Indolent Cancer Research Articles

Aggressive Prostate Cancer Detection with an 8-Protein Biomarker Panel

Prostate cancer treatment has risk associated with patients’ being overdiagnosed leading to an overtreatment epidemic. In the United States 1 in 9 males are diagnosed with prostate cancer with approximately 10% of these patients having aggressive forms usually requiring surgery. To diagnose these patients, physicians most often rely on the Prostate Specific Antigen (PSA) blood test and the digital rectal exam. PSA is currently the only biomarker approved for prostate cancer diagnostics, but cannot discern cancer from other prostate conditions, such as Benign Prostatic Hyperplasia (BPH) or Prostatitis. Most importantly, PSA cannot identify the aggressive forms of prostate cancer. These inaccuracies lead to unnecessary treatments including surgery of indolent prostate cancer patients that adversely affect the patients’ quality of life. Measurements of small panels of molecular biomarkers in serum holds tremendous potential for cancer diagnostics and personalized therapy. We are evaluating a new protein panel for prostate cancer including PSA, CD-14, ERG, GOLM-1, PEDF-1, IGF-1, VEGF-D and IGFBP-3 that may be indicative of prostate cancer or cancer progression. We designed a microfluidic immunoarray that features miniaturisation, low sample volume, sensitivity adjustable to the sample characteristics, rapid analysis, and low reagent consumption. A protocol was developed for the simultaneous assay of this 8-protein panel in serum that features online capture and detection with a semi-automated multiple protein immunoarray. A nanostructured sensor array with bound capture antibody in the microfluidic device captures the biomarker proteins from the sample, and a sandwich immunoassay is completed following a concurrent injection of target protein standards or sample, biotinylated secondary antibody and polymerized horseradish peroxidase into the detection chamber. Ultra-low limits of detection (LOD) in the sub fg ml-1 range were achieved for the proteins in the panel. Using this strategy, 8-16 proteins can be detected simultaneously within 30 minutes. Measurements of the biomarker panel tested with prostate cancer patient samples and statistical analyses to assess diagnostic utility will be described.

Semi-Automated Electrochemical Microfluidic Immunoarray for Cancer Diagnostics

Over-expression of Parathyroid hormone-related peptide (PTHrP) is recognized as the main causative agent of the paraneoplastic syndrome, humoral hypercalcemia of malignancy (HHM). PTHrP is known to be indicative of progression and metastasis of several human cancers. The established prognosis method of PTHrP, immunoradiometric assay (IRMA), is unable to determine the peptide levels prior to the advancement of hypercalcemia due to insufficient sensitivity. Prostate specific antigen (PSA) is a biomarker that has been extensively used as a diagnostic tool in prostate cancer. Unfortunately, PSA is limited in its’ inability to distinguish cancer from other prostate conditions such as Benign Prostatic Hyperplasia (BPH) or Prostatitis. These inaccuracies lead to unnecessary treatments including surgery on indolent cancer patients that adversely affect the patients’ quality of life. Therefore, there is strong appeal for the development of ultrasensitive, low cost multiplexed detection of appropriate biomarkers in clinically relevant ranges to assist the diagnosis and progression of cancers. Here we have employed a lab-developed microfluidic immunoarray for small samples, that features automation, miniaturisation, sensitivity adjustable to the sample characteristics, rapid analysis, and low reagent consumption for the detection of PTHrP and PSA in human cancer patient serum. The immunoarrays employ nanostructured sensors decorated with capture antibodies to perform a sandwich immunoassay using poly-horseradish peroxidase (poly-HRP) with about 80 HPRs per molecule that links to a secondary antibody bound to analytes on the sensor for high sensitivity detection. Incubation times were tailored to obtain limits of detection (LOD) in sub-fg mL-1 without a significant compromise in sensitivity leading to a simple, quick cancer diagnostics and personalized cancer therapy strategies. This may be able to transform the current methods of prostate cancer diagnosis. This system will be utilized to evaluate PTHrP peptides as aggressive prostate cancer biomarkers by analysis of human serum samples from patients.

Cancer overdiagnosis: a biological challenge and clinical dilemma.

For cancer screening to be successful, it should primarily detect cancers with lethal potential or their precursors early, leading to therapy that reduces mortality and morbidity. Screening programmes have been successful for colon and cervical cancers, where subsequent surgical removal of precursor lesions has resulted in a reduction in cancer incidence and mortality. However, many types of cancer exhibit a range of heterogeneous behaviours and variable likelihoods ofprogression and death. Consequently, screening for some cancers may have minimal impact on mortality and may do more harm than good. Since the implementation of screening tests for certain cancers (for example, breast and prostate cancers), a spike in incidence of in situ and early-stage cancers has been observed, but a link to reduction in cancer-specific mortality has not been as clear. It is difficult to determine how many of these mortality reductions are due to screening and how many are due to improved treatments of tumours. In cancers with lower incidence but high mortality (for example, pancreatic cancer), screening has focused on high-risk populations, but challenges similar to those for general population screening remain, particularly with regard to finding lesions with difficult-to-characterize malignant potential (for example, intraductal papillary mucinous neoplasms). More sensitive screening methods are detecting smaller and smaller lesions, but this has not been accompanied by a comparable reduction in the incidence of invasive cancers. In this Opinion article, we focus on the contribution of screening in general and high-risk populations to overdiagnosis, the effects of overdiagnosis on patients and emerging strategies to reduce overdiagnosis of indolent cancers through an understanding of tumour heterogeneity, the biology of how cancers evolve and progress, the molecular and cellular features of early neoplasia and the dynamics of the interactions of early lesions with their surrounding tissue microenvironment.

MON-550 Have New ATA Guidelines Changed the Diagnosis and Management of Thyroid Cancer? A Population-Based Study

Background : Thyroid cancer incidence is increasing in the United States, predominantly papillary thyroid cancer (PTC). Overdiagnosis of clinically indolent thyroid cancer contributes to the rise in incidence and adds to treatment and monitoring burdens. In March 2015, a symposium at the Endocrine Society introduced guidelines by the American Thyroid Association (ATA) for management of differentiated thyroid cancers (DTC).This included changes in recommendations for biopsy of sub-centimeter thyroid nodules and consideration of lobectomy for small, localized cancers. Objective : To identify how 2015 ATA guidelines on management of DTC have changed practice in a population-based study. Study Design : Population-based retrospective cohort study Methods : We utilized the Rochester Epidemiology Project (REP) database to identify all new cases of thyroid cancer in Olmsted County, MN between 2000 and 2017. We extracted information about demographics, mechanism of detection of the thyroid cancer, parameters of the tumor including pathologic type, size, and invasiveness, and initial management approach. Clinically relevant cancers were identified as those with aggressive histology (anaplastic, medullary, undifferentiated, Hurthle cell) or AJCC 8 Stage 3-4 differentiated thyroid cancers. Results: Between 2000 and 2017, a total of 313 new cases of thyroid cancer were diagnosed in Olmsted County, of which 249 were prior to March 1, 2015, and 64 thereafter. The cohort had a mean age of 46.5 years (SD 15.1), 70% female, predominantly Caucasian (87%), and 94% with PTC. Patients diagnosed before and after the index date had similar distributions of thyroid cancer histology, mean tumor size, mechanism of detection, and frequency of clinically relevant cancers. The percentage of thyroid cancers ≤ 1cm was reduced after the index date, but this was not significant (27% vs 37%, p=0.15). In patients with both ≤ 1cm PTC and ≤ 4cm PTC, there was a significant increase towards less intensive management (lobectomy, active surveillance, ethanol ablation) compared to complete thyroidectomy (total, near total, subtotal) (≤ 1cm: 22% vs 47%, p=0.04; ≤4cm: 13% vs 26%, p=0.01). Conclusion: In our study, we find that changes in ATA guidelines have not yet led to changes to changes in parameters of newly detected thyroid cancers in our population based study. However, there has been a significant trend towards less invasive management of microPTC and ≤ 4cm PTC, though there are still many patients having complete thyroidectomies with microPTC. Further studies will need to include how changes in management will impact outcomes of cancer recurrence, costs and burdens of follow-up care and patient’s quality of life.

A Rich Array of Prostate Cancer Molecular Biomarkers: Opportunities and Challenges.

Prostate cancer is the most prevalent non-skin cancer in men and is the leading cause of cancer-related death. Early detection of prostate cancer is largely determined by a widely used prostate specific antigen (PSA) blood test and biopsy is performed for definitive diagnosis. Prostate cancer is asymptomatic in the early stage of the disease, comprises of diverse clinico-pathologic and progression features, and is characterized by a large subset of the indolent cancer type. Therefore, it is critical to develop an individualized approach for early detection, disease stratification (indolent vs. aggressive), and prediction of treatment response for prostate cancer. There has been remarkable progress in prostate cancer biomarker discovery, largely through advancements in genomic technologies. A rich array of prostate cancer diagnostic and prognostic tests has emerged for serum (4K, phi), urine (Progensa, T2-ERG, ExoDx, SelectMDx), and tumor tissue (ConfirmMDx, Prolaris, Oncoytype DX, Decipher). The development of these assays has created new opportunities for improving prostate cancer diagnosis, prognosis, and treatment decisions. While opening exciting opportunities, these developments also pose unique challenges in terms of selecting and incorporating these assays into the continuum of prostate cancer patient care.

A review of the propriety of thyroid ultrasound referrals and their follow-up burden.

The overdiagnosis of thyroid nodules and indolent thyroid cancers represents an increasing burden on health services, with thyroid ultrasound (US) imaging often representing the initial entry point into the thyroid nodule diagnostic pathway. The aim of this study was to retrospectively review thyroid US referrals to a single Irish hospital to determine if the stated indications for imaging had been appropriate, to review the results of the scans, and to assess the follow-up required in each case. Patient demographics, scan indications, results, and outcomes were retrospectively reviewed for all patients undergoing thyroid ultrasound from 2012 to 2016. Data were analyzed using GraphPad Prism and expressed in mean ± standard deviation. In total, 318 patients (mean age 53 ± 15 years, 85% female) had at least one ultrasound. Most US scans were performed for appropriate indications in order to follow up known thyroid nodular disease and/or malignancy (34.3%), to assess new thyroid goiters or discrete neck lumps (33.3%), and to follow up incidental findings from other imaging modalities (12.6%). However, scans were also requested (in the absence of any palpable goiter or mass) for choking/neck pain/swallowing complaints (12.3%), hypo/hyperthyroidism (6.6%), and miscellaneous reasons (0.6%) that were deemed either potentially or likely inappropriate. Of these scans, approximately half of the identified nodule(s) were deemed unlikely to be related to the stated symptoms, but which subsequently required follow-up imaging ± biopsy. No cases of malignancy were identified. In our center, a significant percentage of thyroid US scans along with their subsequent follow-up were potentially avoidable.

The new ISUP 2014/WHO 2016 prostate cancer grade group system: first résumé 5years after introduction and systemic review of the literature.

To systematically and comprehensively review and summarize the most recent literature assessing the value of the new grading system introduced by the International Society of Urological Pathology (ISUP) in 2014 and accepted by the World Health Organization (WHO) in 2016. A systematic literature search in the PubMed database was performed up to November 2018. Overall, 15 studies in the period from 2016 to 2018 evaluating the new grading system have been selected for evidence synthesis. The main goals of the new ISUP 2014/WHO 2016 grading system were to establish (I) a more accurate and simplified grade stratification, (II) less overtreatment of indolent prostate cancer as well as (III) an improved patient communication. The majority of the studies chose biochemical recurrence as an endpoint for evaluation and statistically assigns the new ISUP 2014/WHO 2016 grading system a higher prognostic accuracy than the former Gleason grading. However, in only a subset of studies it was clearly evident that the historical samples were not only re-grouped according to the new grade groups but also re-graded according to the new histomorphological 2014 ISUP criteria. The vast majority of the studies support an improved prognostic accuracy of the ISUP 2014/WHO 2016 grade groups and endorse its worldwide application.

MP24-05 SELF-IDENTIFIED AFRICAN AMERICANS AND PROSTATE CANCER RISK: WEST AFRICAN GENETIC ANCESTRY IS ASSOCIATED WITH PROSTATE CANCER DIAGNOSIS AND WITH HIGHER GLEASON SUM ON BIOPSY

INTRODUCTION AND OBJECTIVES:Concerns about overtreatment of clinically indolent prostate cancer (PrCa) have led to recommendations for less screening, fewer biopsies, and the management of low-risk PrCa by active surveillance rather than immediate definitive treatment. However the risk of missing or failing to treat an aggressive prostate PrCa can be a significant source of anxiety. The uncertainty is particularly keen for African American (AA) men who are about 1.7 times more likely to be diagnosed with PrCa and about 2.4 times more likely to die of this disease. Many studies show that genetic factors play a role in the increased risk of PrCa in AA. The AA population, as many other populations in the Americas, is genetically heterogeneous with varying degrees of admixture from West Africans, Europeans and Native Americans. Recommendations for PrCa screening and management rarely consider potential differences in risk within the AA population.METHODS:96 consecutive eligible self-identified AA men were pro...

Understanding Pathways to the Diagnosis of Thyroid Cancer: Are There Ways We Can Reduce Over-Diagnosis?

The incidence of thyroid cancer has rapidly increased, and ecological evidence suggests this is due in some part to over-diagnosis. Understanding pathways to diagnosis could help determine whether unnecessary diagnosis can be avoided. A population-based sample (n = 1007) of thyroid cancer patients diagnosed between July 2013 and August 2016 was recruited from Queensland, Australia (response rate 67%). Information from structured telephone interviews was used to describe diagnostic pathways for thyroid cancer, to investigate factors associated with diagnostic pathways, and to assess the most prevalent modes of diagnoses by which the lowest-risk, potentially over-diagnosed thyroid cancers (intrathyroidal microcarcinomas) are detected. Only 38% of participants presented with symptoms potentially related to thyroid cancer. Older age at diagnosis was associated with a lower prevalence of symptomatic diagnosis (prevalence ratio [PR] = 0.46 [confidence interval (CI) 0.31-0.68] for 70-79 vs. <30 years), as was frequent medical contact, while living in rural/regional areas was associated with a higher prevalence of symptomatic diagnosis (PR = 1.17 [CI 1.00-1.37] for rural/regional areas vs. major cities). Symptomatic diagnosis also occurred more for those whose tumors had adverse histopathological features (larger size, lymph node involvement, lymphovascular invasion). The likelihood of diagnosis of intrathyroidal microcarcinomas was greatest for those having surgical resection or monitoring for benign thyroid disease (PR = 3.87 [CI 2.81-5.32] and PR = 2.21 [CI 1.53-3.18], respectively). A minority of newly detected thyroid cancer cases were diagnosed because of symptoms. Access to medical care and factors related to cancer aggressiveness were associated with how diagnoses occurred. The likelihood of diagnosing the lowest-risk thyroid cancers was higher in situations related to management of other thyroid conditions. Adherence to thyroid management guidelines could reduce some thyroid cancer over-diagnosis, but ultimately better diagnostic tools are needed to differentiate between indolent cancers and those of clinical significance.

Aggressive Variants of Follicular- and Parafollicular-Derived Thyroid Carcinoma

Abstract There are several aggressive variants of thyroid carcinoma including those of papillary thyroid carcinoma, poorly differentiated thyroid carcinoma, anaplastic thyroid carcinoma, and medullary thyroid carcinoma that are important to recognize. Among thyroid malignancies, papillary thyroid carcinoma represents the most common form of endocrine cancer. Papillary thyroid carcinoma usually presents as an indolent cancer with high overall survival rates approaching 96%. However, a minority of thyroid carcinomas with distinctive histopathology (eg, tall cell, columnar cell, solid, hobnail, diffuse sclerosing, and diffuse follicular variant) behaves more aggressively and may not respond to routine treatment, leading to higher mortality. Other aggressive follicular-derived thyroid malignancies are represented by poorly differentiated thyroid carcinoma and anaplastic thyroid carcinoma, which are associated with an especially unfavorable prognosis. The most important aggressive parafollicular thyroid malignancy encountered is medullary thyroid carcinoma. This review describes the clinical, pathological, and molecular findings for these aggressive thyroid malignancies and underscores current concepts and controversies related to these tumors.

MRI targeted biopsy dramatically increases detection of clinically significant prostate cancer while reducing the risk of indolent cancer detection.

108 Background: MRI fusion prostate biopsy has been shown to improve detection of clinically significant prostate cancer, however the degree of this benefit is poorly characterized in large clinical trials. Methods: 1750 MRI targeted plus sextant biopsies were performed in 1742 male patients from 2007 to 2017. Patient demographics, PSA, prostate volume, primary and secondary Gleason scores, Johns Hopkins Grade Groups, number of MRI targeted lesions, number of cores obtained, and biopsy yield were recorded. Results: The patient population consisted of men averaging 62.9-year-old (36-86) with a mean PSA 9.6ng/mL, and prostate volume of 59.2 ml. A total of 804 cancers were detected on sextant biopsy and 839 were detected on MRI targeted biopsy. Relative to targeted biopsy, sextant biopsy detected only significantly more Gleason 6 disease (14% vs 21.5%, p &lt; 0.0001) than targeted biopsy. Targeted biopsy detected more Gleason 7 (21% vs 16.6%, p = 0.0009) and Gleason 8-10 (13.4% vs 9.4%). Additionally, Gleason 7 sub-stratification demonstrated substantially more Gleason 4+3 detection in targeted group vs sextant biopsy (4% vs 0.5%, p &lt; 0.0001). When stratified by Grade Group targeted biopsy detected 76% more Grade Group 3-5 cancers (p &lt; 0.0001) and 17.7% less Gleason Group 1-2 cancers (p &lt; 0.0001). Only 1.7% of Grade Group 3-5 cancers were detected on sextant biopsy alone, where as 15.7% of Grade Group 3-5 cancers were detected on targeted biopsy alone. Conclusions: MRI targeted biopsy significantly increases the likelihood of detecting clinically significant cancer and decreases the risk of indolent cancer detection. These finding strongly support the use of MRI targeted biopsy when possible.

Combining urinary DNA methylation and cell-free microRNA biomarkers for improved monitoring of prostate cancer patients on active surveillance

PurposeProstate cancer (CaP) patients with low-grade tumors are enrolled in active surveillance (AS) programs and monitored with digital rectal exams (DREs), prostate-specific antigen (PSA) tests, and periodic invasive biopsies. Patients are “reclassified” with higher-risk disease if they show signs of disease progression. However, AS patients who will reclassify cannot be easily identified upfront and suffer morbidities associated with biopsy. Biomarkers derived from noninvasively obtained specimens such as serum or urine samples are promising alternatives to monitor patients with clinically insignificant cancer. Previously, we have characterized and validated a urinary DNA methylation panel and a serum miRNA panel for the prediction of patient reclassification in 2 independent AS cohorts. In this exploratory study, we have investigated cell-free miRNAs in the urinary supernatant combined with urinary DNA methylation markers to form an integrative panel for prediction of AS patient reclassification. MethodsPost-DRE urine was collected from 103 CaP patients on active surveillance. Urinary sediment DNA methylation levels of selected genes were previously analyzed using qPCR-based MethyLight assay. Using qRT-PCR, we analyzed the urinary supernatants for relative quantities of 10 miRNAs previously shown to be associated with AS reclassification. Logistic regression and Receiver Operating Characteristics curve analyses were performed to assess the predictive ability of miRNAs and DNA methylation biomarkers. ResultsWe identified a 3-marker panel, consisting of miR-24, miR-30c and CRIP3 methylation, that was significant for prediction of patient reclassification (Odds ratio = 2.166, 95% confidence interval = 1.22–3.847) with a negative predictive value of 90.9%. Our 3-marker panel also demonstrated additive value to PSA for prediction of patient reclassification (c-statistic = 0.717, ROC bootstrapped 1000 iteration P = 0.041). ConclusionA urinary integrated panel of methylation and miRNA markers is a promising approach to identify AS patients at risk for reclassification. Our 3-marker panel, with its high negative predictive value, would be beneficial to identify and preclude AS patients with truly indolent cancer and to personalize monitoring strategies for AS patients.

Abstract P5-18-10: BHLHE40-AS1 is an enhancer associated long noncoding RNA critical to breast cancer progression

Abstract Increased emphasis on breast cancer screening has led to a dramatic increase in diagnosis of ductal carcinoma in situ (DCIS). DCIS lesions are nonobligate precursors of invasive ductal carcinoma (IDC) and thus, the current standard-of-care is aggressive therapy to prevent invasive and metastatic disease. However, only ˜40% of DCIS cases are predicted to progress leading to a current state of overtreatment and overdiagnosis. Thus, there is a critical need to identify functional determinants of progression of DCIS to IDC to allow discrimination between indolent and aggressive breast cancers and refine patient treatment strategies.We propose that long noncoding RNAs (lncRNAs) functionally drive breast cancer progression and their expression can discriminate between innocuous and potentially invasive DCIS. Using biopsies from women with tandem DCIS and IDC lesions, we identified 35 lncRNAs whose expression can distinguish between pre-invasive and invasive disease. From this candidate list, the lncRNA BHLHE40-AS1 is found enriched in multiple breast cancer progression models, in HER2+ cell lines, and HER2+ patient tumors. Functionally, BHLHE40-AS1 is found to support tumor cell cycle and motility and may serve as a clinically relevant biomarker and therapeutic target in invasive breast cancer. Further, BHLHE40-AS1 is expressed from a known super-enhancer that preliminary evidence suggests undergoes altered chromatin looping during breast cancer progression. Interestingly, over half of the candidate lncRNAs are associated with enhancer regions. Current studies are investigating super-enhancers, and associated lncRNAs that become acquired during breast cancer progression. Citation Format: DeVaux RS, Schimjawicz H, Coarfa C, Behbod F, Herschkowitz JI. BHLHE40-AS1 is an enhancer associated long noncoding RNA critical to breast cancer progression [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-10.

Fludarabine and Rituximab in Relapsed or Refractory Hairy Cell Leukmia Variant: A Case Report and Review of Literature

Hairy cell leukemia (HCL) is a rare chronic B cell leukemia morphologically characterized by cells with an abundant cytoplasm and hair-like projections that can be found in the peripheral blood and bone marrow. The treatment for HCL is splenectomy or chemotherapy with the purine analogs pentostatin and cladribine. However, patients continue to relapse. Retreatment with the same or alternate purine analogs produces lower response rates and a shorter duration of response. Fludarabine is another purine analog widely used in treating indolent lymphoid cancers, often in combination with rituximab. Here, we report a case of HCL variant in a 60-year-old man who experienced multiple relapses after splenectomy and retreatment with cladribine. The patient was then treated with fludarabine and rituximab combination chemotherapy. After the treatment, he achieved complete remission that continued for 35 months.

Evaluating the Effect of Lymph Node Status on Survival in Large Colon Cancer.

Objective: This study aimed to investigate the effect of lymph node status on survival in large colon cancer.Methods: In the first cohort, patients diagnosed with non-metastatic colon cancer (N = 176,834) were identified from the Surveillance, Epidemiology, and End Results (SEER) database between January 1988 and December 2005. Further analyses were conducted in the other cohort (N = 855) from the Fudan University Shanghai Cancer Center (FUSCC) database.Results: In the SEER cohort, CSS differences increased as the tumor enlarged until a threshold tumor size group (tumor measuring 7–8 cm, P < 0.001) was reached, in which node positivity showed the maximum negative effect on CSS; multivariate Cox analyses showed that tumors measuring 7–8 cm presented a significant lower risk of cancer-specific mortality compared with those measuring 2–4 cm [hazard ratio (HR) = 1.087; 95% confidence interval (CI) = 1.014–1.165, P = 0.018]. In the FUSCC cohort, N0 tumors measuring 21–40 mm presented a higher risk of recurrence compared with those measuring 41–80 mm.Conclusions: Mortality risk of node positivity increased as tumor enlarged until a threshold tumor size (tumor size of 7–8 cm) was reached, mainly resulting from larger tumors without lymph node involvement being a surrogate for biologically indolent colon cancer of tumor recurrence. Our study could provide both researchers and clinicians a better understanding of colon cancer biology.

Head-to-head Comparison of Transrectal Ultrasound-guided Prostate Biopsy Versus Multiparametric Prostate Resonance Imaging with Subsequent Magnetic Resonance-guided Biopsy in Biopsy-naïve Men with Elevated Prostate-specific Antigen: A Large Prospective Multicenter Clinical Study

BackgroundThere is growing interest to implement multiparametric magnetic resonance imaging (mpMRI) and MR-guided biopsy (MRGB) for biopsy-naïve men with suspected prostate cancer. ObjectivePrimary objective was to compare and evaluate an MRI pathway and a transrectal ultrasound-guided biopsy (TRUSGB) pathway in biopsy-naïve men with prostate-specific antigen levels of ≥3ng/ml. Design, setting, and populationA prospective, multicenter, powered, comparative effectiveness study included 626 biopsy-naïve patients (from February 2015 to February 2018). InterventionAll patients underwent prebiopsy mpMRI followed by systematic TRUSGB. Men with suspicious lesions on mpMRI also underwent MRGB prior to TRUSGB. MRGB was performed using the in-bore approach. Outcome measurements and statistical analysisClinically significant prostate cancer (csPCa) was defined as grade group ≥2 (Gleason score ≥3+4) in any core. The main secondary objectives were the number of men who could avoid biopsy after nonsuspicious mpMRI, the number of biopsy cores taken, and oncologic follow-up. Differences in proportions were tested using McNemar's test with adjusted Wald confidence intervals for differences of proportions with matched pairs. Results and limitationsThe MRI pathway detected csPCa in 159/626 (25%) patients and insignificant prostate cancer (insignPCa) in 88/626 patients (14%). TRUSGB detected csPCa in 146/626 patients (23%) and insignPCa in 155/626 patients (25%). Relative sensitivity of the MRI pathway versus the TRUSGB pathway was 1.09 for csPCa (p=0.17) and 0.57 for insignPCa (p<0.0001). The total number of biopsy cores reduced from 7512 to 849 (–89%). The MRI pathway enabled biopsy avoidance in 309/626 (49%) patients due to nonsuspicious mpMRI. Immediate TRUSGB detected csPCa in only 3% (10/309) of these patients, increasing to 4% (13/309) with 1-yr follow-up. At the same time, TRUSGB would overdetect insignPCa in 20% (63/309). “Focal saturation” by four additional perilesional cores to MRGB improved the detection of csPCa in 21/317 (7%) patients. Compared with the literature, our proportion of nonsuspicious mpMRI cases is significantly higher (27–36% vs 49%) and that of equivocal cases is lower (15–28% vs 6%). This is probably due to the high-quality standard in this study. Therefore, a limitation is the duplication of these results in less experienced centers. ConclusionsIn biopsy-naïve men, the MRI pathway compared with the TRUSGB pathway results in an identical detection rate of csPCa, with significantly fewer insignPCa cases. In this high-quality standard study, almost half of men have nonsuspicious MRI, which is higher compared with other studies. Not performing TRUS biopsy is at the cost of missing csPCa only in 4%. Patient summaryWe compared magnetic resonance imaging (MRI) with MRI-guided biopsy against standard transrectal ultrasound biopsy for the diagnosis of prostate cancer in biopsy-naïve men. Our results show that patients can benefit from MRI because biopsy may be omitted in half of men, and fewer indolent cancers are detected, without compromising the detection of harmful disease. Men also need fewer needles to make a diagnosis.

A New Perspective on Breast Cancer Diagnostic Guidelines to Reduce Overdiagnosis

Overdiagnosis of breast cancer, defined as diagnosing a cancer that would otherwise not cause symptoms or death in a patient’s lifetime, costs US health care system over $1.2 billion annually. Overdiagnosis rates, estimated to be around 10% − 40%, may be reduced if indolent breast cancer subtypes can be identified and followed with noninvasive imaging rather than biopsy. However, there are no validated guidelines for radiologists to decide when to choose imaging options recognizing cancer subtypes. The aim of this study is to optimize breast cancer diagnostic decisions based on cancer subtypes using a large-scale finite-horizon Markov decision process (MDP) model with 4.6 million states to help reduce overdiagnosis. We develop and prove the optimality of a divide-and-conquer algorithm that relies on tight upper bounds on the optimal decision thresholds to find an exact optimal solution. We project the high-dimensional MDP onto two lower-dimensional MDPs and obtain feasible upper bounds on the optimal decision thresholds. We use real data from two private mammography databases and demonstrate our model performance through a previously validated simulation model that has been used by the policy makers to set the national screening guidelines in the US. We find that a decision-analytical framework optimizing diagnostic decisions while accounting for breast cancer subtypes has a strong potential to improve the quality of life and alleviate the immense costs of overdiagnosis. Our model leads to a 20% reduction in overdiagnosis on the screening population, which translates into an annual savings of approximately $300 million for the US health care system.

Optimal sampling scheme in men with abnormal multiparametric MRI undergoing MRI-TRUS fusion prostate biopsy

ObjectivesTo determine the implications of different prostate sampling schemes on the diagnosis of clinically significant prostate cancer (csPCA, ISUP group 2–5) and clinically insignificant prostate cancer (ciPCA, ISUP group 1) in men with abnormal multiparametric magnetic resonance imaging (mpMRI) undergoing MRI-transrectal ulrasound fusion targeted biopsies. Materials and MethodsThis is a retrospective analysis of a cohort including all men who had a single lesion on mpMRI of the prostate performed between January 2016 and June 2017. All men underwent an MRI-transrectal ulrasound fusion biopsy and systematic (SBx) sampling of the prostate, which combined and were considered the standard of reference. The hypothetical 3 biopsy sampling schemes were defined as follows: Targeted biopsy only (TBx), TBx + ipsilateral SBx (ipsi-SBx) and TBx + contralateral SBx (contra-SBx) and were evaluated for the detection of csPCA and ciPCA. Sensitivity and 95% intervals were calculated, McNemar test was used to compare sensitivities between the various sampling schemes. ResultsTBx + SBx detected csPCa in 47% (55 of 116) of the 116 men who met eligibility criteria. Sensitivity and 95% confidence intervals for csPCa detection was 85.5% (73.3%–93.5%), 96.4% (87.5%–99.6%), and 92.7 (82.4%–98%) for TBx alone, TBx + ipsi-SBx and TBx + contra-SBx, respectively. csPCa detection rates were higher for both TBx + ipsi-SBx and TBx + contra-SBx compared to TBx alone. Clinically insignificant cancers alone were detected in 7.7% (9 of 116), 10.3% (12 of 116), and 14.6% (17 of 116) of the cohort by TBx only and TBx + ipsi-SBx, and TBx + contra-SBx, respectively. ConclusionsTBx + ipsi-SBx may increase the detection of csPCa while limiting overdiagnosis of indolent cancers.

Lower urinary tract symptoms and prostate cancer: is PSA testing in men with symptoms wise?

The best evidence to date shows that, overall, the harms of prostate cancer screening in asymptomatic men outweigh the benefits. A 2013 Cochrane review found that screening asymptomatic men did not save lives from the disease, and leads to detection of indolent prostate cancers that would not have gone on to cause harm in a man’s lifetime.1 This is known as overdiagnosis. Further weight was added to the results of the Cochrane review in the recent 10-year follow-up results from the cluster randomised trial of PSA testing for prostate cancer (CAP), which found that one-off PSA testing of asymptomatic men did not save lives from prostate cancer.2 For symptomatic men, however, the clinical situation is different. Current clinical guidelines from the National Institute for Health and Care Excellence (NICE) recommend that GPs consider a PSA test and digital rectal examination (DRE) in men presenting with lower urinary tract symptoms (LUTS) to investigate suspected prostate cancer.3 For the purposes of this article we defined LUTS as: nocturia, urgency, frequency, incomplete voiding, intermittency, terminal dribble, hesitancy, straining, weak or split stream, and/or post-micturation dribble. LUTS are very common in men, and have been estimated to be present in around 80% of men aged >60 years.4 The 2013 Cochrane review stated that ‘... the presence of LUTS, typically due to benign prostatic obstruction, are very common in the ageing male and are not considered to increase prostate …

Identification of the Fraction of Indolent Tumors and Associated Overdiagnosis in Breast Cancer Screening Trials.

It is generally accepted that some screen-detected breast cancers are overdiagnosed and would not progress to symptomatic cancer if left untreated. However, precise estimates of the fraction of nonprogressive cancers remain elusive. In recognition of the weaknesses of overdiagnosis estimation methods based on excess incidence, there is a need for model-based approaches that accommodate nonprogressive lesions. Here, we present an in-depth analysis of a generalized model of breast cancer natural history that allows for a mixture of progressive and indolent lesions. We provide a formal proof of global structural identifiability of the model and use simulation to identify conditions that allow for parameter estimates that are sufficiently precise and practically actionable. We show that clinical follow-up after the last screening can play a critical role in ensuring adequately precise identification of the fraction of indolent cancers in a stop-screen trial design, and we demonstrate that model misspecification can lead to substantially biased estimates of mean sojourn time. Finally, we illustrate our findings using the example of Canadian National Breast Screening Study 2 (1980-1985) and show that the fraction of indolent cancers is not precisely identifiable. Our findings provide the foundation for extended models that account for both in situ and invasive lesions.