martin Lorente

Hospital de la Santa Creu i Sant Pau. Barcelona

Introduction

• Ovarian cancer is the fifth leading cause of cancer death in women in

developed countries. Estimated incidence of 225,000 women and

140,000 deaths per year worldwide

• Optimal surgery and platinum-based chemotherapy are the mainstay

of front-line treatment but about 80% will relapse

• Up to 15% of epithelial OC cases are familial. Inherited mutations in

BRCA1/2 account for the majority of familial OC with an increased

lifetime risk of developing OC 40-60% BRCA1 and 11-30% BRCA2

Globocan 2012. Ford D et al Am J Hum Genet 1998. National Cancer Institute 2017. Ford D et al Am J Hum Genet 1998

Ovarian Cancer (OC): Multiples Diseases

• Different types with different behaviour

• Most Common – High grade serous ovarian cancer (HGSOC)

• HGSOC: Associated with characteristics of genomic instability (TP53) and homologous recombination deficiency (BRCA)

Defining BRCAness Phenotype

• Ovarian cancers in women

with BRCA1/2 germline

mutations are characterized by

an improved response to

platinum-based chemotherapy

at first and subsequent

relapses and better outcomes

(PFS, OS)

Tan D JCO 2008; Fong FC JCO 2010; Audeh MW Lancet 2010; Ledermann J Lancet 2014; Fong FC NEJM 2009

Defining BRCAness Phenotype

• BRCA1/2 germline mutated populations have also shown

exceptional sensitivity to PARP inhibitors (PARPi)

Tan D JCO 2008; Fong FC JCO 2010; Audeh MW Lancet 2010; Ledermann J Lancet 2014; Fong FC NEJM 2009

Use BRCA deficiency for treatment

Olaparib

Rucaparib

Veliparib

Niraparib

BMN-673

Tewari Clin Cancer Res 2015

Targeting BRCA in Ovarian Cancer:

An approach for personalizing

management of OC

PARP inhibitors in clinical trials

Response by BRCA status:

ORR 41% with BRCAm vs 24% BRCAwt

Gelmon et al. Lancet Oncol 2011

Study 19: To assess the efficacy and safety of

oral Olaparib as maintenance treatment

A randomised, double-blind, placebo-controlled Phase II maintenance

study 265 patients in 82 investigational sites in 16 countries

Olaparib

400 mg po bid

Randomised 1:1

Placebo

po bid

Patients:

• Platinum-sensitive high-grade serous

ovarian cancer

• 2 previous platinum regimens

• Last chemotherapy was platinum-

based, to which they had

a maintained PR or CR prior to

enrolment

Treatment

until

disease

progression

Primary end point: Progression free survival

Ledermann J et al. N Engl J Med 2012

Olaparib met the primary endpoint of improving PFS

in the OVERALL study population

Ledermann J et al. N Engl J Med 2012

More than 50% patients had a known

deleterious BRCAm (Pre-planned BRCA testing)

Patients with a known BRCA status increased from 98 (37%) to 254 (95.8%) out of 265: • 136 (51.3%) patients had a known deleterious BRCAm (BRCAm dataset) • 118 (44.5%) patients were defined as BRCA1/2 wild type for this analysis • 11 (4.2%) patients had neither a tumour nor a germline result available

Ledermann J et al. N Engl J Med 2012

Olaparib significantly prolonged PFS in

platinum-sensitive relapsed HGSOC –Patients with a BRCA mutation receive greater treatment benefit

–Non-mutation carriers may also benefit from olaparib treatment

0

Time from randomization (months)

0

1.0

Pro

po

rti

on

of

pati

en

ts

pro

gressio

n-f

re

e

3 6 9 12 15

Olaparib BRCAm

Olaparib BRCAwt

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

BRCAm (n=136) BRCAwt (n=118)

Olaparib Placebo Olaparib Placebo

Median PFS,

months

11.2 4.3 7.4 5.5

HR=0.18

P<0.00001

HR=0.53

P=0.007

BRCAm (n=136) BRCAwt (n=118)

Olaparib Placebo Olaparib Placebo

Median PFS,

months

11.2 4.3 7.4 5.5

HR=0.18

P<0.00001

HR=0.53

P=0.007

Placebo BRCAm

Placebo BRCAwt

Ledermann et al. N Eng J Med 2012. Ledermann et al. Lancet Oncol 2014

BRCAness Phenotype

• BRCA germline mutations

• BRCA somatic mutations

• Similar to germline BRCAm, PFS was longer in somatic BRCAm population compared with wildtype

• Germline or somatic HR mutations was highly predictive of primary platinum and PARPi sensitivity and improved overall survival

Hennessy JCO 2010/ Pennington CCR 2014

WHO TO TEST?

In the past we used to refer patients to genetic

counseling based on their family history and personal

history

Nowadays we have a broaden vision of the disease

which supports that this policy is not accurate enough

• Frequency of BRCA1/2 mutations in women with OC is unclear (3-27%). 1001 women enrolled

onto a population-based case-control study were screened

• Germ-line mutations were found in 14.4% of patients (22.6% HGSOC; 8.4% endometrioid;

6%CC; 0% carcinosarcoma)

• 44% had not reported family history of breast or OC

• BRCAm was associated with better outcomes (RR, PFS, OS)

Conclusions: BRCA status has a major influence on survival, treatment outcomes and treatment

selection and SHOULD BE OFFERED TO ALL WOMEN DIAGNOSED WITH NON-MUCINOUS OC

REGARDLESS OF FAMILY HISTORY

Alsop K JCO 2012

WHO TO TEST?

What about SOMATIC Testing?

Ovarian cancer in women with BRCA somatic mutation (BRCAg wt) is also characterized by an improved response to platinum-based chemotherapy and PARP inhibitors and by better outcomes with longer PFS and improved OS

Olaparib approved by EMA as first-in-class treatment for advanced BRCA-MUTATED (germline and somatic) ovarian cancer (January 2015)

BRCA somatic mutation testing expands the number of patients who would benefit from personalized medicine

WHEN TO TEST?

Initial diagnosis preferable

PRO

• Access to pathology

• Biomarker of response to platinum-based chemotherapy

• Prognostic factor

• Likely PARPi will be approved in front-line setting

• Genetic counselling

CON: Evidence supporting temporal heterogeneity in OC

WHICH ONE FIRST?

GERMLINE TESTING

• Well-established

• Lymphocyte DNA more

reliable

• Need for genetic counselling

• Wildtype, still need to test

somatic mutation

SOMATIC TESTING

• Streamline testing

• Less need for genetic

counselling

• Require good quality of DNA

• Technical Considerations

BRCAness Phenotype

• BRCA germline mutations

• BRCA somatic mutations (Hennessy JCO 2010)

• Other Homologous Recombination DNA repair defects (Kristeleit

ECC0 2015. Pennington CCR 2014)

Levine. Nature 2011

HRD Assays: Lines of Research

• Next-generation sequencing assays. Gene expression analysis.

– BROCA: analysis of mutations of key HR genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, RAD51D).

– 60-genes signature of “BRCAness”…

High correlation with response to platinum-based therapy an overall survival. NOT VALIDATED.

• Functional ex-vivo assays: RAD51 nuclear foci formation by immunofluorescence or other DNA repair complexes by immunohistochemistry

• PRO: Dynamic and functional biomarker

• CON: Requires fresh tissue. Reproducibility.

• Genome scars.

– ARIEL 2. Rucaparib and genomic LOH assay (Foundation Medicine)

– NOVA trial. Niraparib and HRD score (myChoice HRDTM Myriad)

HRD Assays: ARIEL 2 • Different mechanisms can lead to HRD with the final result of genomic

instability and large areas of genomic scaring (uniparental deletions)

• HRD causes genome wide LOH that can be measured by NGS

• TCGA and AOCS developed LOH cutoff based on overall survival to

identify patients with HGSOC with BRCA-like signature

McNeish IA ASCO 2015. TCGA Nature 2011. Wang Clin Cancer Res 2012

CONCLUSIONS

• BRCAness profile is now beyond mutations in BRCA germline

• This profile predicts platinum and PARPi sensitivity and better

clinical outcomes

• BRCA testing in the germline and in the tumor expands up to

20% the number of patients who would benefit from targeted

treatments

• Ideally, patients should be tested at diagnosis

• The validation of HRD assays and multiple gene sequencing panels

to guide treatment selection is under evaluation

• Clinical trials on-going will offer additional insight

GRACIAS

ARIEL 2 (Part 1): Phase 2 trial to prospectively

identify OC responders to rucaparib using tumor genetic analysis

Kristeleit et al ECCO 2015

Efficacy Analysis ARIEL 2 (Part 1)

PFS in tBRCAmut and tBRCA-like vs. biomarker negative

patients

Duration of response in tBRCAmut

and tBRCA-like vs. biomarker

negative patients

Kristeleit et al ECCO 2015

ENGOT-OV16/NOVA Phase 3 randomized double-blind of maintenance with niraparib

vs. placebo in patients with platinum sensitive OC

Mirza ESMO 2016

Tesaro. WorldCDx 2015

HRD Assays: HRD Score

HRD Assays: HRD Score

The HRD test does not identify origin of mutation (germline or somatic) It is based on sequencing ~54,000 SNP regions of the genome and the BRCA1/2 genes (myChoice HRDTM Myriad)

Tesaro. WorldCDx 2015

gBRCA Mutated gBRCA Wild Type

NOVA Trial: PFS by gBRCA status

Mirza ESMO 2016

NOVA Trial: Exploratory Analysis PFS in

gBRCAwt Subgroups

Mirza ESMO 2016

• To identify potential biomarker drivers of efficacy is urgently needed

• The presence of HRD may be a valid strategy for selection for DNA repair inhibitors as PARPi

• The actual HRD assays do not seem to be accurate enough to identify patients who don’t benefit from PARPi

Conclusions