Laura Cortesi BRCA12 Mutations Cancer Risks BRCA1 BRCA2 Breast cancer to age 80 5085 5085 Ovarian cancer to age 80 2060 up to 27 Male breast cancer Slight incr 6 Prostate cancer ID: 1041110
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1. NonBreast/NonOvarianBRCA1/2 related neoplasms: a growing entityLaura Cortesi
2. BRCA1/2 Mutations: Cancer RisksBRCA1BRCA2Breast cancer to age 8050-85%50-85%Ovarian cancer to age 8020-60%up to 27%Male breast cancer Slight incr. ~6%Prostate cancerSlight incr. Slight incr.Pancreatic cancerNo incr. 1.5-5%Melanoma No incr.Slight incrDaly MD: NCCN 2018 genetic/familial high-risk assessment clinical practice guidelines in oncology
3. Cortesi L. et al. Eur J Hum Genet. 2003 Mar;11(3):210-4.Italian family with two independent mutations: 3358T/A in BRCA1 and 8756delA in BRCA2 genes
4. Cancers Associated With BRCA1 and BRCA2 MutationsOther Than Breast and OvarianMersch J. et al. Cancer. 2015 Jan 15;121(2):269-75
5. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarianMersch J. et al. Cancer. 2015 Jan 15;121(2):269-75
6. SIR for 1072 individuals with BRCA mutations CancerBRCA1 SIRPBRCA2 SIRPBreast36.9<0.0127.7<0.01Ovarian139.1<0.0174.9<0.01Prostate3.80.094.80.02Pancreatic 4.7 0.02421.7<0.01Melanoma 3.30.040.80.88Mersch J. et al. Cancer. 2015 Jan 15;121(2):269-75
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12. Cortesi L, Int J Gynecol Cancer 2009Distribution of Second Primary Malignancies Suggests a Bidirectional Effect Between Breast and Endometrial CancerA Population-Based Study
13. Corso, JCRCO 2018
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18. BRCA+&PROSTATE CANCERSCREENING
19. Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT StudyBancroft E.K. et al. 2014 [Eur Urol 2014;66:489–99] -2015 corrigendum Study Design
20. Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT StudyBancroft E.K. et al. 2014 [Eur Urol 2014;66:489–99] -2015 corrigendum Fig. 2 – Consort diagram for the first round of screening.BRCA1 = breast cancer 1, early onset; BRCA2 = breast cancer 2, early onset; PSA = prostate-specific antigen; PPV = positive predictive value.* Controls were men who had a negative predictive genetic test for the BRCA mutation in their family.
21. Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT StudyBancroft E.K. et al. 2014 [Eur Urol 2014;66:489–99] -2015 corrigendum
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24. Figure 1. Genomic Aberrations in DNA Repair in Patients with Metastatic, Castration-Resistant Prostate Cancer.
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27. Clarke, N. ASCO 2018
28. BRCA+&PANCREATIC CANCERSCREENING
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30. A 49-expert multidisciplinary international consortium met to discuss pancreatic screening and vote on statements. Consensus was considered reached if ≥75% agreed or disagreedAgreementDisagreementa screening programme should detect and treat T1N0M0 margin-negative PC and high-grade dysplastic precursor lesions Consensus was not reached for the age to initiate screening or stop surveillance.first-degree relatives (FDRs) of patients with PC from a familial PC kindred with at least two affected FDRs; patients with Peutz–Jeghers syndrome; and p16, BRCA2 and hereditary non-polyposis colorectal cancer (HNPCC) mutation carriers with ≥1 affected FDR.There was no consensus on the need for EUS fine-needle aspiration to evaluate cysts.endoscopic ultrasonography (EUS) and/or MRI/magnetic resonance cholangiopancreatography not CT or ERCPThere was disagreement on optimal screening modalities and intervals for follow-up imagingPanINs and IPMN are a potential target for early detection and treatment.There was no consensus on resect any solid lesion > 5 mmWhen surgery is recommended it should be performed at a high-volume centreThere was great disagreement as to which screening abnormalities were of sufficient concern to for surgery to be recommended.
31. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriersGolan T, BJC 2014
32. Family history as a marker of platinum sensitivity in pancreatic adenocarcinomaFogelman D, Can Chemoth Pharm 2015
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35. Clinical Trial for BRCA2 pancreatic cancer N°PhaseDrugsCriteriaNCT02309632ScreeningAnnual ImagingPJS,BRCA1,BRCA2,ATMFAMMM,HNPCC,HPNCT02000089Prospective ObservationalHuman synthetic secretinPC, PJS, BRCA1/2, HNPCCNCT01585805II RandomizedGemcitabine, cisplatin with or without veliparib or veliparib aloneBRCA1/2, Stage III/IV PCNCT01233505IVeliparib, oxaliplatin, capecitabineAdvanced PC, BRCA1/2NCT00892736IVeliparibAdvanced PC, BRCA1/2NCT01339650 IABT-767Advanced PC, BRCA1/2NCT01078662IIOlaparibAdvanced PC, BRCA1/2
36. ConclusionsTo date screening of HRIs has had unsatisfactory outcomesMore efforts will need to improve early diagnosisAs shown in breast and ovarian cancer, patients with PC and BRCA1/2 mutations are more sensitive to platinum-derived drugsNew drugs, such as PARP-inhibitors, seem provide a better outcome in phase II trialsWhich role of immunotherapy in IPC?
37. BR: 33Pan: 64D: 6672862010: BRCA2 9106C/T (Stop2960)HBCCaso N: 1366 Br: 4263262013: Adenocarcinoma duttale moderatamente differenziato del pancreas di 3,5 cmBr: 40D: 422016: BRCA + evidenza di incremento di micro, con focalità RM di 6 mm + altra focalita'.
38. DETECTION RATE BRCA 21.3%DETECTION RATE BRCA 24.5%
39. Chromosome 13 13q12-13BRCA2 1 2 3 4 5 6 7 8 9 10 11 12 14 16 18 20 22 24 25 26 27 13 15 17 19 21 23 c.-227 c.1910 c.6842 c.8488 c.96499871delT8247_8248delGA 7558C>T4889C>G9098_9099insA7180A>T3847_3848delGT9097dupA5621_5624delTTAA 7480C>T6468_6469delT51_52delAC8246_8247delAGExonsNucleotidesMutations7/16 (43.7%) mutations within a region defined by c.7180-c.8248 (EXON14, 15 and 18)
40. DETECTION RATE BRCA 21.3%DETECTION RATE BRCA 24.5 %
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42. OVERALL PATIENTS WITH PANCREATIC CANCERPATIENTS WITH PANCREATIC CANCER IN BRCA FAMILYPATIENTS WITH PANCREATIC CANCER IN GENERAL POPULATIONETA’ alla diagnosi di k pancreas65,8 aa(360 pts)65,7 aa(31 pts)72 aa [1] OS 12 mesi133 (37%)13 (42%)24%OS ≥ 5 anni13 (4%)1 (3%)OS a 5 aa 5% [2] In vita alla compilazione dell’albero19 (6%)3 (10%)[1] AIOM 2016, [2] AIRTUM 2016
43. Skin cancer risk in BRCA1/2 mutation carriersP.V. Gumaste, L.A. Penn, R.M. Cymerman, T. Kirchhoff, D. Polskyand B. McLellanBritish Journal of Dermatology (2015) 172, pp1498–1506
44. Ov: 6161Pr: 65D: 65Pr: 7578Pan: 79D: 797286CBR:3437CSU: 52LUNG: 59D: 59Pan: 42D: 42BRCA2 c.6468_6469delTCSFBOC+Caso N: 2955 40362016: carcinosi peritoneale da ca sieroso grado 3 origine ovarica
45. BR: 33Pan: 64D: 6672862010: BRCA2 9106C/T (Stop2960)HBCCaso N: 1366 Br: 4263262013: Adenocarcinoma duttale moderatamente differenziato del pancreas di 3,5 cmBr: 40D: 422016: BRCA + evidenza di incremento di micro, con focalità RM di 6 mm + altra focalita'.
46. BR: 33OV: 60D: 602010: BRCA1 184T/C, Leu22SerFOCCaso N: 2182Ov: 47Lung: 5757OV: 45D: 45Pr:D:
47. Mel: 45657076Ov: 4748ST: 81D: 82BLADDER: 69D: 74BRCA2 8250G/C, Gln2674HisHBOCCaso N: 1558 403833Liver: 83D: 84BR: 6974ST: 78D: 79Esof:: 85D: 85 BR: 67D: 67BR: 53D: 53BR: 70D: 78
48. EOBCHBC/HBOC/SHBOC/FBOC/SFBOCBOCHOCMBC SFBC+BRCAPRO or Tyrer-Cuzick > 40% in unaffected womanTNBC ≤ 60High Grade OCFamilies eligible for BrCa1 and/or BrCa2 Emend. Ottobre 2016
49. Come comportarci in ambulatorio in presenza di mutazioni BRCA o possibili?Pr CaPCMelBRCA1PSA a*DRE** aBRCA2PSA aDRE aEUS/RM aBSFE*** a* annual;**Digital Rectal Examination;*** Body Skin Full Examination