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Background Failing to take endocrine therapy (ET) as prescribed (nonadherence) increases risk of morbidity and mortality from breast cancer recurrence. We explored predictors of nonadherence, including demographic, clinical, treatment, and personal factors, among women newly prescribed ET for early stage breast cancer. We also examined predictors of their thoughts about stopping treatment (TST). Methods A baseline survey prior to ET assessed demographics, illness beliefs, beliefs about medicines, fear of recurrence, symptoms, and negative affect. A follow-up survey at 3 months repeated these measures with additional questions about nonadherence and TST. Nonadherence and TST were analyzed using logistic and multiple regression, respectively. Patient record review provided clinical data. The baseline survey was completed by 125 women, with a 96% retention rate at follow-up. Results Thirty-six percent reported nonadherence, and 30% reported TST. Results of regression analyses showed that TST was most strongly associated with symptom severity at follow-up, whereas, lower coherence beliefs, and the absence of comorbid conditions were the strongest predictors of actual nonadherence. Conclusion This is the first longitudinal study to examine concurrently the association of demographic, personal and treatment factors with nonadherence, and TST. Findings have potentially important clinical implications; interventions to improve adherence and reduce TST may need to target women's understanding of their diagnosis and treatment, illness beliefs, and symptoms prior to starting therapy.

Purpose Biosimilars are a cost-effective alternative to biologics that could improve patients' access to expensive biological medicines. Currently, there are little data on doctors' perceptions of biosimilars and in what situations they are comfortable prescribing biosimilars. In this study, we investigated medical specialists' perceptions of biosimilars and the factors associated with the acceptance of biosimilars. Methods A national sample of 110 of 327 medical specialists working in the areas of rheumatology, dermatology, gastroenterology, oncology and haematology completed an online questionnaire examining attitudes towards prescribing biosimilars, indication extrapolation and switching patients to a biosimilar. Results Most specialists held positive views of biosimilars, with between 54 and 74% confident in the safety, efficacy, manufacturing and pharmacovigilance of biosimilars. Seventy-one percent of specialists agreed that they would prescribe biosimilars for all or some conditions meeting relevant clinical criteria. Specialists were less confident about indication extrapolation and switching patients from an existing biologic. Acceptance of biosimilars was significantly associated with a lower perceived time to explain a biosimilar to a patient and lower number of weekly patient appointments. The most common situations that they would not prescribe a biosimilar was where there was a lack of clinical data supporting efficacy (32%), or evidence of adverse effects (17%). Conclusions Medical specialists held generally positive attitudes towards biosimilars but were less confident in indication extrapolation and switching patients from a biologic. Providing clinicians with guidance on how to explain biosimilars to patients and written patient material may help overcome some of the barriers to the use of biosimilars. Copyright © 2017 John Wiley & Sons, Ltd.

Background SHON nuclear expression (SHON-Nuc+) was previously reported to predict clinical outcomes to tamoxifen therapy in ERα+ breast cancer (BC). Herein we determined if SHON expression detected by specific monoclonal antibodies could provide a more accurate prediction and serve as a biomarker for anthracycline-based combination chemotherapy (ACT). Methods SHON expression was determined by immunohistochemistry in the Nottingham early-stage-BC cohort (n = 1,650) who, if eligible, received adjuvant tamoxifen; the Nottingham ERα− early-stage-BC (n = 697) patients who received adjuvant ACT; and the Nottingham locally advanced-BC cohort who received pre-operative ACT with/without taxanes (Neo-ACT, n = 120) and if eligible, 5-year adjuvant tamoxifen treatment. Prognostic significance of SHON and its relationship with the clinical outcome of treatments were analysed. Results As previously reported, SHON-Nuc+ in high risk/ERα+ patients was significantly associated with a 48% death risk reduction after exclusive adjuvant tamoxifen treatment compared with SHON-Nuc− [HR (95% CI) = 0.52 (0.34–0.78), p = 0.002]. Meanwhile, in ERα− patients treated with adjuvant ACT, SHON cytoplasmic expression (SHON-Cyto+) was significantly associated with a 50% death risk reduction compared with SHON-Cyto− [HR (95% CI) = 0.50 (0.34–0.73), p = 0.0003]. Moreover, in patients received Neo-ACT, SHON-Nuc− or SHON-Cyto+ was associated with an increased pathological complete response (pCR) compared with SHON-Nuc+ [21 vs 4%; OR (95% CI) = 5.88 (1.28–27.03), p = 0.012], or SHON-Cyto− [20.5 vs. 4.5%; OR (95% CI) = 5.43 (1.18–25.03), p = 0.017], respectively. After receiving Neo-ACT, patients with SHON-Nuc+ had a significantly lower distant relapse risk compared to those with SHON-Nuc− [HR (95% CI) = 0.41 (0.19–0.87), p = 0.038], whereas SHON-Cyto+ patients had a significantly higher distant relapse risk compared to SHON-Cyto− patients [HR (95% CI) = 4.63 (1.05–20.39), p = 0.043]. Furthermore, multivariate Cox regression analyses revealed that SHON-Cyto+ was independently associated with a higher risk of distant relapse after Neo-ACT and 5-year tamoxifen treatment [HR (95% CI) = 5.08 (1.13–44.52), p = 0.037]. The interaction term between ERα status and SHON-Nuc+ (p = 0.005), and between SHON-Nuc+ and tamoxifen therapy (p = 0.007), were both statistically significant. Conclusion SHON-Nuce+ in tumours predicts response to tamoxifen in ERα+ BC while SHON-Cyto+ predicts response to ACT.

Disseminated Tumour Cells (DTC) have been found in the bone marrow (BM) of up to 70% of patients with breast cancer metastatic to axillary lymph nodes. They are a biologically and therapeutically interesting tumour cell population. Although there is uncertainty about their relationship to cancer prognosis, DTC provide a valuable window into the processes by which primary tumour (PT) cells disseminate. DTC can be enriched from BM by immunoaffinity using antibodies directed against epithelial cell markers such as EpCAM. To better understand the changing gene expression patterns that may accompany breast cancer metastasis, we have compared the whole genome RNA expression profiles of matched PT, axillary lymph node metastases (LNM), and EpCAM-enriched cells from the BM of seven patients. Compared to PT, axillary LNM had consistently altered expression of RNAs encoding matrix metalloproteinases (MMP), growth factors, transcription factors, as well as downstream targets of Catenin-a, Tumour Necrosis Factor (TNF)-a and miR-22. Once the gene expression patterns of potentially contaminating BM cells were subtracted, compared to PT and LNM EpCAM-enriched MB cells had consistently elevated expression of RNAs encoding metabolic enzymes, ribosomal proteins, and DNA-binding factors such as YB-1. The gene expression changes we identify are candidate mediators of breast cancer metastases and represent attractive targets for further study on a cell by cell basis. Citation Format: Reuben J Broom, Cherie Blenkiron, Richard Harman, Erica Whineray Kelly, Stephen Allpress, Katherine Gale, Sam Rice, Peter Shin, Anna Brown, Annette Lasham, Cristin Print. Gene expression in synchronous primary, axillary nodal and disseminated breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-05-16.

The oral multi-targeted tyrosine kinase inhibitor sunitinib malate is a standard first-line therapy in clear-cell metastatic renal cell carcinoma (mRCC). Sunitinib is usually administered daily for 4 weeks, followed by 2 weeks without treatment. Some patients experience worsening of disease symptoms during the treatment break. We report three cases of mRCC in whom continuous daily dosing and dose escalation were evaluated. In two cases, sunitinib was well tolerated at doses of 75 mg continuously and in all cases escalation of dose enabled regain of disease control. This suggests that continuous higher daily dosing of sunitinib is feasible and may provide additional clinical benefit for selected patients who experience minimal toxicity on the standard schedule.

Background The mTOR inhibitors have improved outcomes for patients with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for preselecting patients who are more likely to benefit from these agents. We undertook an exploratory translational study evaluating molecular cytogenetic changes in the context of outcomes from treatment with everolimus. Patients and Methods Ten patients with clear cell mRCC treated with everolimus were enrolled. Pretreatment tissue specimens were analyzed for molecular cytogenetic changes using fluorescence in situ hybridization and progression-free survival (PFS) data were obtained. Gene probes chosen for this analysis were: Von Hippel Lindau, fragile histidine triad, fibroblast growth factor receptor ( FGFR ) 1, FGFR3 , PDGFβ , PDGFRβ , epidermal growth factor receptor, and myelocytomatosis viral oncogene. Results Median PFS was 8.75 months. Two patients with the longest PFS (28 months and 23 months) had gain of PDGFβ and PDGFRβ. This was also observed in 3 other patients who had a PFS of 11.5 months, 8 months, and 5.5 months, respectively. Cytogenetic evolution was observed between primary and metastatic specimens. Conclusion PDGFβ and PDGFRβ gene status might be of relevance to everolimus therapy. Further research evaluating the utility of these potential biomarkers is required.

Patients with metastatic renal cell carcinoma (mRCC) and a good performance status typically receive an anti-vascular endothelial growth factor receptor (VEGFR) TKI (sunitinib or pazopanib) as initial therapy. Upon disease progression or intolerance, there are four orally administered agents approved in the second-line setting (including cytokine-refractory). However, head-to-head comparative trial data are limited. In this study, an indirect statistical comparison of safety and efficacy was undertaken between axitinib, sorafenib, pazopanib and everolimus in second-line therapy mRCC.A systematic review of major databases was conducted from January 2005 to June 2013 for randomized controlled trials (RCTs) evaluating at least one of the four agents in second-line mRCC. Bayesian mixed treatment comparison models were fitted to assess relative effectiveness on multiple endpoints such as objective response rates, dose-limiting grade III/IV toxicities, treatment discontinuations and progression-free survival (PFS).Four RCTs met the inclusion criteria. All four agents seem able to induce tumor shrinkage and to provide patients with a clinically meaningful PFS benefit. Axitinib was superior to pazopanib [hazard ratio (HR) 0.64; 95 % credible interval (95 % Crl) 0.42-0.96] and sorafenib (HR 0.70; 95 % Crl 0.57-0.87) in terms of PFS. However, axitinib was associated with an elevated risk of fatigue and to a lesser extent stomatitis.Keeping in mind the caveats associated with cross-trial statistical comparisons, axitinib provides superior PFS relative to pazopanib and sorafenib. Everolimus, an mammalian target of rapamycin inhibitor, is mechanistically distinct from the other agents and remains a useful option for patient's post-anti-VEGFR TKI failure.

Background Isolated liver metastases occur rarely in patients with metastatic breast cancer. The success of liver resection (LR) for other metastatic disease has led centres to explore the option of LR for patients with isolated breast cancer liver metastases (BCLM). A number of small series have been published in the literature, however the evidence is conflicting. This study aimed to systematically review the literature to determine the perioperative outcome and survival of patients undergoing LR for BCLM. Methods An electronic search of Medline and Embase databases was performed to identify all published series. Patient demographics, management, peri-operative outcome and overall survival (OS) were obtained. Results A total of 1705 articles were identified of which 531 included patients with non-colorectal and non-neuroendocrine metastases. 43 articles including 1686 patients, met all the inclusion and exclusion criteria. R0 resection was achieved in 83% (683/825). Morbidity and 30-day mortality rates were 20% (174/852) and 0.7% (6/918), respectively. The median OS was 36 months (12–58 months). The median 1-, 3-and 5-year OS were 90%, 56% and 37%, respectively. Conclusions LR for BCLM can be carried out with acceptable peri-operative risks in selected patients with survival outcomes that appear to be superior to chemotherapy alone.

Objectives Adjuvant endocrine therapy for early-stage breast cancer has greatly reduced the morbidity and mortality associated with breast cancer recurrence. Despite this, a significant proportion of women report fears of cancer recurrence. This study examined the associations between fear of cancer recurrence (FoR) and illness perceptions, medication beliefs, and treatment side effects in women taking adjuvant endocrine therapy following breast cancer. Methods A total of 153 post-menopausal women with early-stage breast cancer completed a postal survey. Analyses were conducted to examine the association between FoR and illness perceptions, medication beliefs, treatment side effects, demographic factors, and emotional distress and to identify which of these factors would be most strongly associated with FoR in a regression model. Results All illness perceptions (apart from personal control) were associated with FoR, as were patient beliefs about endocrine therapy. Although treatment side effects, being unemployed, and higher levels of anxiety and depression were associated with FoR, only illness perceptions (identity, treatment control, timeline, and emotional representation) and medication necessity beliefs were significantly correlated with FoR in the final model. Conclusions It appears that, in addition to directly targeting FoR, it may be worthwhile to address the illness and medication beliefs supporting the fear. Additionally, helping women to differentiate everyday symptoms from those indicative of breast cancer may help to reduce fear of recurrence. Statement of Contribution What is already known on this subject? A significant proportion of women report fear of cancer recurrence following breast cancer. The literature shows that illness perceptions, side effects of treatment, and beliefs about medicines are related to fear of recurrence among cancer patients. However, because these variables have often been looked at in isolation, it is not clear whether some perceptions or cues are more likely to relate to fear of recurrence than others. What does this study add? This study shows illness perceptions and medication beliefs are strongly related to fears of cancer recurrence. The results point to ways in which the self-regulatory model of illness may be used to reduce patients' fear of recurrence. The study results show that women with higher fear of recurrence may be balancing a tension between believing that they need to take the medication to protect their future health alongside concerns that the treatment may not be working.

Because bone metastases cause significant pain, we developed a questionnaire to evaluate its nature, severity, and impact. This 16-item questionnaire is the Functional Assessment of Cancer Therapy-Bone Pain (FACT-BP). We also developed a 13/18-item questionnaire, the Functional Assessment of Chronic Illness Therapy-Treatment Satisfaction-Bone Treatment Convenience and Satisfaction Questionnaire (FACIT-TS-BTCSQ), to evaluate patients' expectations and acceptance of bone-specific therapies. We evaluated the performance of these scales in two clinical trials. In both trials, we enrolled patients with metastatic breast cancer, who had progressive bone metastases despite first-line therapy with pamidronate or clodronate. We administered intravenous zoledronic acid to 31 patients in one trial and oral ibandronate to 30 patients in the other. Patients completed the FACT-BP questionnaire and FACIT-TS-BTCSQ at baseline, then at Weeks 4, 8, and 12. The FACT-BP scale showed good internal consistency reliability [Cronbach's alpha (alpha)=0.93-0.96]. There was evidence of construct validity, and known-group validity was supported by score shifts in the anticipated direction (Cohen's d effect size=0.36). The FACT-BP score reflected clinical change as evidenced by differences in performance status. This cross-sectional anchor-based criterion suggested reasonable clinically important differences (effect size=0.36). The FACIT-TS-BTCSQ showed good internal consistency reliability for treatment expectation (alpha=0.87) and treatment experience (alpha's=0.89-0.92). The FACT-BP scale is meaningful and appears appropriate for broader use. The assessment of satisfaction (FACIT-TS-BTCSQ) raised questions that will require further research.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR), if elevated, is associated with worse outcomes in several malignancies. OBJECTIVE: Investigation of NLR at baseline and during therapy for metastatic renal cell carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 1199 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC cohort) and 4350 patients from 12 prospective randomized trials (validation cohort). INTERVENTION: Targeted therapies for metastatic renal cell carcinoma. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: NLR was examined at baseline and 6 (± 2) wk later. A landmark analysis at 8 wk was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate using Cox or logistic regression models, adjusted for variables in IMDC score and NLR values at baseline. RESULTS AND LIMITATIONS: Higher NLR at baseline was associated with shorter OS and PFS (Hazard Ratios [HR] per 1 unit increase in log-transformed NLR = 1.69 [95% confidence interval {CI} = 1.46-1.95] and 1.30 [95% CI = 1.15-1.48], respectively). Compared with no change (decrease < 25% to increase < 25%, reference), increase NLR at Week 6 by 25-50% and > 75% was associated with poor OS (HR=1.55 [95% CI=1.10-2.18] and 2.31 [95% CI=1.64-3.25], respectively), poor PFS (HR=1.46 [95% CI=1.04-2.03], 1.76 [95% CI=1.23-2.52], respectively), and reduced objective response rate (odds ratios = 0.77 [95% CI=0.37-1.63] and 0.24 [95% CI=0.08-0.72], respectively). By contrast, a decrease of 25-50% was associated with improved outcomes. Findings were confirmed in the validation cohort. The study is limited by its retrospective design. CONCLUSIONS: Compared with no change, early decline of NLR is associated with favorable outcomes, whereas an increase is associated with worse outcomes. PATIENT SUMMARY: We found that the proportion of immune cells in the blood is of prognostic value, namely that a decrease of the proportion of neutrophils-to-lymphocytes is associated with more favorable outcomes while an increase had the opposite effect.

Bisphosphonates are considered standard therapy in the treatment of patients with bone metastases from breast cancer. While bisphosphonate use has increased in recent years, it is important to appreciate that these agents are not a panacea. Some of the newer and more potent bisphosphonates are expensive, both in terms of drug acquisition costs and in terms of patient time, as they require frequent return visits to the clinic for intravenous therapy. Furthermore, the use of the potent intravenous bisphosphonates has been associated with serious toxicity, including renal dysfunction and osteonecrosis of the jaw. In many patients who receive these drugs, the course of their disease is not materially altered. Therefore, there is growing interest in the role of biochemical markers of bone turnover as predictors of which patients are going to derive the most palliative benefit from bisphosphonates. Of these markers, urinary N-telopeptide (uNTX) has been extensively investigated. This article reviews th...

BACKGROUND: It is unknown whether lymph node metastases (LNM) and their localization negatively affect clinical outcome in metastatic renal cell carcinoma (mRCC) patients. OBJECTIVE: To evaluate the clinicopathological features, survival outcome, and treatment response in mRCC patients with LNM versus those without LNM after treatment with targeted therapies (TT). DESIGN, SETTING, AND PARTICIPANTS: Patients (n=2996) were first analyzed without consideration of lymph node (LN) localization or histologic subtype. Additional analyses (n=1536) were performed in subgroups of patients with supradiaphragmatic (SPD) LNM, subdiaphragmatic (SBD) LNM, and patients with LNM in both locations (SPD+/SBD+) without histologic considerations, and then separately in clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC) patients, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was overall survival (OS) and the secondary outcome was progression-free survival (PFS). RESULTS AND LIMITATIONS: All patients with LNM had worse PFS (p=0.001) and OS (p

BACKGROUND:A significant subgroup of metastatic renal cell carcinoma (mRCC) patients discontinue vascular endothelial growth factor-targeted therapies (VEGF-TT) because of toxicity. Whether clinical outcomes differ in patients who receive second-line (2L) targeted therapy on the basis of reason for discontinuation of first-line (1L) therapy is unknown.PATIENTS AND METHODS:Patients from 15 International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) centers who started 2L targeted therapy were included and the reason for discontinuation of 1L therapy retrospectively collected. Treatment outcomes of 2L, including response, time to treatment failure, and overall survival (OS) were assessed.RESULTS:In total, 1124 patients were identified: 866 patients (77%) discontinued 1L VEGF-TT because of disease progression, and 208 patients (19%) because of toxicity. The reason for discontinuation of 1L therapy did not differ according to IMDC risk group. Compared with patients who stopped 1L VEGF-TT because of disease progression, patients who stopped because of toxicity had greater clinical benefit (nonprogressive disease as best response) in 2L treatment (68% vs. 56%; adjusted odds ratio, 1.58; 95% confidence interval [CI], 1.07-2.35; P = .023) and longer OS (17.4 vs. 11.2 months; adjusted hazard ratio, 0.69; 95% CI, 0.56-0.84; P = .0002) adjusted for type of therapy, time to initiation of 2L treatment, IMDC risk group, and number of metastases at initiation of 2L treatment.CONCLUSION:mRCC patients who discontinue 1L VEGF-TT because of toxicity have better outcomes with 2L therapy than patients who stop therapy because of disease progression. These findings should be taken into consideration when designing clinical trials for 2L therapies in mRCC. BACKGROUND: A significant subgroup of metastatic renal cell carcinoma (mRCC) patients discontinue vascular endothelial growth factor-targeted therapies (VEGF-TT) because of toxicity. Whether clinical outcomes differ in patients who receive second-line (2L) targeted therapy on the basis of reason for discontinuation of first-line (1L) therapy is unknown.PATIENTS AND METHODS: Patients from 15 International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) centers who started 2L targeted therapy were included and the reason for discontinuation of 1L therapy retrospectively collected. Treatment outcomes of 2L, including response, time to treatment failure, and overall survival (OS) were assessed.RESULTS: In total, 1124 patients were identified: 866 patients (77%) discontinued 1L VEGF-TT because of disease progression, and 208 patients (19%) because of toxicity. The reason for discontinuation of 1L therapy did not differ according to IMDC risk group. Compared with patients who stopped 1L VEGF-TT because of disease progression, patients who stopped because of toxicity had greater clinical benefit (nonprogressive disease as best response) in 2L treatment (68% vs. 56%; adjusted odds ratio, 1.58; 95% confidence interval [CI], 1.07-2.35; P = .023) and longer OS (17.4 vs. 11.2 months; adjusted hazard ratio, 0.69; 95% CI, 0.56-0.84; P = .0002) adjusted for type of therapy, time to initiation of 2L treatment, IMDC risk group, and number of metastases at initiation of 2L treatment.CONCLUSION: mRCC patients who discontinue 1L VEGF-TT because of toxicity have better outcomes with 2L therapy than patients who stop therapy because of disease progression. These findings should be taken into consideration when designing clinical trials for 2L therapies in mRCC.

Chemotherapy-induced diarrhoea (CID) has a significant impact. A medicinal food product (ReCharge) containing iron-saturated lactoferrin and anhydrous milk fat reduces the detrimental effects of chemotherapy on the gut in animals. We report results of a randomised blinded placebo-controlled phase IIb trial investigating the efficacy and safety of ReCharge in preventing CID. Eligible patients were adults due to start the first cycle of a 2- or 3-week-cycle chemotherapy regimen, had an Eastern Cooperative Oncology Group (ECOG) status of 3 or less, had adequate haematological, liver and renal function and provided written informed consent. Patients (197) were randomised to ReCharge or placebo. They consumed 100-g study product for 2 weeks before and 6 weeks after starting chemotherapy, completed daily diaries for 8 weeks and attended clinic visits until 12 weeks (2-week cycles) or 14 weeks (3-week cycles). The primary outcome was days with CID. The mean number of days with diary-recorded CID was marginally but not statistically significantly lower on ReCharge than placebo (−2.0, 95 % CI (−4.7 to 0.7), p = 0.2). The proportion reporting diarrhoea in the previous cycle at the clinic visit was 30 % lower (p = 0.012) on ReCharge. Missing diary data may have contributed to the discrepancy. No significant differences were found in quality of life or other adverse events. We found no clear evidence that ReCharge reduced CID as measured by patient self-report diary. The converse finding of benefit as recorded at clinic visits and incomplete adherence to diary completion indicates that further research is required into methods for measuring CID.

Bone metastases from renal cell carcinoma (RCC) are a major cause of morbidity. Post hoc analysis has suggested that bone turnover markers can identify patients at risk of skeletal-related events (SREs) among those receiving zoledronic acid. This study sought to evaluate the effect on bone metastases of everolimus alone compared with everolimus plus zoledronic acid.Thirty treatment-naive patients with RCC and ≥ 1 bone metastases were randomized 1:1 to everolimus (10 mg daily) versus everolimus plus zoledronic acid (4 mg intravenously 4-weekly). Bone-specific assessments were performed at baseline and at weeks 1, 4, 8, and 12. Treatment was continued on allocated arm until progression per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1). The primary outcome measure was urine N-telopeptide (uNTX) level, with secondary measures of plasma C-telopeptide (CTX), quality of life (Functional Assessment of Cancer Therapy-Bone Pain [FACT-BP], Brief Pain Inventory [BPI]), progression-free survival (PFS), SREs, and safety.After 12 weeks, reduction in mean uNTX and CTX on everolimus plus zoledronic acid relative to everolimus was 68.4% (95% CI, 60.1%-74.9%; P.0001) and 76.2% (95% CI, 67.3%-82.7%; P.0001), respectively. There was no evidence of a difference for FACT-BP (P = .5), but evidence was favorable for BPI Severity (P = .05) and BPI Interference (P = .06). Median PFS was 7.5 months (95% CI, 3.4-11.2) on everolimus plus zoledronic acid and 5.4 months (95% CI, 3.2-6.3) on everolimus (P = .009). Median time to first SRE was 9.6 months (95% CI, 4.3-15.5) on everolimus plus zoledronic acid and 5.2 months (95% CI, 1.6-8.2) on everolimus (P = .03).In this RCC population, the addition of zoledronic acid to everolimus significantly reduced bone resorption markers and may prolong tumor control.

Bone is a common site of metastatic spread in patients with advanced renal cell carcinoma (RCC) occurring in around one-third of patients enrolled in clinical trials evaluating modern systemic therapies for this disease. Until recently, limited systemic therapeutic options were available for advanced RCC. Nowadays, a quiver of agents have demonstrated activity, including compounds targeting the vascular endothelial growth factor (VEGF) axis and those targeting the mammalian target of rapamycin (mTOR). Despite a detailed biological understanding of how these drugs work, their effect on bony metastases is less clear. Data suggesting that bisphosphonates (namely zoledronic acid) benefit patients with bone metastases from advanced RCC was gathered prior to the targeted therapy era; therefore, there is some uncertainty about their role in patients on modern RCC therapies. This review summarizes the current targeted therapies registered for use in advanced RCC and postulates how some of them might affect the behavior of bone metastases. It also explores the data available on the role of bisphosphonates for bone metastases from RCC, describes methods of assessing response to therapy for bone metastases and delineates future expectations for the treatment of bone metastases from advanced RCC.

544 Background: Sunitinib (SU) and Pazopanib (PZ) have been compared head-to-head in the first-line phase III COMPARZ study in metastatic renal cell carcinoma (mRCC). We compared SU versus PZ, to confirm outcomes and subsequent second-line therapy efficacy in a population-based setting. Methods: We used the IMDC to assess overall survival (OS), progression-free survival (PFS), response rate (RR) and performed proportional hazard regression adjusting for IMDC prognostic groups. Second-line OS2 and PFS2 were also evaluated. Results: We obtained data from 3,606 patients with mRCC treated with either first line SU (n=3226) or PZ (n=380) with an overall median follow-up of 43.5 months (m) (CI95% 41.4 – 46.4). IMDC risk group distribution for favorable prognosis was 440 (17.3%) for SU vs 72 (25%) for PZ, intermediate prognosis 1414 (55.6%) for SU vs 153 (53%) for PZ, poor prognosis 689 (27.1%) for SU vs 62 (22%) for PZ, p= 0.0027. We found no difference between SU vs. PZ for OS (20.1 [CI95% 18.76-21.42] vs. 23.68 m [CI95% 19.54 - 28.81] p=0.19), PFS (7.22 [CI95% 6.76 - 7.78] vs. 6.83 m [CI95% 5.58 - 8.27] p=0.49). The RR was similar in both groups (Table 1). Adjusted HR for OS and PFS were 0.952 (CI95% 0.788 – 1.150 p=0.61) and 1.052 (CI95% 0.908 – 1.220 p = 0.49), respectively. We also found no difference in any second-line treatment between either post-SU vs. post-PZ groups for OS2 (12.88 [CI95% 11.89 – 14.19] vs. 12.91 m [CI95% 10.3 – 19.1] p=0.47) and PFS2 (3.67 [CI95% 3.38 – 3.87] vs. 4.53 m [CI95% 3.08 – 5.35] p=0.4). There was no statistical difference in OS2 and PFS2 if everolimus was used after SU or PZ (p = 0.33 and p = 0.41, respectively) or if axitinib was used after SU or PZ (p = 0.73 and p = 0.72, respectively). Conclusions: We confirmed in real world practice, that SU and PZ have similar efficacy in the first-line setting for mRCC and do not affect outcomes with subsequent second-line treatment. [Table: see text]

503 Background: A significant minority of mRCC patients prematurely discontinue first-line (1L) VEGF-TT due to toxicity. Whether clinical outcomes differ in patients receiving second line (2L) TT based on reason for discontinuation of 1L are unknown. Methods: Patients from 15 International mRCC Database Consortium (IMDC) centers who started 2L TT were included and the reason for discontinuation of 1L collected. Treatment outcomes of 2L, including response, time to treatment failure (TTF) and overall survival (OS) were assessed. Results: 1124 patients were identified: 866 patients (77%) discontinued 1L VEGF-TT due to progression, 208 patients (19%) due to toxicity. 50 patients (4%) who discontinue due to other reasons were excluded. The reason for discontinuation of 1L did not differ by IMDC risk group at start of 1L VEGF-TT (p=0.54) or 2L therapy (p=0.52). Median time from 1L VEGF-TT initiation to start of 2L in patients who progressed or stopped prematurely due to toxicity was 9.8 and 7.9 months, respectively. Compared to patients who stopped 1L VEGF-TT due to progression, patients who stopped due to toxicity had longer drug free interval between 1L and 2L (1.4 vs. 0.7 months; p

August 2015 e41 Conclusion: Target exposure post IAM was similar to systemic full dose administration but with minimal systemic effects. Our findings are being validated in larger studies in animals and humans using different targets and classes of drugs. IAM could enable safe, inexpensive and early study of novel drugs at the first-in-man stage and the study of established drugs in vulnerable populations.

e15578 Background: Third line targeted therapy efficacy in mRCC is not well characterized and is not reimbursed in many jurisdictions worldwide. Methods: The IMDC consists of consecutive patient se...

4558 Background: A small proportion of patients with mRCC may not require immediate targeted therapy (TT). Their clinicopathological features and prognoses are not well characterized. Methods: A retrospective analysis was conducted in mRCC patients who did not start TT until at least 1 year after diagnosis of metastatic disease (delayed TT). Patients treated with traditional immunotherapy were excluded. For comparison, patients that received immediate TT within 1 month of metastatic diagnosis were used (immediate TT). Results: 467/3202 (14.6%) mRCC patients had delayed TT. The majority of patients (96.6%) in delayed group had prior nephrectomy. Compared to patients who received immediate TT (n = 800), patients with delayed TT were more likely to have clear cell histology (87.8% vs. 82.7%, p = 0.02), lower grade primary lesions (low/int grade: 38.3% vs. 31.2%, p= 0.03), less likely to have sarcomatoid features (7.1% vs. 13.1%, p = 0.002), greater percentage of normal LDH (74.8% vs. 67.1%, p = 0.02) and les...

e15605 Background: Dovitinib is an anti-VEGFR tyrosine kinase inhibitor (TKI) which also inhibits FGFR-1,-2,-3 and PDGFRβ. VEGFR inhibitors are known to cause cardiotoxicity. We sought to assess th...

404 Background: The neutrophil to lymphocyte ratio (NLR) is a marker of inflammation. We evaluated whether NLR is independently prognostic when adjusted for the International mRCC Database Consortium (IMDC) model and evaluated change in NLR ("NLR conversion") as a predictive marker of response to targeted therapy. Methods: A total of 5,227 metastatic renal cell carcinoma (mRCC) patients treated with targeted therapy were included; 1,199 patients in the training cohort from the IMDC and 4028 patients as the validation cohort from pooled prospective randomized controlled trials involving targeted therapy. NLR was examined at initiation of first-line targeted therapy and at 6 weeks after. The prognostic role of NLR and NLR conversion on overall survival (OS) and progression free survival (PFS) was assessed using Cox regression models adjusting for IMDC prognostic score. Results: Median baseline NLR was 3.4 and 2.9 in the training and validation cohorts, respectively. NLR >3.0 at baseline was independently associated with OS and PFS in both the training and validation cohorts (Table). A decrease in NLR by week 6 was associated with longer OS (21.1 vs. 9.7 months; HR 0.57, p

430 Background: Third-line targeted therapy efficacy in metastatic renal cell carcinoma (mRCC) is not well characterized and many funding bodies do not provide reimbursement for it. Methods: The International mRCC Database Consortium (IMDC) consists of consecutive patient series from 25 cancer centers. It was queried for specific sequences of targeted therapy and third-line therapy. Kaplan Meier estimates were used for survival. Cox proportional hazards models were used to adjust hazard ratios for confounders. Patients that stopped second-line therapy were divided into two groups: those that went onto third-line therapy and those did not. Results: 4,050 patients were treated with first-line targeted therapy, of which 2,011 (49.6%) had second-line therapy and 879 (21.7%) had third-line targeted therapy. The most common third-line therapies were everolimus 25%, sorafenib 14%, sunitinib 13%, temsirolimus 11%, pazopanib 10%, and axitinib 6%. IMDC prognostic groups at third-line therapy initiation were 6% favorable risk, 67% intermediate risk, and 27% poor risk. Overall response rate for third-line therapy was 10.5% and 50.9% had stable disease in those patients that were evaluable. Median PFS was 5.1 months (95% CI, 4.5-5.7) and median OS from third-line therapy initiation was 12.0 months (95% CI, 10.7-12.9). Patients stopping second-line therapy that move on to third-line therapy vs. those that do not receive third line therapy have a median OS from stopping second-line therapy of 13.1 vs. 2.3 mons (p

We report a case of a postmenopausal patient with hormone receptor-positive breast cancer who, while receiving tamoxifen, experienced relapse with isolated ovarian metastases 4.5 years after her primary treatment. After resection of her pelvic disease, she commenced anastrozole, and while receiving this, remained disease free for an additional 7.5 years before experiencing relapse again with isolated metastatic disease in an unusual location: intracardiac disease causing superior vena cava obstruction.

Aim: NLR is a marker of host inflammation and adds independent prognostic information to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model (Templeton et al. ASCO GU 2014). Here we evaluate the impact of change in NLR after exposure to targeted therapy. Methods: We included patients with mRCC treated with targeted therapy for which NLR data were available at start of first-line treatment, and 6 and 12 weeks thereafter (± 2 weeks). Change from below to above (or vice versa) NLR cut-offs between 2.5 and 5.0 by week 6 and 12 were studied. Median overall survival (OS) and progression free survival (PFS) was estimated using the Kaplan Meier method, the impact of conversion on OS and PFS was evaluated by Cox regression analyses. The impact of NLR conversion on objective response rates (ORR) was evaluated by binary logistic regression. Results: Data comprising 1199 pts from 9 Consortium sites were evaluated. Median age was 62 years; 23%, 52%, 25% were in the favorable, intermediate and poor prognostic groups, respectively. Sunitinib was first line treatment in 74%. Median baseline NLR was 3.5. Compared with pts without change in NLR, a fall was associated with longer OS, PFS and higher ORR for all cut-offs tested. A rise in NLR showed opposite effects for the 3 endpoints. Data for change in NLR by week 6 using a cut-off of 3.0 are shown in the table. Similar results were observed for changes by week 12. NLR week 0 -> NLR week 6 (cut-off 3.5) H -> L H -> H L -> H L -> L N 320 276 58 545 OS median (mo) 19.4 8.1 14.3 28.9 HR*; P 0.54; 2.20; PFS median (mo) 8.6 3.9 6.6 11.7 HR * ; P 0.56; 2.20; ORR N (%) 91 (32) 29 (12) 6 (11) 176 (35) OR*; P 3.48; 0.16; 0.002 * adjusted for IMDC score. H, high (i.e. NLR > 3.5); L, low (i.e. NLR ≤ 3.5). HR, hazard ratio; mo, months; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression free survival. Conclusions: NLR is a readily available and inexpensive biomarker. Changes in NLR as early as 6 weeks after exposure to targeted therapy appear to have both prognostic and predictive value. Prospective validation of change in NLR is warranted. Disclosure: All authors have declared no conflicts of interest.

4569 Background: Dovitinib is an anti-VEGFR tyrosine kinase inhibitor which also inhibits FGFR-1,-2,-3 and PDGFRβ. We studied its activity as 1st-line therapy in patients with metastatic clear-cell...

443 Background: Dovitinib is an anti-VEGFR tyrosine kinase inhibitor, differentiated by its inhibition of FGFR-1,-2,-3 and PDGFRβ. We evaluated its activity as 1st-line therapy in patients with metastatic clear-cell renal cell carcinoma (mCCRCC) in correlation with status of genes relevant to its mechanism of action. Methods: 31 treatment-naïve patients with mCCRCC were enrolled in this single-arm, single-site, phase II study (ACTRN12612000140853) and received dovitinib at 500mg 5 days on/2 days off until progression. Patients were offered an optional post-treatment biopsy to elucidate resistance mechanisms. The primary endpoint was progression free survival (PFS) using RECIST 1.1. Secondary endpoints include response rate (RR) and efficacy by FGFR gene status (FISH and DNA sequence using Sequenom OncoCarta panel). Results: Accrual occurred over 15 months from March 2012. Median patient age was 64 years and 72% were male. ECOG performance status was 0 in 45% and 1 in 55%. Heng prognostic group was favorable-risk in 38%, intermediate-risk in 52% and poor-risk in 10%. 38% of patients had bone metastases. Four patients stopped treatment due to toxicity and 1 patient withdrew (investigator decision). Median PFS was 6.2 months (inter quartile range: 3.3 to 8.2). Of 28 evaluable patients, best response was; PR (29%), SD (53%) and PD (18%). All-cause grade 3/4 adverse events (AE’s) occurring in ≥5% of patients were; fatigue (16%), abdominal pain (13%), pancreatitis (10%), gout (7%), diarrhea (7%), bone pain (7%), hypercalcaemia (7%), elevated lipase (7%) and pulmonary embolism (7%). No Grade 5 AE’s occurred. Pre-treatment tumor tissue is available for analysis from primary and metastatic sites from 93% and 54% of patients respectively. To date, 6 patients have donated post-progression tumor tissue. Gene status (FISH) for FGFR-1,-2,-3, PDGFβ and PDGFRβ is available for 20 primary and 17 metastatic specimens. Conclusions: Dovitinib has activity when administered in the 1st-line setting of mCCRCC with a tolerable safety profile at this dosing schedule. Correlation of this activity to relevant gene status in tumor samples from study patients will be presented. Clinical trial information: ACTRN12612000140853.

402 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause morbidity, and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (Z) reduces skeletal-related-events (SREs) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving Z. We sought to evaluate the effect on BM of RAD001 (R) (everolimus) alone compared to R+Z in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to R 10mg daily vs. R+Z 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl]). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates, or radiotherapy within 4 wks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, wks-1, 4, 8, and 12. Treatment was continued on allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12 wks. The primary endpoint was urine N-telopeptide (uNTX) level with secondary endpoints being plasma C-telopeptide (CTX), quality of life (FACT-BP, BPI), progression free survival (PFS), SREs, and safety. Results: Heng prognostic group poor, intermediate, and good risk was 20.0%, 46.7%, 33.3% in R+Z and 40.0%, 46.7%, 13.3% in R. Over first 12 wks, the reduction in mean: uNTX on R+Z relative to R was 68.4% (95% CI (60.1%, 74.9%); pst SRE was 9.6 mo (95% CI 4.3, 15.5) on R+Z and 5.2 mo (95% CI 1.6-8.2) on R (p = 0.03). Conclusions: Addition of Z to R significantly reduced bone resorption markers in this RCC population of pts with the adverse prognostic feature of BM. Pts receiving R+Z had prolonged time to 1st SRE and PFS; larger studies are required to further evaluate the addition of bone-specific to targeted therapies in this disease. Clinical trial information: ACTRN12609000980235.

e15054 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause major morbidity and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (ZOL) reduces skeletal-related-events (SRE’s) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving ZOL. We sought to evaluate the effect on BM of RAD001 (everolimus) alone compared to RAD001 plus ZOL in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to RAD001 10mg daily (Arm A) vs. RAD001 + ZOL 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl], Arm B). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates or radiotherapy within 4 weeks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, weeks 1,4,8 and12. Treatment was continued on the allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12-weeks. The primary endpoint was urine N-telopeptide (uNTX) levels with plasma C-telopeptide (CTX) being secondary. Secondary objectives include comparison of quality of life (QoL) and pain (FACT-BP, BPI scores), SREs, safety and efficacy (PFS, RR). Results: Heng prognostic group was poor, intermediate and favorable-risk in; 40.0%, 46.7%, 13.3% respectively in Arm A and 20.0%, 46.7%, 33.3% (Arm B). 53.3% (Arm A) and 60.0% (Arm B) of pts had prior nephrectomy. Over the first 12 weeks, the reduction in mean CTX on Arm B relative to Arm A was 77% (95% CI (68%, 83%); p

e15050 Background: The mTOR inhibitors have improved outcomes for pts with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for pre-selecting pts who are likely to benefit from these agents. We undertook an exploratory translational study evaluating cytogenetic changes in the context of benefit from everolimus therapy. Methods: 10 pts with clear cell mRCC treated with everolimus therapy were enrolled. 2 pts had both primary & metastatic specimens. Pre-treatment paraffin-embedded tissue specimens were analysed for cytogenetic changes using fluorescence in situ hybridisation (FISH) & clinical data including Progression-free Survival (PFS) (RECIST 1.1) were obtained. The gene probes chosen for this analysis were: VHL, FHIT, PDGFβ, PDGFRβ, FGFR1, FGFR3, EGFR, MYC, PTEN & IGH@. Results: Results are displayed in the table. The median PFS was 7.5 months (mo), including 4 pts who remain on treatment. 8 pts were treated 1st-line, one 2nd-line & one 3rd-line. The longest responder (PFS 28 mo, 3rd-line) had a normal VHL status but loss of FHIT. 2 pts with the longest PFS had gain of both PDGFβ & PDGFRβ. Changes were observed between the primary & metastatic specimens including the acquisition of gain of PDGFβ & MYC (these pts remain progression-free on treatment). Conclusions: Loss of FHIT but a normal VHL status was seen in one pt with mRCC who had an enduring response to everolimus. Concomitant gain of PDGFβ & PDGFRβ was observed in 5 pts including 2 with prolonged benefit. Acquisition of gains in gene status suggests evolution of genetic changes between primary & metastatic specimens. [Table: see text]

403 Background: The mTOR inhibitors have improved outcomes for pts with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for pre-selecting pts who are likely to respond to these agents. We undertook an exploratory translational study evaluating cytogenetic changes in the context of response to everolimus therapy. Methods: 10 pts with mRCC treated with everolimus therapy were enrolled. Pre-treatment paraffin-embedded tissue specimens were analysed for cytogenetic changes using fluorescence in situ hybridisation (FISH) and clinical data including PFS (RECIST 1.1) were obtained. The gene probes chosen for this analysis were; VHL, FHIT, FGFR1/3, PDGFb, PDGFRb, EGFR, MYC and IGH@. Results: Results are displayed in the table below. The median PFS was 8.25mo (months). Eight pts were treated 1st-line (on clinical trial), one 2nd-line and one 3rd-line. The longest responder (PFS 25.5mo, 3rd-line) had a normal VHL status but loss of FHIT. Two pts with the longest PFS and one with a PFS of 5.5mo had gain of both PDGFb and PDGFRb. Gain of FGFR1 and FGFR3 was seen in two and three pts respectively. Two specimens were unsuitable for full analysis. Conclusions: Loss of FHIT but a normal VHL status was seen in one pt with mRCC who had an enduring response to everolimus. Concomitant gain of PDGFband PDGFRb was observed in three pts with a good response. FGFR1/3 may be of relevance in the setting of alternative targeted therapies. Further research evaluating the utility of these potential biomarkers is required. [Table: see text]

1040 Background: Despite extensive work evaluating molecular differences between primary tumors, circulating tumor cells, disseminated tumor cells (DTCs) and established metastases, it is not apparent which genetic alterations are required to form viable, independent bone metastases (BM). A major limitation in exploring the genetic differences between DTCs and established BM is the paucity of fresh BM tissue available. Methods: Ten breast cancer patients with BM underwent a CT-guided BM biopsy and a bone marrow aspiration (for DTCs). Tumor cells were enriched by immunomagnetic separation and RNA was extracted from each sample. Gene expression profiling was conducted using Illumina Human Ref-8 bead arrays. Microarray data was analyzed using BeadStudio software to identify differentially expressed genes. Ingenuity Pathway Analysis software was used to identify genes integral to specific pathways involved in tumor dissemination. Results: The yield of analyzable malignant cells from BM and bone marrow aspirates was 60% and 80%, respectively. A signature of 133 genes was identified that was differentially expressed between the two sample types. Paired analysis of samples from the same patients identified a subset of 161 genes, of which 52 overlapped with the initial unmatched signature. Several genes relevant to breast cancer metastasis to bone (i.e., osteopontin, CTGF, parathyroid hormone receptor, EGFR) were significantly over-expressed in the BM compared to the DTCs. Conclusions: Results suggest that there are specific subsets of genes, which are required for DTCs in the bone marrow to form overt BM. A number of genes identified are already known to participate in osteolytic BM formation. This signature may allow identification of patients at increased risk for developing BM. No significant financial relationships to disclose.

e16145 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common and associated with poor outcomes. While the multi-tyrosine kinase inhibitors (TKI's) sunitinib and sorafenib have advanced the treatment of metastatic RCC, their efficacy on BM is unknown. Urinary N-telopeptide (uNTX) is a marker of bone turnover measured in nmol/mmol creatinine. Elevated uNTX levels correlate with an increased risk of skeletal related events and mortality in patients receiving bisphosphonates for BM from a range of primaries. In this pilot biomarker study we sought to prospectively evaluate the effects on BM of these multi-TKI's in RCC patients. Methods: Eligible patients had advanced RCC, at least one BM evident on imaging and no bisphosphonate exposure within 4 weeks. UNTX levels (OsteoMark) were measured at; baseline and weeks-1, 4, 8 and 12 after commencing either sunitinib or sorafenib. The primary endpoint was the percentage change (Ch) in uNTX levels from baseline. Serum samples were also collected for KIT and VEGFR-2 (Quantikine). Patients also completed pain (including bone pain) and quality of life questionnaires. Results: The uNTX results on the first 9 patients are presented in the table below (7 received sunitinib and 2 sorafenib). In this group, sVEGFR-2 and sKIT levels fell by week-1 and 4 respectively and at week-12 the mean % changes (95% CI) were -34% (-0.53,-0.14) and -38% (-0.58,-0.18). Conclusions: In patients with BM from RCC and at least moderately elevated uNTX levels at baseline, these multi-TKI's show a significant trend to decrease uNTX levels, but perhaps not as effectively as bone-specific therapies (e.g. bisphosphonates) do in other malignancies. SVEGFR-2 and sKIT levels also fell across the patient group over the same period. This pilot data raises questions about the activity of the multi-TKI's in BM from RCC and further research is needed. [Table: see text] [Table: see text]

1024 Background: The occurrence of changes in tumor receptor profile (ER, PR and HER-2/neu) between primary and metastatic tissue has been recognised and may have significant treatment implications. Previous reports on receptor discordance rates have tended to be from sub-studies of clinical trials. We sought to evaluate the degree of ER, PR and HER-2/neu receptor discordance in patients treated at two Canadian cancer centres. Methods: Archival data was collected on patients for whom tissue from both primary and metastatic sites was available. Patients with recurrences in the breast or axilla were excluded. ER, PR and HER-2/neu status in the primary and metastasis were compared. Additional information including adjuvant therapy and time to metastasis biopsy was gathered. Results: To date, data is available on 80 patients. Hormone receptor (HR) status was available for 96% of primaries and 56% of metastases. HR status on both the primary and the metastasis was performed in 51% of cases. The discordance rate for ER was 21% (2-sided p=0.0096). 12% of patients changed from ER+ to ER- and 9% changed from ER- to ER+. The discordance rate for PR was 37% (2-sided p=0.0001), with all of these patients changing from PR+ to PR-. No significant HR discordance was found among different adjuvant hormone therapy subgroups. There was no correlation between HR discordance and time to rebiopsy. No discordance for HER-2/neu was found. Conclusions: Significant discordance for HR status was observed, 21% for ER and 37% for PR. HER-2/neu discordance was not observed. We are currently exploring the practical implications of these discordance rates on the management of advanced breast cancer patients in a prospective trial. No significant financial relationships to disclose.