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The effect of physical activity on breast cancer risk may be partly mediated by sex steroid hormones. This review synthesized and appraised the evidence for an effect of physical activity on sex steroid hormones. Systematic searches were performed using MEDLINE (Ovid), EMBASE (Ovid), and SPORTDiscus to identify experimental studies and prospective cohort studies that examined physical activity and estrogens, progestins, and/or androgens, as well as sex hormone binding globulin (SHBG) and glucocorticoids in pre- and postmenopausal women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to appraise quality of the evidence. Twenty-eight randomized controlled trials (RCT), 81 nonrandomized interventions, and six observational studies were included. Estrogens, progesterone, and androgens mostly decreased, and SHBG increased, in response to physical activity. Effect sizes were small, and evidence quality was graded moderate or high for each outcome. Reductions in select sex steroid hormones following exercise supports the biological plausibility of the first part of the physical activity-sex hormone-breast cancer pathway. The confirmed effect of physical activity on decreasing circulating sex steroid hormones supports its causal role in preventing breast cancer.See related reviews by Lynch et al., p. 11 and Drummond et al., p. 28.

We undertook a systematic review and appraised the evidence for an effect of circulating sex steroid hormones and sex hormone-binding globulin (SHBG) on breast cancer risk in pre- and postmenopausal women. Systematic searches identified prospective studies relevant to this review. Meta-analyses estimated breast cancer risk for women with the highest compared with the lowest level of sex hormones, and the DRMETA Stata package was used to graphically represent the shape of these associations. The ROBINS-E tool assessed risk of bias, and the GRADE system appraised the strength of evidence. In premenopausal women, there was little evidence that estrogens, progesterone, or SHBG were associated with breast cancer risk, whereas androgens showed a positive association. In postmenopausal women, higher estrogens and androgens were associated with an increase in breast cancer risk, whereas higher SHBG was inversely associated with risk. The strength of the evidence quality ranged from low to high for each hormone. Dose-response relationships between sex steroid hormone concentrations and breast cancer risk were most notable for postmenopausal women. These data support the plausibility of a role for sex steroid hormones in mediating the causal relationship between physical activity and the risk of breast cancer.See related reviews by Lynch et al., p. 11 and Swain et al., p. 16.

Epidemiologic research suggests that physical activity is associated with a reduced risk of breast cancer, but the causal nature of this link is not clear. Investigating mechanistic pathways can provide evidence of biological plausibility and improve causal inference. This project will examine three putative pathways (sex steroid hormones, insulin signaling, and inflammation) in a series of two-stage systematic reviews. Stage 1 used Text Mining for Mechanism Prioritisation (TeMMPo) to identify and prioritize relevant biological intermediates. Stage 2 will systematically review the findings from studies of (i) physical activity and intermediates and (ii) intermediates and breast cancer. Ovid MEDLINE, EMBASE, and SPORTDiscus will be searched using a combination of subject headings and free-text terms. Human intervention and prospective, observational studies will be eligible for inclusion. Meta-analysis will be performed where possible. Risk of bias will be assessed using the Cochrane Collaboration tool, or the ROBINS-I or ROBINS-E tool, depending on study type. Strength of evidence will be assessed using the GRADE system. In addition to synthesizing the mechanistic evidence that links physical activity with breast cancer risk, this project may also identify priority areas for future research and help inform the design and implementation of physical activity interventions.See related reviews by Swain et al., p. 16 and Drummond et al., p. 28.

BACKGROUND: The ACTIVATE Trial examined the efficacy of a wearable-based intervention to increase physical activity and reduce sedentary behavior in breast cancer survivors. This paper examines the effects of the intervention on health-related quality of life (HRQoL) and fatigue at 12 weeks (T2; end of intervention) and 24 weeks (T3; follow-up). METHODS: Inactive and postmenopausal women who had completed primary treatment for stage I-III breast cancer were randomized to intervention or waitlist control. Physical activity and sedentary behavior were measured by Actigraph and activPAL accelerometers at baseline (T1), end of the intervention (T2), and 12 weeks follow-up (T3). HRQoL and fatigue were measured using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). Primary intervention effects were evaluated comparing intervention and waitlist group at T2 using repeated measures mixed effects models. RESULTS: Overall, 83 women were randomized and trial retention was high (94%). A 4.6-point difference in fatigue score was observed between groups at T2 (95% CI: 1.3, 7.8) indicating improvement in fatigue profiles in the intervention group. In within groups analyses, the intervention group reported a 5.1-point increase in fatigue from baseline to T2 (95% CI: 2.0, 8.2) and a 3.3-point increase from baseline to T3 (95% CI: 0.1, 6.41). CONCLUSIONS: Despite small improvements in fatigue profiles, no effects on HRQoL were observed. While the ACTIVATE Trial was associated with improvements in physical activity and sedentary behavior, more intensive or longer duration interventions may be needed to facilitate changes in HRQoL.

BACKGROUND: This brief report examines the maintenance of moderate to vigorous physical activity (MVPA) and sedentary behavior changes approximately 12 weeks after the delivery of the ACTIVATE Trial primary intervention (use of the Garmin Vivofit 2 activity tracker coupled with a behavioral feedback and goal-setting session and 5 telephone-delivered health coaching sessions). We also examine the efficacy of an abridged intervention (use of the Garmin Vivofit 2 only) in the waitlist control group. METHODS: A pre-post design was employed to examine the secondary aims of the ACTIVATE Trial (n = 80; mean age = 62 years). MVPA and sedentary behavior were measured using Actigraph and activPAL accelerometers after delivery of the primary intervention (T2), and again 12 weeks later (T3). Linear mixed models with random effects were used to examine within-group changes in MVPA and sitting time variables. RESULTS: After the 12-week follow-up period, women in the primary intervention group had maintained their higher levels of MVPA (change from T2 to T3 = 14 min/wk; 95% CI = -18 to 46; P = .37). However, their sitting time increased slightly, by 7 min/d (95% CI = -20 to 34; P = .58), but it did not return to its preintervention level. After receiving the Garmin Vivofit 2, the waitlist control group increased their MVPA by 33 min/wk (95% CI = 3-64; P = .03) and reduced their sitting time by 38 min/d (95% CI = -69 to -7; P = .02) over the same 12-week period. CONCLUSION: The secondary outcomes from the ACTIVATE Trial suggest that wearable technology may generate sustainable changes in MVPA and sitting time. Wearable technology alone may be sufficient to change behavior, at least in the short term.

BACKGROUND: The benefits of an active lifestyle after a breast cancer diagnosis are well recognized, but the majority of survivors are insufficiently active. The ACTIVATE Trial examined the efficacy of an intervention (use of the Garmin Vivofit 2 activity monitor coupled with a behavioral feedback and goal-setting session and 5 telephone-delivered health coaching sessions) to increase moderate to vigorous physical activity (MVPA) and reduce sedentary behavior in breast cancer survivors. METHODS: This randomized controlled trial recruited 83 inactive, postmenopausal women diagnosed with stage I-III breast cancer who had completed primary treatment. Participants were randomly assigned to the intervention group or to the control group, and the intervention was delivered over a 12-week period. MVPA and sedentary behavior were measured with Actigraph and activPAL accelerometers at baseline (T1) and at the end of the intervention (T2). RESULTS: Retention in the trial was high, with 80 (96%) of participants completing T2 data collection. At T2, there was a significant between-group difference in MVPA (69 min/wk; 95% CI = 22-116) favoring the intervention group. The trial resulted in a statistically significant decrease in both total sitting time and prolonged bouts (≥20 min) of sitting, with between-group reductions of 37 min/d (95% CI = -72 to -2) and 42 min/d (95% CI = -83 to -2), respectively, favoring the intervention group. CONCLUSION: Results from the ACTIVATE Trial suggest that the use of wearable technology presents an inexpensive and scalable opportunity to facilitate more active lifestyles for cancer survivors. Whether or not such wearable technology-based interventions can create sustainable behavioral change should be the subject of future research.

A 35-year-old woman with primary infertility underwent an ovarian cystectomy for a 5 x 4 cm left adnexal mass. There was no macroscopic evidence of metastatic disease. The final pathology report revealed a poorly differentiated serous cystadenocarcinoma. Because the patient desired to retain child-bearing capacity, she refused a surgical staging of her ovarian cancer. She elected to receive combination chemotherapy. This was then followed by a negative reassessment laparotomy. The patient was diagnosed with recurrent, metastatic ovarian carcinoma 10 years later.

A 35-year-old woman with primary infertility underwent an ovarian cystectomy for a 5 x 4 cm left adnexal mass. There was no macroscopic evidence of metastatic disease. The final pathology report revealed a poorly differentiated serous cystadenocarcinoma. Because the patient desired to retain child-bearing capacity, she refused a surgical staging of her ovarian cancer. She elected to receive combination chemotherapy. This was then followed by a negative reassessment laparotomy. The patient was diagnosed with recurrent, metastatic ovarian carcinoma 10 years later.

We investigated if gene copy number (GCN) alterations of the epidermal growth factor receptor (EGFR), as detected by silver enhanced in situ hybridisation (SISH), could be used to select patients for EGFR mutation testing. Resected lung adenocarcinoma specimens with adequate tumour were identified. EGFR SISH was performed using the Ventana Benchmark Ultra platform. EGFR GCN was classified according to the Colorado Classification System. EGFR mutations were scanned by high resolution melting and confirmed by Sanger sequencing. Thirty-four of 96 tumours were EGFR SISH positive (35%), and 31 of 96 tumours harboured one or more EGFR mutations (32%). Of 31 EGFR-mutant tumours, 18 were EGFR SISH positive (58%). There was a statistically significant relationship between the presence of an EGFR mutation and EGFR GCN (p = 0.003). Thirteen of 31 EGFR-mutant tumours were EGFR SISH negative (42%), and 16 of 65 EGFR-wild type tumours were EGFR SISH positive (24%). The sensitivity, specificity, positive predictive value and negative predictive value were 58%, 75%, 52.9% and 79%, respectively. Despite a significant relationship between EGFR GCN alterations and EGFR mutations, our results indicate that EGFR GCN as detected by SISH is not a suitable way to select patients for EGFR mutation testing.

INTRODUCTION: The International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma recommends identification of pathologic patterns in metastatic samples where possible. We investigated the clinical relevance of these patterns. METHODS: Patients with a surgical biopsy of lung adenocarcinoma from a metastatic site were included. Slides were reviewed by an anatomical pathologist identifying the histologic patterns of solid with mucin, acinar, micropapillary, papillary, and assigning a major adenocarcinoma subtype according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. EGFR and KRAS mutation testing were performed on formalin-fixed, paraffin-embedded blocks. Mutations were detected by high resolution melting assay with high resolution melting-positive samples confirmed by Sanger sequencing. RESULTS: One-hundred patients were included. The major histologic subtype prevalence was as follows: solid (50), acinar (29), micropapillary (20), and papillary (1). Of 100 patients, 45 received no systemic therapy with no overall survival differences seen by histologic subtype and 55 received systemic therapy (chemoradiotherapy with curative intent or palliative chemotherapy). Worse survival was seen in the major solid histologic subtype compared with major acinar (hazard ratio 0.32 [95% confidence interval 0.15-0.68], p = 0.003) and micropapillary subtypes (hazard ratio 0.34 [95% confidence interval, 0.17-0.69], p = 0.003). The major solid histologic subtype was less likely to harbor EGFR mutations (p = 0.006) and was less frequent in never smokers (p = 0.010) compared with other histologic subtypes. CONCLUSION: The major solid histologic subtype of lung adenocarcinoma at metastatic sites is associated with shorter overall survival on systemic anticancer therapy. Furthermore, the major solid histologic subtype is

Cancer cachexia is a highly debilitating paraneoplastic disease observed in more than 50% of patients with advanced cancers and directly contributes to 20% of cancer deaths. Loss of skeletal muscle is a defining characteristic of patients with cancer cachexia and is associated with poor survival. The present study reveals the involvement of a myogenic transcription factor Myocyte Enhancer Factor (MEF) 2C in cancer-induced skeletal muscle wasting. Increased skeletal muscle mRNA expression of Suppressor of Cytokine Signaling (Socs) 3 and the IL-6 receptor indicative of active IL-6 signaling was seen in skeletal muscle of mice bearing the Colon 26 (C26) carcinoma. Loss of skeletal muscle structural integrity and distorted mitochondria were also observed using electron microscopy. Gene and protein expression of MEF2C was significantly downregulated in skeletal muscle from C26-bearing mice. MEF2C gene targets myozenin and myoglobin as well as myokinase were also altered during cachexia, suggesting dysregulated oxygen transport capacity and ATP regeneration in addition to distorted structural integrity. In addition, reduced expression of calcineurin was observed which suggested a potential pathway of MEF2C dysregulation. Together, these effects may limit sarcomeric contractile ability and also predispose skeletal muscle to structural instability; associated with muscle wasting and fatigue in cachexia.