Transcript Breast cancer and fertility preservation Modern trends

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
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.
Breast cancer
• 2/3 women < 40 y/o at diagnosis  tumor > 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)
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 agerelated 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.
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 (+)
• 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)
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 ?
How is adjuvant
treatment selected ?
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
5-yr diseasefree survival
rates
higher rate of
late relapse
higher relapse
rate in the first
5 years
Gene expression array panels  if
(+)  likely to benefit from C/T
If chemotherapy improves the prognosis ?
•
Europe and Canada  only antihormone ± ovarian suppression
•
USA  offered C/T, particularly for pts < 40 y/o at diagnosis
• ER(-), PR(-)  >1cm or <1cm with high grade or HER-2 (+)  C/T
• HER-2(+)  trastuzumab for up to a year
How much will adjuvant
treatment reduce risk
for recurrence or death
from breast cancer ?
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)
• 2nd generation regimen  44% ↓ in 15-yr mortality
– 6 months of fluorouracil, epirubicin, and cyclophosphamide (FEC)
– fluorouracil, adriamycin (doxorubicin), and cyclophosphamide (FAC)
• 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
• 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
What are the chances
that adjuvant therapy
will induce loss of
fertility and how can
this risk be minimized ?
• 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/m2 cyclophosphamide for 12-16 weeks = adding ~10 years to her ovarian
reproductive age or 1.5-3.0 years per cycle
• 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.
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
...
Will pregnancy after a
breast cancer
diagnosis increase the
chance of recurrence
and miscarriage ?
• 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)
What are the fertility
preservation options and
how would they be
inserted into the breast
cancer treatment plan ?
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
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
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
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
Tamoxifen
letrozole
• Tamoxifen: selective estrogen receptor modulator
• Letrozole: 3rd generation aromatase inhibitor
• both effective for breast cancer treatment and
ovulation induction (OI)
• add low-dose gonadotropin for good outcome
• E2 level: letrozole + gonadotropin* <<
tamoxifen + gonadotropin
* recurrence rate of breast cancer not ↑ at 2-yr F/U
COS for IVF in breast cancer
• Goals:
letrozole + rFSH  encouraging results
− To minimized the elevation of E2 levels during stimulation cycle
− To shorten the course of COS
− To maximize the number of oocytes
• Protocol for ER/PR(+) patients
initiate on day of TVOR, for 5~7 days to suppress E2
rFSH (150-300IU) ± hMG
* TVOR performed 3-5 days
after last letrozole dose 
risk of letrozole to embryos is
negligible
5mg
x 6~7 d
leading
follicle
14 mm
> 2 follicles
at 18-19 mm
Oocyte cryopreservation
• no partner, not want to use donor sperm
• ovarian stimulation  TVOR  IVF (creation of unnecessary
embryos can be prevented !!)
• 1st 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
• 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
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
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.
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
• 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
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
Facilitating fertility preservation
consultation
Timely
consultation
Time
&Cost
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.
Conclusions
• COS is required for both embryo and oocyte cryopreservation,
and an increase in peak E2 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.
THANK YOU !!