Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo.

Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is linked to increased PI3K-AKT signaling, enhanced organismal growth, and cancer development. Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten(FV/+) mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency, including the thyroid, prostate, and uterus. Progression to carcinoma in sensitive organs ensues in the absence of overt AKT activation. Carcinoma in the uterus, a cancer-resistant organ, requires a second clonal event associated with the spontaneous activation of AKT and downstream signaling. In summary, this PTEN noncatalytic missense mutation exposes a core tumor suppressor function distinct from inhibition of canonical AKT signaling that predisposes to organ-selective cancer development in vivo.

Chronic comorbid conditions among adult cancer survivors in the United States: Results from the National Health Interview Survey, 2002-2018.

BACKGROUND: Cancer survivors develop other chronic medical conditions because of shared risk factors and delayed effects of cancer treatment. This study investigated trends in the prevalence of chronic diseases and estimated their population sizes among adult cancer survivors in the United States from 2002 to 2018. METHODS: Using 2002-2018 National Health Interview Survey data, this study calculated the age-sex-race/ethnicity-adjusted prevalences and estimated the population sizes for the following chronic conditions among cancer survivors: hypertension, diabetes, stroke, heart disease, chronic obstructive pulmonary disease (COPD)/asthma, hepatitis, arthritis, liver disease, kidney disease, and morbid obesity. This study also examined multiple chronic conditions (MCC; 3 or more health conditions). MCC trends were further examined by sociodemographic factors to identify high-risk populations. Parallel analyses were performed for participants without a cancer history to provide a reference. RESULTS: Among 30,728 cancers survivors, increasing trends were observed in the prevalence of hypertension, diabetes, kidney disease, liver disease, and morbid obesity, whereas decreasing prevalence trends were observed for ischemic heart disease, COPD, and hepatitis. Cancer survivors with MCC increased from 4.7 million in 2002 to 8.1 million in 2018 (the prevalence increased from 43.7% to 46.6%). The increase was more pronounced among survivors aged 18 to 44 years. Among adults without a cancer history, the MCC prevalence also increased, although more slowly than among survivors. CONCLUSIONS: The number of adult cancer survivors in the United States with comorbid illnesses has increased substantially over the past 2 decades. Optimal management of comorbid conditions and aggressive interventions for risk reduction may benefit the cancer survivor population.

Phase I Study of Veliparib on an Intermittent and Continuous Schedule in Combination with Carboplatin in Metastatic Breast Cancer: A Safety and [18F]-Fluorothymidine Positron Emission Tomography Biomarker Study.

BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPis) are U.S. Food and Drug Administration (FDA) approved for treatment of BRCA-mutated metastatic breast cancer. Furthermore, the BROCADE studies demonstrated benefit of adding an oral PARPi, veliparib, to carboplatin and paclitaxel in patients with metastatic breast cancer harboring BRCA mutation. Given multiple possible dosing schedules and the potential benefit of this regimen for patients with defective DNA repair beyond BRCA, we sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple-negative (TNBC) or hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2) negative with defective Fanconi anemia (FA) DNA-repair pathway based on FA triple staining immunofluorescence assay. MATERIALS AND METHODS: Patients received escalating doses of veliparib on a 7-, 14-, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-3'-deoxythymidine (18 FLT) positron emission tomography (PET) imaging. RESULTS: Forty-four patients (39 TNBC, 5 HR positive/HER2 negative with a defective FA pathway) received a median of 5 cycles (range 1-36). Observed dose-limiting toxicities were grade (G) 4 thrombocytopenia (n = 4), G4 neutropenia (n = 1), and G3 akathisia (n = 1). Common grade 3-4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of the 43 patients evaluable for response, 18.6% achieved partial response and 48.8% had stable disease. Median progression-free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1-21 along with carboplatin at area under the curve 5. Patients with partial response had a significant drop in maximum standard uptake value (SUVmax ) of target lesions between baseline and early in cycle 1 based on 18 FLT-PET (day 7-21; ptrend = .006). CONCLUSION: The combination of continuous dosing of veliparib and every-3-week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUVmax on 18 FLT-PET scan during the first cycle of this therapy can identify patients who are likely to have a response. IMPLICATIONS FOR PRACTICE: The BROCADE studies suggest that breast cancer patients with BRCA mutation benefit from addition of veliparib to carboplatin plus paclitaxel. This study demonstrates that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in imaging-based early response assessment, the authors demonstrate that decrease in [18]fluoro-3'-deoxythymidine positron emission tomography (FLT-PET) SUVmax during cycle 1 of therapy is associated with response. Collectively, this study established a safety profile of veliparib and carboplatin in advanced breast cancer while also providing additional data on the potential for FLT-PET imaging modality in monitoring therapy response.

Optimism and coping: do they influence health outcomes in women with breast cancer? A systemic review and meta-analysis.

BACKGROUND: Optimism, coping, and resilience may be independent predictors of anxiety, distress, depression, or health-related quality of life (HRQOL) in women with breast cancer. METHODS: Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) searches of PubMed, PsycINFO, and Google Scholar databases from January 1, 1990, to April 30, 2018, for articles (i.e., studies) determining the impact of optimism, coping, or resilience on anxiety, distress, depression, or HRQOL in women with breast cancer. Articles included only those that measured optimism by the life orientation test (LOT) or LOT-revised (R), coping by the COPE, brief (B)-COPE, or religious (R)-COPE, and resilience by the CD-Resilience Scale (CD-RIS). RESULTS: Forty-one out of 52 (79%) studies showed that optimism is a statistically significant predictor of study-specific aspects of anxiety, distress, depression, or HRQOL. In a meta-analysis focused on depression, optimism was a statistically significant predictor of depression. Coping style is a statistically significant predictor for study-specific aspects of anxiety, distress, depression, or HRQOL in 41/43 (95%) studies. The coping studies were too heterogeneous in their outcome variables to perform meta-analyses. There were too few studies (n = 6) on resilience to draw any conclusions. CONCLUSIONS: Despite many limitations of this literature, including the heterogeneity of study designs, differing sample sizes, across different countries, cultures, ethnicities, and races, most studies support that optimism and coping are predictors of anxiety, distress, depression, or HRQOL. Awareness of these psychological constructs and their potential impact on anxiety, depression, and HRQOL are a high priority.

Metastatic breast cancer patient perceptions of somatic tumor genomic testing.

BACKGROUND: To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, and comprehension of tumor genomic testing. METHODS: In a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the present secondary analysis (n = 58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed (n = 40) using paired Wilcoxon signed rank and McNemar's test of agreement. RESULTS: There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or self-efficacy (median time on study: 7.6 months). Depression and anxiety were positively associated with each other and both negatively associated with self-efficacy. Self-efficacy decreased from pre- to post-genomic testing (p = 0.05). Objective genetics comprehension did not significantly change from pre- to post-genomic testing, but patients expressed increased confidence in their ability to teach others about genetics (p = 0.04). Objective comprehension was significantly lower in non-white patients (p = 0.02) and patients with lower income (p = 0.04). CONCLUSIONS: This is the only study, to our knowledge, to longitudinally evaluate multiple psychological metrics in MBC as patients undergo tumor genomic testing. Overall, psychological dimensions remained stable over the duration of tumor genomic testing. Among patients with MBC, depression and anxiety metrics were negatively correlated with patient self-efficacy. Patients undergoing somatic genomic testing had limited genomic knowledge, which varied by demographic groups and may warrant additional educational intervention. CLINICAL TRIAL INFORMATION: NCT01987726, registered November 13, 2013.

Randomized placebo-controlled pilot trial of omega 3 fatty acids for prevention of aromatase inhibitor-induced musculoskeletal pain.

PURPOSE: Aromatase inhibitor (AI)-induced joint symptoms negatively impact drug adherence and quality of life in breast cancer survivors. Mechanisms underlying symptoms may include inflammation. It is hypothesized that n - 3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties and may reduce symptoms. METHODS: We conducted a randomized, double-blind, placebo-controlled study comparing 4.3 g/day n - 3 PUFA supplements vs placebo for 24 weeks in postmenopausal breast cancer patients starting adjuvant AIs. Primary endpoints were adherence and tolerability; secondary outcomes included inflammatory cytokines and symptoms assessed by the Brief Pain Inventory short form (BPI-SF) and Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) at 0, 12, and 24 weeks. RESULTS: Forty-four women were randomized, of which 35 completed the study. Adherence was ≥ 88% based on these 35 patients with pill counts as well as change in red blood cell (RBC) n - 3 PUFAs. Common toxicities included grade 1 flatulence (55% of both groups) and belching (45% of n - 3 group). Mean pain severity scores (BPI-SF) did not change significantly by time or treatment arm. Quality of life, based on FACT-ES scores, significantly decreased within placebo (p = 0.04), but not the n - 3 group (p = 0.58), with a trend toward between-group differences (p = 0.06) at 12 weeks, but no significant differences at 24 weeks. RBC n - 3 levels were strongly positively correlated with FACT-ES at 12 weeks, but attenuated at 24 weeks. CONCLUSION: High-dose n - 3 PUFA supplementation is feasible and well tolerated when administered with AIs. Additional studies are needed to evaluate efficacy in prevention of joint symptoms.

Improving Adherence to Endocrine Therapy in Women With HR-Positive Breast Cancer.

Aromatase inhibitors (AIs) are the standard treatment for postmenopausal women with hormone receptor-positive breast cancers. One of the most common side effects of AIs is joint pain; it is also the most frequently cited reason for nonadherence and discontinuation before completion of the prescribed treatment course. Nonadherence and, in particular, discontinuation, can lead to increased rates of breast cancer mortality. The prevalence of AI-induced arthralgias is about 50%, and there are several interventions, including switching to a different AI, that can increase adherence. The healthcare professional plays a part in fostering adherence by communicating the side effects of AIs to patients before the initiation of treatment, as well as explaining the strategies for addressing these side effects, should they occur.

Management of bone health in postmenopausal women on aromatase inhibitors (AIs): a single health care system experience.

INTRODUCTION: Aromatase inhibitors (AIs) are the preferred therapy for postmenopausal women with early-stage estrogen receptor-positive breast cancers. However, their use causes bone loss and increased risks of osteoporosis and fractures. METHODS: This is a retrospective review of all postmenopausal women with breast cancer diagnosed and treated with AI between 2010 and 2015. Of the 564 women identified, 319 were eligible. RESULTS: The median age at AI initiation was 65 years (range 51-85 years), and the median duration of AI therapy was 28 months (1-72 months). The median number of DEXA scans per woman was 1 (0-4), performed at a median frequency of 24 months (1-48 months). Recommendations for calcium and vitamin D were in 66 and 59% of women, respectively. There were 52 (16%) women who received antiresorptive treatments with bisphosphonates (69%), denosumab (25%), or both drugs (6%). Based on guideline recommendations from six societies, starting antiresorptive treatment was unnecessary in 15-54% of women. CONCLUSIONS: In this single health system experience, women start antiresorptive drugs that are unnecessary in 15-52%. These results highlight the nonuniformity in guideline recommendations, and this has implications for quality of care, cost-effectiveness, and value-of-care analyses for preventing fractures.

Cardiotoxic effects of anthracycline-based therapy: what is the evidence and what are the potential harms?

Despite the known cardiotoxic effects of doxorubicin and other anthracyclines, no evidence-based guidelines exist for the surveillance and prevention of chemotherapy-induced cardiotoxicity in adult survivors of breast cancer who have had limited previous doses of anthracyclines (ie, total cumulative dose 240 mg/m2), or limited-dose anthracyclines followed by trastuzumab-based regimens. Nonetheless, some national and international cardio-oncology and cardiac-imaging organisations recommend increased cardiac surveillance during or after treatment, measurement of cardiac biomarkers and other surrogate endpoints, and in some cases initiation of cardioprotective drug therapy in asymptomatic women. However, two unintended potential harms of such approaches are medicalisation (definition and treatment of subclinical heart problems without high-level evidence for a consequent reduction in the incidence of subsequent heart failure or cardiac deaths) and increased health-care costs when the value of providing that care is unknown. Whether existing cardio-oncology or imaging guideline recommendations will provide increased value or cause increased distress and lower health-related quality of life is unknown. Further research is needed to assess the long-term benefits, harms, and value of expanded cardiac surveillance, use of surrogate cardiac biomarkers, and prophylactic cardioprotective therapy in asymptomatic women with limited exposure to anthracyclines.

Protective role of miR-155 in breast cancer through RAD51 targeting impairs homologous recombination after irradiation.

Cell survival after DNA damage relies on DNA repair, the abrogation of which causes genomic instability and development of cancer. However, defective DNA repair in cancer cells can be exploited for cancer therapy using DNA-damaging agents. DNA double-strand breaks are the major lethal lesions induced by ionizing radiation (IR) and can be efficiently repaired by DNA homologous recombination, a system that requires numerous factors including the recombinase RAD51 (RAD51). Therapies combined with adjuvant radiotherapy have been demonstrated to improve the survival of triple-negative breast cancer patients; however, such therapy is challenged by the emergence of resistance in tumor cells. It is, therefore, essential to develop novel therapeutic strategies to overcome radioresistance and improve radiosensitivity. In this study we show that overexpression of microRNA 155 (miR-155) in human breast cancer cells reduces the levels of RAD51 and affects the cellular response to IR. miR-155 directly targets the 3'-untranslated region of RAD51. Overexpression of miR-155 decreased the efficiency of homologous recombination repair and enhanced sensitivity to IR in vitro and in vivo. High miR-155 levels were associated with lower RAD51 expression and with better overall survival of patients in a large series of triple-negative breast cancers. Taken together, our findings indicate that miR-155 regulates DNA repair activity and sensitivity to IR by repressing RAD51 in breast cancer. Testing for expression levels of miR-155 may be useful in the identification of breast cancer patients who will benefit from an IR-based therapeutic approach.

Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial.

Importance: Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. Objective: To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. Design, Setting, Participants: Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. Interventions: Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. Main Outcomes and Measures: The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). Results: Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% [1-sided 95% CI, -4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks. Conclusions and Relevance: Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option. Trial Registration: clinicaltrials.gov Identifier: NCT00869206.

Integrin-linked kinase as a novel molecular switch of the IL-6-NF-κB signaling loop in breast cancer.

Substantial evidence has clearly demonstrated the role of the IL-6-NF-κB signaling loop in promoting aggressive phenotypes in breast cancer. However, the exact mechanism by which this inflammatory loop is regulated remains to be defined. Here, we report that integrin-linked kinase (ILK) acts as a molecular switch for this feedback loop. Specifically, we show that IL-6 induces ILK expression via E2F1 upregulation, which, in turn, activates NF-κB signaling to facilitate IL-6 production. shRNA-mediated knockdown or pharmacological inhibition of ILK disrupted this IL-6-NF-κB signaling loop, and blocked IL-6-induced cancer stem cells in vitro and estrogen-independent tumor growth in vivo Together, these findings establish ILK as an intermediary effector of the IL-6-NF-κB feedback loop and a promising therapeutic target for breast cancer.

Risk factors for anthracycline-associated cardiotoxicity.

PURPOSE: Carbonyl reductase (CBR) catalyzes anthracycline metabolism, and single nucleotide polymorphisms (SNPs) in CBR impact metabolic efficiency. In pediatric patients, homozygosity for the major allele (G) in the CBR3 gene was associated with increased risk of anthracycline cardiotoxicity. We hypothesized that CBR SNPs contribute to cardiotoxicity in adults. METHODS: We retrospectively identified female breast cancer patients in the Columbus Breast Tissue Bank Registry treated with adriamycin and cytoxan (AC) from 2003 to 2012. We selected patients who developed cardiomyopathy, defined as a drop in ejection fraction to <50 % or >15 % decrease from pre-therapy. Univariate and multivariate logistic regressions were performed to identify cardiotoxicity risk factors. SNPs were genotyped, and frequency of the major allele (G)/minor allele (A) of the CBR3 and CBR1 genes was calculated. RESULTS: We identified 52 cases of cardiotoxicity after AC and 110 controls. Multivariate analysis showed that trastuzumab (p = 0.009), diabetes (p = 0.05), and consumption of >8 alcoholic drinks/week (p = 0.024) were associated with higher cardiotoxicity risk. Moderate alcohol consumption (<8 drinks/week) was associated with lower risk (p = 0.009). No association was identified between CBR SNPs and cardiotoxicity (CBR1 p = 0.261; CBR3 p = 0.556). CONCLUSIONS: This is the first study to evaluate SNPs in the CBR pathway as predictors of AC cardiotoxicity in adults. We did not observe any significant correlation between cardiotoxicity and SNPs within the CBR pathway. Further investigation into CBR SNPs in a larger adult sample is needed. Additional exploration into genomic predictors of anthracycline cardiotoxicity may allow for the development of preventative and therapeutic strategies for those at risk.

Induction of ATM/ATR pathway combined with Vγ2Vδ2 T cells enhances cytotoxicity of ovarian cancer cells.

Many ovarian cancer cells express stress-related molecule MICA/B on their surface that is recognized by Vγ2Vδ2 T cells through their NKG2D receptor, which is transmitted to downstream stress-signaling pathway. However, it is yet to be established how Vγ2Vδ2 T cell-mediated recognition of MICA/B signal is transmitted to downstream stress-related molecules. Identifying targeted molecules would be critical to develop a better therapy for ovarian cancer cells. It is well established that ATM/ATR signal transduction pathways, which is modulated by DNA damage, replication stress, and oxidative stress play central role in stress signaling pathway regulating cell cycle checkpoint and apoptosis. We investigated whether ATM/ATR and its down stream molecules affect Vγ2Vδ2 T cell-mediated cytotoxicity. Herein, we show that ATM/ATR pathway is modulated in ovarian cancer cells in the presence of Vγ2Vδ2 T cells. Furthermore, downregulation of ATM pathway resulted downregulation of MICA, and reduced Vγ2Vδ2 T cell-mediated cytotoxicity. Alternately, stimulating ATM pathway enhanced expression of MICA, and sensitized ovarian cancer cells for cytotoxic lysis by Vγ2Vδ2 T cells. We further show that combining currently approved chemotherapeutic drugs, which induced ATM signal transduction, along with Vγ2Vδ2 T cells enhanced cytotoxicity of resistant ovarian cancer cells. These findings indicate that ATM/ATR pathway plays an important role in tumor recognition, and drugs promoting ATM signaling pathway might be considered as a combination therapy together with Vγ2Vδ2 T cells for effectively treating resistant ovarian cancer cells.

Stopping paclitaxel premedication after two doses in patients not experiencing a previous infusion hypersensitivity reaction.

PURPOSE: Paclitaxel-based chemotherapy continues to be an integral component of breast cancer treatment. Prolonged use of paclitaxel may result in repeated doses of premedications that can have unwanted side effects. Infusion hypersensitivity reactions occurring beyond the second dose of paclitaxel are infrequent and not well characterized. We previously published the results of a small, prospective pilot trial demonstrating the safety and feasibility of discontinuing premedications in patients who received the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction. In this study, we aimed to retrospectively characterize the incidence of rescue medication using this abbreviated premedication regimen in our institution following the publication of the pilot study. METHODS: Patients with stages I-IV breast cancer who received paclitaxel from January 2011 through June 2013 were screened for eligibility. Patients who did not experience an infusion hypersensitivity reaction with their first or second dose of paclitaxel and discontinued paclitaxel premedication for subsequent doses were included in this analysis. The primary endpoint was to estimate the incidence of rescue medication use for the treatment of paclitaxel infusion hypersensitivity during doses three to six of paclitaxel in the study population. RESULTS: In total, 449 patients received paclitaxel-based chemotherapy for the treatment of breast cancer during the interval time period. After receiving the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction, 234 breast cancer patients had their premedications discontinued for all remaining paclitaxel doses. These patients tolerated future paclitaxel doses without severe or life-threatening complications related to infusion hypersensitivity. The majority of patients did not have any symptoms of an infusion reaction, with only two of these patients requiring rescue medication to treat an infusion hypersensitivity reaction with subsequent paclitaxel doses (0.85; 95 % confidence interval (CI), 0.10-3.05 %). CONCLUSIONS: Discontinuation of paclitaxel premedications in breast cancer patients who have not experienced an infusion hypersensitivity reaction with the first two doses of paclitaxel is not associated with increased rate of rescue medication use for infusion hypersensitivity.

Histone H1 phosphorylation in breast cancer.

Breast cancer is the second leading cause of cancer-related deaths in women. The need for new clinical biomarkers in breast cancer is necessary to further predict prognosis and therapeutic response. In this article, the LC-MS histone H1 phosphorylation profiles were established for three distinct breast cancer cell lines. The results show that the extent of H1 phosphorylation can distinguish between the different cell lines. The histone H1 from the metastatic cell line, MDA-MB-231, was subjected to chemical derivitization and LC-MS/MS analysis. The results suggest that the phosphorylation at threonine 146 is found on both histone H1.2 and histone H1.4. Cell lines were then treated with an extracellular stimulus, estradiol or kinase inhibitor LY294002, to monitor changes in histone H1 phosphorylation. The data show that histone H1 phosphorylation can increase and decrease in response to extracellular stimuli. Finally, primary breast tissues were stained for the histone H1 phosphorylation at threonine 146. Variable staining patterns across tumor grades and subtypes were observed with pT146 labeling correlating with tumor grade. These results establish the potential for histone H1 phosphorylation at threonine 146 as a clinical biomarker in breast cancer.

Heterogeneous atypical cell populations are present in blood of metastatic breast cancer patients.

INTRODUCTION: Circulating tumor cells (CTCs) are commonly isolated from the blood by targeting the epithelial cell adhesion molecule (EpCAM) through positive selection. However, EpCAM can be downregulated during metastatic progression, or it can be initially not present. We designed the present prospective trial to characterize CTCs as well as other circulating cell populations in blood samples from women with metastatic breast cancer without EpCAM-dependent enrichment and/or isolation technology. METHODS: A total of 32 patients with metastatic breast cancer were enrolled, and blood samples were processed using a previously described negative depletion immunomagnetic methodology. Samples from healthy volunteers were run as controls (n = 5). Multistep sequential labeling was performed to label and fix cell-surface markers followed by permeabilization for cytokeratins (CK) 8, 18 and 19. Multiparametric flow cytometry (FCM) analysis was conducted using a BD LSR II flow cytometer or a BD FACSAria II or FACSAria III cell sorter. Immunocytochemical staining on postenrichment specimens for DAPI, EpCAM, CD45, CK, epidermal growth factor receptor and vimentin was performed. Expression of these markers was visualized using confocal microscopy (CM). RESULTS: CD45-negative/CK-positive (CD45- CK+) populations with EpCAM + and EpCAM - expression were identified with both FCM and CM from the negatively enriched patient samples. In addition, EpCAM + and EpCAM - populations that were CK + and coexpressing the pan-hematopoietic marker CD45 were also noted. There were more CK + EpCAM - events/ml than CK + EpCAM + events/ml in both the CD45- and CD45+ fractions (both statistically significant at P ≤ 0.0005). The number of CK + CD45- and CK + CD45+ events per milliliter in blood samples (regardless of EpCAM status) was higher in patient samples than in normal control samples (P ≤ 0.0005 and P ≤ 0.026, respectively). Further, a significant fraction of the CK + CD45+ events also expressed CD68, a marker associated with tumor-associated macrophages. Higher levels of CD45-CK + EpCAM - were associated with worse overall survival (P = 0.0292). CONCLUSIONS: Metastatic breast cancer patients have atypical cells that are CK + EpCAM - circulating in their blood. Because a substantial number of these patients do not have EpCAM + CTCs, additional studies are needed to evaluate the role of EpCAM - circulating cells as a prognostic and predictive marker.

Treatment-related mortality with everolimus in cancer patients.

INTRODUCTION: The overall incidence and odds of fatal adverse events (FAEs) after exposure to everolimus are not well defined. We performed a comprehensive meta-analysis of published randomized controlled trials (RCTs) to determine the role of everolimus in treatment-related mortality in patients with cancer. METHODS: PubMed databases and abstracts from the proceedings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium were searched for RCTs of everolimus either alone or in combination with another agent compared with the control arm without everolimus and that reported deaths from an adverse event from January 1966 to July 2013. The primary objective was to determine the difference of FAEs between everolimus-treated patients and control group patients. RESULTS: In total, 2,997 patients with multiple solid tumors from nine RCTs were included. The overall incidence of FAEs in cancer patients treated with everolimus was 0.7% (95% CI 0.3%-1.1%) compared with 0.4% (95% CI 0.0%-0.7%) in cancer patients who did not receive everolimus. The odds ratio of FAEs was greater in everolimus-treated patients (Peto odds ratio = 3.80, 95% CI 1.59-9.07, p = .003). In subgroup analyses, no significant difference was found in the incidence or odds of FAEs by everolimus administration (alone or in combination) or tumor type (breast cancer vs. nonbreast cancer; p = .63). CONCLUSION: In patients with cancer, everolimus is associated with a small but significant increase in the odds of a treatment-related fatal events.