Feasibility Randomised Control Trial of OptiMal: A Self-Management Intervention for Cancer Survivors.

PURPOSE: Cancer survivors can experience symptoms such as fatigue, pain and distress that persist for many months following treatment. These enduring symptoms often impact on participation in self-care activities, returning to school and/or work, and leisure and social activities. Self-management support is increasingly recognised as a core aspect of cancer survivorship care to reduce the impact of persistent symptoms. The purpose of this study was to examine the feasibility and potential effectiveness of a group-based self-management intervention, OptiMal, to improve the physical and psychological health of cancer survivors. OptiMal is a six-week intervention comprising weekly sessions on fatigue, stress and physical activity, diet and effective communication strategies. METHODS: A feasibility randomised control trial was undertaken. Individuals up to two years after cancer treatment were randomised to OptiMal or usual care. Feasibility was examined through recruitment and retention metrics. Potential effectiveness was tested through patient-reported outcomes collected at baseline and three months post-intervention. Descriptive and inferential statistics were used to analyse study data. RESULTS: Recruitment for this study was 32.5% (80/246 eligible individuals) with 77.5% retention at three-month follow-up (82.5% for intervention group and 72.5% for control group). Of those who attended the intervention, 19 (73%) attended all OptiMal sessions, indicating high adherence to the intervention. The majority of participants had breast cancer and were between 12 and 24 months post-treatment. The intervention group (n = 29) had statistically significant greater improvements in anxiety (p = 0.04) and health-related quality of life (health index score: p = 0.023, visual analogue score: p = 0.035) at three months post-intervention than the control group. CONCLUSIONS: Recruitment and retention in this study was similar to other cancer trials and the high adherence rate indicates that OptiMal is an acceptable self-management intervention for cancer survivors and warrants further investigation. OptiMal is intended to address symptoms reported across different cancer types. However, a limitation of this study was that the majority of participants had breast cancer, and therefore, generalisability of findings cannot be assumed for other cancer types. Future studies of OptiMal therefore need to use different strategies to recruit survivors of other cancer types.

Implementing a physiotherapy led cancer exercise programme in a National Cancer Centre: the FIXCAS study.

OBJECTIVES: To examine the feasibility of implementing a 10-week exercise-based cancer rehabilitation programme in a national cancer centre. DESIGN: A single-arm prospective feasibility study. SETTING: An outpatient physiotherapy department. PARTICIPANTS: Forty de-conditioned cancer survivors (<1 year post completion of treatment). INTERVENTIONS: A 10-week programme of twice weekly group-based supervised exercise sessions. MAIN OUTCOME MEASURES: A mixed methods approach was used. The primary outcome of the study was feasibility, evaluated in terms of recruitment, adherence, attrition and stakeholder acceptance of the programme. Secondary outcomes examined the effect of the exercise intervention on physical function and quality of life measures. RESULTS: Forty patients (age 60 (SD 10.6) years; n = 12 breast cancer, n = 11 lung cancer, n = 7 prostate cancer, n = 5 colorectal cancer, n = 5 other) participated. In total 82% (n = 33) participants completed the post-programme assessment. Deterioration of health and concerns over COVID-19 were the most common reasons for dropout (both n = 2). Adherence to both the supervised exercise classes and home exercise programme was high (78% and 94% respectively). No adverse events were recorded during the intervention or assessments. Qualitative feedback from stakeholders highlighted the acceptability of the programme as well as many perceived benefits of the exercise programme. Improvements in three quality of life sub-scales (physical function, role function and emotional function), physical activity levels and aerobic fitness levels were found post-intervention. CONCLUSION: It appears feasible to offer a 10-week exercise programme to patients attending a national cancer centre, with adequate recruitment, retention and adherence rates and high acceptability among stakeholders. CONTRIBUTION OF THE PAPER.

Patient knowledge, personal experience, and impact of the first wave of the COVD-19 pandemic in an Irish oncology cohort.

BACKGROUND: Oncology patients have had to make many changes to minimise their exposure to COVID-19, causing stress. Despite education, some patients still do not recognise potential COVID symptoms. AIMS: We assessed patient knowledge of COVID, and its impact on their behaviours, concerns, and healthcare experience. METHODS: A 16-page questionnaire was distributed to 120 oncology patients attending the day unit of a tertiary Irish cancer centre for systemic anti-cancer therapy (May/June 2020). The Irish 7-day COVID incidence during this period ranged from 2 to 11 cases/100,000 people. RESULTS: One hundred and one responses were received, 1% had tested positive for COVID, and 31% had undergone testing. Participant insight into their knowledge about COVID and their own behaviour was limited in some cases. Seventy-five percent reported total compliance with restrictions, but many were not fully compliant. Self-reported confidence in knowledge was high, but did not predict demonstrated knowledge. Sixty percent did not recognise two or more symptoms; 40% did not self-identify as high-risk. Patients reported more health-related worry (72%), loneliness (51%), and lower mood (42%) since the pandemic began. Financial toxicity worsened, with increased financial worry (78%), reductions in household income (40%), and increased costs due to lockdown (62%). Use of facemasks introduced new communications barriers for 67% of those with hearing loss. CONCLUSIONS: Despite self-reported confidence in knowledge, some patient's recognition of COVID symptoms and the preventative strategies they should use are not optimal, highlighting the need for further education in this regard. COVID has been a significant stressor for patients and more practical, financial, and psychological supports are needed.

Associations Among Physical Activity, Skeletal Related Events, and Patient Reported Outcomes in Patients with Bone Metastases.

OBJECTIVES: Emerging evidence supports exercise as a therapeutic intervention for patients with bone metastases. However, exercise prescription in practice is limited by concerns regarding skeletal-related events (SREs). This study examined associations among habitual physical activity levels, history of SREs, and patient reported outcomes in patients with bone metastases. DATA SOURCES: A total of 58 patients with bone metastases (n = 45 breast cancer; n = 13 prostate cancer; mean time since cancer diagnosis 5.8 [4.7] years) were assessed. Habitual physical activity levels were collected by accelerometry. Standardized subjective assessment collected history of SREs, quality of life (EORTC-QLQ-C30 and EORTC-BM22), pain (Brief Pain Inventory), sleep quality (Pittsburgh Sleep Quality Questionnaire), and perceptions about exercise (Exercise Benefits/Barriers Scale). Participants spent a mean of 77.37% (standard deviation 14.3)% of waking hours sedentary and a mean of 20.14% (standard deviation 13.4)% of waking hours in light intensity activity. Almost half (n = 28) completed ≥150 min/wk moderate-to-vigorous intensity activity. Higher levels of moderate-to-vigorous intensity activity were associated with lower pain scores, better perceived physical function, lower functional interference scores, and better quality of life. Patients with a history of fracture since diagnosis spent more time sedentary and in light intensity activity in comparison to those with no fracture history (P < .05). CONCLUSION: Moderate-to-vigorous intensity physical activity may have multiple benefits for patients with bone metastases. Reducing sedentary behavior may be a key target for patients with a history of fracture. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses play a key role in providing education on the benefits of exercise, overcoming barriers to physical activity and timely referrals.

Extramural venous invasion (EMVI) in colorectal cancer is associated with increased cancer recurrence and cancer-related death.

INTRODUCTION: Colorectal cancer (CRC) outcomes vary depending on tumour biology, with several features used to predict disease behaviour. Extramural venous invasion (EMVI) is associated with negative outcomes and its presence has been established as an indicator of more aggressive disease in CRC. METHODS: A prospectively maintained database was examined for patients undergoing curative resection for non-metastatic CRC between 2012 and 2018 in a tertiary institution. Clinicopathological factors were compared to assess their impact on recurrence, all-cause mortality and cancer-related death. Kaplan Meier analysis of the association between EMVI and these endpoints was performed, and univariable and multivariable analysis was carried out to establish the relationship of predictive factors in oncological outcomes. RESULTS: Eighty-eight (13.5%) of 654 patients developed recurrence. The mean time to recurrence was 19.8 ± 13.5 months. There were 36 (5.5%) cancer-related deaths at a mean duration of follow-up of 46.3 ± 21.6 months. Two hundred and sixty-six patients had extramural venous invasion (40.7%). EMVI was significantly associated with reduced overall recurrence-free survival, systemic recurrence-free survival, and increased cancer-related death on univariate analysis (p < 0.001 for all, Fig. 1), and multivariable analysis (OR 1.8 and 2.1 respectively, p < 0.05 for both). CONCLUSION: EMVI is associated with a poor prognosis, independent of stage, nodal status and other histopathological features. The presence of EMVI should be strongly considered as an indication for adjuvant therapy.

Pregnancy-associated breast cancer: evaluating maternal and foetal outcomes. A national study.

PURPOSE: Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. METHODS: This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. RESULTS: We identified 155 patients-71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I-III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. CONCLUSION: PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Phase Ib Trial of Copanlisib, A Phosphoinositide-3 Kinase (PI3K) Inhibitor, with Trastuzumab in Advanced Pre-Treated HER2-Positive Breast Cancer "PantHER".

BACKGROUND: Activation of the phosphoinositide-3 kinase (PI3K) pathway is a resistance mechanism to anti-human epidermal growth factor receptor 2 (HER2) therapy. This phase Ib trial was conducted to determine the maximum tolerated dose (MTD) of copanlisib, an intravenous (IV) pan-class I PI3K inhibitor, combined with trastuzumab. METHODS: Patients with advanced HER2-positive breast cancer and disease progression following at least one prior line of HER2 therapy in the metastatic setting were treated with copanlisib (45 or 60 mg) IV on days 1, 8 and 15 of a 28-day cycle with a fixed dose of trastuzumab 2 mg/kg weekly. RESULTS: Twelve patients were enrolled. The MTD was determined as copanlisib 60 mg plus trastuzumab 2 mg/kg weekly. The most common adverse events of any grade occurring in more than two patients were hyperglycaemia (58%), fatigue (58%), nausea (58%) and hypertension (50%). Stable disease was confirmed at 16 weeks in six participants (50%). PIK3CA mutations were detected in archival tumour of six participants (50%). PIK3CA hotspot mutations, were detectable in pre- and on-treatment plasma of all participants. Pre- and post-treatment tumour biopsies for two patients identified temporal genomic heterogeneity, somatic mutations in the TRRAP gene, which encodes a PI3K-like protein kinase, and emergent somatic mutations related to protein kinase signalling. CONCLUSION: Copanlisib and trastuzumab can be safely administered with fair overall tolerability. Preliminary evidence of tumour stability was observed in patients with heavily pre-treated, metastatic HER2 positive breast cancer. Several potential biomarkers were identified for further study in the current phase 2 clinical trial. NCT: 02705859.

Prevalence of Insomnia in an Oncology Patient Population: An Irish Tertiary Referral Center Experience.

BACKGROUND: The NCCN Guidelines for Survivorship recommend dedicated sleep assessment. Reported insomnia prevalence in the general Irish population is 6% to 15%. Reported insomnia prevalence internationally among new/recently diagnosed patients with cancer varies from 30.9% to 54.3%. Insomnia prevalence has not been previously quantified in an Irish oncology cohort. METHODS: A 40-item questionnaire was prospectively administered to ambulatory patients with cancer aged ≥18 years. Prespecified criteria to define insomnia syndrome combined those of the International Classification of Sleep Disorders, version 1, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The Hospital Anxiety and Depression Scale-Depression/Anxiety (HADS-D/A) was used to screen for potential confounding variables. RESULTS: The response rate to the questionnaire was 87% (294/337). The predominant respondent age group was 55 to 64 years (26%; 77/294), 70.7% were female (208/294), and the most common cancer subtypes were breast (37.4%), colorectal (12.9%), and lung (12.2%). A total of 62% (183/294) of patients reported sleep disturbance after diagnosis, 63% (115/183) reported moderate/severe distress related to this disturbance, and 37% (61/183) reported a significant impact on physical function. Although 33% (98/294) met insomnia syndrome criteria, only 34% (33/98) of these patients had a preexisting history of sleep disturbance. Female sex, age <65 years, cancer subtype, alcohol consumption, and HADS-D/A ≥11 were associated with statistically significant higher odds ratios (OR) of insomnia syndrome. Multivariate analysis identified breast cancer (OR, 3.17; P=.01), age <65 years (OR, 1.8; P=.03), and alcohol consumption (OR, 2.3; P=.005) as independent predictors of insomnia syndrome. CONCLUSIONS: Insomnia syndrome prevalence in this cohort is comparable to that reported previously and supports dedicated sleep assessment. This study identifies potentially modifiable risk factors for insomnia and demonstrates additional utility of the HADS score in identifying patients at risk.

Prostate Cancer Risk by BRCA2 Genomic Regions.

A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval [CI] 4.46-15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR = 3.31, 95% CI 1.97-5.57; hazard ratio = 2.34, 95% CI 1.09-5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23-72%) by the age of 75 yr and 78% (95% CI 54-94%) by the age of 85 yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort. PATIENT SUMMARY: In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene.

Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study.

BACKGROUND: BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies. OBJECTIVE: To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods. RESULTS AND LIMITATIONS: Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute PCa risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20-8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24-7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses. CONCLUSIONS: The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers. PATIENT SUMMARY: In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.

Risks of breast or ovarian cancer in BRCA1 or BRCA2 predictive test negatives: findings from the EMBRACE study.

PURPOSE: BRCA1/BRCA2 predictive test negatives are proven noncarriers of a BRCA1/BRCA2 mutation that is carried by their relatives. The risk of developing breast cancer (BC) or epithelial ovarian cancer (EOC) in these women is uncertain. The study aimed to estimate risks of invasive BC and EOC in a large cohort of BRCA1/BRCA2 predictive test negatives. METHODS: We used cohort analysis to estimate incidences, cumulative risks, and standardized incidence ratios (SIRs). RESULTS: A total of 1,895 unaffected women were eligible for inclusion in the BC risk analysis and 1,736 in the EOC risk analysis. There were 23 incident invasive BCs and 2 EOCs. The cumulative risk of invasive BC was 9.4% (95% confidence interval (CI) 5.9-15%) by age 85 years and the corresponding risk of EOC was 0.6% (95% CI 0.2-2.6%). The SIR for invasive BC was 0.93 (95% CI 0.62-1.40) in the overall cohort, 0.85 (95% CI 0.48-1.50) in noncarriers from BRCA1 families, and 1.03 (95% CI 0.57-1.87) in noncarriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20-3.17) in the overall cohort. CONCLUSION: Our results did not provide evidence for elevated risks of invasive BC or EOC in BRCA1/BRCA2 predictive test negatives.

Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies.

BACKGROUND: The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies. METHODS: Baseline tumour biopsies were available from 74 patients with HER2-positive breast cancer who were enrolled in the phase II TCHL neoadjuvant study (ICORG 10-05) assessing TCH (docetaxel, carboplatin, trastuzumab) (n = 38) versus TCL (docetaxel, carboplatin, lapatinib) (n = 10) versus TCHL (docetaxel, carboplatin, trastuzumab, lapatinib) (n = 40), each for six cycles. Activating mutations in PIK3CA and ERBB family genes were identified using mass spectrometry-based genotyping. Phosphatase and tensin homolog (PTEN) expression was assessed by immunohistochemistry. RESULTS: PIK3CA and/or ERBB family mutations were detected in 23 (31.1%) tumour samples tested, whereas PTEN expression was low in 31.1% of cases tested. Mutation frequency was similar in each treatment arm (31.3% in TCH arm, 30% in TCL arm and 31.3% in TCHL arm) and was not influenced by oestrogen receptor (ER) status (27.6% in ER-negative patients, 33.3% in ER-positive patients) or progesterone receptor (PR) status (32.6% in PR-negative patients, 29% in PR-positive patients). There was no significant difference in pathological complete response (pCR) rates between 47 patients with wild-type (WT) tumours and 22 patients whose tumours carried mutations (in either PIK3CA or ERBB family genes) (42.5% vs. 54.5%; p = 0.439). Similarly, there was no significant difference in pCR rates between patients with PIK3CA/ERBB family mutated/PTEN-low (i.e., PI3K-activated) tumours and patients without PI3K activation (50% vs. 44%; p = 0.769). However, in the TCHL (but not the TCH) group, the pCR rate was higher for 9 patients with PIK3CA/ERBB family mutated tumours than for 20 patients with PIK3CA/ERBB family WT tumours (77.8% vs. 35%; p = 0.05). CONCLUSIONS: Our results indicate that patients who receive neoadjuvant TCHL and have PIK3CA/ERBB family mutated tumours may be more likely to have a pCR than patients with WT tumours. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01485926 . Registered on 2 December 2011.

Comparison of Oncotype DX® Recurrence Score® with other risk assessment tools including the Nottingham Prognostic Index in the identification of patients with low-risk invasive breast cancer.

Oncotype DX® is a gene expression assay that quantifies the risk of distant recurrence in patients with hormone receptor positive early breast cancer, publicly funded in Ireland since 2011. The aim of this study was to correlate Oncotype DX® risk groupings with traditional histopathological parameters and the results of other risk assessment tools including Recurrence Score-Pathology-Clinical (RSPC), Adjuvant Risk Index (Adj RI), Nottingham Prognostic Index (NPI) and the Adjuvant! Online 10-year score (AO). Patients were retrospectively identified from the histopathology databases of two Irish hospitals and patient and tumour characteristics collated. Associations between categorical variables were evaluated with Pearson's chi-square test. Correlations were calculated using Spearman's correlation coefficient and concordance using Lin's concordance correlation coefficient. Statistical analysis was performed using SPSS software, version 22.0.In our 300 patient cohort, Oncotype DX® classified 59.7% (n = 179) as low, 30% (n = 90) as intermediate, and 10.3% (n = 31) as high risk. Overall concordance between the RS and RSPC, Adj RI, NPI, and AO was 67.3% (n = 202), 56.3% (n = 169), 59% (n = 177), and 36.3% (n = 109), respectively. All risk assessment tools classified the majority of patients as low risk apart from the AO 10-year score, with RSPC classifying the highest number of patients as low risk. This study demonstrates that there is good correlation between the RS and scores obtained using alternative risk tools. Concordance with NPI is strong, particularly in the low-risk group. NPI, calculated from traditional clinicopathological characteristics, is a reliable alternative to Oncotype DX® in the identification of low-risk patients who may avoid adjuvant chemotherapy.

Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial.

BACKGROUND: The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel. METHODS: tAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0-1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m2 intravenously administered epirubicin and 600 mg/m2 intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m2 paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as the other group, with the addition of 1250 mg/m2 gemcitabine to the paclitaxel cycles, administered intravenously as a 0·5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546). FINDINGS: Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10-10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63-68] in the gemcitabine group vs 65% [62-67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0·97 [95% CI 0·86-1·10], p=0·64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]). INTERPRETATION: The addition of gemcitabine to anthracycline and taxane-based adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease-free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup. FUNDING: Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer.

Developing and validating a theoretical measure of modifiable influences on hormonal therapy medication taking behaviour in women with breast cancer.

OBJECTIVE: Taking adjuvant hormonal therapy for 5-10 years is recommended to prevent breast cancer recurrence in those with oestrogen positive disease. Despite proven clinical efficacy many women do not take their hormonal therapy as prescribed. This study reports the development and initial validation of a questionnaire measuring the behavioural determinants of hormonal therapy medication taking behaviour (MTB) based on the theoretical domains framework (TDF). DESIGN: Women with Stage I-III breast cancer (N = 223) completed the questionnaire based on the TDF. The TDF is an integrative framework consisting of 14 domains of behaviour change determinants to inform intervention design. MAIN OUTCOME MEASURES: Items were developed from previous research, in-depth patient interviews and consultation with health professionals. Confirmatory factor analysis (CFA) was undertaken to generate the model of best fit. RESULTS: The final questionnaire consisted of eight domains and CFA produced a reasonable fit (χ2(810) = 942, p < .001; RMSEA = .03; CFI = .93 and WRMR = .91) as well as internal consistency (r = .16 to .64). There were adequate levels of discriminant validity for the majority of the domains. CONCLUSIONS: A TDF-based measure of the behavioural determinants of MTB was developed. Further research is needed to confirm the reliability and validity of this measure.

Economic impact of 21-gene recurrence score testing on early-stage breast cancer in Ireland.

The 21-gene test is a validated multi-gene diagnostic test that predicts chemotherapy (CT) benefit in oestrogen receptor positive (ER+), lymph node-negative (N0) breast cancer (BC) patients (pts). Ireland was the first public health care system to reimburse this test in Europe. Study objectives were to assess the impact of this test on decision-making and to analyse the economic impact of testing. Between October 2011 and February 2013, a national, retrospective, cross-sectional observational study of ER+, N0 BC pts tested with the 21-gene test was conducted. Surveyed breast medical oncologists, provided the assumption for the decision impact analysis that grade (G) 1 pts would not have received CT before testing and G2/3 pts would have received CT before testing. Descriptive statistical analyses were performed. 592 pts were identified; Low, intermediate and high recurrence score were identified in 53, 36 and 10 % pts, respectively. 384 (70 %) pts had G2, 129 (22 %) G3 and 76 (13 %) G1 tumours. Post testing, 345 pts (59 %) experienced a change in CT decision; 339 changed to hormone therapy alone and 6 advised to receive CT. 172 (30 %) pts received CT, 12 (3.9 %) of pts with low scores, 108 (50.9 %) of intermediate risk and 50 (90.9 %) of pts with high risk scores. Net reduction in CT use was 58 % and net savings achieved were €793,565. Since public reimbursement, the introduction of the 21-gene test has resulted in a significant reduction in chemotherapy administration and cost savings for the Irish public healthcare system.

Women's experiences of hormonal therapy for breast cancer: exploring influences on medication-taking behaviour.

PURPOSE: Five to 10 years of adjuvant hormonal therapy is recommended to prevent breast cancer recurrence. This study investigated modifiable influences on adjuvant hormonal therapy medication-taking behaviour (MTB) in women with stage I-III breast cancer. METHODS: Semi-structured face-to-face interviews among women with stage I-III breast cancer prescribed adjuvant hormonal therapy purposively sampled by their MTB at two cancer centres. Thematic analysis was conducted based on the Framework approach, with the Theoretical Domains Framework (TDF) informing the analysis framework; the TDF is an integrative framework consisting of 14 domains of behavioural change to inform intervention design. RESULTS: Thirty-one women participated in interviews (14 adherent/persistent; 7 non-adherent/persistent; 10 non-persistent). Three domains identified both barriers and enablers to hormonal therapy MTB across the three MTB strata: beliefs about consequences, intentions and goals and behaviour regulation, but their influence was different across the strata. Other domains influenced individual MTB strata. Key enablers for adherent/persistent women were identified within the domain beliefs about consequences (breast cancer recurrence), intentions and goals (high-priority), beliefs about capabilities (side effects) and behaviour regulation (managing medication). Barriers were identified within the domain behaviour regulation (no routine), memory, attention and decision processes (forgetting) and environmental context and resources (stressors) for non-adherent/persistent women and intentions and goals (quality of life), behaviour regulation (temporal self-regulation), reinforcement, beliefs about consequences (non-necessity) and social influences (clinical support) for non-persistent women. CONCLUSION: This study identified modifiable influences on hormonal therapy MTB. Targeting these influences in clinical practice may improve MTB and hence survival in this population.

Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer.

BACKGROUND: Germline BRCA mutations are associated with worse prostate cancer (PCa) outcomes; however, the most appropriate management for mutation carriers has not yet been investigated. OBJECTIVE: To evaluate the response of BRCA carriers to conventional treatments for localised PCa by analysing metastasis-free survival (MFS) and cause-specific survival (CSS) following radical prostatectomy (RP) or external-beam radiation therapy (RT). DESIGN, SETTING, AND PARTICIPANTS: Tumour features and outcomes of 1302 patients with local/locally advanced PCa (including 67 BRCA mutation carriers) were analysed. RP was undergone by 535 patients (35 BRCA); 767 received RT (32 BRCA). Median follow-up was 64 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Median survival and 3-, 5-, and 10-yr survival rates were estimated using the Kaplan-Meier method. Generated survival curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA mutations. RESULTS AND LIMITATIONS: A total of 67 BRCA carriers and 1235 noncarriers were included. At 3, 5, and 10 yr after treatment, 97%, 94%, and 84% of noncarriers and 90%, 72%, and 50% of carriers were free from metastasis (p<0.001). The 3-, 5- and 10-yr CSS rates were significantly better in the noncarrier cohort (99%, 97%, and 85%, respectively) than in carriers (96%, 76%, and 61%, respectively; p<0.001). Multivariate analysis confirmed BRCA mutations as an independent prognostic factor for MFS (hazard ratio [HR]: 2.36; 95% confidence interval [CI], 1.38-4.03; p=0.002) and CSS (HR: 2.17; 95% CI, 1.16-4.07; p=0.016). CONCLUSIONS: BRCA carriers had worse outcomes than noncarriers when conventionally treated for local/locally advanced PCa. PATIENT SUMMARY: Prostate cancer patients with germline BRCA mutations had worse outcomes than noncarriers when conventionally treated with surgery or radiation therapy.

Lymphocyte telomere length is long in BRCA1 and BRCA2 mutation carriers regardless of cancer-affected status.

BACKGROUND: Telomere length has been linked to risk of common diseases, including cancer, and has previously been proposed as a biomarker for cancer risk. Germline BRCA1 and BRCA2 mutations predispose to breast, ovarian, and other cancer types. METHODS: We investigated telomere length in BRCA mutation carriers and their non-carrier relatives and further examined whether telomere length is a modifier of cancer risk in mutation carriers. We measured mean telomere length in DNA extracted from whole blood using high-throughput quantitative PCR. Participants were from the EMBRACE study in United Kingdom and Eire (n = 4,822) and comprised BRCA1 (n = 1,628) and BRCA2 (n = 1,506) mutation carriers and their non-carrier relatives (n = 1,688). RESULTS: We find no significant evidence that mean telomere length is associated with breast or ovarian cancer risk in BRCA mutation carriers. However, we find mutation carriers to have longer mean telomere length than their non-carrier relatives (all carriers vs. non-carriers, Ptrend = 0.0018), particularly in families with BRCA2 mutations (BRCA2 mutation carriers vs. all non-carriers, Ptrend = 0.0016). CONCLUSIONS: Our findings lend little support to the hypothesis that short mean telomere length predisposes to cancer. Conversely, our main and unexpected finding is that BRCA mutation carriers (regardless of cancer status) have longer telomeres than their non-mutation carrier, non-cancer-affected relatives. The longer telomere length in BRCA2 mutation carriers is consistent with its role in DNA damage response. Overall, it seems that increased telomere length may be a consequence of these mutations, but is not itself directly related to the increased cancer risk in carriers. IMPACT: The finding that mutation carriers have longer mean telomere lengths than their non-carrier relatives is unexpected but biologically plausible and could open up new lines of research into the functions of the BRCA proteins. To our knowledge, this is the largest study of telomere length in BRCA mutation carriers and their relatives. The null cancer-risk association supports recent large prospective studies of breast and ovarian cancer and indicates that mean telomere length would not be a useful biomarker in these cancers. Cancer Epidemiol Biomarkers Prev; 23(6); 1018-24. ©2014 AACR.

Febrile neutropenia risk assessment tool: improving clinical outcomes for oncology patients.

PURPOSE: To develop, implement and evaluate the effectiveness of a nurse-led risk assessment tool to reduce the incidence of febrile neutropenia (FN) and evaluate the nurse's role in FN risk assessment in a hospital-based oncology unit. METHODS AND SAMPLE: A FN risk assessment tool was developed, implemented and evaluated. A comparative prospective observational chart review was undertaken to evaluate the tool. Clinical data were collected from 459 patients' records from August 2008 through July 2009. Patients had no intervention during the first six months (n = 233). Patients in the following six months (n = 226) had the FN risk assessment completed and appropriate granulocyte-colony stimulating factor prescribed. A self-questionnaire was utilised to evaluate the nurses' role in FN risk assessment. KEY RESULTS: The incidence of FN was reduced by 52% (p = 0.02). Hospital days, dose reductions and treatment delays were reduced. Nurses felt they were the most appropriate person to carry out the assessment. CONCLUSIONS: Through consistent risk assessment, nurses could determine which patients were at high risk of developing FN leading to significant reduction in life-threatening infections, hospitalisations, dose reductions and delays. Nurses can be confident and competent in decision-making to reduce life-threatening infections through the use of an FN risk assessment tool.