Breast cancer during pregnancy of Luminal A type overexpressed CXCL13.

Pregnancy-associated breast cancer has been increasing. In this study, we analyzed patients with breast cancer that occurred during pregnancy (PrBC) and compared their genetic profiles with those of patients with breast cancer that did not occur during pregnancy, within 1 year after childbirth nor during lactation (non-PrBC). We performed gene expression analyses of patients with PrBC and non-PrBC using microarrays and qRT-PCR. Microarray analysis showed that 355 genes were upregulated in the luminal-type PrBC group compared to those in the non-PrBC group. The C-X-C motif chemokine ligand 13 (CXCL13) gene was the most upregulated in the PrBC group compared to that in the non-PrBC group, especially in the luminal A-type (p = 0.016). This result was corroborated by the qRT-PCR analysis of microdissected cancer cells (p < 0.001). A negative correlation was observed between CXCL13 and estrogen receptor 1 (ESR1) mRNA expression levels in luminal A-type breast carcinoma (p < 0.001). Our results provide clues for a better understanding of breast cancer pathogenesis during pregnancy.

Risk of obstetric and perinatal complications in women presenting with breast cancer during pregnancy and the first year postpartum in Sweden 1973-2017: A population-based matched study.

INTRODUCTION: For women presenting with breast cancer during pregnancy, treatment guidelines were historically restricted to only surgical treatment. Over the past decades, chemotherapy administered during pregnancy has been gradually introduced. Although breast cancer treatments during ongoing pregnancy have been deemed safe, detailed information on potential obstetric risks is lacking. We aimed to assess the risk of adverse obstetric and perinatal outcomes of breast cancer in pregnancy and within 1 year postpartum and in relation to trimester at breast cancer diagnosis, tumor stage, and cancer treatment during pregnancy. MATERIAL AND METHODS: Population-based matched study. Women diagnosed with breast cancer during pregnancy in 1973-2017 were identified in the Swedish Cancer Register and the Medical Birth Register, with additional information from the National Quality Register for Breast Cancer. Each birth with maternal breast cancer (n = 208 pregnant, n = 672 postpartum) was matched by age, calendar year, and birth order to 10 unexposed births from cancer-free women in the population (n = 2080 and n = 6720). Adjusted conditional logistic and multinomial regression models were used to estimate odds ratios and relative risk ratios, commonly denoted relative risks (RR) with 95% confidence intervals (CI), of adverse obstetric and perinatal outcomes. RESULTS: Breast cancer during pregnancy was associated with higher risks of preterm birth, both planned (RR 67.1, 95% CI 33.2-135.6) and spontaneous preterm birth (RR 3.8, 95% CI 2.0-7.5), and low birthweight (<2500 g: RR 7.5, 95% CI 4.9-11.3). The associated risks were higher if the breast cancer was diagnosed in the second trimester, and of similar magnitude irrespective of stage and treatment groups. There was a higher risk of low birthweight for gestational age (<25th centile) if breast cancer was diagnosed in the first trimester (RR 2.8, 95% CI 1.1-7.3). Risks of other pregnancy complications were similar to those of unexposed women, as were risks of neonatal mortality and malformations. Postpartum breast cancer was only associated with bleeding during pregnancy (RR 1.6, 95% CI 1.0-2.8). CONCLUSIONS: Preterm birth and related adverse outcomes were more common in women diagnosed with breast cancer during pregnancy. Reassuringly, breast cancer was not associated with other maternal pregnancy complications or adverse outcomes in children.

Systematic Review of Survival Outcomes of Pregnancy-Associated Breast Cancer in Asian Countries.

Pregnancy-associated breast cancer (PABC) is a rare type of gestational cancer. It poses a significant challenge in diagnosis and management, especially in Asian countries with limited resources. We carried out a systematic literature review and narrative synthesis to identify survival outcomes for women with PABC in Asia. We searched MEDLINE, PubMed, Cochrane Library and the reference lists of the included English language articles for those conducted between January 2010 and August 2022. The search terms were pregnancy-associated breast cancer, breast cancer AND pregnancy, survival of PABC and prognosis of PABC patients. PABC is defined as breast cancer diagnosed either during pregnancy or 1 year-5 years postpartum. This review included observational studies conducted in Asian countries. The final 11 articles met the selection criteria and were analysed. Five of the studies had high quality methods as assessed using the Joanna Briggs Institute (JBI) checklist. We reported study design, year of diagnosis, country, definition of PABC, control group, age of participants, median follow-up time, survival outcomes and pregnancy as prognostic factors. Only five studies reported that PABC patients had a poor overall or disease-free survival rate compared to the control. Pregnancy was a significant independent prognostic factor of breast cancer in only two studies. This review highlights that pregnancy has an unconfirmed association with breast cancer survival in Asia. Most studies that found a non-significant association had small samples, thus there is a need for large-scale multinational epidemiological studies in Asia to establish the survival outcomes in PABC patients.

Ultrafast DCE-MRI for discriminating pregnancy-associated breast cancer lesions from lactation related background parenchymal enhancement.

OBJECTIVE: To investigate the utility of ultrafast dynamic-contrast-enhanced (DCE) MRI in visualization and quantitative characterization of pregnancy-associated breast cancer (PABC) and its differentiation from background-parenchymal-enhancement (BPE) among lactating patients. MATERIALS AND METHODS: Twenty-nine lactating participants, including 10 PABC patients and 19 healthy controls, were scanned on 3-T MRI using a conventional DCE protocol interleaved with a golden-angle radial sparse parallel (GRASP) ultrafast sequence for the initial phase. The timing of the visualization of PABC lesions was compared to lactational BPE. Contrast-noise ratio (CNR) was compared between the ultrafast and conventional DCE sequences. The differences in each group's ultrafast-derived kinetic parameters including maximal slope (MS), time to enhancement (TTE), and area under the curve (AUC) were statistically examined using the Mann-Whitney test and receiver operator characteristic (ROC) curve analysis. RESULTS: On ultrafast MRI, breast cancer lesions enhanced earlier than BPE (p < 0.0001), enabling breast cancer visualization freed from lactation BPE. A higher CNR was found for ultrafast acquisitions vs. conventional DCE (p < 0.05). Significant differences in AUC, MS, and TTE values were found between the tumor and BPE (p < 0.05), with ROC-derived AUC of 0.86 ± 0.06, 0.82 ± 0.07, and 0.68 ± 0.08, respectively. The BPE grades of the lactating PABC patients were reduced as compared with the healthy lactating controls (p < 0.005). CONCLUSION: Ultrafast DCE MRI allows BPE-free visualization of lesions, improved tumor conspicuity, and kinetic quantification of breast cancer during lactation. Implementation of this method may assist in the utilization of breast MRI for lactating patients. CLINICAL RELEVANCE: The ultrafast sequence appears to be superior to conventional DCE MRI in the challenging evaluation of the lactating breast. Thus, supporting its possible utilization in the setting of high-risk screening during lactation and the diagnostic workup of PABC. KEY POINTS: • Differences in the enhancement slope of cancer relative to BPE allowed the optimal visualization of PABC lesions on mid-acquisitions of ultrafast DCE, in which the tumor enhanced prior to the background parenchyma. • The conspicuity of PABC lesions on top of the lactation-related BPE was increased using an ultrafast sequence as compared with conventional DCE MRI. • Ultrafast-derived maps provided further characterization and parametric contrast between PABC lesions and lactation-related BPE.

Characterization of the immune environment in pregnancy-associated breast cancer.

Pregnancy-associated breast cancer (PrBC) is a rare and clinically challenging condition. Specific immune mechanisms and pathways are involved in maternal-fetal tolerance and tumor-host immunoediting. The comprehension of the molecular processes underpinning this immune synergy in PrBC is needed to improve patients' clinical management. Only a few studies focused on the immune biology of PrBC and attempted to identify bona fide biomarkers. Therefore, clinically actionable information remains extremely puzzling for these patients. In this review article, we discuss the current knowledge on the immune environment of PrBC, in comparison with pregnancy-unrelated breast cancer and in the context of maternal immune changes during pregnancy. A particular emphasis is given to the actual role of potential immune-related biomarkers for PrBC clinical management.

Pregnancy-associated breast cancer (PrBC) affects about 4% of women with breast cancer who are of childbearing age. Managing these tumors is difficult due to interactions between the mother, fetus and tumor. These interactions cause changes in the immune system of patients with PrBC. Understanding how the immune system responds to PrBC may lead to better ways of managing the disease. This review focuses on the current knowledge of the immune system in PrBC, including which components can be used as biomarkers to improve clinical management.

Women's Health Care Committee, Japan Society of Obstetrics and Gynecology: Annual report-2023.

The Women's Health Care Committee was established in 2010 with the goal of improving women's health. In the current academic year, there are six subcommittees focusing on conducting the following surveys: (1) the current status of pregnancy-associated breast cancer in Japan; (2) surgery for disorders of sex development; (3) diagnosis and treatment of premenstrual syndrome and premenstrual dysphoric disorder; (4) obstetrics and gynecology-based treatment for patients with eating disorders in Japan; (5) multi-drug-resistant bacterial infections in the field of obstetrics and gynecology; and (6) changing the methodology of the treatment of dysmenorrhea and continuing medical education. The activities of each subcommittee are described below. This report is based on the Japanese version of the annual report (Acta Obst Gynaec Jpn 2023;75(6):662-86).

Timing of Presentation and Outcomes of Women with Stage IV Pregnancy-Associated Breast Cancer (PABC).

BACKGROUND: Pregnancy-associated breast cancer (PABC) and concurrent, or early development of, stage IV disease is uncommon. Given this rarity, and complexities surrounding pregnancy, data are limited regarding PABC treatment and outcomes. We evaluated oncologic, obstetric, and fetal outcomes of women with stage IV PABC in relation to presentation timing and treatment. PATIENTS AND METHODS: Our retrospective review of an institutional database identified women with stage IV PABC from 1998 to 2018. PABC was defined as diagnosis during pregnancy or ≤ 1 year postpartum. Clinicopathologic, treatment, and outcome variables were compared between women diagnosed during pregnancy versus postpartum. RESULTS: We identified 77 women (median age 35 years; interquartile range [IQR] 32-37 years): 51 (66%) in the postpartum group and 26 (34%) in the pregnant group, including 9 with therapeutic or spontaneous abortion. Among 17 women who continued pregnancy, no obstetric or fetal complications were noted. Clinicopathologic and treatment variables did not differ between groups. Of 43 women dead from disease, 15 had triple negative (TN) tumors. Median overall survival (OS) of TN tumors was 14 months (range 5-39 months); OS was associated with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2) positive tumors (p < 0.01). At 31 months (range 0-137 months) median follow-up, the 5-year OS was 34% (95% confidence interval 21-46%), and did not differ among pregnant and postpartum groups (p = 0.2). CONCLUSIONS: Women with stage IV TN PABC had high mortality rates despite multimodality therapy. Timing of presentation did not affect management decisions or OS, even for women who completed pregnancy. Further research to understand PABC biology, focusing on TN tumors, is warranted.

Lapses in breast cancer screening for highly penetrant mutation carriers during pregnancy and lactation.

BACKGROUND AND OBJECTIVES: Screening for breast cancer in highly penetrant mutation carriers during pregnancy and lactation is challenging and consensus guidelines are lacking. This study evaluates the lapse in screening and the interval pregnancy-associated breast cancer rate. METHODS: A single-institution retrospective cohort study of pregnant and lactating patients with known pathogenic germline mutations was performed. Lapse in screening was defined as the interval between the last screening imaging exam obtained before last menstrual period and the subsequent screening imaging. RESULTS: Out of 685 patients, 42 had 1-3 evaluable pregnancies (54 total - 28 managed in High Risk Breast Clinic and 26 by OB/GYN). Mutations were observed in patients in BRCA1 (49%), BRCA2 (36%), CDH1 (5%), CHEK2 (2%), ATM (2%), NF1 (3%), and MSH2 (3%). The average screening lapse was 25 [19, 30] months for patients followed in the High Risk Clinic versus 32.5 [21, 65.75] months for patients followed with Routine Care (p = 0.035). We identified three cases of pregnancy-associated breast cancer (interval cancer rate 6%). CONCLUSIONS: Patients with highly penetrant mutations are at risk for the development of interval pregnancy-associated breast cancer. Development of consistent screening guidelines and adherence to those guidelines is needed for this patient population.

Women's Health Care Committee, Japan Society of Obstetrics and Gynecology: Annual report-2022.

The Women's Health Care Committee was instituted in 2010 with the goal of improving women's health. In the current academic year, there are 6 subcommittees focusing on conducting the following surveys: (1) Current status of pregnancy-associated breast cancer in Japan; (2) Surgery for disorders of sex development; (3) Diagnosis and treatment of premenstrual syndrome and premenstrual dysphoric disorder; (4) Obstetrics and gynecology-based treatment for patients with eating disorders in Japan; (5) Multi-drug-resistant bacterial infections in the field of obstetrics and gynecology; and (6) Changing methodology of treatment of dysmenorrhea and continuing medical education. The activities of each subcommittee are detailed below. This report is based on the Japanese version of the annual report (Acta Obst Gynaec Jpn 2022;74(6): XXX-XXX).

Prognosis of breast cancer diagnosed during pregnancy and early postpartum according to immunohistochemical subtype: A matched case-control study.

PURPOSE: Pregnancy-associated breast cancer (PABC) poses a clinical challenge and its prognosis remains controversial. During the pregnancy and postpartum periods, the breast undergoes biological events that may uniquely influence disease behavior and treatment response. This study aimed to assess if a PABC diagnosis influences survival compared to non-PABC. METHODS: A single-center record review was performed to identify PABC patients diagnosed from January 2007 through June 2018. Two controls were matched to each PABC case by stage, immunohistochemical (IHC) subtype, age (± 3) and year of diagnosis (± 2). Disease-free survival (DFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was used to assess the impact of PABC on outcomes. RESULTS: 125 PABC patients (pregnant: 62; postpartum: 63) and 250 controls were included. Median follow-up was 67.7 and 73.4 months, respectively. 4-year DFS was 62% in pregnant vs 78% in controls (p = 0.010), and 63% in postpartum vs 83% in controls (p = 0.034). Subanalysis by IHC subtype revealed a significantly inferior DFS in PABC with hormone receptor-positive/HER2-negative (p = 0.032) and HER2-positive disease (p = 0.005) compared to corresponding non-PABC patients. 4-year OS was similar between case groups and controls. Multivariate analysis supported the independent impact of pregnant and postpartum status on DFS (p < 0.05). CONCLUSION: Patients diagnosed during pregnancy and early postpartum are at high risk of recurrence. Further research is warranted to better characterize PABC tumor biology and enable the identification of novel therapeutic interventions to improve treatment outcomes.

Pregnancy-associated breast cancer: nationwide Dutch study confirms a discriminatory aggressive histopathologic profile.

PURPOSE: Breast cancer is the most common type of malignancy in pregnant women, occurring approximately once in every 3000 pregnancies. Pregnancy-associated breast cancer (PABC) is commonly defined as breast cancer diagnosed during or within one year after pregnancy, and it accounts for up to 6.9% of all breast cancers in women younger than 45 years old. Whether these cancers arise before or during pregnancy, and whether they are stimulated by the high hormonal environment of pregnancy, is currently unknown. This study assesses the histopathological profile of PABC in a large Dutch population-based cohort. METHODS: We identified 744 patients with PABC (in this cohort defined as breast cancer diagnosed during or within 6 months after pregnancy) diagnosed between 1988 and 2019, in the nationwide Dutch Pathology Registry (PALGA). An age-matched PALGA cohort of unselected breast cancer patients (≤ 45 years), diagnosed between 2013 and 2016, was used as a control. Histopathologic features of both cohorts were compared. RESULTS: The median age of PABC patients was 34.3 years old (range 19-45 years) and most breast cancers were diagnosed during pregnancy (74.2%). As compared to age-matched controls, PABC patients had tumors of higher Bloom-Richardson grade (grade I: 1.5% vs. 12.4%, grade II: 16.9% vs. 31.3%, grade III: 80.3% vs. 39.5%, p < 0.0001). Furthermore, estrogen (ER)- and progesterone (PR)-receptor expression was less frequently reported positive (ER: 38.9% vs. 68.2% and PR: 33.9% vs. 59.0%, p < 0.0001), while a higher percentage of PABC tumors overexpressed HER2 (20.0% vs. 10.0%, p < 0.0001). The most observed intrinsic subtype in PABC was triple-negative breast cancer (38.3% vs. 22.0%, p < 0.0001), whereas hormone-driven cancers were significantly less diagnosed (37.9% vs. 67.3%, p < 0.0001). CONCLUSION: This study, based on a large population-based cohort of 744 PABC Dutch patients, underlines the more aggressive histopathologic profile compared to age-matched breast cancer patients ≤ 45 years. Further in-depth genetic analysis will be performed to unravel the origin of this discriminating phenotype. It definitely calls for timely detection and optimal treatment of this small but delicate subgroup of breast cancer patients.

Current Recommendations for Breast Imaging of the Pregnant and Lactating Patient.

During pregnancy and lactation, the breast undergoes unique changes that manifest as varied clinical and imaging findings. Understanding the expected physiologic changes of the breast as well as recognizing the best imaging modalities for a given clinical scenario can help the radiologist identify the abnormalities arising during this time. Discussion with the patient about the safety of breast imaging can reassure patients and improve management. This article reviews the physiologic changes of the breast during pregnancy and lactation; the safety and utility of various imaging modalities; upto-date consensus on screening guidelines; recommendations for diagnostic evaluation of breast pain, palpable abnormalities, and nipple discharge; and recommendations regarding advanced modalities such as breast MRI. In addition, the commonly encountered benign and malignant entities affecting these patients are discussed.

Prognosis of pregnancy-associated breast cancer: a meta-analysis.

BACKGROUND: Pregnancy-associated breast cancer (PABC) is defined as breast cancer that is diagnosed during pregnancy and/or the postpartum period. Definitions of the duration of the postpartum period have been controversial, and this variability may lead to diverse results regarding prognosis. Moreover, evidence on the dose-response association between the time from the last pregnancy to breast cancer diagnosis and overall mortality has not been synthesized. METHODS: We systematically searched PubMed, Embase, and the Cochrane Library for observational studies on the prognosis of PABC published up to June 1, 2019. We estimated summary-adjusted hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). Subgroup analyses based on diagnosis time, PABC definition, geographic region, year of publication and estimation procedure for HR were performed. Additionally, dose-response analysis was conducted by using the variance weighted least-squares regression (VWLS) trend estimation. RESULTS: A total of 54 articles (76 studies) were included in our study. PABC was associated with poor prognosis for overall survival (OS), disease-free survival (DFS) and cause-specific survival (CSS), and the pooled HRs with 95% CIs were 1.45 (1.30-1.63), 1.39 (1.25-1.54) and 1.40 (1.17-1.68), respectively. The corresponding reference category was non-PABC patients. According to subgroup analyses, the varied definition of PABC led to diverse results. The dose-response analysis indicated a nonlinear association between the time from the last delivery to breast cancer diagnosis and the HR of overall mortality (P < 0.001). Compared to nulliparous women, the mortality was almost 60% higher in women with PABC diagnosed at 12 months after the last delivery (HR = 1.59, 95% CI 1.30-1.82), and the mortality was not significantly different at 70 months after the last delivery (HR = 1.14, 95% CI 0.99-1.25). This finding suggests that the definition of PABC should be extended to include patients diagnosed up to approximately 6 years postpartum (70 months after the last delivery) to capture the increased risk. CONCLUSION: This meta-analysis suggests that PABC is associated with poor prognosis, and the definition of PABC should be extended to include patients diagnosed up to approximately 6 years postpartum.

Clinical features and survival of pregnancy-associated breast cancer: a retrospective study of 203 cases in China.

BACKGROUND: Pregnancy-associated breast cancer (PABC) is an aggressive disease, and since Chinese authority began to encourage childbearing in 2015, the incidence of PABC has increased. This study investigated the characteristics and survival of PABC patients. METHODS: Patients with PABC who underwent surgery at Fudan University, Shanghai Cancer Center between 2005 and 2018 were enrolled. Data concerning the tumor characteristics, maternal state (whether first or non-first pregnancy) and survival outcome were recorded. Pearson Chi-square tests were used to compare the characteristics of the tumors, and Kaplan-Meier methods were used to perform the survival analysis. RESULTS: Overall, 203 PABC patients were recruited. Since 2015, 65.5% of non-first pregnant women were diagnosed with breast cancer, it's 5.7 fold of the incidence of PABC in non-first pregnant women. No significant differences in tumor characteristics were observed between the patients who were in their first pregnancy and those in non-first pregnancy. Among the entire PABC population, luminal B breast cancer accounted for the largest proportion (38.4%), followed by triple-negative breast cancer (TNBC, 30.0%). The distribution of the molecular subtypes of PABC and non-PABC differed (P < 0.001) as follows: in the PABC patients, Luminal B 38.4%, Triple negative breast cancer (TNBC) 30.1%, Human Epidermal Growth Factor Receptor 2 (HER-2) overexpression 15.8%, and Luminal A 10.8%; in the non-PABC patients, Luminal A 50.9%, Luminal B 20.1%, TNBC 17.4%, and HER-2 overexpression 8.0%. The 3-year disease free survival (DFS) of all PABC patients was 80.3%. The 3-year DFS of the patients in the first-pregnancy group was 78.4%, and that of the patients in the non-first-pregnancy group was 83.7% (P = 0.325). CONCLUSIONS: Our study proved that the proportion of women who developed PABC during the second or third pregnancy was extremely high relative to the newborn populations. The patients in the PABC population tended to present more luminal B and TNBC breast cancer than the non-PABC patients.

Surgery for Pregnancy-Associated Breast Cancer.

Surgery in the form of both mastectomy and breast conservation is the main step in the treatment of breast cancer. Numerous studies have shown an equivalent long-term survival for breast conserving surgery (BCS) and mastectomy . Patients desire and tumor characteristics, especially size and multicentricity, are the key factors that affect the decision between these two types of surgery . Patients with any contraindication for radiotherapy or previous history of radiation to the breast field are not suitable for BCS . There are few absolute contraindications for BCS , and early pregnancy is listed among them; mastectomy is preferred in the first trimester of pregnancy to avoid the impact of delaying radiation therapy on outcome of the cancer.

Real-World Data Analysis of Pregnancy-Associated Breast Cancer at a Tertiary-Level Hospital in Romania.

Background and objectives: Breast cancer is among the most common cancer types encountered during pregnancy. Here, we aimed to describe the characteristics, management, and outcomes of women with pregnancy-associated breast cancer at a tertiary-level hospital in Romania. Material and Methods: We retrospectively and prospectively collected demographic, oncological, and obstetrical data for women diagnosed with cancer during pregnancy, and who elected to continue their pregnancy, between June 2012 and June 2020. Complete data were obtained regarding family and personal medical history and risks factors, cancer diagnosis and staging, clinical and pathological features (including histology and immunohistochemistry), multimodal cancer treatment, pregnancy management (fetal ultrasounds, childbirth, and postpartum data), and infant development and clinical evolution up to 2020. Cancer therapy was administered following national guidelines and institutional protocols and regimens developed for non-pregnant patients, including surgery and chemotherapy, while avoiding radiotherapy during pregnancy. Results: At diagnosis, 16.67% of patients were in an advanced/metastatic stage, while 75% were in early operable stages. However, the latter patients underwent neoadjuvant chemotherapy rather than up-front surgery due to aggressive tumor biology (triple negative, multifocal, or HER2+). No patient achieved complete pathological remission, but only one patient relapsed. No recurrence was recorded within 12 months among early-stage patients. Conclusions: In this contemporary assessment of real-world treatment patterns and outcomes among patients with pregnancy-associated breast cancer, our findings were generally consistent with globally observed treatment outcomes, underscoring the need for a multidisciplinary team and reference centers.

Parity predisposes breasts to the oncogenic action of PAPP-A and activation of the collagen receptor DDR2.

BACKGROUND: Women who had children at a young age (less than 25) show a reduced overall risk of breast cancer. However, epidemiological studies showed that for all other women, pregnancy increases the risk of breast cancer and the risk remains higher for decades. Further, even in women who had children at a young age, there is a transient increase risk that peaks 6 years after pregnancy. Women diagnosed with breast cancer following pregnancy show a higher rate of metastasis. Yet, the factors that increase the predisposition of post-partum breasts to more aggressive cancers remain unknown. Pregnancy-associated plasma protein A (PAPP-A) is a secreted protease that is overexpressed in more than 70% of breast cancers. However, PAPP-A is a collagen-dependent oncogene. We initiated this study to test the effect of PAPP-A on the predisposition of post-partum breasts. METHODS: We used PAPP-A mouse models for the analysis of its effect on virgin, involuting, or post-partum mammary glands. We performed second-harmonic generation microscopy for the analysis of collagen, defined tumor-associated collagen signature (TACS), the rate of mammary tumors, and the status of the collagen-DDR2-Snail axis of metastasis. We knockdown DDR2 by CRISPR and performed invasion assays. A transcriptomic approach was used to define a PAPP-A and parity-dependent genetic signature and assess its correlation with breast cancer recurrence in humans. RESULTS: We confirmed that post-partum mammary glands have a higher level of collagen than virgin glands and that this collagen is characterized by an anti-proliferative architecture. However, PAPP-A converts the anti-proliferative post-partum collagen into pro-tumorigenic collagen. We show that PAPP-A activates the collagen receptor DDR2 and metastasis. Further, deletion of DDR2 by CRISPR abolished the effect of PAPP-A on invasion. We defined a PAPP-A-driven genetic signature that identifies patients at higher risk of metastasis. CONCLUSIONS: These results support the notion that information about pregnancy may be critical in the prognosis of breast cancer as passage through a single pregnancy predisposes to the oncogenic action of PAPP-A. Our data indicate that history of pregnancy combined with the expression of PAPP-A-driven genetic signature may be useful to identify patients at higher risk of metastatic disease.

Prognostic Impact of Pregnancy in Korean Patients with Breast Cancer.

BACKGROUND: Pregnancy concurrent with, shortly before, or after breast cancer poses unique challenges because hormonal changes in pregnancy potentially interact with breast cancer outcomes. MATERIALS AND METHODS: We studied a cohort of 3,687 female patients of reproductive age (<50 years) with breast cancer, linking a large institutional database and the nationwide claims database to comprehensively capture exposure status and tumor characteristics. Exposures included breast cancer during pregnancy, postpartum breast cancer (<12 months after delivery), and pregnancy after breast cancer. RESULTS: Forty-five patients with postpartum breast cancer were significantly more likely to have advanced stage, hormone receptor-negative tumor and to be younger than 35 years at diagnosis than those without postpartum breast cancer. This trend was not observed with 18 patients with breast cancer during pregnancy. The unadjusted 5-year survival rates were 77% versus 96% for patients with postpartum breast cancer versus their counterparts, 89% versus 96% for patients with breast cancer during pregnancy versus their counterparts, and 98% versus 96% for patients with pregnancy after breast cancer versus their counterparts, respectively. In the multivariable analyses, postpartum breast cancer exhibited hazard ratios for death of 1.57 (95% confidence interval [CI], 0.82-2.99), whereas those for breast cancer during pregnancy and pregnancy after breast cancer were 1.09 (95% CI, 0.15-7.91) and 0.86 (95% CI, 0.26-2.83), respectively. CONCLUSION: Postpartum breast cancer, but not breast cancer during pregnancy, was associated with advanced stage, younger age at diagnosis (<35 years), hormone receptor-negative disease, and poorer survival. Pregnancy after breast cancer did not compromise overall survival. IMPLICATIONS FOR PRACTICE: Although pregnancy around the time of diagnosis of breast cancer is expected to become increasingly common with maternal age at first childbirth on the rise, data on the prognostic impact of pregnancy have been inconsistent and rare from Asian populations. In this investigation of a Korean patient cohort with breast cancer, pregnancy-associated breast cancer was associated with advanced stage, younger age at diagnosis (<35 years), hormone receptor-negative disease, and poorer survival. This adverse impact of pregnancy on the prognosis was apparent with postpartum breast cancer but not observed with breast cancer during pregnancy. Pregnancy after breast cancer did not compromise overall survival.

Neonatal outcomes of pregnancy-associated breast cancer: Population-based study on 11 million births.

BACKGROUND: As the age at first pregnancy continues to rise in the United States so does the incidence of breast cancer diagnosed during pregnancy. Our objective was to evaluate temporal trends in the incidence of pregnancy-associated breast cancer (PABC) and to measure neonatal outcomes associated with PABC. METHODS: We conducted a population-based cohort study using the 1999-2012 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) from the United States. Logistic regression models, adjusted for maternal baseline characteristics, examined the effect of PABC on neonatal outcomes. RESULTS: There were 11 846 300 deliveries between 1999 and 2012, of which 772 cases of PABC were identified, resulting in an overall incidence of 6.5 cases/100 000 pregnancies. There was a significant increase in the incidence of PABC during the study period (P < 0.05). Women with PABC tended to be older, of white ethnicity, belong to a higher income quartile and to be treated in an urban teaching hospital. In pregnancies complicated by breast cancer, there was a greater risk of preterm delivery (OR 4.84, 95% CI 4.05-5.79) and preterm premature rupture of membranes (OR 1.79, 95% CI 1.06-3.05). No associations were observed between PABC and intrauterine growth restriction, congenital anomalies or intrauterine fetal demise. CONCLUSION: There is an uptrend in the incidence of PABC and therefore, the need for counseling these patients is also increasing. Although pregnancies with the diagnosis of maternal breast cancer are more prone to premature births, it is encouraging that these babies do not appear to be at increased risk for congenital anomalies, growth restriction, or fetal demise.

Contemporary management of breast cancer during pregnancy and subsequent lactation in a multicenter cohort of young women with breast cancer.

The incidence of breast cancer diagnosed during pregnancy is increasing. We sought to characterize patient, treatment, pregnancy and lactation factors among young women with newly diagnosed breast cancer during pregnancy in a prospective cohort study. We identified all women who were pregnant when diagnosed with invasive breast cancer among those enrolled in the Young Women's Breast Cancer Study (NCT01468246), and collected details on pregnancy, birth and lactation from surveys, and treatment information medical record review. Of 1302 enrolled participants, 976 women with invasive breast cancer completed full baseline surveys, among whom 39 (4.0%) patients reported being pregnant at diagnosis. Median age at diagnosis was 34 years (range: 25-40), with stage distribution: I, 28%; II, 44%; III, 23%; and IV, 5%. 74% of patients (29/39) had grade 3 tumors, 59% (23/39) ER-positive, and 31% (12/39) HER2-positive disease. 23 (59%) had surgery during pregnancy, 4 (17%) during the first trimester. Among the women who had surgery during pregnancy, 61% (14/23) underwent lumpectomy, 35% (8/23) unilateral, and 4% (1/23) bilateral mastectomy. All patients who had chemotherapy (51%, 20/39) received it in second and third trimesters, and had ACx4. There were 31 live births, 2 spontaneous, and 5 therapeutic abortions. Among live births, 16 (41%) were before 37 weeks of gestation. Three women reported breastfeeding. Within 6 months after delivery, comprehensive staging in 13 patients showed upstaging in four patients. In a contemporary cohort of young women with breast cancer, pregnancy at diagnosis is relatively uncommon. Treatment during pregnancy can generally be consistent with standard surgical and chemotherapy approaches, with attention to timing of therapies. Longer-term outcomes including effects of some timing issues including delayed use of anti-HER2 therapy on patient outcomes warrant further research.