ARID1A Mutation in Metastatic Breast Cancer: A Potential Therapeutic Target

Distant metastasis is the principal cause of mortality for breast cancer patients. Targeting specific mutations that have been acquired during the evolution process of advanced breast cancer is a potential means of enhancing the clinical efficacy of treatment strategies. In metastatic breast cancer, ARID1A is the most prevalent mutation of the SWI/SNF complex, which regulates DNA repair, recombination, and gene transcription. The low expression of ARID1A is associated with poor disease-free survival and overall survival of patients with luminal A or HER2-rich breast cancer. In addition, ARID1A plays a prominent role in maintaining luminal characteristics and has an advantage for identifying responses to treatment, including endocrine therapies, HDAC inhibitors and CDK4/6 inhibitors. The therapeutic vulnerabilities initiated by ARID1A alterations encourage us to explore new approaches to cope with ARID1A mutant-related drug resistance or metastasis. In this review, we describe the mutation profiles of ARID1A in metastatic breast cancer and the structure and function of ARID1A and the SWI/SNF complex as well as discuss the potential mechanisms of ARID1A-mediated endocrine resistance and therapeutic potential.

Download Full-text

Clinical benefit of treatment after trastuzumab emtansine for HER2-positive metastatic breast cancer: a real-world multi-centre cohort study in Japan (WJOG12519B)

Breast Cancer ◽

10.1007/s12282-020-01192-y ◽

2021 ◽

Author(s):

Takamichi Yokoe ◽

Sasagu Kurozumi ◽

Kazuki Nozawa ◽

Yukinori Ozaki ◽

Tetsuyo Maeda ◽

...

Keyword(s):

Breast Cancer ◽

Cohort Study ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Real World ◽

Treatment Strategies ◽

Metastatic Breast ◽

Trastuzumab Emtansine ◽

Breast Cancer Patients ◽

Her2 Positive

Abstract Background Trastuzumab emtansine (T-DM1) treatment for human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer after taxane with trastuzumab and pertuzumab is standard therapy. However, treatment strategies beyond T-DM1 are still in development with insufficient evidence of their effectiveness. Here, we aimed to evaluate real-world treatment choice and efficacy of treatments after T-DM1 for HER2-positive metastatic breast cancer. Methods In this multi-centre retrospective cohort study involving 17 hospitals, 325 female HER2-positive metastatic breast cancer patients whose post-T-DM1 treatment began between April 15, 2014 and December 31, 2018 were enrolled. The primary end point was the objective response rate (ORR) of post-T-DM1 treatments. Secondary end points included disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS). Results The median number of prior treatments of post-T-DM1 treatment was four. The types of post-T-DM1 treatments included (1) chemotherapy in combination with trastuzumab and pertuzumab (n = 102; 31.4%), (2) chemotherapy concomitant with trastuzumab (n = 78; 24.0%), (3), lapatinib with capecitabine (n = 63; 19.4%), and (4) others (n = 82; 25.2%). ORR was 22.8% [95% confidence interval (CI): 18.1–28.0], DCR = 66.6% (95% CI 60.8–72.0), median PFS = 6.1 months (95% CI 5.3–6.7), median TTF = 5.1 months (95% CI 4.4–5.6), and median OS = 23.7 months (95% CI 20.7–27.4). Conclusion The benefits of treatments after T-DM1 are limited. Further investigation of new treatment strategies beyond T-DM1 is awaited for HER2-positive metastatic breast cancer patients.

Download Full-text

Liquid Biopsy: New Tool to Overcome CDKi Resistance Mechanism in Luminal Metastatic Breast Cancer

10.20944/preprints202103.0063.v1 ◽

2021 ◽

Author(s):

Miriam González-Conde ◽

Celso Yanez ◽

Rafael López-López ◽

Clotilde Costa

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Liquid Biopsy ◽

Hormone Receptors ◽

Endocrine Resistance ◽

Metastatic Breast ◽

Luminal Breast Cancer ◽

Breast Cancer Patients ◽

Her2 Breast Cancer

Breast cancer is the most commonly diagnosed cancer in women worldwide. Approximately, 70 % of breast cancer patients express hormone receptors (HR) (Luminal subtype). Adjuvant endocrine treatments are the standard of care in HR+/HER2- breast cancer. Over time, about 50% of those patients develop endocrine resistance and metastatic breast cancer. Cyclin-dependent kinase inhibitors (CDKi) in combination with an aromatase inhibitor or fulvestrant have demonstrated superior efficacy increasing progression-free survival, with a safe toxicity profile, in HR+/HER2- metastatic breast cancer patients. CDKi blocks kinases 4/6 ATP-binding domain preventing G1/S cell cycle transition. Despite this, not all patients respond to CDKi and those who respond, finally develop resistance to combination therapy. Different studies, in tumour tissue or cell lines, have tried to elucidate the mechanisms underlying this progression, but there are still no conclusive data. In the last few years, liquid biopsy has contributed relevant information to this knowledge. Liquid biopsy can be performed in real-time, non-invasively and be repeated whenever needed. Circulating tumour material are potential prognostic markers in metastatic luminal breast cancer to determine patient prognosis, monitor disease and treatment selection. The objective of this review is to outline the different studies carried out in HR+ metastatic breast cancer patients treated with CDKi plus endocrine therapy using liquid biopsy approaches looking for possible resistance mechanisms.

Download Full-text

SHP2 is a multifunctional therapeutic target in drug resistant metastatic breast cancer

Oncogene ◽

10.1038/s41388-020-01488-5 ◽

2020 ◽

Vol 39 (49) ◽

pp. 7166-7180

Author(s):

Hao Chen ◽

Sarah Libring ◽

Kasi Viswanatharaju Ruddraraju ◽

Jinmin Miao ◽

Luis Solorio ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Kinase Inhibitor ◽

Therapeutic Potential ◽

Tyrosine Phosphatase ◽

3D Culture ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

Growth And Survival

AbstractMetastatic breast cancer (MBC) is an extremely recalcitrant disease capable of bypassing current targeted therapies via engagement of several growth promoting pathways. SH2 containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase known to facilitate growth and survival signaling downstream of numerous receptor inputs. Herein, we used inducible genetic depletion and two distinct pharmacological inhibitors to investigate the therapeutic potential of targeting SHP2 in MBC. Cells that acquired resistance to the ErbB kinase inhibitor, neratinib, displayed increased phosphorylation of SHP2 at the Y542 activation site. In addition, higher levels of SHP2 phosphorylation, but not expression, were associated with decreased survival of breast cancer patients. Pharmacological inhibition of SHP2 activity blocked ERK1/2 and AKT signaling generated from exogenous stimulation with FGF2, PDGF, and hGF and readily prevented MBC cell growth induced by these factors. SHP2 was also phosphorylated upon engagement of the extracellular matrix (ECM) via focal adhesion kinase. Consistent with the potential of SHP2-targeted compounds as therapeutic agents, the growth inhibitory property of SHP2 blockade was enhanced in ECM-rich 3D culture environments. In vivo blockade of SHP2 in the adjuvant setting decreased pulmonary metastasis and extended the survival of systemic tumor-bearing mice. Finally, inhibition of SHP2 in combination with FGFR-targeted kinase inhibitors synergistically blocked the growth of MBC cells. Overall, our findings support the conclusion that SHP2 constitutes a shared signaling node allowing MBC cells to simultaneously engage a diversity of growth and survival pathways, including those derived from the ECM.

Download Full-text

The Effectiveness of Lapatinib in HER2-Positive Metastatic Breast Cancer Patients Pretreated With Multiline Anti-HER2 Treatment: A Retrospective Study in China

Technology in Cancer Research & Treatment ◽

10.1177/15330338211037812 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110378

Author(s):

Xinzhao Wang ◽

Lin Wang ◽

Qian Yu ◽

Zhaoyun Liu ◽

Chao Li ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Disease Free Survival ◽

Metastatic Breast ◽

Second Line ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Free Survival ◽

Line Setting

Background: The aim of this study was to evaluate the effectiveness of lapatinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Methods: We retrospectively reviewed the medical records of patients who received lapatinib for salvage treatment at any line setting from January 1, 2007 to August 31, 2019 at Shandong Cancer Hospital and Institute. Results: A total of 115 (89.1%) patients were included in the study. In the overall cohort, the median disease-free survival (DFS) was 19.0 months; the median progression-free survival (PFS), 6.3 months; and median overall survival (OS), 88.0 months, with 32.2% of patients alive at 5 years. In the second line setting, the median PFS among trastuzumab, lapatinib, and trastuzumab plus lapatinib were 4.2 months, 5.2 months, and 7.3 months, respectively ( P = 0.004). No significant differences between the median PFSs and OSs of the different line salvage treatments with lapatinib was observed (all P > 0.05). For brain metastasis patients, the median PFSs in first line, second line, and more than 3 lines were 7.2 months, 4.5 months, and 6.3 months, respectively. Conclusions: Our findings suggest that patients would benefit more from trastuzumab plus lapatinib than from lapatinib or trastuzumab alone for second line treatment in the advanced stages of the disease. Lapatinib could be used as an alternative selection for HER2-positive metastasic breast cancer patients when there is disease progression after trastuzumab or pyrotinib treatment, which is used as part of China’s national health insurance.

Download Full-text

Assessment of Survival and Cardiotoxicity of Adjuvant Trastuzumab among HER2 Breast Cancer Patients in an Oncology Centre in Malaysia

Journal of Clinical and Health Sciences ◽

10.24191/jchs.v3i1.6156 ◽

2018 ◽

Vol 3 (1) ◽

pp. 33

Author(s):

Harissa Husainy Hasbullah ◽

Anita Bustamam ◽

Tho Lye Munn ◽

Vincent Phua

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Disease Free Survival ◽

Metastatic Breast ◽

Left Ventricular ◽

Rank Test ◽

Breast Cancer Patients ◽

Adjuvant Trastuzumab ◽

Her2 Breast Cancer

Introduction: Adjuvant trastuzumab has been used in human epidermal growth factor-2 (HER2) breast cancer to improve survival but with concern of cardiotoxicity. Our study is the first to review efficacy and toxicity of adjuvant trastuzumab in Malaysia. Methods: This is a retrospective cohort study on HER2 non metastatic breast cancer patients in University Malaya Medical Centre diagnosed between October 2006 and May 2011. Two cohorts were created based on whether or not they received adjuvant trastuzumab. Disease free survival (DFS) and overall survival (OS) for both groups were estimated using Kaplan Meier method and compared using Log rank test. Cox proportional hazards regression models analysed for potential covariates of age, tumour size and grade, node and estrogen receptor (ER) status. Trastuzumab cardiotoxicity was defined as left ventricular systolic dysfunction or heart failure with or without symptoms and graded using Common Terminology Criteria for Adverse Events (CTCAE 4.0). Results: 170 HER2 non metastatic breast cancer patients were identified. Thirty-three received trastuzumab and 136 did not. Median age was 53.4 ± 10.3 years old. Significantly more ER negative patients received trastuzumab. Four years DFS in ‘trastuzumab’ versus ‘no trastuzumab’ cohort was 90.9% vs 74.5% (p = 0.027). Four years OS was 91% vs 84.7% (p = 0.30) respectively. Majority tolerated trastuzumab with no toxicity. Five patients (15.2%) experienced cardiotoxicity (all grade I).Conclusions: Adjuvant trastuzumab significantly improved DFS in HER2 breast cancer. Treatment was well tolerated. With this we propose the justification for adjuvant trastuzumab in HER2 breast cancer in our population.

Download Full-text

Comparison of Methods of Measuring HER-2 in Metastatic Breast Cancer Patients Treated With High-Dose Chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.6.1698 ◽

2001 ◽

Vol 19 (6) ◽

pp. 1698-1706 ◽

Cited By ~ 60

Author(s):

Lyndsay N. Harris ◽

Vlayka Liotcheva ◽

Gloria Broadwater ◽

Michael J. Ramirez ◽

Peter Maimonis ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Metastatic Breast Cancer ◽

Prognostic Factor ◽

Alkylating Agents ◽

Disease Free Survival ◽

Metastatic Breast ◽

High Dose ◽

Breast Cancer Patients ◽

Her 2

PURPOSE: HER-2 is overexpressed in 20% to 30% of human breast cancer and is associated with poor outcome. Studies suggest an association between HER-2 overexpression and resistance to alkylating agents. To further evaluate this relationship, we assessed the interaction of HER-2, measured by different methods, and outcome after dose intensification with alkylating agents in metastatic breast cancer. PATIENTS AND METHODS: From 1988 to 1995 at Duke University, 425 patients with metastatic breast cancer were enrolled in a study of high-dose alkylating agents (HDC) with autologous cellular support after doxorubicin-based therapy (AFM). HER-2 was measured in serum for shed extracellular domain (ECD) and in tissue by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). RESULTS: HER-2 ECD was positive in 29% (19 of 65) of patients pre-AFM and in 11.7% (34 of 290) pre-HDC. Higher pre-AFM and higher pre-HDC HER-2 ECD predicted worse overall survival (P = .045 and P = .0096, respectively). HER-2 overexpression by IHC and FISH showed no correlation with worse disease-free survival or overall survival. FISH and ECD were highly specific for IHC (97.3% and 97.7% respectively). However, ECD had a low sensitivity for IHC—only 22% of patients with HER-2 in the primary tumor shed ECD into the serum. CONCLUSION: These data suggest that the method of measuring HER-2 is important in predicting clinical outcome. HER2 ECD may identify a poor prognosis subgroup of HER-2–positive tumors. Lack of association of HER2 by IHC/FISH with worse outcome suggests that therapy with AFM and/or HDC therapy may be able to overcome the effect of this prognostic factor or it may not be a prognostic factor in this setting.

Download Full-text

Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer

Scientific Reports ◽

10.1038/s41598-021-87645-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kanako Hagio ◽

Toraji Amano ◽

Hideyuki Hayashi ◽

Takashi Takeshita ◽

Tomohiro Oshino ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Metastatic Breast Cancer ◽

Endocrine Resistance ◽

Metastatic Breast ◽

Targeted Sequencing ◽

Breast Cancer Patients ◽

Somatic Gene ◽

Estrogen Receptor Positive ◽

Gene Alterations

AbstractClinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients’ prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

Download Full-text

Ca2+ Signaling as the Untact Mode during Signaling in Metastatic Breast Cancer

Cancers ◽

10.3390/cancers13061473 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1473

Author(s):

Dongun Lee ◽

Jeong Hee Hong

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Metastasis ◽

Therapeutic Potential ◽

Tumor Development ◽

Treatment Strategies ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

The Brain ◽

Ca2 Channels

Metastatic features of breast cancer in the brain are considered a common pathology in female patients with late-stage breast cancer. Ca2+ signaling and the overexpression pattern of Ca2+ channels have been regarded as oncogenic markers of breast cancer. In other words, breast tumor development can be mediated by inhibiting Ca2+ channels. Although the therapeutic potential of inhibiting Ca2+ channels against breast cancer has been demonstrated, the relationship between breast cancer metastasis and Ca2+ channels is not yet understood. Thus, we focused on the metastatic features of breast cancer and summarized the basic mechanisms of Ca2+-related proteins and channels during the stages of metastatic breast cancer by evaluating Ca2+ signaling. In particular, we highlighted the metastasis of breast tumors to the brain. Thus, modulating Ca2+ channels with Ca2+ channel inhibitors and combined applications will advance treatment strategies for breast cancer metastasis to the brain.

Download Full-text

Hotspot ESR1 mutations are multimodal and contextual drivers of breast cancer metastasis

10.1101/2021.02.10.430701 ◽

2021 ◽

Author(s):

Zheqi Li ◽

Yang Wu ◽

Megan E. Yates ◽

Nilgun Tasdemir ◽

Amir Bahreini ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Metastasis ◽

De Novo ◽

Endocrine Resistance ◽

Treatment Strategies ◽

Metastatic Breast ◽

Estrogen Receptor Α ◽

Breast Cancer Metastasis ◽

Cell Models

AbstractConstitutively active estrogen receptor-α (ER/ESR1) mutations have been identified in approximately one third of ER+ metastatic breast cancer. Although these mutations are known mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant, but not local recurrences. In concordance with transcriptomic profiling of ESR1 mutant tumors, genome-edited Y537S and D538G cell models have a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally confers enhanced cell-cell contacts while decreased cell-ECM adhesion. Context-dependent migratory phenotypes revealed co-targeting of Wnt and ER as vulnerability. Mutant ESR1 exhibits non-canonical regulation of several metastatic pathways including secondary transactivation and de novo FOXA1-driven chromatin remodeling. Collectively, our data supports evidence for ESR1 mutation-driven metastases and provides insight for future preclinical therapeutic strategies.SignificanceContext and allele-dependent transcriptome and cistrome reprogramming in genome-edited ESR1 mutation cell models elicit diverse metastatic phenotypes, including but not limited to alterations in cell adhesion and migration. The gain-of-function mutations can be pharmacologically targeted, and thus may be key components of novel therapeutic treatment strategies for ER-mutant metastatic breast cancer.

Download Full-text