Immediate evaluation of global longitudinal strain at initiation of trastuzumab treatment in breast cancer patients.

BACKGROUND: Global longitudinal strain (GLS) is recommended to detect subclinical changes preceding reduced left ventricular ejection fraction (LVEF) in trastuzumab related cardiotoxicity. Since the possibility to detect signs of acute myocardial deterioration at treatment initiation is not clarified, the objective of this study was to assess changes in GLS and biomarkers within the first 2 weeks of trastuzumab treatment. METHODS: In a prospective cohort study, 45 patients with non-metastatic breast cancer (age 54, LVEF 62.8%, GLS -19.9%, 40% hypertension) scheduled for trastuzumab treatment were included. Echocardiography and measurement of troponin and NT-proBrain-Natriuretic-Peptide were conducted before initiation of trastuzumab, at days 3, 7, and 14 and after 3, 6, and 9 months. RESULTS: A significant deterioration in LVEF from 62.8% (SD±3.6) to 58.4% (SD±4.1) (p < 0.0001), GLS from -19.9 (SD±2.1) to -18.1 (SD±2.5) (p = 0.004), s' (p < 0.0001), e' septal (p = 0.008), and s' RV (p < 0.0001) occurred at 9 months and was preceded by significant changes in these parameters within the first 14 days. After 14 days, 12 patients (27%) had a ≥10% deterioration in GLS, which was associated with significantly lower LVEF at 55.2% (SD±4.1) at 9 months compared to patients with < 10% early deterioration in GLS (LVEF = 59.5% (SD±3.5) (p = 0.001)). No difference in plasma concentrations of biomarkers was observed between the two groups. CONCLUSION: In this study deteriorations in key echocardiographic parameters within normal limits were detected during the first 2 weeks of trastuzumab treatment, and an early ≥10% deterioration in GLS was associated with a lower LVEF at 9 months.

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.

Codebook for rating clinical communication skills based on the Calgary-Cambridge Guide.

BACKGROUND: The aim of the study was to confirm the validity and reliability of the Observation Scheme-12, a measurement tool for rating clinical communication skills. METHODS: The study is a sub-study of an intervention study using audio recordings to assess the outcome of communication skills training. This paper describes the methods used to validate the assessment tool Observation Scheme-12 by operationalizing the crude 5-point scale into specific elements described in a codebook. Reliability was tested by calculating the intraclass correlation coefficients for interrater and intrarater reliability. RESULTS: The validation of the Observation Scheme-12 produced a rating tool with 12 items. Each item has 0 to 5 described micro-skills. For each item, the codebook described the criteria for delivering a rating from 0 to 4 depending on how successful the different micro-skills (or number of used jargon words) was accomplished. Testing reliability for the overall score intraclass correlation coefficients was 0.74 for interrater reliability and 0.86 for intrarater reliability. An intraclass correlation coefficient greater than 0.5 was observed for 10 of 12 items. CONCLUSION: The development of a codebook as a supplement to the assessment tool Observation Scheme-12 enables an objective rating of audiotaped clinical communication with acceptable reliability. The Observation Scheme-12 can be used to assess communication skills based on the Calgary-Cambridge Guide.

Effect of selenium supplementation on changes in HbA1c: Results from a multiple-dose, randomized controlled trial.

AIM: To investigate the effect of selenium supplementation at different dose levels on changes in HbA1c after 6 months and 2 years in a population of low selenium status. MATERIALS AND METHODS: The Denmark PRECISE study was a single-centre, randomized, double-blinded, placebo-controlled, multi-arm, parallel clinical trial with four groups. In total, 491 volunteers aged 60 to 74 years were randomly assigned to treatment with 100, 200 or 300 µg selenium/day as selenium-enriched yeast or placebo-yeast. HbA1c measurements were available for 489 participants at baseline, 435 at 6 months, and 369 after 2 years of selenium supplementation. Analyses were performed by intention to treat. RESULTS: The mean (SD) age, plasma-selenium concentration, and blood HbA1c at baseline were 66.1 (4.1) years, 86.5 (16.3) ng/g and 36.6 (7.0) mmol/mol, respectively. During the initial 6-month intervention period, mean HbA1c (95% CI) decreased by 1.5 (-2.8 to -0.2) mmol/mol for 100 µg/d of selenium supplementation and by 0.7 (-2.0 to 0.6) mmol/mol for the 200 and 300 µg/d groups compared with placebo (P = 0.16 for homogeneity of changes across the four groups). After 2 years of selenium supplementation, HbA1c had decreased significantly in all treatment groups, with no difference between active treatment and placebo. CONCLUSIONS: Selenium supplementation in an elderly European population of low selenium status did not significantly affect HbA1c levels after 2 years. Our findings corroborate a possible U-shaped response of selenium supplementation on glucose metabolism.

Treatment of advanced HR+/HER2- breast cancer with new targeted agents in combination with endocrine therapy: a review of efficacy and tolerability based on available randomized trials on everolimus, ribociclib, palbociclib and abemaciclib.

INTRODUCTION: Recently, new targeted agents have been developed, which can prolong the effect of endocrine treatment (ET) by targeting resistance pathways in HR+/HER2- advanced breast cancer. This review examines available studies of everolimus, an mTOR inhibitor, and the CDK 4/6 inhibitors ribociclib, palbociclib and abemaciclib in terms of efficacy, tolerability and safety. MATERIAL AND METHODS: A systematic literature search was performed in Pubmed. Evaluation of the quality of the identified studies was based on selected elements from the GRADE guidelines. RESULTS: The literature search yielded eight randomized trials that all presented a significant increase in the progression free survival (PFS)/time to progression (TTP) for the targeted agents plus ET vs ET only. The improvement was evident as first-line therapy with an increase in PFS of 10-11 months when adding a CDK4/6 inhibitor to ET, as well as in patients previously treated for metastatic disease, with an increase of 5-6 months. The common adverse events (AEs) of the CDK 4/6 inhibitors were due to myelosuppression. In addition, abemaciclib was associated with liver toxicity and diarrhea, and ribociclib with liver toxicity and QTcF prolongation. The most common grade 3/4 AE of everolimus was stomatitis. The majority (five) of the trials had no serious limitations, and thus the quality of evidence was high. DISCUSSION: The new targeted agents are all associated with an improvement of the PFS with an acceptable tolerability, and they should be offered to women with advanced HR+/HER2- breast cancer both as first-line therapy as well as among patients previously treated in metastatic regimens. However, further data regarding the impact on overall survival are required to evaluate the full benefit for patients. Price and differences in AEs could become substantial arguments for the choice of therapy for the individual patient.

Translation and cultural adaptation of the Communication Assessment Tool (CAT), developing a Danish and Norwegian version.

OBJECTIVE: To translate and cultural adapt the 14-item Communication Assessment Tool (CAT) into Norwegian and Danish, making them as similar as possible. DESIGN: This was a translation and validation study including individual interviews for content and face validity and a patient survey for internal consistency and floor-ceiling effect. SETTING: Outpatient clinic at the Department of Internal Medicine, Lillebaelt Hospital, Denmark and a Norwegian general practice. PARTICIPANTS: Ten patients were included for individual interviews and 440 participants completed the survey. MAIN OUTCOME MEASURE: Translation and validation of the CAT. RESULTS: Despite minor differences in the use of words in the translated versions of CAT, the final versions were very similar. Based on the content and face validation and after agreement with the developers, it was decided to include a 'non-applicable' answering option, not a part of the original version. The use of 'non-applicable' for each item ranged from 0% to 30% in Norway and from 0% to 6.1% in Denmark. The overall CAT score, i.e. items rated excellent, were 55.5% in Norway and 50.3% in Denmark. For each item, the CAT score ranged between 31.3% and 69.8% in Norway and 33.7% and 57.4% in Denmark. CONCLUSION: The translated and validated CAT can be used to measure patients' perspectives on clinicians' communication skills in Denmark and Norway.

Trends in breast cancer in the elderly in Denmark, 1980-2012.

BACKGROUND: Breast cancer is the most frequent malignancy among women worldwide and the second most common cause of cancer-related death in developed countries. The aim of the present analysis is to describe trends in incidence, mortality, prevalence, and relative survival in Denmark from 1980 to 2012 focusing on age, comparing persons aged 70 years or more with those aged less than 70 years. MATERIAL AND METHODS: Cancer of the breast was defined as ICD-10 code C50. Data derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. RESULTS: The proportion of patients diagnosed with breast cancer over the age of 70 years increased with time to 29% of women and 44% of men in 2012. Incidence rates increased with time and peaked around 2010 in all age groups except for those aged 90 years or more. Mortality rates were clearly separated by age with increasing mortality rates by increasing age group for both women and men. Relative survival increased over time in all age groups, but patients aged 70 years or more had a poorer relative survival than those aged less than 70 years. In 2012, 58 521 persons (all ages) were alive in Denmark after a diagnosis of breast cancer. CONCLUSION: Poorer survival of Danish breast cancer patients over the age of 70 years is likely to be due to inferior treatment and non-adherence to treatment guidelines. There is a need for clinical trials focusing on patients over the age of 70 years.

Long non-coding RNA expression profiles predict metastasis in lymph node-negative breast cancer independently of traditional prognostic markers.

INTRODUCTION: Patients with clinically and pathologically similar breast tumors often have very different outcomes and treatment responses. Current prognostic markers allocate the majority of breast cancer patients to the high-risk group, yielding high sensitivities in expense of specificities below 20%, leading to considerable overtreatment, especially in lymph node-negative patients. Seventy percent would be cured by surgery and radiotherapy alone in this group. Thus, precise and early indicators of metastasis are highly desirable to reduce overtreatment. Previous prognostic RNA-profiling studies have only focused on the protein-coding part of the genome, however the human genome contains thousands of long non-coding RNAs (lncRNAs) and this unexplored field possesses large potential for identification of novel prognostic markers. METHODS: We evaluated lncRNA microarray data from 164 primary breast tumors from adjuvant naïve patients with a mean follow-up of 18 years. Eighty two patients who developed detectable distant metastasis were compared to 82 patients where no metastases were diagnosed. For validation, we determined the prognostic value of the lncRNA profiles by comparing the ability of the profiles to predict metastasis in two additional, previously-published, cohorts. RESULTS: We showed that lncRNA profiles could distinguish metastatic patients from non-metastatic patients with sensitivities above 90% and specificities of 64-65%. Furthermore; classifications were independent of traditional prognostic markers and time to metastasis. CONCLUSIONS: To our knowledge, this is the first study investigating the prognostic potential of lncRNA profiles. Our study suggest that lncRNA profiles provide additional prognostic information and may contribute to the identification of early breast cancer patients eligible for adjuvant therapy, as well as early breast cancer patients that could avoid unnecessary systemic adjuvant therapy. This study emphasizes the potential role of lncRNAs in breast cancer prognosis.

Randomised controlled trial of the effect of long-term selenium supplementation on plasma cholesterol in an elderly Danish population.

Although cross-sectional studies have shown a positive association between Se and cholesterol concentrations, a recent randomised controlled trial in 501 elderly UK individuals of relatively low-Se status found that Se supplementation for 6 months lowered total plasma cholesterol. The Danish PRECISE (PREvention of Cancer by Intervention with Selenium) pilot study (ClinicalTrials.gov ID: NCT01819649) was a 5-year randomised, double-blinded, placebo-controlled trial with four groups (allocation ratio 1:1:1:1). Men and women aged 60-74 years (n 491) were randomised to 100 (n 124), 200 (n 122) or 300 (n 119) µg Se-enriched yeast or matching placebo-yeast tablets (n 126) daily for 5 years. A total of 468 participants continued the study for 6 months and 361 participants, equally distributed across treatment groups, continued for 5 years. Plasma samples were analysed for total and HDL-cholesterol and for total Se concentrations at baseline, 6 months and 5 years. The effect of different doses of Se supplementation on plasma lipid and Se concentrations was estimated by using linear mixed models. Plasma Se concentration increased significantly and dose-dependently in the intervention groups after 6 months and 5 years. Total cholesterol decreased significantly both in the intervention groups and in the placebo group after 6 months and 5 years, with small and nonsignificant differences in changes in plasma concentration of total cholesterol, HDL-cholesterol, non-HDL-cholesterol and total:HDL-cholesterol ratio between intervention and placebo groups. The effect of long-term supplementation with Se on plasma cholesterol concentrations or its sub-fractions did not differ significantly from placebo in this elderly population.

Ensemble-based classification using microRNA expression identifies a breast cancer patient subgroup with an ultralow long-term risk of metastases.

BACKGROUND: Current clinical markers overestimate the recurrence risk in many lymph node negative (LNN) breast cancer (BC) patients such that a majority of these low-risk patients unnecessarily receive systemic treatments. We tested if differential microRNA expression in primary tumors allows reliable identification of indolent LNN BC patients to provide an improved classification tool for overtreatment reduction in this patient group. METHODS: We collected freshly frozen primary tumors of 80 LNN BC patients with recurrence and 80 recurrence-free patients (mean follow-up: 20.9 years). The study comprises solely systemically untreated patients to exclude that administered treatments confound the metastasis status. Samples were pairwise matched for clinical-pathological characteristics to minimize dependence of current markers. Patients were classified into risk-subgroups according to the differential microRNA expression of their tumors via classification model building with cross-validation using seven classification methods and a voting scheme. The methodology was validated using available data of two independent cohorts (n = 123, n = 339). RESULTS: Of the 80 indolent patients (who would all likely receive systemic treatments today) our ultralow-risk classifier correctly identified 37 while keeping a sensitivity of 100% in the recurrence group. Multivariable logistic regression analysis confirmed independence of voting results from current clinical markers. Application of the method in two validation cohorts confirmed successful classification of ultralow-risk BC patients with significantly prolonged recurrence-free survival. CONCLUSION: Profiles of differential microRNAs expression can identify LNN BC patients who could spare systemic treatments demanded by currently applied classifications. However, further validation studies are required for clinical implementation of the applied methodology.

Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer.

Expression of HOX transcript antisense intergenic RNA (HOTAIR)--a long non-coding RNA--has been examined in a variety of human cancers, and overexpression of HOTAIR is correlated with poor survival among breast, colon, and liver cancer patients. In this retrospective study, we examine HOTAIR expression in 164 primary breast tumors, from patients who do not receive adjuvant treatment, in a design that is paired with respect to the traditional prognostic markers. We show that HOTAIR expression differs between patients with or without a metastatic endpoint, respectively. Survival analysis shows that high HOTAIR expression in primary tumors is significantly associated with worse prognosis independent of prognostic markers (P = 0.012, hazard ratio (HR) 1.747). This association is even stronger when looking only at estrogen receptor (ER)-positive tumor samples (P = 0.0086, HR 1.985). In ER-negative tumor samples, we are not able to detect a prognostic value of HOTAIR expression, probably due to the limited sample size. These results are successfully validated in an independent dataset with similar associations (P = 0.018, HR 1.825). In conclusion, our findings suggest that HOTAIR expression may serve as an independent biomarker for the prediction of the risk of metastasis in ER-positive breast cancer patients.

Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study.

BACKGROUND: Women treated for breast cancer (BC) often suffer genitourinary syndrome of menopause. These symptoms may be alleviated by vaginal estrogen therapy (VET) or menopausal hormone therapy (MHT). However, there are concerns of risks of recurrence of BC and death following treatment. METHODS: Our study included longitudinal data from a national cohort of postmenopausal women, diagnosed 1997-2004 with early-stage invasive estrogen receptor-positive nonmetastatic BC, who received no treatment or 5 years of adjuvant endocrine therapy. We ascertained prescription data on hormone therapy, VET or MHT, from a national prescription registry. We evaluated mortality and risk of recurrence associated with use of VET and MHT vs non-use using multivariable models adjusted for potential confounders. RESULTS: Among 8461 women who had not received VET or MHT before BC diagnosis, 1957 and 133 used VET and MHT, respectively, after diagnosis. Median follow-up was 9.8 years for recurrence and 15.2 years for mortality. The adjusted relative risk of recurrence was 1.08 (95% confidence interval [CI] = 0.89 to 1.32) for VET (1.39 [95% CI = 1.04 to 1.85 in the subgroup receiving adjuvant aromatase inhibitors]) and 1.05 (95% CI = 0.62 to 1.78) for MHT. The adjusted hazard ratios for overall mortality were 0.78 (95% CI = 0.71 to 0.87) and 0.94 (95% CI = 0.70 to 1.26) for VET and MHT, respectively. CONCLUSIONS: In postmenopausal women treated for early-stage estrogen receptor-positive BC, neither VET nor MHT was associated with increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors.

Long-Term Selenium-Yeast Supplementation Does Not Affect Bone Turnover Markers: A Randomized Placebo-Controlled Trial.

Higher selenium status has been associated with lower bone turnover markers (BTM) in epidemiological studies. However, the long-term impact of selenium supplementation on BTMs has not been studied. We investigated the effects of selenium supplementation on BTMs including osteocalcin (OC), procollagen type I N-terminal propeptide (PINP), collagen type I cross-linked C-telopeptide (CTX), and bone alkaline phosphatase (BALP) in the short (6 months) and long term (5 years). A total of 481 Danish men and women (60-74 years) were randomized to receive placebo-yeast versus 100, 200, or 300 µg selenium as selenium-enriched yeast daily for 5 years. Plasma selenium concentration was measured using inductively coupled plasma mass spectrometry, and BTMs were measured in nonfasted samples at baseline, 6 months, and 5 years. Data were analyzed by ANCOVA to investigate the shape of the dose-response relationships. Covariates included age, body mass index, baseline selenium status, baseline BTM, smoking, alcohol, supplement use, and medication. Plasma selenium concentration (mean 86.5 µg/d at baseline) increased significantly with increasing selenium supplementation to 152.6, 209.1, and 253.7 µg/L after 6 months and remained elevated at 5 years (158.4, 222.4, and 275.9 µg/L for 100, 200, and 300 µg supplemental selenium/d, respectively (p < 0.001)). There was no change in plasma selenium concentration in the placebo-treated group. There was no significant effect of selenium supplementation on OC (6 months p = 0.37; 5 years p = 0.63), PINP (6 months p = 0.37; 5 years p = 0.79), CTX (6 months p = 0.91; 5 years p = 0.58) or BALP (6 months p = 0.17; 5 years p = 0.53). The relatively replete baseline selenium status in the study participants may explain this lack of effect. Testing in more deficient populations may provide further insights into the impact of selenium supplementation on bone health. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

No difference in the frequency of locus-specific methylation in the peripheral blood DNA of women diagnosed with breast cancer and age-matched controls.

There is no doubt that aberrant somatic (tumor-specific) methylation significantly contributes to the carcinogenic process. However, the question of the relevance of methylation pattern changes, acquired by individuals during their development and lifetime or inherited through the germline, to the pathology of different diseases, remains open. Recently, a number of studies addressed the question of the prevalence of aberrant methylation of cancer-related genes in peripheral blood leukocyte (PBL) DNA and indicated a strong possibility that the presence of constitutional methylation of different genes might predispose for cancer development. Here, we have used the methlyation-sensitive high-resolution melting approach to examine the methylation status of the BRCA1, BRCA2, APC, RASSF1A and RARß2 genes in PBLs of a group of women diagnosed with breast cancer, and an age-matched control group with no signs of breast cancer. No significant differences in the frequency of methylation of the above genes were found between cases and controls in our study. Hence, testing for the presence of methylation of cancer-related genes in PBL DNA from women diagnosed with sporadic breast cancer and classified for testing without any pathological or clinical selection criteria does not seem to have clinical applicability.

Communication Skills Training: A Means to Promote Time-Efficient Patient-Centered Communication in Clinical Practice.

PURPOSE: We hypothesized that health care providers would behave in a more patient-centered manner after the implementation of communication skills training, without causing the consultation to last longer. METHODS: This study was part of the large-scale implementation of a communication skills training program called "Clear-Cut Communication With Patients" at Lillebaelt Hospital in Denmark. Audio recordings from real-life consultations were collected in a pre-post design, with health care providers' participation in communication skills training as the intervention. The training was based on the Calgary-Cambridge Guide, and audio recordings were rated using the Observation Scheme-12. RESULTS: Health care providers improved their communication behavior in favor of being more patient-centered. Results were tested using a mixed-effect model and showed significant differences between pre- and postintervention assessments, with a coefficient of 1.3 (95% Cl: 0.35-2.3; P=0.01) for the overall score. The consultations did not last longer after the training. CONCLUSIONS: Health care providers improved their communication in patient consultations after the implementation of a large-scale patient-centered communication skills training program based on the Calgary-Cambridge Guide. This did not affect the length of the consultations.

Comparison of the Metastasis Predictive Potential of mRNA and Long Non-Coding RNA Profiling in Systemically Untreated Breast Cancer.

Several gene expression signatures based on mRNAs and a few based on long non-coding RNAs (lncRNAs) have been developed to provide prognostic information beyond clinical evaluation in breast cancer (BC). However, the comparison of such signatures for predicting recurrence is very scarce. Therefore, we compared the prognostic utility of mRNAs and lncRNAs in low-risk BC patients using two different classification strategies. Frozen primary tumor samples from 160 lymph node negative and systemically untreated BC patients were included; 80 developed recurrence-i.e., regional or distant metastasis while 80 remained recurrence-free (mean follow-up of 20.9 years). Patients were pairwise matched for clinicopathological characteristics. Classification based on differential mRNA or lncRNA expression using seven individual machine learning methods and a voting scheme classified patients into risk-subgroups. Classification by the seven methods with a fixed sensitivity of ≥90% resulted in specificities ranging from 16-40% for mRNA and 38-58% for lncRNA, and after voting, specificities of 38% and 60% respectively. Classifier performance based on an alternative classification approach of balanced accuracy optimization also provided higher specificities for lncRNA than mRNA at comparable sensitivities. Thus, our results suggested that classification followed by voting improved prognostic power using lncRNAs compared to mRNAs regardless of classification strategy.

Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial.

BACKGROUND: The ExteNET trial demonstrated improved invasive disease-free survival (iDFS) with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, versus placebo in patients with human epidermal growth factor receptor 2-positive (HER2+)/hormone receptor-positive (HR+) early-stage breast cancer (eBC). PATIENTS AND METHODS: ExteNET was a multicenter, randomized, double-blind, phase III trial of 2840 patients with HER2+ eBC after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. The primary endpoint was iDFS. Descriptive analyses were performed in patients with HR+ eBC who initiated treatment ≤ 1 year (HR+/≤ 1-year) and > 1 year (HR+/> 1-year) post-trastuzumab. RESULTS: HR+/≤ 1-year and HR+/> 1-year populations comprised 1334 (neratinib, n = 670; placebo, n = 664) and 297 (neratinib, n = 146; placebo, n = 151) patients, respectively. Absolute iDFS benefits at 5 years were 5.1% in HR+/≤ 1-year (hazard ratio, 0.58; 95% confidence interval [CI], 0.41-0.82) and 1.3% in HR+/>1-year (hazard ratio, 0.74; 95% CI, 0.29-1.84). In HR+/≤ 1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; hazard ratio, 0.79; 95% CI, 0.55-1.13). Of 354 patients in the HR+/≤ 1-year group who received neoadjuvant therapy, 295 had residual disease, and results showed absolute benefits of 7.4% at 5-year iDFS (hazard ratio, 0.60; 95% CI, 0.33-1.07) and 9.1% at 8-year OS (hazard ratio, 0.47; 95% CI, 0.23-0.92). There were fewer central nervous system events with neratinib. Adverse events were similar to those previously reported. CONCLUSION: Neratinib significantly improved iDFS in the HER2+/HR+/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population.

Neoadjuvant chemotherapy for primary operable breast cancer.

INTRODUCTION: Neoadjuvant chemotherapy (NACT) has been found useful in downstaging tumours in women with primary operable breast cancer without increasing mortality. As a result of several studies supporting this, the Danish Breast Cancer Cooperative Group implemented new guidelines for the treatment of primary operable T2 N0/N1 M0 ductal carcinomas in late 2016, treating patients with six cycles of NACT. This study aimed to conduct a quality assessment of the efficacy of the NACT regime based on real-time data from a single Danish hospital. METHODS: A retrospective observational study was conducted at Odense University Hospital, Denmark, from the introduction of the NACT regime to December 2018. Patients were identified using the surgical department's registry. Through medical chart review, predefined outcomes were collected on tumour characteristics, surgical outcomes, treatment response and type of NACT treatment. Descriptive statistics and Fisher's exact test were used on relevant data. RESULTS: Among the 64 patients, 67% completed a recommended NACT regime. A 55% majority underwent lumpectomy and 64% were spared axillary dissection. Complete pathological response was found in 28% of patients. After treatment, 38% of the pre-NACT N1 patients were downstaged to N0. CONCLUSIONS: This study indicated that the NACT regime was a favourable treatment strategy for these patients. Two-thirds of patients were able to undergo a recommended NACT regime. The majority of patients were both spared axillary dissection and mastectomy. FUNDING: none. TRIAL REGISTRATION: not relevant.

Long-Term Risk of Heart Failure in Breast Cancer Patients After Adjuvant Chemotherapy With or Without Trastuzumab.

OBJECTIVES: This study sought to evaluate the long-term risk of developing heart failure (HF) in patients receiving trastuzumab therapy. BACKGROUND: Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer, but it can induce left ventricular dysfunction with reduced ejection fraction or HF during treatment. The long-term risk of HF is less well described. METHODS: In a nationwide Danish retrospective cohort study, 9,901 patients scheduled for adjuvant treatment for early-stage breast cancer were identified in the Danish Breast Cancer Cooperative Group database. Of these, 8,812 patients (25% HER2-positive; 51.7 ± 8.5 years of age) received chemotherapy including anthracycline; and if they were HER2 positive, trastuzumab was added. The primary endpoint was a diagnosis of HF assessed before and after 18 months in a landmark analysis to distinguish short- and long-term risks. RESULTS: Median follow-up was 5.4 years (interquartile range [IQR]: 4.1 to 6.8 years). In the trastuzumab group, 60 patients had HF by 9 years versus 51 in the group who were treated with chemotherapy alone, corresponding to incidence rates per 1,000 patient years of 5.3 (95% confidence interval [CI]: 4.1 to 6.8) versus 1.4 (95% CI: 1.1 to 1.8), respectively. The cumulative incidence of HF was higher in the trastuzumab group at both the short- and long-term (p < 0.01), yielding adjusted hazard ratios of 8.7 (95% CI: 4.6 to 16.5; p < 0.01) for early HF and 1.9 (95% CI: 1.2 to 3.3; p = 0.01) for late HF associated with trastuzumab treatment. CONCLUSIONS: Trastuzumab treatment is associated with a 2-fold increased risk of late HF compared with chemotherapy treatment alone.

Linkage disequilibrium mapping of a breast cancer susceptibility locus near RAI/PPP1R13L/iASPP.

BACKGROUND: Previous results have suggested an association of the region of 19q13.3 with several forms of cancer. In the present study, we investigated 27 public markers within a previously identified 69 kb stretch of chromosome 19q for association with breast cancer by using linkage disequilibrium mapping. The study groups included 434 postmenopausal breast cancer cases and an identical number of individually matched controls. METHODS AND RESULTS: Studying one marker at a time, we found a region spanning the gene RAI (alias PPP1R13L or iASPP) and the 5' portion of XPD to be associated with this cancer. The region corresponds to a haplotype block, in which there seems to be very limited recombination in the Danish population. Studying combinations of markers, we found that two to four neighboring markers gave the most consistent and strongest result. The haplotypes with strongest association with cancers were located in the gene RAI and just 3' to the gene. Coinciding peaks were seen in the region of RAI in groups of women of different age. In a follow-up to these results we sequenced 10 cases and 10 controls in a 44 kb region spanning the peaks of association. This revealed 106 polymorphisms, many of which were not in the public databases. We tested an additional 44 of these for association with disease and found a new tandem repeat marker, called RAI-3'd1, located downstream of the transcribed region of RAI, which was more strongly associated with breast cancer than any other marker we have tested (RR = 2.44 (1.41-4.23, p = 0.0008, all cases; RR = 6.29 (1.49-26.6), p = 0.01, cases up to 55 years of age). CONCLUSION: We expect the marker RAI-3'd1 to be (part of) the cause for the association of the chromosome 19q13.3 region's association with cancer.