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Breast Cancer Research

Breast Cancer Risk Factors

Breast Cancer Research  is presenting our Retrospective Collection on "Breast Cancer Risk Factors." Celebrating 'Breast Cancer Awareness Month (1 October- 31 October)', with this Collection, we aim to gain valuable insights into the multifaceted aspects of breast cancer risk to promote awareness, prevention, and early detection.

NEW CROSS-JOURNAL COLLECTIONS Find out more by clicking the links below:

Artif icial Intelligence in Breast Imaging PDGFB in Br east Cancer Initiation,Progression, and Metastasis

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Single-cell transcriptional atlas of tumor-associated macrophages in breast cancer

Authors: Yupeng Zhang, Fan Zhong and Lei Liu

Challenges and improvements in HER2 scoring and histologic evaluation: insights from a national proficiency testing scheme for breast cancer diagnosis in China

Authors: Xuemin Xue, Lei Guo, Changyuan Guo, Liwei Xu, Lin Li, Lin Yang, Xin Wang, Wei Rao, Pei Yuan, Jiali Mu, Jiangtao Li, Bingning Wang, Quan Zhou, Weicheng Xue, Fei Ma, Wenjing Yang…

Analysis of ductal carcinoma in situ by self-reported race reveals molecular differences related to outcome

Authors: Siri H. Strand, Kathleen E. Houlahan, Vernal Branch, Thomas Lynch, Belén Rivero-Guitiérrez, Bryan Harmon, Fergus Couch, Kristalyn Gallagher, Mark Kilgore, Shi Wei, Angela DeMichele, Tari King, Priscilla McAuliffe, Christina Curtis, Kouros Owzar, Jeffrey R. Marks…

Elevated expression of Aurora-A/ AURKA in breast cancer associates with younger age and aggressive features

Authors: L. M. Ingebriktsen, R. O. C. Humlevik, A. A. Svanøe, A. K. M. Sæle, I. Winge, K. Toska, M. B. Kalvenes, B. Davidsen, A. Heie, G. Knutsvik, C. Askeland, I. M. Stefansson, E. A. Hoivik, L. A. Akslen and E. Wik

Systematic assessment of HER2 status in ductal carcinoma in situ of the breast: a perspective on the potential clinical relevance

Authors: Mieke R. Van Bockstal, Jelle Wesseling, Ester H. Lips, Marjolein Smidt, Christine Galant and Carolien H. M. van Deurzen

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Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib

Authors: Nusayba Bagegni, Shana Thomas, Ning Liu, Jingqin Luo, Jeremy Hoog, Donald W. Northfelt, Matthew P. Goetz, Andres Forero, Mattias Bergqvist, Jakob Karen, Magnus Neumüller, Edward M. Suh, Zhanfang Guo, Kiran Vij, Souzan Sanati, Matthew Ellis…

Choosing the right cell line for breast cancer research

Authors: Deborah L Holliday and Valerie Speirs

Triple-negative breast cancer molecular subtyping and treatment progress

Authors: Li Yin, Jiang-Jie Duan, Xiu-Wu Bian and Shi-cang Yu

Breast asymmetry and predisposition to breast cancer

Authors: Diane Scutt, Gillian A Lancaster and John T Manning

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

Authors: Suzanne A Eccles, Eric O Aboagye, Simak Ali, Annie S Anderson, Jo Armes, Fedor Berditchevski, Jeremy P Blaydes, Keith Brennan, Nicola J Brown, Helen E Bryant, Nigel J Bundred, Joy M Burchell, Anna M Campbell, Jason S Carroll, Robert B Clarke, Charlotte E Coles…

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Editor-in-Chief

Lewis Chodosh , University of Pennsylvania, USA

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BCR's 20th Anniversary

20 years ago Breast Cancer Research published its first articles with BMC. Well-respected in the field, the journal has continually placed in the first quartile of the ‘Oncology’ category of Journal Citation Reports. Over the past decade, Breast Cancer Research (BCR) has also become the highest ranked breast cancer focused title in the field.

Look back at the journal’s milestone achievements and article highlights .

Featured Review - Artificial intelligence in mammographic phenotyping of breast cancer risk: a narrative review

In this review, we provide a useful reference for AI researchers investigating image-based breast cancer risk assessment while indicating key priorities and challenges that, if properly addressed, could accelerate the implementation of AI-assisted risk stratification to future refine and individualize breast cancer screening strategies.

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Single-cell rna-sequencing: opening new horizons for breast cancer research.

1. Introduction

2. the functional principle and workflow of scrna-seq, 2.1. single-cell isolation, 2.2. reverse transcription, amplification, and sequencing, 2.2.1. pcr after polya tailing, 2.2.2. template-switching-based pcr, 2.2.3. in vitro transcription (ivt), 2.3. data analysis, 3. application of scrna-seq in breast cancer, 3.1. application of scrna-seq in exploring the heterogeneity of breast cancer, 3.2. application of scrna-seq in tme of breast cancer, 3.3. application of scrna-seq in therapy of breast cancer, 3.4. application of scrna-seq in drug resistance of breast cancer, 3.5. application of scrna-seq in metastasis of breast cancer, 4. potential future directions of scrna-seq in breast cancer research, 5. conclusions, author contributions, conflicts of interest.

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Xiang, L.; Rao, J.; Yuan, J.; Xie, T.; Yan, H. Single-Cell RNA-Sequencing: Opening New Horizons for Breast Cancer Research. Int. J. Mol. Sci. 2024 , 25 , 9482. https://doi.org/10.3390/ijms25179482

Xiang L, Rao J, Yuan J, Xie T, Yan H. Single-Cell RNA-Sequencing: Opening New Horizons for Breast Cancer Research. International Journal of Molecular Sciences . 2024; 25(17):9482. https://doi.org/10.3390/ijms25179482

Xiang, Lingyan, Jie Rao, Jingping Yuan, Ting Xie, and Honglin Yan. 2024. "Single-Cell RNA-Sequencing: Opening New Horizons for Breast Cancer Research" International Journal of Molecular Sciences 25, no. 17: 9482. https://doi.org/10.3390/ijms25179482

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• Published: 06 September 2024

GATA3 and markers of epithelial-mesenchymal transition predict long-term benefit from tamoxifen in ER-positive breast cancer

• Josefine Sandström 1 ,
• Jens Bomanson 1 ,
• Gizeh Pérez-Tenorio 1 ,
• Carolin Jönsson 1 ,
• Bo Nordenskjöld 1 ,
• Tommy Fornander 2 ,
• Linda S. Lindström   ORCID: orcid.org/0000-0002-7722-7532 2 , 3 &
• Olle Stål   ORCID: orcid.org/0000-0002-8290-0592 1  

npj Breast Cancer volume  10 , Article number:  78 ( 2024 ) Cite this article

Metrics details

• Breast cancer

GATA binding protein 3 (GATA3) is essential for normal development of the mammary gland and associated with ER-positive breast cancer. Loss of GATA3 has been associated with epithelial-mesenchymal transition (EMT) in experimental studies. We investigated tumoral GATA3 in a cohort of postmenopausal patients with lymph-node negative breast cancer, randomized to adjuvant tamoxifen or control. Nuclear GATA3 expression was assessed with immunohistochemistry and GATA3 gene expression with Agilent microarrays. High GATA3 nuclear expression was associated with a lower rate of distant recurrence in ER-positive breast cancer (HR = 0.60, 95% CI 0.39–0.93). Low gene expression of GATA3 was associated with limited long-term benefit from adjuvant tamoxifen (interaction: p  = 0.033). GATA3 gene expression was associated with the epithelial markers CDH1 (E-cadherin) and FOXA1, whereas negatively associated with several mesenchymal markers. Low expression of CDH1 was associated with marginal tamoxifen benefit (HR = 0.80 (0.43–1.49)), whereas patients with higher expression showed a significant benefit (HR = 0.33 (0.20–0.55), interaction: p  = 0.029). In ER-positive breast cancer, diminished expression of GATA3 is associated with markers of EMT and poor long-term benefit from tamoxifen.

Introduction

Breast cancer commonly arises in luminal cells of the mammary gland expressing the estrogen receptor (ER). The expression of ER in the tumor is a cornerstone for the selection of adjuvant treatment. Patients with ER-positive breast cancer receiving endocrine therapy have initially a good prognosis, but studies with long-term follow-up have shown that there is a continuous risk of late relapse of the disease for these patients 1 , 2 , 3 . The endocrine treatment lasts for five or even ten years and there is a need for better prediction of overtreatment as well as of development of treatment resistance and late relapse.

The range of target genes regulated by ER is dependent on the phosphorylation of ER at different sites and cofactors that bind to DNA in the proximity of ER-binding sites 4 . GATA binding protein 3 (GATA3) and forkhead box A1 (FOXA1) are two proteins forming a strong transcriptional network together with ER. This network is required for correct development of the mammary gland 5 , 6 . ER-positive tumors often express GATA3, but a low GATA3 expression has been associated with worse prognosis 7 , 8 . However, whether GATA3 is an independent prognostic factor, and whether it predicts the benefit from tamoxifen, has yet not been settled. The importance of phosphorylated ER (pER) for the efficacy of tamoxifen has been previously studied by others and by us 9 , 10 , 11 , 12 . The receptor is phosphorylated at different sites by intracellular signaling molecules including MAP-kinase (pERser118), S6K1 (pERser167) and, PKA and PAK1 (pERser305) 11 , 12 , 13 , 14 .

Loss of functional GATA3 can arise due to mutations in the gene, which have been found in 10–15% of ER-positive breast cancer 15 . Mutations seldom silence the GATA3 gene- or protein expression but could alter its function. Without functional GATA3, or perhaps with too much of a function, the transcriptional landscape will change. Experimental studies suggest that loss of GATA3 expression is associated with epithelial-mesenchymal transition (EMT), which in turn might facilitate dissemination of tumor cells and the establishment of metastases 16 . To the best of our knowledge, the relationship between GATA3 and EMT factors in human breast tumors has not been thoroughly investigated.

The functionality of GATA3 can be disrupted by gene mutations or could be reduced by decreased gene expression or increased protein degradation. Here, we investigate the tumoral expression of GATA3 in a cohort of postmenopausal patients with lymph-node negative breast cancer, randomized to adjuvant tamoxifen or no systemic treatment. With gene expression data from the same cohort, we analyze several genes involved in EMT and cell adhesion in relation to GATA3 in ER-positive breast cancer. Furthermore, we examine the long-term prognosis and benefit from adjuvant tamoxifen in association to GATA3 and related factors.

Patient cohort

In a trial conducted by the Stockholm Breast Cancer Study Group, postmenopausal breast cancer patients with a negative lymph node status and tumor size not exceeding three cm were randomized to adjuvant tamoxifen, 40 mg daily for two years or no tamoxifen, the Stockholm tamoxifen trial STO-3 17 . The trial recruited patients regardless of ER status. Patient entry to the study was from November 1976 to May 1990. In 1983, tamoxifen-treated recurrence-free patients were randomized, if consenting, to three more years of tamoxifen or no further treatment with tamoxifen. The follow-up period lasted at most to 30 years with a median of 22.6 years of follow-up.

Figure 1 shows a flowchart of the study cohort. For 912 of the 1780 patients in the trial, formalin-fixed paraffin-embedded tumor tissue was available and used to construct tissue micro arrays (TMAs) with three tissue cores from each tumor. Previously, data for samples on the TMA were compared with data of the original cohort of 1780 patients 9 . The results showed no bias with respect to tumor size, ER status, or treatment arm. The STO‐3 trial was approved by the ethics committee at Karolinska Institutet (KI) in Stockholm, Sweden, and participants provided oral consent (KI 76–51). Further, the ethics committee at KI approved retrospective studies on archived tumor tissue for the present cohort, with the purpose to evaluate prognostic and treatment predicting factors (KI 97–451 with amendments 030201 and 2017 2066-32). Further need for patient consent was waived by the ethics committee.

Flowchart of included patients. Formalin-fixed paraffin-embedded (FFPE), Gene expression (GEX).

Biomarkers previously investigated in this cohort

Immunohistochemistry of ER, progesterone receptor (PgR) and HER2 was previously assessed 18 , 19 . Further, for ER phosphorylated at two different sites (pER), pERs167 and pERs305, data were available 9 , 10 . The antibodies used for ER, PgR and HER2 were, respectively, the CONFIRM™ mouse anti-ER antibody (clone 6F11) and the CONFIRM™ mouse anti-PR antibody (clone 16) from Ventana Medical Systems, and the DAKO AO0485 polyclonal rabbit antibody according to the guidelines provided by the manufacturer. The antibodies for pER were a rabbit polyclonal pERα ser305 primary antibody (Bethyl Laboratories, Montgomery, TX) and anti-pERs167 from Cell Signaling Technologies (Danvers, MA).

GATA3 protein staining

The GATA3 protein was investigated with immunohistochemistry on TMA sections. Several studies comparing antibody sensitivity revealed the L50-823 as the most sensitive GATA3 antibody compared to another commonly used antibody, HG3-31, reviewed in Kandalaft et al. 20 . The PT-link station was used for deparaffinization and antigen retrieval in a low-pH buffer (K800521-2, EnVision FLEX Target Retrieval Solution, DakoCytomation, Glostrup, Denmark), starting at 65 °C, gradually increasing and ending at 96 °C for 20 min and cooled down to 65 °C. Inactivation of endogenous peroxidase in 3% hydrogen peroxide in water was followed by blocking in serum-free protein block for 10 min (DPB-125, Spring Bioscience, Freemont, CA). TMA sections were incubated in a moisturized chamber at 4 °C during 24 h with the anti-GATA3 mouse monoclonal antibody diluted 1:500 (L50-823, Merck KGaA, Darmstadt, Germany). Secondary anti-mouse antibody (K4000, DakoCytomation Envision+ HRP system, Agilent Technologies, CA) was applied for 30 min at room temperature and protein staining was developed with 3,3’-diaminobenzidine chromogen and substrate buffer, dilution 1:50, for 8 min (K3467, DakoCytomation, Agilent Technologies, CA) and counterstained with hematoxylin for 1 min. All washing steps were in phosphate buffered saline including 0.5% bovine serum albumin. The tissue was dehydrated, and cover glass was mounted with Pertex (00871, Histolab, Askim, Sweden). Slides were visualized using the Aperio CS2 brightfield digital scanner at ×400 magnification and analyzed with the ImageScope software (Leica biosystems, Buffalo Grove, IL).

GATA3 protein grading

Of the 912 tumors, 749 were successfully stained and graded for GATA3 protein expression. Nuclear staining intensity was graded in three steps: negative (0), weak (1) and strong (2). Frequency of positive tumor nuclei were scored as follows; 0% (0), 1–10% (1), 11–50% (2), 51–89% (3) and ≥90% (4). For statistical analysis, the nuclear staining was divided in low and high, with a cut-off defining the group with high expression as strong nuclear staining in >50% of tumor cells. Primary grading was performed by two independent observers (J.S. and J.B.), blinded to clinical data, and secondary grading was performed jointly by the two observers to reach consensus.

Gene expression analysis

Messenger RNA was extracted from FFPE breast tumor tissue and 652 samples were available for microarray gene-expression analysis using custom-designed arrays, containing 32.1 K probes, detecting about 21.5 K unique genes (Agilent Technologies, CA) 21 . The Prediction Analysis of Microarray 50 (PAM50) intrinsic subtype analysis classifier was used as described by Parker et al. 22 .

We selected a number of genes encoding proteins known to interact with GATA3 or EMT. FOXA1 is a strong transcriptional partner of GATA3 and NOTCH3 might upregulate GATA3. Several factors related to EMT are known from the literature. Among them, we selected E-cadherin (CDH1), an epithelial marker frequently lost in EMT. On the other hand, N-cadherin (CDH2) and the intermediate filament protein vimentin (VIM) are expressed in mesenchymal cells. In addition, we selected alpha-smooth muscle actin (ACTA2) that is associated with the TGF-β pathway, which in turn can drive the EMT process. Finally, the EMT-activating transcription factors Snail (SNAI1) and Twist-related protein 1 (TWIST1) were included in the list of genes analyzed.

Expression levels of GATA3 and other genes were analyzed by tertiles (T1-T3) in the association analyses. In the survival analyses, the lowest tertile (T1) was used as cut-off for GATA3, CDH1 and FOXA1, as the low expression was expected to stand out from the group as more aggressive. For the EMT-related genes, the cut-off was set at the highest tertile (T3), as a high expression of these genes was expected to stand out from the remaining group as more aggressive. In the multiple regression analysis, the gene-expression levels were analyzed as continuous variables.

Statistical analyses were performed using Statistica 14 (TIBCO Software Inc.). For comparisons of GATA3 protein expression with other characteristics, the Pearson χ2 test was applied for 2 × 2 tables. For associations of GATA3 gene expression in three categories with other factors, the Spearman rank order correlation was applied. Distribution of GATA3 in the PAM50 molecular signatures was compared with the Kruskal–Wallis test. Multiple linear regression analysis was used to investigate how each mesenchymal marker could be predicted by GATA3, FOXA1 and NOTCH3. Distant recurrence-free interval (DRFI) time distributions were compared, and plots were drawn with the Kaplan–Meier method, visualizing time from randomization to first event of distant metastasis. Hazard ratios (HRs) of distant metastasis were estimated using the Cox proportional hazards model. Cox models were furthermore applied in multivariable analysis and in interaction analysis exploring the expression of genes as potential predictive factors for tamoxifen treatment benefit. A p -value of less than 0.05 was considered significant.

Overall, 70% of the tumors exhibited high nuclear GATA3 expression and GATA3 was strongly associated with ER status. Among ER-positive tumors, high nuclear and mRNA GATA3 expression, was seen in 84% and 41% of the cases, respectively. Corresponding numbers for ER-negative tumors were 19% and 5%, respectively ( p  < 0.0001 for both). Accordingly, the PAM50 molecular subtypes differed in relation to GATA3, for both nuclear and mRNA expression, with Luminal A showing the highest levels and the Basal subtype the lowest (Fig. 2 ). Therefore, we restricted the analyses in the following to patients with ER-positive breast cancer and the tertiles for GATA3 were from now on based on this subgroup.

The fraction of tumors with high GATA3 protein expression ( a ) and gene expression levels ( b ) in relation to the PAM50 subtypes. Kruskal–Wallis H-test, p  < 0.0001 for both comparisons.

Associations of GATA3 with clinicopathological variables and pER

Nuclear GATA3 was more frequently expressed at high levels in small and PgR-positive tumors (Table 1 ). HER2 positivity was significantly associated with low GATA3 gene expression levels and a similar trend was seen for GATA3 protein expression (Tables 1 and 2 ). Both protein and gene expression levels of GATA3 were associated with ER phosphorylated at serine-305 (pERs305), whereas the association of GATA3 with pERs167 was less clear.

There was a significant correlation between GATA3 mRNA and protein levels (Table 1 ), but this relationship showed differences dependent on pER. For tumors with a positive status of pERs167, nuclear GATA3 was frequently highly expressed also at low GATA3 mRNA levels, resulting in no correlation between gene and protein expression levels.

On the other hand, the subgroup of pERs167- negative tumors showed a significant gene to protein correlation (Fig. 3 ). In contrast, the status of pERs305 did not markedly affect the correlation between gene and protein expression levels.

The relationship between GATA3 gene and protein expression by the status of pERs167 ( a ) and pERs305 ( b ). The p -values refer to Spearman rank order correlation and error bars refer to standard error of the mean. Tertile (T).

Associations of GATA3 with epithelial and mesenchymal biomarkers

Based on previous experimental research showing that the loss of GATA3 may contribute to EMT, we next analyzed the relationship between GATA3 and the expression of several genes associated with this process. Comparing gene-expression levels, GATA3 was negatively correlated with all the mesenchymal biomarkers investigated, including ACTA2, CDH2, SNAI1, TWIST1 and VIM (Table 3 ). For GATA3 protein levels, the same was true for three of the biomarkers. Furthermore, the gene expression of GATA3 was positively associated with CDH1, FOXA1, and NOTCH3.

Since the transcription factors GATA3 and FOXA1 have been suggested to inhibit EMT, and NOTCH3 could be a contributing factor, we performed multiple regression analysis to investigate these factors as independent predictors of CDH1 and the mesenchymal markers, respectively (Table 4 ). GATA3 turned out to be the variable that most consistently correlated with the markers investigated.

Distant recurrence-free interval in relation to GATA3

Patients with high tumoral nuclear GATA3 expression had a longer DRFI than those with low GATA3 levels (HR = 0.60, 95% CI 0.39–0.93, p  = 0.023, Fig. 4a ). When adjusting for treatment and other tumor characteristics, including tumor size, PgR and HER2, the statistical significance for GATA3 was lost (HR = 0.81, 95% CI 0.50–1.31, p  = 0.39), whereas tumor size (>20 mm vs ≤20 mm; HR = 2.16, 95% CI 1.39–3.36, p  = 0.00067) and tamoxifen (HR = 0.45, 95% CI 0.30–0.67, p  < 0.0001) were significant. We did not find a significant association of GATA3 gene expression levels with DRFI (T2-T3 vs T1; HR = 1.06, 95% CI 0.71–1.57, p  = 0.78, Fig. 4b ).

Distant recurrence-free interval (DRFI) in relation to GATA 3 nuclear expression ( a ) and GATA3 gene expression ( b ). HR Hazard ratio, CI Confidence interval.

The benefit from adjuvant tamoxifen in relation to GATA3 and related factors

Given that GATA3 and ER interact, the benefit from tamoxifen could potentially be dependent on expression levels of GATA3. Whereas patients with ER-positive tumors with intermediate to high GATA3 mRNA levels showed significant benefit from tamoxifen (HR = 0.39 (0.24–0.64), p  = 0.00014), those with levels in the bottom tertile did not as evidently benefit (HR = 0.61 (0.31–1.17), p  = 0.14) (Fig. 5 ). The difference was more pronounced when considering the long-term prognosis. For patients still alive and without a distant recurrence after five years, there was no further benefit from tamoxifen in the group with low GATA3 (HR = 1.10 (0.46–2.61), p  = 0.83), in contrast to the group with higher levels (HR = 0.35 (0.19–0.64), p  = 0.00064). A test for interaction between GATA3 and tamoxifen for this period was significant ( p  = 0.033). The efficacy of tamoxifen did not significantly differ for patients with low or high tumoral nuclear GATA3 protein expression (HR = 0.53 (0.23–1.23) and HR = 0.52 (0.34–0.79), respectively), however the number of patients in the former group was small.

DRFI for the tamoxifen and control groups in patients with low ( a ) and medium/high ( b ) GATA3 levels. DRFI for the tamoxifen and control groups, in patients alive and free of distant recurrence after five years, with low ( c ) and medium/high ( d ) GATA3. Hazard ratio (HR), tamoxifen (TAM), tertile (T).

The GATA3-associated genes CDH1 and FOXA1 in addition tended to predict the efficacy of tamoxifen. Patients with CDH1 levels in the bottom tertile experienced no evident benefit from tamoxifen (HR = 0.80 (0.43–1.49), p  = 0.49), whereas those with higher levels did (HR = 0.33 (0.20–0.55), p  = 0.000021), and the interaction was significant ( p  = 0.029, Fig. 6a, b ). Although a similar interaction between FOXA1 and tamoxifen did not reach statistical significance ( p  = 0.22), the benefit from the treatment was more evident in the group with higher levels as compared with the group with low levels (HR = 0.41 (0.26–0.63), p  = 0.000075) and (HR = 0.71 (0.32–1.58), p  = 0.40), respectively, (Fig. 6c, d ). Moreover, the EMT biomarkers CDH2 and VIM tended to predict less tamoxifen benefit when expressed at higher levels as compared to low levels (Fig. 6E–H ). For the remaining EMT markers, the benefit from tamoxifen was similar comparing groups with low/intermediate versus high levels (tests for interaction, all p  > 0.7).

DRFI for the tamoxifen and controls groups in patients with low ( a ) and medium/high tumor CDH1 ( b ), in patients with low ( c ) and medium/high tumor FOXA1 ( d ), in patients with low ( e ) and medium/high tumor CDH2 ( f ), in patients with low ( g ) and medium/high tumor VIM ( h ). Hazard ratio (HR), tamoxifen (TAM), tertile (T).

GATA3, known as a marker used to identify mammary or urothelial origin of metastases from unknown primary tumors, is widely expressed in breast tumors and has been suggested as a potential prognostic and/or treatment predictive biomarker 23 , 24 . A quantitative decrease or functional loss of GATA3 seems to interfere with the characteristics of the tumor 25 . In line with previously published data, we see a distinct nuclear expression of GATA3 in more than 80% of ER-positive tumors as compared to in only about 20% of the ER-negative tumors 7 , 26 , 27 . GATA3 positivity was largely associated with a PAM50 Luminal subtype, supporting its functional role as co-regulator of the ER and its association with differentiation.

The ER protein is phosphorylated at distinct sites when regulated. The tight connection between ER and GATA3 suggests that the two proteins may regulate each other. We found a significant association between pERs305 and high GATA3 expression. We suggest that this might be related to PKA, which, besides its involvement in ERs305 phosphorylation 11 , has been shown to interact with GATA3 28 . Overall, there was a strong association of GATA3 gene expression with GATA3 protein expression. Interestingly, in tumors phosphorylated at ERs167, GATA3 gene- and protein expression did not correlate. Hypothetically, a stabilization of the GATA3 protein could be affected by intracellular signaling proteins associated with ER phosphorylation, supported by the finding that MAPK controls GATA3 protein stability by a post-transcriptional mechanism 29 . Furthermore, S6K1, that phosphorylates ER at serine 167, interacts with ER in a positive feedback loop also involving GATA3 30 .

We found low GATA3 protein levels to be significantly associated with increased risk of distant recurrence when compared to high GATA3 protein levels in the group of patients with ER-positive tumors. Mehra et al. reported already in 2005 that detection of GATA3 with immunohistochemistry could predict outcome of breast cancer, also when adjusting for other prognostic factors 8 . Several studies have found similar results 7 , 27 , 31 , although the independent prognostic value was absent in one of the studies when the analysis was restricted to ER-positive breast cancer 31 , similar to our results. Moreover, GATA3 was not independently prognostic in a huge study comprising more than 3000 patients 32 . We did not see a prognostic value of GATA3 gene-expression levels in the present cohort. This contrasts with some other gene-expression studies with microarray data, reviewed by Fang et al, showing that GATA3 is prognostic 33 . Taken together, GATA3 appears as a favorable prognostic factor, but the question of its importance as an independent factor needs further elucidation, considering the choice of cut-off for positivity as well as the influence of breast cancer therapy.

GATA3 is highly correlated with ER and thus a potential predictive marker of benefit from hormonal therapy. Using a breast cancer model with parental and tamoxifen-resistant MCF7 cells, endocrine resistance was associated with downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers 34 . One important factor for the transcriptional landscape was GATA3. Further studies have indicated that GATA3 counteracts EMT. The protein complex GATA3/G9A/MTA3 represses ZEB2, and other genes involved in EMT, leading to suppression of metastasis from human breast cancer cells in mice. In turn, ZEB2 repressed the expression of G9A and MTA3 35 . Moreover, ectopic expression of GATA3 in GATA3-negative triple-negative breast cancer cells led to increased CDH1 expression and decreased expression of some mesenchymal markers 16 . A similar transcriptional change could also be related to mutations of GATA3 36 . Here, the results give support for the experimental findings of an inverse relationship between GATA3 and EMT in a large series of ER-positive tumors. GATA3 expression correlated with high expression of E-cadherin and FOXA1 and low expressions of all five mesenchymal markers investigated.

Besides a prognostic value, one could ask whether GATA3 is a treatment predictive factor. In a minor series of 28 ER-positive cases of breast cancer, lack of GATA3 expression was associated with unresponsiveness to hormonal therapy 37 . Furthermore, GATA3 mRNA expression was associated with longer progression-free survival in patients with ER-positive breast cancer treated with first-line tamoxifen for recurrent disease 38 . To the best of our knowledge, there are no previous reports on the relationship of GATA3 with the efficacy of adjuvant endocrine therapy based on a randomized trial. In the present study, we were able to show that a substantial benefit from tamoxifen was restricted to patients with intermediate/high GATA3 mRNA expression, most evident when focusing on late relapse. We found similar patterns for FOXA1 and E-cadherin, both of which are closely related to GATA3, whereas CDH2 (N-cadherin) and VIM (vimentin) tended to show opposite associations. When the transcriptional landscape of ER is altered upon loss of GATA3, one might speculate that the anti-tumoral effects of tamoxifen is diminished.

One strength with this study is that it is based on a randomized clinical trial and long-term follow-up. The study limitations include that the cohort is confined to postmenopausal patients with lymph-node negative disease, and it is not known if the results related to tamoxifen benefit can be translated to the use of aromatase inhibitors. Another limitation is that we lack data on GATA3 mutations for this cohort. GATA3 is the third most mutated gene in luminal breast cancer. In part, the results of the present study might be applicable to tumors with GATA3 mutation as such mutations affect gene transcription patterns and EMT 36 , 39 , 40 .

In conclusion, GATA3 expression is associated with ER-positive breast cancer and particularly with the Luminal A subtype. Diminished expression of GATA3 in ER-positive tumors is associated with changes of gene expression resembling EMT. Both such changes and GATA3 expression itself were related to the efficacy of adjuvant tamoxifen therapy.

Data availability

Restrictions apply to the availability of these data according to GDPR. Data were obtained from the STO Trialist Group and are available from the authors with the permission from the STO Trialist Group.

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Acknowledgements

This study was funded by the Swedish Cancer Society (Cancerfonden, grant No. 190268 to O.S. and grant No. 222081 and 220552SIA to L.S.L., ALF medicine (grant number Lio-795201, O.S. and grant number FoUI-974882 to L.S.L.), Onkologiska Klinikernas i Linköpings forskningsfond, 2019 to J.S., Swedish Research Council (Vetenskapsrådet, grant number 2020-02466 to L.S.L.). The funders played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.

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Josefine Sandström, Jens Bomanson, Gizeh Pérez-Tenorio, Carolin Jönsson, Bo Nordenskjöld & Olle Stål

Department of Oncology and Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden

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Conception and design: J.S., O.S. Data acquisition: J.S., J.B., B.N., T.F., L.S.L. Formal analysis: J.S., J.B., O.S. Data interpretation: all authors. Funding acquisition: J.S., O.S., L.S.L. Writing—original draft: J.S., O.S. Writing—review & editing: all authors. The final version was approved by all authors.

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Sandström, J., Bomanson, J., Pérez-Tenorio, G. et al. GATA3 and markers of epithelial-mesenchymal transition predict long-term benefit from tamoxifen in ER-positive breast cancer. npj Breast Cancer 10 , 78 (2024). https://doi.org/10.1038/s41523-024-00688-6

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Advances in Breast Cancer Research

A polyploid giant cancer cell (PGCC) from triple-negative breast cancer.

NCI-funded researchers are working to advance our understanding of how to prevent, detect, and treat breast cancer. They are also looking at how to address disparities and improve quality of life for survivors of the disease.

This page highlights some of what's new in the latest research for breast cancer, including new clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.

Early Detection of Breast Cancer

Breast cancer is one of a few cancers for which an effective screening  test, mammography , is available. MRI ( magnetic resonance imaging ) and  ultrasound  are also used to detect breast cancer, but not as routine screening tools for people with average risk.

Ongoing studies are looking at ways to enhance current breast cancer screening options. Technological advances in imaging are creating new opportunities for improvements in both screening and early detection.

One technology advance is 3-D mammography , also called breast tomosynthesis . This procedure takes images from different angles around the breast and builds them into a 3-D-like image. Although this technology is increasingly available in the clinic, it isn’t known whether it is better than standard 2-D mammography , for detecting cancer at a less advanced stage.

NCI is funding a large-scale randomized breast screening trial, the Tomosynthesis Mammographic Imaging Screening Trial (TMIST) , to compare the number of advanced cancers detected in women screened for 5 years with 3-D mammography with the number detected in women screened with 2-D mammography. 

Two concerns in breast cancer screening, as in all cancer screening, are:

• the potential for diagnosing tumors that would not have become life-threatening ( overdiagnosis )
• the possibility of receiving false-positive test results, and the anxiety that comes with follow-up tests or procedures

As cancer treatment is becoming more individualized, researchers are looking at ways to personalize breast cancer screening. They are studying screening methods that are appropriate for each woman’s level of risk and limit the possibility of overdiagnosis.

For example, the Women Informed to Screen Depending on Measures of Risk (WISDOM) study aims to determine if risk-based screening—that is, screening at intervals that are based on each woman’s risk as determined by her genetic makeup, family history , and other risk factors—is as safe, effective, and accepted as standard annual screening mammography.

WISDOM is also making a focused effort to enroll Black women in the trial. Past studies  tended to contain a majority of White women and therefore, there is less data on how screening can benefit Black women. Researchers are taking a number of steps to include as many Black women as possible in the study while also increasing the diversity of all women enrolled.

Breast Cancer Treatment

The mainstays of breast cancer treatment are surgery , radiation , chemotherapy , hormone therapy , and targeted therapy . But scientists continue to study novel treatments and drugs, along with new combinations of existing treatments.

It is now known that breast cancer can be divided into subtypes based on whether they:

• are hormone receptor (HR) positive which means they express  estrogen and/or progesterone receptors  ( ER , PR )

Shortening Radiation Therapy for Some with Early Breast Cancer

A condensed course was as effective and safe as the standard course for women with higher-risk early-stage breast cancer who had a lumpectomy.

As we learn more about the subtypes of breast cancer and their behavior, we can use this information to guide treatment decisions. For example:

• The NCI-sponsored TAILORx clinical trial. The study, which included patients with ER-positive, lymph node-negative breast cancer, found that a test that looks at the expression of certain genes can predict which women can safely avoid chemotherapy.
• The RxPONDER trial found that the same gene expression test can also be used to determine treatment options in women with more advanced breast cancer. The study found that some postmenopausal women with HR positive, HER-2 negative breast cancer that has spread to several lymph nodes and has a low risk of recurrence do not benefit from chemotherapy when added to their hormone therapy. 
• The OFSET trial is comparing the addition of chemotherapy to usual treatment ( ovarian function suppression plus hormone therapy) to usual treatment alone in treating premenopausal estrogen receptor (ER)-positive/HER2-negative breast cancer patients who are at high risk of their cancer returning. This will help determine whether or not adding chemotherapy helps prevent the cancer from returning.  

Genomic analyses, such as those carried out through  The Cancer Genome Atlas (TCGA) , have provided more insights into the molecular diversity of breast cancer and eventually could help identify even more breast cancer subtypes. That knowledge, in turn, may lead to the development of therapies that target the genetic alterations that drive those cancer subtypes.

HR-Positive Breast Cancer Treatment 

Hormone therapies have been a mainstay of treatment for HR-positive cancer. However, there is a new focus on adding targeted therapies to hormone therapy for advanced or metastatic HR-positive cancers. These treatments could prolong the time until chemotherapy is needed and ideally, extend survival. Approved drugs include:

Drug Combo Effective for Metastatic Breast Cancer in Younger Women

Ribociclib plus hormone therapy were superior to standard chemotherapy combos in a recent trial.

• Palbociclib (Ibrance) ,  ribociclib (Kisqali) , and  everolimus (Afinitor) have all been approved by the FDA for use with hormone therapy for treatment of advanced or metastatic breast cancer. Ribociclib has been shown to increase the survival of patients with metastatic breast cancer . It has also shown to slow the growth of metastatic cancer in younger women when combined with hormone therapy.
• Elacestrant (Orserdu) is approved for HR-positive and HER2-negative breast cancer that has a mutation in the ESR1 gene, and has spread. It is used in postmenopausal women and in men whose cancer has gotten worse after at least one type of hormone therapy.
• Abemaciclib (Verzenio) can be used with or after hormone therapy to treat advanced or metastatic HR-positive, HER2-negative breast cancer. In October 2021, the Food and Drug Administration ( FDA ) approved abemaciclib in combination with hormone therapy to treat some people who have had surgery for early-stage HR-positive, HER2-negative breast cancer.
• Alpelisib (Piqray)  is approved to be used in combination with hormone therapy to treat advanced or metastatic HR-positive, HER2-negative breast cancers that have a mutation in the PIK3CA gene .
• Sacituzumab govitecan-hziy (Trodelvy) is used for HR-positive and HER2-negative breast cancer that has spread or can't be removed with surgery. It is used in those who have received hormone therapy and at least two previous treatments. It has shown to extend the amount of time that the disease doesn't get worse ( progression-free survival ) and also shown to improve overall survival .

HER2-Positive Breast Cancer Treatment 

The FDA has approved a number of targeted therapies to treat HER2-positive breast cancer , including:

• Trastuzumab (Herceptin) has been approved to be used to prevent a relapse in patients with early-stage HER2-positive breast cancer. 
• Pertuzumab (Perjeta) is used to treat metastatic HER2-positive breast cancer, and also both before surgery ( neoadjuvant ) and after surgery ( adjuvant therapy ). 
• Trastuzumab and pertuzumab together can be used in combination with chemotherapy to prevent relapse in people with early-stage HER2-positive breast cancer.  Both are also used together in metastatic disease, where they delay progression and improve overall survival. 
• Trastuzumab deruxtecan (Enhertu) is approved for patients with advanced or metastatic HER2-positive breast cancer who have previously received a HER2-targeted treatment. A 2021 clinical trial showed that the drug lengthened the time that people with metastatic HER2-positive breast cancer lived without their cancer progressing. The trial also showed that it was better at shrinking tumors than another targeted drug, trastuzumab emtansine (Kadcyla).
• Tucatinib (Tukysa) is approved to be used in combination with trastuzumab and capecitabine (Xeloda) for HER2-positive breast cancer that cannot be removed with surgery or is metastatic. Tucatinib is able to cross the blood–brain barrier, which makes it especially useful for HER2-positive metastatic breast cancer, which tends to spread to the brain. 
• Lapatinib (Tykerb)  has been approved for treatment of some patients with HER2-positive advanced or metastatic breast cancer, together with capecitabine or letrozole.
• Neratinib Maleate (Nerlynx) can be used in patients with early-stage HER2-positive breast cancer and can also be used together with capecitabine (Xeloda) in some patients with advanced or metastatic disease.
• Ado-trastuzumab emtansine (Kadcyla) is approved to treat patients with metastatic HER2-positive breast cancer who have previously received trastuzumab and a taxane . It's also used in some patients with early-stage HER2-positive breast cancer who have completed therapy before surgery ( neoadjuvant ) and have residual disease at the time of surgery.

HER2-Low Breast Cancer

 A newly defined subtype, HER2-low, accounts for more than half of all metastatic breast cancers. HER2-low tumors are defined as those whose cells contain lower levels of the HER2 protein on their surface. Such tumors have traditionally been classified as HER2-negative because they did not respond to drugs that target HER2. 

However, in a clinical trial, trastuzumab deruxtecan (Enhertu) improved the survival of patients with HER2-low breast cancer compared with chemotherapy , and the drug is approved for use in such patients. 

Immunotherapy Improves Survival in Triple-Negative Breast Cancer

For patients whose tumors had high PD-L1 levels, pembrolizumab with chemo helped them live longer.

Triple-Negative Breast Cancer Treatment 

Triple-negative breast cancers (TNBC) are the hardest to treat because they lack both hormone receptors and HER2 overexpression , so they do not respond to therapies directed at these targets. Therefore, chemotherapy is the mainstay for treatment of TNBC. However, new treatments are starting to become available. These include:

• Sacituzumab govitecan-hziy (Trodelvy)  is approved to treat patients with TNBC that has spread to other parts of the body . Patients must have received at least two prior therapies before receiving the drug.
• Pembrolizumab (Keytruda)  is an immunotherapy drug that is approved to be used in combination with chemotherapy for patients with locally advanced or metastatic TNBC that has the PD-L1 protein. It may also be used before surgery (called neoadjuvant ) for patients with early-stage TNBC, regardless of their PD-L1 status.
• PARP inhibitors, which include olaparib (Lynparza) and talazoparib (Talzenna) , are approved to treat metastatic HER2-negative or triple-negative breast cancers in patients who have inherited a harmful BRCA gene mutation. Olaparib is also approved for use in certain patients with early-stage HER2-negative or triple-negative breast cancer. 
• Drugs that block the androgen receptors  or prevent androgen production are being tested in a subset of TNBC that express the androgen receptor.

For a complete list of drugs for breast cancer, see Drugs Approved for Breast Cancer .

NCI-Supported Breast Cancer Research Programs

Many NCI-funded researchers working at the NIH campus, as well as across the United States and world, are seeking ways to address breast cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some are more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in breast cancer.

TMIST is a randomized breast screening trial that compares two Food and Drug Administration (FDA)-approved types of digital mammography, standard digital mammography (2-D) with a newer technology called tomosynthesis mammography (3-D).

The  Breast Specialized Programs of Research Excellence (Breast SPOREs)  are designed to quickly move basic scientific findings into clinical settings. The Breast SPOREs support the development of new therapies and technologies, and studies to better understand tumor resistance, diagnosis, prognosis, screening, prevention, and treatment of breast cancer.

The NCI Cancer Intervention and Surveillance Modeling Network (CISNET) focuses on using modeling to improve our understanding of how prevention, early detection, screening, and treatment affect breast cancer outcomes.

The Confluence Project , from NCI's Division of Cancer Epidemiology and Genetics (DCEG) , is developing a research resource that includes data from thousands of breast cancer patients and controls of different races and ethnicities. This resource will be used to identify genes that are associated with breast cancer risk, prognosis, subtypes, response to treatment, and second breast cancers. (DCEG conducts other breast cancer research as well.)

The Black Women’s Health Study (BWHS) Breast Cancer Risk Calculator allows health professionals to estimate a woman’s risk of developing invasive breast cancer over the next 5 years. With the NCI-funded effort, researchers developed a tool to estimate the risk of breast cancer in US Black women. The team that developed the tool hopes it will help guide more personalized decisions on when Black women—especially younger women—should begin breast cancer screening. 

The goal of the Breast Cancer Surveillance Consortium (BCSC) , an NCI-funded program launched in 1994, is to enhance the understanding of breast cancer screening practices in the United States and their impact on the breast cancer's stage at diagnosis, survival rates, and mortality.

There are ongoing programs at NCI that support prevention and early detection research in different cancers, including breast cancer. Examples include:

• The  Cancer Biomarkers Research Group , which promotes research in cancer biomarkers and manages the Early Detection Research Network (EDRN) . EDRN is a network of NCI-funded institutions that are collaborating to discover and validate early detection biomarkers. Within the EDRN, the Breast and Gynecologic Cancers Collaborative Group conducts research on breast and ovarian cancers.
• NCI's Division of Cancer Prevention  houses the Breast and Gynecologic Cancer Research Group which conducts and fosters the development of research on the prevention and early detection of  breast and gynecologic cancers.

Breast Cancer Survivorship Research

NCI’s Office of Cancer Survivorship, part of the Division of Cancer Control and Population Sciences (DCCPS), supports research projects throughout the country that study many issues related to breast cancer survivorship. Examples of studies funded include the impact of cancer and its treatment on physical functioning, emotional well-being, cognitive impairment , sleep disturbances, and cardiovascular health. Other studies focus on financial impacts, the effects on caregivers, models of care for survivors, and issues such as racial disparities and communication.

Breast Cancer Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for breast cancer prevention , screening , and treatment . 

Breast Cancer Research Results

The following are some of our latest news articles on breast cancer research and study updates:

• How Breast Cancer Risk Assessment Tools Work
• Can Some People with Breast Cancer Safely Skip Lymph Node Radiation?
• Study Adds to Debate about Mammography in Older Women
• Pausing Long-Term Breast Cancer Therapy to Become Pregnant Appears to Be Safe
• A Safer, Better Treatment Option for Some Younger Women with Breast Cancer
• Shorter Course of Radiation Is Effective, Safe for Some with Early-Stage Breast Cancer

View the full list of Breast Cancer Research Results and Study Updates .

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Connected and supported: a scoping review of how online communities provide social support for breast cancer survivors

Affiliations.

• 1 VITAM - Centre for Sustainable Health Research, Integrated University Health and Social Services Center of Capitale-Nationale, Quebec City, QC, Canada. [email protected].
• 2 Evidence-Based Practice Center, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA.
• 3 Milken Institute School of Public Health, The George Washington University, Washington, DC, USA.
• 4 Knowledge and Evaluation Research (KER) Unit, Mayo Clinic, Rochester, MN, USA.
• 5 Department of English, University of Cincinnati, Cincinnati, OH, USA.
• 6 VITAM - Centre for Sustainable Health Research, Integrated University Health and Social Services Center of Capitale-Nationale, Quebec City, QC, Canada.
• 7 Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.
• 8 Universidad Peruana Cayetano Heredia, Lima, Peru.
• 9 Centre Hospitalier Universitaire de Québec-Université Laval Research Centre, Quebec City, QC, Canada.
• 10 Faculty of Nursing, Laval University, Quebec City, QC, Canada.
• 11 Department of Family and Emergency Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada.
• PMID: 39196462
• DOI: 10.1007/s11764-024-01660-w

Purpose: To (i) assess how and to what extent online communities are used among breast cancer survivors (BCS) as a source of social support, (ii) describe the kind of support BCS access through online communities, and (iii) explore how these communities foster social support for BCS that promotes well-being and reduces the challenges of survivorship.

Methods: We conducted a scoping review. A professional librarian performed a comprehensive search in multiple databases from January 2010 to May 2023. The review process adhered to the Johana Briggs Institute's method guidelines and the PRISMA-ScR reporting system.

Results: Fifteen studies were included. Participants used social media, cancer support communities, message boards, or websites for information and emotional support. Qualitative findings resulted in four themes: to reassure; to empower; to promote equity, diversity, and inclusion; and to demonstrate for BCS the drawbacks of online support.

Conclusions: We underscore that a variety of internet websites and social media platforms are valuable for and appreciated by BCS, especially as a source of social support and human connectedness. Our study raises the existing gap in cultural/ethnic representation in this field and shows that institutional and organizational efforts are needed to address gaps in information regarding access to social support for multiethnic BCS women.

Implications for cancer survivors: This data synthesis will empower the BCS community by sharing how they can strengthen and support their peers and community via their participation in online communities that connect and support cancer survivors in healthcare spaces.

Keywords: Breast cancer; Cancer survivors; Health promotion; Online communities; Social support.

© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

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• Luo G, Zhang Y, Etxeberria J, Arnold M, Cai X, Hao Y, Zou H. Projections of lung cancer incidence by 2035 in 40 countries worldwide: population-based study. JMIR Public Health Surveill. 2023;9(1):e43651. - PubMed - PMC - DOI
• CCSA. Committee, Canadian Cancer Statistics. Canadian Cancer Society web page 2019.
• Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, Jemal A, Kramer JL, Siegel RL. Cancer treatment and survivorship statistics, 2019. CA: A Cancer J Clin. 2019;69(5):363–85.
• Dafni U, Tsourti Z, Alatsathianos I. Breast cancer statistics in the European Union: incidence and survival across European countries. Breast Care (Basel). 2019;14(6):344–53. - PubMed - DOI
• Ganz PA, Stanton AL. Psychosocial and physical health in post-treatment and extended cancer survivorship. Clinical psycho-oncology: an international perspective. West Sussex: John Wiley & Sons; 2012; p. 237–47.

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• v.18(3); 2022 Jul

Update of the 100 Most Cited Articles on Breast Cancer: A Bibliometric Analysis

Ahmet necati Şanlı.

1 Department of General Surgery, Abdulkadir Yuksel State Hospital, Gaziantep, Turkey

The aim of this study was to perform a bibliometric analysis of the 100 most cited articles related to breast cancer.

Materials and Methods:

The research was done on the Web of Science (WOS) database. Only research articles were included in the study. Results were obtained by typing the term “breast cancer” in the WOS Search box. The results were sorted according to the number of WOS core citations and all database citations, the first author of the article, the institution of the first author, publication year, article category, and countries.

The most cited article had 10236 citations. Nearly three-quarters (70%) of the articles were from the USA and most articles were published by Harvard University. Thirty-seven percent of the articles were in the medicine, general and internal medicine categories.

Conclusion:

This bibliometric analysis identified the 100 most cited research articles about breast cancer and provided a record of historical developments and trends in breast cancer research.

• The result of this research about the 100 most cited articles on breast cancer may help to understand important studies on breast cancer and shed light on future studies.

Introduction

Breast cancer is the most prevalent cancer globally, as well as a leading cause of cancer-related death among women ( 1 ).  Substantial support for breast cancer awareness and research funding has helped created advances in the diagnosis and treatment of breast cancer ( 2 ). Early detection, a novel personalized approach to treatment, and a better knowledge of the disease have all contributed to an improvement in breast cancer survival rates and a steady decline in the number of deaths related with the disease ( 3 ). Current guidance on preventing and treating breast cancer, as well as what might cause it, has come mainly from information discovered from research studies ( 4 ). The most significant component of the methodological qualities of studies is associated with an increase in citations and a high impact factor of the journal in which it was published ( 5 ). To the best of our knowledge, there is only one early study that has performed a bibliometric analysis of the attributes of the 100 most cited articles about studies concerning breast cancer ( 6 ). The aim of this study was to evaluate the current status of the 100 most frequently cited articles.

Materials and Methods

A Web of Science (WOS) (Clarivate Analytics, Philadelphia, PA, United States) search was used to collect the information for this investigation. The journals indexed in the Science Citation Index Expanded (SCI-E) were included. There were no restrictions on the journals. Over 9200 of the world’s most influential publications from 178 scientific areas are now indexed in the Science Citation Index Expanded™. More than 53 million records and 1.18 billion cited references date from 1900 to the present ( 7 ).

Inclusion Criteria

The term “breast cancer” was typed into the search box of WOS basic research with the selection of all the years and the search was performed on 11.02.2022. The search produced 621,351 published articles between 1978 and 2022. As filters, English language, SCI-E scope and research article type were selected, resulting in a reduction to 376,105 articles. These were then ranked in order of citation frequency, from highest to lowest. The study was conducted by generating a shortlist of the top 100 cited publications from this search list, which were classified by journal, study category, country and location where the research was published, authors, and publication date.

Exclusion Criteria

Articles in indexes other than SCI-E, published in languages other than English, and other types of articles, such as reviews, meeting abstracts, letters, book chapters, etc., were excluded. Also, cancer statistics articles were excluded, despite receiving more citations than the included research articles.

Written informed consent was not necessary because no patient data was included in the study. The study complied with the Declaration of Helsinki.

Statistical Analysis

No inferential statistical analysis was undertaken. All the data is given in percentages, numbers and charts.

The articles included in the study are listed according to the total number of citations in the WOS database and in the all databases (WOS database, Arabic Citation Index, BIOSIS Citation Index, Chinese Science Citation Database, Data Citation Index, Russian Science Citation Index and SciELO Citation Index). According to our results, the most cited article was by Charles M. Perou and his colleagues, with 10,236 citations in the WOS database, and the least cited article was by Lisa A Carey and her colleagues, with 1,403 citations. Considering the number of publications, the most cited author was D.J. Slamon with 25,000 citations, followed by B. Fisher with 11,809 citations, T. Sorlie with 11,343 citations, Charles M. Perou with 10,236 citations, and N.K. Aaronson with 9247 citations ( Table 1 ). It was evident that all articles received more than 1000 citations and all were published between 1985 and 2021. Twelve of the most cited articles were published in 2007, and there was one publication each for 1987, 1992, 1993, 1995, 2000, 2018, and 2021 among the most cited articles ( Figure 1 ).

Distribution of the most cited articles by publication year

These most cited articles were published in 20, high-impact factor journals, with 24 articles published in the New England Journal of Medicine, 13 in Nature, 11 in the Journal of Clinical Oncology, and 11 in Science ( Table 2 ). Seventy of the studies originated from the United States of America (USA), 13 publications from the United Kingdom (UK), six from Italy and three from Canada ( Figure 2 ).

Countries from which publications originate

The articles were sourced from 51 different centers. The institution with the most publications was Harvard University with eight articles, followed by the University of Pittsburgh with six articles, the IRCCS European Institute of Oncology (IEO) with five articles, and the University of North Carolina with five articles, while 32 institutions had only one publication each ( Table 3 ).

According to WOS publication categories, 37% of the articles were in the field of medicine, general and internal medicine, medicine, research & experimental, cell biology; pathology and surgery were the least published categories in this list. In addition, when the categories we created according to the content of the articles were examined, most articles were on genetics and drug research (47% and 24%, respectively) ( Table 4 ).

Discussion and Conclusion

Citation analysis is used to find important papers on a certain subject. It aids in the analysis of scientific influence while also acknowledging substantial/pioneering contributions made by predecessors and noteworthy research advancement. There are numerous bibliometric article analyses conducted in various areas of medicine ( 8 , 9 , 10 , 11 ).  To the best of our knowledge, there is only one previous article about the 100 most cited articles concerning breast cancer, and it was published in 2017 ( 6 ). Since research areas can change due to advances in science and technology, we found that the total number of citations in this study, which we aimed to evaluate the current status of the 100 most frequently cited articles, reached 280,906, an increase of approximately 1.6 times compared to 2017. This result suggests that interest in quality publications on breast cancer has increased. Also, 41 of the articles in the list were found to have changed. The vast majority of articles on the list were on chemotherapy and genetic studies.

The number of citations may be related to the time since publication. As the publication time increases, the number of citations also increases. In our study, we observed that 12 articles from 2007 and 9 articles from 2005 entered the list ( Figure 1 ). However, many factors, such as the content of the article, its quality and the journal in which it was published, can affect the number of citations. Therefore, although it was published in 2021, the study by Xi Wang and his colleagues was the fourth most cited article ( 6 ).

As expected, the most cited articles were published in the medical journals with the highest impact factors. In the present study, most articles were published in the New England Journal of Medicine, followed by articles in Nature, the Journal of Clinical Oncology, and Science, respectively. The first three articles on the list were published in Nature, Science and the Journal of the National Cancer Institute, respectively. It is feasible to hypothesize that the audience of a general medical journal is particularly interested in the topic of breast cancer, or that authors of breast cancer research choose popular medical journals to reach more researchers and readers. One of the important points in the study was that 70% of the articles originated from the USA. Similar to our study, in the bibliographic studies in the literature, 70%–93% of the research articles were USA based ( 8 , 9 , 10 , 11 ). The fact that these quality studies originate from the USA can be explained by the large patient population and the presence of many well-funded cancer centers.

The first most cited article was “Molecular portraits of human breast tumours” written by Perou et al. ( 12 ) in 2000. In this study, in which they made a molecular portrait of breast cancer, they created a molecular subtype classification of breast cancer ( 12 ). Today, this molecular classification is still in use and therefore the topic of this article remains relevant.

The second most cited article was “Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene” written by  Slamon et al. ( 13 )  in 1987. In this study, they showed that the HER-2/neu oncogene may play a role in the biological behavior and pathogenesis of human breast cancer. Also, they found that amplification of the HER-2/neu gene is an important predictor of both overall survival and time to relapse in patients with breast cancer, and that the HER-2/neu oncogene plays a role in the biological behavior and pathogenesis of human breast cancer.

The third most cited article was “The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology” written by Aaronson et al. ( 14 ) in 1993. The EORTC QLQ-C30 questionnaire was developed as a reliable and valid measure of cancer patients’ quality of life in multicultural clinical research settings in this multicenter survey performed by the European Organization for Research and Treatment of Cancer.

The other most cited articles are in the fields of chemotherapy, gene expression, tumor genetics, pathology, and surgery. Research in these areas has made important contributions to the understanding of breast cancer. According to WOS categories, 91% of the articles were in the field of general internal medicine, multidisciplinary sciences was the second most common category, and cancer research came third. Surgery was one of the least-published fields. As the biological behavior and pathogenesis of breast cancer are better understood, studies on chemotherapy drugs have come to the fore. A possible reason for the increase in these types of studies is the increase in funding for drug research in the treatment of breast cancer. For this reason, research on surgery may have lagged behind.

Although citation analysis is a useful method that can provide insight into trends in the literature, it is not without flaws. Only the WOS database was used in this study. Thus, publications that may be indexed in other databases, such as Scopus and Google Scholar, were not included in the list of this study. Also, self-citations, lectures and textbooks were not evaluated. A search was made by typing only the term “breast cancer” in the WOS search box. Other terms that may be related to breast cancer, such as “breast, breast neoplasm, breast surgery, etc.,” were not searched. Another limitation was that the research area was examined according to the research categories determined by WOS. A more detailed investigation could not be made.

In conclusion, in this study, in which a bibliographic analysis of the 100 most cited articles in WOS on breast cancer was performed, it was observed that the number of citations increased by 1.6 times in the last 5 years. It was found that the most cited articles were published in high impact factor journals, especially the New England Journal of Medicine, most publications were from 2007, and the most cited articles were from the USA and Harvard University. Most studies focused on gene expression and chemotherapy. The result of this research may help to understand important studies on breast cancer and shed light on future studies.

Ethics Committee Approval: No ethical approval was obtained because this study did not involve a prospective evaluation, did not involve laboratory animals and only involved non-invasive procedures (e.g. faecal samples, voided urine etc).

Informed Consent: N/A

Peer-review: Externally peer-reviewed.

Financial Disclosure: The authors declared that this study received no financial support.

• Frontiers in Endocrinology
• Cancer Endocrinology
• Research Topics

Application of Nanomaterials in the Diagnosis and Treatment of Breast Cancer

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Breast cancer, the most prevalent malignancy among women globally, poses a significant threat to women's health. With over 2.3 million new cases and 670,000 deaths in 2022, advancements in treatment are urgently needed. Traditional therapies, including surgery, radiotherapy, and chemotherapy, have shown promise but face challenges due to tumor heterogeneity and drug resistance. Additionally, implant-related complications in breast reconstruction add to patient concerns. Thus, developing novel diagnostics and therapies is imperative. Nanomaterials, with their unique properties, offer potential solutions. They have demonstrated promise in breast cancer research, enhancing detection, diagnosis, and treatment. By conjugating with specific ligands/receptors, nanomaterials can improve diagnostic accuracy and enable molecular typing of breast cancer. Nanodelivery systems enhance drug targeting and stability, while nanotechnologies like phototherapy and hyperthermia provide new treatment strategies. Notably, several nanoplatforms have already been licensed for cancer therapy, with numerous others in clinical trials. However, challenges remain. Ensuring biocompatibility and safety, achieving precision targeting and smart drug release, designing multi-functional nanoplatforms, addressing production costs and clinical application, overcoming interdisciplinary research shortages, and realizing personalized treatment are urgent issues. Enhancing the performance of nanomaterials and deepening the understanding of nano-biology (tumor) are expected to drive the development of nanoscience and clinical medicine, thereby improving the current status of breast cancer diagnosis and treatment. The goal of this Research Topic is to explore the application of nanomaterials in breast cancer diagnosis and treatment, addressing key challenges such as biocompatibility, safety, precise targeting, drug loading and release efficiency, and clinical translation. By harnessing nanotechnology, we aim to develop innovative solutions that overcome these obstacles, ultimately achieving widespread and effective use of nanomaterials in breast cancer care. The current Research Topic will focus on the latest applications of nanomaterials in breast cancer diagnosis and treatment, exploring the underlying molecular mechanisms. This exploration aims to offer a fresh perspective on clinical advancements in breast cancer management and nanomaterials technology innovation. We welcome original research articles and comprehensive reviews on the following nanomaterials-related topics, among others: • Imaging Diagnosis of Breast Cancer • Detection of Breast Cancer Biomarkers • Breast Cancer Vaccines • Real-Time Navigation in Breast Cancer Surgery • Drug/Gene/Micromolecule Delivery Systems Targeting Breast Cancer • Postoperative Reconstruction for Breast Cancer.

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Breast Cancer Research and Treatment

Innovative Concepts

• © 2023
• Ouissam Al Jarroudi 0 ,
• Khalid El Bairi 1 ,
• Giuseppe Curigliano 2

Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco

You can also search for this editor in PubMed   Google Scholar

Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy

• Focuses on treatment options for breast cancer, such as radiotherapy, systemic therapy and immunotherapy
• Addresses ongoing research in screening, diagnosis and management for all subtypes of breast cancer
• Edited and authored by leading experts in the field

Part of the book series: Cancer Treatment and Research (CTAR, volume 188)

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About this book

• Breast Cancer Treatment
• Triple-negative Breast Cancer
• Tumor-infiltrating Lymphocytes
• Immune Checkpoint Inhibitors
• Screening programs for breast cancer
• Precision surgery for the treatment of breast cancer
• HER2- positive breast cancer
• Biomarkers in Breast Cancer
• Luminal B breast cancer
• Onco-immunology of breast cancer

Table of contents (14 chapters)

Front matter, antibody–drug conjugates: a new therapeutic approach for triple-negative breast cancer.

• Ouissam Al Jarroudi, Khalid El Bairi, Giuseppe Curigliano, Said Afqir

Immune-Checkpoint Inhibitors: A New Line of Attack in Triple-Negative Breast Cancer

Screening programs for breast cancer: toward individualized, risk-adapted strategies of early detection.

• Dario Trapani, Josè Sandoval, Pamela Trillo Aliaga, Liliana Ascione, Pier Paolo Maria Berton Giachetti, Giuseppe Curigliano et al.

Transversal Perspectives of Integrative Oncology Care in Gastric and Lobular Breast Cancer

• Emilio Francesco Giunta, Gianluca Arrichiello, Annalisa Pappalardo, Piera Federico, Angelica Petrillo

Assessment and Response to Neoadjuvant Treatments in Breast Cancer: Current Practice, Response Monitoring, Future Approaches and Perspectives

• Vincenzo Sabatino, Alma Pignata, Marvi Valentini, Carmen Fantò, Irene Leonardi, Michela Campora

Estimating the Benefit of Preoperative Systemic Therapy to Reduce the Extent of Breast Cancer Surgery: Current Standard and Future Directions

• Giacomo Montagna

A Precise Approach for Radiotherapy of Breast Cancer

• Samantha Sigurdson, Stephane Thibodeau, Martin Korzeniowski, Fabio Ynoe Moraes

Fast Mimicking Diets and Other Innovative Nutritional Interventions to Treat Patients with Breast Cancer

• Federica Giugliano, Laura Boldrini, Jacopo Uliano, Edoardo Crimini, Ida Minchella, Giuseppe Curigliano

Mechanisms of Endocrine Resistance in Hormone Receptor-Positive Breast Cancer

• Antonio Marra, Dario Trapani, Emanuela Ferraro, Giuseppe Curigliano

Innovative Therapeutic Approaches for Patients with HER2-Positive Breast Cancer

• Beatrice Taurelli Salimbeni, Emanuela Ferraro, Luca Boscolo Bielo, Giuseppe Curigliano

Breast Cancer Brain Metastases: Achilles’ Heel in Breast Cancer Patients’ Care

• Emanuela Ferraro, Andrew D. Seidman

New Concepts in Cardio-Oncology

• Paola Zagami, Eleonora Nicolò, Chiara Corti, Carmine Valenza, Giuseppe Curigliano

Next-Generation Sequencing for Advanced Breast Cancer: What the Way to Go?

• Dario Trapani, Edoardo Crimini, José Sandoval, Giuseppe Curigliano

The Global Landscape on the Access to Cancer Medicines for Breast Cancer: The ONCOLLEGE Experience

• Csongor György Lengyel, Baker Shalal Habeeb, Sara Cecilia Altuna, Dario Trapani, Shah Zeb Khan, Sadaqat Hussain

Editors and Affiliations

Ouissam Al Jarroudi, Khalid El Bairi

Giuseppe Curigliano

About the editors

Dr. Ouissam Al Jarroudi, MD, is a distinguished medical oncologist practicing in the medical oncology department at Mohammed VI University Hospital in Oujda, Morocco. She holds a position as a professor at the Faculty of Medicine and Pharmacy, affiliated with Mohammed Ist University. Dr. Al Jarroudi has pursued various fellowships at renowned institutions such as the Department of Medical Oncology at Paul Brousse Hospital, Assistance Publique - Hopitaux de Paris, and Léon Bérard Center in France.

Dr. Al Jarroudi's research is primarily focused on prognostic and predictive biomarkers in breast cancer and she is currently a member of the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO).

Khalid El Bairi is a clinical research fellow and an investigator in OVANORDEST studies. He is currently pursuing clinical and translational research in medical oncology. He has published many peer-reviewedarticles in the field of predictive and prognostic cancer biomarkers to improve survival outcomes in several WoS and Medline-indexed journals. His research focuses particularly on biomarkers for digestive and gynecological cancers such as ovarian and colorectal malignancies. He is currently a member of various international scientific societies such as the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), the European Society of Gynaecological Oncology (ESGO), and the American Association for Cancer Research (AACR). He is also an editor and reviewer for various journals and a guest editor for several special issues on emerging topics in gynecological cancers such as platinum-resistant ovarian cancer. He is also highly interested in teaching evidence-based medicine, clinical research methods, and publishing ethics to medical and PhD students and was selected for the 70th Lindau Nobel Laureate Meeting as a young scientist. He is also involved in “global oncology” initiatives through providing free training to young researchers across LMICs. He joined the ASCO Trainee & Early Career Advisory Group as a member for the 2022-2024 term and NCODA (National Community Oncology Dispensing Association, Inc.) as an advisory member of its International Executive Council in 2023.

Giuseppe Curigliano, MD PhD, is Associate Professor of Medical Oncology at the University of Milano and the Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy. He is a clinician and researcher specializing in early drug development for patients with solid tumors with a special commitment to breast cancer. He has been a member of the Italian National Health Council since 2018 and, in 2019, he served as Chair of the Scientific Committee of The Lega Nazionale Lotta ai Tumori. He has served as a Member of the ESMO Breast Cancer Faculty since 2001 and he is currently the Faculty Coordinator. He has alsoserved on the Scientific Committee for the St Gallen Conference since 2011 and was the Scientific Co-Chair in St Gallen 2017 and 2019. He has been an Editorial Board Member for Annals of Oncology since 2014, and serves as Co-Editor in Chief of The Breast, Co-Editor in Chief of Cancer Treatment Reviews, Associate Editor of the European Journal of Cancer, Editor of the Journal of Clinical Oncology. He also serves on the European School of Oncology (ESO) faculty committee.  

Bibliographic Information

Book Title : Breast Cancer Research and Treatment

Book Subtitle : Innovative Concepts

Editors : Ouissam Al Jarroudi, Khalid El Bairi, Giuseppe Curigliano

Series Title : Cancer Treatment and Research

DOI : https://doi.org/10.1007/978-3-031-33602-7

Publisher : Springer Cham

eBook Packages : Medicine , Medicine (R0)

Copyright Information : The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023

Hardcover ISBN : 978-3-031-33601-0 Published: 05 January 2024

Softcover ISBN : 978-3-031-33604-1 Due: 18 January 2025

eBook ISBN : 978-3-031-33602-7 Published: 04 January 2024

Series ISSN : 0927-3042

Series E-ISSN : 2509-8497

Edition Number : 1

Number of Pages : VIII, 368

Number of Illustrations : 5 b/w illustrations, 28 illustrations in colour

Topics : Oncology , Gynecology , Cancer Research

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Elle Macpherson’s breast cancer: when the media reports on celebrity cancer, are we really getting the whole story?

NHMRC Emerging Leader Research Fellow, University of Sydney

Senior Lecturer and Coordinator, Health and Medical Humanities, University of Sydney

Professor of Clinical Epidemiology, Sydney School of Public Health, University of Sydney

Disclosure statement

Brooke Nickel receives fellowship funding from the National Health and Medical Research Council (NHMRC). She is on the Scientific Committee of the Preventing Overdiagnosis Conference.

Katy Bell receives funding from the National Health and Medical Research Council (NHMRC). She is an Investigator for Wiser Healthcare, an Australian research collaboration that aims to promote better value care for all Australians https://www.wiserhealthcare.org.au/ .

Claire Hooker does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

University of Sydney provides funding as a member of The Conversation AU.

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Celebrity supermodel Elle Macpherson disclosed in an interview with The Australian Women’s Weekly earlier this week that seven years ago she was diagnosed with breast cancer.

Media coverage around the world said Macpherson had rejected some “conventional” treatments for the type of breast cancer she had disclosed, known as HER2-positive oestrogen receptive intraductal carcinoma.

This is not the first time we’ve seen powerful celebrity stories about cancer have the potential to influence the public health narrative. Sometimes these celebrity stories have changed cancer screening and treatment .

For instance, after singer Kylie Minogue announced her breast cancer diagnosis in 2005 there was an unprecedented increase in mammography bookings.

Actor Angelina Jolie’s op-ed in The New York Times in 2013 about her preventative double mastectomy for breast cancer may have inadvertently fuelled overtesting among women not at high risk.

And when actor Ben Stiller announced in 2016 that the prostate-specific antigen (PSA) test he had taken in his late 40s had saved his life, this was in contradiction to international screening guidelines . These recommend men under 55 do not use the PSA test because prostate cancer can often be overdiagnosed .

Should we be worried about the latest news?

Organisations, such as Breast Cancer Network Australia, have made public statements , worried that Macpherson’s comments might encourage an approach to treating invasive breast cancers that includes the use of non-evidence-based “wellness” products and interventions.

But media coverage of Macpherson’s situation has largely missed a key piece of information: her breast cancer is not invasive.

The type she disclosed is commonly known as ductal carcinoma in situ or DCIS . This is a cluster of pre-invasive or non-invasive breast cancer cells. It differs from invasive breast cancer in that the lesions are contained and have not spread. This means that treatments for invasive and non-invasive breast cancer differ .

In fact, Macpherson appears to have followed recommended treatment for her cancer. She did have surgery, a lumpectomy to remove the DCIS. Guidelines recommend patients weigh up the possible benefits and risks of the additional treatments that Macpherson said her doctor offered: mastectomy surgery, radiation, chemotherapy, and hormone therapy. Together with their treating team, each patient may decide whether any of these additional treatments are right for their individual situation.

There are ongoing research trials looking into who is most likely to benefit from these additional treatments, and who might not need them at all. Therefore, Macpherson’s decision to decline the additional treatments may have been both a reasonable and a conventional decision for a woman with non-invasive breast cancer.

This missing information from the media is also a missed opportunity to discuss less invasive options for the management of DCIS.

The rate of DCIS has increased greatly since the introduction of breast cancer screening. You can detect it on a mammogram but it rarely causes symptoms. Many of these lesions are unlikely to ever cause a problem in a woman’s lifetime. As a result of this some cases of DCIS are considered to be over-diagnosed .

Now options such as active surveillance (closely monitoring but not providing treatment unless the condition progresses) are considered reasonable and are being robustly evaluated in research trials to help reduce overtreatment.

We need to be wary of simplistic narratives about celebrity cancer journeys that don’t necessarily tell the whole story. This should also include scepticism over “wellness” narratives as these can lead to non-evidence-based treatment choices that waste consumers’ money and may cause them harm.

We all need to get better at being appropriately sceptical about health information without losing trust in proven health interventions.

I’m worried about my breast cancer. What should I do?

A breast cancer diagnosis can create a flood of different emotions, and presents a woman with many uncertainties including the effectiveness of treatments, and about their potential side effects and long-term impacts.

Women can ask their health professionals questions about possible management options, including:

what are my options? One of these options might be to choose less treatment, including an active surveillance approach for low-risk DCIS

what are the possible benefits and harms of those options?

how likely are each of those benefits and harms to happen to me?

The Conversation approached Elle Macpherson’s spokesperson to clarify details about her diagnosis and treatment but did not receive a response before publication.

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• Triple Negative Breast Cancer

Double trouble for triple-negative breast cancer

A team of MUSC Hollings Cancer Center researchers has discovered one way in which triple-negative breast cancer (TNBC) cells become resistant to immunotherapy and have tested a two-pronged treatment strategy that was able to restore sensitivity to immunotherapy in a preclinical model. The team, led by Besim Ogretmen, Ph.D. , SmartState Endowed Chair in Lipidomics and Drug Discovery at MUSC, reports its findings in Cell Reports.

TNBC accounts for 10% to 20% of all breast cancer cases and is highly aggressive, with five-year survival rates markedly lower than for other breast cancers. It is twice as likely to occur in women under 40 than those older than 50 and is more common in Black women. TNBC is often diagnosed late, even after it has metastasized, making it difficult to treat.

TNBC earns its “triple-negative” moniker because patients with the disease already have three strikes against them. Because TNBC cells lack two necessary receptors, hormone-based therapies, a mainstay of breast cancer treatments, won’t work. Neither will therapies that specifically target the protein HER2, as patients with TNBC lack it or have only very low levels. These three strikes leave patients with TNBC, particularly metastatic TNBC, with few treatment options.

“There's not a magic bullet target for triple-negative breast cancer,” said Wyatt Wofford, an M.D., Ph.D. candidate in the Ogretmen Lab at MUSC and lead author of the Cell Reports article. “Typically, response rates for TNBC are around 15% to 20%, and so that leaves about 80% of your patients who have metastatic TNBC with no good option for therapy.”

"Use of immunotherapy by itself or the metastatic pathway inhibitor by itself did almost nothing. The cancer cells just weren’t listening. And then, when you combined these two together, there was a really pronounced response. The tumors stopped growing and even started to regress.” -- Wyatt Wofford

In recent years, immunotherapy has proved to be a breakthrough therapy for many blood cancers but has had limited success in solid tumors like TNBC. The checkpoint inhibitor pembrolizumab has been approved for recurrent TNBC for patients with at least 10% of their tumor cells expressing the immunosuppressive protein PD-L1. PD-L1 on the surface of cancer cells binds with PD-1 on the surface of immune cells known as T-cells, preventing them from do

The Ogretmen Lab studies sphingolipids, which are fat molecules that provide rigidity and stability to the cell membrane. One of the sphingolipids is ceramide. Enzymes synthesize a variety of ceramides, each with a different fatty acid chain length and a different role in cancer development and progression.

One of those enzymes, ceramide synthase 4 (CERS4), created ceramides that were important to maintaining membrane stability.

“The ceramide that this enzyme generates seems to be important to keep the tumor cell membrane intact so that everything stays where it needs to be,” said Ogretmen. “When you lose this ceramide, the PD-L1 protein doesn’t stay on the surface of the cells.”

In their study, Ogretmen and Wofford found that when levels of that enzyme dropped and not enough of the ceramides it produced were available, the membrane became unstable, enabling PD-LI to drop down inside the tumor cell.

There, hidden inside the cell, PD-L1 was not exposed to the immunotherapeutic agent as it was while on the surface. With this finding, Ogretmen and Wofford identified a mechanism by which TNBC becomes resistant to immunotherapy. They also showed that the internalized PD-L1 could promote cellular pathways linked to metastasis.

The MUSC team next wanted to know whether they could make the tumor cells once again vulnerable to immunotherapy. The researchers treated a mouse model of TNBC lacking the enzyme CERS4 with both a PD-L1 inhibitor and an existing anti-cancer drug that blocks one of the metastatic cellular pathways promoted by the internalized PD-L1.

“In this study, we were looking not only to study how TNBC becomes more resistant to immunotherapy but to use what we learned to make these cancer cells more responsive to immunotherapy." -- Dr. Besim Ogretmen

Before treatment, the mice uniformly developed lung metastases. However, after treatment, the cell membrane of the tumor regained its stability, and PD-L1 remained on the surface of the cell where it was exposed to immunotherapy and unable to promote tumor growth and metastasis.

Ogretmen and Wofford turned to Ozgur Sahin Ph.D. , SmartState Endowed Chair in the Department of Biochemistry and Molecular Biology, to do the drug studies. Wofford still remembers how excited he was when he first saw the results of these studies.

“When we looked at how the tumors were growing over time, use of immunotherapy by itself or the metastatic pathway inhibitor by itself did almost nothing. It was almost like you were giving the cancer cells water – they just weren’t listening,” he said. “And then, when you combined these two together,  there was a really pronounced response. The tumors stopped growing and even started to regress.”

For Ogretmen, the discovery of a biological mechanism for resistance in TNBC, although interesting in itself, is exciting largely because it will allow researchers to manipulate that mechanism to restore sensitivity to treatment.

“In this study, we were looking not only to study how TNBC becomes more resistant to immunotherapy but to use what we learned to make these cancer cells more responsive to immunotherapy,” he said.

Currently, it is not feasible to move forward to the clinic with the pathway inhibitor tested in the study. The team’s next steps are to identify other compounds, ideally existing, approved drugs that act on the same metastatic pathway and that could be used in a combination therapy with a PD-L1 inhibitor in patients with TNBC.

“We have some new leads and exciting results,” said Ogretmen. “We are making progress at finding more viable combinations that we can actually take into the clinic.”

Wofford W, Kim J, Kim D, Janneh AH, Lee HG, Atilgan FC, Oleinik N, Kassir MF, Saatci O, Chakraborty P, Tokat UM, Gencer S, Howley B, Howe P, Mehrotra S, Sahin O, Ogretmen B. Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response. Cell Rep. 2024 Aug 27;43(8):114532. doi: 10.1016/j.celrep.2024.114532.

About the Author

Kimberly McGhee

Categories: Cancer , Research , Innovation