Design and methods of the mobile assessment of cognition, environment, and sleep (MACES) feasibility study in newly diagnosed breast cancer patients.

Endocrine therapy (ET) for breast cancer treatment is associated with cognitive complaints, but their etiology is poorly understood. To address this, we developed and implemented an ambulatory assessment protocol consisting of wearable activity monitors, brief surveys of affect, context, and perceived impairments, and ultra-brief performance-based measures of cognition. Newly diagnosed, ER/PR+, stage 0-III, female breast cancer patients, were recruited. Ambulatory assessments were conducted on smart phones and wearable activity monitors were used to monitor sleep and physical activity. Participants were asked to complete five 7-day measurement bursts (one before starting ET and one each month for 4 consecutive months while on ET). We observed a consent rate of 36%, 27 women completed the study. Of the women that withdrew, 91% dropped prior to the midpoint of follow up. There were no significant differences in demographics, clinical breast cancer characteristics, sleep or physical activity patterns, or measures of cognition between women who completed versus withdrew. Women who did not complete the study provided fewer valid days of baseline data. In conclusion, while some women may be overwhelmed with their cancer diagnosis, we did not identify any predictive characteristics of women whom did not complete the study. This novel method enables the prospective study of psychological changes associated with cancer treatment, capturing a wide array of information about behavior, experience, and cognition, thus providing a picture of the lived experiences of cancer patients before and during exposure to ET.

Technology-based supportive care for metastatic breast cancer patients.

PURPOSE: Metastatic breast cancer (MBC) patients are living longer. However, symptom burden remains a significant issue. Technology-based interventions may assist. The purpose of this study was to test a virtual assistant for addressing symptoms in MBC using the Amazon Echo Show with Alexa. METHODS: In this partial crossover randomized trial, the immediate treatment group was exposed to the intervention, called Nurse AMIE (Addressing Metastatic Individuals Everyday) for 6 months. The comparison group was unexposed for the first 3 months and then exposed for 3 months. The randomized controlled trial (RCT) during the first 3 months allowed for the evaluation of intervention effects on symptoms and function. The partial crossover maximized exposure to the intervention for evaluation of feasibility, usability, and satisfaction. RCT outcome data were collected at baseline and 3 months. Feasibility, usability, and satisfaction data were collected throughout the first 3 months of intervention exposure. RESULTS: Forty-two MBC patients were randomized (1:1). Participants were 53 ± 11 years old and 4 ± 7 years from diagnosis with metastatic disease. No significant effects on psychosocial distress, pain, sleep disturbance, fatigue (vitality), quality of life, or chair stands were noted, despite high levels of acceptability (51%), feasibility (65%), and satisfaction (70%). CONCLUSION: A high level of participant acceptability, feasibility, usability, and satisfaction all suggest further research on this platform is warranted. The lack of statistically significant effects on symptoms, quality of life, and function may be the result of small sample size. GOV REGISTRATION NUMBER: NCT04673019 (registration date: December 17, 2020).

Women with metastatic breast cancer don't just follow step-count trends, they exceed them: an exploratory study.

PURPOSE: Metastatic breast cancer (MBC) patients are living longer at the cost of several side effects, affecting their physical and mental health. Physical activity can help women with MBC to improve their wellbeing. Technology-based exercise interventions have shown promising outcomes; however, studies that document their benefits on health behaviors are lacking. Therefore, we aimed to document the impact of virtual assistant technology on enhancing daily step counts in women with MBC. METHODS: A total of 38 women with MBC participated in the 90-day Nurse AMIE (Addressing Metastatic Individuals Everyday) for Amazon Echo Show study, an artificial intelligence-based supportive care intervention. Each day, Nurse AMIE asked four symptom questions (sleep, pain, fatigue, and distress) and daily step counts. Based on participants' answers, an algorithm provided an activity to assist with symptom management. RESULTS: During the first week of the intervention, mean step counts per day were 4935 ± 2884, and during the last week of the intervention, mean step counts per day were 1044 steps higher, for an average of 5979 ± 2651 steps. Non-significant differences were observed between the first and last week (p = 0.211) and between the first and last day (p = 0.099), despite an improvement of 21.2% over time and significant differences between baseline and the other days. CONCLUSION: Women with MBC benefited from the Nurse AMIE for Amazon Echo Show intervention. Despite improvements over time (> 20%), we cannot conclude that the intervention significantly enhanced participants' daily step counts. Larger studies using virtual assistant technologies are required, and this study should be considered a first step in this direction.

Addressing metastatic individuals everyday: Rationale and design of the nurse AMIE for Amazon Echo Show trial among metastatic breast cancer patients.

Background: Metastatic Breast Cancer (MBC) patients often feel their symptom-related needs are unmet, despite visiting their doctors up to once a week. Novel approaches are needed to address symptoms without requiring additional appointments. Technology based symptom management approaches to address symptoms have not been well tested. Methods: Nurse AMIE (Addressing Metastatic Individuals Everyday) is a technology based supportive care platform that provides guideline-concordant symptom management interventions in response to patient reported symptoms. We have previously successfully implemented a tablet version of Nurse AMIE. However, some eligible patients chose not to participate because they were overwhelmed by the technology. To address this barrier, we translated the Nurse AMIE platform to the Amazon Echo Show, which allowed for voice-based interactions. Forty-two MBC patients were randomized 1:1 to receive the Nurse AMIE for Echo Show immediately for six months, or to receive the same intervention for three months, after a three month delay. The primary outcome was change in physical distress over three months, and secondary outcomes included feasibility, acceptability, patient reported outcomes and usability. Conclusions: Results from the Nurse AMIE for Echo Show trial will identify the feasibility, acceptability, and preliminary effects of the Nurse AMIE for Echo Show on patient reported outcomes. Untested novel technologies, particularly voice-based artificial intelligence devices may an effective and scalable vehicle through which we can deliver supportive care interventions. Clinicaltrialsgov identifier: NCT04673019.

Adapting an Evidence-Based Exercise and Education Program for Older Breast Cancer Survivors for the REJOIN Trial.

Physical activity (PA) promotes survival and mitigates symptoms in older breast cancer survivors (BCS), especially to reduce joint pain associated with adjuvant hormonal treatment. The purpose is to describe the adaptation process for an evidence-based exercise and education curriculum (i.e., Fit & Strong!) to support older BCS participating in the Using Exercise to Relieve Joint Pain and Improve Aromatase Inhibitor Adherence in Older Breast Cancer Survivors trial. We reviewed all educational materials with scientific/clinical experts to identify necessary content changes. Next, we conducted semistructured phone interviews with BCS to review all educational materials and conducted a real-time pretest for the trial. Overall, BCS found the adapted materials and experience acceptable (mean score of 9.2/10 for satisfaction). Content changes included simplifying exercise instructions, prioritizing content related to the trial goals, and updating photographs. Because of COVID, the pretest was conducted via Zoom. Our multistep adaptation process provided an acceptable intervention to meet the needs of older BCS. Lessons learned will be applied to the forthcoming pilot trial.

Influence of Glutathione-S-Transferase A1*B Allele on the Metabolism of the Aromatase Inhibitor, Exemestane, in Human Liver Cytosols and in Patients Treated With Exemestane.

Exemestane (EXE) is used to treat postmenopausal women diagnosed with estrogen receptor positive (ER+) breast cancer. A major mode of metabolism of EXE and its active metabolite, 17ß-dihydroexemestane, is via glutathionylation by glutathione-S-transferase (GST) enzymes. The goal of the present study was to investigate the effects of genetic variation in EXE-metabolizing GST enzymes on overall EXE metabolism. Ex vivo assays examining human liver cytosols from 75 subjects revealed the GSTA1 *B*B genotype was associated with significant decreases in S-(androsta-1,4-diene-3,17-dion-6α-ylmethyl)-L-glutathione (P = 0.034) and S-(androsta-1,4-diene-17ß-ol-3-on-6α-ylmethyl)-L-gutathione (P = 0.014) formation. In the plasma of 68 ER+ breast cancer patients treated with EXE, the GSTA1 *B*B genotype was associated with significant decreases in both EXE-cysteine (cys) (29%, P = 0.0056) and 17ß-DHE-cys (34%, P = 0.032) as compared with patients with the GSTA1*A*A genotype, with significant decreases in EXE-cys (Ptrend = 0.0067) and 17ß-DHE-cys (Ptrend = 0.028) observed in patients with increasing numbers of the GSTA1*B allele. A near-significant (Ptrend = 0.060) trend was also observed for urinary EXE-cys levels from the same patients. In contrast, plasma and urinary 17ß-DHE-Gluc levels were significantly increased (36%, P = 0.00097 and 52%, P = 0.0089; respectively) in patients with the GSTA1 *B*B genotype. No significant correlations were observed between the GSTM1 null genotype and EXE metabolite levels. These data suggest that the GSTA1*B allele is associated with interindividual differences in EXE metabolism and may play a role in interindividual variability in overall response to EXE. SIGNIFICANCE STATEMENT: The present study is the first comprehensive pharmacogenomic investigation examining the role of genetic variability in GST enzymes on exemestane metabolism. The GSTA1 *B*B genotype was found to contribute to interindividual differences in the metabolism of EXE both ex vivo and in clinical samples from patients taking EXE for the treatment of ER+ breast cancer. Since GSTA1 is a major hepatic phase II metabolizing enzyme in EXE metabolism, the GSTA1*B allele may be an important biomarker for treatment outcomes and toxicities.

Group-led creative writing and behavioural health in cancer: a randomised clinical trial.

BACKGROUND: Cancer diagnosis can adversely affect mental well-being and overall clinical outcome. We evaluated the efficacy of a group-led creative writing workshop (CWW) on mood in patients with cancer prospectively. METHODS: We conducted a single-institution phase II study. Sixty adult patients with cancer (any type or stage) were randomised 2:1 to CWW (4×CWW sessions, bimonthly over 8 weeks) versus active control (AC) (independent writing at home with the help of a book, four sessions, bimonthly over 8 weeks). The total study duration was 6 months with a follow-up of up to 3 months. PRIMARY OBJECTIVE: changes in overall mood, depression and anxiety symptoms before and after intervention in both arms. Emotional Thermometer Scale (ETS) was used to assess changes in patients' mood. Additionally, the Patient Health Questionnaire (PHQ)-9 and General Anxiety Disorder Scale (GAD)-7 were used to evaluate depression and anxiety symptoms. RESULTS: Of 50 evaluable patients (CWW 34, AC 17), 26 patients in the CWW arm attended at least one class and 19 attended at least four classes. Patients in CWW had significant immediate improvement in the overall ETS (post vs preclass scores; p<0.0001, 95% CI -4.31 to -2.47). Four of the five subscale ETS scores were significantly lower for the CWW arm: distress (p=0.0346, 95% CI -2.6 to -0.1), anxiety (p=0.0366, 95% CI -4.1 to -0.2), depression (p=0.0441, 95% CI -3.9 to -0.1) and anger (p=0.0494, 95% CI -3.3 to 0). No significant differences were seen in the AC arm. No significant differences were observed in the PHQ-9 or the GAD-7 scores. CONCLUSION: CWW had a positive effect on mood based on ETS scores, suggesting a potential therapeutic benefit among patients with cancer.

Current therapeutic approaches in the management of hemophilia-a consensus view by the Romanian Society of Hematology.

Hemophilia A (HA) and hemophilia B (HB) are rare disorders, being caused by the total lack or under-expression of two factors from the coagulation cascade coded by genes of the X chromosome. Thus, in hemophilic patients, the blood does not clot properly. This results in spontaneous bleeding episodes after an injury or surgical intervention. A patient-centered regimen is considered optimal. Age, pharmacokinetics, bleeding phenotype, joint status, adherence, physical activity, personal goals are all factors that should be considered when individualizing therapy. In the past 10 years, many innovations in the diagnostic and treatment options were presented as being either approved or in development, thus helping clinicians to improve the standard-of-care for patients with hemophilia. Recombinant factors still remain the standard of care in hemophilia, however they pose a challenge to treatment adherence because they have short half-life, which where the extended half-life (EHL) factors come with the solution, increasing the half-life to 96 hours. Gene therapies have a promising future with proven beneficial effects in clinical trials. We present and critically analyze in the current manuscript the pros and cons of all the major discoveries in the diagnosis and treatment of HA and HB, as well as identify key areas of hemophilia research where improvements are needed.

Study design and methods for the using exercise to relieve joint pain and improve AI adherence in older breast cancer survivors (REJOIN) trial.

BACKGROUND: Aromatase Inhibitors (AIs) are recommended for survival in post-menopausal breast cancer survivors (BCS) with hormone-sensitive disease. AI Adherence is suboptimal, especially in older BCS. Joint pain is a common AI-related symptom that is associated with low AI adherence. The Using Exercise to Relieve Joint Pain in Older Breast Cancer Survivors (REJOIN) Trial will evaluate the efficacy of a self-management intervention (exercise + education) to increase knowledge/self-efficacy for symptom management, reduce joint pain and potentially increase AI adherence in older BCS planning to take AIs. METHODS: This randomized controlled pilot trial will include sedentary BCS, 65 years and older, diagnosed with stage I-III hormone-sensitive breast cancer, who have completed primary cancer treatment and are planning to initiate AIs. We will adapt an evidence-based physical activity program for older adults that includes bi-weekly, supervised exercise sessions plus 30 min of education. The 16-week intervention program includes: 8-weeks of supervised sessions plus 8-weeks of self-guided home sessions with periodic phone coaching. We will conduct geriatric assessments plus measurements of exercise, joint pain, and AI adherence (baseline, 4, 6 and 12 months). DISCUSSION: REJOIN is one of the first trials to exclusively target older BCS using a self-management intervention, informed by geriatric assessment and exercise physiology, to improve health outcomes in survivorship. The REJOIN trial could lay the foundation for transdisciplinary research that bridges the gap between clinical and public health perspectives in healthy aging, with the opportunity to translate clinical interventions into non-pharmacological tools for a growing, yet underserved population of older survivors. TRIAL REGISTRATION: NCT03955627.

The exercise in all chemotherapy trial.

BACKGROUND: Multiple international organizations have called for exercise to become standard practice in the setting of oncology care. The feasibility of integrating exercise within systemic chemotherapy has not been investigated. METHODS: Patients slated to receive infusion therapy between April 2017 and October 2018 were screened for possible inclusion. The study goal was to establish the acceptability and feasibility of embedding an exercise professional into the chemotherapy infusion suite as a method of making exercise a standard part of cancer care. The exercise prescriptions provided to patients were individualized according to results of brief baseline functional testing. RESULTS: In all, 544 patients were screened, and their respective treating oncologists deemed 83% of them to be medically eligible to participate. After further eligibility screening, 226 patients were approached. Nearly 71% of these patients (n = 160) accepted the invitation to participate in the Exercise in All Chemotherapy trial. Feasibility was established because 71%, 55%, 69%, and 63% of the aerobic, resistance, balance, and flexibility exercises prescribed to patients were completed. Qualitative data also supported the acceptability and feasibility of the intervention from the perspective of patients and clinicians. The per-patient cost of the intervention was $190.68 to $382.40. CONCLUSIONS: Embedding an exercise professional into the chemotherapy infusion suite is an acceptable and feasible approach to making exercise standard practice. Moreover, the cost of the intervention is lower than the cost of other common community programs. Future studies should test whether colocating an exercise professional with infusion therapy could reach more patients in comparison with not colocating. LAY SUMMARY: Few studies have tested the implementation of exercise for patients with cancer by embedding an exercise professional directly into the chemotherapy infusion suite. The Exercise in All Chemotherapy trial shows that this approach is both acceptable and feasible from the perspective of clinicians and patients.

Impact of lack of surgery on outcomes in elderly women with nonmetastatic breast cancer-A surveillance, epidemiology, and end results 18 population based study.

Elderly women with early-stage, nonmetastatic breast cancer do not always receive recommendations for definitive surgical treatment. The reasons vary and include patient and provider-related reasons.We queried the surveillance, epidemiology, and end results database from 2010 to 2013 for women age 60 and older with stage I/II/III invasive breast cancer for whom local treatment was known. We divided the patients into 3 groups: patients for whom surgery was performed; patients for whom surgery was recommended but not performed; patients for whom surgery was not recommended and not performed. We used Kaplan-Meier method to generate OS curves and the Cox proportional hazard test to compare survival outcomes.A total of 119,404 patients were eligible for study with a median age between 70 and 74 years old. Compared with patients who received breast surgery, patients who did not receive surgery had a worse overall survival (OS) (hazard ratio [HR], 7.39; 95% confidence interval [CI], 6.98-7.83, P < .001). Patients who were recommended but ultimately did not undergo surgery had better OS than those who were recommended against surgery (adjusted HR, 0.60; 95% CI, 0.53-0.69). However, their survival was significantly inferior to patients who underwent surgery (adjusted HR, 2.81; 95% CI 2.48-3.19). Similar results were found regardless of age, tumor stage, estrogen receptor, or human epidermal growth factor receptor 2 status and were recapitulated in analyses of cancer-specific survival.Upfront definitive breast surgery should be performed in medically-fit elderly patients with early-stage, nonmetastatic breast cancer given significant survival benefit.

Effect of creative writing on mood in patients with cancer.

OBJECTIVE: To determine the feasibility of conducting creative writing workshops (CWW) for patients with cancer to promote improvement in mood. METHOD: We piloted a prospective study to determine the feasibility of conducting CWW over a 4-week period. Patients were randomised 2:1 to either an intervention arm (IA) or to standard of care (SOC). Patients in the IA attended four 2-hour long weekly CWW × 4 weeks, whereas those receiving SOC did not participate in the CWW. We used a validated emotion thermometer scale (ETS) to assess changes in patient's mental health before and after intervention. Patients with metastatic or unresectable cancer were included. PRIMARY ENDPOINT: (1) Feasibility and (2) mood scores before and after CWW using ETS. RESULTS: A total of 16 patients were enrolled: 11 in the IA vs 5 in SOC. Seven out of 11 (63%) patients enrolled in the IA attended at least 75% of classes. Patients in the IA showed a trend towards mood improvement relative to the SOC when comparing initial and final ETS scores. Within the IA group significantly lower postclass total ETS scores were observed relative to preclass ETS scores. Also, a significant decreasing trend over time was observed in the preclass total ETS scores for participants in the IA group. CONCLUSIONS: It is feasible for patients with cancer to attend CWW. Our results also show a positive effect on mood in the CWW arm. Further prospective clinical studies are needed to evaluate the effect of this intervention in patients with cancer.

Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study.

BACKGROUND: In the Mammary Oncology Assessment of LEE011's (Ribociclib's) Efficacy and Safety (MONALEESA-2) study, combination treatment with the selective inhibitor of cyclin-dependent kinases 4/6 ribociclib with letrozole significantly improved progression-free survival (PFS) versus letrozole alone in postmenopausal women with hormone receptor-positive HR+/HER2- advanced breast cancer (ABC). Herein we present results from the subset of US patients enrolled in MONALEESA-2. PATIENTS AND METHODS: Postmenopausal women with HR+/HER2- ABC without previous treatment for advanced disease were randomized (1:1) to ribociclib 600 mg/d (3 weeks on/1 week off) with letrozole 2.5 mg/d (continuous) or placebo with letrozole. The primary end point was locally assessed PFS. RESULTS: Overall, 213 US patients were enrolled in MONALEESA-2 (ribociclib, n = 100; placebo, n = 113). Baseline characteristics were similar between treatment groups and consistent with the global population. With a median follow-up of 27 months, 38 (38%) and 29 (26%) patients in the ribociclib and placebo groups, respectively, had continued to receive treatment. Median PFS was 27.6 months with ribociclib and 15.0 months with placebo (hazard ratio, 0.53). The most common all-cause adverse events were neutropenia (ribociclib, 72.0% [n = 72]; placebo, 4.6% [n = 5]), nausea (ribociclib, 69.0% [n = 69]; placebo, 44.0% [n = 48]), and fatigue (ribociclib, 60.0% [n = 60]; placebo, 50.5% [n = 55]). Two patients (ribociclib, 2.0%; placebo, 0%) experienced febrile neutropenia. CONCLUSION: In the US subset of MONALEESA-2, ribociclib with letrozole showed superior efficacy versus letrozole alone. These findings are consistent with the global population and support first-line use of ribociclib with letrozole in patients with HR+/HER2- ABC.

Identification and Quantification of Novel Major Metabolites of the Steroidal Aromatase Inhibitor, Exemestane.

Exemestane (EXE) is an aromatase inhibitor used for the prevention and treatment of estrogen receptor-positive breast cancer. Although the known major metabolic pathway for EXE is reduction to form the active 17ß-dihydro-EXE (17ß-DHE) and subsequent glucuronidation to 17ß-hydroxy-EXE-17-O-ß-D-glucuronide (17ß-DHE-Gluc), previous studies have suggested that other major metabolites exist for exemestane. In the present study, a liquid chromatography-mass spectrometry (LC-MS) approach was used to acquire accurate mass data in MSE mode, in which precursor ion and fragment ion data were obtained simultaneously to screen novel phase II EXE metabolites in urine specimens from women taking EXE. Two major metabolites predicted to be cysteine conjugates of EXE and 17ß-DHE by elemental composition were identified. The structures of the two metabolites were confirmed to be 6-methylcysteinylandrosta-1,4-diene-3,17-dione (6-EXE-cys) and 6-methylcysteinylandrosta-1,4-diene-17ß-hydroxy-3-one (6-17ß-DHE-cys) after comparison with their chemically synthesized counterparts. Both underwent biosynthesis in vitro in three stepwise enzymatic reactions, with the first involving glutathione conjugation. The cysteine conjugates of EXE and 17ß-DHE were subsequently quantified by liquid chromatography-mass spectrometry in the urine and matched plasma samples of 132 subjects taking EXE. The combined 6-EXE-cys plus 6-17ß-DHE-cys made up 77% of total EXE metabolites in urine (vs. 1.7%, 0.14%, and 21% for EXE, 17ß-DHE, and 17ß-DHE-Gluc, respectively) and 35% in plasma (vs. 17%, 12%, and 36% for EXE, 17ß-DHE, and 17ß-DHE-Gluc, respectively). Therefore, cysteine conjugates of EXE and 17ß-DHE appear to be major metabolites of EXE in both urine and plasma.

The C-Terminal Intact Forms of Periostin (iPTN) Are Surrogate Markers for Osteolytic Lesions in Experimental Breast Cancer Bone Metastasis.

Periostin is an extracellular matrix protein that actively contributes to tumor progression and metastasis. Here, we hypothesized that it could be a marker of bone metastasis formation. To address this question, we used two polyclonal antibodies directed against the whole molecule or its C-terminal domain to explore the expression of intact and truncated forms of periostin in the serum and tissues (lung, heart, bone) of wild-type and periostin-deficient mice. In normal bones, periostin was expressed in the periosteum and specific periostin proteolytic fragments were found in bones, but not in soft tissues. In animals bearing osteolytic lesions caused by 4T1 cells, C-terminal intact periostin (iPTN) expression disappeared at the invasive front of skeletal tumors where bone-resorbing osteoclasts were present. In vitro, we found that periostin was a substrate for osteoclast-derived cathepsin K, generating proteolytic fragments that were not recognized by anti-periostin antibodies directed against iPTN. In vivo, using an in-house sandwich immunoassay aimed at detecting iPTN only, we observed a noticeable reduction of serum periostin levels (- 26%; P < 0.002) in animals bearing osteolytic lesions caused by 4T1 cells. On the contrary, this decrease was not observed in women with breast cancer and bone metastases when periostin was measured with a human assay detecting total periostin. Collectively, these data showed that mouse periostin was degraded at the bone metastatic sites, potentially by cathepsin K, and that the specific measurement of iPTN in serum should assist in detecting bone metastasis formation in breast cancer.

Interest Among Primary Care Patients in Group Problem-Solving Gameplay for Mental Health.

Mental health programs to improve problem-solving skills and reduce stress through social gameplay can improve psychiatric outcomes, but little is known about whether adult patients are interested in using them. Primary care patients (n = 467) completed a cross-sectional survey to assess interest in using 2 types of group programs for mental health. A significantly greater percentage (23.7%) of patients expressed interest in a gameplay-based program than in interpersonal therapy (17.6%) (P < .001). Lonely patients and younger patients were more likely to report interest in gameplay. Results suggest that diverse patient populations are interested in using gameplay programs for mental health.

Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102.

Purpose The mammalian target of rapamycin inhibitor everolimus targets aberrant signaling through the PI3K/AKT/mammalian target of rapamycin pathway, a mechanism of resistance to anti-estrogen therapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that everolimus plus the selective ER downregulator fulvestrant would be more efficacious than fulvestrant alone in ER-positive metastatic breast cancer resistant to aromatase inhibitor (AI) therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase II study included 131 postmenopausal women with ER-positive, human epidermal growth factor receptor 2-negative, AI-resistant metastatic breast cancer randomly assigned to fulvestrant (500 mg days 1 and 15 of cycle 1, then day 1 of cycles 2 and beyond) plus everolimus or placebo. The study was designed to have 90% power to detect a 70% improvement in median progression-free survival from 5.4 months to 9.2 months. Secondary end points included objective response and clinical benefit rate (response or stable disease for at least 24 weeks). Prophylactic corticosteroid mouth rinses were not used. Results The addition of everolimus to fulvestrant improved the median progression-free survival from 5.1 to 10.3 months (hazard ratio, 0.61 [95% CI, 0.40 to 0.92]; stratified log-rank P = .02), indicating that the primary trial end point was met. Objective response rates were similar (18.2% v 12.3%; P = .47), but the clinical benefit rate was significantly higher in the everolimus arm (63.6% v 41.5%; P = .01). Adverse events of all grades occurred more often in the everolimus arm, including oral mucositis (53% v 12%), fatigue (42% v 22%), rash (38% v 5%), anemia (31% v. 6%), diarrhea (23% v 8%), hyperglycemia (19% v 5%), hypertriglyceridemia (17% v 3%), and pneumonitis (17% v 0%), although grade 3 to 4 events were uncommon. Conclusion Everolimus enhances the efficacy of fulvestrant in AI-resistant, ER-positive metastatic breast cancer.

MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: A study on 939 patients.

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN.

Immunotherapy for triple-negative breast cancer: Existing challenges and exciting prospects.

Patients with breast tumors that do not express the estrogen receptor, the progesterone receptor, nor Her-2/neu are hence termed "triple negatives", and generally have a poor prognosis, with high rates of systemic recurrence and refractoriness to conventional therapy regardless of the choice of adjuvant treatment. Thus, more effective therapeutic options are sorely needed for triple-negative breast cancer (TNBC), which occurs in approximately 20% of diagnosed breast cancers. In recent years, exploiting intrinsic mechanisms of the host immune system to eradicate cancer cells has achieved impressive success, and the advances in immunotherapy have yielded potential new therapeutic strategies for the treatment of this devastating subtype of breast cancer. It is anticipated that the responses initiated by immunotherapeutic interventions will explicitly target and annihilate tumor cells, while at the same time spare normal cells. Various immunotherapeutic approaches have been already developed and tested, which include the blockade of immune checkpoints using neutralizing or blocking antibodies, induction of cytotoxic T lymphocytes (CTLs), adoptive cell transfer-based therapy, and modulation of the tumor microenvironment to enhance the activity of CTLs. One of the most important areas of breast cancer research today is understanding the immune features and profiles of TNBC and devising novel immune-modulatory strategies to tackling TNBC, a subtype of breast cancer notorious for its poor prognosis and its imperviousness to conventional treatments. On the optimal side, one can anticipate that novel, effective, and personalized immunotherapy for TNBC will soon achieve more success and impact clinical treatment of this disease which afflicts approximately 20% of patients with breast cancer. In the present review, we highlight the current progress and encouraging developments in cancer immunotherapy, with a goal to discuss the challenges and to provide future perspectives on how to exploit a variety of new immunotherapeutic approaches including checkpoint inhibitors and neoadjuvant immunotherapy for the treatment of patients with TNBC.