Gene expression profiles do not consistently predict the clinical treatment response in locally advanced breast cancer

Neoadjuvant treatment offers an opportunity to correlate molecular variables to treatment response and to explore mechanisms of drug resistance in vivo. Here, we present a statistical analysis of large-scale gene expression patterns and their relationship to response following neoadjuvant chemotherapy in locally advanced breast cancers. We analyzed cDNA expression data from 81 tumors from two patient series, one treated with doxorubicin alone (51) and the other treated with 5-fluorouracil and mitomycin (30), and both were previously studied for correlations between TP53 status and response to therapy. We observed a low frequency of progressive disease within the luminal A subtype from both series (2 of 36 versus 13 of 45 patients; P = 0.0089) and a high frequency of progressive disease among patients with luminal B type tumors treated with doxorubicin (5 of 8 patients; P = 0.0078); however, aside from these two observations, no other consistent associations between response to chemotherapy and tumor subtype were observed. These specific associations could possibly be explained by covariance with TP53 mutation status, which also correlated with tumor subtype. Using supervised analysis, we could not uncover a gene profile that could reliably (>70% accuracy and specificity) predict response to either treatment regimen.     

乳腺癌骨转移患者的内乳淋巴显像

目的：通过内乳淋巴显像探讨乳腺癌患者内乳淋巴结转移及向对侧引流与骨转移的关系。方法：对35例乳腺癌切除术后并发生骨转移的患者和28例无骨转移的患者进行了内乳淋巴显像。仪器为GE公司产Millennium VG5 with Hawkeye，配低能高分辨率准直器。结果：①经内乳淋巴显像诊断骨转移组内乳淋巴结总的转移率、患侧向对侧引流率为62.9%，57.1%，同时有内乳淋巴转移和向对侧引流为40.0%；无骨转移组分别为32.1%，21.4%，10.7%,两组比较差异均有显著性（P均<0.05）。②仅有向对侧引流是骨转移组（17.1%）高于无转移组（10.7%），但差异无显著性。仅有内乳淋巴转移两组结果相似（22.9%和21.4%）。③骨转移组中，肿瘤位于内、中区的内乳淋巴结转移率（37.1%）及向对侧引流率（37.1%）均较外侧区者高（25.9%和20.0%）。结论：内乳淋巴结转移同时有向对侧引流极易发生骨骼转移；尚无内乳淋巴转移仅有向对侧引流者应高度警惕。     

Denosumab for treatment of breast cancer bone metastases and beyond

INTRODUCTION: Bone metastases develop in approximately 70 - 85% of patients with metastatic breast cancer, are incurable and can result in debilitating skeletal complications. Bone-modifying agents to treat breast cancer bone metastases include bisphosphonates. Denosumab is a humanized monoclonal IgG2 antibody targeting receptor activator of NF-κB ligand (RANKL) and provides an alternative therapy for treatment of breast cancer bone metastases. AREAS COVERED: This review provides an overview on denosumab and the RANKL-RANK pathway. Denosumab pharmacokinetics, pharmacodynamics, efficacy, safety and tolerability are discussed. Based on the review of clinical studies, denosumab is efficacious in the treatment of breast cancer bone metastases. Adverse events rates of denosumab are similar to those for bisphosphonates. Preclinical studies have indicated a role of the RANKL-RANK pathway in non-bone-related mechanisms such as mammary gland development and tumorigenesis. EXPERT OPINION: Clinical use of denosumab remains limited and its place in therapy will continue to be defined. Clinical questions, such as the optimal duration of therapy, remain unanswered and need to be addressed.     

Denosumab for treatment of breast cancer bone metastases and beyond

Introduction: Bone metastases develop in approximately 70 – 85% of patients with metastatic breast cancer, are incurable and can result in debilitating skeletal complications. Bone-modifying agents to treat breast cancer bone metastases include bisphosphonates. Denosumab is a humanized monoclonal IgG2 antibody targeting receptor activator of NF-κB ligand (RANKL) and provides an alternative therapy for treatment of breast cancer bone metastases.

Areas covered: This review provides an overview on denosumab and the RANKL–RANK pathway. Denosumab pharmacokinetics, pharmacodynamics, efficacy, safety and tolerability are discussed. Based on the review of clinical studies, denosumab is efficacious in the treatment of breast cancer bone metastases. Adverse events rates of denosumab are similar to those for bisphosphonates. Preclinical studies have indicated a role of the RANKL–RANK pathway in non-bone-related mechanisms such as mammary gland development and tumorigenesis.

Expert opinion: Clinical use of denosumab remains limited and its place in therapy will continue to be defined. Clinical questions, such as the optimal duration of therapy, remain unanswered and need to be addressed.     

Long-term variability of bone turnover markers in patients with non-metastatic breast cancer

Variability of bone marker measurements is a major problem in their clinical application. Most studies on marker variability have been performed in healthy subjects and over relatively short intervals of time. We prospectively evaluated the long-term variability of bone markers in 102 postmenopausal women diagnosed with primary breast cancer. During follow up (8-48, median 30 mo.), no patient developed bone metastases or other skeletal disease. Patients were seen every 3 months and exactly timed blood/urine specimens were obtained. All analyses were performed after study end by the same technician, using a single batch of reagents per analyte. The coefficient of variation was calculated as CV (%) = square root(sigma(CVi2)/n) (CVi = SD/mean x 100; n = n of CVi). The least significant change (LSC) was then LSC (%) = Z x CV x square root(2). Z = 1.96 for a 95% confidence interval (LSC-95). In a subset of n = 10 patients with no potential interference during follow-up, lowest CVs were recorded for serum (s) calcium (5%), sTAP (12%) and sBAP (14%). The LSC-95 for these markers were 14%, 33% and 39%, respectively. Highest CVs were seen with urine (56%) and serum (42%) CTX (LSC-95: 155%, 117% resp.). We conclude that in breast cancer patients without bone metastases, long-term variability varied greatly between markers. For certain markers, the LSC seems considerably higher than previously reported.     

Serum bone alkaline phosphatase and CA 549 in breast cancer with bone metastases.

A monoclonal radioimmunometric assay for bone alkaline phosphatase (BAP) developed by Hybritech, USA, with an upper limit of normal of 40 U/l, was examined in 125 patients with breast cancer. Eleven patients who remained tumour free for 5-6 years had small intra-individual variations of BAP. The median value in 33 patients with multiple bone metastases of 60 U/l was elevated when compared with that in 40 patients with no evidence of metastases (22 U/l) and 34 U/l in 16 with limited bone disease (1-2 hot spots). By contrast, only 2 out of 25 patients with extensive local recurrence, lung, or hepatic metastases, without bone involvement showed an increase of BAP (< 200 U/l). The BAP levels were compared to total alkaline phosphatase (TAP), the breast cancer marker CA 549 (HybriBREScan). Longitudinal studies of 15 patients with bony metastases showed that TAP and BAP were well correlated only when the TAP was elevated; CA 549 and BAP could vary independently. The main use of BAP in patients with bone metastases appears to be an aid to the monitoring of treatment; however, it is not significantly raised in limited bone metastases.     

Cutaneous metastases in breast cancer

Cutaneous metastases occur more often in breast cancer than in other diseases in women. Presentation often is ambiguous because the metastases can mimic other common processes (e.g., cellulitis, lymphedema). Accurate differential diagnosis identifies less obvious manifestations of progressive disease and allows for appropriate management. Although interventions are aimed at halting disease progression, cutaneous metastases indicate an incurable diagnosis. Treatment focuses on delaying progressive disease, controlling symptoms, and maintaining quality of life. The care of skin metastases evolves as the tumor spreads and more tissue destruction occurs. Skin management and topical interventions increase comfort, decrease distress, and create feelings of control in this population.     

Bone mineral density and bone turnover in postmenopausal women treated for breast cancer

Chemotherapy and endocrine treatments for breast cancer are believed to increase risk of osteoporosis by causing early menopause in premenopausal women and by further depleting estrogen levels in postmenopausal women. Multivariate analyses were used to evaluate the contributions of 7 predictors (age, body mass index [BMI], family history of osteoporosis, months since menopause, past use of chemotherapy, and current use of tamoxifen or aromatase inhibitors) in explaining variability in bone mineral density (BMD) at the hip and the spine and bone turnover in 249 postmenopausal women who are breast cancer survivors. This report was an analysis of baseline data from a federally funded (1 R01 NR07743-01A1) intervention study on osteoporosis prevention. Mean age of the women was 58.5 years, and average BMI was 26.7 kg/m; 98% were white. All had measurable bone loss, 167 had chemotherapy, 76 were on tamoxifen, and 21 were on aromatase inhibitors. Women with higher BMI had higher BMD at the hip (P < .001) and the spine (P = .004). Women on tamoxifen had lower measures of bone formation (Alkphase B) (P < .001), suggesting less bone turnover, and higher BMD at the hip (P = .035). There was a trend for women who had received chemotherapy to have lower BMD at the spine (P = .06). The implications of these findings are discussed in the article.     

Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer

The role of lysophosphatidic acid (LPA) in cancer is poorly understood. Here we provide evidence for a role of LPA in the progression of breast cancer bone metastases. LPA receptors LPA(1), LPA(2), and LPA(3) were expressed in human primary breast tumors and a series of human breast cancer cell lines. The inducible overexpression of LPA(1) in MDA-BO2 breast cancer cells specifically sensitized these cells to the mitogenic action of LPA in vitro. In vivo, LPA(1) overexpression in MDA-BO2 cells enhanced the growth of subcutaneous tumor xenografts and promoted bone metastasis formation in mice by increasing both skeletal tumor growth and bone destruction. This suggested that endogenous LPA was produced in the tumor microenvironment. However, MDA-BO2 cells or transfectants did not produce LPA. Instead, they induced the release of LPA from activated platelets which, in turn, promoted tumor cell proliferation and the LPA(1)-dependent secretion of IL-6 and IL-8, 2 potent bone resorption stimulators. Moreover, platelet-derived LPA deprivation in mice, achieved by treatment with the platelet antagonist Integrilin, inhibited the progression of bone metastases caused by parental and LPA(1)-overexpressing MDA-BO2 cells and reduced the progression of osteolytic lesions in mice bearing CHO-beta3wt ovarian cancer cells. Overall, our data suggest that, at the bone metastatic site, tumor cells stimulate the production of LPA from activated platelets, which enhances both tumor growth and cytokine-mediated bone destruction.     

乳腺癌骨转移骨相关事件对患者生存期的影响

目的:探讨乳腺癌骨转移骨相关事件(skeletal-related events,SREs)的发生及SREs对患者生存期的影响。方法:选择复旦大学附属中山医院和上海市黄浦区中心医院收治的乳腺癌骨转移患者。将患者分为不伴SREs组和伴SREs组,比较两组患者的基本临床特征、骨转移特征,分析SREs的特点及SREs对乳腺癌骨转移患者的骨转移生存期(BS)和总生存期(OS)的影响。结果:乳腺癌骨转移患者共104例,不伴SREs组和伴SREs组分别为46例、58例。两组间年龄、手术方式、肿瘤组织类型、美国癌症联合会(American Joint Committee on Cancer,AJCC)分期、骨转移间歇期、骨转移部位等差异无统计学意义,骨转移数目差异有统计学意义(P=0.006)。骨相关事件间歇期0~48个月,中位时间为5.5(1.0,20.5)个月。SREs以骨痛最多,占70.6%。不伴SREs组和伴SREs组间BS(HR=1.043,95%CI 0.608~1.790,P=0.878)和OS(HR=0.927,95%CI0.543~1.581,P=0.781)差异无统计学意义。结论:SREs不增加乳腺癌骨转移患者的死亡风险。     

放疗对乳腺癌骨转移后癌痛的疗效分析

Objective To investigate the radiotherapy curative effects on pains of bone metastases of breast cancer. Methods To analysis 32 patients retrospectively, in which 22 patients received radiotherapy(17 moderate pain, 5 severe pain, 6 dysfunction). Result 16 patients obtained complete remission with 6 cases partial response to radiation. Karnorfsky's score was improved and malfunction disappeared. Conclusion Radiotherapy is a simple and effective treatment on bone metastases of breast cancer with quick and persistent pain relieves.     

Analysis of radiotherapy curative effects on pains of bone metastases of breast cancer

Themainreasonoffailtreatmentofbreastcarcinomaisremotemetastasis,inwhichboneisthemostcommonplacetometastasis．Bonemetastasisofbreastcancercaninduceseverepainandmal－function,whichmakegreatinfluenceonpatientslivingquality．２１２breastcancerpatentsweretreatedbetweenJanuary１９８９andDe－cember１９９６,３２patientshappenedbonemetastasisaftertreatment．１Materialsandmethods１．１Materials３２breastcancerpatientswithbonemetastasiswereanalyzed,allthepatientswerefemale,aged３０～７１years,andm…     

Markers of bone turnover in postmenopausal women receiving hormone replacement therapy.

We investigated the effects of hormone replacement therapy (n = 27) on biochemical markers of bone turnover in a cross-sectional study of 127 postmenopausal women (according to WHO guidelines 18 patients had normal bone mineral density and 109 suffered from bone loss). Urinary excretion of free deoxypyridinoline and C- or N-telopeptide fragments of type I collagen served as bone resorption markers, serum osteocalcin as a bone formation marker. In women with no hormone replacement therapy, only C- and N-telopeptides correlated significantly with the lumbal T-score as an index for bone mineral density. Patients with bone loss receiving hormone replacement therapy exhibited significantly lower C-telopeptide, N-telopeptide and osteocalcin levels than those with no therapy (mean -45%, -43% and -26%, respectively), while deoxypyridinoline showed no significant differences. Among the markers investigated, C- and N-telopeptides seemed to be more reliable to detect therapeutic effects on bone metabolism. We present a preliminary model to evaluate bone turnover and resorption/formation rate.     

High predictivity of galactosyl-hydroxylysine in urine as an indicator of bone metastases from breast cancer

We measured the urinary excretion of galactosyl-hydroxylysine (GH) and hydroxyproline in two groups of women with breast cancer, with (M+, n = 24) and without (Mo, n = 30) clinical, scintigraphic, or radiological evidence of bone metastases. Both these compounds are excreted in larger amounts in the M+ group than in the Mo patients. However, GH, which is a specific marker for bone collagen, provides better predictivity for bone metastases than does hydroxyproline: 92% sensitivity and 90% specificity vs 74% and 79%, respectively, for hydroxyproline.     

帕米磷酸二钠与89锶联合治疗乳腺癌多发骨转移的临床观察

目的探讨帕米磷酸二钠联合。89锶／放射性核素治疗乳腺癌多发骨转移的临床价值。方法108例乳腺癌多发骨转移患者随机分为3组，分别接受帕米磷酸二钠、89锶（89SrCl2）的单独治疗及两者的联合治疗。结果帕米磷酸二钠组89Srcl2组、联合治疗组止痛有效率分别为77．8％、75．O％、97．2％，骨转移病灶控制有效率分别为30．6％、36．1％、63．9％，联合治疗组疗效明显高于帕米磷酸二钠组和89SrCI2组（P均〈0．05），而帕米磷酸二钠组和89锶组间差异无统计学意义（P〉0．05）。结诊帕米磷酪二钠联合89srcl2治疗乳腺多发骨转移在止痛、骨转移病灶控制方面疗效明显优于各药单药治疗。     

Qualitative intravascular catheter tip cultures do not predict catheter-related bacteremia

During a 5-month period, we evaluated the sensitivity, specificity, and predictive value of qualitative cultures of intravenous catheters submitted to a university hospital microbiology laboratory. Of 36 catheters submitted for culture from nonseptic patients, 10 (28%) grew one or more microorganisms on qualitative culture. Of 44 catheters cultured from septic patients, 20 (45%) grew one or more microorganisms, but only 5 grew microorganisms that also were isolated from blood cultures. The sensitivity, specificity, and positive predictive values for catheter-related bacteremia were 71%, 96%, and 17%, values similar to those reported for quantitative methods. Although acceptable in terms of sensitivity and specificity, the very low positive predictive value suggests that catheter-related bacteremia cannot be predicted reliably by this test. We conclude, therefore, that nonstandardized qualitative IV catheter cultures have minimal value as predictors of bacteremia and recommend that they not be performed in clinical microbiology laboratories.     

Serum levels of melanoma-inhibiting activity do not predict relapse in melanoma patients

Melanoma-inhibiting activity (MIA) is a 107 amino-acid protein secreted from melanoma cells and frequently detectable at high concentration in the serum of patients with advanced melanoma. Early studies suggested that MIA may be a useful serum tumor-marker for detection of recurrent or progressive disease. We evaluated the sensitivity of serum MIA levels in predicting the risk of relapse in patients with American Joint Committee on Cancer (AJCC) Stage II, III, and IV melanoma. MIA was measured by ELISA in serum from 39 patients with AJCC Stage II, III and IV disease at a single time-point 1 month to 5 years after they were rendered free of disease. Twenty-three of the 39 patients recurred, with a median follow-up of 4.5 months. Only four of the 23 patients who recurred had shown elevated MIA values (17% sensitivity). Of the 16 patients who remain free of disease (median follow-up 3.5 years, range 11 months to 6.3 years), one patient had an elevated MIA. There was no significant difference in the proportion of patients with elevated serum MIA between the patients who recurred and those who remained free of disease. In this series, serum MIA was not a sensitive marker for relapse in patients who were clinically free of disease after treatment.     

Symptom clusters in cancer patients with bone metastases

Purpose The purpose of this study is to explore whether bone pain “clusters” with other symptoms in patients with bone metastases. Materials and methods Patients with bone metastases referred to a palliative radiotherapy clinic were asked to rate their symptom distress using the Edmonton Symptom Assessment Scale (ESAS). Analgesic consumption during the previous 24 h was captured at initial consultation. To determine interrelationships between symptoms, a principal component analysis (PCA) with “varimax rotation” was performed on the nine ESAS symptoms. This study defined a “symptom cluster” as two or more symptoms that occur together, are stable, and are relatively independent of other clusters. Patients were followed 1, 2, 4, 8, and 12 weeks post-radiation treatment by telephone. Statistical analysis was performed at each time point for both responders and nonresponders to radiation (response was defined in accordance to the International Bone Metastases Consensus Working Party). Results Five hundred eighteen patients with bone metastases provided complete baseline data using the ESAS. The four most prevalent symptoms were poor sense of well-being (93.5%), fatigue (92.3%), pain (84.1%), and drowsiness (81.8%). Three clusters were identified and accounted for 66% of the total variance at baseline. Cronbach’s alpha coefficient demonstrated high internal reliability in the clusters, with a coefficient ranging from 0.61 to 0.81. It was observed that the clusters changed post-radiation in both responders and nonresponders and that pain clustered with different symptoms (or remained a separate symptom in responders). In nonresponders, three symptom clusters were consistently present, except in week 8. Conclusion Radiotherapy influenced the structure of symptom clusters in both responders and nonresponders. There was evidence that pain clustered out in responders of radiation to pain. It was found that pain clustered with fatigue, drowsiness, and poor sense of well-being at baseline. However, these findings must be heeded with caution, as more work is needed to clearly define symptom clusters and to understand the effects of radiation in the symptom experience of patients with bone metastases.