Recent Discoveries of Macromolecule- and Cell-Based Biomarkers and Therapeutic Implications in Breast Cancer

Wu, Hsing‐Ju; Chu, Pei-Yi

doi:10.3390/ijms22020636

Cited by 45 publications

(36 citation statements)

References 302 publications

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“…According to recent statistics, breast cancer (BC) is the most common malignant tumour worldwide and the primary cause of cancer-related death in women [1]. BC is a molecular disease.…”

Section: Introductionmentioning

confidence: 99%

Neoadjuvant Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors Combined with Endocrine Therapy in HR+/HER2− Breast Cancer: A Systematic Review and Meta-Analysis

et al. 2021

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Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors have been advocated for adjuvant therapy of metastatic hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)− breast cancer (BC). However, the efficiency of adding CDK 4/6 inhibitors to neoadjuvant therapy was not unequivocal. Objective: The aim of the study was to evaluate the efficiency and toxicity of neoadjuvant CDK 4/6 inhibitors + endocrine therapy (ET) versus neoadjuvant endocrine monotherapy or standard neoadjuvant chemotherapy in HR+/HER2− BC. Method: We searched PubMed, the Cochrane Library, Web of Science, and Embase online databases for randomized controlled trials and single-arm studies written in English until April 2021. Results: Five studies comparing CDK 4/6 inhibitors + ET as neoadjuvant treatments to ET alone and 2 studies comparing neoadjuvant CDK 4/6 inhibitors + ET to neoadjuvant chemotherapy were analysed. Neoadjuvant CDK 4/6 inhibitors + ET improved the rate of complete cell cycle arrest (CCCA: central Ki67 < 2.7%, odds ratio [OR] = 7.91, 95% confidence interval [CI] = 4.81–13.03, p < 0.001), increased the risk of adverse events (AEs; especially ≥3 AEs; AEs of all grades: OR = 9.10, 95% CI = 2.39–34.58, p = 0.001; AEs ≥3: OR = 12.24, 95% CI = 4.17–35.88, p < 0.001), led to no significant differences in pathological complete response (pCR) in patients with BC (OR = 0.34, 95% CI = 0.04–2.85, p = 0.318) compared to endocrine monotherapy. Moreover, subgroup analysis showed that the 3 types of CDK 4/6 inhibitors all improved the rate of CCCA (ribociclib: OR = 10.31, 95% CI = 3.59–29.61, p < 0.001; palbociclib: OR = 7.39, 95% CI = 1.26–43.40, p = 0.027, and abemaciclib: OR = 8.28, 95% CI = 3.41–20.11, p < 0.001). Compared to neoadjuvant chemotherapy, neoadjuvant CDK 4/6 inhibitors plus ET decreased the risk of AEs ≥3 (OR = 0.50, 95% CI = 0.29–0.87, p = 0.015) and showed similar ability to reach pCR (OR = 0.50, 95% CI = 0.12–2.07, p = 0.342) and reduce the residual cancer burden (RCB, RCB 0–1: OR = 0.47, 95% CI = 0.18–1.22, p = 0.121; RCB 2–3: OR = 2.30, 95% CI = 0.89–5.91, p = 0.084). Conclusions: The results suggested that combination therapy had increased efficacy and toxicity compared to endocrine monotherapy and showed similar efficacy to and better safety than neoadjuvant chemotherapy.

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“…According to recent statistics, breast cancer (BC) is the most common malignant tumour worldwide and the primary cause of cancer-related death in women [1]. BC is a molecular disease.…”

Section: Introductionmentioning

confidence: 99%

Neoadjuvant Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors Combined with Endocrine Therapy in HR+/HER2− Breast Cancer: A Systematic Review and Meta-Analysis

et al. 2021

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“…Routinely used predictive features, including clinicopathological parameters (age, tumor size, lymph node status, and histological grade) and biomarkers (ER, PR, and HER2) are insufficient for personalized clinical decisions in BC patients (3). Novel prognostic BC biomarkers have been intensively investigated as recently reviewed by Wu et al (4). In particular, robust biomarkers are in demand for HER2-positive disease to improve selection of patients for current and emerging therapies of HER2-positive metastatic BC (5) as well as for prediction of resistance for anti-HER2 therapies, recurrence (6,7), and particular consequences of the disease (8).…”

Section: Introductionmentioning

confidence: 99%

Intratumoral Heterogeneity and Immune Response Indicators to Predict Overall Survival in a Retrospective Study of HER2-Borderline (IHC 2+) Breast Cancer Patients

et al. 2021

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Breast cancer (BC) categorized as human epidermal growth factor receptor 2 (HER2) borderline [2+ by immunohistochemistry (IHC 2+)] presents challenges for the testing, frequently obscured by intratumoral heterogeneity (ITH). This leads to difficulties in therapy decisions. We aimed to establish prognostic models of overall survival (OS) of these patients, which take into account spatial aspects of ITH and tumor microenvironment by using hexagonal tiling analytics of digital image analysis (DIA). In particular, we assessed the prognostic value of Immunogradient indicators at the tumor–stroma interface zone (IZ) as a feature of antitumor immune response. Surgical excision samples stained for estrogen receptor (ER), progesterone receptor (PR), Ki67, HER2, and CD8 from 275 patients with HER2 IHC 2+ invasive ductal BC were used in the study. DIA outputs were subsampled by HexT for ITH quantification and tumor microenvironment extraction for Immunogradient indicators. Multiple Cox regression revealed HER2 membrane completeness (HER2 MC) (HR: 0.18, p = 0.0007), its spatial entropy (HR: 0.37, p = 0.0341), and ER contrast (HR: 0.21, p = 0.0449) as independent predictors of better OS, with worse OS predicted by pT status (HR: 6.04, p = 0.0014) in the HER2 non-amplified patients. In the HER2-amplified patients, HER2 MC contrast (HR: 0.35, p = 0.0367) and CEP17 copy number (HR: 0.19, p = 0.0035) were independent predictors of better OS along with worse OS predicted by pN status (HR: 4.75, p = 0.0018). In the non-amplified tumors, three Immunogradient indicators provided the independent prognostic value: CD8 density in the tumor aspect of the IZ and CD8 center of mass were associated with better OS (HR: 0.23, p = 0.0079 and 0.14, p = 0.0014, respectively), and CD8 density variance along the tumor edge predicted worse OS (HR: 9.45, p = 0.0002). Combining these three computational indicators of the CD8 cell spatial distribution within the tumor microenvironment augmented prognostic stratification of the patients. In the HER2-amplified group, CD8 cell density in the tumor aspect of the IZ was the only independent immune response feature to predict better OS (HR: 0.22, p = 0.0047). In conclusion, we present novel prognostic models, based on computational ITH and Immunogradient indicators of the IHC biomarkers, in HER2 IHC 2+ BC patients.

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“…The identification of clinically useful biomarkers is challenging due to several limitations, including tumor heterogeneity, since a single biomarker may not have sufficient sensitivity and specificity to predict response to therapy and tumor behavior [88]. The lack of standardized protocols and precise cutoff values, the need for a complete assessment of sensitivity, specificity and reproducibility are also obstacles for the validation of these biomarkers in clinical practice [89]. The development of affordable biomarkers also poses a challenge due to the high cost needed for use in clinical practice [90].…”

Section: Final Considerationsmentioning

confidence: 99%

Molecular Biomarkers Predict Pathological Complete Response of Neoadjuvant Chemotherapy in Breast Cancer Patients: Review

Freitas

Causin

Varuzza

et al. 2021

Cancers

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Neoadjuvant chemotherapy (NAC) is often used to treat locally advanced disease for tumor downstaging, thus improving the chances of breast-conserving surgery. From the NAC response, it is possible to obtain prognostic information as patients may reach a pathological complete response (pCR). Those who do might have significant advantages in terms of survival rates. Breast cancer (BC) is a heterogeneous disease that requires personalized treatment strategies. The development of targeted therapies depends on identifying biomarkers that can be used to assess treatment efficacy as well as the discovery of new and more accurate therapeutic agents. With the development of new “OMICS” technologies, i.e., genomics, transcriptomics, and proteomics, among others, the discovery of new biomarkers is increasingly being used in the context of clinical practice, bringing us closer to personalized management of BC treatment. The aim of this review is to compile the main biomarkers that predict pCR in BC after NAC.

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Recent Discoveries of Macromolecule- and Cell-Based Biomarkers and Therapeutic Implications in Breast Cancer

Cited by 45 publications

References 302 publications

Neoadjuvant Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors Combined with Endocrine Therapy in HR+/HER2− Breast Cancer: A Systematic Review and Meta-Analysis

Neoadjuvant Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors Combined with Endocrine Therapy in HR+/HER2− Breast Cancer: A Systematic Review and Meta-Analysis

Intratumoral Heterogeneity and Immune Response Indicators to Predict Overall Survival in a Retrospective Study of HER2-Borderline (IHC 2+) Breast Cancer Patients

Molecular Biomarkers Predict Pathological Complete Response of Neoadjuvant Chemotherapy in Breast Cancer Patients: Review

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