Focus sul test BRCA. Nicoletta Resta. DIMO -UOC Lab. Genetica Medica Università degli Studi di Bari

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2 Focus sul test BRCA Nicoletta Resta DIMO -UOC Lab. Genetica Medica Università degli Studi di Bari

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4 Numbers of ovarian cancer in Italy 4800 new cases in 2015 in Italy 3251 deaths in % III e IV stage

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6 Looking for BRCA 1 and BRCA s Localisation of the breast cancer susceptibility gene (BRCA1) on 17q Identification of BRCA1 by US scientists3 BUT BRCA1 mutations accounted for: 4 Most, but not all, families with many cases of both early onset breast and ovarian cancer that set Just under half of all families affected by multiple breast cancer cases But no families affected by both male and female breast cancer Smith SA, et al. Genes Chromosomes Cancer. 1994;10:71 6. Miki Y, et al. Science 1994;266: Futreal PA. Science. 1994;266: Wooster R, et al. Science 1994;265: Wooster R, et al. Nature 1995;378: BRCA2 localised to chromosome 13q Search for BRCA Identification of BRCA2 by UK scientists 6

7 Romero I et al. Endocrinology 2012; 153: OC subtypes: mutations

8 OC subtypes: mutations

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10 What is the function of BRCA 1 and BRCA 2? Tumor suppressor genes involved in DNA repair Autosomally transmitted (chromosomes 17 and 13) When mutated: higher incidence of hereditary breast and ovarian cancer (HBOC syndrome)

11 NHEJ HR SCID topi nulli AT-like Sindrome di Nijmegen Leucemia 1 caso Tumori ereditari della mammella e ovaio G1 predominante Rapido ma con errori Meccanismo d emergenza Ricombinazione meiotica Mantenimento dei telomeri checkpoint

12 What is the function of BRCA 1 and BRCA 2? HOMOLOGOUS RECOMBINATION

13 Mechanisms of chemosensitivity in BRCA carriers

14 What is the function of BRCA 1 and BRCA 2? Impairment of BRCA1 and BRCA2 function leads to DNA instability, telomere shortening and higher risk of endocrine related cancer (breast and ovary)

15 13-18% of women with an epithelial malignant OC, carries a germline mutation in either BRCA1 or BRCA2 while only 0.4% has a mutation in an MMR gene. In 2.5% of epithelial malignant OC patients, germline mutations in other genes, such as BRIP1, RAD51C, RAD51D, BARD1, PALB2 have been found. Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer NATURE REVIEWS CLINICAL ONCOLOGY George A. et al 2016

16 Risk of Breast /Ov Cancer in BRCA 1/2 carriers Table 4. Estimated Cumulative Breast and Ovarian Cancer Risks in Carriers of BRCA1 and BRCA2 Pathogenic Variants Study Breast cancer risk (%) by age 70 y (95% CI) Antoniou et al. (2003) [124] Ovarian cancer risk (%) by age 70 y (95% CI) BRCA1 BRCA2 BRCA1 BRCA2 65 (44 78) 45 (31 56) 39 (18 54) 11 (2.4 19) Chen et al. (2007) [125] 55 (50 59) 47 (42 51) 39 (34 45) 17 (13 21) CI = confidence interval. From: Genetics of Breast and Gynecologic Cancers (PDQ ) PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US);

17 Among the general population, the likelihood of having any BRCA variant is : General population (excluding Ashkenazim): about 1 in 400 (~0.25%) Women with breast cancer (any age): 1 in 50 (2%) Women with breast cancer (younger than 40 years): 1 in 10 (10%) Men with breast cancer (any age): 1 in 20 (5%) Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10% 15%)

18 Reasons to perform BRCA1/2 test in ovarian cancer patients

19 Reasons to perform BRCA1/2 test in ovarian cancer patients Identification of unaffected mutation carriers Prognostic importance/prediction of tumor behaviour Impact on patient treatment - Platinum sensitivity - Sensitivity to intraperitoneal chemotherapy - Sensitivity to other chemotherapy - Pegylated liposomal doxorubicin - Trabectedin - PARP inhibition

20 BRCA mutation is not limited to younger patients, with family history and high grade histotypes At least 25% of BRCA 1-2 mutation carriers are >60 yrs old Approximately 35%-40% of BRCA 1-2 mutation carriers do not have a family history of cancer Histologic type (except mucinous) is not a sufficient criterion for BRCA testing Malander S, et al. European journal of cancer 2004;40:422-8; Risch HA, et al. Journal of the National Cancer Institute 2006;98: ; Soegaard M, et al. Clinical cancer research 2008;14: ; Walsh T, et al. Proceedings of the National Academy of Sciences of the United States of America 2011;108: ; Alsop K, et al. Journal of clinical oncology 2012;30: ; Song H, et al. Human molecular genetics 2014;23:

21 Germline BRCA test BRCA mutation frequency in 1001 patients with non mucinous ovarian cancer Germline BRCA mutation detected in: 14.1% of the studied population 6.3% of clear cell subtype 8.4% of endometrioid subtype 16.6% of serous histotype 17.1% of high grade serous subtype 15.6% <40 yrs old 24.2% yrs old 17.1% yrs old 8.3% >60 yrs old 44% with no family history of both ovarian and breast cancer Alsop K, et al. J Clin Oncol 2012; 30:

22 BRCA mutation can be germline or somatic

23 BRCA mutation can be germline or somatic 10-15% ( 18%) delle pazienti con OC ha una mutazione germinale in BRCA1 o ,5%, 2,5-4% ha una mutazione esclusivamente somatica in BRCA1 /BRCA2 Totale 19-22% di OCs sono mutati in BRCA2 e 1 Weren R.D.A. et al Hum Mut 2016

24 BRCA mutational status evaluation In which patients? BRCA mutational status (either somatic o germline) should be evaluated in all patients with non mucinous OC diagnosis. When? Ideally at diagnosis, to complete the diagnostic step to both provide information for therapeutic choices and implement access to genetic counseling for screening.

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26 Somatic BRCA test

27 Overall study design and flow chart Questo approccio permetterà di individuare pazienti con mutazioni esclusivamente somatiche che beneficerebbero di un eventuale trattamento con Olaparib e che sfuggirebbero all attenzione se l analisi fosse condotta esclusivamente su sangue. Obiettivo secondario: I dati derivanti dalla caratterizzazione molecolare saranno analizzati e correlati alle caratteristiche istologiche, età alla diagnosi e presenza di familiarità neoplastica ovarica e non.

28 Pre-test genetic Counselling Il somatico può svelare il germinale Il contrario no I I I III IV K polmone 45 wt 11 8 K mammella triplo neg. 49 K ovarico bil 54 K ovaio 45 BRCA1 c.5062_5064delgtt

29 Somatic BRCA test

30 Seminars in Oncology 44 (2017) Key raccomandations for genetic testing on ovarian cancer tumor tissue samples

31 Somatic BRCA test

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35 L approccio multigenico ha ed avrà sempre più bisogno di linee guida rivisitate, nuove raccomandazioni, management changes linee guida per pazienti non affette con mutazioni in PALB2, BRIP1, BARD1, RAD51C e RAD51D...

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