1. Breast cancer and fertility preservation Modern trends University of Kansas School of Medicine Fertility and Sterility Vol. 95, No. 5, April 2011 Presented by Hsing-Chun Tsai 2012.08.07

2. Background In USA, 5~7% of cases of invasive breast cancer (~11,000/year) occur in women under age 40 at diagnosis. Less than 10% of women who develop invasive breast cancer under age 40 have children postdiagnosis. –half desire to do so –no studies indicate ↑ risk of relapse or death for women who became pregnant after diagnosis –Receipt of cytotoxic chemotherapy is a major factor in the low rate of live births after diagnosis.

3. Breast cancer 2/3 women 2cm, and/or involved axillary LNs (stage II or higher)  gonadotoxic chemotherapy > 2/3 women < 40 y/o at diagnosis  hormone receptor (+)  5 years of antihormone therapy with Tamoxifen ± GnRHa * Tamoxifen (selective estrogen receptor modulator)

4. The problem is... Amenorrhea is therapeutically desirable to reduce recurrence and improve survival. Delay childbearing by > 5 years –↓ chance of having a child –Cytotoxic chemotherapy will significantly add to age- related follicular depletion Even women who regain menses after C/T ± antihormone therapy are likely to have undergone significant follicle depletion and reproductive aging of 10 years or more.

5. As breast cancer mortality continues to decrease, it becomes a major issue for young breast cancer patients Fertility preservation As breast cancer mortality continues to decrease, it becomes a major issue for young breast cancer patients Timing: Classically, fertility preservation procedures are performed in the 2~4 weeks interval between surgery and initiation of adjuvant chemotherapy.  depending on menstrual cycle at the time of referral to fertility specialist Neoadjuvant therapy  complicated –window for optimal preservation is dramatically narrowed –during follicle stimulation, tumor is still in place  particularly if the tumor is estrogen receptor (+)

6. Successful cancer treatment strategy for reproductive age patients  initial focus of oncologists –Many young cancer patients fail to receive the information about fertility preservation!!  grief and regret –Only half of young patients feel that concerns about fertility are addressed adequately at the time of diagnosis. To review... PubMed database –Benefits of adjuvant systemic therapy given to young breast cancer patients and its effect on fertility –Fertility preservation options (interdigitate into the treatment plan)

7. Key questions 1.How is adjuvant treatment selected ? 2.How much will adjuvant treatment reduce risk for recurrence or death from breast cancer ? 3.What is the chance that adjuvant therapy will result in loss of fertility and how can this risk be minimized ? 4.Will any of the fertility preservation procedures or pregnancy result in higher risk of relapse ? 5.What are the fertility preservation options and how would they be inserted into the breast cancer treatment plan ?

8. How is adjuvant treatment selected ?

9. Adjuvant treatment selected based on both stage and biological characteristics 15-year mortality rate for women under 50 y/o Low-risk, LN(-): 12.5% High risk, LN(-): 25% LN(+): 50% Biological markers: Estrogen and progesterone receptor (ER and PR) Proliferation (usually by Ki-67) Presence of growth factor receptors, such as HER-2 neu

10. 5-yr disease- free survival rates higher rate of late relapse higher relapse rate in the first 5 years

11. If chemotherapy improves the prognosis ? Europe and Canada  only antihormone ± ovarian suppression USA  offered C/T, particularly for pts < 40 y/o at diagnosis Gene expression array panels  if (+)  likely to benefit from C/T

12. ER(-), PR(-)  >1cm or <1cm with high grade or HER-2 (+)  C/T HER-2(+)  trastuzumab for up to a year

13. How much will adjuvant treatment reduce risk for recurrence or death from breast cancer ?

14. In general, adjuvant therapy in premenopausal women is likely to reduce recurrence and death by >50% Early generation regimen  40% ↓ in recurrence and 1/3 ↓ in 15-yr mortality; for low-risk, LN(-) pts –6-12 cycles of cyclophosphamide, MTX, fluorouracil (CMF) –4 cycles of anthracycline and cyclophosphamide (AC) 2 nd generation regimen  44% ↓ in 15-yr mortality –6 months of fluorouracil, epirubicin, and cyclophosphamide (FEC) –fluorouracil, adriamycin (doxorubicin), and cyclophosphamide (FAC)

15. Tamoxifen alone  ↓ mortality by ~30% for ER(+) pts under 50 and by 40% for those under 40 Tamoxifen + anthracycline-containing regimen  ↓ mortality by 57% for ER(+) pts under 50 Taxanes  ↑ benefit with anthracycline + cyclophosphamide, except luminal A cancer Overall 3% absolute ↑ in survival; ↓ dose of A and C TAC x 6 cycles TAC x 4 cycles – taxane q3w (q2w) x 4 cycles/ weekly x 12 cycles

16. Trastuzumab (herceptin)  improves relapse-free and overall survival by ~50% in HER-2 (+) tumors intravenous bisphosphonates every 3-6 months for 2-3 years  ↓ recurrence by 1/3 in premenopausal women with ER(+) tumors given Tamoxifen + GnRHa

17. What are the chances that adjuvant therapy will induce loss of fertility and how can this risk be minimized ?

18. The primary determinants of C/T induced loss of fertility: –AGE at the time of C/T –Dose and number of cycles of alkylating agents received –Exposure to anthracycline, taxanes, platinum (to lesser extent) Alkylating agent: Cyclophosphamide –Oldest and most effective drugs for breast cancer –One of the most potent in reducing ovarian follicular reserve 2.4-3g/m 2 cyclophosphamide for 12-16 weeks = adding ~10 years to her ovarian reproductive age or 1.5-3.0 years per cycle

19. Amenorrhea –CMF x 6 cycles or AC x 4 cycles  33% –FEC or FAC x 6 cycles or AC x 6 cycles  50-65% –permanent in 90% of pts >40 y/o, and in 95% of pts >45 y/o 15-50% of patients < 40 y/o at diagnosis will recover menses.

20. Alternative chemotherapy regimens reducing follicular damage for luminal B tumors: FEC x 6 cycles  FEC x 3 cycles followed by docetaxel x 3 cycles –less ovarian damage due to ↓ amount of alkylating agents for Her-2(+) tumors: TP (carboplatin) as effective as TAC –completely avoid cyclophosphamide for triple negative tumors: selectively benefit from cis- or carboplatin + poly-(ADP-ribose) polymerase (PARP) inhibitors –trials ongoing, less gonadotoxic

21. ... Will pregnancy after a breast cancer diagnosis increase the chance of recurrence and miscarriage ?

22. Becoming pregnant after diagnosis of breast cancer DOES NOT result in worse outcomes. ↓ risk of relapse, particularly for pts who waited for 2 years after diagnosis to conceive theoretical risk of undergoing ovarian harvest before C/T and later reimplantation: reintroduction of viable tumor cells micrometastastic to the ovary serial sectioning of ovary after prophylactic oophorectomy  the chance in pts without clinical systemic metastases at diagnosis is <1% miscarriage rates: breast cancer vs. controls: 24% and 18% age-adjusted RR associated with breast cancer history: 1.7 (95% CI: 1.1-2.8)

23. What are the fertility preservation options and how would they be inserted into the breast cancer treatment plan ?

24. Fertility preservation options GnRHa Controlled ovarian stimulation (COS) with cryopreservation of mature oocytes or embryos Cryopreservation of immature oocytes or IVM Cryopreservation of ovarian tissue Donor egg Surrogacy Adoption

25. GnRH agonists If GnRHa or antagonist can protect human oocytes from gonadotoxic dose of chemotherapy ? ------ controversial Badawy et al.: “breast cancer with adjuvant C/T”  POF GnRHa (goserelin 3.6 mg): 11.4% (significantly lower) no GnRHa: 66.6%  prove protective effect of GnRHa but F/U period was too short 3 RCT, 8 non-RCT  no significance ongoing trial: SWOG

26. Embryo cryopreservation Clinically well established technique: adequate time for ovarian stimulation and a partner or donor sperm available −ovarian stimulation  TVOR  IVF (2~5 weeks) −Society of Assisted Reproductive Technologies: current live-birth rate per transfer using frozen embryos is 35.6% in US women < 35 y/o exposure to a high estrogen milieu  not safe for women with ER(+) breast cancer due to the potential for accelerated tumor growth Ongoing debate: short-term ↑ in hormone in COS  ↑ risk of breast cancer

27. Prevention of the elevated serum E2 level with COS in breast ca. pts natural cycle IVF  not realistic option due to less embryo per cycle and no time for multiple IVF cycles Conventional COS protocol  ↑ E2 level may adversely affect tumor growth Alternative approaches: COS with Tamoxifen or letrozole alone or concurrently with gonadotropins

28. Tamoxifen letrozole Tamoxifen: selective estrogen receptor modulator Letrozole: 3 rd generation aromatase inhibitor both effective for breast cancer treatment and ovulation induction (OI) add low-dose gonadotropin for good outcome E 2 level: letrozole + gonadotropin* << tamoxifen + gonadotropin * recurrence rate of breast cancer not ↑ at 2-yr F/U

29. COS for IVF in breast cancer Goals: letrozole + rFSH  encouraging results −To minimized the elevation of E 2 levels during stimulation cycle −To shorten the course of COS −To maximize the number of oocytes Protocol for ER/PR(+) patients 5mg x 6~7 d rFSH (150-300IU) ± hMG leading follicle 14 mm > 2 follicles at 18-19 mm initiate on day of TVOR, for 5~7 days to suppress E 2 * TVOR performed 3-5 days after last letrozole dose  risk of letrozole to embryos is negligible

30. Oocyte cryopreservation no partner, not want to use donor sperm ovarian stimulation  TVOR  IVF (creation of unnecessary embryos can be prevented !!) 1 st live birth from cryopreserved human oocytes in 1986, and > 900 healthy babies born worldwide till now still considered experimental in USA current live-birth rates from frozen-thawed oocytes comparable to frozen-thawed embryo cycles −No ↑ rate of congenital anomaly

31. To date, most human oocytes cryopreserved at metaphase II stage either by slow freezing or vitrification method from 1998-2008, vitrified group vs. slow frozen group: −oocyte survival rate: 81% vs. 68% −live-birth rate per ET: 34% vs. 14% mature oocyte cryopreservation is still challenging !! −extremely sensitive to temperature change −have limited capacity for repairing cytoplasmic damage −cryoprotectants and intracellular ice formation during freezing-thawing procedure  depolymerization of meiotic spindle  aneuploidy

32. Vitrification of oocytes Solidification of liquid by rapid cooling  eliminates ice crystal formation  ↑ oocyte survival and ↓ ultrastructure damage Smith et al.: embryos from vitrified oocytes had significantly enhanced clinical (38%) pregnancy rates compared with embryos resulting from slow frozen oocytes (13%) use of high conc. of vitrification solutions  chemically and osmotically toxic to human oocytes ice formation during warming can be detrimental to living cells no standard vitrification protocol of oocytes

33. Cryopreservation of immature oocytes Germinal vesicle (GV) oocytes can be an attractive alternative. Does not require full ovarian stimulation −pts who cannot delay cancer treatment or have ER(+) tumors −at high risk for OHSS, like PCOS Still not very successful … −GV oocytes vulnerable to cryoinjury and easily compromised for normal maturation and fertilization capacity −The cytoplasmic structure in the immature oocyte can be a more critical factor for cryoinjury than metaphase spindle of mature oocyte.

34. Cryopreservation of ovarian tissue for pts need treatment without delay or unwilling to undergo ovarian stimulation ovarian harvest by LSC  freezing of thin slices of ovarian cortex (mainly composed of primordial follicles, resistant to freeze-thaw injury with 70-80% survival rate)  transplantation proven successful in both animals and humans only 13 healthy human babies born

35. Urgent, but physical and psychological state of the pts should be evaluated before the procedure … AGE: > 40 y/o  not good candidates for ovarian tissue banking routine evaluation of ovarian reserve with endocrine tests + TVS: FSH, inhibin A & B, AMH Safety, risk of reintroduction of cancer cells occult ovarian involvement is rare in breast cancer to date, > 30 cases of ovarian transplantation done current experience not sufficient to assess its safety

36. Ovarian transplantation ~ experimental procedure~ Orthotopic transplantation transplanted onto the remaining ovary (  ) or ovarian fossa Heterotopic transplantation can avoid invasive procedures and make recovery of oocyte easy repeated transplantation required  shortened life span of ovarian grafts hostile pelvic environment: previous radiation or severe adhesion Optimal site is unknown.  SC tissue of forearm, between rectus sheath and rectus m., breast tissue no successful case

37. Facilitating fertility preservation consultation Time &Cost Timely consultation

38. Conclusions Informed decision making regarding future fertility for young breast cancer patients can lead to decreased patient regret and improved quality of life. Use of less gonadotoxic regimens for adjuvant or neoadjuvant chemotherapy may be considered in young patients. Embryo cryopreservation is a well-established technology and suitable for women who have a partner. Oocyte cryopreservation is an alternative option that can avoid ethical and legal issues.

39. Conclusions COS is required for both embryo and oocyte cryopreservation, and an increase in peak E 2 levels with COS may accelerate the tumor growth in ER(+) breast cancer. −using tamoxifen or letrozole with gonadotropin as alternative Cryopreservation of ovarian tissue is experimental procedure. Timely fertility consultation is necessary.

40. THANK YOU !!