High-risk Breast Cancer Research Articles

Routine Clinical Breast Examination Is a Low-Yield Practice Among Women at High Risk of Breast Cancer.

For women at increased risk of breast cancer, the National Comprehensive Cancer Network (NCCN) guidelines recommend clinical encounters every 6-12 months. While screening mammography has corresponded with a relative risk reduction in breast cancer mortality of approximately 20%, evidence validating clinical breast examination (CBE) as an efficacious screening modality is deficient. Our study aimed to assess the conventional merit of regular CBE for breast cancer detection among individuals at increased risk of breast cancer development. Women > 18 years with documented high-risk encounters at Corewell Health West from 1 January 2018 to 31 December 22 were retrospectively reviewed. High-risk criteria included genetic predisposition, 5-year (> 1.7%) or lifetime (> 20%) Tyrer-Cuzick and/or Gail Model risk estimations, thoracic radiotherapy before age 30 years, lobular carcinoma in-situ, or atypical hyperplasia. Patients with a history of breast cancer or bilateral prophylactic mastectomy prior to 2018 were excluded. Of the 9171 cumulative high-risk encounters among 2493 women, only one breast cancer was detected by CBE. CBE resulted in 1 (0.04%) cancer diagnosis compared with 30 (1.2%) detected on screening imaging and 10 (0.4%) self-reported. Of the 30 image-detected cancers, 28 (93.3%) had no detectable clinical findings at the time of preoperative consultation. Self-reported and CBE-detected cancers were more likely to be of higher clinical stage compared with imaging-detected malignancies. The role of routine CBE as a cancer detection modality in the high-risk patient population appears to be limited. Telemedicine can be offered to individuals who have completed screening imaging but are unable to commit and/or are inconvenienced by in-person high-risk breast cancer assessments.

Breast Cancer Adjuvant Radiotherapy in Up-Front to Chemotherapy: Is There a Worthwhile Benefit? A Preliminary Report.

We administered a new breast cancer (BC) adjuvant therapy sequence that delivered postoperative radiotherapy (PORT) before chemotherapy (CT). Our aim was to assess the gain in time to start PORT and the G2-G3 acute-subacute toxicity rate of whole breast adjuvant hypofractionated radiotherapy (AH-RT) administered up-front to the third-generation adjuvant CT (A-CT) in high-risk nodal positive BC in a preliminary report at 2 years. This retrospective study analysed the duration of treatment and safety of AH-RT administered up-front to A-CT in high-risk nodal positive BC patients (pts). Data on 45 pts treated between 2022-2023 were collected. All pts underwent the third-generation A-CT after AH-RT 15-5 fractions with or without a boost. Acute toxicity was scored according to CTCAE v5.0 for skin, pulmonary, and cardiac adverse events. Univariate and multivariate analyses were conducted to assess significant prognosticators for skin/lung/heart acute toxicities in the AH-RT 5-15 fractions arms and CT (p < 0.005). A reduction in the time to PORT initiation and overall adjuvant treatment time was recorded. RT was initiated 5 median weeks after surgery, and A-CT was performed 9 median weeks after surgery. The median duration of the entire adjuvant treatment was 35 weeks after surgery. At 6 months mean follow-up, no significant differences in G2-G3 toxicity were noted between the different hypofractionated RT arms, irrespective of the CT schedules, irradiated volumes, or boost (SIB or sequential) in univariate and multivariate analyses. In the multivariate analysis, no significant effects in CT schedules and AH-RT 5-15 arms for skin/lung acute toxicities (p = 0.077 and p = 0.68; 0.67 and 0.87, respectively) were recorded. As a new PORT approach in BC, AH-RT up-front to the third-generation A-CT appeared safe with a low acute toxicity profile, providing an advantage in shortening the time from surgery to PORT initiation and the overall adjuvant treatment time.

Cost-Effectiveness of Adjuvant Abemaciclib and Ribociclib in High-Risk Hormone Receptor-Positive Early Breast Cancer: An Indian Perspective.

Incorporating adjuvant cyclin-dependent kinase (CDK) 4/6 inhibitors abemaciclib and ribociclib along with endocrine therapy has been shown to improve invasive disease-free survival (iDFS) for hormone receptor-positive (HR+) human epidermal receptor 2-negative (HER2-) early breast cancer (EBC). This study assesses the cost-effectiveness of this strategy, along with adjuvant aromatase inhibitors from an Indian perspective. A Markov chain model evaluated the cost-effectiveness of abemaciclib and ribociclib with letrozole compared with letrozole alone for HR+/HER2- EBC from a payer perspective in India. Key measures included lifetime quality-adjusted life-years (QALY), life-years (LY), and total costs. This study explores two scenarios for effectiveness: a best-case (BC) scenario, where the benefit of CDK4/6 inhibitors in improving iDFS lasts a lifetime, and a worst-case (WC) scenario, where benefits disappear after 5 years. Probabilistic sensitivity analyses (PSA) were used to account for simulation uncertainty. In the BC scenario, abemaciclib added 2.17 QALY and 4.96 LY, incurring ₹2,317,957.7 ($27,756.65 in US dollars [USD]) in additional costs. However, the incremental cost-effectiveness ratio (ICER) for abemaciclib exceeded India's willingness-to-pay threshold in the BC and WC scenarios. In the BC scenario, ribociclib added 0.98 QALY and 2.58 LY with added costs of ₹1,711,504.32 ($20,494.6 USD). The ICER for ribociclib also surpassed India's threshold in both scenarios. PSA showed that neither drug was cost-effective at the current market prices in either BC/WC scenario. The cost of abemaciclib and ribociclib needs to be reduced by at least 78.61% and 87.19%, respectively, to be cost-effective in the BC scenario. The combination of adjuvant abemaciclib or ribociclib with letrozole is not cost-effective for HR+/HER2- EBC in India in either the BC or WC scenario.

Does Laterality in Breast Cancer still have the Importance to be Studied? A Meta-analysis of Patients with Breast Cancer.

Breast cancer (BC) is one of the most common cancers in the world. Studies show that left-sided BC in pre and post-menopausal women leads to double the risk of worse morbidity and mortality and the reasons are uncertain. Finding the relationship between BC laterality and other possible risk factors can be advantageous for the prognosis of BC. This present study aimed to analyze the relationship between BC laterality and possible risk factors. A total of 6089 studies were screened. 23 studies from 1971 to 2021 met the inclusion criteria and were included in the meta-analysis. A pooled relative risk was generated via meta-analysis with a 95% confidence interval. Left-side BC laterality was significant (p < 0.00001) in the women populations compared to the right side based on the pooled size with possible high-risk factors, including handedness, older women, body mass index, people with black skin, invasive type carcinoma, and estrogen receptor-negative BC. These findings suggest that there may be a complex interplay of genetic, environmental, and lifestyle factors that contribute to left-side BC laterality. Results suggest an increased rate of BC on the left side, with high-risk factors contributing to BC laterality, which may be useful in predicting prognosis. This study provides significant insights into the relationship between high-risk factors and BC laterality. By identifying potential risk factors associated with left-side BC, it may be possible to improve the ability to predict prognosis and develop more targeted treatment strategies. This information could be particularly useful for healthcare providers and patients, as it may guide decisions regarding screening, prevention, and treatment, ultimately improving patient outcomes and reducing the overall burden of BC.

Evaluating Danish Breast Cancer Group locoregional radiotherapy guideline adherence in clinical treatment data 2008–2016: The DBCG RT Nation study

Background and purposeGuideline adherence in radiotherapy is crucial for maintaining treatment quality and consistency, particularly in non-trial patient settings where most treatments occur. The study aimed to assess the impact of guideline changes on treatment planning practices and compare manual registry data accuracy with treatment planning data. Materials and methodsThis study utilised the DBCG RT Nation cohort, a collection of breast cancer radiotherapy data in Denmark, to evaluate adherence to guidelines from 2008 to 2016. The cohort included 7448 high-risk breast cancer patients. National guideline changes included, fractionation, introduction of respiratory gating, irradiation of the internal mammary lymph nodes, use of the simultaneous integrated boost technique and inclusion of the Left Anterior Descending coronary artery in delineation practice. Methods for structure name mapping, laterality detection, detection of temporal changes in population mean lung volume, and dose evaluation were presented and applied. Manually registered treatment characteristic data was obtained from the Danish Breast Cancer Database for comparison. ResultsThe study found immediate and consistent adherence to guideline changes across Danish radiotherapy centres. Treatment practices before guideline implementation were documented and showed a variation among centres. Discrepancies between manual registry data and actual treatment planning data were as high as 10% for some measures. ConclusionNational guideline changes could be detected in the routine treatment data, with a high degree of compliance and short implementation time. Data extracted from treatment planning data files provides a more accurate and detailed characterisation of treatments and guideline adherence than medical register data.

A nomogram for predicting the risk of cancer-related cognitive impairment in breast cancer patients based on a scientific symptom model

Cancer-related cognitive impairment is a significant clinical challenge observed in patients with breast cancer, manifesting during or after treatment. This impairment leads to deteriorations in memory, processing speed, attention, and executive functioning, which profoundly impact patients' occupational performance, daily living activities, and overall quality of life. Grounded in the Symptom Science Model 2.0, this study investigates the contributing factors to Cancer-related cognitive impairment in breast cancer patients and develops a predictive nomogram for this demographic. Employing both univariate and multivariate logistic regression analyses, this investigation delineates the predictive factors influencing outcomes in breast cancer patients. A nomogram was constructed leveraging these identified predictive factors, accompanied by internal validation through bootstrap resampling methodology (1000 bootstrap samples). The efficacy of the predictive model was assessed by employing the Hosmer–Lemeshow goodness-of-fit test and calibration curves. The prevalence of cognitive impairment in breast cancer patients was identified to be 45.83%.Multivariate logistic regression analysis identified the independent predictors of Cancer-related cognitive impairment in breast cancer patients as place of residence, educational level, chemotherapy, benefit finding, post-traumatic growth, anxiety, fear of cancer progression, and fasting blood glucose levels. these factors were integrated into the nomogram. The Hosmer–Lemeshow goodness-of-fit test demonstrated that the prediction model was appropriately calibrated (χ2 = 11.520, P = 0.174). Furthermore, the model exhibited an area under the curve of 0.955 (95% CI 0.939 to 0.971) and a sensitivity of 0.906, evidencing its robust discriminative capacity and accuracy. Utilizing the Symptom Science Model 2.0 as a framework, this study comprehensively examines the multifaceted factors influencing Cancer-related cognitive impairment in breast cancer patients, spanning five critical domains: complex symptoms, phenotypic characterization, biobehavioral factors, social determinants of health, and patient-centered experiences. A predictive nomogram model was established, demonstrating satisfactory predictive accuracy and capability. This model is capable of identifying breast cancer patients with cognitive impairments with high precision. The findings furnish empirical evidence in support of the early detection, diagnosis, and intervention strategies for high-risk breast cancer patients afflicted with Cancer-related cognitive impairment.

Novel Treatment Strategies for Hormone Receptor (HR)-Positive, HER2-Negative Metastatic Breast Cancer.

Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs-selective estrogen receptor modulators-or SERDs-selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR+/HER2- BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination.

Biomarkers in breast cancer 2024: an updated consensus statement by the Spanish Society of Medical Oncology and the Spanish Society of Pathology.

This revised consensus statement of the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathological Anatomy (SEAP) updates the recommendations for biomarkers use in the diagnosis and treatment of breast cancer that we first published in 2018. The expert group recommends determining in early breast cancer the estrogen receptor (ER), progesterone receptor (PR), Ki-67, and Human Epidermal growth factor Receptor 2 (HER2), as well as BReast CAncer (BRCA) genes in high-risk HER2-negative breast cancer, to assist prognosis and help in indicating the therapeutic options, including hormone therapy, chemotherapy, anti-HER2 therapy, and other targeted therapies. One of the four available genetic prognostic platforms (Oncotype DX®, MammaPrint®, Prosigna®, or EndoPredict®) may be used in ER-positive patients with early breast cancer to establish a prognostic category and help decide with the patient whether adjuvant treatment may be limited to hormonal therapy. In second-line advanced breast cancer, in addition, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and estrogen receptor 1 (ESR1) should be tested in hormone-sensitive cases, BRCA gene mutations in HER2-negative cancers, and in triple-negative breast cancer (TNBC), programmed cell death-1 ligand (PD-L1). Newer biomarkers and technologies, including tumor-infiltrating lymphocytes (TILs), homologous recombination deficiency (HRD) testing, serine/threonine kinase (AKT) pathway activation, and next-generation sequencing (NGS), are at this point investigational.

Prognostic utility of ctDNA detection in the monarchE trial of adjuvant abemaciclib plus endocrine therapy (ET) in HR+, HER2-, node-positive, high-risk early breast cancer (EBC).

LBA507 Background: In monarchE (NCT03155997), 2 years of adjuvant abemaciclib + ET resulted in sustained improvement in invasive disease-free survival (IDFS; HR=0.680, 7.6% absolute benefit at 5 years) in patients (pts) with HR+, HER2-, node-positive, high-risk EBC. Here, we investigate the prognostic value of ctDNA detection and dynamics in pts from monarchE. Methods: Samples were analyzed from a selected pt subset (n=1397; abemaciclib + ET arm, n=685; ET arm, n=712), enriched for overall IDFS events compared to the total monarchE study population (IDFS event rate: 31% [433/1397] vs 18% [992/5637]). Pts had blood collected pre-study treatment (baseline) and at 3, 6, or 24 months. ctDNA detection was performed using the personalized, tumor informed Signatera ctDNA assay (Natera, Inc) and whole exome sequencing (WES) of matched primary tumor and normal required for assay design was performed. Results: Among 1397 pts, 65% (n=910) had sufficient plasma samples and WES performed, and all 910 had successful ctDNA assay testing. Among these 910 pts, the IDFS event rate was 27% (abemaciclib + ET, 23% [101/438]; ET alone, 31% [146/472]). Rates of ctDNA positivity (at baseline and any change from baseline) and associated IDFS events are shown in Table. Among pts with ctDNA positivity, 87% had an IDFS event in comparison to 15% with persistent ctDNA negative (-) status during the study. Conclusions: In a pt subset from monarchE enriched for IDFS events, ctDNA detection was relatively infrequent (&lt;20%); however, its detection at any time during the 24 months of study therapy was adversely prognostic. As compared to pts who had remaining ctDNA positive (+), pts who had clearance of ctDNA on therapy had lower risk of IDFS events, but the event risk still remained clinically meaningful in these pts. Clinical trial information: NCT03155997 . [Table: see text]

Quantitative Analysis of 99mTc-MDP SPECT-CT Data in Diagnosing Bone Metastases in Breast Cancer Patients

Background: In patients with advanced breast cancer (BC), distant metastases happen mainly in the skeleton. This study aimed to investigate the role of 99mTc-MDP SPECT/CT in the differential diagnosis of malignant bone lesions from degenerative benign bone diseases in female BC patients. Methods and Results: The study included 39 female BC patients who underwent a baseline 99mTc-MDP SPECT/CT bone scans. After lesion detection, a quantitative radiotracer uptake analysis was conducted, and the standardized uptake value (SUVmax) was identified in each patient, and the data were then statistically analyzed. SUVmax values were significantly higher in BC patients with malignant metastasis than in patients with degenerative changes (33.04±15.3 vs. 13.25±5.46 g/mL, P&lt;0.05). The SUVmax cut-off value of 22.75 g/mL (25th percentile) obtained through box plot analysis can help to discriminate metastatic from degenerative lesions. The logistic regression analysis indicated that the SUVmax was a significant predictor of metastatic BL (P&lt;0.001, OR = 159.90, B=5.07). Conclusion: Our results suggested that quantitative analysis of the 99mTc-MDP SPECT-CT data can improve diagnostic accuracy in differentiating malignant metastatic bone lesions from degenerative bone lesions in high-risk BC patients.

Emerging drugs in breast cancer: a focus on antibody–drug conjugates and novel treatment options in luminal disease

SummaryRecent years have seen the introduction of several new drugs and novel treatment approaches in early and advanced-stage breast cancer, leading to relevant improvements in outcome. Still, further reduction of recurrence risk in high-risk early breast cancer is required as is further improvement of disease control in metastatic disease, preferentially with parallel improvement of tolerability. Several antibody–drug conjugates are currently under clinical development, among them drugs targeting HER2, HER3 and TROP2; in addition, bispecific HER2-directed antibodies are a promising class of drugs. In hormone receptor-positive disease, optimizing treatment options in patients progressing on prior CDK4/6-inhibitor-based therapies is a focus of clinical research and recent developments encompass small molecule growth-factor pathway inhibitors such as the AKT inhibitor capivasertib, novel PIK3Ca inhibitors such as inavolisib as well as selective oestrogen receptor degraders and modulators. This article is intended as a short review of promising novel drugs in later clinical development in the field of breast cancer.

Toxicity differences in CDK 4/6 inhibitors seen in Asian and Pacific Islanders.

e13086 Background: Cyclin-dependent kinases (CDK) 4/6 inhibitors are the standard of care, first line treatment for hormone receptor positive metastatic breast cancer and adjuvant high-risk hormone receptor positive early stage breast cancer along with endocrine therapy. There have been multiple clinical trials validating the effectiveness, along with toxicities of these agents; however, the majority of these trials lack ethnic diversity. This shortcoming limits the ability to apply these findings in diverse patient populations, especially among Asian and Pacific Islanders in Hawaii. Objective: To determine if the toxicity profile of CDK 4/6 inhibitors in women with breast cancer is different among patients at a community oncology practice in Hawaii, in which the majority of patients are Asian, Pacific Islander or a combination of both when compared to three landmark trials. Methods: A retrospective analysis of thirty-two patients with hormone receptor positive, HER2 negative metastatic or high risk breast cancer who started endocrine therapy and CDK 4/6 inhibitor therapy (abemaciclib, ribociclib, or palbociclib) between 2018-2023. Graded toxicities of each individual patient based on CTCAE criteria V. 5, along with demographic data was reviewed and compared to three main registration trials for these agents (MONARCH-3, MONALEESA-2, PALOMA-2). Results: Combined results from the three large randomized trials reported an average of 75% of participants were Caucasian, as compared to 15% in the Hawaii data. While 19% percent of participants from the combined large randomized trials reported being of Asian descent, none of these trials reported a breakdown of Asians versus Pacific Islanders. In the Hawaii sample, 41% were reported as Pacific Islander and 41% reported as Asian, 15% Caucasian, with the final 3% reported as Hispanic. Collective analysis of the FDA registration trials contained 0% Pacific Islander, 19.8% Asian, 74.3% White, 1.5% Black, and 4.4% Other. The majority of all toxicities of all grades were higher in the Hawaii population as compared to the three national trials, except for neutropenia with ribociclib and diarrhea with palbociclib (Table). Conclusions: The Hawaii analysis that was primarily comprised of Asians and Pacific Islanders revealed an increased incidence of toxicities, despite starting at lower doses rates for all CDK 4/6 inhibitors. This data analysis begins to highlight the importance of representative populations in clinical trials for the most effective and safest care of diverse populations. [Table: see text]

Adopting combination machine learning models could reduce hospital length of stay for oncology patients.

11084 Background: Integra Connect previously created in-patient (IP) admission prediction model based on OCM data. One of the challenges for practices in a value-based care (VBC) program is to provide continuous care-coordination during and after an IP admission. Our objective is to show how adopting combination machine learning (ML) models can predict IP length of stay (LOS). Potential benefits include an overall reduction in LOS which could minimize the risk of hospital acquired conditions. Methods: ML models were trained on 5 major cancer types (Lung Cancer, Multiple Myeloma, Lymphoma, Small Intestine / Colorectal Cancer, High-risk Breast Cancer') from 7 OCM practices of PP4-PP9 data, excluding surgery IP admission. The top 5 cancer types accounted for ~50% of total in-patient admissions and ~50% of total LOS in days. The IP admissions were divided into 4 major cohorts in terms of LOS in days (1-3: class 1, 4-8: class 2, 9-15: class 3, and more than 15: class 4). To reduce the overall LOS, we adopted two ML models: 1) To classify LOS, a multi-classification model (Model1, an eXtreme Gradient Boosted Trees Classifier) and 2) To predict the LOS for classes 1-3, a regression-based model (Model2, an eXtreme Gradient Boosted Trees Regressor with Early Stopping). Class 4 cohort had a wide range (16- 90+ days) for LOS and therefore was excluded from Model2. The other three cohorts belonged to Q1, IQR, and Q4, respectively. Model1 was trained on 4,280 randomly selected sample IP admissions to balance each class and Model2 was trained on 19,636 IP admissions, both with 102 features. Results: The models were tested on PP10-PP11 claims excluding 0 days LOS. Model1 predicted 296 (3,945) IP admissions in class 4 of which 88 were true positives. Assuming at least a 10% reduction in associated total LOS translated to lower LOS of 1-3% for 5 (7) practices. The remaining 3,649 IP admissions were used to predict LOS by Model2. The difference between actual LOS and Predicted LOS was found as 18%-24%. To address model prediction errors, we defined the target LOS to be predicted LOS with an upper bound of at least 10%. This led to reductions of 6% -16% across practices. Finally, combining the results of both ML models we determined that the potential to lower LOS was at least 6% and at most 19%. Conclusions: Our ML models identified opportunities to reduce LOS across multiple OCM cancer practices for 5 major cancer types. We also identified a cohort of patients with critical condition (class 4) that is vital for practice transformation initiatives. These identified reduction in LOS for oncology patients provides cost reduction and quality improvement opportunities in VBC programs. In the future, more opportunities to lower LOS will be explored with a re-admission prediction model.

The SURVIVE study: Liquid biopsy guided surveillance after intermediate- to high-risk early breast cancer.

TPS620 Background: Current guidelines limit routine breast cancer (BC) follow-up to clinical examinations and breast imaging. This is based on the results of two large cohort studies conducted in the 1980s that showed no improvement in overall survival (OS) by an intensified screening for distant metastases. Thus, imaging for distant metastases should currently only be performed in patients with specific symptoms. To detect distant relapse in a pre-symptomatic stage, we suggest the evaluation of a liquid biopsy-guided intensified surveillance, analyzing tumor markers (CA 27.29, CA 125 and CEA), circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Methods: Funded by the German Federal Ministry of Education and Research, the SURVIVE study is the first large, randomized BC surveillance trial to investigate the potential survival benefit of a liquid biopsy guided follow-up care in intermediate- to high-risk early breast cancer patients. The trial is a German multicenter, controlled phase 3 superiority study, in which 3500 patients are randomized in a 1:1 ratio to standard vs. liquid biopsy guided intensified follow-up care. Eligible patients are adults with confirmed primary invasive intermediate to high-risk early BC, defined as an indication for (neo-)adjuvant chemotherapy, and/or large tumor size (&gt; 50 mm), and/or positive lymph nodes (≥ pN1mi), and/or high grade (≥ G3). Primary anti-tumor therapy (surgery, adjuvant chemo- or radiotherapy) must have been completed previously. Patient enrollment during adjuvant endocrine, antibody- or targeted therapy is allowed. The total study duration is 144 months. Stratification factors are study site as well as HR-, HER2- and nodal status at surgery.Both study arms receive standard follow-up according to national guidelines, and the intensified surveillance arm will be tested for standard tumor markers, CTCs and ctDNA via tumor-informed approach (RaDaR assay). Pre-specified abnormal findings of any of the liquid biopsy markers indicative of minimal residual disease trigger complete staging. In the event of confirmed disease recurrence, guideline-based treatment follows, otherwise, liquid biopsy testing continues. If applicable, study participants may enter interventional trials. Statistics:The two primary objectives are to determine whether intensified, liquid biopsy-guided surveillance leads to better OS or an overall lead-time effect, compared to standard surveillance. OS will be analyzed in the ITT population using Kaplan Meier methods and cox regression models, the overall lead time effect is a purely descriptive composite measure. Secondary objectives include IDFS, DDFS, DRFS, BCSS and quality of life (QoL). Aims: We propose a liquid biopsy guided follow-up method, with high sensitivity and specificity for the earlier detection of distant (oligo-)metastases, to enable earlier initiation of therapy. Clinical trial information: NCT05658172 .

Therapeutic response and outcomes with less common breast cancer subtypes in the I-SPY trial 2011-2022.

582 Background: Uncommon histologies are over-represented among high-risk breast cancer (BC) and denote an area with limited trial data and of significant unmet medical need. To better understand trial outcomes in this group and identify signals of tumor responsiveness, we report pathologic complete response (pCR) and early event-free survival (EFS) by disease subtype in the I-SPY2 trial. Additionally, the I-SPY2 trial currently utilizes a combination of tumor molecular signature and receptor status to determine response predictive subtype (RPS) first developed from 987 I-SPY2 patients (1). We report disease response rates for those who received what is now known to be optimal RPS guided therapy. Methods: The I-SPY2 platform trial tests novel agents given neo-adjuvantly with a chemotherapy backbone in high-risk BC (HER2 positive, triple negative and high molecular risk estrogen receptor positive BC). Histologic images of research biopsies, local biopsy and surgical pathology reports were reviewed centrally by I-SPY pathologists. Receptor subtype distribution and pCR rates were summarized. EFS was estimated using the Kaplan Meier method. Association between pCR and EFS was evaluated using the Cox proportional hazard model with significance assessed by the log rank test. Results: 144/2118 (7%) of I-SPY2 participants were identified with metaplastic (60), lobular (55), mucinous (9), micropapillary (8), neuroendocrine (4) and other (8) BCs. Tumor receptor status, pCR rate and EFS by tumor type are shown in the Table. For the full cohort, pCR was associated with better EFS (hazard ratio (95% CI): 0.12 (0.02 - 0.88), p = 0.01). Within metaplastic (metapBC) 11/32 (34%) and 5/28 (18%) patients had a pCR with or without checkpoint blockade, respectively. By RPS group, 9 of 18 (50%) (13 metapBC, 3 other, 2 lobular) in the HER2-Immune+ group who received RPS optimized therapy had a pCR. In this group 6/13 (46%) with metapBC had a pCR. In the HER2+ driven RPS groups, pCR rate in the HER+HER2orBasal was 88% (7/8) and 0% (0/3) in the HER2+Luminal. Conclusions: High pCR rates observed in metapBC and other among subsets of often difficult to treat BC subtypes support novel approaches and provide a roadmap for future study of uncommon BCs. Outcomes were improved when therapy matched RPS vulnerabilities. Participants presenting with uncommon BC subtypes will be prospectively identified in the I-SPY2.2 trial to further develop effective approaches for this group. 1. Wolf et al, Cancer Cell 2022. Clinical trial information: NCT01042379 . [Table: see text]

Relevance of timing intake of everolimus (EVE) combined with adjuvant endocrine therapy (ET) in patients (pts) with high-risk early breast cancer: Results of a sub-study of the UCBG-UNIRAD trial.

542 Background: We reported the benefit of taking evening tamoxifen compared to morning/afternoon as adjuvant treatment for high-risk breast cancers in the UNIRAD phase III trial (NCT01805271) (1). Here, we examine the relevance of EVE timing intake in this trial. Methods: 1,277 pts with high-risk HR+/ HER2- primary BC were randomly assigned to adjuvant ET with placebo or EVE (1). Patients prospectively reported in a diary the daily timing for ET and EVE intake among four 6-h slots (06:00 to 11:59 (morning), 12:00 to 17:59 (afternoon), 18:00 to 23:59 (evening), or 24:00 to 05:59 (night). The association between EVE, ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial. Results: EVE timing was recorded by 513 of 632 patients (81.2%). Patients declaring EVE intake in the morning (n= 248, 48 %) or in the afternoon (n=52, 10%) were older than those declaring evening (n=207, 40 %) or night (n=6,1%) intakes ( p&lt;0.001). They were more likely to be postmenopausal (p=0.001) and to take AI rather than tamoxifen (p = 0.03). Only 17 patients (3%) changed EVE intake timing throughout the study. EVE intake dialy times were binned into 2 categories for analyses: morning/afternoon group (n=300) and evening/night group (n = 213). The patients who took morning/afternoon EVE chose another timing for ET in 38% of the cases compared to 17.1% in evening/Night EVE group (p&lt;0.01). The timing of EVE intake was not significantly associated with definitive EVE withdrawal ( p=0.62) in the whole population. Time to EVE withdrawal was significantly longer in the patients taking tamoxifen rather than AI (17.2 vs 10.9 months, p = 0.0047). Prolonged duration of EVE treatment was associated with evening/night intakes of both EVE and tamoxifen, compared to other drug timing modalities (p = 0.04). With a median follow-up of 85months, 15 patients relapsed locally (3%), 55 developed metastases (11%), 36 patients died (7%). Overall, EVE intake timing was not associated with DFS (HR=0.84 [95% CI, 0.53 - 1.35], p=0.4). There was a significant interaction between EVE timing intake and ET type ( P interaction= 0.001). Patients on evening/night EVE combined with tamoxifen had a reduced likelihood of relapse compared to those taking morning/afternoon EVE (HR = 0.17 [0.05- 0.59], p = 0.005). In contrast, no significant EVE effect was found in the AI group (HR = 1.56 [0.92 2.64], p = 0.1). Evening/Night intake of EVE plus tamoxifen was independently associated with DFS (HR 0.13 [0.03-0.6], p = 0.002) after adjustment for age, nodal status, tumor size, ET timing intake, and EVE dose (2.5, 5 or 10 mg). Conclusions: These exploratory results are consistent with a role of circadian rhythm in the efficacy of EVE when given with tamoxifen in pts with high risk early breast cancer. 1. S. Giacchetti et al, Abst 546, ASCO 2023. Clinical trial information: NCT01805271 .

Estimating benefit from dose dense adjuvant chemotherapy for early breast cancer in the PANTHER randomized phase 3 trial.

521 Background: Adjuvant dose dense chemotherapy for early breast cancer improves patient outcomes across all subgroups compared with standard interval treatment. However, the effect of dose dense treatment based on individual patient risk and over time, and the performance of the PREDICT model at this setting are not well-studied. Methods: This is an exploratory analysis from the phase 3 PANTHER trial (NCT00798070) that compared adjuvant sequential epirubicin/cyclophosphamide (EC) and docetaxel (D) administered in either tailored dose dense (tDD EC/D, every 2 weeks) or standard interval schedule (FEC/D, every 3 weeks) to patients with high-risk resected early breast cancer. Dose tailoring in the experimental arm was performed according to a predefined algorithm based on hematologic and non-hematologic toxicity. We evaluated the performance of PREDICT in terms of calibration and discrimination in the entire cohort and subgroups of interest, conducted a subpopulation treatment effect pattern plot (STEPP) analysis and observed the relative treatment effect over time. Results: The intention-to-treat population consists of n=2003 randomized patients. Median follow-up was 10.3 years (interquartile range, 9.1 – 10.5 years). PREDICT consistently underestimated 5-year (absolute difference 1.4%) and 10-year overall survival (absolute difference 6.6%) in the entire population and across all subgroups, but mostly so in the highest risk patients where the difference between observed and predicted 10-year survival reached 20.4% for patients with tumors larger than 5 cm. Discriminatory accuracy was lower for 10-year than for 5-year survival (AUC 0.728 and 0.786, respectively), although the difference in model performance between the two treatment groups was small. In STEPP analysis, absolute benefit from tDD EC/D in the primary endpoint of breast cancer relapse free survival was stable across risk-defined overlapping subpopulations and ranged from 3.8% in the lowest risk patients to 3.6% in the highest risk ones. There was no evidence of differential treatment effect through time (pinteraction &gt;0.1 for all time-to-event endpoints). Conclusions: In this largely node-positive population, PREDICT consistently overestimated risk for death in all patient subgroups. We could not reliably identify any subgroup not benefiting from dose dense treatment, which should be the standard of care for primary resected high-risk breast cancer. Clinical trial information: NCT00798070 .

The efficacy of primary progesterone on survival in early breast cancer: A real world scenario.

e12522 Background: Surgery performed during progestogenic milieu improves survival in breast cancer patients. We previously proved efficacy of pre-operative progesterone in high-risk, operable breast cancer. In another multicenter randomized trial, intra-operative peri-tumoral local anesthetic injection showed 29% reduction in mortality. In this study, several patients had also received progesterone injection since this is adopted as standard of care across some centers including ours. We assessed the effectiveness of pre-operative progesterone in patients who were randomized in the local anesthetic study. Methods: We analyzed 1583 patients randomized on the local anesthetic study during December 2011-October 2018 with respect to receipt of progesterone. All patient who had breast lump of ≥2cm and/or node positive were eligible to receive progesterone injection before surgery. Kaplan Meier curves were plotted along with Cox regression analysis to study factors affecting disease-free and overall survival. Results: Of 1583, 454 patients did not receive, and 1129 patients received progesterone before surgery. The median age of whole cohort was 51 years, median pT size was 3 cm, 45% were node positive, 60% ER/PR+ and 24%TNBC. At median follow-up of 68 (0·5-72) months in surviving patients, there were a total of 292 DFS events (progesterone arm-193, no-progesterone arm-99). The 5-year disease-free survival (DFS) was 86.5% in the progesterone arm and 79.2% in the no-progesterone arm (HR-0.57,0.45-0.73, P&lt;0.001). The 5-year overall survival (OS) was 90.5% in the progesterone arm and 82.8% in the no-progesterone arm (HR-0.47,0.36-0.63,P&lt;0.001). On Cox Regression analysis (Table), administration of progesterone injection was an independent prognostic factor for DFS (HR-0.53,0-41-0.70, p&lt;0.001) and OS (HR-0.44,0-32-0.60, p&lt;0.001) both. Conclusions: The receipt of pre-operative progesterone improved outcomes in the setting of another randomized trial. It should be administered to all high risk (T2/N1) breast cancer patients who are planned for surgery first. [Table: see text]

Delays in receipt of neoadjuvant chemotherapy compared to upfront surgery in patients with operable breast cancer.

e13561 Background: Delays in time from breast cancer (BC) diagnosis to BC treatment initiation (BCTI) including upfront breast surgery (UBS) or neoadjuvant chemotherapy (NACT), can negatively impact BC survival. We evaluated odds of delay in BCTI among patients (pts) who received NACT compared to pts who received UBS. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis of non-metastatic BC between 1/1/2010 – 12/31/2020, who were treated with NACT followed by surgery or UBS followed by adjuvant chemotherapy (AC). Pts who did not receive NACT or UBS within 180 days of diagnosis were excluded. The cohort was stratified by first BC treatment (NACT or UBS), and time to NACT (TTNACT) or time to surgery (TTS) was recorded for each patient in days. Pts were categorized into sub-cohorts by receptor status and clinical stage: 1) Hormone Receptor positive/HER-2 negative (HR+/HER2-) lymph node (LN)+; 2) HER-2 positive (HER2+) cT2+ or LN+; and 3) triple negative BC (TNBC) cT2+ or LN+. Logistic regression adjusted for demographic, socioeconomic, and tumor characteristics was used to identify delays in BCTI &gt; 60 days. Multiple imputation was used for missing data. Inverse probability treatment weighting (IPTW) was done as a sensitivity analysis. Results: We identified 218,049 eligible pts, 75% were White, 18% were Black, and 8.6% were Hispanic. Median age was 53 years (range 18-90). There were 145,697 (67%) pts who received NACT with median TTNACT of 32 days (range 0-180), and 9.8% had a delay &gt; 60 days (Table). There were 72,353 (33.0%) pts who received UBS followed by AC, with a median TTS of 33 days (range 0-180), and 13% with a delay &gt; 60 days. In multivariable analysis, pts who received UBS had higher odds of BCTI delays compared to NACT, with OR 1.50 (95%CI 1.42-1.57) [HR+/HER2-], OR 1.49 (95%CI 1.41-1.58) [HER2+], and OR 1.26 (95%CI 1.18-1.34) [TNBC]. Results from IPTW analysis were similar, groups were well balanced, and pts who received UBS had higher odds of BCTI OR 1.50 (95%CI 1.44-1.57) [HR+/HER2-], OR 1.75 (95%CI 1.67-1.83) [HER2+], and OR 1.46 (95%CI 1.38-1.53) [TNBC]. Conclusions: Among high clinical risk BC patients who received surgery and chemotherapy, those who underwent NACT were less likely to experience delays in BCTI compared to pts who received UBS first. Among eligible pts, use of NACT may reduce delays in BCTI. [Table: see text]

Automated digital oncologic data review for breast cancer research: AI-enabled mCODE and field-of-interest extraction framework.

e12647 Background: Enhancing outcomes in cancer care and research can be optimally achieved by accelerating data extraction from unstructured electronic health resources. Understanding the association between treatment response markers and long-term outcomes is crucial for refining cancer therapeutic approaches and improving patient prognosis. In this study, we explore the association of oncologic outcomes with pathologic complete response (pCR) in high-risk early-stage breast cancer treated with neoadjuvant chemotherapy (NACT) using automated oncologic data extraction framework. Methods: Patients with primary stage I-III breast cancer who received NACT followed by mastectomy, with or without immediate breast reconstruction from January 2010 to August 2023 were retrospectively analyzed. We extracted pCR results and data on clinical and pathological stage, tumor subtype, grade, and treatment regimens and factors affecting postoperative complications from electronic medical records based on the AI enabled-mCODE (Minimal Common Oncology Data Elements) and fields of interest extraction framework. Employing mixed-effects Cox models, we explored the association between pCR and event-free survival (EFS), distant recurrence free Survival (DRFS) and overall survival (OS). Survival curves of patients were estimated using Kaplan-Meier method. Multivariate analysis was performed to evaluate the predictive factors for pCR. Results: Overall, 2725 patients were analyzed. The median age was 50.6 years. The median follow-up was 67 months. pCR was achieved in 31.0%. Hazard ratio for pCR vs. non-pCR were 0.34 for EFS (95% CI, 0.25-0.45), 0.32 for DRFS (95% CI, 0.23-0.43), 0.21 for OS (95% CI, 0.13-0.34), varying from 0.13 to 0.56 for EFS, 0.12 to 0.48 for DRFS and 0.07 to 0.40 for OS. The presence of pCR remained prognostic for event-free survival in multivariate models adjusted for age, tumor size, and nodal status at baseline. Conclusions: This study confirms that patients achieving pCR after NACT have better long-term survival outcomes that patients who do not. Oncologic data extraction from unstructured electronic medical records using AI-enabled extraction framework can be expected to enhance robust cancer research and generate valuable insights from real-world practice settings for tailored therapeutic decision-making. [Table: see text]