Does the effect of weight lifting on lymphedema following breast cancer differ by diagnostic method: results from a randomized controlled trial

The lymphedema diagnostic method used in descriptive or intervention studies may influence results found. The purposes of this work were to compare baseline lymphedema prevalence in the physical activity and lymphedema (PAL) trial cohort and to subsequently compare the effect of the weight-lifting intervention on lymphedema, according to four standard diagnostic methods. The PAL trial was a randomized controlled intervention study, involving 295 women who had previously been treated for breast cancer, and evaluated the effect of 12 months of weight lifting on lymphedema status. Four diagnostic methods were used to evaluate lymphedema outcomes: (i) interlimb volume difference through water displacement, (ii) interlimb size difference through sum of arm circumferences, (iii) interlimb impedance ratio using bioimpedance spectroscopy, and (iv) a validated self-report survey. Of the 295 women who participated in the PAL trial, between 22 and 52% were considered to have lymphedema at baseline according to the four diagnostic criteria used. No between-group differences were noted in the proportion of women who had a change in interlimb volume, interlimb size, interlimb ratio, or survey score of ≥5, ≥5, ≥10%, and 1 unit, respectively (cumulative incidence ratio at study end for each measure ranged between 0.6 and 0.8, with confidence intervals spanning 1.0). The variation in proportions of women within the PAL trial considered to have lymphoedema at baseline highlights the potential impact of the diagnostic criteria on population surveillance regarding prevalence of this common morbidity of treatment. Importantly though, progressive weight lifting was shown to be safe for women following breast cancer, even for those at risk or with lymphedema, irrespective of the diagnostic criteria used.

Evaluation of fibroin-based scaffolds for ocular tissue reconstruction

The epithelium of the corneolimbus contains stem cells for regenerating the corneal epithelium. Diseases and injuries affecting the limbus can lead to a condition known as limbal stem cell deficiency (LSCD), which results in loss of the corneal epithelium, and subsequent chronic inflammation and scarring of the ocular surface. Advances in the treatment of LSCD have been achieved through use of cultured human limbal epithelial (HLE) grafts to restore epithelial stem cells of the ocular surface. These epithelial grafts are usually produced by the ex vivo expansion of HLE cells on human donor amniotic membrane (AM), but this is not without limitations. Although AM is the most widely accepted substratum for HLE transplantation, donor variation, risk of disease transfer, and rising costs have led to the search for alternative biomaterials to improve the surgical outcome of LSCD. Recent studies have demonstrated that Bombyx mori silk fibroin (hereafter referred to as fibroin) membranes support the growth of primary HLE cells, and thus this thesis aims to explore the possibility of using fibroin as a biomaterial for ocular surface reconstruction. Optimistically, the grafted sheets of cultured epithelium would provide a replenishing source of epithelial progenitor cells for maintaining the corneal epithelium, however, the HLE cells lose their progenitor cell characteristics once removed from their niche. More severe ocular surface injuries, which result in stromal scarring, damage the epithelial stem cell niche, which subsequently leads to poor corneal re-epithelialisation post-grafting. An ideal solution to repairing the corneal limbus would therefore be to grow and transplant HLE cells on a biomaterial that also provides a means for replacing underlying stromal cells required to better simulate the normal stem cell niche. The recent discovery of limbal mesenchymal stromal cells (L-MSC) provides a possibility for stromal repair and regeneration, and therefore, this thesis presents the use of fibroin as a possible biomaterial to support a three dimensional tissue engineered corneolimbus with both an HLE and underlying L-MSC layer. Investigation into optimal scaffold design is necessary, including adequate separation of epithelial and stromal layers, as well as direct cell-cell contact. Firstly, the attachment, morphology and phenotype of HLE cells grown on fibroin were directly compared to that observed on donor AM, the current clinical standard substrate for HLE transplantation. The production, transparency, and permeability of fibroin membranes were also evaluated in this part of the study. Results revealed that fibroin membranes could be routinely produced using a custom-made film casting table and were found to be transparent and permeable. Attachment of HLE cells to fibroin after 4 hours in serum-free medium was similar to that supported by tissue culture plastic but approximately 6-fold less than that observed on AM. While HLE cultured on AM displayed superior stratification, epithelia constructed from HLE on fibroin maintained evidence of corneal phenotype (cytokeratin pair 3/12 expression; CK3/12) and displayed a comparable number and distribution of ÄNp63+ progenitor cells to that seen in cultures grown on AM. These results confirm the suitability of membranes constructed from silk fibroin as a possible substrate for HLE cultivation. One of the most important aspects in corneolimbal tissue engineering is to consider the reconstruction of the limbal stem cell niche to help form the natural limbus in situ. MSC with similar properties to bone marrow derived-MSC (BM-MSC) have recently been grown from the limbus of the human cornea. This thesis evaluated methods for culturing L-MSC and limbal keratocytes using various serum-free media. The phenotype of resulting cultures was examined using photography, flow cytometry for CD34 (keratocyte marker), CD45 (bone marrow-derived cell marker), CD73, CD90, CD105 (collectively MSC markers), CD141 (epithelial/vascular endothelial marker), and CD271 (neuronal marker), immunocytochemistry (alpha-smooth muscle actin; á-sma), differentiation assays (osteogenesis, adipogenesis and chrondrogenesis), and co-culture experiments with HLE cells. While all techniques supported to varying degrees establishment of keratocyte and L-MSC cultures, sustained growth and serial propagation was only achieved in serum-supplemented medium or the MesenCult-XF„¥ culture system (Stem Cell Technologies). Cultures established in MesenCult-XF„¥ grew faster than those grown in serum-supplemented medium and retained a more optimal MSC phenotype. L-MSC cultivated in MesenCult-XFR were also positive for CD141, rarely expressed £\-sma, and displayed multi-potency. L-MSC supported growth of HLE cells, with the largest epithelial islands being observed in the presence of L-MSC established in MesenCult-XF„¥ medium. All HLE cultures supported by L-MSC widely expressed the progenitor cell marker £GNp63, along with the corneal differentiation marker CK3/12. Our findings conclude that MesenCult-XFR is a superior culture system for L-MSC, but further studies are required to explore the significance of CD141 expression in these cells. Following on from the findings of the previous two parts, silk fibroin was tested as a novel dual-layer construct containing both an epithelium and underlying stroma for corneolimbal reconstruction. In this section, the growth and phenotype of HLE cells on non-porous versus porous fibroin membranes was compared. Furthermore, the growth of L-MSC in either serum-supplemented medium or the MesenCult-XFR culture system within fibroin fibrous mats was investigated. Lastly, the co-culture of HLE and L-MSC in serum-supplemented medium on and within fibroin dual-layer constructs was also examined. HLE on porous membranes displayed a flattened and squamous monolayer; in contrast, HLE on non-porous fibroin appeared cuboidal and stratified closer in appearance to a normal corneal epithelium. Both constructs maintained CK3/12 expression and distribution of £GNp63+ progenitor cells. Dual-layer fibroin scaffolds consisting of HLE cells and L-MSC maintained a similar phenotype as on the single layers alone. Overall, the present study proposed to create a three dimensional limbal tissue substitute of HLE cells and L-MSC together, ultimately for safe and beneficial transplantation back into the human eye. The results show that HLE and L-MSC can be cultivated separately and together whilst maintaining a clinically feasible phenotype containing a majority of progenitor cells. In addition, L-MSC were able to be cultivated routinely in the MesenCult-XF® culture system while maintaining a high purity for the MSC characteristic phenotype. However, as a serum-free culture medium was not found to sustain growth of both HLE and L-MSC, the combination scaffold was created in serum-supplemented medium, indicating that further refinement of this cultured limbal scaffold is required. This thesis has also demonstrated a potential novel marker for L-MSC, and has generated knowledge which may impact on the understanding of stromal-epithelial interactions. These results support the feasibility of a dual-layer tissue engineered corneolimbus constructed from silk fibroin, and warrant further studies into the potential benefits it offers to corneolimbal tissue regeneration. Further refinement of this technology should explore the potential benefits of using epithelial-stromal co-cultures with MesenCult-XF® derived L-MSC. Subsequent investigations into the effects of long-term culture on the phenotype and behaviour of the cells in the dual-layer scaffolds are also required. While this project demonstrated the feasibility in vitro for the production of a dual-layer tissue engineered corneolimbus, further studies are required to test the efficacy of the limbal scaffold in vivo. Future in vivo studies are essential to fully understand the integration and degradation of silk fibroin biomaterials in the cornea over time. Subsequent experiments should also investigate the use of both AM and silk fibroin with epithelial and stromal cell co-cultures in an animal model of LSCD. The outcomes of this project have provided a foundation for research into corneolimbal reconstruction using biomaterials and offer a stepping stone for future studies into corneolimbal tissue engineering.

Measuring reef complexity and rugosity from monocular video bathymetric reconstruction

Topographic structural complexity of a reef is highly correlated to coral growth rates, coral cover and overall levels of biodiversity, and is therefore integral in determining ecological processes. Modeling these processes commonly includes measures of rugosity obtained from a wide range of different survey techniques that often fail to capture rugosity at different spatial scales. Here we show that accurate estimates of rugosity can be obtained from video footage captured using underwater video cameras (i.e., monocular video). To demonstrate the accuracy of our method, we compared the results to in situ measurements of a 2m x 20m area of forereef from Glovers Reef atoll in Belize. Sequential pairs of images were used to compute fine scale bathymetric reconstructions of the reef substrate from which precise measurements of rugosity and reef topographic structural complexity can be derived across multiple spatial scales. To achieve accurate bathymetric reconstructions from uncalibrated monocular video, the position of the camera for each image in the video sequence and the intrinsic parameters (e.g., focal length) must be computed simultaneously. We show that these parameters can be often determined when the data exhibits parallax-type motion, and that rugosity and reef complexity can be accurately computed from existing video sequences taken from any type of underwater camera from any reef habitat or location. This technique provides an infinite array of possibilities for future coral reef research by providing a cost-effective and automated method of determining structural complexity and rugosity in both new and historical video surveys of coral reefs.

Bone tissue engineering : reconstruction of critical sized segmental bone defects in the ovine tibia

Well-established therapies for bone defects are restricted to bone grafts which face significant disadvantages (limited availability, donor site morbidity, insufficient integration). Therefore, the objective was to develop an alternative approach investigating the regenerative potential of medical grade polycaprolactone-tricalcium phosphate (mPCL-TCP) and silk-hydroxyapatite (silk-HA) scaffolds. Critical sized ovine tibial defects were created and stabilized. Defects were left untreated, reconstructed with autologous bone grafts (ABG) and mPCL-TCP or silk-HA scaffolds. Animals were observed for 12 weeks. X-ray analysis, torsion testing and quantitative computed tomography (CT) analyses were performed. Radiological analysis confirmed the critical nature of the defects. Full defect bridging occurred in the autograft and partial bridging in the mPCL-TCP group. Only little bone formation was observed with silk-HA scaffolds. Biomechanical testing revealed a higher torsional moment/stiffness (p < 0.05) and CT analysis a significantly higher amount of bone formation for the ABG group when compared to the silk-HA group. No significant difference was determined between the ABG and mPCL-TCP groups. The results of this study suggest that mPCL-TCP scaffolds combined can serve as an alternative to autologous bone grafting in long bone defect regeneration. The combination of mPCL-TCP with osteogenic cells or growth factors represents an attractive means to further enhance bone formation.

Application of a human bone engineering platform to an in vitro and in vivo breast cancer metastasis model

Breast cancer in its advanced stage has a high predilection to the skeleton. Currently, treatment options of breast cancer-related bone metastasis are restricted to only palliative therapeutic modalities. This is due to the fact that mechanisms regarding the breast cancer celI-bone colonisation as well as the interactions of breast cancer cells with the bone microenvironment are not fully understood, yet. This might be explained through a lack of appropriate in vitro and in vivo models that are currently addressing the above mentioned issue. Hence the hypothesis that the translation of a bone tissue engineering platform could lead to improved and more physiological in vitro and in vivo model systems in order to investigate breast cancer related bone colonisation was embraced in this PhD thesis. Therefore the first objective was to develop an in vitro model system that mimics human mineralised bone matrix to the highest possible extent to examine the specific biological question, how the human bone matrix influences breast cancer cell behaviour. Thus, primary human osteoblasts were isolated from human bone and cultured under osteogenic conditions. Upon ammonium hydroxide treatment, a cell-free intact mineralised human bone matrix was left behind. Analyses revealed a similar protein and mineral composition of the decellularised osteoblast matrix to human bone. Seeding of a panel of breast cancer cells onto the bone mimicking matrix as well as reference substrates like standard tissue culture plastic and collagen coated tissue culture plastic revealed substrate specific differences of cellular behaviour. Analyses of attachment, alignment, migration, proliferation, invasion, as well as downstream signalling pathways showed that these cellular properties were influenced through the osteoblast matrix. The second objective of this PhD project was the development of a human ectopic bone model in NOD/SCID mice using medical grade polycaprolactone tricalcium phosphate (mPCL-TCP) scaffold. Human osteoblasts and mesenchymal stem cells were seeded onto an mPCL-TCP scaffold, fabricated using a fused deposition modelling technique. After subcutaneous implantation in conjunction with the bone morphogenetic protein 7, limited bone formation was observed due to the mechanical properties of the applied scaffold and restricted integration into the soft tissue of flank of NOD/SCID mice. Thus, a different scaffold fabrication technique was chosen using the same polymer. Electrospun tubular scaffolds were seeded with human osteoblasts, as they showed previously the highest amount of bone formation and implanted into the flanks of NOD/SCID mice. Ectopic bone formation with sufficient vascularisation could be observed. After implantation of breast cancer cells using a polyethylene glycol hydrogel in close proximity to the newly formed bone, macroscopic communication between the newly formed bone and the tumour could be observed. Taken together, this PhD project showed that bone tissue engineering platforms could be used to develop an in vitro and in vivo model system to study cancer cell colonisation in the bone microenvironment.

Spatial inequalities in colorectal and breast cancer survival : premature deaths and associated factors

This study examines the influence of cancer stage, distance to treatment facilities and area disadvantage on breast and colorectal cancer spatial survival inequalities. We also estimate the number of premature deaths after adjusting for cancer stage to quantify the impact of spatial survival inequalities. Population-based descriptive study of residents aged <90 years in Queensland, Australia diagnosed with primary invasive breast (25,202 females) or colorectal (14,690 males, 11,700 females) cancers during 1996-2007. Bayesian hierarchical models explored relative survival inequalities across 478 regions. Cancer stage and disadvantage explained the spatial inequalities in breast cancer survival, however spatial inequalities in colorectal cancer survival persisted after adjustment. Of the 6,019 colorectal cancer deaths within 5 years of diagnosis, 470 (8%) were associated with spatial inequalities in non-diagnostic factors, i.e. factors beyond cancer stage at diagnosis. For breast cancers, of 2,412 deaths, 170 (7%) were related to spatial inequalities in non-diagnostic factors. Quantifying premature deaths can increase incentive for action to reduce these spatial inequalities.

Prevalence of breast cancer treatment sequelae over 6 years of follow-up

Background: There is a need to better describe and understand the prevalence of breast cancer treatment-related adverse effects amenable to physical therapy and rehabilitative exercise. Prior studies have been limited to single issues and lacked long term follow-up. The Pulling Through Study provides data on prevalence of adverse effects in breast cancer survivors followed over six years. Methods: A population-based sample of Australian women (n=287) diagnosed with invasive, unilateral breast cancer was followed for a median of 6.6 years and prospectively assessed for treatment-related complications at 6, 12, 18 months, and 6 years post-diagnosis. Assessments included post-surgical complications, skin or tissue reaction to radiation therapy, upper-body symptoms, lymphedema, 10% weight gain, fatigue, and upper-quadrant function. The proportion of women with positive indication for each complication and one or more complication was estimated using all available data at each time point. Women were only considered to have a specific complication if they reported the highest two levels of the Likert scale for self-reported issues. Results: At six years post-diagnosis over 60% of women experienced one or more side effects amenable to rehabilitative intervention. The proportion of women experiencing 3 or more side effects decreased throughout follow-up, while the proportion experiencing no side effects remained stable around 40% from 12 months to six years. Weight gain was the only complication to increase in prevalence over time. Conclusion: These data support the development of a multi-disciplinary prospective surveillance approach for the purposes of managing and treating adverse effects in breast cancer survivors.

Prognostic significance of IGF and ECM induced signalling proteins in breast cancer patients

Breast cancer is a leading contributor to the burden of disease in Australia. Fortunately, the recent introduction of diverse therapeutic strategies have improved the survival outcome for many women. Despite this, the clinical management of breast cancer remains problematic as not all approaches are sufficiently sophisticated to take into account the heterogeneity of this disease and are unable to predict disease progression, in particular, metastasis. As such, women with good prognostic outcomes are exposed to the side effects of therapies without added benefit. Furthermore, women with aggressive disease for whom these advanced treatments would deliver benefit cannot be distinguished and opportunities for more intensive or novel treatment are lost. This study is designed to identify novel factors associated with disease progression, and the potential to inform disease prognosis. Frequently overlooked, yet common mediators of disease are the interactions that take place between the insulin-like growth factor (IGF) system and the extracellular matrix (ECM). Our laboratory has previously demonstrated that multiprotein insulin-like growth factor-I (IGF-I): insulin-like growth factor binding protein (IGFBP): vitronectin (VN) complexes stimulate migration of breast cancer cells in vitro, via the cooperative involvement of the insulin-like growth factor type I receptor (IGF-IR) and VN-binding integrins. However, the effects of IGF and ECM protein interactions on the dissemination and progression of breast cancer in vivo are unknown. It was hypothesised that interactions between proteins required for IGF induced signalling events and those within the ECM contribute to breast cancer metastasis and are prognostic and predictive indicators of patient outcome. To address this hypothesis, semiquantitative immunohistochemistry (IHC) analyses were performed to compare the extracellular and subcellular distribution of IGF and ECM induced signalling proteins between matched normal, primary cancer, and metastatic cancer among archival formalin-fixed paraffin-embedded (FFPE) breast tissue samples collected from women attending the Princess Alexandra Hospital, Brisbane. Multivariate Cox proportional hazards (PH) regression survival models in conjunction with a modified „purposeful selection of covariates. method were applied to determine the prognostic potential of these proteins. This study provides the first in-depth, compartmentalised analysis of the distribution of IGF and ECM induced signalling proteins. As protein function and protein localisation are closely correlated, these findings provide novel insights into IGF signalling and ECM protein function during breast cancer development and progression. Distinct IGF signalling and ECM protein immunoreactivity was observed in the stroma and/or in subcellular locations in normal breast, primary cancer and metastatic cancer tissues. Analysis of the presence and location of stratifin (SFN) suggested a causal relationship in ECM remodelling events during breast cancer development and progression. The results of this study have also suggested that fibronectin (FN) and ¥â1 integrin are important for the formation of invadopodia and epithelial-to-mesenchymal transition (EMT) events. Our data also highlighted the importance of the temporal and spatial distribution of IGF induced signalling proteins in breast cancer metastasis; in particular, SFN, enhancer-of-split and hairy-related protein 2 (SHARP-2), total-akt/protein kinase B 1 (Total-AKT1), phosphorylated-akt/protein kinase B (P-AKT), extracellular signal-related kinase-1 and extracellular signal-related kinase-2 (ERK1/2) and phosphorylated-extracellular signal-related kinase-1 and extracellular signal-related kinase-2 (P-ERK1/2). Multivariate survival models were created from the immunohistochemical data. These models were found to fit well with these data with very high statistical confidence. Numerous prognostic confounding effects and effect modifications were identified among elements of the ECM and IGF signalling cascade and corroborate the survival models. This finding provides further evidence for the prognostic potential of IGF and ECM induced signalling proteins. In addition, the adjusted measures of associations obtained in this study have strengthened the validity and utility of the resulting models. The findings from this study provide insights into the biological interactions that occur during the development of breast tissue and contribute to disease progression. Importantly, these multivariate survival models could provide important prognostic and predictive indicators that assist the clinical management of breast disease, namely in the early identification of cancers with a propensity to metastasise, and/or recur following adjuvant therapy. The outcomes of this study further inform the development of new therapeutics to aid patient recovery. The findings from this study have widespread clinical application in the diagnosis of disease and prognosis of disease progression, and inform the most appropriate clinical management of individuals with breast cancer.

Silk fibroin in ocular surface reconstruction : what is its potential as a biomaterial in ophthalmics?

Hardly a month goes by within the scientific literature without some new material “X” being reported as a suitable material on which to grow cell type “Y”, for the potential purpose of treating disease “Z”. Thus when fibroin, a protein found in silk, was first proposed as a biomaterial for cell growth [1] it joined a long list of other materials of both natural as well as synthetic origin. Nevertheless, in the second decade of the Asian Century it is perhaps befitting that a material of so much importance to the continent’s cultural and economic history, should become the focus of cutting-edge biomedical research. Sentiments aside, however, silk fibroin possesses quite a unique combination of properties which make it a promising candidate for repairing the eye and especially for treating damage to the cornea, the transparent window at the front of the eye.

Exercise for health : a randomized, controlled trial evaluating impact of a pragmatic, translational exercise intervention on quality of life, function and treatment-related side effects following breast cancer

Purpose Exercise for Health was a randomized, controlled trial designed to evaluate two modes of delivering (face-to-face [FtF] and over-the-telephone [Tel]) an 8-month translational exercise intervention, commencing 6-weeks post-breast cancer surgery (PS). Methods Outcomes included quality of life (QoL), function (fitness and upper-body) and treatment-related side effects (fatigue, lymphoedema, body mass index, menopausal symptoms, anxiety, depression and pain). Generalised estimating equation modelling determined time (baseline [5-weeks PS], mid-intervention [6-months PS], post-intervention [12-months PS]), group (FtF, Tel, Usual Care [UC]) and time-by-group effects. 194 women representative of the breast cancer population were randomised to the FtF (n=67), Tel (n=67) and UC (n=60) groups. Results: There were significant (p<0.05) interaction effects on QoL, fitness and fatigue, with differences being observed between the treatment groups and the UC group. Trends observed for the treatment groups were similar. The treatment groups reported improved QoL, fitness and fatigue over time and changes observed between baseline and post-intervention were clinically relevant. In contrast, the UC group experienced no change, or worsening QoL, fitness and fatigue, mid-intervention. Although improvements in the UC group occurred by 12-months post-surgery, the change did not meet the clinically relevant threshold. There were no differences in other treatment-related side-effects between groups. Conclusion This translational intervention trial, delivered either face-to-face or over-the-telephone, supports exercise as a form of adjuvant breast cancer therapy that can prevent declines in fitness and function during treatment and optimise recovery post-treatment.

Partitioning of persistent organic pollutants (POPs) between human serum and breast milk : a literature review

The literature was reviewed to assess the relationship between the lipid adjusted concentration in human serum and breast milk (expressed as the serum/milk ratio) of a broad range of POPs in paired samples. Thirteen studies were identified, including seven studies that reported serum/milk ratios for polychlorinated dibenzo-dioxins and -furans (PCDD/Fs), ten for polychlorinated biphenyls (PCBs), five for polybrominated diphenyl ethers (PBDEs), and five for organochlorine pesticides (OCPs). Mean serum/milk ratios ranged between 0.7 and 25 depending on the compound and congener. For PCDD/Fs, PCBs and PBDEs, a clear trend of increasing mean serum/milk ratio by increasing molar volume, hydrophobicity and number of halogen substitutes was observed. The mean serum/milk ratios reported by the 13 studies summarized here will aid comparison between human POPs exposure studies using either serum or milk samples. More studies are needed to allow a valid comparison between data obtained from analysis of breast milk and serum samples for a broader range of POPs. Furthermore such studies may shed light on compound specific factors as well as other determinants that may affect the partitioning and partition kinetics of POPs between serum and breast milk.

Bodyweight and other correlates of symptom detected breast cancers in a population offered screening

Objective: To determine factors associated with symptom detected breast cancers in a population offered screening. Methods We interviewed 1,459 Australian women aged 40–69, 946 with symptom detected and 513 with mammogram detected invasive breast cancers ≥1.1 cm in diameter, about their personal, mammogram and breast histories before diagnosis and reviewed medical records for tumour characteristics and mammogram dates, calculating ORs and 95% confidence intervals (CIs) for symptom- vs mammogram-detected cancers in logistic regression models. Results: Lack of regular mammograms (<2 mammograms in the 4.5 years before diagnosis) was the strongest correlate of symptom detected breast cancer (OR=3.04 for irregular or no mammograms). In women who had regular mammograms (≥2 mammograms in the 4.5 years before diagnosis), the independent correlates of symptom detected cancers were low BMI (OR <25kg/m2 vs ≥30kg/m2=2.18, 95% CI 1.23-3.84; p=0.008), increased breast density (available in 498 women) (OR highest quarter vs lowest =3.50, 95% CI 1.76-6.97; ptrend=0.004), high grade cancer and a larger cancer (each p<0.01). In women who did not have regular mammograms, the independent correlates were age <50 years, a first cancer and a ≥2cm cancer. Smoking appeared to modify the association of symptom detected cancer with low BMI (higher ORs for low BMI in current smokers) and estrogen receptor (ER) status (higher ORs for low BMI in ER− cancers). Conclusion: Women with low BMI may benefit from a tailored approach to breast cancer detection, particularly if they smoke.