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The Breast 21 (2012) 550e555

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The Breast

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Original article

Pregnancy-associated breast cancers: Do they differ from other breast cancers inyoung women?

Anne-Sophie Genin a,*, Bénédicte Lesieur a, Joseph Gligorov b, Martine Antoine c, Lise Selleret a,Roman Rouzier a

aDepartment of Obstetrics and Gynecology, Tenon University Hospital, 4 rue de la Chine, 75020 Paris, FrancebDepartment of Medical Oncology, Tenon University Hospital, 4 rue de la Chine, 75020 Paris, FrancecDepartment of Pathology, Tenon University Hospital, 4 rue de la Chine, 75020 Paris, France

a r t i c l e i n f o

Article history:Received 10 January 2012Received in revised form22 March 2012Accepted 6 May 2012

Keywords:Breast cancerPregnancyPost-partumImmuno-phenotype

* Corresponding author. Tel.: þ33 01 56 01 68 76;E-mail address: asgenin@hotmail.com (A.-S. Genin

0960-9776/$ e see front matter � 2012 Elsevier Ltd.doi:10.1016/j.breast.2012.05.002

a b s t r a c t

The impact of pregnancy in the physiopathology of pregnancy-associated breast cancer (PABC) is stillunclear.

We compared the characteristics of PABCs and breast cancers not associated with pregnancy (non-PABCs) in terms of their loco-regional invasion and histological phenotype.

We conducted a retrospective chart review on women less than 43 years of age treated for breastcancer from January 1, 2004 to December 31, 2010. We compared age at diagnosis, loco-regional invasionand histological data.

We recorded 282 breast cancers in 276 patients. Forty-one tumors (14.5%) were PABCs. PABC patientswere significantly younger than non-PABC patients. Compared with the non-PABCs, PABCs were twicemore frequent advanced tumors (T3-4) and have twice more frequent HER2 over-expression andhormone negative status.

The more aggressive histological profile observed in the PABCs, especially in post-partum tumors andwomen older than 35 years of age, seems to be a direct consequence of the association with pregnancy.

� 2012 Elsevier Ltd. All rights reserved.

Introduction

Childbearing is considered to have a protective effect on breastcancer risk in the long term. However, recent pregnancy increasesthe risk of breast cancer, especially among women older than 35years of age. This “dual” effect of pregnancy was first reported in1994 by Lambe,1 who observed that pregnancy increases the risk ofbreast cancer within the 15 years following delivery and hasa protective effect after 15 years.

Pregnancy-associated breast cancer (PABC) is defined as breastcancer diagnosed during pregnancy or the post-partum period(from one to 5 years after delivery according to the authors).2 As themost common definition includes only one year post-partum, weconsidered the post-partum period as the year following thedelivery.

The incidence of PABC among pregnancies is estimated to bebetween 1/10,000 to 1/3000 in developed countries. In previousstudies, the rate of PABC in women younger than 45 years of age

fax: þ33 01 56 01 60 62.).

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varies from 2.6% to 7%3,4 and even rises to 15.6% in women youngerthan 35 years of age.5 Among breast cancer cases in the globalpopulation, the incidence of PABC increases. In a large study cohortof 16,620 patients aged 15e44 years of age, Andersson found thatPABC, which represents 7% (1161 cases) of all breast cancers in thiscohort, doubled in incidence, from 16.0 to 37.4/100,000 childbirthsduring the study period (1963e2002). In this population, 30.1% ofPABC patients were between the ages of 25 and 29.3 This increase inthe incidence of PABC is similar to the increased incidence in allbreast cancers. Given that the incidence of breast cancer rises withage and because women tend to delay childbearing until after theage of 30 in developed countries, the increasing incidence of PABCis expected to continue.

The prognosis of PABC is frequently poor. Whether this poorprognosis is due to the association with pregnancy remainsa subject of debate. Beadle and Murphy reported no difference inthe risk of mortality between PABC and non-PABC.5,6 However,other studies founded inverse results.7,8 Furthermore, large cohortstudies tend also to find an increased risk of cause-specific death inPABC patients compared to non-PABC patients with a hazard ratio(HR) from 1.23 to 1.95.9,10 The difference in the mortality rate was

A.-S. Genin et al. / The Breast 21 (2012) 550e555 551

almost perceptible in the first 5 years following treatment andbecame undetectable after 8 years. One bias is that these resultswere calculated after adjusting for age or for age and the initialextent of disease only. In a recent study, after adjusting for age,tumor size, stage, receptors status and race, similar results werefound, but the difference was reduced and marginally significant(HR ¼ 1.14, p ¼ 0.046).11 The worse outcome was higher amongtumors diagnosed post-partum rather than during pregnancy,4,9

and the prognosis improved as the time from deliveryincreased.12 At the time of diagnosis, PABCs were reported to belocally more advanced in tumor size5,6,8 but data for node statuswere contradictory.5e9,11 The reason for the poor outcome of thePABCs remains debatable. If a delay in diagnosis could be involvedand favors a larger tumor size, then it is not the only factor impli-cated, as a worse outcome is observed even after adjusting fortumor size. Some authors tend to point to the role of the tumorstromal environment.13 Another hypothesis is that the poor prog-nosis observed in PABC could result from the tumor characteristicsthemselves. Histologically, PABC has been previously reported tohave a higher frequency of hormone negative status.5e7,11 Fewstudies reported data on the HER2 and the Ki67 status. Recently, nodifference regarding the HER2 status was found between PABC andcontrols matched on age.6 Regarding the differences between PABCdiagnosed during the pregnancy or during the post-partum period,recent studies reported no difference concerning tumor size andnodes involvement,6,7 and also no difference regarding the grade,the hormonal status and the lymph vascular space invasion.7

The goal of this study was to discover whether PABC hasa distinct histological profile compared to non-PABC in a populationof women aged 20e43 years. As some characteristics could berelated to the age, we also compared histological profiles accordingto 2 age groups (�35 years of age and>35 years of age). In a secondway, we analyzed gestational and post-partum tumors separately.

Methods

Patients’ selection

Inclusion criteria were: female patient aged 20e43 years whounderwent mammary surgery for breast cancer, irrespective ofaxillary surgery, at Tenon University Hospital, France, betweenJanuary 1, 2004 and December 31, 2010. We determined thethreshold of 43 years of age as it corresponded to the oldest PABCpatient in our cohort. All the patients who underwent surgery wereprospectively recorded in the institutional database for the FrenchNational Health Care Assurance. We retrospectively listed all the2516 women who underwent breast surgery at our institutionusing this database. Patients younger than 20 or older than 43 yearsof age were excluded (N ¼ 2001). Among the 515 patients aged20e43 years, we excluded patients with benign disease (N ¼ 239),leading to the inclusion of 276 patients. We recorded the followingclinical data for all patients included: the age at diagnosis and thepregnancy-associated status as defined by a diagnosis of cancermade during the gestation period or during the year following thelast delivery. Patients who did not fulfill these criteria wereconsidered to have non-PABC. For the PABC patients, the term ofpregnancy if pregnant, or the time since delivery if post-partum,were noted.

Histological data were obtained from the surgical specimen forpatients without neo-adjuvant chemotherapy (NAC) or from thepre-treatment biopsy for patients who underwent NAC. Thefollowing data were reported: tumor type, histological gradeaccording to Ellis and Easton, status for estrogen (ER) and proges-terone receptors (PR), HER2 expression, rate of Ki67 and lymphvascular space invasion (LVSI). A tumor was considered to have

a positive hormonal status if the ER and/or the PR scores werehigher or equal to 10%. The threshold for considering that Ki67 levelwas elevated was 20% as it corresponded to the threshold used byour institution at the time of patients’ management.

Node classification was determined based on the surgical lym-phadenectomy results. Patients who underwent NAC wereexcluded for node invasion analysis. Tumor size was obtained fromthe histological reports for patients without NAC or was estimatedby palpation and/or imaging for patients who were treated withNAC. Patients with bilateral breast cancer were counted twice (oncetime for each side).

Statistical analysis

Means were analyzed using the ManneWhitney 2-tailed test.The frequencies were analyzed using the Chi-2 square test forcontingency tables larger than 2 � 2 and the Fisher exact test fortables 2 � 2. A p < 0.05 was considered significant.

Results

During the study period, 276 patients aged 20e43 years,including 6 patients with bilateral tumors, underwent surgery forbreast cancer. Among the 282 studied tumors, 41 (14.5%) wereassociated with pregnancy.

Comparison of PABC versus non-PABC in the entire study population

PABC patients are significantly younger than non-PABC patients(mean age ¼ 34.9 years vs. 38.5 years, p < 0.0001). As presented inTable 1 and in the Fig. 1, PABC was more common in the group ofwomen between 30 and 40 years of age. This repartition accordingto age classes in PABC was different from that in the non-PABCpopulation, where the incidence of breast cancers increasescontinuously with age. In women under 35 years of age, nearly onethird of breast cancers are associated with pregnancy.

Patients’ characteristics are presented in Table 1. The histo-logical type was similar in both groups, with a large majority beingdiagnosed with ductal invasive carcinomas. In situ tumors havethe same frequency between the 2 groups. Invasive tumors aretwice as locally advanced in PABC patients, as 27% of T3-4 tumorswere found in the PABC group compared with 12% in the non-PABC group (p ¼ 0.021). No difference was observed in the nodeinvolvement and histological characteristics such as grade, prolif-eration index Ki67 or LVSI. PABC tumors were twice as likely to behormone negative (42% vs. 21%, p ¼ 0.005), both for ER (44% vs.21%, p ¼ 0.002) and PR (50% vs. 30%, p ¼ 0.017), and positive forHER2 over-expression (31% vs. 16%, p ¼ 0.038). Triple negativetumors tended to be more frequent in PABC (28%) than in non-PABC (17%); however, the difference did not reach significance(p ¼ 0.126).

To determine if this more aggressive immuno-histologicalprofile in PABC might be related to the younger age of patients,we analyzed these characteristics according to 2 age groups:younger or older than 35 years of age. We chose this threshold as ithas been commonly used to define age risk in young patients. Datawere reported in Table 2. No difference in terms of histologicalparameters was seen between the PABCs and the non-PABCs inpatients younger than 35 years of age. However, PABC patients inthis age group had twice the rate of T3-4 tumors (35%) than in non-PABC patients of the same age group (18%, p ¼ 0.047) and PABCpatients in the older group (20%, p ¼ 0.004). The comparisonbetween the 2 age groups did not reveal a difference in the histo-logical characteristics of the PABC patients, whereas the non-PABCyounger patients were more likely to be hormone negative (34% vs.

A.-S. Genin et al. / The Breast 21 (2012) 550e555552

17%, p ¼ 0.016) and triple negative (30% vs. 13%, p ¼ 0.001)compared to the non-PABC patients over 35 years of age. In thePABC patients over 35 years of age, the immuno-histological profiletended to be similar to that observed in the patients younger than35 years of age with more a frequent hormone negative status andHER2 over-expression compared to the non-PABC patients of thesame age group (ER negative: 50% vs. 17%, p ¼ 0.002, PR negative:50% vs. 20%, p ¼ 0.005, hormonal negative: 45% vs. 17%, p ¼ 0.008,HER2 over-expression: 55% vs. 16%, p < 0.0001). Triple negativetumors tended to be more frequent in PABC patients over 35 yearsof age (25%) than in non-PABC patients of the same age group (13%),but the difference did not reach significance (p ¼ 0.167).

Fig. 1. According to age, the incidence of PABC and non-PABC in the entire studypopulation.

Table 1Patients and tumors characteristics.

Non-PABC PABC p

(N, % amongnon-PABC)

(N, % amongPABC)

All 241 41Age at diagnosis <0.0001Mean (years) 38,5 34.9�30 years 11 5% 3 7%>30e�35 years 37 15% 17 41%>35e�40 years 89 37% 15 37%>40 years 104 43% 6 15%Histological type 0.73Ductal invasive 209 87% 36 88%Lobular invasive 15 6% 1 2%Other invasive 17 7% 4 10%Ductal in situ 33 14% 5 12%Tumor classification 0.041Tis 33 14% 5 12%T1 83 34% 17 41%T2 94 39% 8 20%T3 18 7% 8 20%T4 13 5% 3 7%Node classification a 0.481pN0 75 48% 11 41%pN1 60 38% 9 33%pN2 17 11% 6 22%pN3 4 3% 1 4%Grade b 0.2511 31 15% 3 8%2 74 36% 9 25%3 98 47% 21 58%ER status b 0.002Negative 43 21% 16 44%Positive 161 77% 19 53%PR status b 0.017Negative 63 30% 18 50%Positive 142 68% 17 47%HR status b 0.005Negative 43 21% 15 42%Positive 162 78% 20 56%HER 2 status b 0.038Negative 171 82% 24 67%Positive 34 16% 11 31%Triple negative b 35 17% 10 28% 0.118Ki 67 b 0.302Low <20% 60 29% 13 36%High �20% 144 69% 21 58%LVSIb 0.342Absent 99 48% 20 56%Present 99 48% 14 39%

PABC ¼ Pregnancy-Associated-Breast-Cancer, non-PABC ¼ non-Pregnancy-Associ-ated-Breast-Cancer, ER ¼ Estrogen Receptors, PR ¼ Progesterone Receptors,HR ¼ Hormonal Receptors, LVSI ¼ Lymphovascular Space Invasion.

a Tis and neo-adjuvant chemotherapy (NAC) excluded (N ¼ 156 in non-PABCgroup, N ¼ 27 in PABC group).

b Tis excluded.Tumor classification is determined by pT for patients who do not received NAC

and by size estimated by imaging for patients who received NAC. The resultsfor hormonal, HER2, Ki67 and LVSI status do not reach 100% as there are somemissing data.

Table 2The characteristics of PABC and non-PABC in invasive tumors according to agegroups.

Non-PABC (N, %) PABC (N, %) p1

Tumor classification�35years Tis 4 8% 4 20% 0.047

T1 15 31% 7 35%T2 20 42% 2 10%T3 5 10% 6 30%T4 4 8% 1 5%

>35years Tis 29 15% 1 5% 0.436T1 68 35% 10 48%T2 74 38% 6 29%T3 13 7% 2 10%T4 9 5% 2 10%

p2 0.525 0.004Node classification*�35years N0 13 45% 5 36% 0.805

N1 9 31% 5 36%N2 6 21% 4 29%N3 1 3% 0 0%

>35years N0 62 49% 6 46% 0.567N1 51 40% 4 31%N2 11 9% 2 15%N3 3 2% 1 8%

p2 0.28 0.608Grade**�35years 1 5 11% 1 6% 0.804

2 12 27% 5 31%3 26 59% 8 50%

>35years 1 26 16% 2 10% 0.1532 62 38% 4 20%3 72 44% 13 65%

p2 0.197 0.638ER status**�35years Negative 15 34% 6 38% 0.68

Positive 29 66% 9 56%>35years Negative 28 17% 10 50% 0.002

Positive 132 80% 10 50%p2 0.017 0.557PR status**�35years Negative 20 45% 8 50% 0.598

Positive 24 55% 7 44%>35years Negative 33 20% 10 50% 0.005

Positive 128 78% 10 50%p2 0.001 0.845HR status**�35years Negative 15 34% 6 38% 0.68

Positive 29 66% 9 56%>35years Negative 28 17% 9 45% 0.008

Positive 133 81% 11 55%p2 0.016 0.767HER 2 over-expression**�35years No 36 82% 10 63% 0.221

Yes 8 18% 5 31%

Table 2 (continued )

Non-PABC (N, %) PABC (N, %) p1

>35years No 135 82% 9 45% <0.0001Yes 26 16% 11 55%

p2 0.748 0.203Triple negative**�35years 13 30% 5 31% 0.631>35years 22 13% 5 25% 0.167p2 0.001 0.677Ki67**�35years <20% 11 25% 5 31% 0.563

�20% 32 73% 10 63%>35years <20% 49 30% 8 40% 0.301

�20% 112 68% 11 55%p2 0.535 0.601LVSI**�35years Absent 24 55% 9 56% 0.577

Present 19 43% 5 31%>35years Absent 75 46% 11 55% 0.578

Present 80 49% 9 45%p2 0.389 0.588

PABC ¼ Pregnancy-Associated-Breast-Cancer, non-PABC ¼ non-Pregnancy-Associ-ated-Breast-Cancer, ER ¼ Estrogen Receptors, PR ¼ Progesterone Receptors,HR ¼ Hormonal Receptors. Tumor classification is determined by pT for patientswho do not received NAC and by size estimated by imaging for patients whoreceived NAC. The results for hormonal, HER2, Ki67 and LVSI status do not reach100% as there are some missing data.p1 ¼ comparison between PABC and non-PABC.p2 ¼ comparison between group �35 years and group >35 years.*= Tis and neo-adjuvant chemotherapy (NAC) excluded (N = 156 in non-PABC group,N = 27 in PABC group).**=Tis excluded.

A.-S. Genin et al. / The Breast 21 (2012) 550e555 553

Comparison of gestational and post-partum tumors

We then analyzed gestational and post-partum (PP) tumorsseparately. As the number of in situ tumors was very small in theentire PABC group (N¼ 5), we studied only invasive tumors. AmongPABC patients, 11 (30.6%) were diagnosed during pregnancy and 25(69.4%) were diagnosed during the year following delivery. Resultsare shown in Table 3.

When comparing the gestational PABC group with the non-PABC group, we found no difference regarding tumor size, lymphnode involvement, LVSI or HER2 status. Gestational PABC weremore frequently negative for ER (p ¼ 0.03) but not for PR, and havelower Ki67 rate (p ¼ 0.04). The comparison between gestationaland PP tumors revealed no significant differences, although PPtumors tended to be more locally advanced with higher tumor sizeand more frequent lymph node invasion and tended to be moreproliferative with higher rates of Ki67.

When comparing the PP and the non-PABC groups, the PPtumors were more locally advanced (T3-4 tumors: 40% vs. 15%,p ¼ 0.003) and, although not reaching significance, node invasiontended to be more frequent (72% vs. 52%, p¼ 0.08). PP tumors wereof a higher grade (grade 3: 68% vs. 47%, p ¼ 0.03) and had a worseimmuno-histological phenotype with a higher frequency ofhormone negative status (44% vs. 21%, p ¼ 0.01), both for ER (44%vs. 21%, p ¼ 0.01) and for PR (56% vs. 30%, p ¼ 0.01), and a higherfrequency of HER2 over-expression (36% vs. 16%, p ¼ 0.02). Therewas no difference noted in the proliferation index Ki67 and in LVSI.

Discussion

In this retrospective chart review study amongwomen under 43years of age, PABC represented 14.5% of all breast cancers. Nearlyone third of breast cancers in women younger than 35 years of ageoccurred during pregnancy or the post-partum period (N ¼ 20/68,29%). The PABC patients are younger than the non-PABC patients,even in this selected young population. The PABCs were locally

more advanced with greater tumor size at diagnosis, but they didnot have higher frequencies of lymph node invasion. The PABCs hada poorer immuno-histological prognostic profile than the non-PABCs, with twice as many tumors being negative for hormonalreceptors, both ER and PR, and over-expressing HER2. Triplenegative tumors tended also to be found with higher frequency inthe PABC group; however, this result did not reach significance. Thispoorer phenotype was largely due to the post-partum tumors,which seemed to be more aggressive than the gestational tumors.However, given the small number of gestational tumors in ourcohort (N ¼ 11), the statistical analysis of this sub-group lackedpower and needed to be prudently re-envisioned. There was nodifference in the immuno-histological characteristics of the tumorsin patients younger than 35 years of age. In this age group, both thePABCs and the non-PABCs had high rates of hormone negativestatus and of over-expression of HER2. Interestingly, in the group ofwomen older than 35 years of age, the PABCs had the sameimmuno-histological profile as breast cancers in women youngerthan 35 years, whereas the non-PABCs did not.

The proportion of PABC in our study population is greater thanthat reported by other authors in large cohort studies, where inci-dencevaries from2.6% to7%ofbreast cancers.3,4,9 This result couldbedue to older patients in those studies (upper age ¼ 45 or 49 years ofage), as breast cancer ismore common but less frequently associatedwith pregnancy inwomen older than 40 years of age. This could alsobe due to the time period of the studies: these very large cohortsreport results from the 1960s, a time when PABC was less frequent.

Our results that showed the size of the tumor as being larger inPABCs were concordant with the literature.5e9,11 We did not findsignificant differences with regard to node involvement, which issimilar to data presented by Rodriguez11 and Mathelin,7 but not byother authors.5,6,8 We found a high frequency of hormone negativestatus in the PABC group, which is concordant with otherreports.5e7,11 HER2 expression was previously reported only once toour knowledge, with no difference found between PABC and non-PABC.6 In the present study,we foundmore frequent over-expressionof HER2 in the PABC group. These apparently conflicting results couldbe the consequenceof theabsenceof age-matching inourpopulation.

Some mechanisms may potentially explain the associationbetween pregnancy and a worse outcome. The changes that occurin the hormone systemic environment during gestation (higherlevels of estrogen) and lactation (increase in the prolactin level)may play a role. Indeed, even though most PABCs do not expresshormone receptors, their growth could be promoted by highestrogen levels during pregnancy through interactions with thestroma.14 The tumor micro-environment seems to be a major factorin tumor growth and invasion. Some authors have reported that theextracellular matrix (ECM) modifications during the mammarygland involution following delivery or the end of lactation aresimilar to wound healing repair and inflammation,15 which areknown to favor tumor proliferation. In vivo, Mc Daniel showed thatthe injection of tumor cells with the ECM from involuting breastswhen compared to the ECM of the breasts of nulliparous ratsshowed an increase in metastasis through increased angiogen-esis.16 The ECM modifications during the mammary gland involu-tion could explain the poorer prognosis of PABC by promotingmetastasis, but we also demonstrated that PABC has a poor prog-nostic immuno-histological status. It has been hypothesized thatthe tumor sub-type reflects the origin of the initial tumor process:ER-negative tumors would derive from the earliest progenitors,whereas ER-positive tumors would derive from transit-amplifyingcells. During pregnancy, the physiologically intense increase inthe number of mammary epithelial cells could promote theexpansion of stem or transit-amplifying cells. If pregnancy occurs ina woman who already have alterations in such a cell, the cell

Table 3The characteristics of invasive tumors among gestational, post-partum and non-PABC groups.

Non-PABC(N, %)

Gestational-BC (N,%)

PPeBC (N,%) p (gestational vs Non-PABC) p (PPeBC vs Non-PABC) p (gestational-BC vs PPeBC)

All 208 11 25Tumor classification 0.411 0.007 0.304T1 83 40% 7 64% 10 40%T2 94 45% 3 27% 5 20%T3 18 9% 1 9% 7 28%T4 13 6% 0 0% 3 12%Node classificationa 0.54 0.062 0.144N0 75 48% 6 67% 5 28%N1 60 38% 2 22% 7 39%N2 17 11% 1 11% 5 28%N3 4 3% 0 0% 1 6%Histological type 0.294 0.323 0.144Ductal 176 85% 8 73% 23 92%Other 32 15% 3 27% 2 8%Grade 0.822 0.037 0.1591 31 15% 1 9% 2 8%2 74 36% 4 36% 5 20%3 98 47% 4 36% 17 68%ER status 0.032 0.011 0.748Negative 43 21% 5 45% 11 44%Positive 161 77% 5 45% 14 56%PR status 0.537 0.011 0.392Negative 63 30% 4 36% 14 56%Positive 142 68% 6 55% 11 44%HR status 0.155 0,01 0.755Negative 43 21% 4 36% 11 44%Positive 162 78% 6 55% 14 56%HER 2 status 0.778 0.019 0.357Negative 171 82% 8 73% 16 64%Positive 34 16% 2 18% 9 36%Triple negative 35 17% 3 27% 7 28% 0.373 0,17 0.312Ki 67 0.041 0.98 0.092Low <20% 60 29% 6 55% 7 28%High �20% 144 69% 4 36% 17 68%LVSI 1 0.247 0.237Absent 99 48% 5 45% 15 60%Present 99 48% 5 45% 9 36%

BC ¼ Breast Cancer, PP ¼ Post-Partum, non-PABC ¼ non-Pregnancy-Associated-Breast-Cancer, ER ¼ Estrogen Receptors, PR ¼ Progesterone Receptors, HR ¼ HormonalReceptors, LVSI ¼ Lymphovascular Space Invasion.

a Neo-adjuvant chemotherapy excluded (N ¼ 9 in gestationnal group, N ¼ 18 in post-partum group, N ¼ 156 in non-PABC group). The results for histological grade,hormonal, HER2, Ki67 and LVSI status do not reach 100% as there are some missing data.

A.-S. Genin et al. / The Breast 21 (2012) 550e555554

expansion due to pregnancy would promote proliferation of anabnormal clone, which could acquire other mutations and entera malignant transformation. Modifications during the involution ofthe mammary gland, with important proteolysis and possible basalmembrane disruption, will help these malignant cells invade.17

Furthermore, it has been reported that the ECM from the invo-luting breast promotes tumor growth in ER-negative cell lines butnot in ER-positive cell lines.18 Indeed, the poorer immuno-histological profile seen in PABC potentially could reflect thetumor stromal environment.

Further studies are needed to improve our knowledge of PABCphysiology. PABC patients have to be referred to reference centersand registries are necessary to collect more information on theseentities through pertinent epidemiological data.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Ethical approval

All the patients were informed that the data concerning theirtumor could be used for scientific use and gave consent. The studywas in accordance with local ethical committee.

References

1. Lambe M, Hsieh CC, Trichopoulos D, Ekbom A, Pavia M, Adami HO. Transientincrease in the risk of breast cancer after giving birth. N Engl J Med1994;331:5e9.

2. Rugo H. Management of breast cancer diagnosed during pregnancy. Curr TreatOptions Oncol 2003;4(2):165e73.

3. Andersson TM, Johansson AL, Hsieh CC, Cnattingius S, Lambe M. Increasingincidence of pregnancy-associated breast cancer in Sweden. Obstet Gynecol2009;114:568e72.

4. Lethaby A, O’Neill M, Mason B, Holdaway IM, Harvey VJ. Overall survival frombreast cancer in women pregnant or lactating at or after diagnosis. Int J Cancer1996;67:751e5.

5. Beadle BM, Woodward WA, Middleton LP, Tereffe W, Strom EA, Litton JK, et al.The impact of pregnancy on breast cancer outcomes in women<or¼35 years.Cancer 2009;115(6):1174e84. 15.

6. Murphy CG, Mallam D, Stein S, Patil S, Howard J, Sklarin N, et al. Current orrecent pregnancy is associated with adverse pathologic features but notimpaired survival in early breast cancer. Cancer 2011. Nov 2011.

7. Mathelin C, Annane K, Treisser A, Chenard MP, Tomasetto C, Bellocq JP, et al.Pregnancy and post-partum breast cancer: a prospective study. Anticancer Res2008;28(4C):2447e52.

8. Moreira WB, Brandao ED, Soares AN, Murta de Lucena CE, Antunes CM. Prog-nosis for patients diagnosed with pregnancy-associated breast cancer: a pairedcase-control study. Sao Paulo Med J 2010;128(3):119e24.

9. Stensheim H, Møller B, van Dijk T, Fosså SD. Cause-specific survival for womendiagnosed with cancer during pregnancy or lactation: a registry-based cohortstudy. J Clin Oncol 2009;27(1):45e51.

10. Johansson A, Andersson T, Hsieh CC, et al. Increased mortality in women withbreast cancer detected during pregnancy and different periods postpartum.Cancer Epidemiol Biomarkers Prev 2011;20(9):1865e72.

A.-S. Genin et al. / The Breast 21 (2012) 550e555 555

11. Rodriguez A, Chew H, Cress R, Xing G, McElvy S, Danielsen B, et al. Evidence ofpoorer survival in pregnancy-associated breast cancer. Obstet Gynecol2008;112:71e8.

12. Bladström A, Anderson H, Olsson H. Worse survival in breast cancer amongwomen with recent childbirth: results from a Swedish population-basedregister study. Clin Breast Cancer 2003;4:280e5.

13. Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer2006;6:281e91.

14. Gupta P, Proia D, Cingoz O, Weremowicz J, Naber SP, Weinberg RA, et al.Systemic stromal effect of estrogen promote the grouwth of estrogen receptor-negative cancers. Cancer Res 2007;67(5):2062e71.

15. O’Brien J, Lyons T, Monks J, Lucia MS, Wilson RS, Hines L, et al. Alternativelyactivated macrophages and collagen remodeling characterize the post-partuminvoluting mammary gland accross species. Am J Pathol 2010;176:1241e55.

16. Mc Daniel S, Rumer K, Biroc S, Metz RP, Singh M, Porter W, et al. Remodeling ofthe mammary microenvironment after lactation promotes breast tumor cellmetastasis. Am J Pathol 2006;168:608e20.

17. Polyak K. Pregnancy and breast cancer: the other side of the coin. Cancer Cell2006;9(3):151e3.

18. Bemis L, Schedin P. Reproductive state of rat mammary gland stromamodulates human breast cancer cell migration and invasion. Cancer Res2000;60:3414e8.