Higher densities of Foxp3<Superscript>+</Superscript> regulatory T cells are associated with better prognosis in triple-negative breast cancer

Purpose

The role of Forkhead Box Protein 3 (Foxp3) expressing regulatory T cells (Tregs) in breast cancer remains unclear. We examined the abundance and localisation of total T cells, B cells and Tregs within samples from triple-negative breast cancers (TNBCs) and asked whether these parameters were associated with clinicopathological features of the cancer or clinical outcomes.

Methods

Samples from TNBCs diagnosed between 2003 and 2010 in Singapore were divided into “high” and “low” intra-tumoural or stromal groups, based on whether they had higher or lower than median densities of specific tumour-infiltrating lymphocyte populations (CD3⁺ total T cells, Foxp3⁺CD3⁺ Tregs, or CD20⁺ B cells) in the intra-tumoural space or stroma.

Results

Of the 164 samples, patients bearing tumours with high Tregs within their intra-tumoural, but not stromal, areas experienced significantly longer overall and disease-free survival compared to individuals with low Treg densities. These “high intra-tumoural Treg” tumours were also characterised by relatively higher frequencies of CD8⁺ T cells and CD20⁺ B cells, and expressed significantly higher levels of some genes associated with inflammation, immune cell functions and trafficking, altogether consistent with a more “immune-activated” tumour microenvironment, in contrast to tumours bearing lower densities of Tregs.

Conclusions

In summary, the combination of high densities of intra-tumoural Tregs, CD8⁺ T cells and CD20⁺ B cells represents a favourable prognostic panel in TNBCs. These data also indicate new avenues for further investigation on the interaction between immune cell types within the tumour microenvironment and highlight the potential of Treg density and localisation within tumours to affect clinical outcome.

     

The correlation of CD19 + CD24 + CD38 + B cells and other clinicopathological variables with the proportion of circulating Tregs in breast cancer patients

Background

T regulatory cells (Tregs) are known to negatively control immune response. The frequency of these cells was inversely correlated with clinical outcomes of breast cancer. CD19⁺CD24^hiCD38^hi cells also play a critical role in inflammation and autoimmune disease. However, their function in tumor immune response is less studied. In this study we aimed to determine the role of CD19⁺CD24^hiCD38^hi cells and some other clinicopathological variables in increasing the proportion of Tregs in breast cancer patients.

Methods

We selected 47 patients with invasive ductal breast carcinoma and 50 healthy controls and obtained their blood samples.

Results

The proportion of circulating CD4⁺CD25⁺Foxp3⁺ Tregs and CD19⁺CD24^hiCD38^hi cells was significantly increased in breast cancer patients. We also found that increased proportion of Tregs in breast cancer is correlated with HER2 amplification, advanced clinical stages, serum TGF-β1 and increased CD19⁺CD24^hiCD38^hi cells in the peripheral blood.

Conclusion

Altogether, our data suggest that as much as Tregs, CD19⁺CD24^hiCD38^hi B cells could also have a part in the suppression of immune response in breast cancer.

     

Immunotherapy in Breast Cancer: the New Frontier

Purpose of review

This review summarizes current immunotherapies in breast cancer, with an emphasis on immune checkpoint inhibitors and vaccines.

Recent findings

Combination immunotherapy with checkpoint inhibitors and cytotoxic therapies have shown promising results. Active clinical trials are ongoing in both early stage and metastatic settings for triple negative, HER2+, and hormone-positive breast cancer patients.

Summary

Ongoing challenges remain in defining biomarkers that predict response to immunotherapy, determining the optimal combination immunotherapies, and enhancing the immunogenicity of breast cancer subtypes.

     

Body image and psychological distress in women with breast cancer: a French online survey on patients’ perceptions and expectations

Background

Altered body image caused by alopecia, loss of eyebrows or eyelashes, or mastectomy is a major source of psychological distress in women with breast cancer.

Objective

To identify and to assess patients’ perceptions and expectations regarding altered body image.

Method

Opinion survey conducted among patients treated for breast cancer and member of French online support groups. Anonymous online self-administered survey sent to women with breast cancer.

Results

85% of the women interviewed experienced alopecia during treatment and 67% of them loss of eyebrows or eyelashes. About half of patients suffering alopecia and loss of eyebrows or eyelashes reported fearing what others think. Mastectomy was experienced by 84% of the women in our study, but only 32% of them reported fearing what others think. 87% of our study cohort received information about the possibility of adverse events. 70, 56, and 60% of women felt helped by information they received for the management of alopecia, loss of eyebrows or eyelashes, or mastectomy, respectively.

Conclusion

This study confirms that altered body image is a critical psychosocial issue for women with breast cancer. Effective information can be a source of reassurance and may constitute one of the most important sources of emotional support.

     

A population-based audit of ethnicity and breast cancer risk in one general practice catchment area in North London,UK: implications for practice

Objectives

To conduct a pilot population-based study within a general practice catchment area to determine whether the incidence of breast cancer was increased in the Ashkenazi population.

Design

Population-based cohort study.

Setting

A single general practice catchment area in North London.

Participants

1947 women over the age of 16 who responded to a questionnaire about ethnicity and breast cancer.

Main outcome measures

Incidence of breast cancer, ethnicity.

Results

This study showed a 1.5-fold (95% CI 0.93–2.39) increase in breast cancer risk in the Ashkenazim compared with the non-Ashkenazi white population. The increased incidence was for both premenopausal and postmenopausal breast cancer (expected incidence pre:post is 1:4 whereas in the Ashkenazim it was 1:1; 51 and 52% of cases respectively). This increase was not shown in the Sephardim. Asians had a reduction in incidence (OR = 0.44; 95% CI 0.10–1.89). Results were adjusted for other risk factors for breast cancer.

Conclusion

This study showed a 1.5-fold increase in breast cancer rates in Ashkenazim compared with the non-Jewish white population when adjusted for age (i.e. corrections were made to allow comparison of age groups) and this is not observed in the Sephardic population. The proportion of premenopausal breast cancer was just over double that of the general population. This is the first general practice population-based study in the UK to address this issue and has implications for general practitioners who care for patients from the Ashkenazi community.

     

Adolescent diet and risk of breast cancer

Background

Early life exposures, including diet, have been implicated in the etiology of breast cancer.

Methods

A nested case-control study was conducted among participants in the Nurses' Health Study who completed a 24-item questionnaire about diet during high school. There were 843 eligible cases diagnosed between onset of study (1976) and before the return of the high school diet questionnaire (1986), who were matched 10:1 with controls on the basis of age.

Results

Women who had, during adolescence, a higher consumption of eggs, vegetable fat and fiber had a lower risk of breast cancer, whereas risk of breast cancer was increased among women who consumed more butter.

Conclusions

A possible association of elements of adolescent diet with risk of breast cancer is reported, but the findings require confirmation in prospective study.

     

Metastasis of breast cancer prior to invasion

Purpose

The landscape of HER2+ metastatic breast cancer (mBC) treatment is changing due to the availability of new anti-HER2 drugs. The purpose of this study was to assess the current treatment patterns and sequences used in HER2+ mBC in the real-world setting. Secondary objectives were to describe the factors that influence the decision to prescribe a first and second-line antitumour treatment.

Methods

Retrospective chart review of 3068 cases in Spain, Italy, the Netherlands and the UK.

Results

First and second-line treatments and regimens are consistent with the clinical guidelines, especially for recently initiated treatments. Age and performance status (PS) of patients impact treatment patterns: younger patients received more innovative treatments than elderly patients. In addition, while most patients received a first antitumor treatment, the rate of patients who continue to subsequent lines of therapy is low (55% transitioning from 1st to 2nd line; 58% from 2nd to 3rd line). Age and PS are key factors in the decision to prescribe further antitumor treatment.

Conclusion

Fewer HER2+ mBC patients than expected receive a second and third line therapy. Guidelines should make specific recommendations for older patients or those with a poor PS.

     

African American patients with breast cancer have worse prognosis than white patients in certain subtypes and stages

Purpose

Racial disparity of breast cancer in each subtype and substage is not clear.

Methods

We reviewed 156,938 patients with breast cancer from 2010 to 2012 from the National Cancer Institute Surveillance, Epidemiology, and End Results database. Breast cancer was subtyped by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status as HR+/HER2?, HR+/HER2+, HR?/HER2+, and HR?/HER2?.

Results

African American (AA) patients had worse overall survival (OS) and breast cancer cause-specific survival (BCSS) in HR+/HER2? stages III and IV breast cancer and HR?/HER2+ stage IV cancer; they had worse OS but not BCSS in HR+ /HER2? stage II cancer and HR?/HER2? stage II cancer.

Conclusion

AA patients with breast cancer had worse survival in certain subtype and stage, especially in ER+ breast cancer.

     

Antitumor and anticancer stem cell activities of eribulin mesylate and antiestrogens in breast cancer cells

Background

Eribulin mesylate (eribulin), a non-taxane microtubule dynamic inhibitor, has been widely used in the treatment of patients with advanced or metastatic breast cancer. The combined antitumor and anticancer stem cell (CSC) activities of eribulin with endocrine therapeutic agents have not yet been examined in breast cancer cells. We herein investigated the combined effects of eribulin and antiestrogens.

Methods

A panel of eight breast cancer cell lines, including five estrogen receptor (ER)-positive and three ER-negative cell lines, was used. These cells were treated with eribulin and/or the antiestrogen, 4-hydroxytamoxifen or fulvestrant. Their growth inhibitory activities and effects on cell cycle progression, apoptosis, and the CSC population were investigated. CSCs were detected using the CD44/CD24/EpCAM, Aldefluor, and mammosphere assays.

Results

The 50 % growth inhibitory concentrations of eribulin were 0.38–2.64 nM for the eight cell lines tested. Eribulin exhibited significant antitumor activity under estrogen-supplemented conditions in ER-positive breast cancer cells. The combined antitumor activity of eribulin with an antiestrogen was evaluated using the combination index. The combination index was 0.43–1.46 for ER-positive cell lines. The additive antitumor effect of eribulin with 4-OHT was only significant in MCF-7 cells. Eribulin induced the accumulation of G2/M and apoptosis, while antiestrogens induced the retardation of G1–S cell cycle and apoptosis, respectively. Estrogen markedly increased the proportion of CSCs, whereas antiestrogens inhibited increases in ER-positive cell lines. Moreover, eribulin decreased the proportion of CSCs in either ER-positive or ER-negative cell lines. The combined treatment of eribulin with an antiestrogen did not additively decrease the proportion of CSCs in ER-positive cell lines.

Discussion

The results of the present study demonstrated that eribulin had potent antitumor effects on estrogen-stimulated ER-positive breast cancer cells and the combined treatment of eribulin with an antiestrogen resulted in a weakly additive antitumor effect. We herein suggested for the first time that eribulin exhibited anti-CSC effects on either ER-positive or ER-negative breast cancer cells.

     

Breast self-exam and patient interval associate with advanced breast cancer and treatment delay in Mexican women

Purpose

The objective of this study was to compare treatment intervals in breast cancer patients according to the detection method (breast self-exam vs screening).

Patients and methods

We conducted a retrospective analysis including 291 breast cancer patients at a Mexican tertiary referral hospital.

Results

Breast cancer detection method was mostly breast self-exam (60%). The median patient interval was 60.5 days, and was associated with marital status and socioeconomic level. Differences between the two groups were statistically significant for global interval, p = 0.002; however, health system interval was not statistically different.

Conclusion

In our country, breast cancer screening is opportunistic, with several weaknesses within its management and quality systems. Our study showed that even in specialized health care centers, breast cancer is detected by self-exam in up to 2/3 of patients, which can explain the advanced stages at diagnosis in our country. In developing countries, the immediate health care access for breast cancer patients should be prioritized as an initial step to reduce the global treatment initiation interval in order to reduce mortality.

     

Therapeutic alliance and treatment outcome in psychodynamic psychotherapy of depressed breast cancer patients: the same old story or different from other populations?

Background

A good therapeutic alliance is associated with better treatment outcomes in diverse types of psychotherapy and patient populations, but little is known about therapeutic alliance in psychotherapies with cancer patients. This study examines the association of therapeutic alliance and treatment outcome in short term psychodynamic psychotherapy (STPP) for breast cancer patients.

Methods

Within a randomized controlled trial, 47 completers of STPP could be included in the analyses. The therapeutic alliance was assessed by patients and therapists at treatment termination with the Helping Alliance Questionnaire. Outcome was defined as no diagnosis of depression assessed with Structured Clinical Interview for DSM-IV (SCID-I) and a reduction of the HADS-depression score by at least two points at treatment termination.

Results

Patients’ alliance ratings were significantly associated with outcome (r = 0.46, p = 0.015), while, in contrast to findings in non-cancer populations, therapists’ ratings were unrelated. There was no association between patients’ and therapists’ ratings of therapeutic alliance. Especially success and working related aspects of patients’ alliance scores were associated with outcome. Patients’ and therapists’ alliance scores were unrelated to any of their baseline characteristics, therapist characteristic or treatment variables.

Conclusion

We conclude that therapists should regularly assess the quality of patients’ perceived therapeutic alliance in the course of psychotherapy with breast cancer patients to improve psychotherapy outcome. The breast cancer patients’ perspective should be actively inquired and considered throughout treatment by therapists. Possible discrepancies between both judgements can be addressed in treatment.

     

New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth

Purpose

Combining molecular therapies with chemotherapy may offer an improved clinical outcome for chemoresistant tumours. Sphingosine-1-phosphate (S1P) receptor antagonist and sphingosine kinase 1 (SK1) inhibitor FTY720 (FTY) has promising anticancer properties, however, it causes systemic lymphopenia which impairs its use in cancer patients. In this study, we developed a nanoparticle (NP) combining docetaxel (DTX) and FTY for enhanced anticancer effect, targeted tumour delivery and reduced systemic toxicity.

Methods

Docetaxel, FTY and glucosamine were covalently conjugated to poly(lactic-co-glycolic acid) (PLGA). NPs were characterised by dynamic light scattering and electron microscopy. The cellular uptake, cytotoxicity and in vivo antitumor efficacy of CNPs were evaluated.

Results

We show for the first time that in triple negative breast cancer cells FTY provides chemosensitisation to DTX, allowing a four-fold reduction in the effective dose. We have encapsulated both drugs in PLGA complex NPs (CNPs), with narrow size distribution of ~ 100 nm and excellent cancer cell uptake providing sequential, sustained release of FTY and DTX. In triple negative breast cancer cells and mouse breast cancer models, CNPs had similar efficacy to systemic free therapies, but allowed an effective drug dose reduction. Application of CNPs has significantly reversed chemotherapy side effects such as weight loss, liver toxicity and, most notably, lymphopenia.

Conclusions

We show for the first time the DTX chemosensitising effects of FTY in triple negative breast cancer. We further demonstrate that encapsulation of free drugs in CNPs can improve targeting, provide low off-target toxicity and most importantly reduce FTY-induced lymphopenia, offering potential therapeutic use of FTY in clinical cancer treatment.

     

Prognostic and predictive value of tumor-infiltrating lymphocytes in breast cancer: a systematic review and meta-analysis

Background

Breast cancer is the most common invasive cancer to affect women in the world. Studies showed tumor-infiltrating lymphocytes can exhibit both beneficial and harmful effects on the biology and clinical outcome of breast cancer, the conclusion still remains incomplete. Here, we conducted a meta-analysis to evaluate the relationship between tumor-infiltrating lymphocytes and breast cancer.

Methods

A comprehensive search strategy was used to search relevant literatures in PubMed and the ISI Web of Science. The correlation among TILs and breast cancer clinicopathological features and prognosis was analyzed by using Review Manager 5.3 and Stata 12.0.

Result

Seventeen eligible studies consisting of 12,968 participants were included. We found that higher value of tumor-infiltrating lymphocytes had no relationship with breast cancer clinicopathological variables. Interestingly, it was correlated with response to neoadjuvant chemotherapy in majority (pooled RR 2.43, 95 % CI 1.99–2.97). Moreover, higher value of total tumor-infiltrating lymphocytes (both intraepithelial and stromal) was associated with better prognosis (pooled HR 0.88, 95 % CI 0.83–0.94), whereas some subtypes predicted a worse prognosis.

Conclusion

This meta-analysis indicated that high value of total TILs is not associated with breast cancer clinicopathological features, but can predict a favorable outcome for neoadjuvant chemotherapy in majority except for hormone receptor (?) subtype. And higher total TILs (both intraepithelial TILs and stromal TILs) may be the potential better prognostic indicators, while some subtypes like PD-1⁺ TILs and Foxp3⁺ TILs show a worse prognosis.

     

Amplification of <Emphasis Type="Italic">SOX4</Emphasis> promotes PI3K/Akt signaling in human breast cancer

Purpose

The PI3K/Akt signaling axis contributes to the dysregulation of many dominant features in breast cancer including cell proliferation, survival, metabolism, motility, and genomic instability. While multiple studies have demonstrated that basal-like or triple-negative breast tumors have uniformly high PI3K/Akt activity, genomic alterations that mediate dysregulation of this pathway in this subset of highly aggressive breast tumors remain to be determined.

Methods

In this study, we present an integrated genomic analysis based on the use of a PI3K gene expression signature as a framework to analyze orthogonal genomic data from human breast tumors, including RNA expression, DNA copy number alterations, and protein expression. In combination with data from a genome-wide RNA-mediated interference screen in human breast cancer cell lines, we identified essential genetic drivers of PI3K/Akt signaling.

Results

Our in silico analyses identified SOX4 amplification as a novel modulator of PI3K/Akt signaling in breast cancers and in vitro studies confirmed its role in regulating Akt phosphorylation.

Conclusions

Taken together, these data establish a role for SOX4-mediated PI3K/Akt signaling in breast cancer and suggest that SOX4 may represent a novel therapeutic target and/or biomarker for current PI3K family therapies.

     

Breast Cancer Heterogeneity: Roles in Tumorigenesis and Therapeutic Implications

Purpose of review

Breast cancer heterogeneity constitutes a significant investigational and therapeutic challenge. Here we review recent findings on breast cancer heterogeneity, focusing on its extent across the distinct molecular subtypes, the degree of spatial and temporal intra-tumor heterogeneity, and possible approaches to dissect and counteract it.

Recent findings

Recent massively parallel sequencing studies have solidified the notion that estrogen receptor (ER)-positive and ER-negative breast cancers have divergent genetic landscapes. Numerous studies have addressed the origins of heterogeneity and the challenges it poses for patient management; however, its dynamic evolution in the light of novel targeted therapies is yet to be fully understood.

Summary

Tumor heterogeneity poses diagnostic and therapeutic challenges. Implementation of novel methodologies, such as single cell sequencing and analysis of cell-free DNA, might afford us the means to comprehend intra-tumor heterogeneity with greater precision, and to overcome the diagnostic and therapeutic challenges posed by it.

     

Programmed cell death protein 1 expression is an independent prognostic factor in gastric cancer after curative resection

Background

Programmed cell death protein 1 (PD-1) and its ligand PD-L1 downregulate T cell activation and are related to immune tolerance. The aim of this study was to clarify the significance of PD-1 and PD-L1 expression and to analyze the relationships among PD-1, PD-L1, and Foxp3 expression in gastric cancer.

Methods

A total of 105 patients who underwent curative gastrectomy for stage II/III gastric cancer were included in this study. PD-1, PD-L1, and Foxp3 expression were examined by immunohistochemistry and related to prognostic factors by univariate and multivariate analyses.

Results

PD-1 expression was correlated with both PD-L1 and Foxp3 expression. Disease-free survival (DFS) was significantly poorer in PD-1-positive patients than in PD-1-negative patients (3-year DFS, 36.1 % vs. 64.7 %, respectively; p < 0.05). Overall survival also tended to be poorer in PD-L1-positive patients than in PD-L1-negative patients. Univariate analysis identified sex, T factor, lymphatic invasion, and PD-1 positivity as significant predictors of poor DFS. Multivariate analysis confirmed male sex, lymphatic invasion, and positive PD-1 expression as independent prognostic indicators.

Conclusions

PD-1 expression is associated with a poor prognosis and is correlated with PD-L1 and Foxp3 expression in patients with gastric cancer.

     

Racial disparities in chemotherapy administration for early-stage breast cancer: a systematic review and meta-analysis

Background

MicroRNAs constitute a large family of non-coding RNAs, which actively participate in tumorigenesis by regulating a set of mRNAs of distinct signaling pathways. An altered expression of these molecules has been found in different tumorigenic processes of breast cancer, the most common type of cancer in the female population worldwide.

Purpose

The objective of this review is to discuss how miRNAs become master regulators in breast tumorigenesis.

Methods

An integrative review of miRNAs and breast cancer literature from the last 5 years was done on PubMed. We summarize recent works showing that the defects on the biogenesis of miRNAs are associated with different breast cancer characteristics. Then, we show several examples that demonstrate the link between cellular processes regulated by miRNAs and the hallmarks of breast cancer. Finally, we examine the complexity in the regulation of these molecules as they are modulated by other non-coding RNAs and the clinical applications of miRNAs as they could serve as good diagnostic and classification tools.

Conclusion

The information presented in this review is important to encourage new directed studies that consider microRNAs as a good tool to improve the diagnostic and treatment alternatives in breast cancer.

     

Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic,differentiating, and chemotherapeutic agents in triple-negative breast cancer

Background

A combination of entinostat, all-trans retinoic acid, and doxorubicin (EAD) induces cell death and differentiation and causes significant regression of xenografts of triple-negative breast cancer (TNBC).

Methods

We investigated the mechanisms underlying the antitumor effects of each component of the EAD combination therapy by high-throughput gene expression profiling of drug-treated cells.

Results

Microarray analysis showed that entinostat and doxorubicin (ED) altered expression of genes related to growth arrest, inflammation, and differentiation. ED downregulated MYC, E2F, and G2M cell cycle genes. Accordingly, entinostat sensitized the cells to doxorubicin-induced growth arrest at G2. ED induced interferon genes, which correlated with breast tumors containing a higher proportion of tumor-infiltrating lymphocytes. ED also increased the expression of immune checkpoint agonists and cancer testis antigens. Analysis of TNBC xenografts showed that EAD enhanced the inflammation score in nude mice. Among the genes differentially regulated between the EAD and ED groups, an all-trans retinoic acid (ATRA)-regulated gene, DHRS3, was induced in EAD-treated xenografts. DHRS3 was expressed at lower levels in human TNBC metastases compared to normal breast or primary tumors. High expression of ED-induced growth arrest and inflammatory genes was associated with better prognosis in TNBC patients.

Conclusions

Entinostat potentiated doxorubicin-mediated cell death and the combination induced inflammatory signatures. The ED-induced immunomodulation may improve immunotherapy. Addition of ATRA to ED may potentiate inflammation and contribute to TNBC regression.

     

Rolle des Pathologen in Hinblick auf therapeutische Entscheidungen beim Magenkarzinom

Background

The role of pathologists in gastric cancer management is expanding to tumor subtyping analogous to recent genetic findings and the detection of biomarkers to reveal additional therapeutic options.

Objective

The purpose of this article is to provide an overview of the current role of pathologists in gastric cancer and particularly with respect to guiding therapeutic decisions.

Methods

This article is based on a selective literature review using PubMed database and World Health Organization (WHO) publications in particular on the clinically relevant problems in gastric cancer which pathologists are currently confronted with.

Conclusion

New sequencing techniques recently allowed a molecular-based classification of gastric carcinoma. The results underline the overlap between morphologically and molecularly defined subtypes which can provide guidelines for biomarker exploration aimed at disclosing new therapeutic options.