Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors.

Paclitaxel is a common chemotherapy drug associated with the development of chronic paclitaxel-induced peripheral neuropathy (PIPN). PIPN is associated with neuroinflammatory mechanisms in pre-clinical studies. Here, we evaluated for differential gene expression (DGE) in peripheral blood between breast cancer survivors with and without PIPN and for neuroinflammatory (NI) related signaling pathways and whole-transcriptome profiles from other experiments. Pathway impact analysis identified 8 perturbed NI related pathways. Expression profile analysis found 15 experiments having similar whole-transcriptome profiles of DGE related to neuroinflammation and PIPN. These findings suggest that perturbations in pathways associated with neuroinflammation are found in cancer survivors with PIPN

Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer (“METRIC”): a randomized multicenter study

Breast cancer; CancerCàncer de mama; CàncerCáncer de mama; CáncerThe METRIC study (NCT#0199733) explored a novel antibody–drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1–14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine.Funding provided by Celldex Therapeutics, Inc

Recurrence of hepatitis C virus during leucocytopenia and spontaneous clearance after recovery from cytopenia: a case report

<p>Abstract</p> <p>Introduction</p> <p>There is little information about the risk of HCV recurrence in immunosuppressed patients. Although the presence of antibodies to HCV and the absence of HCV-RNA is usually considered to indicate viral elimination, the virus may not be completely eliminated but may be under control of an effective immune response.</p> <p>Case presentation</p> <p>A 69 year old man presented with jaundice, elevated ALT, AST, lipase and concomitant abdominal pain. He was found to be positive for HCV-RNA (genotype 3a) and was diagnosed with acute hepatitis C. Six weeks later no HCV-RNA was detected, and the patient was diagnosed with hyperthyreosis and started on propylthiouracil. After 4 weeks of propylthiouracil treatment, the patient developed leucocytopenia, followed by liver function deterioration and reappearance of HCV-RNA. Propylthiouracil was discontinued and his leukocyte counts increased. Twenty-eight weeks after onset of acute hepatitis C, no HCV-RNA was detected.</p> <p>Conclusion</p> <p>This case history shows the risk of recurrence of HCV during leucocytopenia. These findings indicate that patients who are anti-HCV positive but HCV-RNA negative may be at risk of cytopenia-induced HCV reactivation.</p

Pharmacogenetic testing affects choice of therapy among women considering tamoxifen treatment

Abstract Background Pharmacogenetic testing holds major promise in allowing physicians to tailor therapy to patients based on genotype. However, there is little data on the impact of pharmacogenetic test results on patient and clinician choice of therapy. CYP2D6 testing among tamoxifen users offers a potential test case of the use of pharmacogenetic testing in the clinic. We evaluated the effect of CYP2D6 testing in clinical practice to determine whether genotype results affected choice of hormone therapy in a prospective cohort study. Methods Women planning to take or currently taking tamoxifen were considered eligible. Participants were enrolled in an informational session that reviewed the results of studies of CYP2D6 genotype on breast cancer recurrence. CYP2D6 genotyping was offered to participants using the AmpliChip CYP450 Test. Women were classified as either poor, intermediate, extensive or ultra-rapid metabolizers. Results were provided to clinicians without specific treatment recommendations. Follow-up was performed with a structured phone interview 3 to 6 months after testing to evaluate changes in medication. Results A total of 245 women were tested and 235 completed the follow-up survey. Six of 13 (46%) women classified as poor metabolizers reported changing treatment compared with 11 of 218 (5%) classified as intermediate, extensive or ultra-rapid metabolizers (P &lt; 0.001). There was no difference in treatment choices between women classified as intermediate and extensive metabolizers. In multi-variate models that adjusted for age, race/ethnicity, educational status, method of referral into the study, prior knowledge of CYP2D6 testing, the patients' CYP2D6 genotype was the only significant factor that predicted a change in therapy (odds ratio 22.8; 95% confidence interval 5.2 to 98.8). Genetic testing did not affect use of co-medications that interact with CYP2D6. Conclusions CYP2D6 genotype testing led to changes in therapy among poor metabolizers, even in the absence of definitive data that an alternative medicine improved outcomes. Pharmacogenetic testing can affect choice of therapy, even in the absence of definitive data on clinical impact

Prognostic scores in brain metastases from breast cancer

<p>Abstract</p> <p>Background</p> <p>Prognostic scores might be useful tools both in clinical practice and clinical trials, where they can be used as stratification parameter. The available scores for patients with brain metastases have never been tested specifically in patients with primary breast cancer. It is therefore unknown which score is most appropriate for these patients.</p> <p>Methods</p> <p>Five previously published prognostic scores were evaluated in a group of 83 patients with brain metastases from breast cancer. All patients had been treated with whole-brain radiotherapy with or without radiosurgery or surgical resection. In addition, it was tested whether the parameters that form the basis of these scores actually have a prognostic impact in this biologically distinct group of brain metastases patients.</p> <p>Results</p> <p>The scores that performed best were the recursive partitioning analysis (RPA) classes and the score index for radiosurgery (SIR). However, disagreement between the parameters that form the basis of these scores and those that determine survival in the present group of patients and many reported data from the literature on brain metastases from breast cancer was found. With the four statistically significant prognostic factors identified here, a 3-tiered score can be created that performs slightly better than RPA and SIR. In addition, a 4-tiered score is also possible, which performs better than the three previous 4-tiered scores, incl. graded prognostic assessment (GPA) score and basic score for brain metastases (BSBM).</p> <p>Conclusion</p> <p>A variety of prognostic models describe the survival of patients with brain metastases from breast cancer to a more or less satisfactory degree. However, the standard brain metastases scores might not fully appreciate the unique biology and time course of this disease, e.g., compared to lung cancer. It appears possible that inclusion of emerging prognostic factors will improve the results and allow for development and validation of a consensus score for broad clinical application. The model that is based on the authors own patient group, which is not large enough to fully evaluate a large number of potential prognostic factors, is meant to illustrate this point rather than to provide the definitive score.</p

Efficacy and safety of ultra-low dose 0.005% estriol vaginal gel for the treatment of vulvovaginal atrophy in postmenopausal women with early breast cancer treated with nonsteroidal aromatase inhibitors: a phase II, randomized, double-blind, placebo-controlled trial

Objective: To assess the efficacy and safety of ultra-low dose 0.005% estriol vaginal gel in women with breast cancer receiving nonsteroidal aromatase inhibitors (NSAIs) and experiencing treatment-related vulvovaginal symptoms and signs. Methods: Women with hormone receptor-positive early breast cancer receiving NSAIs were randomized to either estriol vaginal gel or placebo for 12 weeks. Vaginal maturation, vaginal pH, and total and individual scores of symptoms and signs of vulvovaginal atrophy were assessed at baseline and at weeks 3 and 12; sexual functioning was also evaluated using the Female Sexual Functioning Index (FSFI) questionnaire, as well as circulating estrogens, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Results: Sixty-one women with a mean age of 59 years were included: 50 received 0.005% estriol vaginal gel and 11 received placebo. Active treatment significantly improved maturation value and pH, vaginal dryness and global scores of symptoms and signs. Active treatment also increased the total FSFI score and all the FSFI domains, with the exception of pain. Small oscillations were observed in FSH and LH, which remained within the postmenopausal range. Estriol levels increased initially and normalized by week 12, and estradiol and estrone remained mostly undetectable throughout the study. Conclusions: Ultra-low dose 0.005% estriol vaginal gel showed efficacy in improving the symptoms and signs of vulvovaginal atrophy. These results, together with minimal oscillations in hormonal levels throughout the treatment, support the use of ultra-low dose 0.005% estriol vaginal gel as a treatment option for vulvovaginal atrophy in women with breast cancer receiving NSAIs with an indication for treatment with vaginal estrogens

A randomized, phase II, three-arm study of two schedules of ixabepilone or paclitaxel plus bevacizumab as first-line therapy for metastatic breast cancer

The aim of this phase II trial was to estimate the objective response rate (ORR) of two different schedules of ixabepilone [weekly or every 3 weeks (Q3W)] combined with bevacizumab, relative to a reference arm of weekly paclitaxel and bevacizumab. Patients with human epidermal growth factor receptor 2-normal, chemotherapy-naïve metastatic breast cancer (MBC) were randomized 3:3:2 to ixabepilone 16 mg/m(2) weekly plus bevacizumab 10 mg/kg Q2W (Arm A: n = 46); ixabepilone 40 mg/m(2) Q3W (reduced to 32 mg/m(2) after four cycles of treatment) plus bevacizumab 15 mg/kg Q3W (Arm B: n = 45); or paclitaxel 90 mg/m(2) weekly plus bevacizumab 10 mg/kg intravenous infusion Q2W (Arm C: n = 32). Of 123 randomized patients, 122 were treated. All were followed for ≥19 months; 5 % of patients remained on study treatment at the time of this analysis. Grade 3 or 4 neutropenia was more common in Arm B (60 %) than Arms A (16 %) or C (22 %); other adverse events were similar. The investigator-assessed ORR was 48, 71, and 63 % for Arms A, B, and C, respectively. Median progression-free survival (randomized patients) was 9.6 months in Arm A, 11.9 months in Arm B, and 13.5 months in Arm C. In conclusion, ixabepilone Q3W plus bevacizumab has clinical activity as first-line therapy for MBC relative to paclitaxel plus bevacizumab, but with significantly greater risk of grade 3 or 4 neutropenia. In addition, these data suggest that weekly dosing of ixabepilone may be less active than Q3W dosing, but with less neutropenia

Menopausal-Related Symptoms in Women One Year After Breast Cancer Surgery.

CONTEXT: Approximately 60% to 100% of women with breast cancer experience at least one menopausal-related symptom. Little is known about associations between menopausal status and symptoms in women 12 months after breast cancer surgery. OBJECTIVES: The purpose of this study was to evaluate for differences in occurrence, severity, and distress of symptoms between pre- and postmenopausal women 12 months after breast cancer surgery. METHODS: Women with breast cancer (n = 327) completed the Menopausal Symptoms Scale, which evaluated the occurrence, severity, and distress of 46 common menopausal-related symptoms. Regression analyses were used to evaluate between-group differences in the seven symptoms that occurred in 30% and more of the sample (i.e., hot flashes, night sweats, depression, daytime sweats, joint pain or stiffness, wake during the night, and numbness or tingling). RESULTS: Of the 327 patients with breast cancer, who completed the 12-month assessment, 35.2% were premenopausal and 64.8% were postmenopausal before surgery. In the conditional models, when significant interactions were found, the differences in symptom occurrence rates between pre- and postmenopausal patients depended on their age. CONCLUSION: Regardless of menopausal status, women reported relatively high occurrence rates for several menopausal symptoms. Associations between symptom occurrence rates and menopausal status depended on the patient\u27s age. During the development of a survivorship care plan, clinicians need to assess symptom burden within the context of a woman\u27s menopausal status and salient demographic and clinical characteristics. This approach will assist with the prescription of more effective interventions

Pre-Surgery Demographic, Clinical, and Symptom Characteristics Associated with Different Self-Reported Cognitive Processes in Patients with Breast Cancer

Cancer related cognitive impairment (CRCI) is a common and persistent symptom in breast cancer patients. The Attentional Function Index (AFI) is a self-report measure that assesses CRCI. AFI includes three subscales, namely effective action, attentional lapses, and interpersonal effectiveness, that are based on working memory, inhibitory control, and cognitive flexibility. Previously, we identified three classes of patients with distinct CRCI profiles using the AFI total scores. The purpose of this study was to expand our previous work using latent class growth analysis (LCGA), to identify distinct cognitive profiles for each of the AFI subscales in the same sample (i.e., 397 women who were assessed seven times from prior to through to 6 months following breast cancer surgery). For each subscale, parametric and non-parametric statistics were used to determine differences in demographic, clinical, and pre-surgical psychological and physical symptoms among the subgroups. Three-, four-, and two-classes were identified for the effective action, attentional lapses, and interpersonal effectiveness subscales, respectively. Across all three subscales, lower functional status, higher levels of anxiety, depression, fatigue, and sleep disturbance, and worse decrements in energy were associated with worse cognitive performance. These and other modifiable characteristics may be potential targets for personalized interventions for CRCI