Laguna Hills Research Articles

Identification of patients with DCIS with low-risk clinicopathology who benefit from radiation therapy with and without endocrine therapy after breast-conserving surgery assessed with the 7-gene biosignature.

528 Background: Ductal carcinoma in situ (DCIS) accounts for 20% of breast cancers. For most patients with DCIS, the standard treatment involves breast-conserving surgery (BCS) followed by radiotherapy (RT). Adjuvant endocrine therapy (ET) is typically recommended for hormone receptor-positive disease. However, prospective trials have failed to identify a low-risk CP group not benefitting from RT with respect to ipsilateral breast recurrence (IBR), with no modern trials evaluating ET. We utilized the 7-gene predictive DCIS biosignature to assess the effects of RT and/or ET on 10yr IBR in women with low-risk CP DCIS. Methods: Women (n=926) from four DCIS cohorts treated with BCS had tissue samples analyzed at a CLIA lab (Laguna Hills, CA). Low-risk CP was defined with RTOG 9804-like criteria (margin negative by no-ink on tumor) or MSKCC-like criteria using nomogram-weighted factors (low-risk score<220, excluding number of re-excisions, using negative margin, and RT treatment). Women with either low-risk CP criteria were classified as molecular Low Risk (DS≤2.8, no Residual Risk subtype, RRt) or High Risk (DS>2.8 +/- RRt) using the 7-gene DCIS biosignature. Ten-year IBR Kaplan-Meier rates and Cox proportional hazard ratios (HR) were calculated for ET and RT. Results: Overall, 66% of 926 women were classified as low risk by one of the CP criteria. Patients with low-risk CP treated without ET (n=315) had 10yr IBR rates of 13% after BCS without RT and 7% with RT (HR=0.51, p=.10), while those treated with ET (n=291) had 10yr IBR rates of 9% after BCS without RT and 4% with RT (HR=0.39, p=.09). Overall, 37% of women were classified as low risk (n=338) by the biosignature and had a 10yr IBR rate of 5.6% after BCS with no significant ET (HR=0.66, p=.41) or RT benefit (HR=0.88, p=.78) in multivariable analysis. Of patients with low-risk CP, 48% of those treated without ET were classified as High Risk by the biosignature and had elevated 10yr IBR rates without RT (21%) and a substantial RT benefit (HR=0.31, p=.03, n=151), while 59% of those treated with ET after BCS were classified by the biosignature as High Risk and had elevated 10yr IBR rates without RT (14%) and a 9% absolute reduction from RT (HR=0.22, p=.02, n=173). Patients with concordant low-risk CP and biosignature Low Risk (n=269) had a 5.5% 10yr IBR rate after BCS and no significant RT (HR=1.10 95% CI 0.33 to 3.7, p=.87) or ET benefit (HR=0.44, 95%CI 0.1 to 1.6, p=.22) in multivariable analysis. Conclusions: The 7-gene biosignature provided better identification of patients with low 10yr IBR rates and no significant RT benefit compared to using CP low-risk criteria. Importantly, the biosignature classified over half of women with low-risk CP treated with ET as High Risk. This group received a substantial benefit from RT, while those with biosignature Low Risk did not.

Abstract PO5-15-11: A Novel Biosignature to Predict Radiation Therapy Response in Early-Stage Invasive Breast Cancer Treated with Breast-Conserving Surgery

Abstract Introduction: Radiation therapy (RT) is a standard component of treatment for most patients with early-stage, hormone receptor-positive, invasive breast cancer (BC) following breast-conserving surgery (BCS). RT recommendations are primarily based on clinicopathologic (CP) factors, such as tumor size, nodal status, and histological grade. While these factors provide prognostic information, their ability to accurately identify patients at a higher risk of ipsilateral breast recurrence (IBR) or those who will significantly benefit from RT is unclear. Therefore, incorporation of additional predictive markers beyond CP factors is warranted and there remains a need to refine the selection criteria for patients who will derive the greatest benefit from RT. In this study, we aimed to explore the role of immune and metabolic signaling axes as potential predictive markers for RT response in hormone receptor-positive breast cancer patients. Methods: A cohort of 939 women from Sweden were diagnosed with BC between 1987 and 2004. A subset of 471 patients was diagnosed with T1-T2N0M0 BC and underwent BCS with negative margins. Patients were treated with BCS plus/minus RT (median dose 50Gy) based upon physician preference. Biomarkers were assayed in formalin-fixed paraffin-embedded tissue micro arrays using multiplex immunofluorescence and multi-spectral imaging in a CLIA lab (Laguna Hills, CA). Immune and metabolic axes were defined employing biomarkers and used to classify patients into three risk groups: 1) Low Risk (lower baseline risk and no RT benefit), 2) Elevated Risk (higher baseline risk and significant RT benefit), and 3) Residual Risk (higher baseline risk and suboptimal RT benefit). Risk groups were analyzed for IBR rate using Kaplan-Meier and Cox proportional hazards analyses. Risk group prognosis and RT prediction was assessed for RT-risk group interaction in multivariable analysis, adjusting for CP factors. Results: Among the patients with complete biomarker data, 261 were hormone receptor-positive, and had a median follow-up of 140 months. Median age was 62 years (28-88 years), and median tumor size was 1.1 cm (0.1-4 cm). Some patients (21%) received endocrine therapy (ET), and most (76%) received RT, with 79% of patients who received ET also receiving RT. In the overall population, RT following BCS was associated with a reduction in HR for recurrence (HR=0.3, 95%CI [0.1, 0.5], p< 0.001). Patients classified as Low Risk (41%) did not have a significant benefit from RT (HR=0.9, 95%CI [0.1, 8.3], p=0.95) in multivariable analysis adjusted for CP factors. For patients who were classified as Elevated Risk (31%), multivariable analysis showed a higher IBR rate without RT (HR=5.7, 95%CI [1.3, 25.1], p< 0.021) relative to the Low Risk group who had a significant benefit from RT (HR=0.1, 95%CI [0.02, 0.2], p< 0.001). Patients classified into the Residual Risk group (28%) had no significant reduction from RT (HR=0.7, 95%CI [0.2, 2.0], p=0.61). However, in multivariable analysis adjusted for CP factors, patients treated with RT in the Residual Risk group had higher IBR rates (HR=3.7, 95%CI [1.6, 8.7], p=0.0026) compared to RT-treated patients in other risk groups. The biosignature was predictive for RT benefit in multivariable analysis adjusted for CP factors (p-interaction < 0.001). Conclusions:The biosignature used in this study demonstrated the potential to identify patients who may derive limited benefit from RT, allowing for tailored therapeutic approaches. These findings underscore the importance of individualized treatment decisions based on risk stratification. Further clinical validation and refinement of risk stratification strategies are warranted to optimize outcomes in hormone receptor-positive, BC patients undergoing BCS. Citation Format: Troy Bremer, Karuna Mittal, Chirag Shah, Frank Vicini, Steven Shivers, Charlotta Wadsten. A Novel Biosignature to Predict Radiation Therapy Response in Early-Stage Invasive Breast Cancer Treated with Breast-Conserving Surgery [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-15-11.

Intraocular Straylight and Multifocal Soft Contact Lens Fit With a Myopia Control Approach.

Center-distance multifocal contact lenses (MFCLs) are used to slow myopia progression. We examined the effect of two MFCLs on intraocular straylight values in myopic individuals. Twenty-five young myopic adults were enrolled and were fit with three contact lenses (Biofinity sphere, Biofinity Multifocal, and NaturalVue Multifocal) in a random order over two study visits. Pupil size (NeurOptics VIP-300, Laguna Hills, CA) and contact lens centration were measured. Right eye intraocular straylight measurements were collected (OCULUS C-Quant; Wetzlar, Germany) and compared with a spectacle trial lens. Log straylight (LogSL) values and straylight residuals were analyzed using repeated-measures analyses of variance with Tukey-corrected post hoc t -tests. The mean participant age (±SD) was 24.1±1.5 years, and right eye spherical equivalent refractive error was -3.38±1.53 DS. There was no difference in mesopic pupil size between visits ( P =0.68) and no difference in contact lens centration between lenses ( P =0.99). LogSL values differed by lens type ( P =0.004). LogSL with the spectacle trial lens was significantly greater than with each contact lens type (all P <0.05), but there were no significant differences in LogSL between the three contact lenses (all P >0.05). There was no difference between the three contact lens designs for straylight residuals ( P =0.33). Measured intraocular straylight for both MFCLs was not different than with a spherical soft contact lens. A significant increase in intraocular straylight with spectacle trial lens correction was observed compared with all contact lenses.

Limitations in the Application of Clinicopathologic Factors Alone in Predicting Radiation Benefit for Women with Low-Risk DCIS after Breast Conserving Surgery: The Impact of a 7-Gene Biosignature Based on 10-Year Ipsilateral Breast Recurrence (IBR) Rates

Most women diagnosed with ductal carcinoma in situ (DCIS) receive radiotherapy (RT) after breast conserving surgery (BCS); however, clinical trials show that over 70% of women with BCS alone will not have a recurrence and therefore not benefit from RT. Traditionally, clinicopathologic (CP) factors have been used to select for whom to de-escalate treatment, but prospective trials have failed to identify a low risk CP group that did not benefit from RT with respect to local control. This study assessed the re-classification of patients with low-risk CP into Risk groups defined by the 7-gene biosignature and compared to 10-yr IBR rates. Women (n = 926) from four international DCIS cohorts treated with BCS had formalin-fixed paraffin embedded tissue samples analyzed at a CLIA lab (Laguna Hills, CA). CP low-risk patients were identified using a) RTOG-9804-like criteria [Nuclear Grade 1 or 2 & Size ≤2.5 cm & non-Palpable & Screen Detected & margin negative (no-ink on tumor)] and b) MSKCC-like criteria [low-risk score<220, determined using nomogram weighted factors (excluding: number of re-excisions and RT treatment), and using no-ink-on-tumor instead of close margin]. The 7-gene DCIS biosignature combined biomarkers with CP factors (age, size, palpability, and margin status) using an algorithm reporting a Decision Score (DS) and Residual Risk subtype (RRt). Women with low-risk CP were classified into biosignature Low Risk (DS≤2.8, no RRt) or High Risk (DS>2.8 +/- RRt) groups. 10yr in-breast event (IBR) rates with and without RT were assessed by Kaplan-Meier rates and Cox proportional hazard analyses. Overall, 37% of all women were classified into the biosignature Low Risk group, while 51% and 34% were classified into CP low-risk groups (RTOG-9804-like, MSKCC-like, respectively). The biosignature Low Risk group (n = 338) had a 10-yr IBR risk of 5.6% after BCS and no significant RT benefit (absolute RT benefit = 0.8%, p = 0.70), 99% negative predictive value (NPV) for RT benefit. CP low-risk groups had 10-yr IBR rates of 12% and 8% after BCS without RT with absolute 6% (p = 0.04) and 4% (p = 0.1) IBR rate reductions with RT. The biosignature reclassified 51% and 63% of CP low-risk patients into the biosignature High Risk group. Importantly, these patients had higher IBR rates without RT (20% and 12%) and significant 13% (p = 0.005) and 8% (p = 0.01) absolute IBR rate reductions from RT. CP low-risk patients with concordant biosignature Low Risk demonstrated no significant RT benefit. The 7-gene predictive biosignature more reliably identified patients with low 10-yr IBR rates and no significant RT benefit than the traditional CP low-risk criteria (RTOG-9804-like, MSKCC-like). Importantly, those CP low-risk patients who were re-classified as biosignature High Risk had increased 10-year IBR rates and significant RT benefit.

A Biosignature Integrating Immune and Metabolic Signaling Axes to Assess Limited Radiation Therapy Response in Early-Stage Breast Cancer from a Low-Risk Cohort

Radiation therapy (RT) post breast conserving surgery (BCS) reduces in-breast recurrence (IBR) rate in early-stage invasive breast cancer (BC) patients. The RT treatment recommendation is often driven by clinicopathological (CP) factors; however, CP factors alone have limited ability to identify which women significantly benefit from RT, or those with higher IBR risk after BCS plus RT. Biologic factors driving unique phenotypes, in addition to CP, may improve prediction of RT response. In this study we evaluated the role of immune and metabolic signaling axes in predicting RT response in hormone receptor positive, HER2 negative, early-stage BC patients. Biomarkers from immune and metabolic signaling axes were studied in a cohort of 939 women from Sweden, at a CLIA certified lab (Laguna Hills, CA). Formalin fixed paraffin embedded tissues were assayed for protein expression using multiplex immunofluorescence and multi-spectral imaging. Immune and metabolic axes were assessed using biomarkers combined with a non-linear model, adjusting for patient age. RT prediction by the model was assessed, along and adjusted for CP factors and also among patients over 50-yrs. The model defined patient risk groups that were analyzed for IBR rate using Kaplan Meier analyses and Cox proportional hazards to test for RT-risk group interaction. Within the cohort, 440 patients had hormone receptor positive, HER2 negative BC treated with BCS (negative margins) and +/- RT without chemotherapy, where 296 patients had complete biomarker data. CP factors individually were not predictive for RT benefit, but grade was prognostic for IBR rate (p = 0.02) after BCS without RT. In multivariable analysis, adjusting for CP factors (grade, palpability, continuous size and age), the model was predictive for RT benefit (p-interaction = 0.046), identifying patients (n = 129) with worse RT benefit (HR = 7.8) compared to baseline RT benefit. The model was not prognostic for IBR rate in patients treated with BCS without RT (16% 10-yr IBR rate) but identified patients with increased IBR rates after BCS plus RT (HR = 3.9, p<0.001), where corresponding 10-yr IBR rates increased from 3% to 15%. The model was also predictive for RT benefit in women over 50-yrs (p-interaction = 0.05). The model identified 28% of women over 50-yrs who had increased IBR rates after BCS plus RT (HR = 4.0, p = 0.004), where corresponding 10-yr IBR rates increased from 3% to 12%. The model incorporating metabolic and immune signaling axes assessed in the study was predictive for RT benefit among women with early-stage hormone receptor positive, HER2 negative BC. While CP factors were not predictive of RT benefit, the inclusion of metabolic and immune signaling axes improved identification of patients with high residual risk after BCS plus RT and can potentially aid in personalized treatment of early-stage breast cancer based on individualized risk.

Analytical validation of the 7-gene biosignature for prediction of recurrence risk and radiation therapy benefit for breast ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS), is a noninvasive breast cancer, representing 20-25% of breast cancer diagnoses in the USA. Current treatment options for DCIS include mastectomy or breast-conserving surgery (BCS) with or without radiation therapy (RT), but optimal risk-adjusted treatment selection remains a challenge. Findings from past and recent clinical trials have failed to identify a 'low risk' group of patients who do not benefit significantly from RT after BCS. To address this unmet need, a DCIS biosignature, DCISionRT (PreludeDx, Laguna Hills, CA), was developed and validated in multiple cohorts. DCISionRT is a molecular assay with an algorithm reporting a recurrence risk score for patients diagnosed with DCIS intended to guide DCIS treatment. In this study, we present results from analytical validity, performance assessment, and clinical performance validation and clinical utility for the DCISionRT test comprised of multianalyte assays with algorithmic analysis. The analytical validation of each molecular assay was performed based on the Clinical and Laboratory Standards Institute (CLSI) guidelines Quality Assurance for Design Control and Implementation of Immunohistochemistry Assays and the College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) recommendations for analytic validation of immunohistochemical assays. The analytic validation showed that the molecular assays that are part of DCISionRT test have high sensitivity, specificity, and accuracy/reproducibility (≥95%). The analytic precision of the molecular assays under controlled non-standard conditions had a total standard deviation of 6.6 (100-point scale), where the analytic variables (Lot, Machine, Run) each contributed <1% of the total variance. Additionally, the precision in the DCISionRT test result (DS) had a 95%CI ≤0.4 DS units under controlled non-standard conditions (Day, Lot, and Machine) for molecular assays over a wide range of clinicopathologic factor values. Clinical validation showed that the test identified 37% of patients in a low-risk group with a 10-year invasive IBR rate of ~3% and an absolute risk reduction (ARR) from RT of 1% (number needed to treat, NNT=100), while remaining patients with higher DS scores (elevated-risk) had an ARR for RT of 9% (NNT=11) and 96% clinical sensitivity for RT benefit. The analytical performance of the PreludeDx DCISionRT molecular assays was high in representative formalin-fixed, paraffin-embedded breast tumor specimens. The DCISionRT test has been analytically validated and has been clinically validated in multiple peer-reviewed published studies.

PO-04-039 DIELECTRIC IMAGING-GUIDED ULTRA-LOW TEMPERATURE CRYOABLATION FOR ATRIAL FIBRILLATION

Ultra-low temperature cryoablation(ULTC) can be used to create transmural ablation lesions in the left atrium (LA). With a circular catheter configuration, this energy modality can be used to create continuous ablation lesions around the pulmonary veins(PVs). The same catheter configuration can be used to isolate the posterior wall(PW) by creating multiple overlapping circular ablation lesions. Isolation of the PVs and the PW can be assessed using pacing maneuvers. Three-dimensional voltage mapping may provide additional information on the extent of the ablation lesions. A recently introduced dielectric imaging-based mapping system can be used to generate voltage maps and to visualize the ULTC ablation catheter. To evaluate the feasibility of ULTC, guided by dielectric imaging-based electroanatomic mapping. Patients with atrial fibrillation were consented for catheter ablation with the iCLAS cryoablation system(Adagio Medical, Laguna Hills, USA). Ablation included isolation of the PV’s and LA PW if deemed necessary. The KODEX-EPD system(EPD Solutions, Best, the Netherlands) was used in conjunction with a circular mapping catheter to create pre- and postablation voltage maps. If the postablation voltage map revealed incomplete ablation lesions, additional energy applications were applied. Patients visited the outpatient clinic at 3 months post ablation. All patients were enrolled in a prospective registry study that was approved by the local ethics committee. Six patients (4 male, 4 persistent AF, age 66±7 years, LAVI 38±14ml/m2) were treated. The PVs were targeted in all patients, while the PW was targeted in 5 patients. A postablation voltage map was generated in 5 patients, which revealed incomplete PV isolation in 2 patients and incomplete PW isolation in 1 patient. Additional ablation in these patients resulted in acute electrical isolation of all targets. Isolation of the PVs was achieved using a median of 11[IQR:9-15] energy applications and 11[8.5-14] minutes of ablation. Isolation of the PW required 6[6-7] applications and 3[3-3.5] minutes of ablation energy. Total mapping time was 14.5[12.5-22.5] minutes, total fluoroscopy time was 16[12.5-18.5] minutes, and the total procedure time was 107.5[67.25-123.5] minutes. At 3 months follow up, only 1 patient had recurrence of atrial arrhythmia. Longer follow up is ongoing. Dielectric imaging-based electroanatomic mapping can be used to evaluate lesions of ULTC.

Abstract P1-04-06: Characterization of recurrence risk after lumpectomy and radiotherapy in HER2-positive ductal carcinoma in situ of the breast, using 7-gene predictive biosignature: Implications for the NSABP-B43 trial results

Abstract Background: HER2-positive versus HER2-negative ductal carcinoma in situ (DCIS) of the breast has been associated with an increased risk of local recurrence after breast-conserving surgery (BCS) and radiotherapy (RT). In recognition of this, the NASBP-B43 trial was designed to determine if two doses of trastuzumab would improve local control with BCS plus RT in HER2-positive DCIS. The trial demonstrated a non-statistically significant advantage with the addition of trastuzumab in reducing ipsilateral breast recurrence (IBR). The predictive 7-gene DCIS biosignature, DCISionRT with Residual Risk Subtype (PreludeDxTM, Laguna Hills, CA) has been shown to classify DCIS patients into two distinct groups of patients with substantially different rates of IBR following BCS plus RT. Based upon these differences in outcome, we assessed the IBR rate in patients with HER2(+) DCIS treated with BCS and RT who were or were not in the Residual Risk Subtype group defined using DCISionRT, while accounting for the varying clinicopathologic profile of the patients. Materials &amp; Methods: DCISionRT was evaluated in a subset of 178 women with HER2(+) DCIS treated with BCS and RT as part of a multinational cohort of 926 patients from the United States, Sweden, and Australia, who were used in the validation studies for DCISionRT. Central pathology review and biosignature testing were performed at a CLIA-certified lab (Laguna Hills, CA). HER2(+) DCIS was defined as patients with a HER2(3+) immunohistochemistry &amp;gt;10% per ASCO/CAP guidelines. The IBR rate was calculated for the overall group of HER2(+) patients and those in the Residual Risk group. Individual patient outcome and biosignature results were analyzed using Kaplan Meier and Cox Proportional Hazard analyses. Results: The biosignature classified 113 of the 178 (63%) HER2(+) women into the Residual Risk group (DS&amp;gt;2.8 with RRt). Patients in the Residual Risk group had a significantly greater IBR (HR=8.3; 95%CI: 1.1,50, p=.012) over 10-years, with a corresponding 10-year total IBR rate of 16.2% (95%CI: 9.7%, 26.5%) versus 1.6% (95%CI: 0.2%, 10.9%) for all other HER2(+) patients. In univariate analysis, younger patients tended to have higher IBR rate after BCS plus RT, but only Residual Risk was significantly associated with IBR rate after BCS plus RT. Moreover, multivariable analysis demonstrated that the Residual Risk group was eight times more likely to recur after BCS and RT, while clinicopathologic factors (age, grade, tumor size) were not associated with higher IBR rates. Conclusion: The DCISionRT Residual Risk group was predictive for 10-year IBR risk after BCS plus RT in women with HER2(+) DCIS. Approximately 40% of patients with HER2(+) DCIS would be expected to achieve low rates of recurrence with BCS and RT, while about 60% of these women (classified in the Residual Risk group) would have higher recurrence rates and may benefit from further therapy, such as HER2-directed therapies. These findings suggest that if the results of the B43 trial were re-analyzed using the predictive 7-gene biosignature (DCISionRT with Residual Risk Subtype), better clarity could be gained on the true impact of trastuzumab on IBR rates in patients with HER2(+) DCIS and the patients most likely to benefit from this additional therapy. Table 1. Univariate and Multivariable Cox Proportional Hazards Analyses. Citation Format: Frank Vicini, Chirag Shah, Rachel Rabinovitch, Pat Whitworth, Julie A. Margenthaler, Brian J. Czerniecki, DAVID J. DABBS, Sheila Weinmann, Michael Leo, G Bruce Mann, Fredrik Wärnberg, jess Savala, Steven C. Shivers, Karuna Mittal, Troy Bremer. Characterization of recurrence risk after lumpectomy and radiotherapy in HER2-positive ductal carcinoma in situ of the breast, using 7-gene predictive biosignature: Implications for the NSABP-B43 trial results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-06.

Abstract PD15-07: PD15-07 7-gene predictive biosignature improves risk stratification for breast ductal carcinoma in situ patients compared to clinicopathologic criteria, identifying a low risk group not clinically benefiting from adjuvant radiotherapy

Abstract Background: Prognostic and predictive tools are needed to optimize treatment for women diagnosed with ductal carcinoma in situ (DCIS). While radiotherapy (RT) is standard of care for DCIS after breast conserving surgery (BCS), those at low-risk for ipsilateral breast recurrence (IBR) risk may be treated without RT. Low-risk has been defined as the absence of high risk clinicopathologic (CP) factors, including larger (&amp;gt;2 cm), palpable, or high nuclear grade (NG) tumors, and younger age (&amp;lt; 50 yrs). However, prospective trials have failed to identify low risk patients (pts) who do not clinically benefit from RT after BCS (RTOG 9804). DCISionRT® (PreludeDxTM, CA) is a 7-gene predictive biosignature providing a validated score (DS) to assess the 10-yr IBR risk and RT benefit, using individual tumor biology and CP factors. This study assessed total 10-yr IBR rates, RT benefit, and number needed to treat (NNT) for risk groups defined by biosignature and CP criteria. Methods: DCIS patients (n=926) from four international cohorts (median follow up 8.5 yrs, 1-3rd quartile 5.8 – 10.2 yrs) treated with BCS (negative margins), with (n=641) and without RT (n=335), had formalin-fixed paraffin-embedded tissues analyzed at a CLIA lab (PreludeDx, Laguna Hills, CA) for DCISionRT with a Residual Risk subtype (RRt). A biosignature Low Risk group (DS≤2.8 without RRt) was contrasted to a High Risk group comprising Elevated Risk (DS&amp;gt;2.8 without RRt) and Residual Risk (DS&amp;gt;2.8 with RRt) groups. Low-risk CP groups were RTOG 9804-like (NG1-2, non-palpable, negative margins, screening detected) or (age &amp;gt;50 and NG 1-2). Total 10-yr IBR rates were evaluated using Cox Proportional Hazards and Kaplan Meier analysis by treatment, biosignature and CP risk groups. NNT was determined with 10-yr IBR rate differences with RT. Results: The biosignature classified 37% (n=338) of women as Low Risk and 63% (n=588) as High Risk. Among women who did not receive RT, biosignature Low Risk pts had lower IBR than biosignature High Risk pts (5.6% vs. 25.7%, p&amp;lt;.001). About half of pts defined as CP low-risk by 9804-like (51%) or favorable Age/NG (58%) criteria were reclassified by the biosignature to High Risk. These pts had significant RT benefit: 9804-like group - HR 0.3, p=.007, absolute 10-yr IBR reduction of 12.7%, and for favorable Age/NG group - HR .34, p=0.012, absolute 10-yr IBR reduction of 11.2%. The corresponding NNTs were ~8-9. Overall, RT significantly reduced IBR for biosignature High Risk patients (p&amp;lt;.001, n=588), with an absolute 17.7% reduction and a NNT of ~6. For patients in CP high risk groups, 23% of not-9804-like and 31% of (age&amp;lt; 50 or NG 3) pts were reclassified as biosignature Low Risk. RT did not significantly reduce IBR in any Low Risk Biosignature group, including those in CP high-risk groups. IBR for not-9804-like group was 5.9% vs 3.0% without and with RT, p=.52, and for (age&amp;lt; 50 or NG 3) pts was 4.4% vs 3% without and with RT, p=.70. For CP low-risk and biosignature Low Risk groups, RT reduced IBR by 0%. Overall, RT did not significantly reduce IBR rate for biosignature Low Risk patients (p=.71, n=338), with a 0.8% absolute 10-yr IBR rate difference and a NNT of ~100. Conclusion: In a large multicenter population, DCISionRT was a better predictor of 10-yr prognosis and RT benefit than CP criteria alone. Pts with biosignature Low Risk disease, comprising about 1/3 of CP high-risk pts, had no significant RT benefit. Whereas pts with biosignature High Risk disease, comprising about 1/2 of CP low-risk pts, significantly benefited from RT, highlighting the lack of accuracy of these CP factors in assessing RT benefit. Table 1. Ten-Year Risk of Ipsilateral Breast Recurrence (IBR) Citation Format: Rachel Rabinovitch, Frank Vicini, Chirag Shah, Julie A. Margenthaler, Brian J. Czerniecki, Pat Whitworth, DAVID J. DABBS, G Bruce Mann, Fredrik Wärnberg, Sheila Weinmann, Michael Leo, Jess Savala, Steven C. Shivers, Karuna Mittal, Troy Bremer. PD15-07 7-gene predictive biosignature improves risk stratification for breast ductal carcinoma in situ patients compared to clinicopathologic criteria, identifying a low risk group not clinically benefiting from adjuvant radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-07.

Abstract P4-02-02: Changes in treatment recommendation for patients with Ductal Carcinoma In Situ using a 7-gene predictive biosignature: Analysis of the PREDICT Study

Abstract Background: The role of adjuvant radiotherapy (RT) following breast conserving surgery (BCS) for women with ductal carcinoma in situ (DCIS) remains controversial. Although there is Level 1 evidence supporting the use of RT in reducing the risk of local recurrence, prognostic and predictive tools are needed to better stratify individual risks and benefits of RT. The DCISionRT® Test (PreludeDx, Laguna Hills, CA) is a 7-gene predictive biosignature that uses tumor biology in conjunction with clinicopathologic factors. The test provides a validated score (DS) for women receiving BCS that assesses 10-year risk of DCIS recurrence and development of invasive breast cancer with and without adjuvant RT. We established a registry to evaluate the decision impact of the 7-gene predictive biosignature on DCIS treatment recommendations. Methods: The PREDICT study is a prospective, multi-institutional registry for patients who received DCISionRT testing as part of their routine care. The registry includes females 26 and older who are diagnosed with DCIS and are candidates for BCS and eligible for RT or systemic therapy. Treating physicians completed treatment recommendation forms before and after receiving test reports to capture surgical, radiation and hormonal treatment (HT) recommendations and patient preferences. The primary endpoint is to identify the proportion of patients where testing led to a change in RT recommendation. Additional analyses include changes in recommendations in patient subgroups based on clinicopathologic factors or clinician specialty. Results: Analysis was performed in 2,308 patients treated at 63 clinical sites. The median age of patients was 62 years, 18% were 50 or younger, nuclear grade was high in 33%, and tumor size was 2.5 cm or greater in 11%. Test results were DS Low Risk (DS ≤ 3) for 63% of women and 37% were DS Elevated Risk (DS &amp;gt; 3). Overall, RT recommendation (yes/no) was changed for 38% of women after the 7-gene biosignature testing and HT recommendation was changed for 11%. There was a net decrease in RT recommendation from 71% pre-assay to 53% post-assay (p&amp;lt; 0.001), where RT recommendations decreased 53% in DS Low Risk patients but increased 25% in DS Elevated Risk patients. Surgeons were more likely to change their RT recommendation (47%) than radiation oncologists (35%). When test results indicated DS Elevated Risk, both surgeons (79%) and radiation oncologists (88%) were likely to recommended RT, but when the results were DS Low risk, surgeons were more likely than radiation oncologists to recommend omitting RT (82% vs. 60%, respectively). Compared to traditional clinicopathologic features, the factor most strongly associated with RT recommendation was the biosignature result with other factors of importance being patient preference, tumor size and grade. Conclusions: This analysis demonstrates significant changes in recommendations to add or omit RT based on the 7-gene predictive biosignature in 2,308 patients. The integration of DCISionRT into clinical decision processes has substantial impact on recommendations aimed at optimal management to prevent over- or under-treatment. Table 1. Impact of the 7-gene predictive biosignature on adjuvant radiation recommended by clinicopathologic features. Citation Format: Pat Whitworth, Steven C. Shivers, Chirag Shah, Rakesh Patel, Karuna Mittal, Troy Bremer, Charles Cox. Changes in treatment recommendation for patients with Ductal Carcinoma In Situ using a 7-gene predictive biosignature: Analysis of the PREDICT Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-02.

Abstract OT3-11-03: The PREDICT Registry Australia: A prospective registry to evaluate the clinical utility of a 7-gene predictive biosignature on treatment decisions in patients with ductal carcinoma in situ

Abstract Background: For women with ductal carcinoma in situ (DCIS) treated with breast conserving surgery (BCS), the benefit of adjuvant radiation therapy (RT) remains controversial. Since there is level 1 evidence supporting the role of RT in reducing the risk of local recurrence, current guidelines generally recommend RT for all women having BCS even though the absolute benefit is variable. In response to the need for prognostic and predictive tools to better assess risk and RT benefit, a 7-gene predictive biosignature (DCISionRT, PreludeDx, Laguna Hills, CA) was developed. The test provides a validated score (DS) for assessing 10-year risk of recurrence and RT benefit using individual tumor biology, as assessed by clinical and pathologic biomarkers. The primary objective of the PREDICT registries is to understand the decision impact such a tool has on treatment decisions. Prospective Clinical Trial Design: This is a multicenter, prospective, observational registry for women diagnosed with DCIS in Australia. After DCIS diagnosis, sites will send the most representative tissue block or sections mounted on charged slides to the PreludeDx lab for biosignature testing. Treating physicians will complete a treatment recommendation survey before and after receiving the biosignature test results. Test results, treatment recommendations, patient preferences and clinicopathologic features will be stored in a de-identified registry for participating institutions from a variety of geographic regions across Australia. Women will then be followed for up to 10 years with completion of a follow-up form. The study has been approved by the North Shore Local Health District Human Research Ethics Committee, St Leonards, NSW, Australia. Universal Trial Number (UTN): U1111-1266-0439; ANZCTR: ACTRN12621000695808; ClinicalTrials.gov: NCT04916808. Eligibility Criteria: The study includes females age 26 or older who are candidates for BCS and eligible for RT and/or systemic treatment. Subjects must not have been previously treated for DCIS or have previous or current invasive or micro-invasive breast cancer. Specific Aims: The primary endpoints are changes in treatment recommendations for surgical, radiation and hormonal therapy. Secondary endpoints are identification of key drivers for treatment recommendations, including age, size, grade, necrosis, hormone receptor status, patient preference and biosignature status. Statistical Methods: Changes in pre- and post-DCISionRT treatment recommendations will be analyzed using McNemar’s test (alpha level = 0.05). Multivariate logistic regression will be used to determine odds ratios of clinicopathologic factors leading to pre- and post-test treatment recommendations. Pre-test covariates include patient age, tumor size, palpability, margin status, hormone receptor status, nuclear grade, tumor necrosis, family history of breast cancer, race, ethnicity and patient preference, as well as physician specialty (surgeons vs. radiation oncologists) and post-test covariates will also include the DCISionRT Decision Score (DS). Differences in recurrence-free and overall survival will be assessed by Kaplan-Meier survival analysis using the log-rank test and/or the Cox Proportional Hazards model. Statistical analyses will be carried out using R (https://www.r-project.org) or SAS. An early interim analysis based on the first 200 enrolled patients is currently underway. Present and Planned Accrual: We are planning to enroll up to 1,500 women from up to 100 sites across Australia. A similar registry has recently completed enrollment of 2,500 women from 68 sites in the US. Citation Format: Yvonne Zissiadis, G Bruce Mann, David Speakman, Christobel Saunders, Christopher Pyke, Daniel De Viana, Melissa Bochner, James R. French, Marcus Dreosti, Sally Baron-Hay, Alexandra Feetham, Kim Kirkham, Shane Ryan, Karuna Mittal, Steven C. Shivers, Troy Bremer. The PREDICT Registry Australia: A prospective registry to evaluate the clinical utility of a 7-gene predictive biosignature on treatment decisions in patients with ductal carcinoma in situ [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-11-03.

New and Emerging Trabecular Meshwork Bypass Stents

Minimally invasive glaucoma surgery procedures are newly developed surgical modalities for the management of glaucoma. Their target is to lower intraocular pressure with minimal eye trauma and fewer complications. The first-generation iStent® (Glaukos Corp, Laguna Hills, CA, USA) is the first minimally invasive glaucoma surgery device to be approved for the treatment of open-angle glaucoma. It allows aqueous humour to be drained directly from the anterior chamber to Schlemm’s canal, bypassing the trabecular meshwork, which is believed to be the main site of outflow resistance. The second-generation iStent inject® (Glaukos Corp, Laguna Hills, CA, USA) is a smaller implant that allows simultaneous implantation of two stents, which could theoretically result in lower intraocular pressure. The Hydrus® Microstent (Alcon, Geneva, Switzerland) is another trabecular implant that dilates and scaffolds Schlemm’s canal. This articles reviews publications about all trabecular meshwork bypass stents, comparing them in terms of their efficacy and safety.

Phacoemulsification with and without iStent: A Systematic Review and Meta-Analysis of Comparative Studies

Background: The iStent (Glaukos Corporation; Laguna Hills, CA, USA) is one of the minimally invasive glaucoma devices. It can be inserted at the time of phacoemulsification or as a stand-alone procedure to lower the intraocular pressure (IOP). Objective: Our aim was to conduct a systematic review and meta-analysis comparing the effect of iStent insertion at the time of phacoemulsification with phacoemulsification alone in patients with ocular hypertension or open-angle glaucoma. Methods: We searched EMBASE, MEDLINE (OVID and PubMed), CINAHL, and Cochrane Library for articles published between 2008 and June 2022 (PRISMA 2020 for the checklist). Studies comparing the IOP-lowering effect of iStent with phacoemulsification versus phacoemulsification alone were included. The endpoints were IOP reduction (IOPR) and the mean reduction in the number of glaucoma drops. A quality-effects model was used to compare both surgical groups. Results: Ten studies were included, reporting on 1,453 eyes. Eight hundred fifty three eyes had the combined iStent and phacoemulsification, and 600 eyes underwent phacoemulsification alone. IOPR was higher in the combined surgery at of 4.7 ± 2 mm Hg compared to 2.8 ± 1.9 mm Hg in phacoemulsification alone. A greater decrease in postoperative eye drops was noted in the combined group having a decrease of 1.2 ± 0.3 eye drops versus of 0.6 ± 0.6 drops in isolated phacoemulsification. The quality effect model showed an IOPR weighted mean difference (WMD) of 1.22 mm Hg (confidence interval [CI]: [–0.43, 2.87]; Q = 315.64; p < 0.01; I2 = 97%) and decreased eye drops WMD 0.42 drops (CI: [0.22, 0.62]; Q = 42.6; p < 0.01; I2 = 84%) between both surgical groups. Subgroup analysis shows that the new generation iStent may be more effective in reducing IOP. Conclusion: iStent has a synergetic effect with phacoemulsification. The reduction of IOP and glaucoma eye drops was higher when iStent is combined with phacoemulsification compared with isolated phacoemulsification.

Abstract B016: Guiding de-escalation of treatment for patients with DCIS using a predictive 7-gene biosignature: Identification of a clinically low-risk patient group

Abstract Background: NCCN treatment guidelines support de-escalation of radiotherapy (RT) for “low risk” patients with ductal carcinoma in situ (DCIS) treated with breast conserving surgery (BCS) for which improved specificity in identifying patients with low in-breast recurrence (IBR) rates who are unlikely to benefit from RT is needed. “low risk” has been defined as the absence of “high risk” clinicopathological (CP) factors, which include younger age (&amp;lt;50 yrs) or tumors that are 2 cm or larger, palpable, or high nuclear grade. However, these CP factors have failed to identify a patient group with lower recurrence risk that do not clinically benefit from RT after BCS. Thus, the clinical utility of a Low Risk group identified by the predictive 7-gene biosignature was characterized overall and for patient subsets meeting “low risk” or “high risk” CP criteria. Methods: DCIS patients (n=926) from four international cohorts treated with BCS (negative margins) with (n=641) and without RT (n=335) were evaluated for CP criteria (age&amp;lt;50 or grade 3, and RTOG 9804 like) and clinical outcomes. Formalin-fixed paraffin-embedded tissue samples for each patient were analyzed at a CLIA lab (PreludeDx, Laguna Hills, CA) for the predictive 7-gene biosignature with a Residual Risk subtype (RRt). The biosignature reported a decision score (DS) of 0-10 and presence/absence of the RRt subtype. A Low Risk group (DS≤2.8 without RRt) was compared with the combined Elevated Risk (DS&amp;gt;2.8 without RRt) and Residual Risk groups (DS&amp;gt;2.8 with RRt), where 10-yr total IBR rates were evaluated using Cox Proportional Hazards and Kaplan Meier analysis by treatment, biosignature Risk group, and CP criteria. Results: The biosignature classified 37% of women treated with BCS as Low Risk (n=338) and 63% (n=588) were classified into the combined Elevated/Residual Risk group. Among patients who did not receive RT, those in the Elevated/Residual Risk group had higher IBR rates (p&amp;lt;.001) than those in the Low Risk group, with corresponding 10-yr IBR rates of 25.7% (95% CI: 18.8%, 34.4%) vs 5.6% (95% CI: 2.5%, 12.1%), respectively. RT did not reduce the IBR rate in the Low Risk group (p=0.71), where the 10-yr IBR rate was 4.8% (95% CI: 2.5%, 9.1%) after RT, corresponding to a number needed to treat (NNT) of ~100. However, the Elevated/Residual Risk group benefited from RT (p&amp;lt;0.001), with a 17.7% (95% CI: 9.4%, 26%) absolute 10-year IBR rate reduction, corresponding to a NNT of 6. The biosignature reclassified 35-40% of patients with “high risk” CP criteria into the Low Risk group. IBR rates in the Low Risk group for patients with “high risk” CP were not significantly different than those with “low risk” CP criteria. Conclusion: The 7-gene biosignature was a better predictor of prognosis and RT benefit than standard CP risk stratification, identifying a low risk group with no significant benefit from RT. The 10-yr IBR rate with or without RT remained consistent in the biosignature Low Risk group independent of CP criteria, further supporting identification of a true low risk group who may forgo RT. Citation Format: Rachel Rabinovitch, Frank A. Vicini, Chirag Shah, Julie Margenthaler, Brian Czerniecki, Pat Whitworth, Sheila Weinmann, Michael C. Leo, Fredrik Wärnberg, G. Bruce Mann, Steven C. Shivers, David Dabbs, Karuna Mittal, Troy Bremer. Guiding de-escalation of treatment for patients with DCIS using a predictive 7-gene biosignature: Identification of a clinically low-risk patient group [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B016.

Prospective 12-month outcomes of combined iStent inject implantation and phacoemulsification in Asian eyes with normal tension glaucoma

BackgroundGlaucoma is the leading cause of irreversible blindness. Normal tension glaucoma (NTG) is a subset of open-angle glaucoma, demonstrating glaucomatous optic nerve damage in the absence of raised intraocular pressure (IOP). NTG is more prevalent in Asian populations. While generally slow-progressing, NTG may be associated with significant central visual field loss. In recent years, minimally invasive glaucoma surgery has been added to the armamentarium of glaucoma surgery. This prospective study aims to evaluate 12-month surgical outcomes of combined iStent inject (Glaukos Corporation, Laguna Hills, CA) implantation and phacoemulsification in Asian eyes with NTG.MethodsThis is a prospective, single-centre case series of 30 eyes followed up until 12 months after surgery. Outcome measures included IOP, number of glaucoma medications, best-corrected visual acuity (BCVA) and intra and postoperative complications.ResultsMean age of subjects was 73.1 ± 6.3 years. Majority were ethnic Chinese (n = 27, 90%). Baseline medicated mean IOP was 13.8 ± 2.4 mmHg and mean number of glaucoma medications was 1.3 ± 0.7. Mean Humphrey visual field mean deviation was − 13.7 ± 7.6. The mean IOP reduction at all timepoints from postoperative month (POM) 3 onwards was statistically significant (all P < 0.05), with mean reduction of 1.2 mmHg (95% CI: 0.1–2.2, P = 0.037) by POM12. There was statistically significant reduction in mean number of medications from postoperative day (POD) 1 onwards (all P < 0.05), with mean decrease of 1.0 medication (95% CI: 0.9–1.1, P < 0.001) by POM12. By POM12, 25 (83.3%) eyes were medication-free. Three (10%) eyes had stent occlusion by iris requiring laser iridoplasty. One eye had gross hyphema which resolved on conservative management before POM1. Mean BCVA improved from the baseline 0.3 ± 0.3 logMAR to 0.1 ± 0.1 logMAR postoperatively (P < 0.001). There were no major adverse or sight-threatening events. No eyes required further glaucoma surgery during the 12-month follow-up period.ConclusionAsian eyes with NTG which underwent combined iStent inject implantation and phacoemulsification demonstrated a significant and sustained reduction in IOP and glaucoma medications, up to 12 months postoperatively.

Assessing the benefit of adjuvant endocrine therapy in patients following breast-conserving surgery with or without radiation stratified by a 7-gene predictive DCIS biosignature.

502 Background: Breast conserving surgery (BCS) followed by radiotherapy (RT) has been the mainstay for DCIS treatment. Adjuvant endocrine therapy (ET) has often been recommended based on multiple randomized clinical trials (RCT). However, these studies have failed to identify subsets of patients who did or did not benefit from adjuvant RT/ET therapy after BCS. We evaluated the association of a 7-gene predictive DCIS biosignature (PreludeDx, Laguna Hills, CA) to assess the impact of ET on 10-yr ipsilateral breast recurrence (IBR) risk after BCS alone or with RT. Methods: DCISionRT with integrated Residual Risk subtype (RRt) reported a decision score (DS) and three risk groups, a) Low Risk (DS≤2.8), b) Elevated Risk (DS &gt; 2.8 without RRt) and c) Residual Risk (DS &gt; 2.8 with RRt). DCISionRT/RRt was evaluated in 926 patients from 4 cohorts who were treated with BCS alone or with RT/ET. The three risk groups were assessed for 10-yr total (invasive and in situ) IBR risk by Kaplan Meier and Cox proportional hazards survival analysis. Results: DCISionRT/RRt classified 338 (37%) women as Low Risk, 399 (43%) as Elevated Risk, and 189 (20%) as Residual Risk. Overall, patients treated with ET had a significantly lower 10-yr IBR risk in multivariable analysis independent of RT (HR = 0.55, p = 0.033). In the Low Risk group treated with BCS without RT, the average 10-yr IBR risk was 5.6% (95% CI 2.5-12.1%, n = 124) and was not significantly different with vs without ET (p = 0.33). The 10-yr IBR risk after BCS alone was 22.6% in the Elevated Risk group and 50.3% in the Residual Risk group. Compared to BCS alone, the 10-year IBR risk tended to be lower in patients prescribed ET without RT in the Elevated (11.6%, 95% CI 3.9-32%) and Residual (15.4%, 95% CI 4.1-49%) Risk groups. 10-yr IBR risk was not significantly reduced by RT within the Low Risk group (p = 0.7) but was significantly reduced to 6.3% (95% CI 3.4-12%) by RT within the Elevated Risk (HR = 0.2, p &lt; 0.001) and to 12.5% (95% CI 6.4-23%) within the Residual Risk (HR = 0.2, p &lt; 0.001) groups. 10-yr IBR risk was significantly higher after RT in the Residual (HR = 2.5, p = 0.013) vs. Elevated Risk groups. After BCS and RT, there was no significant reduction in 10-yr IBR risk for those treated with vs without ET in the Elevated (p = 0.22) and Residual (p = 0.87) risk groups. Conclusions: The DCISionRT/RRt biosignature demonstrated prognostic and predictive RT response in Elevated and Residual Risk patients. Consistent with prior RCT data, ET was associated with lower 10-yr IBR risk overall, and within the DCISionRT Elevated and Residual Risk groups without RT. However, neither ET nor RT were asssociated with significant risk reduction in the Low Risk group. There was no added benefit of ET in the Elevated and Residual Risk groups after BCS+RT; the Residual Risk group patients still had a high IBR risk after RT.

0421 The pupillary light reflex detects hyperarousal and discriminates between adults with nil versus modest insomnia symptoms

Abstract Introduction Physiologic and psychologic hyperarousal is a leading candidate mechanism behind insomnia symptoms. Increased levels of physiologic arousal have been demonstrated in insomnia patients versus healthy sleepers using a variety of methods including brain PET, Multiple Sleep Latency Testing, ambulatory core body temperature, and sympathetic nerve microneurography. All of these methods, however, are expensive, or technologically intensive, or invasive. In contrast, the pupillary light reflex (PLR) is comparatively inexpensive, portable, easy to measure, and well-tolerated by patients. The average constriction velocity (ACV) in response to a controlled light stimulus is an indicator of physiologic arousal, with more rapid constriction indicating greater arousal. Methods Forty community volunteers provided informed written consent to measurement of their PLR after a period of dark adaptation with the NeurOptics PLRTM-3000 Pupillometer (Laguna Hills, CA), which continuously measures pupil size to a precision of 0.1 mm, at a frequency of 30 Hz. None of the participants were seeking or receiving mental health services, were taking psychotropics, or were using any prescribed or over the counter medication that might affect the PLR. Participants also completed the Patient Health Questionnaire-9 (PHQ-9) and the Insomnia Severity Index (ISI). The protocol was approved by the local IRB. Results Sixteen of the volunteers had an ISI score &amp;gt; 4 (“modest ISI”), and 24 had an ISI score &amp;lt; 4 (nil ISI). The overall sample was 26.4 + 9.1 years old, 62.5% female, and 30% non-white, with no significant differences between the ISI score groups. The “nil ISI” and “modest ISI” groups had ISI scores of 1.2 + 1.3 versus 8.7 + 3.6 (p&amp;lt;0.001), PHQ-9 scores of 1.5 + 1.3 versus 5.4 + 4.4 (p&amp;lt;0.005), and ACV of -2.7 + 0.6 versus -3.1 + 0.5 mm/sec (p&amp;lt;0.05), respectively. Conclusion This small study of community volunteers showed PLR evidence of relative hyperarousal in those participants with modest levels of insomnia symptoms. With further development, the PLR may have promise in practical identification of a “hyperarousal subtype” of insomnia patients. Support (If Any) None

Automated Pupillometry for Prediction of Electroencephalographic Reactivity in Critically Ill Patients: A Prospective Cohort Study.

BackgroundElectroencephalography (EEG) is widely used to monitor critically ill patients. However, EEG interpretation requires the presence of an experienced neurophysiologist and is time-consuming. Aim of this study was to evaluate whether parameters derived from an automated pupillometer (AP) might help to assess the degree of cerebral dysfunction in critically ill patients.MethodsProspective study conducted in the Department of Intensive Care of Erasme University Hospital in Brussels, Belgium. Pupillary assessments were performed using the AP in three subgroups of patients, concomitantly monitored with continuous EEG: “anoxic brain injury”, “Non-anoxic brain injury” and “other diseases”. An independent neurologist blinded to patient's history and AP results scored the degree of encephalopathy and reactivity on EEG using a standardized scale. The mean value of Neurologic Pupil Index (NPi), pupillary size, constriction rate, constriction and dilation velocity (CV and DV) and latency for both eyes, obtained using the NPi®-200 (Neuroptics, Laguna Hills, CA, USA), were reported.ResultsWe included 214 patients (mean age 60 years, 55% male). EEG tracings were categorized as: mild (n = 111, 52%), moderate (n = 65, 30%) or severe (n = 16, 8%) encephalopathy; burst-suppression (n = 19, 9%) or suppression background (n = 3, 1%); a total of 38 (18%) EEG were classified as “unreactive”. We found a significant difference in all pupillometry variables among different EEG categories. Moreover, an unreactive EEG was associated with lower NPi, pupil size, pupillary reactivity, CV and DV and a higher latency than reactive recordings. Low DV (Odds ratio 0.020 [95% confidence intervals 0.002–0.163]; p < 0.01) was independently associated with an unreactive EEG, together with the use of analgesic/sedative drugs and high lactate concentrations. In particular, DV values had an area under the curve (AUC) of 0.86 [0.79–0.92; p < 0.01] to predict the presence of unreactive EEG. In subgroups analyses, AUC of DV to predict unreactive EEG was lower (0.72 [0.56–0.87]; p < 0.01) in anoxic brain injury than Non-anoxic brain injury (0.92 [0.85–1.00]; p < 0.01) and other diseases (0.96 [0.90–1.00]; p < 0.01).ConclusionsThis study suggests that low DV measured by the AP might effectively identify an unreactive EEG background, in particular in critically ill patients without anoxic brain injury.

Efficacy of GentleWave System and Passive Ultrasonic Irrigation with Minimally Invasive and Conventional Instrumentation Technique against Enterococcus faecalis Lipoteichoic Acid in Infected Root Canals

IntroductionThis study evaluated the effectiveness of the GentleWave System (GWS; Sonendo, Laguna Hills, CA) and passive ultrasonic irrigation (PUI) in removing Enterococcus faecalis lipoteichoic acid (LTA) from infected root canals with a minimally invasive technique (MIT) and the conventional instrumentation technique (CIT). MethodsSixty extracted human maxillary first premolars were included. All teeth were dentin pretreated and inoculated with LTA prepared from E. faecalis. First, 12 teeth were cryogenically ground to investigate the viability of recovering intraradicular E. faecalis LTA. Afterward, 48 teeth were randomly divided into the following groups: GWS + MIT, GWS + CIT, PUI + MIT, and GWS + CIT (all n = 12). Teeth were instrumented with a Vortex Blue (Dentsply Sirona, Ballaigues, Switzerland) rotary file size 15/.04 for MIT and 35/.04 for CIT. Samples were collected before and after a root canal procedure with sterile/apyrogenic paper points and after cryogenically ground for intraradicular LTA analysis. LTA was quantified with an LTA enzyme-linked immunosorbent assay kit. ResultsE. faecalis LTA was recovered from 100% of the samples (48/48) before the root canal procedure. GWS + MIT and GWS + CIT were the most effective protocols against E. faecalis LTA, with no difference between them (P > .05). PUI + CIT was more effective than PUI + MIT (P < .05) but less effective than GWS + MIT and GWS + CIT (P < .05). The GWS groups showed more root canals with undetected E. faecalis LTA after treatment than all groups tested. ConclusionsGWS + MIT and GWS + CIT were the most effective protocols against E. faecalis LTA in infected root canals.

Abstract OT1-09-02: The PREDICT Registry: A prospective registry to evaluate the effect of a predictive assay on treatment decisions in patients with DCIS following breast conserving therapy

Abstract Background. The benefits of adjuvant radiation therapy (RT) in patients with ductal carcinoma in situ (DCIS) treated with breast conserving surgery (BCS) remains controversial. Although there is level-I evidence supporting the role of RT in reducing the risk of local recurrence, the absolute benefit is variable. Current guidelines generally recommend RT for all patients having BCS, but it is important to develop prognostic and predictive tools to better assess risk and understand the impact such a tool would have on treatment decisions. The DCISionRT Test(PreludeDx, Laguna Hills, CA) is a biologic signature that provides a validated score for assessing 10-year risk of recurrence and RT benefit using individual tumor biology as assessed by clinical and pathologic biomarkers. Methods. This is a prospective cohort study for patients diagnosed with DCIS of the breast. Treating physicians complete a treatment recommendation survey before and after receiving DCISionRT test results. Test results, treatment recommendations, patient preferences and clinico-pathologic features are stored in a de-identified registry for participating institutions from a variety of geographic regions across the US. The study will also collect 5- and 10-year recurrence and survival data. The study includes females over age 25 who are candidates for BCS and eligible for RT and/or systemic treatment with sufficient tissue to generate test results. Subjects must not have been previously treated for DCIS or have previous or current invasive or micro-invasive breast cancer. The primary endpoints are changes in treatment recommendations for surgical, radiation and hormonal therapy. Secondary endpoints are identification of key drivers for treatment recommendations, including age, size, grade, necrosis, hormone receptor status and other clinico-pathologic factors. Changes in treatment recommendations will be assessed using McNemar's test with an alpha level of 0.05. Differences in recurrence-free and overall survival will be evaluated by Kaplan-Meier survival analysis using the log-rank test and/or the Cox Proportional Hazards model. A planned early interim analysis based on the first 200 patients has been recently completed and reported. Results. As of July 9, 2021, 1,986 patients have been accrued from 64 institutions. Ten additional institutions are currently in the process of joining the study. We are planning to enroll up to 2,500 patients from up to 100 institutions. Citation Format: Steven C Shivers, Pat W Whitworth, Rakesh Patel, Troy Bremer, Charles E Cox. The PREDICT Registry: A prospective registry to evaluate the effect of a predictive assay on treatment decisions in patients with DCIS following breast conserving therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-09-02.