Ipsilateral Breast Recurrence 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.

A phase III randomized trial of radiotherapy optimization for low-risk HER2-positive breast cancer (HERO): NRG-BR008.

TPS613 Background: Breast radiotherapy (RT) is the standard of care for patients with early-stage breast cancer (BC) who undergo breast-conserving surgery (BCS). However, the magnitude of benefit of RT is less clear in BCS patients with low-risk disease who receive effective systemic therapy. Among patients with early-stage HER2-positive (HER2+) BC, 10-year locoregional recurrence has been reported as low as 1.5% following BCS, adjuvant chemotherapy and HER2-targeted therapy, and RT. Given these exceedingly favorable outcomes, with the addition of HER2-directed therapy, we seek to evaluate the feasibility of omitting RT among patients with early-stage HER2+ BC following BCS and appropriate systemic therapy. Methods: This is a phase III randomized trial for patients ≥40 years with early-stage, node-negative, HER2+ (IHC/FISH) BC treated with BCS with negative margins and sentinel lymph node biopsy or axillary dissection. Patients undergoing primary surgery must have pathologic T1 (≤2 cm) N0 disease, while patients receiving neoadjuvant therapy must have clinical T1-2 (with radiographically T≤3.0 cm) N0 disease and exhibit a pathologic complete response (ypT0N0) at surgery. All patients must receive cytotoxic chemotherapy and HER2-targeted therapy, either in the adjuvant or neoadjuvant setting. Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1 cm), estrogen-receptor status (positive; negative), and systemic therapy sequencing (adjuvant vneoadjuvant). Patients will be randomized to standard breast RT in addition to continuation of trastuzumab to complete one year of treatment (Arm 1), or trastuzumab alone (Arm 2). Endocrine therapy will be recommended for patients with hormone-receptor positive tumors. The primary endpoint is the recurrence-free interval (RFI). Secondary endpoints include time to ipsilateral breast recurrence, locoregional recurrence, disease-free survival, and overall survival, in addition to the 7-year ipsilateral breast recurrence rate among those not receiving RT. A health-related quality of life sub-study will assess differences in patient-reported breast pain and worry. We estimate a 7-year RFI of 97.5% with RT and allow for a clinically acceptable decrement of 3.63% without RT (7-year RFI of 93.87%; HR 2.5) to establish omission of RT as non-inferior. NRG-BR008 aims to enroll 1,300 patients over 4.5 years, yielding 80% power to detect the non-inferiority of RT omission with a one-sided α=0.05. We expect to observe the required 38 RFI events within 6 years of additional follow-up. The NRG-BR008/HERO trial opened to accrual in March 2023. Accrual is 13/1,300 as of 02-05-2024. Clinical trial information: NCT05705401 .

Abstract PO1-22-09: Current margin assessment practice for breast-conserving surgery in China: a single institution audit

Abstract Background The appropriate negative margin width following breast-conserving surgery (BCS) for both ductal carcinoma in situ (DCIS) and invasive carcinoma (IC) has witnessed a shift towards de-escalation in international guidelines. However, there are limited nationwide data regarding margin assessment practice for BCS in China. This study aims to clarify the current real-world status of margin assessment from a single institution audit and secondarily to update the evidence on the association between margin width and local recurrence. Methods Eligible cases were derived from an extensive series of consecutive unselected patients with early invasive breast cancer who were treated with BCS at the Department of Breast Surgery in Shanghai Cancer Center Fudan University (FUSCC) between January 2015 and December 2017. Patient demographic and clinicopathological information as well as follow-up data were extracted from the hospital's electronic medical records. Pathological evaluation of negative margins was defined as no ink on tumor for IC in accordance with the SSO/ASTRO consensus guidelines released in 2014. Where applicable, margins were categorized as tumor on ink (involved), close margins (no tumor on ink but ≤1 mm), clear margins (1-2 mm), wide margins (2-5 mm), and wider margins (>5 mm). The positive margin rate (PMR), reoperation rate, and ipsilateral breast recurrence (IBR) rate were calculated according to different margin widths. Multivariable analyses of factors associated with re-excision were performed using binary logistic regression. Kaplan‒Meier survival curve analysis was performed for local recurrence-free survival (LRFS). Results A total of 2707 patients were enrolled in the current study, with a total PMR of 2.7%. The distribution of margin width revealed that wider margins (>5 mm) were optimized by most surgical oncologists (2092/2707, 77.3%) for BCS in our center. Additionally, the reoperation rates were 1.9% in the whole population, accounting for 48.3%, 7.5%, 4.2%, 0.8%, and 0.4% in each margin group. Specifically, among 247 patients with margins ≤2 mm, 41 (16.6%) received reoperation either by margin re-excision or mastectomy. Multivariable analyses identified that lobular histology, no selective additional resection and in situ pathology of involved/close margins are independent factors of re-excision recommendation. With a median follow-up of 54.3 months, the incidence of IBR was 1.7% in the whole cohort, representing for 5.2%, 4.2%, 2.8%, 1.9%, and 1.3% in each margin group, respectively. Kaplan‒Meier survival curve analysis showed a marginally significant difference in 5-year LRFS between groups with margins >2 mm and margins ≤2 mm (95.9% vs 97.8%, Table 1). Conclusions A wider margin width was preferably adopted in the routine practice of BCS. Our audit was aligned with previous evidence that a minimum clear margin of 2 mm is associated with a lower reoperation rate but favorable local control. Patients with margins no more than 2 mm were more likely to have re-excision in cases of lobular histology, no selective additional resection, and in situ pathology of involved/close margins. Ipsilateral breast recurrence models by margin status Citation Format: Feilin Qu, Cheng-Jia Shen, Wen-Tao Yang, Jun-Jie Li, Guangyu Liu, Zhi-Ming Shao. Current margin assessment practice for breast-conserving surgery in China: a single institution audit [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 PO1-22-09.

Abstract PO1-19-01: NRG-BR008: A Phase III Randomized Trial of Radiotherapy Optimization for Low-risk HER2-positive Breast Cancer (HERO)

Abstract Background: Breast radiotherapy (RT) is the standard of care for patients with early-stage breast cancer (BC) who undergo breast-conserving surgery (BCS). However, the magnitude of benefit of RT is less clear in BCS patients with low-risk disease who receive effective systemic therapy. Among patients with early-stage HER2-positive (HER2+) BC, 10-year locoregional recurrence has been reported as low as 1.5% following BCS, adjuvant chemotherapy and HER2-targeted therapy, and RT. Given these exceedingly favorable outcomes, with the addition of HER2-directed therapy, we seek to evaluate the feasibility of omitting RT among patients with early-stage HER2+ BC following BCS and appropriate systemic therapy. Methods: This is a phase III randomized trial for patients ≥40 years with early-stage, node-negative HER2+ (IHC/FISH) BC treated with BCS with negative margins and sentinel lymph node biopsy or axillary dissection. Patients undergoing primary surgery must have pathologic T1 (< 2 cm) N0 disease, while patients receiving neoadjuvant therapy must have clinical T1-2 (with radiographically T< 3.0 cm) N0 disease and exhibit a pathologic complete response (ypT0N0) at surgery. All patients must receive cytotoxic chemotherapy and HER2-targeted therapy, either in the adjuvant or neoadjuvant setting. Stratification is by age (< 60; ≥60), tumor size (≤1 cm; >1 cm), estrogen-receptor status (positive; negative), and systemic therapy sequencing (adjuvant vs neoadjuvant). Patients will be randomized to standard breast RT in addition to continuation of trastuzumab to complete a year of treatment (Arm 1), or trastuzumab alone (Arm 2). Endocrine therapy will be recommended for patients with hormone-receptor positive tumors. The primary endpoint is the recurrence-free interval (RFI). Secondary endpoints include the time to ipsilateral breast recurrence, locoregional recurrence, disease-free survival, and overall survival, in addition to the 7-year ipsilateral breast recurrence rate among those not receiving RT. A health-related quality of life sub-study will assess differences in patient-reported breast pain and worry. We estimate a 7-year RFI of 97.5% with RT and allow for a clinically acceptable decrement of 3.63% without RT (7-year RFI of 93.87%; HR 2.5) to establish omission of RT as non-inferior. NRG-BR008 aims to enroll 1,300 patients over 4.5 years, yielding 80% power to detect the non-inferiority of RT omission with a one-sided α=0.05. We expect to observe the required 38 RFI events within 6 years of additional follow-up. The NRG-BR008/HERO trial opened to accrual in March, 2023. NCT05705401. Support: U10CA180868, -180822, UG1CA189867, U24CA196067; Susan G. Komen Foundation (JR) Citation Format: Lior Braunstein, Melissa Mitchell, Hanna Bandos, William Sikov, Atif Khan, Peter Chen, Patricia Ganz, Reshma Jagsi, Julia White, Reena Cecchini, Hyejoo Kang, Shannon Puhalla, Kelly Bolton, Eileen Connolly, Erica Stringer-Reasor, Kimberly Gergelis, Thomas Julian, Eleftherios Mamounas, Norman Wolmark. NRG-BR008: A Phase III Randomized Trial of Radiotherapy Optimization for Low-risk HER2-positive Breast Cancer (HERO) [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 PO1-19-01.

Abstract PO5-23-05: The Impact of Bi-Annual Diagnostic Imaging on Detecting Ipsilateral Breast Recurrence in Patients Undergoing Breast Conserving Surgery for Breast Cancer

Abstract Introduction: Breast conserving surgery (BCS) represents the preferred option for surgical treatment for a majority of patients with early-stage breast cancer who are eligible for this approach. When compared with mastectomy approaches, BCS provides patients with equivalent survival while preserving the affected breast. It is necessary to achieve clear surgical margins as positive lumpectomy margins are associated with an increased risk for ipsilateral breast tumor recurrence. With advances in imaging techniques, as well as effective systemic therapy and contemporary radiation therapy, local recurrence after BCS has decreased and overall survival for patients has improved. Retrospective studies have quantified the recurrence rate in unifocal breast cancer as 8 - 15% at 20 years. The NCCN recommends annual mammography at least 6 months after post-lumpectomy radiation therapy, but there is little data regarding more frequent surveillance after lumpectomy in the early post-operative setting. The purpose of this study was to evaluate the impact of short interval surveillance mammography on the detection of early in-breast recurrence in patients undergoing BCS. Methods: Our IRB-approved Breast Cancer Database was queried for patients enrolled from 11/2009 to 6/2023 who underwent breast conservation surgery for a diagnosis of in situ or invasive breast cancer in this retrospective analysis. Per our institutional protocol, patients were recommended to undergo diagnostic mammography of the treated breast(s) every 6 months for 2 years after BCS. After the initial 2 year period, bilateral mammography was performed annually in the absence of other indications. Additional supplemental imaging such as breast ultrasound and MRI were performed at physician discretion and based on patient risk and breast density. Variables of interest included the presence of pathogenic germline mutations, family history of breast cancer, and disease characteristics. Our primary endpoint was ipsilateral breast tumor recurrence. Results: Of 2491 patients who underwent breast conservation surgery for in situ or invasive breast cancer, 191 (7.7%) developed recurrent disease, including ipsilateral and contralateral recurrence, and distant disease, in the study period. A total of 83 (3.2%) patients developed ipsilateral breast recurrence during the entire study period. Of those, 19 (22.9%) were detected within the first two years after surgery. Six of the 19 patients (31.6%) had their recurrences detected on yearly diagnostic mammography while 6 (31.6%) patients had their recurrences detected on interval 6-month unilateral diagnostic imaging. In both groups, 5/6 recurrences were invasive disease after an original diagnosis of invasive cancer, and the remaining patient had recurrent DCIS. The remaining 7/19 patients (36.8%) had their ipsilateral recurrences detected on palpation or other diagnostic imaging. In this group as well, there was one case of recurrent DCIS, with the remaining 6 cases representing recurrent invasive cancer. Of the 19 patients with ipsilateral recurrences, none had pathogenic germline mutations. 4 of the 19 patients (21%) had positive margins after their initial lumpectomy surgery with re- excisions required to achieve clear margins. Conclusion: Interval diagnostic surveillance imaging every 6 months after breast conserving surgery identified almost one-third of the ipsilateral breast tumor recurrences that occurred within the first 2 years after surgery in our population. While our numbers are small, the relationship of re-excision lumpectomy surgery to subsequent risk for local recurrence has been described by others, and bears further study. Particularly in view of our observation that the majority of in-breast recurrences were invasive, our data supports the practice of more frequent imaging follow up in the first 2 years after breast conserving surgery. Citation Format: Pabel Miah, Laura Fiedler, Anthony Baez, Athanasios Sevdalis, Alyssa Marmer, Charles DiMaggio, Linda Pak, Richard Shapiro, Karen Hiotis, Deborah Axelrod, Amber Guth, Freya Schnabel. The Impact of Bi-Annual Diagnostic Imaging on Detecting Ipsilateral Breast Recurrence in Patients Undergoing Breast Conserving Surgery for Breast Cancer [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 PO5-23-05.

Abstract PO4-23-02: Blue Dye-Only for Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy in Patients with Initially Node-positive Breast Cancer

Abstract Importance: Randomized trials evaluated the false negative rate (FNR) of sentinel lymph node biopsy (SLNB) in initially node-positive (cN1/2) breast cancer (BC) patients who downstaged after neoadjuvant chemotherapy (NAC): the studies were negative, as they found FNR above 10%. However, the FNR was adequate when the lymph node was marked with a clip before NAC or at least 3 lymph nodes were removed. SLNB using a combination of blue dye and a radiotracer (Technetium-99) was encouraged to facilitate identification and maximize SLNB results in this scenario. However, radiotracer is unavailable in many services around the world, particularly in low- and middle-income countries (LMIC), but the feasibility and the recurrence rates of SNLB with the use of blue dye-only, in previous cN1/2 patients, are unknown. Objective: The aim of this study was to evaluate the feasibility, proportion of patients undergoing SLNB without axillary dissection (AD) and mean number of resected sentinel nodes (SN), and recurrence rates (axillary recurrence [AR], ipsilateral breast recurrence [IBR], new contralateral primary, disease-free survival [DFS] and overall survival [OS]) of SNLB with the use of blue dye-only in initially node-positive BC (cN1/2). Design, Setting, and Participants: From 2013 to 2023, a cohort of patients undergoing NAC was evaluated at a public institution in Brazil (Hospital Geral de Fortaleza - HGF). Radiotracer and clips were not available. Patients with prior cN1/2 were identified and evaluated. AD was not recommended in cases of negative histopathological results for lymph node metastases after SLNB using blue dye-only. Inflammatory, cN0 and cN3 BC patients were excluded. Results: Among 119 cN1/2 BC patients treated with NAC, 100 (84%) cases underwent SLNB with blue dye-only and 70 (59%) had SLNB alone. The median of SN were 3.1 and 55 (78%) cases had 3 or more SN. No events related to blue dye occurred. The median age of these 70 patients was 49 (25-84) years, and most cases were T2 (n=40/57.1%), followed by T3 (n=18/25.7%), T4 (n=6/8.6%) and T1 (n=6/8.6%), while N1 predominated in axillary status (n=64/91.4%). Regarding breast cancer subtype, there were 19 (27.1%) hormone receptor-positive/HER2-negative, 16 (22.9%) hormone receptor-negative/HER2-positive, 21 (30%) hormone receptor-positive/HER2-positive and 14 (20%) triple-negative cases. 55 (79%) patients received regimens containing anthracyclines and taxanes. Anti-HER2 therapy was used in all cases, but pertuzumab associated with trastuzumab were available in only 8 patients (8/37). Breast-conserving surgery was performed in 40 (57%) cases while total mastectomy in 30 (43%). Patients with hormone-positive BC received endocrine therapy. Adjuvant radiotherapy was made in all cases, except one who underwent mastectomy. After 36 months of median follow-up, no axillary recurrences were observed. One patient had a new primary in the contralateral breast. Three patients had distant disease and two died. Conclusions: This cohort found that the use of SLNB with blue dye-only in Initially cN1/2 BC patients who achieved complete response after NAC is feasible, with very low axillary recurrence rates, like previous reports in the literature that used a combination of tracers. These data reinforce the need for further studies in this scenario, as it maintains the possibility of avoiding AD in places with difficult access to oncological treatment, especially in LMIC. Figure 1 - Flowchart cN: Clinical node stage; BC: Breast cancer; NAC: Neoadjuvant chemotherapy; SNLB: Sentinel lymph node biopsy; AD: Axillary dissection; SN: Sentinel node Table 1 - Demographic Characteristics Citation Format: Francisco Pimentel Cavalcante, Felipe Zerwes, Alessandra Souza, Patricia Ziegelmann, Ryane Alcantara, Amanda Cardoso, Andre Mattar, Eduardo Millen, Antonio Frasson. Blue Dye-Only for Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy in Patients with Initially Node-positive Breast Cancer [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 PO4-23-02.

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.

Abstract PO2-22-03: Reirradiation for locally recurrent breast cancer: a long-term single centre experience

Abstract Background: About 10–15% of patients with breast cancer will eventually develop an ipsilateral breast recurrence. The management of cancer relapse in previously irradiated tissues is a challenging therapeutic issue, and data on breast re-irradiation are currently lacking. Hence, the aim of this work was to report our experience with breast re-irradiation for non-metastatic recurrent breast cancer. Material and Methods: All patients who underwent a breast or chest wall re-irradiation in the Institut Curie, Paris, France between 2003 and 2019 were identified. Those who underwent re-irradiation only in other volumes than the ipsilateral breast were excluded. Local recurrence-free (LRFS), overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), and metastasis-free survival (MFS) were evaluated. Physician-reported acute and late toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Results: Between 2003 and 2019, 21.372 patients underwent a breast irradiation in our institution. Of these, 453 received a new irradiation to the controlateral breast and/or lymph nodes, 105 to the homolateral lymph nodes without breast/chest wall re-irradiation and 28 received a second course of radiotherapy (RT) to the homolateral breast. These 28 patients were included in this study. Median follow up after re-irradiation was 45.5 months (IQR 33.5-79.75 months). The median age at the time of second breast RT was 63 years (IQR, 49-78). The median RT dose to the breast/chest wall was 60 Gy (interquartile range (IQR) 50-66 Gy) for the first irradiation and 48 Gy (IQR 30-50 Gy) for the second. The median cumulative dose was 100 Gy (IQR 92-114 Gy). The median time between the two courses of RT was 47 months (IQR 22.75-109.5 months). Eighteen (64%) patients were treated with a curative intent and 10 (36%) for palliative purposes. Ten (36%) had a macroscopic breast residue at re-irradiation. The second RT course was performed with electrons, photons and a combination of both in 13 (46%), 8 (29%) and 6 (21%) patients, respectively. At 2 years, LRFS, OS, DSS, PFS and MFS were respectively 59%, 79%, 82%, 50% and 75% in the whole cohort. 2-year-LRFS (72% vs 31%, p=0.02), OS (94% vs 50%, p< 0.01), DSS (94% vs 56%, p< 0.01) and PFS (61% vs 20%, p=0.02) differed significantly between patients treated in a curative or in a palliative intent, but not MFS (78% vs 69%, p=0.77). Among patients, 8 (29%) remained relapse-free 5 years after the second course of RT. Only one patient experienced an acute grade 3 adverse event (dermatitis), and 1 presented a late grade 3 one (skin fibrosis). One patient with major cardiovascular risk factors died of myocardial infarction 13 months after the second left breast irradiation. Conclusion: Breast or chest wall re-irradiation appears to be feasible with good disease control in patients treated with a curative intent, and acceptable toxicity rates. In addition, a significant number of patients were disease-free 5 years after the second course of RT. Prospective larger data with longer follow-up are needed to confirm these findings. Citation Format: Jérémy Baude, Rémi Dendale, Alain Fourquet, Youlia Kirova. Reirradiation for locally recurrent breast cancer: a long-term single centre experience [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 PO2-22-03.

Abstract PO4-08-04: Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer

Abstract Introduction: While outcomes are similar following breast-conserving surgery (BCS) or mastectomy among patients with sporadic breast cancer, data are still controversial for germline BRCA pathogenic variant carriers. We previously compared outcome following BCS between BRCA pathogenic variant carriers and non-carriers, and reported higher ipsilateral breast recurrence and comparable prognosis in the carriers. The purpose of this current study was to compare outcomes among BRCA pathogenic variant carriers undergoing BCS versus mastectomy in long-term follow-up period. Methods: Women with a BRCA pathogenic variant and a stage 0-III breast cancer who underwent definitive surgery from 1987–2021 were retrospectively identified from institutional database. Factors including clinicopathologic information and treatment characteristics were identified. Subsequent local recurrence, regional recurrence, distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) rates were compared between BCS and mastectomy using Kaplan-Meier method and log-rank test. The chi-square test and t-test were used to compare patient characteristics between the two groups. Results: A total of 232 BRCA mutation carriers with 257 cancers including 25 patients with synchronous bilateral breast cancer were identified. Surgical treatment included BCS for 82 cancers and mastectomy for 175 cancers including nipple-sparing mastectomy for 51 cancers. Patient age at surgery and cancer stage did not statistically differ between BCS and mastectomy groups. Comparing to patients choosing mastectomy, patients who underwent BCS were less likely to be aware of their genetic status before surgery and were more likely to receive radiation therapy (p < 0.001). Contralateral risk reducing mastectomy was performed in 22.5% (18/80) in the BCS group and 48.7% (74/152) in the mastectomy group (p < 0.001) concurrently or at any time after the first definitive surgery. Risk reducing salpingo-oophorectomy was performed in 40% (32/80) in the BCS group and 49% (75/152) in the mastectomy group (p = 0.17). At 7.5 years median follow-up, local recurrence rate was statistically higher in the BCS group than in the mastectomy group (20.0% in BSC vs. 4.6% in mastectomy, p = 0.043). In patients who underwent nipple-sparing mastectomy, 4.0% (2/51) had local subcutaneous recurrence and no nipple-areolar recurrence was observed. Median duration from the first definitive surgery to ipsilateral local recurrence was 10.0 years in the BCS group and 2.3 years in the mastectomy group. Regional lymph node recurrence (11.2% in BCS vs. 6.4% in mastectomy, p = 0.62), distant recurrence (13.7% vs. 9.2%, p = 0.84), CBC (15.0% vs. 8.6%, p = 0.70), BCSS (88.8% vs. 94.1%, p = 0.65) and OS (87.5% vs. 94.1%, p = 0.49) rates did not statistically differ between two groups. Conclusions: With 7.5 years median follow-up, higher local recurrence rate was observed in BCS than in mastectomy among BRCA pathogenic variant carriers. Our results found no statistical difference between BCS and mastectomy in regional recurrence, distant recurrence, CBC, and prognosis, indicating relatively higher risk in BCS. While BCS could be an option for BRCA pathogenic variant carriers willing to continue high-risk breast surveillance, shared decision making should be carefully performed based on the long-term local recurrence risk. Citation Format: Kumiko Kida, Junko Takei, Misato Suzuki, Megumi Okawa, Sakurako Kazama, Sakiko Kondo, Michiko Yamanaka, Atsushi Yoshida. Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer [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 PO4-08-04.

Abstract B083: Association of socioeconomic deprivation with breast cancer incidence, survival and ipsilateral recurrence by molecular subtype in Scotland, United Kingdom

Abstract Cancer disparities reflect the interplay of biological, environmental, and socioeconomic determinants. In the United States, disentangling racial and ethnic disparities in breast cancer (BC) including the effects of health care access and socioeconomic deprivation is challenging, given the latter highly correlated with race and ethnicity. In Scotland, United Kingdom (UK), the population is 96% White and there is a single payer National Health Service (NHS). The Scottish Index of Multiple Deprivation (SIMD) measures the extent to which a geographic area is deprived across seven domains: income, employment, education, health, access to services, crime and housing. Scotland is renowned for high-quality electronic health records including breast tumor estrogen receptor (ER) status collected since 1997 and Progesterone Receptor and HER2 since 2009, which can be linked to hospital data and mortality. To gain a better understanding of individual patients’ SIMD status (measured in quintiles) at BC diagnosis with incidence and survival, we used data on 62,378 women diagnosed with invasive BC between 2000 and 2016. For ipsilateral breast recurrence (IBR) outcomes, we used a subset of data for BC diagnosed 2007-2008 where manual case-note review was performed for 3495 patients from 10 years post-diagnosis. Screen-detected ER+ tumor incidence increased over time, particularly in the least deprived quintile [Average Annual Percentage Change = 2.9% with 95% CI from 1.2 to 4.7]. No marked differences were observed for non-screen-detected ER+ tumors or ER- tumors by SIMD. Most versus least deprived SIMD-quintile was associated with significantly higher mortality for luminal A and HER2-enriched tumors in multivariable Cox proportional hazard models adjusted for mode of detection and confounders (aHR = 1.46 [1.13, 1.88] and 2.10 [1.23, 3.59] respectively) but weaker non-significant associations for luminal B and triple negative BC tumors (aHR <1.20). Among 2,819 ER+ tumors, 423 patients had IBR (15%) and 438 died: SIMD was related to death (p=0.018) with the most deprived more likely to have died in the first decade of follow-up (17.7% vs 12.9%). We found no significant differences by SIMD in prognostic tumor characteristics (grade, TNM stage, treatment, screen-detection) or risk of IBR. Among 676 patients diagnosed with ER- tumors, 185 had IBR (27%) and 105 died: 50% had mastectomy and the most deprived had an increased 5-year IBR risk compared to the least deprived (aHR 3.03 [1.41-6.53]). Our analysis shows socioeconomic deprivation is associated with differential BC incidence trends for screen-detected ER+ tumors and higher mortality and IBR for selected tumor subtypes. The lack of inequities for triple negative tumors by SIMD and survival, and IBR for ER+ tumors may be due to standardized treatment protocols and healthcare access. The association with socioeconomic deprivation and survival for HER2+ and recurrence among ER- tumors requires further study on potential other factors such as co-morbidities and adherence to treatment. Citation Format: Ines Mesa-Eguiagaray, Hayley Dunlop, Sarah Wild, Sheila M. Bird, Linda Williams, Peter S. Hall, Jonine D. Figueroa. Association of socioeconomic deprivation with breast cancer incidence, survival and ipsilateral recurrence by molecular subtype in Scotland, United Kingdom [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B083.

Early and Intermediate Treatment Outcome After Postoperative External Beam Accelerated Partial Breast Irradiation in Patients With Early-Stage Breast Cancer

Purpose/ObjectivesTo prospectively evaluate early and intermediate outcome after APBI in early-stage breast cancer patients. Materials/MethodsInclusion criteria were defined according to the APBI ASTRO CONSENSUS STATEMENT. The prescribed dose was 26-28 Gy in 5 fractions on 5 consecutive days. Regular follow-up visits with objective and subjective evaluation of treatment tolerance were performed after 0 and 2 weeks, 6 months and at annual intervals. ResultsBetween 02/2017-01/2020, 175 patients with breast conserving surgery met the inclusion criteria for APBI. Mean age was 65.7 years (range 46-88). 13% of patients were diagnosed with DCIS/Tis, 5/35/37% with T1a/b/c, and 10% with T2 stages, respectively. The mean volume of PTV was 119 cc (range 45-465), the ratio of mean PTV: whole breast volume ratio was 21% (7-53%). Mean follow-up was 42 months (median 45, range 0 – 67). Acute toxicity after 2 weeks was low with 69/26/5% grade 0/1/2.1, 2, 3, 4 and 5-year follow-up data was available from 146/134/107/73/25 patients. Patient-reported cosmetic outcomes were assessed excellent or good in 97.9/98.5/98.1/98.6/100%.Regarding grade 2 toxicities, as by now 3/2/2/0/0% G2 fibrosis, 1/1/0/0/0% G2 atrophy, no G2 skin telangiectasia or breast edema occurred. So far, none of the patients have experienced G3 toxicity or higher. The remaining patients had grade 0 or 1 toxicity only.Five ipsilateral breast recurrences (one marginally to PTV, four out-of-field) and five distant recurrences were recorded by now (03/2023). The 4-year in-breast recurrence rate was 2.5%. Eight patients died, two of them from disease. For all patients, the 4-year overall, cancer specific and disease-free survival rates were 97.1%, 99.4%, and 95.3%, respectively. ConclusionsHerewith we showed high early and intermediate term treatment tolerance and disease control of APBI using 26-28Gy in 5f/1w in carefully selected early breast cancer patients. APBI is highly appreciated by patients and efficient, as an additional advantage for busy centers.

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.

Nipple-Sparing Mastectomy With Immediate Reconstruction After Breast-Conserving Therapy and Radiation: Complications and Oncologic Safety.

Nipple-sparing mastectomy (NSM) offers improved, patient-centered outcomes with demonstrated oncologic safety (Ann Surg Oncol 2020;27:344-351). Indications for NSM continue to expand to patients outside of the traditional eligibility criteria, including those with prior breast-conserving therapy (BCT) with radiotherapy. Currently, limited data exist evaluating both short- and long-term outcomes in patients proceeding to NSM after prior BCT. All patients undergoing bilateral NSM in a single institution from 2002 through 2017 with history of prior BCT were included in the final cohort, without exclusions. A retrospective chart review was performed to identify patient demographics, operative details, and complications. Outcomes assessed included early complications (<30 days from NSM), late complications (>30 days), rates of prosthetic failure, unplanned reoperations, and reconstructive failures, as well as oncologic safety. Student t, χ2, and Fisher exact tests were used to analyze outcomes of paired (BCT vs non-BCT) breasts within each patient. A total of 17 patients undergoing 34 NSMs were included. Each had a history of BCT and either ipsilateral breast recurrence (64.7%), risk-reducing NSM (23.5%), or a new contralateral primary cancer (11.8%). The cohort had a mean age of 51.1 years. With regard to acute complications (ischemia, infection, nipple-areolar complex or flap ischemia or necrosis, and wound dehiscence), there was no significant difference noted between breasts with prior BCT versus no prior BCT overall (41.2% vs 35.3%, respectively; P = 0.724). Complications occurring after 30 days postoperatively (capsular contracture, contour abnormality, animation deformity, bottoming out, rotation, and rippling) in prior BCT breasts versus no prior BCT had no significant differences overall (58.8% vs 41.2% respectively; P = 0.303). The mean follow-up was 5.5 years, during which no patients had a reported locoregional or distant recurrence in either breast. No significant differences in early or late complications were identified between breasts in patients undergoing bilateral NSM with a history of unilateral BCT and XRT. In the 5.5 years of follow-up, there were no recurrences, lending support to NSM for management of recurrent disease in addition to National Comprehensive Cancer Network-recommended total mastectomy. We propose that NSM should not be contraindicated in patients exposed to radiation with BCT.

Reduced-Dose Radiation Therapy and Concurrent Paclitaxel Chemotherapy in Lymph Node-Positive Breast Cancer: Long-Term Follow-up of a Single-Institution Prospective Study

Administration of concurrent chemotherapy and radiotherapy (RT) is advantageous as it addresses local disease, potential sites of metastatic disease and delivering both together may provide a synergistic effect resulting in better tumor control. The purpose of this analysis was to report long-term overall survival, disease free survival and local control from our institutional study of post-operative doxorubicin/cyclophosphamide followed by concurrent paclitaxel and reduced dose radiotherapy in patients with node-positive breast cancer. 44 women with Stage II or III pathologically confirmed node-positive breast cancer were enrolled in a Phase II, prospective, single-arm trial from June 2000 through December 2004. All patients received breast-conserving surgery and 4 cycles of doxorubicin /cyclophosphamide followed by 4 cycles of paclitaxel delivered every 3 weeks. Radiation was delivered concurrently with the first 2 cycles of paclitaxel. The diffusing capacity for carbon monoxide (DLCO) was measured to evaluate functional lung volume. Pulmonary function tests with DLCO were obtained before and after RT, after completion of chemotherapy, and annually for 5 years. At a median follow-up of 205 months, overall survival is 75% and progression free survival is 70.5%. There were 2 ipsilateral breast recurrences, both considered new primaries, yielding a local recurrence free survival of 95.5%. The two patients who experienced a local recurrence were successfully salvaged and are disease free. There were no cases of radiation pneumonitis and no significant change in the diffusing capacity for carbon monoxide. With long-term follow-up, the use of concurrent chemotherapy with low dose radiation as adjuvant treatment for node-positive breast cancer continues to demonstrate excellent disease-free survival, overall survival and local control with acceptable toxicity.

Partial Breast Irradiation Compared with Whole Breast Irradiation: A Systematic Review and Meta-Analysis.

Early stage-breast cancer is among the most common cancer diagnoses. Adjuvant radiotherapy is an essential component of breast conserving therapy, and several options exist for tailoring its extent and duration. This study assesses the comparative effectiveness of partial breast irradiation (PBI) compared with whole breast irradiation (WBI). A systematic review was completed to identify relevant randomized clinical trials (RCTs) and comparative observational studies. Independent reviewers working in pairs selected studies and extracted data. Randomized trial results were pooled using a random effects model. Prespecified main outcomes were ipsilateral breast recurrence (IBR), cosmesis, and adverse events (AEs). 14 RCTs and 6 comparative observational studies with 17,234 patients evaluated the comparative effectiveness of PBI. PBI was not significantly different from WBI for IBR at 5 years (RR 1.34 [95% CI, 0.83-2.18]; high strength of evidence [SOE]) and 10 years (RR 1.29 [95% CI, 0.87-1.91]; high SOE). Evidence for cosmetic outcomes was insufficient. Significantly fewer acute AEs were reported with PBI compared to WBI, with no significant difference in late AEs. Data from subgroups according to patient, tumor, and treatment characteristics were insufficient. Intraoperative radiotherapy was associated with higher IBR at 5, 10, and >10 years (high SOE) compared to WBI. Ipsilateral breast recurrence was not significantly different between PBI and WBI. Acute AEs were less frequent with PBI. This evidence supports the effectivness of PBI among selected patients with early-stage, favorable risk breast cancer who are similar to those represented in the included studies.

Association of quantitative MRI features of DCIS with surgical upstaging and recurrence after treatment.

e12540 Background: Ductal carcinoma in situ (DCIS) is a common preinvasive breast cancer typically identified on screening mammography. Pure DCIS is nonlethal, but 20-25% of DCIS cases identified on core biopsy upstage to invasive cancer at surgery and about half progress to invasive disease if not treated. As a result, most DCIS patients undergo excision and radiation therapy. DCIS score is a multigene assay that can aid in radiation treatment decision-making and serve as a surrogate marker of ipsilateral breast recurrence (IBR) risk. Breast MRI can accurately depict DCIS span and has potential to assess biology and IBR risk. We sought to assess the associations of advanced quantitative MRI features with upstaging and DCIS score. Methods: In this IRB-approved single institution prospective clinical trial, patients recommended for biopsy of calcifications or those who had residual calcifications after a biopsy yielding pure DCIS consented to receive a multiparametric breast MRI (dynamic contrast-enhanced and diffusion-weighted) prior to surgery. The following quantitative MRI features were obtained: functional tumor volume (FTV), volume transfer constant (Ktrans), extracellular extravascular volume fraction (ve), background parenchymal enhancement (BPE), and apparent diffusion coefficient (ADC). Patients with biopsy-proven DCIS were followed through completion of surgery to determine upstaging. DCIS score was performed in those with sufficient excision-proven pure DCIS. Associations of MRI features with invasive upstaging and DCIS score and were evaluated by Spearman’s correlation and the Wilcoxon rank-sum test. Results: Of the 120 patients enrolled in the study, 57 (48%) were diagnosed with pure DCIS on core biopsy. Fifty-five patients underwent surgery, 13 of whom (24%) upstaged to invasive disease. Thirty-eight pure DCIS lesions had sufficient tissue to generate a DCIS Score. Several MRI features were associated with upstaging and DCIS Score: Ktrans (p &lt; 0.01) was significantly higher in lesions that upstaged to invasive disease. Higher DCIS scores were associated with lower Ktrans (p = 0.04) and ve (p = 0.05) values. No statistically significant associations were observed between FTV, BPE, or ADC and invasive upstaging or DCIS Score. Conclusions: This trial suggests advanced quantitative MRI features may help identify DCIS lesions at risk for upstaging to invasive disease and IBR. Specifically, an imaging feature of vascular permeability (Ktrans) showed an expected positive association with upstaging. Imaging features of vascular permeability (Ktrans and ve) showed counterintuitive inverse associations with DCIS Scores. Future research in larger cohorts is needed to validate these findings, better determine the biological reasons for these associations, and determine whether MRI features can be used clinically to optimize DCIS treatment. Clinical trial information: NCT03495011 .

Comparison of conventional clinical models and a multigene assay to assess DCIS risk in a prospective single center study.

e12578 Background: Ductal carcinoma in situ (DCIS) is a preinvasive breast cancer typically excised and treated with adjuvant therapy. While there is consensus that this results in overtreatment, there is little agreement on who may avoid radiation or endocrine therapy. Two freely available prediction models, Van Nuys Prognostic Index (VNPI) and Memorial Sloan Kettering Nomogram (MSK-N), are commonly used to identify low-risk DCIS based on standard clinicopathological features. Oncotype DCIS is a newer commercially available tissue-based multigene assay also used to assess risk, but its use is limited due to cost and unclear value over VNPI and MSK-N. We sought to compare these tests’ agreement in determining DCIS ipsilateral breast recurrence (IBR) risk and potential to de-escalate therapy. Methods: In this subanalysis from a prospective single center clinical trial, we analyzed 38 patients with newly diagnosed pure DCIS confirmed at excision. Each risk assessment tool presents risk in a different manner. Oncotype DCIS provides multiple assessments: a raw score (0-100), a DCIS Score Category (low, intermediate, high), and a Refined Score incorporating clinical features (10-year IBR risk). The VNPI calculates a raw score (4-12) and assigns a risk category (low, intermediate, high). MSK-N calculates a 10-year IBR risk. The tests were dichotomized as low vs. not-low risk categories using these thresholds: DCIS Score Category = low, DCIS Refined Score ≤ 10% IBR risk, VNPI risk category = low, MSK-N ≤ 10% IBR risk. Agreement of the 4 models (DCIS Score Category, DCIS Refined Score, VNPI, MSK-N) were compared using Spearman’s rank correlation for continuous data; percent agreement and Cohen’s kappa (k) were used to compare categorized data. Results: There was poor agreement of continuous risk assessments across the 4 models, with only VNPI and DCIS Refined Score showing significant but moderate correlation (r = 0.53, p = 0.001; others ranged r = 0-0.27, p &gt; 0.1). The number of cases identified as low-risk for each assay was DCIS Score Category = 14 (37%), DCIS Refined Score = 3 (8%), VNPI = 1 (3%), and MSK-N = 0. Percent agreement of low vs. not-low risk categorizations between DCIS Refined Score, VNPI, and MSK-N was 92-97%, but each assay classified 3 or fewer cases as low-risk and kappa was not significant (k = 0-0.48, p &gt; .1). DCIS Score Category demonstrated 63-71% agreement with the other 3 assays (k = 0-0.26). Only 1 case was classified as low-risk DCIS on multiple tests. Conclusions: DCIS risk models have poor agreement for determining IBR risk. DCIS Score Category initially identified many low-risk lesions; however, inclusion of clinical features to create a Refined Score decreased this substantially, providing very few additional low-risk cases for de-escalation over VNPI or MSK-N. Additional studies are needed to determine precise IBR rates when these models are used for adjuvant therapy decision-making. Clinical trial information: NCT03495011 .

Regularly scheduled physical examinations and the detection of breast cancer recurrences.

Follow-up care of early breast cancer (EBC) patients usually includes routinely scheduled physical examinations. While ASCO guidelines recommend a physical exam every three to six months for the first three years, little evidence supports this schedule. We evaluated recurrence detection of patients transferred into a single centre survivorship program that follows ASCO recommendations. Patients with EBC referred to the Wellness Beyond Cancer Program (WBCP) who had breast cancer recurrence between February 1, 2013, and January 1, 2019 were reviewed. Descriptive analyses were used to present patient and disease characteristics stratified by type of recurrence and mode of cancer detection. Of 206 recurrences, 135 were distant recurrences (65.5%), 41 were ipsilateral breast recurrences (19.9%), and 30 were contralateral breast primaries (14.6%). Distant recurrences were primarily detected via patient-reported symptoms (125/135, 92.6%). 53.7% (22/41) of ipsilateral breast recurrences were detected by patients and 41.5% (17/41) by routine imaging. Contralateral breast primaries were primarily detected by imaging 83.3% (25/30) and patient-reported symptoms 16.7% (5/30). Only 2/206 (1.14%) recurrences/new primaries were detected by healthcare providers at routinely scheduled follow-up visits. Despite following ASCO guidelines, healthcare providers rarely detect recurrences at routinely scheduled follow-up appointments. Our data suggests that approximately 35, 000 follow-up visits were required for healthcare providers to detect these 2 recurrences. While reduced in-person visits may affect other aspects of follow-up care (e.g. toxicity management), it appears unlikely, provided patients attend regular screening tests, that less frequent in-person follow-up is associated with worse breast cancer-related outcomes.

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 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.