Risk Of Breast Cancer Recurrence Research Articles

Abstract P4-03-18: Group-based trajectories of endocrine therapy adherence and risk of recurrence in a Danish premenopausal breast cancer cohort

Abstract Background: Adjuvant endocrine therapy (AET) approximately halves the risk of recurrence among the two-thirds of premenopausal breast cancer patients whose tumors overexpress the estrogen receptor (ER+). AET is recommended for a minimum five-year duration, but many premenopausal women discontinue AET prematurely. Adherence to AET is dynamic and influenced by many behavioral, societal, clinical, and genetic factors. Describing longitudinal patterns of AET adherence is an important first step towards identifying patients at highest risk of nonadherence–-and therefore recurrence–-who may benefit from adherence-enhancing interventions. We used group-based trajectory models to (1) describe AET adherence patterns, and (2) estimate associations between AET adherence and breast cancer recurrence in a Danish premenopausal, ER+ breast cancer cohort. Methods: Our cohort included 4,487 premenopausal women diagnosed with ER+, stage I–III primary breast cancer registered in the Danish Breast Cancer Group (DBCG) clinical database and treated with AET (2002–2011). We followed all patients from initiation of AET until recurrence, mortality, 10 years of follow-up, another primary malignancy, or the end of available follow-up. We excluded individuals with less than 1.5 years of follow-up as breast cancer recurrences that occur in this time are unlikely to be related to AET. At semi-annual follow-up visits, women were registered as having received (or not) a six-month supply of AET. We created daily indicators to determine if a woman had at least 80% of days covered by an AET fill within each six-month period for the first 4.5 years following AET initiation, yielding 9 variables indicating time-varying adherence. We used these indicators to characterize adherence trajectory groups. We defined recurrence as local, regional or distant metastases or contralateral breast cancer registered in the DBCG using follow-up data through 2017. We fit Cox regression models, adjusted for age and clinical factors, to estimate the association between adherence trajectory groups and recurrence. Results: We identified distinct trajectory groups in the cohort (Table 1)—high adherence (69%), slow decline (23%), and quick decline (8%). Women with quick decline were more likely to have stage I disease, have no positive lymph nodes, to not be treated with chemotherapy, and to have lumpectomy instead of mastectomy when compared to women with high adherence. Compared with high adherence women, the estimated rate of breast cancer recurrence was higher among those with slow decline (HR=1.12, 95%CI=1.04–1.21) and those with quick decline (HR=1.38, 95%CI=1.22–1.56). Conclusions: Group-trajectory modeling facilitated empirical description of AET adherence patterns in a premenopausal breast cancer cohort. As expected, women who more rapidly became AET-nonadherent were at increased risk of breast cancer recurrence compared with those who remained adherent. Future analyses will explore the contribution of specific socioeconomic, genetic, and clinical factors to AET adherence patterns, which will inform the design of interventions to improve AET adherence and reduce recurrence risk in breast cancer patients. Table 1. Trajectory group and the observed proportion of individuals adherent to their adjuvant endocrine therapy (AET) over 4.5 years of follow-up Citation Format: Kirsten M. Woolpert, Julie A. Schmidt, Thomas P. Ahern, Timothy L. Lash, Lindsay J. Collin, Bent Ejlertsen, Deirdre Cronin-Fenton. Group-based trajectories of endocrine therapy adherence and risk of recurrence in a Danish premenopausal breast cancer cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-18.

Abstract PD11-06: PD11-06 Circulating tumor DNA association with residual cancer burden after neoadjuvant therapy in triple negative breast cancer in TBCRC 030

Abstract Background. Patients (pts) with early triple negative breast cancer (eTNBC) are at increased risk of breast cancer recurrence and death. Recent studies have focused on escalation of therapy, with current treatment standard of at least five drugs – and associated toxicities - for eTNBC. Though presence of residual disease after neoadjuvant therapy (NAT) as measured by residual cancer burden (RCB) helps guide addition of adjuvant treatment, more effective tools to tailor therapy are limited. Persistence of circulating tumor DNA (ctDNA) in the setting of residual disease is associated with high risk of distant recurrence. However, more sensitive minimal residual disease (MRD) assays are needed to potentially guide optimization of systemic therapy. Methods. TBCRC 030 is a phase II randomized study of 12 weeks of NAT single agent cisplatin or paclitaxel for stage II-III TNBC, followed by surgery. The primary objective of the parent study was to correlate baseline biomarker for homologous recombination deficiency and RCB by study arm. From this group, responders (RCB 0/1) and non-responders (RCB 2/3) from both study arms who did not receive additional NAT prior to surgery were selected for analysis from the study cohort, matched on baseline nodal status and tumor size. As a post hoc study amendment, available pts were followed for event free survival (EFS). Plasma samples were collected prior to treatment initiation (W0), at three weeks (W3), and at twelve weeks, prior to surgery (W12). Whole genome sequencing (WGS) was performed on primary tumor tissue to identify somatic mutations and design for each pt a tumor-informed, ctDNA assay tracking up to 1000 mutations to detect MRD. Detection limit was computed for each tested sample as previously described. For each sample assayed, we report tumor fraction (TFx) when MRD was detected and the detection limit at 90% power when MRD was not detected. Results. Of 139 study pts, 68 had complete tissue and plasma samples and no receipt of additional NAT. Of these, 22 were responders. These responders, and 22 matched non-responders were identified for analysis. Data from 22 pts – 11 responders, 11 non-responders - are described here; full analysis on all 44 pts will be presented at the meeting. Personalized ctDNA assays were designed targeting 434 to 1000 variants (median 1000) and applied to 66 plasma samples. At W0, 100% (22/22) were positive for ctDNA; 73% (16/22) and 55% (12/22) were positive at W3, and W12, respectively. In pts with T1-T2 tumors median TFx was 4.1e-3(7.8e-6, 3.4e-2) and 4.7e-1(4.3e-2, 9.0e-1) in pts with T3-T4 tumors. TFx decreased from W0 to W3 and from W0 to W12 in responders (Table 1). By W12, ctDNA had cleared in 7/8 pts with RCB 0, 1/3 with RCB 1, 2/8 with RCB 2, and 0/3 with RCB 3. Overall, ctDNA levels were broad with median TFx of 1.5e-3 (range 2.9e-6 to 0.90). Detection limit at 90% power for all tested samples was a median of 8.8e-6 (range 9.9e-7 to 6.8e-3). To investigate whether ctDNA persistence after NAT was associated with BC recurrence, we analyzed a separate group of all 8 pts with known recurrence and with complete data and samples. All pts had persistent ctDNA at W12 (median TFx 6.8e-3, [2.9e-6 to 6.6e-2]). Conclusions. After 3 weeks of NAT for eTNBC, ctDNA TFx decreased, with a 3900-fold change in responders and 18-fold change in non-responders. By W3, TFx for most pts with RCB 0/1 were below the 1 in 10,000 limit of detection for many currently available assays, emphasizing the need for sensitive tests to potentially guide therapy. Additional studies will determine if ctDNA-guided approaches in eTNBC can improve pt outcomes. Table 1: Tumer Fraction and Tumer Fraction Fold Change by Response to Neoadjuvant Therapy Citation Format: Heather A. Parsons, Timothy Blewett, Xiangying Chu, Sainetra Sridhar, Katheryn Santos, Kan Xiong, Vandana Abramson, Ashka Patel, Ju Cheng, Adam M. Brufsky, Justin Rhoades, Jeremy Force, Ruolin Liu, Tiffany A. Traina, Lisa Carey, Mothaffar Rimawi, Ahmed Elkhanany, Vered Stearns, Jennifer M. Specht, Harold Burstein, Antonio C. Wolff, Eric Winer, Nabihah Tayob, Ian Krop, Todd Golub, Erica L. Mayer, Viktor Adalsteinsson. PD11-06 Circulating tumor DNA association with residual cancer burden after neoadjuvant therapy in triple negative breast cancer in TBCRC 030 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-06.

Abstract P2-11-08: Multimodal Prediction of Breast Cancer Recurrence Assays and Risk of Recurrence

Abstract Background: Hormone receptor positive breast cancer constitutes about 70% of newly diagnosed early-stage disease in the United States, and gene-expression based recurrence assays such as Oncotype DX (ODX) are strongly recommended by guidelines to aid in treatment decisions. However, recurrence assays are costly, time-consuming, underutilized in low resource settings, and unavailable in developing countries. Deep Learning (DL) using hematoxylin and eosin (H&E) stained digital pathology has been shown to approximate gene expression patterns for multiple cancer types, and may provide a cost-effective, fast, and scalable method to predict risk of recurrence in community settings. Methods: We first developed a model for ODX using only DL on pathology, comprised of two Xception-based modules, trained on 1,039 slides from The Cancer Genome Atlas (TCGA) tessellated into 10x magnification image tiles. The first module predicts tumor likelihood, and was trained using pathologist annotations for tumor regions versus normal stroma. The second module was trained to predict ODX score, estimated from gene expression data within TCGA. Patient-level predictions were calculated by weighting the predicted recurrence score by tumor likelihood for all tiles within a slide. Separately, ODX score was predicted from clinical variables using the University of Tennessee Nomogram, which incorporates grade, progesterone receptor, size, age, and histologic subtype. Finally, we developed a combined model by fitting a logistic regression to the DL pathologic model and the clinical nomogram predictions. Performance of the clinical nomogram, pathologic, and combined models were then compared in a single-institution external validation cohort of patients diagnosed with breast cancer between 2006 and 2020, all of whom had the commercial ODX assay run. Results: We identified 428 cases for our diverse validation cohort (69% White, 24% Black, 6% Asian, and 3% Hispanic) with mean ODX score of 18. Chemotherapy was administered for 104 (24.3%) of patients, the remaining 323 (75.4%) received endocrine therapy alone. Area under the receiver operating characteristic curve (AUROC) for prediction of high ODX score (≥ 26) of the combined model was 0.83 (95% confidence interval [CI] 0.78 – 0.89) in the validation cohort, which was higher than either the DL pathology model (AUROC 0.80, 95% CI 0.75 – 0.85, p = 0.026) or the Tennessee nomogram (AUROC 0.77, 85% CI 0.70 – 0.83, p = 0.003). Performance was similar in Black (AUROC 0.86, 95% CI 0.78 – 0.94) and White (AUROC of 0.81, 95% CI 0.74 – 0.88) subgroups. The combined model was more accurate in prediction of recurrence-free interval in patients receiving endocrine therapy (hazard ratio [HR] 2.02 per standard deviation [SD], 95% CI 1.16 – 3.52, p = 0.013, Concordance [C]-index 0.75) than the clinical nomogram (HR 1.75 per SD, 95% CI 1.09 – 2.81, p = 0.021, C-index 0.68). No model was prognostic in patients receiving chemotherapy. Pathologist review of heatmaps of DL model predictions identified lymphovascular invasion, necrosis, high grade, and infiltrative borders as features contributing to model prediction of high risk. Conclusions: DL can improve on existing clinical prediction of breast cancer with low recurrence risk. This approach could improve the speed at which treatment decisions are made due to the time-consuming nature of genomic testing and simultaneously reduce the cost of care. Given the equal performance in racial subgroups, this approach has promise for application in global health settings where genomic assays are not widely available or are prohibitively expensive. Citation Format: Frederick M. Howard, James M. Dolezal, Sara Kochanny, Galina Khramtsova, Jasmine Vickery, Andrew Srisuwananukorn, Anna Woodard, Nan Chen, Rita Nanda, Charles Perou, Olufunmilayo I. Olopade, Dezheng Huo, Alexander Pearson. Multimodal Prediction of Breast Cancer Recurrence Assays and Risk of Recurrence [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-08.

Abstract P2-03-23: Retrospective evaluation of outcomes in a real-world, prospective cohort using EndoPredict: Results from the Charité registry

Abstract Background: EndoPredict is a prognostic and predictive gene expression assay that provides an EPclin risk score, which can be used to identify individuals with low enough risk of distant breast cancer recurrence that they may forgo chemotherapy. In clinical studies, EndoPredict has been validated to predict risk of distant recurrence up to 15 years and chemotherapy benefit. To date, real-world studies evaluating patient outcomes after prospective EndoPredict testing have been limited. Here, we report on outcomes collected via survey from patients enrolled in a registry created to generate real-world evidence from over 800 patients routinely tested with EndoPredict at Charité University Hospital Berlin. Methods: Female patients with hormone receptor positive, HER2 negative primary breast cancer with up to three positive lymph nodes who received prospective EndoPredict testing at Charité University Hospital Institute of Pathology between 2011 and 2016 were contacted to complete a survey for participation in this study. Surveys included questions on treatment and recurrence history. Patient demographics, clinical characteristics of the cancer, and EndoPredict results were retrieved from Charité records. All patients received EndoPredict test results before decision making on systemic treatment. After testing, treatment included either adjuvant endocrine therapy or adjuvant endocrine therapy plus adjuvant chemotherapy, and may have included radiotherapy. Cox proportional hazards models were fit with binary EPclin risk category (high, low) or continuous EPclin risk score predicting 5-year distant recurrence or recurrence of any kind. Analyses were performed across all survey responses, and in subsets of patients stratified by adjuvant chemotherapy treatment. Kaplan-Meier estimates of 5-year risk of recurrence were also calculated. Results: 842 patient survey responses were returned with informed consent and met study inclusion criteria. The median age at diagnosis was 54 years (IQR 49, 63), and across survey responses, 63.5% (N=535/842) of patients were lymph node negative, 60.9% (N=513/842) were T1, and 43.9% (N=370/842) were treated with adjuvant chemotherapy. Among included patients, 49.5% (N=417/842) were classified as EPclin low-risk and 50.5% (N=425/842) were high-risk. The concordance between EPclin risk category and chemotherapy status was 0.89 with 5.5% (N=23/417) of EPclin low-risk and 81.6% (N=347/425) of EPclin high-risk patients receiving treatment with chemotherapy. In the subset of patients not treated with adjuvant chemotherapy (N=472/842, 55.7%), continuous EPclin score was a significant predictor of distant recurrence (N=469; HR: 4.34, 95% CI 1.75-9.58); p = 2.4 × 10-3), and recurrence of any kind (N=468; HR: 3.39, 95% CI 1.61-6.58); p = 1.9 × 10-3). In EPclin low-risk patients treated with endocrine therapy alone, there was a low risk of 5-year distant recurrence (1.6%, 95% CI 0.7%-3.4%). In EPclin high-risk patients the risk of distant recurrence at 5 years was 6.8% (95% CI 2.6%-17.4%) in patients without chemotherapy and 3.6% (95% CI 2.1%-6.3%) in patients treated with chemotherapy. In an exploratory subgroup analysis in patients with node negative and node positive disease, risk of 5-year distant recurrence in EPclin low-risk patients without chemotherapy was 1.3% (95% CI 0.5%-3.5%) and 2.4% (95% CI 0.6%-9.2%), respectively. Conclusion: In this real-world cohort of patients with prospective routine testing with EndoPredict, EPclin scores were a significant predictor for patient-reported outcomes. Patients with EPclin low-risk scores had a low risk of 5-year distant recurrence even in the absence of chemotherapy treatment. This real-world result supports previous clinical studies demonstrating that patients with EPclin low-risk scores can safely forgo chemotherapy. Citation Format: Wolfgang D. Schmitt, Paul Jank, Inga Hoffmann, Berit M. Pfitzner, Lauren Lenz, Wyatt Clegg, Elke Keil, Sarah Ratzel, Elizabeth S. Cogan, Jens-Uwe Blohmer, Pauline Wimberger, Ralf Kronenwett, David Horst, Carsten Denkert. Retrospective evaluation of outcomes in a real-world, prospective cohort using EndoPredict: Results from the Charité registry [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-23.

Abstract P3-03-08: Depression and breast cancer recurrence among female veterans in the United States: a retrospective cohort study

Abstract Background: The importance of mental health to improve the quality of cancer survivorship and outcomes is gaining increased attention. Major depressive disorder (MDD) has been associated with higher breast cancer (BC) incidence, BC-specific and all-cause mortality. The effect of MDD on BC recurrence remains under-studied. The Veterans Health Administration (VHA) provides a unique opportunity to examine this relationship as it mandates annual MDD screening in the primary care setting and reports national screening rates of 96%. Objective: To examine the relationship between pre-existing MDD and BC recurrence among a diverse cohort of women in the United States. Methods: We established a retrospective cohort of women (age ≥ 18 years) diagnosed with early-stage incident BC from 2010 through 2019 using the VHA’s electronic medical record database. We used a two-year window to identify women with clinically diagnosed MDD prior to their BC diagnosis. Our outcome of interest was BC recurrence (local recurrence/second primary and distant recurrence). We used multivariable proportional hazards regression to examine the association between MDD and BC recurrence, accounting for competing risk of death. Our analyses were adjusted for age, race, ethnicity, marital status, priority group rating (proxy for socioeconomic status), rurality of primary residence, geographical region, cancer stage, year of BC diagnosis, and comorbidity burden. Priority group rating is a metric that incorporates patients’ income, receipt of VHA assistance benefits, capacity for gainful employment, and severity of service-connected conditions. We conducted subgroup analyses by tumor subtype. RESULTS: Our cohort consists of 6,045 women with BC, of whom 1,750 (29.0%) had a pre-existing MDD diagnosis. The median length of follow-up from BC diagnosis was 4.5 years (IQR=4.8 years). The average age at BC diagnosis was 57 years (SD=11 years) overall and 56 years (SD=10 years) among women with MDD. Sixty-one percent of women were white, 29% were black, 27% were married, and 28% were rural dwelling. Forty-four percent of invasive carcinomas were localized and 21% were regional. Thirty-five percent of patients had ductal carcinoma in situ. Women with MDD had a higher average Charlson Comorbidity Index score (mean=0.75, SD=1.13 vs. mean=0.58, SD=1.03) and proportion with a priority group rating between 1-4 (40% vs. 32%). The distribution of other described patient characteristics among women with MDD were similar to the overall cohort. On multivariable analysis, women with MDD had a 31% (95% CI: 1.11, 1.56) higher risk of BC recurrence compared to women without MDD. MDD was associated with a 29% (95% CI: 1.01, 1.66) and 33% (95% CI: 1.05, 1.67) higher risk of local recurrence/second primary and distant recurrence, respectively. The relationship between MDD and BC recurrence remained significant after adjusting for tumor subtype (HR=1.40, 95% CI: 1.07, 1.83). In subgroup analyses stratified by tumor subtype, MDD was associated with a higher risk of BC recurrence among women with estrogen receptor positive versus negative tumors (HR=1.65, 95% CI: 1.27, 2.14 vs. HR=0.71, 95% CI: 0.34, 1.46) and HER2/neu negative versus positive tumors (HR=1.53, 95% CI: 1.16, 2.00 vs. HR=1.24, 95% CI: 0.51, 2.96). The interaction between estrogen receptor status and MDD was statistically significant (p-interaction=0.02). CONCLUSION: Women with incident BC should be screened for MDD early in the cancer care continuum given the prevalence of MDD and association with increased risk of local recurrence/second primary and distant BC recurrence. Further research is needed to understand the interplay between these two diseases and their treatments. Citation Format: Maya Aboumrad, Brian Shiner, Avonne Connor, Bradley V. Watts, Kala Visvanathan. Depression and breast cancer recurrence among female veterans in the United States: a retrospective cohort study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-08.

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence.

Abemaciclib [Verzenio® (USA) or Verzenios® (EU)] is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved in combination with adjuvant endocrine therapy for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), node-positive, early breast cancer with a high risk of recurrence. In a phase III trial, abemaciclib plus endocrine therapy reduced the risk of recurrence of breast cancer compared with endocrine therapy alone, including in patients who had previously received neoadjuvant chemotherapy, in patients with high- and low-scoring Ki-67 tumours, and in both premenopausal and postmenopausal patients. The tolerability profile of abemaciclib plus endocrine therapy was acceptable and manageable, with diarrhoea, infections and neutropenia being the most common adverse events. Thus, abemaciclib in combination with standard endocrine therapy is a valuable additional treatment option for patients with HR+, HER2-, node-positive early breast cancer with a high risk of recurrence.

Blood-Based mRNA Tests as Emerging Diagnostic Tools for Personalised Medicine in Breast Cancer.

Molecular diagnostic tests help clinicians understand the underlying biological mechanisms of their patients' breast cancer (BC) and facilitate clinical management. Several tissue-based mRNA tests are used routinely in clinical practice, particularly for assessing the BC recurrence risk, which can guide treatment decisions. However, blood-based mRNA assays have only recently started to emerge. This review explores the commercially available blood mRNA diagnostic assays for BC. These tests enable differentiation of BC from non-BC subjects (Syantra DX, BCtect), detection of small tumours <10 mm (early BC detection) (Syantra DX), detection of different cancers (including BC) from a single blood sample (multi-cancer blood test Aristotle), detection of BC in premenopausal and postmenopausal women and those with high breast density (Syantra DX), and improvement of diagnostic outcomes of DNA testing (variant interpretation) (+RNAinsight). The review also evaluates ongoing transcriptomic research on exciting possibilities for future assays, including blood transcriptome analyses aimed at differentiating lymph node positive and negative BC, distinguishing BC and benign breast disease, detecting ductal carcinoma in situ, and improving early detection further (expression changes can be detected in blood up to eight years before diagnosing BC using conventional approaches, while future metastatic and non-metastatic BC can be distinguished two years before BC diagnosis).

Toward model-informed precision dosing for tamoxifen: A population-pharmacokinetic model with a continuous CYP2D6 activity scale

BackgroundTamoxifen is important in the adjuvant treatment of breast cancer. A plasma concentration of the active metabolite endoxifen of > 16 nM is associated with a lower risk of breast cancer-recurrence. Since inter-individual variability is high and > 20 % of patients do not reach endoxifen levels > 16 nM with the standard dose tamoxifen, therapeutic drug monitoring is advised. However, ideally, the correct tamoxifen dose should be known prior to start of therapy. Our aim is to develop a population pharmacokinetic (POP-PK) model incorporating a continuous CYP2D6 activity scale to support model informed precision dosing (MIPD) of tamoxifen to determine the optimal tamoxifen starting dose. MethodsData from eight different clinical studies were pooled (539 patients, 3661 samples) and used to develop a POP-PK model. In this model, CYP2D6 activity per allele was estimated on a continuous scale. After inclusion of covariates, the model was subsequently validated using an independent external dataset (378 patients). Thereafter, dosing cut-off values for MIPD were determined. ResultsA joint tamoxifen/endoxifen POP-PK model was developed describing the endoxifen formation rate. Using a continuous CYP2D6 activity scale, variability in predicting endoxifen levels was decreased by 37 % compared to using standard CYP2D6 genotype predicted phenotyping. After external validation and determination of dosing cut-off points, MIPD could reduce the proportion of patients with subtherapeutic endoxifen levels at from 22.1 % toward 4.8 %. ConclusionImplementing MIPD from the start of tamoxifen treatment with this POP-PK model can reduce the proportion of patients with subtherapeutic endoxifen levels at steady-state to less than 5 %.

Superior survival for breast-conserving therapy over mastectomy in patients with breast cancer: A population-based SEER database analysis across 30 years.

It has been believed that breast-conserving therapy (lumpectomy plus adjuvant radiation, Lum + RT) and mastectomy without radiation (Mast + NoRT) have equivalent survival outcomes. However, there is a need to re-evaluate the role of lumpectomy plus adjuvant radiation due to changed breast cancer management over time. This study aimed to conduct a population-based study that compare long-term oncologic survival outcomes after Lum + RT vs Mast + NoRT. The Surveillance, Epidemiology and End Results database was used to identify female breast cancer patients with a primary localized breast cancer diagnosis from 1988 to 2018. The standardized incidence/mortality ratio (SIR/SMR) for breast cancer recurrence (BCR) and breast cancer-specific death (BSD) was estimated by the SEER*Stat program. Cumulative incidences of BCR and BSD were assessed using Gray's method. We evaluated the effects of Lum + RT vs. Mast + NoRT on breast cancer recurrence-free survival (BRFS) and breast cancer-specific survival (BCSS). Fine-Gray competing risk model analyses, propensity score-adjusted Kaplan-Meier analyses and Cox proportional hazards model analyses were applied. A total of 205,788 women were included in the study. Patients who underwent Lum + RT had higher SIR of BCR (4.14 [95% confidence interval, CI: 3.94-4.34] vs. 1.11 [95% CI: 1.07-1.14]) and lower SMR (9.89 [95% CI: 9.71-10.08] vs. 17.07 [95% CI: 16.82-17.33]) than patients who underwent Mast + NoRT. Lum + RT was associated with higher competing risk of BCR (adjusted hazard ratio [HR]: 1.996, 95% CI: 1.925-2.069, p < 0.001) and lower competing risk of BSD when compared to Mast + RT (adjusted HR: 0.584, 95% CI: 0.572-0.597, p < 0.001). Multivariate Cox regression analysis revealed similar results (adjusted HR after PSW for BRFS: 1.792, 95% CI 1.716-1.871, p < 0.001; adjusted HR after PSW for BCSS: 0.706, 95% CI 0.688-0.725, p < 0.001). These findings persisted in the sensitivity and subgroup analyses. The present study further confirmed superior long-term survival with lumpectomy plus adjuvant radiation over mastectomy independent of patient characteristics including age, race, time period, historic subtype, tumor size, historic grade and stage, indicating that this benefit may result from the treatment itself.

Hormone Receptor-Positive / HER2-Negative Early Breast Cancer High-Risk Population: An Algorithm for Optimization Systemic Adjuvant Treatment Based on 2022 Updates.

Prognostic and predictive factors for early and late distant distance recurrence risk in estrogen-receptor positive and HER2-receptor negative early breast cancer are well known, but not all these variables work equally for the prediction. The following are the most widely accepted variables for categorizing risk levels: clinic-pathologic features (tumor size, lymph node involvement, histological grade, age, menopausal status, Ki-67 expression, estrogen, and progesterone expression), primary systemic treatment response (pathologic response and/or Ki-67 downstaging), and gene expression signatures stratification. Treatment guidelines from cancer societies and collaborative groups, online predict-tools, real-world data and experts' opinion recommends different adjuvant strategies (chemotherapy, endocrine therapy, ovarian suppression, olaparib, or abemaciclib) depending on the low (< 10%), intermediate (10%-20%) or high-risk of distance recurrence at least in the first 5 years. Multiple randomized prospective trials were updated in 2022, that evidence allow us to perform a stratification of risk in pre- and postmenopausal women with estrogen-receptor positive and HER2-receptor negative early breast cancer based on a combination of clinic-pathologic features and genomic assays and guide the adjuvant systemic treatment recommendation for those with high risk.

Integrative analyses of radiation-related genes and biomarkers associated with breast cancer.

In addition to significantly reducing breast cancer recurrence risk, radiotherapy also prolongs patients' lives. However, radiotherapy-related genes and biomarkers still remain poorly understood. The present study aimed to identify radiation-associated genes in breast cancer. Breast cancer data were downloaded from Gene Expression Omnibus (GEO) and UCSC Xena database. The gene ontology (GO) enrichment and gene set enrichment analysis (GSEA) were performed for annotation and integrated discovery. Protein-protein interaction (PPI) network was constructed by STRING database and hub genes were identified. Then, immunohistochemistry and tissue expression of key genes was analyzed by using the Human Protein Atlas (HPA) and GEPIA database. Genes associated with prognosis were identified by performing univariate cox analysis. We identified 341 differentially expressed genes related to radiotherapy in breast cancer patients. PPI analysis revealed a total of 129 nodes and 516 interactions and identified five hub genes (EGFR, FOS, ESR1, JUN, and IL6). In addition, 11 SDEGs THBS1, SERPINA11, NFIL3, METTL7A, KCTD12, HSPA6, EGR1, DDIT4, CCDC3, C11orf96, and BCL2A1 candidate genes can be used as potential diagnostic markers. The calibration curve and ROC indicate good probability consistencies of 3-years and 5-year survival rates of patients between estimation and observation. Our findings provide novel insight into the functional characteristics of breast cancer through integrative analysis of GEO data and suggest potential biomarkers and therapeutic targets for breast cancer.

Meta-Analysis of the Oncological Safety of Autologous Fat Grafting After Breast Cancer on Basic Science and Clinical Studies.

The purpose of the present study was to comprehensively evaluate the oncological safety of autologous fat grafting after breast cancer by combining experimental and clinical studies. All studies published before August 2021 were collected by searching PubMed, Cochrane, Embase, Web of Science, SINOMED, and China National Knowledge Infrastructure. After screening the research and extracting the data, RevMan was used to perform the meta-analysis. Five basic science studies and 26 clinical studies, involving a total of 10,125 patients, were eventually included. In the basic science studies, adipose-derived stem cells promoted breast cancer growth, but fat grafting and adipose-derived stem cells plus fat grafting were not associated with breast cancer growth. An overall analysis of clinical studies showed that autologous fat grafting does not increase the risk of breast cancer recurrence. Subgroup analyses indicated that autologous fat grafting did not increase the risk of breast cancer recurrence in Asian or Caucasian patients, in patients undergoing breast-conserving surgery or modified radical mastectomy, in patients with in situ carcinomas or invasive carcinomas, or in patients undergoing postoperative radiotherapy. This study combined experimental and clinical studies to conclude that autologous fat grafting does not increase the risk of breast cancer recurrence. However, the experimental results suggest that adipose-derived stem cells should be used with caution after breast cancer surgery. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Obesity and metabolic syndrome are associated with short-term endocrine therapy resistance in early ER + breast cancer.

Increased body mass index (BMI) and metabolic syndrome (MS) are associated with increased breast cancer recurrence risk. Whether this is due to intrinsic tumor biology or modifiable factors of the obese state remains incompletely understood. Oncotype DX Recurrence Scores of 751 patients were stratified by BMI to assess association with tumor-intrinsic recurrence risk. Cellular proliferation by Ki67 after 10-21days of presurgical letrozole treatment was used to stratify endocrine therapy response (sensitive-ln(Ki67) < 1; intermediate-ln(Ki67)1-2; resistant-ln(Ki67) > = 2). BMI at the time of surgery and MS variables were collected retrospectively for 143 patients to analyze association between therapy response and BMI/MS. Additionally, PI3K pathway signaling was evaluated by immunohistochemistry of phosphorylated Akt and S6. There was no significant association between BMI and recurrence score (p = 0.99), and risk score distribution was similar across BMI groups. However, BMI was associated with short-term endocrine therapy resistance, with a significant enrichment of intermediate and resistant tumors in patients with obesity (55%, p = 0.0392). Similarly, the relative risk of an endocrine therapy-resistant tumor was 1.4-fold greater for patients with MS (p = 0.0197). In evaluating PI3K pathway mediators, we found patients with 3 or more MS criteria had more tumors with pAkt scores above the median (p = 0.0436). There were no significant differences in S6 activation. Our findings suggest the association between obesity/metabolic syndrome and breast cancer recurrence is better reflected by response to treatment than tumor-intrinsic properties, suggesting interventions to reverse obesity and/or MS may improve outcomes for breast cancer recurrence.

DOK7 CpG hypermethylation in blood leukocytes as an epigenetic biomarker for acquired tamoxifen resistant in breast cancer.

Breast cancer (BC) is among the most common cause of cancer 10.4% and one of the leading causes of death among 20-50 years old women in the world. Tamoxifen drug is the first line therapy for BC however tamoxifen resistance (TR) has shown in 30-50% of cases that may face BC recurrence. Hence, TR early detection reduces BC recurrence and fatalities. The epigenetic alteration that happens by hypermethylation of tumor suppressor genes and hypomethylation of oncogenes has been suggested to be useful in early cancer or drug resistance diagnosis. This is the first study to investigate DOK7 CpG hypermethylation in blood leukocytes of 31 TR (ER+) BC compared to 29 tamoxifen sensitive BC to evaluate DOK7 as a potential TR biomarker. DNA was extracted from blood samples of all participants and MSRE-PCR and real-time PCR were used for quantification of CpG methylation alterations. The means of DOK7 CpG hypermethylation were obtained as 85.03%, 29.1% and 57.34% in TR, TS and normal control respectively. Significant hypermethylation were found among TR vs. TS (p < 0.001), TS vs. normal (p < 0.001) and TR vs. normal controls (p < 0.03). Online databases expression and survival analysis of DOK7 showed increasing expression in TS groups vs. TR groups which have consistency with our methylation alteration results. The sensitivity and specificity of the TR epigenetic test were determined using ROC analysis showed 89.66% and 96.77% respectively and showed that 37.5% above hypermethylation is at risk for TR and breast cancer recurrence. There is a significant difference in the methylation ratio of DOK7 between tamoxifen resistant and tamoxifen sensitive groups that may be useful in the early diagnosis of tamoxifen resistance in BC cases and cancer recurrence prevention.

OR30-4 Role of ABCA1 in Myeloid Cell Function and Breast Cancer Progression

Abstract Breast cancer is the second leading cause of cancer related deaths in women in the United States, with most mortalities associated with recurrent metastasis. Interestingly, high cholesterol levels are associated with an increased risk of breast cancer recurrence and poor prognosis, while therapies that lower cholesterol concentrations are associated with a good prognosis. Previous work has identified a metabolite of cholesterol, 27-Hydroxycholesterol (27HC), as being able to promote the progression and metastasis of breast cancer. 27HC does so by acting on myeloid immune cells. Within the tumor microenvironment, macrophages are abundant cells in the myeloid lineage. When macrophages were treated with 27HC, their ability to activate T cells was impaired. Those T cells that were activated, had a decreased anti-cancer cytotoxic response. Subsequent work has identified the Liver×Receptor (LXR) as mediating the immune-suppressive effects of 27HC. However, the mechanism by which LXR activity within myeloid cells inhibits subsequent T cell activity is unknown.ABCA1 is a classic target gene of LXR and is known to facilitate cholesterol efflux from the cell. Our analysis of publicly available transcriptome indicates that ABCA1 expression within breast tumors is associated with good prognosis. These somewhat paradoxical observations suggest that ABCA1 exhibits a pro-immune and anti-cancer effect – opposite to what we would expect for LXR activation. Therefore, the goal of the current work is to determine the effect of manipulation of ABCA1 within macrophages and its consequent effect on T cells in vitro and in context to breast cancer metastasis. Our results to date indicate that knocking down ABCA1 using siRNA by targeting the 3' UTR decreased the expression of genes associated with macrophage function and interaction with T cells. Importantly, many of those effects were rescued by over- expression of ABCA1.In summary, our results indicate that although ABCA1 is a target gene of LXR, the induction of ABCA1 by LXR may be compensatory rather than driving the immunosuppressive effects of 27HC. Thus, we hypothesize that ABCA1 plays a pro-immune function and could be a potential therapeutic target to boost the immune system. Presentation: Tuesday, June 14, 2022 10:30 a.m. - 10:45 a.m.

235 (PB-059) Poster - PAM50 genomic test in the management of early breast cancer – the importance of clinical-pathological data

Background: The PAM50 test provides important prognostic information for therapeutic decision in hormone-receptor positive (HR+) and HER2-negative (HER2-) early breast cancer. This genomic signature estimates the risk of recurrence (ROR) at 10 years, for patients treated with adjuvant hormone therapy (HT) alone. It also allows the determination of breast cancer intrinsic subtype. However, its validation results only from retrospective studies. We aimed to analyze the correlation between histopathological variables and risk of breast cancer recurrence, as well as the agreement between subtype-like, obtained by immunohistochemistry (IHC) and breast cancer intrinsic subtype, obtained through this molecular analysis.

Australian fertility preservation guidelines for people with cancer 2022: review and recommendations.

Australian fertility preservation guidelines for people with cancer 2022: review and recommendations.

Event-Free Survival in Patients with Early HER2-Positive Breast Cancer with a Pathological Complete Response after HER2-Targeted Therapy: A Pooled Analysis.

Simple SummaryThe current standard of care for patients with HER2-positive early breast cancer who have a pathological complete response after neoadjuvant HER2-targeted therapy plus chemotherapy is continuation of HER2-targeted therapy in the adjuvant setting. However, it is not clear how long-term outcomes differ by the HER2-targeted regimen received in each setting. To investigate this question, we pooled patient-level data (n = 1763) from neoadjuvant studies of trastuzumab and pertuzumab to evaluate outcomes with respect to single versus dual HER2 targeting in the neoadjuvant and adjuvant settings. Patients treated with dual HER2-targeted therapy in both the neoadjuvant and adjuvant settings had the highest 4-year event-free survival rates, suggesting that this treatment approach may provide the most benefit for patients with HER2-positive early breast cancer.The standard-of-care for patients with pathological complete response (pCR) after neoadjuvant human epidermal growth factor receptor 2 (HER2)-targeted therapy plus chemotherapy is continuation of HER2-targeted therapy in the adjuvant setting. Our objective was to evaluate risk of recurrence or death in these patients and determine if outcomes differed by the HER2-targeted regimen received in each setting. We analyzed patient-level data from five randomized trials evaluating trastuzumab, pertuzumab, or both as part of systemic neoadjuvant and adjuvant therapy for HER2-positive early breast cancer, and assessed event-free survival (EFS) in 1763 patients. Patients with pCR had decreased risk of an EFS event versus those with residual disease (unadjusted hazard ratio [HR] = 0.35; 95% confidence interval [CI]: 0.27–0.46). Regardless of pCR status, after adjusting for baseline factors, reduction in EFS event risk was greater in patients administered pertuzumab/trastuzumab in both settings versus those administered only trastuzumab in both settings (HR = 0.36; 95% CI: 0.26–0.49), or pertuzumab/trastuzumab in the neoadjuvant setting and only trastuzumab in the adjuvant setting (HR = 0.67; 95% CI: 0.47–0.96). Patients with pCR had longer EFS than those with residual disease. Patients treated with pertuzumab/trastuzumab in both the neoadjuvant and adjuvant settings had the lowest risk of breast cancer recurrence.

ICSDA: a multi-modal deep learning model to predict breast cancer recurrence and metastasis risk by integrating pathological, clinical and gene expression data.

Breast cancer patients often have recurrence and metastasis after surgery. Predicting the risk of recurrence and metastasis for a breast cancer patient is essential for the development of precision treatment. In this study, we proposed a novel multi-modal deep learning prediction model by integrating hematoxylin & eosin (H&E)-stained histopathological images, clinical information and gene expression data. Specifically, we segmented tumor regions in H&E into image blocks (256 × 256 pixels) and encoded each image block into a 1D feature vector using a deep neural network. Then, the attention module scored each area of the H&E-stained images and combined image features with clinical and gene expression data to predict the risk of recurrence and metastasis for each patient. To test the model, we downloaded all 196 breast cancer samples from the Cancer Genome Atlas with clinical, gene expression and H&E information simultaneously available. The samples were then divided into the training and testing sets with a ratio of 7: 3, in which the distributions of the samples were kept between the two datasets by hierarchical sampling. The multi-modal model achieved an area-under-the-curve value of 0.75 on the testing set better than those based solely on H&E image, sequencing data and clinical data, respectively. This study might have clinical significance in identifying high-risk breast cancer patients, who may benefit from postoperative adjuvant treatment.

Postoperative Outcomes following a Multidisciplinary Approach to HIV-positive Breast Cancer Patients

Background:Improvements in human immunodeficiency virus (HIV) treatment resulted in drastic increases in the lifespan of HIV-positive individuals, resulting in higher rates of non-AIDS-defining cancers. We describe our postoperative outcomes in HIV+ breast cancer (BC) patients, highlighting our multidisciplinary experience with this high-risk population.Methods:A 7-year multi-institutional retrospective review of all HIV+ BC patients who underwent surgical intervention was performed. Patient demographics, therapeutic interventions, and treatment outcomes were collected.Results:Twenty-four patients were identified, including one male patient (4.2%). Most patients were African American (83.3%). Mean age was 52.1 + 9.7 years at the time of diagnosis in HIV+ BC patients. Surgical interventions included lumpectomy (n = 16, 66.7%), simple mastectomy (n = 3, 12.5%), and skin-sparing mastectomy (n = 5. 20.8%). All patients were on antiretroviral therapy, and 81.3% had undetectable viral loads at the time of operation. Seventeen patients (70.8%) underwent breast reconstruction, with three (17.7%) undergoing delayed reconstruction. Thirty-day postoperative complications occurred in three patients (17.6%), including flap necrosis (11.8%), infection (11.8%), dehiscence (5.9%), and return to OR (11.8%). Three patients (12.5%) experienced recurrence at a median of 18 months since operation. Mean follow-up was 51.4 + 33.3 months since BC diagnosis.Conclusions:While postoperative complication rates in HIV+ patients trended higher (17.6%) compared with the existing data on breast reconstruction patients overall (10.1%), HIV+ patients did not exhibit increased risk of BC recurrence (12.5%) compared with BC patients overall (12-27%). This highlights the importance of a combined multidisciplinary approach involving infectious disease, breast surgery, and plastic and reconstructive surgery to optimize surgical and oncologic outcomes in these high-risk patients.