Clinical verification of sensitivity to preoperative chemotherapy in cases of androgen receptor-expressing positive breast cancer.
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ABSTRACT:
SUBMITTER: Asano Y
PROVIDER: S-EPMC4716546 | biostudies-other | 2016 Jan
REPOSITORIES: biostudies-other
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Project description:PurposeThe body mass index (BMI) is commonly used as a simple indicator of obesity; patients with early-stage breast cancer who are obese (OB) per BMI measurements have been shown to have high postoperative recurrence and low survival rates. On the other hand, it has been shown that lymphocytes present in the vicinity of malignant growths that are involved in the tumors' immune responses influence the efficacy chemotherapy. Therefore, we hypothesized that OB patients with breast cancer have a lower density of tumor-infiltrating lymphocytes (TILs), which may influence the therapeutic effect of preoperative chemotherapy (POC). In this study, we measured pretreatment BMI and TILs in patients with breast cancer who underwent POC, examined the correlations between these two factors, and retrospectively analyzed their therapeutic outcomes and prognoses.MethodsThe participants in this study were 421 patients with breast cancer who underwent surgical treatment after POC between February 2007 and January 2019. The patient's height and weight were measured before POC to calculate the BMI (weight [kg] divided by the square of the height [m2]). According to the World Health Organization categorization, patients who weighed under 18.5 kg/m2 were classified as underweight (UW), those ≥18.5 kg/m2 and > 25 kg/m2 were considered normal weight (NW), those ≥25 kg/m2 and < 30 kg/m2 were overweight (OW), and those ≥30 kg/m2 were OB. The TILs were those lymphocytes that infiltrated the tumor stroma according to the definition of the International TILs Working Group 2014.ResultsThe median BMI was 21.9 kg/m2 (range, 14.3-38.5 kg/m2); most patients (244; 64.5%) were NW. Among all 378 patients with breast cancer, the TIL density was significantly lower in OB than in NW and OW patients (vs. NW: p = 0.001; vs. OW: p = 0.003). Furthermore, when examining patients with each breast cancer type individually, the OS of those with TNBC who had low BMIs was significantly poorer than that of their high-BMI counterparts (log rank p = 0.031).ConclusionsOur data did not support the hypothesis that obesity affects the tumor immune microenvironment; however, we showed that being UW does affect the tumor immune microenvironment.
| S-EPMC8529767 | biostudies-literature
Project description:PurposeHormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer is associated with low levels of stromal tumor-infiltrating lymphocytes (sTIL) and PD-L1, and demonstrates poor responses to checkpoint inhibitor therapy. Evaluating the effect of standard chemotherapy on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches to treating HR+/HER2- breast tumors.Experimental designHR+/HER2- breast tumors were analyzed before and after neoadjuvant chemotherapy. sTIL were assessed histologically; CD8+ cells, CD68+ cells, and PD-L1 staining were assessed immunohistochemically; whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed.ResultsNinety-six patients were analyzed from two cohorts (n = 55, Dana-Farber cohort; n = 41, MD Anderson cohort). sTIL, CD8, and PD-L1 on tumor cells were higher in tumors with basal PAM50 intrinsic subtype. Higher levels of tissue-based lymphocyte (sTIL, CD8, PD-L1) and macrophage (CD68) markers, as well as gene expression markers of lymphocyte or macrophage phenotypes (NanoString or CIBERSORT), correlated with favorable response to neoadjuvant chemotherapy, but not with improved distant metastasis-free survival in these cohorts or a large gene expression dataset (N = 302). In paired pre-/postchemotherapy samples, sTIL and CD8+ cells were significantly decreased after treatment, whereas expression analyses (NanoString) demonstrated significant increase of multiple myeloid signatures. Single gene expression implicated increased expression of immunosuppressive (M2-like) macrophage-specific genes after chemotherapy.ConclusionsThe immune microenvironment of HR+/HER2- tumors differs according to tumor biology. This cohort of paired pre-/postchemotherapy samples suggests a critical role for immunosuppressive macrophage expansion in residual disease. The role of macrophages in chemoresistance should be explored, and further evaluation of macrophage-targeting therapy is warranted.
| S-EPMC6677598 | biostudies-literature
Project description:Background: Numerous studies have focused on the PI3K/AKT/mTOR pathway in estrogen receptor positive (ER) breast cancer (BC), as a linear signal transduction pathway and reported its association with worse clinical outcomes. To gain better insight into the relative contribution of each of the signalling pathways which lie downstream to PI3K (namely AKT and mTOR) to BC outcomes, we have developed a novel in silico approach which assessed the activation of each of these signalling pathways separately. Methods: By analysing gene expression and matched proteomic data in ER-positive patients from the TCGA repository, we developed gene signatures that reflect the level of expression of phosphorylated-Serine473-AKT (pAKT) and phosphorylated-Serine2448-mTOR (p-mTOR) separately, capturing their corresponding level of pathway activation. Using pooled analysis of gene-expression data from over 7,000 patients with ER-positive early BC, we then investigated the association between pathway activation and outcomes. Results: Our analysis revealed that the pAKT pathway activation (as measured by the developed signature) was associated with luminal A BC while the p-mTOR pathway activation was more associated with luminal B BC (Kruskal-Wallis test p<10-10). pAKT pathway activation was significantly associated with better outcomes (multivariable HR, 0.79; 95% CI, 0.74 to 0.85; p=2.5x10-10) whereas p-mTOR pathway activation showed worse outcomes (multivariable HR, 1.1; 95% CI, 1.1 to 1.2; p=9.9x10-4). Similar associations between activation and outcomes were obtained when the analysis was performed in patients who were treated with hormonal therapy. Additionally, pAKT pathway activation predicted better outcomes irrespective of the BC molecular subtypes (luminal A multivariable HR, 0.85; 95% CI, 0.75 to 0.96; p=0.01; luminal B HR, 0.91; 95% CI, 0.83 to 0.99; p=0.033). pAKT pathway activation was associated with PIK3CA mutations (p=0.0001) while p-mTOR pathway activation was associated with p53 mutations (p=0.04). Finally, we show that pAKT pathway activation was associated with less response to Everolimus. Conclusions: Our data show that pAKT and p-mTOR pathway activation have differing impact on prognosis and suggest that they are not linearly connected in luminal breast cancers. These findings add to our understanding of signalling through the PI3K pathway and could have important implications for the treatment of luminal BC.
2018-12-14 | GSE123832 | GEO
Project description:INTRODUCTION:Triple negative breast cancer (TNBC) is a heterogeneous collection of biologically diverse cancers, which contributes to variable clinical outcomes. Previously, we identified a TNBC subtype that has a luminal phenotype and expresses the androgen receptor (AR+). TNBC cells derived from these luminal AR + tumors have high frequency phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. The purpose of this study was to determine if targeting phosphoinositide 3-kinase (PI3K) alone or in combination with an AR antagonist is effective in AR + TNBC. METHODS:We determined the frequency of activating PIK3CA mutations in AR + and AR- TNBC clinical cases. Using AR?+?TNBC cell line and xenograft models we evaluated the effectiveness of PI3K inhibitors, used alone or in combination with an AR antagonist, on tumor cell growth and viability. RESULTS:PIK3CA kinase mutations were highly clonal, more frequent in AR + vs. AR- TNBC (40% vs. 4%), and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR + TNBC cells. We also analyzed the combination of bicalutamide +/- the pan-PI3K inhibitor GDC-0941 or the dual PI3K/mTOR inhibitor GDC-0980 in xenograft tumor studies and observed additive effects. CONCLUSIONS:While approximately one third of TNBC patients respond to neoadjuvant/adjuvant chemotherapy, recent studies have shown that patients with AR + TNBC are far less likely to benefit from the current standard of care chemotherapy regimens and novel targeted approaches need to be investigated. In this study, we show that activating PIK3CA mutations are enriched in AR?+?TNBC; and, we show that the growth and viability of AR + TNBC cell line models is significantly reduced after treatment with PI3K inhibitors used in combination with an AR antagonist. These results provide rationale for pre-selection of TNBC patients with a biomarker (AR expression) to investigate the use of AR antagonists in combination with PI3K/mTOR inhibitors.
| S-EPMC4187324 | biostudies-literature
Project description:BackgroundThe effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated.MethodsPatients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was <10%, and the percentage of Ki-67-positive tumour cells was reduced by >30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate.ResultsA total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4-56.7; P = 0.025).ConclusionsThe standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer.Clinical trial registrationClinical Trial Registration: UMIN-CTR as UMIN000007074.
| S-EPMC7283228 | biostudies-literature
Project description:BackgroundWe 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.MethodsClinicopathological 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.ResultsBetween 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).ConclusionsThis 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.
| S-EPMC4985347 | biostudies-literature
Project description:In silico approaches are increasingly considered to improve breast cancer treatment. One of these treatments, neoadjuvant TFAC chemotherapy, is used in cases where application of preoperative systemic therapy is indicated. Estimating response to treatment allows or improves clinical decision-making and this, in turn, may be based on a good understanding of the underlying molecular mechanisms. Ever increasing amounts of high throughput data become available for integration into functional networks. In this study, we applied our software tool ExprEssence to identify specific mechanisms relevant for TFAC therapy response, from a gene/protein interaction network. We contrasted the resulting active subnetwork to the subnetworks of two other such methods, OptDis and KeyPathwayMiner. We could show that the ExprEssence subnetwork is more related to the mechanistic functional principles of TFAC therapy than the subnetworks of the other two methods despite the simplicity of ExprEssence. We were able to validate our method by recovering known mechanisms and as an application example of our method, we identified a mechanism that may further explain the synergism between paclitaxel and doxorubicin in TFAC treatment: Paclitaxel may attenuate MELK gene expression, resulting in lower levels of its target MYBL2, already associated with doxorubicin synergism in hepatocellular carcinoma cell lines. We tested our hypothesis in three breast cancer cell lines, confirming it in part. In particular, the predicted effect on MYBL2 could be validated, and a synergistic effect of paclitaxel and doxorubicin could be demonstrated in the breast cancer cell lines SKBR3 and MCF-7.
| S-EPMC3857210 | biostudies-literature
Project description:Androgen receptor (AR) is widely expressed in different subtypes of breast cancer (BC). However, it is unclear how AR functions in HER2 positive (+) BC. Knockdown of AR with shRNAs and a new generation anti-androgen drug, Enzalutamide, were used to explore the involvement of AR on the growth of HER2?+?BC cells (HCC1954 and SKBR3). AR shRNA or Enzalutamide inhibited the growth of SKBR3 cells at a similar extend compared to trastuzumab, an approved HER2 targeted drug. Combining Enzalutamide with trastuzumab further decreased the growth of HCC1954 and SKBR3 cells compared with single agent alone in vitro. Biochemical analysis revealed that inhibiting AR resulted in decreased HER2 phosphorylation and activation of Erk and Akt, without affecting the HER2 and HER3 expression. The in vivo efficacy of Enzalutamide was further tested using the HCC1954 xenograft model. Enzalutamide impaired the growth of HCC1954 tumor at a level comparable to that by trastuzumab. Enzalutamide decreased Ki67 staining and increased activated caspase3 staining compared with vehicle control in HCC1954 tumors. Our results indicate AR plays an important role in promoting the growth of HER2?+?BC by cross-talking with the HER2 signaling. AR drug may be used as an alternative second line therapy for treating HER2?+?BC.
| S-EPMC5674043 | biostudies-literature
Project description:Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.
| S-EPMC5858523 | biostudies-literature
Project description:Core needle biopsy (Cx) primary cancer specimens were collected at Okayama University Hospital in Japan from hormone receptor positive /HER2 negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Thirty clinical TNM stage I and II women were enrolled in this study. The study was approved by the Institutional Review Board and all patients signed informed consent forms. Patients received preoperative hormone therapy daily for two weeks before surgery. Premenopausal patients received tamoxifen (40 mg) and postmenopausal patients received letrozole (2.5 mg). All patients underwent a mastectomy or breast-conserving surgery. Surgical samples after treatment were also collected. Hormone and HER2 receptor statuses were determined in the diagnostic Cx specimens before hormone therapy. Cases with ≥1% positive nuclear staining for estrogen receptors (ER) or progesterone receptors (PgR) with IHC were considered hormone receptor-positive. Cases with either 0 or 1 positive IHC staining for HER2 or with an HER2 gene copy number < 2.0 by fluorescent in situ hybridization (FISH) analysis were considered HER2−. Specimens for gene expression analysis were collected into RNA and later stored at -80°C. Gene expression profiling was performed using Affymetrix U133A gene chips. Expression data were normalized using the MAS5 algorithm, mean centered to 600, and log2 transformed before further analysis.
2017-04-19 | GSE80077 | GEO