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Estrogen Receptor-Positive (ER+) Breast Cancers

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 31087

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Special Issue Editors

Prof. Dr. Christos Papadimitriou

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Guest Editor

Second Department of Surgery, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
Interests: early breast cancer; adjuvant chemotherapy; chemotherapy for metastatic breast cancer; clinical trials; mTOR inhibitors; CDK4/6 inhibitors; endocrine therapy
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Dimitrios Mavroudis

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Head, Department of Medical Oncology, University of Crete Medical School, Heraklion, Greece
Interests: biology of early breast cancer; clinical trials; circulating tumor cells; adjuvant chemotherapy; chemotherapy for metastatic breast cancer; endocrine resistance; mTOR inhibitors; CDK4/6 inhibitors
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Nicholas Pavlidis

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Emeritus Professor, University of Ioannina, Greece and Dean, European School of Oncology College, Greece
Interests: breast cancer; cancer of unknown primary; cancer and pregnancy; cancer education

Special Issue Information

Dear Colleagues,

The majority of breast cancers express estrogen and/or progesterone receptors (ER and PR). ER is the primary transcription factor driving oncogenesis in hormone receptor-positive (HR+) breast cancer; it is both the predictor and the target of response to antiestrogen therapy. In tumors without concomitant HER2 amplification, endocrine therapy, aimed at the therapeutic blockade of ER signaling, forms the backbone of treatment for all disease stages; adjuvant endocrine therapy alone reduces the relative risk of recurrence by nearly 40%. Endocrine therapies include aromatase inhibitors (AIs), gonadotropin-releasing hormone (GnRH) agonists, selective ER modulators (SERMs), and selective ER downregulators (SERDs). Despite its wide therapeutic efficacy, endocrine therapy eventually fails in the majority of patients with metastatic and in a proportion of patients with ER+, HER2- early breast cancer who develop endocrine resistance, resulting in disease recurrence. A number of resistance mechanisms can lead to estrogen-independent growth of HR+ breast cancer as a result of genetic and epigenetic alterations, which could be exploited as novel therapeutic targets. This Special Issue focuses on the biology of ER and the implications of ESR1 mutations in HR+ breast cancer, the role of neoadjuvant therapy, the use of multigene assays to select treatment for early disease, the optimal management of premenopausal patients with ER+ breast cancer, the role of extended adjuvant endocrine therapy, the molecular mechanisms mediating endocrine resistance emphasizing the prominent role of the PI3K/Akt/mTOR and CDK4/6/retinoblastoma protein pathways in cancer cell growth and survival, the molecularly targeted agents to overcome or delay endocrine resistance, and potential predictive biomarkers for accurate patient stratification.

Prof. Dr. Christos Papadimitriou
Prof. Dr. Dimitrios Mavroudis
Prof. Dr. Nicholas Pavlidis
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ER+ and/or PR+ breast cancer
endocrine therapy
neoadjuvant therapy
adjuvant chemotherapy
gene expression assays
chemotherapy for metastatic breast cancer
endocrine resistance
mTOR inhibitors
CDK4/6 inhibitors
PI3K inhibitors
AKT inhibitors

Published Papers (9 papers)

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Research

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13 pages, 1882 KiB

Open AccessArticle

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

by Paraskevi Apostolou, Vasiliki Dellatola, Christos Papadimitriou, Despoina Kalfakakou, Elena Fountzilas, Eleni Faliakou, Georgios Fountzilas, Ourania Romanidou, Irene Konstantopoulou and Florentia Fostira

Cancers 2021, 13(9), 2106; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092106 - 27 Apr 2021

Cited by 5 | Viewed by 3092

Abstract

CHEK2 germline pathogenic variants predispose to breast cancer and possibly to other malignancies, with their spectrum and frequency being variable among populations. Τhe majority of CHEK2-associated breast tumors are hormone receptor positive; however, relevant clinical outcomes are not well defined. Herein, we illustrate the histopathological characteristics and clinical outcomes of 52 Greek breast cancer patients who are CHEK2 carriers. Genetic analysis was performed by Sanger/massively parallel sequencing, followed by MLPA. Subsequent haplotype analysis investigated possible founder effects. Blood relatives were offered cascade testing. CHEK2 variant spectrum was characterized by variability, while influenced by founder effects. The majority of carriers, i.e., 60.8%, were diagnosed with breast cancer before the age of 45. Notably, 91.5% of breast tumors were hormone receptor positive. Hormone therapy and mastectomy at diagnosis seem to have a positive trend on overall survival, after a median follow-up of 9.5 years. Remarkably, 41.9% of patients underwent risk-reducing surgery, one third of which involved salpingo-oophorectomy. Nearly half of families responded to cascade testing. Our data highlight the need for guideline-adherent choices, based on the evidence that CHEK2 carriers are at moderate risk for breast cancer and no risk for ovarian cancer, while underscore the possible role of chemoprevention with tamoxifen. Full article

(This article belongs to the Special Issue Estrogen Receptor-Positive (ER+) Breast Cancers)

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20 pages, 3665 KiB

Open AccessArticle

Amongst Women Stratified to Receive Endocrine Therapy on the Basis of Their Tumor Estrogen and Progesterone Receptor Levels, Those with Higher Tumor Progesterone Receptor Levels Had a Better Outcome Than Those with Lower Levels of Tumor Progesterone Receptor

by Tai-Han Lin, Hong-Wei Gao, Guo-Shiou Liao, Jyh-Cherng Yu, Ming-Shen Dai, Jar-Yi Ho and Cheng-Ping Yu

Cancers 2021, 13(4), 905; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040905 - 21 Feb 2021

Cited by 5 | Viewed by 2290

Abstract

Background: To realize the association between stratified expression levels of ER and PgR and long-term prognosis of breast cancer patients who received adjuvant hormone therapy, this study aimed to propose better prognostic cut-off levels for estrogen receptor (ER) and progesterone receptor (PgR). Methods: Patients who received adjuvant hormone therapy after surgical intervention were selected. The ER and PgR status and their effects on breast cancer-specific survival (BCSS) and disease-free survival (DFS) over 5 and 10 years were evaluated. Next, subgroups were generated based on ER and PgR expression percentage and Allred scores. Survival curves were constructed using the Kaplan–Meier method. Results: ER and PgR expression were significantly associated with better prognosis in 5 years, whereas only PgR expression was significantly associated during the 10-year follow-up. The optimal cut-off values for better 5-year BCSS were ER > 50%; ER Allred score > 7; PgR ≥ 1%; or PgR Allred score ≥ 3; the corresponding values for DFS were ER > 40%; ER Allred score > 6; PgR > 10%; or PgR Allred score ≥ 3. In the long-term follow-up, PgR of > 50% or Allred score of > 5 carriers revealed a better prognosis of both BCSS and DFS. Conclusion: Patients with a PgR expression > 50% or an Allred score > 5 exhibited better 10-year BCSS and DFS. Full article

(This article belongs to the Special Issue Estrogen Receptor-Positive (ER+) Breast Cancers)

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14 pages, 858 KiB

Open AccessArticle

Development of a Prognostic Tool to Guide the Decision to Extend Adjuvant Aromatase Inhibitors for up to Ten Years in Postmenopausal Early Breast Cancer Patients

by Camille Moreau-Bachelard, Loïc Campion, Marie Robert, Olivier Kerdraon, Céline Renaudeau, Maud Aumont, Jean-Marc Classe, Mario Campone and Jean-Sébastien Frénel

Cancers 2020, 12(12), 3725; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123725 - 11 Dec 2020

Cited by 3 | Viewed by 1592

Abstract

Background: The selection of women with hormone receptor-positive (HR+) early breast cancer (EBC) at high risk of relapse after five years (yrs.) of adjuvant aromatase inhibitors (AIs) is crucial, as the benefit of extending AIs is counterbalanced by toxicity. We developed a clinicopathological tool to estimate the residual risk of relapse after five years of adjuvant AIs. Methods: The Institut de Cancérologie de l’Ouest (ICO) database was used to determine a prognostic score of post-five-year AI relapse. Cox regression models estimated our score’s prognostic performance. Results: In total, 1105 women were included. Median follow-up was 44 months (IQR = 21–70) post-AI treatment. From the Cox models, we designed a dichotomous prognostic score including the number of macrometastases, age (>70 yrs. vs. ≤70 yrs.), tumor size (≥T2 vs. not), and mitotic activity (≥2 vs. not). Overall, 77.5% of patients were classified as being at low risk and 22.5% at high risk of late recurrence. Low-risk patients had a five- to ten-year local or distant recurrence risk of 7.6% (95% CI, 5.4% to 10.6%) as compared with 26.9% (95% CI, 19.9% to 35.7%) for the high-risk roup. Conclusion: In this study, we developed a simple tool to identify women at high risk of relapse despite completing five years of AIs. Full article

(This article belongs to the Special Issue Estrogen Receptor-Positive (ER+) Breast Cancers)

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17 pages, 4290 KiB

Open AccessArticle

Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence

by Kamal Pandey, Nahee Park, Kyung-Soon Park, Jin Hur, Yong Bin Cho, Minsil Kang, Hee-Jung An, Sewha Kim, Sohyun Hwang and Yong Wha Moon

Cancers 2020, 12(12), 3566; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123566 - 29 Nov 2020

Cited by 62 | Viewed by 6980

Abstract

Breast cancer represents the number one global cancer burden in women and the hormone receptor (HR)-positive subtype comprises approximately 70% of breast cancers. Unfortunately, acquired resistance ultimately occurs in almost all cases, even though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a highly effective therapy for HR-positive/human epidermal growth factor receptor 2-negative subtype. Here, we investigated mechanisms of resistance to CDK4/6 inhibitor and potential therapeutic strategies using our palbociclib-resistant preclinical model. We observed that cyclin E was significantly overexpressed in palbociclib-resistant cells, and similar association was also confirmed in pleural effusion samples collected from HR-positive breast cancer patients. After confirmation of cyclin E-CDK2 interaction by co-immunoprecipitation, we demonstrated CDK2 inhibition combined with palbociclib synergistically suppressed proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice. We also proved that enhancing C-MYC-mediated senescence is a novel mechanism behind the synergism created by targeting both CDK2 and CDK4/6. Furthermore, the clinical relevance of cyclin E as a therapeutic target was supported by significant association between CCNE1 overexpression and poor prognosis based on large-scale public gene expression data sets in HR-positive breast cancer patients. Therefore, we propose cyclin E-CDK2 signaling as a promising therapeutic target for overcoming cyclin E-associated resistance to CDK4/6 inhibitor. Full article

(This article belongs to the Special Issue Estrogen Receptor-Positive (ER+) Breast Cancers)

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16 pages, 2514 KiB

Open AccessArticle

Degree of Early Estrogen Response Predict Survival after Endocrine Therapy in Primary and Metastatic ER-Positive Breast Cancer

by Masanori Oshi, Yoshihisa Tokumaru, Fernando A. Angarita, Li Yan, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe

Cancers 2020, 12(12), 3557; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123557 - 28 Nov 2020

Cited by 41 | Viewed by 3303

Abstract

Endocrine therapy is the gold-standard treatment for ER-positive/HER2-negative breast cancer. Although its clear benefit, patient compliance is poor (50–80%) due to its long administration period and adverse effects. Therefore, a predictive biomarker that can predict whether endocrine therapy is truly beneficial may improve patient compliance. In this study, we use estrogen response early gene sets of gene set enrichment assay algorithm as the score. We hypothesize that the score could predict the response to endocrine therapy and survival of breast cancer patients. A total of 6549 breast cancer from multiple patient cohorts were analyzed. The score was highest in ER-positive/HER2-negative compared to the other subtypes. Earlier AJCC stage, as well as lower Nottingham pathological grade, were associated with a high score. Low score tumors enriched only allograft rejection gene set, and was significantly infiltrated with immune cells, and high cytolytic activity score. A low score was significantly associated with a worse response to endocrine therapy and worse survival in both primary and metastatic breast cancer patients. The hazard ratio was double that of ESR1 expression. In conclusion, the estrogen response early score predicts response to endocrine therapy and is associated with survival in primary and metastatic breast cancer. Full article

(This article belongs to the Special Issue Estrogen Receptor-Positive (ER+) Breast Cancers)

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12 pages, 2009 KiB

Open AccessArticle

Early Changes of the Standardized Uptake Values (SUV_max) Predict the Efficacy of Everolimus-Exemestane in Patients with Hormone Receptor-Positive Metastatic Breast Cancer

by Marianna Sirico, Ottavia Bernocchi, Navid Sobhani, Fabiola Giudici, Silvia P. Corona, Claudio Vernieri, Federico Nichetti, Maria Rosa Cappelletti, Manuela Milani, Carla Strina, Valeria Cervoni, Giuseppina Barbieri, Nicoletta Ziglioli, Martina Dester, Giulia Valeria Bianchi, Filippo De Braud and Daniele Generali

Cancers 2020, 12(11), 3314; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113314 - 10 Nov 2020

Cited by 6 | Viewed by 2249

Abstract

Background: The mTORC1 inhibitor everolimus has been approved in combination with the aromatase inhibitor exemestane for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (HR+ mBC) progressing on prior therapy with a non-steroidal aromatase inhibitor. To date, no predictive biomarkers of tumor sensitivity/resistance for everolimus-based treatments have been identified. We hypothesized that precocious changes in the Standardized Uptake Volume (∆SUV%), as assessed by ¹⁸F-Fluorodeoxyglucosepositron-emission tomography (¹⁸F-FDG PET/CT), may be a marker of everolimus efficacy. Methods: This was a retrospective study including 31 HR+ HER2- patients treated with everolimus and exemestane in two Italian centers between 2013 and 2018. The objective of the study was to investigate ∆SUV% as a predictive marker of everolimus antitumor efficacy. ¹⁸F-FDG PET/CT scans were performed at baseline and after three months of treatment. Patients were defined as long responders (LRs) if disease progression occurred at least 10 months after treatment initiation and long survivors (LSs) if death occurred later than 36 months after starting therapy. ROC analysis was used to determine the optimal cut-off values of ∆SUV% to distinguish LRs from non-LRs and LSs from non-LSs. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier method. Results: The SUVmax values decreased significantly from baseline to 3 months after therapy (p = 0.003). Dynamic changes of SUVmax (Delta SUV) had a higher accuracy in discriminating long-responders from non-long-responders (AUC = 0.67, Delta SUV cut-off = 28.8%) respects to its ability to identify long survivors from no-long survivors (AUC = 0.60, Delta SUV cut-off = 53.8%). Patients were divided into groups according to the Delta SUV cut-offs and survival outcomes were evaluated: patients with a decrease of ∆SUV% ≥ 28.8% had significantly better PFS (10 months-PFS: 63.2%, 95% CI: 37.9–80.4% and 16.7%, 95% CI: 2.7–41.3% respectively, p = 0.005). As regard as OS, patients with ∆SUV% ≥ 53.8% had longer OS when compared to patients with ∆SUV% < 53.8% (36 month-OS: 82.5% vs. 45.9% vs. p = 0.048). Conclusion: We found two precocious ∆SUV% thresholds capable of identifying HR+ HER2-mBC patients, which would achieve long-term benefit or long-term survival during everolimus-exemestane therapy. These results warrant further validation in prospective studies and should be integrated with molecular biomarkers related to tumor metabolism and mTORC1 signaling. Full article

(This article belongs to the Special Issue Estrogen Receptor-Positive (ER+) Breast Cancers)

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Review

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22 pages, 1748 KiB

Open AccessReview

From Micro to Long: Non-Coding RNAs in Tamoxifen Resistance of Breast Cancer Cells

by Jéssica Fernanda Barazetti, Tayana Shultz Jucoski, Tamyres Mingorance Carvalho, Rafaela Nasser Veiga, Ana Flávia Kohler, Jumanah Baig, Hend Al Bizri, Daniela Fiori Gradia, Sylvie Mader and Jaqueline Carvalho de Oliveira

Cancers 2021, 13(15), 3688; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153688 - 22 Jul 2021

Cited by 11 | Viewed by 4051

Abstract

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality among women. Two thirds of patients are classified as hormone receptor positive, based on expression of estrogen receptor alpha (ERα), the main driver of breast cancer cell proliferation, and/or progesterone receptor, which is regulated by ERα. Despite presenting the best prognosis, these tumors can recur when patients acquire resistance to treatment by aromatase inhibitors or antiestrogen such as tamoxifen (Tam). The mechanisms that are involved in Tam resistance are complex and involve multiple signaling pathways. Recently, roles for microRNAs and lncRNAs in controlling ER expression and/or tamoxifen action have been described, but the underlying mechanisms are still little explored. In this review, we will discuss the current state of knowledge on the roles of microRNAs and lncRNAs in the main mechanisms of tamoxifen resistance in hormone receptor positive breast cancer. In the future, this knowledge can be used to identify patients at a greater risk of relapse due to the expression patterns of ncRNAs that impact response to Tam, in order to guide their treatment more efficiently and possibly to design therapeutic strategies to bypass mechanisms of resistance. Full article

(This article belongs to the Special Issue Estrogen Receptor-Positive (ER+) Breast Cancers)

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Graphical abstract

20 pages, 1947 KiB

Open AccessReview

A Tale of Ice and Fire: The Dual Role for 17β-Estradiol in Balancing DNA Damage and Genome Integrity

by Sara Pescatori, Francesco Berardinelli, Jacopo Albanesi, Paolo Ascenzi, Maria Marino, Antonio Antoccia, Alessandra di Masi and Filippo Acconcia

Cancers 2021, 13(7), 1583; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071583 - 30 Mar 2021

Cited by 18 | Viewed by 3268

Abstract

17β-estradiol (E2) regulates human physiology both in females and in males. At the same time, E2 acts as a genotoxic substance as it could induce DNA damages, causing the initiation of cellular transformation. Indeed, increased E2 plasma levels are a risk factor for the development of several types of cancers including breast cancer. This paradoxical identity of E2 undermines the foundations of the physiological definition of “hormone” as E2 works both as a homeostatic regulator of body functions and as a genotoxic compound. Here, (i) the molecular circuitries underlying this double face of E2 are reviewed, and (ii) a possible framework to reconcile the intrinsic discrepancies of the E2 function is reported. Indeed, E2 is a regulator of the DNA damage response, which this hormone exploits to calibrate its genotoxicity with its physiological effects. Accordingly, the genes required to maintain genome integrity belong to the E2-controlled cellular signaling network and are essential for the appearance of the E2-induced cellular effects. This concept requires an “upgrade” to the vision of E2 as a “genotoxic hormone”, which balances physiological and detrimental pathways to guarantee human body homeostasis. Deregulation of this equilibrium between cellular pathways would determine the E2 pathological effects. Full article

(This article belongs to the Special Issue Estrogen Receptor-Positive (ER+) Breast Cancers)

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14 pages, 1403 KiB

Open AccessReview

The Emerging Role of Extracellular Vesicles in Endocrine Resistant Breast Cancer

by Giusi La Camera, Luca Gelsomino, Amanda Caruso, Salvatore Panza, Ines Barone, Daniela Bonofiglio, Sebastiano Andò, Cinzia Giordano and Stefania Catalano

Cancers 2021, 13(5), 1160; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13051160 - 08 Mar 2021

Cited by 10 | Viewed by 2566

Abstract

Breast cancer is the most common solid malignancy diagnosed in females worldwide, and approximately 70% of these tumors express estrogen receptor α (ERα), the main biomarker of endocrine therapy. Unfortunately, despite the use of long-term anti-hormone adjuvant treatment, which has significantly reduced patient mortality, resistance to the endocrine treatments often develops, leading to disease recurrence and limiting clinical benefits. Emerging evidence indicates that extracellular vesicles (EVs), nanosized particles that are released by all cell types and responsible for local and systemic intercellular communications, might represent a newly identified mechanism underlying endocrine resistance. Unraveling the role of EVs, released by transformed cells during the tumor evolution under endocrine therapy, is still an open question in the cancer research area and the molecular mechanisms involved should be better defined to discover alternative therapeutic approaches to overcome resistance. In this review, we will provide an overview of recent findings on the involvement of EVs in sustaining hormonal resistance in breast cancer and discuss opportunities for their potential use as biomarkers to monitor the therapeutic response and disease progression. Full article

(This article belongs to the Special Issue Estrogen Receptor-Positive (ER+) Breast Cancers)

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