Current Accrual Research Articles

NRG-BR007: A phase III trial evaluating de-escalation of breast radiation (DEBRA) following breast-conserving surgery of stage 1, HR+, HER2-, RS ≤18 breast cancer.

TPS622 Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that breast-conserving surgery (BCS) alone is non-inferior to BCS plus RT for IBR and breast preservation in women intending endocrine therapy (ET) for stage 1 invasive breast cancer (ER and/or PR-positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (≤11, >11-18/MammaPrint Low). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (moderate or ultra hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER and/or PR-positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS ≤18 (diagnostic core biopsy or resected specimen); (a “low risk” MammaPrint is permissible if completed as part of usual care prior to screening). Primary endpoint is IBR (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% v 91.6% for the omission-of-RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1%/yr. Some T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. Current accrual (02-05-2024) is 805 screened and 716 randomly assigned. Clinical trial information: NCT04852887 .

Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-NORTH AMERICA): NRG-GI008.

TPS3641 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines vserial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Current accrual (as of 02-02-2024) is 240/1,912. NCT05174169. Support: U10-CA-180868, -180822; UG1CA-189867; Natera, Inc. Clinical trial information: NCT05174169 .

Abstract PO2-19-02: NRG-BR009: Phase III Trial Evaluating Addition of Adjuvant Chemotherapy to Ovarian Function Suppression + Endocrine Therapy in Premenopausal Women with pN0-1, HR+/HER2- Breast Cancer and Oncotype Recurrence Score ≤25 (OFSET)

Abstract Background: Identifying pts with HR-positive/HER2-negative breast cancer (BC) who benefit from adjuvant chemotherapy (ACT) has been a major research focus over the past 20 years. Development and clinical application of genomic classifiers such as the 21-gene recurrence score (RS) has contributed to the biologic understanding of BC and has refined pt selection for ACT. The TAILORx and RxPONDER clinical trials demonstrated that RS identifies many postmenopausal pts with node-negative and node-positive BC and RS < 25, who do not benefit from the addition of ACT to endocrine therapy (ET). However, both trials also showed that certain subsets of premenopausal pts (node-negative/high clinical risk/RS 16-20, node-negative/RS 21-25, and node-positive/RS < 25) benefited from the addition of ACT to ET. Most premenopausal pts in these two trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR-positive/HER2-negative BC in the SOFT and TEXT trials, many questioned whether all or part of the observed ACT benefit in the TAILORx/RxPONDER trials may have been the result of chemotherapy-induced OFS. To address this question, OFSET is a Phase III, multicenter clinical trial evaluating the addition of ACT to OFS+ET vs. OFS+ET alone. Methods: We hypothesize that the addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR-positive/HER2-negative tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival (IDFS), overall survival (OS), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and health-related quality of life (HRQOL). Eligible pts must be node-negative with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS < 25. Stratification is by nodal status/RS status (pN0 RS 16-25 vs pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 vs ≥40). Pts are randomized after surgery to either OFS+ET or ACT followed by OFS+ET. ET is an aromatase inhibitor per investigator discretion, but tamoxifen is allowed if pts do not tolerate the AI or if OFS is incomplete. Radiation therapy will be administered per investigator discretion according to protocol guidelines. The HRQOL sub-study will assess differences in severe menopausal symptoms, measured by the FACT ESS-19 score, between the arms, as well as increased pain severity (PROMIS) during ACT+OFS+ET compared to OFS+ET. Blood and tumor specimens will be collected for future research. The accrual of 3,960 pts is anticipated to be completed in seven years and seven mos. Based on data from NSABP B-28 and RxPONDER, the 5-year IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on data from TAILORx, the 5-year IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of the pts to be pN0 and 44% pN1, a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET vs. OFS+ET, with one-sided alpha of 0.025 and 80% power will require 380 IBCFS events, which are expected to occur ~11 years after study initiation. The OFSET study is expected to be activated in the third quarter of 2023. Current accrual (06-19-2023) is 0/3,960 Support: U10CA180868, U10CA180822, UG1CA189867, U24CA196067. NCT05879926. Citation Format: Eleftherios Mamounas, Gong Tang, Shannon Puhalla, Sandra Swain, Patricia Ganz, N. Lynn Henry, Reena Cecchini, Sonya Reid, Priya Rastogi, Charles Geyer, Julia White, Amy Clark, Tufia Haddad, Gregory Vidal, Norman Wolmark. NRG-BR009: Phase III Trial Evaluating Addition of Adjuvant Chemotherapy to Ovarian Function Suppression + Endocrine Therapy in Premenopausal Women with pN0-1, HR+/HER2- Breast Cancer and Oncotype Recurrence Score ≤25 (OFSET) [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 PO2-19-02.

Abstract PO5-18-10: Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104)

Abstract Background: Currently, axillary surgery for breast cancer is considered a staging procedure that does not seem to influence breast cancer mortality since the risk of developing metastasis depends mainly on the biological behavior of the primary (seed-and-soil model). Based on this, postsurgical therapy should be considered based on biological tumor characteristics. Retrospective data of cancer registry trials showed a strong correlation between breast pathologic complete response (pCR) and nodal pCR depending on intrinsic subtypes. Improvements in systemic treatments for breast cancer have increased the rates of pCR in patients receiving neoadjuvant systemic therapy (NAST), offering the opportunity to decrease, and perhaps eliminate, surgery in patients who have a pCR. Trial design: The EUBREAST network designed a clinical trial (NCT04101851) in which only patients with the highest likelihood of having a pCR after NAST (triple-negative or HER2-positive breast cancer) will be included, and type of surgery will be defined according to the response to NAST rather than on the classical T and N status at presentation. In the ongoing trial, axillary surgery will be eliminated (no axillary sentinel lymph node biopsy [SLNB]) for initially clinical node-negative (cN0) patients with radiologic complete remission (rCR) and a breast pCR (ypT0/ypTis) as determined in the lumpectomy specimen. The trial design is a multicenter single-arm study with a limited number of patients (N=440 as the screening population with an expected 80% pCR-rate) which might give practice-changing results in a short period, sparing the time and the costs of a randomized comparison. Patients will be recruited in European countries (Austria, Germany, Italy, and Spain) over 48 months. Inclusion criteria: -Written informed consent -Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy). Multifocal or multicentric tumors are allowed if breast-conserving surgery (BCS) is planned. -Age at diagnosis at least 18 years -imaging techniques with estimated tumor stage between cT1-T3 before NAST -triple-negative (TNBC) or HER2-positive invasive breast cancer -TNBC is defined by: ER-negative (< 10% positive cells in IHC) and PgR-negative (< 10% positive cells in IHC), HER2-negative -clinically and sonographically tumor-free axilla before core biopsy (cN0/iN0) -in cases with cN0 and iN+, a negative core biopsy or fine-needle aspiration biopsy of the sonographically suspected lymph node is required -no evidence for distant metastasis (M0) -standard NAST with rCR -planned BCS with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation) Primary objective: 3-year rate of axillary recurrence-free survival (ARFS) after BCS Statistics: The calculated total case number for per-protocol analysis is N=350, and the expected total number of screened patients is N=440. The assumption for acceptable 3-year ARFS ≥98.5% in the experimental arm is based on previous study findings. Timelines: -First patient in: January 2021 -Last patient in: December 2024 -Primary outcome analysis: Q1/2027 Current accrual: In June 2023, 255 patients were recruited; the majority of them in Germany. Contact: Prof. Dr. Toralf Reimer (eubreast-01@kliniksued-rostock.de), study chair Dr. Oreste D. Gentilini (gentilini.oreste@hsr.it), study co-chair Funding by Else Kroener-Fresenius Foundation, German Society of Senology, University of Rostock (Germany), and San Raffaele Hospital (Milan, Italy). Citation Format: Toralf Reimer, Bernd Gerber, Thorsten Kuehn, Nikola Bangemann, Anke Kleine-Tebbe, Andrea Stefek, Ulrike Doerste, Carolin Hammerle, Oliver Hoffmann, Alexander Hein, Isabel Rubio, Florentia Peintinger, Keyur Mehta, Sibylle Loibl, Edoardo Botteri, Oreste Gentilini. Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104) [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 PO5-18-10.

Abstract PO5-20-04: A Phase II Study of Ribociclib and Endocrine Treatment of Physician’s Choice for Locoregional Recurrent, Resected Hormone Receptor Positive HER2 Negative Breast Cancer (RaPhLRR Study)

Abstract Background Hormone receptor positive (HR+) breast cancer (BC) is the most common subtype of BC (70-80%). This subset tends to have good prognosis, therefore most patients with localized disease have excellent long-term survival, approaching 100% 5-year relative survival. However, 10% of patients experience loco-regional recurrence (LRR) within 5 year of final surgical management of the primary disease-well within the typical treatment window of adjuvant endocrine therapy. Few studies exists to guide the systemic treatment of patients who have suffered LRR of HR+ HER2 - BC. The randomized controlled CALOR trial demonstrated no benefit to systemic cytotoxic chemotherapy for this subgroup of patients and persistent high rate of subsequent recurrences (50% within 10 years on LRR event). There is no standard of care for managing this patient population. The combination of ribociclib and endocrine therapy (ET) (fulvestrant and aromatase inhibitors) is FDA approved for management of unresectable recurrences and metastatic HR+HER- BC (MONALEESA trials). CDK4/6 inhibitors have been investigated in early BC setting too, several trials showing positive results (monarchE, NATALEE). Data is needed to investigate their use in patients with LRR. Trial design This is a multicenter, single arm phase II study to evaluate efficacy and safety of ribociclib and ET in patients with LRR of HR+HER2- BC. Treatment includes ribociclib for 36 months, 600 mg daily for 21 days, 28-day cycle plus physician’s choice ET for 60 months (fulvestrant or AIs). Ribociclib dose was chosen based on approved dose in metastatic BC. Eligibility Criteria Patients ≥ 18 of age, with LRR of BC (ipsilateral breast, axilla, regional lymph nodes, chest wall), histologically confirmed estrogen receptor positive and/or progesterone receptor positive, HER 2 negative. Patients must have adequate local treatment for LRR (surgery and/or radiation) with negative microscopic margins, no evidence of distant metastatic disease. Prior treatment with neo-adjuvant and adjuvant chemotherapy and ET is allowed, no prior CDK 4/6 inhibitor in the last 12 months. Pre and post-menopausal women are allowed. Patient must enroll within 6 months of the last local therapy. Specific aims Primary objective: to estimate subsequent recurrence-free survival (RFS) at 3 years for ribociclib when administered with ET in patients with HR + HER2- BC with adequately resected local recurrence. Secondary objectives: to estimate distant metastasis-free survival and overall survival, to evaluate safety and tolerability, to identify predictors of LRR. Correlative analysis will explore prognostic and predictive biomarkers of treatment with ribociclib and ET and potential molecular mechanisms of resistance to treatment. Statistical Methods From previous published data (J Clin Oncol. 2018 Apr 10;36(11):1073-1079), we assume that patients receiving standard of-care management following recurrence would have a recurrence free survival (RFS) rate of 80% at 3 years and that treatment with ribociclib + ET will increase it by 7%. We wish to have at least 80% power at that significance level of 0.0487 to correctly detect that improvement in RFS rate at 3 years from 80 to 87%. Because only an improvement in RFS rate is of clinical interest, we have a directional hypothesis, and have used a 1-sided alpha. Using a one-sample survival study design, with assumed accrual duration of 3-years and additional follow-up time of 3 years, the minimum sample size requirement is N=180 patients. Target accrual The minimum sample size requirement is N=180 patients. A bigger sample size of N=200 patients will achieve a power of at least 84%. Current accrual is 6/200. This study will be open at up to 35 sites. Contact information The study is being administered through the HCRN, it can be identified as BRE20-468, NCT05467891, ocdanciu@uic.edu Citation Format: Oana Danciu, Nancy Chan, Kari Wisinski, Trish Millard, Kathleen Kemmer, Sneha Phadke, Zhengjia Chen, Ana Cuesta Fernandez, Melanie Clark, Alison Conlin, Coral Omene, Sima Ehsani, Stephanie Dublis, Vijayakrishna K. Gadi. A Phase II Study of Ribociclib and Endocrine Treatment of Physician’s Choice for Locoregional Recurrent, Resected Hormone Receptor Positive HER2 Negative Breast Cancer (RaPhLRR Study) [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 PO5-20-04.

Abstract PO4-19-02: Genetic risk estimation in breast cancer and assessing health disparities

Abstract Background: Breast Cancer (BC) incidence and the distribution of BC risk factors vary between racial and ethnic groups within the United States. It has been demonstrated that providing education on individualized breast cancer risk will improve patient uptake to recommended BC screening and prevention strategies. Most clinical risk assessment tools, including the validated IBIS model were derived from data using non-Hispanic white women. Consortia have also now identified over 300 common genetic susceptibility loci for BC, summarized by the polygenic risk score (PRS). When combined with clinical risk assessment tools, such as the IBIS or BCRAT models, the PRS can further refine risk estimation for patients. To date, most studies on the use of PRS have been done in non-Hispanic white women. While these PRS still perform well in racial minorities, there has been a recognized need to improve racial and ethnic diversity in genomic research cohorts. Herein, we aim to combine clinical risk assessment models that are already used in routine clinical practice with information derived from PRS testing in women of racial minorities to determine if this can improve risk estimation, patient understanding, and uptake to recommended breast cancer screening and prevention strategies. Design: This is a minimal risk prospective study with a single arm incorporating the PRS into a standard breast cancer risk reduction consultation, followed by annual surveys over 10 years to determine if and how the information provided by the PRS influenced patient decisions regarding recommended BC screening and prevention. Patients will have IBIS and BCRAT risks calculated at baseline visit. A survey of patient perceptions/understanding of risk, intention to undergo screening, and use of preventive medicine is completed after baseline visit prior to receiving the PRS results. Blood sample is obtained at baseline and DNA samples are analyzed for approximately 300 SNPs on a custom-designed, targeted SNP panel from ThermoFisher Scientific by the Mayo Clinic Genomics Laboratory. This PRS result is then combined with the clinical risk assessments (IBIS and BCRAT scores) using the R package Individualized Coherent Absolute Risk Estimators (iCare) tool to provide a new estimate of breast cancer risk for 5year, 10year, and lifetime risk. Patients are seen for follow-up to review results and then complete a second survey to assess their understanding of the results, BC risk, and how the PRS impacted their decision to undergo screening/prevention strategies. Eligibility Criteria: Women who self-identify as African American/Black or Hispanic/Latinx between 30-75 years old with any of the following: 1.)IBIS score of ≥5% for the 10 year risk OR BCRAT score of ≥ 3 % for the 5 year risk. 2.) History of biopsy proven atypical hyperplasia 3.) History of biopsy proven lobular carcinoma in situ. Specific Aims: Aim 1: The primary aim of this study is to explore if the addition of PRS to the BCRAT and IBIS score will improve intentions to undergo recommended breast cancer screening strategies such as mammography, MRI, or molecular breast imaging in women of underserved racial minorities Aim 2: To explore if the addition of the PRS to the BCRAT and IBIS risk score will aid women of racial minorities in deciding whether to take preventative endocrine therapy. Aim 3: To understand how individualized risk assessment and information on PRS may alter perceived risk of breast cancer. Statistical Methods Analysis will be mostly descriptive. Continuous variables will be summarized as mean (standard deviation) or median (range) and categorical variables will be reported as frequency (percentage). Kaplan-Meier method will be used to estimate the long-term cumulative risk of cancer. Current Accrual: 3. Target Accrual: 50 Citation Format: Lauren Cornell, Sandhya Pruthi, Linda Hasadsri, Sarah McLaughlin. Genetic risk estimation in breast cancer and assessing health disparities [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 PO4-19-02.

Abstract PO1-19-02: A phase III trial evaluating De-escalation of Breast Radiation (DEBRA) following breast-conserving surgery (BCS) of stage 1, HR+, HER2-, RS ≤18 breast cancer: NRG-BR007

Abstract Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX® have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 invasive breast cancer (ER &/or PR positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (< 60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (< 11, 11-18). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to < 70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER &/or PR positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS of ≤18 (diagnostic core biopsy or resected specimen). Primary endpoint is in-breast recurrence (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% vs 91.6% for the omission of RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1% per yr. Some of the T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. Current accrual (07-07-2023) is 555 screened and 488 randomized (~96% of predicted accrual). Support: U10CA180868, -180822, UG1CA189867, UG1CA189867; Susan G. Komen Foundation (JRW). NCT: 04852887. Citation Format: Julia White, Reena Cecchini, Eleanor Harris, Eleftherios Mamounas, Daniel Stover, Patricia Ganz, Reshma Jagsi, Stewart Anderson, Carmen Bergom, Valérie Théberge, Mahmoud El-Tamer, Richard Zellars, Dean Shumway, Guang-Pei Chen, Thomas Julian, Norman Wolmark. A phase III trial evaluating De-escalation of Breast Radiation (DEBRA) following breast-conserving surgery (BCS) of stage 1, HR+, HER2-, RS ≤18 breast cancer: NRG-BR007 [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 PO1-19-02.

NRG-BR007: A phase III trial evaluating de-escalation of breast radiation (DEBRA) following breast-conserving surgery (BCS) of stage 1, HR+, HER2-, RS ≤18 breast cancer.

TPS623 Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 invasive breast cancer (ER &/or PR positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (<11, 11-18). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER &/or PR positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS of ≤18 (diagnostic core biopsy or resected specimen). Primary endpoint is in-breast recurrence (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% vs 91.6% for the omission of RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1% per yr. Some of the T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. Current accrual (02-08-2023) is 370 screened and 323 randomized (~87% of predicted accrual). Clinical trial information: NCT04852887 .

Abstract OT1-07-01: Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104)

Abstract Background: Currently, axillary surgery for breast cancer is considered a staging procedure that does not seem to influence breast cancer mortality since the risk of developing metastasis depends mainly on the biological behavior of the primary (seed-and-soil model). Based on this, postsurgical therapy should be considered based on biological tumor characteristics. Retrospective data of cancer registry trials showed a strong correlation between breast pathologic complete response (pCR) and nodal pCR depending on intrinsic subtypes. Improvements in systemic treatments for breast cancer have increased the rates of pCR in patients receiving neoadjuvant systemic therapy (NAST), offering the opportunity to decrease, and perhaps eliminate, surgery in patients who have a pCR. Trial design: The EUBREAST network designed a clinical trial (NCT04101851) in which only patients with the highest likelihood of having a pCR after NAST (triple-negative or HER2-positive breast cancer) will be included, and type of surgery will be defined according to the response to NAST rather than on the classical T and N status at presentation. In the ongoing trial, axillary surgery will be eliminated (no axillary sentinel lymph node biopsy [SLNB]) for initially clinical node-negative (cN0) patients with radiologic complete remission (rCR) and a breast pCR (ypT0/ypTis) as determined in the lumpectomy specimen. The trial design is a multicenter single-arm study with a limited number of patients (N=440 as the screening population with an expected 80% pCR-rate) which might give practice-changing results in a short period, sparing the time and the costs of a randomized comparison. Patients will be recruited in European countries (Austria, Germany, Italy, and Spain) over 36 months. Inclusion criteria: -Written informed consent -Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy). Multifocal or multicentric tumors are allowed if breast-conserving surgery (BCS) is planned. -Age at diagnosis at least 18 years -imaging techniques with estimated tumor stage between cT1-T3 before NAST -triple-negative (TNBC) or HER2-positive invasive breast cancer -TNBC is defined by: ER-negative (< 10% positive cells in IHC) and PgR-negative (< 10% positive cells in IHC), HER2-negative -clinically and sonographically tumor-free axilla before core biopsy (cN0/iN0) -in cases with cN0 and iN+, a negative core biopsy or fine-needle aspiration biopsy of the sonographically suspected lymph node is required -no evidence for distant metastasis (M0) -standard NAST with rCR -planned BCS with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation) Primary objective: 3-year rate of axillary recurrence-free survival (ARFS) after BCS Statistics: The calculated total case number for per-protocol analysis is N=350, and the expected total number of screened patients is N=440. The assumption for acceptable 3-year ARFS ≥98.5% in the experimental arm is based on previous study findings. Timelines: -First patient in: January 2021 -Last patient in: December 2023 -Primary outcome analysis: Q1/2027 Current accrual: In June 2022, 150 patients were recruited in Germany and Italy. Contact: Prof. Dr. Toralf Reimer (eubreast-01@kliniksued-rostock.de), study chair Dr. Oreste D. Gentilini (gentilini.oreste@hsr.it), study co-chair Funding by Else Kroener-Fresenius Foundation, German Society of Senology, University of Rostock (Germany), and San Raffaele Hospital (Milan, Italy) Citation Format: Toralf Reimer, Thorsten Kuehn, Angrit Stachs, Anke Kleine-Tebbe, Nikola Bangemann, Andrea Stefek, Carolin Hammerle, Jörg Heil, Antje Nixdorf, Gabriele Bonatz, Agnieszka Nolte, Isabel T. Rubio, Florentia Peintinger, Keyur Mehta, Sibylle Loibl, Edoardo Botteri, Oreste Davide Gentilini. Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104) [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 OT1-07-01.

NRG-BR007: A phase III trial evaluating de-escalation of breast radiation (DEBRA) following breast-conserving surgery (BCS) of stage 1, hormone receptor+, HER2-, RS ≤18 breast cancer.

TPS613 Background: Approximately 50% of newly diagnosed breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX® have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 breast cancer (ER &/or PR positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), & (RS <11, RS 11-18). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (hypo- or conventional-fractionated whole breast RT with/without boost, APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER &/or PR positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS of ≤18 (diagnostic core biopsy or resected specimen). Primary endpoint is in-breast recurrence. Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% vs 91.6% for the omission of RT group). The study is powered to detect a non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 (835 per arm) pts are required to be randomized. Conservative loss to follow-up is 1% per yr. Some of the T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, pts will be required to register (1,714 pts) to ensure that our final randomized cohort is 1,670 pts. Current accrual (2-2-2022) is 52 screened and 45 randomized. Support: U10CA180868, -180822, NCT04852887. Clinical trial information: NCT04852887.

T Cell Costimulation Blockade with Abatacept Nearly Eliminates Early Severe Acute Graft Versus Host Disease after HLA-Mismatched (7/8 HLA Matched) Unrelated Donor Transplant, with a Favorable Impact on Disease-Free and Overall Survival

HLA mismatched unrelated donor (MMURD) HCT plays a critical role in the treatment of high-risk hematologic malignancies in ethnic minorities and others lacking a fully matched donor. However, the high incidence of severe (Grade III-IV) acute GVHD (AGVHD) and resultant mortality remain critical barriers to success. T cell costimulation blockade with CTLA4-Ig has been demonstrated to potently inhibit T cell activation, and is FDA-approved for rheumatoid arthritis and renal transplant. We previously completed a pilot study adding 4 doses of the ‘abatacept’ formulation of CTLA4-Ig to calcineurin inhibitor (CNI) + methotrexate (MTX) GVHD prophylaxis in URD HCT (BBMT 19:1638-49, 2013). Based on robust immune reconstitution and a low rate of AGVHD, we initiated a multicenter phase II trial of abatacept (10 mg/kg/dose, Days -1, +5, +14, +28) plus CNI/MTX (‘ABA2‘) in patients undergoing URD HCT (Clinicaltrials.gov # NCT01743131).ABA2 has 2 cohorts: (1) 8/8 URD (a randomized double-blind stratum vs CNI/MTX, current accrual =133 of 140 patients) and (2) 7/8 MMURD (a single-arm stratum with 43 patients, enrollment completed in Nov, 2016). The 7/8 stratum was non-randomized due to ethical concerns related to the high risk of death from severe AGVHD in 7/8 URD HCT in the absence of adjunctive immunosuppression. The 7/8 stratum thus underwent a pre-specified comparison to CIBMTR matched controls. Here we report the results from the 7/8 stratum with a follow-up of 227-1544 days (median 559).The primary outcome was the incidence of severe (Gr III-IV) AGVHD prior to day +100. Key secondary outcomes were Gr II-IV AGVHD, chronic GVHD (CGVHD), graft failure, engraftment, transplant-related mortality (TRM), relapse, disease-free survival (DFS) and overall survival (OS). Key inclusion criteria were age >6, myeloablative conditioning and a high-risk heme malignancy. Key exclusion criteria were the use of ATG, alemtuzumab, or other T cell depletion, or a cord blood graft. Stopping rules were in place for TRM and PTLD, neither of which were met. We compared ABA2 to two CIBMTR matched control cohorts: (1) 7/8 URD HCT using CNI + MTX (n =127) or (2) CNI/MTX plus anti-thymocyte globulin (‘+ATG’, n = 128). Matching was based on age, performance score and disease stage, with similar baseline characteristics (Table 1).42 of 43 ABA2 patients received all 4 abatacept doses, and all 43 successfully engrafted donor cells, with no delay in median neutrophil (17 days) or platelet (18 days) engraftment. ABA2 was associated with a marked reduction in the cumulative incidence of grade III-IV AGVHD at day 100, with only 2.3% Gr III-IV AGVHD in ABA2 vs 30% in CNI+MTX and 22% in +ATG (p =0.0070 and 0.025, Fig. 1A, 2A). Grade II-IV AGVHD was similar in ABA2 vs controls (44.9% in ABA2 vs 53% in CNI+MTX and 45% in +ATG, p= 0.08 and 0.36). CGVHD was also similar: 40% at 12 months in ABA2 vs 41% in CNI+MTX and 37% in +ATG (p =ns). Importantly, the reduction in severe AGVHD in ABA2 was achieved without significant impact on patient safety, resulting in striking improvement in 12 month TRM (12.5% vs 34% in CNI+MTX and 27% in +ATG (p = 0.002 and 0.04, Fig. 1B, 2B). Also noteworthy, there was no increase in relapse in ABA2, with 7.5% relapse at 12 months compared to 15% in CNI+MTX and 11% in +ATG (p=0.04 and 0.26). Detailed analyses of viral reactivation and other infectious outcomes are ongoing, but uncontrolled infections were not a major problem. This led to very promising rates of DFS and OS in ABA2: 81% 12 month DFS, which was better than both CNI+MTX (50%) and +ATG (63%), p=0.0003 and 0.016, Fig. 1C, 2C). The same was true for OS: 85.4% OS at 12 months in ABA2, vs CNI+MTX (57%) and +ATG (68%, p=0.0025 and 0.048 respectively, Fig. 1D, 2D). These survival advantages are stable thus-far through 2 years.Our results strongly suggest that the administration of 4 doses of abatacept for GVHD prophylaxis is safe and highly effective at preventing severe AGVHD, lessens the risk for TRM and improves survival in MMURD HCT for heme malignancies. Our results also suggest that the administration of 4 doses of abatacept prior to day +30 may not be sufficient to impact CGVHD, thus trials to assess the effect of longer courses of abatacept are warranted. These results are the first to demonstrate significant efficacy of in vivo T cell costimulation blockade in enhancing outcomes after MMURD HCT, which could significantly expand the donor pool and improve outcomes for patients requiring these high-risk transplants. [Display omitted] DisclosuresNorkin:Celgene: Honoraria, Research Funding. Pulsipher:Jazz Pharmaceuticals: Other: advisory board, education; CSL Behring: Other: advisory board Feb 2017; Chimerix: Other: Advisory board Dec 2015; Novartis Pharmaceuticals Corporation: Consultancy, Other: Phase II steering committee; Adaptive: Other: Advisory board 6/17. Kean:Juno: Research Funding; Regeneron: Research Funding; Kymab Ltd: Research Funding; Bristol Myers Squibb: Consultancy.

Earnings management, corporate governance, and ownership structure of Philippine initial public offerings

Prior studies examined the effect of corporate governance variables on discretionary current accrual, the most widely used measurement of earnings management. The principal-agent conflict implies that the size of the board, the percent of independent directors, CEO duality, and auditor prestige limit discretionary current accruals (DCA). This paper extends past studies by examining the effect of ownership structure on discretionary current accruals. The study determines the level of income-increasing earnings management of initial public offerings (IPOs) in the Philippines and the factors that explain it. Particularly, the paper examines the effect of ownership concentration and largest shareholder ownership on discretionary current accruals. The study uses a final sample of 105 IPO firms in Philippine Stock Exchange (PSE) from 2008 to 2018. Employing the modified Jones’s (1991) model to measure discretionary current accrual and multiple regression analysis, the study finds -4.19% discretionary current accrual on the average. It also reveals that the 2002 Philippine Code of Corporate Governance (PCCG) is ineffective in curbing earnings management. In addition, there is an insignificant relationship between the size of the board, CEO duality, ownership concentration, largest shareholder ownership and auditor prestige, and earnings management. Furthermore, the paper finds a significant relationship between the percent of independent directors, industry sector, return on assets (ROA) and cash flow from operations and earnings management.

Abstract A083: Diversifying breast cancer clinical trial accrual: An approach to recruitment at a Comprehensive Cancer Center

Abstract Background: Breast cancer (BC) prevention clinical trials (CTs) play a vital role in the progress of preventative measures and treatments for all races and ethnicities. However, Northern European whites (NE/W) continue to be disproportionally enrolled (e.g., 93.5% were non-Hispanic white in the STAR trial), while minorities such as Asians, blacks, Latinas, and Native Americans (NA) lag in participation. Current studies suggest that minorities are not approached as frequently as NE/W; however, they are just as willing to participate. Here we present a successful recruitment strategy to improving minority accrual in CTs at a Comprehensive Cancer Center located in Duarte, CA. Method: Results from community focus groups suggested the need to mentor local youth who strive to pursue a career in the medical field. Consequently, from February 2016 to July 2018, four bilingual, bicultural clinical research assistants (CRAs) were recruited from the catchment area of City of Hope (CoH). The CRAs, in collaboration with seven surgeons, two radiologists, and one medical oncologist, led the recruitment for three nontherapeutic BC prevention CTs at CoH. Results: All four CRAs were 1) first-generation American, 2) fluent in Spanish or Vietnamese, 3) born and raised in Southern California, and 4) pre-health. Of the 3,148 patients who were screened, 398 were eligible for enrollment, 369 consented, and 58 declined. Primary languages and races/ethnicities of those who declined include the following: 7% Armenian, 9% Chinese, 78% English, 2% Thai, and 5% Spanish; 28% Asian, 3% black, 28% Latina, 2% NA, and 67% white (22% NE, 17% Middle Eastern/North African). Demographics of the consenting population include the following: primary language - >1% Armenian, 4% Chinese, 89% English, >1% Korean, and 7% Spanish; race/ethnicity - 14% Asian, 6% black, 30% Latina, 5% NA, and 75% white (40% NE). Of the white population (n = 277), 11% were Middle Eastern/North African, 53% NE, and 36% Latina. Accrual surpassed both the CoH catchment area (11.3% Asian, 8% black, 24% Hispanic, 1% NA, and 32% NE/W) and the CoH interventional/nontherapeutic CT population (10% Asian/Pacific Islander, 4% black, 21% Hispanic, >1% NA, and 55% NE/W). Conclusion: Contrary to current accrual of CTs, here we show that minorities can have a large representation in CT accrual, as long as they are provided the opportunity. Accrual of Asians, Latinas, and NAs exceeded the catchment area and accrual of other CoH CTs. Interestingly, Chinese-speaking women comprised the highest declination group of the non-English speakers, and Asians and Latinas declined the most outside of non-whites. Cultural competency and bilingualism appear to be characteristics of a CRA that may help in accruing minority women into CTs. Our findings suggest that they are just as willing to participate, and the first step is to simply ask. Citation Format: Tanya A. Chavez, Christine Thai, Angelica Sanchez, Laura L. Kruper, Veronica C. Jones, Sharon Clancy, Amy C. Polverini, Lisa D. Yee, Courtney A. Vito, Noé R. Chávez, Alan Nuñez, Ellen J. Rippberger, Angela K. Wong, Karen Herold, Chidimma M.K. Kalu, Jackelyn A. Alva-Ornelas, Jerneja Tomsic, Krista M. Round, Margarita Robles, Ombeni Idassi, Kendall J. Kennedy, Terry Hyslop, Carola M. Zalles, Christopher Sistrunk, Victoria L. Seewaldt. Diversifying breast cancer clinical trial accrual: An approach to recruitment at a Comprehensive Cancer Center [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A083.

The Role of Accruals in the Prediction of Future Earnings

Although past accruals can explain current earnings, whether current accruals can predict future earnings has not been examined. I introduce three regression-based prediction models to predict future earnings: using only cash flows only, both cash flows and accruals, and earnings, to determine whether current accruals contribute to the prediction of future earnings. I find a cash flows and accruals model is more precise than a cash flows-only model, but the earnings model is the most precise. This result suggests that current earnings are a more accurate predictor of future earnings, and that accruals’ persistence is less important in prediction of future earnings. I also document that predictions based on these models are more precise than time series-based predictions, but not as precise as analysts’ forecasts. Additionally, I investigate how current earnings management negatively affects prediction of future earnings and hypothesize that current accrual management and real earnings management are positively associated with the prediction errors of the three models. The result shows that only the measure of real earnings management is positively associated with prediction error.

The implementation of good corporate governance model and auditor independence in earnings' quality improvement

The general objective of this research is to explore the model of earnings quality monitoring and to examine the effect of auditor independence on the relationship between corporate governance mechanism and earnings quality. Specifically, this research is aimed to investigate the impact of ownership structure, commissioner board structure, audit committee structure, internal audit function, and internal control activity, on earnings quality by involving an interaction of these variables with auditor independence. Earnings quality is measured with two proxies. The first proxy is performance-adjusted discretionary accruals or also called Total Accrual, while the second utilizes Total Current Accrual. Achieving all objectives above, the author develops a model and analyses this model in two stages. In the first stage, the model is explored using analysis technique of correlation and regression. Second, fittingness of model is attested using regression analysis with a variety of variable controls and sample controls. Research object is the manufacture companies listed in Indonesia Stock Exchange in period 2011-2015. The Sample includes 112 companies with 560 data of research. After conducting outlier test, the suitable amount of data is 553. The Result of hypothesis test indicates that the model of earnings quality monitoring is constructed from the interaction of many variables. Corporate governance mechanism consists of variables such as ownership structure (managerial ownership and institutional ownership), commissioner board structure, audit committee structure, internal audit function, and internal control activity. Adjusted R-Square value is reaching for 3.3% with significance-value of 0.001. Partially, commissioner board structure, internal audit function, and internal control activity have a significant effect on earnings quality. Auditor independence does not moderate the impact of corporate governance components on earnings quality.

Stock return predictability when growth and accrual measures are negatively correlated

Purpose For most companies, growth measures such as asset growth are positively correlated with accrual measures. Just like investment in fixed assets, current accrual represents one form of investment and is an integral part of a firm’s business growth. This makes it difficult to distinguish between the growth-based and earnings quality-based interpretations of the accrual effects, because high accruals can represent both high growth and inflated earnings. The purpose of this paper is to add to the literature by examining an issue that has not received much attention: the correlation between asset growth and accruals and its implication on stock return predictability. The authors address the issue using Fama and Macbeth’s (1973) cross-sectional regressions that are conditional on the correlations between the two variables. Design/methodology/approach The authors partition firms based on whether the correlation between current accrual and asset growth in the past five years is positive (ρ+) or negative (ρ−). The authors refer to these two types of firms such as “positive correlation” and “negative correlation” groups. For both groups, the authors examine whether firms with higher asset growth and higher accruals are associated with lower future stock returns. The authors implement Fama and MacBeth’s cross-sectional regressions incorporating the effect of correlations between growth and accrual measures. In addition, the authors regress hedge portfolio returns on Fama and French (1993) three-factor and Fama and French (2015) five-factor models to see if the intercepts (a’s) from these regressions are significantly different from 0. Findings For each year, the authors partition firms based on whether the correlation between asset growth and current accrual is positive or negative. For both the “positive correlation” and “negative correlation” firms, the authors examine the association between accruals and future stock returns. The authors find that accruals remain strong in predicting future stock returns for both groups. The accrual effects from the “negative correlation” group cannot be attributed to the growth-based hypothesis because for these firms, when accruals are high, growth measures tend to be relatively low and vice versa. The effects are most likely driven by the alternative hypothesis that investors overvalue the accrual part of earnings. Research limitations/implications There exist a few issues when investors actually implement these strategies. These include liquidity costs, institutional holdings and short sale constraints. Lesmond (2008) concludes that the bulk of the trading profits is derived from the short side of the trade, but that this position suffers from high liquidity costs that reduces institutional holdings with consequent short sale constraints. The net gains after taking into account these issues remain an open question be addressed in the future. Practical implications The empirical results indicate that investors can do an implementable portfolio strategy of going long for a year on an initially equally weighted lowest asset growth (accrual) decile portfolio and going short for a year on an initially equally weighted highest asset growth (accrual) decile portfolio, which produces significant abnormal returns. The results further show that these abnormal returns can be improved if investors classify stocks into “the positive correlation” and “negative correlation” groups and implement trading similar trading strategies. Originality/value The empirical evidence finds that firm-year observations that exhibit a negative correlation between growth and accrual measures represents a significant 30 percent of the total firm-year observations during the sample period from July 1974 to June 2017. This highlights the necessity to undertake a detailed analysis on the issue. The authors continue to find accrual effects among these groups of firms. Therefore, the accrual effect cannot be attributed to the diminishing marginal return hypothesis. This is the main contribution of the paper.

INSIGHT MM: a large, global, prospective, non-interventional, real-world study of patients with multiple myeloma.

With the introduction of new drugs with different mechanisms of action, multiple myeloma (MM) patients’ outcomes have improved. However, the efficacy seen in clinical trials is often not seen in real-world settings and data on the effectiveness of MM therapies are needed. INSIGHT MM is a prospective, global, non-interventional, observational study that is enrolling approximately 4200 patients with newly diagnosed or relapsed/refractory MM, making it the largest study of its kind to date. The study aims to describe contemporary, real-world patterns of patient characteristics, clinical disease presentation, therapies chosen, clinical outcomes (response, treatment duration, time-to-next-therapy, progression-free and overall survival), safety, healthcare resource utilization and quality of life. One interim analysis has been conducted to date; current accrual is approximately 3094 patients. Trial registration number: NCT02761187

Abstract OT2-04-04: Multi-institution phase II trial of intraoperative electron beam radiotherapy boost at the time of breast conserving surgery with oncoplastic reconstruction in women with early-stage breast cancer

Abstract Background: In women amenable to breast conserving therapy, lumpectomy followed by adjuvant whole breast irradiation (WBI) remains the standard of care. Randomized trials demonstrate that addition of a lumpectomy cavity boost significantly reduces the risk of ipsilateral breast tumor recurrences but also increases the risk of breast fibrosis. Contemporary randomized trials define the lumpectomy cavity boost volume as a 1.7 cm isometric expansion on the lumpectomy cavity as delineated on CT. However, identifying the lumpectomy cavity can be challenging, especially in women that receive adjuvant chemotherapy and in cases in which surgical clips are not present. Recently, the use of oncoplastic techniques in breast conserving surgery has increased. These techniques are used to prevent the poor cosmetic results that can occur when a large volume of breast tissue is resected. Women that undergo oncoplastic reconstruction represent especially difficult cases for lumpectomy cavity delineation. Retrospective series have evaluated the use of intraoperative electron radiotherapy (IOERT) as a boost prior to WBI in women receiving lumpectomy without oncoplastic reconstruction. In the largest series of IOERT boost prior to WBI the local control rate of this approach was >99%. Prospective data regarding IOERT boost in women undergoing oncoplastic reconstruction are limited. The advantages of this approach include direct visualization/irradiation of the tumor bed, sparing the skin of irradiation, and reducing the treatment time by ˜1 week. We hypothesize that IOERT boost followed by WBI will result in acceptably low rates of grade 3 fibrosis in women undergoing lumpectomy with oncoplastic reconstruction. Trial Design: This is a single-arm, prospective study to evaluate the safety, toxicity and efficacy of IOERT boost at the time of breast conserving surgery in women with early-stage breast cancer undergoing oncoplastic reconstruction. Eligible women will receive 1 dose of 8 Gy to the surgical bed after lumpectomy but prior to oncoplastic reconstruction. Women will then receive adjuvant WBI of 40 Gy in 15 fractions or 50 Gy in 25 fractions. Eligibility: Key criteria include age≥18 yo, clinically node-negative stage I/II, any breast cancer subtype. Specific Aims: To determine the rate of grade 3 breast fibrosis at 1 year. Additional aims include surgical complication rates, cosmesis, and local regional cancer control. Statistical Methods: Safety will be evaluated by the rate of surgical complications necessitating hospital readmission or return to the operating room within 30 days of surgery+IOERT. If ≥4 events in the first 10 patients, ≥7 events in the first 20 patients, or ≥9 events in the first 30 patients are seen, the study will be halted. We hypothesize that the grade 3 fibrosis rate in our study will be ≤5%. Assuming an actual rate of 4%, an unacceptable rate of 9%, and a drop-out rate of 10%, the expected sample size is 176. Sites: Ohio State University, Avera Medical Group, University of North Carolina-Chapel Hill Patient Accrual: Current accrual is 5/176. Contact Information: Jose Bazan (jose.bazan2@osumc.edu) Funding Source: Intraop Medical Citation Format: Bazan JG, Stephens J, Agnese D, Skoracki R, Arneson K, Reiland J, Gupta G, Gallagher K, McElroy S, Gupta N, White JR. Multi-institution phase II trial of intraoperative electron beam radiotherapy boost at the time of breast conserving surgery with oncoplastic reconstruction in women with early-stage breast cancer [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 OT2-04-04.

Abstract OT2-03-01: Multi-institution phase II trial of intraoperative electron beam radiotherapy boost at the time of breast conserving surgery with oncoplastic reconstruction in women with early-Stage breast cancer

Abstract Background: In women amenable to breast conserving therapy, lumpectomy followed by adjuvant whole breast irradiation (WBI) remains the standard of care. Randomized trials have demonstrated that the addition of a lumpectomy cavity boost significantly reduces the risk of ipsilateral breast tumor recurrences but also increases the risk of breast fibrosis. Contemporary randomized trials define the lumpectomy cavity boost volume as a 1.7 cm isometric expansion on the lumpectomy cavity as delineated on CT. However, identifying the lumpectomy cavity can be challenging, especially in women that receive adjuvant chemotherapy and in cases in which surgical clips are not present. Recently, the use of oncoplastic techniques in breast conserving surgery has increased. These techniques are used to prevent the poor cosmetic results that can occur when a large volume of breast tissue is resected. Women that undergo oncoplastic reconstruction represent especially difficult cases for lumpectomy cavity delineation. Retrospective series have evaluated the use of intraoperative electron radiotherapy (IOERT) as a boost prior to WBI in women receiving lumpectomy without oncoplastic reconstruction. In the largest series of IOERT boost prior to WBI the local control rate of this approach was >99%. Prospective data regarding IOERT boost in women undergoing oncoplastic reconstruction are limited. Advantages of this approach include direct visualization/irradiation of the tumor bed, sparing the skin of irradiation, and reducing the treatment time by ˜1 week. We hypothesize that IOERT boost followed by WBI will result in acceptably low rates of grade 3 fibrosis in women undergoing lumpectomy with oncoplastic reconstruction. Trial Design: This is a single-arm, prospective study to evaluate the safety, toxicity and efficacy of IOERT boost at the time of breast conserving surgery in women with early-stage breast cancer undergoing oncoplastic reconstruction. Eligible women will receive 1 dose of 8 Gy to the surgical bed after lumpectomy but prior to oncoplastic reconstruction. Women will then receive adjuvant WBI of 40 Gy in 15 fractions or 50 Gy in 25 fractions. Eligibility: Key inclusion criteria include age≥18 yo, clinically node-negative stage I/II, any breast cancer subtype. Specific Aims: Our primary aim is to determine the rate of grade 3 breast fibrosis at 1 year. Additional aims include surgical complication rates, cosmesis, and local regional cancer control. Statistical Methods: Safety will be evaluated by the rate of surgical complications necessitating hospital readmission or return to the operating room within 30 days of surgery+IOERT. If ≥4 events in the first 10 patients, ≥7 events in the first 20 patients, or ≥9 events in the first 30 patients are seen, the study will be halted. We hypothesize that the grade 3 fibrosis rate in our study will be ≤5%. Assuming an actual rate of 4%, an unacceptable rate of 9%, and a drop-out rate of 10%, the expected sample size is 176. Patient Accrual: Current accrual is 0 of 176. Contact Information: Soyhum McElroy (soyhun.mcelroy@osumc.edu) or Jose Bazan (jose.bazan2@osumc.edu) Funding Source: Intraop Medical Citation Format: Bazan JG, Stephens J, Terando A, Skoracki R, McElroy S, Sexton J, Gupta N, White J. Multi-institution phase II trial of intraoperative electron beam radiotherapy boost at the time of breast conserving surgery with oncoplastic reconstruction in women with early-Stage breast cancer [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 OT2-03-01.

Abstract OT3-04-03: PARTNER randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

Abstract Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC subgroup show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Trial design: 3 stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Methods: Stage 1 Safety: both research arms combined. Stage 2 Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pickthewinner” design with 53 patients in each research arm. This allows a 90% power, 5% onesided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3 Efficacy:anticipated pCR ˜55-60% for all trial patients and ˜60-65% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure required gBRCA patients are enrolled. Enrichment design is applied with overall significance level 0.05(α) = 0.025(αall)+ 0.025(αgBRCA) and 80% power. Target accrual: 527 [gBRCA 220] Current accrual: 56 Sites activated: 15 [expected number of sites 30-50]. Citation Format: Abraham J, Vallier A-L, Qian W, Grybowicz L, Thomas S, Machin A, Harvey C, Chiu E, McAdam K, Hughes-Davies L, Roylance R, Copson E, Armstrong A, Provenzano E, Tischkowitz M, McMurtry E, Earl H. PARTNER randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [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 OT3-04-03.