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Background: The integration of the non-cross-resistant chemotherapeutic agents capecitabine and vinorelbine into an intensified dose-dense sequential anthracycline- and taxane-containing regimen in high-risk early breast cancer (EBC) could improve efficacy, but this combination was not examined in this context so far. Methods: Patients with stage II/IIIA EBC (four or more positive lymph nodes) received post-operative intensified dose-dense sequential epirubicin (150mg/m2 every 2 weeks) and paclitaxel (225mg/m2 every 2 weeks) with filgrastim and darbepoetin alfa, followed by capecitabine alone (dose levels 1 and 3) or with vinorelbine (dose levels 2 and 4). Capecitabine was given on days 1-14 every 21 days at 1000 or 1250 mg/m2 twice daily (dose levels 1/2 and 3/4, respectively). Vinorelbine 25 mg/m2 was given on days 1 and 8 of each 21-day course (dose levels 2 and 4). Results: Fifty-one patients were treated. There was one dose-limiting toxicity (DLT) at dose level 1. At dose level 2 (capecitabine and vinorelbine), five of 10 patients experienced DLTs. Therefore evaluation of vinorelbine was abandoned and dose level 3 (capecitabine monotherapy) was expanded. Hand-foot syndrome and diarrhoea were dose limiting with capecitabine 1250 mg/m2 twice daily. At 35.2 months' median follow-up, the estimated 3-year relapse-free and overall survival rates were 82% and 91%, respectively. Administration of capecitabine monotherapy after sequential dose-dense epirubicin and paclitaxel is feasible in node-positive EBC, while the combination of capecitabine and vinorelbine as used here caused more DLTs. Trial registration: Current Controlled Trials ISRCTN38983527.
Introduction: Current prognostic gene expression profiles for breast cancer mainly reflect proliferation status and are most useful in ER-positive cancers. Triple negative breast cancers (TNBC) are clinically heterogeneous and prognostic markers and biology-based therapies are needed to better treat this disease.
Methods: We assembled Affymetrix gene expression data for 579 TNBC and performed unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC. We used n = 394 cases for discovery and n = 185 cases for validation. Sixteen metagenes emerged that identified basal-like, apocrine and claudin-low molecular subtypes, or reflected various non-neoplastic cell populations, including immune cells, blood, adipocytes, stroma, angiogenesis and inflammation within the cancer. The expressions of these metagenes were correlated with survival and multivariate analysis was performed, including routine clinical and pathological variables.
Results: Seventy-three percent of TNBC displayed basal-like molecular subtype that correlated with high histological grade and younger age. Survival of basal-like TNBC was not different from non basal-like TNBC. High expression of immune cell metagenes was associated with good and high expression of inflammation and angiogenesis-related metagenes were associated with poor prognosis. A ratio of high B-cell and low IL-8 metagenes identified 32% of TNBC with good prognosis (hazard ratio (HR) 0.37, 95% CI 0.22 to 0.61; P < 0.001) and was the only significant predictor in multivariate analysis including routine clinicopathological variables.
Conclusions: We describe a ratio of high B-cell presence and low IL-8 activity as a powerful new prognostic marker for TNBC. Inhibition of the IL-8 pathway also represents an attractive novel therapeutic target for this disease.
Background: Current prognostic gene signatures for breast cancer mainly reflect proliferation status and have limited value in triple-negative (TNBC) cancers. The identification of prognostic signatures from TNBC cohorts was limited in the past due to small sample sizes.
Methodology/Principal Findings: We assembled all currently publically available TNBC gene expression datasets generated on Affymetrix gene chips. Inter-laboratory variation was minimized by filtering methods for both samples and genes. Supervised analysis was performed to identify prognostic signatures from 394 cases which were subsequently tested on an independent validation cohort (n = 261 cases).
Conclusions/Significance: Using two distinct false discovery rate thresholds, 25% and <3.5%, a larger (n = 264 probesets) and a smaller (n = 26 probesets) prognostic gene sets were identified and used as prognostic predictors. Most of these genes were positively associated with poor prognosis and correlated to metagenes for inflammation and angiogenesis. No correlation to other previously published prognostic signatures (recurrence score, genomic grade index, 70-gene signature, wound response signature, 7-gene immune response module, stroma derived prognostic predictor, and a medullary like signature) was observed. In multivariate analyses in the validation cohort the two signatures showed hazard ratios of 4.03 (95% confidence interval [CI] 1.71–9.48; P = 0.001) and 4.08 (95% CI 1.79–9.28; P = 0.001), respectively. The 10-year event-free survival was 70% for the good risk and 20% for the high risk group. The 26-gene signatures had modest predictive value (AUC = 0.588) to predict response to neoadjuvant chemotherapy, however, the combination of a B-cell metagene with the prognostic signatures increased its response predictive value. We identified a 264-gene prognostic signature for TNBC which is unrelated to previously known prognostic signatures.
Introduction: We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy.
Methods: Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years.
Results: In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results.
Conclusions: Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy.
Background: In this study, we examined patients who had non-progressive disease for at least 2 years after diagnosis of inoperable locoregional recurrent or metastatic breast cancer under continuous trastuzumab treatment. Our primary goal was to assess the long-term outcome of patients with durable response to trastuzumab.
Methods: 268 patients with HER2-positive inoperable locally recurrent or metastatic breast cancer and non-progressive disease for at least 2 years under trastuzumab treatment were documented retrospectively or prospectively in the HER-OS registry, an online documentation tool, between December 2006 and September 2010 by 71 German oncology centers. The study end point was time to tumor progression.
Results: Overall, 47.1% of patients (95% confidence interval (CI): 39.9–54.1%) remained in remission for more than 5 years, while the median time to progression was 4.5 years (95% CI: 4.0–6.6 years). Lower age (<50 years) and good performance status (ECOG 0) at time of trastuzumab treatment initiation as well as complete remission after initial trastuzumab treatment were associated with longer time to progression. Interruption of trastuzumab therapy correlated with shorter time to progression.
Conclusions: HER2-positive patients, who initially respond to palliative treatment with trastuzumab, can achieve a long-term tumor remission of several years.
Heterogenous subtypes of breast cancer need to be analyzed separately. Pooling of datasets can provide reasonable sample sizes but dataset bias is an important concern. We assembled a combined dataset of 579 Affymetrix microarrays from triple negative breast cancer (TNBC) in Gene Expression Omnibus (GEO) series GSE31519. We developed a method for selecting comparable datasets and to control for the amount of dataset bias of individual probesets.
Evidence about distribution patterns of brain metastases with regard to breast cancer subtypes and its influence on the prognosis of patients is insufficient. Clinical data, cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans of 300 breast cancer patients with brain metastases (BMs) were collected retrospectively in four centers participating in the Brain Metastases in Breast Cancer Registry (BMBC) in Germany. Patients with positive estrogen (ER), progesterone (PR), or human epidermal growth factor receptor 2 (HER2) statuses, had a significantly lower number of BMs at diagnosis. Concerning the treatment mode, HER2-positive patients treated with trastuzumab before the diagnosis of BMs showed a lower number of intracranial metastases (p < 0.001). Patients with a HER2-positive tumor-subtype developed cerebellar metastases more often compared with HER2-negative patients (59.8% vs. 44.5%, p = 0.021), whereas patients with triple-negative primary tumors had leptomeningeal disease more often (31.4% vs. 18.3%, p = 0.038). The localization of Brain metastases (BMs) was associated with prognosis: patients with leptomeningeal disease had shorter survival compared with patients without signs of leptomeningeal disease (median survival 3 vs. 5 months, p = 0.025). A shorter survival could also be observed in the patients with metastases in the occipital lobe (median survival 3 vs. 5 months, p = 0.012). Our findings suggest a different tumor cell homing to different brain regions depending on subtype and treatment. View Full-Text
Background: The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC).
Methods: First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization.
Results: Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR).
Conclusion: Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.
Neue Therapieentwicklungen zur Behandlung von Patientinnen mit fortgeschrittenem Mammakarzinom konzentrieren sich zurzeit sowohl auf die Identifikation von Patientinnen für zielgerichtete Therapieansätze als auch auf die Weiterentwicklung von immuntherapeutischen Ansätzen. Die Datenlage zu den CDK4/6-Inhibitoren konnte vervollständigt werden und ist konsistent in dieser Klasse von Substanzen (Palbociclib, Ribociclib und Abemaciclib). Weitere Signalwege, die untersucht werden, sind der PI3K-und der AKT-Signalweg sowie verschiedene Ansatzpunkte zu deren Hemmung. Für beide Wirkmechanismen liegen auch erste Studienergebnisse vor, die vor Kurzem vorgestellt wurden. Außerdem wachsen die Erkenntnisse zu den PARP-Inhibitoren, für die auch untersucht wird, in welcher Population sie am effektivsten eingesetzt werden können. Dieser Review-Artikel soll die aktuellen Studien zusammenfassen und einen Ausblick der neuesten Entwicklungen geben.
New therapeutic developments aimed at treating women with advanced breast cancer currently focus both on identifying patients eligible for targeted therapeutic concepts and on the continuing development of immune therapies. The data on CDK4/6 inhibitors are now complete and consistent in this class of substances (palbociclib, ribociclib and abemaciclib). Further pathways under investigation are PI3K and AKT signalling pathways along with diverse approaches to their inhibition. Initial study results were also presented recently on both mechanisms of action. Insights into the PARP inhibitors, moreover, are increasing; studies in this respect are also examining in which population they can be used most effectively. This review offers a summary of the recent studies and an outline of the latest developments.