AbstractBackground.The form of microsatellite instability (MSI) affecting tetranucleotide repeats known as elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has emerged as a new potential biomarker in multiple cancers. In colorectal cancer (CRC), the correlation between EMAST and MSI mutations remain inconclusive.Materials and Methods.We evaluated 1,505 patients with CRC using five EMAST markers (D20S82, D20S85, D8S321, D9S242, and MYCL1) and the Bethesda panel of MSI markers. Most commonly, mutations involved in CRCs were identified by MassArray Assay, and DNA repair genes were analyzed by next‐generation sequencing. Clinical characteristics and prognostic relevance were correlated with EMAST and MSI.Results.Tumors that were EMAST positive and MSI high (MSI‐H) were detected in 159 (10.6%) and 154 (10.2%) of 1,505 patients with CRC. Patients were divided into four groups according to EMAST and MSI status (EMAST‐positive and MSI‐H, EMAST‐positive and microsatellite‐stable [MSS], EMAST‐negative and MSI‐H, and EMAST‐negative and MSS). The EMAST‐positive and MSI‐H group was associated with female predominance, higher prevalence of proximal colon tumors, early stage tumors, poorly differentiated tumors, mucinous histology, and higher incidence of mutations in PI3KCA, BRAF, TGFBR, PTEN, and AKT1 compared with other groups. Furthermore, compared with only EMAST‐positive tumors or only MSI‐H tumors, tumors that were both EMAST‐positive and MSI‐H had a higher frequency of MLH1, MSH3, MSH6, PMS2, and EXO1 gene mutations. Finally, the presence of EMAST‐positive and MSI‐H tumors was a good prognostic indicator in CRC.Conclusion.High mutations in several DNA repair genes in EMAST‐positive and MSI‐H tumors suggest that this subtype of CRC might be more suitable for treatment with immune therapy.Implications for Practice.Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is a unique molecular subtype of colorectal cancer (CRC). The current study demonstrated that the EMAST‐positive and MSI‐high (MSI‐H) group was associated with female predominance, higher prevalence of proximal colon tumors, early stage tumors, poorly differentiated tumors, mucinous histology, and higher incidence of mutations in PI3KCA, BRAF, TGFBR, PTEN, and AKT1 compared with other groups. Most importantly, high mutations in DNA repair genes and MSI‐related genes in EMAST‐positive and MSI‐H tumors suggest that this subtype of CRC might be more suitable for treatment with immune therapy compared with MSI‐H tumors alone.
AbstractBackground.CDK12 loss‐of‐function (LOF) genomic alterations are associated with focal tandem duplications (FTDs) in ovarian and prostate cancers. Because these FTDs may produce fusion‐induced neoantigens (FINAs), CDK12 alteration is a candidate biomarker for immune checkpoint inhibitor sensitivity. Here we determine the prevalence of CDK12‐LOF alterations and their association with FTDs across diverse tumor types.Materials and Methods.A total of 142,133 tumor samples comprising 379 cancer types were sequenced (August 2014 to April 2018) by hybrid capture‐based comprehensive genomic profiling (Foundation Medicine, Cambridge, MA) as part of routine clinical care. Results were analyzed for base substitutions, short insertions/deletions, rearrangements, and copy number alterations. CDK12‐LOF genomic alterations were assessed for zygosity status and association with FTDs/focal copy number gain.Results.CDK12 genomic alterations were detected in 1.1% of all cases, most frequently in prostate cancer (5.6%), but were also observed at >1% frequency in 11 cancer types. Across multiple cancer types, including prostate, gastric/esophageal, ovarian, breast, and endometrial cancer, the number of FTDs was significantly increased in CDK12‐LOF versus CDK12 wild‐type cases. Notably, CDK12‐LOF was not consistently associated with a homologous recombination deficiency genomic signature. Quantitative assessment of CDK12‐associated FTDs by measurement of single copy number gains identified novel likely deleterious CDK12 kinase‐domain mutations in prostate and ovarian cancers.Conclusion.Detection of CDK12‐LOF genomic alterations and their association with FTDs in a diverse spectrum of malignancies suggests that immunotherapy approaches targeting FINAs derived from CDK12‐associated FTDs may be a broadly applicable strategy that could be explored across cancer types in a tumor‐agnostic manner.Implications for Practice.CDK12 inactivation in ovarian and prostate cancer results in the generation of focal tandem duplications, which can cause fusion‐induced neoantigens. In prostate cancer, CDK12 alterations have demonstrated promise as a potential predictive biomarker for response to immune checkpoint blockade. This study evaluated genomic profiling data from >142,000 tumors to determine the prevalence of CDK12 loss‐of‐function genomic alterations across tumor types and demonstrated that CDK12 alterations are associated with the tandem‐duplicator phenotype in cancer types other than ovarian and prostate cancer. The association of CDK12 alterations with focal tandem duplications across broad cancer types suggests that CDK12 inactivation warrants further investigation as a pan‐cancer biomarker for immunotherapy benefit.
AbstractThe oncogenic role ERBB2 amplification is well established in breast and gastric cancers. This has led to the development of a well‐known portfolio of monoclonal antibodies and kinase inhibitors targeting the ERBB2 kinase. More recently, activating mutations in the ERBB2 gene have been increasingly reported in multiple solid cancers and were shown to play an oncogenic role similar to that of ERBB2 amplification. Thus, ERBB2 mutations define a distinct molecular subtype of solid tumors and serve as actionable targets. However, efforts to target ERBB2 mutation has met with limited clinical success, possibly because of their low frequency, inadequate understanding of the biological activity of these mutations, and difficulty in separating the drivers from the passenger mutations. Given the current impetus to deliver molecularly targeted treatments for cancer, there is an important need to understand the therapeutic potential of ERBB2 mutations. Here we review the distribution of ERBB2 mutations in different tumor types, their potential as a novel biomarker that defines new subsets in many cancers, and current data on preclinical and clinical efforts to target these mutations.Implications for Practice.A current trend in oncology is to identify novel genomic drivers of solid tumors and developing precision treatments that target them. ERBB2 amplification is an established therapeutic target in breast and gastric cancers, but efforts to translate this finding to other solid tumors with ERBB2 amplification have not been effective. Recently the focus has turned to targeting activating ERBB2 mutations. The year 2018 marked an important milestone in establishing ERBB2 mutation as an important actionable target in multiple cancer types. There have been several recent preclinical and clinical studies evaluating ERBB2 mutation as a therapeutic target with varying success. With increasing access to next‐generation sequencing technologies in the clinic, oncologists are frequently identifying activating ERBB2 mutations in patients with cancer. There is a significant need both from the clinician and bench scientist perspectives to understand the current state of affairs for ERBB2 mutations.
AbstractBackground.Aromatase inhibitors (AIs) used in breast cancer induce loss in bone mineral density (BMD) and are reported to increase fracture risk.Materials and Methods.Using a population‐based BMD registry, we identified women aged at least 40 years initiating AIs for breast cancer with at least 12 months of AI exposure (n = 1,775), women with breast cancer not receiving AIs (n = 1,016), and women from the general population (n = 34,205). Fracture outcomes were assessed to March 31, 2017 (mean, 6.2 years for AI users).Results.At baseline, AI users had higher body mass index (BMI), higher BMD, lower osteoporosis prevalence, and fewer prior fractures than women from the general population or women with breast cancer without AI use (all p < .001). After adjusting for all covariates, AI users were not at significantly greater risk for major osteoporotic fractures (hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.93–1.42), hip fracture (HR, 0.90; 95% CI, 0.56–1.43), or any fracture (HR, 1.06; 95% CI, 0.88–1.28) compared with the general population.Conclusion.Higher baseline BMI, BMD, and lower prevalence of prior fracture at baseline may offset the adverse effects of AI exposure. Although confirmatory data from large cohort studies are required, our findings challenge the view that all women with breast cancer initiating AI therapy should be considered at high risk for fractures.Implications for Practice.In a population‐based observational registry that included 1,775 patients initiating long‐term aromatase inhibitor therapy, risk for major osteoporotic fracture, hip fracture, or any fracture was similar to the general population. Higher baseline body mass index, bone mineral density, and lower prevalence of prior fracture at baseline may offset the adverse effects of aromatase inhibitor exposure.
AbstractBackground.With the advent of immunotherapy, substantial progress has been made in improving outcomes for patients with advanced cancer. However, not all patients benefit equally from treatment, and confounding immune‐related issues may have an impact. Several studies suggest that antibiotic use (which alters the gut microbiome) may result in poorer outcomes for patients treated with immune checkpoint inhibitors (ICI).Materials and Methods.This is a large, single‐site retrospective review of n = 291 patients with advanced cancer treated with ICI (n = 179 melanoma, n = 64 non‐small cell lung cancer, and n = 48 renal cell carcinoma). Antibiotic use (both single and multiple courses/prolonged use) during the periods 2 weeks before and 6 weeks after ICI treatment was investigated.Results.Within this cohort, 92 patients (32%) received antibiotics. Patients who did not require antibiotics had the longest median progression‐free survival (PFS), of 6.3 months, and longest median overall survival (OS), of 21.7 months. With other clinically relevant factors controlled, patients who received a single course of antibiotics had a shorter median OS (median OS, 17.7 months; p = .294), and patients who received multiple courses or prolonged antibiotic treatment had the worst outcomes overall (median OS, 6.3 months; p = .009). Progression‐free survival times were similarly affected.Conclusion.This large, multivariate analysis demonstrated that antibiotic use is an independent negative predictor of PFS and OS in patients with advanced cancer treated with ICIs. This study highlighted worse treatment outcomes from patients with cumulative (multiple or prolonged courses) antibiotic use, which warrants further investigation and may subsequently inform clinical practice guidelines advocating careful use of antibiotics.Implications for Practice.Antibiotic use is negatively associated with treatment outcomes of immune checkpoint inhibitors (ICI) in advanced cancer. Cumulative antibiotic use is associated with a marked negative survival outcome. Judicious antibiotic prescribing is warranted in patients receiving treatment with ICI for treatment of advanced malignancy.
AbstractBackground.DNA copy number variations (CNVs) are a hallmark of cancer, and the current study aimed to demonstrate the profile of the CNVs for oral cavity squamous cell carcinoma (OSCC) and elucidate the clinicopathological associations and molecular mechanisms of a potential marker derived from CNVs, mixed‐lineage leukemia translocated to chromosome 3 protein (MLLT3), in OSCC carcinogenesis.Materials and Methods.CNVs in 37 OSCC tissue specimens were analyzed using a high‐resolution microarray, the OncoScan array. Gene expression was analyzed by real‐time polymerase chain reaction in 127 OSCC and normal tissue samples. Cell function assays included cell cycle, migration, invasion and chromatin immunoprecipitation assays.Results.We found a novel copy number amplified region, chromosome 9p, encompassing MLLT3 via the comparison of our data set with six other OSCC genome‐wide CNV data sets. MLLT3 overexpression was associated with poorer overall survival in patients with OSCC (p = .048). MLLT3 knockdown reduced cell migration and invasion. The reduced invasion ability in MLLT3‐knockdown cells was rescued with double knockdown of MLLT3 and CBP/p300‐interacting transactivator with ED rich carboxy‐terminal domain 4 (CITED4; 21.0% vs. 61.5%). Knockdown of MLLT3 impaired disruptor of telomeric silencing‐1‐like (Dot1L)‐associated hypermethylation in the promoter of the tumor suppressor, CITED4 (p < .001), and hence dysregulated HIF‐1α‐mediated genes (TWIST, MMP1, MMP2, VIM, and CDH1) in OSCC cells.Conclusion.We identified unique CNVs in tumors of Taiwanese patients with OSCC. Notably, MLLT3 overexpression is related to the poorer prognosis of patients with OSCC and is required for Dot1L‐mediated transcriptional repression of CITED4, leading to dysregulation of HIF‐1α‐mediated genes.Implications for Practice.This article reports unique copy number variations in oral cavity squamous cell carcinoma (OSCC) tumors of Taiwanese patients. Notably, MLLT3 overexpression is related to the poorer prognosis of patients with OSCC and is required for Dot1L‐mediated transcriptional repression of CITED4, leading to dysregulation of HIF‐1α‐mediated genes.
AbstractBackground.The efficacy of sentinel lymph node (SLN) mapping for high‐risk endometrial cancer remains unclear. This prompted us to evaluate the sensitivity, negative predictive value (NPV), and false‐negative (FN) rate of cervical injection of indocyanine green (ICG) SLN mapping in patients with endometrial cancer.Materials and Methods.This prospective interventional study was performed at a single university teaching hospital. Consecutive patients with early‐stage endometrial cancer who underwent laparoscopic surgical staging were included. Cervical injection of ICG and near‐infrared SLN identification and biopsy were performed for all study patients followed by systematic pelvic lymphadenectomy, whereas para‐aortic lymphadenectomy was performed in all patients with high‐risk histologies. SLN detection rates, sensitivity, NPV, and FN rates were calculated.Results.Between July 2016 and July 2018, 131 patients were enrolled. The overall SLN detection rate was 93.1%, with a bilateral detection rate of 61.8%. Four positive SLNs were identified in four patients. Lymph node metastasis was observed in four additional patients without positive SLNs. These four patients belonged to a group of patients with a high‐risk subtype. Three of the four patients had isolated para‐aortic node metastases. In low‐risk endometrial cancers, the sensitivity of the SLN technique to identify nodal metastatic disease was 100% (95% confidence interval [CI] 31.0–100), with an NPV and FN rate of 100% (95% CI 95.1–100) and 0%, respectively. In high‐risk endometrial cancers, the sensitivity, NPV, and FN rate were 20% (95% CI 1.0–70.1), 83.3% (95% CI 61.8–94.5), and 80%, respectively.Conclusion.Cervical injection of ICG and SLN mapping yielded a low sensitivity and a high FN rate for the identification of node metastasis in endometrial cancer with high‐risk histologies.Implications for Practice.The efficacy of sentinel lymph node (SLN) mapping for high‐risk endometrial cancer remains unclear. This study enrolled 131 patients with early‐stage endometrial cancer who underwent cervical injection of indocyanine green SLN mapping followed by systematic pelvic lymphadenectomy and para‐aortic lymphadenectomy. The key result was that SLN mapping yielded a low sensitivity and a high false‐negative rate for the identification of node metastasis in endometrial cancer with high‐risk histologies. The SLN strategy in these patients may increase the risk of missed diagnosis of isolated para‐aortic node metastases and seems to be unacceptable in clinical practice.
AbstractBackground.How to best support patients with neuroendocrine tumors (NETs) remains unclear. Improving quality of care requires an understanding of symptom trajectories. Objective validated assessments of symptoms burden over the course of disease are lacking. This study examined patterns and risk factors of symptom burden in NETs, using patient‐reported outcomes.Subjects, Materials, and Methods.A retrospective, population‐based, observational cohort study of patients with NETs diagnosed from 2004 to 2015, who survived at least 1 year, was conducted. Prospectively collected patient‐reported Edmonton Symptom Assessment System scores were linked to provincial administrative health data sets. Moderate‐to‐severe symptom scores were presented graphically for both the 1st year and 5 years following diagnosis. Multivariable Poisson regression identified factors associated with record of moderate‐to‐severe symptom scores during the 1st year after diagnosis.Results.Among 2,721 included patients, 7,719 symptom assessments were recorded over 5 years following diagnosis. Moderate‐to‐severe scores were most frequent for tiredness (40%–51%), well‐being (37%–49%), and anxiety (30%–40%). The proportion of moderate‐to‐severe symptoms was stable over time. Proportion of moderate‐to‐severe anxiety decreased by 10% within 6 months of diagnosis, followed by stability thereafter. Changes were below 5% for other symptoms. Similar patterns were observed for the 1st year after diagnosis. Primary tumor site, metastatic disease, younger age, higher comorbidity burden, lower socioeconomic status, and receipt of therapy within 30 days of assessment were independently associated with higher risk of elevated symptom burden.Conclusion.Patients with NETs have a high prevalence of moderate‐to‐severe patient‐reported symptoms, with little change over time. Patients remain at risk of prolonged symptom burden following diagnosis, highlighting potential unmet needs. Combined with identified patient and disease factors associated with moderate‐to‐severe symptom scores, this information is important to support symptom management strategies to improve patient‐centered care.Implications for Practice.This study used population‐level, prospectively collected, validated, patient‐reported outcome measures to appraise the symptoms burden and trajectory of patients with neuroendocrine tumors (NETs) after diagnosis. It is the largest and most detailed analysis of patient‐reported symptoms for NETs. Patients with NETs present a high burden of symptoms at diagnosis that persists up to 5 years later, highlighting unmet needs. Early and comprehensive symptom screening and management programs are needed. This information should serve to devise pathways and policies to better support patients, evaluate supportive interventions, and assess the effectiveness of symptom management at the provider, institutional, and system levels.
AbstractBackground.Pregnancy concurrent with, shortly before, or after breast cancer poses unique challenges because hormonal changes in pregnancy potentially interact with breast cancer outcomes.Materials and Methods.We studied a cohort of 3,687 female patients of reproductive age (<50 years) with breast cancer, linking a large institutional database and the nationwide claims database to comprehensively capture exposure status and tumor characteristics. Exposures included breast cancer during pregnancy, postpartum breast cancer (<12 months after delivery), and pregnancy after breast cancer.Results.Forty‐five patients with postpartum breast cancer were significantly more likely to have advanced stage, hormone receptor‐negative tumor and to be younger than 35 years at diagnosis than those without postpartum breast cancer. This trend was not observed with 18 patients with breast cancer during pregnancy. The unadjusted 5‐year survival rates were 77% versus 96% for patients with postpartum breast cancer versus their counterparts, 89% versus 96% for patients with breast cancer during pregnancy versus their counterparts, and 98% versus 96% for patients with pregnancy after breast cancer versus their counterparts, respectively. In the multivariable analyses, postpartum breast cancer exhibited hazard ratios for death of 1.57 (95% confidence interval [CI], 0.82–2.99), whereas those for breast cancer during pregnancy and pregnancy after breast cancer were 1.09 (95% CI, 0.15–7.91) and 0.86 (95% CI, 0.26–2.83), respectively.Conclusion.Postpartum breast cancer, but not breast cancer during pregnancy, was associated with advanced stage, younger age at diagnosis (<35 years), hormone receptor‐negative disease, and poorer survival. Pregnancy after breast cancer did not compromise overall survival.Implications for Practice.Although pregnancy around the time of diagnosis of breast cancer is expected to become increasingly common with maternal age at first childbirth on the rise, data on the prognostic impact of pregnancy have been inconsistent and rare from Asian populations. In this investigation of a Korean patient cohort with breast cancer, pregnancy‐associated breast cancer was associated with advanced stage, younger age at diagnosis (<35 years), hormone receptor‐negative disease, and poorer survival. This adverse impact of pregnancy on the prognosis was apparent with postpartum breast cancer but not observed with breast cancer during pregnancy. Pregnancy after breast cancer did not compromise overall survival.
AbstractBackground.The aim of this study was to determine the potential prognostic roles of the perioperative interleukin‐6 (IL‐6) level and its dynamic changes in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE).Materials and Methods.Sixty patients with hepatitis B virus‐associated HCC receiving TACE were enrolled in the study. Serum IL‐6 levels were determined at baseline and 1 day after TACE by immunoassay. Response to TACE was evaluated after a 4–6‐week interval. Factors associated with tumor response were analyzed by univariate and multivariate analysis in a Cox regression model. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive performance of the included variables on tumor response in patients with HCC undergoing TACE.Results.The serum IL‐6 level was significantly elevated 1 day after TACE. Patients in the low postintervention IL‐6 level group had a high probability of achieving an objective response (OR) (66.7% vs. 18.8%, p = .021). Post‐TACE IL‐6 level (≤12.7 pg/mL) and post‐/pre‐TACE neutrophils ratio (>2.47) were independently correlated with OR after TACE. ROC curve analysis showed that a combined index based on those two factors exhibited optimal predictive power of tumor response among all the included variables (area under the curve = 0.740, 95% confidence interval: 0.601–0.879). Additionally, high post‐TACE plasma IL‐6 level was associated with maximum tumor size, vascular invasion, post‐TACE aspartate aminotransferase, and Barcelona Clinic Liver Cancer stage.Conclusion.Our study suggests that the post‐treatment serum IL‐6 level, rather than pretreatment or dynamic changes of IL‐6, serves as a powerful predictor for tumor response. These findings provide evidence to help discriminate between patients who will particularly benefit from TACE and those who require more personalized therapeutic regimens and rigorous surveillance.Implications for Practice.Transarterial chemoembolization (TACE) is a major therapeutic regimen for advanced hepatocellular carcinoma. Thus, identification of early practical markers of tumor response to TACE is of high importance. This study indicated that the post‐treatment serum interleukin‐6 (IL‐6) level, rather than the pretreatment or dynamic changes of IL‐6, serves as a powerful predictor for tumor response. A combined index based on the post‐TACE IL‐6 level and post‐/pre‐TACE neutrophils ratio is optimal for predetermining an objective response after TACE, which may be helpful in guiding individualized treatments and surveillance.
AbstractBackground.With the exception of trastuzumab, therapies directed at receptor tyrosine kinases (RTKs) in gastroesophageal adenocarcinomas (GEA) have had limited success. Recurrent fibroblast growth factor receptor 2 (FGFR2) alterations exist in GEA; however, little is known about the genomic landscape of FGFR2‐altered GEA. We examined FGFR2 alteration frequency and frequency of co‐occurring alterations in GEA.Subjects, Materials, and Methods.A total of 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture‐based genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA, and microsatellite instability was determined on 95 or 114 loci. Descriptive statistics were used to compare subgroups.Results.We identified a total of 269 (4.0%) FGFR2‐altered cases consisting of FGFR2‐amplified (amp; 193, 72% of FGFR2‐altered), FGFR2‐mutated (36, 13%), FGFR2‐rearranged (re; 23, 8.6%), and cases with multiple FGFR2 alterations (17, 6.3%). Co‐occurring alterations in other GEA RTK targets including ERBB2 (10%), EGFR (8%), and MET (3%) were observed across all classes of FGFR2‐altered GEA. Co‐occurring alterations in MYC (17%), KRAS (10%), and PIK3CA (5.6%) were also observed frequently. Cases with FGFR2amp and FGFR2re were exclusively microsatellite stable. The median TMB for FGFR2‐altered GEA was 3.6 mut/mb, not significantly different from a median of 4.3 mut/mb seen in FGFR2 wild‐type samples.Conclusion.FGFR2‐altered GEA is a heterogenous subgroup with approximately 20% of FGFR2‐altered samples harboring concurrent RTK alterations. Putative co‐occurring modifiers of FGFR2‐directed therapy including oncogenic MYC, KRAS, and PIK3CA alterations were also frequent, suggesting that pretreatment molecular analyses may be needed to facilitate rational combination therapies and optimize patient selection for clinical trials.Implications for Practice.Actionable receptor tyrosine kinase alterations assayed within a genomic context with therapeutic implications remain limited to HER2 amplification in gastroesophageal adenocarcinomas (GEA). Composite biomarkers and heterogeneity assessment are critical in optimizing patients selected for targeted therapies in GEA. Comprehensive genomic profiling in FGFR2‐altered GEA parallels the heterogeneity findings in HER2‐amplified GEA and adds support to the utility of genomic profiling in advanced gastroesophageal adenocarcinomas.
The NEO‐CLASSIC study provided valuable insight for the clinical efficacy and tolerability profiles of perioperative chemotherapy with oxaliplatin and capecitabine, plus gastrectomy, in patients with localized resectable gastric cancer.The study was designed to explore the potential survival benefits of an eight‐cycle, perioperative oxaliplatin and capecitabine (XELOX) schedule in the above‐mentioned setting and to explore the feasibility of prolonging the cycles of preoperative chemotherapy. The projected endpoint was not met.Background.This multicenter, open‐label study (NEO‐CLASSIC) evaluated the efficacy and safety of oxaliplatin and capecitabine (XELOX), plus D2 gastrectomy, in localized resectable gastric cancer.Methods.Patients aged 18–75 years with histologically‐confirmed gastric adenocarcinoma (stage T2–4a/N+M0) were given eight cycles of XELOX (four preoperatively, four postoperatively). Each 3‐week cycle comprised capecitabine 1,000 mg/m2 twice daily on days 1–14 and oxaliplatin 130 mg/m2 on day 1. Curative D2 gastrectomy was scheduled 2–4 weeks after the last preoperative cycle. The primary objective of the study was to determine the objective response rate (ORR) of XELOX in the preoperative setting. Sample size was calculated by assuming that a minimum of 47 cases would be required to increase the ORR by 15% (from 40% to 55%). With an estimated 10% dropout rate, 55 patients would have to be recruited.Results.Fifty‐five patients were enrolled, and one was excluded because of screening failure. R0 resections were achieved in 45 of 54 intent‐to‐treat patients (83.3%), and four patients received R1 resections (Fig. 1). There were no complete responses, 27 (50.0%) partial responses, 22 cases (40.7%) of stable disease, and 4 (7.4%) of progressive disease. The objective response rate was 50.0%. Median follow‐up was 52.97 months; 30 patients (55.6%) had disease progression (Table 1), and median progression‐free survival was 20.10 (95% confidence interval: 4.31—35.89) months; median overall survival was 30.77 months (95% confidence interval was not yet available) (Fig. 2). Fifty‐four patients completed 209 cycles of preoperative chemotherapy; 42 patients received 133 cycles of postoperative chemotherapy (Table 3). The rate of grade 3–4 adverse events was 8.5% (29/342 cycles); the most frequent events were neutropenia (9/342 cycles) and leukopenia (4/342 cycles).Conclusion.These findings suggest that combination therapy with capecitabine and oxaliplatin as perioperative chemotherapy, followed by D2 gastrectomy, is effective and safe in late‐stage, locally advanced gastric cancer. Although enrollment exceeded the 47 patients required to identify an increase in the ORR by 15% (from 40% to 55%), results did not meet the primary endpoint.
AbstractBackground.RAS testing is used to select patients with anti‐epidermal growth factor receptor (EGFR) therapies sensitivity in metastatic colorectal cancer (mCRC). However, other biomarkers such as BRAF, PIK3CA/PTEN, and p‐IGF‐1R+/MMP7+ (double positive [DP] phenotype) have not been prospectively assessed to predict anti‐EGFR resistance.Materials and Methods.We designed a multicenter prospective trial (NCT01276379) to evaluate whether the biomarkers BRAF mutation, PIK3CA mutation/PTEN loss, and DP phenotype can improve the prediction for 12‐months progression‐free survival (PFS) over the use of clinical variables exclusively in patients with RAS wild‐type (WT) mCRC treated with standard chemotherapy plus biweekly cetuximab as first‐line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12‐month PFS based on the analysis of clinical and selected biomarkers (α = .05, β = .2). The discriminatory capacity of the biomarkers was evaluated using receiver operating characteristic curves.Results.We included 181 RAS WT patients. The biomarker distribution was as follows: BRAF mutant, 20 patients (11%); PIK3CA mutated/PTEN loss, 98 patients (58%); DP, 23 patients (12.7%). The clinical variables in the clinical score were progression status >0, left‐sided tumor, and resectable liver metastasis as the only metastatic site. The area under the curve (AUC) of the score containing the clinical variables was 0.67 (95% confidence interval [CI], 0.60–0.75). The AUC of the score with clinical variables and BRAF mutational status was 0.68 (0.61–0.75, p = .37). The AUC of the score with clinical variables and PI3KCA mutation/PTEN status was 0.69 (0.61–0.76, p = .32). The AUC of the score with clinical variables and DP phenotype was 0.66 (0.58–0.73, p = .09).Conclusion.The addition of BRAF, PIK3CA/PTEN, and DP to a clinical score does not improve the discrimination of 12‐month PFS.Implications for Practice.This prospective biomarker design study has important clinical implications because many prospective clinical trials are designed with the hypothesis that BRAF mutation per se and MEK and PIK3CA downstream pathways are critical for colorectal tumor survival. The results lead to the question of whether these pathways should be considered as passengers instead of drivers.
AbstractBackground.The effectiveness and cost‐effectiveness of using neoadjuvant FOLFIRINOX (nFOLFIRINOX) for patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC) are unknown. Our objective was to determine whether nFOLFIRINOX is more effective or cost‐effective for patients with BR/LA PDAC compared with upfront resection surgery and adjuvant gemcitabine plus capecitabine (GEM/CAPE) or gemcitabine monotherapy (GEM).Materials and Methods.We performed a decision‐analysis to assess the value of nFOLFIRINOX versus GEM/CAPE or GEM using a mathematical simulation model. Model transition probabilities were estimated using published and institutional clinical data. Model outcomes included overall and disease‐free survival, quality‐adjusted life‐years (QALYs), cost in U.S. dollars, and cost‐effectiveness expressed as an incremental cost‐effectiveness ratio. Deterministic and probabilistic sensitivity analyses explored the uncertainty of model assumptions.Results.Model results found median overall survival (34.5/28.0/22.0 months) and disease‐free survival (15.0/14.0/13.0 months) were better for nFOLFIRINOX compared with GEM/CAPE and GEM. nFOLFIRINOX was the optimal strategy on an efficiency frontier, resulting in an additional 0.35 life‐years, or 0.30 QALYs, at a cost of $46,200/QALY gained compared with GEM/CAPE. Sensitivity analysis found that cancer recurrence and complete resection rates most affected model results, but were otherwise robust. Probabilistic sensitivity analyses found that nFOLFIRINOX was cost‐effective 92.4% of the time at a willingness‐to‐pay threshold of $100,000/QALY.Conclusion.Our modeling analysis suggests that nFOLFIRINOX is preferable to upfront surgery for patients with BR/LA PDAC from both an effectiveness and cost‐effectiveness standpoint. Additional clinical data that further define the long‐term effectiveness of nFOLFIRINOX are needed to confirm our results.Implications for Practice.Increasingly, neoadjuvant FOLFIRINOX has been used for borderline resectable and locally advanced pancreatic cancer with the goal of rendering them resectable and decreasing risk of recurrence. Despite many efforts to show the benefits of neoadjuvant over adjuvant therapies, clinical evidence to guide this decision is largely lacking. Decision‐analytic modeling can provide a methodologic platform that integrates the best available data to quantitatively explore clinical decisions by simulating a hypothetical clinical trial. This modeling analysis suggests that neoadjuvant FOLFIRINOX is preferable to upfront surgery and adjuvant therapies by various outcome metrics including quality‐adjusted life years, overall survival, and incremental cost‐effectiveness ratio.
AbstractBackground.The Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) scale is commonly used by physicians and nurses in oncology, as it correlates with cancer morbidity, mortality, and complications from chemotherapy and can help direct clinical decisions and prognostication. This retrospective cohort study aimed to identify whether ECOG‐PS scores rated by oncologist versus nurses differ in their ability to predict clinical outcomes.Materials and Methods.Over 19 months, 32 oncologists and 41 chemotherapy nurses from a single academic comprehensive cancer center independently scored ECOG‐PS (range: 0–5) for a random sample of 311 patients with cancer receiving chemotherapy. Logistic regression models were fit to evaluate the ability of nurse and physician ECOG‐PS scores, as well as the nurse‐physician ECOG‐PS score difference (nurse minus physician), to predict the occurrence of chemotherapy toxicity (CTCAE v4, grade ≥3) and hospitalizations within 1 month from ECOG‐PS ratings, as well as 6‐month mortality or hospice referrals.Results.Physician/nurse ECOG‐PS agreement was 71% (Cohen's κ = 0.486, p < .0001). Nurse ECOG‐PS scores had stronger odds ratio for 6‐month mortality or hospice (odds ratio [OR], 3.29, p < .0001) than physician ECOG‐PS scores (OR, 2.71, p = .001). Furthermore, ECOG‐PS ratings by nurses, but not physicians, correlated with 1‐month chemotherapy toxicity (OR, 1.44, p = .021) and 1‐month hospitalizations (OR, 1.57, p = .041). Nurse‐physician disagreement, but only when physicians gave “healthier” (lower) ratings, was also associated with worse outcomes (chemotherapy toxicity OR = 1.51, p = .045; 1‐month hospitalization OR, 1.86, p = .037; 6‐month mortality or hospice OR, 2.99, p < .0001).Conclusion.Nurse ECOG‐PS ratings seem more predictive of important outcomes than those of physicians, and physician‐nurse disagreement in ECOG‐PS ratings predicts worse outcomes; scoring by nurses may result in additional clinical benefit.Implications for Practice.Nurse‐rated Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) scores, compared with those rated by oncologists, better predicted hospitalizations and severe chemotherapy toxicity within 1 month from ECOG‐PS assessment, as well as mortality or hospice referrals within 6 months. Physician‐nurse disagreement in ECOG‐PS scoring was associated with worse hospitalization, chemotherapy toxicity, and mortality and hospice referral rates. Rating performance statuses of patients with cancer by nurses instead or in addition to oncologists can result in additional clinical benefits, such as improved prognostication, as well as better informed clinical decision making regarding whether or not to administer chemotherapy, the need for additional supportive care, and goals of care discussions.
AbstractBackground.A standard approach to treating resectable esophageal adenocarcinoma is chemoradiotherapy (CRT) followed by surgery; however, recurrence is common. To improve this, we designed a single‐arm, phase II trial that added an epidermal growth factor receptor (EGFR) inhibitor, cetuximab (C), to CRT, with the hypothesis that EGFR inhibition would improve pathologic complete response (pCR) rate.Materials and Methods.We aimed to increase the pCR rate from 25% to 45%. A Simon two‐stage design (α and β of 0.10) required pCR/enrolled 5/18 for stage 1 and 14/40 total. CRT: oxaliplatin 85 mg/m2 days 1, 15, and 29; infusional 5‐fluorouracil 180 mg/m2/24 hours × 35 days; C 400 mg/m2 day 1 then 250 mg/m2 days 8, 15, 22, and 29 and radiation (intensity modulated radiotherapy [IMRT] allowed) 180 cGy/day × 25 fractions (Monday through Friday). Following esophagectomy, adjuvant chemotherapy (CT): weekly docetaxel 35 mg/m2 and C 250 mg/m2 5 out of 6 weeks for two cycles.Results.Of 21 eligible patients enrolled, 17 had surgery; 4 died before operation (due to pulmonary embolism 4 days after CRT, G3 diarrhea, progressive disease during CRT, sepsis/hypoxia during CRT, and acute respiratory distress syndrome [ARDS]). pCR = 7/17. Three postoperative deaths due to ARDS resulted in seven total study‐related deaths. Of the 14 remaining patients, 12 started and completed adjuvant CT. Two of seven patients with pCR died, both of ARDS. Out of the 21 eligible subjects in this study, 13 have died and 8 remain alive. The use of IMRT did not correlate with ARDS.Conclusion.This regimen demonstrated promising activity. Toxicity was significant, with seven study‐related deaths leading to closure after stage 1. All postoperative deaths were due to ARDS. This regimen is not recommended.Implications for Practice.Esophageal cancer is a disease with a high death rate. The current treatment involves giving chemotherapy plus radiation followed by surgery, but this cures only a quarter of patients. In order to improve survival, better treatments are needed. This trial evaluated the addition of a novel drug, cetuximab, to chemotherapy plus radiation. Unfortunately, the side effects were too great and the study was stopped early.
AbstractBackground.PALOMA‐2 confirmed that first‐line palbociclib + letrozole improved progression‐free survival (hazard ratio, 0.58; 95% confidence interval, 0.46–0.72) in postmenopausal women with estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC). This analysis evaluated palbociclib‐associated hematologic adverse events (AEs) and provides insight on managing these AEs.Materials and Methods.Postmenopausal women with ER+/HER2− ABC were randomly assigned 2:1 to letrozole (2.5 mg daily continuously) plus oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments were performed at baseline, days 1 and 15 (first two cycles) and day 1 of subsequent cycles, and included white blood cell, platelet, and absolute neutrophil count (ANC).Results.PALOMA‐2 randomized 666 women to palbociclib + letrozole (n = 444) or placebo + letrozole (n = 222). Neutropenia was the most common AE (95.3%) with palbociclib (grade 3, 55.6%; grade 4, 11.5%) and was managed by dose modifications; progression‐free survival was similar between patients who experienced grade ≥ 3 neutropenia versus those who did not. Median (range) time to onset of neutropenia with palbociclib + letrozole was 15 (12–700) days (grade ≥ 3, 28.0 [12–854] days); median duration of each neutropenia episode grade ≥ 3 was 7.0 days. Asian ethnicity and low baseline ANC were associated with increased risk of grade 3/4 neutropenia with palbociclib (p < .001).Conclusion.Palbociclib + letrozole was generally well tolerated. Neutropenia, the most frequently reported AE in women with ER+/HER2− ABC, was mostly transient and manageable by dose modifications in patients who experienced grade ≥ 3 neutropenia, without appearing to compromise efficacy. (Pfizer; NCT01740427)Implications for Practice.Palbociclib demonstrated an acceptable safety profile in PALOMA‐2 in women with estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC) receiving first‐line palbociclib + letrozole. Although hematologic adverse events (AEs) are typically expected with anticancer therapies and are often clinically significant, palbociclib‐related hematologic AEs, particularly neutropenia (most frequent AE), were transient/manageable by dose reduction, interruption, or cycle delay, which is in contrast to the more profound neutropenia associated with chemotherapy. Palbociclib dose adjustments decreased hematologic AE severity without appearing to compromise efficacy, supporting palbociclib + letrozole as a first‐line treatment for ER+/HER2− ABC.
AbstractBackground.A dexamethasone‐sparing regimen consisting of palonosetron plus 1‐day dexamethasone for the prevention of chemotherapy‐induced nausea and vomiting (CINV) has been studied previously. Here, we evaluate the noninferiority of the dexamethasone‐sparing regimen in overall antiemetic control using a meta‐analysis based on individual patient data (IPD).Materials and Methods.We conducted a systematic review for randomized trials reporting CINV outcomes for the comparison of palonosetron plus 1‐day dexamethasone (d1 arm) versus the same regimen followed by dexamethasone on days 2–3 after chemotherapy (d3 arm) in chemotherapy‐naïve adult patients undergoing either moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC)‐containing chemotherapy. PubMed and MEDLINE were searched electronically. A manual search was also conducted. The primary endpoint was complete response (CR; no emesis and no rescue medication) in the overall 5‐day study period. The noninferiority margin was set at −8.0% (d1 arm−d3 arm).Results.Five studies (n = 1,194) were eligible for analysis and all IPD was collected. In the overall study period, the d1 arm showed noninferiority to the d3 arm for CR as well as complete control (pooled risk difference in CR rate − 1.5%, 95% confidence interval [CI] −7.1 to 4.0%, I2 = 0%; in complete control rate − 2.4%, 95% CI −7.7 to 2.9%, I2 = 0%). There was no significant interaction between dexamethasone regimen and risk factors (type of chemotherapy, sex, age, and alcohol consumption).Conclusion.This IPD meta‐analysis indicates that the dexamethasone‐sparing regimen is not associated with a significant loss in overall antiemetic control in patients undergoing MEC or AC‐containing chemotherapy, irrespective of known risk factors for CINV.Implications for Practice.Although dexamethasone in combination with other antiemetic agents has been used to prevent chemotherapy‐induced nausea and vomiting (CINV), it is of clinical importance to minimize total dose of dexamethasone in patients undergoing multiple cycles of emetogenic chemotherapy. This individual‐patient‐data meta‐analysis from five randomized controlled trials (1,194 patients) demonstrated a noninferiority of the dexamethasone‐sparing regimen for complete response and complete control of CINV. The outcomes were comparable across patients with different characteristics. These findings thus help physicians minimize use of the steroid and further reduce the burden of dexamethasone‐related side effects in patients undergoing multiple consecutive courses of emetogenic chemotherapy.
AbstractThis article provides an overview of radiofrequency ablation (RFA) and microwave ablation (MWA) for treatment of primary liver tumors and hepatic metastasis. Only studies reporting RFA and MWA safety and efficacy on liver were retained. We found 40 clinical studies that satisfied the inclusion criteria. RFA has become an established treatment modality because of its efficacy, reproducibility, low complication rates, and availability. MWA has several advantages over RFA, which may make it more attractive to treat hepatic tumors. According to the literature, the overall survival, local recurrence, complication rates, disease‐free survival, and mortality in patients with hepatocellular carcinoma (HCC) treated with RFA vary between 53.2 ± 3.0 months and 66 months, between 59.8% and 63.1%, between 2% and 10.5%, between 22.0 ± 2.6 months and 39 months, and between 0% and 1.2%, respectively. According to the literature, overall survival, local recurrence, complication rates, disease‐free survival, and mortality in patients with HCC treated with MWA (compared with RFA) vary between 22 months for focal lesion >3 cm (vs. 21 months) and 50 months for focal lesion ≤3 cm (vs. 27 months), between 5% (vs. 46.6%) and 17.8% (vs. 18.2%), between 2.2% (vs. 0%) and 61.5% (vs. 45.4%), between 14 months (vs. 10.5 months) and 22 months (vs. no data reported), and between 0% (vs. 0%) and 15% (vs. 36%), respectively. According to the literature, the overall survival, local recurrence, complication rates, and mortality in liver metastases patients treated with RFA (vs. MWA) are not statistically different for both the survival times from primary tumor diagnosis and survival times from ablation, between 10% (vs. 6%) and 35.7% (vs. 39.6), between 1.1% (vs. 3.1%) and 24% (vs. 27%), and between 0% (vs. 0%) and 2% (vs. 0.3%). MWA should be considered the technique of choice in selected patients, when the tumor is ≥3 cm in diameter or is close to large vessels, independent of its size.Implications for Practice.Although technical features of the radiofrequency ablation (RFA) and microwave ablation (MWA) are similar, the differences arise from the physical phenomenon used to generate heat. RFA has become an established treatment modality because of its efficacy, reproducibility, low complication rates, and availability. MWA has several advantages over RFA, which may make it more attractive than RFA to treat hepatic tumors. The benefits of MWA are an improved convection profile, higher constant intratumoral temperatures, faster ablation times, and the ability to use multiple probes to treat multiple lesions simultaneously. MWA should be considered the technique of choice when the tumor is ≥3 cm in diameter or is close to large vessels, independent of its size.
The combination of pexidartinib and binimetinib was safe and tolerable and demonstrated encouraging signs of efficacy in two patients with advanced gastrointestinal stromal tumor (GIST) refractory to tyrosine kinase inhibitors (TKIs).Molecular profiling of GISTs at diagnosis and upon progression may provide insight into the mechanisms of response or resistance to targeted therapies.Additional trials are needed to further explore combined KIT and MEK inhibition in treatment‐naïve and TKI‐refractory patients with advanced GIST.Background.Nearly all patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Dual inhibition of KIT and MAPK pathways has synergistic antitumor activity in preclinical GIST models.Methods.This was an investigator‐initiated, phase I, dose escalation study of the MEK inhibitor binimetinib combined with pexidartinib, a potent inhibitor of CSF1R, KIT, and FLT3, in patients with advanced or metastatic GIST who progressed on imatinib. The primary endpoint was phase II dose determination; secondary endpoints included safety, tolerability, and efficacy. An expansion cohort to further evaluate safety and efficacy was planned.Results.Two patients were treated at dose level one (binimetinib 30 mg b.i.d. and pexidartinib 400 mg every morning and 200 mg every evening), after which the study was terminated by the manufacturer. No dose‐limiting toxicities (DLTs) were reported, and treatment was well tolerated. The only grade ≥3 treatment‐emergent adverse event (TEAE) was asymptomatic elevated creatine phosphokinase (CPK). Both patients had a best response of stable disease (SD) by RECIST. Progression‐free survival (PFS) and overall survival (OS) were 6.1 and 14.6 months, respectively, in one patient with five prior lines of therapy. The second patient with NF1‐mutant GIST had a 27% decrease in tumor burden by RECIST and remains on study after 19 months of treatment.Conclusion.Pexidartinib combined with binimetinib was tolerable, and meaningful clinical activity was observed in two imatinib‐refractory patients.
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