Fertility preservation after breast cancer - a guide for oncologists


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What oncologists ( and their patients) need to know about preserving fertility in young women with breast cancer

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  • 1) Women who undergo chemotherapy or radiation during their reproductive years face a 40-80% chance of losing their fertility, and male cancer patients have a 30-75% risk. The actual risk depends on patient age and quantity and type of cancer therapy. (Quinn 2007)
    2) **Include statistic from study about survivors not remembering discussing risk of infertility and fertility preservation before therapy
  • McShane script: Prior to consideration of fertility preservation, it is useful to review the basic requirements for conception. These include viable sperm, reasonable oocyte (egg) quality, and a normal endometrial cavity which can gestate the pregnancy. The normal semen analysis per WHO standards is 20 million/cc with a volume of 1-5 cc’s, 50% or greater motility, and 40% normal forms. However, it is certainly possible to achieve pregnancy with lesser sperm quality although assisted reproduction may be required.
  • McShane script: Certainly cancer chemotherapy may impair ovarian reserve even after one course. So it is recommended that indicators of ovarian reserve be tested prior to active attempts at fertility preservation for cancer patients. Anti-mullerian hormone levels can be performed anytime during a woman’s cycle. Follicle stimulation hormone and estradiol levels on day two to four of the cycle as well as antral follicle count may also be informative. A good option is to initiate the basic testing while awaiting a referral to a reproductive endocrinologist for interpretation of the results and consideration of various fertility preservation options.
    Additional Notes:
    “Since there is significant variation in fertility with age, the clinical assessment of a woman’s “ovarian reserve” typically involves not just age but also changes in the release of pituitary follicle-stimulating hormone FSH and corresponding production of estradiol and inhibin B by granulosa cells with ovarian follicles.” (Woodruff 2007)
  • 1) Even if menses resume following cancer therapy, the patient’s ovarian reserve may be greatly reduced and she may be at risk for premature ovarian failure. Patients may have the opportunity to freeze remaining oocytes.
  • 1) Rates of amenorrhea range from 13% to 62% in women 30 to 40 years of age and 57% to 96% in women over 40.
    Additional Notes:
    Kim: “Even women who regain menses after cytotoxic chemotherapy +/- antihormonal therapy are likely to have undergone significant follicle depletion and reproductive aging of 10 years or more (16-19).
    Kim” “The primary determinants of chemotherapy-induced amenorrhea and/or loss of fertiltiy are age of the women at the time of chemotherapy, dose and number of cycles of akylating agent received, and to a lesser extent exposure to anthracyclines, taxanes, and platinum analogs.”
    Kim: “Amenorrhea is likely to be permanent in 90% of women over 40 and 95% of women over 45 (50-53)
  • Additional Notes:
    Woodruff: The time required for oocyte maturation with ovulation induction is generally about 2 weeks from the onset of menses. Hence, if the decision to undergo conventional IVF and embryo freezing is made much after day 3 of the menstrual cycle, the day of menstrual cycle by when ovulation induction is usually initiated, the patient will have to wait until the onset of the next menstrual period prior to initiating ovulation induction.
    ASCO Guidelines: “There are little human data available for the newer agents such as taxanes.
  • If we like flow charts, we could include them and add additional script:
    ‘On day 3 of the menstrual cycle, patients begin 12 days of hormone stimulating medications…….Following retrieval, oocytes can be immediately vitrified or inseminated and frozen as embryos…..’
  • McShane script: The foundation of successful IVF is the recruitment of multiple oocytes since human reproduction is inherently inefficient. The goal of an IVF cycle is usually retrieval of 10 or 15 oocytes which results in the generation of 3 to 5 good quality embryos after insemination and culture.
  • McShane script: If the patient has a partner, the use of in vitro fertilization (IVF) with embryo cryopreservation is the most established technique for fertility preservation prior to extensive chemotherapy. The major issue with this approach is that the timing must be synchronized with the woman’s menstrual cycle. The IVF process requires approximately two weeks of intensive medication and monitoring which begins with the woman’s menstrual period. This in many cases involves a delay of therapy which is of concern to both patients and their oncologist. Prior to the IVF cycle, the partner’s semen analysis, determination of ovarian reserve as well as TSH (thyroid stimulating hormone), and prolactin serum levels should be obtained. Ideally, the resulting embryos would be replaced in the woman’s own uterus after cancer therapy. This requires normal uterine configuration, but gestational carrier can be used if the uterus is not normal or if assessing uterine status would further delay therapy.
  • McShane Script: There has been some concern about the risk of stimulating tumor growth especially in estrogen receptor positive tumors since ovarian stimulation which is required in order to generate multiple oocytes. The current approach for hormonally dependent cancer is to use gonadotropins FSH and comibination FSH/LH with letrozole (Femara), an aromatase inhibitor which does not raise estradiol levels in circulation as much as the typical gonadotropin stimulation. Other short term risks of the therapy include low risk to the surgical complications from the transvaginal oocyte retrieval as well as ovarian hyperstimulation syndrome which is typically no more than mild in the case of a woman who is not conceiving during the stimulation cycle.
    The long term risks of stimulation are less well known and are likely modified by the use of SERMs. These include possible increase in ovarian cancer.
    Additional Notes:
    Kamen and McShane: “In 167 women undergoing ovarian stimulation with gonadotropins, mean maximum serum estradiol values reached 605 pg/mL and on days 6 to 10, progesterone level averaged 46ng/mL. This compares with an average preovulatory estradiol level of 250 pg/mL and progesterone value of 8.9 ng/mL during a normal menstrual cycle.”
    Missing citation: “Because estrogen exposure is a risk factor for breast cancer, several studies have investigated whether ovarian stimulation leads to increased risk of this disease.
    But studies have shown a non-significant increase.
    -Cohort of 3375 women treated with IVF; non-significant increase in breast cancer incidence after 8.1 years of follow-up; women over 40, however, were at increased risk
    -however, studies thus far have less than 10 years of follow-up
    Available studies, despite limited, are reassuring
    Nonetheless Letrozole or Tamoxifen are recommended to be used during ovarian stimulation before chemotherapy to lower peak estradiol levels”
    Kim: “Although tamoxifen or letrozole can induce ovulation or stimulate follicular growth, it does not generate enough follicles for embryo cryopreservation. To make it a more practical method, use of low-dose gonadotropin in combination with tamoxifen or letrozole has been attempted with good results (73).
    “In terms of peak E2 levels, ovarian stimulation with letrozole plus gonadotropin resulted in a much lower levels compared with tamoxifen plus a gonadotropin. Moreover, when letrozole plus gonadotropin is used for COS, recurrence rates of breast cancer do not appear to be increased at 2 years of follow-up.”
    Jensen: With letrozole, significantly lower peak estradiol levels and a nearly 50% reduction in gonadotropin requirement compared with age-matched controls (cancer-free) undergoing in vitro fertilization.
    “Azim et al prospectively compared 79 women with breast cancer who underwent ovarian stimulation plus letrozole with 136 women with breast cancer who did not undergo ovarian stimulation before cancer treatment…similar in age and stage of disease as well as risks of calculated relapse and mortality…median follow-up of 23 months in the ovarian stimulation group and 33 months for controls…no difference in noted recurrence or survival. The authors concluded that ovarian stimulation with gonadotropins and letrozole is unlikely to cuase significantly increased risk of recurrence, althought they acknowledged that a longer follow-up is needed.”
    1) Kamen 2009: Using letrozole or tamoxifen concurrent with FSH have not shown higher cancer recurrence rates in initial studies
    Letrozole has been demostrated to produce lower peak estradiol levels with an equal number of oocytes harvested compared with the use of FSH alone in women undergoing IVF.
    Tamoxifen demonstrated similar peak estradiol levels but fewer oocytes when compared to FSH-only cycles
    Tamoxifen is an antagonist of estrogen receptors
    Letrozole is an aromatase inhibitor, and prevents aromatase from producing estrogen by competitive inhibition
    ASCO Guidelines: “Short term breast cancer recurrence rates after ovarian stimulation using letrozole or tamoxifen concurrent with follicle stimulating hormone (FSH) administration have been compared with nonrandomized controls and no increase in cancer recurrence has been noted in these initial studies. Only a small percentage of cancer survivors have yet returned to utilize their embryos but the initial pregnancy rates are encouraging. Nevertheless, long-term follow-up with a larger number of patients is needed to evaluate the safety and efficacy of this approach.”
  • McShane Script: If the patient does not have a male partner or if she desires to cryopreserve her oocytes rather than embryos, oocyte preservation via vitrification has become a viable alternative in recent years. The classicial approach to embryo cryopreservation did not work well for oocytes but fortunately, a newer approach has evolved in the last several years which appears to be very viable and can be used for social indications or oocyte donation as well as oncofertility. To generate multiple oocytes for retrieval, the time requirement and the time within the menstrual cycle are the same as for an IVF cycle. The risks short term of the stimulation, retrieval and possible ovarian hyperstimulation syndrome are the same. Given that vitrification is a newer procedure, the risk to the offspring at this time is relatively unknown.
    Additional Notes:
    Kim: “Vitrification is a solidification of liquid by an extreme elevation in viscosity while rapid cooling takes place and eliminates ice crystal formation and growth”
    Dr. Kondapolli: oocyte turned into glass
    Jensen: “Recent technological advances have now improved oocyte cryopreservation such that oocytes can survive the freezing or vitrification process approximately 50% to 60% of the time, with fertilization rates of 60% to 70% with use of intracytoplasmic sperm injection.
  • McShane Script: Cryopreservation of ovarian cortical tissue which would require a laparoscopic approach is an experimental process. This could be done immediately, independent of the woman’s menstrual cycle but does involve the risk of laparoscopy and general anesthesia. The ultimate replacement of the cortical strips or maturation of the oocytes from the cortical strips after thawing has been successful in a small number of cases worldwide.
    **To what detail should we describe these procedures?
  • ASCO Guidelines: “ To offset this relatively large loss [due to ischemia], typically the cortex from an entire ovary is cryopreserved in adults.”
    “Ovarian cryopreservation and transplantation procedures should only be performed in centers with the necessary expertise under IRB-approved protocols that include follow-up for recurrent cancer.
  • In ovarian cortical tissue cryopreservation,
    Basic steps…..
  • Additional Notes:
    Woodruff: “Freezing sections of ovarian cortex or freezing wither mature or immature oocytes, still have more limited availability, though with time and increased interest in these techniques both success and availability will increase.”
  • Additional Notes:
    Kim: Becoming pregnancy after a diagnosis of breast cancer does not appear to resutl in worse outcomes in case-control studies or cohort studies (4,5,7,8). In fact, in several series, pregnancy after a daignosis of breast cancer appeared to result in reduced risk of relapse (7-9), particularly for women who waited for 2 years after diagnosis to conceive (9).
    Jensen: “Cancer survivors often desire, yet fear pregnancy after cancer therapy, particularly that for hormone-responsive malignancies like breast cancer.”
    - “Multiple studies have shown that pregnancy after breast cancer treatment does not appear to adversely affect recurrence or survival. In particular a large population-bases student examined more than 10,000 women with primary breast cancer who were younger than 45 years at the time of diagnosis; only 371 had a full-term delivery after cancer treatment. A multivariate analysis including age at diagnosis, stage of disease, and pregnancy history before diagnosis showed that women who had a full-term pregnancy after cancer diagnosis had a reduced risk of dying (0.73; 95% confidence interval, 0.54-0.99) compared with other women with breast cancer. The author concluded that no evidence exists to suggest that pregnancy after breast cancer had a negative influence on prognosis.”
    Jensen: Patients express concern of birth defects; large studies of offsprings of cancer survivors have showed no statistically significant increase in childhood malignancies or genetic malformations.
  • **Include this topic briefly or no?
    To discuss with this slide:
    Assess uterus and hormones. Goal: mature endometrium
    Not all embryos and oocytes survive thaw
    Embryos and oocytes graded for quality
    Implantation rate per embryo a bit lower than fresh embryos
    Studies indicate no higher rate of birth defects
    But greater risk for low birth rate (other greater risks?)
    Additional notes:
    Woodruff: “At the time of the patient’s choosing, embryos can be thawed and transferred into either the patient’s own uterus, providing that her uterus is viable for pregnancy, or that of another woman (gestational surrogate).
  • 1) These studies may be biased, as the healthiest patients are more likely to desire and achieve pregnancy, referred to as the “healthy mother effect” Kamen 2009.
  • Fertility preservation after breast cancer - a guide for oncologists

    1. 1. Doctor, help me to have a baby ! Life after breast cancer Dr Aniruddha Malpani www.drmalpani.com
    2. 2. The young woman with breast cancer Early diagnosis, because of better awareness and better imaging techniques, means the diagnosis is being made more often in younger women Newer treatment protocols and the increasing role of neo-adjuvant chemotherapy translates into more effective treatment and better survival rates
    3. 3. IVF specialists are seeing two types of breast cancer patients: Newly diagnosed patients ; and Long-term survivors.
    4. 4. Long term survivors
    5. 5. Newly diagnosed patients Need to cope with diagnosis of a life-threatening disease. Significant shock and emotional distress Shortened “window of opportunity” for treatment. Time is of the essence. Please refer as soon as possible !
    6. 6. Refer to Specialty multi-disciplinary clinic for a second opinion ? Surgical oncologist for staging? Medical oncologist for chemotherapy ? Radiation therapist ? Please also refer to IVF specialist for fertility preservation !
    7. 7. Having babies enhances quality of life for survivors Many cancer survivors have a strong urge to have a family. Their brush with death makes them better parents
    8. 8. Cancer-related Infertility Chemotherapy compromises future fertility. More powerful drugs = better survival and more infertility Infertility is a source of long-term distress in survivors – especially if this could have been prevented !
    9. 9. You have breast cancer ! You need to discuss many emotionally-charged topics Cancer-related infertility and fertility preservation also need to be discussed because you can take proactive steps toward preserving their fertility Their future ability to have children will significantly improve their quality of life.
    10. 10. The two things every oncologist needs to know about fertility Breast cancer chemotherapy damages ovarian reserve and can cause infertility Fertility preservation techniques can help to mitigate this damage
    11. 11. Testing Ovarian Reserve Before Starting Cancer Therapy AMH ( anti Mullerian hormone) blood test – on any day of the cycle Antral follicle count – vaginal ultrasound scan Tests can be ordered before referring to an IVF specialist.
    12. 12. Testing Ovarian Reserve After Cancer Therapy If patient desires future children, ovarian reserve should be tested as soon as possible Even if menses resume, these patients are at risk for premature ovarian failure. Patients may have the opportunity to freeze remaining oocytes.
    13. 13. Chemotherapy induced Amenorrhea Rates of amenorrhea depend on patient age; and type and dose of treatment Most women who remain amenorrheic after 1 year have premature ovarian failure. Resumption of menses does not mean ovulation. They often have decreased ovarian reserve
    14. 14. Dramatic improvements in preserving fertility Take proactive steps to preserve fertility before initiating cytotoxic therapy Decisions should be made as early as possible. Even one dose of chemo can impair fertility We can freeze ◦ Embryos ◦ Eggs ◦ Ovarian tissue
    15. 15. IVF for Freezing Embryos and Oocytes Menstruation Menstruation Stimulate Ovaries Stimulate Ovaries Oocyte Retrieval Oocyte Retrieval Inseminate oocytes Inseminate oocytes Freeze Embryos Freeze Embryos Embryo Cryopreservation Embryo Cryopreservation Freeze oocytes Freeze oocytes Oocyte Vitrification Oocyte Vitrification
    16. 16. Following hormonal stimulation, oocytes are aspirated directly from the ovaries, using ultrasound guidance. About 10-15 oocytes are retrieved (which typically produces 3 quality embryos)
    17. 17. In Vitro Fertilization
    18. 18. Embryo Cryopreservation Most established procedure. First choice if patient has a partner Needs 2 weeks of ovarian stimulation with daily injections of follicle-stimulating hormones from Day 1 of menses Chemo has to be postponed for a few weeks
    19. 19. Hormone-sensitive cancers For women with hormone-sensitive breast cancers, alternative hormonal stimulation approaches using letrozole and tamoxifen have been developed , to theoretically reduce the potential risk of estrogen exposure
    20. 20. Oocyte Vitrification Partner not required New technology- fast freezing of vitrification. Much better results • Fast freezing prevents ice crystal formation that can damage DNA No increase in congenital anomalies compared with naturally conceived infants.
    21. 21. Cryopreservation of Ovarian Cortical Tissue Experimental. May be only option for patients who can not delay treatment or are unwilling to undergo ovarian stimulation Summary of procedure: ◦ Retrieve ovarian tissue by laproscopy ◦ Freeze strips of ovarian cortical tissue ( contains primordial follicles) ◦ Later, reimplant tissue; hip, arm ◦ Or graft ovarian tissue onto the remaining ovary
    22. 22. Cryopreservation of Ovarian Cortical Tissue Advantages: no partner or donor sperm needed, available to prepubertal patients, no hormonal stimulation, no time delay Disadvantages: ◦ Experimental procedure; few live births ◦ 25% follicles die because of initial ischemia (particularly for women over 40, few follicles remain) ◦ Concern for reimplantation of cancer cells with ovarian tissue implantation (not suitable if there may be metastases in the ovaries)
    23. 23. Retrieval and In Vitro Maturation ( IVM) of Immature Oocytes Another option might include aspiration of immature oocytes from the small “antral” follicles of the ovary with maturation of these oocytes in a laboratory setting in the future.
    24. 24. Newly diagnosed patient Your major focus is to design the best treatment plan. You have lots of things to do Establish a diagnosis Stage the disease Select the best protocol Refer to a medical oncologist Refer to a radiation therapist Refer to a support groups Discuss costs
    25. 25. Think of the future as well ! Many young cancer survivors feel they received inadequate information on their fertility preservation options. Fertility preservation gives patients hope for a high quality life after cancer Please discuss this proactively
    26. 26. Doctor, why didn’t you tell me to freeze my eggs ? This is a question your survivors will ask you when their cancer is treated and they come for a 5year followup How will you answer ? You will have wasted their golden opportunity
    27. 27. Pregnancy after Cancer Recommended after 2 years because most disease recurrences occur within this time frame For women receiving hormone therapy such as tamoxifen are recommended to wait 5 years before conceiving, to allow completion of therapy. Current studies do not indicate increased risk of recurrence or decreased risk of survival, even in hormonally sensitive tumors; however, studies are limited.
    28. 28. Using Frozen Embryos and Oocytes
    29. 29. Potential health benefits of pregnancy? Pregnancy does not decrease breast cancer survival rates May improve survival Pregnancy is safe or even beneficial However, bias of “healthy mother effect”
    30. 30. Referrals to IVF specialist Oncologists should refer interested patients to reproductive specialists as soon as possible Pretreatment fertility counseling and fertility preservation improves quality of life in reproductive age women with breast cancer. “ Losing my hair would be temporary, but losing my ability to have children would be permanent and devastating.”
    31. 31. Additional online educational resources www.savemyfertility.org www.fertilehope.org www.myoncofertility.org
    32. 32. FAQs How long does each treatment take? Is it safe to delay the chemo ? Does egg/tissue freezing really work? What are the success rates of each treatment? How many babies have been born? What is the safety of fertility treatments (especially for hormone sensitive cancers)?
    33. 33. FAQs How long can the eggs/embryos be stored ? What happens if the patient dies or gets divorced? How much do the treatments cost? Insurance coverage? Financial assistance? What is the birth defect rate of children born to cancer survivors?
    34. 34. FAQs Does having children after cancer increase the chance of the child having cancer? Does pregnancy increase the risk of recurrence? How long should a patient wait to attempt pregnancy or IVF after completing cancer treatment? What are the age limits for these treatments and how do they affect outcome (e.g. over 40)?
    35. 35. FAQs GnRH analogs for ovarian suppression Contraception BRCA gene mutations and IVF/PGD ( preimplantation genetic diagnosis)
    36. 36. Please protect your patient’s fertility !