Onco-fertility. Fertility issues in young women with breast cancer in Japan. National Cancer Center Hospital, Tokyo Chikako Shimizu, MD

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1 Onco-fertility Fertility issues in young women with breast cancer in Japan National Cancer Center Hospital, Tokyo Chikako Shimizu, MD

2 COI disclosure Chikako Shimizu receives contracted research fund from Pfizer, Chugai and Eli-lily.

3 Outline Introduction Characteristics of breast cancer in young women Methods of fertility preservation Issues faced in the clinic Future perspective

4 Breast cancer in young women The social trend towards later marriage and pregnancy

5 I want to have a child in the future even though I have a cancer I am not sure if I was successful in telling my doctors about my fear about both cancer and fertility. There is no communication between my oncologist and obstetrician.

6 Service and information needs of cancer patients < 35 years Male Female Illness and treatment Fertility diet exercise N=243

7 Younger age is a risk factor for worse prognosis Nixon. J Clin Oncol 1994; 12: Kataoka et al.

8 Breast cancer in young women is phenotypically malignant Kataoka. Breast Cancer 2014

9 AGING AND DECLINE IN QUANTITY OF OOCYTES 30 s chance of natural conception 25% Over 40 chance of natural conception 12% % of non-growing follicules 40 歳 PLoS ONE, 5,2010 Human ovarian reserve from conception to the menopause: WallaceWHB, kelsey TW

10 Aging during adjuvant endocrine therapy

11 Decrease of ovarian reserve Oktem & Oktay. Cancer 110; , 2007 Ben-Aharon I. Reproduction 2012.

12 Ovarian protection using LHRH-analogue Author Bawady Del Mastro Leonard Gelber Munster Elgindy POEMS Year NEJM2015 n design R2 R3 R3 R2 R3 R2 R3 LHRHA goserelin triptorelin goserelin goserelin triptorelin triptorelin goserelin chemo FAC A, A+T, CMF C+/-A+/-T AC+/-T FAC, FEC, AC, AC-T FAC Standard CTx (3-8 Mo) Eligible age NR Median (range) 30 (26-33) 39(24-45) NR 37 ( (21-43) 33 (18-40) 37 (25-49) % ER+ NR 81% NR 0% 73% 0% 0% Endpoint definition Menstrual resumption/ spontaneous ovulation Menstrual resumption endpoint %POF@3M outcome 90% vs 33% (p<0.001) Pregnancy outcome ASCO guideline update (J Clin Oncol, 2013) Currently, there is insufficient evidence regarding the effectiveness of GnRHa and other means in fertility preservation In a true emergency or rare or extreme circumstances that where proven options are not available, prividers may consider GnRHa an option, preferablely as part of clinical trial. 91% vs 74% (p<0.001) Menstrual resumption % Menstrual resumption % more than 2 menstrual 6M NS 70% vs 57% (p=0.284) Menstrual resumption % menstrua 2Y 88.5% vs 90.5% (NS) Menstrual resumption % menstral resumption@12m 72% vs 60% (p=0.15) Amenorrhea>6M & postmenopausal FSH level % ovarian failure@2yr 8% vs 22% (p=0.04, n=135) NR 3 vs 1 NR 1 vs 1 0 vs 2 21% vs 11% Modified from Turner et al. Ann Oncol. 2013

13 Prediction of ovarian function after chemotherapy using anti-mullerian hormone Ruddies, Breast Cancer Res Treat 2014

14 Assisted Reproductive Technology IVF-ET (ART) (ICSI) 日産婦誌 2010

15 Barriers for communicating with patients about fertility preservation: health care providers Survey for breast 1. High risk of recurrence 2. Lack of communication with reproductive specialists 3. Time constraints in the clinic Shimizu, Breast Cancer 2013 Survey for reproductive 1. High or unknown risk of recurrence 2. Lack of knowledge about breast cancer Shimizu, Int J Clin Oncol, 2014 Network of breast oncologists and reproductive specialists Clinical guide that provide the latest information about breast oncology and reproductive technology Decision aid for patients may help reduce the clinical burden of healthcare providers

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17 Evidence-based Clinical Guideline on Pregnancy and Reproductive Technology for Women with Breast Cancer CQ1-3 Communicating with patients and healthcare providers CQ4-6 Pregnancy in breast cancer patients CQ7-17 Breast cancer treatment for patients who wish to preserve fertility CQ18-28 Reproductive technology for patients with breast cancer CQ29-32 Clinical management before attempting pregnancy and after pregnancy Published Sep 2014 Evidence is scarce!!!

18 International Society of Fertility Preservation Model for Development of Onco-fertility Program J Assist Reprod Gen 2012; 29: 469

19 The practice flow : fertility preservation 1. Ask patients if they wish for future parenthood 2. Evaluate cancer prognosis, cancer treatment & fertility 3. Inform patients about methods of fertility preservation 4. Decision making 5. Egg collection (+/-IVF) cryopreservation 6. Cancer treatment 7. Embryo transfer

20 Time constraints vs. E2 elevation by ovarian hyperstimulation

21 Ovarian tissue cryopreservation Donnez J et al. Hum. Reprod. Update 2006

22 Age-dependent deterioration of quantity and quality of eggs

23 Does pregnancy affect cancer outcome? Matched case-control study ER, N, adjuvant Tx, age, year of Dx 乳癌術後の妊娠は安全か? Before wide usage of assisted reproductive technology Azim H A et al. JCO 2013;31:73-79

24 Conflicts faced in onco-fertility clinic Safety of ovarian hyperstimulation (especially in neoadjuvant setting) Time restriction for egg collection Safety of suboptimal cancer treatment High risk of complication : pregnancy and delivery in older women Pregnancy in patients with worse prognosis/ metastasis

25 Primary objective To assess the risk of BC relapse associated with temporary interruption of ET to permit pregnancy. a piece of information to guide patient decision? Secondary objective To evaluate factors associated with pregnancy success after interruption of ET.? IBCSG / BIG 8-13

26 Trial schema Screening/eligibility: Patients with ER+ early breast cancer Age 18 and 42 years at enrollment Completing 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 Up to 2 years break to allow conception, delivery ± breast feeding ET resumption to complete 5 (-10) yrs Follow-up 1 + CT mos 10 yrs 2 No more than 1 month prior enroll. Translational research Plasma for ctdna Serum for ovarian function (AMH, FSH,E2) Serum PRL/TSH Transvaginal US (Optional AFC) Serum progesterone Plasma for ctdna Transvaginal US (AFC optional) Selected centers: Endometrial biopsy Serum for ovarian function (AMH, FSH,E2) Serum PRL/TSH 3-6 months post ET restart: Plasma for ctdna 2 nd trimester of pregnancy: Plasma for ctdna IBCSG / BIG 8-13

27 Decision-aid for patients Information to collect to make personal decision

28 Counseling by oncology team & fertility specialists improves QOL & decreases decision regret Letourneau JM et al. Cancer 2012

29 Personalizing Cancer Care Personalizing care means understanding the biology of the patient as well as the tumor and how genotype can impact outcome Personalized cancer care extends beyond cancer treatment, of course, to assessment of cancer risk, end-of-life care, and cancer survivorship Personalizing cancer care also relates to how we communicate with our patients as individuals, not statistics, as people with serious illness who live in a social network that involves family members, coworkers, friends, and others. Finally, personalizing cancer care means that we make every effort to understand the biologic, clinical, social, and economic diversity of cancer patients and ensure that all patients have access to highquality cancer care delivered in their community by providers they can relate to and trust. Richard L. Schilsky. ASCO Presidential Address 2009.

30 Thank you!