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

TUM TUMORE RE OVARI ARICO E BRC BRCA: A: CAM AMBI BIARE ARE IL FUTUR UTURO SI PUO PUO'

Aula Delle Piane P .O. Sant'Anna AOU Città della Salute e della Scienza

Torino

8 Maggio 2019

Giorgia Mangil Ostetricia e Ginecologia Ginecologia Oncologica Ospedale San Raffaele Milano

Fertilità e gravidanza nelle pazienti a rischio -

Risks of developing specific cancers varies between carriers of BRCA1 and BRCA2 mutations

40‒85% risk of breast cancer 40‒85% risk of breast cancer 26‒65% risk of

• varian cancer

15‒25% risk of

• varian cancer

5‒10% risk of male breast cancer

1% risk

• f male

breast cancer 2‒9% risk of male pancreatic cancer (no prostate risk) 4‒6% risk of male pancreatic/ prostate cancer

BRCA1 mutation risks BRCA2 mutation risks

40‒85% risk of breast cancer 26‒65% risk of

• varian cancer

Pruthi S, et al. Mayo Clinic Proceedings 2010;85:1111‒1120. Ferla R, et al. Annals of Oncology 2007;18 (Suppl 6):vi93‒vi98. 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.

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

• ncologica

Rischio cumulativo a 80 anni BRCA1 tumore al seno : 72% tumore dell’ovaio : 44% BRCA2 tumore al seno : 69%% tumore dell’ovaio : 17%%

La potenziale perdita di fertilità legata alla patologia

• ncologica 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

Adapted from Peccatori et al., Hum Rep 2018 Gentilmente da Somigliana

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

BRCA mutation carriers show normal

• varian response in in vitro

fertilization cycles

Moran Shapira, B.Med.Sc.,a Hila Raanani, M.D.,b Baruch Feldman, M.D., Ph.D.,b Naama Srebnik, M.D.,c Sanaz Dereck-Haim, B.Sc.,b Daphna Manela, R.N.B.A.,b Masha Brenghausen, Ph.D.,b 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 Tamar Perri, M.D.,b Talia Eldar-Geva, M.D., Ph.D.,c and Dror Meirow, M.D.a,b

TABLE 1

Patient characteristics, COH course, and results in BRCA mutation carriers and matched controls. Characteristic BRCAD (n [ 62) Non-carriers (n [ 62) P value Age (y) 31.92 3.61 (25–40) 32.09 3.54 (24–40) .78 Day-3 FSH (mIU/mL)a 7.2 2.24 (2.4–12.1) 7.25 2.82 (3.4–17) 1 Day-3 E2 (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 Stimulation days 10.16 2.21 (5–16) 10.36 1.51 (6–14) .13 Maximum E2 (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 Poor response rate (%) 8.06 6.45 1 Zygotes 8.06 5.73 (0–26) 9.65 6.45 (1–26) .84 Fertilization rate 0.69 0.21 (0–1) 0.64 0.2 (0–1) .3

• 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

Association of BRCA1 Mutations With Occult Primary Ovarian Insufficiency: A Possible Explanation for the Link Between Infertility and Breast/Ovarian Cancer Risks

Kutluk Oktay, Ja Yeon Kim, David Barad, and Samir N. Babayev

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L R E P O R T

• NUMBER

• JANUARY

Table 2. Age, FSH, and Oocyte Number Comparisons Among BRCA Mutation–Negative, –Positive, and –Untested Women Variable BRCA Mutation Status P All Positive (n 12) All Negative (n 33) Untested (n 35) BRCA1 Positive (n 8)† All Negative and Untested (n 68)‡ 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 3.0 2.7 2.3 3.4 2.5 Oocytes Mean 7.9 11.3 13.5 7.4 12.4 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 Abbreviations: FSH, follicle-stimulating hormone; NS, not significant; SD, standard deviation.

†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

ORIGINAL ARTICLE

Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients

• M. Lambertini1,2*, O. Goldrat3, A. R. Ferreira4, J. Dechene3, H. A. Azim Jr 5, J. Desir6, A. Delbaere3,

M.-D. t’Kint de Roodenbeke1, E. de Azambuja1, M. Ignatiadis1 & I. Demeestere3

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) )

BRCA – mutated: Yes 29 - No 72

median AMH level: 1.8 lg/l and 2.6 mg/l ;P = 0.109)

A consistent trend for reduced reproductive potential and performance of cryopreservation strategies was observed in BRCA-mutated breast cancer patient

BRCA-positive cohort (N 5 10, 34.5%) BRCA-negative cohort (N 5 19, 65.5%) P valuesa (BRCA-positive versus BRCA-negative) BRCA1-positive (N 5 5, 50.0%) BRCA2-positive (N 5 5, 50.0%) BRCA-positive cohort (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

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

BRCA-positive cohort (N 5 19, 26.4%) BRCA-negative cohort (N 5 53, 73.6%) P valuesa (BRCA-positive versus BRCA-negative) BRCA1-positive (N 5 14, 73.7%) BRCA2-positive (N 5 5, 26.3%) BRCA-positive cohort (N 5 19, 100%) Type of surgery, N (%) Unilateral 3 (21.4) 0 (0.0) 3 (15.8) 4 (7.6) 0.371 Bilateral 11 (78.6) 5 (100) 16 (84.2) 49 (92.4) Fragments, median (IQR) 17 (13–20) 25 (20–28) 17 (13–23) 18 (14–22) 0.913 Follicle densityb, median (IQR) 5 (3–6) 4 (3–12) 4.5 (3–7) 6 (4–10) 0.318 Not evaluated, N (%) 1 (7.1) 0 (0.0) 1 (5.3) 3 (5.7) Number of oocytes, median (IQR) 3 (0–8) 1 (0–3) 2 (0–8) 2 (1–6) 0.682 Not collected, N (%) 7 (50) 0 (0.0) 7 (36.8) 18 (34.0) Number of oocytes per fragment, median (IQR) 0.08 (0–0.24) 0.08 (0.03–0.20) 0.08 (0–0.24) 0.14 (0.06–0.29) 0.193 Not evaluated, N (%) 8 (57.1) 1 (20.0) 9 (47.4) 28 (52.8) Number of oocytes per mm2, median (IQR) 0.24 (0–1.10) 0.37 (0.90–0.78) 0.33 (0–1.00) 0.78 (0.20–1.20) 0.153 Not evaluated, N (%) 8 (57.1) 1 (20.0) 9 (47.4) 28 (52.8) Number of cryopreserved oocytes, median (IQR) 1 (0–1) 1 (0–2) 1 (0–1) 0 (0–1) 0.422 Not collected, N (%) 7 (50.0) 0 (0.0) 7 (36.8) 18 (34.0)

aCalculated excluding the unknown values. bNumber of follicles per mm2.

IQR, interquartile range.

ORIGINAL ARTICLE

Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients

• M. Lambertini1,2*, O. Goldrat3, A. R. Ferreira4, J. Dechene3, H. A. Azim Jr 5, J. Desir6, A. Delbaere3,

M.-D. t’Kint de Roodenbeke1, E. de Azambuja1, M. Ignatiadis1 & I. Demeestere3

number of oocytes : per fragment 0.08 vs 0.14; P = 0.193 per square millimeter 0.33 vs 0.78 p= 0.153 women in the BRCA-positive cohort tended to have a numerically lower number of

• ocytes per fragment and per square millimeter

Two patients were transplanted after chemotherapy.

San Raffaele Scientific Institute

Lo stato mutazionale al momento della diagnosi e del consulto di onco- fertilità non è noto

Crioconservazione ovocitaria : possible recupero ovocitario minore Minor risposta alle gonatropine Possibile PGD Crioconservazione tissutale: Rischio per insorgenza tumore ovarico Interventi ripetuti In caso di riempianto di tessuto ovarico è necessario conoscere lo stato del BRCA Riposizionare sull’ ovaio residuo

J Clin Endocrinol Metab. 2016 Apr; 101(4): 1364–1371. Published online 2016 Jan 11. doi: 10.1210/jc.2015-3878 PMCID: PMC4880171 PMID: 26751194

Long-Term Safety of Letrozole and Gonadotropin Stimulation for Fertility Preservation in Women With Breast Cancer

There was no significant difference in the relapse-free survival between the FP and control groups, P = .57 who underwent FP 47 subjects with BRCA mutations 26 fertility preservation

Table 2. Impact of BRCA Mutations on Response to Ovarian Stimulation With Letrozole-FSH Protocol. Variables and Outcomes BRCA negative or untested (n ¼ 97) BRCA positive (n ¼ 21) P Value Adjusted P Valuea (95% CI) Age 33.2 (3.2) 32.7 (2.4) .680 BMI, kg/m2 22.1 (3.1) 23.5 (5.2) .695

• No. of total oocytes

16.4 (7.7) 11.0 (8.0) .015 .002 (10.6 to 2.5)

• No. of mature oocytes

10.6 (5.1) 7.4 (5.7) .047 .008 (7.2 to 1.1) Fertilization rate, % 79.3 (16.4) 74.0 (24.8) .277 .053 (20.1 to 0.2)

• No. of embryos frozen

8.2 (4.7) 5.1 (4.4) .013 .003 (7.1 to 1.5)

Abbreviations: BMI, body mass index; CI, confidence interval; SD, standard deviation.

aAdjusted for age and body mass index. Starting and total gonadotropin use did not differ between the groups. Results were given as mean (SD). A P value .05 was

considered statistically significant. Original Article

Ovarian Stimulation in Patients With Cancer: Impact of Letrozole and BRCA Mutations on Fertility Preservation Cycle Outcomes

Volkan Turan, MD1,2, Giuliano Bedoschi, MD1,3, Volkan Emirdar, MD1, Fred Moy, MD1, and Kutluk Oktay, MD, PhD, FACOG1,4

Reproductive Sciences 2018, Vol. 25(1) 26-32

ª The Author(s) 2017

Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1933719117728800 journals.sagepub.com/home/rsx

Dati contrastanti in letteratura

pregnancy

Pregnancy does not impair breast cancer prognosis Danforth

1991,Azim 2013

There is a general consensus that childbearing should be delayed until 3–5 years after completion of treatment This recommendation might vary according to cancer biology and stage Averette 1999, Ives 2007 Age plays an essential role

The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation

Adriana Valentini,

NIH Public Access

Author Manuscript

Breast Cancer Res Treat. Author manuscript; available in PMC 2014 November 01.

Published in final edited form as: Breast Cancer Res Treat. 2013 November ; 142(1): 177–185. doi:10.1007/s10549-013-2729-1.

• Fig. 2.

Breast cancer-specific survival for subjects with and without a pregnancy: from date of diagnosis

Page 12

• Fig. 3.

Breast cancer-specific survival in subjects with and without a pregnancy after breast cancer: follow-up from date of last birth

Pregnancy concurrent with or after a diagnosis of breast cancer does not appear to adversely affect survival among BRCA1/2 mutation carriers

v oocyte cryopreservation at 35- 40 years

• ld may not be effective

v few low quality oocytes can usually be retrieved oocyte cryopreservation could be an option for women at an earlier age

PGD

BRCA1/2 is an autosomal dominant condition It is an accepted indication for PGD (Preimplantation Genetic Diagnosis) 59% of counselled BRCA 1/2 carriers state that it should be offered

Shenfield et al., 2003; Chan et al., 2017; Gietel-Habets et al., 2017 Gentilmente concessa da E Somigliana

PGD

In women desiring parenthood but refusing the risk of vertical transmission, PGD should be considered. In these women, fertility preservation at a young age is highly valuable.

Carrying BRCA mutations is not a disease

In 2003 the Ethics Taskforce of the European Society of Human Reproduction and Embryology stated that:

“it is acceptable to perform preimplantation genetic diagnosis (PGD) for late

• nset and multifactorial diseases, including hereditary breast and ovarian cancer

(HBOC) “ In 2008 were the first to report a live birth following PGD for BRCA1 mutation (Jasper)

Hereditary breast and ovarian cancer and reproduction: an observational study on the suitability of preimplantation genetic diagnosis for both asymptomatic carriers and breast cancer survivors

Inge A. P. Derks-Smeets • Christine E. M. de Die-Smulders • Shari Mackens • Ron van Golde • Aimee D. Paulussen • Jos Dreesen • Herman Tournaye • Pieter Verdyck • Vivianne C. G. Tjan-Heijnen • Madelon Meijer-Hoogeveen • Jacques De Greve • Joep Geraedts • Martine De Rycke • Maryse Bonduelle • Willem M. Verpoest

v Male carriers v Asymptomatic female carriers v Breast cancer survivors 70 Couples underwent PGD for BRCA1/2 42/71 carriers (59.2 %) were female 145 PGD cycles were performed

294 (40.8 %) as BRCA-negative

23.9 % resulted in a clinical pregnancy 3 cycles involved PGD on embryos cryopreserved before chemotherapy 2 children 38 children 2 BRCA

In 2003 the European Society of Human Reproduction and Embryology (ESHRE) ethics taskforce considered PGD acceptable for conditions like hereditary breast and ovarian cancer (Shenfield et al., 2003). Accordingly, PGD for BRCA mutations is growing and has become the most common indication in some settings (Gietel-Habets et al., 2017).

Carrying BRCA mutations is not a disease

Oocytes cryopreservation in young age would anticipate the detrimental effects of the reduced ovarian reserve and would consent to collect top quality young oocytes. PGD is not a therapy per se, it exclusively selects unaffected embryos The effectiveness of oocytes cryopreservation in a urgent setting is not

• nly limited by the reduced ovarian reserve but also by the PGD policy

BRCA patients : risk of cancer diagnosis and cancer mortality women should receive comprehensive information to reach a shared decision

.Women should be informed in depth about possible advantages of v Preservation fertility v risk

standardized clinical management cannot be recommended

Human Reproduction, Vol.33, No.2 pp. 181–187, 2018 Advanced Access publication on December 1, 2017 doi:10.1093/humrep/dex356

OPINION

Fertility preservation in women harboring deleterious BRCA mutations: ready for prime time?

Fedro Alessandro Peccatori1, Giorgia Mangili2,*, Alice Bergamini2, Francesca Filippi3, Fabio Martinelli4, Federica Ferrari5, Stefania Noli1,3,6, Emanuela Rabaiotti2, Massimo Candiani2, and Edgardo Somigliana3,6

“La volevo ringraziare per a v e r i n s i s t i t o s u l l ‘ i m p o r t a n z a d i t a l e procedura..Io in quel momento non ne volevo s a p e r e , n o n v o l e v o assolutamente ritardare l'inizio della chemio. Le sono grata perchè l'aver f a t t o q u a l c o s a p e r garantirmi la possibilità di avere un figlio alla fine di questa brutta esperienza mi ha permesso di vivere q u e s t i m e s i c o n p i ù serenità (nessuna angoscia nel momento in cui le m e s t r u a z i o n i s i s o n o interrotte). Mi sono sentita al sicuro, almeno da questo punto di vista.”

European Institute

• f Oncology

National Cancer Institute San Raffaele Scientific Institute Fondazione Ca’ Granda, Ospedale Maggiore Policlinico Università degli Studi di Milano Fedro PECCATORI Alice BERGAMINI Emanuela RABAIOTTI Massimo CANDIANI Edgardo SOMIGLIANA ENRICO PAPALEO VERONICA SARAIS