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11 pages, 1674 KiB

Open AccessArticle

Prognostic Capability of TNBC 3-Gene Score among Triple-Negative Breast Cancer Subtypes

by Jhajaira M. Araujo, Gabriel De la Cruz-Ku, Melanie Cornejo, Franco Doimi, Richard Dyer, Henry L. Gomez and Joseph A. Pinto

Cancers 2022, 14(17), 4286; https://doi.org/10.3390/cancers14174286 - 1 Sep 2022

Cited by 3 | Viewed by 2500

Abstract

Background: Triple-negative breast cancer (TNBC) is a complex and molecularly heterogeneous entity, with the poorest outcome compared with other breast cancer subtypes. Previously, we developed a TNBC 3-gene score with a significant prognostic capability. This study aims to test the 3-gene score in [...] Read more.

Background: Triple-negative breast cancer (TNBC) is a complex and molecularly heterogeneous entity, with the poorest outcome compared with other breast cancer subtypes. Previously, we developed a TNBC 3-gene score with a significant prognostic capability. This study aims to test the 3-gene score in the different TNBC subtypes. Methods: Data from 204 TNBC patients treated with neoadjuvant chemotherapy were retrieved from public datasets and pooled (GSE25066, GSE58812, and GSE16446). After removing batch effects, cases were classified into Lehman’s TNBC subtypes and then the TNBC 3-gene score was used to evaluate the risk of distant recurrence in each subgroup. In addition, the association with tumor-infiltrating lymphocyte (TILs) levels was evaluated in a retrospective group of 72 TNBC cases. Results: The TNBC 3-gene score was able to discriminate patients with different risks within the pooled cohort (HR = 2.41 for high vs. low risk; 95%CI: 1.50–3.86). The score showed predictive capability in the immunomodulatory subtype (HR = 4.16; 95%CI: 1.63–10.60) and in the mesenchymal stem-like subtype (HR = 18.76; 95%CI: 1.68–208.97). In the basal-like 1, basal-like-2, and mesenchymal subtypes, the observed differential risk patterns showed no statistical significance. The score had poor predictive capability in the luminal androgen receptor subtype (p = 0.765). In addition, a low TNBC 3-gene score was related to a high level of TIL infiltration (p < 0.001). Conclusions: The TNBC 3-gene score is able to predict the risk of distant recurrence in TNBC patients, specifically in the immunomodulatory and mesenchymal stem-like subtype. Despite a small sample size in each subgroup, an improved prognostic capability was seen in TNBC subtypes with tumor-infiltrating components. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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16 pages, 2520 KiB

Open AccessArticle

How Reliable Are Gene Expression-Based and Immunohistochemical Biomarkers Assessed on a Core-Needle Biopsy? A Study of Paired Core-Needle Biopsies and Surgical Specimens in Early Breast Cancer

by Hani Saghir, Srinivas Veerla, Martin Malmberg, Lisa Rydén, Anna Ehinger, Lao H. Saal, Johan Vallon-Christersson, Åke Borg, Cecilia Hegardt, Christer Larsson, Alaa Haidar, Ingrid Hedenfalk, Niklas Loman and Siker Kimbung

Cancers 2022, 14(16), 4000; https://doi.org/10.3390/cancers14164000 - 18 Aug 2022

Cited by 4 | Viewed by 2588

Abstract

In early breast cancer, a preoperative core-needle biopsy (CNB) is vital to confirm the malignancy of suspected lesions and for assessing the expression of treatment predictive and prognostic biomarkers in the tumor to choose the optimal treatments, emphasizing the importance of obtaining reliable [...] Read more.

In early breast cancer, a preoperative core-needle biopsy (CNB) is vital to confirm the malignancy of suspected lesions and for assessing the expression of treatment predictive and prognostic biomarkers in the tumor to choose the optimal treatments, emphasizing the importance of obtaining reliable results when biomarker status is assessed on a CNB specimen. This study aims to determine the concordance between biomarker status assessed as part of clinical workup on a CNB compared to a medically untreated surgical specimen. Paired CNB and surgical specimens from 259 patients that were part of the SCAN-B cohort were studied. The concordance between immunohistochemical (IHC) and gene expression (GEX) based biomarker status was investigated. Biomarkers of interest included estrogen receptor (ER; specifically, the alpha variant), progesterone receptor (PgR), Ki67, HER2, and tumor molecular subtype. In general, moderate to very good correlation in biomarker status between the paired CNB and surgical specimens was observed for both IHC assessment (83–99% agreement, kappa range 0.474–0.917) and GEX assessment (70–97% agreement, kappa range 0.552–0.800), respectively. However, using IHC, 52% of cases with low Ki67 status in the CNB shifted to high Ki67 status in the surgical specimen (McNemar’s p = 0.011). Similarly, when using GEX, a significant shift from negative to positive ER (47%) and from low to high Ki67 (16%) was observed between the CNB and surgical specimen (McNemar’s p = 0.027 and p = 0.002 respectively). When comparing biomarker status between different techniques (IHC vs. GEX) performed on either CNBs or surgical specimens, the agreement in ER, PgR, and HER2 status was generally over 80% in both CNBs and surgical specimens (kappa range 0.395–0.708), but Ki67 and tumor molecular subtype showed lower concordance levels between IHC and GEX (48–62% agreement, kappa range 0.152–0.398). These results suggest that both the techniques used for collecting tissue samples and analyzing biomarker status have the potential to affect the results of biomarker assessment, potentially also impacting treatment decisions and patient survival outcomes. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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14 pages, 2111 KiB

Open AccessArticle

Matrix Metalloproteinase-1 (MMP1) Upregulation through Promoter Hypomethylation Enhances Tamoxifen Resistance in Breast Cancer

by Hyeon Woo Kim, Jae Eun Park, Minjae Baek, Heejoo Kim, Hwee Won Ji, Sung Hwan Yun, Dawoon Jeong, Juyeon Ham, Sungbin Park, Xinpei Lu, Han-Sung Kang and Sun Jung Kim

Cancers 2022, 14(5), 1232; https://doi.org/10.3390/cancers14051232 - 27 Feb 2022

Cited by 16 | Viewed by 2950

Abstract

Background: Tamoxifen (tam) is widely used to treat estrogen-positive breast cancer. However, cancer recurrence after chemotherapy remains a major obstacle to achieve good patient prognoses. In this study, we aimed to identify genes responsible for epigenetic regulation of tam resistance in breast cancer. [...] Read more.

Background: Tamoxifen (tam) is widely used to treat estrogen-positive breast cancer. However, cancer recurrence after chemotherapy remains a major obstacle to achieve good patient prognoses. In this study, we aimed to identify genes responsible for epigenetic regulation of tam resistance in breast cancer. Methods: Methylation microarray data were analyzed to screen highly hypomethylated genes in tam resistant (tamR) breast cancer cells. Quantitative RT-PCR, Western blot analysis, and immunohistochemical staining were used to quantify expression levels of genes in cultured cells and cancer tissues. Effects of matrix metalloproteinase-1 (MMP1) expression on cancer cell growth and drug resistance were examined through colony formation assays and flow cytometry. Xenografted mice were generated to investigate the effects of MMP1 on drug resistance in vivo. Results: MMP1 was found to be hypomethylated and overexpressed in tamR MCF-7 (MCF-7/tamR) cells and in tamR breast cancer tissues. Methylation was found to be inversely associated with MMP1 expression level in breast cancer tissues, and patients with lower MMP1 expression exhibited a better prognosis for survival. Downregulating MMP1 using shRNA induced tam sensitivity in MCF-7/tamR cells along with increased apoptosis. The xenografted MCF-7/tamR cells that stably expressed short hairpin RNA (shRNA) against MMP1 exhibited retarded tumor growth compared to that in cells expressing the control shRNA, which was further suppressed by tam. Conclusions: MMP1 can be upregulated through promoter hypomethylation in tamR breast cancer, functioning as a resistance driver gene. MMP1 can be a potential target to suppress tamR to achieve better prognoses of breast cancer patients. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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22 pages, 5901 KiB

Open AccessArticle

Epigenetic Priming with Decitabine Augments the Therapeutic Effect of Cisplatin on Triple-Negative Breast Cancer Cells through Induction of Proapoptotic Factor NOXA

by Wataru Nakajima, Kai Miyazaki, Masahiro Sakaguchi, Yumi Asano, Mariko Ishibashi, Tomoko Kurita, Hiroki Yamaguchi, Hiroyuki Takei and Nobuyuki Tanaka

Cancers 2022, 14(1), 248; https://doi.org/10.3390/cancers14010248 - 4 Jan 2022

Cited by 5 | Viewed by 3730

Abstract

Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and [...] Read more.

Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and its effectiveness in treating TNBCs are not fully understood. We analyzed the effects of decitabine on nine TNBC cell lines and examined genes associated with its cytotoxic effects. According to the effect of decitabine, we classified the cell lines into cell death (D)-type, growth inhibition (G)-type, and resistant (R)-type. In D-type cells, decitabine induced the expression of apoptotic regulators and, among them, NOXA was functionally involved in decitabine-induced apoptosis. In G-type cells, induction of the cyclin-dependent kinase inhibitor, p21, and cell cycle arrest were observed. Furthermore, decitabine enhanced the cytotoxic effect of cisplatin mediated by NOXA in D-type and G-type cells. In contrast, the sensitivity to cisplatin was high in R-type cells, and no enhancing effect by decitabine was observed. These results indicate that decitabine enhances the proapoptotic effect of cisplatin on TNBC cell lines that are less sensitive to cisplatin, indicating the potential for combination therapy in TNBC. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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14 pages, 1001 KiB

Open AccessArticle

Sample Preparation Approach Influences PAM50 Risk of Recurrence Score in Early Breast Cancer

by Tonje G. Lien, Hege Oma Ohnstad, Ole Christian Lingjærde, Johan Vallon-Christersson, Marit Aaserud, My Anh Tu Sveli, Åke Borg, on behalf of OSBREAC, Øystein Garred, Elin Borgen, Bjørn Naume, Hege Russnes and Therese Sørlie

Cancers 2021, 13(23), 6118; https://doi.org/10.3390/cancers13236118 - 4 Dec 2021

Cited by 8 | Viewed by 3160

Abstract

The PAM50 gene expression subtypes and the associated risk of recurrence (ROR) score are used to predict the risk of recurrence and the benefits of adjuvant therapy in early-stage breast cancer. The Prosigna assay includes the PAM50 subtypes along with their clinicopathological features, [...] Read more.

The PAM50 gene expression subtypes and the associated risk of recurrence (ROR) score are used to predict the risk of recurrence and the benefits of adjuvant therapy in early-stage breast cancer. The Prosigna assay includes the PAM50 subtypes along with their clinicopathological features, and is approved for treatment recommendations for adjuvant hormonal therapy and chemotherapy in hormone-receptor-positive early breast cancer. The Prosigna test utilizes RNA extracted from macrodissected tumor cells obtained from formalin-fixed, paraffin-embedded (FFPE) tissue sections. However, RNA extracted from fresh-frozen (FF) bulk tissue without macrodissection is widely used for research purposes, and yields high-quality RNA for downstream analyses. To investigate the impact of the sample preparation approach on ROR scores, we analyzed 94 breast carcinomas included in an observational study that had available gene expression data from macrodissected FFPE tissue and FF bulk tumor tissue, along with the clinically approved Prosigna scores for the node-negative, hormone-receptor-positive, HER2-negative cases (n = 54). ROR scores were calculated in R; the resulting two sets of scores from FFPE and FF samples were compared, and treatment recommendations were evaluated. Overall, ROR scores calculated based on the macrodissected FFPE tissue were consistent with the Prosigna scores. However, analyses from bulk tissue yielded a higher proportion of cases classified as normal-like; these were samples with relatively low tumor cellularity, leading to lower ROR scores. When comparing ROR scores (low, intermediate, and high), discordant cases between the two preparation approaches were revealed among the luminal tumors; the recommended treatment would have changed in a minority of cases. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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16 pages, 2076 KiB

Open AccessArticle

High Levels of Expression of Cartilage Oligomeric Matrix Protein in Lymph Node Metastases in Breast Cancer Are Associated with Reduced Survival

by Konstantinos S. Papadakos, Catharina Hagerling, Lisa Rydén, Anna-Maria Larsson and Anna M. Blom

Cancers 2021, 13(23), 5876; https://doi.org/10.3390/cancers13235876 - 23 Nov 2021

Cited by 8 | Viewed by 2256

Abstract

Cartilage oligomeric matrix protein (COMP) is a regulator of the extracellular matrix and is expressed primarily in the cartilage. Recently, COMP expression was also documented in breast cancer patients both in sera and tumor biopsies, in both of which it could serve as [...] Read more.

Cartilage oligomeric matrix protein (COMP) is a regulator of the extracellular matrix and is expressed primarily in the cartilage. Recently, COMP expression was also documented in breast cancer patients both in sera and tumor biopsies, in both of which it could serve as an independent prognostic marker. This study aimed to assess COMP as a potential biomarker in the group of metastatic breast cancer patients. Levels of COMP were measured by ELISA in serum samples of 141 metastatic breast cancer patients. Biopsies from primary tumors, synchronous lymph node metastases, and distant metastases were stained for COMP expression. The levels of serum COMP were higher in patients with ER- and HER2-positive tumors when compared to triple-negative tumors and correlated with the presence of bone and lung metastases, circulating tumor cell count, and clusters. Most of the primary tumors expressing COMP (70%) retained the expression also in the lymph node metastases, which correlated with visceral metastases and reduced survival. In conclusion, COMP appears as a valuable biomarker in metastatic breast cancer patients indicating a more severe stage of the disease. Serum COMP levels were associated with specific types of metastases in patients with metastatic breast cancer emphasizing that further studies are warranted to elucidate its potential role as a monitoring marker. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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12 pages, 6492 KiB

Open AccessArticle

Reproducibility of mRNA-Based Testing of ESR1, PGR, ERBB2, and MKI67 Expression in Invasive Breast Cancer—A Europe-Wide External Quality Assessment

by Ramona Erber, Arndt Hartmann, Peter Andreas Fasching, Matthias Ruebner, Robert Stöhr, Matthias Wilhelm Beckmann, Miriam Zentgraf, Verena Popp, Jodi Weidler, Iris Simon, Steffi Becker, Hanna Huebner, Josephine Fischer, Elena Guerini Rocco, Giuseppe Viale, Anne Cayre, Frederique Penault-Llorca, Tamara Caniego Casas, Belén Pérez-Miés, José Palacios, Paul Jank, Carsten Denkert, Lina Khoury, Thomas Mairinger and Fulvia Ferrazzi Show full author list Hide full author list

Cancers 2021, 13(18), 4718; https://doi.org/10.3390/cancers13184718 - 21 Sep 2021

Cited by 7 | Viewed by 3516

Abstract

Estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2 immunohistochemistry (IHC) together with HER2 in situ hybridization (ISH) are utilized to classify invasive breast cancer (IBC) into predictive molecular subtypes. As IHC evaluation may be hampered by analytical errors, gene expression assays could [...] Read more.

Estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2 immunohistochemistry (IHC) together with HER2 in situ hybridization (ISH) are utilized to classify invasive breast cancer (IBC) into predictive molecular subtypes. As IHC evaluation may be hampered by analytical errors, gene expression assays could offer a reliable alternative. In this first Europe-wide external quality assessment (EQA) study, we investigated performance of mRNA-based Xpert^® Breast Cancer STRAT4 (CE-IVD) in five European laboratories. The cohort comprised ten pre-therapy IBC core biopsies diagnosed in the coordinating center (CC). STRAT4 binary (positive or negative) mRNA results of each marker (ESR1, PGR, ERBB2, MKI67) were compared with the gold standard IHC/ISH performed by the CC. Sensitivity, specificity, and accuracy of ESR1 and ERBB2 mRNA were 100% for all samples. In contrast, PGR expression was falsely negative for one case by two sites and MKI67 falsely negative for two cases (respectively by four and one sites). These cases had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. Our EQA shows that STRAT4 mRNA assay may be a reproducible method to evaluate ER, PgR, HER2, and Ki-67 status. However, cases with expression values close to assay cut-offs should be carefully reviewed. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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14 pages, 16693 KiB

Open AccessArticle

Variability in Breast Cancer Biomarker Assessment and the Effect on Oncological Treatment Decisions: A Nationwide 5-Year Population-Based Study

by Balazs Acs, Irma Fredriksson, Caroline Rönnlund, Catharina Hagerling, Anna Ehinger, Anikó Kovács, Rasmus Røge, Jonas Bergh and Johan Hartman

Cancers 2021, 13(5), 1166; https://doi.org/10.3390/cancers13051166 - 9 Mar 2021

Cited by 33 | Viewed by 4532

Abstract

We compared estrogen receptor (ER), progesterone receptor (PR), human epidermal growth-factor receptor 2 (HER2), Ki67, and grade scores among the pathology departments in Sweden. We investigated how ER and HER2 positivity rates affect the distribution of endocrine and HER2-targeted treatments among oncology departments. [...] Read more.

We compared estrogen receptor (ER), progesterone receptor (PR), human epidermal growth-factor receptor 2 (HER2), Ki67, and grade scores among the pathology departments in Sweden. We investigated how ER and HER2 positivity rates affect the distribution of endocrine and HER2-targeted treatments among oncology departments. All breast cancer patients diagnosed between 2013 and 2018 in Sweden were identified in the National Quality Register for Breast Cancer. Cases with data on ER, PR, HER2, Ki67, grade, and treatment were selected (43,261 cases from 29 departments following the guidelines for biomarker testing). The ER positivity rates ranged from 84.2% to 97.6% with 6/29 labs out of the overall confidence intervals (CIs), while PR rates varied between 64.8% and 86.6% with 7/29 labs out of the CIs. HER2 positivity rates ranged from 9.4% to 16.3%, with 3/29 labs out of the overall CIs. Median Ki67 varied between 15% and 30%, where 19/29 labs showed significant intra-laboratory variability. The proportion of grade-II cases varied between 42.9% and 57.1%, and 13/29 labs were outside of the CI. Adjusting for patient characteristics, the proportion of endocrine and anti-HER2 treatments followed the rate of ER and HER2 positivity, illustrating the clinical effect of inter- and intra-laboratory variability. There was limited variability among departments in ER, PR, and HER2 testing. However, even a few outlier pathology labs affected endocrine and HER2-targeted treatment rates in a clinically relevant proportion, suggesting the need for improvement. High variability was found in grading and Ki67 assessment, illustrating the need for the adoption of new technologies in practice. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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21 pages, 2488 KiB

Open AccessArticle

Granulocyte Colony Stimulating Factor Expression in Breast Cancer and Its Association with Carbonic Anhydrase IX and Immune Checkpoints

by Shawn C. Chafe, Nazia Riaz, Samantha Burugu, Dongxia Gao, Samuel C. Y. Leung, Anna F. Lee, Cheng-Han Lee, Shoukat Dedhar and Torsten O. Nielsen

Cancers 2021, 13(5), 1022; https://doi.org/10.3390/cancers13051022 - 1 Mar 2021

Cited by 7 | Viewed by 3099

Abstract

Purpose: Granulocyte colony-stimulating factor (G-CSF) and hypoxia modulate the tumour immune microenvironment. In model systems, hypoxia-induced carbonic anhydrase IX (CAIX) has been associated with G-CSF and immune responses, including M2 polarization of macrophages. We investigated whether these associations exist in human breast cancer [...] Read more.

Purpose: Granulocyte colony-stimulating factor (G-CSF) and hypoxia modulate the tumour immune microenvironment. In model systems, hypoxia-induced carbonic anhydrase IX (CAIX) has been associated with G-CSF and immune responses, including M2 polarization of macrophages. We investigated whether these associations exist in human breast cancer specimens, their relation to breast cancer subtypes, and clinical outcome. Methods: Using validated protocols and prespecified scoring methodology, G-CSF expression on carcinoma cells and CD163 expression on tumour-associated macrophages were assayed by immunohistochemistry and applied to a tissue microarray series of 2960 primary excision specimens linked to clinicopathologic, biomarker, and outcome data. Results: G-CSF_high expression showed a significant positive association with ER negativity, HER2 positivity, presence of CD163+ M2 macrophages, and CAIX expression. In univariate analysis, G-CSF_high phenotype was associated with improved survival in non-luminal cases, although the CAIX+ subset had a significantly adverse prognosis. A significant positive association was observed between immune checkpoint biomarkers on tumour-infiltrating lymphocytes and both G-CSF- and CAIX-expressing carcinoma cells. Immune checkpoint biomarkers correlated significantly with favourable prognosis in G-CSF_high/non-luminal cases independent of standard clinicopathological features. Conclusions: The prognostic associations linking G-CSF to immune biomarkers and CAIX strongly support their immunomodulatory roles in the tumour microenvironment. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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Review

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28 pages, 1336 KiB

Open AccessReview

Immunological Landscape of HER-2 Positive Breast Cancer

by Santiago Moragon, Cristina Hernando, Maria Teresa Martinez-Martinez, Marta Tapia, Belen Ortega-Morillo, Ana Lluch, Begoña Bermejo and Juan Miguel Cejalvo

Cancers 2022, 14(13), 3167; https://doi.org/10.3390/cancers14133167 - 28 Jun 2022

Cited by 6 | Viewed by 2766

Abstract

Understanding the biological aspects of immune response in HER2+ breast cancer is crucial to implementing new treatment strategies in these patients. It is well known that anti-HER2 therapy has improved survival in this population, yet a substantial percentage may relapse, creating a need [...] Read more.

Understanding the biological aspects of immune response in HER2+ breast cancer is crucial to implementing new treatment strategies in these patients. It is well known that anti-HER2 therapy has improved survival in this population, yet a substantial percentage may relapse, creating a need within the scientific community to uncover resistance mechanisms and determine how to overcome them. This systematic review indicates the immunological mechanisms through which trastuzumab and other agents target cancer cells, also outlining the main trials studying immune checkpoint blockade. Finally, we report on anti-HER2 vaccines and include a figure exemplifying their mechanisms of action. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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28 pages, 4518 KiB

Open AccessReview

Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer

by Jonas Busk Holm, Ann H. Rosendahl and Signe Borgquist

Cancers 2021, 13(24), 6286; https://doi.org/10.3390/cancers13246286 - 14 Dec 2021

Cited by 15 | Viewed by 4210

Abstract

Obesity is associated with an increased risk of breast cancer, which is the most common cancer in women worldwide (excluding non-melanoma skin cancer). Furthermore, breast cancer patients with obesity have an impaired prognosis. Adipose tissue is abundant in the breast. Therefore, breast cancer [...] Read more.

Obesity is associated with an increased risk of breast cancer, which is the most common cancer in women worldwide (excluding non-melanoma skin cancer). Furthermore, breast cancer patients with obesity have an impaired prognosis. Adipose tissue is abundant in the breast. Therefore, breast cancer develops in an adipose-rich environment. During obesity, changes in the local environment in the breast occur which are associated with breast cancer. A shift towards a pro-inflammatory state is seen, resulting in altered levels of cytokines and immune cells. Levels of adipokines, such as leptin, adiponectin, and resistin, are changed. Aromatase activity rises, resulting in higher levels of potent estrogen in the breast. Lastly, remodeling of the extracellular matrix takes place. In this review, we address the current knowledge on the changes in the breast adipose tissue in obesity associated with breast cancer initiation and progression. We aim to identify obesity-associated biomarkers in the breast involved in the interplay between obesity and breast cancer. Hereby, we can improve identification of women with obesity with an increased risk of breast cancer and an impaired prognosis. Studies investigating mammary adipocytes and breast adipose tissue in women with obesity versus women without obesity are, however, sparse and further research is needed. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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23 pages, 1937 KiB

Open AccessReview

Triple-Negative Breast Cancer Histological Subtypes with a Favourable Prognosis

by Gábor Cserni, Cecily M. Quinn, Maria Pia Foschini, Simonetta Bianchi, Grace Callagy, Ewa Chmielik, Thomas Decker, Falko Fend, Anikó Kovács, Paul J. van Diest, Ian O. Ellis, Emad Rakha, Tibor Tot and European Working Group for Breast Screening Pathology

Cancers 2021, 13(22), 5694; https://doi.org/10.3390/cancers13225694 - 14 Nov 2021

Cited by 53 | Viewed by 7209

Abstract

Triple-negative breast cancers (TNBC), as a group of tumours, have a worse prognosis than stage-matched non-TNBC and lack the benefits of routinely available targeted therapy. However, TNBC is a heterogeneous group of neoplasms, which includes some special type carcinomas with a relatively indolent [...] Read more.

Triple-negative breast cancers (TNBC), as a group of tumours, have a worse prognosis than stage-matched non-TNBC and lack the benefits of routinely available targeted therapy. However, TNBC is a heterogeneous group of neoplasms, which includes some special type carcinomas with a relatively indolent course. This review on behalf of the European Working Group for Breast Screening Pathology reviews the literature on the special histological types of BC that are reported to have a triple negative phenotype and indolent behaviour. These include adenoid cystic carcinoma of classical type, low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, low-grade mucoepidermoid carcinoma, secretory carcinoma, acinic cell carcinoma, and tall cell carcinoma with reversed polarity. The pathological and known molecular features as well as clinical data including treatment and prognosis of these special TNBC subtypes are summarised and it is concluded that many patients with these rare TNBC pure subtypes are unlikely to benefit from systemic chemotherapy. A consensus statement of the working group relating to the multidisciplinary approach and treatment of these rare tumour types concludes the review. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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15 pages, 1095 KiB

Open AccessReview

Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies

by Abeer J. Al-Qasem, Carla L. Alves and Henrik J. Ditzel

Cancers 2021, 13(21), 5397; https://doi.org/10.3390/cancers13215397 - 27 Oct 2021

Cited by 9 | Viewed by 3915

Abstract

The introduction of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has revolutionized the treatment landscape for patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) and has become the new standard treatment. However, resistance to this combined therapy inevitably develops and [...] Read more.

The introduction of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has revolutionized the treatment landscape for patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) and has become the new standard treatment. However, resistance to this combined therapy inevitably develops and represents a major clinical challenge in the management of ER+ ABC. Currently, elucidation of the resistance mechanisms, identification of predictive biomarkers, and development of novel effective combined targeted treatments to overcome the resistance are active areas of research. Given the heterogeneity of the resistance mechanisms towards combined CDK4/6i and ET, identification of a single universal predictive biomarker of resistance is unlikely. Novel approaches are being explored, including examination of multiple genetic alterations in circulating cell-free tumor DNA in liquid biopsies from ABC patients with disease progression on combined CDK4/6i and ET treatment. Here, we review the molecular basis of the main known resistance mechanisms towards combined CDK4/6i and ET and associated potential biomarkers. As inhibiting key molecules in the pathways driving resistance may play an important role in the selection of therapeutic strategies for patients who experience disease progression on combined CDK4/6i and ET, we also review preclinical and early phase clinical data on novel combination therapies for these patients. Full article

(This article belongs to the Special Issue Novel Biomarkers: Validity, Evaluation and Biological Roles for Breast Cancer)

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