Evolution of breast cancer therapeutics: Breast tumour kinase’s role in breast cancer and hope for breast tumour kinase targeted therapy

There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific with reduced toxicity leading to further increases in patients’ overall survival; the ongoing progress in understanding recurrence, resistant and spread also needs to be maintained. Better understanding of breast cancer pathology, molecular biology and progression as well as identification of some of the underlying factors involved in breast cancer tumourgenesis and metastasis has led to the identification of novel therapeutic targets. Over a number of years interest has risen in breast tumour kinase (Brk) also known as protein tyrosine kinase 6; the research field has grown and Brk has been described as a desirable therapeutic target in relation to tyrosine kinase inhibition as well as disruption of its kinase independent activity. This review will outline the current “state of play” with respect to targeted therapy for breast cancer, as well as discussing Brk’s role in the processes underlying tumour development and metastasis and its potential as a therapeutic target in breast cancer.     

β-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis

A role of WNT signaling for primary breast cancers of the basal-like subtype and as a predictor of brain metastasis has been described. However, a responsible WNT ligand has not been identified. To further clarify this question, we comparatively investigated 22 human breast cancer brain metastases as well as the highly invasive human breast cancer cell line MDA-MB-231 and the weakly motile MCF-7 as models for the basal-like and the luminal A subtype. WNT5A and B were found overexpressed in MDA-MB-231 cells as compared with MCF-7. This corresponded to reduction of MDA-MB-231 invasiveness by WNT inhibitors, whereas MCF-7 invasion was enhanced by recombinant WNT5B and abolished by WNT and Jun-N-terminal kinase antagonists. Expression and subcellular distribution of β-catenin remained uninfluenced. Consistently, β-catenin was not localized in the nuclei of brain metastases while there was strong nuclear c-Jun staining. Similar to MDA-MB-231, metastases showed expression of WNT5A/B and the alternative WNT receptors ROR1 and 2. These findings were validated using external gene expression datasets (Gene Expression Omnibus) of different breast cancer subtypes and brain metastases. Hierarchical cluster analysis yielded a close relation between basal-like cancers and brain metastases. Gene set enrichment analyses confirmed WNT pathway enrichment not only in basal-like primaries but also in cerebral metastases of all subtypes. In conclusion, WNT signaling seems highly relevant for basal-like and other subtypes of breast cancers metastasizing into the brain. β-catenin-independent WNT signaling, presumably via ROR1-2, plays a major role in this context.     

Addition of the p110α inhibitor BYL719 overcomes targeted therapy resistance in cells from Her2-positive-PTEN-loss breast cancer

Tumor Biology - Breast cancer is one of the leading causes of death for women worldwide. Among various subtypes of breast cancer, human epidermal growth factor receptor 2 (HER2)-positive and...     

Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype?

Significant research has been conducted to better understand the extensive, heterogeneous molecular features of triple-negative breast cancer (TNBC). We reviewed published TNBC molecular classifications to identify major groupings that have potential for clinical trial development. With the ultimate aim to streamline translational medicine, we linked these categories of TNBC according to their gene-expression signatures, biological function, and clinical outcome. To this end, we define five potential clinically actionable groupings of TNBC: 1) basal-like TNBC with DNA-repair deficiency or growth factor pathways; 2) mesenchymal-like TNBC with epithelial-to-mesenchymal transition and cancer stem cell features; 3) immune-associated TNBC; 4) luminal/apocrine TNBC with androgen-receptor overexpression; and 5) HER2-enriched TNBC. For each defined subtype, we highlight the major biological pathways and discuss potential targeted therapies in TNBC that might abrogate disease progression. However, many of these potential targets need clinical validation by clinical trials. We have yet to know how we can enrich the targets by molecular classifications.     

Novel HER2–targeted therapies for HER2–positive metastatic breast cancer

Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of all breast cancers. Before the development of HER2-directed monoclonal antibodies, HER2–positive breast cancer was associated with a rather poor prognosis. With the advent of monoclonal HER2–targeting antibodies (trastuzumab and pertuzumab) and antibody-drug conjugates (trastuzumab emtansine [T-DM1] and trastuzumab deruxtecan), clinical outcomes for HER2–positive breast cancer have dramatically changed, and a greater proportion of patients in the nonmetastatic setting are cured. However, in the metastatic setting, resistance to anti-HER2 treatments still remains a major therapeutic challenge, underscoring the importance of developing novel HER2-directed therapies. Over the last year, there has been a dramatic shift in the current treatment paradigms for HER2–positive metastatic breast cancer, with recent U.S. Food and Drug Administration approvals of trastuzumab deruxtecan (DS-8201), neratinib, and tucatinib in combination with trastuzumab and capecitabine. The authors summarize recent phase 3 data with novel HER2–targeted therapies as well as phase 1 and 2 data with other novel HER2–targeting agents.     

The ��2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells

In this study, ??2-AR level was found to be up-regulated in MCF-7 cells overexpressing Her2 (MCF-7/Her2). Correlation of ??2-AR level with Her2 status was demonstrated in breast cancer tissue samples. Constitutive phosphorylation of ERK, mRNA expression up-regulation of catecholamine-synthesis enzymes, and increased epinephrine release were detected in MCF-7/Her2 cells. ??2-AR expression induced by epinephrine and involvement of ERK signaling were validated. The data indicate that Her2 overexpression and excessive phosphorylation of ERK cause epinephrine autocrine release from breast cancer cells, resulting in up-regulation of ??2-AR expression. The data also showed that catecholamine prominently stimulated Her2 mRNA expression and promoter activity. The activation and nuclear translocation of STAT3 triggered by isoproterenol were observed. Enhanced binding activities of STAT3 to the Her2 promoter after isoproterenol stimulation were verified. Using STAT3 shRNA and dominant negative STAT3 mutant, the role of STAT3 in isoproterenol-induced Her2 expression was further confirmed. The data support a model where ??2-AR and Her2 comprise a positive feedback loop in human breast cancer cells.     

Primary metastatic breast cancer in the era of targeted therapy – Prognostic impact and the role of breast tumour surgery

BackgroundExcept for meeting the individual palliative need, the benefit of breast surgery in primary metastatic breast cancer (PMBC), also known as de novo metastatic breast cancer, on long-term outcomes remains controversial. Twenty-four hundred and one patients with metastatic breast cancer, enrolled between 2000 and 2011 in two prospective non-interventional studies on targeted therapy, were screened with respect to this question.MethodsOne study investigated trastuzumab therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer in addition to mainly first-line chemotherapy. The other observed bevacizumab added to chemotherapy as first-line treatment for mostly HER2-negative disease.ResultsFive-hundred and seventy (24%) patients presented with PMBC, and valid information on resection of the primary tumour was available for 568 women. Out of these, 426 (75%) underwent local resection. The latter group was characterised by less overall metastatic burden and a lower proportion of T4 tumours. No major differences were observed with respect to age, hormone receptor and HER2 status, visceral disease and performance status. Numerically, the surgery group showed a slightly favourable progression-free survival (PFS, medians: 13.6 versus 11.8 months; P = 0.18) and overall survival (OS, 34.1 versus 31.7; P = 0.23). However, in multivariable analysis, including all other univariably significant parameters, no trend for better outcome after surgery remained detectable, neither for PFS (hazard ratio 0.99; P = 0.92) nor for OS (0.95; P = 0.71).ConclusionsOur findings suggest no major survival benefit for local resection in the overall PMBC population treated with modern targeted therapies. However, further analyses are warranted to define specific risk groups, which may benefit from surgical removal of the primary.     

Is there a role of breast pathologist in diagnostic challenges of discordances in ER,PR, and HER2 between primary breast cancer and brain metastasis?

Journal of Neuro-Oncology - In Table 2 of the original publication, there were errors in the baseline scores for the PedsQL TM 3.0 Cancer Module questionnaire, so a corrected version of...     

Will nanotechnology influence targeted cancer therapy?

The rapid development of techniques that enable synthesis (and manipulation) of matter on the nanometer scale and the development of new nanomaterials will play a large role in disease diagnosis and treatment, specifically in targeted cancer therapy. Targeted nanocarriers are an intriguing means to selectively deliver high concentrations of cytotoxic agents or imaging labels directly to the cancer site. Often, solubility issues and an unfavorable biodistribution can result in a suboptimal response of novel agents even though they are very potent. New nanoparticulate formulations allow simultaneous imaging and therapy ("theranostics"), which can provide a realistic means for the clinical implementation of such otherwise suboptimal formulations. In this review, we did not attempt to provide a complete overview of the rapidly enlarging field of nanotechnology in cancer; rather, we presented properties specific to nanoparticles and examples of their uses, which show their importance for targeted cancer therapy.     

Hormone therapy in breast cancer: the end of tamoxifen?

The rise of aromatase inhibitors changes our habits in hormonal treatment in breast cancer. In premenopausal women tamoxifen with ovarian suppression remains reference treatment although the succession of the two treatments has not been explored as far as treatment duration is concerned. In post menopausal women the use of AI in the first line treatment gives a greater chance of response and a longer response duration than tamoxifen with a good tolerance profile. When both treatments are used, total duration of endocrine therapy (time to chemotherapy) is significantly longer for patients who receive AI in first line than for patients who receive tamoxifen first. In adjuvant treatment, tamoxifen and ovarian suppression remain references in premenopausal patients; therefore trials using aromatase inhibitors with LH-RH agonists are running. In post menopausal women aromatase inhibitors are challenging tamoxifen. Three large trials proved their superiority over tamoxifen. In the adjuvant setting AI may represent a beneficial approach, they can be used up front or in sequence with tamoxifen. The ideal combination or sequence of therapies requires investigations. At last duration of hormonal treatment remains an open deal.     

Targeting αV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain metastasis model

Brain metastases commonly occur in patients with breast, lung and melanoma systemic cancers. The anti-α(V) integrin monoclonal antibody intetumumab binds cell surface proteins important for adhesion, invasion and angiogenesis in the metastatic cascade. The objective of this study was to investigate the anti-metastatic effect of intetumumab in a hematogenous breast cancer brain metastasis model. Female nude rats received intra-carotid infusion of human brain-seeking metastatic breast cancer cells (231BR-HER2) and were randomly assigned into four groups: (1) control; (2) intetumumab mixed with cells in vitro 5?min before infusion without further treatment; (3) intetumumab intravenously 4?h before and weekly after cell infusion; (4) intetumumab intravenously weekly starting 7?days after cell infusion. Brain metastases were detected by magnetic resonance imaging (MRI) and immunohistochemistry. Comparisons were made using the Kruskal-Wallis test and Dunnett's test. Survival times were estimated using Kaplan-Meier analysis. All control rats with brain tissue available for histology (9 of 11 rats) developed multiple brain metastases (median?=?14). Intetumumab treatment either in vitro prior to cell infusion or intravenous before or after cell infusion prevented metastasis formation on MRI and decreased the number of metastases on histology (median?=?2, p?=?0.0055), including 30?% of animals without detectable tumors at the end of the study. The overall survival was improved by intetumumab compared to controls (median 77+ vs. 52?days, p?=?0.0277). Our results suggest that breast cancer patients at risk of metastases might benefit from early intetumumab treatment.     

In-utero exposures and breast cancer risk: joint effect of estrogens and insulin-like growth factor?

Initial evidence from observational studies led to the suggestion that high maternal estrogens in-utero are central factors in the development of adult breast cancer. Subsequently, several studies attempted to illuminate this hypothesis, but few of the more detailed observational studies show a clear and strong association between prenatal estrogen exposure and breast cancer risk in adulthood. To date, the potential underlying biological mechanisms remain unclear and controversial. However, recent observations of a relation between insulin-like growth factor-1 (IGF-1) and breast cancer risk may shed new light on the role of in-utero exposure, early growth, and risk of breast cancer. More research is needed to elucidate this potential mechanism.     

Obesity and poor breast cancer prognosis: an illusion because of hormone replacement therapy?

High body mass index (BMI) and use of hormone replacement therapy (HRT) increase the risk of postmenopausal breast cancer. It has been shown that BMI modifies the effect of HRT, as its influence is most pronounced in lean women. We investigated the influence of BMI and HRT on prognosis in 2640 postmenopausal women diagnosed with breast cancer in Sweden in 1993–1995, taking into account HRT and mammography before diagnosis. Logistic and Cox regression were used. In non-users of HRT, obese women (BMI >30) compared with normal weight women (BMI <25) had a similar prognosis (hazard ratio (HR) 1.1, 95% confidence interval (CI) 0.8–1.6), despite larger tumours found in obese women. Obese HRT users had less favourable tumour characteristics and poorer prognosis compared with normal weight women (HR 3.7, 95% CI 1.9–7.2). The influence of BMI on breast cancer prognosis was similar whether diagnosed by mammographic screening or not. We found a similar prognosis of postmenopausal breast cancer-specific death regardless of BMI in non-users of HRT, but among HRT users obesity was associated with a poorer breast cancer prognosis.     

Targeted therapies in breast cancer: are heart and vessels also being targeted?

The concept of 'targeted' therapies implies that such drugs only act on cells that specifically express the particular target, therefore giving rise to a low incidence of side effects. However, targeted therapies currently approved for the treatment of breast cancer have demonstrated a relatively high incidence of cardiovascular events. The anti-HER2 agents trastuzumab and lapatinib may cause left ventricular dysfunction or even congestive heart failure. Bevacizumab, an antiangiogenic drug, has been shown to increase the risk of hypertension, cardiovascular dysfunction and thromboembolic events. In addition, several anti-human epidermal growth factor receptor 2 (HER2) and antiangiogenic agents plus their combinations are currently being developed and evaluated for the treatment of breast cancer. In this review, we aim to assess the incidence of cardiac adverse events associated with targeted therapies designed to block HER2 and angiogenic pathways.