• Endocrine therapy
• Neoadjuvant
• Predictive biomarkers
• Rebiopsy
• Therapeutic response

• Breast cancer
• HR+/HER2−
• Neoadjuvant chemotherapy
• Propensity score matching
• Recurrence-free survival

• Humans
• Female
• Breast Neoplasms/drug therapy
• Breast Neoplasms/pathology
• Breast Neoplasms/mortality
• Breast Neoplasms/metabolism
• Chemotherapy, Adjuvant/methods
• Neoadjuvant Therapy/methods
• Propensity Score
• Middle Aged
• Retrospective Studies
• Adult
• Receptor, ErbB-2/metabolism
• Aged
• Receptors, Progesterone/metabolism
• Prognosis
• Receptors, Estrogen/metabolism

• 23ywa19 The study has funded by the Program of Taizhou Science and Technology Bureau,Zhejiang Province

• Breast cancer
• biomarker
• liposome
• malignancy.
• mammography
• targeted delivery

• Humans
• Breast Neoplasms/drug therapy
• Female
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/therapeutic use
• Drug Delivery Systems/methods
• Liposomes

• HR‐positive/HER2‐negative breast cancer
• National Cancer Database
• neoadjuvant endocrine treatment
• overall survival
• surgery

• Adult
• Aged
• Female
• Humans
• Middle Aged
• Antineoplastic Agents, Hormonal/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/pathology
• Breast Neoplasms/surgery
• Chemotherapy, Adjuvant/standards
• Mastectomy
• Neoadjuvant Therapy/standards
• Receptor, ErbB-2/metabolism
• Receptors, Estrogen/metabolism
• Receptors, Progesterone/metabolism
• Treatment Outcome

• 2022KW-01 Key Research and Development Program of Shaanxi Province
• 2022SF-001 Key Research and Development Program of Shaanxi Province
• YXJLRH2022056 Basic-clinical Cross-disciplinary Plan' of Xi'an Jiaotong University, China

• breast cancer

• P50 CA116201 NCI NIH HHS
• M.P.G. reports funding from the Mayo Clinic Breast Cancer Specialized Program of Research Excellence grant (P50CA 116201), the Prospect Creek Foundation, the George M. Eisenberg Foundation for Charities and the Regis Foundation.
• S.J. report funding from Eagles 5th District Cancer Telethon Funds for Cancer Research.
• J.N.I reports funding from the Mayo Clinic Breast Cancer Specialized Program of Research Excellence grant (P50CA 116201) and the George M. Eisenberg Foundation for Charities.
• J.M.R. reports funding from the Mayo Clinic Breast Cancer Specialized Program of Research Excellence grant (P50CA 116201).
• M.M.A. reports funding from the Mayo Clinic Breast Cancer Specialized Program of Research Excellence grant (P50CA 116201).
• J.R.H. reports funding from the Mayo Clinic Breast Cancer Specialized Program of Research Excellence grant (P50CA 116201), the Prospect Creek Foundation and the George M. Eisenberg Foundation for Charities.

• endocrine resistance
• immunohistochemistry
• molecular subtyping

• Breast cancer
• ER+
• HR+
• HR+/HER2-
• Pre-operative therapy
• endocrine therapy
• neoadjuvant therapy
• postmenopausal

• Female
• Humans
• Breast Neoplasms/drug therapy
• Neoadjuvant Therapy/methods
• Postmenopause
• Pandemics
• Antineoplastic Agents, Hormonal/therapeutic use
• COVID-19
• Receptor, ErbB-2

• Aromatase inhibitors
• Breast cancer
• HER2+
• HER2-Enriched subtype

• Aromatase Inhibitors
• Biomarkers, Tumor/metabolism
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Clinical Trials as Topic
• Female
• Humans
• Ki-67 Antigen/genetics
• Ki-67 Antigen/metabolism
• Neoplasm Recurrence, Local/genetics
• Receptor, ErbB-2/genetics
• Receptor, ErbB-2/metabolism
• Receptors, Estrogen/genetics
• Receptors, Estrogen/metabolism
• Receptors, Progesterone/metabolism

• 25351 Cancer Research UK
• 8671 Cancer Research UK

• breast cancer
• endocrine therapies
• human epidermal growth factor receptor-2
• oestrogen receptor
• resistance

• Antineoplastic Agents, Hormonal/pharmacology
• Antineoplastic Agents, Hormonal/therapeutic use
• Breast Neoplasms/pathology
• Endocrine System
• Female
• Hormones
• Humans
• Neoplasm Recurrence, Local/drug therapy
• Receptor, ErbB-2/metabolism

• Department of Health

Endocrine therapy (ET) is an effective first-line therapy for women with estrogen receptor-positive (ER + ) breast cancers. While both ionizing radiation (RT) and ET are used for the treatment of women with ER+ breast cancer, the most effective sequencing of therapy and the effect of ET on tumor radiosensitization remains unclear. Here we sought to understand the effects of inhibiting estrogen receptor (ER) signaling in combination with RT in multiple preclinical ER+ breast cancer models. Clonogenic survival assays were performed using variable pre- and post-treatment conditions to assess radiosensitization with estradiol, estrogen deprivation, tamoxifen, fulvestrant, or AZD9496 in ER+ breast cancer cell lines. Estrogen stimulation was radioprotective (radiation enhancement ratios [rER]: 0.51–0.82). Conversely, when given one hour prior to RT, ER inhibition or estrogen depletion radiosensitized ER+ MCF-7 and T47D cells (tamoxifen rER: 1.50–1.60, fulvestrant rER: 1.76–2.81, AZD9496 rER: 1.33–1.48, estrogen depletion rER: 1.47–1.51). Combination treatment resulted in an increase in double-strand DNA (dsDNA) breaks as a result of inhibition of non-homologous end joining-mediated dsDNA break repair with no effect on homologous recombination. Treatment with tamoxifen or fulvestrant in combination with RT also increased the number of senescent cells but did not affect apoptosis or cell cycle distribution. Using an MCF-7 xenograft model, concurrent treatment with tamoxifen and RT was synergistic and resulted in a significant decrease in tumor volume and a delay in time to tumor doubling without significant toxicity. These findings provide preclinical evidence that concurrent treatment with ET and RT may be an effective radiosensitization strategy.

CDK4/6 inhibitors have an established role in the treatment of hormone receptor positive HER2-negative advanced breast cancer. All studies conducted in metastatic breast cancer showed a benefit in delaying progression when added to standard endocrine therapy, regardless of therapy line, pretreatment, menopausal status, site of metastasis, CDK4/6 inhibitor used and associated endocrine therapy. A benefit in overall survival has also been demonstrated. In early breast cancer, only the MonarchE study has shown an improved invasive disease-free survival with abemaciclib taken for 2 years, whereas the Penelope-B did not meet the primary endpoint and the PALLAS study was terminated early for futility. Studies conducted in the neoadjuvant setting might help to explain the discordant results.

•

CDK4/6 inhibitors increase PFS in advanced breast cancer in all subgroups.

• CDK4/6 inhibitors
• Early setting
• Endocrine therapy
• Hormone receptor positive breast cancer

Whereas the genomic landscape of endocrine‐resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non‐responsiveness to endocrine treatment in luminal early breast cancer.

In this study, 622 estrogen receptor‐expressing breast cancer cases treated with short‐term preoperative endocrine therapy (pET) from the WSG‐ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3‐week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post‐pET Ki67 <10%) versus slightly, moderately, and severely impaired (post‐pET Ki67 10%–19%, 20%–34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next‐generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization.

ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53‐mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen‐ and aromatase inhibitor‐based pET (p = 0.0005 each).

We conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53‐mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.

• TP53
• Ki67
• breast cancer
• endocrine proliferative response
• preoperative endocrine therapy

Oral cancer is the most dreadful cancer worldwide with a 5-year survival rate of approximately 50%. Anticancer therapies such as chemotherapy and radiotherapy result in severe side effects.

We aimed to evaluate the in vitro anticancer activity of Asiatic acid (AA) on bone-invasive oral squamous cell carcinoma (BHY) cell line.

This was an in vitro laboratory setting.

BHY cell lines were used for the experiment. Confocal microscopy was used to observe cellular alterations. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to determine the IC50 concentration of AA and flow cytometry to analyze the percentage of cells in each phase of the cell cycle post treatment. Immunoblot assays and semiquantitative reverse transcriptase-polymerase chain reaction (rt-PCR) were used to study the expression level of genes involved.

Student's t-test and one-way analysis of variance were used for statistical analysis.

IC50 concentration of AA was 15.6 μM. On flow cytometry analysis, treatment with 15.6 μM and 31.25 μM of AA for 24 h increased the percentage of cells in the G2/M phase to 45.63% and 53.12%, respectively, compared to 9.62% in control group. Immunoblot analysis and semiquantitative rt-PCR demonstrated an upregulation of p53, cyclin-dependent kinase inhibitors (p21 and p27), caspase-3, caspase-9, cytochrome c and Bax in a time-dependent manner and downregulation of cyclins and anti-apoptotic protein Bcl-2 (**P < 0.05, ***P < 0.001 versus control) post AA treatment.

AA induces apoptosis via the mitochondrial-dependent pathway and causes cell cycle arrest at the G2/M phase in BHY cell line.

• Anticancer
• Asiatic acid
• BHY cell line

• Cyclin-dependent kinase 4/6 inhibitors
• Endocrine therapy
• Hormone receptor+/epidermal growth factor receptor 2− breast cancer
• Neoadjuvant chemotherapy
• Neoadjuvant treatment

Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki67_2W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67_B). The POETIC trial aimed to test these two hypotheses.

POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0–1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing.

Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1–74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75–1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9–92·0) for patients in the POAI group and 90·4% (88·7–91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67_B and Ki67_2W (low–low) was 4·3% (95% CI 2·9–6·3), 8·4% (6·8–10·5) with high Ki67_B and low Ki67_2W (high–low) and 21·5% (17·1–27·0) with high Ki67_B and Ki67_2W (high–high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low–low group was 10·1% (95% CI 3·2–31·3), 7·7% (3·4–17·5) in the high–low group, and 15·7% (10·1–24·4) in the high–high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported.

POAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67_B or low POAI-induced Ki67_2W do well with adjuvant standard endocrine therapy (giving consideration to clinical–pathological factors), whereas those whose POAI-induced Ki67_2W remains high might benefit from further adjuvant treatment or trials of new therapies.

Cancer Research UK.

For patients with locally advanced estrogen receptor or progesterone receptor-positive breast cancer, neoadjuvant endocrine therapy (NET) facilitates down-staging of the tumor and increased rates of breast-conserving surgery. However, NET remains under-utilized, and there are very limited clinical guidelines governing which therapeutic agent to use, or the optimal duration of treatment in postmenopausal women. This literature review aims to discuss the evidence surrounding (1) biomarkers for patient selection for NET, (2) the optimal neoadjuvant endocrine agent for postmenopausal women with locally advanced breast cancer, and (3) the optimal duration of NET. In addition, we make initial recommendations towards developing a clinical guideline for the prescribing of NET.

A wide-ranging search of online electronic databases was conducted using a truncated PIC search strategy to identify articles that were relevant to these aims and revealed a number of key findings.

Randomized trials have consistently demonstrated that aromatase inhibitors are more effective than tamoxifen, in terms of objective response rate and rate of BCS, and should be used as first-line NET. The three available aromatase inhibitors have so far been demonstrated to be biologically equivalent, with the choice of aromatase inhibitor not having been shown to affect clinical outcomes. There is increasing evidence for extending the duration of NET beyond 3 to 4 months, to at least 6 months or until maximal clinical response is achieved. While on-treatment levels of the proliferation marker Ki67 are predictive of long-term outcome, the choice of adjuvant therapy in patients who have received NET and then surgery is best guided by the preoperative endocrine prognostic index, or PEPI, which incorporates Ki67 with other clinical parameters.

This study reveals that in appropriately selected patients, NET can provide equivalent clinical benefit to neoadjuvant chemotherapy in the same cohort, if suitable treatments and durations are chosen. Our findings highlight the need for better defined biomarkers both for guiding patient selection and for measuring outcomes. Development of standard guidelines for the prescribing of NET has the potential to improve both clinical outcomes and quality of life in this patient cohort.

• Aromatase inhibitors
• Neoadjuvant endocrine therapy
• Selective estrogen receptor modulators

• cancer screening
• breast cancer

• Adult
• Aged
• BRCA1 Protein/genetics
• BRCA2 Protein/genetics
• Circulating Tumor DNA/blood
• Female
• Humans
• Indoles/therapeutic use
• Middle Aged
• Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors
• Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
• Rad51 Recombinase/metabolism
• Recombinational DNA Repair/genetics
• Triple Negative Breast Neoplasms/drug therapy
• Triple Negative Breast Neoplasms/genetics
• Whole Genome Sequencing

• 27815 Cancer Research UK
• 23433 Cancer Research UK
• 23916 Cancer Research UK
• C38317/A24043 Cancer Research UK
• 22932 Cancer Research UK
• A23916 Cancer Research UK
• A15777 Cancer Research UK
• 100183 Wellcome Trust
• A23433 Cancer Research UK
• Wellcome Trust
• Breast Cancer Now (BCN)
• Cancer Research UK (CRUK)
• Wellcome Trust (Wellcome)

Background: Cancer and fibroadenoma are the most common breast tumors in women of reproductive age. Nuclear factor erythroid 2-related factor 2 (Nrf2) and the nuclear factor kappaB (NF-κB) transcription factor play an important role in the inflammatory process and in cell proliferation. However, few studies have analyzed these markers in breast cancer and fibroadenoma in women of reproductive age.

Results: Light microscopy showed a higher concentration of anti-Nrf2 and anti-NF-κB-stained nuclei in breast cancer than in fibroadenoma. The mean percentage of stained nuclei for Nrf2 was 7.12 ± 5.2 and 43.21 ± 19.83 in the control and study groups, respectively (p < 0.0001). The mean percentage of anti-NF-κB was 10.75 ± 7.09 and 56.14 ± 21.19 (mean ± standard deviation) in the control and study groups, respectively (p < 0.0001). Histological grade 3 tumors showed a significantly higher expression of Nrf2 and NF-κB than grade 1 tumors (p < 0.05).

Material and methods: This study was approved by the Institutional Review Board of Federal University of Piaui and all patients assigned an inform consent term prior to the study initiation. Nrf2 and NF-κB expression was evaluated by immunohistochemistry in 66 patients, divided into two groups, control (fibroadenoma, n = 36) and study (cancer, n = 30). The data were analyzed using ANOVA test and the statistical significance was established at p < 0.05.

Conclusion: Nrf2 and NF-κB expression was significantly higher in breast cancer than in fibroadenoma, in addition to having a greater association with more aggressive tumors.

• NF-κB
• NRF2
• breast cancer
• fibroadenoma
• immunohistochemistry

• 18F-ISO-1
• TMEM-97, proliferation
• breast cancer
• σ-2

Matrix metalloproteinases (MMPs) 2 and 9 may play an important role in cell proliferation and dissemination of cancer. However, few studies have compared the expression of these proteins between breast cancer and fibroadenoma.

A randomized, double-blind study was carried out in 66 premenopausal women, aged 20-49 years, who had been diagnosed with fibroadenoma or breast cancer. The patients were divided into two groups: Group A, control (fibroadenoma, n=36) and Group B, study (cancer, n=30). Immunohistochemical analysis was performed using tissue samples of fibroadenoma and breast cancer to assess MMP-2 and MMP-9 antigen expression. Cells were considered positive if exhibiting brown cytoplasmic staining. Fisher’s exact test was used to compare the percentage of cases with cells expressing MMP-2 and MMP-9 in control and study groups (p < 0.05).

Light microscopy showed a higher concentration of cells with positive cytoplasmic staining for MMP-2 and MMP-9 expression in breast cancer than in fibroadenoma. The percentage of cases with cells expressing MMP-2 in the control and study groups was 41.67% and 86.11%, respectively (p < 0.0009), whereas the percentage of cases with cells expressing MMP-9 in groups A and B was 66.67% and 93.33%, respectively (p<0.0138). MMP-2 and MMP-9 positive expression was significantly higher in moderately differentiated tumors compared to well and poorly differentiated tumors, p <0.005 and p<0.001, respectively.

The current study shows that MMP-2 and MMP-9 protein expression was significantly higher in the breast cancer than in the fibroadenoma and also in moderately differentiated breast cancer.

• breast neoplasms
• fibroadenoma
• immunohistochemistry
• matrix metalloproteinase-2
• matrix metalloproteinase-9

The overexpression of Metallothionein-1 (MT-1) may play an important role in breast cancer; however, few studies have compared MT-1 expression between breast cancer and fibroadenoma. A cross-sectional controlled study was performed in 66 premenopausal women, aged 20–49 years, who had been histologically diagnosed with breast fibroadenoma or breast cancer. The patients were divided into two groups: group A, control (fibroadenoma, n = 36) and group B, study (breast cancer, n = 30). Immunohistochemistry was performed on tissue samples of fibroadenoma and breast cancer patients to evaluate the expression of metallothionein using an anti-MT-1 polyclonal antibody (rabbit polyclonal anti-metallothionein-Catalog Number biorbyt-orb11042) at a dilution of 1:100. The data were analyzed using NOVA (p < 0.05). Microscopic analysis showed a higher concentration of anti-MT-1-stained nuclei in breast cancer tissues than in fibroadenoma tissues. The mean proportion of cells with anti-MT-1-stained nuclei was 26.93% and 9.10%, respectively, in the study and control groups (p < 0.001). Histological grade 3 tumors showed a significantly higher MT-1 expression than hitological grade 1 (p < 0.05), while breast tumors negative for estrogen-, progesterone- and HER2- receptors had a significantly higher MT-1 expression than positive breast tumors positive for these parameters (p < 0.05). MT-1 protein in women of reproductive age was significantly higher in breast cancer than in fibroadenoma in this study. Furthermore, there was higher MT-1 immunoreactivity in more aggressive tumors.

• Aged
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Aromatase Inhibitors/administration & dosage
• Aromatase Inhibitors/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Breast Neoplasms/surgery
• Chemotherapy, Adjuvant
• Drug Administration Schedule
• Female
• Humans
• Letrozole/administration & dosage
• Letrozole/therapeutic use
• Middle Aged
• Neoadjuvant Therapy
• Piperazines/administration & dosage
• Postmenopause
• Protein Kinase Inhibitors/therapeutic use
• Pyridines/administration & dosage
• Receptor, ErbB-2/metabolism
• Receptors, Estrogen/metabolism

• 16591 Cancer Research UK
• C1491/A15955 Cancer Research UK
• Department of Health

• Breast cancer
• endocrine resistance
• hormone-positive disease
• metastatic breast cancer
• targeted therapy

• Anastrozole
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Apoptosis/drug effects
• Biomarkers, Tumor
• Breast Neoplasms/diagnosis
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Cell Proliferation/drug effects
• Centrifugation, Density Gradient
• Class I Phosphatidylinositol 3-Kinases/genetics
• Combined Modality Therapy
• Female
• Heterocyclic Compounds, 3-Ring/administration & dosage
• Humans
• Mutation
• Neoplasm Staging
• Nitriles/administration & dosage
• Proto-Oncogene Proteins c-akt/antagonists & inhibitors
• Proto-Oncogene Proteins c-akt/metabolism
• Receptor, ErbB-2/metabolism
• Receptors, Estrogen/metabolism
• Sequence Analysis, DNA
• Signal Transduction/drug effects
• Treatment Outcome
• Triazoles/administration & dosage

• K22 CA188163 NCI NIH HHS
• R01 CA214893 NCI NIH HHS
• P30 CA014520 NCI NIH HHS
• P30 CA091842 NCI NIH HHS
• UM1 CA186686 NCI NIH HHS

Pre-operative endocrine therapy can be used to down-stage large or locally advanced breast cancers in ER+ disease. In the last four decades, it has evolved from a treatment perceived as an alternative to surgery for those too unfit to undergo surgery or chemotherapy, to the present day where it is a valuable and valid option in the treatment of postmenopausal women with ER-rich (Allred score 7–8, or > 50% staining for ER) breast cancer.

Emerging data from the metastatic setting is translating into neoadjuvant trials, utilising dual endocrine targeting or combinations of endocrine agents and other targeted drugs, including those acting against components of the PI3K pathway and the cell cycle. The routine use of peri-operative endocrine therapy in all ER+ tumours may help to yield important long-term prognostic information, and guide adjuvant endocrine therapy.

Pre-operative endocrine therapy is an exciting and evolving area with emerging new approaches. In this review, established evidence and emerging data on its applications are discussed.

• Aromatase inhibitor
• Breast cancer
• Endocrine therapy
• Neoadjuvant
• Pre-operative
• Tamoxifen

We aimed to analyse clinical and gene expression profiles to predict pathologic complete response and disease-free survival using two consecutive, prospective, preoperative chemotherapy trial cohorts.

Clinicopathological and gene expression data were evaluated in a cohort from two consecutive phase II preoperative studies that included patients with stage IIA–IIIC breast cancer of all subtypes. Analysed specimens were obtained before preoperative chemotherapy, and cDNA microarray analyses were performed using the Affymetrix Gene Chip U133 plus 2.0.

Between December 2005 and December 2010, 122 patients were analysed. The pathologic complete response rate was significantly higher in HER2+ and HR−/HER2− cancers. Age, pathologic complete response, HR−/HER2− status, and lymph node positivity (⩾4) were significant poor prognostic factors for disease-free survival. For the cDNA microarray analyses, sufficient tumour samples were available from 78 of the 107 patients (73%). An 8-gene signature predictive of pathologic complete response and a 17-gene signature predictive of prognosis were identified. Patients were categorised into low-risk (n=45) and high-risk groups (n=33) (HR 70.0, P=0.004).

This study yielded preliminary data on the expression of specific genes predicting pathologic complete response and disease-free survival in a cohort of chemonaïve breast cancer patients. Further validation may distinguish those who would benefit most from perioperative chemotherapy as well as those needing further intervention.

Preclinical studies in endometrial cancer (EC) show that metformin reduces cellular proliferation by PI3K-AKT-mTOR inhibition. We tested the hypothesis that short-term presurgical metformin reduces cellular proliferation in atypical endometrial hyperplasia (AEH) and endometrioid EC, and assessed the feasibility of using phosphorylated PI3K-AKT-mTOR proteins as tissue end points.

Women with AEH or EC received metformin 850 mg twice a day or no drug in the presurgical window between diagnosis and hysterectomy. Before and after the window, tissue samples were obtained; serum markers of insulin resistance (e.g. homeostasis model of assessment of insulin resistance index) were determined; and anthropometrics measured (e.g. BMI). Cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus were assessed by immunohistochemistry and scored blinded to treatment.

Twenty-eight metformin-treated and 12 untreated patients, well matched for age and BMI, completed the study. Metformin treatment (median 20 days, range 7–34) was associated with a 17.2% reduction in tumour Ki-67 (95% CI −27.4, −7.0, P=0.002), in a dose-dependent manner. Tumour PI3K-AKT-mTOR protein phosphostatus varied but the effects were not significant after adjusting for changes in controls.

Short-term metformin was associated with reduced Ki-67 expression in EC. Changes in tumour PI3K-AKT-mTOR protein phosphostatus were seen in both groups. Future studies should address the variability attributed to different sampling techniques including devascularisation of the uterus at hysterectomy.

Luminal breast cancer, as defined by oestrogen and/or progesterone expression by immunohistochemistry, accounts for up to 75% of all breast cancers. In this population, endocrine therapy is likely to account for most of the gains obtained with the administration of adjuvant systemic treatment. The role of adjuvant chemotherapy in these patients remains debatable since it is known that only a small fraction of patients will derive meaningful benefit from this treatment whilst the majority will be exposed to significant and unnecessary chemotherapy-related toxicities, in particular the elderly and frail. Therefore, neoadjuvant endocrine therapy (NET) becomes an attractive option for selected patients with hormonal-receptor positive locally advanced breast cancer. In this review, we discuss the current role of NET and future perspectives in the field.

• aromatase inhibitors
• breast neoplasm
• endocrine therapy
• locally advanced breast cancer
• luminal breast cancer
• neoadjuvant therapy

Breast cancer is not one disease, but can be categorized into four major molecular subtypes according to hormone receptor [estrogen receptor (ER) and progesterone receptor (PgR)] and human epidermal growth factor receptor type 2 (HER2) expression status. Ki67 labeling index and/or multigene assays are used to classify ER-positive, HER2-negative breast cancer into luminal A and luminal B (HER2-negative) subtypes. To date, most studies analyzing predictive or prognostic factors in ER-positive breast cancer have been performed in postmenopausal women, mainly using patients and samples in adjuvant aromatase inhibitor trials. In contrast, even the clinical roles of PgR and Ki67 have been little analyzed so far in premenopausal women. PgR is one of the estrogen-responsive genes, and it has been reported that plasma estradiol levels are related to expression levels of estrogen-responsive genes including PGR in ER-positive breast cancer. In this article, biological differences, especially differences in expression of PgR and Ki67 in ER-positive breast cancer between pre- and postmenopausal women are discussed. Clinical roles of PgR and Ki67 in ER-positive breast cancer differ between pre- and postmenopausal women. We suggest that the mechanisms of development and estrogen-dependent growth of ER-positive breast cancer might differ according to menopausal status.

• Breast cancer
• Progesterone receptor
• Estrogen receptor
• Ki67
• Menopausal status

• anastrozole
• endocrine treatment
• fulvestrant
• hormone-receptor-positive cancer
• large operable or locally advanced breast cancer
• neo-adjuvant

• Aged
• Aged, 80 and over
• Anastrozole
• Antineoplastic Agents, Hormonal/therapeutic use
• Breast Neoplasms/drug therapy
• Estradiol/analogs & derivatives
• Estradiol/therapeutic use
• Female
• Fulvestrant
• Humans
• Middle Aged
• Nitriles/therapeutic use
• Postmenopause/drug effects
• Triazoles/therapeutic use

• Breast cancer
• Image analysis
• Immunohistochemistry
• Ki67
• Slide scanning

• apoptosis
• cell proliferation
• chemoprevention
• neoplasm metastasis
• nimbolide