Ricombinazione omologa nel carcinoma ovarico: BRCA e oltre

F. Raspagliesi MD

raspagliesi@istitutotumori.mi.it

Ricombinazione omologa nel

carcinoma ovarico: BRCA e oltre

BRCA1 and BRCA2 mutation carriers had better OS and PFS than non-carriers, regardless of stage, grade or

Histotype

Prognosis Identify unaffected carriers

The results of BRCA

testing in a woman with ovarian cancer can help to identify family

members at risk

Fase II and III studies on maintenance therapy with PARP inhibitors showed an improvement of

therapeutic results in ovarian cancer patients with HRD

Therapy

BRCA “ molecular signature in ovarian cancer”

• In a clinicopathological analysis patients with hereditary cancer had a longer DFI after primary chemotherapy, as well as a longer survival Boyd J, JAMA 2000.

• However, at 10 years this benefit is only mantained in BRCA2m patients

For example in Study 10 patients with BRCAm treated with Olaparib had an 82% reduction of risk of progression or death compared with placebo (HR 0.18)

This was greater than in olaparib treated non BRCAm patients who had a 46% reduction of roisk vs placebo (HR 0.54)

Poli ADP Polimerasi (PARP)

DNA Repair systems

Fanconi anemia proteins

Kinases

Phosphorylate

Ricombinasi

HR Deficient

Potentially HR Deficient

BRCA-1 BRCA-2

40-85% risk of Breast cancer

26-65% risk of Ovarian cancer

40-85% risk of Breast cancer

10-25% risk of Ovarian cancer

BRCA Epidemiology

Different studies suggest that BRCA mutation may be present in 15- 44% of individuals with no family history of breast/ovarian cancer The prevalence of germline BRCA pathogenic variants

• >10% in patients affected by OC regardless of age (at the diagnosis) and family history Soegaard M,. Clin. Cancer Res. 2008,

• 17-20% in patients affected by serous OC Alsop K J ClinOncol 2012

• 23-25% if high grade Rust KBJOG. 2018

• 30-40% in case of platinum sensitive disease

IARC criteria

1,500 variants

Genetic variants include nonsense, frameshift, splicesite, and some missense mutations, as well as large deletion duplications and re-arrangements

3,800 mutations

ENIGMA Evidence-based Network for the interpretation of Germline Mutant Alleles

Tumour Suppressor genes and cancer predisposition

How to evaluate HR deficiency

HRD can be tested using three main strategies

Germline mutation screening of HRD related genes

Somatic mutation screening of HRD related genes

Evaluation of “genomic scar” ( genomic instability secondary to HRD) in BRCAwt patients

• A high LOH (> 14-16%), suggests the presence HRD (ARIEL 2 – Rucaparib PSR)

• LOH can also be evaluated together with telomeric allelic imbalance and large- scale transitions to generate an HRD score (MyChoices HRD test, Myriad

Genetics) >42 – benefit from maintenance niraparib in the NOVA trial.

Loss-of-function mutations involving other HR pathway genes

• hypermethylation of the BRCA1 promoter - EMSY amplification - ATM, ATR, BARD1, BRIP1, MRE11A, PALB2, RAD50, RAD51D, RAD54, NBS1, CHEK1, and CHEK2, components of the Fanconi anemia repair pathway

Multiplex Ligation Probe dependent Amplification (MLPA)

Multiplex Amplicon Quantification (MAQ).

BRCA 1-2 somatic vs blood testing

Tumour Blood

Methods not yet validated Does not identify patients with somatic mutations

Types of mutations not well defined Tumor Genetic profile may change with progression and chemotherapy

Response to PARPi – only preliminary data Need high % of tumor cell / DNA

Analysis not always possible

Require additional expertise in pathology

Tumour Blood

Can detect somatic and germline mutation Validated methods are available Analisys feasible in 100% of cases Identifies a greater number of patient who

may benefit from PARPi

Patients , pathways and procedures well established

Less extensive genetic conseling and less involvement of the family

Strong association with PARPi response Reverted BRCA1/2 mutation can identify

patients resistant to treatment

Sample is easy obtained with High quality DNA

348 pts of French cohort

PARPi Clinical Studies

Clinical outcomes to PARP inhibitors in the platinum sensitive

recurrent are similiarly improved in sBRCAm and in gBRCAm ovarian cancer patients compared to BRCAwt patient

Clinical Outcomes Studies

Clinical outcomes to standard platinum treatment are similarly improved in sBRCAm and in gBRCAm ovarian cancer patients

compared to BRCAwt patient

Scientific Evidence

Multiple evidence ( Loss of heterozygosity , clonality, mutual exclusivity) indicate biologic equivalence of sBRCA and gBRCA testing

Edwards SL, Nature2008; NorquistB, J Clin Oncol 2011; Patch AM, Nature2015; Sakai W. Cancer research2009

WHO SHOULD BE TESTED

NCCN

Women with familiar history of ovarian cancer, fallopian tube, peritoneum cancer

SGO

Women with diagnosis of ovarian, tubal and peritoneal cancer even in absence of family history

ASCO

Women with diagnosis of Ovarian tubal and

peritoneal cancer even in absence of family history

ESMO

Patients with HG tumors should be tested for

germline BRCA mutation Consideration should be given to testing tumors for a somatic mutation

AIOM Recommendation – 2019

Thank You