AbstractBackground.The molecular phenotype of circulating tumor cells (CTCs) was associated with clinical outcome of patients with breast cancer. CTCs isolated from patients with metastatic breast cancer (MBC) display a unique microRNA (miRNA) expression profile. The aim of this study was to enhance the prognostic accuracy of the CTC phenotype in patients with MBC, by incorporating miRNA into a combined prediction model.Subjects, Materials, and Methods.CTCs were detected by CellSearch and enriched by magnetic cell sorting. miRNA deep sequencing and quantitative polymerase chain reaction were used to screen and verify potentially CTC‐specific miRNA candidates. Patients with MBC were enrolled from two independent cohorts, and overall survival (OS) and chemotherapy response were analyzed.Results.We screened and identified that miR‐106b was an upregulated molecule in patients with MBC with CTC ≥5/7.5 mL (n = 16) compared with patients with CTC = 0/7.5 mL (n = 16) and healthy donors (n = 8). The expression of CTC‐specific miR‐106b correlated with vimentin and E‐cadherin in CTC and acted as an independent factor for predicting OS (hazard ratio 2.157, 95% confidence interval [CI] 1.098–4.239, p = .026). Although CTC‐specific miR‐106b, E‐cadherin, and vimentin showed a prognostic potential independently, the prognostic performance for OS based on the combination of three markers was significantly enhanced in Cohort 1 (area under the curve [AUC] 0.752, 95% CI 0.658–0.847, n = 128) and further validated in Cohort 2 (AUC 0.726, 95% CI 0.595–0.856, n = 91). Besides, a combined model incorporating miR‐106b was associated with therapy response.Conclusion.The phenotypic assemblies of CTC incorporating miR‐106b show enhanced prognostic accuracy of overall survival in patients with MBC.Implications for Practice.In order to enhance the prognostic accuracy of the circulating tumor cell (CTC) phenotype in patients with metastatic breast cancer (MBC), this study screened and identified a CTC‐specific microRNA (miRNA), miR‐106b, as an upregulated molecule based on the comparison of miRNA profile between CTCs, primary tumors, and healthy blood donors. By incorporating miR‐106b into a combined prediction model, the prognostic accuracy of the CTC phenotype for patients with MBC was greatly improved in both the training and validation cohorts. This work provides clinical evidence supporting the prognostic potential of CTC‐specific miRNA for patients with MBC. These results indicate that developing CTC‐specific miRNAs as new biomarkers will help to further optimize personalized therapy.
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.
The Oncologist RSS feed -- Early Online Editions of Accepted Articles
Subscribe to Early View from The Oncologist feed