Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab in early HER2-positive breast cancer in the APHINITY trial.

BACKGROUND: Trastuzumab increases the incidence of cardiac events (CEs) in patients with breast cancer (BC). Dual blockade with pertuzumab (P) and trastuzumab (T) improves BC outcomes and is the standard of care for high-risk human epidermal growth factor receptor 2 (HER2)-positive early BC patients. We analyzed the cardiac safety of P and T in the phase III APHINITY trial. PATIENTS AND METHODS: Left ventricular ejection fraction (LVEF) ≥ 55% was required at study entry. LVEF assessment was carried out every 3 months during treatment, every 6 months up to month 36, and yearly up to 10 years. Primary CE was defined as heart failure class III/IV and a significant decrease in LVEF (defined as ≥10% from baseline and to <50%), or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF, or CEs confirmed by the cardiac advisory board. RESULTS: The safety analysis population consisted of 4769 patients. With 74 months of median follow-up, CEs were observed in 159 patients (3.3%): 83 (3.5%) in P + T and 76 (3.2%) in T arms, respectively. Most CEs occurred during anti-HER2 therapy (123; 77.4%) and were asymptomatic or mildly symptomatic decreases in LVEF (133; 83.6%). There were two cardiac deaths in each arm (0.1%). Cardiac risk factors indicated were age > 65 years, body mass index ≥ 25 kg/m2, baseline LVEF between 55% and <60%, and use of an anthracycline-containing chemotherapy regimen. Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 patients (81.9%). CONCLUSIONS: Dual blockade with P + T does not increase the risk of CEs compared with T alone. The use of anthracycline-based chemotherapy increases the risk of a CE; hence, non-anthracycline chemotherapy may be considered, particularly in patients with cardiovascular risk factors.

Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial.

BACKGROUND: The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life. RESULTS: The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months [95% confidence interval (CI), 7.26-9.07]} versus placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified hazard ratio [HR] 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm. CONCLUSION: SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.

Anthracycline-induced cardiotoxicity in patients with early-stage breast cancer: the Canadian Cancer Trials Group (CCTG) MA.21 experience.

PURPOSE: Anthracyclines are frequently used in adjuvant treatment for early-stage breast cancer (ESBC). The purpose of this study was to evaluate cardiotoxic effects in the first five years after treatment with different anthracycline-based regimens. METHODS: CCTG MA.21 (NCT000142) was a phase III trial in ESBC that compared cyclophosphamide (75 mg/m2) orally for 14 days, epirubicin (60 mg/m2) and fluorouracil, IV days one and eight (CEF) for six cycles; dose-dense epirubicin (120 mg/m2) and cyclophosphamide, IV every 2 weeks for six cycles with concurrent G-CSF then paclitaxel every 2 weeks for four cycles (ddEC/T); doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks for four cycles then four cycles q3 weekly paclitaxel (175 mg/m2) (AC/T). ENDPOINTS: LVEF decline; LV function changes (heart failure), or Grade 3-4 cardiac ischemia/infarction. A competing risk analysis was performed with endpoints of cardiotoxicity or recurrence in first 5 years after completion of chemotherapy. RESULTS: 2104 women were randomized. Compliance with cardiac LVEF assessments was 70% at 5 years in all arms. The 5-year cumulative risks of any cardiac event for CEF, ddECT, and AC/T were 22.3% (95%CI 18.9 to 25.7), 14.2% (95%CI 11.0 to 17.3), and 8.1% (95%CI 5.8 to 10.4), respectively, p < 0.0001. At 5 years, women in the ddEC/T and AC/T group had significantly lower risk of cardiotoxicity than those given CEF (HR 0.599 and 0.371, respectively). Most events were asymptomatic drop in LVEF. CONCLUSIONS: Asymptomatic changes in LVEF accounted for most of the cardiotoxicity. The majority of cardiac events occurred in year one although occurrence of cardiotoxicity over time highlights the need for improved risk stratification to guide cardiac surveillance strategies.

Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Effect of obesity, dyslipidemia, and diabetes on trastuzumab-related cardiotoxicity in breast cancer.

Background: Clinical trials have demonstrated an increased risk of cardiotoxicity in patients with breast cancer (bca) receiving trastuzumab-based therapy. Diabetes, dyslipidemia, and obesity are known risk factors for cardiovascular disease. Studies have yielded conflicting results about whether those factors increase the risk of cardiotoxicity in patients with bca receiving trastuzumab. Methods: In this retrospective cohort study, data were collected for 243 patients with bca positive for her2 (the human epidermal growth factor receptor 2) who were receiving trastuzumab and who were referred to The Ottawa Hospital Cardio-oncology Referral Clinic between 2008 and 2013. The data collected included patient demographics, reason for referral, cardiac function, chemotherapy regimen (including anthracycline use), and 3 comorbidities (diabetes, dyslipidemia, obesity). Rates of symptomatic cancer treatment-related cardiac dysfunction (sctcd) and asymptomatic decline in left ventricular ejection fraction (adlvef) were calculated for patients with and without the comorbidities of interest. Results: Of the 243 identified patients, 104 had either diabetes, dyslipidemia, or obesity. In that population, the most likely reason for referral to the cardio-oncology clinic was adlvef. The combination of 2 or 3 comorbidities significantly increased the incidence of sctcd in our population, reaching a rate of 67% for patients with obesity and dyslipidemia [relative risk (rr): 2.2; p = 0.04], 69% for patients with obesity and diabetes (rr: 2.3; p = 0.02), and 72% for patients with all 3 risk factors (rr: 2.4; p = 0.08). Conclusions: The combination of 2 or 3 comorbidities significantly increases the incidence of symptomatic cancer treatment-related cardiotoxicity. Patients with bca experiencing cancer treatment-related cardiotoxicity who have a history of diabetes, dyslipidemia, and obesity might require more proactive strategies for prevention, detection, and treatment of cardiotoxicity while receiving trastuzumab-based treatment.

Clinical experience of patients referred to a multidisciplinary cardio-oncology clinic: an observational cohort study.

Introduction: Cardiovascular disease is the 2nd leading cause of long-term morbidity and mortality in cancer survivors. Cardio-oncology clinics (cocs) have emerged to address the issue; however, there is a paucity of data about the demographics and clinical outcomes of patients seen in the coc setting. Methods: Cancer patients referred to The Ottawa Hospital coc were included in this retrospective observational study. Data collected were patient demographics, cancer type and stage, reason for referral, cardiac risk factors, cardiac assessments and treatment, and clinical outcomes. Results: Between 2008 and 2015, 779 patients (516 women, 66%; 263 men, 34%) were referred to the coc. Median age of the patients at cancer diagnosis was 60 years (range: 18-90 years). The most frequent reasons for referral were decreased left ventricular ejection fraction (33%), pre-chemotherapy assessment (14%), and arrhythmia (14%). Treatment with cardiac medication was given in 322 patients (41%), 181 (56%) of whom received more than 2 cardiac medications, with 57 (18%) receiving an angiotensin-converting enzyme inhibitor (acei), 46 (14%) receiving an acei and a beta-blocker, and 38 (12%) receiving a beta-blocker. Of 163 breast cancer patients, 129 (79%) were able to complete targeted therapy with coc co-management. Most of the 779 patients (n = 643, 83%) were alive at the time of the last data collection. Conclusions: This cohort study is one of the largest to report characteristics and clinical outcomes of patients referred to a coc. Collaboration between oncologists and cardiologists resulted in completion of cancer therapy in most patients. Ongoing analysis of referral patterns, management plans, and patient outcomes will help to guide the cardiac care of oncology patients, ultimately optimizing cancer and cardiac outcomes alike.

A multidisciplinary perspective on the subcutaneous administration of trastuzumab in HER2-positive breast cancer.

Trastuzumab is the standard treatment in Canada for patients with breast cancer positive for her2 (human epidermal growth factor receptor 2), dramatically improving outcomes in that patient group. However, its current intravenous (IV) administration is associated with long infusion times that place a significant burden on health care resources and patient quality of life. In an effort to provide a faster and easier administration method, a subcutaneous (sc) formulation of trastuzumab has been developed. Data from comparative trials demonstrate that the two formulations are comparable with respect to pharmacokinetics and efficacy. They also have similar safety profiles, with the exception of mild local and administration reactions with the sc formulation. Furthermore, the sc formulation is preferred by patients and health care professionals, and greatly reduces administration and chair time. Additional advantages include easier preparation and dosing, reduced drug wastage, and reduced discomfort at the injection site. By using well-thought-out administration procedures, the sc formulation can be given safely and effectively, potentially reducing the burden on health care resources and improving quality of life for patients.

Shared medical appointments for patients with a nondiabetic physical chronic illness: A systematic review.

OBJECTIVES: Shared medical appointments are group appointments, with an optional individual consultation, for patients diagnosed with chronic illnesses. Shared medical appointments improve diabetes management, but little is known about their use for other illnesses. The objective was to determine the effect that shared medical appointments have on patients with a physical chronic illness, healthcare providers, and the healthcare system. METHODS: A systematic review was conducted searching databases from January 1970 to September 2016. Eligible trials evaluated shared medical appointments for patients with a homogeneous chronic illness, excluding diabetes and mental illness. Screening, data extraction, and risk of bias were conducted independently by two authors. Analysis was descriptive. RESULTS: Of 2364 citations, nine randomized trials were included. Shared medical appointments were evaluated for cardiovascular illnesses (four studies), breast cancer, chronic kidney disease, Parkinson's disease, stress urinary incontinence, and carpal tunnel syndrome. Compared to usual care, no negative effects on patient quality of life, knowledge and satisfaction were reported. One study reported no difference in healthcare provider satisfaction. Another study showed fewer hospital admissions for patients who attended shared medical appointments. DISCUSSION: Few rigorous studies evaluated the use of shared medical appointments for chronic illnesses. Overall, there appears to be no patient harms. Further studies should include more objective outcomes and larger sample sizes.

An international survey of healthcare providers' knowledge of cardiac complications of cancer treatments.

BACKGROUND: Cardio-oncology is a young sub-specialty that addresses the needs of cancer patients at risk of, or who have experienced cancer therapy related cardiac dysfunction (CTRCD). This study assessed clinicians' understanding of cardio-oncology, opinions towards current practice, and approach to diagnosing and managing CTRCD. METHODS: A 45-question survey was administered online via Survey Monkey and WeChat to health care providers (HCPs) comprising of cardiologists, oncologists, and others from September 2017 to March 2018. Implementation of the survey followed a modified Dillman's Total Design Method. RESULTS: In total, 160 responses were collected from 22 countries; majority were from cardiologists (53.8%) and oncologists (32.5%). The remaining 13.7% identified themselves as "others," including general internists, cardio-oncologists, pediatric oncologists, radiation oncologists, cardiac rehabilitation therapists, nurse practitioners, research students, and pharmacists. In the setting of metastatic cancer, there was a difference in risk tolerance for cardiotoxicity between subspecialties. In this case, more cardiologists (36.7%) accepted a 5-10% risk of cardiotoxicity compared to oncologists (20.0%). Majority of cardiologists felt that cardiotoxicity should be monitored, even in asymptomatic cancer patients (55.8%). Only 12% of oncologists selected this response. In contrast, 50.0% of oncologists reported that cardiologists should be involved only when patients develop cardiotoxicity. In comparison, 6.5% of cardiologists selected this response. Majority of cardiologists stated that cardio-oncology clinics would significantly improve cancer patients' prognosis (88.3%); only 45.8% of oncologists shared this opinion. Of all respondents, 66.9% stated they were familiar with a variety of international guidelines for managing cardiotoxicity. Of all oncologists, 65.3% indicated that they referred to these guidelines for clinical decision making. CONCLUSIONS: Despite the growth of cardio-oncology clinics, there are significant knowledge gaps regarding prevention and treatment strategies for CTRCD among health care providers. Knowledge translation from guidelines and collaboration between cardiologists and oncologists are needed to improve cardiovascular outcomes of cancer patients.

Anti-Yo antibody-mediated paraneoplastic cerebellar degeneration associated with cognitive affective syndrome in a patient with breast cancer: a case report and literature review.

Breast cancer is the most common cancer in women, with 15%-25% of those tumours overexpressing the human epidermal growth factor receptor 2 (her2), which is associated with more aggressive disease. On rare occasions, patients present with a paraneoplastic syndrome months to years before their cancer diagnosis. Paraneoplastic cerebellar degeneration (pcd) is associated with fewer than 1% of cancers and is strongly associated with breast and gynecologic malignancies. Anti-Yo antibody is the antibody most frequently identified with the syndrome, and it is associated with a very poor prognosis. Recent studies have implicated a relationship between overexpression of her2 and anti-Yo-mediated pcd. Current pcd treatments include tumour removal, chemotherapy, targeted therapy, and immune-suppressive treatments. Outcomes of pcd are typically poor, and no guidelines for treatment currently exist. Early recognition followed by rapid initiation of treatment remains the cornerstone of therapy. Here, we present a case of anti-Yo-antibody pcd secondary to estrogen and progesterone receptor-negative, her2-positive breast cancer. Despite treatment with mastectomy, chemotherapy, and her2-targeted therapy, no significant neurologic improvement was achieved, and cerebellar cognitive affective syndrome subsequently developed.

The feasibility and acceptability of a physical activity intervention for older people with chronic musculoskeletal pain: The iPOPP pilot trial protocol.

INTRODUCTION: This pilot trial will inform the design and methods of a future full-scale randomized controlled trial (RCT) and examine the feasibility, acceptability and fidelity of the Increasing Physical activity in Older People with chronic Pain (iPOPP) intervention, a healthcare assistant (HCA)-supported intervention to promote walking in older adults with chronic musculoskeletal pain in a primary care setting. METHODS AND ANALYSIS: The iPOPP study is an individually randomized, multicentre, three-parallel-arm pilot RCT. A total of 150 participants aged ≥65 years with chronic pain in one or more index sites will be recruited and randomized using random permuted blocks, stratified by general practice, to: (i) usual care plus written information; (ii) pedometer plus usual care and written information; or (iii) the iPOPP intervention. A theoretically informed mixed-methods approach will be employed using semi-structured interviews, audio recordings of the HCA consultations, self-reported questionnaires, case report forms and objective physical activity data collection (accelerometry). Follow-up will be conducted 12 weeks post-randomization. Collection of the quantitative data and statistical analysis will be performed blinded to treatment allocation, and analysis will be exploratory to inform the design and methods of a future RCT. Analysis of the HCA consultation recordings will focus on the use of a checklist to determine the fidelity of the iPOPP intervention delivery, and the interview data will be analysed using a constant comparison approach in order to generate conceptual themes focused around the acceptability and feasibility of the trial, and then mapped to the Theoretical Domains Framework to understand barriers and facilitators to behaviour change. A triangulation protocol will be used to integrate quantitative and qualitative data and findings.

A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: final analysis of Canadian Cancer Trials Group IND.213.

BACKGROUND: Pelareorep, a serotype 3 reovirus, has demonstrated preclinical and early clinical activity in breast cancer and synergistic cytotoxic activity with microtubule targeting agents. This multicentre, randomized, phase II trial was undertaken to evaluate the efficacy and safety of adding pelareorep to paclitaxel for patients with metastatic breast cancer (mBC). METHODS: Following a safety run-in of 7 patients, 74 women with previously treated mBC were randomized either to paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 every 4 weeks plus pelareorep 3 × 1010 TCID50 intravenously on days 1, 2, 8, 9, 15, and 16 every 4 weeks (Arm A) or to paclitaxel alone (Arm B). Primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate, overall survival (OS), circulating tumour cell counts, safety, and exploratory correlative analyses. All comparisons used a two-sided test at an alpha level of 20%. Survival analyses were adjusted for prior paclitaxel. RESULTS: Final analysis was performed after a median follow-up of 29.5 months. Pelareorep was well tolerated. Patients in Arm A had more favourable baseline prognostic variables. Median adjusted PFS (Arm A vs B) was 3.78 mo vs 3.38 mo (HR 1.04, 80% CI 0.76-1.43, P = 0.87). There was no difference in response rate between arms (P = 0.87). Median OS (Arm A vs B) was 17.4 mo vs 10.4 mo (HR 0.65, 80% CI 0.46-0.91, P = 0.1). CONCLUSIONS: This first, phase II, randomized study of pelareorep and paclitaxel in previously treated mBC did not show a difference in PFS (the primary endpoint) or RR. However, there was a significantly longer OS for the combination. Further exploration of this regimen in mBC may be of interest.

The Framingham risk score underestimates the risk of cardiovascular events in the HER2-positive breast cancer population.

INTRODUCTION: Patients with breast cancer (bca) who overexpress her2 (the human epidermal growth factor receptor 2) are at risk for cardiotoxicity when treated with anthracycline-based chemotherapy and her2-targeted agents. The Framingham risk score (frs) is a validated tool that stratifies patients into high-, intermediate-, or low-risk groups and calculates their 10-year risk of developing cardiovascular disease (cvd) based on past medical history, systolic blood pressure, and measurement of serum lipids. We retrospectively analyzed patients with her2-positive bca to determine whether the frs predicts adverse cardiovascular (CV) events or cardiotoxicity in patients treated using anthracyclines or her2-targeted therapy, or both. METHODS: The frs was determined for patients with bca referred to The Ottawa Hospital Cardiology-Oncology Clinic from October 2008 to August 2014. The patients were stratified into high (≥20%), intermediate (10%-20%), and low (<10%) 10-year cv risk groups. Primary outcomes included cvd-related hospitalizations and deaths, and cardiotoxicity [drop in left ventricular ejection fraction (lvef) of >10% to a lvef ≤50%]. RESULTS: Of the 152 patients included in the analysis (median follow-up: 40.7 months; range: 3.5-263 months), 47 (31%) were classified as high risk; 36 (24%), as intermediate risk; and 69 (45%), as low-risk. The number of cvd-related hospitalizations and deaths was 22, for an overall prevalence of 14%, with significantly more events occurring in high-risk than in low-risk patients (odds ratio: 4.18; 95% confidence limits: 1.47, 11.89). The frs predicted a 10-year risk of any cv event of 11.2% and underestimated the actual rate of cv events in the entire cohort. High frs was not associated with cardiotoxicity (p = 0.82). CONCLUSIONS: In a population of patients with her2-positive bca referred to a cardiology-oncology clinic, the frs does not accurately predict the risk of cv events or cardiotoxicity.

Trastuzumab-induced cardiotoxicity: testing a clinical risk score in a real-world cardio-oncology population.

BACKGROUND: Trastuzumab has improved survival for women with her2-positive breast cancer, but its use is associated with an increased risk of cardiotoxicity. With increased survivorship, the long-term effects of cancer treatment are an important consideration for clinicians and patients. We reviewed the current literature on predicting trastuzumab-related cardiotoxicity and tested a clinical risk score (crs) in a real-world breast cancer population to assess its utility in predicting permanent cardiotoxicity. METHODS: In this retrospective exploratory cohort study of breast cancer patients referred to a cardio-oncology clinic at a tertiary care centre between October 2008 and August 2014, a crs was calculated for each patient, and a sensitivity analysis was performed. RESULTS: Of the 143 patients included in the study, 62 (43%) experienced a cardiac event, and of those 62 patients, 43 (69%) experienced full recovery of cardiac function. In applying the crs, 119 patients (83%) would be considered at low risk, 14 (10%) at moderate risk, and 10 (7%) at high risk to develop heart failure or cardiomyopathy. When applied to the study population, the high-risk cut-off score had a sensitivity of 0.13 [95% confidence interval (ci): 0.08 to 0.20] and a specificity of 0.94 (95% ci: 0.87 to 0.97). The positive predictive value was 0.07 (95% ci: 0.03 to 0.13), and the negative predictive value was 0.93 (95% ci: 0.87 to 0.96). CONCLUSIONS: The crs demonstrated good specificity and negative predictive value for the development of permanent cardiotoxicity in a real-world population of breast cancer patients, suggesting that intensive cardiac monitoring might not be warranted in low-risk patients, but that high-risk patients might benefit from early referral to cardio-oncology for optimization. Further study using the crs in a larger breast cancer population is warranted to identify patients at low risk of long-term trastuzumab-related cardiotoxicity.

TRIM28 interacts with EZH2 and SWI/SNF to activate genes that promote mammosphere formation.

Histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2) is generally associated with H3K27 methylation and gene silencing, as a member of the polycomb repressor 2 (PRC2) complex. Immunoprecipitation and mass spectrometry of the EZH2-protein interactome in estrogen receptor positive, breast cancer-derived MCF7 cells revealed EZH2 interactions with subunits of chromatin remodeler SWI/SNF complex and TRIM28, which formed a complex with EZH2 distinct from PRC2. Unexpectedly, transcriptome profiling showed that EZH2 primarily activates, rather than represses, transcription in MCF7 cells and with TRIM28 co-regulates a set of genes associated with stem cell maintenance and poor survival of breast cancer patients. TRIM28 depletion repressed EZH2 recruitment to chromatin and expression of this gene set, in parallel with decreased CD44hi/CD24lo mammosphere formation. Mammosphere formation, inhibited by EZH2 depletion, was rescued by ectopic expression of EZH2 but not by TRIM28 expression or by EZH2 mutated at the region (pre-SET domain) of TRIM28 interaction. These results support PRC2-independent functions of EZH2 and TRIM28 in activation of gene expression that promotes mammary stem cell enrichment and maintenance.

Symptom practice guide for telephone assessment of patients with cancer treatment-related cardiotoxic dyspnea: Adaptation and evaluation of acceptability.

BACKGROUND: Patients with cancer treatment-related cardiotoxicity, which may manifest as heart failure (HF), can present with dyspnea. Nurses frequently assess, triage and offer self-care strategies to patients experiencing dyspnea in both the cardiology and oncology settings. However, there are no known tools available for nurses to manage patients in the setting of cancer treatment-related cardiotoxicity. The objective of this study was to adapt and evaluate the acceptability of an evidence-informed symptom practice guide (SPG) for use by nurses over the telephone for the assessment, triage, and management of patients experiencing dyspnea due to cancer treatment-related cardiotoxicity. METHODS: The CAN-IMPLEMENT© methodology guided this descriptive study. A systematic search was conducted in four databases to identify cardio-oncology and HF guidelines and systematic reviews. Screening was conducted by two reviewers, with data extracted into a recommendation matrix from eligible guidelines and systematic reviews on: assessment criteria, medications, and/or self-care strategies to manage dyspnea. Healthcare professionals with an expertise in oncology and/or cardiology were recruited using purposeful and snowball sampling. Evaluation of acceptability of the adapted SPG was gathered through semi-structured interviews and a survey with open- and closed-ended questions. Quantitative findings and participant feedback from the interviews and the open-ended survey questions were analyzed descriptively. RESULTS: Of 490 citations, seven HF guidelines were identified. Evidence from these guidelines was added to the original SPG. Eleven healthcare professionals completed the interview and acceptability survey. The adapted SPG was iteratively revised three times during the interviews. The original SPG was adaptable, and participants indicated the adapted SPG was comprehensive, easy to follow, and would be useful in clinical practice. CONCLUSIONS: This study highlights the lack of knowledge tools and available clinical practice guidelines to guide healthcare professionals to assess, triage and/or offer self-care strategies to patients with cancer treatment-related cardiotoxic dyspnea. Moreover, most nurses require assistance to differentiate among the various causes of dyspnea from oncology treatment in order to triage severity appropriately. Further research should focus on evaluating the validity of the adapted SPG in clinical practice.

Can the referring surgeon enhance accrual of breast cancer patients to medical and radiation oncology trials? The ENHANCE study.

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.

A randomized, double-blind, phase II, exploratory trial evaluating the palliative benefit of either continuing pamidronate or switching to zoledronic acid in patients with high-risk bone metastases from breast cancer.

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.

Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.

BACKGROUND: This systematic review addresses the question "What is the optimal targeted therapy for female patients with early-stage human epidermal growth factor receptor 2 (her2)-positive breast cancer?" METHODS: The medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major guideline organizations were also searched. RESULTS: Sixty publications relevant to the targeted therapy portion of the systematic review were identified. In four major trials (hera, National Surgical Adjuvant Breast and Bowel Project B-31, North Central Cancer Treatment Group N9831, and Breast Cancer International Research Group 006), adjuvant trastuzumab for 1 year was superior in disease-free survival (dfs) and overall survival (os) to no trastuzumab; trastuzumab showed no benefit in one trial (pacs 04). A shorter duration of trastuzumab (less than 1 year compared with 1 year) was evaluated, with mixed results for dfs: one trial showed superiority (finher), one trial could not demonstrate noninferiority (phare), another trial showed equivalent results (E 2198), and one trial is still ongoing (persephone). Longer trastuzumab duration (hera: 2 years vs. 1 year) showed no improvement in dfs or os and a higher rate of cardiac events. Newer her2-targeted agents (lapatinib, pertuzumab, T-DM1, neratinib) have been or are still being evaluated in both adjuvant and neoadjuvant trials, either by direct comparison with trastuzumab alone or combined with trastuzumab. In the neoadjuvant setting (neoaltto, GeparQuinto, Neosphere), trastuzumab alone or in combination with another anti-her2 agent (lapatinib, pertuzumab) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response. In the adjuvant setting, lapatinib alone or in combination with trastuzumab, compared with trastuzumab alone (altto) or with placebo (teach), was not superior in dfs. The results of the completed aphinity trial, evaluating the role of dual her2 blockade with trastuzumab and pertuzumab, are highly anticipated. Ongoing trials are evaluating trastuzumab as a single agent without adjuvant chemotherapy (respect) and in patients with low her2 expression (National Surgical Adjuvant Breast and Bowel Project B-47). CONCLUSIONS: Taking into consideration disease characteristics and patient preference, 1 year of trastuzumab should be offered to all patients with her2-positive breast cancer who are receiving adjuvant chemotherapy. Cardiac function should be regularly assessed in this patient population.