Search

Data supporting the clinical utility of multi-target stool DNA (mt-sDNA) at the guideline-recommended 3-year interval have not been reported.Between April 2015 and July 2016, candidates for colorectal cancer screening whose providers prescribed the mt-sDNA test were enrolled. Participants with a positive baseline test were recommended for colonoscopy and completed the study. Those with a negative baseline test were followed annually for 3 years. In year 3, the mt-sDNA test was repeated and colonoscopy was recommended independent of results. Data were analyzed using the Predictive Summary Index (PSI), a measure of the gain in certainty for dichotomous diagnostic tests (where a positive value indicates a net gain), and by comparing observed versus expected colorectal cancers and advanced precancerous lesions.Of 2,404 enrolled subjects, 2,044 (85%) had a valid baseline mt-sDNA result [284 (13.9%) positive and 1,760 (86.1%) negative]. Following participant attrition, the year 3 intention to screen cohort included 591 of 1,760 (33.6%) subjects with valid mt-sDNA and colonoscopy results, with no colorectal cancers and 63 advanced precancerous lesions [22 (34.9%) detected by mt-sDNA] and respective PSI values of 0% (P = 1) and 9.3% (P = 0.01). The observed 3-year colorectal cancer yield was lower than expected (one-sided P = 0.09), while that for advanced precancerous lesions was higher than expected (two-sided P = 0.009).Repeat mt-sDNA screening at a 3-year interval resulted in a statistically significant gain in detection of advanced precancerous lesions. Due to absence of year 3 colorectal cancers, the PSI estimate for colorectal cancer was underpowered and could not be reliably quantified. Larger studies are required to assess the colorectal cancer study findings.Prevention Relevance:Understanding the 3-year yield of mt-sDNA for colorectal cancer and advanced precancerous polyps is required to ensure the clinical appropriateness of the 3-year interval and to optimize mt-sDNA's screening effectiveness.

Supplemental Table S1: Distribution of colorectal lesions among subjects at baseline (T0) and year 3 (T3). Supplemental Table S2: Study subject accountability in the baseline negative population

This Supplemental Text file provides additional information regarding the clinical procedures and sample processing/lab procedures, as well as an explanation of the sensitivity and robustness analyses.

Aim: To investigate the role of optoacoustic imaging combined with gray-scale ultrasound (OA/US) to better differentiate between breast cancer molecular subtypes. Materials and Methods: This prospective 5-center study was performed in the Netherlands between March 2015 and February 2016. Only masses considered suspicious at conventional diagnostic breast ultrasound (US) were included. The study was approved by the institutional ethical boards of the participating hospitals and written informed consent was obtained from all patients. Dedicated breast radiologists evaluated the included masses using OA/US and scored the internal and external OA/US features accordingly. Spearman Correlation was used to analyze the relationship between OA/US features and mitotic figures. The same statistical method was also used to evaluate the correlation between OA/US features and percentages of ER, PR and Ki67. Wilcoxon-Mann-Whitney tests were used to analyze the relationship between OA/US features and molecular subtypes of breast cancer (Luminal A, Luminal B, Triple Negative and HER2-enriched breast cancers). Results: Overall, 209 patients with 215 breast lesions were included in this study. Sixty-seven masses were considered malignant and the 59 masses classified as invasive breast cancers were included in the final mitotic figures, ER, PR, Ki-67 and molecular subtype analyses. Significant correlations were found between OA/US Total Internal Features and ER (p = 0.0333) and Ki-67 (p = 0.0092) percentages. Regarding molecular subtypes, Internal Vessels (p = 0.0257), Total Internal Features (p = 0.0196) and combined Total Internal and External Features (p = 0.0289) helped to differentiate between Luminal A and Luminal B cancers. Internal Vessels (p = 0.0030), Internal Blush (p = 0.0044), Total Internal Hemoglobin (p = 0.0053), Total Internal Features (p = 0.0010), Total Internal divided by Total External Features (p=0.0255) and combined Total Internal and External Features (p = 0.0108) helped to differentiate between Luminal A and Triple Negative breast cancers. Total Internal Features showed a borderline result (p = 0.0551) regarding the differentiation between Triple Negative and HER2-enriched subtypes. Conclusions: The use of OA/US features to non-invasively differentiate between breast cancer molecular subtypes may help to establish an earlier prognosis and treatment planning, potentially decreasing costs and facilitating larger scale diagnosis. Future research with larger sample sizes may confirm these preliminary results. Citation Format: Menezes GL, Mann RM, Meeuwis C, Bisschops B, Veltman J, Lavin PT, van de Vijver MJ, Pijnappel RM. Can optoacoustic imaging combined with ultrasound non-invasively offer prognosis for breast cancer molecular subtypes? [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 P2-08-43.

Purpose: The Imagio™ OA/US breast imaging system, a diagnostic opto-acoustic (OA) imaging device bearing the CE Mark, is in the U.S. FDA Premarket Approval process. OA/US provides both functional (relative oxygenation/de-oxygenation) and anatomic (angiogenesis) information that is co-registered and temporally interleaved in real time with gray-scale ultrasound that may improve discrimination between benign and malignant masses. We recently reported correlation studies demonstrating tumor-zone specific OA attributes in histopathologic grade I versus grade III malignancies. The relationship between OA attributes (individual feature scores or summed feature results) and pathologically-determined prognostic markers (PDPM) in malignant lesions is the subject of this report. Materials and Methods: In this HIPAA-compliant, IRB-approved prospective multi-center trial across 16 U.S clinical sites; 1,808 masses in 1,739 subjects assessed as BI-RADS 3, 4 or 5 were imaged with OA/US. Of these, 655 were invasive malignancies and the subject of this analysis. Each mass was scored by 8 blinded readers on 3 internal zone features of the tumor nidus and 2 external features (0-5, 6) of the tumor boundary and peripheral zones (OA attributes). Pathologic diagnoses were confirmed by an experienced central breast pathologist blinded to the OA assessment. Tumor histologic classification and grading was performed in all subjects.Evaluation of tumor estrogen receptor (ER) and progesterone receptor (PR) were performed at each site by immunohistochemistry (IHC) and was reported as percent of tumor cells expressing the receptor or, as positive if greater than 1%. Tumor HER2-neu expression was reported by IHC as 0, 1+ (negative, not over-expressed), 2+ (indeterminate) and 3+ (over-expressed). All 2+ results reflexed to fluorescence in-situ hybridization (FISH) and reported as over-expressed or not over-expressed. Tumor Ki-67 expression was evaluated with IHC and reported as percent of tumor cells positive for the antigen. Statistical analysis of categorical measures of PDPM is in process and will be performed using a two-way Analysis of Variance (ANOVA) and Tukey HSD (honest significant difference) test for pairwise comparisons. This ANOVA will be repeated for each PDPM to test which specific PDPM sub-categories are related to OA attributes. Correlation coefficients will be generated for PDPM that are continuous, not categorical. All statistical testing will be done at a 5% significance level. Results: A total of 655 invasive and 22 DCIS were scored for internal (nidus) and external (boundary and periphery) OA attributes and compared with PSBC as defined by ER, PR, Her2 and Ki-67 expression. Of these, 108 were Luminal-A (LA), 153 Luminal-B (LB), 80 Triple-negative (TN), 23 Her2-enriched (HER2) and 314 unclassified (including 22 DCIS). OA attributes differentiated LA (99%CI 2.8,3.1) from TN (99%CI 3.1,3.4), p=0.027 and HER2 (99%CI 3.1,3.6), p=0.036. OA features strongly suggested LA vs. LB (99%CI 3.1,3.3) subtype, p=0.060. LB vs.TN(p=0.59) and HER2(p=0.41) were non-significant. TNBC vs. HER2 was p=0.62. Citation Format: Grobmyer SR, Butler R, Neuschler EI, Stavros AT, Aitchison RD, Lavin PT, Tucker FL. Opto-acoustic imaging of breast masses: Correlation with breast biopsy prognostic indicators [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-02-04.

Purpose: The Imagio® breast imaging system, a diagnostic opto-acoustic (OA) imaging device bearing the CE Mark, is in the U.S. FDA Premarket Approval process. OA provides both functional (relative oxygenation/de-oxygenation) and anatomic (angiogenesis) information that is co-registered and temporally interleaved in real time with gray-scale ultrasound that may improve distinction between benign and malignant masses. OA imaging pathology correlation was performed to elucidate the histologic features of OA features of breast cancers. Methods and Materials: A multicenter postmarket surveillance and clinical follow-up study was conducted in five Dutch sites in which 209 women with breast masses underwent OA prior to biopsy. Histopathology examination of the biopsies revealed 146 benign masses (mostly fibroadenomas) and 76 malignant masses (mostly invasive ductal carcinomas). For invasive ductal carcinomas, histologic grade and the features used to assess histologic grade (nuclear pleomorphism, tubule formation, and mitotic count) were assessed. For each mass, 5 pre-determined OA features, 3 internal features, and 2 external features were evaluated. The 3 internal scores (vessels, blush, and hemoglobin) and 2 external features (capsular boundary zone and peripheral boundary zone) were separately and collectively summed for testing relationships with traditional histopathology measures using a two-sided Jonckheere-Terpstra test of ordered outcomes. Distribution differences between benign and malignant masses were performed using a Wilcoxon Rank Sum test for each internal, external, and summed total internal, external, and total score. Results: The mean differences were significantly higher for malignant vs. benign for internal vessels (p=0.0009), internal blush (p=0.0085), external boundary zone (p Conclusion: OA feature summary scores appear to differentiate between benign vs. malignant and correspond to histologic grade and scoring components of histologic grade. The U.S. investigational PIONEER pivotal study (n=2,095) may further confirm these results. Citation Format: van de Vijver M, Lavin PT, Stavros AT. Breast biopsy histology relationships with opto-acoustic imaging of breast masses [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-03.

Background/Objective: Diagnostic specificity remains disappointingly low for ultrasound-based methodologies optimized to achieve near 100% sensitivity. Opto-acoustic (OA) imaging is a fusion of real time co-registered, interleaved laser optic and ultrasound imaging that shows fused functional findings (relative de-oxygenation of hemoglobin) and morphologic information (tumor angiogenesis) within and around breast masses using a hand-held duplex OA probe. We assess the improvement in sensitivities and specificities of nomograms (N) based on regression models to classify (CL) benign (B) vs. malignant (M) and to project probability of malignancy (POM) based on five feature-based metrics scored by 21 independent readers (IRs) and an expert reader. We examine OA feature separation and nomogram performance. Methods: Masses from a series of 100 subjects with 80 biopsies (42 B, 38 M) were blindly evaluated prior to both core biopsy and excision. The OA algorithm was locked. Three internal OA findings (density of vascularity [V], relative blood oxygen saturation [O], and hemoglobin [H]) and two external OA findings (boundary zone [Z] and peri-tumoral radiating vessels [R]) were assigned 0-5/6 ordinal scores. Feature distributions were compared using a two-sided Kruskal-Wallis test. Results: There were consistently significant differences between the feature distributions for benign vs. malignant: density of vascularity (14/21 IRs), relative blood oxygen saturation (11/21 IRs), hemoglobin (16/21 IRs), boundary zone (all IRs), and peri-tumoral radiating vessels (all IRs) always with lower scores for benign vs. malignant. The mean IR sensitivities were near 100% for all IRs. The mean specificities from the nomograms were 49% (POM), 43% (CL), and 48% (averaged). Conclusions: The study results indicate that OA findings can be independently and quickly mastered by practicing IRs to consistently differentiate masses. Nomograms offer further confidence to enhance decision making to differentiate. If confirmed in a larger series, OA findings might be useful in differentiation and thus sparing biopsies in addition to more customized surgeries. Citation Format: Philip Lavin, Thomas Stavros. Opto-acoustic nomograms for improving breast cancer diagnosis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-01-03.