Dear doctor, what about a baby? Myths and facts

Dear doctor, what about a baby? Myths and facts OLIVIA PAGANI BREAST UNIT AND INSTITUTE OF ONCOLOGY OF SOUTHERN SWITZERLAND IBCSG

Background About 15% of patients with BC are diagnosed during their reproductive years In the last decades women tend to delay childbearing for different reasons (i.e. cultural, educational, professional) In an increasing number of patients BC occurs before the completion of their reproductive plans Pagani et al., BCRT 2011;129(2):309-17

Delayed Childbearing Mathews T & Hamilton B; NCHC 2014

Pregnancy rate after cancer: not all alike Thyroid cancer Melanoma Non-Hodgkin's lymphoma Hodgkin's lymphoma All cancers Brain tumors Analysis adjusted for education level, previous pregnancy age Germ cell tumors Acute leukemia Cervical cancer Epithelial ovarian cancer Breast cancer 0.0 0.5 1.0 1.5 Stensheim et al; Int J Cancer 2011 Post-cancer pregnancy rates in 27,556 survivors and compared to controls from the general population from 1967 to 2004.

Fertility and chemotherapy Ovarian reserve 106 105 Primordial follicle population Toxicity risk 104 Pelvic Rx. Alkylating agents platinum agents 103 10 20 30 40 50 Age (years) 60 Taxanes Plant alkaloids Anthracyclines Assessment of individual Patient fertility Anti metabolites Meirow & Wallace 2010

Ovarian reserve after chemotherapy CHEMOTHERAPY

Different approaches for fertility preservation Currently used & experimental Primordial follicles Early growth Mature eggs Stored ovarian tissue Follicle maturation Not practiced ovarian tissue transplantation In-vitro Egg maturation mature Egg embryo Freezing

Early referral ID: initial diagnosis, FPC: fertility preservation counseling BS: breast surgery, OS/OR: ovarian stimulation/oocyte retrieval

Controlled ovarian stimulation: Letrozole 79 letrozole 136 controls Median FU 2 years

Fertility preservation before neoadjuvant chemotherapy Still considered a sticky issue by some doctors Safety of high estrogen levels with the tumor in the breast Safety of delaying neoadjuvant chemotherapy

Consider offering LHRHa during chemo Odds Events, Events, Author Ratio (95% CI) Treated Controls Badawy (2009) 0.06 (0.02, 0.20) 4/39 26/39 Sverrisdottir 1 (2009) 0.19 (0.04, 1.06) 14/22 18/20 Sverrisdottir 2 (2009) 2.03 (0.31, 13.27) 27/29 20/23 Del Mastro (2011) 0.27 (0.14, 0.54) 13/148 35/133 Gerber (2011) 0.56 (0.19, 1.62) 9/30 13/30 Munster (2012) 1.09 (0.22, 5.52) 4/26 3/21 Elgindy 1 (2013) 0.76 (0.18, 3.25) 4/25 5/25 Elgindy 2 (2013) 1.00 (0.25, 4.00) 5/25 5/25 Song (2013) 0.50 (0.25, 1.03) 15/89 27/94 Karimi-Zarchi (2014) 0.05 (0.01, 0.29) 2/21 14/21 Moore (2015) 0.30 (0.10, 0.87) 5/66 15/69 Li M (2008) 0.31 (0.11, 0.89) 8/31 17/32 Sun (2011) 0.38 (0.06, 2.30) 3/11 5/10 Li Jw (2014) 0.44 (0.04, 4.35) 1/54 3/73 Fixed effect (I = 47.1%, p = 0.026) 0.34 (0.25, 0.46) 114/616 206/615 Random effect 0.36 (0.23, 0.57).01.1.5 1 2 8 14 Favors LHRHa / Favors Controls Lambertini et 2015, Annals of Oncology

Transplantation of Ovarian Tissue

Ovarian Tissue Cryopreservation: Success rates Pregnancy rate = 20/80 (25%) Donnez J et al, Lancet 2015; 385(9967):506-7

Adapted from Lambertini Summary

What about pregnancy after breast cancer?

Background Pregnancy after breast cancer does not seem to increase the risk of relapse, and it may even be protective Birth outcome after BC is apparently not different from the general population De Simone, Pagani, Minerva Ginecol. 2017

Pregnancy after breast cancer: DFS 5 studies 655 cases and 4372 controls HR: 0.84 (0.69-1.02) p=0.07 2 studies accounting for the healthy mother effect 440 cases and 1218 controls HR: 0.93 (0.68-1.28) p=0.66 Breast Cancer Res Treat. 2016;160:347-360

Pregnant cases: 333 1. History of 1 BC 2. Became pregnant after BC diagnosis 3. No evidence of relapse before becoming pregnant 4. Known ER-status Matched controls: 874 3 controls/pregnant case History of 1 BC matched according to 1.ER status (+ vs. -) 2.Nodal status (N0 vs. N+) 3.Adjuvant chemo, hormonal (Yes vs. No) 4.Age at diagnosis (< vs. > 35) 5.Year of diagnosis (± 5 years) 1,207 eligible patients Lambertini M et al JNCI 2017

OS Median follow up from conception 4.7 years Azim HA Jr et al JCO 2013;31(1):73-9.

OS according to ER status ER+ patients ER- patients Median follow up from pregnancy 7.2 years Lambertini M et al JNCI 2017

Early pregnancy apparently not detrimental Lambertini M et al JNCI 2017 Better DFS in Pregnant Better DFS in Controls

Fetal Outcome Reference Langagergaard Dalberg Azim Number 216 331 45 Mean age (y) 34.4 34 34 Treatment CTH CTH CTH + T Stillbirth (%) 0.8 Mean GW 38 42 Mean Fetal weight 3.0 3.5 0 39 3.4 0.3 37 42 (88%) 3.5 0.5 39 3.4 Malformations (%) 2 4 3.8 7.5 3 y: year; GW: gestational week; gm: grams Langagergaard V et al; BJC 2005 Dalberg K et al; PLOS Med 2006 Azim HA Jr et al; Breast Cancer Res Treat 2012

What about breast feeding?

Better DFS in Pregnant Better DFS in Controls Gelber S, JCO 19:1671, 2001 Lambertini M et al JNCI 2017

Pregnancy after breast cancer: BRCA1/2mutation 128 cases, 269 controls Mean age: 32.5y (25-42) BRCA1: 82% BRCA2: 18% Mean time to pregnancy: 2.4y (0-16)

What additional evidence DO we need? IBCSG 48-14 / BIG 8-13 POSITIVE TRIAL

Screening/eligibility: Patients with ER+ early breast cancer 18 and 42 years at enrollment Completing 18-30 months of ET (SERMs alone, GnRH analogue + SERM or AIs) 1 Pregnancy desire Stop ET 2 E N R O L L M E N T 3 months wash out POSITIVE SCHEMA Up to 2 years break to allow conception, delivery ± breast feeding ET resumption to complete 5 (-10) yrs Follow-up 1 + CT 2 No more than 1 month prior enroll. 0 3 24 mos 10 yrs Ovarian function evaluation Translational research Uterine evaluation Circulating tumor DNA (ctdna) Genomic evaluation of primary breast tumor Psycho-oncology companion psychological distress, fertility concerns, decisional conflict Accrual: 212 pts overall 26 babies so far 20 countries/183 centers

Trial objectives Primary To assess the risk of BC relapse associated with temporary interruption of ET to permit pregnancy. Secondary To evaluate factors associated with pregnancy success after interruption of ET.

POSITIVE Study Awareness Video https://youtu.be/ripkvmqs_3g Dissemination: Approved by the lead EC in Switzerland ESO Network (available on the ESO YouTube channel) Europa Donna and other Patient Advocates IBCSG and BIG websites Cooperative Groups/Centers websites and social networks Language: IT, currently available with English, German and French subtitles (translation in other languages in progress)

2 Centers activated in Korea so far Joy, the 1 baby born within POSITIVE in 2016 1 patient enrolled on March 23 rd!!! Congratulations!

Conclusions Evaluate sterilization risks. Choose fertility preservation approach. Egg, embryo freezing; results similar to noncancer patients. Not post exposure to chemotherapy. Ovarian tissue freezing- established clinical method.

Conclusions and challenges The available data suggest pregnancy after breast cancer is safe How long to wait between completion of therapy and conception? Is it safe to interrupt ET to conceive? For those who can t conceive egg donation, surrogacy, adoption minefield of bureaucratic and legal issues Desire for pregnancy in an era of prolonged survival in MBC (e.g. HER2+ disease)

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