Breast Events Research Articles

Abstract A012: Using clinical characteristics and molecular markers to predict the risk of subsequent ipsilateral breast events after excision of DCIS

Abstract Purpose: To examine incremental values of estrogen receptor (ER) status, body mass index (BMI), menopausal status, and a multi-gene classifier over commonly used clinical factors (i.e. age, tumor grade, comedonecrosis, surgical margins, and treatment) in predicting risk of ipsilateral recurrence (IR) within five years after DCIS diagnosis. Methods: A derivation cohort consisted of participants in the discovery cohort, a retrospective multicenter cohort study in women undergoing surgical resection for DCIS between 01/01/1998 and 02/29/2016. The validation cohort provided cases meeting the same eligibility criteria as the discovery cohort. This analysis includes 313 participants with RNA-seq data who either developed IR 1-5 years after initial DCIS diagnosis or were free from subsequent breast events at least five years. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of IR in 216 TBCRC participants (76 with IR). We developed the clinical score using clinical predictors (aforementioned clinical factors and ER) and their regression coefficients from the model with the maximum predictive accuracy (e.g. c-index) and the minimum number of predictors, and the summary score integrating the clinical score and multi-gene classifier. Predictive performance of clinical and summary scores was validated in 97 RAHBT patients (20 with IR). Results: In the discovery cohort, ER negativity, but not BMI or menopausal status, was independently associated with a higher IR risk (HR=2.06, 95% CI 1.18-3.58), and adding ER to the clinical factors-based model increased predictive accuracy (c-index 0.68 to 0.70). The clinical score-adjusted HR was 14.96 (95% CI 8.64-25.91) for multi-gene classifier. Summary scores were better in predicting IR risk than clinical scores (c-index 0.82 vs. 0.70). Compared with their low-risk counterparts, the HR was 4.79 (95% CI 2.55-8.98) in the clinical score-defined high-risk group and 29.02 (95% CI 14.23-59.15) in the summary score-defined high-risk group. In the validation cohort, model performance was improved using summary scores as compared to clinical scores (c-index 0.74 vs. 0.58). Conclusion: Combination of clinical factors and multigene classifier provided more accurate risk estimates of IR within five years after excision of DCIS than clinical factors alone. Citation Format: Graham A. Colditz, Ying Liu, Siri H. Strand, Lorraine King, Jeff Marks, Carlo Maley, Robert B. West, E. Shelley Hwang. Using clinical characteristics and molecular markers to predict the risk of subsequent ipsilateral breast events after excision of DCIS [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr A012.

Pathological Complete Response and Oncological Outcomes in Locally Advanced Breast Cancers Treated with Neoadjuvant Radiotherapy: An Australian Perspective

<h3>Purpose/Objective(s)</h3> To assess the degree of post-operative surgical complication rates, pathological complete response (pCR), and oncological outcomes in women with locally advanced (LABC) or high-risk breast cancers treated with neoadjuvant radiotherapy (NART). The working hypothesis is that treatment sequence reversal with neoadjuvant radiotherapy leads to good tumor response and equivocal oncological outcomes in LABC when compared to standard of care. <h3>Materials/Methods</h3> This retrospective multi-institutional review involved 138 clinically-staged patients with 140 breast cancers treated with NART between January 2014 and February 2021. Treatments involved sequential NACT and NART, followed by mastectomy with or without axillary surgery and immediate breast reconstruction. Descriptive statistics were used to assess patient and disease features, treatment regimens, pathological response and factors affecting post-operative complications. Kaplan-Meier curves were performed to assess locoregional recurrence free, distant metastasis free and overall survival outcomes. <h3>Results</h3> Median age was 47 years (IQR 42–52) with a median BMI of 26 (IQR 24-30). The median follow-up was 35.2 months (IQR 17.1-46.5). pCR was achieved in 36.4% (as defined by Chevallier Classification) or 42.1% (as defined by Miller-Payne scores) of patients. Higher pCR rates were achieved for HER2 (76.2%-85.7%) and triple negative phenotypes (47.6%-57.1%). There were 21 Grade 3 surgical complications including 10 Grade 3B breast events and 8 grade 3B donor-site events, where surgical reintervention was required. At the 3 years mark, the locoregional recurrence free survival was 98.1% (95% CI 94.0-99.4%), distant metastasis free survival was 83.6% (95% CI 75.8-89.1%) and overall survival was 95.3% (95% CI 90.2-97.7%). <h3>Conclusion</h3> NART is feasible to facilitate a single-stage mastectomy and immediate breast reconstruction. This study demonstrated comparable rates of post-operative complication to standard of care, and high rates of pCR which translates to high rates of locoregional control, distant metastasis free survival and overall survival.

Accelerated Partial Breast Irradiation (APBI) Using Five Daily Fractions: A Prospective, Phase II, Multi-Center Trial of Cosmetic Outcomes and Toxicity: Final Results

<h3>Purpose/Objective(s)</h3> To report final results of a clinical trial of APBI using intensity modulated radiotherapy (IMRT) to deliver 27 Gy in 5 daily fractions following breast conserving surgery (BCS) prospectively designed to assess the efficacy and cosmetic outcomes of a 1-week, APBI regimen among women with early breast cancer. <h3>Materials/Methods</h3> Women ≥ 50 years, with lymph node-negative, ER positive, HER-2 negative breast cancer or ductal carcinoma in situ (DCIS), ≤ 3cm diameter, following BCS with margins ≥ 2mm, and excellent or good baseline cosmesis received 27 Gy in 5 daily fractions to the seroma plus 1 cm CTV and 0.7 cm PTV margins. Clinical photographs, patient and provider cosmetic scores, breast fibrosis, telangiectasia and pain were collected prospectively, prior to RT and at 6 weeks, 1 and 2 years after RT. The primary endpoint was the proportion of women who retained Excellent or Good cosmesis at 2 years using the EORTC Cosmetic Rating System. Cosmetic failure was deterioration from Excellent or Good to Fair or Poor. A panel of 5 radiation oncologists independently assessed the cosmetic photographs. Secondary endpoints were rates and grades of breast fibrosis, telangiectasia, breast pain, ipsilateral breast tumor recurrence (IBRT), overall (OS), breast cancer-specific survival (BCSS) and subsequent mastectomy. Efficacy outcomes were assessed at clinic visits and by review of charts. ClinicalTrials.gov registration: NCT02681107. <h3>Results</h3> A total of 298 patients were treated between April 25, 2016, and October 31, 2019. At a median follow up of 48 months, the 4-year OS was 98.5% (95% CI 96.1% - 99.5%) and BCSS was 99.7% (95% CI 97.6% - 99.9%). The 4-year IBRT rate was 3.3% (95% CI 1.1% - 6.4%). There were 10 contralateral breast events for a 4-year rate of 3.9% (95% CI 2.2% - 6.9%). There were 10 ipsilateral and 6 contralateral mastectomies. Two patients died of unrelated causes prior to 2 years; 79 patients declined in-clinic attendance due to COVID or competing comorbidities and 217 women had 2-year cosmetic photographs and clinical assessments performed. Consensus of the photo-panel cosmesis at baseline was: Excellent: n=116 (53%), Good: n=102 (47%), Fair: n=1 (0.5%) and Poor: n=0. Consensus overall cosmesis at 2 years was: Excellent: n=141 (65%), Good: n=78 (35%), Fair: n=0 and Poor: n=0. Most patients had either improved (n=168; 77%) or no change (n=43; 20%) in cosmesis at 2-years. No patient had cosmetic failure but 6 (3%) had a change from Excellent to Good at 2 years. Most patients reported either no (79%) or mild (21%) pain, with no moderate or severe pain. Two patients (0.9%) had grade 2 fibrosis and 5 patients (2%) had visible telangiectasia that did not detract from overall cosmesis. <h3>Conclusion</h3> APBI using 27 Gy in 5 fractions using a conformal IMRT technique, achieved excellent 2-year cosmesis with minimal toxicity. The IBRT risk was comparable to the contralateral new breast cancer risk and to local recurrence rates of recently published early breast cancer trials.

A Meta-Analysis of Trials of Partial Breast Irradiation

Partial breast irradiation (PBI) is the delivery of radiation therapy (RT) limited to the tumor bed after breast conserving surgery. The results of recent trials of PBI compared with whole breast irradiation (WBI) have suggested conflicting results with respect to local control and toxicity. The purpose of this meta-analysis was to assess effectiveness of PBI and to compare the different techniques. A meta-analysis of aggregate data from published randomized trials was performed to examine the effectiveness of PBI compared with WBI in patients with invasive breast cancer and ductal carcinoma in situ. Relevant data were extracted. The primary outcome was any ipsilateral breast event (invasive or noninvasive). Secondary outcomes included acute and late toxicity. The results of randomized trials were pooled using a fixed effects model and the inverse variance method. Fifteen trials involving 16,474 patients were identified. The majority of enrolled patients were >60 years of age and had T1N0 grade 1 to 2 disease treated with hormone therapy. The percent of ipsilateral breast events was higher in patients treated with PBI compared with WBI (5.0% vs 2.8%; risk ratio [RR], 1.72; 95% confidence interval [CI], 1.47-2.02). Heterogeneity (P=.0002) was observed between the 4 PBI techniques: external beam RT without computed tomography (CT) planning (RR, 2.06; 95% CI, 1.36-3.12); brachytherapy (RR, 1.21; 95% CI, 0.65-2.25); intraoperative RT (RR, 2.79; 95% CI, 2.08-3.73); and external beam RT with CT planning (RR, 1.25; 95% CI, 0.99-1.58). When external beam RT without CT planning and intraoperative RT trials were excluded, the percent of ipsilateral breast events was 3.3% versus 2.6%, respectively (RR, 1.25; 95% CI, 1.00-1.55; P=.05), and no heterogeneity was observed (P=.92). Overall, acute toxicity was less with PBI, and the effect on late toxicity varied by technique. Overall, WBI was more effective than PBI, but the effectiveness of PBI was technique related. PBI was less effective when given by external beam RT without CT planning or intraoperative therapy. Although PBI given by multicatheter brachytherapy or external beam RT with CT planning tended to be statistically less effective than WBI, the absolute difference between groups for ipsilateral breast events was very small (<1%), supporting these approaches for women considering PBI.

Predicting ipsilateral recurrence in women treated for ductal carcinoma in situ using machine learning and multivariable logistic regression models

PurposeTo develop machine learning (ML) and multivariable regression models to predict ipsilateral breast event (IBE) risk after ductal carcinoma in situ (DCIS) treatment. MethodsA retrospective investigation was conducted of patients diagnosed with DCIS from 2007 to 2014 who were followed for a minimum of five years after treatment. Data about each patient were extracted from the medical records. Two ML models (penalized logistic regression and random forest) and a multivariable logistic regression model were developed to evaluate recurrence-related variables. Results650 women (mean age 56 years, range 27–87 years) underwent treatment for DCIS and were followed for at least five years after treatment (mean 8.0 years). 5.5% (n = 36) experienced an IBE. With multivariable analysis, the variables associated with higher IBE risk were younger age (adjusted odds ratio [aOR] 0.96, p = 0.02), dense breasts at mammography (aOR 3.02, p = 0.02), and < 5 years of endocrine therapy (aOR 4.48, p = 0.02). The multivariable regression model to predict IBE risk achieved an area under the receiver operating characteristic curve (AUC) of 0.75 (95% CI 0.67–0.84). The penalized logistic regression and random forest models achieved mean AUCs of 0.52 (95% CI 0.42–0.61) and 0.54 (95% CI 0.43–0.65), respectively. ConclusionVariables associated with higher IBE risk after DCIS treatment include younger age, dense breasts, and <5 years of adjuvant endocrine therapy. The multivariable logistic regression model attained the highest AUC (0.75), suggesting that regression models have a critical role in risk prediction for patients with DCIS.

Prediction Models and Decision Aids for Women with Ductal Carcinoma In Situ: A Systematic Literature Review.

Simple SummaryDuctal carcinoma in situ (DCIS) is a potential precursor to invasive breast cancer (IBC). Although in many women DCIS will never become breast cancer, almost all women diagnosed with DCIS undergo surgery with/without radiotherapy. Several studies are ongoing to de-escalate treatment for DCIS. Multiple decision support tools have been developed to aid women with DCIS in selecting the best treatment option for their specific goals. The aim of this study was to identify these decision support tools and evaluate their quality and clinical utility. Thirty-three studies were reviewed, in which four decision aids and six prediction models were described. While some of these models might be promising, most lacked important qualities such as tools to help women discuss their options or good quality validation studies. Therefore, the need for good quality, well validated decision support tools remains unmet.Even though Ductal Carcinoma in Situ (DCIS) can potentially be an invasive breast cancer (IBC) precursor, most DCIS lesions never will progress to IBC if left untreated. Because we cannot predict yet which DCIS lesions will and which will not progress, almost all women with DCIS are treated by breast-conserving surgery +/− radiotherapy, or even mastectomy. As a consequence, many women with non-progressive DCIS carry the burden of intensive treatment without any benefit. Multiple decision support tools have been developed to optimize DCIS management, aiming to find the balance between over- and undertreatment. In this systematic review, we evaluated the quality and added value of such tools. A systematic literature search was performed in Medline(ovid), Embase(ovid), Scopus and TRIP. Following the PRISMA guidelines, publications were selected. The CHARMS (prediction models) or IPDAS (decision aids) checklist were used to evaluate the tools’ methodological quality. Thirty-three publications describing four decision aids and six prediction models were included. The decision aids met at least 50% of the IPDAS criteria. However, most lacked tools to facilitate discussion of the information with healthcare providers. Five prediction models quantify the risk of an ipsilateral breast event after a primary DCIS, one estimates the risk of contralateral breast cancer, and none included active surveillance. Good quality and external validations were lacking for all prediction models. There remains an unmet clinical need for well-validated, good-quality DCIS risk prediction models and decision aids in which active surveillance is included as a management option for low-risk DCIS.

Molecular subtypes predict second breast events of ductal carcinoma in situ after breast-conserving surgery.

PurposeCurrently, the prognostic value of molecular subtypes in ductal carcinoma in situ (DCIS) remains unclear. In this study, we explored whether molecular subtypes could predict second breast events (SBEs) in patients after breast‐conserving surgery (BCS).MethodsFrom January 2008 to December 2016, 291 DCIS patients treated with BCS were retrospectively analyzed. Patients were classified into four molecular subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) overexpression, and triple‐negative breast cancer (TNBC). The SBE incidence was calculated by the competing risk model and compared by Gray's test. The disease‐free survival rates were estimated by the Kaplan–Meier method and compared by the log‐rank test. Prognostic factors were evaluated by univariate and multivariate COX proportional hazards regression model.ResultsWith a median follow‐up of 66 months, 12 SBEs were identified. The 5‐year overall SBE incidence of luminal A, luminal B, HER2 overexpression, and TNBC was 2.18%, 4.25%, 15.15%, and 0.00%, respectively. In the univariate analysis, the HER2 overexpression subtype was the predictor of overall (p = 0.005), in situ (p = 0.004), and ipsilateral SBEs (p = 0.008). Patients with endocrine therapy were less likely to develop in situ SBEs (p = 0.039). Additionally, patients with closed (<2 mm) or involved margins were related to a higher risk of contralateral SBEs (p = 0.029). In the multivariate analysis, the HER2 overexpression subtype remained of prognostic values for overall (p = 0.006), in situ (p = 0.029), and ipsilateral SBEs (p = 0.012).ConclusionsThe molecular subtype, especially the HER2 overexpression subtype, was the independent prognostic factor for DCIS patients who underwent BCS.

Is conservative management of ductal carcinoma in situ risky?

Nonsurgical management of ductal carcinoma in situ is controversial and little is known about the long-term consequences of this approach. In this study, we aimed to determine the risk of (a) upstaging to invasive carcinoma at excision and (b) ipsilateral breast cancer events in patients who might have been eligible for nonsurgical management of DCIS trials. Data from women aged 20 years or older with a biopsy diagnosis of DCIS between January 1, 2010 to December 31, 2014 were collated. The women underwent biopsy and surgical resection (lumpectomy or mastectomy) and were treated with radiation or endocrine therapy as per treating physicians’ choice. The development of ipsilateral breast cancer events (IBEs) was analyzed in patients with at least 5 years of follow-up after standard of care therapy for DCIS. Subset-analysis was undertaken to identify the incidence of IBEs in patients eligible for nonsurgical management trials. The study population consisted of 378 patients with matched cases of biopsy and surgical excision. The overall upstaging rate to IBC was 14.3 and 12.9% for COMET, 8.8% for LORIS, and 10.7% for LORD trial “eligible” patients. At 5 years of follow-up, ~11.5% of overall and trial eligible patients developed IBEs of which approximately half were invasive IBEs. In conclusion, women with DCIS who would have been eligible for nonsurgical management trials have a significantly high risk of developing ipsilateral breast events within 5 years of diagnosis. Better selection criteria are needed to identify DCIS patients who are at very low risk for the development of IBC.

Molecular subtyping reveals uniqueness of prognosis in breast ductal carcinoma in situ patients with lumpectomy

BackgroundWe aimed to analyse the discrepancy in clinical features and prognosis between molecular subtypes in primary ductal carcinoma in situ (DCIS) patients with lumpectomy. MethodsPrimary DCIS patients were identified from the Surveillance, Epidemiology, and End Results registries database from 2010 to 2017. Based on immunohistochemistry markers of hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2), enrolled DCIS cases were divided into four molecular subtypes, HR-HER2-, HR-HER2+, HR + HER2+, and HR + HER2-. Clinical features and prognosis were compared between molecular subtypes. Radiotherapy (RT) effects on prognosis were also analysed in each molecular subtype. ResultsA total of 5,628 DCIS cases were retrospectively enrolled in this study. HR-HER2-, HR-HER2+, HR+HER2+, and HR+HER2- are 299 (5.3%), 498 (8.8%), 1,086 (19.3%), and 3,745 (66.5%), respectively. HR + HER2- cases have smaller tumor size (72.6%, P < 0.001) and lower grade (23.5%, P < 0.001). Comedo necrosis is more frequent in HR-HER2- (24.4%, P < 0.001) and HR-HER2+ DCIS cases (24.3%, P < 0.001). In univariate analyses, HR-HER2+ cases have significantly higher ipsilateral breast event (IBE) recurrence than HR+HER2- cases (P = 0.010). HR-HER2- cases show higher disease-specific mortality than HR+HER2+ cases (P = 0.021). In high-risk DCIS cases, RT reduces the absolute 5-year IBE incidence by 1.3%, 0.7%, 1.9%, and 2.6%, respectively in HR-HER2-, HR-HER2+, HR+HER2+, and HR+HER2- cases, respectively. ConclusionIn this population-based study, DCIS cases have diverse clinical and prognostic features for different molecular subtypes. Adjusting treatment strategies according to DCIS molecular subtypes is worth advancing.

Tumour-infiltrating lymphocytes add prognostic information for patients with low-risk DCIS: findings from the SweDCIS randomised radiotherapy trial

BackgroundThe immune microenvironment is an important modulator of tumour progression and treatment response. In invasive breast cancer, assessment of tumour-infiltrating lymphocytes (TILs) provides prognostic and predictive information. However, the clinical impact of TILs for ductal carcinoma in situ (DCIS) has not yet been demonstrated. Patients and methodsPost hoc analysis of the SweDCIS randomised radiotherapy trial including primary DCIS cases following breast-conserving surgery. TILs were assessed on haematoxylin-eosin sections (n = 711) according to the International Immuno-Oncology Biomarker Working Group guidelines. TILs-scores were analysed as continuous and dichotomised (≤5% versus >5%) variable regarding ipsilateral breast events (IBEs) as the predefined primary endpoint. ResultsMost women (61.9%) showed a TILs prevalence of ≤5%. High TILs-scores were associated with larger lesion size, human epidermal growth factor receptor 2 (HER2)-positivity, higher nuclear grade, and KI67-score. DCIS cases with high TILs prevalence had a significant increased cumulative IBE incidence at five years post-surgery (TILslow-versus TILshigh 9% versus 18%; p < 0.001). Among patients with HER2-negative DCIS, high TILs remained an independent poor prognosis marker for IBE risk in multivariable analysis with an adjusted hazard ratio of 2.41 [95%CI 1.17–4.95, p = 0.017]. Including TILs-status provided a refined stratification of patients with general low-risk DCIS (grade <3, size <25 mm, free margin). No interaction between TILs and radiotherapy benefits was detected. ConclusionHigh TILs are associated with higher IBE risk over 5-years post-surgery, particularly for HER2-negative DCIS. Our data indicate that TILs should be integrated into the clinical workup to define patients with low-risk DCIS who can omit adjuvant therapy or patients with potential benefits from immunotherapy.

Abstract P3-18-01: Assessmentof DCISionRT for guiding radiotherapy of DCIS in Sweden

Abstract Background: Radiotherapy (RT) after breast conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces the relative ipsilateral breast event (IBE) risk by 50%. The DCISionRT® test estimates IBE risk in DCIS women treated with BCS, and RT benefit. The test has been validated in five cohorts, including the SweDCIS randomized trial. Swedish national guidelines define low-risk DCIS using clinicopathology criteria. Methods: We determined the number of women irradiated per IBE prevented and treatment-costs based on 10-year outcomes from the SweDCIS trial. Four strategies were compared: no RT (Strategy 1); RT for all (Strategy 2), RT for DCISionRT Elevated Risk only (Strategy 3); Swedish DCIS Guidelines, omit RT for low-risk (Strategy 4). In SweDCIS, women were randomised to RT or not after BCS, 1988-2000 (n=1046). Data for DCISionRT biomarkers (PR, HER2, Ki67, FOXA1, p16/INK4A, SIAH2, COX2) and clinical factors (age, tumor size, margin, palpability) were available for 504 women with negative margins. A decision score (DS, 0-10) was reported. The associations between Low (DS≤3) and Elevated Risk (DS&amp;gt;3) groups, and 10-year recurrences, and RT effect were assessed. Algorithms for mean treatment costs depending on adjuvant RT and type of recurrence, including secondary surgery, reconstruction, RT, and chemotherapy were based on data from 74 women with recurrence (41 invasive/33 in situ). Costs were based on diagnostic related grouping (DRG) in Sweden, 2020 and transformed to US dollar($). Results: In the SweDCIS validation of DCISionRT, the test divided women into Elevated (52%) and Low Risk (48%) groups. In the Elevated Risk group, RT decreased 10-year relative total and invasive recurrence rates, HR 0.32 (95%CI 0.17-0.58) and 0.24 (0.08-0.74), respectively with absolute decrease of 15.5% (5.9-25.0%) and 9.3% (2.0-16.5%). In the Low Risk group, the relative RT benefit was lower, HR 0.53 (0.28-1.02) and 0.84 (0.30-2.31), with decrease of 5.7% (-0.8-12.2%) and 1.2% (-5.7-8.2%). Invasive and in situ recurrences had an average treatment cost of $21,228 and $19,777, respectively. Treatment of recurrences after initial RT was $983 less expensive. RT-cost was $4,899. Strategy 1: For every 1000 women, 186 develop an IBE within 10-years after BCS without RT, with a treatment-cost in Sweden of $3,752,099. Strategy 2: Treating all women with RT prevents 108 IBE with treatment-costs of $6,467,113. Strategy 3: Treating women at DS Elevated Risk with RT prevents 81 IBE and 480 women are spared RT, with treatment-costs of $4,681,394. The cost of the test is not included. Strategy 4: Using Swedish Guidelines, prevents 100 recurrences and 870 receives RT with treatment-costs of $5,998,002. Compared to Strategy 1, Strategies 2, 3 and 4 decrease IBEs with increased treatment-costs. Treatment-costs increased $25,139/IBE prevented by Strategy 2, $11,473/IBE prevented by Strategy 3, and $26,115/IBE prevented by Strategy 4. The number of women irradiated per IBE prevented were 9.3, 6.4, and 10.1 for strategies 2, 3 and 4, respectively, relative to Strategy 1. Conclusion Strategy 1 (to omit RT) had the lowest treatment-costs and the highest number of recurrences. Strategy 3, using DCISionRT had the lowest number irradiated per IBE prevented at the lowest treatment-cost per IBE prevented. Table 1.DCIS BCS +/-RTRT%Recurrences per 1000 womenCost including RT and treatment of recurrence per 1000BCS RT(-)0%186$3,752,099BCS RT(+)100%78$6,467,113DCISionRT52%105$4,681,394Swedish Guidelines*87%86$5,998,002*Low-risk criteria from modified Swedish national guidelines NG 1–2, &amp;lt;1.5 cm, negative margin, and &amp;lt;52 years (mean age for menopause) Citation Format: Fredrik Wärrnberg, Charlotta Wadsten, Andrea Karakatsanis, Roger Olofsson Bagge, Erik Holmberg, Per Karlsson, Henrik Lindman, Pat W Whitworth, Elinor Sawyer, Chirag Shah, Steve Shivers, Frank Vicini, Bruce G Mann, Troy Bremer. Assessmentof DCISionRT for guiding radiotherapy of DCIS in Sweden [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-01.

Abstract P1-22-04: Decision aids and risk prediction models to support decision making about DCIS treatment: A systematic literature review

Abstract Background: Although most low-risk ductal carcinoma in situ (DCIS) lesions will not progress to invasive breast cancer if left untreated, clinical guidelines advise surgery with/without radiotherapy for all women diagnosed with DCIS. There is therefore increasing concern about the possible overtreatment of DCIS. Currently, clinical trials are being conducted to investigate the safety of active surveillance in low-risk DCIS patients. It is hypothesized that, in future, both surgery and active surveillance will be accepted treatment strategies. Active surveillance is offered to women in the ongoing trials and is expected to become a standard DCIS management option in the future. Choosing whether to undergo surgery for DCIS or to opt for active surveillance can be a difficult decision fraught with uncertainty for both patients and oncologists. Good quality decision support tools such as prediction models and patient decision aids to guide decision making about DCIS management, including the option of active surveillance, are therefore urgently needed. The aim of this study is to identify and evaluate the quality of published decision aids and prediction models aiming to support decision making about DCIS treatment. Methods: A systematic literature review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement criteria. The databases Medline(ovid), Embase (ovid), Scopus, and TRIP were searched to identify published manuscripts describing the development and/or evaluation of DCIS decision aids and prediction models. The protocol was published in the PROSPERO database (ID CRD42020212297). The CHARMS (Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies) checklist was used to evaluate the methodological quality of prediction models and the IPDAS (International Patient Decision Aid Standards) checklist was used to evaluate the quality of decision aids. Data extraction was performed by two researchers with discrepancies resolved through consensus. Results: The review identified 10,636 publications, 33 describing the development and/or validation of four decision aids and seven clinical prediction models were selected (Table 1). The decision aids identified met at least 50% of the IPDAS quality criteria. However, most decision aids lacked tools to help patients reflect on the information received and to facilitate discussion of the information with their family and healthcare providers. Most prediction models were designed to predict the risk of a subsequent ipsilateral breast event after a primary DCIS. No models included the option of active surveillance. Sufficient, good quality, external validation was lacking for all prediction models identified. Conclusions: There are only a few decision aids available that can be used to support patients diagnosed with DCIS. These decision aids could be improved to facilitate the processing of information by patients and enhance communication between patients and their support system and healthcare providers. There is no prediction model that considers active surveillance as a management option for DCIS, and based on the available evidence, there is no prediction model that can be recommended for use in clinical practice. More and qualitatively better validations are required in the future. Table 1.Overview of DCIS decision aids and prediction models identifiedDCIS DECISION AIDSDecision aid by Berger-Hoger et al.(2014)Communication aid by De Morgan et al.(2009)onlineDeCISion.org by Ozanne et al.(2016)DCISoptions.org by COMET trial team(SABCS 2020)Target audience:Women with DCISCliniciansClinicians and women with DCISWomen with DCISLanguage:GermanEnglishEnglishEnglishEvaluation study conducted:YesYesNot reportedNot reportedDesign evaluation study:RCTInterviewNot applicableNot applicableSample size evaluation study:6425Not applicableNot applicableMain finding evaluation study:More active patient involvementCommunication tool assists shared decision makingNot applicableNot applicableImplementation study conducted:None retrievedNone retrievedNone retrievedNone retrieved% IPDAS criteria met regarding:Content87%57%65%78%Development process71%59%67%42%Effectiveness100%50%75%75%DCIS PREDICTION MODELSOncotype DCIS(Solin et al. (2013))DCISionRT/PreludeDX(Bremer et al. (2018))Van Nuysprognostic index(Silverstein et al. (1995))MSKCC DCIS nomogram(Rudlof et al. (2010))Patient prognostic score(Sagara et al. (2016))PredictCBC(Giardello et al. (2019))CBC Risk model(Chowdhury et al. (2017))Predicted outcome:Ipsilateral breast eventIpsilateral breast eventIpsilateral breast eventIpsilateral breast eventIpsilateral breast eventContralateral breast cancerContralateral breast cancerTool based on:Multigene assayBiomarkers + clinico-pathological factorsClinicopatho-logical factors onlyClinicopatho-logical factors onlyClinicopatho-logical factors onlyClinicopatho-logical factors onlyClinicopatho-logical factors onlyIntended to support decision making about:Need for adjuvant radiotherapyNeed for adjuvant radiotherapyType of surgery and need for radiotherapyNeed for adjuvant radiotherapyNeed for adjuvant radiotherapyScreening or prophylactic mastectomyScreening or prophylactic mastectomyRisk of bias based on CHARMS:ModerateModerateModerate/HighModerateLowLowLowNumber (external) validations:3193001Reported C-index/AUC0.68None reportedNone reported0.61-0.68None reported0.52None reportedThis work was supported by Cancer Research UK and by KWF Dutch Cancer Society (ref.C38317/A24043) Citation Format: Renée SJM Schmitz, Erica Wilthagen, Frederieke van Duijnhoven, Marja van Oirsouw, Ellen Verschuur, Thomas Lynch, Rinaa S Punglia, Shelley Hwang, Jelle Wesseling, Marjanka K Schmidt, Eveline Bleiker, Ellen G Engelhardt, Grand Challenge PRECISION consortium. Decision aids and risk prediction models to support decision making about DCIS treatment: A systematic literature review [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-22-04.

Abstract P1-22-03: Expression of immune-related genes and breast cancer recurrence in women with ductal carcinoma in situ

Abstract Background. Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer (IBC). High variability in clinical outcomes and propensity for invasion among DCIS is reported, but identifying high-risk DCIS remains a major clinical challenge. Therefore, biomarkers to differentiate patients with indolent DCIS from those who would benefit from therapy are warranted. There are recent data on the role of the tumor immune microenvironment in the progression from DCIS to IBC and the risk of recurrences. However, no comprehensive information on the clinical actionability of DCIS immune-biology is available. We hypothesize that immune escape mechanisms might play a critical role in the transition from DCIS to IBC. Here, we sought to establish whether immune-related gene expression signatures of DCIS might identify women at high risk of disease recurrence and/or progression. Methods. We performed a retrospective nested case-control study including women with pure DCIS, diagnosed between 2009 and 2015 at European Institute Oncology (median follow-up 39,5 months) treated with conserving surgery +/- adjuvant therapy (endocrine therapy or radiotherapy). The study group (cases) was composed of women with DCIS and subsequent ipsilateral breast events (IBE, in situ or invasive). Controls were selected in a 1.1 ratio among DCIS without IBE, matched for age, tumor size, treatment, and hormone receptors (HR), and HER2 status. Stromal tumor-infiltrating lymphocytes (sTILs) were assessed according to the International Immuno-Oncology Biomarker Working Group on Breast Cancer guidelines. RNA extracted from formalin-fixed paraffin-embedded blocks was subjected to gene expression analysis using a next-generation sequencing assay (Oncomine™ Immune Response Research Assay) targeting 395 immune-related genes. Samples that achieve run quality parameters (mapped reads &amp;gt;1 million, valid reads &amp;gt;800.000) were further processed with the Affymetrix Transcriptome Analysis Console software to compare the gene expression between cases and controls (ANOVA, gene-level fold change &amp;lt;-2 or &amp;gt;2).Results. A total of 116 patients were included, 58 cases and 58 controls. High sTILs count was significantly associated with high-grade DCIS (p=&amp;lt;0,0001), the presence of necrosis (p=0,0210) and HER2 expression (p=&amp;lt;0,0001) in both groups. No significant association between sTILs count and the probability of relapse was observed. Gene expression data were available for 56 cases and 56 controls that achieved sequencing quality parameters. Overall, five genes were differentially expressed between cases and controls. In particular, cases showed upregulation of IFNA17 (p-value &amp;lt;0,0001; FDR p-value &amp;lt;0.0001), IFNB1 (p-value &amp;lt;0,0001; FDR p-value &amp;lt;0.0001), PECAM-1 (p-value &amp;lt;0,0001; FDR p-value &amp;lt;0.0001) and significant lower expression of CCL2 (p-value &amp;lt;0,0001; FDR p-value &amp;lt;0.0001) as compared to control group. Other genes that were upregulated in DCIS with IBE included FCGR2B, CD3D, CD40LG, while TCF7, CDKN3, ADORA2A were found to be downregulated (p-value &amp;lt;0.05).Conclusion. Quantitative TILs density assessment remains of modest significance in DCIS prognostication in terms of risk of IBE. We showed that pure DCIS displayed significant differences in the expression of immune-related genes between women with and without subsequent breast cancer recurrence regardless of HR and HER2 status. The activation of immune-related pathways might play a part in the development of IBE in patients with a diagnosis of DCIS. The evaluation of immune-related gene expression profiles might improve risk stratification in patients with DCIS. Citation Format: Elena Guerini Rocco, Caterina Fumagalli, Alberto Concardi, Sergio V. Taormina, Aliana Guerrieri-Gonzaga, Federica Corso, Sara Gandini, Bernardo Bonanni, Giuseppe Viale, Massimo Barberis, Nicola Fusco, Lazzeroni Matteo. Expression of immune-related genes and breast cancer recurrence in women with ductal carcinoma in situ [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-22-03.

Abstract P1-22-02: Subsequent risk of ipsilateral breast events in a multinational DCIS cohort of 48.619 patients: A meta-analysis within the PRECISION consortium

Abstract Background: The PRECISION (PREvent ductal Carcinoma In Situ Invasive Overtreatment Now) CRUK Grand Challenge project focusses on discriminating hazardous from indolent ductal carcinoma in situ (DCIS). Aim of these analyses is to identify factors associated with a lower or higher risk of developing invasive breast cancer after an initial DCIS diagnosis. Knowledge of these factors is crucial in our quest to reducing overtreatment for women with DCIS. Many clinicopathological features are hypothesized to be important factors affecting the risk of a subsequent breast lesion. Most studies performed so far are from trial or single country studies, we now present an integrated analysis of four different cohorts from three countries.Methods: Four cohorts from the three countries participating in PRECISION were identified. A population based cohort from the Netherlands cancer registry (Dutch cohort); a population based, prospective, screening cohort from the United Kingdom (Sloane cohort); a single center cohort from MD Anderson Cancer Center (MDACC) and a subset of DCIS patients abstracted from a population based National Cancer Database Special Study cohort (NCDB subset) in the United States. Patient-level data from these cohorts were combined for this analysis. Subsequent ipsilateral invasive breast cancer (iIBC) and subsequent ipsilateral DCIS (iDCIS) were assessed at five and ten years by Kaplan Meier analysis. The cumulative incidence of iIBC was assessed in three treatment groups: breast conserving surgery only (BCS), breast conserving surgery with radiotherapy (BCS+RT) and mastectomy (MST). Cumulative incidence of iDCIS was assessed in patients receiving BCS or BCS+RT. Additionally, cumulative incidences were calculated for iIBC and IDCIS in patients who received endocrine treatment (ET) after BCS or BCS+RT versus patients who did not receive ET. All cumulative incidences were calculated with death as competing risk. Results: The joint PRECISION cohort consisted of 48,619 patients, diagnosed between 1999 and 2017. Median follow-up was 7.4 years (0.6-17.9). In preliminary analyses, Kaplan Meier curves showed broadly similar risks in iIBC and iDCIS between the four different cohorts. The cumulative incidence of iIBC was 1.6% at five years and 3.5% at 10 years. Five-year cumulative incidence of iIBC was highest in patients receiving BCS (3.4%) compared with patients receiving BCS+RT or MST (1.3%). The cumulative incidence of iDCIS was 1.7% at 5 years and 2.4% at 10 years. Five-year cumulative incidence of iDCIS was higher in patients receiving BCS (3.5%) compared to patients receiving BCS+RT (1.9%). In univariate analyses, the effect of ET on cumulative incidence of both iIBC and iDCIS was modest, especially with respect to radiotherapy. Conclusion: Overall, 5- and 10-year incidence of an ipsilateral in situ or invasive breast lesion was low and similar between the four different cohorts. The incidence of iIBC and iDCIS was higher in patients receiving BCS, compared to women receiving BCS+RT or MST. Table 1.Cohort and patient characteristicsDutch Cohort Sloane MDACCNCDB subsetTotal CohortN=18,995N=8,425N=1,820N=19,379N=48,619Cohort descriptionProspectiveNoYesNoNoPopulation basedYesYesNo, single centerYesScreening and non-screeningYesScreening onlyYesYesMean (min - max)Mean (min - max)Mean (min - max)Mean (min-max)Mean (min-max)Age diagnosis DCIS58.3 (21-94)59.8 (46-88)55.6 (20-90)59.7 (20-98)59.0 (20-98)Year of diagnosis (range)1999-20152003-20121999-20172007-20151999-2017Follow-up in years10.4 (0.5-21.1)5.3 (0.5-9.7)8.7 (0.25-17.8)5.8 (0.5-10.7)7.6 (0.25-2.1)N (%)N (%)N (%)N (%)N (%)GradeGrade 12,844 (15.0)784 (9.3)141 (7.8)3,158 (16.3)6,927 (14.3)Grade 25,952 (31.3)2,328 (27.6)737 (40.5)6,844 (35.3)15,861 (32.6)Grade 38,944 (47.1)5,305 (62.9)933 (51.3)7,848 (40.5)23,030 (47.3)Unknown grade1,255 (6.6)8 (0.1)9 (0.5)1,529 (7.9)2,801 (5.8)Type of surgeryBreast conserving surgery (BCS)11,790 (62.1)5,830 (69.2)1,031 (56.7)14,504 (74.8)33,155 (68.2)Mastectomy (MST)7,205 (37.9)2,595 (30.8)789 (43.4)4,875 (25.2)15,464 (31.8)Adjuvant treatmentRadiotherapy (RT)9,650 (50.8)3,418 (40.6)762 (41.9)10,620 (54.8)24,450 (50.3)Endocrine treatmentNA1,151 (13.6)999 (54.9)8,849 (45.7)10,999 (37.0)5 years Cumulative IncidencesiIBC1.4%2.3%1.6%1.7%1.6%iDCIS1.5%2.0%1.6%1.7%1.7%Vital statusAlive16,472 (86.7)8,147 (96.7)1,668 (91.7)18,161 (93.7)44,448 (91.4)Deceased2,523 (13.3)278 (3.3)152 (8.4)1,218 (6.3)4,171 (8.6)This work was supported by Cancer Research UK and by KWF Dutch Cancer Society (ref.C38317/A24043) Citation Format: Renée SJM Schmitz, Sandra W van den Belt-Dusebout, Chiara Cresta, Yat-Hee Liu, Michael Schaapveld, Karen Clements, Jasmine Timbres, Danalyn T Byng, Marc D Ryser, Yi Ren, Thomas Lynch, Terry Hyslop, Brian Menegaz, Deborah Collyar, Shelley Hwang, Alastair Thompson, Elinor Sawyer, Jelle Wesseling, Esther H Lips, Marjanka K Schmidt, Grand Challenge PRECISION consortium. Subsequent risk of ipsilateral breast events in a multinational DCIS cohort of 48.619 patients: A meta-analysis within the PRECISION consortium [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-22-02.

Abstract GS4-07: The Breast PreCancer Atlas DCIS genomic signatures define biology and correlate with clinical outcomes: An analysis of TBCRC 038 and RAHBT cohorts

Abstract Background. DCIS consists of a molecularly heterogeneous group of premalignant lesions, with variable risk of invasive progression. Understanding biomarkers for invasive progression could help individualize treatment recommendations based upon tumor biology. As part of the NCI Human Tumor Atlas Network (HTAN), we conducted comprehensive genomic analyses on two large DCIS case-control cohorts. Methods. We performed smart3-seq and low-pass whole genome sequencing on two independent, retrospective, longitudinally sampled DCIS case-control cohorts. TBCRC 038 was a multicenter cohort diagnosed with DCIS between 1998 and 2016 at one of the Translational Breast Cancer Research sites; the RAHBT (Resource of Archival Human Breast Tissue) cohort included women identified through the St. Louis Breast Tissue Repository, and the Women’s Health Repository diagnosed between 1997 and 2001. We studied the spectrum of molecular changes present and sought genomic predictors of subsequent ipsilateral breast events (iBEs: DCIS recurrence or invasive progression) in both DCIS epithelium and stroma in formalin fixed paraffin embedded tissue. We generated de novo tumor and stroma-centric subtypes for DCIS that represents fundamental transcriptomic organization. Copy number analysis was performed using low-pass DNA sequencing. Non-negative matrix factorization (NMF) was applied to the RNA expression of all coding genes to identify clusters. A negative-binomial regression model was used to identify differentially expressed genes. Results. We analyzed 677 DCIS samples from 481 patients with 7.1 years median follow-up. In TBCRC samples, we identified three clusters via NMF in TBCRC referred to as ER low, quiescent, and ER high. The ER-low cluster had significantly higher levels of ERBB2 and lower levels of ESR1 compared to quiescent and ER-high clusters. Quiescent cluster lesions were less proliferative and less metabolically active than ER high and ER low subtypes. These findings were replicated in the RAHBT cohort. Focusing on the stromal component of DCIS from laser capture microdissection in RAHBT samples, we identified four distinct DCIS-associated stromal clusters. A “normal-like” stromal cluster with ECM organization and PI3K-AKT signaling; a “collagen-rich” stromal cluster; a “desmoplastic” stromal cluster with high fibroblast and total myeloid abundance, mostly associated with macrophages and myeloid dendritic cells (mDC); and an “immune-dense” stromal cluster. Further, we compared differentially expressed genes in patients with or without subsequent iBEs within 5 years of diagnosis. Hypothesizing that the resulting 812 DE genes (DESeq2) represent multiple routes to subsequent iBEs, we leveraged NMF to identify paths to progression. In both TBCRC and RAHBT cohorts, poor outcome groups exhibited increased ER, MYC signaling, and oxidative phosphorylation, supporting that these pathways are important for DCIS recurrence and progression. Conclusion. Comprehensive genomic profiling in two independent DCIS cohorts with longitudinal outcomes shows distinct DCIS stromal expression patterns and immune cell composition. RNA expression profiles reveal underlying tumor biology that is associated with later iBEs in both cohorts. These studies provide new insight into DCIS biology and will guide the design of diagnostic strategies to prevent invasive progression. Citation Format: Siri H Strand, Belén Rivero-Gutiérrez, Kathleen E Houlahan, Jose A Seoane, Lorraine M King, Tyler Risom, Lunden Simpson, Sujay Vennam, Aziz Khan, Timothy Hardman, Bryan E Harmon, Fergus J Couch, Kristalyn Gallagher, Mark Kilgore, Shi Wei, Angela DeMichele, Tari King, Priscilla F McAuliffe, Julie Nangia, Joanna Lee, Jennifer Tseng, Anna Maria Storniolo, Alastair Thompson, Gaorav Gupta, Robyn Burns, Deborah J Veis, Katherine DeSchryver, Chunfang Zhu, Magdalena Matusiak, Jason Wang, Shirley X Zhu, Jen Tappenden, Daisy Yi Ding, Dadong Zhang, Jingqin Luo, Shu Jiang, Sushama Varma, Cody Straub, Sucheta Srivastava, Christina Curtis, Rob Tibshirani, Robert Michael Angelo, Allison Hall, Kouros Owzar, Kornelia Polyak, Carlo Maley, Jeffrey R Marks, Graham A Colditz, E Shelley Hwang, Robert B West. The Breast PreCancer Atlas DCIS genomic signatures define biology and correlate with clinical outcomes: An analysis of TBCRC 038 and RAHBT cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-07.

Abstract P1-13-03: Radiotherapy vs. endocrine therapy for hormone receptor positive early stage breast cancer accounting for endocrine therapy adherence

Abstract Purpose/Objective(s):. Several trials have compared endocrine therapy (ET) alone vs. ET and radiotherapy (RT) in low risk early stage estrogen receptor (ER)-positive breast cancer and have shown that the addition of RT to ET modestly reduces the rate of loco-regional recurrence (LRR) without altering survival. ET may also yield modest reductions in contralateral breast events. ET alone has thus become a standard strategy in select patients. Data evaluating the efficacy of RT alone are scarce. However, the toxicity of ET is not trivial and its effectiveness is dependent upon treatment adherence. As RT courses become ever shorter and safer, a re-evaluation of the strategy of RT alone is warranted. This analysis reports on the treatment outcomes of ER-positive early stage breast cancer treated with adjuvant RT or ET alone at a multi-hospital health system. We hypothesized that adjuvant RT alone would yield loco-regional control comparable to that of ET alone and that ET adherence would influence outcomes. Materials/Methods:. The shared electronic health record of multiple facilities within a university health system was queried to identify women with pathologic T1-2 N0 breast cancer treated with breast-conserving surgery between 2007 and 2016. Data collection included demographic features, tumor characteristics, treatment type, and evidence of LRR. Analysis was restricted to those patients with ER positive disease who underwent either RT alone or ET alone. Five-year LRR were compared across groups using the Kaplan-Meier method. Results:. 240 patients met inclusion criteria. Of these, 86 were treated with RT alone and 154 with ET alone. Patient, tumor and ET variables are listed in the table below. ET adherence and duration information were available for 135 out of 154 patients who received ET alone. Patients who completed 5 years of ET or whose ET was discontinued due to the disease recurrence or death were categorized as ET-adherence (ET-A). Patients who discontinued ET before reaching 5 years due to other reasons were categorized as ET-non adherence (ET-NA). Median ET duration in ET-A was 60 months (range, 15-101 months) and in ET-NA was 13 months (range, 1-54 months). The 5-year rates of LRR for RT alone vs. ET alone were 4.1 % (95% CI 0-8.8) vs. 5.0 % (95% CI 1.1-8.9). The 5-year rates of LRR for ET-A vs. ET-NA were 2.0 % (95% CI 0-4.7) vs. 16.4 % (95% CI 1.1-31.7). While the difference in the LRR rates between RT alone vs. ET-A was not statistically significant (p= .481), ET-NA was associated with significantly higher LRR rate compared to RT alone or ET-A (p&amp;lt;.05). The rate of ET non-adherent rate was 21.4%. Conclusion:. RT yielded LRR equivalent to overall ET and superior to ET non-adherence. For patients with early stage ER+ breast cancer, a prospective randomized trial comparing RT to ET and evaluating quality of life (QoL) is needed. In light of emerging data, a five-day course of RT can be considered as an alternative to five years of ET, and RT should be strongly considered if ET adherence is in doubt. Table 1.Patient, tumor and treatment characteristicsRT alone (n=86)ET alone (n=154)Median follow-up (months)50.6 (1-135)48 (3-114)Age (median)63 (39-91)74 (50-87)StageT176 (88.4%)142 (92.2%)T210 (11.6%)12 (7.8%)HistologyGrade 38 (9.3%)9 (5.8%)+LVI5 (5.8%)3 (2.0%)Endocrine Therapy (ET)ET duration (median, months)-57 (1-101)ET-Adherent-102 (66.2%)ET-Non adherent-33 (21.4%)ET duration not available-19 (12.3%) Citation Format: Seung Won Seol, Travis Pflederer, Lauren Weller, Chelain Goodman, Eric D Donnelly, John P Hayes, Jonathan B Strauss. Radiotherapy vs. endocrine therapy for hormone receptor positive early stage breast cancer accounting for endocrine therapy adherence [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-13-03.

Long-term risk of subsequent ipsilateral lesions after surgery with or without radiotherapy for ductal carcinoma in situ of the breast

BackgroundRadiotherapy (RT) following breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces ipsilateral breast event rates in clinical trials. This study assessed the impact of DCIS treatment on a 20-year risk of ipsilateral DCIS (iDCIS) and ipsilateral invasive breast cancer (iIBC) in a population-based cohort.MethodsThe cohort comprised all women diagnosed with DCIS in the Netherlands during 1989–2004 with follow-up until 2017. Cumulative incidence of iDCIS and iIBC following BCS and BCS + RT were assessed. Associations of DCIS treatment with iDCIS and iIBC risk were estimated in multivariable Cox models.ResultsThe 20-year cumulative incidence of any ipsilateral breast event was 30.6% (95% confidence interval (CI): 28.9–32.6) after BCS compared to 18.2% (95% CI 16.3–20.3) following BCS + RT. Women treated with BCS compared to BCS + RT had higher risk of developing iDCIS and iIBC within 5 years after DCIS diagnosis (for iDCIS: hazard ratio (HR)age < 50 3.2 (95% CI 1.6–6.6); HRage ≥ 50 3.6 (95% CI 2.6–4.8) and for iIBC: HRage<50 2.1 (95% CI 1.4–3.2); HRage ≥ 50 4.3 (95% CI 3.0–6.0)). After 10 years, the risk of iDCIS and iIBC no longer differed for BCS versus BCS + RT (for iDCIS: HRage < 50 0.7 (95% CI 0.3–1.5); HRage ≥ 50 0.7 (95% CI 0.4–1.3) and for iIBC: HRage < 50 0.6 (95% CI 0.4–0.9); HRage ≥ 50 1.2 (95% CI 0.9–1.6)).ConclusionRT is associated with lower iDCIS and iIBC risk up to 10 years after BCS, but this effect wanes thereafter.

Prognostic and Predictive Value of HER2 Expression in Ductal Carcinoma In Situ: Results from the UK/ANZ DCIS Randomized Trial.

HER2 is overexpressed more frequently in ductal carcinoma in situ (DCIS) than in invasive breast cancer but its prognostic significance and predictive role for radiotherapy has not been clearly established. We investigated the prognostic and predictive value of HER2 overexpression in DCIS. HER2 expression was evaluated by IHC using the HercepTest™ in samples from UK/ANZ DCIS trial participants (n = 755) with IHC 3+ expression categorized as HER2 positive for primary analyses. Sensitivity analyses included HER2 categorization as negative (IHC 0,1+), equivocal (IHC 2+), and positive (IHC 3+) and analyses restricted to a nested case-control component where 181 cases (with recurrence) were matched to 362 controls by treatment arm and age. Two-hundred and forty-five (34.4%) of evaluable 713 samples [181 ipsilateral breast events (IBE)] were HER2 positive. HER2 overexpression was associated with significantly increased risk of IBE [HR = 2.29; 95% confidence interval (95% CI), 1.64-3.14; P < 0.0001] and in situ IBE (DCIS-IBE; HR = 2.90; 95% CI, 1.91-4.40; P < 0.0001), but not of invasive IBE (I-IBE; HR = 1.40; 95% CI, 0.81-2.42; P = 0.23; Pheterogeneity = 0.04). Inclusion of HER2 significantly improved [Δχ2 (1d.f.) 12.25; P = 0.0005] a prognostic model of clinicopathological and treatment variables, HER2 being an independent predictor of IBE (multivariate HR = 1.91; 95% CI, 1.33-2.76; P = 0.0004). Radiotherapy benefit in preventing DCIS-IBE was significantly greater (Pheterogeneity = 0.04) in HER2-positive DCIS (HR = 0.16; 95% CI, 0.07-0.41) compared with HER2-negative DCIS (HR = 0.58; 95% CI, 0.28-1.19). HER2 overexpression is associated with significantly increased risk of in situ recurrence and is also predictive of radiotherapy benefit, with greater reductions in in situ but not invasive recurrences in HER2-positive DCIS.

Patient-Derived Xenograft Engraftment and Breast Cancer Outcomes in a Prospective Neoadjuvant Study (BEAUTY).

Patient-derived xenografts (PDX) are a research tool for studying cancer biology and drug response phenotypes. While engraftment rates are higher for tumors with more aggressive characteristics, it is uncertain whether engraftment is prognostic for cancer recurrence. In a prospective study of patients with breast cancer treated with neoadjuvant chemotherapy (NAC) with taxane ± trastuzumab followed by anthracycline-based chemotherapy, we report the association between breast cancer events and PDX engraftment using tumors derived from treatment naïve (pre-NAC biopsies from 113 patients) and treatment resistant (post-NAC at surgery from 34 patients). Gray test was used to assess whether the cumulative incidence of a breast cancer event differs with respect to either pre-NAC PDX engraftment or post-NAC PDX engraftment. With a median follow-up of 5.7 years, the cumulative incidence of breast cancer relapse did not differ significantly according to pre-NAC PDX engraftment (5-year rate: 13.6% vs. 13.4%; P = 0.89). However, the incidence of a breast event was greater for patients with post-NAC PDX engraftment (5-year rate: 50.0% vs. 19.6%), but this did not achieve significance (P = 0.11). In treatment-naïve breast cancer receiving standard NAC, PDX engraftment was not prognostic for breast cancer recurrence. Further study is needed to establish whether PDX engraftment in the treatment-resistant setting is prognostic for cancer recurrence.

Application of RSClin to guide treatment recommendations for premenopausal patients with early-stage hormone-positive breast cancer and intermediate risk oncotype recurrence scores.

e12511 Background: The RSClin model, which incorporates the Oncotype Recurrence Score (RS) and clinicopathologic features, was recently developed to further tailor prognosis and prediction of chemotherapy benefit for patients with early-stage hormone positive (HR+) breast cancer (BC) (Sparano et al, 2020). The RSClin calculator is available online to assist treatment planning for situations where chemotherapy benefit is uncertain. Covariates include Oncotype RS, tumor grade, tumor size and patient age. The risk calculator generates a 10-year distant recurrence risk and absolute chemotherapy benefit. This tool may be especially helpful to determine treatment management for premenopausal patients with early-stage HR+ BC with intermediate risk (IR) Oncotype RS (16-25). We retrospectively applied RSClin to this patient population to determine if it would have changed treatment recommendations. Methods: We identified premenopausal women with node-negative early-stage BC with IR RS (16-25) within our large Oncotype database. Using the RSClin model, we selected &gt;5% absolute chemotherapy benefit as a reasonable cutoff to recommend chemotherapy. We compared the treatment recommendation based on RSClin with the treatment previously recommended by breast oncologists at our large academic medical center in New York City. Results: There were 86 patients who met criteria with a median age of 46 years. Of these, 26 patients (30%) were recommended chemotherapy plus endocrine therapy (ET) and 60 (70%) were recommended ET alone. After applying the RSClin model (data available for 83/86 patients), 19 (23%) would have resulted in a change in treatment recommendation and 64 (77%) would have remained unchanged. Overall, 8 (10%) would have withheld chemotherapy when it was previously offered and 11 (13%) would have recommended chemotherapy when it was previously excluded. There were 8 (9%) secondary invasive breast events in this population, with 2 (2%) being ipsilateral, 3 (3%) being contralateral and 3 (3%) metastatic at a median follow up of 46.9 months. Conclusions: The RSClin model would have changed management of premenopausal patients with IR RS in 23% of patients. This model, although not yet prospectively validated, may help individualize therapy for patients with less definitive treatment plans. Using RSClin, we can aim to minimize recurrence rates and avoid unnecessary chemotherapy in selected patients. This model is easy to apply and will have important clinical utility moving forward.