Front. Oncol.Frontiers in OncologyFront. Oncol.2234-943XFrontiers Media S.A.10.3389/fonc.2020.580345OncologyReviewBreast Cancer During Pregnancy: A Marked Propensity to Triple-Negative PhenotypeAllouchSoumaya1†GuptaIshita12†MalikShaza1Al FarsiHalema F.1VranicSemir1*Al MoustafaAla-Eddin12*‡1College of Medicine, QU Health, Qatar University, Doha, Qatar2Biomedical Research Center, Qatar University, Doha, Qatar
Edited by: Hee Jeong Kim, Asan Medical Center, South Korea
Reviewed by: Chantal Reyna, University of Cincinnati, United States; Pierre-Yves Desprez, California Pacific Medical Center, United States; Juan Palazzo, Baptist Hospital of Miami, United States
*Correspondence: Ala-Eddin Al Moustafa, aalmoustafa@qu.edu.qa; ala-eddin.almoustafa@mcgill.ca; Semir Vranic, svranic@qu.edu.qa
This article was submitted to Women's Cancer, a section of the journal Frontiers in Oncology
†These authors have contributed equally to this work
‡This work is dedicated to the memory of my beloved ex-wife “Naima Bachnou” who passed away because of breast cancer during pregnancy
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Breast and cervical cancers comprise 50% of all cancers during pregnancy. In particular, gestational breast cancer is considered one of the most aggressive types of cancers, which is a rare but fatal disease. However, the incidence of this type of cancer is increasing over the years and its prevalence is expected to rise further as more women delay childbearing. Breast cancer occurring after pregnancy is generally triple negative with specific characterizations of a poorer prognosis and outcome. On the other hand, it has been pointed out that this cancer is associated with a specific group of genes which can be used as precise targets to manage this deadly disease. Indeed, combination therapies consisting of gene-based agents with other cancer therapeutics is presently under consideration. We herein review recent progress in understanding the development of breast cancer during pregnancy and their unique subtype of triple negative which is the hallmark of this type of breast cancer.
breast cancerpregnancygene deregulationdelayed childbearingtriple-negativeQUCP-CMED-2019-1, QUHI-CMED-19/20-1, QUCG-CMED-20/21-2Qatar University10.13039/501100004252
Breast cancer is the most common type of cancer in females affecting more than 2.1 million women and causing more than half a million deaths annually (1). The etiology of breast cancer is complex and heterogeneous with numerous pathological characteristics; these directly correlate with available treatment options and disease prognosis (2). Based on microarray and unsupervised cluster analysis studies, breast cancer is classified into four molecular subtypes with distinct gene expression patterns and clinical outcomes (3). These subtypes include luminal (A and B), human epidermal growth factor receptor 2 (HER2)-type, and triple-negative breast cancers (TNBC) (4–6).
TNBC possesses molecular characteristics and clinical aggressiveness that is analogous to that of basal-like cancer (7). TNBC lacks estrogen receptor (ER), progesterone receptor (PR), and HER2 expression and accounts for ~15% of all breast cancer cases (7). More intriguingly, the described subtype of breast cancer is reportedly associated with high-grade invasive ductal carcinomas and, when compared with other subtypes, TNBC was found to be larger with higher metastatic propensity to lungs, brain and other visceral organs.
Since the majority of basal-like cancers are also TNBC and more than 80% of TNBC are basal-like breast cancers, it has been postulated that TNBC and basal-like phenotypes are essentially analogous (8). Using gene expression profiling, the molecular heterogeneity of TNBC was well defined. One study subclassified TNBC into six molecular subtypes including basal-like 1, basal-like 2, immunomodulatory, mesenchymal-like, mesenchymal stem-like, and luminal androgen receptor (LAR) subtype (9). Furthermore, TNBC molecular subtyping revealed three subtypes, LAR, basal-like with low immune response and high M2-like macrophages and basal-enriched with high immune response and low M2-like macrophages (10). Despite histological differences, the metastatic characteristics of the highlighted TNBC subtypes remain comparable (11). In addition to the metastatic potential of TNBC, it is vital to note that once TNBC metastasizes the window between relapse and death becomes very narrow (12). Dent et al. reports that patients with TNBC were more likely to experience significant relapses and higher rates of death when compared with women suffering from other types of breast cancers (12). The same group also reports a four folds increase in the likelihood of visceral metastasis in TNBC patients when compared with other types of breast cancer (13).
Breast cancer risk factors are various; nonetheless, a strong association between pregnancy and breast cancer has been well established (14, 15). Although early age pregnancy is considered generally protective against breast cancer, this protection is deferred. Nevertheless, the period immediately subsequent to pregnancy is characterized by a risk of breast cancer development (16). During the last 30 years, diagnosis of cancer during pregnancy has become more common due to the present trend of delaying pregnancy or childbearing to an older age (17). Pregnancy-associated breast cancer (PABC) is an upcoming issue; in this review, we aim at illustrating recent advances in understanding the development and progression of PABC and their associated genes with emphasis on TNBC to review current and potential management options.
Gestational cancer is defined as cancer diagnosed during pregnancy or the first postpartum year (18). Pregnancy-associated melanoma, breast and cervical cancers are the most common malignancies during pregnancy; both cervical and breast cancers account for 50% of all gestational cancers (19). Hematological cancers including leukemia and lymphoma comprise 25% of gestational cancer cases, while ovarian, thyroid and colon cancers are less common (19).
Pregnancy-associated breast cancer (PABC), also known as “gestational breast cancer” is defined as breast cancer diagnosed either during pregnancy or up to one year postnatal (20) and affects around 1 in 3,000 pregnant women (21). In comparison with nulliparous women, breast cancer in pregnant women is histologically similar; approximately 75%–90% of the tumors are invasive ductal carcinomas with no-special-type (NST) (21–26). While, invasive lobular carcinoma (ILC) and other histological types are uncommon in patients with PABC (23, 27–29). Previous studies have showed that postpartum period is linked to a higher risk of developing more aggressive, high-grade breast cancer (14, 16, 23, 26, 30–32) with high tumor nuclear grade (29, 33, 34) and poorly differentiated tumors (24). PABC is also associated with lymphovascular invasion (22, 23, 33), more frequent lymph node involvement and larger tumor size (21–23, 27, 35–40). Similar to nulliparous women, PABC tends to commonly metastasize to lung, liver, brain, and skeletal system (41). Women with PABC have a poorer clinical outcome and disease-free survival with a higher mortality rate compared with nulliparous women (42–45).
With regards to steroid receptors, the previous data showed that estrogen and progesterone play major roles in breast tumorigenesis (46–48), and their effects on breast cells are mediated by their respective receptors, the ER and the PR (49, 50). Earlier studies evaluated tumor histology as well as the prognostic and predictive markers (ER, PR, HER‐2/neu, p53, and Ki‐67) in PABC; in comparison to age-matched non-pregnant women, their findings show that PABC exhibit lower expression of ER/PR and higher expression Ki‐67, p53 HER2 (23, 25, 26, 43, 51–53). However, a study by Shousha showed that during pregnancy or early lactation, the expression of HER-2/neu was negative; however HER2 expression was noticed after delivery or at the end of lactation indicating suppression of HER-2/neu expression during pregnancy and lactation (32). Low ER positivity was observed in women with PABC, plausibly due to decreased ER levels during pregnancy (22, 51, 54, 55). It has been indicated that increased estrogen levels can aid in preventing ER-positive tumors (56). Furthermore, multiparous women (≥3 live births) who never breastfed were at a higher risk of ER–/PR– breast cancers compared with multiparous women with a history of breastfeeding (57). A study by Harvell et al. analyzed the presence of breast cancer subtypes in PABC and found that the presence of Luminal A, Luminal B, Her2-positive, TNBC, and basal-like subtypes in PABC (58). Other studies also confirmed TNBC, Luminal B and HER2-positive as the most common subtypes among PABC while luminal A subtype was rare (25, 52, 59–61) (Table 1).
Prevalence of molecular subtypes of breast cancer in pregnancy-associated breast cancer (PABC).
Population (Year)
Prevalence of Molecular Subtypes (%)
Reference
Luminal A
Luminal B
HER2-Positive
TNBC
Chinese (2020)
10.8%
30.4%
15.8%
17.4%
(61)
Chinese (2019)
7.1%
47.1%
22.9%
22.9%
(25)
Korean (2018)
7.7%–21%
21.1%
17.3%
35.9%–40.4%
(59, 60)
Hungarian (2014)
0%
32.8%
18%
48.4%
(52)
Several risk factors have been associated with PABC including hormonal changes, immune suppression during pregnancy as well as diagnostic challenges related to increased postpartum breast density and subsequent breast cancer diagnosis (14, 30). Breast involution is considered an important risk factor due to its shared features with pro-inflammatory microenvironment (26, 62–64), thus, providing suitable grounds for tumor growth and spread (65). Possible mechanisms of PABC include breast differentiation and involution (14, 66, 67). Following lactation, breast remodeling is a regulated program that involves the stimulation of fibroblasts, endothelial cells and immune cells. These cells then activate breast cells enhancing wound closure and remodeling of damaged tissue leading to the growth and development of transformed cells (14, 66). Moreover, an in-vitro and in-vivo study showed that involuting breast can assist the growth of existing tumor cells (66). In-vivo data showed that weaning-induced involution maintained ductal development of normal cells, however, in tumor cells they promoted invasion. Intriguingly, Yang et al. reported that early age at menarche, nulliparity, and late age at first birth increased the risk of luminal A breast cancer without any association with TNBC (68). On the contrary, all highlighted factors were identified as risk factor for TNBC in several other studies (69–74). Women’s race was also identified as a risk factor for TNBC. For instance, in comparison with white women, African-American women were found to be at a higher risk for TNBC, especially at a young age (<45 years) (71, 75, 76). A study by Ma et al. showed a protective effect of breastfeeding against development of TNBC (69). While data from the African American breast cancer epidemiology and Risk (AMBER) Consortium, showed that breastfeeding decreased the risk of TNBC associated with multiparity (77). Several other studies have revealed a significant correlation between PABC and high-grade breast cancers (16, 78–80); high grade morphology can be linked with PABC up to 10 years following pregnancy.
PABCs frequently display a higher incidence of the TNBC phenotype in comparison with cancers affecting nulliparous women. TNBCs comprise around 30%–40% of all PABC cases (52, 81) and are more likely to occur in recent pregnancy associated (within 1-2 years) breast cancers (52, 81). However, another study showed that TNBC risk can be present beyond 2 years postpartum; being one of the reasons for overall poor prognosis that characterizes tumors detected after pregnancy (16).
Molecular Features of Pregnancy-Associated Breast Cancer
To further understand the carcinogenic molecular pathways effected during pregnancy, leading to breast cancer development, it is crucial to investigate associated gene deregulation patterns as well as mutations and their role in breast cancer development. In comparison with normal epithelium, in PABC several hormone target genes regulating the mitotic phase were overexpressed (58); four of these genes MKI6, AURKA, BIRC5, and MMP11 are included in the Oncotype DX (82). Furthermore, the expression of tumor suppressor, p63 was downregulated in PABC; its expression correlates with enhanced invasion and aggressive feature of PABC (58, 83).
Azim et al. aimed at identifying the effects of pregnancy and involution on certain gene expression patterns in breast cancer cells compared with normal breast tissue (84). The authors found that the expression of PD-1, PD-L1, and gene sets related to SRC, IGF1, and β-catenin were higher compared with non-parous breast cancer females. However, this difference in the expression did not reach statistical significance. Therefore, in order to confirm this important finding with high statistical significance, more studies and larger patient sample sizes are necessary, which may lead to important therapeutic avenues based on these gene targets. During pregnancy, in response to growth hormones, expression of ER, PR, and IGF-1 is elevated and is linked with increase in breast cancer cell proliferation (14). In this context, in-vivo studies showed loss of PD-L1 to correlate with fetal resorption and increase in fetal lethality (85, 86), hence the expression pattern of PD-1 and its ligand PD-L1 in PABC was assessed. Another study analyzed PD-1 and PD-L1 expression in both tumor-infiltrating lymphocytes (TILs) in PABC and nulliparous women; PD-L1 was strongly elevated in PABC TILs in comparison with controls, independent of tumor characteristics (87). On the other hand, in TILs PD-1 was expressed in both PABC and nulliparous women (87). Research has shown that high stromal TILs and PD-L1 expression to be frequently present in TNBC (88). A similar study by Acs et al. (2017) assessed PD-1, PD-L1, and CTLA-4 expression in PABC and non-PABC women; the expression of PD-1, PD-L1 was seen in peritumoral lymphocytes, however there was no expression of CTLA-4 and elevated PD-L1 expression was associated with early-onset of breast cancer and poor prognosis (89).
Furthermore, certain pathways were also found to be highly activated in parous breast cancer females including the G protein-coupled receptor (GPCR) and the serotonin receptor signaling pathways (84). GPCR signaling pathway plays a vital role in multiple cellular processes and mediates the activation of around 3% of the genes (90). Consequently, any aberration within this pathway may contribute to various diseases including cardiac, inflammatory and neoplastic (91). However, GPCRs are large family of receptors and only two of these receptors (CXCR4 and GPR30) were found to be highly expressed in breast cancers (84). The upregulations of these genes may induce breast cancer growth and metastasis (92). Moreover, activation of those GPCRs happens upon their binding to their ligands, which triggers the subsequent Ca2+ mobilization and kinase cascade activation leading to the induction of the expression of genes that are crucial for cellular growth (93).
The interplay between pregnancy and breast cancer has been an intriguing research topic over the years (94–96). Schedin et al. showed that many alterations- both inflammatory and non-inflammatory- occur in postpartum breasts causing a tumor inducing microenvironment (14). To further illustrate the mechanisms through which this takes place, Asztalos et al. reported that the involution process works to restore the status of breast tissue -prior to pregnancy- by inducing apoptosis, detachment of cells from the basement membrane (97), and other inflammation related events (62). The created inflammatory environment may initiate and contribute to the progression of breast cancer, especially through promoting tumor cell proliferation (14, 98). More importantly, a multitude of studies report different genetic patterns of PABC as compared to those detected in nulliparous women (16, 52, 81). Notably, estrogens can also bind to a known subtype of GPCRS, G protein estrogen receptor (GPER), thus contributing to breast cancer initiation and progression (99). The upregulation of serotonin induces tumorigenesis through induction of cellular proliferation (100). Furthermore, serotonin receptor pathway helps in the regulation of the expression of cathepsin S (CTSS) and is highly expressed in several cancer subtypes in which it correlates with their progression (101). The aggressiveness of pregnancy associated-TNBC, its poor prognosis and lack of treatment modalities makes it pivotal to study its genetic patterns and identify novel treatment options.
Molecular Features of Pregnancy Associated Triple-Negative Breast Cancers
Several variations are mainly ascribed to TNBC subgroup that was reportedly more predominant in PABCs (16, 52, 81); however, the exact mechanism by which pregnancy induces TNBC is yet to be fully elucidated. Among the different subtypes of breast cancer, CTSS is involved in invasion and is highly expressed in TNBC (102). Another factor that might contribute to the poor prognosis of TNBC is that TNBC increases the levels tryptophan-2,3-dioxygenase (TDO2) enzyme through inflammatory signals (103). TDO2 is a critical enzyme in catabolism of tryptophan, and its upregulation increases the production of tryptophan metabolites that exhibit antiapoptotic effects in TNBC cells (102).
Nevertheless, studies that specifically addressed the impact of pregnancy on development of TNBC are scarce. Asztalos et al. found a unique gene expression pattern for a specific set of genes in parous females who developed breast cancer in comparison to nulliparous breast cancer females. Differently expressed genes included 14 genes such as CXCL1, CXCL12, ELN, ERBB2, ESR1, FBN1, IL1A, IL8, MMP12, MMP2, PGR, TGFB3, THBS1, and TIMP2. Four of these genes (CXCL1, IL1A, IL8, MMP12) were upregulated, while the remaining 10 genes were down regulated in TNBC. Notably, downregulation of three of these genes (ESR1, PGR, ERBB2) are features of TNBC (104). Three of the upregulated genes (CXCL1, IL1A, IL8) are involved in inflammatory responses. Furthermore, inflammation and wound-healing involve macrophage cell influx, increased levels TGF-β1 and β3, MMPs-2, -3, and -9, and presence of fibronectin and laminin; these are linked with tumor progression and result in metastasis (14, 105–107). The interaction between cells and fibronectin via β1 integrins results in the onset of human breast cancer (108). Upregulated expression of TGF-β triggers matrix deposition and growth of fibroblasts in the healing wound, thus, accelerating tumor growth (107, 109). Indeed, MMPs are essential for the process of angiogenesis and lymphangiogenesis; both processes are essential in wound healing and tumor initiation and progression (110, 111). These findings further support the hypothesis that inflammation could contribute to the development of TNBC after pregnancy.
Interestingly, Azim et al. reported that the receptor activator of the nuclear factor κB ligand (RANKL) is found to be repressed in TNBC compared with other types of breast cancer, while the receptor activator for nuclear factor κB (RANK) was found to be highly expressed in TNBC (112). However, the link between these TNBC patients and pregnancy was not been found (113). Table 2 summarizes function of the identified genes in normal cells and PABC.
Genes reported to having unique pattern of expression in triple-negative breast cancers (TNBC) patients and their associated functions.
Gene
Function in Normal Cells
Function in PABC
Reference
CTSS
Promotes antigen processing.
Angiogenesis, tumor progression, and invasion.
(102)
CXCL1
Inflammation.
Decreased relapse-free survival and metastasis.
(114)
CXCL12
Embryogenesis, Inflammation, and Immunity.
Promotes tumor growth and metastasis.
(115)
ELN
Provides elasticity to organs and tissues.
Enhances tumor migration and progression.
(116)
ERBB2/HER2
Potentiates intracellular signaling.
Promotes metastasis and lower overall survival rates.
(117)
ESR1
Encodes estrogen receptor.
Downregulation is associated with worse outcome and poorly differentiated carcinomas.
(118)
FBN1
Structural support in elastic and non-elastic connective tissues.
Promotes tumor migration and invasion.
(119)
IL1A
Inflammation and hematopoiesis.
Promotes angiogenesis.
(120, 121)
IL8
Inflammation.
Promotes metastasis.
(122)
MMP12
Tissue remodeling.
Promotes angiogenesis and tumor progression.
(123)
RANKL
Regulation of T cell-dependent immune response.
Triggers endocrine therapy resistance and tumor progression.
(124)
PD-1
Negative regulator of immune response.
Promotes cancer immune evasion.
(125)
Src
Involved in embryonic development and cell growth.
Promotes malignancy and is associated with poor prognosis.
(126)
TGF-β3
Aids in embryogenesis, cellular differentiation and wound healing.
Promotes tumor progression and is associated with poor prognosis.
(127)
THBS1
Mediates cell-to-cell and cell-to-matrix interactions.
Involved in platelet aggregation, angiogenesis, and tumorigenesis.
(128)
TIMP2
Suppress proliferation of endothelial cells and maintain tissue homeostasis.
Promotes progression of cancer.
(129)
All information regarding the functions of those genes was collected form GeneBank (https://www.ncbi.nlm.nih.gov/genbank/).
Tumor suppressors, BRCA1/2 are involved in DNA damage repair, cell cycle control, transcription and ER type alpha activity (130). Mutations in BRCA1/2 are considered as risk factors for the onset of breast cancer (131); Atchley et al. reported a significant association between mutations in breast cancer susceptibility gene 1 (BRCA1) and TNBC, with more than 2/3 of BRCA1 mutations cases being of TNBC phenotype (132). Earlier studies have indicated that BRCA1/2 mutation carriers can be at a higher risk for PABC (133, 134). A study by Johannsson et al. analyzed the incidence of PABC in carriers of BRCA1 and BRCA2 mutations in comparison with premenopausal Swedish women aged ≤ 40 with sporadic PABC (133). The study showed that BRCA1/2 carriers are at an increased risk for PABC and hence should be monitored carefully during pregnancy and in the postpartum period (133). Another study revealed a significantly higher (25%) PABC frequency among BRCA1/2 mutation carriers compared with non-PABC cases (135). Although deleterious BRCA1 mutations are frequently encountered on both sporadic and hereditary TNBC (136), no link between pregnancy and these mutations has been found. Similarly, no association between TNBC and mutations in BRCA2 gene were reported (137). Based on the previous discussion, we underline here that the exact link between pregnancy and TNBC remains to be elucidated.
Signaling Networks in Pregnancy-Associated Breast Cancer
Earlier investigations suggested various underlying molecular mechanisms underpinning the onset of PABC. In an in-vivo study by Wagner et al. (138), using WAP-Cre/Rosa-LacZ transgenic mice, the authors identified a mixed population of alveolar cells called parity-induced mammary epithelial cells (PI-MECs) in the mammary gland of parous, non-pregnant female mice; these cells were not present in nulliparous females. PI-MECs rely on the transcription factor p63 for survival (138–142); one-time pregnant mice (MMTV–Her2/Neu mouse model) lacking p63 have lower tumors, thus indicating a tumor-promoter role for PI-MECs (138). Furthermore, another study showed that increased expression of p63 inhibits the p53 and STAT3 pathways; however, p63 enhances the expression of the pro-survival signaling STAT5 pathway, thus, initiating PI-MEC-induced tumorigenesis (142) (Figure 1). On the other hand, another study found loss of p63 during pregnancy reduced cyclin D1 levels, thus, suggesting a role of p63 in inducing PI-MEC survival post-partum (143). As shown in Figure 1, p63 levels increases cyclin D1which in turn inhibits estrogen receptor-alpha (ER-a) transactivation, further inhibiting the expression of BRCA1 (144). Following BRCA1 inhibition, PTEN is inactivated thereby activating mdm2 and blocking p53 (145) (Figure 1), which leads to genomic instability. Alternatively, pregnancy aids premalignant MECs evasion of apoptotic signaling through the activation of the JAK-STAT5 axis (146–148). In addition, receptor tyrosine kinases initiate downstream oncogenic signaling pathways such as PI3K/Akt which further activate either glycogen synthase kinase 3-beta (GSK3-β) or mdm2 (Figure 1).
Molecular pathways in pregnancy-associated breast cancer (PABC). Schematic diagram showing various pathways that are involved in the onset and progression of PABC.
On the other hand, in pregnant women, GPCRs are activated (84), these growth factors enhance focal adhesion kinase (FAK) which in turn activates RhoA/Rac1/cdc42/ROCK complex, thereby initiating cell migration (149) (Figure 1).
However, further understanding of the underlying molecular mechanisms of PABC is needed to help pave the way for the development of possible therapeutic strategies.
Diagnosis of Pregnancy-Associated Breast Cancer
Since pregnancy associated TNBCs have a poor prognosis and diagnostic delays may occur in pregnancy due to effects of pregnancy related hormones, increased awareness can help in paving the way for appropriate treatment.
Vis a vis PABC diagnosis, assessing breast symptoms during pregnancy and postpartum period can be perplexing due to hormonally induced changes in breast tissue that can result in augmented firmness and nodularity (150). Furthermore, postpartum lactational mastitis symptoms may mimic locally advanced or inflammatory breast cancer. The majority of PABCs are diagnosed after presenting with a palpable mass (151). To determine the scope of disease is critical in treatment decision-making.
Breast imaging includes mammography, ultrasound, and magnetic resonance imaging (MRI). While ultrasound is proven to be safe and commonly used in pregnancy (152), mammography confers minimal dose to the fetus with abdominal shielding (153). Contrast-enhanced breast MRI can be a useful diagnostic tool in non-PABC, however, in pregnancy, the safety of gadolinium still remains controversial. A free gadolinium is considered toxic as it can cross the placenta and stay in the amniotic fluid, which can be taken in by the fetus re-entering the fetal circulation (154). In addition, prone positioning required during breast MRI can apply a sustained pressure on the gravid uterus, disrupting uterine blood flow (154). In case of metastatic PABC, diagnostic workup prior to the delivery is required to enable therapeutic interventions. Generally, the pregnant patient is subjected to either chest X-ray with abdominal shielding, liver ultrasound or non-contrast supine MRI to check for lung, liver or bone metastasis, respectively (153).
Based on the imaging results, biopsy [fine needle aspiration (FNAC) or core needle biopsy (CNB)] is done for definite diagnosis of a breast mass (155). Although, FNAC is less traumatic with a low complication rate than CNB and generally does not require local anesthesia, FNAC provides inadequate information about the histopathological type, grade, steroid receptors, HER2 expression, and intrinsic behavior of the tumor (155, 156). Hence, CNB is considered as a more reliable method of pathological diagnosis of breast cancer (156). The tissue obtained from a biopsy is tested to determine the status of the hormone receptors (ER, PR) as well as Her2 and proliferation index (Ki-67) (157). Biopsies are performed either under ultrasound or stereotactic guidance (158). In addition, during the first and second trimesters of pregnancy, incisional or excisional biopsy can be safely done (159).
Once diagnosis of breast cancer has been completed by imaging methods and histopathology, it is essential not to postpone the treatment. It can be given post-delivery if the patient is in near term. If the patient is close to term, the treatment must commence (160).
Treatment of Pregnancy-Associated Breast Cancer
Treatment options for PABC remain challenging and may require special considerations. Surgery (e.g., modified radical mastectomy) is usually considered as the primary line of treatment in breast cancer during pregnancy but neoadjuvant chemotherapy has been widely used as a primary treatment option for advanced HER2-positive and TNBC (161). There are several concerns regarding the use of neoadjuvant chemotherapy that pertain to the potential peripartum complications and the impact on the fetal outcome (162). However, studies have shown that during the first trimester, chemotherapeutic agents are not advised as they may be potentially teratogenic (161). On the other hand, after completion of the first trimester, chemotherapeutic agents may be safely administered without the risk of fetal malformations (161). Multiple studies that explored the use of chemotherapeutic drugs for the treatment of breast cancer during pregnancy showed that the majority of drugs (taxanes and vinorelbine) are non-toxic during the second and third trimesters of pregnancy. However, these drugs may increase the risk of intrauterine growth restriction and preterm labor. Cytotoxic drugs may also induce both maternal and infant leukopenia, hence, chemotherapy after 35 weeks of gestation is contraindicated to avoid delivery of a leukopenic infant (161). Other drugs including methotrexate, trastuzumab and tamoxifen should also be avoided during pregnancy due to their effect on the central nervous system, cardiac, gastrointestinal and skeletal malformations, oligohydramnios (low levels of amniotic fluid), preterm labor, and spontaneous abortions (163–165). All these considerations should be taken into account when optimizing treatment options of breast cancer during pregnancy. A recent 4th ESO-ESMO guideline also emphasizes the need of an individual basis approach following the international guidelines and an expanded multidisciplinary team that will involve gynecologists/obstetricians as well as perinatologists, in addition to patients’ own preferences (166).
Adjuvant chemotherapy is helpful and encouraged in patients with high-risk breast cancer including those with PABC. High-risk prognostic factors include estrogen and progesterone receptor negative status, HER2 status, high tumor grade, high TNM, and younger age of the patient (167). Patients that are treated with neoadjuvant chemotherapy and extensive residual disease (burden) are also strong candidates for adjuvant chemotherapy.
Radiation therapy is not advised during pregnancy as it can pose a high risk for fetal toxicity and malformations, childhood cancers and delays in neurocognitive development (168, 169). However, adjuvant radiotherapy (postpartum) can be safely used as in other breast cancer cases and following strict indications for adjuvant radiotherapy.
Breast cancer in young women (age < 40 years) tend to recur and therefore younger age of diagnosis, and hence longer lifespan places these patients at a statistically increased risk of recurrence and distant metastasis over time (170). Van Nes and van de Velde recommended mastectomy in younger patients over breast-conserving treatment (170). Any delay in treatment due to fallacies regarding risk of local and systemic therapy may worsens oncologic outcomes. Ambiguities regarding the safety of diagnostic modalities and treatment of PABC may lead to worse outcomes in the group of younger pregnant women with breast cancer. However, recent studies provide robust data on the safety of diagnostic procedures that can enable a successful treatment of patients with this challenging malignancy.
Sentinel lymph node biopsy (SLNB) is a part of routine management of breast cancer and has been widely used in clinical practice. SLNB recommendation is proposed for patients with clinically node negative breast cancers, those with or without 1–2 suspicious lymph nodes on imaging, and for patients that were not treated with neoadjuvant systemic therapy (171). In contrast to the American Society of Clinical Oncology (ASCO) guidelines, the National Comprehensive Cancer Network (NCCN) guideline indicates lack of scientific evidence regarding the use of SLNB in pregnant women. While, the NCCN also advises that SLNB use should be an individualized decision, but not directly offered to pregnant women < 30 weeks’ gestation. Of note, NCCN does not recommend the use of isosulfan or methylene blue dyes for SLNB in pregnancy while use of radioactive tracer (e.g., technetium 99m sulfur colloid) is also supported by limited scientific data regarding the fetal radiation dose (171).
Conclusions And Future Directions
PABC incidence increases as women choose delayed childbirth, and while it is a rare form of breast cancer with a significant propensity for triple-negative phenotype; Nevertheless, PABC is a diagnostically and therapeutically challenging disease bearing various risks for affected woman and fetus. Although immunotherapy with immune checkpoint inhibitors may be a promising therapeutic approach for patients with PABC, it can trigger various autoimmune side effects or immune-related adverse events (irAEs); there are several endocrine-related irAEs (172). The most common endocrinopathies reported from clinical trials include hypothyroidism and hypophysitis in patients treated with anti-PD-1/PD-L1 antibodies and anti-CTLA4, respectively (173–178). In addition, hypopituitarism, type 1 diabetes mellitus and primary adrenal insufficiency have also been reported (172). On the other hand, treatment with Dasatinib alone or combined with immune checkpoint inhibitors could be another therapeutic rationale given that PABC frequently overexpress the corresponding receptors Src and PD-L1. Nevertheless, despite the overall poor outcome, we believe that the complete gene and miRNA profiles of PABC can aid in identifying novel therapeutic targets and biomarkers to manage this rare, but fatal disease. In conclusion, the etiology of PABC remains largely unknown, thus, further cellular and animal models in addition to preclinical and clinical studies in the field are necessary.
Author Contributions
AA conceptualized the study. SA, IS, SM, HFA, SV and AA wrote, reviewed, and edited the manuscript. AA, HFA and SV acquired the funding. All authors have read and agreed to the published version of the manuscript. All authors contributed to the article and approved the submitted version.
Funding
Our lab is supported by grants from Qatar University: # QUCP-CMED-2019-1, QUHI-CMED-19/20-1, and QUCG-CMED-20/21-2.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
The authors would like to thank Mrs. A. Kassab for her critical reading of the manuscript.
Abbreviations
AMBER, African American breast cancer epidemiology and Risk Consortium; ASCO, American Society of Clinical Oncology; AURKA, Aurora Kinase A; BIRC5, Baculoviral IAP Repeat Containing 5; BRCA, Breast cancer susceptibility gene; Ca2+, Calcium ions; cdc, Cell division control protein; CNB, Core needle biopsy; CTLA4, Cytotoxic T-Lymphocyte Associated Protein 4; CXCL, C-X-C Motif Chemokine Ligand; CXCR, C-X-C Motif Chemokine Receptor 4; ELN, Elastin; ER/ESR, Estrogen receptor; ERBB2, Erb-B2 Receptor Tyrosine Kinase 2; FAK, Focal adhesion kinase; FBN, Fibrillin; FNAC, Fine needle aspiration; GPCR, G protein-coupled receptor; GSK3-β, glycogen synthase kinase 3-beta; HER2, human epidermal growth factor receptor 2; IGF1, Insulin Like Growth Factor 1; IL, Interleukin; ILC, Invasive lobular carcinoma; irAEs, Immune-related adverse events; JAK, Janus Kinase; LAR, Luminal androgen receptor; mdm2, Mouse double minute 2 homolog; MMP, Matrix metallopeptidase; MMTV, Mouse mammary tumor virus; MRI, Magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; NST, No-special-type; p53, Tumor protein 53; p63, Tumor protein 63; PABC, Pregnancy-associated breast cancer; PD-1, Programmed cell death protein 1; PD-L1, Programmed cell death-ligand 1; PGR/PR, Progesterone receptor; PI-MECs, Parity-induced mammary epithelial cells; PTEN, Phosphatase And Tensin Homolog; Rac1, Rac Family Small GTPase 1; RANKL, Receptor activator of the nuclear factor κB ligand; RhoA, Ras Homolog Family Member A; ROCK, Rho Associated Coiled-Coil Containing Protein Kinase; SLNB, Sentinel lymph node biopsy; src, SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase; STAT, Signal Transducer And Activator Of Transcription; TDO2, Tryptophan-2,3-dioxygenase; TGF, Transforming growth factor; TILs, Tumor-infiltrating lymphocytes; TNBC, Triple-negative breast cancer.
ReferencesW. H. O. (WHO). Breast Cancer. Geneva, Switzerland: WHO (2020).
TaoZShiALuCSongTZhangZZhaoJ. Breast Cancer: Epidemiology and Etiology. Cell Biochem Biophys (2015) 72(2):333–8. doi: 10.1007/s12013-014-0459-6TamimiRMColditzGAHazraABaerHJHankinsonSERosnerB. Traditional breast cancer risk factors in relation to molecular subtypes of breast cancer. Breast Cancer Res Treat (2012) 131(1):159–67. doi: 10.1007/s10549-011-1702-0PerouCMSørlieTEisenMBvan de RijnMJeffreySSReesCA. Molecular portraits of human breast tumours. Nature (2000) 406(6797):747–52. doi: 10.1038/35021093KoboldtDCFultonRSMcLellanMDSchmidtHKalicki-VeizerJMcMichaelJF. Comprehensive molecular portraits of human breast tumours. Nature (2012) 490(7418):61–70. doi: 10.1038/nature11412SørlieTTibshiraniRParkerJHastieTMarronJSNobelA. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci (2003) 100(14):8418. doi: 10.1073/pnas.0932692100LachapelleJFoulkesWD. Triple-negative and basal-like breast cancer: implications for oncologists. Curr Oncol (Toronto Ont) (2011) 18(4):161–4. doi: 10.3747/co.v18i4.824FoulkesWDSmithIEReis-FilhoJS. Triple-Negative Breast Cancer. N Engl J Med (2010) 363(20):1938–48. doi: 10.1056/NEJMra1001389LehmannBDBauerJAChenXSandersMEChakravarthyABShyrY. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest (2011) 121(7):2750–67. doi: 10.1172/JCI45014JézéquelPLoussouarnDGuérin-CharbonnelCCampionLVanierAGouraudW. Gene-expression molecular subtyping of triple-negative breast cancer tumours: importance of immune response. Breast Cancer Res (2015) 17:43. doi: 10.1186/s13058-015-0550-yHudisCAGianniL. Triple-negative breast cancer: an unmet medical need. Oncologist (2011) 16 Suppl 1:1–11. doi: 10.1634/theoncologist.2011-S1-01DentRTrudeauMPritchardKIIHannaWMKahnHKSawkaCA. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res (2007) 13(15 Pt 1):4429–34. doi: 10.1158/1078-0432.Ccr-06-3045DentRHannaWMTrudeauMRawlinsonESunPNarodSA. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat (2009) 115(2):423–8. doi: 10.1007/s10549-008-0086-2SchedinP. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer (2006) 6(4):281–91. doi: 10.1038/nrc1839LambeMHsiehCTrichopoulosDEkbomAPaviaMAdamiHO. Transient increase in the risk of breast cancer after giving birth. N Engl J Med (1994) 331(1):5–9. doi: 10.1056/nejm199407073310102AsztalosSPhamTNGannPHHayesMKDeatonRWileyEL. High incidence of triple negative breast cancers following pregnancy and an associated gene expression signature. SpringerPlus (2015) 4:710–0. doi: 10.1186/s40064-015-1512-7AntonelliNMDottersDJKatzVLKullerJA. Cancer in pregnancy: a review of the literature. Part I. Obstet Gynecol Surv (1996) 51(2):125–34. doi: 10.1097/00006254-199602000-00022JiYIIKimKT. Gynecologic malignancy in pregnancy. Obstet Gynecol Sci (2013) 56(5):289–300. doi: 10.5468/ogs.2013.56.5.289PavlidisNA. Coexistence of Pregnancy and Malignancy. Oncologist (2002) 7(4):279–87. doi: 10.1634/theoncologist.2002-0279LittonJKTheriaultRL. Breast cancer and pregnancy: current concepts in diagnosis and treatment. Oncologist (2010) 15(12):1238–47. doi: 10.1634/theoncologist.2010-0262KeyserEAStaatBCFausettMBShieldsAD. Pregnancy-associated breast cancer. Rev Obstet Gynecol (2012) 5(2):94–9. doi: 10.1136/ijgc-00009577-200303001-00301IshidaTYokoeTKasumiFSakamotoGMakitaMTominagaT. Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation: analysis of case-control study in Japan. Jpn J Cancer Res (1992) 83(11):1143–9. doi: 10.1111/j.1349-7006.1992.tb02737.xMiddletonLPAminMGwynKTheriaultRSahinA. Breast carcinoma in pregnant women. Cancer (2003) 98(5):1055–60. doi: 10.1002/cncr.11614CallihanEBGaoDJindalSLyonsTRMantheyEEdgertonS. Postpartum diagnosis demonstrates a high risk for metastasis and merits an expanded definition of pregnancy-associated breast cancer. Breast Cancer Res Treat (2013) 138(2):549–59. doi: 10.1007/s10549-013-2437-xWangBYangYJiangZZhaoJMaoYLiuJ. Clinicopathological characteristics, diagnosis, and prognosis of pregnancy-associated breast cancer. Thoracic Cancer (2019) 10(5):1060–8. doi: 10.1111/1759-7714.13045MichielettoSSaibeneTEvangelistaLBarbazzaFGrigolettoRRossiG. Preliminary monocentric results of biological characteristics of pregnancy associated breast cancer. Breast (2014) 23(1):19–25. doi: 10.1016/j.breast.2013.10.001ParenteJTAmselMLernerRChineaF. Breast cancer associated with pregnancy. Obstet Gynecol71 (1988) (6 Pt 1):861–4:(1988).
TobonH. H, LF: Breast cancer during pregnancy. Breast Dis (1993) 6:127–34.
FisherCJEganMKSmithPWicksKMillisRRFentimanIS. Histopathology of breast cancer in relation to age. Br J Cancer (1997) 75(4):593–6. doi: 10.1038/bjc.1997.103LyonsTRSchedinPJBorgesVF. Pregnancy and breast cancer: when they collide. J Mammary Gland Biol Neoplasia (2009) 14(2):87–98. doi: 10.1007/s10911-009-9119-7AliSAGuptaSSehgalRVogelV. Survival outcomes in pregnancy associated breast cancer: a retrospective case control study. Breast J (2012) 18(2):139–44. doi: 10.1111/j.1524-4741.2011.01201.xShoushaS. Breast carcinoma presenting during or shortly after pregnancy and lactation. Arch Pathol Lab Med (2000) 124(7):1053–60. doi: 10.1043/0003-9985(2000)124<1053:BCPDOS>2.0.CO;2KolliasJElstonCWEllisIORobertsonJFBlameyRW. Early-onset breast cancer–histopathological and prognostic considerations. Br J Cancer (1997) 75(9):1318–23. doi: 10.1038/bjc.1997.223BertheauPSteinbergSMCowanKMerinoMJ. Breast cancer in young women: clinicopathologic correlation. Semin Diagn Pathol (1999) 16(3):248–56.
McCreadyJArendtLMGloverEIyerVBriendelJLLyleSR. Pregnancy-associated breast cancers are driven by differences in adipose stromal cells present during lactation. Breast Cancer Res (2014) 16(1):R2. doi: 10.1186/bcr3594PetrekJA. Breast cancer during pregnancy. Cancer (1994) 74(S1):518–27. doi: 10.1002/cncr.2820741341GuineeVFOlssonHMöllerTHessKRTaylorSHFaheyT. Effect of pregnancy on prognosis for young women with breast cancer. Lancet (1994) 343(8913):1587–9. doi: 10.1016/s0140-6736(94)93054-6RibeiroGJonesDAJonesM. Carcinoma of the breast associated with pregnancy. Br J Surg (1986) 73(8):607–9. doi: 10.1002/bjs.1800730805JoshiSDialaniVMarottiJMehtaTSSlanetzPJ. Breast disease in the pregnant and lactating patient: radiological-pathological correlation. Insights Into Imaging (2013) 4(5):527–38. doi: 10.1007/s13244-012-0211-yUsmaniKMoranEMHaiderWAfzalHAhmadN. Breast cancer in pregnant and lactating women. J Environ Pathol Toxicol Oncol (1995) 14(3-4):227–34:(1995).
AmantFDeckersSVan CalsterenKLoiblSHalaskaMBrepoelsL. Breast cancer in pregnancy: recommendations of an international consensus meeting. Eur J Cancer (2010) 46(18):3158–68. doi: 10.1016/j.ejca.2010.09.010MathelinCAnnaneKTreisserAChenardMPTomasettoCBellocqJP. Pregnancy and post-partum breast cancer: a prospective study. Anticancer Res (2008) 28(4c):2447–52.
JohanssonALVAnderssonTM-LHsiehC-CJirströmKCnattingiusSFredrikssonI. Tumor characteristics and prognosis in women with pregnancy-associated breast cancer. Int J Cancer (2018) 142(7):1343–54. doi: 10.1002/ijc.31174SullivanMPatelASWangJHelenowskiIBKhanSA. Molecular Subtype Distribution of Pregnancy-Associated Breast Cancer. Am J Clin Pathol (2013) 140(suppl_1):A091–1. doi: 10.1093/ajcp/140.suppl1.091GeninASAntoineMAractingiSRouzierR. Pregnancy stimulates tumor angiogenesis in breast carcinoma. Anticancer Res (2014) 34(1):125–31.
HendersonBERossRKPikeMCCasagrandeJT. Endogenous hormones as a major factor in human cancer. Cancer Res (1982) 42(8):3232–9.
KeyTJPikeMC. The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol (1988) 24(1):29–43. doi: 10.1016/0277-5379(88)90173-3BernsteinLRossRK. Endogenous hormones and breast cancer risk. Epidemiol Rev (1993) 15(1):48–65. doi: 10.1093/oxfordjournals.epirev.a036116AndersonE. The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Res (2002) 4(5):197–201. doi: 10.1186/bcr452DicksonRBStancelGM. Chapter 8: Estrogen Receptor-Mediated Processes in Normal and Cancer Cells. JNCI Monogr (2000) 2000(27):135–45. doi: 10.1093/oxfordjournals.jncimonographs.a024237ElledgeRMCioccaDRLangoneGMcGuireWL. Estrogen receptor, progesterone receptor, and HER-2/neu protein in breast cancers from pregnant patients. Cancer (1993) 71(8):2499–506. doi: 10.1002/1097-0142(19930415)71:8<2499::aid-cncr2820710812>3.0.co;2-sMadarasLKovacsKASzaszAMKenesseyITokesAMSzekelyB. Clinicopathological features and prognosis of pregnancy associated breast cancer - a matched case control study. Pathol Oncol Res (2014) 20(3):581–90. doi: 10.1007/s12253-013-9735-9ChuangS-CLinC-HLuY-SHsiungCA. Association of pregnancy and mortality in women diagnosed with breast cancer: A Nationwide Population Based Study in Taiwan. Int J Cancer (2018) 143(10):2416–24. doi: 10.1002/ijc.31777BonnierPRomainSDilhuydyJMBonichonFJulienJPCharpinC. Influence of pregnancy on the outcome of breast cancer: a case-control study. Societe Francaise de Senologie et de Pathologie Mammaire Study Group. Int J Cancer (1997) 72(5):720–7. doi: 10.1002/(sici)1097-0215(19970904)72:5<720::aid-ijc3>3.0.co;2-uNugentPO’ConnellTX. Breast Cancer and Pregnancy. Arch Surg (1985), 20(11):1221–4. doi: 10.1001/archsurg.1985.01390350007001MerkelDE. Pregnancy and breast cancer. Semin Surg Oncol (1996) 12(5):370–5. doi: 10.1002/(sici)1098-2388(199609/10)12:5<370::Aid-ssu13>3.0.Co;2-tWorkMEJohnEMAndrulisILKnightJALiaoYMulliganAM. Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry. Br J Cancer (2014) 110(5):1367–77. doi: 10.1038/bjc.2013.807HarvellDMEKimJO’BrienJTanA-CBorgesVFSchedinP. Genomic signatures of pregnancy-associated breast cancer epithelia and stroma and their regulation by estrogens and progesterone. Hormones Cancer (2013) 4(3):140–53. doi: 10.1007/s12672-013-0136-zBaeSYKimSJLeeJLeeESKimE-KParkHY. Clinical subtypes and prognosis of pregnancy-associated breast cancer: results from the Korean Breast Cancer Society Registry database. Breast Cancer Res Treat (2018) 172(1):113–21. doi: 10.1007/s10549-018-4908-6BaeSYJungSPJungESParkSMLeeSKYuJH. Clinical Characteristics and Prognosis of Pregnancy-Associated Breast Cancer: Poor Survival of Luminal B Subtype. Oncology (2018) 95(3):163–9. doi: 10.1159/000488944HanB-yLiX-gH.-y. ZhaoX. Hu and H. Ling: Clinical features and survival of pregnancy-associated breast cancer: a retrospective study of 203 cases in China. BMC Cancer (2020) 20(1):244. doi: 10.1186/s12885-020-06724-5SteinTMorrisJSDaviesCRWeber-HallSJDuffyM-AHeathVJ. Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res BCR (2004) 6(2):R75–91. doi: 10.1186/bcr753JindalSGaoDBellPAlbrektsenGEdgertonSMAmbrosoneCB. Postpartum breast involution reveals regression of secretory lobules mediated by tissue-remodeling. Breast Cancer Res BCR (2014) 16(2):R31–1. doi: 10.1186/bcr3633O’BrienJSchedinP. Macrophages in breast cancer: do involution macrophages account for the poor prognosis of pregnancy-associated breast cancer? J Mammary Gland Biol Neoplasia (2009) 14(2):145–57. doi: 10.1007/s10911-009-9118-8LyonsTRO’BrienJBorgesVFConklinMWKeelyPJEliceiriKW. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med (2011) 17(9):1109–15. doi: 10.1038/nm.2416McDanielSMRumerKKBirocSLMetzRPSinghMPorterW. Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. Am J Pathol (2006) 168(2):608–20. doi: 10.2353/ajpath.2006.050677RussoJMailoDHuYFBaloghGSheriffFRussoIH. Breast differentiation and its implication in cancer prevention. Clin Cancer Res (2005) 11(2 Pt 2):931s–6s.
YangXRChang-ClaudeJGoodeELCouchFJNevanlinnaHMilneRL. Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst (2011) 103(3):250–63. doi: 10.1093/jnci/djq526MaHUrsinGXuXLeeETogawaKDuanL. Reproductive factors and the risk of triple-negative breast cancer in white women and African-American women: a pooled analysis. Breast Cancer Res (2017) 19(1):6. doi: 10.1186/s13058-016-0799-9YangXRShermanMERimmDLLissowskaJBrintonLAPeplonskaB. Differences in Risk Factors for Breast Cancer Molecular Subtypes in a Population-Based Study. Cancer Epidemiol Biomarkers Prev (2007) 16(3):439–43. doi: 10.1158/1055-9965.Epi-06-0806TriversKFLundMJPorterPLLiffJMFlaggEWCoatesRJ. The epidemiology of triple-negative breast cancer, including race. Cancer Causes Control (2009) 20(7):1071–82. doi: 10.1007/s10552-009-9331-1DolleJMDalingJRWhiteEBrintonLADoodyDRPorterPL. Risk Factors for Triple-Negative Breast Cancer in Women Under the Age of 45 Years. Cancer Epidemiol Biomarkers Prev (2009) 18(4):1157–66. doi: 10.1158/1055-9965.Epi-08-1005IslamTMatsuoKItoHHosonoSWatanabeMIwataH. Reproductive and hormonal risk factors for luminal, HER2-overexpressing, and triple-negative breast cancer in Japanese women. Ann Oncol (2012) 23(9):2435–41. doi: 10.1093/annonc/mdr613AmbrosoneCBZirpoliGHongCCYaoSTroesterMABanderaEV. Important Role of Menarche in Development of Estrogen Receptor-Negative Breast Cancer in African American Women. J Natl Cancer Inst (2015) 107(9). doi: 10.1093/jnci/djv172LundMJTriversKFPorterPLCoatesRJLeyland-JonesBBrawleyOW. Race and triple negative threats to breast cancer survival: a population-based study in Atlanta, GA. Breast Cancer Res Treat (2009) 113(2):357–70. doi: 10.1007/s10549-008-9926-3AmirikiaKCMillsPBushJNewmanLA. Higher population-based incidence rates of triple-negative breast cancer among young African-American women : Implications for breast cancer screening recommendations. Cancer (2011) 117(12):2747–53. doi: 10.1002/cncr.25862PalmerJRViscidiETroesterMAHongCCSchedinPBetheaTN. Parity, lactation, and breast cancer subtypes in African American women: results from the AMBER Consortium. J Natl Cancer Inst (2014) 106(10). doi: 10.1093/jnci/dju237BasaranDTurgalMBeksacKOzyuncuOAranOBeksacMS. Pregnancy-associated breast cancer: clinicopathological characteristics of 20 cases with a focus on identifiable causes of diagnostic delay. Breast Care (Basel Switzerland) (2014) 9(5):355–9. doi: 10.1159/000366436LangerAMohallemMStevensDRouzierRLereboursFChérelP. A single-institution study of 117 pregnancy-associated breast cancers (PABC): Presentation, imaging, clinicopathological data and outcome. Diagn Interv Imaging (2014) 95(4):435–41. doi: 10.1016/j.diii.2013.12.021MurphyCGMallamDSteinSPatilSHowardJSklarinN. Current or recent pregnancy is associated with adverse pathologic features but not impaired survival in early breast cancer. Cancer (2012) 118(13):3254–9. doi: 10.1002/cncr.26654PilewskieMGorodinskyPFoughtAHansenNBethkeKJerussJ. Association between recency of last pregnancy and biologic subtype of breast cancer. Ann Surg Oncol (2012) 19(4):1167–73. doi: 10.1245/s10434-011-2104-6PaikSShakSTangGKimCBakerJCroninM. A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer. N Engl J Med (2004) 351(27):2817–26. doi: 10.1056/NEJMoa041588HsiaoY-HSuYATsaiH-DMasonJTChouM-CManY-g. Increased invasiveness and aggressiveness in breast epithelia with cytoplasmic p63 expression. Int J Biol Sci (2010) 6(5):428–42. doi: 10.7150/ijbs.6.428AzimHJrBrohéeSPeccatoriFADesmedtCLoiSLambrechtsD. Biology of breast cancer during pregnancy using genomic profiling. Endocrine Rel Cancer (2014) 21:545–54. doi: 10.1530/ERC-14-0111D’AddioFRiellaLVMfarrejBGChabtiniLAdamsLTYeungM. The link between the PDL1 costimulatory pathway and Th17 in fetomaternal tolerance. J Immunol (2011) 187(9):4530–41. doi: 10.4049/jimmunol.1002031HabichtADadaSJurewiczMFifeBTYagitaHAzumaM. A link between PDL1 and T regulatory cells in fetomaternal tolerance. J Immunol (2007) 179(8):5211–9. doi: 10.4049/jimmunol.179.8.5211BlancoLJrPincusJSiziopikouK. Abstract PD6-07: PD-L1 is highly expressed in tumor infiltrating lymphocytes in pregnancy associated breast cancer. Cancer Res (2017) 77(4 Supplement):PD6-07-PD6-07. doi: 10.1158/1538-7445.Sabcs16-pd6-07SabatierRFinettiPMamessierEAdelaideJChaffanetMAliHR. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget (2015) 6(7):5449–64. doi: 10.18632/oncotarget.3216ÁcsBMadarasLTőkésA-MKovácsAKKovácsEOzsvári-VidákovichM. PD-1, PD-L1 and CTLA-4 in pregnancy-related - and in early-onset breast cancer: A comparative study. Breast (Edinburgh Scotland) (2017) 35:69–77. doi: 10.1016/j.breast.2017.06.013MauricePGuillaumeJ-LBenleulmi-ChaachouaADaulatAMKamalMJockersR. GPCR-interacting proteins, major players of GPCR function. Adv Pharmacol (2011) 62:349–80. doi: 10.1016/B978-0-12-385952-5.00001-4De FrancescoEMSotgiaFClarkeRBLisantiMPMaggioliniM. G protein-coupled receptors at the crossroad between physiologic and pathologic angiogenesis: old paradigms and emerging concepts. Int J Mol Sci (2017) 18(12):2713. doi: 10.3390/ijms18122713De FrancescoEMSotgiaFClarkeRBLisantiMPMaggioliniM. G Protein-Coupled Receptors at the Crossroad between Physiologic and Pathologic Angiogenesis: Old Paradigms and Emerging Concepts. Int J Mol Sci (2017) 18(12). doi: 10.3390/ijms18122713MaggioliniMSantollaMFAvinoSAielloFRosanoCGarofaloA. Identification of two benzopyrroloxazines acting as selective GPER antagonists in breast cancer cells and cancer-associated fibroblasts. Future Med Chem (2015) 7(4):437–48. doi: 10.4155/fmc.15.3SaundersCMBaumM. Breast cancer and pregnancy: a review. J R Soc Med (1993) 86(3):162–5.
RuizRHerreroCStrasser-WeipplKTouyaDSt LouisJBukowskiA. Epidemiology and pathophysiology of pregnancy-associated breast cancer: A review. Breast (2017) 35:136–41. doi: 10.1016/j.breast.2017.07.008CaseAS. Pregnancy-associated Breast Cancer. Clin Obstet Gynecol (2016) 59(4):779–88. doi: 10.1097/grf.0000000000000235SchedinPJThackrayLBMalonePFontaineSCFriisRRStrangeR. Programmed cell death and mammary neoplasia. Cancer Treat Res (1996) 83:3–22. doi: 10.1007/978-1-4613-1259-8_1AsztalosSGannPHHayesMKNonnLBeamCADaiY. Gene expression patterns in the human breast after pregnancy. Cancer Prev Res (Phila) (2010) 3(3):301–11. doi: 10.1158/1940-6207.capr-09-0069BartonMFilardoEJLolaitSJThomasPMaggioliniMProssnitzER. Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives. J Steroid Biochem Mol Biol (2018) 176:4–15. doi: 10.1016/j.jsbmb.2017.03.021PaiVPMarshallAMHernandezLLBuckleyARHorsemanND. Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival. Breast Cancer Res (2009) 11(6):R81. doi: 10.1186/bcr2448GochevaVJoyceJA. Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle (2007) 6(1):60–4. doi: 10.4161/cc.6.1.3669GautamJBaeYKKimJA. Up-regulation of cathepsin S expression by HSP90 and 5-HT7 receptor-dependent serotonin signaling correlates with triple negativity of human breast cancer. Breast Cancer Res Treat (2017) 161(1):29–40. doi: 10.1007/s10549-016-4027-1RogersTJChristensonJLGreeneLIIO’NeillKIIWilliamsMMGordonMA. Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression. Mol Cancer Res (2019) 17(1):30–41. doi: 10.1158/1541-7786.mcr-18-0246AsztalosSPhamTNGannPHHayesMKDeatonRWileyEL. High incidence of triple negative breast cancers following pregnancy and an associated gene expression signature. Springerplus (2015) 4:710(2015). doi: 10.1186/s40064-015-1512-7SchedinPO’BrienJRudolphMSteinTBorgesV. Microenvironment of the involuting mammary gland mediates mammary cancer progression. J Mammary Gland Biol Neoplasia (2007) 12(1):71–82. doi: 10.1007/s10911-007-9039-3CoussensLMWerbZ. Inflammation and cancer. Nature (2002) 420(6917):860–7. doi: 10.1038/nature01322SchäferMWernerS. Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol (2008) 9(8):628–38. doi: 10.1038/nrm2455WhiteDEKurpiosNAZuoDHassellJABlaessSMuellerU. Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell (2004) 6(2):159–70. doi: 10.1016/j.ccr.2004.06.025WakefieldLMRobertsAB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev (2002) 12(1):22–9. doi: 10.1016/s0959-437x(01)00259-3FerraraNKerbelRS. Angiogenesis as a therapeutic target. Nature (2005) 438(7070):967–74. doi: 10.1038/nature04483SaharinenPTammelaTKarkkainenMJAlitaloK. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol (2004) 25(7):387–95. doi: 10.1016/j.it.2004.05.003AzimHAPeccatoriFABrohéeSBranstetterDLoiSVialeG. RANK-ligand (RANKL) expression in young breast cancer patients and during pregnancy. Breast Cancer Res (2015) 17(1):24. doi: 10.1186/s13058-015-0538-7LeeEMcKean-CowdinRMaHSpicerDVVan Den BergDBernsteinL. Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women. J Clin Oncol (2011) 29(33):4373. doi: 10.1200/JCO.2010.33.6446BiècheIChaveyCAndrieuCBussonMVacherSLe CorreL. CXC chemokines located in the 4q21 region are up-regulated in breast cancer. Endocr Relat Cancer (2007) 14(4):1039–52. doi: 10.1677/erc.1.01301SunYMaoXFanCLiuCGuoAGuanS. CXCL12-CXCR4 axis promotes the natural selection of breast cancer cell metastasis. Tumour Biol (2014) 35(8):7765–73. doi: 10.1007/s13277-014-1816-1KrishnanRClearyEG. Elastin gene expression in elastotic human breast cancers and epithelial cell lines. Cancer Res (1990) 50(7):2164–71.
TanMYuD. “Molecular Mechanisms of ErbB2-Mediated Breast Cancer Chemoresistance”. In: Madame Curie Bioscience Database [Internet]. Austin, TX: Landes Bioscience (2013).
ChenJ-QRussoJ. ERalpha-negative and triple negative breast cancer: molecular features and potential therapeutic approaches. Biochim Biophys Acta (2009) 1796(2):162–75. doi: 10.1016/j.bbcan.2009.06.003LienH-CLeeY-HJuangY-LLuY-T. Fibrillin-1, a novel TGF-beta-induced factor, is preferentially expressed in metaplastic carcinoma with spindle sarcomatous metaplasia. Pathology (2019) 51(4):375–83. doi: 10.1016/j.pathol.2019.02.001VoronovEShouvalDSKrelinYCagnanoEBenharrochDIwakuraY. IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci USA (2003) 100(5):2645–50. doi: 10.1073/pnas.0437939100SingerCFKronsteinerNHudelistGMartonEWalterIKubistaM. Interleukin 1 system and sex steroid receptor expression in human breast cancer: interleukin 1alpha protein secretion is correlated with malignant phenotype. Clin Cancer Res (2003) 9(13):4877–83. doi: 10.1136/ijgc-00009577-200303001-00301BendreMSGaddy-KurtenDMon-FooteTAkelNSSkinnerRANicholasRW. Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res (2002) 62(19):5571–9.
DecockJThirkettleSWagstaffLEdwardsDR. Matrix metalloproteinases: protective roles in cancer. J Cell Mol Med (2011) 15(6):1254–65. doi: 10.1111/j.1582-4934.2011.01302.xPhungernKAntoniaKRJoanneE. The NF-KB pathway and endocrine therapy resistance in breast cancer. Endocrine Rel Cancer (2019) 26(6):R369–80. doi: 10.1530/ERC-19-0087BardhanKAnagnostouTBoussiotisVA. The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation. Front Immunol (2016) 7:550. doi: 10.3389/fimmu.2016.00550WheelerDLIidaMDunnEF. The role of Src in solid tumors. Oncologist (2009) 14(7):667–78. doi: 10.1634/theoncologist.2009-0009GhellalALiCHayesMByrneGBundredNKumarS. Prognostic significance of TGF beta 1 and TGF beta 3 in human breast carcinoma. Anticancer Res (2000) 20(6b):4413–8.
HuangTSunLYuanXQiuH. Thrombospondin-1 is a multifaceted player in tumor progression. Oncotarget (2017) 8(48):84546–58. doi: 10.18632/oncotarget.19165RemacleAMcCarthyKNoëlAMaguireTMcDermottEO’HigginsN. High levels of TIMP-2 correlate with adverse prognosis in breast cancer. Int J Cancer (2000) 89(2):118–21. doi: 10.1002/(sici)1097-0215(20000320)89:2<118::aid-ijc3>3.0.co;2-8KingMCMarksJHMandellJB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science (2003) 302(5645):643–6. doi: 10.1126/science.1088759ChanJLJohnsonLNCSammelMDDiGiovanniLVoongCDomchekSM. Reproductive Decision-Making in Women with BRCA1/2 Mutations. J Genet Couns (2017) 26(3):594–603. doi: 10.1007/s10897-016-0035-xAtchleyDPAlbarracinCTLopezAValeroVAmosCIIGonzalez-AnguloAM. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol (2008) 26(26):4282–8. doi: 10.1200/jco.2008.16.6231JohannssonOLomanNBorgAOlssonH. Pregnancy-associated breast cancer in BRCA1 and BRCA2 germline mutation carriers. Lancet (1998) 352(9137):1359–60. doi: 10.1016/s0140-6736(05)60750-7CullinaneCALubinskiJNeuhausenSLGhadirianPLynchHTIsaacsC. Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers. Int J Cancer (2005) 117(6):988–91. doi: 10.1002/ijc.21273HouNOgundiranTOjengbedeOMorhason-BelloIZhengYFackenthalJ. Risk factors for pregnancy-associated breast cancer: a report from the Nigerian Breast Cancer Study. Ann Epidemiol (2013) 23(9):551–7. doi: 10.1016/j.annepidem.2013.06.008SilvaEGatalicaZSnyderCVranicSLynchJFLynchHT. Hereditary breast cancer: part II. Management of hereditary breast cancer: implications of molecular genetics and pathology. Breast J (2008) 14(1):14–24. doi: 10.1111/j.1524-4741.2007.00516.xRiahiAGourabiMEChabouni-BouhamedH. Dissimilarity between sporadic, non-BRCA1/2 families and hereditary breast cancer, linked to BRCA genes, in the Tunisian population. Breast Cancer (2016) 23(5):807–12. doi: 10.1007/s12282-015-0648-1WagnerKUBoulangerCAHenryMDSgagiasMHennighausenLSmithGH. An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal. Development (2002) 129(6):1377–86.
MatulkaLATriplettAAWagnerK-U. Parity-induced mammary epithelial cells are multipotent and express cell surface markers associated with stem cells. Dev Biol (2007) 303(1):29–44. doi: 10.1016/j.ydbio.2006.12.017BoothBWBoulangerCASmithGH. Alveolar progenitor cells develop in mouse mammary glands independent of pregnancy and lactation. J Cell Physiol (2007) 212(3):729–36. doi: 10.1002/jcp.21071ChangTHTKunasegaranKTarulliGADe SilvaDVoorhoevePMPietersenAM. New insights into lineage restriction of mammary gland epithelium using parity-identified mammary epithelial cells. Breast Cancer Res (2014) 16(1):R1. doi: 10.1186/bcr3593YallowitzARAlexandrovaEMTalosFXuSMarchenkoNDMollUM. p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis. Cell Death Differ (2014) 21(4):645–54. doi: 10.1038/cdd.2013.199ForsterNSaladiSVvan BragtMSfondourisMEJonesFELiZ. Basal Cell Signaling by p63 Controls Luminal Progenitor Function and Lactation via NRG1. Dev Cell (2014) 28(2):147–60. doi: 10.1016/j.devcel.2013.11.019WangCFanSLiZFuMRaoMMaY. Cyclin D1 Antagonizes BRCA1 Repression of Estrogen Receptor α Activity. Cancer Res (2005) 65(15):6557–67. doi: 10.1158/0008-5472.Can-05-0486LeeCKimJ-SWaldmanT. Activated PI3K signaling as an endogenous inducer of p53 in human cancer. Cell Cycle (Georgetown Tex.) (2007) 6(4):394–6. doi: 10.4161/cc.6.4.3810HaricharanSDongJHeinSReddyJPDuZToneffM. Mechanism and preclinical prevention of increased breast cancer risk caused by pregnancy. Elife (2013) 2:e00996. doi: 10.7554/eLife.00996DuZLiY. RCAS-TVA in the mammary gland: an in vivo oncogene screen and a high fidelity model for breast transformation? Cell Cycle (2007) 6(7):823–6. doi: 10.4161/cc.6.7.4074DuZPodsypaninaKHuangSMcGrathAToneffMJBogoslovskaiaE. Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models. Proc Natl Acad Sci USA (2006) 103(46):17396–401. doi: 10.1073/pnas.0608607103GuptaSKMalhotraSSMalikAVermaSChaudharyP. Cell Signaling Pathways Involved During Invasion and Syncytialization of Trophoblast Cells. Am J Reprod Immunol (2016) 75(3):361–71. doi: 10.1111/aji.12436RojasKBilbroNManassehD-MBorgenPI. A Review of Pregnancy-Associated Breast Cancer: Diagnosis, Local and Systemic Treatment, and Prognosis. J Women’s Health (2019) 28(6):778–84. doi: 10.1089/jwh.2018.7264Al-AmriAM. Clinical presentation and causes of the delayed diagnosis of breast cancer in patients with pregnancy associated breast cancer. J Family Community Med (2015) 22(2):96–100. doi: 10.4103/2230-8229.155383WhitworthMBrickerLMullanC. Ultrasound for fetal assessment in early pregnancy. Cochrane Database System Rev (2015) 2015(7):CD007058. doi: 10.1002/14651858.CD007058.pub3Committee Opinion No. 723. Guidelines for Diagnostic Imaging During Pregnancy and Lactation. Obstet Gynecol (2017) 130(4):e210–6. doi: 10.1097/aog.0000000000002355WagnerLApplegateKACR practice guideline for imaging pregnant or potentially pregnant adolescents and women with ionizing radiation.American College of Radiology (2008). 1–15.
MitraSDeyP. Fine-needle aspiration and core biopsy in the diagnosis of breast lesions: A comparison and review of the literature. CytoJournal (2016) 13:18–8. doi: 10.4103/1742-6413.189637SahaAMukhopadhyayMDasCSarkarKSahaAKSarkarDK. FNAC Versus Core Needle Biopsy: A Comparative Study in Evaluation of Palpable Breast Lump. J Clin Diagn Res JCDR (2016) 10(2):EC05–EC8. doi: 10.7860/JCDR/2016/15889.7185Penault-LlorcaFVialeG. Pathological and molecular diagnosis of triple-negative breast cancer: a clinical perspective. Ann Oncol (2012) 23:vi19–22. doi: 10.1093/annonc/mds190LangerAMohallemMBermentHFerreiraFGogAKhalifaD. Breast lumps in pregnant women. Diagn Intervent Imaging (2015) 96(10):1077–87. doi: 10.1016/j.diii.2015.07.005CollinsJCLiaoSWileAG. Surgical management of breast masses in pregnant women. J Reprod Med (1995) 40(11):785–8.
LenhardMSBauerfeindIUntchM. Breast cancer and pregnancy: challenges of chemotherapy. Crit Rev Oncol Hematol (2008) 67(3):196–203. doi: 10.1016/j.critrevonc.2008.02.007MolckovskyAMadarnasY. Breast cancer in pregnancy: a literature review. Breast Cancer Res Treat (2008) 108(3):333–8. doi: 10.1007/s10549-007-9616-6RingAESmithIEJonesAShannonCGalaniEEllisPA. Chemotherapy for breast cancer during pregnancy: an 18-year experience from five London teaching hospitals. J Clin Oncol (2005) 23(18):4192–7. doi: 10.1200/jco.2005.03.038LoiblSSchmidtAGentiliniOKaufmanBKuhlCDenkertC. Breast Cancer Diagnosed During Pregnancy: Adapting Recent Advances in Breast Cancer Care for Pregnant Patients. JAMA Oncol (2015) 1(8):1145–53. doi: 10.1001/jamaoncol.2015.2413SekarRStonePR. Trastuzumab use for metastatic breast cancer in pregnancy. Obstet Gynecol (2007) 110(2 Pt 2):507–10. doi: 10.1097/01.Aog.0000267133.65430.44LoiblSvon MinckwitzGGwynKEllisPBlohmerJUSchlegelbergerB. Breast carcinoma during pregnancy. International recommendations from an expert meeting. Cancer (2006) 106(2):237–46. doi: 10.1002/cncr.21610Paluch-ShimonSCardosoFPartridgeAHAbulkhairOAzimJr HABianchi-MicheliG. ESO–ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4). Ann Oncol (2020) 31(6):674–96. doi: 10.1016/j.annonc.2020.03.284KuererHMGwynKAmesFCTheriaultRL. Conservative surgery and chemotherapy for breast carcinoma during pregnancy. Surgery (2002) 131(1):108–10. doi: 10.1067/msy.2002.115357GreskovichJr JFMacklisRM. Radiation therapy in pregnancy: risk calculation and risk minimization. Semin Oncol (2000) 27(6):633–45.
OtakeMSchullWJLeeS. Threshold for radiation-related severe mental retardation in prenatally exposed A-bomb survivors: a re-analysis. Int J Radiat Biol (1996) 70(6):755–63. doi: 10.1080/095530096144644van NesJGvan de VeldeCJ. The preferred treatment for young women with breast cancer–mastectomy versus breast conservation. Breast (2006) 15 Suppl 2:S3–10. doi: 10.1016/s0960-9776(07)70009-7National Comprehensive Cancer Network. NCCN Guidelines.Plymouth Meeting, PA 19462. Harborside Press, LLC (2020).
CukierPSantiniFCScarantiMHoffAO. Endocrine side effects of cancer immunotherapy. Endocrine Rel Cancer (2017) 24(12):T331. doi: 10.1530/erc-17-0358CorselloSBarnabeiAMarchettiPDe VecchisLSalvatoriRTorinoF. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab (2013) 98:1361–75. doi: 10.1210/jc.2012-4075ByunDJWolchokJDRosenbergLMGirotraM. Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol (2017) 13(4):195–207. doi: 10.1038/nrendo.2016.205EggermontAMMChiarion-SileniVGrobJ-JDummerRWolchokJDSchmidtH. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med (2016) 375(19):1845–55. doi: 10.1056/NEJMoa1611299González-RodríguezERodríguez-AbreuD. Immune Checkpoint Inhibitors: Review and Management of Endocrine Adverse Events. Oncologist (2016) 21(7):804–16. doi: 10.1634/theoncologist.2015-0509O’DonnellPHPlimackERBellmuntJBergerRMontgomeryRBHeathK. Pembrolizumab (Pembro; MK-3475) for advanced urothelial cancer: Results of a phase IB study. J Clin Oncol (2015) 33(7_suppl):296–6. doi: 10.1200/jco.2015.33.7_suppl.296TopalianSLSznolMMcDermottDFKlugerHMCarvajalRDSharfmanWH. Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab. J Clin Oncol (2014) 32(10):1020–30. doi: 10.1200/jco.2013.53.0105‘Oh, my dear Thomas, you haven’t heard the terrible news then?’ she said. ‘I thought you would be sure to have seen it placarded somewhere. Alice went straight to her room, and I haven’t seen her since, though I repeatedly knocked at the door, which she has locked on the inside, and I’m sure it’s most unnatural of her not to let her own mother comfort her. It all happened in a moment: I have always said those great motor-cars shouldn’t be allowed to career about the streets, especially when they are all paved with cobbles as they are at Easton Haven, which are{331} so slippery when it’s wet. He slipped, and it went over him in a moment.’ My thanks were few and awkward, for there still hung to the missive a basting thread, and it was as warm as a nestling bird. I bent low--everybody was emotional in those days--kissed the fragrant thing, thrust it into my bosom, and blushed worse than Camille. "What, the Corner House victim? Is that really a fact?" "My dear child, I don't look upon it in that light at all. The child gave our picturesque friend a certain distinction--'My husband is dead, and this is my only child,' and all that sort of thing. It pays in society." leave them on the steps of a foundling asylum in order to insure [See larger version] Interoffice guff says you're planning definite moves on your own, J. O., and against some opposition. Is the Colonel so poor or so grasping—or what? Albert could not speak, for he felt as if his brains and teeth were rattling about inside his head. The rest of[Pg 188] the family hunched together by the door, the boys gaping idiotically, the girls in tears. "Now you're married." The host was called in, and unlocked a drawer in which they were deposited. The galleyman, with visible reluctance, arrayed himself in the garments, and he was observed to shudder more than once during the investiture of the dead man's apparel. HoME香京julia种子在线播放
ENTER NUMBET 0016hnsunmi.com.cn hisike.com.cn www.frokin.com.cn www.jxtj.org.cn www.pufeikekj.org.cn www.rjneiy.com.cn www.qinxi.net.cn www.nmjcdf.com.cn sheatour.com.cn vietlotto.org.cn