'I presumed the pain would eventually get better by itself'; challenges with access to rehabilitation for upper limb dysfunction after breast cancer treatment - Descriptive and qualitative findings from a cross-sectional survey.

Purpose: Sixty percent of breast cancer patients develop persistent upper limb pain and dysfunction, but only limited knowledge exists about how these symptoms relate to rehabilitation access.

Methods: A postal survey was sent to patients treated at a London University Teaching Hospital (2018-2020). Data were collected on pain (Pain Detect), shoulder function (Disability of Shoulder Arm and Hand (DASH)), quality-of-life (QoL) (EQ-5D-5L), and clinical characteristics, including treatment and access to rehabilitation.

Employing multiple synchronous outcome samples per subject to improve study efficiency.

Background: Accuracy can be improved by taking multiple synchronous samples from each subject in a study to estimate the endpoint of interest if sample values are not highly correlated. If feasible, it is useful to assess the value of this cluster approach when planning studies. Multiple assessments may be the only method to increase power to an acceptable level if the number of subjects is limited.

Correlation between DNA damage responses of skin to a test dose of radiation and late adverse effects of earlier breast radiotherapy.

Aim: To correlate residual double strand breaks (DSB) 24h after 4Gy test doses to skin in vivo and to lymphocytes in vitro with adverse effects of earlier breast radiotherapy (RT).

Patients And Methods: Patients given whole breast RT ⩾5years earlier were identified on the basis of moderate/marked or minimal/no adverse effects despite the absence ('RT-Sensitive', RT-S) or presence ('RT-Resistant', RT-R) of variables predisposing to late adverse effects. Residual DSB were quantified in skin 24h after a 4Gy test dose in 20 RT-S and 15 RT-R patients.

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.

Background: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.

Methods: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day.

A phase II trial to assess the activity of gemcitabine and docetaxel as first line chemotherapy treatment in patients with unresectable leiomyosarcoma.

Background: Gemcitabine and docetaxel have been shown to be active in pre-treated relapsed leiomyosarcoma. This study investigated the combination as first line treatment in patients with unresectable locally advanced/metastatic leiomyosarcoma.

Methods: Patients received gemcitabine 900 mg/m(2) days 1 and 8, and docetaxel 100 mg/m(2) day 8, administered 3-weekly for up to 8 cycles, with GCSF support on days 9-15.

Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039).

Purpose: Not all breast cancers respond to lapatinib. A change in Ki67 after short-term exposure may elucidate a biomarker profile for responsive versus nonresponsive tumors.

Experimental Design: Women with primary breast cancer were randomized (3:1) to 10 to 14 days of preoperative lapatinib or placebo in a multicenter phase II trial (ISRCTN68509377).

Differences in the transcriptional response to fulvestrant and estrogen deprivation in ER-positive breast cancer.

Purpose: Endocrine therapies include aromatase inhibitors and the selective estrogen receptor (ER) downregulator fulvestrant. This study aimed to determine whether the reported efficacy of fulvestrant over anastrozole, and high- over low-dose fulvestrant, reflect distinct transcriptional responses.

Experimental Design: Global gene expression profiles from ERα-positive breast carcinomas before and during presurgical treatment with fulvestrant (n = 22) or anastrozole (n = 81), and corresponding in vitro models, were compared.

Predictive performance of microarray gene signatures: impact of tumor heterogeneity and multiple mechanisms of drug resistance.

Gene signatures have failed to predict responses to breast cancer therapy in patients to date. In this study, we used bioinformatic methods to explore the hypothesis that the existence of multiple drug resistance mechanisms in different patients may limit the power of gene signatures to predict responses to therapy. In addition, we explored whether substratification of resistant cases could improve performance.

Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast.

Micropapillary carcinoma (MPC) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and a pattern of copy number aberrations (CNAs) distinct from that of grade- and oestrogen receptor (ER)-matched invasive carcinomas of no special type (IC-NSTs). The aims of this study were to determine whether MPCs are underpinned by a recurrent fusion gene(s) or mutations in 273 genes recurrently mutated in breast cancer. Sixteen MPCs were subjected to microarray-based comparative genomic hybridization (aCGH) analysis and Sequenom OncoCarta mutation analysis.

Taxane benefit in breast cancer--a role for grade and chromosomal stability.

Chromosomal instability, which is a characteristic of many human cancers, contributes to intratumour heterogeneity and has been functionally implicated in resistance to taxane therapy in tumour models. However, defining the status of tumour chromosomal instability in a given tumour to test this hypothesis remains challenging. Measurements of numerical and structural chromosomal heterogeneity demonstrate that histological grade correlates with chromosomal instability in oestrogen receptor (ER)-positive breast cancer.

Phosphorylation of AKT pathway proteins is not predictive of benefit of taxane therapy in early breast cancer.

Results from the NSABP B-28 trial suggest AKT activation may predict reduced benefit from taxanes following standard anthracycline therapy. Pre-clinical data support a link between PI3 K/AKT signalling and taxane resistance. Using the UK taxotere as adjuvant chemotherapy trial (TACT), we tested the hypothesis that activation of AKT or downstream markers, p70S6K or p90RSK, identifies patients with reduced benefit from taxane chemotherapy.

Mutation profiling of adenoid cystic carcinomas from multiple anatomical sites identifies mutations in the RAS pathway, but no KIT mutations.

Aims: The majority of adenoid cystic carcinomas (AdCCs), regardless of anatomical site, harbour the MYB-NFIB fusion gene. The aim of this study was to characterize the repertoire of somatic genetic events affecting known cancer genes in AdCCs.

Methods And Results: DNA was extracted from 13 microdissected breast AdCCs, and subjected to a mutation survey using the Sequenom OncoCarta Panel v1.

Expression of key oestrogen-regulated genes differs substantially across the menstrual cycle in oestrogen receptor-positive primary breast cancer.

Plasma estradiol (E2) and progesterone vary markedly through the menstrual cycle. Data on whether these differences in hormone levels affect gene expression in oestrogen receptor-positive (ER+) tumours are inconsistent. We wished to determine whether there are substantial changes in the expression of oestrogen-regulated genes (ERGs) in ER+ breast cancer through the menstrual cycle.

Correlation of age and HRT use with breast density as assessed by Quantra™.

Breast density is a significant predictor in the risk of developing breast cancer. Several methods are available for assessing breast density, but most are subject to intra-observer variability and are unable to assess the breast as a three-dimensional structure. Using Quantra(™) to quantify breast density, we have correlated this with risk factors to determine what impact these variables have on breast density.

Correlation of in vitro lymphocyte radiosensitivity and gene expression with late normal tissue reactions following curative radiotherapy for breast cancer.

Background And Purpose: Identification of mechanisms of late normal tissue responses to curative radiotherapy that discriminate individuals with marked or mild responses would aid response prediction. This study aimed to identify differences in gene expression, apoptosis, residual DNA double strand breaks and chromosomal damage after in vitro irradiation of lymphocytes in a series of patients with marked (31 cases) or mild (28 controls) late adverse reaction to adjuvant breast radiotherapy.

Materials And Methods: Gene expression arrays, residual γH2AX, apoptosis, G2 chromosomal radiosensitivity and G0 micronucleus assay were used to compare case and control lymphocyte radiation responses.

Effectiveness and molecular interactions of the clinically active mTORC1 inhibitor everolimus in combination with tamoxifen or letrozole in vitro and in vivo.

Introduction: Strategies to improve the efficacy of endocrine agents in breast cancer (BC) therapy and to delay the onset of resistance include concomitant targeting of the estrogen receptor alpha (ER) and the mammalian target of rapamycin complex 1 (mTORC1), which regulate cell-cycle progression and are supported by recent clinical results.

Methods: BC cell lines expressing aromatase (AROM) and modeling endocrine-sensitive (MCF7-AROM1) and human epidermal growth factor receptor 2 (HER2)-dependent de novo resistant disease (BT474-AROM3) and long-term estrogen-deprived (LTED) MCF7 cells that had acquired resistance associated with HER2 overexpression were treated in vitro and as subcutaneous xenografts with everolimus (RAD001-mTORC1 inhibitor), in combination with tamoxifen or letrozole. End points included proliferation, cell-cycle arrest, cell signaling, and effects on ER-mediated transactivation.

Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer.

Purpose: To investigate whether suppression of plasma estradiol and estrone sulfate levels by the aromatase inhibitors (AIs) anastrozole and letrozole is related to body mass index (BMI) in postmenopausal women with early estrogen receptor (ER) -positive breast cancer. Recent studies have reported that the AI anastrozole has lower effectiveness than tamoxifen in women with high BMI. This effect with high BMI might hypothetically be a result of reduced inhibition of aromatase and suppression of plasma estrogen levels and might be overcome by the use of an increased dose of anastrozole or, alternatively, the use of a more potent AI such as letrozole.

Polymorphisms of CYP19A1 and response to aromatase inhibitors in metastatic breast cancer patients.

Single nucleotide polymorphisms (SNPs) in the gene encoding aromatase (CYP19A1) have been associated with differential benefit from letrozole treatment in metastatic breast cancer (mBC) patients, but validation is lacking. The aim was to investigate whether polymorphic variation of CYP19A1 and enzymes involved in estrogen and aromatase inhibitors (AIs) metabolism are associated with efficacy of AIs. 308 Women with estrogen-receptor-positive metastatic mBC treated with a third-generation AI were identified retrospectively.

ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer.

Introduction: Estrogen receptor-α (ER) and human epidermal growth factor receptor 2 (HER2) positivity are inversely correlated by standard criteria. However, we investigated the quantitative relation between ER and HER2 expression at both RNA and protein levels in HER2+ve and HER2-ve breast carcinomas.

Methods: ER and HER2 levels were assessed with immunohistochemistry (IHC) and (for HER2) fluorescent in situ hybridization (FISH) and by quantitative reverse transcription-polymerase chain reaction (q-RT-PCR) in formalin-fixed primary breast cancers from 448 patients in the National Cancer Research Institute (NCRI) Adjuvant Breast Cancer Trial (ABC) tamoxifen-only arm.