Treatment In Adjuvant Setting Research Articles

Muscle strength in breast cancer patients receiving different treatment regimes.

BackgroundMuscle dysfunction and sarcopenia have been associated with poor performance status, an increased mortality risk, and greater side effects in oncologic patients. However, little is known about how performance is affected by cancer therapy. We investigated muscle strength in breast cancer patients in different adjuvant treatment settings and also compared it with data from healthy individuals.MethodsBreast cancer patients (N = 255) from two randomized controlled exercise trials, staged 0–III and aged 54.4 ± 9.4 years, were categorized into four groups according to their treatment status. In a cross‐sectional design, muscle function was assessed bilaterally by isokinetic dynamometry (0°, 60°, 180°/s) as maximal voluntary isometric contraction (MVIC) and maximal isokinetic peak torque (MIPT) in shoulder rotators and knee flexors and extensors. Additionally, muscular fatigue index (FI%) and shoulder flexibility were evaluated. Healthy women (N = 26), aged 53.3 ± 9.8 years, were tested using the same method. Analysis of covariance was used to estimate the impact of different cancer treatments on skeletal muscle function with adjustment for various clinical and socio‐demographic factors.ResultsConsistently, lower muscle strength was measured in shoulder and knee strength in patients after chemotherapy. On average, patients had up to 25% lower strength in lower extremities and 12–16% in upper extremities in MVIC and MIPT during cancer treatment compared with healthy women. No substantial difference between patient groups in shoulder strength, but significantly lower shoulder flexibility in patients with radical mastectomy was measured. Chemotherapy‐treated patients had consistently higher FI%. No serious adverse events were reported.ConclusionsBreast cancer patients showed markedly impaired muscle strength and joint dysfunctions before and after anticancer treatment. The significant differences between patients and healthy individuals underline the need of exercise therapy as early as possible in order to prevent or counteract the loss of muscle function after curative surgery as well as the consequences of neo‐/adjuvant chemotherapy.

Mammographic density: a potential monitoring biomarker for adjuvant and preventative breast cancer endocrine therapies.

Increased mammographic density (MD) has been shown beyond doubt to be a marker for increased breast cancer risk, though the underpinning pathobiology is yet to be fully elucidated. Estrogenic activity exerts a strong influence over MD, which consequently has been observed to change predictably in response to tamoxifen anti-estrogen therapy, although results for other selective estrogen receptor modulators and aromatase inhibitors are less consistent. In both primary and secondary prevention settings, tamoxifen-associated MD changes correlate with successful modulation of risk or outcome, particularly among pre-menopausal women; an observation that supports the potential use of MD change as a surrogate marker where short-term MD changes reflect longer-term anti-estrogen efficacy. Here we summarize endocrine therapy-induced MD changes and attendant outcomes and discuss both the need for outcome surrogates in such therapy, as well as make a case for MD as such a monitoring marker. We then discuss the process and steps required to validate and introduce MD into practice as a predictor or surrogate for endocrine therapy efficacy in preventive and adjuvant breast cancer treatment settings.

Enhanced Survival with Implantable Scaffolds That Capture Metastatic Breast Cancer Cells In Vivo.

The onset of distant organ metastasis from primary breast cancer marks the transition to a stage IV diagnosis. Standard imaging modalities often detect distant metastasis when the burden of disease is high, underscoring the need for improved methods of detection to allow for interventions that would impede disease progression. Here, microporous poly(ε-caprolactone) scaffolds were developed that capture early metastatic cells and thus serve as a sentinel for early detection. These scaffolds were used to characterize the dynamic immune response to the implant spanning the acute and chronic foreign body response. The immune cell composition had stabilized at the scaffold after approximately 1 month and changed dramatically within days to weeks after tumor inoculation, with CD11b(+)Gr1(hi)Ly6C(-) cells having the greatest increase in abundance. Implanted scaffolds recruited metastatic cancer cells that were inoculated into the mammary fat pad in vivo, which also significantly reduced tumor burden in the liver and brain. Additionally, cancer cells could be detected using a label-free imaging modality termed inverse spectroscopic optical coherence tomography, and we tested the hypothesis that subsequent removal of the primary tumor after early detection would enhance survival. Surgical removal of the primary tumor following cancer cell detection in the scaffold significantly improved disease-specific survival. The enhanced disease-specific survival was associated with a systemic reduction in the CD11b(+)Gr1(hi)Ly6C(-) cells as a consequence of the implant, which was further supported by Gr-1 depletion studies. Implementation of the scaffold may provide diagnostic and therapeutic options for cancer patients in both the high-risk and adjuvant treatment settings. Cancer Res; 76(18); 5209-18. ©2016 AACR.

Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer.

Around, 30–40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer.

MP07-03 PRIMARY TUMOR ANDROGEN RECEPTOR SIGNALING AS A PREDICTOR OF CASTRATE RESISTANCE

You have accessJournal of UrologyProstate Cancer: Markers II1 Apr 2016MP07-03 PRIMARY TUMOR ANDROGEN RECEPTOR SIGNALING AS A PREDICTOR OF CASTRATE RESISTANCE Ashley Ross, Brian Shinder, Jeffrey Tosoian, Nicholas Erho, Mohammed Alshalalfa, Kasra Yousefi, Paula Hurley, Elai Davicioni, Felix Feng, Phuoc Tran, and Edward Schaeffer Ashley RossAshley Ross More articles by this author , Brian ShinderBrian Shinder More articles by this author , Jeffrey TosoianJeffrey Tosoian More articles by this author , Nicholas ErhoNicholas Erho More articles by this author , Mohammed AlshalalfaMohammed Alshalalfa More articles by this author , Kasra YousefiKasra Yousefi More articles by this author , Paula HurleyPaula Hurley More articles by this author , Elai DavicioniElai Davicioni More articles by this author , Felix FengFelix Feng More articles by this author , Phuoc TranPhuoc Tran More articles by this author , and Edward SchaefferEdward Schaeffer More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2206AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recent results of STAMPEDE, CHAARTED, and RTOG 0521 have suggested a clinical benefit to the early use of docetaxel in the treatment of localized high risk, locally advanced and newly metastatic prostate cancer (PCa). Docetaxel therapy is not without toxicity however (neuropathy, neutropenia and associated deaths). Improved selection of men with early castrate resistance is thus paramount to personalized use of chemotherapy in the adjuvant treatment setting. Here we investigate whether early signs of androgen insensitivity could be detected in the primary tumors of men with PCa that metastasized after local therapy and subsequently developed castrate resistant disease. METHODS We identified 52 men with complete clinical follow up who presented with localized PCa and were treated by surgery only with eventual development of metastasis. Genome wide expression profiling was performed on the primary tumors of all men. All patients initiated androgen deprivation therapy (ADT) at the time of metastasis, and serial PSA values were obtained at least annually. Castration-resistant prostate cancer (CRPC) was defined as two consecutive rises in PSA in the castrate state (i.e. serum T < 50). An androgen response signature (ARS) was genomically derived to include canonical androgen regulated genes. Factors associated with CRPC were tested in a Cox proportional hazards model. RESULTS Forty-one (79%) men progressed to CRPC at a median of 15 months from ADT initiation. On multivariable analysis, no pathological features or risk models available in the peri-operative period (Gleason score, lymph node involvement, CAPRA-S score, etc.) were predictive of developing CRPC. Ability to reach a nadir PSA value of <0.2ng/ml after initiation of ADT upon metastasis was a significant predictor (hazard ratio [HR] 3.02, 95% confidence interval [CI] 1.77-5.29). Importantly, higher ARS scores in the primary tumor were predictive of subsequent progression to CRPC. Specifically, greater than median ARS score was associated with a 54% reduction in the risk of CRPC (HR 0.46, 95% CI 0.24-0.87). CONCLUSIONS Androgen signaling in primary tumors may be predictive of progression to CRPC. These novel findings may translate to better selection of men who could benefit from early initiation of androgen independent therapies such as chemotherapy or immunotherapeutics. Further prospective validation is warranted. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e77 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Ashley Ross More articles by this author Brian Shinder More articles by this author Jeffrey Tosoian More articles by this author Nicholas Erho More articles by this author Mohammed Alshalalfa More articles by this author Kasra Yousefi More articles by this author Paula Hurley More articles by this author Elai Davicioni More articles by this author Felix Feng More articles by this author Phuoc Tran More articles by this author Edward Schaeffer More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Ovarian sertoli-leydig cell tumors: A multicenter long-term clinicopathological analysis of 27 patients.

Information on the clinical behavior of ovarian Sertoli-Leydig cell tumors (SLCTs) as well as its prognostic factors and optimal management is limited due to a substantially low incidence of the disease. Also, limited data is available regarding the role of chemotherapy in the management of SLCTs. The aim of the study is to evaluate clinicopathological features and outcome of patients with ovarian SLCTs. Twenty-seven patients with SLCT treated at two centers were reviewed retrospectively during 21 years. The median age was 45 years (range, 16-81) and the mean follow-up time was 86 months (range, 16-181). Twenty-three patients had stage IA, three patients had IC, and one patient had stage II disease. Eleven tumors (41%) were well-differentiated and 16 (59%) tumors were intermediately differentiated. Nine patients underwent unilateral salpino-oophorectomy and one patient, with a history of infertility, underwent cystectomy for fertility preservation. Eight patients with intermediately differentiated types of SLCT received adjuvant systemic chemotherapy including the combination bleomycin, etoposide, and cisplatin (BEP). Recurrence occurred in one patient with intermediated differentiated type SLCT with heterologous elements. She received four cycles of BEP chemotherapy. Twelve months later, she underwent cytoreductive surgery and received six cycles of cisplatin plus carboplatin. She died 24 months after the initial diagnosis. SLCTs of the ovary are usually in early stage, unilateral, and benign. Fertility-sparing surgery is the preferred option in young women. In the adjuvant treatment setting, although information about chemotherapy is limited, BEP is a commonly used regimen. The degree of differentiation and the presence of heterologous elements relate to a poor prognosis.

Cancer Treatment-Induced Bone Loss in women with breast cancer.

Osteoporosis is one of the most frequent diseases in postmenopausal women, leading to an increased fracture risk due to the physiologic loss of the bone protective effects of estrogen. Hereby, several risk factors for fracture such as prevalent fracture, low bone mineral density (BMD), age, low body mass index, family history, tendency to falls, smoking, use of SSRIs, glucocorticoid use etc. have been identified. In addition, the further reduction in endogenous estrogens with chemotherapy (CHT), GnRH analoga or aromatase inhibitors (AIs) continuously increases fracture risk. Breast cancer (BC) on the other hand is the most frequent cancer type in women. Recent reports indicate a continuous increased incidence, whereas mortality, due to early diagnosis and treatment improvements, is decreasing. Dependent on specific tumor characteristics, radiation, CHT, antibody treatment as well as endocrine treatment have been included into the adjuvant clinical treatment setting. Some but not all of these cancer-specific treatments interfere with bone turnover, leading to an accelerated bone loss referred to as cancer treatment-induced bone loss (CTIBL). Whereas CHT leads to an unspecific increase in bone resorption, AI reduces residual serum endogenous estrogen level and is associated with a decrease in BMD and increased fracture risk. Independent of the type of AI administered, bone loss is 2-3-fold increased compared with healthy, age-matched postmenopausal controls. Therefore, several guidelines have emerged to help managing CTIBL in women with BC including strategies to identify and treat those at highest risk for fractures. This review summarizes the current knowledge on CTIBL and fracturing risk and indicates preventative strategies.

Abstract P1-12-06: Co-SOFT: The cognitive function substudy of the suppression of ovarian function trial (SOFT)

Abstract Background: Cognitive impairment is a potential side-effect of breast cancer (BC) treatment. Estrogen is an important neuromodulator that affects cognition. Estrogen depletion by oophorectomy or GnRH agonists may adversely affect cognition in non-oncological settings, but there are few data regarding the cognitive effects of ovarian function suppression (OFS) in women with breast cancer. Patients and Methods: Between November 2003 and January 2011, 3066 premenopausal women with hormone receptor-positive BC were randomised on the SOFT trial to 5 years of adjuvant endocrine therapy with tamoxifen alone, tamoxifen+OFS or exemestane+OFS. OFS was achieved by the GnRH agonist triptorelin, oophorectomy or ovarian irradiation. Prior chemotherapy was allowed, provided women had premenopausal estradiol levels at enrolment. Women eligible for Co-SOFT must not have received any prior adjuvant endocrine therapy. At study entry (t1), and approximately 1 year after SOFT randomisation (t2), objective cognitive function was assessed with a brief computerized test battery comprising 7 tasks (CogState Ltd: cogstate.com). Subjective cognitive function, psychological distress, fatigue, insomnia and quality of life were also assessed. Co-SOFT recruited 86 of a planned 321 patients from 27 of 426 SOFT centres between November 2007 and January 2011, when Co-SOFT was closed as the SOFT trial completed accrual. The protocol-specified primary comparison was the change in the composite score of the CogState tasks over 1 year for women randomised to tamoxifen versus tamoxifen+OFS. However, due to low accrual this was modified, prior to any analysis, to compare the tamoxifen versus the pooled tamoxifen+OFS and exemestane+OFS groups. Cognitive test scores were standardized according to age-specific norms, averaged to compute the composite score and then change between t1 and t2 calculated; a negative change in composite score indicates deterioration in cognitive function. Change in composite score was compared using Wilcoxon rank sum test. Results: Of 86 Co-SOFT enrolled patients, 74 underwent both t1 and t2 CogState testing and were included in the primary analysis (7 withdrew consent/declined assessment, 5 missed testing due to scheduling). Of these 74 women, 20 were randomised to tamoxifen and 54 to OFS+tamoxifen (28) or OFS+exemestane (26). Baseline characteristics were well balanced between the 2 groups. During the first year 49 women utilised GnRH alone for OFS, 4 had GnRH followed by oophorectomy and 1 had oophorectomy alone. There was no significant difference in the changes in the CogState composite scores from t1 and t2 for patients randomised to tamoxifen alone compared with OFS+oral endocrine therapy (median, -0.057 versus -0.146 respectively, p=0.51). There were no significant between-group differences in the changes from t1 and t2 for any of the 7 individual cognitive tasks comprising the composite score. Conclusions: The results of this 1-year longitudinal substudy suggest that the addition of OFS to oral endocrine therapy does not significantly affect cognitive function in the setting of adjuvant BC treatment. Co-SOFT was limited by small sample size, so further investigation of the impact of OFS on cognitive function in BC patients is warranted. Citation Format: Kelly-Anne Phillips, Yang Feng, Karin Ribi, Jürg Bernhard, Fabio Puglisi, Meritxell Bellet, Simon Spazzapan, Per Karlsson, Daniel R Budman, Khalil Zaman, Ehtesham A Abdi, Susan M Domchek, Meredith M Regan, Alan S Coates, Richard D Gelber, Paul Maruff, Frances Boyle, John F Forbes, Gini F Fleming, Prudence A Francis. Co-SOFT: The cognitive function substudy of the suppression of ovarian function trial (SOFT) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-06.

Vasculotide reduces endothelial permeability and tumor cell extravasation in the absence of binding to or agonistic activation of Tie2

Angiopoietin-1 (Ang1) activation of Tie2 receptors on endothelial cells (ECs) reduces adhesion by tumor cells (TCs) and limits junctional permeability to TC diapedesis. We hypothesized that systemic therapy with Vasculotide (VT)—a purported Ang1 mimetic, Tie2 agonist—can reduce the extravasation of potentially metastatic circulating TCs by similarly stabilizing the host vasculature. In vitro, VT and Ang1 treatments impeded endothelial hypermeability and the transendothelial migration of MDA-MB-231•LM2-4 (breast), HT29 (colon), or SN12 (renal) cancer cells to varying degrees. In mice, VT treatment inhibited the transit of TCs through the pulmonary endothelium, but not the hepatic or lymphatic endothelium. In the in vivo LM2-4 model, VT monotherapy had no effect on primary tumors, but significantly delayed distant metastatic dissemination to the lungs. In the post-surgical adjuvant treatment setting, VT therapeutically complemented sunitinib therapy, an anti-angiogenic tyrosine kinase inhibitor which limited the local growth of residual disease. Unexpectedly, detailed investigations into the putative mechanism of action of VT revealed no evidence of Tie2 agonism or Tie2 binding; alternative mechanisms have yet to be determined.

Incidence of bisphosphonate-related osteonecrosis of the jaw in high-risk patients undergoing surgical tooth extraction

As the most suitable approach for preventing bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients undergoing surgical tooth extraction is still under discussion, the present study evaluates the incidence of BRONJ after surgical tooth extraction using a standardized surgical protocol in combination with an adjuvant perioperative treatment setting in patients who are at high-risk for developing BRONJ.High-risk patients were defined as patients who received intravenous bisphosphonate (BP) due to a malignant disease. All teeth were removed using a standardized surgical protocol. The perioperative adjuvant treatment included intravenous antibiotic prophylaxis starting at least 24 h before surgery, a gastric feeding tube and mouth rinses with chlorhexidine (0.12%) three times a day. In the follow-up period patients were examined every 4 weeks for the development of BRONJ. Minimum follow-up was 12 weeks.In 61 patients a total number of 184 teeth were removed from 102 separate extraction sites. In eight patients (13.1%) BRONJ developed during the follow-up. A higher risk for developing BRONJ was found in patients where an additional osteotomy was necessary (21.4% vs. 8.0%; p = 0.0577), especially for an osteotomy of the mandible (33.3% vs. 7.3%; p = 0.0268). Parameters including duration of intravenous antibiotic prophylaxis, the use of a gastric feeding tube and the duration of intravenous BP therapy showed no statistical impact on the development of BRONJ. Furthermore, patients currently undergoing intravenous BP therapy showed no higher risk for BRONJ compared with patients who have paused or completed their intravenous BP therapy (p = 0.4232).This study presents a protocol for surgical tooth extraction in high-risk BP patients in combination with a perioperative adjuvant treatment setting, which reduced the risk for postoperative BRONJ to a minimum. However, the risk for BRONJ increases significantly if an additional osteotomy is necessary, especially in the mandible.

Oxaliplatin-Induced Pulmonary Toxicity in Gastrointestinal Malignancies: Two Case Reports and Review of the Literature.

Oxaliplatin is a common chemotherapy drug, used mainly for colon and gastric cancer. Most common side effects are peripheral sensory neuropathy, hematological toxicity, and allergic reactions. A less common side effect is pulmonary toxicity, characterized mainly by interstitial pneumonitis. The incidence of this side effect is unknown, but the toxicity can be fatal. Twenty-six cases of pulmonary toxicity have been described in the literature, seven in the setting of adjuvant treatment. We describe two fatal cases of pulmonary injury related to oxaliplatin and a review of the literature.

Cytotoxic agents and radiation therapy: mechanisms of action and clinical applications

AbstractBackgroundThe combination of radiation therapy and chemotherapy is rooted in its ability to help achieve locoregional and systemic control, therefore increasing the overall disease-free survival of patients. Understanding the mechanistic actions of cytotoxic agents and their targets on the cell cycle, as well as the governing pharmacokinetic principles can improve treatment delivery. The adjuvant treatment setting can overcome barriers such as hypoxia and genetically driven treatment resistance.PurposeThe purpose of this review is to present theoretical frameworks behind the chemoradiation paradigm and to describe current chemoradiation practices in radiation oncology.MethodologyA review was conducted using the US National Library of Medicine, National Institutes of Health database (PubMed) using the following search keywords: chemoradiation, spatial cooperation, chemotherapeutic agents, pharmacokinetics, anti-vascular agents, tumour vasculature and tumour hypoxia.Results and conclusionsCurrent research has reported several rationales for the beneficial combination of radiation and chemotherapy to eradicate oncological diseases. Mechanisms of action and biological approaches are showing that concurrent treatments, as well as novel agents such as anti-vascular and anti-angiogenic agents may benefit improved treatment outcomes by reducing micro hypoxic environments in tumours. In addition, chemotherapy administered in tandem with radiation enhances cell-killing effects by targeting the cell cycle.

Primary brachytherapy as a radical treatment for endometrial carcinoma

Surgery is the primary treatment for endometrial cancer, with radiation therapy having an established place in the adjuvant treatment setting. However, there is a population of patients with endometrial cancer who may not be suitable for surgery and primary radiation therapy as a treatment option. This article describes the place of radiotherapy in the management of endometrial cancer and describes the author's own experiences with primary brachytherapy in those patients who are unsuitable for surgery.

Genomic signatures for predicting survival and adjuvant chemotherapy benefit in patients with non-small-cell lung cancer

BackgroundImproved methods are needed for predicting prognosis and the benefit of delivering adjuvant chemotherapy (ACT) in patients with non-small-cell lung cancer (NSCLC).MethodsA novel prognostic algorithm was identified using genomic profiles from 332 stage I-III adenocarcinomas and independently validated on a separate series of 264 patients with stage I-II tumors, compiled from five previous studies. The prognostic algorithm was used to interrogate genomic data from a series of patients treated with adjuvant chemotherapy. Those genes associated with outcome in the adjuvant treatment setting, independent to prognosis were used to train an algorithm able to classify a patient as either a responder or non-responder to ACT. The performance of this signature was independently validated on a separate series of genomic profiles from patients enrolled in a randomized controlled trial of cisplatin/vinorelbine vs. observation alone (JBR.10).ResultsNSCLC patients exhibiting the high-risk, poor-prognosis form of the 160-gene prognosis signature experienced a 2.80-times higher rate of 5-year disease specific death (log rank P < 0.0001) compared to those with the low-risk, good prognosis profile, adjusted for covariates. The prognosis signature was found to especially accurate at identifying early stage patients at risk of disease specific death within 24 months of diagnosis when compared to traditional methods of outcome prediction.Separately, NSCLC patients with the 37-gene ACT-response signature (n = 70, 64 %), benefited significantly from cisplatin/vinorelbine (adjusted HR: 0.23, P = 0.0032). For those patients predicted to be responders, receiving this form of ACT conferred a 25 % improvement in the probability of 5-year-survival, compared to observation alone and adjusted for covariates. Conversely, in those patients predicted to be non-responders, ACT was observed to offer no significant survival benefit (adjusted HR: 0.55, P = 0.32).The two gene signatures overlap by one gene only SPSB3, which interacts with the oncogene MET. In this study, higher levels of SPSB3 which were associated with favorable prognosis and benefit from ACT.ConclusionsThese complimentary prognostic and predictive gene signatures may assist physicians in their management and treatment of patients with early stage lung cancer.

Topoisomerase 2 alpha: a real predictor of anthracycline efficacy?

Anthracyclines are frequently used in the adjuvant setting for breast cancer treatment since it is considered that anthracycline-based chemotherapy treatment benefits breast cancer patients. Nonetheless, these drugs are associated with severe side effects and predictive factors, for sensitivity to anthracyclines, are warranted in clinical practice. Topoisomerase 2 alpha (TOP2A) is considered to be the molecular target of these drugs. The potential predictive value of TOP2A amplification and overexpression has been extensively studied in breast cancer patients treated with anthracyclines. However, results are not conclusive. In this paper, we review some of the published studies addressing the predictive value of TOP2A as well as the cellular functions of this enzyme and its status in breast cancer tissue.

352 DNA REPAIR TARGETING AND RADIOTHERAPY: A FOCUS ON THE THERAPEUTIC RATIO

Radiotherapy (RT) results in the production of a variety of ionizing radiation-induced lesion in DNA. Specific pathways of DNA repair are required to repair the variety of lesions, which include DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), DNA base alterations, and DNA-DNA or DNA-protein cross-links. Nonrepaired DNA damage can lead to normal and tumor cell death via apoptosis, mitotic catastrophe, autophagy, or terminal growth arrest senescence. Targeting the sensing and repair of DNA damage is an exciting concept. This must be combined with precision RT to limit the volume of irradiated normal tissue, including the use of image-guided radiotherapy (IGRT) and brachytherapy. The therapeutic ratio of combined targeting of DNA combined with RT could also be preserved using biological approaches and includes the following: (1) the documentation of relative defects in DNA damage sensing and repair in malignant cells; (2) the preferential use of certain DNA repair pathways (eg, base excision repair or homologous recombination) in malignant tissues compare with normal tissues; (3) the targeting of repair defects in chronically hypoxic cells; and (4) optimal scheduling of a DNA repair inhibitor in the neoadjuvant, concurrent, or adjuvant combined treatment settings. In this review, we discuss the general rationale and the optimal timing and duration of DNA repair inhibition during fractionated RT with the emphasis on preserving the therapeutic ratio of cancer treatment.

HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy

BackgroundHER2 and TOP2A parameters (gene status, mRNA and protein expression) have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy.MethodsIn a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization), mRNA expression (quantitative reverse transcription PCR), as well as HER2 and TopoIIa protein expression (immunohistochemistry).ResultsHER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A. TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001). Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively). Multivariate analysis adjusted for nodal involvement, hormone receptor status, Ki67 score and HER2/TOP2A parameters revealed HER2/TOP2A co-amplification (21.2% of HER2 amplified tumors) as an independent favorable prognostic factor for DFS (HR = 0.13, 95% CI: 0.02-0.96, p = 0.046); in contrast, increased HER2/TOP2A mRNA co-expression was identified as an independent adverse prognostic factor for both DFS (HR = 2.41, 95% CI: 1.31-4.42, p = 0.005) and OS (HR = 2.83, 95% CI: 1.42-5.63, p = 0.003), while high TOP2A mRNA expression was an independent adverse prognostic factor for OS (HR = 2.06, 95% CI: 1.23-3.46, p = 0.006). None of the parameters tested was associated with response to paclitaxel.ConclusionsThis study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12611000506998.

Targeted Taxane Delivery Systems: Recent Advances

Taxanes (paclitaxel and docetaxel) are among the most active cytotoxic agents in use in oncology, being widely used in adjuvant and advanced treatment settings in multiple tumor types. Due to the impressive benefits offered by the taxanes, different strategies are in development, aimed at reducing their systemic toxicity and the need for premedication, while improving anti-tumor spectra and treatment efficacy. Although a remarkable amount of effort has been aimed at overcoming delivery difficulties, very few compounds have reached clinical trials, and some of those few have failed advanced trials. This mini-review reports the most recent developments in advanced taxane delivery approaches, with particular focus on receptor-targeted delivery systems. Keywords: Taxanes, conjugates, micelles, nanoparticles, chemotherapy, cancer, drug delivery, cancer cells, EGFR, POLYMERIC MICELLES

Baseline diastolic dysfunction as a predictive factor of trastuzumab-mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer

To evaluate the interest in assessing left ventricular diastolic function at baseline for prediction of trastuzumab-mediated cardiotoxicity (TMC) in the setting of adjuvant treatment for breast cancer. The study included 118 women presenting with HER2-positive early-stage invasive breast cancer. Patients received trastuzumab therapy over 1 year, concurrent with six cycles of docetaxel (n = 53), or following anthracycline-based chemotherapy with a cumulative dose of 300 mg/m(2) (n = 45) or 600 mg/m(2) (n = 20) of epirubicine. RNA was performed before anthracycline-based chemotherapy, before trastuzumab treatment (baseline), and every 3 months during treatment. Left ventricular ejection fraction (LVEF) and peak ejection rate (PER) were calculated to evaluate LV systolic function; peak filling rate (PFR), and time to peak filling rate (TPFR) were also calculated to evaluate LV diastolic function. Eighteen patients (15%) developed grade 1 or 2 TMC during follow-up. No significant difference was observed for age, cardiovascular risk factors, fasting blood glucose level, heart rate, systolic blood pressure, baseline LVEF, PER, and PFR between patients with and without TMC. In contrast, patients with TMC showed a longer TPFR at baseline (median [Q1-Q3]: 165 ms [149-190] vs. 142 ms [130-162]; P < 0.001). Furthermore, by logistic regression analysis, baseline TPFR >180 ms and the cumulative dose of epirubicin remained independent predictors of TMC. Patients receiving 600 mg/m(2) of epirubicin before trastuzumab showed a higher incidence of TMC (35%) than did both patients who previously received 300 mg/m(2) of epirubicin (13%) and those who received only docetaxel associated with trastuzumab (9%). Impaired left ventricular diastolic function before treatment is an independent predictor of trastuzumab-mediated cardiotoxicity. The evaluation of diastolic function could allow optimal risk stratification before the introduction of trastuzumab.

Intravenous KITENIN shRNA Injection Suppresses Hepatic Metastasis and Recurrence of Colon Cancer in an Orthotopic Mouse Model

KITENIN (KAI1 C-terminal interacting tetraspanin) promotes invasion and metastasis in mouse colon cancer models. In the present study, we evaluated the effects of KITENIN knockdown by intravenous administration of short hairpin RNAs (shRNAs) in an orthotopic mouse colon cancer model, simulating a primary or adjuvant treatment setting. We established orthotopic models for colon cancer using BALB/c mice and firefly luciferase-expressing CT-26 (CT26/Fluc) cells. Tumor progression and response to therapy were monitored by bioluminescence imaging (BLI). In the primary therapy model, treatment with KITENIN shRNA substantially delayed tumor growth (P = 0.028) and reduced the incidence of hepatic metastasis (P = 0.046). In the adjuvant therapy model, KITENIN shRNA significantly reduced the extent of tumor recurrence (P = 0.044). Mice treated with KITENIN shRNA showed a better survival tendency than the control mice (P = 0.074). Our results suggest that shRNA targeting KITENIN has the potential to be an effective tool for the treatment of colon cancer in both adjuvant and metastatic setting.