Global Registry of Acute Coronary Events Score Underestimates Post-Acute Coronary Syndrome Mortality among Cancer Patients.

Background Patients with prior cancer are at increased risk of acute coronary syndrome (ACS) with poorer post-ACS outcomes. We aimed to ascertain if the Global Registry of Acute Coronary Events (GRACE) score accurately predicts mortality risk among patients with ACS and prior cancer. Methods We linked nationwide ACS and cancer registries from 2007 to 2018 in Singapore. A total of 24,529 eligible patients had in-hospital and 1-year all-cause mortality risk calculated using the GRACE score (2471 prior cancer; 22,058 no cancer). Results Patients with prior cancer had two-fold higher all-cause mortality compared to patients without cancer (in-hospital: 22.8% versus 10.3%, p < 0.001; 1-year: 49.0% vs. 18.7%, p < 0.001). Cardiovascular mortality did not differ between groups (in-hospital: 5.2% vs. 4.8%, p = 0.346; 1-year: 6.9% vs. 6.1%, p = 0.12). The area under the receiver operating characteristic curve of the GRACE score for prediction of all-cause mortality was less for prior cancer (in-hospital: 0.64 vs. 0.80, p < 0.001; 1-year: 0.66 vs. 0.83, p < 0.001). Among patients with prior cancer and a high-risk GRACE score > 140, in-hospital revascularization was not associated with lower cardiovascular mortality than without in-hospital revascularization (6.7% vs. 7.6%, p = 0.50). Conclusions The GRACE score performs poorly in risk stratification of patients with prior cancer and ACS.

Factors Predictive of Primary Resistance to Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Primary resistance to immune checkpoint inhibitors (ICI) is observed in routine clinical practice. We sought to determine factors predictive of primary resistance to ICI monotherapy, defined by the Society for Immunotherapy of Cancer (SITC) as progression within 6 months of ICI treatment with patients receiving at least 6 weeks of ICI monotherapy, in patients with advanced non-small-cell lung cancer (NSCLC). METHOD: Patients with stage IV NSCLC treated with at least 6 weeks of single-agent ICI at two tertiary hospitals in Singapore were included. A multivariate logistic regression model was utilised to elucidate factors predictive of primary resistance to ICI. RESULTS: Of the 108 eligible patients, 59 (54.6%) experienced primary resistance. The majority were male (65.7%), smokers (66.3%), Chinese (79.6%), had adenocarcinoma (76.9%), received Pembrolizumab (55.6%) and received immunotherapy treatment in the later line setting (≥2 lines) (61.1%). Female gender (aOR = 3.16, p = 0.041), a sixth-week neutrophil-to-lymphocyte ratio (NLR) of ≥3) (aOR = 3.454, p = 0.037) and a later line of immunotherapy treatment (≥2 lines) (aOR = 2.676, p = 0.040) were factors predictive of primary resistance to ICI monotherapy in patients with advanced NSCLC. CONCLUSIONS: Using SITC criteria, an elevated NLR (≥3) at 6 weeks, female gender and a later line of immunotherapy treatment (≥2 lines) were predictive factors of developing primary resistance to ICI monotherapy in patients with advanced NSCLC.

Comparison of out-of-pocket costs and adherence between the two arms of the prospective, randomized abiraterone food effect trial.

PURPOSE: Abiraterone acetate, prescribed for metastatic prostate cancer, has enhanced absorption with food. This effect was exploited in a randomized trial which showed noninferiority of PSA decline for 250 mg abiraterone with a low-fat meal (LOW) compared to 1,000 mg abiraterone fasting (STD). Drug was obtained via patient insurance. Patient out-of-pocket costs and adherence were surveyed. METHODS: Trial participants were randomized to STD or LOW, and surveys of adherence and out-of-pocket costs were administered at baseline and just before coming off study (follow-up). RESULTS: Out-of-pocket costs were available from 20 of 36 STD and 21 of 36 LOW patients. Median out-of-pocket costs for a month of drug were $0 (LOW) and $5 (STD); mean costs were $43.61 (LOW) and $393.83 (STD). The two groups did not differ significantly (p = 0.421). Maximum out-of-pocket cost was $1,000 (LOW) and $4,000 (STD). Monthly out-of-pocket costs > $500 were found in 1 LOW and 5 STD patients. For adherence, only 11 STD and 19 LOW patients had questionnaires completed at both baseline and follow-up. STD adherence was 98.18% at baseline and 91.69% at follow-up, differing significantly (p = 0.0078). LOW adherence was 96.52% at baseline and 97.86% at follow-up, not differing significantly (p = 0.3511). Adherence did not correlate with demographics. At follow-up, increasing adherence correlated significantly with decreasing dose (p = 0.013; rho = - 0.458). CONCLUSIONS: Out-of-pocket costs did not differ significantly in this limited analysis. Adherence was significantly different in STD as the trial progressed, which was not found in LOW. TRIAL REGISTRATION: ClinicalTrials.gov NCT01543776; registered March 5, 2012.

Risk factors for immune-related adverse events from anti-PD-1 or anti-PD-L1 treatment in an Asian cohort of nonsmall cell lung cancer patients.

Immune-related adverse events (IrAEs) of immune checkpoint inhibitors (ICIs) can be serious and unpredictable. We examine the incidence rate and risk factors for IrAEs in an Asian cohort of nonsmall cell lung cancer (NSCLC) patients treated with immunotherapy. Between June 2014 and August 2020, we retrospectively analysed IrAEs in NSCLC patients treated with anti-PD-1 or anti-PD-L1 inhibitors at the National University Cancer Institute, Singapore. A Poisson regression model was used to estimate the effect of risk factors on incidence rate of any grade IrAEs. One hundred and forty-one patients were enrolled. Median age was 63. Majority were male (67%) with Eastern Cooperative Oncology Group (ECOG) PS 0-1 (77%). More than half (56%) received pembrolizumab. Eleven percent harboured epidermal growth factor receptor (EGFR) mutation. Eighteen percent received concomitant chemotherapy. Median number of cycles was 4, and median duration of treatment was 2.1 months. IrAEs were seen in 71 (50.4%) patients, with an incidence rate of 99 events per 1000 person-months. Fatigue (25%), rash (10.5%) and pneumonitis (7.9%) were the most common IrAEs. Twenty out of 152 IrAEs (13.2%) were Grade 3 or higher in severity: most common being pneumonitis (5.3%), fatigue (3.3%) and transaminitis (1.3%). Multivariable analysis demonstrated that concomitant chemotherapy use, higher BMI and presence of EGFR mutation are significant predictors for IrAEs (P < .0001; P = .016; P = .007). Our findings can help guide risk stratification and monitoring of IrAEs among NSCLC patients on immunotherapy.

Radical radiotherapy in older patients with muscle invasive bladder cancer.

BACKGROUND: Muscle invasive bladder cancer (MIBC) is prevalent in the older patients, who are a vulnerable population with multiple co-morbidities and at increased risk of complications. Radical cystectomy is often not suitable, hence radical radiotherapy (RT) is an alternative option. We reviewed the outcomes of older patients treated with RT with or without concurrent chemotherapy (CRT) at our institution. METHODS: We retrospectively reviewed patients aged 65 years and above treated with radical RT for MIBC at our institution between March 2002 to January 2017. Data was collected from institutional medical records and RT databases. The primary outcome was 2- and 5-year overall survival (OS), recurrence free survival (RFS), and toxicities. Univariate cox proportional hazard regression models were performed to identify independent factors with significant impact on survival. RESULTS: We identified 45 patients (34 males, 11 females) with a median age of 77 years (range 65-95). All patients received maximal transurethral resection of the bladder tumour prior to RT. Median dose of total RT was 64 Gy (range 50-69.8 Gy). Twenty one patients (47%) received CRT. Planned treatment was completed in 42 (93.3%) patients. Median follow-up was 31 months (range 1-147 months). The 2- and 5-year OS was 64% and 44%, respectively. The 2- and 5-year RFS was 68% and 49%, respectively. Median RFS was 34 months (range 8-121 months). Median OS was 56 months (range 18-100 months). Univariate analysis showed that performance status (0-1 vs. 2-3; HR 2.7, 95% CI 1.07-6.8, p = 0.035) and International Society of Geriatric Oncology (SIOG) group (≤2 vs. >2; HR 3.23, 95% CI 1.12-8.64, p = 0.019) were significantly associated with increased hazard for death. One patient (2%) had grade 3 cystitis. CONCLUSION: Radical RT is well tolerated in older patients with MIBC. We report outcomes similar to published data. Older patients should be considered for curative treatment despite their age. However, careful selection is warranted as frail patients (PS ≥2; SIOG >2) may benefit less.

Pushing the limits of immune-related response: a case of "extreme pseudoprogression".

The advent of immune checkpoint targeted immunotherapy has seen a spectrum of immune-related phenomena in both tumor responses and toxicities. We describe a case of pseudoprogression that pushes the limits of immune-related response criteria and challenges the boundaries and definitions set by trial protocols. A middle-aged man with conventional clear cell renal cell carcinoma (RCC) had received multiple prior systemic treatments including vascular endothelial growth factor receptor tyrosine kinase inhibitors, as well as multiple surgeries and radiotherapy treatments. He was eventually started on nivolumab-the anti-programmed death receptor-1 monoclonal antibody approved for the treatment of advanced RCC. Clinical deterioration was observed soon after a 100 mg dose of nivolumab, with onset of acute renal failure and declining performance status. Radiologic progression was documented in multiple sites including worsening tumor infiltration of his residual kidney. The patient was on palliative treatment and visited by the home hospice team in an end-of-life situation. The patient unexpectedly improved and went on to achieve a durable tumor response. The case is illustrative of an extreme manifestation of pseudoprogression, and impels us to probe the assumptions and controversies surrounding this phenomenon.

Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression.

Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL-1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor-associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target.

Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA.

Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection. Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity. Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy. Here we report sequencing of cancer exomes in serial plasma samples to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1-2 years. For each case, exome sequencing was performed on 2-5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab, and following subsequent treatment with lapatinib, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.

Green and black tea intake in relation to prostate cancer risk among Singapore Chinese.

PURPOSE: Tea is one of the most commonly consumed beverages worldwide. To date, observational data from prospective cohort studies investigating the relationship between green and black tea intake and prostate cancer risk are sparse and equivocal. In a population-based, prospective cohort study of Chinese men in Singapore, we investigated the relationship between green and black tea intake and prostate cancer risk. METHODS: Tea consumption data for 27,293 men were collected at baseline (between 1993 and 1998) using a validated food frequency questionnaire. After an average of 11.2 years of follow-up, 298 men had developed prostate cancer. Proportional hazards regression methods were used to assess the associations between tea intake and prostate cancer risk. RESULTS: There was no association between daily green tea intake and prostate cancer risk, compared with no green tea intake [hazard ratio (HR) = 1.08; 95 % confidence interval (CI) 0.79, 1.47]. For black tea, a statistically significant positive association and trend were observed for daily intake compared with no black tea intake (HR = 1.41, 95 % CI 1.03, 1.92; p for trend <0.01) CONCLUSIONS: Few prospective data are available from populations that have both a high level and wide range of black and green tea intake; this study represents a unique opportunity to evaluate their individual effects on prostate cancer risk. Our findings support the notion that green tea intake does not protect against prostate cancer and that black tea intake may increase prostate cancer risk.

How many adenocarcinoma lung cancers come from bronchioloalveolar carcinoma?

BACKGROUND: There is emerging evidence that bronchioloalveolar carcinoma (BAC) is the forerunner of peripheral adenocarcinoma lung cancers (ALC). Since advanced stage ALC is often diagnosed on cytology alone, we hypothesized that the incidence of BAC is underreported and that a large proportion of ALC in our population are part of the BAC-adenocarcinoma sequence. METHODS: We reviewed the pretreatment computed tomographic (CT) scans of 69 patients with ALC and looked for characteristic features of BAC. RESULTS: The median patient age was 63, and the majority were of Chinese descent (75.4%). Women comprised 43.5% of the patients (30 patients) and never-smokers comprised 47.8% (33 patients). Only 15 patients (21.7%) had surgical specimens. The presence of BAC components was reported in the pathology of 16 patients (23.2%). CT features classically associated with BAC were found in 35 patients (50.7%). These included air bronchograms or bubble-like lucencies in 24 patients (34.8%), ground-glass opacities in 19 (27.5%), consolidation or pneumonic picture in 11 (15.9%), diffuse small or miliary nodules in 10 (14.5%), and the CT angiogram sign in 4 (5.8%). CONCLUSIONS: We found provocative radiologic evidence that a large proportion of our ALC cases arise from BAC. The CT findings are consistent with current understanding of the likely pathogenesis of peripheral ALC.

Targeted therapy at the end of life for patients with lung cancer.

The use of chemotherapy at the end of life is increasing. We characterized the use of targeted therapies in relation to the end of life in non-small cell lung cancer (NSCLC) patients who died in our institution. The frequency of systemic anticancer therapy usage at the end of life was consistent with that reported in other recent studies. The use of targeted therapies, especially epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), was strikingly more common than that of conventional chemotherapy. Targeted therapy was frequently initiated within the last 3 months of life. Targeted agents were also used in sequence, in combination, and in investigational protocols. We conclude that targeted agents, in particular EGFR TKIs, are now the drugs of choice in the systemic treatment of NSCLC at the end of life.

Calcium intake increases risk of prostate cancer among Singapore Chinese.

Consumption of dairy products, the primary source of calcium in Western diets, has been found to be positively associated with prostate cancer. In an Asian diet, nondairy foods are the major contributors of calcium. Thus, a study of dietary calcium and prostate cancer in Asians can better inform on whether calcium, as opposed to other dairy components, is responsible for the dairy foods-prostate cancer association. We examined calcium intake and prostate cancer risk among 27,293 men in the Singapore Chinese Health Study that was established between 1993 and 1998. As of December 31, 2007, 298 incident prostate cancer cases had been diagnosed among the cohort members. Diet was assessed at baseline with a validated 165-item food-frequency questionnaire. It is hypothesized that there is greater net absorption of calcium in smaller individuals. Therefore, the calcium-prostate cancer association was also assessed in stratified analyses by median body mass index. Vegetables were the largest contributor of daily calcium intake in the study population. Overall, we observed a modest, statistically nonsignificant 25% increase in prostate cancer risk for the 4th (median = 659 mg/d) versus 1st (median = 211 mg/d) quartiles of calcium intake after adjustment for potential confounders. The association became considerably stronger and achieved statistical significance (hazard ratio, 2.03; 95% confidence interval, 1.23-3.34; P for trend = 0.01) for men with a below median body mass index (22.9 kg/m(2)). Dietary calcium might be a risk factor for prostate cancer even at relatively low intake.

Cigarette smoking and risk of prostate cancer among Singapore Chinese.

Prospective epidemiologic studies conducted in Western populations support an association between current smoking and aggressive subtypes of prostate cancer. In Singapore, where prostate-specific antigen is not used for population-wide screening, prostate cancer incidence has tripled within the past two decades. Using Cox regression methods, we examined the relationship between smoking and prostate cancer established between 1993 and 1998 in a cohort of 27,293 Singapore Chinese men. As of December 2006, 250 incident prostate cancer cases were diagnosed. In our cohort, 42.2% reported never smoking cigarettes, 15.7% quit over 5 years ago (long-term former), 5.7% quit within the past 5 years (recent former), and 36.4% were current smokers. From multivariable models, we observed no association with smoking status, age at starting to smoke, years smoked, or number of cigarettes per day. Among recent former and current smokers combined, we observed a small positive association for earlier age at starting to smoke that was somewhat stronger for nonadvanced disease (hazard ratio = 1.63, 95% confidence interval: 0.85, 3.12, for <15 years versus nonsmokers). Smoking was not a major risk factor for prostate cancer in our Singapore Chinese cohort, a traditionally low risk population with parallel increases in incidence and mortality.

Debulking nephrectomy followed by a "watch and wait" approach in metastatic renal cell carcinoma.

OBJECTIVE: Debulking nephrectomy has been shown to improve survival in metastatic renal cell carcinoma and is now a standard procedure. However, it remains controversial if debulking nephrectomy should routinely be followed by interferon. We report on the clinical course of metastatic renal cell carcinoma patients after debulking nephrectomy who did not receive routine systemic anticancer therapy. PATIENTS AND METHODS: Fifteen consecutive metastatic renal cell carcinoma patients were put on a "watch and wait" protocol after debulking nephrectomy. This included regular computer tomographic scans done at 6 to 8 weeks after debulking nephrectomy, and subsequently 3 to 4 monthly. Systemic treatment was instituted only after disease progression. RESULTS: At a median follow-up of 18 months, 80% of patients had progressed. However, a third of the patients had at least 6 months of progression-free interval, and 3 of 15 patients had not progressed at prolonged follow-up durations of 18, 23, and 46 months. A third of the patients remained alive and the median survival for the cohort was 25 months. Preoperative predictive factors for nonprogression after debulking nephrectomy included absence of abnormal laboratory indices, single organ system metastases, and good performance status. CONCLUSIONS: There is a subset of metastatic renal cell carcinoma patients who will have an indolent course after debulking nephrectomy. Toxic systemic therapies may be avoided in such patients for a significant period of time.