Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.

Background: The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study. Patients and methods: A total of 668 postmenopausal women with HR+, HER2- recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point. Results: At the time of the second interim analysis, the median duration of follow-up was 26.4 months. Median PFS was 25.3 months [95% confidence interval (CI) 23.0-30.3] for ribociclib plus letrozole and 16.0 months (95% CI 13.4-18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457-0.704; log-rank P = 9.63 × 10-8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517-1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1 months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity. Conclusions: The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy. Clinical trials number: NCT01958021.

Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study.

BACKGROUND: Existing evidence suggests that proinflammatory cytokines play an intermediary role in postchemotherapy cognitive impairment. This is one of the largest multicentered, cohort studies conducted in Singapore to evaluate the prevalence and proinflammatory biomarkers associated with cognitive impairment in breast cancer patients. PATIENTS AND METHODS: Chemotherapy-receiving breast cancer patients (stages I-III) were recruited. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, interferon-γ and tumor necrosis factor-α] were evaluated at 3 time points (before chemotherapy, 6 and 12 weeks after chemotherapy initiation). The FACT-Cog (version 3) was utilized to evaluate patients' self-perceived cognitive disturbances and a computerized neuropsychological assessment (Headminder) was administered to evaluate patients' memory, attention, response speed and processing speed. Changes of cognition throughout chemotherapy treatment were compared against the baseline. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations on self-perceived cognitive disturbances and each objective cognitive domain. RESULTS: Ninety-nine patients were included (age 50.5 ± 8.4 years; 81.8% Chinese; mean duration of education = 10.8 ± 3.3 years). Higher plasma IL-1ß was associated with poorer response speed performance (estimate: -0.78; 95% confidence interval (CI) -1.34 to -0.03; P = 0.023), and a higher concentration of IL-4 was associated with better response speed performance (P = 0.022). Higher concentrations of IL-1ß and IL-6 were associated with more severe self-perceived cognitive disturbances (P = 0.018 and 0.001, respectively). Patients with higher concentrations of IL-4 also reported less severe cognitive disturbances (P = 0.022). CONCLUSIONS: While elevated concentrations of IL-6 and IL-1ß were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment. This study is important because cytokines would potentially be mechanistic mediators of chemotherapy-associated cognitive changes.

Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer.

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Factors related to postoperative pain among patients who underwent radiofrequency ablation of hepatocellular carcinoma.

AIM: To evaluate the incidence and associated factors of postoperative intense pain and haemodynamic changes during radiofrequency ablation of hepatocellular carcinoma. MATERIALS AND METHODS: A total of 123 consecutive hepatocellular carcinoma patients who underwent radiofrequency ablation were prospectively recruited. Patient factors, tumour characteristics, procedural factors, intraoperative haemodynamic changes, complications, postoperative events, laboratory values before and after ablation, and postoperative pain were evaluated. Postoperative pain was scored using a visual analogue scale after the procedure. RESULTS: The mean age of the patients was 65.6 ± 9.6 years. In multiple logistic regression analysis, patients who underwent general anaesthesia [odds ratio (95% CI): 2.68 (1.23-5.81); p = 0.013] and had more postoperative nausea and vomiting episodes [3.10 (1.11-8.63); p = 0.036] were associated with intense pain. These findings remain robust after propensity score matching. For mean difference values between before and after RFA, higher in change in aspartate transaminase (p = 0.026), alanine transaminase (p = 0.016) and white blood cell count (p = 0.015), and lower in change in haemoglobin (p = 0.009) were also correlated with intense pain. There was no significant difference in haemodynamic changes between the general anaesthesia and local anaesthesia group during ablation. CONCLUSION: General anaesthesia, postoperative nausea and vomiting, and laboratory factors were associated with postoperative intense pain in patients who underwent radiofrequency ablation. Counselling and modification of analgesics should be considered in patients with related factors for intense pain.

Outcomes in breast cancer-does ethnicity matter?

Ethnic or racial differences in breast cancer (BC) survival outcomes have been reported, but current data are largely restricted to comparisons between African Americans and non-Hispanic whites. Most analyses have traditionally been based on self-reported race which may not always be accurate, or are oversimplified in their classification. With increasing globalization, quantification of the genetic ancestry from genomic data may offer a solution to infer the complex makeup from admixture of races. Focusing on the larger and the latest studies, we will discuss recent findings on the differing host and tumor biology that may be driving these disparities, in addition to the extrinsic environmental or lifestyle factors. Socioeconomic disparities with lower cancer literacy may lead to late presentation, poorer adherence to treatment, and other lifestyle factors such as unhealthy diet, obesity, and inadequate physical activity. These hardships may also result in greater allostatic load, which is in turn associated with aggressive BC features in disadvantaged populations. Epigenetic reprogramming may mediate the effects of the environment or lifestyle factors on gene expression, with ensuing differences in BC characteristics and outcome. There is increasing evidence that germline genetics can influence somatic gene alterations or expression, as well as modulate the tumor or immune microenvironment. Although the precise mechanisms remain elusive, this may account for the varying distribution of different BC subtypes across ethnicities. These gaps in our knowledge highlight the need to interrogate the multiomics landscape of BC in diverse populations, ideally in large-scale collaborative settings with standardized methodology for the comparisons to be statistically robust. Together with improving BC awareness and access to good quality health care, a holistic approach with insights of the biological underpinnings is much needed to eradicate ethnic disparities in BC outcomes.

Brain metastases in Asian HER2-positive breast cancer patients: anti-HER2 treatments and their impact on survival.

BACKGROUND: In Asia, large-scale studies on anti-HER2 treatment in HER2-positive breast cancer patients with brain metastases are limited. We studied the treatment patterns of these patients in Asia to evaluate the impact of anti-HER2 treatment on the time to occurrence of brain metastases (TTBM) and survival after brain metastasis (BM). METHODS: A retrospective study of HER2-positive breast cancer patients diagnosed with BM between January 2006 and December 2008 in six Asian countries was conducted. Demographics, tumour characteristics, treatment details, and events dates were collected from medical records. RESULTS: Data from 280 patients were analysed. Before BM, 63% received anti-HER2 treatment. These patients had significantly longer TTBM than those without anti-HER2 treatment (median 33 vs 19 months; P<0.002). After BM, 93% received radiotherapy, 57% received chemotherapy, and 41% received anti-HER2 treatment (trastuzumab and/or lapatinib). Use of both anti-HER2 agents, primarily sequentially, after BM demonstrated the longest survival after BM and was associated with a significant survival benefit over no anti-HER2 treatment (median 26 vs 6 months; hazard ratio 0.37; 95% CI 0.19-0.72). CONCLUSION: Anti-HER2 treatment before BM was associated with longer TTBM. Anti-HER2 treatment after BM was associated with a survival benefit, especially when both trastuzumab and lapatinib were utilised.

Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population.

Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR) = 1.43, 95 % confidence interval (CI) = 1.26-1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR = 1.39, 95 % CI = 1.20-1.61) and ER-negative (per-allele OR = 1.55, 95 % CI = 1.28-1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14-1.68), 1.48 (1.25-1.74), and 1.58 (1.28-1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12-1.43) at rs1219648, 1.22 (1.07-1.38) at rs2981582, 1.21 (1.07-1.36) at rs2981579, and 1.18 (1.04-1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95 % CI) of 1.16 (1.00-1.34), 1.15 (1.02-1.29), and 1.15 (1.01-1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90 % for those with a combination of 6 or more risk alleles, compared to patients with ≤3 risk alleles.

Validation of the AJCC 8th prognostic system for breast cancer in an Asian healthcare setting.

AIMS: We aim to validate the AJCC 8th edition prognostic staging system for breast cancer in an Asian setting. METHODS: Clinico-pathologic information and cancer-specific survival (CSS) outcomes of 6287 stage I to III patients with invasive breast cancer who underwent upfront surgery at SingHealth institutions in Singapore from 2006 to 2014 were analyzed. Survival distributions for the different staging systems were estimated by the Kaplan-Meier method and compared using the log-rank tests. Multivariable Cox proportional hazards models were used, with Akaike Information Criterion (AIC) and Harrell's Concordance Index (C-index) to compare both staging systems. Among patients with positive hormone-receptor status, 84.8% received endocrine therapy. Among the cohort, 60.3% of received chemotherapy; 82.1% of node positive patients received chemotherapy and 86.0% of HER2-enriched patients in whom chemotherapy was also indicated received adjuvant HER2-targeted therapy. Ninety-seven percent of patients received anthracyclines and/or taxanes containing chemotherapy regime. RESULTS: The median follow up was 64 months. 2921 patients (46.5%) were discordant between the anatomic and prognostic systems of which 363 (5.8%) were upstaged and 2558 (40.7%) were down-staged. For all patients, stages in both the prognostic and anatomic systems were discriminating for 5-year CSS. Controlling for age, ethnicity and receipt of chemotherapy, the prognostic staging system model (AIC = 7538.87, C = 0.79) presented slightly better explanation and concordance of survival times than the anatomic staging system model (AIC = 7607.31, C = 0.77). CONCLUSION: The prognostic staging system was better than the anatomic staging system in predicting outcomes but the anatomic system remains relevant due to its ease of use.

Clinical efficacy of capecitabine as first-line chemotherapy in metastatic breast cancer--how low can you go?

Sixty-three patients received capecitabine at 1000 mg/m2 twice daily every 2 out of 3 weeks as first-line treatment for advanced disease at our institution. Forty-five patients (71%) had previously received adjuvant or neoadjuvant chemotherapy. The median number of capecitabine cycles administered was 5(1-40). Forty-eight patients had measurable disease with response rate (RR) of 29%. The median time to progression (TTP) was 18(2-122) weeks. Seven patients (11%) had TTP of >1 yr, four of whom received more than 10(24-40) cycles of capecitabine. Thirty-seven percent of patients still needed dose reductions. Our retrospective audit is consistent with a previously published study which used a higher starting dose of capecitabine as first-line chemotherapy. For a subgroup of patients, capecitabine can result in a long TTP with minimal toxicity. The benefit of continuing capecitabine beyond a fixed number of cycles should be investigated further. Schedules using even lower doses of capecitabine for longer periods may also be of interest.

Risk of death from cardiovascular disease following breast cancer in Southeast Asia: a prospective cohort study.

Breast cancer incidence and survival is high in Southeast Asia. As such, many women diagnosed with breast cancer are at risk of dying of other causes. Given the increased risk of cardiotoxicity induced by breast cancer treatments, it is important to identify patients at high risk of cardiovascular disease (CVD) mortality. The aim of this study was to investigate if this risk varies by age and ethnicity. Patient details were obtained from 5,868 Chinese, Malay, and Indian women diagnosed with in situ or non-metastasized invasive breast cancer at the National University Hospital of Singapore and KK Women's and Children's Hospital in Singapore. Death causes were obtained from the National Registry of Births and Deaths. Flexible parametric survival models estimated CVD mortality rates and hazard ratios. During a median follow-up of six years, 1,010 deaths occurred of which 6.8% were due to CVD. CVD mortality rates of older women peaked within the first year following diagnosis and increased over time since diagnosis. Indian had more than double the risk of CVD mortality than Chinese, independent of age at diagnosis and stage. Taking ethnicity and age into account may promote CVD risk stratification and management in (Southeast Asian) women with breast cancer.

Right ventricular function and exercise performance late after primary repair of tetralogy of Fallot with the transannular patch in infancy.

To evaluate the late effects of chronic pulmonary regurgitation against the putative benefits from the current surgical trend of primary repair of tetralogy of Fallot with a transannular patch in infancy, 10 patients > 10 years after early primary repair and 7 matched normal controls underwent exercise stress test and cine magnetic resonance imaging assessment of ventricular functions. Right ventricular impaired diastolic function and decreased exercise capacity, both significantly associated with pulmonary regurgitation in patients, indicated that early primary repair of tetralogy may not prevent late ventricular dysfunction and diminished exercise performance if chronic regurgitation results from right ventricular outflow tract reconstruction.

Reducing the risk of peripherally inserted central catheter line complications in the oncology setting.

At our institution, a retrospective review of peripherally inserted central catheters (PICCs) in oncology patients had previously demonstrated a complication rate of 40.7%. Since then we have implemented strategies to reduce complications including staff and patient education, insertion technique modification and PICC maintenance utilizing a PICC nurse. The objectives of this study were to evaluate the recent PICC complication rate and to compare it with the previously reported findings. Prospectively collected PICC complication data and medical records from all patients with solid tumours who had PICCs inserted in 2003 were analysed. A historical cohort comparative analysis was performed using our PICC complication rate from 2000 to 2001. Eighty-eight PICC lines were inserted in 73 patients under radiological guidance. The median PICC dwell time was 44 days (1-524 days). The overall complication rate was 15.9% (14/88) or 2.0 complications per 1,000 PICC-days. Infections developed in 5.7% (5/88) and thrombotic events occurred in 4.5% (4 /88) of PICCs. The mean time to complication was 45 days. The complication rate for 2003 was significantly lower than the rate for 2001 (P = 0.006), especially of infective complications (P = 0.004). Strategies introduced to reduce PICC complications may have been the reason for this improvement.