Introduction – Treatment for breast cancer is associated with a risk of chronic shoulder and upper limb morbidity in up to 30% of patients. There is currently no consensus for the possible reason for this often repeated finding in the literature. Previous research has suggested that development of fibrotic tissue in response to cancer treatments such as surgery and radiotherapy could be an underlying cause of musculoskeletal dysfunction and pain. This study investigated if any genetic variants in several key fibrosis-modulating genes could be shown to be associated with risk of upper limb musculoskeletal dysfunction and pain in breast cancer survivors. Participants and Methods – A cross sectional study design was employed, using a candidate gene approach. A total of 326 South African breast cancer survivors were recruited from a tertiary hospital in the Western Cape (343 total, minus 17 samples with insufficient data collected). Each participant was scored for symptom severity using the shoulder pain and disability index (SPADI) questionnaire. Participants were then grouped for symptom severity using low, med or high SPADI scores. The low SPADI group served as controls (controls n=273, cases n=70). Participants were invited to donate a blood sample from which DNA was extracted. Each DNA sample was genotyped at seven polymorphic sites; three in TGF-ß, two in ATM, one in SOD2 and one in XRCC1, using PCR technologies and TaqMan allelic-discrimination probes. The resultant genotypes were analysed using multivariate analysis, including inferred haplotype analysis to search for association to shoulder pain and morbidity after treatment. A logistic regression analysis was also performed to investigate the association between SPADI score and age of participant. Results – When participant age was compared with symptom severity, it was found that younger participants were more likely to have moderate-to-severe symptoms than older participants. There was a significant difference in the minor allele frequencies between case and control groups for the rs4880 (C>T, SOD2) polymorphism. The T allele was present more in the case group than in controls, with minor allele frequencies of 0.67 vs 0.55 respectively. No other independent associations were noted for any of the remainder variants tested. When haplotypes were inferred for genes SOD2 and ATM, combinations between the rare alleles at rs4880 and rs1800058 (C>T, ATM) were associated (F=4.35, pT and ATM rs1800058 is recommended for further study, in addition to the rs4880 polymorphism in SOD2. These novel results are suggesting that there may be an association between fibrotic genes and the development of upper limb sequelae after treatment for breast cancer. A larger case-control study would be required to validate and explore these findings.

Context: Medical management for head and neck cancer (HNC) often includes neck dissection surgery, a side effect of which is shoulder dysfunction. There is no consensus for which patient-reported outcome measure (PRO) is most appropriate to quantify shoulder dysfunction in this population. Objective: The aims of this research study were to: (1) use Rasch methodologies to assess construct validity and overall appropriateness of test score interpretation of Disability of the Arm, Shoulder and Hand (DASH), QuickDASH, Shoulder Pain and Disability Index (SPADI) and Neck Dissection Impairment Index (NDII) in the HNC population; (2) determine appropriateness of use of University of Washington Quality of Life (UW-QoL) shoulder subscale as a screening tool for shoulder impairment; (3) recommend a new PRO, or combination of PROs, that more accurately portrays the construct of shoulder dysfunction in the HNC population. Design: One hundred and eight-two individuals who had received a neck dissection procedure within the past 2 weeks to 18 months completed the PROs. Rasch methodologies were utilized to address the primary aim of the study through consideration of scale dimensionality [principal components analysis, item and person fit, differential item functioning (DIF)], scale hierarchy (gaps/redundancies, floor/ceiling effects, coverage of ability levels), response scale structure, and reliability (person and item reliability and separation statistics). The secondary aim was addressed through correlational analysis of the UW-QoL (shoulder subscale), DASH, QuickDASH, SPADI and NDII. Results: The DASH did not meet criteria for unidimensionality, and was deemed inappropriate for utilization in this sample. The QuickDASH, SPADI and NDII were all determined to be unidimensional. All scales had varying issues with person and item misfit, DIF, coverage of ability levels, gaps/redundancies, and optimal rating scale requirements. The NDII meets most requirements. All measures were found to meet thresholds for person and item separation and reliability statistics. The third aim of this study was not addressed because the NDII was determined to be appropriate for this population. Conclusions: Rasch analysis indicates the NDII is the most appropriate measure studied for this population. The QuickDASH and SPADI are recommended with reservation. The DASH and the UW-QoL (shoulder subscale) are not recommended.