Breast Cancer & Fertility Preservation

This study is the first randomized controlled trial (RCT) to compare the effectiveness of tamoxifen, a selective estrogen receptor modulator (SERM), and the aromatase inhibitor letrozole to a standard ovarian stimulation protocol in women preserving fertility before breast cancer treatment.

Study Background

WHAT

• Does ovarian stimulation (+/-) letrozole or tamoxifen impact the number of mature oocytes retrieved in women trying to preserve fertility before starting breast cancer treatment?

• Hypothesis: there are no differences between treatments in oocyte retrieval success

WHY

• Breast cancer treatment can save lives but negatively impact fertility

• Ovarian stimulation for fertility preservation exposes women with breast cancer to high levels of estrogen (temporarily)

• Unclear efficacy of counterbalancing estrogen exposure by addition of tamoxifen or letrozole to standard ovarian stimulation treatment

WHERE

• Ten sites in the Netherlands (three non-university + seven university hospitals) plus one university hospital in Belgium

WHEN

• January 2014-December 2018

WHO

• 162 women diagnosed with breast cancer

  • ages 18-43 years

  • choosing to preserve oocytes or embryos prior to cancer treatment

• Excluded women taking medications that strongly inhibited metabolizing enzyme p450 2D6 (CYP2D) — examples: fluoxetine, paroxetine

HOW

• Randomized, open-label, two-sided superiority trial

  • Open-label: nurse or local investigator used web-based permuted block randomization program to assign women to treatment groups

  • Randomized 1:1:1 to standard ovarian stimulation (OS): OS + tamoxifen 60 mg daily: OS + letrozole 5 mg daily

• Stratified women by usage of oral contraception at start of ovarian stimulation, + estrogen receptor (ER) status, and + lymph nodes for the intended follow-up of these women (and these parameters may influence prognosis)

• Treatments by Group*:

  • OS

    • Cycle Day 2 started 225IU recombinant injectable FSH (Puregon, Gonal-F, or Ovaleap) and continued until follicles 18-20 mm

    • Day 5 of stimulation added 0.25mg GnRH antagonist (Cetrotide or Orgalutran) until day of trigger

    • Trigger = 0.2 mg GnRH agonist (Decapeptyl or Triptofem) used for oocyte maturation

  • OS + Tamoxifen

    • Cycle Day 2 started recombinant injectable FSH 225IU and oral tamoxifen 60 mg daily

    • Tamoxifen stopped on day of GnRH agonist trigger (variable date based on ovarian stimulation progress)

  • OS + Letrozole

    • Cycle Day 2 started recombinant injectable FSH 225IU and oral letrozole 5 mg daily

    • Letrozole stopped on day of GnRH agonist trigger then resumed on day of retrieval to prevent rebound E2 increase

  *Luteal and random starts to ovarian stimulation were permitted due to time sensitivity of breast cancer treatments

  • All groups expected to have follicle aspiration (“retrieval”) 34-36h post-GnRH agonist trigger

  • Cryopreserved MIIs alone or as day 3-5 embryos created via ICSI per local freezing protocols

Statistics

• Followed intention-to-treat (ITT) principles

• Estimated needed to enroll 159 women for sufficient power analysis

• When 25% of recruits were enrolled, a pre-planned independent interim analsysis was performed by the Data Safety Monitoring Board—> trial advised to proceed as planned

  Results

• 162 women in ITT analysis: 55 OS, 54 OS + tamoxifen, 53 OS + letrozole

• Average age = 32 years across groups

• Breast cancer status: similar tumor staging between groups, though three women in OS + letrozole group had bilateral vs. unilateral tumors - more cancer treatment details found here in the Supplemental Index

• Only data from first ovarian cycle collected, though nineteen women completed two cycles and one woman completed three cycles

• 48% of women started OS in follicular stage vs. 15% in luteal phase vs. 35% random start in menstrual cycle

• Three cancelled cycles in OS, 1 in OS + tamoxifen, 2 in OS + letrozole

• The number of cumulative-oocyte complexes (COCs) retrieved was a mean (standard deviation) of 13.6 (11.6) in OS, 12.5 (10.4) in OS + tamoxifen, and 14.2 (9.4) in OS + letrozole

• After adjustments for OCPs, + ER status, and + lymph nodes, there were no differences in # of COCs collected or # of oocytes or embryos cryopreserved

• Peak estradiol was lower in OS + letrozole vs. OS alone

• Safety: one woman in OS group admitted to hospital for ovarian hyperstimulation syndrome (OHSS)

Protocol Violations:

• seven women were prescribed a lower dose of FSH (150/175/200 IU)

• two women were prescribed a higher dose of FSH (250/300 IU)

• three women prescribed urinary FSH instead of recombinant FSH

• three women received flare-up or agonist protocols

• one woman trigged by hCG instead of GnRH agonist

• one woman treated in hospital that wasn’t participating in trial

Authors’ Conclusions

(+) study design reflective of clinical practice (needing to do “emergency” IVF at any point in menstrual cycle; used standard OS protocol (GnRH antagonist for down regulation then GnRH agonist for trigger) to minimize OHSS risk; collected baseline breast cancer data that can be used in follow-up studies

(-) developed power analysis based off scant, low-quality literature; higher SD in oocytes retrieved —> harder to detect group differences; lacked power to analyze subgroups based on age, BRCA status or timing of OS start; lack oocyte retrieval rates —> should include in larger, longer-term studies

No evidence that there is a difference in mature oocytes between OS vs. OS + tamoxifen vs. OS + letrozole.

This Pharmacist’s Conclusions

(+) head-to-head comparisons, multi-site included two countries and both academic and non-academic institutions; pre-planned interim analysis to ensure safety

(+/-) medication deviations from trial protocol reflective of real-life scenarios; lack of hCG trigger included in trial design (understandable decision)

(-) three years into trial changed focus from safety to efficacy; 46% had regular menstrual cycles in OS group vs. 53% in OS + tamoxifen vs. 64% in OS + letrozole; 58% nulliparous in OS group vs. 78% in OS + tamoxifen vs. 62% in OS + letrozole

Resources

Balkenende EME, Dahhan T, Beerendonk CCM, et al. Fertility preservation for women with breast cancer: a multicentre randomized controlled trial on various ovarian stimulation protocols. Hum Reprod. 2022;37(8):1786-1794. doi:10.1093/humrep/deac145

Marklund A, Lekberg T, Hedayati E, et al. Relapse Rates and Disease-Specific Mortality Following Procedures for Fertility Preservation at Time of Breast Cancer Diagnosis. JAMA Oncol. Published online August 25, 2022. doi:10.1001/jamaoncol.2022.3677

Rosenberg E, Fredriksson A, Einbeigi Z, Bergh C, Strandell A. No increased risk of relapse of breast cancer for women who give birth after assisted conception. Hum Reprod Open. 2019;2019(4):hoz039. Published 2019 Dec 18. doi:10.1093/hropen/hoz039