Vitamin D threshold to prevent aromatase inhibitor-induced arthralgia: a prospective cohort study

Aromatase inhibitor (AI)-associated arthralgia limits adherence to therapy in breast cancer. The pathophysiology may involve vitamin D status. We wished to establish the optimal concentration of 25(OH)D that prevents or minimizes arthralgia. We used a prospective cohort of 290 women starting AI in whom baseline vitamin D was measured. All received daily vitamin D₃ (800 IU) with calcium. Women with baseline 25(OH)D concentration <30 ng/ml also received 16,000 IU of D₃ orally every 2 weeks. The primary outcome was incident or worsening joint pain derived from baseline and 3-month visual analogic scale (VAS) for joint pain. Regression models were used to analyse the association between vitamin D concentrations at 3 months and pain adjusting for age, BMI, season when the sample was drawn, aromatase inhibitor (exemestane vs. letrozole/anastrozole), prior tamoxifen therapy, baseline NTX, and previous fracture. 90% of women had a 25(OH)D <30 ng/ml at baseline. After supplementation (daily 800 IU and additional 16,000 IU every 2 weeks), 50% of them still failed to reach adequate concentrations at 3 months. In the whole cohort, there was an increase in joint pain (mean 1.16 points SD 2.66; P < 0.001) and the increase was significantly (P = 0.02) attenuated in those that reached concentrations of 25(OH)D of ≥40 ng/ml, with a lower risk of incident arthralgia (OR 0.12 ** [0.03 to 0.40]). A target concentration of 40 ng/ml 25OHD may prevent development of AI arthralgia but higher loading doses are required to attain this level in women with deficiency at baseline.     

Genetic determinants of aromatase inhibitor-related arthralgia: the B-ABLE cohort study

A major side effect of aromatase inhibitor (AI) therapy is AI-related arthralgia (AIA), which often leads to therapy discontinuation. We aimed to identify genetic variants associated with AIA and therapy discontinuation in the first year of AI treatment. Our prospective cohort study included 343 postmenopausal women with early breast cancer starting AI therapy. Single nucleotide polymorphisms (SNPs) in candidate genes involved in estrogen and vitamin D signaling were selected. Univariate and multivariate linear/logistic regressions were fitted in order to asses the association between studied SNPs and AIA intensity (visual analogic scale score) at 3 and 12 months of follow-up, worsening pain, and therapy discontinuation. We also tested for a priori-defined interactions by introducing multiplicative terms in the regression equations. SNPs in CYP17A1 and VDR genes appeared significantly associated with AIA (P = 0.003, P = 0.012, respectively). One SNP in CYP27B1 gene was related to therapy discontinuation [P = 0.02; OR 0.29 (0.09–0.99)]. We revealed interactions between CYP27B1 and both CYP17A1 (P = 0.01) and VDR SNPs (P = 0.06). Furthermore, an additive effect on pain intensity was shown for unfavorable alleles, with two points higher mean absolute pain increase and up to 5.3-fold higher risk of worsening pain compared to favorable genotypes. SNPs in CYP17A1, VDR, and CYP27B1 genes predict the risk of AIA. Their determination would be useful to trigger the monitoring strategies in women at risk of therapy discontinuation.     

Practical guidance for the management of aromatase inhibitor-associated bone loss

BackgroundRecent studies indicate that women with breast cancer are at increased risk of fracture compared with their age-matched peers. Current treatment guidelines are inadequate for averting fractures in osteopenic women, especially those receiving aromatase inhibitor (AI) therapy. Therefore, we sought to identify clinically relevant risk factors for fracture that can be used to assess overall fracture risk and to provide practical guidance for preventing and treating bone loss in women with breast cancer receiving AI therapy.MethodsSystematic review of pertinent information from published literature and meeting abstracts through December 2007 was carried out to identify factors contributing to fracture risk in women with breast cancer. An evidence-based medicine approach was used to select risk factors that can be used to determine when to initiate bisphosphonate treatment of aromatase inhibitor-associated bone loss (AIBL).ResultsFracture risk factors were chosen from large, well-designed, controlled, population-based trials in postmenopausal women. Evidence from multiple prospective clinical trials in women with breast cancer was used to validate AI therapy as a fracture risk factor. Overall, eight fracture risk factors were validated in women with breast cancer: AI therapy, T-score <-1.5, age >65 years, low body mass index (BMI <20 kg/m²), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking. Treatment recommendations were derived from randomized clinical trials.ConclusionsThe authors recommend the following for preventing and treating AIBL in women with breast cancer. All patients initiating AI therapy should receive calcium and vitamin D supplements. Any patient initiating or receiving AI therapy with a T-score ≥-2.0 and no additional risk factors should be monitored every 1–2 years for change in risk status and bone mineral density (BMD). Any patient initiating or receiving AI therapy with a T-score <-2.0 should receive bisphosphonate therapy. Any patient initiating or receiving AI therapy with any two of the following risk factors—T-score <-1.5, age >65 years, low BMI (<20 kg/m²), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking—should receive bisphosphonate therapy. BMD should be monitored every 2 years, and treatment should continue for at least 2 years and possibly for as long as AI therapy is continued. To date, the overwhelming majority of clinical evidence supports zoledronic acid 4 mg every 6 months to prevent bone loss in women at high risk. Although there is a trend towards fewer fractures with zoledronic acid, studies completed to date have not been designed to capture significant differences in fracture rate, and longer follow-up is needed.     

Strategies to prevent chemotherapy-induced bone loss in women with breast cancer

Treatment-induced osteoporosis is an increasing problem for women diagnosed with breast cancer. As more women receive adjuvant endocrine therapy and chemotherapy, and breast cancer survival improves, the impact of cancer treatment on bone health and the morbidity associated with chemotherapy-induced bone loss becomes more of a significant medical concern. Endocrine agents like aromatase inhibitors and luteinizing hormone-releasing hormone agonists decrease the production of ovarian and adrenal estrogens and are widely used in the adjuvant and metastatic settings for treatment of women with hormone receptor-positive breast cancer. Estrogen is important for bone health. It stimulates osteoblasts and maintains bone integrity. As bone density decreases, the risk of fracture increases. This can include fractures of the wrist, femur, and vertebrae. Several potent bisphosphonates have been developed to prevent or treat cancer treatment-induced bone loss.     

Serum 25-hydroxyvitamin D and postmenopausal breast cancer survival: a prospective patient cohort study

Introduction  

Vitamin D has been postulated to be involved in cancer prognosis. Thus far, only two studies reported on its association with recurrence and survival after breast cancer diagnosis yielding inconsistent results. Therefore, the aim of our study was to assess the effect of post-diagnostic serum 25-hydroxyvitamin D [25(OH)D] concentrations on overall survival and distant disease-free survival.     

A prospective study of aromatase inhibitor therapy,vitamin D,C-reactive protein and musculoskeletal symptoms

This study compared type, severity and location of musculoskeletal symptoms and associations with 25-hydroxyvitamin D (25(OH)D) and C-reactive protein (CRP) concentrations between women initiating aromatase inhibitor (AI) therapy and an unexposed comparison group. A 6-month prospective cohort study was conducted, enrolling 100 breast cancer patients prior to initiating AI treatment and an unexposed comparison group of 200 postmenopausal women. Multivariate associations were assessed with generalized linear models. At baseline, 55% of breast cancer patients and 63% of the comparison group reported any musculoskeletal symptoms. Among the unexposed group, prevalence and severity of symptoms remained constant with no statistically significant change over 6 months. Among breast cancer patients, but not unexposed women, the pain severity score significantly increased over the 6 month period for joint (P _trend < 0.001), muscle (P _trend = 0.004), and bone pain (P _trend = 0.01). Women treated with AIs were more likely to report pain in wrists/palms (63% at 6 months) compared to unexposed women (31% at 6 months) (P < 0.001). 25(OH)D concentrations increased over the study period among breast cancer patients (P _trend = 0.004). An increase in pain severity and prevalence was observed among breast cancer patients despite an increase in 25 (OH)D concentration. CRP concentrations were not associated with symptoms. Musculoskeletal symptoms are common among postmenopausal women. Breast cancer patients initiating AI treatment were at increased risk for developing new onset and more severe joint, muscle and bone pain compared to unexposed women, with a distinct distribution. AI-associated symptoms were not associated with 25(OH)D or CRP concentrations.     

Job loss and reemployment after a cancer diagnosis in Koreans - a prospective cohort study

Patients undergoing treatment for cancer have reported a variety of work-related problems. The aim of this study was to investigate the impact of a cancer diagnosis on employment status, and to identify relevant associated factors. This prospective cohort study was conducted at the National Cancer Center in Korea. Male patients newly diagnosed with stomach, liver, or colorectal cancers were recruited. Patients were interviewed and asked to complete an employment questionnaire every 3 months for 24 months. Clinical, sociodemographic and work-related factors were assessed. There were 305 male patients who had a primary diagnosis of cancer and underwent appropriate treatment. Of the 305 male patients who were employed at the time of diagnosis, 53% lost their job, and of these 23% later reemployed. In a multivariate Cox regression analysis, job loss was significantly associated with years of education, job characteristics and disease stage. Reemployment was significantly associated with disease stage and cancer site. Change of employment was common among cancer patients in Korea. With an understanding of the factors involved, it should be possible to reduce unnecessary work cessation, and increase the rate of employment of cancer survivors.     

Risk factors for thyroid cancer: a prospective cohort study

Given the higher incidence rate of thyroid cancer among women compared to men and evidence that smoking and alcohol consumption may be inversely related to thyroid cancer risk, we examined thyroid cancer risk in association with menstrual, reproductive and hormonal factors, and cigarette and alcohol consumption, in a prospective cohort study of 89,835 Canadian women aged 40-59 at recruitment who were enrolled in the National Breast Screening Study (NBSS). Linkages to national cancer and mortality databases yielded data on cancer incidence and deaths from all causes, respectively, with follow-up ending between 1998 and 2000. Cox proportional hazards models (using age as the time scale) were used to estimate hazard ratios and 95% confidence intervals for the association between each of the potential risk factors and risk of thyroid cancer overall and by the main histologic subtypes. During a mean of 15.9 years of follow-up, we observed 169 incident thyroid cancer cases. There was no evidence of altered overall thyroid cancer risk with any of the menstrual, reproductive, or hormonal factors. There was evidence of a decreased risk of papillary thyroid cancer among women with 5 or more live births (vs. nulliparous). Age at which smoking commenced, duration of smoking, number of cigarettes smoked per day, pack-years of smoking and alcohol consumption were not associated with altered thyroid cancer risk. The present study provides little support for associations with hormonal factors, smoking, or alcohol consumption, but there is a need for additional prospective data.     

Endogenous hormones and breast cancer: A prospective cohort study

A cohort study is under way in New York City to evaluate how levels of endogenous reproductive hormones influence the risk of breast cancer. The study, in which approximately 15,000 women are being recruited, utilizes a prospective design in which volunteers are asked to provide repeated specimens of serum during the period 1985–1992. A case-control study nested within the cohort is planned by which specimens from all cases arising in the population and from a randomly selected sample of time-matched controls will be analyzed and compared. As of December 31, 1989, 13,609 volunteers had donated blood specimens, about 50% of whom had already donated more than once. Of the 187 incident breast cancer cases who are expected to arise in the cohort before the end of 1992, 77 have been detected thus far.     

Pain threshold,anxiety and other factors affect intensity of postoperative pain in gastric cancer patients: A prospective cohort study

ObjectiveThis prospective cohort study explored factors related to postoperative pain in gastric cancer patients.MethodsA total of 236 patients who underwent gastrectomy were enrolled. All patients enrolled in the study completed the Hospital Anxiety and Depression Scale (HADS) questionnaire and Life Orientation Test-Revised (LOT-R) questionnaire on the day before surgery. Heat pain threshold (HPT), cold pain threshold (CPT) and pressure pain threshold (PPT) were measured for all patients one day prior to surgery and demographic details were collected. All patients were connected to a patient-controlled intravenous analgesia (PCIA) pump at the end of the surgery. The occurrence of postoperative pain was used as a dependent variable, and multivariate logistic regression analyses were conducted to screen for factors affecting postoperative pain.ResultsIn total, 83 patients (35.2%) had postoperative pain. Body mass index (BMI) ≥28 kg/m² [odds ratio (OR): 2.67; 95% confidence interval (95% CI): 1.07−6.67], total gastrectomy (OR: 2.64; 95% CI: 1.42−4.91), preoperative anxiety score ≥8 (OR: 2.37; 95% CI: 1.12−5.02), heat pain threshold ≤4.9 s (OR: 2.14; 95% CI: 1.06−4.32), pressure pain threshold ≤4 g (OR: 2.05; 95% CI: 1.05−4.03), and female gender (OR: 1.99; 95% CI: 1.04−3.83) were risk factors for postoperative pain. ConclusionsObesity, wide range of gastrectomy, high preoperative anxiety, low HPT and PPT, and female gender are associated with increased risk for postoperative pain.     

Sleep duration and breast cancer: a prospective cohort study

Breast cancer incidence has increased during recent decades for reasons that are only partly understood. Prevalence of sleeping difficulties and sleepiness has increased, whereas sleeping duration per night has decreased. We hypothesized that there is an inverse association between sleep duration and breast cancer risk, possibly due to greater overall melatonin production in longer sleepers. This population-based study includes information from women born in Finland before 1958. Sleep duration, other sleep variables, and breast cancer risk factors were assessed by self-administered questionnaires given in 1975 and in 1981. Breast cancer incidence data for 1976 to 1996 was obtained from the Finnish Cancer Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox proportional hazards models adjusting for potential confounders. Altogether, 242 cases of breast cancer occurred over the study period among the 12,222 women with sleep duration data in 1975. For these women, the HRs for breast cancer in the short (< or =6 hours), average (7-8 hours), and long sleep (> or =9 hours) duration groups were 0.85 (CI, 0.54-1.34), 1.0 (referent), and 0.69 (CI, 0.45-1.06), respectively. Analysis restricted to the 7,396 women (146 cases) whose sleep duration in 1975 and 1981 were in the same duration group (stable sleepers) yielded HRs of 1.10 (CI, 0.59-2.05), 1.0, and 0.28 (CI, 0.09-0.88), with a decreasing trend (P = 0.03). This study provides some support for a decreased risk of breast cancer in long sleepers.     

Breast cancer metastasis to the bone: mechanisms of bone loss

Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. Osteolytic lesions are the end result of osteoclast activity; however, osteoclast differentiation and activation are mediated by osteoblast production of RANKL (receptor activator for NFκB ligand) and several osteoclastogenic cytokines. Osteoblasts themselves are negatively affected by cancer cells as evidenced by an increase in apoptosis and a decrease in proteins required for new bone formation. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies.     

Cancer,fatigue and the return of patients to work-a prospective cohort study

Fatigue is a highly prevalent and debilitating symptom in cancer survivors. The aim of this study was to assess the impact of fatigue and other cancer-related symptoms on the return to work of cancer survivors. A prospective inception cohort study with 12 months of follow-up was initiated. At 6 months following the first day of sick leave, levels of fatigue, depression, sleep problems, physical complaints, cognitive dysfunction and psychological distress were assessed, in addition to clinical, sociodemographic and work-related factors. Data were obtained from one academic hospital and two general hospitals in the Netherlands. 235 patients who had a primary diagnosis of cancer and underwent treatment with curative intent were included. The rate of return to work was measured at 6, 12 and 18 months. Hazard ratios (HRs) for the duration of sick leave up to 18 months following the first day of sick leave were calculated. The rate of return to work increased from 24% at 6 months to 64% at 18 months following the first day of sick leave. Fatigue, diagnosis, treatment type, age, gender, depression, physical complaints and workload were all related to the time taken to return to work. Fatigue scores were also strongly related to diagnosis, physical complaints, and depression scores. Fatigue at 6 months predicted a longer sick leave with a hazard ratio of 0.71 (95% Confidence Interval (C.I.) 0.59-0.85), adjusted for diagnosis, treatment type, age and gender. In a multivariate Cox regression analysis, diagnosis, treatment, age, physical complaints and workload remained the only significant predictors of duration of the sick leave. 64% of cancer survivors returned to work within 18 months. Fatigue levels predicted the return to work. This was independent of the diagnosis and treatment, but not of other cancer-related symptoms. Better management of cancer-related symptoms is therefore needed to facilitate the return to work of cancer patients.     

Clinical value of serum bone resorption markers for predicting clinical outcomes after use of bone modifying agents in metastatic bone tumors: A prospective cohort study

Bone modifying agents (BMAs) have become a standard treatment to prevent skeletal-related events (SREs) in bone metastases (BMs). The aim of our study is to determine the clinical value of serum bone resorption markers for predicting clinical outcomes after using BMAs in patients with BM. Patients were enrolled between May 2013 and October 2017 at the Nagoya University Hospital, Japan. We prospectively observed changes in pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase 5b (TRACP-5b) during treatment with BMAs. The relationship between serum markers before and after treatment and clinical outcomes such as progression of bone disease (BD), SREs and overall survival (OS) were evaluated. Pearson chi-square test and Kaplan–Meier product limit methods were used for analysis. Sixty-seven patients were analyzed. The primary tumor sites were 21 lung, 16 breast and 30 others. Forty and 27 patients were treated with Denosumab and Zoledronic acid, respectively. Progression of BDs, SREs and death were observed in 10, 16 and 31 cases, respectively. The median follow-up period after using BMAs was 12.3 (range 0.3–66.3) months. ICTP at 3–4 weeks was significantly correlated with increasing BD progression, SREs and death after treatment in both the whole and lung cancer cohorts. Base line ICTP and TRACP-5b were also associated with increasing BD progression in the whole cohort. Our study showed that early posttreatment ICTP is useful for predicting BD progression, SREs and OS after use of BMAs in patients with BM and even in patients with lung cancer BM.     

Cigarette smoking and risk of glioma: a prospective cohort study

The etiology of glioma, the most commonly diagnosed malignant brain tumor among adults in the United States, is poorly understood. N-nitroso compounds are known carcinogens, which are found in cigarette smoke and can induce gliomas in rats. On this basis, it has been hypothesized that cigarette smoking may be associated with an increased risk of glioma. We investigated the association between cigarette smoking and glioma risk in the National Breast Screening Study, which included 89,835 Canadian women aged 40-59 years at recruitment between 1980 and 1985. Linkages to national cancer and mortality databases yielded data on cancer incidence and deaths from all causes, respectively, with follow-up ending between 1998 and 2000. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between cigarette smoking and risk of glioma. During a mean of 16.4 years of follow-up, we observed 120 incident glioma cases. Among ever smokers, women who reported having quit smoking had a 51% increase in risk of glioma compared with never smokers (HR = 1.51, 95% CI = 0.97-2.34), while current smokers did not appear to have an increase in risk. When the association with former smokers was further examined by years since quitting, women who had quit smoking >10 years before baseline were at a decreased risk of glioma compared with women who had quit within the 10 years prior to baseline (HR = 0.55, 95% CI = 0.29-1.07), indicating that the association between former smokers and glioma may be driven by women, who recently quit smoking. Compared with nonsmokers, duration of cigarette smoking, number of cigarettes smoked per day and pack-years of smoking were associated with increased glioma risk, although the increases in risk were relatively modest. The present study provides some support for a positive association between cigarette smoking and risk of glioma.     

Combining Src inhibitors and aromatase inhibitors: A novel strategy for overcoming endocrine resistance and bone loss

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes.     

Incense use and respiratory tract carcinomas: a prospective cohort study

BACKGROUND.

Incense use is an integral part of daily life in large parts of Asia. The burning of incense is a powerful producer of particulate matter and the smoke contains a multitude of well‐characterized carcinogens. However, to the authors' knowledge, no convincing association has been reported between exposure to incense smoke and the development of cancer. Therefore, the relation between incense use and the risk of respiratory tract carcinomas was analyzed in a prospective cohort study.

METHODS.

Between 1993 and 1998, a population‐based cohort of 61,320 Singapore Chinese who were free of cancer and ages 45 to 74 years completed a comprehensive interview regarding living conditions and dietary and lifestyle factors. Through linkage to population‐based registries, the cohort was followed through 2005 and cancer occurrence determined. The relative risk for these cancers associated with incense use was estimated using a Cox proportional hazards model.

RESULTS.

A total of 325 upper respiratory tract (UPT) carcinomas and 821 lung carcinomas were observed during follow‐up. Incense use was associated with a significantly increased risk of UPT carcinomas other than nasopharyngeal, whereas no overall effect was observed on lung cancer. The duration and intensity of incense use were associated with an increased risk of squamous cell carcinomas in the entire respiratory tract (P for trend = .004), whereas there was no significant association noted between incense use and nonsquamous cell carcinomas. The relative risk of squamous cell carcinomas among long‐term incense users was 1.8 (95% confidence interval [95% CI], 1.2‐2.6; P = .004) in the entire respiratory tract.

CONCLUSIONS.

The results of the current study indicate that long‐term use of incense is associated with an increased risk of squamous cell carcinoma of the respiratory tract. Cancer 2008. © 2008 American Cancer Society.