Assessing fracture risk in early stage breast cancer patients treated with aromatase-inhibitors: An enhanced screening approach incorporating trabecular bone score

AbstractIntroductionAromatase-inhibitors (AIs) are commonly used for treatment of patients with hormone-receptor positive breast carcinoma, and are known to induce bone density loss and increase the risk of fractures. The current standard-of-care screening tool for fracture risk is bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). The fracture risk assessment tool (FRAX®) may be used in conjunction with BMD to identify additional osteopenic patients at risk of fracture who may benefit from a bone-modifying agent (BMA). The trabecular bone score (TBS), a novel method of measuring bone microarchitecture by DXA, has been shown to be an independent indicator of increased fracture risk. We report how the addition of TBS and FRAX®, respectively, to BMD contribute to identification of elevated fracture risk (EFR) in postmenopausal breast cancer patients treated with AIs.Methods100 patients with early stage hormone-positive breast cancer treated with AIs, no prior BMAs, and with serial DXAs were identified. BMD and TBS were measured from DXA images before and following initiation of AIs, and FRAX® scores were calculated from review of clinical records. EFR was defined as either: BMD ≤−2.5 or BMD between −2.5 and −1 plus either increased risk by FRAX® or degraded microstructure by TBS.ResultsAt baseline, BMD alone identified 4% of patients with EFR. The addition of FRAX® increased detection to 13%, whereas the combination of BMD, FRAX® and TBS identified 20% of patients with EFR. Following AIs, changes in TBS were independent of changes in BMD. On follow-up DXA, BMD alone detected an additional 1 patient at EFR (1%), whereas BMD+ FRAX® identified 3 additional patients (3%), and BMD+FRAX®+TBS identified 7 additional patients (7%).ConclusionsThe combination of FRAX®, TBS, and BMD maximized the identification of patients with EFR. TBS is a novel assessment that enhances the detection of patients who may benefit from BMAs

Dose-dense adjuvant chemotherapy for primary breast cancer

Adjuvant chemotherapy has been proven to reduce significantly the risk for relapse and death in women with operable breast cancer. Nevertheless, the prognosis for patients presenting with extensive axillary lymph node involvement remains suboptimal. In an attempt to improve on the efficacy of existing chemotherapy, a phase III intergroup trial led by the Cancer and Leukemia Group B (CALGB 97-41) was designed, which tested a mathematical model of tumor growth based on the Norton–Simon hypothesis. This hypothesis, developed about 3 decades ago, and the kinetic model derived from it, created the basis of the concepts of dose density and sequential therapy, both of which were tested in CALGB 97-41. This large prospective randomized trial demonstrated that shortening the time interval between each chemotherapy cycle while maintaining the same dose size resulted in significant improvements in disease-free and overall survival in patients with node-positive breast carcinoma. This finding is highly relevant and has immediate implications for clinical practice

Thin film contamination effects on laser-induced damage of fused silica surfaces at 355 nm

Fused silica windows were artificially contaminated to estimate the resistance of target chamber debris shields against laser damage during NIF operation. Uniform contamination thin films (1 to 5 nm thick) were prepared by sputtering various materials (Au, Al, Cu, and B4C). The loss of transmission of the samples was first measured. They were then tested at 355 nm in air with an 8-ns Nd:YAG laser. The damage morphologies were characterized by Nomarski optical microscopy and SEM. Both theory and experiments showed that metal contamination for films as thin as 1 nm leads to a substantial loss of transmission. The laser damage resistance dropped very uniformly across the entire surface (e.g. 6 J/cm2 for 5 nm of Cu). The damage morphology characterization showed that contrary to clean silica, metal coated samples did not produce pits on the surface. B4C coated silica, on the other hand, led to a higher density of such damage pits. A model for light absorption in the thin film was coupled with a simple heat deposition and diffusion model to perform preliminary theoretical estimates of damage thresholds. The estimates of the loss due to light absorption and reflection pointed out significant .differences between metals (e.g. Al and Au). The damage threshold predictions were in qualitative agreement with experimental measurements

Serum HER2 Level Measured by Dot Blot: A Valid and Inexpensive Assay for Monitoring Breast Cancer Progression

Human epidermal growth factor receptor 2 (HER2) is one of the most important prognostic and predictive factors for breast cancer patients. Recently, serum HER2 ECD level of patients detected by enzyme-linked immunoabsorbent assay (ELISA) has been shown to predict tumor HER2 status and reveal its association with tumor progression, recurrence and poor prognosis. In this study, we established a new method, dot blot assay, to measure the serum HER2 level in breast cancer patients and further to evaluate the clinical value for monitoring breast cancer progression. We found that the serum HER2 level measured by dot blot assay was significantly correlated with tissue HER2 status in breast cancer patients (P = 0.001), and also significantly correlated with HER2 level measured by ELISA (P = 1.06×10−11). Compared with ELISA method, the specificity and sensitivity of dot blot assay were 95.3% and 65.0%, respectively. The serum HER2 levels of patients with grade III or ER-negative were higher than those with grade I–II (P = 0.004) and ER-positive (P = 0.033), respectively. Therefore, the novel dot blot method to detect serum HER2 level is a valid and inexpensive assay with potential application in monitoring breast cancer progression in clinical situations

Clinical utility of serum HER2/neu in monitoring and prediction of progression-free survival in metastatic breast cancer patients treated with trastuzumab-based therapies

INTRODUCTION: The purpose of this retrospective study was to determine the clinical utility of serum HER2/neu in monitoring metastatic breast cancer patients undergoing trastuzumab-based therapy and to compare these results with those obtained using cancer antigen (CA) 15-3. We also sought to determine whether early changes in serum HER2/neu concentrations could be a predictor of progression-free survival. METHODS: Sera were obtained retrospectively from 103 women at four medical institutions. Patients eligible for participation were women with metastatic breast cancer who had HER2/neu tissue overexpression and were scheduled to be treated with trastuzumab with or without additional therapies as per the established practices of the treating physicians. A baseline serum sample for each patient was taken before trastuzumab-based therapy was started. Patients were subsequently monitored over 12 to 20 months and serum samples were taken at the time of clinical assessment and tested with Bayer's HER2/neu and CA15-3 assays. RESULTS: Concordance between clinical status in patients undergoing trastuzumab-based treatment and HER2/neu and CA15-3 used as single tests was 0.793 and 0.627, respectively, and increased to 0.829 when the tests were used in combination. Progression-free survival times did not differ significantly in patients with elevated baseline HER2/neu concentrations (≥ 15 ng/mL) and those with normal concentrations (<15 ng/mL). However, progression-free survival differed significantly (P = 0.043) according to whether the patient's HER2/neu concentration at 2 to 4 weeks after the start of therapy was >77% or ≤ 77% of her baseline concentration. The median progression-free survival times for these two groups were 217 and 587 days, respectively. A similar trend was observed for a subcohort of patients treated specifically with a combination of trastuzumab and taxane. CONCLUSION: These findings indicate that serum HER2/neu testing is clinically valuable in monitoring metastatic breast cancer patients undergoing trastuzumab-based treatment and provides additional value over the commonly used CA15-3 test. The percentage of baseline HER2/neu concentrations in the early weeks after the start of therapy may be an early predictor of progression-free-survival

Incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel

<p>Abstract</p> <p>Background</p> <p>To determine the incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel.</p> <p>Methods</p> <p>We studied the incidence and duration of amenorrhea induced by two chemotherapy regimens: (i) 6 cycles of 5-fluorouracil 500 mg/m², epirubicin 100 mg/m²and cyclophosphamide 500 mg/m²on day 1 every 3 weeks (6FEC) and (ii) 3 cycles of FEC 100 followed by 3 cycles of docetaxel 100 mg/m²on day 1 every 3 weeks (3FEC/3D). Reversible amenorrhea was defined as recovery of regular menses and, where available (101 patients), premenopausal hormone values (luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol) in the year following the end of chemotherapy.</p> <p>Results</p> <p>One hundred and fifty-four premenopausal patients were included: 84 treated with 6FEC and 70 with 3FEC/3D. The median age was 43.5 years (range: 28–58) in the 6FEC arm and 44 years (range: 29–53) in the 3FEC/3D arm. Seventy-eight percent of patients were treated in the context of the PACS 01 trial. The incidence of chemotherapy-induced amenorrhea at the end of chemotherapy was similar in the two groups: 93 % in the 6FEC arm and 92.8 % in the 3FEC/3D arm. However, in the year following the end of chemotherapy, more patients recovered menses in the 3FEC/3D arm than in the 6FEC arm: 35.5 % versus 23.7 % (p = 0.019). Among the 101 patients for whom hormone values were available, 43 % in the 3FEC/3D arm and 29 % in the 6FEC arm showed premenopausal levels one year after the end of chemotherapy (p < 0.01). In the 3FEC/3D group, there was a statistically significant advantage in disease-free survival (DFS) for patients who were still amenorrheic after one year, compared to patients who had recovered regular menses (p = 0.0017).</p> <p>Conclusion</p> <p>Our study suggests that 3FEC/3D treatment induces more reversible amenorrhea than 6FEC. The clinical relevance of these findings needs to be investigated further.</p

Polarized Growth in the Absence of F-Actin in Saccharomyces cerevisiae Exiting Quiescence

Polarity establishment and maintenance are crucial for morphogenesis and development. In budding yeast, these two intricate processes involve the superposition of regulatory loops between polarity landmarks, RHO GTPases, actin-mediated vesicles transport and endocytosis. Deciphering the chronology and the significance of each molecular step of polarized growth is therefore very challenging.We have taken advantage of the fact that yeast quiescent cells display actin bodies, a non polarized actin structure, to evaluate the role of F-actin in bud emergence. Here we show that upon exit from quiescence, actin cables are not required for the first steps of polarized growth. We further show that polarized growth can occur in the absence of actin patch-mediated endocytosis. We finally establish, using latrunculin-A, that the first steps of polarized growth do not require any F-actin containing structures. Yet, these structures are required for the formation of a bona fide daughter cell and cell cycle completion. We propose that upon exit from quiescence in the absence of F-actin, secretory vesicles randomly reach the plasma membrane but preferentially dock and fuse where polarity cues are localized, this being sufficient to trigger polarized growth

Incidence of chemotherapy-induced amenorrhea associated with epirubicin, docetaxel and navelbine in younger breast cancer patients

<p>Abstract</p> <p>Background</p> <p>The rates of chemotherapy-induced amenorrhea (CIA) associated with docetaxel-based regimens reported by previous studies are discordant. For navelbine-based chemotherapies, rates of CIA have seldom been reported.</p> <p>Methods</p> <p>Of 170 premenopausal patients recruited between January 2003 and September 2008, 78 were treated with fluorouracil plus epirubicin and cyclophosphamide (FEC), 66 were treated with docetaxel plus epirubicin (TE), and 26 were treated with navelbine plus epirubicin (NE). Patient follow-up was carried up every 3-4 months during the first year, then every 9-12 months during subsequent years.</p> <p>Results</p> <p>In univariate analysis, the rates of CIA were 44.87% for the FEC regimen, 30.30% for the TE regimen and 23.08% for the NE regimen (<it>P </it>= 0.068). Significant differences in the rates of CIA were not found between the FEC and TE treatment groups (<it>P </it>> 0.05), but were found between the FEC and NE treatment groups (<it>P </it>< 0.05). Furthermore, no significant differences were found between the TE and NE regimens (<it>P </it>> 0.05). Tamoxifen use was a significant predictor for CIA (<it>P </it>= 0.001), and age was also a significant predictor (<it>P </it>< 0.001). In multivariate analysis, age (<it>P </it>< 0.001), the type of chemotherapy regimens (<it>P </it>= 0.009) and tamoxifen use (<it>P </it>= 0.003) were all significant predictors.</p> <p>Conclusions</p> <p>Age and administration of tamoxifen were found to be significant predictive factors of CIA, whereas docetaxel and navelbine based regimens were not associated with higher rates of CIA than epirubicin-based regimen.</p