8 Maggio 2019 Risks of developing specific cancers varies between - PowerPoint PPT Presentation

Giorgia Mangil TUM TUMORE RE OVARI ARICO E BRC BRCA: A: Ostetricia e Ginecologia Ginecologia Oncologica CAM AMBI BIARE ARE IL Ospedale San Raffaele Milano FUTUR UTURO SI PUO PUO' Fertilità e gravidanza nelle pazienti a rischio - Aula Delle Piane P .O. Sant'Anna AOU Città della Salute e della Scienza Torino 8 Maggio 2019

Risks of developing specific cancers varies between carriers of BRCA1 and BRCA2 mutations BRCA1 mutation risks BRCA2 mutation risks 40 ‒ 85% risk of breast 40 ‒ 85% risk of breast 40 ‒ 85% risk of breast cancer cancer cancer 26 ‒ 65% risk of 26 ‒ 65% risk of 15 ‒ 25% risk of ovarian cancer ovarian cancer ovarian cancer 1% risk 5 ‒ 10% risk of of male male breast breast cancer cancer 2 ‒ 9% risk of 4 ‒ 6% risk of male male pancreatic pancreatic/ cancer (no prostate Pruthi S, et al. Mayo Clinic Proceedings 2010;85:1111 ‒ 1120. prostate risk) Ferla R, et al. Annals of Oncology 2007;18 (Suppl 6):vi93 ‒ vi98. cancer Kirchhoff T, et al. Clin Cancer Res 2004;10:2918 ‒ 2921. Greer JB, Whitcomb DC. Gut 2007;56:601–605. Tai YC, et al. J Natl Cancer Inst 2007;99:1811–1814.

Rischio cumulativo a 80 anni BRCA1 BRCA2 tumore al seno : 69%% tumore al seno : 72% tumore dell’ovaio : 44% tumore dell’ovaio : 17%% ü Molte pazienti al momento della diagnosi di tumore non hanno ancora completato il loro desiderio riproduttivo e l’infertilità rappresenta una delle maggior preoccupazioni ü La preservazione della fertilità deve essere uno degli obiettivi prima della cura oncologica

La potenziale perdita di fertilità legata alla patologia oncologica è considerata nelle donne in età riproduttiva un evento traumatico, di portata comparabile alla diagnosi stessa di cancro (Lee et al., 2011; Treves et al., 2014; Armuand et al., 2015). Ø impatto a livello individuale : depressione, ansia e crollo dell'autostima; Ø impatto sulla relazione di coppia : tensioni relazionali, alterazione della sfera sessuale (calo di frequenza dei rapporti intimi, perdita di desiderio o riduzione del piacere) Ø impatto sulle relazioni sociali allargate : isolamento, sentimenti di invidia verso donne che hanno conseguito facilmente una gravidanza, senso di inadeguatezza e di impotenza rispetto alla propria condizione

+ BRCA e infertilità : esiste una relazione? Che cosa fare

San Raffaele Scientific Institute v pazienti con mutazione ammalate v pazienti non malate con mutazione Lo stato mutazionale al momento della diagnosi e del consulto di onco- fertili non è noto

Ovarian Reserve Study Mutation N. (case+Ctr) Outcome Main results Oktay et al ., 2010 BRCA 1/2 8+33 Oocytes after COH 7 vs 12 ( p=0.02 ) for BRCA1 Finch et al ., 2013 BRCA 1/2 902+908 Age at menopause: 49 vs 50 yrs ( p=0.001 ) Lin et al ., 2013 BRCA 1/2 382+765 Age at menopause 50 vs 53 yrs ( p<0.001 ) Titus et al ., 2013 BRCA 1/2 24+60 AMH 1.2 vs 2.2 ng/ml ( p<0.001 ) Wang et al ., 2014 BRCA1 62+54 AMH 0.5 e 1.0 ng/ml ( p<0.05 ) Giordano et al ., 2016 BRCA1 33+23 AMH 1.3 vs 1.8. ( p<0.005 ) Collins et al ., 2013 BRCA 1/2 819+1021 Age at Menopause 51 vs 51 ( p=NS ) Michaelson-Cohen et al ., 2014 BRCA 1/2 41+324 AMH 2.7 vs 2.0 ( p=NS ) Shapira et al ., 2015 BRCA 1/2 62+62 Oocytes after COH 14 vs 15 ( p=NS ) Van Tilborg et al ., 2016 BRCA 1/2 124+131 AMH 1.9 vs 1.8 ( p=NS ) Dati contrastanti in letteratura Adapted from Peccatori et al., Hum Rep 2018 Gentilmente da Somigliana

TABLE 1 Patient characteristics, COH course, and results in BRCA mutation carriers and matched controls. BRCA mutation carriers show normal BRCA D (n [ 62) Characteristic Non-carriers (n [ 62) P value Age (y) 31.92 � 3.61 (25 – 40) 32.09 � 3.54 (24 – 40) .78 ovarian response in in vitro Day-3 FSH (mIU/mL) a 7.2 � 2.24 (2.4 – 12.1) 7.25 � 2.82 (3.4 – 17) 1 Day-3 E 2 (pmol/L) a 157.3 � 72.1 (37 – 305) 165.1 � 71.23 (70 – 294) .67 Total stimulation dose (IU) b 2,482 � 1,658 (747 – 9,000) 2,658 � 1,399 (1,125 – 7,200) .23 fertilization cycles Stimulation days 10.16 � 2.21 (5 – 16) 10.36 � 1.51 (6 – 14) .13 Maximum E 2 (pmol/L) 7,625 � 4,383 (540 – 17,020) 7,986 � 4,429 (1,073 – 17,000) .65 Oocyte yield 13.75 � 7.6 (1 – 35) 14.75 � 8.8 (3 – 38) .49 Moran Shapira, B.Med.Sc., a Hila Raanani, M.D., b Baruch Feldman, M.D., Ph.D., b Naama Srebnik, M.D., c Poor response rate (%) 8.06 6.45 1 Sanaz Dereck-Haim, B.Sc., b Daphna Manela, R.N.B.A., b Masha Brenghausen, Ph.D., b Zygotes 8.06 � 5.73 (0 – 26) 9.65 � 6.45 (1 – 26) .84 Liat Geva-Lerner, M.D., Ph.D., d Eitan Friedman, M.D., b Efrat Levi-Lahad, M.D., Ph.D., e Doron Goldberg, M.D., c Fertilization rate 0.69 � 0.21 (0 – 1) 0.64 � 0.2 (0 – 1) .3 Tamar Perri, M.D., b Talia Eldar-Geva, M.D., Ph.D., c and Dror Meirow, M.D. a,b Note: Values are mean � SD unless otherwise noted. For continuous parameters, numbers in parentheses represent range of outcomes. a Data presented for non-cancer patients only. a Sackler School of Medicine, Tel-Aviv University, Tel Aviv; b Division of Obstetrics and Gynecology, Chaim Sheba Medical b Data were available for 70% of patients. Shapira. IVF performance in BRCA mutation carriers. Fertil Steril 2015. Conclusion(s): Both healthy and cancer-affected BRCA mutation carriers demonstrated normal ovarian response in IVF cycles Table 2. Age, FSH, and Oocyte Number Comparisons Among BRCA Mutation–Negative, –Positive, and –Untested Women BRCA Mutation Status VOLUME 28 NUMBER 2 JANUARY 10 2010 � � All Positive All Negative Untested BRCA1 Positive All Negative and Untested Variable (n � 12) (n � 33) � (n � 35) (n � 8)† (n � 68)‡ P J OURNAL OF C LINICAL O NCOLOGY O R I G I N A L R E P O R T Age, years NS Mean 33.1 32.8 33.0 33.9 32.9 SD 2.8 2.9 2.9 2.7 2.9 Day-2 FSH, mU/mL NS 5.7 7.1 6.4 6.2 6.7 Association of BRCA1 Mutations With Occult Primary 3.0 2.7 2.3 3.4 2.5 Ovarian Insufficiency: A Possible Explanation for the Link Oocytes Mean 7.9 11.3 13.5 7.4 12.4 Between Infertility and Breast/Ovarian Cancer Risks 95% CI§ 4.6 to 13.8 9.1 to 14.1 11.4 to 16.0 3.1 to 17.7 10.8 to 14.2 Kutluk Oktay, Ja Yeon Kim, David Barad, and Samir N. Babayev Abbreviations: FSH, follicle-stimulating hormone; NS, not significant; SD, standard deviation. � P positive v negative � .025. † P BRCA1 mutation–positive v –negative and untested combined � .03. ‡ P positive v negative and untested combined � .003. §Analysis was performed after log conversion because of non-normal distribution. Thus, 95% CIs were used instead of SDs. Conclusion : BRCA1 mutations are associated with occult primary ovarian insufficiency

Annals of Oncology 29: 237–243, 2018 doi:10.1093/annonc/mdx639 Published online 10 October 2017 BRCA – mutated: Yes 29 - No 72 ORIGINAL ARTICLE median AMH level: 1.8 lg/l and 2.6 mg/l ;P = 0.109) Reproductive potential and performance of fertility preservation strategies in BRCA -mutated breast cancer patients M. Lambertini 1,2 *, O. Goldrat 3 , A. R. Ferreira 4 , J. Dechene 3 , H. A. Azim Jr 5 , J. Desir 6 , A. Delbaere 3 , M.-D. t’Kint de Roodenbeke 1 , E. de Azambuja 1 , M. Ignatiadis 1 & I. Demeestere 3 1 Department of Medicine, Institut Jules Bordet and Universite ´ Libre de Bruxelles (U.L.B.), Brussels, Belgium; 2 Breast Cancer Translational Research Laboratory, Institut BRCA-positive : dose of gonadotropins : 2775 versus 2025 IU; P =0.085 longer duration of stimulation : 11.5 versus 9 days P= 0.110 tended to retrieve :6.5 versus 9; P = 0.145 cryopreserve :3.5 versus 6; P =0.121) ) P values a BRCA -positive cohort ( N 5 10, 34.5 % ) BRCA -negative cohort ( BRCA- positive BRCA1- positive BRCA2- positive BRCA- positive ( N 5 19, 65.5 % ) versus ( N 5 5, 50.0 % ) ( N 5 5, 50.0 % ) cohort BRCA- negative) ( N 5 10, 100 % ) Total FSH dose (IU), median (IQR) 2775 (2700–2850) 2775 (1800–3000) 2775 (1800–3000) 2025 (1575–2425) 0.085 Type of stimulation, N (%) Follicular 3 (60.0) 3 (60.0) 6 (60.0) 11 (57.9) 1.000 Random 2 (40.0) 2 (40.0) 4 (40.0) 8 (42.1) Stimulation days, median (IQR) 11 (10–11) 12 (12–12) 11.5 (10–12) 9 (8–11) 0.110 E2 at trigger (pmol/l), median (IQR) 419 (95–442) 187 (159–238) 213 (95–442) 200 (92–615) 0.909 P at trigger (pmol/l), median (IQR) 1.37 (0.81–1.76) 0.45 (0.45–1.50) 1.09 (0.45–1.76) 0.84 (0.59–1.40) 0.854 Number of oocytes, median (IQR) 7 (3–7) 6 (3–7) 6.5 (3–7) 9 (5–13) 0.145 Number of mature oocytes, median (IQR) 7 (3–7) 4 (2–5) 4.5 (2–7) 7 (5–9) 0.299 Maturation rate, median (IQR) 1.0 (1.0–1.0) 0.7 (0.7–0.7) 0.8 (0.7–1.0) 0.9 (0.7–1.0) 0.888 Number of cryopreserved oocytes, median (IQR) 5 (2–7) 3 (2–4) 3.5 (2–7) 6 (4–12) 0.121 Poor response rate, N (%) 2 (40.0) 2 (40.0) 4 (40.0) 2 (11.1) 0.147 A consistent trend for reduced reproductive potential and performance of cryopreservation strategies was observed in BRCA-mutated breast cancer patient

ORIGINAL RESEARCH published: 11 April 2019 doi: 10.3389/fendo.2019.00235 Association of BRCA Mutations and Anti-müllerian Hormone Level in Young Breast Cancer Patients Kyung-A Son, Dong-Yun Lee* and DooSeok Choi Le mutazione BRCA hanno: AMH : 2.6 ng/ml vs 3.85 ng/ml p=0.004 BRCA 1: 2.56 ng/mL, P = 0.001 BRCA 2: 2.64 ng/mL, P = 0.036 Nessuna differenza fra BRCA 1 e BRCA2