Terapia hormonal y fertilidad

Transcription

1 Madrid, 6 de Octubre de 2017 Terapia hormonal y fertilidad Sara López-Tarruella Cobo MD, PhD

2 BC incidence focused on young patients Cumulative BC in females SEER % Incidence BC in females by 6-year eras SEER BC is the leading cause of cancer deaths in women <40 yr >40% of all cancer in women <40 yr Anders et al Semin Oncol 2004;

3 BC proportion by subtypes on young patients HR-HER2+ HR+HER2+ TNBC California women ( ) HR+HER AYA pts 1319 pts Keegan et al BCRT 2012; Carey JAMA 2006; Sweeney et al CEBP 2014

4 BC survival by subtype on young patients BC in young women is correlates with inferior survival & higher incidence of negative clinicopathologic features Anders et al JCO 2008; Azim et al CCR 2012

5 World Fertility Patterns ility/world-fertility-patterns-2015.pdf

6 World Fertility Data 2015 (Spain) Total Fertility Mean age at childbearing fertility/wfd2015.shtml

7 Ovarian Reserve & BC treatment [Chemotherapy (aprox 6 mo)*] [Endocrine Therapy (5-10 yrs)] Wallace et al PlosONE 2010

8 Young women with BC have unique concerns FERTILITY: Premature menopause and infertility related to treatment; pregnancy and/or egg harvesting issues complicating treatment decisions (participating CTs ) PSYCHOLOGICAL DISTRESS & SOCIAL SUPPORT: shock of facing an unexpected cancer diagnosis at such a young age; facing mortality early; not seeing children to adulthood; depression and social support; size of social network related to emotional support; higher risk for genetic predisposition to cancer; racial/ethnic disparities PHYSICAL CHANGES & SIDE EFFECTS: body image RELATIONSHIPS: spousal relationships challenges related to communication and sexuality with sexual function reported as more problematic than loss of interest; fathers of young families; parents illness acceptance; care of young children amid the complex reactions of family, friends and partners WORK & FINANCES: early career disruptions; health insurance issues; unemployment Rana et al Cogent Med 2017; Ruddy et al JAYAO 2013; Letourneau et al Cancer 2012

9 Fertility concerns of BC patients Web-based survey of fertility issues in young BC women 57% substantial concern at diagnosis about becoming infertile with treatment (73% concerned) Greater concern about infertility was associated with wish for children/more children, #prior pregnancies and prior difficulty conceiving 29% infertility concerns influenced treatment decisions 72% discussed fertility concerns with their doctors (51% addressed adequately) time matters! Women overestimated their risk of becoming postmenopausal with Rx Partridge et al JCO 2004; Llarena et al JNCI 2015; Stensheim et al IJC 2011; Ruddy et al JCO 2014; King et al Oncologist 2012

10 Treatment PLAN (tumor board) Assess fertility risk Patient commun. Treatment duration) Assess BC recurrence risk Patient communication & plannification (pros/cons) FU-SURVIVORSHIP Luminal BC treatment timeline in young patients SURGERY RDT NACT Adj_CT Adj_ET ExtA_ET DIAGNOSIS TREATMENT Whose job is it? FERTILITY unit referral Fertility preservation options Pursue fertility preservation FERTILITY unit IVF (incl. Egg donation) Surrogacy, adoption or fostering? ObGyn dept. Risk of pregnancy evaluation (age, comorbidities?) Gardino er al JARG 2010; Netter 2010

11 Potential future decisions regarding fertility preservation Quinn et al AJOG 2013

12 Pregnancy after BC Is it possible after BC treatment? Pregnancy after adolescent and adult cancer:population-based matched cohort study (Norway) female cancer survivors and controls Chances of subsequent pregnancy depend on the type of cancer Female cancer survivors 40% less chance of becoming pregnant vs general population Stensheim et al Int J Cancer 2011

13 Pregnancy after BC Is it possible after BC treatment? Fertility in women of reproductive age after breast cancer treatment (Cleveland Clinic) *mean FU 3.9 yrs since treatment 26 % BC women documented fertility counseling (vs 15.6 % liter.) 7% pregnancy rate (<40 yr) Of pts who became pregnant 55% pursued agnrh option and/or underwent fertility consultation 3 yrs mean time from BC treatment to pregnancy McCray et al Ann Surg Oncol 2016

14 Pregnancy after BC Should pregnancy after BC be considered safe? Safety of pregnancy following BC diagnosis: A meta-analysis of 14 studies 41 % reduced risk of death vs women who did not get pregnant Results could be partially confounded by selection bias or the healthy mother effect & lack of information in HR+ pts Lambertini et al BMC Medicine 2016; Azim et al Eur J Cancer 2011

15 Pregnancy after BC Should pregnancy after BC be considered safe? Multicenter retrospective cohort (333 pregnant: 874 nonpregnant) EU Pregnancy is not protective against BC recurrence of an endocrine-sensitive BC (57%) at least during the first 5 years after pregnancy BUT there is a lack of detrimental effect irrespective of ER status Median FU 7.2 yrs: no difference in DFS nor OS regardless of pregnancy outcome, pregnancy interval since diagnosis or breast-feeding status Azim et al JCO 2013; Lambertini et al ASCO 2017 LBA 10066

16 De Pedro et al Ecancermedicalscience 2015; Langagergaard et al BJC 2006; Anderson et al JAMA Oncol 2017; Black et al BRC 2017; Pagani et la BCRT 2011; Dalberg et al PLoS Med 2006 Pregnancy after BC Risk for the pregnancy and fetus Congenial abnormalities: Similar neonatal outcomes ref general population High induced abortion rate (up to 30%) (?) Obstetric/birth complications: C-section, preterm birth, low birth rate seem higher for BC survivors Cardiac FU for anthracyclines pre-treatad

17 Fertility preservation Available strategies in BC patients Lamnbertini et al J Thor Dis 2013

18 Fertility preservation How effective are these methods? Systematic review of RCTs, case control and cohort studies reporting on the primary outcome of mortality/recurrence after COH in women with early BC, or secondary outcomes of oocyte yield and peak oestrogen concentration (15 Any statements regarding safety of COH are based on a limited number of observational studies. High quality evidence is unlikely to become available for ethical and practical reasons BC heterogeneity makes the results difficult to generalize to individual cases The largest study reported recurrences in 6/120 (5.0%) women who received COH plus LET vs 12/217 (5.5%) women who did not undergo COH (mean FU 5.0 versus 6.9 yrs; HR for recurrence 0.77) Co-administration of 5 mg of LET daily commencing on Day 2 and continuing throughout COH is recommended as it reduces peak oestradiol concentrations without significantly decreasing oocyte yield Use of GnRH agonist trigger is beneficial as oestradiol concentrations rapidly decrease post-administration and rates of ovarian hyperstimulation are lower than with an hcg trigger, without a corresponding reduction in clinical pregnacy or live birth rates in cryopreservation cycles Protective effect of TAM has not been evaluated although theoretically may be of benefit due to its action on ER Rodgers Human Rep 2017

19 Fertility preservation How effective are these methods? IVF outcomes, cancer patients versus non cancer patients Ovarian stimulation followed by IVF forms an important fertility preservation strategy, though live born rates following thawed embryo transfer in these patients are still lacking. Shapiira et al J Assit reprod Genet 2015

20 Fertility preservation Is the BC treatment delay acceptable? Many retrospective data (potential bias) BC heterogeneity factor (HR+ BC vs TNBC or HER2+) <3 mo threshold to impact prognosis (Calif Cancer Reg >24000 pts) Cold et al BJC 2005; Lohrisch et al JCO 2006; Jara et al BCRT 2011; Raphael et al BCRT 2016.Chavez-McGregor et al JAMA Oncol 2016

21 Fertility preservation Controlled ovarian stimulation protocols Conventional vs ramdon-start COS protocols Risks of supraphysiologic E2 levels: TAM or LET (higher #oocytes) in HR+ tumors alhrh in risk for OHSS Oktay et al JCO 2005; Cakmak et al Ferti & Ester 2013

22 CT & Fertility (luminal BC) Incidence of CT induced amenorrhea Patient time inversely correlates with postct amenorrhea Lamnbertini et al J Thor Dis 2013; Taylan et al WJCO 2017

23 CT & Fertility (luminal BC) Does fertility desire impact CT election? Treatment plan Dose & combination of agents Patient age at the time cancer treatment begins and ends Duration of treatment Baseline risk factors for infertility Baseline ovarian reserve Pre-existing infertility Under research Patient variation in polymorphisms for drug metabolizing enzymes; new therapies Long-term sequela Until better data are available, clinicians need to be cautious when using the limited and incomplete information currently available. The use of platinum agents can further adversely impact fertility and increased toxicity may compromise standard duration and dosing of systemic treatment, and this needs to be clearly communicated to pts Jungheim et al pter_31 counseling_and_consentingwomen with_cancer_on_their_oncofertility_options- a_clinical_perspective.pdf ; Paluch-Shimon et al Breast 2017

24 CT & Fertility (luminal BC) alhrh & ovarian protection from CT OR for premature ovarian failure by study definition, of pts treated with concurrent LHRHa vs CT alone (controls) 12 RCTs (1231 pts) Temporary OS with LHRHa in young BC pts associated with a reduced risk of CTinduced POF and seems to increase the pregnancy rate, without an apparent negative consequence on prognosis OR for premature ovarian failure defined as amenorrhea 12 mo after the end of CT, of pts treated with concurrent LHRHa vs CT alone (control) Lambertini et al Ann Oncol 2015

25 CT & Fertility (luminal BC) POEMS-SWOG S0230 trial alhrh & ovarian protection from CT HR neg Moore et al NEJM 2015

26 CT & Fertility (luminal BC) alhrh & ovarian protection from CT PROMISE TRIAL POEMs trial OPTION trial Lambertini et al Eur J Cancer 2017; Leonard et al Ann Oncol 2017

27 CT & Fertility (luminal BC) alhrh & ovarian protection from CT Potential weaknesses Utility of self-reported menstrual status (highly unreliable surrogate for fertility) Lack of placebo control (instead of GnRHa) or blinding Lack of correction for the difference in desire to conceive between study and control group Use of amenorrhea as the sign of ovarian failure: for BC patients, CT often induces occult ovarian insufficiency that most frequently presents as irregular or even normal appearing periods rather than amenorrhea, serum AMH is the most reliable quantitative biomarker for ovarian reserve or appropriate criteria with serum FSH levels for defining ovarian failure Taylan et al WJCO 2017; Lambertini et al Ann Oncol 2015; Moore et al NEJM 2015

28 Endocrine therapy & Fertility (luminal BC) Are fertility concerns or family building intentions involved in thedecision making regarding ET? What is the elective ET or ET-strategy for patients with reproductive instinct (TAM vs alhrh+ais vs ET extention)? Which is the minimun time for ET treatment recommended if a patient would like to have children in the future? When is recommended interval of ET interruption before attempting a pregnancy? Should we re-introduce ET after delivery, when and how long? Family-building wishes & AE profile effect on the adherence to adjuvant ET? Benedict et al CBC 2016

29 Endocrine therapy & Fertility (luminal BC) Peccatori et al ESMO Ed 2017

30 Endocrine therapy & Fertility (luminal BC) The PREFER trial (GIM) PREFER-FERTILITY PREFER-PREGNANCY Lambertini et al BMC Cancer 2017

31 BC & Fertility & BRCA mut carriers (luminal BC) Up to 10% of the cases of BC diagnosed in young pts related to a hereditary condition Ovarian reserve in women with BRCA mutations? Association between BRCA mut and diminished ovarian reserve Ovarian stimulation yielded significantly lower ovarian response rates in BRCA mut carriers particularly (BRCA1) Alterations in DNA repair related to BRCA mut may also make oocytes more vulnerable to CT HGUGM series De pedro et al Ecancermedicalscience 2015; Lambertini et al CTR 2017; Lobo et al 2017

32 BC & Fertility & BRCA mut carriers (luminal BC) Fear of exposure to estrogen limits access to fertility preservation via embryo or oocyte cryopreservation? Ovarian cryopreservation can be used when there is insufficient time to perform ovarian stimulation (NOT requirement of hormonal stimulation) but still experimental and safety concerns De pedro et al Ecancermedicalscience 2015; Lambertini et al CTR 2017

33 BC & Fertility & BRCA mut carriers (luminal BC) Lambertini et al 1541O_PR ESMO 2017

34 BC & Fertility & BRCA mut carriers (luminal BC) Indication of undergoing preventive bilateral salpingooophorectomy and its consequences (narrow fertility-window ) Recommended to be performed by the age of yrs after the completion of childbearing Preimplantation genetic diagnosis for BRCA mutations during in vitro fertilisation to prevent mutation transmission to the embryo? De pedro et al Ecancermedicalscience 2015; Lambertini et al CTR 2017;

35 BC guidelines (BCY3) fertility related recommendations Discussion of these issues at diagnosis, elicitation of patient interest in future fertility and appraising patients of the risks of amenorrhea and potential infertility as well as premature menopause have been recommended as an important component of quality oncology care and are reinforced here. Appropriate early referrals for fertility preservation strategies, based on existing practice guidelines, as well as psychosocial support surrounding this extremely complex issue should also be made Paluch-Shimon et al Breast 2017; Haddadi et al APJCP 2015; Lambertini et al Eur J Cancer 2017

36 Questions to guide fertility discussions & assess decision support needs Benedict et al CBC 2017

37 MUCHAS GRACIAS POR LA ATENCIÓN