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Background: Despite widespread use of repeated doses of potent bone-targeting agents (BTA) in oncology patients, relatively little is known about their in vivo effects on bone homeostasis, bone quality, and bone architecture. Traditionally bone quality has been assessed using a trans-iliac bone biopsy with a 7 mm “Bordier” core needle. We examined the feasibility of using a 2 mm “Jamshidi™” core needle as a more practical and less invasive technique. Methods: Patients with metastatic breast cancer on BTAs were divided according to the extent of bone metastases. They were given 2 courses of tetracycline labeling and then underwent a posterior trans-iliac trephine biopsy and bone marrow aspirate. Samples were analyzed for the extent of tumor invasion and parameters of bone turnover and bone formation by histomorphometry. Results: Twelve patients were accrued, 1 had no bone metastases, 3 had limited bone metastases (LSM) (3 lesions). Most of the primary tumors were estrogen receptor (ER)/progesterone receptor (PR) positive. The procedure was well tolerated. The sample quality was sufficient to analyze bone trabecular structure and bone turnover by histomorphometry in 11 out of 12 patients. There was a good correlation between imaging data and morphometric analysis of tumor invasion. Patients with no evidence or minimal bone metastases had no evidence of tumor invasion. Most had suppressed bone turnover and no detectable bone formation when treated with BTA. In contrast, 6 out of 7 patients with extensive bone invasion by imaging and evidence of tumor cells in the marrow had intense osteoclastic activity as measured by the number of osteoclasts. Of these 7 patients with ESM, 6 were treated with BTA with 5 showing resistance to BTA as demonstrated by the high number of osteoclasts present. 3 of these 6 patients had active bone formation. Based on osteoblast activity and bone formation, 3 out of 6 patients with ESM responded to BTA compared to all 3 with LSM. Compared to untreated patients, all patients treated with BTA showed a trend towards suppression of bone formation, as measured by tetracycline labelling. There was also a trend towards a significant difference between ESM and LSM treated with BTA, highly suggestive of resistance although limited by the small sample size. Discussion: Our results indicate that trans-iliac bone biopsy using a 2 mm trephine shows excellent correlation between imaging assessment of tumor invasion and tumor burden by morphometric analysis of bone tissues. In addition, our approach provides additional mechanistic information on therapeutic response to BTA supporting the current clinical understanding that the majority of patients with extensive bone involvement eventually fail to suppress bone turnover (Petrut B, et al. 2008). This suggests that antiresorptive therapies become less effective as disease progresses.

Objectives. To determine the spectrum of mutations in the Mediterranean fever gene (MEFV) of Iranian Jews with familial Mediterranean fever (FMF) and to analyse their clinical manifestations. Methods. FMF patients with both parents of Iranian-Jewish (IJ) extraction or with one IJ parent (IJ–other, 10 of each) were characterized for clinical manifestations, and the B30.2 (PRYSPRY) domain of their MEFV was sequenced for mutations. Results. Only one rare mutation, R653H, and one new mutation, G632S were present in the IJ group (in 2/10 patients), whereas the new, and common mutations were present in the IJ–other patients (8/10 patients). The new mutation was traced thrice to an IJ ancestor, and although carried asymptomatically by family members, it was over-represented in the patients (3/28 unrelated IJ alleles) compared non-affected IJ subjects (1/126 alleles, P = 0.03) or with non-Jewish Iranians (0/108 alleles, P = 0.001). The mutation was associated with a distinct phenotype regarding sites involved in the attack (P = 0.001), mild severity, sole expression of febrile episodes (P = 0.01) and a male bias (P = 0.01). In two 3D PRYSPRY models the G632S mutation was localized to a surface loop and close to a putative binding site. Conclusions. Iranian Jews with FMF have a unique spectrum of mutations including a newly described mutation with a non-typical phenotype. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the association between the HER2 score as provided by the Oncotype DX Recurrence Score (RS) assay, tumor characteristics, and outcomes in early-stage, ER + HER2-negative breast cancer (BC)., Methods: All women insured by the Clalit Health Services, with early-stage, ER + HER2-negative BC who underwent RS testing between 2008 and 2011 were included. Patient/tumor characteristics and Kaplan-Meier estimates for distant recurrence-free survival (DRFS) and overall survival (OS) were compared by HER2 category, based on the HER2 score provided by the RS assay: lower HER2 score group representing the lower third of the HER2 score range (≤ 8.5); higher HER2 score group representing the upper 2 thirds of the HER2 score range (8.6-10.7)., Results: 1535 patients were included (948 node negative, 587 node positive); 330 (21.5%) were categorized as lower HER2 score and 1205 (78.5%) as higher HER2 score. Compared to the higher HER2 score group, the lower score group included a significantly higher proportion of patients with RS ≥ 26 in both node-negative (41% vs. 13.6%, P < .001) and node-positive diseases (36% vs. 19.4%, P < .001). Compared to the higher HER2 score group, the lower score group had significantly lower Oncotype ER and PR scores and lower proportion of lobular disease. Age and tumor size were comparable between the HER2 score groups. Within each RS category, DRFS and OS were not associated with the HER2 score., Conclusion: Lower HER2 score was associated with higher RS results. Further study is desired to elucidate the role and significance of HER2 expression in early-stage, ER + HER2-negative., Competing Interests: Declarations Competing interests Author HG reports personal fee from: AstraZeneca (Honorarium), Gilead (Honorarium and consulting), Eli-Lilly (Honorarium and consulting), MSD (Honorarium and consulting), Novartis (Honorarium and consulting), Pfizer (Honorarium and consulting), Roche (Honorarium), Rhenium Oncotest (Honorarium and consulting), all not related to the submitted manuscript. Author RY reports personal fees from: Roche (consulting, invited speaker, Research grant), Pfizer (consulting), Novartis (consulting, invited speaker), Rhenium (consulting), Medison (invited speaker), MSD (consulting, invited speaker), Astra-Zeneca (consulting, invited speaker), Eli Lilly (consulting, invited speaker), Gilead (consulting), Stemline (invited speaker, consulting) all not related to submitted manuscript. Author SPS reports: Roche (consultancy, advisory board, speaker's bureau, travel grant), Novartis (consultancy, advisory board, speaker's bureau), Pfizer (consultancy, advisory board, speaker's bureau, travel grant, Institutional independent research grant), Astra-Zeneca (consultancy, advisory board, speaker's bureau), Gilead (consultancy, advisory board, speaker's bureau, travel grant), Eli Lily (consultancy, advisory board, speaker's bureau), MSD (consultancy, advisory board, speaker's bureau), Stemline (consultancy), all via institutional fees and not related to the submitted manuscript. Author AS reports: Roche(consultancy, advisory board, speaker's bureau, travel grant), Novartis (consultancy, advisory board, speaker's bureau), Pfizer (consultancy, advisory board, speaker's bureau, travel grant, institutional independent research grant), Astra-Zeneca (consultancy, advisory board, speaker's bureau), Gilead (consultancy, advisory board, speaker's bureau, travel grant), Lily (consultancy, advisory board, speaker's bureau), MSD (consultancy, advisory board, speaker's bureau), Stemline (consultancy), all via institutional fees and not related to the submitted manuscript. Author AS reports: Eli Lilly (consulting, advisory board, speakers bureau), Pfizer (consulting, advisory board, speakers bureau), Roche (consulting, advisory board, speakers bureau, research grant), Novartis (consulting, advisory board, speakers bureau, research grant), Gilead (consulting, advisory board), MSD (consulting, advisory board, speakers bureau, travel grant), Astra-Zenca (consulting, advisory board), Progenetics (consulting, advisory board), Rhenium (consulting, advisory board), Neopharm (travel grant), Celgene (travel grant), Medison (travel grant), all not related to the submitted work. Author ABS reports being a consultant for Oncotest Rhenium, and Exact Sciences, related to the submitted manuscript, and to Pfizer, Can-Fite, and MDI, not related to the submitted manuscript. Author SMS reports: research grant from Can-Fite, AstraZeneca, Bioline RX, BMS, Halozyme, Clovis Oncology, CTG Pharma, Exelexis, Geicam, Halozyme, Incyte, Lilly, Moderna, Teva pharmaceuticals, and Roche, and owning stocks and options in CTG Pharma, DocBoxMD, Tyrnovo, VYPE, Cytora, and CAN-FITE, all not related to the submitted manuscript. All other authors have no conflicts of interest. This study was funded by Oncotest-Rhenium. The funder played no role in the design and conduct of the analysis or its interpretation, and the decision to submit the manuscript for publication., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Whether germline BRCA (gBRCA) pathogenic variants (PV) affect prognosis of women with triple negative breast cancer (TNBC) and whether it has implications for treatment decisions in the neoadjuvant setting is unclear., Methods: This is a retrospective two-center cohort study comprising all women with early stage TNBC who have completed genetic testing and were treated with neoadjuvant dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and carboplatin. All eligible patients treated between 10.2014 and 3.2020 were included. Data on clinico-pathological, pathological response, overall survival (OS) and disease-free survival (DFS) were evaluated. Differences in clinico-pathological features and outcomes were analyzed according to gBRCA status., Results: Sixty-four women were included in the final analysis, of which 31 had gBRCA PV (gBRCA carriers) and 33 were gBRCA wild-type. Clinico-pathological characteristics were similar between both groups. The odds for pathological complete response (pCR) were significantly higher in gBRCA carriers (74.2%) compared to BRCA wild-type women (48.5%), p = 0.035. At a median follow-up of 30 months, gBRCA carriers had significantly favorable OS (HR = 8.64, 95% CI 1.08-69.21, p = 0.042). The difference in DFS did not reach statistical significance (HR = 7.4, 95% CI 0.91-60.27, p = 0.062). The favorable OS for gBRCA carriers remained significant in multivariate analysis (p = 0.029) and was noted regardless of pathological response (p = 0.018)., Conclusion: Compared to wild-type, gBRCA carriers with locally advanced TNBC treated with neoadjuvant chemotherapy containing carboplatin had a higher pCR rate and better outcomes. These results strengthen the contention that gBRCA status should be considered when tailoring treatment decisions in women with locally advanced TNBC., (© 2024. The Author(s).)

Data on adjuvant chemotherapy (CT) benefit in ER + HER2‒ early-stage breast cancer (EBC) patients with Recurrence Score (RS) 26-30 are limited. This real-world study evaluated the relationships between the RS, adjuvant treatments, and outcomes in 534 RS 26-30 patients tested through Clalit Health Services (N0: n = 394, 49% CT-treated; N1mi/N1: n = 140, 62% CT-treated). The CT-treated and untreated groups were imbalanced (more high-risk clinicopathologic characteristics in CT-treated patients). With median follow-up of 8 years, Kaplan-Meier estimates for overall survival (OS), distant recurrence-free survival (DRFS), and BC-specific mortality (BCSM) were not significantly different between CT-treated and untreated N0 patients. Seven-year rates (95% CI) in CT-treated vs untreated: OS, 97.9% (94.4-99.2%) vs 97.9% (94.6-99.2%); DRFS, 91.5% (86.6-94.7%) vs 91.2% (86.0-94.6%); BCSM, 0.5% (0.1-3.7%) vs 1.6% (0.5-4.7%). For N1mi/N1 patients, OS/DRFS did not differ significantly between treatment groups; whereas BCSM did (1.3% [0.2-8.6%] vs 6.2% [2.0-17.7%] for CT-treated and untreated patients, respectively, p = 0.024)., (© 2023. The Author(s).)

Background: Despite widespread use of repeated doses of potent bone-targeting agents (BTA) in oncology patients, relatively little is known about their in vivo effects on bone homeostasis, bone quality, and bone architecture. Traditionally bone quality has been assessed using a trans-iliac bone biopsy with a 7 mm "Bordier" core needle. We examined the feasibility of using a 2 mm "Jamshidi™" core needle as a more practical and less invasive technique., Methods: Patients with metastatic breast cancer on BTAs were divided according to the extent of bone metastases. They were given 2 courses of tetracycline labeling and then underwent a posterior trans-iliac trephine biopsy and bone marrow aspirate. Samples were analyzed for the extent of tumor invasion and parameters of bone turnover and bone formation by histomorphometry., Results: Twelve patients were accrued, 1 had no bone metastases, 3 had limited bone metastases (LSM) (<3 lesions) and 7 had extensive bone metastases (ESM) (>3 lesions). Most of the primary tumors were estrogen receptor (ER)/progesterone receptor (PR) positive. The procedure was well tolerated. The sample quality was sufficient to analyze bone trabecular structure and bone turnover by histomorphometry in 11 out of 12 patients. There was a good correlation between imaging data and morphometric analysis of tumor invasion. Patients with no evidence or minimal bone metastases had no evidence of tumor invasion. Most had suppressed bone turnover and no detectable bone formation when treated with BTA. In contrast, 6 out of 7 patients with extensive bone invasion by imaging and evidence of tumor cells in the marrow had intense osteoclastic activity as measured by the number of osteoclasts. Of these 7 patients with ESM, 6 were treated with BTA with 5 showing resistance to BTA as demonstrated by the high number of osteoclasts present. 3 of these 6 patients had active bone formation. Based on osteoblast activity and bone formation, 3 out of 6 patients with ESM responded to BTA compared to all 3 with LSM. Compared to untreated patients, all patients treated with BTA showed a trend towards suppression of bone formation, as measured by tetracycline labelling. There was also a trend towards a significant difference between ESM and LSM treated with BTA, highly suggestive of resistance although limited by the small sample size., Discussion: Our results indicate that trans-iliac bone biopsy using a 2 mm trephine shows excellent correlation between imaging assessment of tumor invasion and tumor burden by morphometric analysis of bone tissues. In addition, our approach provides additional mechanistic information on therapeutic response to BTA supporting the current clinical understanding that the majority of patients with extensive bone involvement eventually fail to suppress bone turnover (Petrut B, et al. 2008). This suggests that antiresorptive therapies become less effective as disease progresses., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Background: The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial., Patients and Methods: The databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013-2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile., Results: The study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36-0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4-1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5-1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2-0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2-0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39-1.23)] or the subgroups., Conclusions: Patients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.

Objectives: To examine the nature of the symptom cluster of emotional distress, fatigue, and cognitive difficulties in young and older breast cancer survivors (BCS); To assess the mediating role of subjective stress and coping strategies (emotional control and meaning-focused coping) in the association between age and symptom cluster., Materials and Methods: Participants were 170 BCS, stages I-III, 1-12 months post-chemotherapy, filled-out the Fatigue, Emotional Control, Meaning-focused Coping, Emotional Distress and the Cognitive Difficulties Questionnaires. Statistical analyses included tests for difference between-groups Pearson correlations and Structural Equation Modeling for the assessment of the study model., Results: Older BCS (aged 60-82) reported lower levels of emotional distress (M = 0.87, SD = 0.87), fatigue (M = 3.85, SD = 2.38), and cognitive difficulties (M = 1.17, SD = 1.07) compared to the younger BCS (aged 24-59) (emotional distress M = 1.17, SD = 0.85, fatigue M = 5.02, SD = 2.32, and cognitive difficulties M = 1.66, SD = 1.23, p < .01-,05). The older survivors reported lower levels of subjective stress and used more emotional control strategies compared to the younger BCS. The empirical model had good fit indices (χ2 = 27.60, p = 0.20, χ2/df = 1.26; CFI = 0.98; TLI = 0.98; NFI = 0.95; RMSEA = 0.04 (90% CI = 0.00, 10) and showed that subjective stress, but not coping strategies, mediated the effect of age on symptom cluster severity., Conclusions: Lower levels of subjective stress, but not coping strategies, mediated the association of age with the symptom cluster of emotional distress, fatigue and cognitive difficulties. Further research is needed to explore differences in subjective stress by age., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: The addition of carboplatin (Cb) to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) has been demonstrated to improve pathologic complete response (pCR) at the expense of increased toxicity. We aimed to evaluate the effectiveness and tolerability of dose-dense anthracycline & cyclophosphamide (ddAC) followed by weekly paclitaxel (wT) in combination with weekly Cb., Methods: Retrospective data was collected on patients with clinical stage I-III TNBC treated with neoadjuvant ddAC-wTCb (four cycles of ddA 60 mg/m 2 and ddC 600 mg/m 2 every 2 weeks followed by 12 cycles of wT 80 mg/m 2 with Cb AUC 1.5). Indices of tolerability and pCR were evaluated and compared to a historical cohort (n = 76) treated with ddAC-T. A secondary objective was to evaluate the rates of pCR by BRCA status., Results: For 43 eligible patients, mean age was 41.5 years, 51% had clinical stage II disease, 81.4% were clinically node positive and 32.6% carried a deleterious BRCA1 mutation. Only 35% completed all scheduled doses of chemotherapy. Grade 3/4 neutropenia was observed in 42.5% of patients. Overall pCR was 51.2%; 44.8% in BRCA wild-type compared to 64.3% in BRCA-associated TNBC (p = 0.232). pCR rates with ddAC-wTCb were similar to historic institutional rates with ddAC-T (51.2% vs. 51.3%, p = 0.987) and were comparable when stratified by BRCA status. In pooled multivariate analysis, only BRCA status (HR 4.00, 95%CI 1.65-9.75, p = 0.002) was significantly associated with pCR., Conclusion: Neoadjuvant ddAC-wTCb is less tolerable in clinical practice compared to most clinical trials, with a pCR comparable to historic rates using non-platinum regimen. The role of Cb in neoadjuvant chemotherapy for BRCA mutated TNBC remains uncertain., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Discordance in estrogen (ER), progesterone (PR), and HER2/neu status between primary breast tumours and metastatic disease is well recognized. In this review, we highlight how receptor discordance between primary tumours and paired metastasis can help elucidate the mechanism of metastasis but can also effect patient management and the design of future trials. Discordance rates and ranges were available from 47 studies (3384 matched primary and metastatic pairs) reporting ER, PR, and HER2/neu expression for both primary and metastatic sites. Median discordance rates for ER, PR, and HER2/neu were 14 % (range 0-67 %, IQR 9-25 %), 21 % (range 0-62 %, IQR 15-41 %), and 10 % (range 0-44 %, IQR 4-17 %), respectively. Loss of receptor expression was more common (9.17 %) than gain (4.51 %). Discordance rates varied amongst site of metastasis with ER discordance being highest in bone metastases suggesting that discordance is a true biological phenomenon. Discordance rates vary for both the biomarker and the metastatic site. Loss of expression is more common than gain. This can affect patient management as it can lead to a reduction in both the efficacy and availability of potential therapeutic agents. Future studies are recommended to explore both the mechanisms of discordance as well as its impact on patient outcome and management.

Introduction: The accrual rate to clinical trials in oncology remains low. In this exploratory pilot study, we prospectively assessed the role that engaging a referring surgeon plays in enhancing nonsurgical oncologic clinical trial accrual., Methods: Newly diagnosed breast cancer patients were seen by a surgeon who actively introduced specific patient-and physician-centred strategies to increase clinical trial accrual. Patient-centred strategies included providing patients, before their oncology appointment, with information about specific clinical trials for which they might be eligible, as evaluated by the surgeon. The attitudes of the patients about clinical trials and the interventions used to improve accrual were assessed at the end of the study. The primary outcome was the clinical trial accrual rate during the study period., Results: Overall clinical trial enrolment during the study period among the 34 participating patients was 15% (5 of 34), which is greater than the institution's historical average of 7%. All patients found the information delivered by the surgeon before the oncology appointment to be very helpful. Almost three quarters of the patients (73%) were informed about clinical trials by their oncologist. The top reasons for nonparticipation reported by the patients who did not participate in clinical trials included lack of interest (35%), failure of the oncologist to mention clinical trials (33%), and inconvenience (19%)., Conclusions: Accrual of patients to clinical trials is a complex multistep process with multiple potential barriers. The findings of this exploratory pilot study demonstrate a potential role for the referring surgeon in enhancing nonsurgical clinical trial accrual.

Previous studies suggest switching from pamidronate to a more potent bone-targeted agent is associated with biomarker and palliative response in breast cancer patients with bone metastases. Until now, this has not been addressed in a double-blind, randomized trial. Breast cancer patients with high-risk bone metastases, despite >3 months of pamidronate, were randomized to either continue pamidronate or switch to zoledronic acid every 4 weeks for 12 weeks. Primary outcome was the proportion of patients achieving a fall in serum C-telopeptide (sCTx) at 12 weeks. Secondary outcomes included difference in mean sCTx, pain scores, quality of life, toxicity, and skeletal-related events (SREs). Seventy-three patients entered the study; median age 61 years (range 37-87). Proportion of patients achieving a fall in sCTx over the 12-week evaluation period was 26/32 (81 %) with zoledronic acid and 18/29 (62 %) with pamidronate (p = 0.095). Mean decrease in sCTx (mean difference between groups = 50 ng/L, 95 % CI 18-84; p = 0.003) was significantly greater in patients who received zoledronic acid. Quality of life, pain scores, toxicity, and frequency of new SREs were comparable between the two arms. While a switch from pamidronate to zoledronic acid resulted in reduction in mean sCTx, there were no significant differences between the arms for proportion of patients achieving a reduction in sCTx, quality of life, pain scores, toxicity or SREs. Given the lack of palliative improvement, the current data do not support a switching strategy.

Background: Despite consensus recommendations for antiemetics in breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy, control of chemotherapy-induced nausea and vomiting (CINV) remains sub-optimal., Objective: To inspect available evidence from randomized controlled trials (RCT) in this population to establish treatment comparisons that have been studied, outcomes that have been reported, and the extent of study heterogeneity. Review of this data helps identify challenges for a systematic review comparing antiemetic regimens, and to identify potential future trials., Methods: A search of Ovid MEDLINE®, Embase and Cochrane CENTRAL was performed. We sought RCTs comparing antiemetic regimens in breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy. We extracted information related to study design, patient characteristics and interventions compared. Patterns of outcome reporting were studied. While performing network meta-analysis was also of interest, studies were judged highly heterogeneous and it was felt findings from such work would be of uncertain validity., Results: From 1062 citations, a total of 30 full texts were retained. Overall, 47 antiemetic regimens were evaluated using 15 different CINV endpoints. Treatment comparisons were diverse and many were informed by single small trials. Reporting of key endpoints was varied and all endpoints were not consistently available. Heterogeneity in patients, chemotherapies administered, and intervention doses were noted., Conclusions: Despite the availability of consensus recommendations for antiemetic use, we identified challenges in synthesizing the evidence base including high diversity in treatment comparisons, varied outcome reporting, and study heterogeneity. These represent challenges to identifying an optimal antiemetic regimen. Future antiemetic trials should incorporate more informed comparator selection, report patient-oriented outcomes in a standard fashion, and provide accessible data for these measures., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Introduction: Non-small cell lung cancer (NSCLC) is the leading global cause of cancer death. While bone metastases (BM) commonly cause morbidity, bone-targeted agent (BTA) use is variable. We investigated the incidence and impact of BM among unselected NSCLC patients., Methods: A retrospective chart review of all NSCLC patients seen at a single institution from January 2007 to January 2008 was performed. Various clinical and pathology data were collected. In BM patients, skeletal related events (SRE), interventions and outcomes were recorded., Results: We identified 383 patients; median age 68 (IQR 60-76); 54% female. Initially 156 patients (41%) were treated with curative intent of whom 91 subsequently relapsed; 227 (59%) were considered palliative from time of diagnosis, including 22 with early stage disease not amenable to radical therapy. Of 296 patients with advanced NSCLC, common metastatic sites were: lung/pleura (80%), mediastinal nodes (69%), bone (39%), brain (30%), and liver (24%). Of 118 patients with BM, 69 (59%) had ≥1 SREs (range 1-18). Common SREs were radiotherapy (63%), pathologic fractures (22%), spinal cord compression (6%) or surgery to bone (5%). Opioid analgesia was required in 69% of BM patients, only 6% of patients with BM received BTA. Overall survival (OS) in pts with mNSCLC was 7.3 months (IQR 3.1-20.5). Pts with BM had significantly shorter OS compared to those without BM (5.8 versus 10.2 months, p=0.03)., Conclusions: BM are common in patients with advanced NSCLC and associated with shorter survival. In this cohort, despite SREs occurred in many patients, BTA were rarely used., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Renal cell carcinona is the most common kidney tumor. In Israel more than 600 cases are diagnosed annually. Risk factors for renal cell carcinoma include obesity, smoking, hypertension, and diabetes; 20-30% of the patients are diagnosed with metastatic disease, and 70-80% of patients are diagnosed with an early non-metastatic tumor. The treatment of an early non-metastatic tumor is resection. At present, the role of adjuvant systemic therapy has not been established; 20-40% of the patients operated on for an early tumor will suffer from metastatic disease recurrence. The lungs are the most common site of metastases. Renal cell carcinoma is relatively refractory to chemotherapy and radiation. In the last decade, an improved understanding of the biology of the tumor, led to the development of biologic therapies targeting specific molecular mechanisms involved in the process of the disease, and a significant expansion of treatment horizon in these patients. The biologic therapies for metastatic renal cell carcinoma belong to two main groups: angiogenesis inhibitors (VEGF-R inhibitors like sunitinib, sorafenib, pazopanib and axitinib), and inhibitors of the mTOR protein (everolimus and temsirolimus). These biologic therapies led to a significant improvement in the patients' survival. Nonetheless, these therapies are associated with a unique profile of side effects like hypertension, mucositis, and hand-foot syndrome with VEGF-R inhibitors therapy, and non-infectious pneumonitis with mTOR inhibitors therapy. The present review will focus on the modern approach to metastatic renal cell carcinoma.

Background: The waiting period to surgery represents a valuable "window of opportunity" to evaluate novel therapeutic strategies. Interventional studies performed during this period require significant multidisciplinary collaboration to overcome logistical hurdles. We undertook a one-year prospective window of opportunity study to assess feasibility., Methods: Eligible newly diagnosed postmenopausal, estrogen receptor positive breast cancer patients awaiting primary surgery received anastrozole daily until surgery. Feasibility was assessed by (a) the proportion of patients who consented and (b) completed the study. Comparison of pre- and poststudy Ki67 labelling index and cleaved caspase 3 scores (CC3) was performed., Results: 22/131 (16.8%) patients were confirmed eligible and 20/22 (91%) patients completed the study. 19/20 (95%) patients agreed to undergo optional additional tissue biopsies. The mean duration of anastrozole use was 24.7 (15-44) days. There were a statistically significant decline in mean Ki67 indices of 48.8% (p < 0.001) and a trend towards significance in the decline of CC3 (p = 0.17) when comparing pre- with posttreatment values., Conclusion: window of opportunity trials in breast cancer are a feasible way of assessing the biologic efficacy of different therapies in the presurgical setting. The majority of eligible women were willing to participate including undergoing additional tissue biopsies.

Objective: To evaluate the safety and efficacy of tamoxifen co-administration during conventional controlled ovarian hyperstimulation (COH) protocols for a fertility-preservation IVF cycle in breast cancer patients., Design: Two groups: retrospective descriptive cohort study and prospective study., Setting: Breast cancer oncology and fertility-preservation centers in a tertiary hospital., Patient(s): Two groups of breast cancer patients: premenopausal patients treated with adjuvant tamoxifen; and patients undergoing in vitro fertilization (IVF) for fertility preservation., Intervention(s): Fertility-preservation cycles, tamoxifen co-administration during conventional IVF., Main Outcome Measure(s): Endocrine records, and IVF results., Result(s): Estradiol (E2) levels were chronically high (mean 2663 pmol/L, maximum: 10,000 pmol/L) in 38 of 46 breast cancer patients treated with adjuvant tamoxifen. Co-administration of tamoxifen (48 cycles) during conventional IVF or without tamoxifen (26 cycles), using either the long gonadotropin-releasing hormone-agonist or-antagonist protocols, resulted, respectively, in a mean of 12.65 and 10.2 oocytes retrieved, and 8.5 and 6.4 embryos cryopreserved. Average peak E2 levels were 6,924 pmol/L and 5,093 pmol/L, respectively, but long-term recurrence risk (up to 10 years) was not increased., Conclusion(s): In breast cancer patients, co-administration of tamoxifen during conventional COH for fertility preservation does not interfere with IVF results. The high serum E2 levels during COH should be considered safe, as it simulates the high prevalence of persistently high serum E2 levels in premenopausal breast cancer patients safely treated with adjuvant tamoxifen., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The optimal frequency of intravenous (IV) bisphosphonate administration is unclear. We thus performed a study evaluating the effects of switching from 3-4 to 12 weekly therapy in patients with biochemically defined low-risk bone metastases. Patients with serum C-telopeptide (CTx) levels ≤600 ng/L after ≥3 months of 3-4 weekly IV pamidronate were switched to 12 weekly therapy for 48 weeks. Primary endpoint was the proportion of patients maintaining CTx levels in the lower-risk range. All endpoints (serum CTx and bone-specific alkaline phosphatase (BSAP), skeletal-related events (SREs) and self-reported pain) were measured at baseline, 6, 12, 24, 36 and 48 weeks. Treatment failure was defined as biochemical failure (CTx > 600 ng/L) or a SRE. Exploratory biomarkers including; serum TGF-β, activin-A, bone sialoprotein (BSP), procollagen type 1 N-terminal propeptide and urinary N-telopeptide (NTx) were assessed at baseline as predictors for failure to complete treatment. Seventy-one patients accrued and 43 (61 %) completed 48 weeks of de-escalated therapy. Reasons for failure to complete treatment included; biochemical failure (CTx > 600 ng/L) (n = 10, 14.1 %), on-study SRE (n = 9, 12.7 %), disease progression (n = 7, 9.9 % including death from disease [n = 1, 1.4 %]) or patient choice (n = 2, 2.8 %). Elevated baseline levels of CTx, BSAP, NTx and BSP were associated with treatment failure. The majority of patients in this biochemically defined low-risk population could switch from 3-4 weekly to 12 weekly bisphosphonate therapy with no effect on CTx levels or SREs during the 48 week study. Larger trials are required to assess the roles of biomarkers as predictors of adequacy of de-escalated therapy.

Objective: Our objective was to evaluate preferences associated with grade I/II and grade III/IV chemotherapy side effects among breast cancer patients receiving chemotherapy. We also assessed trade-offs that patients are willing to make between treatment side effects and the route and schedule of treatment administration., Methods: In this cross-sectional study, patients receiving chemotherapy for breast cancer completed a one-time Web survey. Conjoint analysis was used to elicit preferences for 17 grade I/II and III/IV side effects associated with available chemotherapies and regimens. In the analysis, the risk of each side effect was increased by 5%, holding all others constant, and the respective impact on patient preferences was identified., Results: A total of 102 women participated (mean age 54 ± 11). Among the grade I/II side effects, a 5% reduction in the risk of sensory neuropathy, nausea, and motor neuropathy had the highest impact on preferences. Among grade III/IV side effects, motor neuropathy, nausea/vomiting, and myalgia made the most difference. An oral twice-daily regimen was most preferred; however, patients were willing to receive an intravenous regimen relative to oral to avoid an increased risk of 5% in the majority of side effects. Avoiding an increased chance of grade III/IV motor neuropathy was associated with willingness to tolerate one of the least preferred administration schedules., Conclusion: This study identified relative preferences among both mild/moderate to severe side effects from the patient perspective. Patients appear to be willing to make trade-offs between side effects and different regimens. These findings may help to inform medical decision-making processes.

Perceptions among women with breast cancer about the relative importance of different potential chemotherapy side effects is not well understood. A survey was performed by women receiving chemotherapy for breast cancer. Grade I/II (mild to moderate) and III/IV (moderate to severe) descriptions of nine common chemotherapy side effects were assigned preference weights using the standard gamble technique. For each hypothetical side effect, patients could choose to stay in the respective side effect state or take a gamble between full health (probability p) or being dead (1 - p). For each side effect, p was varied until the patient was indifferent between these options. The survey also included questions about the importance of survival, slowing cancer growth, and quality of life. This analysis included 69 patients; mean age 54 years (range 35-84), representing all cancer stages. Standard gamble preferences were lowest (i.e., least preferred) for grade III/IV nausea/vomiting (0.621), indicating that patients would, on average, risk a 38 % chance of being dead to avoid having grade III/IV nausea/vomiting for the rest of their lives. The next least preferred side effects were grade III/IV diarrhea (0.677) and grade III/IV sensory neuropathy (0.694). Survival appeared more important than slowing cancer growth and maintaining quality of life across cancer stages. Nevertheless, patients with advanced disease placed less importance on survival (p = 0.09) and higher importance on quality of life (p = 0.05). These standard gamble utilities provide unique insights into chemotherapy toxicities from the patient perspective. Differences in the relative importance of overall survival and quality of life with treatment existed between patients with different stages of disease. These studies should be expanded as the data may also be used to calculate quality-adjusted life expectancy in cost-effectiveness evaluations of breast cancer chemotherapies.

Background: There is a paucity of literature about the benefits of bone-targeted agents for breast cancer patients with bone metastases treated in the non-trial setting. We explored the incidence, consequences, and treatment of bone metastases at a single cancer centre., Methods: Electronic records of metastatic breast cancer patients were reviewed and pertinent information was extracted., Results: Of 264 metastatic breast cancer patients, 195 (73%) developed bone metastases. Of these patients, 176 were eligible for analysis. Median age at bone metastases diagnosis was 56.9 years (IQR 48-67) and initial presentation of bone metastases included asymptomatic radiological findings (58%), bone pain (40%), or a SRE (12.5%). Most patients (88%) received a bone-targeted agent, starting a median of 1.5 months (IQR 0.8-3.30) after bone metastasis diagnosis. 62% of patients had ≥1 SRE. The median time from bone metastasis diagnosis to first SRE was 1.8 months (IQR 0.20-8.43 months). Median number of SREs per patient was 1.5 (IQR 0-3). Overall, 26.8% of all SREs were clinically asymptomatic. Within the entire cohort, 51% required opioids and 20% were hospitalized due to either an SRE or bone pain., Conclusions: Despite extensive use of bone-targeted agents, the incidence of SREs remains high. Nearly half of SREs occur prior to starting a bone-targeted agent. Use of opioids and hospitalizations secondary to bone metastases remain common. More effective treatment options are clearly needed.

Despite advances in adjuvant therapy for breast cancer, bone remains the most common site of recurrence. The goal of therapy for these patients is palliative and focused on maximizing the duration and quality of their life, while concurrently minimizing any disease or treatment-related complications. Bone metastases predispose patients to reduced survival, pain, impaired quality of life and the development of skeletal-related events. With an increased understanding of the pathophysiology of bone metastasis, effective treatments for their management have evolved and are now in widespread clinical use. This article will discuss the pathogenesis of bone metastases and review the key clinical evidence for the efficacy and safety of currently available systemic bone-targeted therapies in breast cancer patients with an emphasis on bisphosphonates and the receptor activator of nuclear factor kappa B ligand (RANKL) inhibitors. We will also discuss novel strategies and therapies currently in development.

Background: The Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy-Bone Pain (FACT-BP) are commonly used measures of patient reported pain outcomes. We report on the performance of the FACT-BP in comparison to the BPI within a small, randomized trial., Methods: Patients with biochemically defined low risk bone metastases were randomized to 4 weekly (control arm) or 12 weekly (de-escalating arm) pamidronate for 1 year. FACT-BP, BPI and serum markers of bone turnover were recorded at baseline and weeks 12, 24, 36 and 48. Mixed effects models were used to compare scores over time between arms. Correlation coefficients were calculated to evaluate the association between FACT-BP and BPI scores, as well as with markers of bone turnover., Results: Nineteen patients were randomized to each study arm. Pain scores determined by the two instruments were moderately to highly correlated with each other. Baseline C-telopeptide (CTx) level was correlated with baseline FACT-BP and BPI scores. Baseline bone-specific alkaline phosphatase showed a non-significant association with pain scores. There were no correlations between the markers of bone turnover and pain scores at week 12., Conclusions: In the current study the FACT-BP and BPI correlated well with each other, and with baseline CTx. The possibility of linking subjective pain scores with objective biomarkers of response requires more investigation.

Bone remains the most common site of breast cancer recurrence. The results of population studies, pre-clinical research and clinical studies in patients with metastatic disease provided a rationale for testing bone-targeted agents in the adjuvant setting. Despite the initial optimism, results from eight prospectively designed, randomized control studies powered to assess the value of adjuvant bone-targeted therapy in early breast cancer are conflicting. Data have shown that, where benefit exists, it tends to be in women with a "low estrogen environment", either through menopause or suppression of ovarian function. In this manuscript, we review clinical data supporting the hypothesis that estrogen levels may play a part in explaining the response of patients to bone-targeted agents in the adjuvant setting. The results presented to date suggest that there may be data supporting a unifying role for estrogen in adjuvant trials. However, in the absence of any prospective randomized trials in which estrogen data has been systematically collected we cannot specifically answer this question. We await the results of the Oxford overview analysis of individual patient data with interest.

Background: In order to design studies assessing the optimal use of bone-targeted agents (BTAs) patient input is clearly desirable., Methods: Patients who were receiving a BTA for metastatic prostate or breast cancer were surveyed at two Canadian cancer centres. Statistical analysis of respondent data was performed to establish relevant proportions of patient responses., Results: Responses were received from 141 patients, 76 (53.9%) with prostate cancer and 65 (46.1%) with breast cancer. Duration of BTA use was <3 months (15.9%) to >24 months (35.2%). Patients were uncertain how long they would remain on a BTA. While most felt their BTA was given to reduce the chance of bone fractures (77%), 52% thought it would slow tumour growth. Prostate patients were more likely to receive denosumab and breast cancer patients, pamidronate. There was more variability in the dosing interval for breast cancer patients. Given a choice, most patients (49-57%) would prefer injection therapy to oral therapy (21-23%). Most patients (58-64%) were interested in enrolling in clinical trials of de-escalated therapy., Conclusion: While there were clear differences in the types of BTAs patients received, our survey showed similarity for both prostate and breast cancer patients with respect to their perceptions of the goals of therapy. Patients were interested in participating in trials of de-escalated therapy. However, given that patients receive a range of agents for varying periods of time and in different locations (e.g. hospital vs. home), the design of future trials will need to be pragmatic to reflect this.

Background: Bone metastases (BM) are common in NSCLC patients. Despite some potential positive effects of bone-targeted therapies, their use in NSCLC is infrequent, which may relate to the overall poor prognosis of advanced lung cancer. We reviewed the literature to evaluate the incidence, consequences and use of bone-targeting agents in lung cancer patients with BM in both the trial and non-trial clinical setting., Methods: Published prospective and retrospective papers investigating lung cancer and BM, in trial and non-trial settings, were identified and are discussed in this review., Results: BM are common in patients with advanced lung cancer and often present symptomatically with pain and skeletal related events (SREs). Patients with high bone turnover marker levels, multiple BM, and history of pathological fractures have shorter overall survival. In randomized studies bone-targeted therapies reduced the risk of SREs and prolonged the time to first SRE. The use of bone-targeted agents may also be associated with a survival benefit., Conclusion: BM are a common problem in advanced lung cancer. While the benefits of bone-targeted therapies have been demonstrated, their use is limited in non-trial populations. If better predictive markers of individual risk were available this might increase the appropriate use of bone-targeted agents.

Background: Bone-targeted agents such as bisphosphonates and the RANKL antibody have revolutionised the care of patients with bone metastases. There has, however been increasing concern about the oral health of these patients and in particular osteonecrosis of the jaw (ONJ), especially with the increasing use of these agents at higher potencies for greater periods of time., Methods: A review of the published data in PubMed and meeting abstracts was performed to examine incidence, risk factors, pathogenesis, clinical course and management of osteonecrosis of the jaw with focus on cancer patients treated with bone-targeted agents (BTA) for bone metastases. This manuscript takes the most frequent and pertinent questions raised by oncologists, dentists and oral and maxillofacial surgeons and tries to give a pragmatic overview of the literature., Results: The incidence of ONJ varies depending on types of bone-targeted agents, duration of treatment and additional risk factors. The causes and pathogenesis of ONJ is not fully elucidated, however bone-targeted therapy induced impaired bone remodelling, microtrauma secondary to jaw activity, and oral bacterial infection seem to be important factors. Since the treatment options for ONJ are limited and not well established, preventive strategies have to be included in patients management., Conclusions: Many unanswered questions remain about the optimal oral care of patients receiving bone-targeted agents. Prospective data collection will remedy this and help to provide practical guidelines for the management and treatment of those patients that require dental intervention.

Background: Bone-targeted agents are widely used for the treatment of osteoporosis, the prevention of cancer-therapy induced bone loss, and for reducing the risk of skeletal related events in patients with metastatic disease. Despite widespread use, relatively little is known about the in vivo effect of these agents on bone homeostasis, bone quality, and bone architecture in humans. Traditionally bone quality has been assessed using a transiliac bone biopsy with a 7 mm "Bordier" core needle. We examined the possibility of using a 2 mm "Jamshidi" core needle as a more practical and less invasive method to assess bone turnover and potentially other tumor effects., Methods: A pilot study on the feasibility of assessing bone quality and microarchitecture and tumor invasion using a 2 mm bone marrow trephine was conducted. Patients underwent a posterior trans-iliac trephine biopsy and bone marrow aspirate. Samples were analyzed for bone microarchitecture, bone density, and histomorphometry. The study plan was to accrue three patients with advanced breast cancer to assess the feasibility of the study before enrolling more patients., Results: The procedure was well tolerated. The sample quality was excellent to analyze bone trabecular microarchitecture using both microCT and histomorphometry. Intense osteoclastic activity was observed in a patient with extensive tumor burden in bone despite intravenous bisphosphonate therapy., Discussion: Given the success of this study for assessing bone microarchitecture, bone density, and histomorphometry assessment using a 2 mm needle the study will be expanded beyond these initial three patients for longitudinal assessment of bone-targeted therapy.