Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

Prospective screening study of 0.5 Tesla dedicated magnetic resonance imaging for the detection of breast cancer in young, high-risk women

BACKGROUND: Evidence-based screening guidelines are needed for women under 40 with a family history of breast cancer, a BRCA1 or BRCA2 mutation, or other risk factors. An accurate assessment of breast cancer risk is required to balance the benefits and risks of surveillance, yet published studies have used narrow risk assessment schemata for enrollment. Breast density limits the sensitivity of film-screen mammography but is not thought to pose a limitation to MRI, however the utility of MRI surveillance has not been specifically examined before in women with dense breasts. Also, all MRI surveillance studies yet reported have used high strength magnets that may not be practical for dedicated imaging in many breast centers. Medium strength 0.5 Tesla MRI may provide an alternative economic option for surveillance. METHODS: We conducted a prospective, nonrandomized pilot study of 30 women age 25–49 years with dense breasts evaluating the addition of 0.5 Tesla MRI to conventional screening. All participants had a high quantitative breast cancer risk, defined as ≥ 3.5% over the next 5 years per the Gail or BRCAPRO models, and/or a known BRCA1 or BRCA2 germline mutation. RESULTS: The average age at enrollment was 41.4 years and the average 5-year risk was 4.8%. Twenty-two subjects had BIRADS category 1 or 2 breast MRIs (negative or probably benign), whereas no category 4 or 5 MRIs (possibly or probably malignant) were observed. Eight subjects had BIRADS 3 results, identifying lesions that were "probably benign", yet prompting further evaluation. One of these subjects was diagnosed with a stage T1aN0M0 invasive ductal carcinoma, and later determined to be a BRCA1 mutation carrier. CONCLUSION: Using medium-strength MRI we were able to detect 1 early breast tumor that was mammographically undetectable among 30 young high-risk women with dense breasts. These results support the concept that breast MRI can enhance surveillance for young high-risk women with dense breasts, and further suggest that a medium-strength instrument is sufficient for this application. For the first time, we demonstrate the use of quantitative breast cancer risk assessment via a combination of the Gail and BRCAPRO models for enrollment in a screening trial

Predictors of adherence to a multifaceted podiatry intervention for the prevention of falls in older people

<p>Abstract</p> <p>Background</p> <p>Despite emerging evidence that foot problems and inappropriate footwear increase the risk of falls, there is little evidence as to whether foot-related intervention strategies can be successfully implemented. The aim of this study was to evaluate adherence rates, barriers to adherence, and the predictors of adherence to a multifaceted podiatry intervention for the prevention of falls in older people.</p> <p>Methods</p> <p>The intervention group (n = 153, mean age 74.2 years) of a randomised trial that investigated the effectiveness of a multifaceted podiatry intervention to prevent falls was assessed for adherence to the three components of the intervention: (i) foot orthoses, (ii) footwear advice and footwear cost subsidy, and (iii) a home-based foot and ankle exercise program. Adherence to each component and the barriers to adherence were documented, and separate discriminant function analyses were undertaken to identify factors that were significantly and independently associated with adherence to the three intervention components.</p> <p>Results</p> <p>Adherence to the three components of the intervention was as follows: foot orthoses (69%), footwear (54%) and home-based exercise (72%). Discriminant function analyses identified that being younger was the best predictor of orthoses use, higher physical health status and lower fear of falling were independent predictors of footwear adherence, and higher physical health status was the best predictor of exercise adherence. The predictive accuracy of these models was only modest, with 62 to 71% of participants correctly classified.</p> <p>Conclusions</p> <p>Adherence to a multifaceted podiatry intervention in this trial ranged from 54 to 72%. People with better physical health, less fear of falling and a younger age exhibited greater adherence, suggesting that strategies need to be developed to enhance adherence in frailer older people who are most at risk of falling.</p> <p>Trial registration</p> <p>Australian New Zealand Clinical Trials Registry <a href="http://www.anzctr.org.au/ACTRN12608000065392.aspx">ACTRN12608000065392</a>.</p

MRI Enhancement in Stromal Tissue Surrounding Breast Tumors: Association with Recurrence Free Survival following Neoadjuvant Chemotherapy

Rationale and Objectives:Normal-appearing stromal tissues surrounding breast tumors can harbor abnormalities that lead to increased risk of local recurrence. The objective of this study was to develop a new imaging methodology to characterize the signal p

MRI Enhancement in Stromal Tissue Surrounding Breast Tumors: Association with Recurrence Free Survival following Neoadjuvant Chemotherapy

Rationale and Objectives:Normal-appearing stromal tissues surrounding breast tumors can harbor abnormalities that lead to increased risk of local recurrence. The objective of this study was to develop a new imaging methodology to characterize the signal p

Body fatness during childhood and adolescence and breast density in young women: a prospective analysis.

INTRODUCTION: Overweight and obesity in childhood and adolescence are associated with reduced breast cancer risk, independent of adult body mass index (BMI). These associations may be mediated through breast density. METHODS: We prospectively examined associations of early life body fatness with adult breast density measured by MRI in 182 women in the Dietary Intervention Study in Children (DISC) who were ages 25-29 at follow-up. Height, weight, and other factors were measured at baseline (ages 8-10) and annual clinic visits through adolescence. We used linear mixed-effects models to quantify associations of percent breast density and dense and non-dense breast volume at ages 25-29 with quartiles of age-specific youth body mass index (BMI) Z-scores, adjusting for clinic, treatment group, current adult BMI, and other well-established risk factors for breast cancer and predictors of breast density. RESULTS: We observed inverse associations between age-specific BMI Z-scores at all youth clinic visits and percent breast density, adjusting for current adult BMI and other covariates (all p values &lt;0.01). Women whose baseline BMI Z-scores (at ages 8-10 years) were in the top quartile had significantly lower adult breast density, after adjusting for current adult BMI and other covariates [least squares mean (LSM): 23.4 %; 95 % confidence interval (CI): 18.0 %, 28.8 %] compared to those in the bottom quartile (LSM: 31.8 %; 95 % CI: 25.2 %, 38.4 %) (p trend &lt;0.01). Significant inverse associations were also observed for absolute dense breast volume (all p values &lt;0.01), whereas there were no clear associations with non-dense breast volume. CONCLUSIONS: These results support the hypothesis that body fatness during childhood and adolescence may play an important role in premenopausal breast density, independent of current BMI, and further suggest direct or indirect influences on absolute dense breast volume. CLINICAL TRIALS REGISTRATION NUMBER: NCT00458588 ; April 9, 2007

Multi-site clinical evaluation of DW-MRI as a treatment response metric for breast cancer patients undergoing neoadjuvant chemotherapy

© 2015 Galbán et al.Purpose: To evaluate diffusion weighted MRI (DW-MR) as a response metric for assessment of neoadjuvant chemotherapy (NAC) in patients with primary breast cancer using prospective multi-center trials which provided MR scans along with c