Ricombinazione omologa nel carcinoma ovarico: BRCA e oltre. F. Raspagliesi MD

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1 Ricombinazione omologa nel carcinoma ovarico: BRCA e oltre F. Raspagliesi MD raspagliesi@istitutotumori.mi.it

2 BRCA molecular signature in ovarian cancer In a pooled analysis of 26 observational studies BRCA mutation carriers (1213) showed a better prognosis than non-carriers(2666); Bolton KL, JAMA 2012 In a clinicopathological analysis patients with hereditary cancer had a longer DFI after primary For example in Study 10 patients with BRCAm treated with Olaparib chemotherapy, as well as a longer survival Boyd had an 82% reduction of risk of progression or death compared with J, JAMA placebo (HR 0.18) This was greater than in olaparib However, treated at 10 non years BRCAm this patients benefit who is only mantained in had a 46% reduction of roisk BRCA2m vs placebo patients (HR 0.54) Prognosis BRCA1 and BRCA2 mutation carriers had better OS and PFS than non-carriers, regardless of stage, grade or Histotype Identify unaffected carriers The results of BRCA testing in a woman with ovarian cancer can help to identify family members at risk Therapy Fase II and III studies on maintenance therapy with PARP inhibitors showed an improvement of therapeutic results in ovarian cancer patients with HRD

3 Fanconi anemia proteins Kinases DNA Repair systems Poli ADP Polimerasi (PARP) Phosphorylate Ricombinasi

4 Potentially HR Deficient HR Deficient

5 BRCA-1 BRCA % risk of Breast cancer 40-85% risk of Breast cancer 26-65% risk of Ovarian cancer 10-25% risk of Ovarian cancer

6 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 % if high grade Rust KBJOG % in case of platinum sensitive disease

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8 Genetic variants include nonsense, frameshift, splicesite, and some missense mutations, as well as large deletion duplications and re-arrangements 3,800 mutations 1,500 variants ENIGMA Evidence-based Network for the interpretation of Germline Mutant Alleles IARC criteria

9 Tumour Suppressor genes and cancer predisposition

10 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 largescale 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

11 Multiplex Ligation Probe dependent Amplification (MLPA) Multiplex Amplicon Quantification (MAQ).

12 BRCA 1-2 somatic vs blood testing Tumour Can detect somatic and germline mutation Identifies a greater number of patient who may benefit from PARPi Less extensive genetic conseling and less involvement of the family Reverted BRCA1/2 mutation can identify patients resistant to treatment Tumour Methods not yet validated Types of mutations not well defined Response to PARPi only preliminary data Need high % of tumor cell / DNA Blood Validated methods are available Analisys feasible in 100% of cases Patients, pathways and procedures wel established Strong association with PARPi response Sample is easy obtained with High quality DNA Blood Does not identify patients with somatic mutations Tumor Genetic profile may change with progression and chemotherapy Analysis not always possible Require additional expertise in pathology

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15 348 pts of French cohort

16 Clinical Outcomes Studies Clinical outcomes to standard platinum treatment are similarly improved in sbrcam and in gbrcam ovarian cancer patients compared to BRCAwt patient 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 Scientific Evidence Multiple evidence ( Loss of heterozygosity, clonality, mutual exclusivity) indicate biologic equivalence of sbrca and gbrca testing

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

18 WHO SHOULD BE TESTED NCCN Women with familiar history of ovarian cancer, fallopian tube, peritoneum cancer ASCO Women with diagnosis of Ovarian tubal and peritoneal cancer even in absence of family history SGO 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

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20 AIOM Recommendation 2019

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22 Thank You