Real-world survival of Danish patients with HER2-positive metastatic breast cancer.

BACKGROUND: The purpose was to investigate the treatment flow of patients with HER2-positive metastatic breast cancer (mBC), progression-free survival (PFS) and overall survival (OS) across treatment lines and adherence to guidelines (defined as trastuzumab, pertuzumab and chemotherapy first line, where 85% received vinorelbine as backbone and T-DM1 second line). Furthermore, we identified clinical markers to predict the risk of developing brain metastases. MATERIAL AND METHODS: Patients with HER2-positive mBC, diagnosed between 01.01.2014-31.12.2019, registered in the database of the Danish Breast Cancer Group were included in this real-word study. Clinical follow-up was assessed until 01.10.2020 and complete follow-up for overall survival until 01.10.2021. Survival data were analyzed using the Kaplan-Meier method with guidelines adherence analyzed as a time-varying covariate, and the risk of CNS metastasis was estimated by the cumulative incidence function. RESULTS: 631 patients were included. 329 (52%) patients followed the guidelines. The median OS for all patients was 42.3 months (95% Cl, 38.2-48.4), and significantly higher for the patients who followed guidelines; NA (95% CI, 78.2-NA). The median PFS for all patients was 13.4 months (95% Cl, 12.1-14.8), 6.6 (95% Cl, 5.8-7.6) and 5.8 (95% Cl, 4.9-6.9) for first, second and third line of treatment, respectively. Patients with ER-negative mBC had a higher risk of developing brain metastases and patients with high tumor burden had a higher risk of developing brain metastases with an adjusted HR of 0.69 (95% CI, 0.49-0.98), p = 0.047 and 2.69 (95% CI, 1.45-5.00), p = 0.002, respectively. CONCLUSION: We found that only half of the patients with HER2-positive mBC, received first and second-line treatment according to national guidelines. Patients receiving treatment according to guidelines had a significantly higher median OS compared to patients who did not. We also found that patients with ER-negative disease or high tumor burden had a significantly higher risk of developing brain metastases.

Prefrontal Plasticity after a 3-Month Exercise Intervention in Older Adults Relates to Enhanced Cognitive Performance.

This study examined exercise intervention effects on older adults' brain structures and function. Brain data were analyzed from 47 healthy adults between 61 and 82 years of age who, in a previous study, showed cognitive improvement following a 3-month intervention. The participants were assigned to a motor exercise intervention group (n = 24), performing exercise training programs for a 12-week period, or a waiting control group (n = 23), abstaining from any exercise program. Structural analysis of the frontal cortex and hippocampus revealed increased gray matter volume and/or thickness in several prefrontal areas in the intervention group and reduced hippocampal gray matter volume in the control group. Importantly, the volume increase in the middle frontal sulcus in the intervention group was associated with a general cognitive improvement after the intervention. Functional analysis showed that the prefrontal functional connectivity during a working memory task differently changed in response to the intervention or waiting in the two groups. The functional connectivity decreased in the intervention group, whereas the corresponding connectivity increased in the control group, which was associated with maintaining cognitive performance. The current longitudinal findings indicate that short-term exercise intervention can induce prefrontal plasticity associated with cognitive performance in older adults.

Risk of breast cancer in Danish women occupationally exposed to organic solvents, including ethanol.

BACKGROUND: Organic solvents have been suggested to increase the risk of breast cancer although the epidemiologic evidence is limited. This study explored the association between organic solvents and breast cancer. METHODS: This nested population-based case-control study comprised 845 women with primary breast cancer initially identified in the Danish Cancer Registry between 2000 and 2003, and 1500 controls matched on year of birth who were randomly selected from the Danish Civil Registration System. Information on occupational exposure to organic solvents, and specifically ethanol, as well as risk factors for breast cancer was collected through structured interviews. RESULTS: For organic solvents, an increased risk was indicated for ever-exposure (odds ratio = 3.20, 95% confidence interval: 2.27-4.52), however, no noteworthy risk patterns were detected when exploring duration of exposure and cumulative exposure. Ever-exposure to organic solvents was associated with an increased risk of estrogen receptor negative and positive tumors as well as pre- and postmenopausal breast cancer. No associations were detected between occupational exposure to ethanol and breast cancer. CONCLUSIONS: This study indicates a positive association between organic solvents and breast cancer.

Cardiovascular disease in women with breast cancer - a nationwide cohort study.

BACKGROUND: There is increasing concern about cardiovascular disease (CVD) after breast cancer (BC). The aim of this study was to estimate the prevalence of different types of CVD in women diagnosed with BC compared to cancer-free controls as well as the incidence of CVD after BC diagnosis. METHODS: We performed a cohort study based on data from national registries covering the entire Danish population. We followed 16,505 cancer-naïve BC patients diagnosed from 2003 to 2007 5 years before and up to 10 years after BC diagnosis compared to 165,042 cancer-free controls. RESULTS: We found that 15.6% of BC patients were registered with at least one CVD diagnosis in hospital records before BC diagnosis. Overall, BC patients and controls were similar with regard to CVD comorbidity before BC diagnosis. After BC diagnosis, the incidence of all CVD diagnoses combined was significantly higher in BC patients than controls up to approximately 6 years after the index date (BC diagnosis). After 10 years, 28% of both BC patients and controls (without any CVD diagnosis up to 5 years before the index date) had at least one CVD diagnosis according to hospital records. However, the incidence of heart failure, thrombophlebitis/thrombosis and pulmonary heart disease including pulmonary embolism remained higher in BC patients than controls during the entire 10-year follow-up period. After 10 years, 2.7% of BC patients compared to 2.5% of controls were diagnosed with heart failure, 2.7% of BC patients compared to 1.5% of controls were diagnosed with thrombophlebitis/thrombosis, and 1.5% of BC patients compared to 1.0% of controls were diagnosed with pulmonary heart disease according to hospital records. Furthermore, we found that the risk of heart failure and thrombophlebitis/thrombosis was higher after chemotherapy. CONCLUSIONS: Focus on CVD in BC patients is important to ensure optimum treatment with regard to BC as well as possible CVD. Strategies to minimise and manage the increased risk of heart failure, thrombophlebitis/thrombosis and pulmonary heart disease including pulmonary embolism in BC patients are especially important.

Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (ß = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (ß = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.

Mortality from cardiovascular disease in women with breast cancer - a nationwide registry study.

BACKGROUND: Only few existing studies have investigated the mortality from cardiovascular disease (CVD) in women with breast cancer (BC). The aim of this study was to investigate CVD mortality in patients with BC compared with a matched control group without BC using national registry data. MATERIAL AND METHODS: We followed 16,505 Danish women diagnosed with BC in 2003-2007 up to 10 years after BC diagnosis compared with 165,042 matched controls from the general Danish population. The matching criteria included gender, age, region of residence, and education. We performed multivariate Cox regression analyses to investigate the influence of preexisting CVD on mortality. Moreover, we used the cumulative incidence and conditional probability functions to study the risk of CVD-related death in the presence of competing risk, i.e., the risk of dying from other causes than CVD. RESULTS: We found that preexisting CVD increased both overall mortality and CVD mortality in both patients with BC and controls. Furthermore, we found that patients with BC were at lower risk of dying from CVD up to 10 years after BC diagnosis compared with controls. The cumulative incidence of CVD as underlying cause of death was 4.0% in patients with BC and 5.7% in controls after 10 years. The most common CVD-related causes of death were ischemic heart disease including acute coronary syndrome, cerebrovascular accident, heart failure, and atrial fibrillation. DISCUSSION: Our study contributes to the growing body of work on BC and comorbidities and highlights the importance of CVD in individuals with BC. Further studies are needed to confirm our finding that patients with BC are at lower risk of dying from CVD up to 10 years after BC diagnosis compared with a matched control group without BC.

Occupational exposure to solar ultraviolet B radiation and risk of subtypes of breast cancer in Danish women.

OBJECTIVES: Previous epidemiological studies have indicated that solar ultraviolet B radiation (UVR) may have a protective effect on breast cancer. However, the evidence remains inconclusive. Despite the fact that outdoor work history may be considered a reliable measure of long-term UVR exposure, objective information on lifetime employment has not been included in previous investigations focusing on breast cancer. To address this issue, we explored the association between occupational UVR exposure and female breast cancer, including subtypes. METHODS: A total of 38 375 women under the age of 70 years were identified with primary breast cancer using the Danish Cancer Registry. Five female controls born on the same year, alive and free of breast cancer at the time of diagnosis of the index case, were randomly selected from the Danish Civil Registration System. The Danish Supplementary Pension Fund Register was used to retrieve full employment history, and a job exposure matrix was used to assess occupational UVR exposure. Conditional logistic regression with adjustment for important confounders was used to estimate the OR. RESULTS: We observed no overall association between occupational UVR exposure and breast cancer. After the age of 50 years, longer duration of UVR exposure (≥20 years: OR=0.83, 95% CI 0.75 to 0.92) and highest cumulative exposure (OR=0.89, 95% CI 0.83 to 0.95) were inversely associated with risk. Our results did not reflect any notable risk difference by oestrogen receptor status. CONCLUSIONS: This study indicates an inverse association between long-term occupational UVR exposure and late-onset breast cancer. This finding needs further attention in future occupational studies.

Denosumab vs. zoledronic acid treatment in post-menopausal breast cancer: a 2-year prospective observational study.

Adjuvant treatment for post-menopausal women with early breast cancer (BC) includes aromatase inhibitors (AI), known to decrease bone mineral density (BMD). In this study, we investigate whether denosumab is a valid second option for patients unable to receive standard adjuvant i.v. zoledronic acid (ZA). In total, 212 patients have been evaluated after they did not receive ZA. Of those 194 were included. After evaluation by an endocrinologist, all patients were offered ZA as their first choice and 15% accepted (N = 29). The remaining 85% were offered denosumab (N = 165). All patients were followed prospectively with blood tests up to 24 months. DXA scans were performed at baseline and 24 months. No difference was observed between the two treatment groups at baseline, with regard to anthropometry and standard biochemistry. Markers of bone turnover (p-PINP, p-CTX, p-bone-specific alkaline phosphatase and p-osteocalcin) all showed significant suppression compared to baseline and remained suppressed throughout the 2 years. BMD showed small and significant increases at the spine (0.024 g/cm2) and total hip (0.019 g/cm2) in the denosumab group but no change at the femoral neck(-0.011g/cm2). In the ZA group, we observed no significant change at the spine (0.015 g/cm2) and total hip (-0.001g/cm2) and a small significant decrease at the femoral neck (-0.037 g/cm2). However, when we compared BMD change between the treatment groups, we found no significant difference.Conclusions: Our data indicate that for BC patients in AI treatment who refused or were not able to receive ZA treatment, denosumab might be recommended as a second choice. Regarding markers of bone turnover and BMD denosumab is equal to ZA.Summary: Women with early breast cancer receiving anti-estrogen treatment are at risk of developing osteoporosis.We followed 194 women receiving zoledronic acid (ZA) or denosumab for up to 2 years.We find that with regard to bone protection, denosumab is a viable alternative to ZA and might be recommended as a second choice.

Patterns in detection of recurrence among patients treated for breast cancer.

PURPOSE: The Danish follow-up program for breast cancer (BC) patients has recently been changed. Today most patients are offered open access to an outpatient clinic, whereas the scheduled visits are phased out. This strategy has been studied in regards to psychological and health-related quality of life outcomes, but not in regards to detection of recurrence and survival. The aim of this study was to quantify the recurrences detected at scheduled outpatient visits in Denmark before the implementation of revised follow-up guidelines. METHODS: We conducted a cross-sectional study among 310 patients with recurrent BC. Information was retrieved on tumor characteristics, type of visit when recurrence was detected, recurrence localization, symptoms reported, and duration of symptoms from the Danish Breast Cancer Group database and medical records. RESULTS: The recurrences were locoregional (26%), locoregional and distant (15%), or distant (59%). Among patients still in outpatient follow-up (n = 199), recurrence was detected at a patient-requested extra outpatient visit (15%), by the general practitioner or other specialist (47%), at a scheduled outpatient visit (21%), or on a scheduled mammogram (11%). Among patients with recurrences detected at scheduled outpatient visits, the majority (88%) reported symptoms related to the recurrence. Most frequent symptoms were pain (37%), dyspnoea (15%), and fatigue (12%). CONCLUSIONS: One-fifth of BC recurrences among patients attending outpatient follow-up were detected at scheduled outpatient visits. Very few of these were asymptomatic. Whether there will be a delay in detection of the symptomatic recurrences when the number of visits is reduced is unknown.

Leukocyte nadir as a predictive factor for efficacy of adjuvant chemotherapy in breast cancer. Results from the prospective trial SBG 2000-1.

Background: Retrospective studies have suggested that chemotherapy-induced leukopenia is associated with improved recurrence-free or overall survival. The SBG 2000-1 trial was designed to verify the favorable prognosis associated with chemotherapy-induced leukopenia in early breast cancer. Patients not experiencing chemotherapy-induced leukopenia were randomized into standard dosed or individually escalated chemotherapy doses based on the grade of leukopenia after a first standard dose.Patients and methods: 1452 women in Sweden and Denmark with operable node-positive or high-risk node-negative breast cancer aged 18-60 years were recruited to participate in this trial. Participants received a first FEC cycle at standard doses (600/60/600 mg/m2). Patients (n = 1052) with nadir leukopenia grade 0-2 after the first cycle were randomized between either 6 standard FEC or 6 tailored FEC courses with doses of epirubicin and cyclophosphamide escalated during courses 2 and 3 and thereafter aimed at achieving grade 3 leukopenia. Patients with nadir leukopenia grade 3-4 after the first course continued treatment with standard FEC. Results of the randomized comparison has been published previously. The present study focuses on chemotherapy-induced leukopenia as a covariable with outcome in randomized and non-randomized patients. The prognostic value of leukopenia after course 3, was studied in a Cox model adjusted for cumulative doses of epirubicin and cyclophosphamide. The association of chemotherapy-induced leukopenia with prognosis was a preplanned secondary endpoint for this trial.Results: The eight-year distant disease-free survival was 73%, 77%, 78% and 83% for patients with leucocyte nadir grade 0, 1, 2 and 3-4, respectively. Higher degree of leukopenia was highly significantly associated to improved distant disease-free survival (HR 0.84, 95% CI 0.74-0.96, p = .008) and overall survival (HR 0.87 (0.76-0.99, p = .032).Conclusion: This prospective study confirms that chemotherapy-induced leukopenia is a covariable with outcome in primary breast cancer, even after adjustment for chemotherapy doses.

Occupational exposure to specific organic solvents and risk of subtypes of breast cancer in a large population of Danish women, 1964-2016.

OBJECTIVE: To explore associations between occupational exposure to four specific organic solvents, respectively, and female breast cancer, including subtypes. METHODS: Using the Danish Cancer Registry, we identified 38 375 women under age 70 years with primary breast cancer. Five randomly selected breast-cancer-free controls per case matched on year of birth were retrieved from the Danish Civil Registration System . A nationwide pension fund was used to retrieve full employment history, and exposure to 1,1,1-trichloroethane, trichloroethylene (TCE), benzene and toluene was assessed using a job exposure matrix. ORs were estimated using conditional logistic regression with adjustment for reproductive factors and socioeconomic status. RESULTS: Overall results indicated no noteworthy associations between the specific organic solvents and breast cancer before and after age 50 years, except for a small increased risk after age 50 in women exposed to TCE (OR=1.15, 95% CI: 0.97-1.36). After age 50 years, exposure to TCE was associated with a small increased risk in women with over 20 years of latency (OR=1.26, 95% CI: 1.02-1.56). Further, an increased risk of oestrogen receptor positive (ER+) tumours was also observed (OR=1.21, 95% CI: 1.01-1.47), and high cumulative exposure and longer latency also increased the risk of this subtype. CONCLUSION: This study provides limited evidence supporting the association between occupational exposure to each of the four organic solvents and breast cancer. The risk of ER+ breast tumours after age 50 years may be increased in women with TCE exposure, and this possible association therefore needs further attention in future studies.

Statin use and risk of contralateral breast cancer: a nationwide cohort study.

BACKGROUND: Statins have demonstrated antineoplastic effects in breast cancer cell lines, particularly in oestrogen receptor (ER)-negative cell lines. However, epidemiological studies have not supported a preventive effect of statin use against breast cancer. Therefore, we examined the association between statin use and contralateral breast cancer (CBC) risk among women with breast cancer. METHODS: We identified 52,723 women with non-metastatic breast cancer during 1996-2012 from the Danish Breast Cancer Group database. We defined time-varying post-diagnosis statin use as minimum two prescriptions lagged by 1 year. Cox regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with statin use. RESULTS: Statin use was associated with a lower CBC risk (HR = 0.88; 95% CI = 0.73-1.05). The inverse association was strongest for long-term use overall (HR = 0.64; 95% CI = 0.43-0.96), although the HR specifically for long-term consistent use and high-intensity use approached unity. Among ER-negative breast cancer patients, statin use was associated with a CBC risk reduction (HR = 0.67; 95% CI = 0.45-1.00). CONCLUSIONS: We found some indication that statins reduce the risk of CBC. Further evaluations are needed to disentangle the equivocal results for long-term use and to establish if ER-negative breast cancer patients may benefit most from statin use.

Mortality after contralateral breast cancer in Denmark.

PURPOSE: How a second breast cancer diagnosis affects survival in comparison with unilateral breast cancer (UBC) is unclear. Prognostic factors for contralateral breast cancer (CBC) are also not well established. We aimed to investigate the survival pattern after CBC with particular focus on time between first and second breast cancer diagnosis and age at CBC diagnosis. METHODS: Within the nationwide Danish Breast Cancer Cooperative Group database, we identified 68,466 breast cancer patients diagnosed during 1978-2012. Patients who subsequently developed CBC were identified in a previously established database (N = 3004). Patients were followed for breast cancer-specific death in the Danish Register of Causes of Death until 2015. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard regression models. Cumulative breast cancer mortality from date of CBC was estimated using the Aalen-Johansen method. RESULTS: Compared with UBC patients, the rate of dying from breast cancer was more than twofold higher following a CBC diagnosis, after adjustment for age, period, tumor characteristics, and treatment of the first breast cancer (HR 2.48; 95% CI 2.31-2.66). Short time interval (< 5 years) was associated with higher breast cancer-specific mortality after CBC among patients < 70 years at CBC diagnosis compared with longer time intervals, but not among patients ≥ 70 years at CBC diagnosis. CONCLUSION: Breast cancer-specific mortality rates were markedly higher after compared with before a CBC diagnosis. We found higher breast cancer-specific mortality after CBC associated with a short interval between diagnoses among patients diagnosed with CBC before age 70 years.

Efficacy and Safety of Pertuzumab and Trastuzumab Administered in a Single Infusion Bag, Followed by Vinorelbine: VELVET Cohort 2 Final Results.

BACKGROUND: VELVET Cohort 1 demonstrated the applicability of pertuzumab, trastuzumab, and vinorelbine as an alternative first-line treatment regimen for patients with HER2-positive locally advanced or metastatic breast cancer (MBC) who cannot receive docetaxel. Co-infusion of pertuzumab and trastuzumab may reduce clinic time and medical resource utilization. We report results from Cohort 2, in which pertuzumab and trastuzumab were co-infused, followed by vinorelbine. PATIENTS AND METHODS: During cycle 1, patients with HER2-positive locally advanced or MBC received loading doses of pertuzumab (840 mg) and trastuzumab (8 mg/kg) on consecutive days, followed by vinorelbine (25 mg/m2) on days two and nine. From cycle 2 onwards, patients received a co-infusion of pertuzumab (420 mg) and trastuzumab (6 mg/kg) on day one, followed by vinorelbine (30-35 mg/m2) on days one and eight (or days two and nine). The primary endpoint was objective response rate (ORR) in patients with measurable disease. Secondary endpoints included progression-free survival (PFS) and safety. RESULTS: Cohort 2 enrolled 107 patients. The ORR was 63.7% (95% confidence interval [CI] 53.0-73.6) in patients with measurable disease (91/107; 85.0%). Median PFS was 11.5 months (95% CI 10.3-15.8). The most common adverse events [AEs] were diarrhea (57.9%), neutropenia (57.0%), and nausea (41.1%). Grade ≥3 AEs occurred in 85 patients (79.4%) and serious AEs in 44 patients (41.1%). Eighteen patients (16.8%) had AEs suggestive of congestive heart failure. CONCLUSION: These results support the feasibility of pertuzumab and trastuzumab co-infusion from a safety perspective and support Cohort 1 conclusions that vinorelbine offers an alternative chemotherapy companion for pertuzumab and trastuzumab. The Oncologist 2017;22:1160-1168 IMPLICATIONS FOR PRACTICE: Combined treatment with pertuzumab, trastuzumab, and docetaxel is the standard of care for first-line HER2-positive metastatic breast cancer. However, some patients cannot, or choose not to, receive docetaxel. VELVET Cohort 2 results support the results from Cohort 1 that suggest that pertuzumab plus trastuzumab and vinorelbine is a suitable alternative for these patients. In addition to this, results from Cohort 2 support the feasibility of administering pertuzumab and trastuzumab together in a single infusion bag, which has the potential to offer greater patient convenience and reduce active health care professional time and medical resource utilization compared with administering them separately.

The effects of individually tailored nurse navigation for patients with newly diagnosed breast cancer: a randomized pilot study.

AIM: Our aim was to determine the feasibility and effectiveness of an individual, nurse-navigator intervention for relieving distress, anxiety, depression and health-related quality of life in women who have been treated for breast cancer (BC) and are experiencing moderate-to-severe psychological and physical symptoms. METHODS: Fifty women with newly diagnosed BC who reported distress (score ≥7 on distress thermometer) before surgery were included consecutively in a pilot study and randomized 1:1 to the intervention or the control group. The intervention comprised repeated screening with patient reported outcome measures and nurse navigation. A total of 66 women who were not distressed (score <7) were followed longitudinally as an observational group. Participants filled in four questionnaires, at baseline, after 6 months and 12 months. The primary outcome was psychological distress and the secondary outcomes were anxiety, depression, health-related quality of life and feasibility of the intervention. RESULTS: Women in the intervention group reported significantly greater satisfaction with treatment and rehabilitation and lower levels of distress (mean 2.7 vs. 5.1, p<.01), anxiety (mean 5.1 vs. 7.8, p = .02) and depression (mean 2.2 vs. 4.4, p = .04) after 12 months compared to the control group. No significant effects were seen on health-related quality of life. CONCLUSIONS: The study shows promising feasibility of the individually tailored nurse-navigation intervention and while no significant effects were observed after 6 months, we did find statistically significant effects on distress, anxiety and depression 12 months after diagnosis. Our results will assist in developing rehabilitation to the most vulnerable patients.

Safety and efficacy of vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer: VELVET Cohort 1 final results.

BACKGROUND: Pertuzumab, trastuzumab, and docetaxel is standard of care for first-line treatment of HER2-positive metastatic breast cancer (MBC). However, alternative chemotherapy partners are required to align with patient/physician preferences and to increase treatment flexibility. We report VELVET Cohort 1 results in which the efficacy and safety of pertuzumab and trastuzumab, administered sequentially in separate infusions, followed by vinorelbine, were evaluated. Cohort 2, where pertuzumab and trastuzumab were administered in a single infusion, followed by vinorelbine, recruited after Cohort 1 was fully enrolled, will be reported later. METHODS: In this multicenter, two-cohort, open-label, phase II study, patients with HER2-positive locally advanced or MBC who had not received chemotherapy or biological therapy for their advanced disease received 3-weekly pertuzumab (840 mg loading, 420 mg maintenance doses) and trastuzumab (8 mg/kg loading, 6 mg/kg maintenance doses), followed by vinorelbine (25 mg/m2 initial dose, 30-35 mg/m2 maintenance doses) on days 1 and 8 or 2 and 9 of each 3-weekly cycle. Study treatment was given until investigator-assessed disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) in patients with measurable disease at baseline per RECIST v1.1. Secondary endpoints included progression-free survival (PFS) and safety. RESULTS: Cohort 1 enrolled 106 patients. Investigator-assessed ORR was 74.2% (95% CI 63.8-82.9) in intent-to-treat patients with measurable disease (89/106 [84.0%]). Median PFS was 14.3 months (95% CI 11.2-17.5) in the intent-to-treat population. Treatment was reasonably well tolerated, with no unexpected toxicities. Diarrhea (61/106 patients [57.5%]) and neutropenia (54/106 [50.9%]) were the most common adverse events (AEs); neutropenia (33/106 [31.1%]) and leukopenia (14/106 [13.2%]) were the most common grade ≥3 AEs. Serious AEs were reported in 32/106 (30.2%) patients. AEs led to study drug discontinuation in 36/106 patients (34.0%). Eighteen of 106 patients (17.0%) had AEs suggestive of congestive heart failure; however, there were no confirmed cases. CONCLUSIONS: The vinorelbine, pertuzumab, and trastuzumab combination is active and reasonably well tolerated. This regimen offers an alternative for patients who cannot receive docetaxel for first-line treatment of HER2-positive locally advanced or MBC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01565083 , registered on 26 March 2012.

Systemic therapy for breast cancer and risk of subsequent contralateral breast cancer in the WECARE Study.

BACKGROUND: Treatment with tamoxifen or chemotherapy reduces the risk of contralateral breast cancer (CBC). However, it is uncertain how long the protection lasts and whether the protective effect is modified by patient, tumor, or treatment characteristics. METHODS: The population-based WECARE Study included 1521 cases with CBC and 2212 age- and year of first diagnosis-matched controls with unilateral breast cancer recruited during two phases in the USA, Canada, and Denmark. Women were diagnosed with a first breast cancer before age 55 years during 1985-2008. Abstraction of medical records provided detailed treatment information, while information on risk factors was obtained during telephone interviews. Risk ratios (RRs) and 95 % confidence intervals (CIs) for CBC were obtained from multivariable conditional logistic regression models. RESULTS: Compared with never users of tamoxifen, the RR of CBC was lower for current users of tamoxifen (RR = 0.73; 95 % CI = 0.55-0.97) and for past users within 3 years of last use (RR = 0.73; 95 % CI = 0.53-1.00). There was no evidence of an increased risk of estrogen receptor-negative CBC associated with ever use of tamoxifen or use for 4.5 or more years. Use of chemotherapy (ever versus never use) was associated with a significantly reduced RR of developing CBC 1-4 years (RR = 0.59; 95 % CI = 0.45-0.77) and 5-9 years (RR = 0.73; 95 % CI = 0.56-0.95) after first breast cancer diagnosis. RRs of CBC associated with tamoxifen or with chemotherapy use were independent of age, family history of breast cancer, body mass index and tumor characteristics of the first breast cancer with the exception that the RR of CBC was lower for lobular histology compared with other histologies. CONCLUSION: Our findings are consistent with previous studies showing that treatment with tamoxifen or chemotherapy is associated with a lower risk of CBC although the risk reduction appears to last for a limited time period after treatment is completed.

Increased pancreatic cancer risk following radiotherapy for testicular cancer.

BACKGROUND: Pancreatic cancer risk is elevated among testicular cancer (TC) survivors. However, the roles of specific treatments are unclear. METHODS: Among 23 982 5-year TC survivors diagnosed during 1947-1991, doses from radiotherapy to the pancreas were estimated for 80 pancreatic cancer patients and 145 matched controls. Chemotherapy details were recorded. Logistic regression was used to estimate odds ratios (ORs). RESULTS: Cumulative incidence of second primary pancreatic cancer was 1.1% at 30 years after TC diagnosis. Radiotherapy (72 (90%) cases and 115 (80%) controls) was associated with a 2.9-fold (95% confidence interval (CI) 1.0-7.8) increased risk. The OR increased linearly by 0.12 per Gy to the pancreas (P-trend<0.001), with an OR of 4.6 (95% CI 1.9-11.0) for ⩾25 Gy vs <25 Gy. Radiation-related risks remained elevated ⩾20 years after TC diagnosis (P=0.020). The risk increased with the number of cycles of chemotherapy with alkylating or platinum agents (P=0.057), although only one case was exposed to platinum. CONCLUSIONS: A dose-response relationship exists between radiation to the pancreas and subsequent cancer risk, and persists for over 20 years. These excesses, although small, should be considered when radiotherapy with exposure to the pancreas is considered for newly diagnosed patients. Additional data are needed on the role of chemotherapy.

Antenna-integrated 0.6 THz FET direct detectors based on CVD graphene.

We present terahertz (THz) detectors based on top-gated graphene field effect transistors (GFETs) with integrated split bow-tie antennas. The GFETs were fabricated using graphene grown by chemical vapor deposition (CVD). The THz detectors are capable of room-temperature rectification of a 0.6 THz signal and achieve a maximum optical responsivity better than 14 V/W and minimum optical noise-equivalent power (NEP) of 515 pW/Hz(0.5). Our results are a significant improvement over previous work on graphene direct detectors and are comparable to other established direct detector technologies. This is the first time room-temperature direct detection has been demonstrated using CVD graphene, which introduces the potential for scalable, wafer-level production of graphene detectors.