scholarly journals Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Elham Sajjadi ◽  
Konstantinos Venetis ◽  
Roberto Piciotti ◽  
Marco Invernizzi ◽  
Elena Guerini-Rocco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mismatch Repair ◽  
Hormone Receptor ◽  
Therapy Resistance ◽  
Genetic Alterations ◽  
Diagnostic Tools ◽  
Breast Cancers ◽  
Comprehensive Overview ◽  
Hormone Receptor Positive ◽  
Status Assessment

AbstractThe clinical outcome of patients with a diagnosis of hormone receptor (HR)+ breast cancer has improved remarkably since the arrival of endocrine therapy. Yet, resistance to standard treatments is a major clinical challenge for breast cancer specialists and a life-threatening condition for the patients. In breast cancer, mismatch repair (MMR) status assessment has been demonstrated to be clinically relevant not only in terms of screening for inherited conditions such as Lynch syndrome, but also for prognostication, selection for immunotherapy, and early identification of therapy resistance. Peculiar traits characterize the MMR biology in HR+ breast cancers compared to other cancer types. In these tumors, MMR genetic alterations are relatively rare, occurring in ~3 % of cases. On the other hand, modifications at the protein level can be observed also in the absence of gene alterations and vice versa. In HR+ breast cancers, the prognostic role of MMR deficiency has been confirmed by several studies, but its predictive value remains a matter of controversy. The characterization of MMR status in these patients is troubled by the lack of tumor-specific guidelines and/or companion diagnostic tests. For this reason, precise identification of MMR-deficient breast cancers can be problematic. A deeper understanding of the MMR biology and clinical actionability in HR+ breast cancer may light the path to effective tumor-specific diagnostic tools. For a precise MMR status profiling, the specific strengths and limitations of the available technologies should be taken into consideration. This article aims at providing a comprehensive overview of the current state of knowledge of MMR alterations in HR+ breast cancer. The available armamentarium for MMR testing in these tumors is also examined along with possible strategies for a tailored pathological characterization.

scholarly journals CDK4/6 inhibitors in breast cancer: beyond hormone receptor-positive HER2-negative disease

2018 ◽  
Vol 10 ◽  
pp. 175883591881834 ◽  
Author(s):  
Adriana Matutino ◽  
Carla Amaro ◽  
Sunil Verma
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Breast Cancers ◽  
Cyclin Dependent Kinase ◽  
Her2 Positive ◽  
Hormone Receptor Positive ◽  
Epidermal Growth

The development of cyclin-dependent kinase (CDK) 4/6 inhibitors has been more prominent in hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancers, with a significant improvement in progression-free survival (PFS) in first and later lines of metastatic breast cancer (MBC) therapy. Preclinical evidence suggests that there is activity of CDK4/6 inhibitors in nonluminal cell lines. Here, we present a review of the current preclinical and clinical data on the use of CDK inhibitors in HER2-positive and triple-negative breast cancer (TNBC).

scholarly journals Endocrine Therapy in Premenopausal Hormone Receptor–Positive Breast Cancer

2016 ◽  
Vol 12 (11) ◽  
pp. 1148-1156 ◽  
Author(s):  
Amye J. Tevaarwerk ◽  
Kari B. Wisinski ◽  
Ruth M. O’Regan
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Systemic Therapy ◽  
Hormone Receptor ◽  
Randomized Trials ◽  
Early Stage ◽  
Premenopausal Women ◽  
Breast Cancers ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

Systemic therapy for premenopausal women with hormone receptor–positive breast cancer has evolved in the last 5 years, but critical questions remain. Recent randomized trials have demonstrated a benefit for the addition of ovarian suppression to endocrine therapy in patients with breast cancers considered to be at high risk for recurrence, whereas those with lower-risk cancers seem to have a favorable outcome with tamoxifen alone. Two large randomized trials have demonstrated a benefit for extending adjuvant tamoxifen beyond 5 years. Currently the choice of systemic therapy is selected empirically but molecular profiling may, in the near future, provide a more conclusive means of selecting an endocrine therapeutic approach for premenopausal patients. Given that a significant subset of hormone receptor–positive cancers are intrinsically resistant to endocrine agents, as well as the finding that inhibiting cyclin-dependent kinases 4 and 6 and mammalian target of rapamycin appears to potentially reverse this resistance in patients with metastatic disease, evaluation of these agents in the early-stage setting is ongoing.

Endocrine therapy-based strategies with different endocrine sensitivity statuses for hormone receptor positive/HER2 negative metastatic breast cancer: A network meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1062-1062
Author(s):  
Jiani Wang ◽  
Yiqun Han ◽  
Jiayu Wang ◽  
Binghe Xu
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Therapy Resistance ◽  
Optimal Treatment ◽  
Hormone Receptor Positive ◽  
Direct Head

1062 Background: Novel endocrine therapies (ETs) and targeted therapeutic regimens have been developed to dramatically improve the outcome of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC). Since the absence of direct head-to-head comparisons for all regimens, decision-making guidelines are urgently needed for different endocrine sensitivity statuses. This study is to evaluate the efficacy of ET-based regimens in patients with HR+/HER2- MBC and to assess the heterogeneity among different compounds with a particular focus on their ability to improve survival outcomes. Methods: This network meta-analysis of phase II/III randomized controlled trials (RCTs) with at least one ET in HR+/HER2- MBC were enrolled. Based on the endocrine responses, participants were stratified into endocrine therapy sensitivity (ETS) and endocrine therapy resistance (ETR) groups. Primary endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed by bayesian algorithms and primarily measured as surface under the cumulative ranking curve (SUCRA). Results: A total of 42 trials (22917 patients) were included. Regarding PFS, cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) +fulvestrant 500mg (F500) was recommended for the ETS group (SUCRA = 76.92%), while chemotherapy was considered as the most effective option for the ETR group (SUCRA = 73.47%). For visceral metastases, CDK4/6i +aromatase inhibitors (AIs) could provide the extreme efficacy for the ETS group (SUCRA = 63.27%) while the CDK4/6i +F500 (SUCRA = 76.17%) as the prior regimen for the ETR group. For bone-only disease, CDK4/6i+F500 was preferred for both the ETS (SUCRA = 67.04%) and the ETR (SUCRA = 70.24%) group. Concerning OS, CDK4/6i+tamoxifen was estimated as the first-rank regimen for the ETS subgroup (SUCRA = 67.04%) and chemotherapy for the ETR subgroup (SUCRA = 60.02%). Regarding resistance category, abemaciclib +F500 was likely the best option with PFS, for both primary (SUCRA = 69.19%) and secondary ETR (SUCRA = 69.09%) settings, as well as primary ETR associated with OS improvement (SUCRA = 67.67%). Pictilisib +F500 could be the optimal treatment with OS for secondary ETR (SUCRA = 60.50%)group. Conclusions: The results showed that CDK4/6i + F500 was probably the most promising option in ETS, visceral ETR and bone-only disease settings in terms of PFS. OS subgroup analysis showed that different endocrine sensitivity statuses required various optimal treatment strategies.

Update of the Oxford Overview: New Insight and Perspectives in the Era of Personalized Medicine

2012 ◽  
pp. 71-79
Author(s):  
Kathleen I. Pritchard ◽  
Jonas Bergh ◽  
Harold J. Burstein
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Meta Analysis ◽  
Breast Cancers ◽  
Breast Cancer Therapy ◽  
Hormone Receptor Positive ◽  
Er Positive ◽  
Adjuvant Breast Cancer ◽  
Great Appreciation ◽  
Positive Breast Cancer

Overview: There is great appreciation for the heterogeneity of breast cancers, particularly of hormone-receptor positive breast cancers. A goal of modern oncology managing such heterogeneity is to determine how to individualize therapy based on the specific pathological and biological features of a given tumor. Two distinctive clinical literatures exist to guide treatment of hormone-receptor-positive breast cancer. The Oxford Overview, a seminal meta-analysis effort, has recently been updated, and suggests that nearly all patients with ER-positive tumors benefit from adjuvant endocrine therapy. In addition, the overview finds that nearly all subsets of patients with ER-positive tumors also benefit from modern adjuvant chemotherapy regimens. Meanwhile, retrospective subset analyses of specific trials or populations suggests that the benefits of chemotherapy are not so uniform, and in particular that molecular diagnostics assays can identify patients who do not warrant chemotherapy. This article will highlight recent data and controversies in personalizing adjuvant breast cancer therapy.

scholarly journals In vitro anti-cancer effect of Crataegus oxyacantha berry extract on hormone receptor positive and triple negative breast cancers via regulation of canonical Wnt signalling pathway

2021 ◽  
Author(s):  
Salini K ◽  
Niranjali Devaraj Sivasithamparam
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Signalling Pathway ◽  
Breast Cancers ◽  
Hormone Receptor Positive ◽  
Anti Cancer ◽  
Canonical Wnt

Abstract Breast cancer treatment strategy depends mainly on the receptor status. Our aim was to identify a herbal preparation, effective against breast cancer, irrespective of hormone sensitivity, and to understand its molecular mechanism. The rich antioxidant composition of Hawthorn ( Crataegus oxyacantha ) makes it a promising anti-cancer drug candidate. Polyphenol-rich methanolic extract of C. oxyacantha berry (M.Co) was found to be cytotoxic on hormone receptor positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cell lines, at a dose (75 mg/ml) safe on normal cells. It could effectively inhibit tumor cell proliferation and arrest cell cycle at G1/S transition in both cell lines. Molecular targets were selected from different levels of canonical Wnt signalling pathway (such as autocrine and antagonistic ligands, receptor, effector, cytoplasmic components, downstream targets and pathway antagonist), since they are frequently found dysregulated in all breast cancers and their aberrant activation is associated with cancer stem cell expansion. M.Co could significantly downregulate the expression of Wnt pathway agonists and upregulate that of Wnt antagonists at transcriptional and translational levels, in both cell lines. To conclude, C. oxyacantha berry extract is effective against breast cancer irrespective of its hormone dependency and cancer growth inhibition at stem cell level can be expected.

Ki-67 is a Luminal B marker that identifies a high-risk subgroup in hormone receptor positive and node negative breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10521-10521
Author(s):  
M. Cheang ◽  
D. Voduc ◽  
S. Leung ◽  
D. Turbin ◽  
P. S. Bernard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Poor Prognosis ◽  
Cox Regression ◽  
Breast Cancers ◽  
Ki 67 ◽  
Node Negative ◽  
Luminal B ◽  
Poor Outcome ◽  
Hormone Receptor Positive

10521 Background: Gene expression profiling studies have revealed prognostically significant intrinsic breast cancer subtypes, designated Luminal A, Luminal B, Basal and Her2. Expression of ER and associated genes characterizes the luminal breast cancers. The Lum B subgroup is associated with poor outcome, but we lack immunohistochemical (IHC) markers to distinguish Lum A and Lum B subgroups. MKI67 is one gene known to be highly expressed in Lum B tumors, encoding the Ki-67 protein, a robust marker of cell proliferation. In this study, we perform IHC analysis of Ki-67 in a large breast cancer tissue microarray. Methods: Our patient cohort consists of 2222 consecutive cases of invasive breast cancer referred to the BC Cancer Agency from 1986 to 1992. Archival paraffin tissue blocks were used to construct a tissue microarray that was then stained for Ki-67 using a commercially available mouse monoclonal antibody. Ki-67 staining was scored quantitatively by automated image analysis and a tumor was positive if the percent positive nuclei was >30%’ Results: Of the 2,222 patients, there are 1,437 Luminal tumors as defined by IHC (ER or PR positive). As Her2 positive status is an established marker of poor prognosis, we excluded these tumors from our analysis. Of the remaining tumors, 9% were Ki-67 positive when using a ki-67 cut off of 30% positive nuclei. In survival analysis of patients ER/PR positive and Her2 negative, we found that Ki-67 identifies a population with poor prognosis (10-yr BCSS 60% vs. 80%). In a multivariate Cox regression we found that Ki-67 is independently prognostic. We repeated Cox regression analysis including only node negative patients and again found that Ki-67 is an independent predictor of poor outcome. Conclusions: Ki-67 has prognostic significance on multivariate survival analysis. Hormone receptor positive and node negative status is typically associated with a favorable outcome for breast cancer. However, Ki-67 is able to identify a small, but clinically significant subgroup with a particularly poor outcome. Defining the Luminal B subtype as (ER or PR) positive and (HER2 or Ki-67) positive, results in a subgroup that contains 18% of hormone receptor positive breast cancers with 10-yr BCSS of 61%. No significant financial relationships to disclose.

Activation of the PI3K/AKT signal transduction pathway is inversely associated with estrogen receptor levels and correlates with survival in hormone receptor-positive Her2/neu-negative breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10588-10588
Author(s):  
A. M. Gonzalez-Angulo ◽  
B. T. Hennessy ◽  
F. Meric-Bernstam ◽  
Y. Lu ◽  
W. F. Symmans ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Pik3ca Mutation ◽  
Significant Proportion ◽  
Stage I ◽  
Akt Pathway ◽  
Breast Cancers ◽  
Hormone Receptor Positive ◽  
Group 2 ◽  
Group 1

10588 Background: Hormone receptor-positive is the most common subtype of breast cancer. Despite the successes of antihormone therapy alone or combined with chemotherapy, a significant proportion of patients (30–40%) will have primary or acquired resistance to this treatment. There is a need to identify molecular markers to distinguish patients unlikely to benefit from therapy as well as novel targeted therapeutics that increase the response rate. Methods: We used a novel functional proteomics technology, reverse phase protein array (RPPA), to quantify expression and activation of 42 steroid and kinase signaling proteins in 64 hormone receptor-positive-Her2/neu-negative breast cancers from patients with stage I to III tumors managed with non-steroidal aromatase inhibitors ± chemotherapy. Unsupervised clustering analysis was used to molecularly group the tumors. Recurrence-free survival (RFS) was estimated with the Kaplan Meier product limit method and comparison was made using the Log-rank test. Correlation coefficients were used to look at the relationships between two variables. Results: Median age was 57 years (23–79). Sixteen patients (25%) had stage I tumors, 32 (50%) had stage II tumors and 16 (25%) had stage III tumors. There were two well-defined and distinct clusters of tumors: Group 1: ER high (n=25) and Group 2: PI3K/AKT activated (n=39). 3-year RFS estimates were 100% for group 1 and 59% for group 2 (p=0.04). There were thus clear inverse correlations between markers of activation of PI3K pathway and expression of ER (R for pAKT vs ER = -0.26, p=0.03). PIK3CA mutation was detected in 12/58 (21%) of hormone receptor-positive breast cancers and these tumors were found to have a proteomic signature distinct from PTEN loss with the former signature associated with a trend to improved RFS (p=0.06). Conclusion: Activation of the PI3K/AKT pathway in hormone receptor- positive-Her2/neu-negative breast cancer is inversely correlated with ER levels and associated with adverse outcome. At least in some cases, PI3K/AKT pathway activation, may be under the control of genomic aberrations. A validation set of 100 tumors treated with tamoxifen is on- going. No significant financial relationships to disclose.

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