'regnancy After Breast Cancer
icoletta Biglia, Nicoletta Tomasi Cont,
]lentinaBounous,Martad'Alonzo,andSilviaPecchio
Introduction
eiving cancer diagnosis can be devastating for many patients bui thanks [o mcesincancertherapiesitisnotadeamsentcnceanymore.Cancersurvivdrates increasingandlifeaftercancerisarealchanceformanypatienisworldwide.In )pe,abouionethirdofcancerpatientshavearelative5-yearsurvivalrategreater
80 % [1]. Similar survivst rates are seen in the United States, Canada and Lrùia. I.owcr suivivd ra{es in developing countries are most likely due io late nosisandlimjtedavailabiliDofup-todaiestandaidticatmenB[2,3]. iltaly,everydayabout30newcasesofcancerarediagnosedinpatientsbelow geof40yearsandmanyofthemarewomenwithbi.eastcancer.About10%of stcancerdiagnosisoccursinpatienisyoungerihan40years[4]. neastcancerinyoungwomenisfrequcmlymoreaggressivethantumoumdiag-]inolderwomen.Oftenmetastasesatloco-regionallymphnodesaredetectcd agnosis and biological and molecular characieristics identify phenotypes M prognosis[5].Asaconsequence.systemictieatmentsinadditiontolocalther-mfiequenilyrecommended.Inspiteofthis,poorersurvivalratesandhigher tfrecurrenceareieportedinthesesubgioupofpatients[6].
i.anks to adjuvant therapies, overall and disease-free survival are improving iineandmostofthepatientilongsurviveiobi.eastcancer.Chemotherapyand rine therai)y extend time to recurrence bui, on the other hand, bring about
short- and long-iem side effects. Among them, ovarian failure with iiuiemenopauseisparticularlyrelevanttoyoungwomen.Inthelastfewyears,
iaMD.PhD(CE).NTCont.V.Bounous.Md'Alonzo.S.Peccliio ncniofGynaecologyandObsietrics.UniversiiyofTorinoSchool
icine, Torino, ltaly
nicoleita.biglia@unito.it; nicolettaiomasi@tiscali.ic
abounous@hotmail.com; mamdalonzo@libero.it: silvia86@alicc.it
gcr lniemational Publishing Switzerland 2015
*_F;.t_..:_=c*s:.(^ed_s:ì_._p_n-e_es,_cance;-i:eà-iiirypreserva'ion
mdiic./i.on,D0II0.1007/978-3-319-17278-1_6
N. B.lg\.la et aL
in life has been observed and man! - _---ia.:n. tt`pirfamilies [7l. l.
72
a trend towards delaying pregnancy to later in iiie iias _„ vvv__
womenreceiveadiagnosisofbreastcancerbeforecompletingtheirfamiliesmh mthefrequencyofpregnancyinwomenaged#yeffiormorewas12%m 1990,16%in1996anditisestimatedthatwinamountto25%in2025m Diagnosisandtreatmentofbreastcanceroftenthi.eatenfertility.Guidelineshigh
`:Fahs`ntchetr'eTt¥:nat:C:n°df:::C:Ssstngfwf'et:,?,:;'e,:tssstì:gw°en,:da°st°tì':::fae,::b°,:Tet|:=
preservationstrategies,inadditiontothechancesoffutureconception,pregnair! Anintemet-basedmrvqreportsthatmorethan50%ofwommatthetimcd and breastfeeding [8, 9]. diagnosisofbreastcancerhavefertilityconcems[10],bwlessthan10%ofw" withpreviousbreastcancersubsequentlybecomepregn"Thisisaroundhalfùi pregnancyrateseeninage-matchedgroupwithoutbreastca"[11].Severalstu+ iesshowdthatfertilitycounsellingremainsinadequateandlacksofastandardisd approach[12|.ThefeffthatpregnancyafterbreastcancercouWworsentheprogm sisdoesinterferewiththereproductivedesireofyoungwomenandimpairsfuu ThereisincreasingevidenceinfavourofthefeasibilityandthesafèvofpT conception. nancyandbreastfeedingafterbreastcancer,therefore,wommwmahistopd successfullytreatedbreastneoplasmshouldbegiventhepossibilùtoconcei%a-ge, mother.__----.---_-`-==-6.2 TheRelationship Between Breastcancer
and Pregnancy
Manyscientificevidenceslinkpregnancyandriskofbreastcancer.Severalepid}
miologicalstudiesshowedaprotectiveeffectofpregnancyagainstbreastc-Tió-.ntprtiondoesnottakeplaceimmediately:forafewyeaftafterpregnant|• _ -:J---a Thic dual effect of
Plt-The protection does not take piace iiiiiii.u,a„„ . .__
thereisatransientincreaseofbreastcancerincidence.Thisdualeffectofpn}•.---. :.i an inrrpadriskforabout5-10yearsafl-nancyonbreastcancerincidence.withanincreasedriskioraDoui|-„,v_
[here ls a lrall>l.,1 ,.,. ~..___ _
---. f^ii^ujpd hv a lifelong protective effect, was described in a_ . __ :_^_,.acp nf
population-basedstudyfromNorwayThisstudyreportedmincreaseofb a pregnancy, followed by a liieioiig ijiu,..„ ,.,. ___ ,
• . ' ---- '--.:no l vears after a full-term pregnancy, followed by long- cancerincidencelasting3yearsafterafull-tempregnancy,followedbylong-population-based study lrom NOTwa} .,,,,... __, .
;eductionofrisk[13].
^n^th~Norwegianregistry-basedstudyinvestigatedtiBrelationshipbe`- _ _____. l f` o7n narolls womel. bi.eastcancerprognosisandreproductivefactomamong16,970parousmm
Another Norwegian regi>ii y-i,a..u u.__,
" " ^-ai`tcino the re|ationship between Parity, age
Di.ea>` iai.--|
ri-o---invasive breast tumour [14]. Analysing the reiationsnip ij.iw -... r___,, . breastcanceroutcome,itwasobservedthatwhendiagnosisoccursbeforemea£• ` .---.--- a :n ujr`men with high parity compared with those wim
. , _ _L_~-^, 50years,survivalisworseinwomenwimhighpanvcompdic;uw,,,...___ DreasL lalll.L V..,_..__ 7 panty.Thisislikelyduetoacombinationofgeneticfactors.moleculucharaciaT
ticsofbreasttumoursinyoui`gpatientsandhormonalmilieu.Nocle"uas- tionwasobservdbetweenpariwandbreastcancersurvivalwhendiagnosiso-inwomenwhowere50yeai.sorolder.Severalstudiestridtoexplainthistime-dependenteffectofpregnanqonbn-
cancerrisk.MoleculmsWlinkedpostnatalmammaqinvolutionprocess-6 PregnancyAfter Breast cance/ 73
susceptibility to neoplastic evolu(ion. It is hypothesised that angiogenesis, alteration of extracellular matrix and inflammatory prmess are involved in this mechanism. The stroma of the mammary gland is greatly modified depending on endocrine sta-tus and reproductive factors. Post-lac[ational tissue remodelling may provide a break in the natural stromal barriers that suppress tumour cell motility and invasion
with increased risk of tumour progression [ 15]. Another hypoihesis involves
mam-mary s(em cells. In mouse models, it was observed that mammam-mary s(em cells a(e highly responsive to steroid hormone signalling, despite their ER and PgR pheno-iypes. Following pregnancy, it was registered a transient increase in the number of mammary stem cells. which may indicate a cellular basis for the short-term increase
in breast cancer risk [16].
Pregnancy-related hormonal changes seem to be involved particularly in the long-tem protective effect. Preclinical models demonstrated that high doses of es(radiol induce apoptosis in long-term deprived, ER-positive breast cancer cell
lines [ 17]. Activation of caspases via the Fas/Fal pathway appears to be involved in
the promotion of apoptosis due to estradiol. me long-term oestrogen deprivation seems to sensi[ise breast cells to estradiol pro-apoptotic effect, with a reduction of number and growth of cancer cells in vitro. Response to estradiol depends on the ER subtypes expressed by the cells. Breast cells expressing ER-P undergo apoptosis, whereas cells expressing ER-oi are protected from apoptosis. A comparative study analysed the oestrogen receptor (ER) expression in nulliparous and parous women. Compared to nulliparous women, a lower expression of ER-a and a higher expres-sion of ER-B was observed in parous women [ 18]. Other authors suggested the fetal antigen hypothesis. Clinical studies found that a high percentage of parous women, but not nulliparous women, show evidence of immunisation to antigens located on breast cancer cells. Fetal cells and breast cancer cells share common antigens: the immune response exerted by matemal immunity against fetal cells may be extended
against cancer cells [ 19].
6.3 PregnahcyAf(er Breastcancer
Several case-control and population-based studies have been perfomed with me aim of understanding the prognostic impaci of pregnancy after breast cancer. None of these studies demonstrated a negative impact of a subsequent pregnancy [20]. In particular, a meta-analysis was perfomed (o investigate the impact of pregnancy on overall survival of women with previous breast cancer [21]. Fourteen studies were included in the meta-analysis, with a total number of 1,244 patients who became pregnant after breast cancer and 18,145 patients who did not. It was observed that women who became pregnant after adequate treatments for breast cancer had a sta-tistically significant improvement in overall survival as compared to the control
group [pooled relative risk (PRR): 0.59; confidence interval (CI): 0.50JO.70].
Analysing each study singularly, 8 siudies reported a significant survival advantage for subsequent pregnancy, whilst the remaining 6 studies showed a not statistically significant trend in favour of pregnancy.
74 N. Biglia et 1
Studyingtheimpactofpregnancyonprognosis.the"healthymothereffect"mm
be kept in mind. This is a relatively old concept introduced by Sankila in 1994, . explainapotentialconfoundingfactorintheinterpretationoftheobservedeffectof pregnancyinwomenwithcancer[22].Itexpressesthepossibilitythatthosewom who got pregnant after breast cancer are a subgroup of patients free of relapse anl healthier than the others. mis could introduce a selection bias: women who becom.
pregnantafterbreastcancerhavebettersurvivalbecausetheybelongtoasubg"i
of patients with good prognosis, independently and not because of a protecti-effect of the pregnancy.
Inthepreviouslycitedmeta-analysis,asubgroupanalysisinordertoovercon
this bias was performed. The outcome of women with pregnancy after breast ca-cer was compared with the outcome of controls who were known to be frec al
relapse. A not statistically significant trend favouring pregnancy after breast ca+ cer was still observed [21]. Even if selection bias may partially contribute to tl
conclude that pregnancy is s±
in women with a history of breast cancer and does not increase the risk recurrence.
risk of death reduction, it seems still reasonable to
In spite of this. a possible negative impact of pregnancy on breast c: particularly in patients-with endocrine-responsive tumour, is still concern. Recently, a study with the aim of investigating the effect of pregn prognosis,
in women with breast cancer according to oestrogen receptor status was c àLcted by Azim et a,. [23]. In the three subgroups ,oestrogen receptor-Posi cohort. oestrogen receptor-negative cohort and all patients) no difference disease-free su-rvival was observed between women who become pregnant those who did not conceive. Further, the pregnant group had better overall vival, again with no interaciion observed according to ER status [23]. In s mary. the study indicates that pregnancy is not protective against a relapsc patients with endocrine-sensitive tumour, but at the same time it does not e a detrimental effect.
Afurtherpointofdiscussionisthetimeintervalbetweentheendofantineo tic treatments and pregnancy. Several studies analysed this relationship with i sistent results. A significant survival improvement was observed only for w who conceive after Z4 months or more (Table 6.1 ). A not significant protection
Table 6.1 Cox.s proportional hazard model for survival in womcn with breast cancer with dependent variable stratified by time from diagnosis
Beta c¢fficient Time to subsequent (monms) pregnancy Hazard ratio (95 qr Cl) 2.20 (0,14-35.42) 0.45 (0.16-1.28) 0.48 (0.270.83) (Each stratified model adjusted for age. lymph node status. and tumor size)
Modified from lvcs A. et al. Pregnancy after breast cancer: population-based study.
6 PregnancyAfter Breast cancer 75
observed for women who delayed pregnancy for ai least 6 months [24]. A large population-based study corroborates the theory that the risk of dying decreases with increasing the gap between diagnosis and childbirth [25].
The optimal timing of pregnancy after breast cancer is sti]] undefined and the decision depends on patient's prognosis, age and personal condition. Because of the reassuring studies on patients who get pregnant 2 years and more after breast cancer and the observation that recurrences occur more frequently in the first few years, a delay of 2-3 years is conventionally recommended.
TTiis time interval would also allow to recover from chemotherapy-induced ovar-ian toxicity. Women with ER-negative breast cancer should be advised to wait at least 6 months from the end of treatments before conceiving, to avoid the possible toxic effect of chemotherapy on growing oocytes.
As to ER-positive breast cancer, current guidelines recommend at least 5 years of endmrine therapy [26]. Furthermore, recent evidence suggests that 10 year§ of tamoxifen confer even greater protection [27]. Because of me teratogenetic effects of tamoxifen, pregnancy during endocrine therapy is contraindicated and an
off-therapy period of 3i months is recommended before conceiving. But the
reproduc-tive potential is declining year by year, because of the physiological loss of ovarian reserve and the harms of chemotherapy. The feasibility of a temporary break of the homonal therapy allowing to conceive and have a fiill-term pregnancy, with subse-quent completion of endocrine treatment is under investigation. A prospective study of the Breast lntemational Group and North American Breast Cancer Group (BIG-NABCG) is currently ongoing. investigating the clinical and biological features contributing to a safe and successful pregnancy in ER-positive breast cancer pa(ients. The analysis will f«us on both oncological outcomes (local and distant recurrences and survival) and obstetrical outcomes (sponianeous abortion, preterm delivery, in(rauterine growth restriction, low weigh( at birth, fe(al malformations). Secondary endpoints of the study are the feasibility and the impact of a temporary break of endocrine therapy to allow conception and the optimal duration of subse-quent homonal therapy after delivery and breastfeeding [28].
6.4 0bstetrical and Neonatal outcome
One of the unnamed concems that patients face is the fear of a potential teratogenic effect of antineoplastic treatments on the offspring. Few data are available on birth outcomes in breast cancer survival: however, no excess risk for the newbom health
is suggested [28].
Some studies found a higher rate of abortion than in general population. This information may be biased because most of the studies did not discriminate between spontaneous and induced abortion. When this issue was considered, the risk of spontaneous abortion did not seem to be higher in breast cancer patients than in general population. On the contrary, the rate of induced abortion is consistently higher, suggesting that unceiiainties of patients and physicians about safety of preg-nancy after breast cancer often lead to dramatic choices [29]. Studies comparing
76 N. Bigliaet
disease-free surviva] in patients who completed their pregnancy to term and pati who had an abortion found a not statistically significant trend towards better come in women who had a full-term pregnancy [23].
Two large studies assessed the obstetrical and neonatal outcomes of pregnanci-following breast cancer. A Danish nationwide cohort study investigated w matemal breast cancer affects birth outcome [30]. Data about pregnancies of 2-women with a his(ory of breas( cancer were matched with a comparison cohoit 10,453 women belonging to general population. Similar rates of low birth weigL s(illbir(h and congeni(al abnormalities were observed in the two groups. A small
-not sta(istically significant higher preterm delivery ra(e was observed in the b
cancer cohort. Mean birth weight was nearly 3,400 g in both groups, as well as m-gestational age ai delivery. Different findings were reported in a Swedish cohort stn. aiming to assess delivery risk and neonatal health [31 ]. Data were extrapola(ed fi-the Swedish Medical Birth Regis(ry and fi-the Swedish Cancer Regis(ry, including 3. mothers with a history of breast caiìcer and 2,870,518 mothers belonging to ge population. An increased risk of delivery complication, caesarean section, p delivery and congeni(al malformations and no differcnce in low birth weight raòe delivery was observed. Authors conclusion is that pregnancy after breast c should be considered at high risk and therefore managed and surveilled accordindL
Usually women with previous breast cancer are more likely to give birth ai older age than the general population. Both studies point out this differencc matemal age. About 50 % of women in breast cancer cohort are 35 years old more at delivery, with a mean age of 34 years, whereas in the comparison group
figures are 1 1 % and 28 years, respectively [30, 31 ]. It is well known that pregn
at an old age is more susceptible to many comorbidities and complications as g tional hypertension, preeclampsia, gestational diabetes and other conditions bring about high risk for pregnancy outcome and require special surveillance. may partially explain the slightly higher rate of pregnancy complications re
in the Swedish study, but uncertainties still exists.
6.5 Breastfeeding After Breastcancer
Many factors, such as personal, cultural. social and environmental factors, influ women's decision about breastfeeding. Beyond these, breast cancer survivors unique physical and emotional factors that might impact their decision and ab to breastfeed.
A qua]itative research explored by an interview the experience and the fec about breastfeeding in a selected groiip of breast cancer survivors [32]. Gene patients alleged the wish to breastfeed, but also anxiety and concems about doing This highlighis the need of prenatal education and information io prepare me spective mother to the challenges of breastfeeding. Breast cancer survivors all physical and emotional problems, mainly because they had to rely primaril}. entirely on one brcast. Treatments for breast cancer can affect lactation. Proximit}.
Pregnancy AfteT Bmasi CanceT 77
he surgical incision to thc nipple-aieo]a complex. dose and type of radia(ion therapy nayreduceorinhibitlactation.mus,manypatientscanbreastfeedfromtheuntreatcd ireast only, with consequent uncertainty about whether or not the milk supply would e sufficient for the infant [32]. Failure to nurse from one breast should not affect the ise of the other and me mother should be reassured about the adequacy of milk pro-luction by a single breast, sufficient for the nutritional need of the newbom.
Another survey analysis was performed investigating the breastfeeding pattems nd habits in breast cancer survivors [33]. Hypoplasia and hypotrophia of the oper-ted and irradiaoper-ted breast were observed, with consequent reduced milk production, iipple pain, physical changes and discomfort during latching. Furthermore, a previ-ius mastectomy was associated with short-lasting breastfeeding. This is not only ustified by the fact that these patients have a single breast to nurse their babies, but .lso women with previous breast conserving surgery used one breast only for lacta-ion. A possible altemative explanation is that body image plays an important role n the success of breastfeeding, and breast-conserving surgery, in spite of mastec-Dmy, may reinforce the feeling of matemal adequacy. A proper breastfeeding coun-elling is a key factor for successful and prolonged breastfeeding in breast cancer urvivors. This experience often brings about a psychological rehabilitation and iatients express satisfaction to have been able to breastfed their babies, even if it equired efforts and sometimes milk supplement.
These results enlighten the reasons of breast cancer survivors to breastfeed and he challenges which they will face and concem them. It is of the utmost importance hat physicians provide practical and continuous support to the mother, especially luring the postpartum period.
Beyond feasibility the safety of breastfeeding after breast cancer treatment emainsanopenquestion.Severalstudieshavedemonstratedtheprotectiveeffectof )reastfeeding on breast cancer risk in general population. A meta-analysis including lata from 47 epidemiological studics, evaluating the relationship between breast-•eeding and breast cancer, has demonstrated a 4.3 % reduction of the relative risk of )reast cancer for each year that a woman breastfeeds [34]. In order to reduce biases, ;tratifications for age, parity, ethnicity and age at fìrst delivery were perfomed, natching women who breastfed and who did not breastfeed on the basis of the same
:haracteristics. The conclusion was that the benefits are statistically significant and
)reastfeeding should be encouraged.
While there is evidence that breastfeeding reduces breast cancer incidence in 5eneral population, there are no solid epidemiological data about breastfeeding Lfter breast cancer. A retrospective case-control study investigated the survival rate )f patients treated for breast cancer who subsequently became pregnam [35]. A •ecent re-analysis of those data was performed, specifically focused on the role of )reastfeeding. A better survival was suggested in women who breastfed. mese data :ould be biased, but it may be supposed mat breastfeeding does not have a detrimen-al effect on breast cancer outcome [36].
The mechanisms undemeath the asscx:iaiion of breastfeeding and reduction of )reast cancer incidence are not known. Several hypotheses were expressed in vari-m studies and were synthesised in a review article [36]. Sovari-me data suggest that
78 N. Biglia et al.
lactation may reduce the carcinogens level in the breast. Another hypothesis is the suck]ing-related blockage of the hypothalamus-pituitary axis leading to lactationa) amenorrhoea. From animal models, it was hypothesised that differentiation of the mammary gland as observed during pregnancy and lactation protects from neoplas-tic evolution. The role of prolactine has been widely studied but with conflicting results. and the impact of this hormone on initiation and promotion of breast canccr in humans remains unclear.
Epithelium changes and stromal ac(ivation which occur in remodelling breast tissue may be associated with a temporary increase in breast cancer incidence. This observation recommends a thorough follow-up of women with history of breasi cancer after pregnancy or lactation. Patients and physicians often tell of the fear of a delay in diagnosis in case of tumour recuiTence. Lactation does not interfere with clinical and radiological evaluation of the breasts. Ultrasound exam can be safel}. perfomied and in case of suspicion, mammography or breast magnetic resonancc imaging can be performed after having drained the lactating breasts [36].
Despite uncertainty, the benefits of breastfeeding to the baby and the mother arc well established. Newboms who are breastfed are pmtected from infections in the short period and are less susceptible to develop autoimmune diseases and metabolic disorders at adult age. Furthermore, a benefit in neu":ognitive developmem of tlìc baby breastfed has been suggested. Breastfeeding bears several advantages for the mother as well. Women who breastfeed have better control of postpartum bleeding. retum swiftly at the usual weight and ane heavily gratified by the emotional bo") which is created with her baby.
In conclusion, current evidence suggests that breast cancer survivors who wish to breastfeed, should be encouraged and supported in their efforts.
6.6 Childbearing Attitudes ofYouhg Breast
Cancer Survivors
Many studies have shown that pregnancy and paienthood are two important issucs for young women with breast cancer. As breast cancer-related mortality declines. the impact of anticancer treatments on reproductive potential is getting more rele-vant, and fertility impairment may worsen the quality of life in a growing number or patients. For some young breast cancer survivors, the threat to their childbearing plans has major emotional and psychological consequences. Literature and clinical practice demonstrate that some women remain fertile and have a spontaneous preg-nancy after a history of cancer. Additionally, (he advent of advanced assisted repfù ductive technology within the oncology field has made fertility preservation an option for women, prior to the initiation of (reatments. As known. other options afc available for infertile women, such as adoption and third-party reproduction, bui most couples crave biological offspring.
Several studies showed that the risk of early menopause and infertility are causes of concem for about the half of young women who receive breast cancer diagnosis. Some pa(ients reported that this fear conditioned treatment decisions [37]. Infertilip
6 PregnancyAfter Breast cancer 79
in cancer pa(ients is associated. more frequently than in general population, to anxi-ety. depressive symp(oms and sexual impairment which have a negative impact on the quality of life.
But even when fertility is preserved, other concems upset breast cancer patients. Women fear that the child might be bom wi(h a birth defec( because of the chemotherapeutic agents they received. They are anxious about a shorter life expectancy and are afraid of having not enough energies to raise children. Furthemore. women feared that the offspring would have a greater susceptibility
to cancer [38].
On the other hand, some patients peiceive the benefits that could be achieved by having cmldren after breast cancer treatmeni Raising a child can be a powerful motivator to stay alive and healthy, ii may strengthen the relationship with the part-ner, it brings back normalcy in their life and it would restore the sense of femininity and sexuality [39]. Breast cancer survivors who are disease-free often feel healthy enough (o consider a pregnancy. This is called a reasonable wellness, which may express the ethical guide into the difficult choice of getting mother.
In clinical practice, gynaecologists and oncologists are frequently faced with the issue of educating women about childbearing after breast cancer. However, some studies suggested that these professionals often feel discomfort and lack of knowl-edge about how .o best educate women with cancer-related fertiliLy ma((ers, leaving women's fertility concems poorly addressed. Attending physicians may perceive the fertility preservation as a low priority issue, compared with the (rea(mem of cancer or they could fear that fertility preservation techniques may dwindle the efficacy of anticancer treatments. Presently, there are guidelines stressing the need to communicate with and educate young patients regarding fertility issues. Oncologists should refer interested and appropriate patients to reproductive special-ists as early as possible, to allow a rapid access to fertility preservation strategies and to avoid delaying the chemotherapy onset [8, 9].
6.7 Breastcancer, Pregnahcyand Breastfeeding
in BRCA1 /2 Mutation Carriers
Reproductive factors influence the risk of breast cancer in the general population, but few data are available in the selected group of women with mutations in BRCAl and BRCA2 genes. BRCAl and BRCA2 are .umour suppressor genes which are involved in multiple processes, including DNA damage repair and recombination, and regulate noimal cell differentiation. During pregnancy and breastfeeding, breast cells divide and differentiate; thus, it could be supposed that reproductive factors have different impacts on breast cancer risk in die BRCA mutation carriers and in general population.
A large retrospective cohort study including women carrying BRCAl/2 muta-tions investigated the impact of pregnancy on breast cancer incidence [40]. No dif-ference was found between parous and nu]liparous women, and the same results were observed in BRCAl and BRCA2 mutation carriers. It does no[ appear that
80
N. Big'ia et al.
parity per se influences the risk of breast cancer in this particular subgroup of
Women.
Inconsistent resul.s aic reported about the asscx:iation between bieastféeding and breasi cancer risk. Some evidences suggest a protective effects of breastféeding, even strongerthaningeneralpopulation,buton]yamongBRCA1mutationcarrieis[41,42].
It is known that hereditary breast cancer is different from sporadic tumour and differences are observed between breast cancer patients with BRCAl and BRCA2 mutations as wel]. This might suggest that the biological pathway for carcinogene-sis is differen[ for these two genes.
Our knowledge about the impact of pregnancy after breast cancer in BRCAl/2 mutation carriers is even poorer. This is partly due to the small proportion of women carrying mutations in these genes. The question is sensible, because of the iypical early age of onset of hereditary breast cancer. A multicenter, case-control study which included women known to carry a BRCA 1 or BRCA 2 mutation and history of breast cancer has been published recently [43]. The cases were patients witti pregnancy-associated breast cancer or pregnancy followjng breast cancer. The con-trols were selected among patients who did not get pregnam after breast cancer diagnosis and who were alive and recurrence-free at the time of the delivery of thc baby in the matched group, in order to reduce potential confounding bias, such as the healthy mother effect. The 15-year survival was excellent in the two groups. around 90 %, and no significant difference was observed between cases and controls after adjustment for several prognostic factors. Despite the limitations of the study` first of all the small sample size, these results are encouraging and future research is recommended to prove the not detrimental effect of pregnancy after breast cancer in this particular subgroup of women [43].
There is an issue in BRCAl/2 mutation carriers that deserves special consider-ation. Some studies suggested that the deficient DNA repair mechanism due to muta-tions in BRCA 1 and BRCA 2 genes may make oocytes more susceptible to DNA-damaging agents. Furthemore, it has been speculated that BRCA mutation carriers may have a lesser ovarian reserve than general population and undergo prc-mature menopause. As a consequence, BRCA mutation carriers may be more sus-ceptible to chemotherapy-induced gonadotoxicity with severe ovarian reserve loss [44]. Diagnosjs of brcast cancer in a young patient wim BRCA mutation raises con-cems about her future fertility. A trend towards earlier referral to fenility specialists underscores the importance of this issue. However, the better approach in this par-ticular group of patients is not an easy choice. On one side data suggest a pcxM response to ovarian stimulation for oocyte retrieva] and cryopreservation. pariicu-larly in BRCAl mutation carriers; on the other side ovarian tissue cryopreservation for BRCA mutation carrier is disputed because of the risk of ovarian cancer and lastly the efficacy of temporary ovarian suppression with GnRH agonists is still
con-(roversial [44].
AIl these findings suggest that BRCA mutation carriers may have a shorter reproductive life, and thjs should be taken into account in the management of young breast cancer patients who desire a future pregnancy. Whether or not the low ovar-ian reserve and poor response to ovarovar-ian stimulation may reduce the fertility poten-tial of women with BRCA mutations is still unknown and further research is needed.
6 PregnancyAfter Breastcancer
81
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