Fertility Preservation for Breast Oncology

Patients

Patricia McShane MDUniversity of Colorado Hospital

Reproductive Endocrinology and Infertility

Quality Survivorship

• In the past, oncologists have needed to focus solely on cancer patients’ survival and potential damage to life-dependent organs, such as cognitive impairment, and pulmonary and cardiac damage. (Quinn 2007)

• But as cancer treatment and rates of cancer survivorship have improved in recent years, considering quality of life after cancer has become increasingly important.

• For many patients, a high quality of life includes the ability to have children.

• Typically three-quarters of recently-diagnosed, young adult cancer patients report a desire to have children in the future (Schover 2007).

• For many patients, surviving cancer increases their desire to have a family; they feel their experience will make them better parents, for reasons such as their increased emotional resilience and greater appreciation for life.

Cancer-related Infertility

• Unfortunately, chemotherapy and radiation therapies can severely compromise patients’ future fertility1.

• Research in the last 10 years has shown that cancer-related infertility is a source of long-term distress in survivors. (Schover 2007)

• One can imagine the anguish of overcoming a life-threatening condition, only to later learn of his or her infertility.

Population affected by Cancer-related Infertility

• The patient population affected by cancer-related infertility should not be underestimated or overlooked.

• The issue of fertility preservation affects about one in every ten cancer patients1.

• Today, 25% of women do not have their first baby until they are between the ages of 30 and 40, so many cancer patients in this age range will not have yet their first child at time of diagnosis (Kim 2011).

• Consequently, both age at cancer diagnosis and cytotoxic effects of cancer therapy threaten female cancer patients’ chance of having a biological child in their future.

• Luckily, assisted reproductive technologies have improved dramatically in recent years, and there are more options for cancer patients to take proactive steps toward protecting their future fertility before initiating cancer therapy.

• However, recent research has suggested that oncologists and recently diagnosed cancer patients are often insufficiently informed about current fertility preservation options1.

• Consequently, the topics of cancer-related infertility and fertility preservation options are often not discussed.

• In a recent Provider Survey at University of Colorado Hospital, less than half of the responding 76 oncologists reported routinely discussing fertility preservation with their patients and only 19% felt well-informed about fertility options.– McShane/Flink 2011

Expanding Fertility Preservation Discussion

• The circumstances challenging oncologists to discuss cancer-related infertility and fertility preservation options are valid.

• Oncologists are responsible for discussing many emotionally-distressing topics with newly diagnosed patients and in a limited timeframe.

• Assisted reproductive technologies have progressed dramatically in recent years, but few relevant educational resources directed toward practicing oncologists currently exist.

• It is important that we expand educational resources and work to incorporate these discussions with patients.

• Unless cancer-related infertility and fertility preservation options are discussed, patients are unable to take proactive steps toward preserving their fertility before undergoing fertility-compromising treatments, and their future ability to have biological children may significantly influence their quality of life as cancer survivors.

Review of Fertility

• Female requirements for fertility:– Reasonable egg quality– Normal endometrial cavity

• Male requirements for fertility:– Viable Sperm– Normal Semen Analysis (WHO):

• 20 million/cc with a volume of 1-5 cc’s• 50% or greater motility• 40% normal forms

Female fertility with age

from Carcio and Rosenthal

Female Ovarian Reserve

• As a mid-pregnancy fetus, a female has her maximum number of primordial follicles1.

• Estimated that dozens of oocytes are consumed monthly to achieve a single ovulation

• At around age 35-38, acceleration in rate of oocyte atresia, until ovarian reserve is exhausted and menopause ensues. (Woodruff 2007)

Testing Ovarian Reserve Before Cancer Therapy

• Because significant variation in fertility exists by age, testing a female’s blood hormone levels will provide insight into her ovarian reserve1.

• A female cancer patient’s blood hormone levels can be tested while awaiting referral to a reproductive endocrinologist.

Testing Ovarian Reserve After Cancer Therapy

• If a cancer patient does not pursue fertility preservation before cancer therapy but the patient desires future children, ovarian reserve should be tested as soon as possible following cancer therapy1.

Defining Infertility

• Regular intercourse for one year without pregnancy

• “inability to conceive during 12 months of unprotected intercourse”

Relative Infertility Risks by Cancer Therapy

Risk Adjuvant Therapies

High Risk Whole abdominal or pelvic radiation doses >6 Gy in adult women

Whole abdominal or pelvic radiation doses >10 Gy in postpubertal girls

Total body irradiation (TBI)

Cranial/brain irradiation >40 Gy

CMF, CEF, or CAF x 6 cycles in women >40 years

Cyclophosphamide 5 g/m2 in women >40 years

Cyclophosphamide 7.5 g/m2 in girls <20 years

Alkylating chemotherapy (e.g., cyclophosphamide, busulfan, melaphan) conditioning for transplant

Any alkylating agent (e.g., cyclophosphamide, ifosfamide, busulfan, BCNU [carmustine], CCNU [lomustine]) + TBI or pelvic radiation

Protocols containing procarbazine: MOPP, MVPP, COPP, ChlVPP, ChlVPP/EVA, BEACOPP, MOPP/ABVD, COPP/ABVD

Moderate Risk

Whole abdomina or pelvic radiation 5 to <10 Gy in postpubertal girls

Spinal radiation doses >25 Gy CMF, CEF, or CAF x 6 cycles in women 30–39 years

AC in women >40 years

Low Risk AC in women 30–39 years

CMF, CEF, or CAF x 6 cycles in women <30 years

Nonalkylating chemotherapy: ABVD, CHOP, COP

AC

No Risk Radioactive iodine

MF

Vincristine

Unknown Risk

Paclitaxel, docetaxel (taxanes used in AC protocols)

Oxaliplatin

Irinotecan

Bevacizumab

Cetuximab

Trastuzumab

Erlotinib

Imatinib

What female organs are affected?

• Surgery: ovaries, uterus, pituitary

• Radiation rx: pelvis, spinal, cranial, total body

• Chemotherapy: fertilehope.org calculator– Link: http://fertilehope.org/tool-bar/risk-

calculator-women-treatment.cfm

What cancer-related damage to female fertility may occur?

• Decreased number of primordial follicles• Affects hormone balance• Interferes with the functioning of the ovaries, fallopian

tubes, uterus, or cervix• Anatomic or vascular changes to the uterus, cervix, or

vagina from surgery or radiation can also compromise natural conception and successful pregnancy, requiring ART or gestational carrier

• Even if a female is initially fertile after cancer treatment, the duration of her fertility may be shortened by premature menopause; decreased ovarian reserve.

• Resumed menses does not promise resumed fertility

• Cancer therapy frequently leads to a period of temporary or permanent amenorrhea in premenopausal women

• Rates of amenorrhea depend on patient age and type and dose of treatment1

• Most women who remain amenorrheic after 1 year do not recover and have premature ovarian failure.

• Resumption of menses does not insure ovulation, or may also have decreased ovarian reserve which will lead to premature ovarian failure

Amenorrhea

Fertility Preservation

• Dramatic improvements in fertility preservation in recent years

• Now cancer patients can take proactive steps to preserve their fertility before initiating cytotoxic cancer therapy

• Important that decisions regarding fertility preservation be made as early as possible because several options require timing with menstrual cycle and even one dose of cancer therapy can impair fertility

Kim: Discussion of how chemotherapy treatments can be

altered to reduce follicular damage

• Chemotherapy regimens can usually be altered somewhat to reduce gonadotoxicity.

Fertility Preservation Options

• Gonadotropin Suppression

• Embryo cryopreservation

• Oocyte vitrification

• Ovarian tissue cryopreservation (experimental)

• Retrieval and in vitro maturation of immature oocytes (experimental)

Gonadotropin Suppression

• Suppression of ovarian function by suppressing GnRH– Depo Lupron

• Ovaries secrete estrogen and progesterone

• Moderate improvement

• Theoretical risk if breast, hormone dependent cancer

Embryo Cryopreservation• Most established procedure• Recommended if patient has a partner• Stat about success rate:• Dependent on menses and requires

hormonal stimulation– Because of menstrual cycles, adjuvant

therapy may be delayed 0 to 4 (6?) weeks– Requires about two weeks of ovarian

stimulation with daily injections of follicle-stimulating hormones from onset of menses

• Clomiphene or gonadotropins (LSH, sometimes in combination with LH)

– Ovarian stimulating medications raise serum estradiol levels

• Do we want to explain procedure of embryo cryopreservation? (i.e. Ultrasounds, blood tests, HCG trigger, ultrasound-guided aspiration

• Following hormonal stimulation, oocytes are aspirated directly from the ovaries, using ultrasound guidance.

• Ideally, at least 10-15 oocytes are retrieved (which typically produces 3 quality embryos)

Basic Steps for Freezing Embryos and Oocytes

MenstruationMenstruation

Stimulate OvariesStimulate Ovaries

Oocyte RetrievalOocyte Retrieval

Inseminate oocytesInseminate oocytes Freeze oocytesFreeze oocytes

Freeze EmbryosFreeze Embryos

Embryo CryopreservationEmbryo Cryopreservation

Oocyte VitrificationOocyte Vitrification

Hormone-sensitive tumors• For women with hormone-sensitive

tumors, alternative hormonal stimulation approaches such as letrozole (or tamoxifen?) have been developed to theoretically reduce the potential risk of estrogen exposure1

In Vitro Fertilization

IVF, Embryo Implantation Rate

0

5

10

15

20

25

30

35

40

Rate of Implantation

(%)

<35 35 - 37 38 - 40 41 - 42

AgeSART 2009

Oocyte Vitrification

• Partner not required• Traditional freezing technique not successful

– Notes: why- damage to DNA, oocyte less able to repair cytoplasmic damage

• new technology- fast freezing– Fast freezing and use of cryoprotectants prevents ice crystal

formation that can damage DNA• May be a good options for patients who do not have a

partner or who have religious or ethical objections to embryo freezing

• As with embryo cryopreservation, letrozole and tamoxifen can be used.

• No apparent increase in congenital anomalies compared with naturally conceived infants.

Cryopreservation of Ovarian Cortical Tissue

• Currently low success rate• Not suitable when risk of cancer

development in ovaries is likely • Promising option (or may be only option)

for breast cancer patients who can not delay treatment or unwilling to undergo ovarian stimulation

• Summary of procedure:– Outpatient procedure; retrieve ovarian

tissue by laproscopy– Freeze strips of ovarian cortical tissue,

which is composed mainly of primordial follicles that are relatively resistant to freeze-thaw injury (about 70%-80% survival)

– Later reimplant tissue; hip, arm, or where else? Or grafting ovarian tissue in or onto the remaining ovary

Cryopreservation of Ovarian Cortical Tissue

• Advantages: no partner or donor sperm needed, available to prepubertal patients, no hormonal stimulation, no time delay

• Disadvantages: – very new, experimental procedure; few live births– quarter or more primordial 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 a suitable procedure if metastases in ovaries possible)

Retrieval and In Vitro Maturation of Immature Oocytes

• Another future option might include aspiration transvaginally of immature oocytes from the small “antral” follicles of the ovary with maturation of these oocytes in a laboratory setting in the future. This again is a speculative approach. (From McShane script)

Fertility Preservation Options for Breast Oncology Patients: Comparison Chart

GnRH Suppression

Ovarian Transposition

Embryo Cyropreservation

Oocyte Vitrification

Cryopreservation of ovarian cortical tissue

Aspiration of immature oocytes?

Established/ Experimental

Established Established Established (?) Experimental, IRB protocol required

Experimental, IRB protocol required

Success for fertility preservation

Moderate Successful for targeted radiation

Successful, if sufficient oocytes retrieved

Successful, if sufficient oocytes retrieved

Only few live births so far

Very experimental

Time Delay No No Yes, 2-6 weeks

Yes, 2-6 weeks

No No

Advantages Outpatient procedure

Does not require partner; may be preferred by individuals with objections to embryo freezing

No time delay No time delay

Dis-advantages

Not suitable if risk of ovarian metastases; experiem

Very experimental; must be conducted under IRB protocol

FP Options and Breast Cancer types

• HR+/-

Options for hormone-sensitive cancers

• What are the alternative stimulation methods fro embryo cryopreservation/oocyte vitrification?– Natural Cycle

• Usually one egg retrieved– Hormone analogs

• Letrozole• Tamoxifen• These may protect the breasts from estrogen while stimulating the ovaries

– In vitro maturation• Retrieve eggs that have started to mature, the continue maturation in vitro• Doesn’t use standard stimulation hormones that would cause levels to rise

• Even for hormone-sensitive cancers, there are fertility preservation options that do not increase estrogen levels.

• From fertilehope.org

Discussing Fertility Preservation with your patients

• While the primary focus of oncologists is usually designing the most effective cancer treatment plan, many young patients feel they received inadequate information regarding cancer-related infertility and fertility preservation options.

• It is important to discuss fertility preservation as early as possible to have the most options with least delay of cancer treatment

• Although oncologists have a list of disappointing news to share with newly diagnosed patients, preserving fertility may give patients hope for a high quality life after cancer

• It is impossible to know whether fertility preservation is important to patients unless discussed, as many patients will not bring up the discussion

• Consequences of not discussing fertility preservation may include psychosocial distress related to infertility after cancer

Oncologists’ Views

• Barriers to Discussion– Age– Cost– Parity– Time delay

From ASCO Guidelines: Table 3 Points of Discussion Between the Patient and Physician

• Cancer and cancer treatments vary in their likelihood of causing infertility. Individual factors such as disease, age, treatment type and dosages, and pre-treatment fertility should be considered in couseling patients about the likelihood of infertility.

• Patients who are interested in fertility preservation should consider their options as soon as possible to maximize the likelihood of success. Some female treatments are dependent upon phase of the menstrual cycle and can only be initiated at monthly intervals. Discussion with reproductive specialists and review of available information from patient advocacy resources (for example, FertileHope.org….) can facilitate decision-making and treatment planning.

• (Reworded) For females, the highest likelihood of success is embryo cryopreservation…

• Aside from hereditary genetic syndromes and in utero exposure to chemotherapy, there is no evidence that a history of cancer, cancer therapy, or fertility interventions increase the risk of cancer or congenital abnormalities in the progeny.

• Treatment-related infertility may be associated with psychosocial distress, and early referral for counseling may be beneficial in moderately distressed people.

Key topics to discuss with patients

• From Kim:– How adjuvant therapy is selected/– How much AT will reduce recurrence or

increase survival– Chance AT will result in loss of fertility– Will fertility preservation procedures or

pregnancy affect chance of recurrence and by how much

– How would fertility preservation procedures fit into adjuvant therapy plan

Ethical and legal considerations

Having Children after Cancer

Using Frozen Embryos and Oocytes

Asses uterus and hormone levelsAsses uterus and hormone levels

Thaw embryos or oocytesThaw embryos or oocytes

Implant EmbryosImplant Embryos Inseminate Oocytes: IVF or ICSIInseminate Oocytes: IVF or ICSI

Implant EmbryosImplant Embryos

Risks to progeny?

• ASCO guidelines: “Aside from hereditary genetic syndromes, however, there is scant evidence that a history of cancer, cancer therapy, or fertility interventions increases the risk of problems in the progeny. Available studies including large registry studies have revealed no increased risk of genetic abnormalities, birth defects, or cancers, aside from hereditary syndromes, in the children of cancer survivors.”

After cancer

• If patient was unable to preserve oocytes or embryos and wants to have children, see REI to test ovarian reserve– Even if not ready to have children or should

wait few years to ensure no cancer recurrence

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.

• Particular concern in cancers that express GnRH receptors, such as HR+ breast cancer

• Women with HR+ tumors advised to take tamoxifen for 5 years after treatment to prevent recurrence

If fertility impaired but children desired

• Gestational carrier if uterine factor or contraindicated

• Oocyte donor –age, menopause, genetic (BRAC)

• Adoption

Potential health benefits of pregnancy?

• Several studies have shown that pregnancy does not decrease breast cancer survival rates and may improve survival

• Some studies show that women who do became pregnant were less likely to die from breast cancer

• Women who became pregnant had smaller tumors and fewer positive nodes than women who did not

• Indicate pregnancy safe or even beneficial• However, “healthy mother effect”1

• Kamen 2009

Referrals to REI

• Oncologists should refer interested and appropriate patients to reproductive specialists as soon as possible, particularly because some fertility preservation procedures are time sensitive to the menstrual cycle

• Patients can be referred to:– University of Colorado Advanced Reproductive Medicine

• Phone number:

• Offices in Denver and Colorado Springs

– Other Centers in Colorado:– Site online to find doctors: (?)

Additional online educational resources

• Oncofertility Consortium– Oncofertility.northwestern.edu

• Savemyfertility.org

• Fertilehope.org

• Myoncofertility.org

References

• The sources I used in this PowerPoint:– Kim SS, Klemp J, Fabian C. Breast cancer and fertility preservation.

Fertil Steril. 2011 Apr;95(5):1535-43. Epub 2011 Jan 26. Review. PubMed PMID: 21272867.

– Kamen B, McShane P. Risk and Impact of Infertility Treatment and Pregnancy on Breast Cancer. Postgrad. Ob. & Gyn.. 2009 Feb; 29 (4).

– Quinn GP, Vadaparampil ST, Gwede CK, Miree C, King LM, Clayton HB, Wilson C, Munster P. Discussion of fertility preservation with newly diagnosed patients: oncologists' views. J Cancer Surviv. 2007 Jun;1(2):146-55. PubMed PMID: 18648955.

– Schover LR. Patient attitudes toward fertility preservation. Pediatr Blood Cancer. 2009 Aug;53(2):281-4. Review. PubMed PMID: 19301387.