Omission Of Radiotherapy Research Articles

Long-term follow-up of bulky classic Hodgkin lymphoma managed with ABVD and PET-guided RT demonstrates excellent outcomes in PET-negative cases.

The outcome of 221 patients with bulky (≥10 cm) classic Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, dacarbazine and consolidative radiotherapy (RT) only in those with a positive end-of-treatment (EOT) positron emission tomography (PET) scan was evaluated. With a median follow-up of 9.6 years, 5- and 10-year progression-free survival (PFS) in EOT PET-negative cases were 94.0% and 90.4%, respectively, and in PET-positive cases, 5/10-year PFS was 64.6% (p < 0.001), with 15% overall receiving RT. Five-year PFS for Deauville (D) score DX/D1-3 was 93.6%, compared with D4 66.7% (p < 0.001) and D5 33.3% (p < 0.001). Omission of RT in EOT PET-negative cases is associated with excellent long-term outcomes in bulky cHL.

Validation of a breast cancer assay for radiotherapy omission: an individual participant data meta-analysis.

There are currently no molecular tests to identify individual breast cancers where radiotherapy (RT) offers no benefit. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify low risk cancers where RT will not further reduce recurrence rates. An individual participant data meta-analysis was performed in 623 cases of node-negative ER+/HER2-negative early breast cancer enrolled in three RT randomized trials for whom primary tumor material was available for analysis. A Cox proportional hazards model on time to locoregional recurrence (LRR) was used to test the interaction between POLAR score and RT. 429 (69%) patients' tumors had a high POLAR score and 194 (31%) had a low score. Patients with high POLAR score had, in the absence of RT, a 10-year cumulative incidence of LRR: 20% (15%-26%) vs 5% (2%-11%) for those with a low score. Patients with a high POLAR score had a large benefit from RT (hazard ratio [HR] for RT vs no RT: 0.37 [0.23-0.60], p < .001). In contrast, there was no evidence of benefit from RT for patients with a low POLAR score (HR: 0.92 [0.42-2.02], p = .832). The test for interaction between RT and POLAR was statistically significant (p = .022). POLAR is not only prognostic for locoregional recurrence but also predictive of benefit from radiotherapy in selected patients. Patients ≥ 50 years with ER+/HER2-negative disease and a low POLAR score could consider omitting adjuvant RT. Further validation in contemporary clinical cohorts is required.

Escalation and De-Escalation of Adjuvant Radiotherapy in Early Breast Cancer: Strategies for Risk-Adapted Optimization.

Postoperative radiotherapy (RT) is recommended after breast-conserving surgery and mastectomy (with risk factors). Consideration of pros and cons, including potential side effects, demands the optimization of adjuvant RT and a risk-adapted approach. There is clear de-escalation in fractionation-hypofractionation should be considered standard. For selected low-risk situations, PBI only or even the omission of RT might be appropriate. In contrast, tendencies toward escalating RT are obvious. Preoperative RT seems attractive for patients in whom breast reconstruction is planned or for defining the tumor location more precisely with the potential of giving ablative doses. Dose escalation by a (simultaneous integrated) boost or the combination with new compounds/systemic treatments may increase antitumor efficacy but also toxicity. Despite low evidence, RT for oligometastatic disease is becoming increasingly popular. The omission of axillary dissection in node-positive disease led to an escalation of regional RT. Studies are ongoing to test if any axillary treatment can be omitted and which oligometastatic patients do really benefit from RT. Besides technical improvements, the incorporation of molecular risk profiles and also the response to neoadjuvant systemic therapy have the potential to optimize the decision-making concerning if and how local and/or regional RT should be administered.

Feasibility of breast conserving surgery alone in HER2-positive exceptional responders to neoadjuvant systemic therapy

It is unknown if radiation therapy provides additional benefit among patients who achieve pathologic complete response (pCR) following neoadjuvant systemic therapy (NST). We sought to assess feasibility of radiation omission after breast conserving surgery in early-stage, node-negative, HER2+ breast cancer patients with pCR after NST. This was a single-arm study of women 30 years and older with cT2N0 disease based on imaging. Six patients were followed with mammography or MRI every 6 months following surgery. The median age of patients was 58 years (IQR: 46–66). At a median follow-up of 31.6 months (range: 21–40 months), no Ipsilateral Breast Tumor Recurrences (IBTR) were identified. This approach was found to be feasible, warranting further study in larger prospective trials.

Omission of Radiotherapy in Primary Mediastinal B-Cell Lymphoma: IELSG37 Trial Results.

The role of consolidation radiotherapy in primary mediastinal B-cell lymphoma (PMBCL) patients is controversial. The IELSG37 trial, a randomized non-inferiority study, aimed to assess whether irradiation can be omitted in PMBCL patients with complete metabolic response (CMR) after induction immunochemotherapy. Primary endpoint was progression-free survival (PFS) at 30 months post-randomization. Patients with CMR were randomly assigned to observation or consolidation radiotherapy (30 Gy). With a non-inferiority margin of 10% (assuming a 30-month PFS of 85% in both arms), a sample size of 540 patients was planned with 376 expected to be randomized. The observed events were considerably lower than expected, therefore, primary endpoint analysis was conducted when ≥95% of patients were followed for ≥30 months. Of 545 patients enrolled, 268 were in CMR after induction and were randomized to observation (n=132) or radiotherapy (n=136). The 30-month PFS was 96.2% in the observation arm and 98.5% in the radiotherapy arm, with a stratified hazard ratio of 1.47 (95%CI, 0.34 to 6.28) and absolute risk difference of 0.68% (95%CI, -0.97% to 7.46%). The 5-year overall survival was 99% in both arms.Non-randomized patients were managed according to local policies. Radiotherapy was the only treatment in 86% of those with Deauville score (DS) 4 and in 57% of those with DS 5. The 5-year PFS and OS of patients with DS 4 (95.8% and 97.5%, respectively) were not significantly different from those of randomized patients. Patients with DS5 had significantly poorer 5-year PFS and OS (60.3% and 74.6%, respectively). This study, the largest randomized trial of radiotherapy in PMBCL, demonstrated favorable outcomes in patients achieving CMR with no survival impairment for those omitting irradiation.

Radiotherapy Trends and Variations in Invasive Non-metastatic Breast Cancer Treatment in the Netherlands: A Nationwide Overview From 2008 to 2019

AimsThis nationwide study provides an overview of trends and variations in radiotherapy use as part of multimodal treatment of invasive non-metastatic breast cancer in the Netherlands in 2008–2019. Materials and MethodsWomen with invasive non-metastatic breast cancer were selected from the population-based Netherlands Cancer Registry. Treatments trends were presented over time. Factors associated with (1) boost irradiation in breast-conserving therapy and (2) regional radiotherapy instead of axillary lymph node dissection (ALND) in N+ disease were identified using multilevel logistic regression analyses. ResultsRadiotherapy use increased from 61% (2008) to 70% (2016), caused by breast-conserving therapy instead of mastectomy, increased post-mastectomy radiotherapy, and increased regional radiotherapy (32% in 2011 to 61% in 2019) instead of ALND in N+ disease. Omission of radiotherapy after breast-conserving surgery (BCS) in 2016–2019 (4–9%, respectively), mainly in elderly, decreased overall radiotherapy use to 67%. Radiotherapy treatment was further de-escalated by decreased boost irradiation in breast-conserving therapy (66% in 2011 to 37% in 2019) and partial (1% in 2011 to 6% in 2019) instead of whole breast irradiation following BCS. Boost irradiation was associated with high-risk features: younger age (OR>75 vs <50:0.04, 95%CI:0.03–0.05), higher grade (OR grade III vs I:11.46, 95%CI:9.90–13.26) and residual disease (OR focal residual vs R0-resection:28.08, 95%CI:23.07–34.17). Variation across the country was found for both boost irradiation use (OR South vs North:0.58, 95%CI:0.49–0.68), and regional radiotherapy instead of ALND (OR Southwest vs North:0.55, 95%CI:0.37–0.80). ConclusionOverall radiotherapy use increased in 2008–2016, while a decreasing trend was observed after 2016, caused by post-BCS radiotherapy omission. Boost irradiation in breast-conserving therapy became omitted in low-risk patients, and regional radiotherapy use increased as an alternative for ALND in N+ disease.

The Breast-Areola Reduction/Reconstruction Technique Addressing the Central Lumpectomy Defect in Ptotic Breasts.

For decades, oncoplastic techniques have been an emerging, yet underutilized approach to breast cancer surgery. Recent developments in breast oncology support the potential for the omission of radiation therapy in a subset of patients eligible for breast-conserving surgery, which makes immediate reconstruction available to a much larger demographic. Although existing oncoplastic methods have offered durable and cosmetically acceptable results in select cases, there remains significant room for improvement. This publication presents a novel option in oncoplastic reconstruction named Breast-Areola Reduction/Reconstruction (BARR) that utilizes the tenets of a superomedial pedicle breast reduction and a Wise-pattern closure to address asymmetry and deformity in treatment of central breast cancers. The BARR technique features principles that are foundational to plastic surgery training, which should augment the acquisition and delivery of oncoplastic surgery in the era of progress to come.

Localized incompletely resected standard risk rhabdomyosarcoma in children and adolescents: Results from the European Paediatric Soft Tissue Sarcoma Study Group RMS 2005 trial.

The authors report the prospective evaluation of reduced dose alkylator chemotherapy combined with radiotherapy for European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) standard risk nonalveolar rhabdomyosarcoma (NA-RMS). Localized node negative Intergroup Rhabdomyosarcoma Study (IRS) II/III NA-RMS at favorable sites (subgroup C), <25 years old, received five cycles of ifosfamide, vincristine, and dactinomycin (IVA) chemotherapy (30 g/m2 ifosfamide) and four cycles of vincristine and dactinomycin (if receiving radiotherapy), or nine cycles of IVA (54 g/m2 ifosfamide) ± radiotherapy. Delayed primary tumor excision was considered for IRS III tumors. The primary end points were event-free survival (EFS) and overall survival (OS). From October 2005 to December 2016, 359 evaluable patients were recruited: orbit, 164 (45.7%); head and neck nonparameningeal, 77 (21.4%); and genitourinary non-bladder/prostate, 118 (32.9%). EFS and OS were 77.4% (95% confidence interval [CI], 72.5-81.6) and 93.5% (95% CI, 90.1-95.8), respectively. Lower dose alkylator chemotherapy and radiotherapy achieved 5-year OS of 93.7% but the difference with higher dose alkylator chemotherapy +/- radiotherapy was not significant (p=0.8003). Adjuvant radiotherapy improved EFS with 5-year estimates of 84.7% versus 65.2% for nonirradiated (p<.0001), but not OS (p=.9298). Omitting radiotherapy for orbital tumors reduced OS (5-year was 87.1% vs. 97.3% for irradiated, p=.0257). Following R0 resection (n=60), radiotherapy did not significantly improve EFS or OS. Radiotherapy for local tumor control allows for reduction of cumulative dose of alkylators in EpSSG standard risk subgroup C RMS patients. The omission of radiotherapy did not affect OS in all patients except those with orbital RMS and was associated with inferior EFS.

Re-Evaluating the Omission of Radiation Therapy in Low-Risk Patients With Early-Stage Breast Cancer

Traditionally, management of early-stage breast cancer has required adjuvant radiation therapy following breast conserving surgery, due to decreased local recurrence and breast cancer mortality. However, over the past decade, there has been an increasing emphasis on potential overtreatment of patients with early-stage breast cancer. This has given rise to questions of how to optimize deintensification of treatment in this cohort of patients while maintaining clinical outcomes. A multitude of studies have focused on identification of a subset of patients with invasive breast cancer who were at low risk of local recurrence based on clinicopathologic features and therefore suitable for RT omission. These studies have failed to identify a subset that does not from RT with respect to local control. Several ongoing trials are evaluating alternative approaches to deintensification while focusing on tumor biology. With regards to ductal carcinoma in situ (DCIS), the role of RT has been questioned since breast conservation was utilized. Paralleling invasive disease studies, studies have sought to use clinicopathologic features to identify low risk patients suitable for RT omission but have failed to identify a subset that does not from RT with respect to local control. Use of new assays in patients with DCIS may represent the ideal approach for risk stratification and appropriate deintensification. At this time, when considering deintensification, individualizing treatment decisions with a focus on shared decision making is paramount.

The pre-operative window of endocrine therapy to inform radiation therapy decisions (POWER) trial: Baseline patient beliefs about breast cancer and endocrine therapy.

11115 Background: The POWER Trial (NCT04272801) aims to determine whether pre-operative endocrine therapy (pre-ET) impacts physician recommendations and patient preferences for adjuvant radiation (RT) and endocrine therapy (AET) among women who qualify for RT omission. While physicians characterize this population as low-risk, they often still recommend RT. The POWER trial captures baseline patient perspectives regarding recurrence and medication tolerance using patient-reported outcome surveys and examines how these influence treatment choices. Methods: POWER Trial participants received 90 days of pre-ET before surgery and treatment decisions regarding RT. Women ≥ 65 years old with ER+ tumors ≤ 2 cm, node negative were eligible. Patient beliefs about their cancer and medications were assessed at baseline using the Beliefs About Illness Questionnaire (BIP-Q), Beliefs About Medicine Questionnaire-ET (BMQ-ET), and Perceived Sensitivity to Medicines (PSM) scale. An additional novel, non-validated questionnaire was created to further evaluate patients’ beliefs. Results: The study cohort included 48 women with mean age of 73.7. Few patients (14.6%) viewed their breast cancer as having a high threat to their health. While half (50.0%) of the participants worried a lot about the return of their breast cancer, only 35.4% thought that a cancer recurrence would be devastating. Participants who worried more about their breast cancer returning were more likely to feel a recurrence would be devastating (Pearson Correlation Coefficient = .67). There was no association between baseline beliefs and RT omission. Most patients (81.3%) did not consider themselves sensitive to medications. Although 81.3% reported side effects as important when deciding to continue or stop medications, almost all participants (95.8%) stated they would continue medications, despite side effects, if it would help lower their risk of recurrence. When specifically asked about AET, 70.8% reported a low level of concern about taking the therapy and 72.9% felt it was necessary. Of study participants, 27 (56.3%) omitted RT and initiated AET, 10 (20.8%) had RT and declined AET, 10 (20.8%) completed RT and initiated AET, and 1 (2.1%) declined RT and AET. Conclusions: This analysis shows that many early-stage ER+ breast cancer patients have a low level of worry about breast cancer recurrence, which may support treatment de-escalation such as RT omission. Most participants are open to taking AET despite the potential for side effects, yet historical data demonstrate low rates of adherence to AET. This discrepancy highlights that patients’ baseline beliefs about themselves and their medications may not align with their actual adherence. Future analysis from the POWER trial will examine how long-term AET adherence relates to baseline patient beliefs. Clinical trial information: NCT04272801 .

Analysis of risk factors for recurrence within 12 months after surgery in patients with breast cancer receiving neoadjuvant therapy at a Brazilian cancer center.

e13039 Background: Early recurrence following treatment for localized breast cancer typically occurs within 5 years, and is commonly linked to high-risk clinicopathologic factors. However, literature focusing on risk factors for earlier recurrence timeframes is scarce, particularly within the neoadjuvant treatment population. Therefore, this study aims to investigate potential predictors for recurrence within 12 months post-surgery in breast cancer patients submitted to neoadjuvant therapy. Methods: This is an observational, descriptive, retrospective study involving 310 patients with recurrent breast cancer who received neoadjuvant therapy between January 2007 and March 2022, at AC Camargo Cancer Center in São Paulo, Brazil. Patients were compared based on relapse time after surgery (&lt;12 months or ≥12 months), and risk factors were analyzed using the Chi-Square test or Fisher’s Exact test. Results: From 310 patients analyzed, 108 relapsed within 12 months and 202 after this period. Factors predicting recurrence in less than 12 months included: Histologic grade (HG) III ( p &lt; 0.01); nuclear grade (NG) III ( p &lt; 0.001); mitotic counts &gt;20/mm2 ( p = 0.02); Ki67 &gt; 20% ( p = 0.010); triple negative breast cancer (TNBC) and HER2+/HR- subtypes ( p &lt; 0.001); interruption of neoadjuvant therapy due to disease progression or toxicity ( p &lt; 0.001); chemotherapy dose reduction or delay ( p = 0.001); omission of adjuvant radiotherapy ( p &lt; 0.001) and interruption of adjuvant HER2 targeted therapy ( p &lt; 0.001). Menopausal status, Residual Cancer Burden (RCB) index, type of surgery and clinical stage showed no significant correlation with the outcome. Conclusions: Recurrence in less than 12 months was associated with intrinsic factors, such as HG III, NG III, high mitotic counts, Ki67 &gt; 20%, TNBC, as well as interruption or delay of neoadjuvant therapy, omission of adjuvant radiotherapy and interruption or delay of HER2 targeted therapy, pointing out potential risk factors in this population.

Evolving Standards of Care in the Management of Localized Colorectal Cancer.

The treatment of patients with localized rectal cancer is complex and requires input from a multidisciplinary team. Baseline local staging and mismatch repair protein testing are vital to develop individualized treatment plans. There are multiple options in terms of treatment modalities and sequencing, including transanal excision, short-course radiation, long-course chemoradiation, chemotherapy doublet or triplet, nonoperative management, and immune checkpoint blockade for patients with mismatch repair deficient tumors. While localized colon cancer is typically treated with surgical resection and consideration of adjuvant chemotherapy, emerging data suggest that neoadjuvant chemotherapy may be beneficial in patients with higher-risk disease. Quality-of-life considerations are imperative to prevent potential chronic effects on psychosocial health, neuropathy, fertility, and bowel, bladder, and sexual function. The omission of radiation or surgery can mitigate these toxicities without diminishing oncologic outcomes. The optimal treatment plan and sequence is not a one-size-fits-all approach but rather should be personalized to the patient's disease burden, tumor location, comorbidities, and preferences.

Predicting completion of endocrine therapy for older patients with early-stage breast cancer.

535 Background: Clinical trials suggest that adjuvant radiotherapy (RT) may be omitted in women aged ≥65 with early-stage, hormone-receptor positive breast cancer provided completion of 5 years of endocrine therapy (ET). However, at the time of RT consult, it is often unknown whether the patient will start ET, or will start ET but not complete 5 years, either of which, if known in advance, would alter RT recommendations. We studied a cohort of patients who would have been eligible for these trials to examine which factors were related to declining or discontinuing ET. Methods: Using a prospectively maintained institutional database, we identified patients age ≥65 who underwent surgery between 2010 and 2017 with stage I breast cancer, hormone receptor positive. Missing data were replaced using multiple imputation. Recurrence statistics were calculated using Kaplan-Meier analysis. Multivariate (MVA) logistic regression was used to assess which factors were associated with not starting or discontinuing ET. Results: We identified 590 patients who met eligibility criteria. 453 (76.8%) patients started ET, of whom 315 (69.5%) completed at least 5 years, 84 (18.5%) stopped ET before 5 years, and 54 patients (11.9%) were lost to follow up. Median follow up was 67.2 months. Among the 137 patients who did not start ET, the most common reasons were osteopenia or osteoporosis (27.7%), arthritis (18.2%), and declined consultation with medical oncology (15.3%). On MVA, not starting ET was significantly associated with older age (OR 1.10, p &lt; 0.0001), osteopenia (OR 2.27, p = 0.005) or osteoporosis (OR 3.82, p = 0.009), or not undergoing radiation (OR 1.92, p = 0.006) or chemotherapy (OR 6.45, p = 0.02). The most common reason for stopping ET was joint pain (50.0%), with other reasons including hot flashes (10.7%) and fatigue (7.1%). Not completing 5 years of ET was significantly associated with older age (OR 1.09, p = 0.002) and prior/current smoking history (OR 1.75, p = 0.037), while patients whose marital status was single or never married were significantly more likely to complete 5 years of ET (OR 0.26, p = 0.019). Recurrence-free survival was lower among the group which never started ET (p &lt; 0.0001) or which stopped ET before 5 years (p &lt; 0.0001) as compared to those who completed 5 years, with 5-year recurrence-free survival of 97.5% (95% CI: 95.6-99.3) for patients who completed 5 years of ET, compared to 88.7% (95% CI: 82.5-95.4) for those who did not undergo ET and 87.6% (95% CI: 80.4-95.6) for those who started ET but did not complete 5 years. Conclusions: Patients who are older, have osteopenia/osteoporosis, or who have declined prior treatment such as chemotherapy or RT are more likely not to start ET, while patients who are older or prior/current smokers are more likely to discontinue ET after starting and single / never married patients are more likely to complete ET. These factors may be used to guide discussion of omission of adjuvant radiotherapy.

The influence of access to care on radiation therapy utilization among older women with breast cancer.

1539 Background: In 2004, the Cancer and Leukemia Group B (CALGB) C9343 trial compared outcomes among women aged ≥ 70 who had stage I, estrogen-receptor positive (ER+) breast cancer (BC) who received a lumpectomy and hormonal therapy, treated with and without radiation therapy (RT). While the trial found that overall survival was not different between groups, RT use did not significantly decline after its publication. We investigated regional variation in RT utilization in the United States (US) and its association to access to healthcare among women aged ≥ 70 diagnosed with localized ER+ BC after partial mastectomy (PM) between 2004–2020. We hypothesize that women with greater access to health care will more often receive RT. Methods: To examine regional variation in the use of RT and its association with access to healthcare, we extracted data from the Surveillance, Epidemiology, and End Results 17 registry. From 2004 – 2020, 105,694 women aged ≥ 70 years who received a PM for localized ER+ BC across 199 US counties with a population &gt; 50,000 were identified. Access to healthcare was measured using six socioeconomic (SES) variables: median household income, % with high school education, % of families above poverty line, % with bachelor’s degree, % speaking English, and % employed, measured from 2015-2019. A multivariable linear regression model tested for association between each variable and RT use. A composite SES score was calculated as the sum of z-scores across all six variables and we identified the top 20 and bottom 20 scoring counties. SES score was used as a surrogate for access to healthcare and was correlated to RT use using a linear regression model. Results: The percentage of women aged ≥ 70 receiving RT after PM for localized ER+ BC varied across counties from 19.0% to 84.6%. In 2004, receipt of RT was similar between the top 20 and bottom 20 counties (67.8% vs 65.2%, respectively). This decreased after publication of CALGB C9343; by 2020 receipt of RT was 58.7% for the top 20 and 49.2% for the bottom 20 SES counties (Table). In linear regression analysis, SES was significantly associated with RT use (p&lt;0.0001). In multivariable linear regression analysis, only % above high school education was significantly associated with RT use (p=0.0205). Conclusions: Among women aged ≥ 70 with localized ER+ BC who underwent PM and who were candidates for omission of RT, those who lived in higher SES counties were more likely to receive RT from 2004 – 2020. Since the CALGB C9343 trial in 2004, RT use has declined; however, the decline was less among those with higher SES and therefore likely less among those with greater access to healthcare. These women may experience over treatment, which may result in personal or system wide harms. [Table: see text]

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 (&lt;60; ≥60), tumor size (≤1 cm; &gt;1-2cm), and RS (≤11, &gt;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 &lt;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 &gt;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 .

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 (&lt;60; ≥60), tumor size (≤1 cm; &gt;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 PS02-03: Is de-escalation of treatment by omission of radiotherapy associated with fear of cancer recurrence and health-related quality of life in women with early breast cancer? An exploratory study

Abstract Background: There is growing interest in treatment optimization in early breast cancer (EBC). PROSPECT (ANZ-1002) provided compelling evidence that a combination of pre-operative MRI and pathological features could identify a substantial group of patients with localised EBC in whom radiotherapy (RT) could be safely omitted. The patient experience of de-escalation or its association with health-related quality of life (HRQoL) and fear of cancer recurrence (FCR), was not examined in PROSPECT but is a key consideration of treatment decision-making. We conducted a retrospective, mixed methods, cross-sectional study to explore this association. Methods: Psychometrically validated measures including the Fear of Cancer Recurrence Inventory Short-Form, Depression Anxiety Stress Scale, Breast Cancer Treatment Outcomes Scale, EORTC QLQ-C30 and its breast-specific module, the BR23, and the Decision Regret Scale were completed by three groups of women with early EBC: Women in the PROSPECT clinical trial who underwent pre-surgical MRI and omitted RT (A), women who underwent pre-surgical MRI and received RT (B); and women who received usual care (no MRI, received RT; C). Between group differences were analysed with ANOVA or equivalent non-parametric tests. A subset from each group participated in a semi-structured interview. These data (n=44) were analysed with directed content analysis. Results: Data from 400 women were analysed. Median age was 65 years, and median time since diagnosis was 4.4 years. There were no group differences in neuroticism, mental health, age, medical comorbidities, parity, or time since diagnosis. Significantly lower FCR was observed in Group A (n=125) than in Group B (n=102; p=.002) or Group C (n=173; p=.001), and when participants were categorized by RT status (omitted RT vs received RT; p&amp;lt; .001). The proportion of women with normal FCR was significantly (p &amp;lt; .05) larger in Group A (62%) than in Group B (35%) or Group C (40%). There were no differences between groups on depression and anxiety. Women in Group A had fewer breast symptoms than in Group B (p=.003) and Group C (p= &amp;lt; .001), fewer arm symptoms than in Group B (p=.004) and Group C (p=.011), and better body image than Group C (p=.041). Compared to Groups B and C, Group A performed better on cosmetic (both p&amp;lt; .001), functional (A vs C: p=.011) and breast-specific pain measures (both p&amp;lt; .001). Pre-operative MRI and omission of RT were highly acceptable and decision regret was low. A secondary analysis was conducted to eliminate any potential impact of disease severity on the analysis. All cases (n=126) with any positive nodes, a Grade 3 tumour and tumour size &amp;gt;20mm were removed. The remaining sample comprised 274 women. The results were similar to the primary analysis. Qualitative analysis showed that women who omitted RT viewed this as appropriate treatment, not undertreatment. Women considered RT toxic but endured it as a necessity, if prescribed. Few women experienced ongoing negative effects from RT but there was a tendency to minimize RT treatment burden. Women managed their FCR by having trust in their treatment and faith in the medical advice they received. Conclusions: In the setting of the PROSPECT trial, treatment de-escalation via omitting RT was associated with less FCR, better HRQoL and functional and cosmetic outcomes and was highly acceptable. Clinicians should consider the potential for preserved HRQoL associated with omission of RT in treatment decision-making. Positive perceptions about tailored care, lower treatment burden, and trust in clinicians appear to be protective against FCR. Future studies should include prospective collection of FCR and HRQoL measures. Citation Format: Bruce Mann, Michelle Sinclair, Phyllis Butow, Janemary Hughes, Allan Park, Leslie Gilham, Allison Rose, Lesley Stafford. Is de-escalation of treatment by omission of radiotherapy associated with fear of cancer recurrence and health-related quality of life in women with early breast cancer? An exploratory 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 PS02-03.

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 &amp;/or PR positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (&amp;lt; 60; ≥60), tumor size (≤1 cm; &amp;gt;1-2cm), and RS (&amp;lt; 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 &amp;lt; 70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER &amp;/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 &amp;gt;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.

Abstract GS03-01: Magnetic Resonance Imaging and a 12-Gene Expression Assay to Optimize Local Therapy for Ductal Carcinoma In Situ: 5-year clinical outcomes of E4112

Abstract BACKGROUND. Advanced diagnostics such as magnetic resonance imaging (MRI) and gene-expression profiles are potentially useful to guide treatment in patients with ductal carcinoma in situ (DCIS). To evaluate these tests, we performed a prospective single arm multicenter study. We have previously reported the impact of MRI on surgical management of DCIS patients, and the effect of a 12-gene DCIS Score (DS) on radiotherapy (RT) use after wide local excision (WLE). We now report a pre-planned analysis of ipsilateral breast events (IBE) at 5-years. METHODS. Adult women with a core needle biopsy diagnosis of DCIS and eligible for WLE based on conventional imaging were registered following consent. All registered patients underwent breast MRI. Those still eligible, and willing, to receive WLE after appropriate follow-up biopsies underwent resection to free margins. DCIS sections were submitted to Exact Sciences for DS. Those with a low DS (&amp;lt; 39) were advised to omit RT; those with intermediate/high (inter/hi) DS (≥39) were advised to receive RT. All participants were monitored at 6-month intervals for any breast cancer event, and for survival. An IBE was defined as the first DCIS or invasive recurrence in the ipsilateral breast following the final WLE. Participants without IBE were censored by date of last contact or date of death for those who died. Follow-up was truncated at 5 years from WLE. Using data available as of 07-06-2023, Kaplan-Meier (K-M) curves were constructed to estimate the time-to-event distributions for subjects who received RT and for those who did not. The 5-year IBE rates and 95% confidence intervals (CIs) were estimated from K-M curves for all subjects with a DS (analogue of Intention to Treat [ITT] analysis), and for the subset who were compliant with their DS-based RT recommendation (Per Protocol analysis). The analyses were repeated for subgroups based on age at DCIS diagnosis (&amp;lt; 50 vs. ≥ 50). RESULTS. Of 339 women evaluable for the previously reported primary analysis (PMID 30653209), 171 (50.4%) underwent WLE with free surgical margins and had DS available for RT recommendations (ITT population). Of these, 7/82 low DS patients underwent RT, and 5/89 inter/hi DS patients declined RT; thus, the adherence to DS-based RT recommendations was 93%. At a median of 5 years of follow-up from final WLE, the ITT population experienced a total of eight IBE events (4.8%, 95% CI 2.4, 9.4) with 5-year IBE rates that were similar for participants with a low DS and for those with a inter/hi DS: 5.1% (95% CI: 1.9, 12.9) and 4.5% (95% CI 1.7, 11.7), respectively. Stratification by age did not alter these results: among women aged &amp;lt; 50 years (n=33), the IBE rate was 6.7% (95% CI 1.0, 38.7) for low DS and 5.6% (95% CI 0.8, 33.4) for inter/hi DS. Among women aged ≥ 50 years (n=138), the IBE rate was 4.7% (95% CI 1.5, 13.8) for low DS and 4.3% (95% CI 1.4, 12.7) for inter/hi DS. In the per-protocol analysis (N=159 adherent to RT recommendations), IBE rates were also similar for participants who had a low DS and no RT [5.5% (95% CI 2.1, 14.1)] and for those with inter/hi DS who received RT [4.8% (95% CI: 1.8% to 12.3%)]. Again, there was no discernible influence by age as categorized above. CONCLUSION. We report the first prospective data on use of DCIS Score for RT decisions, and 5-year IBE rates. We find that DS-based recommendations are followed by &amp;gt;90% of patients. Although the sample size is limited, the data are reassuring in that the IBE rate is similar between the low DS group treated with WLE alone and the inter/hi DS group treated with WLE and radiation, whereas prior studies have shown a marked difference in IBE rates by DS with excision alone. Therefore, this prospective trial provides strong evidence to support the omission of RT after surgery in DCIS patients with low DS, and its use in patients with intermediate/high DS. Citation Format: Seema Khan, Justin Romanoff, Constantine Gatsonis, Habib Rahbar, Ruth Carlos, Sunil Badve, Jean Wright, Constance Lehman, Worta McCaskill-Stevens, Ralph Corsetti, Derrick Spell, Kenneth Blankstein, Linda Han, Jennifer Sabol, John Bumberry, Ilana Gareen, Bradley Snyder, Lynne Wagner, Kathy Miller, Joseph Sparano, Christopher Comstock. Magnetic Resonance Imaging and a 12-Gene Expression Assay to Optimize Local Therapy for Ductal Carcinoma In Situ: 5-year clinical outcomes of E4112 [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 GS03-01.

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 (&amp;lt; 2 cm) N0 disease, while patients receiving neoadjuvant therapy must have clinical T1-2 (with radiographically T&amp;lt; 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 (&amp;lt; 60; ≥60), tumor size (≤1 cm; &amp;gt;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.