Pregnancy-associated Breast Cancer Patients Research Articles

Abstract PO2-13-05: Deciphering pregnancy-associated breast cancer: distinctive molecular profile and clinical implications from GEICAM/2017-07 EMBARCAM study

Abstract Background: Pregnancy-Associated Breast Cancer (PABC) is defined as BC diagnosed during pregnancy, breastfeeding, or within the first year postpartum. This challenging entity has a distinct biology and worst prognosis and presents an increased risk for metastasis and death compared to non-PABC patients. Identification of molecular pathways that define this malignancy is crucial to explain its biological characteristics and potential association with pregnancy as well as serve to identify new biomarkers with preventive and clinical implications. This study assesses the gene expression profile of a PABC cohort from the Registry Study of Pregnancy and Breast Cancer (GEICAM/2017-07 EMBARCAM study, NCT04603820) to identify distinct molecular signatures and altered pathways for this entity. Methods: This was a multicenter, observational and ambispective age-matched cohort of PABC patients (n=46) and non-PABC patients (n=49). We analyzed the expression of 776 genes involved in 23 key breast cancer pathways, using the nCounter® Breast Cancer 360™ Panel (NanoString Technologies) on BC tumor samples, including molecular subtypes by PAM50 gene signature. Associations between individual differential genes and epidemiological and clinical features of these patients were explored. Normalized differential expression values were log2-transformed for statistical analysis in nSolver Software (NanoString Technologies). P-values were adjusted within each gene/signature and on the grouping variable level difference t-test using the Benjamini and Yekutieli False Discovery Rate (FDR) adjustment. Results: PABC patients’ clinical subtypes were distributed as 43,5% HR-positive/HER2-negative, 17,4% HER2-positive and 39,1% triple negative BC. These patients reported higher family history of BC/ovarian cancer compared to non-PABC (52.17% vs 26.53%; p=0.0124). Differential gene expression showed distinct molecular profiles in PABC and non-PABC patients: significantly genes enrichment involved in cell proliferation and p53 signature for PABC patients and higher expression of apoptosis, TGF-β, and PTEN signatures for non-PABC (adj p< 0.05). Furthermore, CDK4 expression signature (adj p=0.124) and DNA damage repair signatures Homologous Recombination Deficiency (HDR) (adj p=0.083) and BRCAness (adj p=0.220) were also upregulated in PABC tumors. The most significantly upregulated genes in PABC patients (CCNA2, DEPDC1, FAM83D, CDC20, CDKN3, TRIP13, TTK, MAD2L1, KIF2C, and UBE2C) (adj p< 0.05) were involved in cell cycle regulation and DNA damage repair. PABC basal-like tumors were found to be significantly more prevalent than non-PABC, as per the PAM50 classification (45.7% vs 20.4%; p=0.020). Interestingly, basal-like PABC showed higher expression of ESR1 than basal-like non-PABC (logFC=1.486; p=0.022). In contrast, luminal A PABC tumors exhibited lower ESR1 expression vs non-PABC (logFC=-1.5; p=0.021). Additionally, HER2-enriched PABC tumors displayed lower B7-H3/CD276 expression compared to HER2-enriched non-PABC (adj p=0.031). Conclusions: Our study shows that PABC is potentially a clinical and molecular different entity with predominance of the basal-like subtype. Moreover, our results suggest the activation of oncogenic pathways related to cell proliferation, DNA damage repair and p53 mutations which may lead to a clinically more aggressive phenotype for PABC patients. Likewise, the enrichment of BRCAness and HRD signatures found in PABC patients in our study may suggest an increased genetic instability due to a breakdown in the DNA damage repair. These findings may be clinically relevant and translate to new treatment options in PABC patients, who may benefit from therapies targeting DNA repair or cell-cycle checkpoints, such as PARP inhibitors. Citation Format: Juan de la Haba-Rodríguez, Regina Peña, Marina Pollan, Yolanda Jerez Gilarranz, Jose Ponce, Antonio Fernández Aramburu, Blanca Cantos, Ana Santaballa Bertrán, Elena Galve, María Eva Pérez, Susana de la Cruz, María Helena López-Ceballos, Yolanda Fernández, Fernando Moreno, Sonia González, Manuel Ruíz - Borrego, Isabel Blancas, José L Alonso-Romero, Álvaro Jiménez-Arranz, Raúl Rincón, Silvia Guil, Alejandra Díaz-Chacón, Rosalía Caballero, Begoña Bermejo, Angel Guerrero. Deciphering pregnancy-associated breast cancer: distinctive molecular profile and clinical implications from GEICAM/2017-07 EMBARCAM study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-05.

Abstract PS13-01: Worse Prognosis for Breast Cancer in the Second and Third Trimesters and Shortly Postpartum:An Update of the Dutch Pregnancy-Associated Breast Cancer Cohort

Abstract Rationale: Pregnancy-Associated Breast Cancer (PABC), often defined as breast cancer during pregnancy (PrBC) or in the first year postpartum (PPBC), is known for its aggressive histopathology and higher stage at diagnosis. In a previous study of the nationwide Dutch PABC Cohort, we observed an impaired survival for patients diagnosed in the second and third trimester of pregnancy. However, the etiology of these differences, and how this relates to the patients diagnosed with breast cancer in the postpartum period (PPBC) or after an abortion (AABC), remains to be elucidated. While we are exploring the etiologic hypotheses, we updated and expanded our database to compare these specific PABC subgroups. Methods: All pathology reports of invasive breast carcinoma between January 1st 1988 and July 1st 2022 were screened for pregnancy-related keywords to find all patients diagnosed with PrBC, PPBC or AABC within one year after childbirth or an interrupted pregnancy (induced abortion or miscarriage before a gestational age of 24 weeks). A local patient series provided 22 additional cases. Pregnant patients were subdivided by gestational trimester at time of diagnosis. The different PrBC, PPBC and AABC subgroups were compared by histopathology, clinical characteristics and outcome. Results: 787 patients were included, of whom 60% were pregnant during their diagnosis. Median age at diagnosis was 34 years. In line with our previous findings, a large majority (68%) of patients had a Bloom & Richardson (B&R) grade III tumor and 37% of tumors were triple negative. Moreover, over a third of patients presented with lymph node metastases (38%). We observed two distinct groups based on histopathology and prognosis: group A, consisting of three patient groups: (I) patients diagnosed in the first trimester of pregnancy, (II) patients diagnosed between 6-12 months postpartum, and (III) patients diagnosed after an abortion, and group B, consisting of two patient groups, (I) patients diagnosed in the second or third trimester of pregnancy or (II) within 6 months after childbirth. Compared to group A, patients in group B more often had B&R grade III tumors: (73% vs. 60%, p=0.002) and more frequently had triple negative tumors (43% vs. 28% in group A, p< 0,001). Survival was significantly worse for patients in group B (5-year OS 67,3% versus 88.2%, p< 0.001). In a multivariable analysis, corrected for grade, type of surgery and overall stage, these differences upheld with an HR of 1.515 (95% CI 1,012 – 2,268). Conclusions: With this extensive update of our nationwide Dutch PABC cohort, we show that especially PrBC patients diagnosed in the second and third trimesters and PPBC patients within six months after childbirth exhibit unfavorable tumor characteristics, with an associated worse prognosis. This highlights the need for in-depth analyses in these specific groups of PABC patients to elucidate the etiologic mechanisms involved. Citation Format: Carsten Bakhuis, Carmen Van Dooijeweert, Britt Suelmann, Janneke Verloop, Pieter Westenend, Sabine Linn, Paul Van Diest, Elsken Van der Wall. Worse Prognosis for Breast Cancer in the Second and Third Trimesters and Shortly Postpartum:An Update of the Dutch Pregnancy-Associated Breast Cancer Cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS13-01.

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.

Survival in pregnancy-associated breast cancer patients compared to non-pregnant controls

BackgroundPregnancy-associated breast cancer (PABC) is a rare entity whose prognosis has previously been studied and is subject to controversy.MethodsSurvival of patients with PABC diagnosed between 2009 and 2021 with breast cancer during pregnancy or until 1 year after childbirth was compared with non-pregnant patients with breast cancer from the same period at La Paz University Hospital. Cox proportional hazards regression was used to compare disease-free (DFS) and overall (OS) survival between the groups, adjusting for grade and pathologic stage.ResultsAmong the 89 included patients with breast cancer, 34 were diagnosed during pregnancy, and 55 were not pregnant. The pregnant patients were more likely to have grade 3 tumors (61.3% vs 37%, p = 0.023) and an advanced stage (pathologic stage III-IV: 44.1% vs 17.6%, p = 0.008). Median follow-up was 47 months for the pregnant group and 46 months for the control group. After adjustments for tumor grade and pathologic stage, OS was comparable between the groups (HR 2.03; 95% CI 0.61 to 6.79; P = 0.25).ConclusionsThe outcome of women diagnosed with PABC is comparable to young non-pregnant controls. However, it should be taken into account that PABC has a more aggressive phenotype.

Abstract 6852: Immune microenvironment profiling of pregnancy associated breast cancer: A transcriptomic and multiplex immunohistochemical analyses

Abstract Background: Pregnancy-associated breast cancer (PABC) is BC diagnosed during pregnancy or within 2 years after pregnancy. Although PABC is a rare subgroup of BC, the outcome of PABC is worse than BC developed in the same age group unrelated to pregnancy. The proliferation and involution of mammary gland during and after pregnancy create a unique immune microenvironment in the breast. Comprehensive profiling of the tumor immune microenvironment in PABC is important but lacking. Methods: We retrospectively identified PABC patients from electronic medical records and their tumor blocks from pathology department in our institution. Age- and stage-matched BC patients were selected as control group. NanoString Breast Cancer 360 Gene Expression panel and Opal Polaris 7 color immunohistochemical (IHC) were utilized to profile PABC from transcriptome and protein levels. Result: PABC (N=26), BC developed 2 years (BC>2Y, N=54) after pregnancy, and matched non-pregnant BC patients (NPBC, N=27) were included in the final analysis respectively. Samples from BC>2Y (remote influence from pregnancy) and NPBC (pregnancy did not contribute to BC) both served as control groups for PABC patients in our study. PAM50 subtyping categorized patients into luminal A(N=42), luminal B(N=26), basal(N=12), and HER2 (N=25) enriched subgroups. In multiplex IHC analysis, CD4+ cells, CD8+ cells, CD20+ cells, and CD68+/CD163+ (M2) cells were all statistically higher in the tumor samples from PABC and BC>2Y than from NPBC. This suggests a potential contribution of pregnancy in the immune microenvironment. In the luminal A subgroup, CD8+ cells, CD20+ cells, and CD68+/CD163+ cells remain statistically higher in the PABC than in the NPBC samples. In NanoString BC360 transcriptomic profiling, immune cell abundance was evaluated from representative gene signatures. Mast cells were significantly lower in the PABC group than in the NPBC group. Cytotoxic T cells are significantly higher both in the PABC and BC>2Y groups than in the NPBC group. Conclusion: We are the first study to profile immune microenvironment using both transcriptomic and IHC methods. Our study is also unique in using NPBC and BC>2Y patients as control groups for PABC patients. CD8+ T cells are statistically higher in PABC patients than in NPBC patients using either transcriptomic profiling or multiplex IHC analysis. M2 macrophages, which promote tumor growth, are abundant in all the PABC and the luminal A PABC samples. Citation Format: I-Chun Chen, Ching-Hsuan Chen, Chia-Lang Hsu, Tzu-Pin Lu, Yen-Shen Lu, Ching-Hung Lin. Immune microenvironment profiling of pregnancy associated breast cancer: A transcriptomic and multiplex immunohistochemical analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6852.

Unveiling the Role of Pregnancy-Associated Plasma Protein A (PAPP-A) in Pregnancy-Associated Breast Cancer: A Comprehensive Review.

Pregnancy-associated breast cancer (PABC) presents unique challenges due to its occurrence during or shortly after pregnancy. Pregnancy-associated plasma protein A (PAPP-A) has emerged as a potential biomarker and regulator in PABC. This comprehensive review examines the role of PAPP-A in PABC, highlighting its involvement in tissue remodeling and cancer progression. Molecular mechanisms linking PAPP-A to breast cancer, including signaling pathways and interactions with other molecules, are explored. The review also discusses the diagnostic and therapeutic implications of PAPP-A dysregulation in PABC, emphasizing the need for further research to elucidate underlying mechanisms and develop targeted therapies. Collaborative efforts among researchers, clinicians, and industry stakeholders are essential for translating findings into clinically relevant interventions to improve outcomes for PABC patients.

Pregnancy-related breast cancer: 14-year experience in a tertiary institution in Hong Kong

BackgroundThe incidence of pregnancy-associated breast cancer (PABC) is increasing. Its tumor characteristics and overall survival compared with those in nonpregnant patients remain controversial. While there have been suggestions that PABC patients have a 40 % increase in the risk of death compared to non-pregnant patients, other studies suggested similar disease outcomes. This study aims to review our local experience with PABC. MethodsTwenty-eight patients diagnosed with PABC and twenty-eight patients diagnosed at premenopausal age randomly selected by a computer-generated system during the same period were recruited. Background characteristics, tumor features, and survival were compared. ResultsAmong the twenty-eight pregnant patients, seventeen were diagnosed during pregnancy, and eleven were diagnosed in the postpartum period. Compared to the non-pregnant breast cancer patients, they presented with less progesterone receptor-positive tumor (35.7 % vs. 64.2 %, p = 0.03). Although there was no statistically significant difference in tumor size (p = 0.44) and nodal status (p = 0.16), the tumor tended to be larger in size (2.94 +/− 1.82 vs 2.40 +/− 1.69 cm) and with more nodal involvement (35.7 % vs 25.0 %). There was also a trend of delayed presentation to medical attention, with a mean duration of 13.1 weeks in the PABC group and 8.6 weeks in the control group. However, the overall survival did not differ (p = 0.63). ConclusionPABC is increasing in incidence. They tend to have more aggressive features, but overall survival remains similar. A multidisciplinary approach is beneficial for providing the most appropriate care.

Breast Cancer in Pregnant Young Women: Clinicopathological Profile, Survival, and Pregnancy Outcomes.

Background Breast cancer is one of the most common cancer types diagnosed during pregnancy; the presence of any neoplasm in pregnant women faces clinical dilemmas and challenges in cancer and pregnancy management. Pregnancy-associated breast cancer (PABC)is defined as breast cancer diagnosed during pregnancy or within one year after delivery. The aim of this study was to describe tumor clinicopathological characteristics and pregnancy outcomes in PABC patients. Materials and methods This is a retrospective cohort assessing PABC patients. Qualitative variables were compared using Fisher's exact test. Kaplan-Meier method was used to calculate survival. Cox regression and logistic regression methods were used to estimate the hazard ratio (HR) and odds ratio (OR), respectively. Results We assessed 16 PABC patients. Women ≤ 35 years of age were mainly diagnosed at advanced stage (88.8%) with ER-negative disease (77.8%). Patients with >4 pathological lymph nodes (25%; p = 0.001) and ER-negative disease (50%; p = 0.646) showed poor five-year overall survival (OS). In the multivariate analysis, nodal involvement was the main predictor associated with poorer OS (HR = 1.4, 90% confidence interval [CI]: 1.14 to 1.8). The following risk factors might influence the risk of preterm delivery: maternal older age, gestational age at diagnosis, and intrauterine exposure to chemotherapy, but an adjusted OR of 0.61 (90% CI: 0.34 to 1), 0.80 (90% CI: 0.66 to 0.9), and 0.013 (90% CI: 0.00 to 0.9), respectively, did not statistically support such an effect. Conclusions Younger women with PABC had a more aggressive pathological profile that might partly explain the poor OS. Obstetrical adverse events related to preterm delivery should be avoided with better planning of specialized strategies.

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

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. 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. 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). 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. 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. • 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.

Breast Carcinogenesis during Pregnancy: Molecular Mechanisms, Maternal and Fetal Adverse Outcomes.

Breast cancer is a common type of cancer diagnosed during pregnancy, with increasing incidence over the last years, as more women choose to delay childbearing. Compared to breast cancer in general population, pregnancy-associated breast cancer (PABC) is significantly different in its terms of epidemiology, diagnostic and therapeutic management, while it exhibits particularly aggressive behavior, deriving from its unique molecular and biological profile. Although not fully elucidated, the pathophysiological basis of PABC can be traced back to a combination of hormonal and immune changes during pregnancy, breast involution and altered gene expression. There is considerable controversy in the existing literature about the influence of PABC on pregnancy outcomes, regarding both short- and long-term effects on maternal and fetal/neonatal health. The majority of PABC patients have advanced-stage disease at initial diagnosis and face a significantly poorer prognosis, with decreased survival rates. The most commonly reported adverse obstetrical-fetal events are preterm delivery and prematurity-associated neonatal morbidity, while other neonatal treatment-associated complications might also occur, even when safe therapeutic options are applied during pregnancy. The objective of the present comprehensive review was to summarize current knowledge and up-to-date evidence about the pathophysiological, molecular and biological basis of PABC, as well as its association with adverse maternal, obstetrical, fetal and neonatal outcomes.

Pregnancy-associated breast cancer (PABC) in young women: a matched case-control study

We analyzed the clinical characteristics and prognosis of early pregnancy-associated breast cancer (PABC). In this matched case-control study, the PABC patients and non-PABC patients were recruited from Hebei Breast Disease Treatment Center in a ratio of 1:2, involving 40 PABC patients (10 pregnant women, 30 postpartum women) diagnosed between January 2011 and December 2017, and 80 non-PABC patients with matched tumor staging, age (±3 years), and year of diagnosis (± 2 years). The pathological characteristics, disease-free survival (DFS), and overall survival (OS) were compared between the groups. The first gravidity age in PABC patients was significantly older than that of non-PABC patients (26.8 years vs. 23.5 years, P < 0.05). Categorized by receptor status, the ratio of hormone receptor (HR)-positive breast cancer was lower in PABC patients than in non-PABC patients (57.5% vs. 70.0%, P = 0.221), while the incidences of HER2− (42.5% vs. 37.5%, P = 0.692) and triple-negative breast cancer (20% vs. 12.5%, P = 0.578) were higher in PABC patients than in non-PABC patients, although no significant differences were detected. Compared with non-PABC patients, PABC patients delivered the first gravidity at an older age, but showed no differences in pathological characteristics, DFS, and OS.

MRI can accurately diagnose breast cancer during lactation.

To test the diagnostic performance of breast dynamic contrast-enhanced (DCE) MRI during lactation. Datasets of 198 lactating patients, including 66 pregnancy-associated breast cancer (PABC) patients and 132 controls, who were scanned by DCE on 1.5-T MRI, were retrospectively evaluated. Six blinded, expert radiologists independently read a single DCE maximal intensity projection (MIP) image for each case and were asked to determine whether malignancy was suspected and the background-parenchymal-enhancement (BPE) grade. Likewise, computer-aided diagnosis CAD MIP images were independently read by the readers. Contrast-to-noise ratio (CNR) analysis was measured and compared among four consecutive acquisitions of DCE subtraction images. For MIP-DCE images, the readers achieved the following means: sensitivity 93.3%, specificity 80.3%, positive-predictive-value 70.4, negative-predictive-value 96.2, and diagnostic accuracy of 84.6%, with a substantial inter-rater agreement (Kappa = 0.673, p value < 0.001). Most false-positive interpretations were attributed to either the MIP presentation, an underlying benign lesion, or an asymmetric appearance due to prior treatments. CAD's derived diagnostic accuracy was similar (p = 0.41). BPE grades were significantly increased in the healthy controls compared to the PABC cohort (p < 0.001). CNR significantly decreased by 11-13% in each of the four post-contrast images (p < 0.001). Breast DCE MRI maintains its high efficiency among the lactating population, probably due to a vascular-steal phenomenon, which causes a significant reduction of BPE in cancer cases. Upon validation by prospective, multicenter trials, this study could open up the opportunity for breast MRI to be indicated in the screening and diagnosis of lactating patients, with the aim of facilitating an earlier diagnosis of PABC. • A single DCE MIP image was sufficient to reach a mean sensitivity of 93.3% and NPV of 96.2%, to stress the high efficiency of breast MRI during lactation. • Reduction in BPE among PABC patients compared to the lactating controls suggests that several factors, including a possible vascular steal phenomenon, may affect cancer patients. • Reduction in CNR along four consecutive post-contrast acquisitions highlights the differences in breast carcinoma and BPE kinetics and explains the sufficient conspicuity on the first subtracted image.

Long-Term Breast Cancer Outcomes of Pregnancy-Associated Breast Cancer (PABC) in a Prospective Cohort.

Simple SummaryThis study explored the characteristics, treatment, and survival outcomes of patients with pregnancy-associated breast cancer (PABC) in Korea. All patients of this study received standard treatments according to the National Comprehensive Cancer Network guideline. Compared to the non-PABC group, the PABC group had a lower percentage of hormone receptor positivity, increased HER2 overexpression, and higher Ki-67 levels. No maternal complications were observed in patients with PABC. In addition, the 5-year disease-free survival and overall survival rates were significantly poorer in the PABC group than in the non-PABC group. After adjusting for tumor characteristics, PABC was still associated with poor prognosis. This is the first report of the PABC population from a prospective cohort. Exploration to elucidate biologic relevance will follow.Background: Given that peak age of breast cancer (BC) is younger in Asians than in Western populations, relatively higher prevalence of pregnancy-associated breast cancer (PABC) has been reported. This study aimed to analyze the characteristics and clinical outcomes of PABC in Korea. Methods: We defined PABC as BC diagnosed during pregnancy or in the first postpartum year. We compared the clinicopathological characteristics and BC outcomes between patients with PABC and non-PABC patients in the prospective YBC cohort from Samsung Medical Center. Results: In total, 1492 patients were initially enrolled, and 1364 patients were included, of which 93 had PABC (6.8%). The median age of patients with PABC was 34 years. Hormone receptor expression was lower (64.6% vs 74.6%) and frequency of HER2 overexpression was higher (26.9% vs 17.6%) in patients with PABC than in non-PABC patients. The 5-year overall survival (OS) rates were 83.2% and 93.4% in patients with PABC and non-PABC patients, respectively (p < 0.001). The 5-year disease-free survival (DFS) rates were 72.2% and 83.8% in PABC and non-PABC patients. Conclusion: Compared to non-PABC patients, patients with PABC had poorer OS and DFS in this prospective cohort. Exploratory biomarker analysis for PABC is warranted.

Distinctive gene expression patterns in pregnancy-associated breast cancer.

Pregnancy-associated breast cancer (PABC) is diagnosed during pregnancy or within 1 year postpartum, but the unique aspects of its etiology and pathogenesis have not been fully elucidated. This study aimed to ascertain the molecular mechanisms of PABC to facilitate diagnosis and therapeutic development. The Limma package was used to characterize the differentially expressed genes in PABC as compared to non-pregnancy-associated breast cancer (NPABC) and normal breast tissue. A total of 871 dysregulated genes were identified in the PABC versus NPABC groups and 917 in the PABC versus normal groups, with notable differences in the expression of MAGE and CXCL family genes. The dysregulated genes between the PABC and normal groups were mainly associated with signal transduction and immune response, while Kyoto Encyclopedia of Genes and Genomes analysis revealed that the dysregulated genes were enriched in immune-related pathways, including the major histocompatibility complex (MHC) class II protein complex, the type I interferon signaling pathway, regulation of α-β T-cell proliferation, and the T-cell apoptotic process. Through protein-protein interaction network construction, CD44 and BRCA1 were identified as prominent hub genes with differential expression in PABC versus NPABC. Furthermore, a cluster with eleven hub genes was identified in PABC versus normal adjacent tissues, of which the expression of EGFR, IGF1, PTGS2, FGF1, CAV1, and PLCB1 were verified to be differentially expressed in an independent cohort of PABC patients. Notably, IGF1, PTGS2, and FGF1 were demonstrated to be significantly related to patient prognosis. Our study reveals a distinctive gene expression pattern in PABC and suggests that IGF1, PTGS2, and FGF1 might serve as biomarkers for diagnosis and prognosis of PABC.

Abstract P3-12-06: Prognosis of pregnancy-associated breast cancer: Inferior outcome in patients diagnosed during second and third gestational trimesters and lactation

Abstract BACKGROUND Pregnancy-associated breast cancer (PABC), although most commonly defined as breast cancer diagnosed during pregnancy or within one year following delivery, knows a variety of definitions, likely related to the diversity of reported clinicopathological features and prognosis. More insight into the different breast cancer subgroups during pregnancy, the time after delivery and the postpartum period is therefore warranted. METHODS Patients with breast cancer diagnosed during pregnancy or within six months after delivery between January 1, 1988 and July 1, 2019, were included. Pregnant patients were subdivided according to gestational trimester, and postpartum patients according to lactational status. To investigate the influence of pregnancy and lactation on the histopathologic profile, these subgroups were compared to non-PABC patients matched for age at diagnosis, year at diagnosis, grade and ER status. Pearson Chi-square tests were used to compare clinicopathologic characteristics, while Kaplan-Meier/logrank/Cox regression methods were used to perform overall survival (OS) analysis. RESULTS Overall, 662 PABC patients were included, of which 73.6% were diagnosed during pregnancy. Median age at diagnosis was 34 years, with a median follow-up of 6.5 years. Overall, PABC patients as a group showed an advanced stage at diagnosis and an inferior OS at 5-years (75.4% vs. 83.2%, p = 0.000) compared to 1,392 non-PABC patients. In subgroup analysis, PABC patients within their first trimester showed a significantly lower tumor size and stage as compared to other trimesters. Patients diagnosed during the first trimester and postpartum non-lactating patients had a relatively good OS (81.3% and 77.9%, respectively) versus patients diagnosed during the second and third trimesters and during lactation (OS 60.0%, 64.9% and 65.6%, respectively, p = 0.003). In multivariate Cox regression, trimester of diagnosis, year of diagnosis, PR status, stage at diagnosis and surgery-or-not were significant contributors to OS. CONCLUSION In this large PABC cohort, uniquely specified by gestational trimester, an inferior outcome was found for patients diagnosed within the second and third gestational trimesters and during postpartum lactation, compared to first trimester and non-lactating postpartum patients. These findings indicate that PABC is clinically a heterogeneous group of breast cancer patients that should be redefined based on trimester of diagnosis and postpartum lactational status. Citation Format: Britt BM Suelmann, Carsten FJ Bakhuis, Carmen van Dooijeweert, Janneke Verloop, Ronald P Zweemer, Sabine C Linn, Elsken van der Wall, Paul J van Diest. Prognosis of pregnancy-associated breast cancer: Inferior outcome in patients diagnosed during second and third gestational trimesters and lactation [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-06.

Clinical characteristics, pregnancy outcomes and ovarian function of pregnancy-associated breast cancer patients: a retrospective age-matched study

BackgroundPregnancy-associated breast cancer (PABC) is a rare disease with increasing incidence. The prognosis, pregnancy outcomes and subsequent ovarian function of PABC patients are attracting attention.MethodsSixty-three PABC patients and 126 age-matched non-PABC patients were obtained in Tongji Hospital from January 2011 to September 2019. The clinical characteristics and ovarian function of PABC patients were compared with those of non-PABC patients. The pregnancy outcomes and neonatal outcomes of patients with breast cancer diagnosed during pregnancy (BCP) were described. Nonparametric tests, the χ2-test Kaplan–Meier, Cox regression and binomial logistic regression were used for analysis.ResultsPABC patients were diagnosed with a more advanced tumour stage (II: 47.6% vs. 45.2%, III: 33.3% vs. 19.8%, IV 3.2% vs. 0%, p = 0.003), which caused worse progression-free survival (PFS) (log-rank p = 0.0138) and breast cancer-specific survival (CSS) (log-rank p = 0.0076) than non-PABC patients. Tumour stage (III/IV vs. 0/I/II) (HR 16.017, 95% CI 5.830 ~ 44.006, p < 0.001) and endocrine therapy (HR 0.254, 95% CI 0.099 ~ 0.653, p = 0.004) were predictors of PFS. Tumour stage (III/IV vs. 0/I/II) (HR 30.875, 95% CI 7.232 ~ 131.820, p < 0.001), endocrine therapy (HR 0.200, 95% CI 0.049 ~ 0.818, p = 0.025) and targeted therapy (HR 0.143, 95% CI 0.028 ~ 0.743, p = 0.021) were predictors for breast CSS. Among the 15 BCP patients, 11 patients voluntarily continued their pregnancy, and the newborns had no obvious birth defects, either in 5 patients who received chemotherapy or in 6 patients who did not receive chemotherapy during pregnancy. Among the patients who received chemotherapy and did not receive endocrine therapy, 24 PABC patients and 48 non-PABC patients experienced chemotherapy-induced amenorrhea. There was no significant difference in resumption of menstruation between the two groups at 6 months and 12 months after the end of chemotherapy. No potential factors affecting resumption of menstruation were found.ConclusionPregnancy at diagnosis or within 1 year after delivery was not a risk factor for a worse prognosis in PABC patients. Compared with non-PABC patients, patients with PABC presented more aggressive tumour characteristics, which could mostly explain the worse prognosis observed in PABC patients. Receiving the appropriate regimen of chemotherapy in the second and third trimesters did not affect the maternal outcomes or neonatal outcomes of BCP patients. The special physiological state during pregnancy and lactation did not interfere with the damage of chemotherapy to ovarian function.

Chasing Hippos: Implications of YAP1 and TAZ Expression in Pregnancy-associated Breast Cancer Tumorigenesis.

The Hippo pathway is a molecular pathway recently associated with tumorigenesis, metastasis, and drug resistance. Pregnancy-associated breast cancer (PABC) is the most common malignancy diagnosed during gestation; however, the molecular mechanisms underlying PABC are largely unknown. The aim of the present study was to evaluate Hippo pathway transducers TAZ and YAP1 expression in PABC in relation to the clinicopathological characteristics of the disease. Formalin-fixed paraffin-embedded (FFPE) tissues from 21 PABC patients treated at Alexandra Hospital in Athens, Greece, were analyzed with immunohistochemistry. Strong nuclear TAZ/YAP1 stanning was found in 48% of the PABC patients analyzed. Hormone receptor negative patients had a statistically significant correlation with strong positive expression of TAZ/YAP1 co-transcription factors. No association was observed with overall and disease-free survival. The Hippo pathway is de-regulated in a subset of PABC patients, highlighting the complex molecular background of the disease, which certainly requires further investigation.

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

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. A single-center record review was performed to identify PABC patientsdiagnosed 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. 125 PABC patients (pregnant: 62; postpartum: 63) and 250 controls were included. Median follow-up was 67.7 and 73.4months, 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). 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 toimprove treatment outcomes.

Pregnancy-associated breast cancer: evaluating maternal and foetal outcomes. A national study.

Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. We identified 155 patients-71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I-III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Genetic instabilities as potential biomarkers for pregnancy-associated breast cancer.

e12559 Background: Pregnancy associated breast cancer (PABC), defined as breast cancer diagnosed during or within one year after pregnancy, occurs approximately once in every 3,000 pregnancies and accounts for up to 6.9% of all breast cancers in women ≤ 45 years. Compared to age-matched non-PABC patients, PABC is generally characterized by a particularly aggressive histopathologic profile (more ER-, PR- and HER2 negative tumors and tumors of higher grade) with a higher mortality rate. Whether these cancers arise before or during pregnancy, and whether their genetic profile differs from non-PABC tumors, is currently unknown. This study assesses the genetic background of PABC by detection of specific DNA copy number alterations (CNA). Methods: We assembled 29 triple-negative PABC patients from the Dutch nationwide pathology database (PALGA). From their formalin-fixed and paraffin embedded (FFPE) tumor tissue blocks, DNA was extracted. Multiplex Ligation-Dependent probe Amplification (MLPA) analysis was performed for detection of CNAs in 20 oncogenes and 2 tumor suppressor genes using the P078-D2 kit (MRC Holland). Individual gene copy number loss (MLPA ratio &lt; 0.7), gain (ratio 1.3-2.0) and amplification (ratio &gt; 2.0) was determined and unsupervised hierarchical cluster analysis was performed to identify differences in copy number (CN) patterns between PABC patients. Chi square statistics were used to interrogate associations with clinicopathologic characteristics. Log-Rank test was used to compare Kaplan Meier survival curves between CN subgroups. Results: Triple negative PABC tumors showed frequent copy number loss on chromosome 17q ( CPD, MED1, TOP2A, MAPT, PPM1D) and 8p ( ZNF703 and ADAM9), as well as frequent copy number gain/amplification of MYC (8q) and CCND1 (11q). Cluster analysis identified 2 clusters of PABC patients based on their tumor copy number patterns: a CN-neutral cluster and a CN-high cluster, the latter demonstrating significantly lower chromosome 17 copy numbers than the former (for PPM1D, ERBB2, CPD, MED1, TOP2A, CDC6 and MAPT). Patients with CN-neutral tumors more often showed lymph node metastases (p = 0.028), were of significantly higher stage (p = 0.031), and demonstrated a worse overall survival (p = 0.036) compared with PABC patients harboring CN-high tumors. Conclusions: We demonstrate different tumor CN patterns within a small group of triple negative PABC-patients, associated with distinct aggressiveness. This will form the basis for further in-depth genetic profiling within a larger Dutch PABC cohort, rendering insight in the disease progression and contributing to the development of more targeted and personalized treatments.