A whole-food, plant-based randomized controlled trial in metastatic breast cancer: weight, cardiometabolic, and hormonal outcomes.

PURPOSE: Breast cancer treatment is associated with weight gain, and obesity and its related cardiometabolic and hormonal risk factors have been associated with poorer outcomes. Dietary intervention may address these risk factors, but limited research has been done in the setting of metastatic breast cancer requiring systemic therapy. METHODS: Women with metastatic breast cancer on stable treatment were randomized 2:1 to an 8-week intervention (n = 21) or control (n = 11). The intervention included weekly assessment visits and an ad libitum whole-food, plant-based (WFPB) diet with provided meals. Cardiometabolic, hormonal, and cancer markers were assessed at baseline, 4 weeks, and 8 weeks. RESULTS: Within the intervention group, mean weight decreased by 6.6% (p < 0.01) after 8 weeks. Fasting insulin decreased from 16.8 uIU/L to 11.2 uIU/L (p < 0.01), concurrent with significantly reduced insulin resistance. Total cholesterol decreased from 193.6 mg/dL to 159 mg/dL (p < 0.01), and low-density lipoprotein (LDL) cholesterol decreased from 104.6 mg/dL to 82.2 mg/dL (p < 0.01). Total testosterone was unchanged, but free testosterone trended lower within the intervention group (p = 0.08) as sex hormone binding globulin increased from 74.3 nmol/L to 98.2 nmol/L (p < 0.01). There were no significant differences in cancer progression markers at week 8, although mean CA 15-3, CA 27.29, and CEA were lower in the intervention group (p = 0.53, p = 0.23, and p = 0.54, respectively) compared to control, when adjusted for baseline. CONCLUSION: WFPB dietary changes during treatment for metastatic breast cancer are well tolerated and significantly improve weight, cardiometabolic and hormonal parameters. Longer studies are warranted to assess the durability of changes. Trial registration First registered at Clinicaltrials.gov (NCT03045289) on February 7, 2017.

A whole food, plant-based randomized controlled trial in metastatic breast cancer: feasibility, nutrient, and patient-reported outcomes.

PURPOSE: Quality of life (QOL) is among the most important outcomes for women with metastatic breast cancer (MBC), and it predicts survival. QOL is negatively impacted by cognitive impairment, fatigue, and weight gain. We assessed whether a whole food, plant-based (WFPB) diet-promoting weight loss is feasible and might improve QOL. METHODS: Women with MBC on stable systemic treatments were randomized 2:1 to 1) WFPB dietary intervention (n = 21) or 2) usual care (n = 11) for 8 weeks. Participants attended weekly education visits and consumed an ad libitum WFPB diet (3 prepared meals/day provided). Patient-reported outcomes and 3-day food records were assessed at baseline and 8 weeks. The effects of WFPB diet on changes in outcomes were assessed by analysis of covariance model controlling for baseline. RESULTS: 20 intervention and 10 control participants completed the trial. Intervention participants were highly adherent to the WFPB diet (94.3 % total calories on-plan). Intervention group nutrient intakes changed significantly including dietary fat (35.8 % to 20.4 % percent calories from fat, p < 0.001) and fiber content (12.7 to 30.8 g fiber/1000 kcal, p < 0.001). Perceived cognitive function (FACT-Cog total + 16.1; 95 % confidence interval [CI] = 0.8-31.7; p = 0.040) and emotional well-being (FACT-B emotional well-being subscale + 2.3; CI = 0.5-4.1; p = 0.016) improved in the WFPB versus the control group. Fatigue, measured by the BFI, improved within the WFPB group for fatigue severity (M = 4.7 ± 2.5[SD] to 3.7 ± 2.3, p = 0.047) and fatigue at its worst (5.8 ± 2.8 to 4.4 ± 2.4, p = 0.011). CONCLUSIONS: Significant dietary changes in this population are feasible and may improve QOL by improving treatment-related symptoms. Additional study is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03045289. Registered 7 February 2017.

Establishing an Integrative Oncology Service: Essential Aspects of Program Development.

PURPOSE OF REVIEW: Over the last 2 decades, integrative oncology (IO) has seen exponential growth within cancer care. It aims to combine evidence-based complementary therapies with conventional treatments to improve the well-being and quality of life for individuals dealing with cancer. The proliferation of integrative medicine programs in major cancer centers globally reflects varying approaches shaped by cultural, demographic, and resource-based factors. RECENT FINDINGS: Drawing upon the expertise of leaders in IO from the Society for Integrative Oncology (SIO) Clinical Practice Committee, this manuscript serves as a practical guide for establishing an IO practice. Collating insights from diverse professionals, including oncologists, integrative oncologists, supportive care physicians, researchers, and clinicians, the paper aims to provide a comprehensive roadmap for initiating and advancing IO services. The primary objective is to bridge the gap between conventional cancer care and complementary therapies, fostering a patient-centric approach to address the multifaceted challenges encountered by individuals with cancer. This paper delineates several key sections elucidating different aspects of IO practice. It delves into the core components necessary for an IO service's foundation, outlines the initial medical consultation process, and presents crucial tools essential for successful consultations. By consolidating insights and expertise, this manuscript seeks to facilitate the integration of IO into mainstream cancer care, ultimately enhancing patient outcomes and experiences.

The effects of high-dose calcitriol and individualized exercise on bone metabolism in breast cancer survivors on hormonal therapy: a phase II feasibility trial.

INTRODUCTION: Cancer treatment-induced bone loss (CTIBL) is a long-term side effect of breast cancer therapy. Both calcitriol and weight-bearing exercise improve bone metabolism for osteoporotic patients, but are unproven in a breast cancer population. We used a novel high-dose calcitriol regimen with an individualized exercise intervention to improve bone metabolism in breast cancer survivors. METHODS: We accrued 41 subjects to this open label, 2 × 2 factorial, randomized feasibility trial. Breast cancer survivors were randomized to receive the following: (1) calcitriol (45 micrograms/week), (2) individualized exercise with progressive walking and resistance training, (3) both, or (4) a daily multivitamin (control condition) for 12 weeks. Primary outcomes included changes in biomarkers of bone formation, bone resorption, and the bone remodeling index, a composite measure of bone formation and resorption. Safety measures included clinical and biochemical adverse events. A main effect analysis was used for these endpoints. RESULTS: Hypercalcemia was limited to three grade I cases with no grade ≥ 2 cases. Among exercisers, 100% engaged in the prescribed aerobic training and 44.4% engaged in the prescribed resistance training. Calcitriol significantly improved bone formation (Cohen's d = 0.64; p < 0.01), resulting in a non-significant increase in the bone remodeling index (Cohen's d = 0.21; p = 31). Exercise failed to improve any of the bone biomarkers. CONCLUSIONS: Both calcitriol and exercise were shown to be feasible and well tolerated. Calcitriol significantly improved bone formation, resulting in a net increase of bone metabolism. Compliance with the exercise intervention was sub-optimal, which may have led to a lack of effect of exercise on bone metabolism.

Use of modified Magee equations and histologic criteria to predict the Oncotype DX recurrence score.

Oncotype DX (Genomic Health, Redwood City, CA, USA, current list price $4,350.00) is a multigene quantitative reverse transcription-polymerase chain reaction-based assay that estimates the risk of distant recurrence and predicts chemotherapy benefit for patients with estrogen receptor (ER)-positive breast cancers. Studies have suggested that standard histologic variables can provide similar information. Klein and Dabbs et al have shown that Oncotype DX recurrence scores can be estimated by incorporating standard histologic variables into equations (Magee equations). Using a simple modification of the Magee equation, we predict the Oncotype DX recurrence score in an independent set of 283 cases. The Pearson correlation coefficient (r) for the Oncotype DX and average modified Magee recurrence scores was 0.6644 (n=283; P<0.0001). 100% of cases with an average modified Magee recurrence score>30 (n=8) or an average modified Magee recurrence score<9 (with an available Ki-67, n=5) would have been correctly predicted to have a high or low Oncotype DX recurrence score, respectively. 86% (38/44) of cases with an average modified Magee recurrence score≤12, and 89% (34/38) of low grade tumors (NS<6) with an ER and PR≥150, and a Ki-67<10%, would have been correctly predicted to have a low Oncotype DX recurrence score. Using an algorithmic approach to eliminate high and low risk cases, between 5% and 23% of cases would potentially not have been sent by our institution for Oncotype DX testing, creating a potential cost savings between $56,550.00 and $282,750.00. The modified Magee recurrence score along with histologic criteria may be a cost-effective alternative to the Oncotype DX in risk stratifying certain breast cancer patients. The information needed is already generated by many pathology laboratories during the initial assessment of primary breast cancer, and the equations are free.

Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease.

Protracted inhibition of osteoblast (OB) differentiation characterizes multiple myeloma (MM) bone disease and persists even when patients are in long-term remission. However, the underlying pathophysiology for this prolonged OB suppression is unknown. Therefore, we developed a mouse MM model in which the bone marrow stromal cells (BMSCs) remained unresponsive to OB differentiation signals after removal of MM cells. We found that BMSCs from both MM-bearing mice and MM patients had increased levels of the transcriptional repressor Gfi1 compared with controls and that Gfi1 was a novel transcriptional repressor of the critical OB transcription factor Runx2. Trichostatin-A blocked the effects of Gfi1, suggesting that it induces epigenetic changes in the Runx2 promoter. MM-BMSC cell-cell contact was not required for MM cells to increase Gfi1 and repress Runx2 levels in MC-4 before OBs or naive primary BMSCs, and Gfi1 induction was blocked by anti-TNF-α and anti-IL-7 antibodies. Importantly, BMSCs isolated from Gfi1(-/-) mice were significantly resistant to MM-induced OB suppression. Strikingly, siRNA knockdown of Gfi1 in BMSCs from MM patients significantly restored expression of Runx2 and OB differentiation markers. Thus, Gfi1 may have an important role in prolonged MM-induced OB suppression and provide a new therapeutic target for MM bone disease.

A Whole Food, Plant-Based Randomized Controlled Trial in Metastatic Breast Cancer: Feasibility, Nutrient, and Patient-Reported Outcomes.

Purpose: Quality of life (QOL) is among the most important outcomes for women with metastatic breast cancer (MBC) and it predicts survival. QOL is negatively impacted by cognitive impairment, fatigue, and weight gain. We assessed whether a whole food, plant-based (WFPB) diet promoting weight loss is feasible and might improve QOL. Methods: Women with MBC on stable systemic treatments were randomized 2:1 to 1) WFPB dietary intervention (n = 21) or 2) usual care (n = 11) for 8 weeks. Participants attended weekly education visits and consumed an ad libitum WFPB diet (3 prepared meals/day provided). Patient-reported outcomes and 3-day food records were assessed at baseline and 8 weeks. The effects of WFPB diet on changes in outcomes were assessed by analysis of covariance model controlling for baseline. Results: 20 intervention and 10 control participants completed the trial. Intervention participants were highly adherent to the WFPB diet (94.3% total calories on-plan). Intervention group nutrient intakes changed significantly including dietary fat (35.8-20.4% percent calories from fat, p < 0.001) and fiber content (22.1 to 40.8 grams fiber/1000 kcal, p < 0.001). Perceived cognitive function (FACT-Cog total + 16.1; 95% confidence interval [CI] = 0.8-31.7; p = 0.040) and emotional well-being (FACT-B emotional well-being subscale + 2.3; CI = 0.5-4.1; p = 0.016) improved in the WFPB versus the control group. Fatigue, measured by the BFI, improved within the WFPB group for fatigue severity (M = 4.7 ± 2.5[SD] to 3.7 ± 2.3, p = 0.047) and fatigue at its worst (5.8 ± 2.8 to 4.4 ± 2.4, p = 0.011). Conclusions: Significant dietary changes in this population are feasible and may improve QOL by improving treatment-related symptoms. Additional study is warranted. Trial registration: ClinicalTrials.gov identifier: NCT03045289. Registered 7 February 2017.

A Whole-Food, Plant-Based Randomized Controlled Trial in Metastatic Breast Cancer: Weight, Cardiometabolic, and Hormonal Outcome.

Purpose: Breast cancer treatment is associated with weight gain, and obesity and its related cardiometabolic and hormonal risk factors have been associated with poorer outcomes. Dietary intervention may address these risk factors, but limited research has been done in the setting of metastatic breast cancer requiring systemic therapy. Methods: Women with metastatic breast cancer on stable treatment were randomized 2:1 to an 8-week intervention (n = 21) or control (n = 11). The intervention included weekly assessment visits and an ad libitum whole food, plant-based (WFPB) diet with provided meals. Cardiometabolic, hormonal, and cancer markers were assessed at baseline, 4 weeks, and 8 weeks. Results: Within the intervention group, mean weight decreased by 6.6% (p < 0.01) after 8 weeks. Fasting insulin decreased from 16.8 uIU/L to 11.2 uIU/L (p < 0.01), concurrent with significantly reduced insulin resistance. Total cholesterol decreased from 193.6 mg/dL to 159 mg/dL (p < 0.01) and low-density lipoprotein (LDL) cholesterol decreased from 104.6 mg/dL to 82.2 mg/dL (p < 0.01). Total testosterone was unchanged, but free testosterone trended lower within the intervention group (p = 0.08) as sex hormone binding globulin increased from 74.3 nmol/L to 98.2 nmol/L (p < 0.01). There were no significant differences in cancer progression markers at week 8, although mean CA 15 - 3, CA 27.29, and CEA were lower in the intervention group (p = 0.53, p = 0.23, and p = 0.54, respectively) compared to control, when adjusted for baseline. Conclusion: WFPB dietary changes during treatment for metastatic breast cancer are well tolerated and significantly improve weight and cardiometabolic and hormonal parameters. Longer studies are warranted to assess the durability of changes. Trial registration: First registered at Clinicaltrials.gov (NCT03045289) on February 7, 2017.

Integrative Oncology Care of Symptoms of Anxiety and Depression in Adults With Cancer: Society for Integrative Oncology-ASCO Guideline.

PURPOSE: To provide evidence-based recommendations to health care providers on integrative approaches to managing anxiety and depression symptoms in adults living with cancer. METHODS: The Society for Integrative Oncology and ASCO convened an expert panel of integrative oncology, medical oncology, radiation oncology, surgical oncology, palliative oncology, social sciences, mind-body medicine, nursing, methodology, and patient advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2023. Outcomes of interest included anxiety or depression symptoms as measured by validated psychometric tools, and adverse events. Expert panel members used this evidence and informal consensus with the Guidelines into Decision Support methodology to develop evidence-based guideline recommendations. RESULTS: The literature search identified 110 relevant studies (30 systematic reviews and 80 randomized controlled trials) to inform the evidence base for this guideline. RECOMMENDATIONS: Recommendations were made for mindfulness-based interventions (MBIs), yoga, relaxation, music therapy, reflexology, and aromatherapy (using inhalation) for treating symptoms of anxiety during active treatment; and MBIs, yoga, acupuncture, tai chi and/or qigong, and reflexology for treating anxiety symptoms after cancer treatment. For depression symptoms, MBIs, yoga, music therapy, relaxation, and reflexology were recommended during treatment, and MBIs, yoga, and tai chi and/or qigong were recommended post-treatment. DISCUSSION: Issues of patient-health care provider communication, health disparities, comorbid medical conditions, cost implications, guideline implementation, provider training and credentialing, and quality assurance of natural health products are discussed. While several approaches such as MBIs and yoga appear effective, limitations of the evidence base including assessment of risk of bias, nonstandardization of therapies, lack of diversity in study samples, and lack of active control conditions as well as future research directions are discussed.Additional information is available at www.asco.org/survivorship-guidelines.

In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2.

Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contributes to MM-related anemia. Searching for hepcidin-inducing cytokines in MM, we quantified the stimulation of hepcidin promoter-luciferase activity in HuH7 cells by MM sera. MM sera activated the hepcidin promoter significantly more than did normal sera. We then examined the role of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6), the major transcriptional regulators of hepcidin. Mutations in both BMP-responsive elements abrogated the activation dramatically, while mutations in the IL-6-responsive signal transducer and activator of transcription 3-binding site (STAT3-BS) had only a minor effect. Cotreatment with anti-BMP-2/4 or noggin-Fc blocked the promoter induction with all MM sera, anti-IL-6 blocked it with a minority of sera, whereas anti-BMP-4, -6, or -9 antibodies had no effect. BMP-2-immunodepleted MM sera had decreased promoter stimulatory capacity, and BMP-2 concentrations in MM sera were significantly higher than in normal sera. Our results demonstrate that BMP-2 is a major mediator of the hepcidin stimulatory activity of MM sera.

Problem-solving skills training in adult cancer survivors: Bright IDEAS-AC pilot study.

PURPOSE: Cancer patients experience significant distress and burden of decision-making throughout treatment and beyond. These stressors can interfere with their ability to make reasoned and timely decisions about their care and lead to low physical and social functioning and poor survival. This pilot study examined the impact of offering Problem-Solving Skills Training (PSST) to adult cancer survivors to help them and their caregivers cope more successfully with post-treatment decision-making burden and distress. PATIENTS AND METHODS: Fifty patients who completed their definitive treatment for colorectal, breast or prostate cancer within the last 6 months and reported distress (level > 2 on the National Comprehensive Cancer Network distress thermometer) were randomly assigned to either care as usual (CAU) or 8 weekly PSST sessions. Patients were invited to include a supportive other (n = 17). Patient and caregiver assessments at baseline (T1), end of intervention or 3 months (T2), and at 6 months (T3) focused on problem-solving skills, anxiety/depression, quality of life and healthcare utilization. We compared outcomes by study arm and interviewed participants about PSST burden and skill maintenance. RESULTS: Trial participation rate was 60%; 76% of the participants successfully completed PSST training. PSST patients reported reduction in anxiety/depression, improvement in QoL (p < 0.05) and lower use of hospital and emergency department services compared to CAU patients (p = 0.04). CONCLUSIONS: The evidence from this pilot study indicates that a remotely delivered PSST is a feasible and potentially effective strategy to improve mood and self-management in cancer survivors in community oncology settings.

The effect of various vitamin D supplementation regimens in breast cancer patients.

Vitamin D deficiency in the patients treated for breast cancer is associated with numerous adverse effects (bone loss, arthralgia, and falls). The first aim of this study was to assess vitamin D status, determined by 25-OH vitamin D levels, among women diagnosed with breast cancer according to demographic/clinical variables and bone mineral density (BMD). The second aim of this study was to evaluate the effect of daily low-dose and weekly high-dose vitamin D supplementation on 25-OH vitamin D levels. This retrospective study included 224 women diagnosed with stage 0-III breast cancer who received treatment at the James P. Wilmot Cancer Center at the University of Rochester Medical Center. Total 25-OH vitamin D levels (D(2) + D(3)) were determined at baseline for all participants. Vitamin D deficiency was defined as a 25-OH vitamin D level < 20 ng/ml, insufficiency as 20-31 ng/ml, and sufficiency as ≥32 ng/ml. BMD was assessed during the period between 3 months before and 6 months following the baseline vitamin D assessment. Based on the participants' baseline levels, they received either no supplementation, low-dose supplementation (1,000 IU/day), or high-dose supplementation (≥50,000 IU/week), and 25-OH vitamin D was reassessed in the following 8-16 weeks. Approximately 66.5% had deficient/insufficient vitamin D levels at baseline. Deficiency/insufficiency was more common among non-Caucasians, women with later-stage disease, and those who had previously received radiation therapy (P < 0.05). Breast cancer patients with deficient/insufficient 25-OH vitamin D levels had significantly lower lumbar BMD (P = 0.03). Compared to the no-supplementation group, weekly high-dose supplementation significantly increased 25-OH vitamin D levels, while daily low-dose supplementation did not significantly increase levels. Vitamin D deficiency and insufficiency were common among women with breast cancer and associated with reduced BMD in the spine. Clinicians should carefully consider vitamin D supplementation regimens when treating vitamin D deficiency/insufficiency in breast cancer patients.

An Atypical Presentation of Hemophagocytic Lymphohistiocytosis (HLH) Secondary to Occult Hodgkin Lymphoma.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome of immune system dysregulation characterized by the phagocytosis of various cells by histiocytes in the bone marrow. HLH can present in one of the two ways: primary HLH, which is caused by mutations in genes essential to T and NK-cell function, and secondary HLH, typically caused by Epstein-Barr virus (EBV) infection or malignancy. Because of the rapid progression and high mortality of this disease, prompt diagnosis is essential to good outcomes. Here, we report the 2-month clinical course of a patient who presented with altered mental status and recurrent fever of unknown origin. Initially, he did not meet diagnostic criteria for HLH and had a negative bone marrow biopsy; however, he eventually progressed to full-blown HLH secondary to occult Hodgkin lymphoma. This case is unusual for the slow and smoldering course of the patient's disease and highlights the importance of aggressively searching for potential malignancies to ensure the initiation of definitive therapy as soon as possible.

A lower Allred score for progesterone receptor is strongly associated with a higher recurrence score of 21-gene assay in breast cancer.

Among the 77 infiltrating breast carcinomas, we found that progesterone receptor (PR) expression was inversely associated with recurrence score (RS, p < .0001). RS is also significantly associated with tubule formation, mitosis, and luminal B subtype. The equation of RS = 17.489 + 2.071 (tubal formation) + 2.926 (mitosis) -2.408 (PR) -1.061 (HER2) + 7.051 (luminal A) + 29.172 (luminal B) predicts RS with an R² of 0.65. In conclusion, PR negativity, luminal B subtype, tubal formation, and mitosis are strongly correlated with a higher RS.

Information and Emotional Support Needs of Families Whose Infant Was Diagnosed With SCID Through Newborn Screening.

Background: Now that severe combined immune deficiency (SCID) has been added to newborn screening panels in all 50 states in the U.S., there is a need to develop and disseminate well-designed educational materials to parents who need information to make informed decisions about treatment and care for identified infants. SCID Compass was designed to address this gap. We summarize the results of two needs assessment activities for parents-a journey mapping exercise and online survey-which will inform the development of a website and new resources. Methods: We conducted in-depth interviews with seven parents of children with SCID identified through newborn screening. Participants were asked to complete a journey map to describe key timepoints related to SCID, starting at diagnosis through present day. This qualitative information informed an online survey that was completed by 76 parents who had a child with SCID. All participants were from the United States. Results: Analysis of journey maps revealed five distinct stages that parents experience: (1) Diagnosis, (2) Pre-Treatment, (3) Treatment, (4) Post-Treatment, and (5) The New Normal. At each stage, parents described unique emotions, challenges, contextual factors that can make a difference in their experience, and information and resource needs. Survey results indicated the highest-rated information needs for parents were understanding available treatment options and what to expect across the SCID lifespan. Emotional support needs included dealing with uncertainty about child's future and additional opportunities to connect with other families. Parents preferred receiving new materials from their healthcare provider or other families, and preferred materials in print, from social media, or online. Several differences were found among subgroups of parents, including those whose child had been identified through newborn screening as well as those considered medically underserved. Conclusions: Findings about unmet parent needs and informational preferences will serve as the foundation for creating a suite of resources for those who have a child with SCID. The materials will be tailored to specific stages of the journey. By using a family-centered approach, we will help to ensure that the materials designed and developed as part of SCID Compass will be understandable, comprehensive, and useful.

The Landscape of Severe Combined Immunodeficiency Newborn Screening in the United States in 2020: A Review of Screening Methodologies and Targets, Communication Pathways, and Long-Term Follow-Up Practices.

Severe combined immunodeficiency (SCID) is T cell development disorders in the immune system and can be detected at birth. As of December 2018, all 53 newborn screening (NBS) programs within the United States and associated territories offer universal screening for SCID. The Association of Public Health Laboratories (APHL), along with the Immune Deficiency Foundation (IDF), surveyed public health NBS system laboratory and follow-up coordinators regarding their NBS program's screening methodologies and targets, protocols for stakeholder notifications, and long-term follow-up practices. This report explores the variation that exists across NBS practices, revealing needs for efficiencies and educational resources across the NBS system to ensure the best outcomes for newborns.

The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice.

The most challenging issue for breast cancer (BC) patients is metastasis to other organs because current therapies do not prevent or eliminate metastatic BC. Here, we show that SM-164, a small molecule inhibitor, which degrades inhibitor of apoptosis proteins (IAPs), eliminated early-stage metastases and reduced progression of advanced BC metastasis from MDA-MB-231 BC cells in bones and lungs of nude mice. Mechanistically, SM-164-induced BC cell death is TNFα-dependent, with TNFα produced by IL-4-polarized macrophages triggering MDA-MB-231 cell apoptosis in combination with SM-164. SM-164 also inhibited expression of RANKL, which mediates interactions between metastatic BC and host microenvironment cells and induces osteoclast-mediated osteolysis. SM-164 did not kill adriamycin-resistant BC cells, while adriamycin inhibited SM-164-resistant BC cell growth, similar to parental cells. We conclude that SM-164 is a promising therapeutic agent for early stage bone and lung metastasis from triple-negative breast cancer that should be given prior to conventional chemotherapy.

Cost-effectiveness of testing for breast cancer susceptibility genes.

OBJECTIVES: Genetic mutations in breast cancer susceptibility genes BRCA1/2 are associated with an increased risk of breast/ovarian cancers. Cost-effective preventive measures are available for women who test positive. The objective of this study was to determine at what risk of mutation it is cost-effective to test women for BRCA1/2 mutations. METHODS: A semi-Markov model accrued costs and quality-adjusted life years (QALYs) annually from the societal perspective. The estimates of health-care costs, life expectancy, likelihood of obtaining a mastectomy or oophorectomy, and patient preferences for treatment and certainty about their BRCA1/2 status were based on the literature. RESULTS: At a 10% probability of mutation (the current guideline), the test strategy generated 22.9 QALYs over the lifetime and cost $118k, while the no-test strategy generated 22.7 QALYs and cost $117k. The incremental cost-effectiveness ratio of the test strategy was $9k and the differences between costs and effects were not substantial. The test strategy remained cost-effective to a probability of mutation of 0%, as long as utility gained from a negative test result was 0.006 or greater. These results were sensitive to the frequency of inconclusive test results and utility gain from a negative test result. CONCLUSIONS: The costs and effectiveness of both the test and no-test strategies are very similar even when there is a small probability of mutation. Current guidelines, which can be used by insurance companies to refuse coverage, could deny some women a cost-effective approach. Further research to decrease the frequency of inconclusive results could improve the cost-effectiveness of this test.

Involvement of hepcidin in the anemia of multiple myeloma.

PURPOSE: Hepcidin is a liver-produced peptide implicated in the anemia of inflammation. Because interleukin (IL)-6 is a potent inducer of hepcidin expression and its levels are elevated in multiple myeloma, we studied the role of hepcidin in the anemia of multiple myeloma. EXPERIMENTAL DESIGN: Urinary hepcidin and serum levels of IL-6, ferritin, C-reactive protein, tumor necrosis factor-alpha, and IL-1 beta were studied in newly diagnosed myeloma patients. In vitro hepcidin induction assay was assessed by real-time PCR assay. RESULTS: Pretreatment urinary hepcidin levels in 44 patients with stage III multiple myeloma were 3-fold greater than normal controls. In the subset of multiple myeloma patients without renal insufficiency (n = 27), a marked inverse correlation was seen between hemoglobin at diagnosis and urinary hepcidin level (P = 0.014) strongly supporting a causal relationship between up-regulated hepcidin expression and anemia. The urinary hepcidin also significantly (P < 0.05) correlated with serum ferritin and C-reactive protein, whereas its correlation with serum IL-6 levels was of borderline significance (P = 0.06). Sera from 14 multiple myeloma patients, with known elevated urinary hepcidin, significantly induced hepcidin mRNA in the Hep3B cells, whereas normal sera had no effect. For 10 patients, the ability of anti-IL-6 and anti-IL-6 receptor antibodies to prevent the serum-induced hepcidin RNA was tested. In 6 of these patients, hepcidin induction was abrogated by the anti-IL-6 antibodies, but in the other 4 patients, the neutralizing antibodies had no effect. CONCLUSIONS: These results indicate hepcidin is up-regulated in multiple myeloma patients by both IL-6-dependent and IL-6-independent mechanisms and may play a role in the anemia of multiple myeloma.

Targeting Akt and heat shock protein 90 produces synergistic multiple myeloma cell cytotoxicity in the bone marrow microenvironment.

PURPOSE: We hypothesized that targeting both Akt and heat shock protein (HSP) 90 would induce cytotoxic activity against multiple myeloma (MM) cells and target the bone marrow (BM) microenvironment to inhibit angiogenesis, osteoclast formation, as well as migration and adhesion of MM cells. EXPERIMENTAL DESIGN: MM cell lines were incubated with perifosine (5 and 10 micromol/L) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; 50 and 100 nmol/L) alone and in combination. RESULTS: The combination of Akt inhibitor perifosine and HSP90 inhibitor 17-DMAG was synergistic in inducing MM cell cytotoxicity, evidenced by inhibition of DNA synthesis and induction of apoptosis. In addition, perifosine and 17-DMAG almost completely inhibited osteoclast formation: perifosine interfered with both early and late stages of osteoclast progenitor development, whereas 17-DMAG targeted only early stages. We next showed that combined therapy overcomes tumor growth and resistance induced by BM stromal cells and endothelial cells as well as the proliferative effect of exogenous interleukin-6, insulin-like growth factor-I, and vascular endothelial growth factor. Moreover, the combination also induced apoptosis and growth inhibition in endothelial cells and inhibited angiogenesis. Finally, we showed that the two agents prevented migration of MM cells toward stromal-derived factor-1 and vascular endothelial growth factor, which are present in the BM milieu, and also prevented adhesion of MM cells to fibronectin. CONCLUSIONS: This study provides the preclinical framework for treatment protocols targeting both the Akt and HSP pathways in MM.