Comparison of a validated decision-support tool to a standard of care triage system for knee osteoarthritis assessment: a proof-of-concept study.

BACKGROUND: Patients with knee osteoarthritis (OA) in northwestern Ontario are referred by their primary care provider (PCP) to a centralized assessment clinic for evaluation by an advanced practice physiotherapist (APP) to determine if they will require surgical management. However, many patients are found to not require surgical management, resulting in delays for patients who do. A decision-support tool was developed to address this issue and to guide treatment options by determining the need for surgical or nonsurgical approaches. METHODS: We used a proof-of-concept method to assess the use of the decision-support tool in northwestern Ontario. Data from 100 consecutive patients assessed for knee OA management were collected from the Thunder Bay centralized assessment clinic. Two levels of agreement analyses (calculated using Cohen κ statistic) were performed, between the APP assessment decision (surgical or non-surgical) and the decision-support tool recommendation, and between the surgeon's decision (surgical or non-surgical) and the decision-support tool recommendation. RESULTS: We found a near-perfect agreement (κ = 0.870, n = 65) between the APP decision and the decision-support tool recommendation, when controlled for patient preference. There was a substantial level of agreement (κ = 0.618, n = 72) between the decision-support tool recommendation and the surgeon's decision. CONCLUSION: The decision-support tool recommendation showed considerable agreement with the decisions of the APP and surgeon indicating that it could be a valuable tool to guide PCPs caring for patients with knee OA. The applicability of a decision-support tool in northwestern Ontario displayed promising results, but further research is needed to examine the feasibility in a primary care setting.

The association of frontal plane alignment to MRI-defined worsening of patellofemoral osteoarthritis: the MOST study.

OBJECTIVE: To determine the sex-specific relation of frontal plane alignment (FPA) to magnetic resonance imaging (MRI)-defined features of patellofemoral osteoarthritis, and also to tibiofemoral osteoarthritis and knee pain. METHOD: The Multicenter Osteoarthritis Study is cohort study comprised of individuals with or at risk of knee osteoarthritis. We determined the sex-specific dose-response relation of baseline FPA to MRI-defined patellofemoral and tibiofemoral structural worsening, and incident knee pain, over 7 years. RESULTS: In women only, greater varus alignment was associated with medial patellofemoral osteophytes (risk ratio [RR] 1.7 [95% CI 1.2, 2.6]) and valgus with lateral patellofemoral osteophytes (RR 1.9 [1.0, 3.6]). In men, greater varus increased risk for medial tibiofemoral cartilage worsening (RR 1.7 [1.1, 2.6]), and valgus for lateral tibiofemoral cartilage worsening (RR 1.8 [1.6, 2.2]). In women, findings were similar for tibiofemoral cartilage, but varus also increased risk for medial bone marrow lesions [BMLs] (RR 2.2 [1.6, 3.1]) and medial osteophytes (RR 1.8 [1.3, 2.5]), and valgus for lateral BMLs (RR 3.3 [2.2, 4.5]) and osteophytes (RR 2.0 [1.2, 3.2]). Varus increased risk of incident pain in men (RR 1.7 [1.4, 2.2]) and women (RR 1.3 [1.0, 1.6]), valgus did so in men only (RR 1.5 [1.1, 1.9]). CONCLUSION: FPA was associated with patellofemoral osteophyte worsening in women, though overall was more strongly associated with tibiofemoral than patellofemoral osteoarthritis feature worsening. FPA in women was more consistently associated with structural worsening, yet men had higher associations with incident pain.

Evidence of increasing public participation in advance care planning: a comparison of polls in Alberta between 2007 and 2013.

BACKGROUND: Advance care planning (ACP) encompasses both verbal and written communications expressing preferences for future health and personal care and helps prepare people for healthcare decision-making in times of medical crisis. Healthcare systems are increasingly promoting ACP as a way to inform medical decision-making, but it is not clear how public engagement in ACP activities is changing over time. METHODS: Raw data from 3 independently conducted public polls on ACP engagement, in the same Canadian province, were analysed to assess whether participation in ACP activities changed over 6 years. RESULTS: Statistically significant increases were observed between 2007 and 2013 in: recognising the definition of ACP (54.8% to 80.3%, OR 3.37 (95% CI 2.68 to 4.24)), discussions about healthcare preferences with family (48.4% to 59.8%, OR 1.41 (95% CI 1.17 to 1.69)) and with healthcare providers (9.1% to 17.4%, OR 1.98 (95% CI 1.51 to 2.59)), written ACP plans (21% to 34.6%, OR 1.77 (95% CI 1.45 to 2.17)) and legal documentation (23.4% to 42.7%, OR 2.13 (95% CI 1.75 to 2.59)). These remained significant after adjusting for age, education and self-rated health status. CONCLUSIONS: ACP engagement increased over time, although the overall frequency remains low in certain elements such as discussing ACP with healthcare providers. We discuss factors that may be responsible for the increase and provide suggestions for healthcare systems or other public bodies seeking to stimulate engagement in ACP.

Validity and sensitivity to change of three scales for the radiographic assessment of knee osteoarthritis using images from the Multicenter Osteoarthritis Study (MOST).

OBJECTIVES: The purpose of this study was to assess the concurrent validity and sensitivity to change of three knee osteoarthritis (OA) grading scales. The Kellgren-Lawrence (KL) and the Osteoarthritis Research Society International (OARSI) joint space narrowing (JSN) grading scales are well-established. The third scale, the compartmental grading scale for OA (CG) is a novel scale which grades JSN, femoral osteophytes, tibial erosion and subluxation to create a total score. METHODS: One sample of 72 posteroanterior (PA) fixed-flexion radiographs displaying mild to moderate knee OA was selected from the Multicenter Osteoarthritis Study (MOST) to study validity. A second sample of 75 radiograph pairs, which showed an increase in OA severity over 30 months, was selected to study sensitivity to change. The three radiographic grading scales were applied to each radiograph in both samples. Spearman's rank correlation coefficients were used to correlate the radiographic grades and the change in grades over 30 months with a Whole-organ Magnetic Resonance Imaging Score (WORMS)-based composite score which included five articular features of knee OA. RESULTS: Correlations between the KL, OARSI JSN and CG grading scales and the magnetic resonance image (MRI)-based score were 0.836, 0.840 and 0.773 (P < 0.0001) respectively while correlations between change in the radiographic grading scales and change in the MRI-based score were 0.501, 0.525 and 0.492 (P < 0.0001). CONCLUSIONS: All three radiographic grading scales showed high validity and are suitable to assess knee OA severity. They showed moderate sensitivity to change; therefore caution should be taken when using ordinal radiographic grading scales to monitor knee OA over time.

Standardized standing pelvis-to-floor photographs for the assessment of lower-extremity alignment.

OBJECTIVES: The objective of this cross-sectional study was to assess the intra-rater, inter-rater and test-retest reliability and concurrent validity of lower-extremity alignment estimated from a photograph [photographic alignment (PA) angle]. METHODS: A convenience sample of participants was recruited from the community. Radiopaque stickers were placed over participants' anterior superior iliac spines. One radiograph and one photograph were taken with the participant standing in a standardized position. The stickers were removed. After 30 min they were reapplied and a second photograph was taken. The hip-knee-ankle (HKA) angle was measured from each radiograph using customized imaging analysis software. The same software was used by three readers to measure the PA angle from each photograph from the first set twice, at least 2 weeks apart. One reader measured the PA angle from the second set of photographs. Reliability was tested using intraclass correlation coefficients (ICC(2,1)), Bland-Altman analyses and the minimal detectable change (MDC95). Concurrent validity was tested using a Pearson's correlation coefficient and Bland-Altman analysis. RESULTS: Fifty adults participated (mean age 41.8 years; mean body mass index 24.7 kg/m(2)). The PA angle was 4.5° more varus than the HKA angle; these measures were highly correlated (r = 0.92). Intra-rater (ICC(2,1) > 0.985), inter-rater (ICC(2,1) = 0.988) and test-retest reliability (ICC(2,1) = 0.903) showed negligible bias (<0.20°). The MDC95 was 2.69°. CONCLUSIONS: The PA angle may be used in place of the HKA angle if a bias of 4.5° is added. A difference of 3° between baseline and follow-up would be considered a true difference.

Valgus malalignment is a risk factor for lateral knee osteoarthritis incidence and progression: findings from the Multicenter Osteoarthritis Study and the Osteoarthritis Initiative.

OBJECTIVE: To study the effect of valgus malalignment on knee osteoarthritis (OA) incidence and progression. METHODS: We measured the mechanical axis from long limb radiographs from the Multicenter Osteoarthritis Study (MOST) and the Osteoarthritis Initiative (OAI) to define limbs with valgus malalignment (mechanical axis of ≥1.1° valgus) and examined the effect of valgus alignment versus neutral alignment (neither varus nor valgus) on OA structural outcomes. Posteroanterior radiographs and knee magnetic resonance (MR) images were obtained at the time of the long limb radiograph and at followup examinations. Lateral progression was defined as an increase in joint space narrowing (on a semiquantitative scale) in knees with OA, and incidence was defined as new lateral narrowing in knees without radiographic OA. We defined lateral cartilage damage and progressive meniscal damage as increases in cartilage or meniscus scores at followup on the Whole-Organ Magnetic Resonance Imaging Score scale (for the MOST) or the Boston Leeds Osteoarthritis Knee Score scale (for the OAI). We used logistic regression with adjustment for age, sex, body mass index, and Kellgren/Lawrence grade, as well as generalized estimating equations, to evaluate the effect of valgus alignment versus neutral alignment on disease outcomes. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: We studied 5,053 knees (881 valgus) of subjects in the MOST cohort and 5,953 knees (1,358 valgus) of subjects in the OAI cohort. In both studies, all strata of valgus malalignment, including 1.1° to 3° valgus, were associated with an increased risk of lateral disease progression. In knees without radiographic OA, valgus alignment >3° was associated with incidence (e.g., in the MOST, adjusted OR 2.5 [95% CI 1.0-5.9]). Valgus alignment >3° was also associated with cartilage damage on MR imaging in knees without OA (e.g., in the OAI, adjusted OR 5.9 [95% CI 1.1-30.3]).We found a strong relationship of valgus malalignment with progressive lateral meniscal damage. CONCLUSION: Valgus malalignment increases the risk of knee OA radiographic progression and incidence as well as the risk of lateral cartilage damage. It may cause these effects, in part, by increasing the risk of meniscal damage.

The role of varus and valgus alignment in the initial development of knee cartilage damage by MRI: the MOST study.

OBJECTIVE: Varus and valgus alignment are associated with progression of knee osteoarthritis, but their role in incident disease is less certain. Radiographic measures of incident knee osteoarthritis may be capturing early progression rather than disease development. The authors tested the hypothesis: in knees with normal cartilage morphology by MRI, varus is associated with incident medial cartilage damage and valgus with incident lateral damage. METHODS: In MOST, a prospective study of persons at risk of or with knee osteoarthritis, baseline full-limb x-rays and baseline and 30-month MRI were acquired. In knees with normal baseline cartilage morphology in all tibiofemoral subregions, logistic regression was used with generalised estimating equations to examine the association between alignment and incident cartilage damage adjusting for age, gender, body mass index, laxity, meniscal tear and extrusion. RESULTS: Of 1881 knees, 293 from 256 persons met the criteria. Varus versus non-varus was associated with incident medial damage (adjusted OR 3.59, 95% CI 1.59 to 8.10), as was varus versus neutral, with evidence of a dose effect (adjusted OR 1.38/1° varus, 95% CI 1.19 to 1.59). The findings held even excluding knees with medial meniscal damage. Valgus was not associated with incident lateral damage. Varus and valgus were associated with a reduced risk of incident lateral and medial damage, respectively. CONCLUSION: In knees with normal cartilage morphology, varus was associated with incident cartilage damage in the medial compartment, and varus and valgus with a reduced risk of incident damage in the less loaded compartment. These results support that varus increases the risk of the initial development of knee osteoarthritis.

Does measurement of the anatomic axis consistently predict hip-knee-ankle angle (HKA) for knee alignment studies in osteoarthritis? Analysis of long limb radiographs from the multicenter osteoarthritis (MOST) study.

OBJECTIVE: Researchers commonly use the femoral shaft-tibial shaft angle (FS-TS) from knee radiographs to estimate the hip-knee-ankle angle (HKA) in studies examining risk factors for knee osteoarthritis (OA) incidence and progression. The objective of this study was to determine the relationship between HKA and FS-TS, depending on the method of calculating FS-TS and the direction and degree of knee deformity. METHODS: 120 full-length digital radiographs were assigned, with 30 in each of four alignment groups (0.0°-4.9°, and ≥5.0° of varus and valgus), from a large cohort of persons with and at risk of knee OA. HKA and five measures of FS-TS (using progressively shorter shaft lengths) were obtained using Horizons Analysis Software, Orthopaedic Alignment & Imaging Systems Inc. (OAISYS). The offsets between HKA and the different versions of FS-TS were calculated, with 95% confidence intervals (CIs). Pearson correlations were calculated. RESULTS: In varus limbs use of a shorter shaft length increased the offset between HKA and FS-TS from 5.1° to 7.0°. The opposite occurred with valgus limbs (from 5.0° to 3.7°). Correlations between HKA and FS-TS for the whole sample of 120 individuals were excellent (r range 1.00-0.88). However, correlations for individual alignment groups were low to moderate, especially for the shortest-shaft FS-TS (r range 0.41-0.66). CONCLUSIONS: The offsets obtained using the shorter FS-TS measurements vary depending on direction and degree of knee deformity, and therefore may not provide reliable predictions for HKA We recommend that full-length radiographs be used whenever an accurate estimation of HKA is required, although broad categories of alignment can be estimated with FS-TS.

A multiple-bundle model to characterize the mechanical behavior of the cruciate ligaments.

Measurements of elongations of the cruciate ligaments have been used to study the behaviors of these ligaments in-vitro and in-vivo, mostly based on simplified two-bundle models of the cruciates. The complex fiber anatomy of the cruciates may suggest a complex deformation behavior across the continuum of their substance that cannot be captured by only two measurement points. In this study, a new methodology was introduced to include more detailed fiber anatomy and to take into consideration the wrapping of the PCL around the intercondylar notch of the femur in deep flexion. The method was used in comparison to the conventional two-bundle models on three sample cadaver knees that underwent a passive flexion up to 150°. The elongation ratios of the bundles were measured as the ratio of change in the length of the bundles over their lengths at 0° flexion. The multiple-bundle models showed ranges of variations across the attachment sites of the cruciates which at all flexion angles were significantly larger than those observed from the conventional two-bundle models. When expressed in percentages, at 150° flexion the ranges of variations in the elongation ratio of the bundles were 32.7%±31.9% and 34%±8.6% for the ACL and PCL, respectively. Results of this study showed that important variations of elongation across the body of the cruciates can be obscured to the conventional two-bundle model of the cruciates, and therefore a more detailed bundle configuration is suggested for the purpose of studying elongation behaviors of these ligaments.

Reliability of lower limb alignment measures using an established landmark-based method with a customized computer software program.

The objective of the study was to evaluate the reliability of frontal plane lower limb alignment measures using a landmark-based method by (1) comparing inter- and intra-reader reliability between measurements of alignment obtained manually with those using a computer program, and (2) determining inter- and intra-reader reliability of computer-assisted alignment measures from full-limb radiographs. An established method for measuring alignment was used, involving selection of 10 femoral and tibial bone landmarks. (1) To compare manual and computer methods, we used digital images and matching paper copies of five alignment patterns simulating healthy and malaligned limbs drawn using AutoCAD. Seven readers were trained in each system. Paper copies were measured manually and repeat measurements were performed daily for 3 days, followed by a similar routine with the digital images using the computer. (2) To examine the reliability of computer-assisted measures from full-limb radiographs, 100 images (200 limbs) were selected as a random sample from 1,500 full-limb digital radiographs which were part of the Multicenter Osteoarthritis Study. Three trained readers used the software program to measure alignment twice from the batch of 100 images, with two or more weeks between batch handling. Manual and computer measures of alignment showed excellent agreement (intraclass correlations [ICCs] 0.977-0.999 for computer analysis; 0.820-0.995 for manual measures). The computer program applied to full-limb radiographs produced alignment measurements with high inter- and intra-reader reliability (ICCs 0.839-0.998). In conclusion, alignment measures using a bone landmark-based approach and a computer program were highly reliable between multiple readers.

Varus and valgus alignment and incident and progressive knee osteoarthritis.

OBJECTIVE: Varus and valgus alignment increase medial and lateral tibiofemoral load. Alignment was associated with tibiofemoral osteoarthritis progression in previous studies; an effect on incident osteoarthritis risk is less certain. This study tested whether alignment influences the risk of incident and progressive radiographic tibiofemoral osteoarthritis. METHODS: In an observational, longitudinal study of the Multicenter Osteoarthritis Study cohort, full-limb x-rays to measure alignment were acquired at baseline and knee x-rays were acquired at baseline and knee x-rays at baseline and 30 months. Varus alignment was defined as ≤178° and valgus ≥182°. Using logistic regression and generalised estimating equations, the associations of baseline alignment and incident osteoarthritis at 30 months (in knees without baseline osteoarthritis) and alignment and osteoarthritis progression (in knees with osteoarthritis) were examined, adjusting. For age, gender, body mass index, injury, laxity and strength, with neutral knees as referent. RESULTS: 2958 knees (1752 participants) were without osteoarthritis at baseline. Varus (adjusted OR 1.49, 95% CI 1.06 to 2.10) but not valgus alignment was associated with incident osteoarthritis. 1307 knees (950 participants) had osteoarthritis at baseline. Varus alignment was associated with a greater risk of medial osteoarthritis progression (adjusted OR 3.59, 95% CI 2.62 to 4.92) and a reduced risk of lateral progression, and valgus with a greater risk of lateral progression (adjusted OR 4.85, 95% CI 3.17 to 7.42) and a reduced risk of medial progression. CONCLUSION: Varus but not valgus alignment increased the risk of incident tibiofemoral osteoarthritis. In knees with osteoarthritis, varus and valgus alignment each increased the risk of progression in the biomechanically stressed compartment.

Tamoxifen resistance in early breast cancer: statistical modelling of tissue markers to improve risk prediction.

BACKGROUND: For over two decades, the Nottingham Prognostic Index (NPI) has been used in the United Kingdom to calculate risk scores and inform management about breast cancer patients. It is derived using just three clinical variables - nodal involvement, tumour size and grade. New scientific methods now make cost-effective measurement of many biological characteristics of tumour tissue from breast cancer biopsy samples possible. However, the number of potential explanatory variables to be considered presents a statistical challenge. The aim of this study was to investigate whether in ER+ tamoxifen-treated breast cancer patients, biological variables can add value to NPI predictors, to provide improved prognostic stratification in terms of overall recurrence-free survival (RFS) and also in terms of remaining recurrence free while on tamoxifen treatment (RFoT). A particular goal was to enable the discrimination of patients with a very low risk of recurrence. METHODS: Tissue samples of 401 cases were analysed by microarray technology, providing biomarker data for 72 variables in total, from AKT, BAD, HER, MTOR, PgR, MAPK and RAS families. Only biomarkers screened as potentially informative (i.e., exhibiting univariate association with recurrence) were offered to the multivariate model. The multiple imputation method was used to deal with missing values, and bootstrap sampling was used to assess internal validity and refine the model. RESULTS: Neither the RFS nor RFoT models derived included Grade, but both had better predictive and discrimination ability than NPI. A slight difference was observed between models in terms of biomarkers included, and, in particular, the RFoT model alone included HER2. The estimated 7-year RFS rates in the lowest-risk groups by RFS and RFoT models were 95 and 97%, respectively, whereas the corresponding rate for the lowest-risk group of NPI was 89%. CONCLUSION: The findings demonstrate considerable potential for improved prognostic modelling by incorporation of biological variables into risk prediction. In particular, the ability to identify a low-risk group with minimal risk of recurrence is likely to have clinical appeal. With larger data sets and longer follow-up, this modelling approach has the potential to enhance an understanding of the interplay of biological characteristics, treatment and cancer recurrence.

Can anatomic alignment measured from a knee radiograph substitute for mechanical alignment from full limb films?

OBJECTIVES: To examine whether categories of anatomic alignment (varus, neutral, valgus) measured from knee X-rays agree with similar categories of mechanical alignment from the full limb film and whether varus anatomic malalignment predicts medial joint space loss on knee X-rays as well as varus mechanical alignment. METHODS: We used data from the Osteoarthritis Initiative (OAI) (full limb and flexed knee X-rays) to examine agreement of anatomic and mechanical alignment and data from Boston Osteoarthritis of the Knee Study (BOKS) to evaluate the association of full limb mechanical alignment vs knee X-ray anatomic alignment with joint space loss. A 4 degree offset was used to correct for the more valgus angulation of the anatomic alignment. RESULTS: Of 143 subjects whose knee X-rays and full limb films were publicly released from the OAI, the agreement of varus, neutral and valgus alignment was only moderate (kappa=0.43, P<0.001). In BOKS, varus mechanical and anatomic alignments measured from full limb and knee X-rays respectively both predicted a high risk of medial joint space loss vs neutral alignment--for mechanical alignment, odds ratio (OR)=4.82 [95% confidence interval (CI) 1.93, 12.00] and for anatomic alignment OR=4.25 (95% CI 2.08, 8.72). CONCLUSIONS: While agreement of alignment from knee X-ray to full limb film was only moderate, varus malalignment measured from a flexed knee predicted the likelihood of progression well. Flexed knee alignment may be more relevant to knee osteoarthritis (OA) risk than that of a fully extended knee, but a measurement of alignment from a short limb is an imperfect surrogate for full limb alignment.

Poor survival outcomes in HER2-positive breast cancer patients with low-grade, node-negative tumours.

We present a retrospective analysis on a cohort of low-grade, node-negative patients showing that human epidermal growth factor receptor 2 (HER2) status significantly affects the survival in this otherwise very good prognostic group. Our results provide support for the use of adjuvant trastuzumab in patients who are typically classified as having very good prognosis, not routinely offered standard chemotherapy, and who as such do not fit current UK prescribing guidelines for trastuzumab.

Is the biology of breast cancer changing? A study of hormone receptor status 1984-1986 and 1996-1997.

Using archived tumours, those from 1984-1986 and 1996-1997 underwent immunohistochemistry for hormone receptors and grade analysis. A significant shift towards more ER-positive and low-grade disease was found; this appears to reflect screening practices, but could still influence survival.

Frequent amplifications and deletions of G1/S-phase transition genes, CCND1 and MYC in early breast cancers: a potential role in G1/S escape.

Uncontrolled growth of cancer cells can be related to dysfunctional cell cycle control, including entry into S-phase, initiating cell division. Cyclin CCND3 and CCNE1 along with CDK2 and CDK6 regulate this checkpoint, and genetic changes, detectable by fluorescence in situ hybridization, are hypothesized to increase the aggressiveness of breast cancer, thereby influencing patient survival. Genomic change was investigated in 106 primary breast cancer samples, where the combined gene copy number changes in one of these four cell cycle regulatory factors was observed in 22% of the 98 tumors of successful analysis, distributed with 15 deletions and 7 amplifications. A trend towards decreased survival was observed with the aberrations, suggesting a prognostic potential of this set of markers, which was supported by an association with tumor grade. For validation of the new set of FISH probes for the G1/S-phase cell cycle factors, two additional markers, frequently amplified in breast cancers, were included in this study: The G1/S phase control gene CCND1 and the proliferation marker MYC. Both markers were amplified in 14% and deleted in 5% of the cases. This is the first report of genomic deletions of MYC in breast cancer.

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer.

Elevated c-Src protein expression has been shown in breast cancer and in vitro evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan-Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (P=0.047) and lower recurrence rates on tamoxifen (P=0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (P<0.05). On subgroup analysis, only ER-positive/progesterone receptor (PgR)-positive tumours were associated with improved survival (P=0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in de novo endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome.