A SNP in steroid receptor coactivator-1 disrupts a GSK3ß phosphorylation site and is associated with altered tamoxifen response in bone.

The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)ß phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3ß increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3ß-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3ß phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.

Lack of association between oestrogen receptor polymorphisms and change in bone mineral density with tamoxifen therapy.

BACKGROUND: Tamoxifen, a selective oestrogen receptor (ER) modulator, increases bone mineral density (BMD) in postmenopausal women and decreases BMD in premenopausal women. We hypothesised that inherited variants in candidate genes involved in oestrogen signalling and tamoxifen metabolism might be associated with tamoxifen effects in bone. METHODS: A total of 297 women who were initiating tamoxifen therapy were enrolled in a prospective multicentre clinical trial. Lumbar spine and total hip BMD values were measured using dual-energy X-ray absorptiometry (DXA) at baseline and after 12 months of tamoxifen therapy. Single-nucleotide polymorphisms (SNPs) in ESR1, ESR2, and CYP2D6 were tested for associations in the context of menopausal status and previous chemotherapy, with a mean percentage change in BMD over 12 months. RESULTS: The percentage increase in BMD was greater in postmenopausal women and in those patients who had been treated with chemotherapy. No significant associations between tested SNPs and either baseline BMD or change in BMD with 1 year of tamoxifen therapy were detected. CONCLUSION: The evaluated SNPs in ESR and CYP2D6 do not seem to influence BMD in tamoxifen-treated subjects.

Do benefits and barriers differ by stage of adoption for colorectal cancer screening?

In 2003, over 148,300 people were expected to be diagnosed and 56,000 to die from colorectal cancer (CRC). First-degree relatives (FDRs) of people with colon cancer have a two- to eight-fold increased risk for CRC. Despite evidence that screening is effective, adherence with screening recommendations in this at-risk population is low. This study's purposes were to (1) identify perceived benefits and barriers of fecal occult blood testing (FOBT), sigmoidoscopy and colonoscopy, and (2) compare demographic characteristics and perceived benefits and barriers by stage of adoption for CRC screening. Participating FDRs (n = 257) completed a 40-min structured telephone interview. Despite high rates of agreement with the benefits of screening, most FDRs were not contemplating being screened. Of those 50 and older, most were in precontemplation for FOBT, sigmoidoscopy and colonoscopy. Older age was related to stage for FOBT and sigmoidoscopy, but not colonoscopy. Lack of provider recommendation also was related to stage. Consistent with theoretical predictions, precontemplators had (1) higher rates of endorsement of specific barriers to screening and (2) lower rates of endorsement of benefits than contemplators or actors. For morbidity and mortality reduction, participation in routine, periodic screening is imperative. These findings can guide development of screening-promoting interventions.

Physical functioning of elderly cancer patients prior to diagnosis and following initial treatment.

BACKGROUND AND OBJECTIVES: Using an instrument to measure physical functioning that was normed to the U.S. population, data were obtained from patients with a new diagnosis of breast, colon, lung, and prostate cancer. Two questions were addressed: (a) after controlling for age, and number of comorbid conditions, do site and stage of cancer predict functional limitations prior to diagnosis; (b) using age adjusted national norms on physical functioning, how well do age, number of comorbid conditions, stage, treatment and cluster of symptoms (pain, fatigue, and insomnia) explain changes in physical function between 3 months prior to and 8 weeks following diagnosis? METHODS: Patients 65 years of age and older were accrued from 24 community oncology settings. Consenting patients were interviewed within 8 weeks of initial treatment. The SF-36 was used to measure physical functioning. Comorbidity and symptom experience were assessed through patient report and site and stage of cancer from record audits. RESULTS: Prior to diagnosis of cancer, patients were comparable in physical functioning to the U.S. population aged 55-64, a full decade younger than the sample of cancer patients. Site and stage of disease did not account for variations in physical functioning prior to diagnosis. Compared against national norms, patients with more extensive treatments (surgery plus adjuvant therapy) reported greater loss in functioning. Pain, fatigue, and insomnia had a consistent and significant effect on losses in functioning unrelated to patients' treatments or their comorbid conditions. CONCLUSIONS: Site and stage of cancer prior to diagnosis do not affect functioning. Older cancer patients report higher functioning than their counterparts in the U.S. population. Changes in functioning following diagnosis varied by cancer site. Treatments were related to loss in functioning, but comorbidity was not. Pain, fatigue, and insomnia were significant and independent predictors of change in patient functioning. This underscores the importance of interventions to manage symptoms early in the course of treatment for individuals.

Improving depressive symptoms among caregivers of patients with cancer: results of a randomized clinical trial.

PURPOSE/OBJECTIVES: Determine the impact of a 16-week supportive nursing intervention on caregivers of patients with newly diagnosed cancer. DESIGN: Randomized clinical trial. SETTING: Two midwestern cancer treatment sites. SAMPLE: Caregivers of newly diagnosed patients. Patients' mean age was 55.73 years; 55% had breast cancer, and 76% were female. Caregivers' mean age was 52.44 years, and 50% were female. 125 dyads consented to participate; 89 dyads completed the study. METHODS: A nursing intervention was delivered to the experimental group that emphasized symptom monitoring/management, education, emotional support, coordination of services, and caregiver preparation to care. Nurses made a total of nine contacts, five in person and four by telephone, over 16 weeks. Centers for Epidemiological Studies-Depression (CES-D) and a symptom inventory were used. Medical record audits were conducted retrospectively. MAIN RESEARCH VARIABLES: Patient and caregiver depression scores and patient symptom experience. FINDINGS: Baseline caregiver depression and the number of patient symptoms at baseline, 9, and 24 weeks were significant predictors of caregiver depression at 9 and 24 weeks. However, no main effect of the experimental condition existed on caregiver depression. At the final observation, a nonsignificant inverse relationship was found between the number of interventions and depression scores for caregivers. CONCLUSIONS: The intervention appeared to be more effective in slowing the rate of deterioration of depressive symptoms than in decreasing levels of depression in this sample of caregivers. Determining the effectiveness of this intervention in decreasing caregiver depression was difficult because caregivers with higher levels of depression were more likely to withdraw from the study. IMPLICATIONS FOR NURSING PRACTICE: Nurses must be vigilant in monitoring caregivers for signs of depression and must intervene to provide emotional support and make appropriate referrals for follow-up care to promote positive outcomes for patients and caregivers.

Predictors of pain and fatigue in the year following diagnosis among elderly cancer patients.

Using data obtained from an inception cohort of 841 patients aged 65 or older newly diagnosed with breast, colon, lung, or prostate cancer, and observed at 6-8, 12-16, 24-30, and 52 weeks, three questions related to patients' experiences with pain and fatigue were posed. First, how do numbers of patients reporting neither pain nor fatigue, either symptom, or both change during the observation year? Second, did number of comorbid conditions, site and stage of cancer, treatment modalities, symptom management medication, and time affect the presence of these two symptoms? Third, do pain and fatigue predict the numbers of co-occurring other symptoms? Findings indicate that during the year patients improved with respect to their reports of pain and/or fatigue. Stage, more comorbidity, and lung cancer were related to both pain and fatigue. Chemotherapy was related to reports of fatigue, but did not have an extended effect on fatigue.

Comparison of changes in physical functioning of elderly patients with new diagnoses of cancer.

BACKGROUND: Controversy surrounds the impact of site of cancer and treatments on functioning of elderly cancer patients. OBJECTIVES: This research determines (1) whether age, gender, comorbid conditions, site and stage of cancer, and treatments are related to losses in physical functioning at 4 observations during the year after diagnosis; (2) whether symptoms are a mediating variable between treatment and function; and (3) which indicators account for true change in functioning in the year after diagnosis. METHODS: An inception cohort of 907 patients aged > or =65 years and newly diagnosed with breast, colon, lung, or prostate cancer were accrued from 24 community oncology programs. Stage and treatment data were obtained from medical records. Physical functioning was measured with the SF-36 subscale. Interviews were conducted at 6 to 8, 12 to 16, 26 to 30, and 52 weeks after diagnosis. RESULTS: Men scored 10 points higher on physical function than women at all observation points. Patients with > or =3 comorbid conditions scored lower in functioning. Interactions between site of cancer and treatment modalities were observed. Pain, fatigue, and numbers of symptoms were independent predictors of loss of function. Surgery, female gender, and number of symptoms predicted reliable change in function. CONCLUSIONS: Elderly patients with cancer report levels of function similar to other chronic conditions. Scores on physical function varied by site of cancer; the pattern of change was similar among sites. Age, comorbidity, treatment modalities, and symptom reports each had an independent effect on loss of functioning. Untreated breast cancer patients had lower functioning, suggesting a possible treatment bias.

Cancer and comorbidity: redefining chronic diseases.

BACKGROUND: A narrow subspecialty model of cancer care has led to cancer treatment often being given outside the full medical context of the patient. The full range of comorbid illness must be considered in all aspects of diagnosis and treatment. This study was conducted to describe the prevalence of comorbidity in cancer patients and examine its relation with multiple demographic and clinical variables. METHODS: A case comparison study of 15,626 population-based incident cases of cancer was conducted between 1984-1992 in 3 metropolitan Detroit counties (a National Cancer Institute Surveillance, Epidemiology, and End Results program). Chronic disease status and demographics were collected by self-report; cancer diagnoses and staging were obtained by medical record review. Univariate and multiple logistic regression analyses were performed. RESULTS: Comorbidity was present in 68.7% of cancer patients, and 32.6% of these individuals had > or = 2 comorbid conditions. Frequency was increased in the elderly, African-American patients (particularly African-American women), smokers, and those with lower socioeconomic status. Rates also appeared to vary by specific tumor site. CONCLUSIONS: Comorbid chronic diseases are common in persons with cancer. The prevalence of comorbidities has important clinical, health service, and research implications. The disease specific model of oncology may limit appropriate care for these patients, and enhanced integration of primary care into the ongoing management of cancer may offer better outcomes.