˜25% of breast cancer patients are pre-menopausal (15% pts <45 yrs) at the time of diagnosis and survivors frequently are concerned regarding future childbearing

100% Breast cancer pts

Premenopausal26%

Postmenopausal74%

ER–46%

ER+54%

ER– 27%

ER+73%

Advanced: 19% Early: 81%

BREAST CANCER PATIENTS

Decision Resources Epidemiology Data & Primary MR.

Is pregnancy safe for women survival after a dignosis of breast cancer?

Is chemotherapy detrimental for ovarian function?

Is LHRH-analogs treatment useful to preserve ovarian function?

What about other options about fertility preservations?

PREGNANCY AFTER BREAST CANCER AND PROGNOSIS

Available data show no adverse effect on survival of pregnancy after a diagnosis of breast cancer

BUT….… there are not prospective studies

Healthy mother effect

PREGNANCY after BREAST CANCER

Only 3% of women <45 yrs and 8% of women <35 yrs at diagnosis had full-term pregnancies (Mueller et al, 2003; Blakely et al, 2004)

It has been also reported an increased chance of spontaneous abortions (25% of cases of pregnancy) in women with a history of breast cancer (Velentgas et al, 1999)

Largillier et al, ASCO 2006

Pregnancy prior to Breast Cancer

Largillier et al, ASCO 2006

Pregnancy after Breast Cancer

Largillier et al, ASCO 2006

Pregnancy prior to Breast Cancer

Available data suggests no adverse effect of subsequent pregnancy on

prognosis of women with breast cancer

However, concerns remain for some women and their physicians

Ongoing perspectives studies should help to answer this question

more definitively

Chemotherapy can compromise ovarian function resulting in premature ovarian failure (POF: defined as menopause before the age of 40 years or hypergonadotropic amenorrhea) and infertility (Byrne et al, 1999)

Dependending on the extent of damage to the ovaries, two forms of POF can be distinguished:1. Acute Ovarian Failure (AOF) = loss of

ovarian function during or shortly after the end of chemotherapy

2. Premature menopause = loss of ovarian function that occurs years after the end of chemotherapy (before age 40 yr)

Sklar et al, J Natl Cancer Inst 2005

• A constant number of resting primordial follicles enter the growth phase at any given time, independent of pituitary gonadotropins

• Later stages of maturation require FSH and LH

• Follicles either mature to ovulation or become atresic

Ovarian Structure

Atresia• Is the degeneration of primordial follicles: • Ovaries have about 2 million primordial follicles at birth

(Ovarian reserve!):– each containing a primary oocyte

• By puberty:– number drops to about 250,000 - 400,000 400 oocytes ovulated during the reproductive years

In the absence of LH/FSH, follicles undergo atresiaOnce follicles are depleted, ovarian hormone production declines

Female Fertility

Figure from: http://www.sydneyivf.com/pages/fertility/infertility/age.cfm

As a woman ages there is a rapid decline in the number of eggs as well as the quality of eggs.

… due to a continual process of atresia, the ovarian reserve of primordial follicles is progressively eroded over time (Gosden et al, 1994)

Lobo, N Engl J Med 2005

In conclusion ….

Gonadotoxic chemotherapy causes marked follicle loss

through, presumably, apoptotic cell death

(Ratts et al, 1995; Tilly et al, 2003)

Age of the patient

Type of the cytotoxic agent(s)

Cumulative dose

The likelihood of gonadal failure depend on the:

Bines et al, 1996; Goodwin et al, 1999; Meirow et al, 1999

Treatment for Early Breast Cancer and the Effect on Fertility

Graph adapted from Goodwin P, Ennis M, Pritchard K, Trudeau M, Hood N. Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 1999;17(8):2365-2370.

Estimated number of women who become menopausal after treatment depending on their age at diagnosis

Risk of Treatment induced Amenorrhea

• Adjuvant endocrine therapy does not cause permanent infertility

• but …. endocrine therapy usually entails years of treatment when pregnancy contraindicated and aging during that time may compromise fertility

Effect of age on risk of premature ovarian failure

Mattle et al, 2005

The chemotherapeutic destruction of an already low follicular reserve, reduces the number of follicles below a certain ‘threshold’ number required to sustain ovarian function, resulting in menopause.

Meirow et al, 1999

Sonmezer, M. et al. Oncologist 2006;11:422-434

Alkylating agents are extremely gonadotoxic because they are not cell cycle-specific and can damage resting primordial follicles, whereas cycle-specific agents such as MTX and 5-FU do not have any effect on ovarian reserve

Degree of gonadal failure associated with

chemotherapeutic agents

Copyright ©2006 AlphaMed Press Sonmezer, M. et al. Oncologist 2006;11:422-434

Degree of gonadotoxicity related to the most commonly used chemotherapy regimens in breast cancer

Dose of Cyclophosphamide (mg/kg)

No. of primordial

follicles

Meirow et al, 1999

Follicular damage from chemotherapy is not an

‘’all or nothing phenomenon’’ A dose-response effect exists A dose of chemotherapy strong enough to destroy 50% of the ovarian primordial reserve does not affect reproductive performance

Studies assessing the impact of breast cancer chemotherapy on fertility issue, often use chemotherapy-induced amenorrhea as a surrogate marker for fertility (Bines et al, 1996; Goodwin et al, 1999; Nabholtz et al, 2002)

BUT… Premenopausal levels of estradiol have been detected in amenorrheic pts after chemotherapy thus indicating persisting ovarian function despite mestrual activity cessation (Braverman et al, 2002) On the other hand, resumption of menstruation after chemotherapy does not imply that also the fertility has been preserved (Schmidt et al, 2005)

The incidence of immediate amenorrhea is lower in younger women, who have a larger primordial follicles pool. They will eventually experience premature ovarian failure (Rivkees et al, 1998; de Bruin et al, 2004; Larsen et al, 2003)

Two measurements of FSH>40 mIU/ml, regardless of mestrual bleeding OVARIAN FAILURE

The fertility is compromised if:• FSH >15 mIU/ml on d3 of the mestrual period• Estradiol >80 pg/ml on d3 of the mestrual period

(Licciardi et al, 1995; Scott et al, 1989)

Adjuvant CMF caused ovarian failure in 40% of women <40 yrs and 76% of those >40 yrs (Bines et al, JCO 1996)

With doxorubicin-based regimens, none of the pts <30 yrs stopped menstruating, whereas 33% of the women 30-39 yrs and 96% of those aged 40-49 yrs experienced amenorrhea (Hortobagyi et al, 1986)

Bines, JCO 1996

Bines, JCO 1996Venturini, JNCI 2005

Marty, NEJM 2005Marty, NEJM 2005

Fornier, Cancer 2005

Percentage of women becoming amenorrheic within 6 months of initiation of chemotherapy by treatment

regimen

FEC-T, fluorouracil, epirubicin, cyclophosphamide followed by docetaxel (n = 9); E-CMF, epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil (CMF; n = 18); A-CMF, doxorubicin and CMF (n = 7).

Anderson RA, 2007

… contradictory results from animal and clinical studies …

LHRHLHRH(hypothalamus)(hypothalamus)

Pituitary gland

OestrogensProgesterone

Ovary

LHRH analogs:downregulation

of LHRH receptors

Gonadotrophins(FSH + LH)

Breast

HYPOTHALAMUS-HYPOPHYSIS-OVARY AXIS

Since cytotoxic drugs most affect tissues with a rapid cellular turnover, it has been suggested that a state of induced gonadal inhibition during chemotherapy may protects the gonads (Rivkees et al, JAMA 1988)

There is no evidence for the presence of FSH or LHRH receptors on primordial follicles, thus there is currently no biological explanation for how LHRH-a can affect ovarian reserve (Clayton et al, Nature 1982)

… the lack of FSH and LHRH receptors on primordial follicles and oocytes does not make gonadal suppression an effective strategy of gonadal protection.

A clinical example of why gonadal suppression does not protect ovaries:prepubertal children who undergo heavy chemotherapy still suffer from ovarian failure (Teinturier et al., 1998).

All of the younger patients who receive heavy gonadotoxic chemotherapy will

suffer from premature ovarian failure (Grigg et al.,

2000).

18 women, 15-40 yrs, Hodgkin’s or non-Hodgkin’s lymphomas

Chemotherapy + LHRH-a

historical matched control group of 18 women (17-40 yrs) treated with chemotherapy alone

COMPARED TO:

94%

39%

…but the mean follow-up was only 1.7+1.0 years in the study group, compared with 7.0+4.9 years in the control group.

Incidence of amenorrhoea vs regular cyclic ovarian activity

Only 4 out of 16 pts in the study group received CTX (cumulative dose: 609-4500 mg/mq) vs 10 out of 18 in the control group (cumulative dose: 531-14531 mg/mq)

There is a limited number of prospective studies in humans…

Short-term follow-up Lack of control group

None, with the exception of the study by Fox et al, used ability to conceive and live births as primary end-points.In the abstract by Fox, spontaneus conception and pregnancy outcomes were suboptimal despite an 83% retention of menstruation.

Single center, prospective, single arm, phase II study

29 pts with breast cancer (stage I-III)

GOSERELIN + CHEMOTHERAPYAll but one pt received CEF q21 for 6 cycles

Goserelin 3.6 mg s.c., at least 1 week before the first cycle of chtPts with HR+, received tamoxifen at the end of chemotherapy and if a resumption of menstrual activity was observed during the 12-month follow-up, they restarted goserelin and continued it for at least 2 yrs

The success of the experimental treatment was defined by:

Resumption of menses within 12 months after the end of chemotherapy

or FSH < 40 IU/l between 3 and 12 months after the last cycle of chemotherapy

RESULTS

Pts with resumption of menses 21 (72%)

Pts without menses but FSH <40 IU/l 7 (25%)

28 (97%)

Expected rate of menses resumption with CEF regimens is nearly 40%

FSH <40 IU/l was not predictive of menses resumption

100 premenopausal consecutive pts candidate to adjuvant chemotherapy after surgery for breast cancer (II-III stage) were enrolled

All pts received LHRH-a concurrently with chemotherapy, independently of HR status

64 pts: GnRH for 1 yr; HR+: TAM for 5 yrs

36 pts: GnRH for 2 yrs; HR+: AI for 2 yrs TAM for 5 yrs

After chemotherapy

Cancer. 2006

CHEMOTHERAPY REGIMENS

26 pts, pT2-3, pN0, HR+8 CMF - CTX: 7200 mg/tot -

11 pts, pT1-3, pN1 (<3), 6 FEC g 1,8 q21 - CTX: 3600 mg/tot -

54 pts, pT1-3, pN1 (3-4), 4 EPI 8 CMF q21 - CTX: 4800 mg/tot -

9 pts, pT1-3, pN>10, 4 EPI High-Dose ChtPBPCs 8 CMF q21 - CTX: 4800 mg/tot-

RESULTS

After a median follow-up of 75 months, NORMAL MENSES were RESUMED by 67% of patients

(100% for pts <40 yr and 56% for pts >40 yr)

The addition of a GnRH analog to adjuvant chemotherapy and temporary estrogen suppression in pts with ER+ disease protected long-term ovarian function, and appeared to improve the expected clinical outcome

but …..

… treatment with LHRH-a has been continued for two yrs in ER- women …. ?

No planned sample size: this is an observational study rather than a phase II study

The lack of a study design and the small number of pts do not allow to draw valid conclusions on clinical outcome

In the only prospective randomized study in humans, including 30 men and 18 women receveing chemotherapy for Hodgkin’s disease, LHRH-a has been demonstrated ineffective in preserving fertility as judged by sperm count and menstrual function.

Waxman et al., Cancer Chemother Pharmacol 1987

30 men and 18 women randomly assigned to

Buserelin + CHT CHT

After 3 yrs of follow-up, all men and control groups became oligo/azospermic, while 4 of 8 women treated with LHRH-a and 6 of 9 female controls became amenorrheic

Fertility Options 1. Wait and See2. IVF3. Oocyte cryopreservation (egg freezing)4. Ovarian tissue cryopreservation5. Ovarian Suppression6. Adoption7. Oocyte and Embryo donation

Issues relating to each option include varying success rates, delays in cancer treatment, availability, cost and the impact on the cancer.

Fertility preservation options in females

ASCO Recommendations on Fertility Preservation in Cancer Patients

(Expert Panel, J Clin Oncol 2006)

Sperm and embryo cryopreservation are considered standard practice…; other available fertility preservation methods should be considered investigational… but ……

Embryo Cryopreservation

It is the only established method for fertility preservation

Survival rates per thawed embryos are in the range of 35%–90%, implantation rates are in the range of 8%–30%, and cumulative pregnancy rates exceed 60% (Sonmezer et al, 2004).

Embryo Cryopreservation

• If the patient has a partner and sufficient time prior to cytotoxic treatment, embryos generated through IVF can be cryopreserved and stored for future use.

• Because adjuvant chemotherapy is commonly initiated 4–6 weeks after surgery, there is usually adequate time to perform ovarian stimulation and IVF. Oocyte retrieval and embryo freezing can also be performed without ovarian stimulation; however, the embryo yield is low and typically no more than a single embryo can be generated (Oktay et al, 2003, Omland et al, 2001).

• Because the effectiveness of IVF diminishes with every round of chemotherapy and because there is a potential for fertilizing a genetically damaged growing oocyte, it is not recommended to perform IVF after chemotherapy is initiated (Ginsburg et al, 2001, Dolmans et al, 2005).

Embryo cryopreservation Requires ovarian stimulation Requires in vitro fertilizationRequires partner or sperm donationDelay in harvest may delay chemotherapyMay be theoretically harmful in hormone-sensitive tumors

Ovarian stimulation increases the number of follicles recruited to grow and increases estrogen production in proportion to the number of follicles recruited. As a result, estrogen can reach levels 10-fold or more higher than those in a natural cycle (Pittaway et al, 1983; Pena et al, 2002, Chen et al, 2003)

Oocyte cryopreservation

• May be a more attractive option to patients without a partner

• Drawbacks:– Requires stimulated ovulation similar to that in IVF

cycles for embryo freezing

– Success rates about 2% (Oktay et al, 2006) – To be suggested when embryo freezing cannot

be performed, especially in single women who do not wish to use donor sperm for in vitro fertilization.

Cryopreservation Issues

• Diagnosis of stage I–III breast cancer of invasive ductal type is not a contraindication for ovarian cryopreservation.

• Nevertheless, prior to cryopreservation, a thorough

evaluation of the patient and the tissue is required to rule out ovarian metastasis, in all cases.

• Moreover, some of the young breast cancer patients may have BRCA gene mutations and, as a result, may harbour a co-existing primary ovarian cancer (Liede

and Narod, 2002 ).

• Even though ovarian cancer is rare prior to the age of 35 years (Massi et al., 1996), these patients should be counselled about that risk.

WARNINGLetrozole: Breast Cancer Drug Not

for Fertility!

May Cause Birth Defects- higher incidence of locomotor and cardiac

malformations -

Letrozole has been used by Canadian fertility specialists to stimulate ovulation in women who are infertile, or unable to become pregnant, as a treatment to increase their chances of becoming pregnant

Biljan et al, 2005

ASCO Recommendations on Fertility Preservation in Cancer Patients

(Expert Panel, J Clin Oncol 2006)

At this time, since there is

insufficient evidence regarding the safety and effectiveness of GnRH analogs and other means of ovarian suppression on female fertility preservation, women interested in ovarian suppression for this purpose are encouraged to partecipate in clinical trials

SWOG 0230 study

It is an ongoing phase III study, in which ER- and PR-negative young breast cancer pts are randomized to receive chemotherapy alone or chemotherapy plus LHRH-a to evaluate the role of LHRH-a in the ovarian function preservation

Prospective, multicenter, randomized, phase III study

PROMISE-GIM6

Premenopausal Women, 18-45 yrs, stage I-III breast cancer, HR+/-, candidate for adjuvant chemotherapy

Chemotherapy Chemotherapy +

TriptorelinPrimary endpoint

Incidence of chemotherapy-induced early menopause (at 1 year following the completion of cht, measured by FSH, E2, menses resumption)

Study start: Sept 2003Projected accrual: 280 pts

CONCERNS ABOUT THE USE OF LHRH-a BEFORE AND DURING CHEMOTHERAPY IN

BREAST CANCER

1.The potential interaction between LHRH-a and chemotherapy

2.The potential detrimental effect on the outcome of the lack of chemotherapy-induced menopause

CAF+TAM CAF TAM

Patients (N) 550 566

DFS (%) 62 p<0.05 67

Eight-year DFS Rates With or Without Tamoxifen

Albain et al, 2002

The National Surgical Adjuvant Breast and Bowel Project (NSABP), which has historically used concurrent chemotherapy and tamoxifen in its trials, has now modified trial designs to mandate sequential use of tamoxifen

Pagani et al., Eur J Cancer 1998

DFS according to amenorrhoea status by ER/PR status: 232 patients with ER/PR- status (a) and 964 patients with ER/PR+status (b).

Is pregnancy safe for women survival from breast cancer?

Is chemotherapy detrimental for ovarian function?

Is LHRHa treatment useful to preserve ovarian function?

What about safety of LHRHa concurrently used with cht?

YES

YES

Waiting for phase III studies

Not yet estabilished