Breast Cancer Initiation Research Articles

Survival analysis for patients with metachronous contralateral breast cancer: Insights from a retrospective study.

Continued advances in the diagnosis and treatment of breast cancer (BC) have led to an increase in the number of long-term BC survivors and an increase in the incidence of metachronous BC in the contralateral breast. Therefore, it is important to understand the factors that influence the development of metachronous BC; however, the impact of the laterality of the initial ipsilateral (I)BC as a risk factor for the development of metachronous contralateral (MC)BC has not been extensively investigated. The present study included 17,082 female patients with stage 0-3 IBC from the prospectively maintained Korean Breast Cancer Registry from 1989-2013 and divided them into two groups: Patients with MCBC (n=88) and those without MCBC (n=16,994). Risk factors that present at the initial BC diagnosis that could significantly influence the development of MCBC were screened for and risks were evaluated using the Fine-Gray subdistribution hazard model. Significant differences in baseline characteristics between MCBC and non-MCBC groups were demonstrated. Patients aged <40 years, those with histological and nuclear grade 3 tumors, and those with the triple-negative BC subtype were significantly more prevalent in the MCBC group than in the non-MCBC group. Additionally, the cumulative incidence of MCBC increased over time, with a notable increase from 0.1% in year 1 to 1.6% in year 10. Survival analysis revealed no significant differences in overall or BC-specific survival between the two groups. Key predictive factors identified for MCBC included an age of <40 years at initial diagnosis, a negative progesterone receptor status, and a Ki-67 score of >14%. Overall, the present study revealed several factors associated with MCBC and emphasized the need for long-term monitoring of BC survivors, considering these newly identified risk factors.

Investigation of BRAF V600E Mutation in Breast Cancer Patients

The B-Raf is the essential protein in signal pathways inside cells which is affected by cell growth direction. The B-Raf protein encoded by the BRAF gene that is located at chromosome 7, BRAF gene is also pointed out as proto-oncogene. This study aimed to detect the substitution at codon 600 causing a change of valine to glutamic acid (V600E) mutation in Iraqi females to assist its role in initiating breast cancer. Sixty biopsies tissue from breast cancer Iraqi women and 20 women with benign lesions were enrolled in this study. DNA was extracted from breast cancer biopsies samples. PCR and DNA Sequencing techniques were used to screen the BRAF V600E gene mutation as it is an essential event in the initiation of cancer. The results revealed that none Iraqi breast cancer women had BRAF V600E mutation, The annotated BRAF gene has been deposited in DDBJ/GenBank under the accession number LC547435. In conclusion: The present data indicate no BRAF V600E mutation in Iraqi breast cancer females and may not possess a role in breast cancer initiation. The current results may be refer to ineffectiveness of Vemurafenib and Encorafenib therapies that specific for patients with the BRAF V600 mutation. Other studies with large numbers of patients are needed to confirm the result of this study, as the high prevalence of breast cancer among Iraqi women.

Breast organoid suspension cultures maintain long-term estrogen receptor expression and responsiveness.

Organoid cultures offer a powerful technology to investigate many different aspects of development, physiology, and pathology of diverse tissues. Unlike standard tissue culture of primary breast epithelial cells, breast organoids preserve the epithelial lineages and architecture of the normal tissue. However, existing organoid culture methods are tedious, difficult to scale, and do not robustly retain estrogen receptor (ER) expression and responsiveness in long-term culture. Here, we describe a modified culture method to generate and maintain organoids as suspension cultures in reconstituted basement membrane (™Matrigel). This method improves organoid growth and uniformity compared to the conventional Matrigel dome embedding method, while maintaining the fidelity of the three major epithelial lineages. Using this adopted method, we are able to culture and passage purified hormone sensing (HS) cells that retain ER responsiveness upon estrogen stimulation in long-term culture. This culture system presents a valuable platform to study the events involved in initiation and evolution of ER-positive breast cancer.

The clinical, molecular, and therapeutic implications of time from primary diagnosis to brain metastasis in lung and breast cancer patients

AbstractPurposeLung cancer (LC) and breast cancer (BC) are the most common causes of brain metastases (BMs). Time from primary diagnosis to BM (TPDBM) refers to the time interval between initial LC or BC diagnosis and development of BM. This research aims to identify clinical, molecular, and therapeutic risk factors associated with shorter TPDBM.MethodsWe retrospectively reviewed all diagnosed LC and BC patients with BM at Harbin Medical University Cancer Hospital from 2016 to 2020. A total of 570 patients with LC brain metastasis (LCBM) and 173 patients with breast cancer brain metastasis (BCBM) patients who met the inclusion criteria were enrolled for further analysis. BM free survival time curves were generated using Kaplan–Meier analyses. Univariate and multivariate Cox regression analyses were applied to identify risk factors associated with earlier development of BM in LC and BC, respectively.ResultsThe median TPDBM was 5.3 months in LC and 44.4 months in BC. In multivariate analysis, clinical stage IV and M1 stage were independent risk factors for early development of LCBM. LC patients who received chemotherapy, targeted therapy, pulmonary radiotherapy, and pulmonary surgery had longer TPDBM. For BC patients, age ≥ 50 years, Ki67 ≥ 0.3, HER2 positive or triple‐negative breast cancer subtype, advanced N stage, and no mastectomy were correlated with shorter TPDBM.ConclusionsThis single‐institutional study helps identify patients who have a high risk of developing BM early. For these patients, early detection and intervention could have clinical benefits.

Detection of contralateral breast cancer in patients with primary breast cancer through AI-assisted mammography.

e13645 Background: Survivors of breast cancer are at an elevated risk for developing contralateral breast cancer (CBC), a risk that surpasses the incidence of initial primary breast cancer within the general population. Consequently, annual mammography screenings are advocated to monitor for ipsilateral recurrence and the emergence of CBC. However, the sensitivity of surveillance mammography exhibits considerable variation, ranging between 45% and 90%, with notably lower detection rates in younger individuals and those with dense breast tissue. This study explores the efficacy of an artificial intelligence (AI) detection algorithm in mammography for the early identification of CBC prior to the official diagnosis. Methods: A retrospective analysis was conducted on patients treated for primary breast cancer from 2000 to 2021 at Seoul National University Hospital. This involved reviewing serial mammograms post-surgery and adjuvant therapy from 460 patients who subsequently developed CBC (CBC group) and 469 patients who did not (control group). These mammograms were evaluated using the Lunit INSIGHT mammogram AI system, which provides a pixel-level abnormality score between 0 and 100, with higher scores indicating increased abnormality. Scores exceeding 10 were considered indicative of CBC, reflecting a 90% sensitivity based on the AI software's tuning dataset. The diagnostic accuracy of AI-assisted mammography was then juxtaposed with that of specialist radiologists' evaluations. Results: At the point of CBC diagnosis, the median AI abnormality score was markedly higher in the CBC group (22.9 [IQR, 2.1-81.1]) compared to the control group's final follow-up mammogram (0.4 [IQR, 0.1-1.5], p&lt;0.001). The AI system's sensitivity for CBC detection paralleled that of radiologist assessments (59.6% for AI vs. 56.5% for radiologists out of 460 detected cancers), with the AI method achieving an AUROC of 0.836 and a specificity of 91.0%. Notably, AI detected 84 cases (30.7%) at least six months and 59 cases (21.5%) more than a year before the official CBC diagnosis. Conclusions: The application of AI in mammography screening has demonstrated significant potential for the early detection of CBC, identifying cases up to a year before formal diagnosis. This underscores the value of integrating AI tools in mammography to enhance early detection rates of CBC among primary breast cancer patients.

Achieving World Health Organization Global Breast Cancer Initiative targets: A situational analysis and action plan in Nigeria.

e13782 Background: Breast cancer [BC] is the leading cause of cancer incidence and mortality in Nigerian women, with five-year survival of 44% vs. 90% in the US. The World Health Organization [WHO], through the Global Breast Cancer Initiative [GBCI], endorses a 3-pillar program that promotes early-stage detection, timely diagnosis, and expeditious treatment. We performed a situational analysis to understand predictors of achieving WHO targets in Nigeria as a basis for implementing an action plan. Methods: We conducted a cross-sectional study using a prospective multi-institutional BC patient database in Nigeria (funded by ASCO), which was expanded sequentially from a single institution in May 2022 to seven institutions representing all geopolitical zones by May 2023. All newly diagnosed BC patients enrolled in the database from 2022-2024 were included. We analyzed univariate associations with WHO GBCI key performance indicators [KPIs] using logistic regression and global p-values. Results: Five-hundred and seventy-one patients were included. Median age was 48 years (IQR 40,56). Conclusions: The utilization of a multi-institutional BC database inclusive of all geopolitical zones in Nigeria provides vital insight for monitoring progress toward WHO targets. Our findings suggest that breast health clinical encounters (through CBE or mammogram) prior to developing BC are associated with reduced diagnostic delays and early-stage BC diagnosis. For those with BC, multiple touchpoints with the healthcare system are associated with increased delays and late-stage diagnosis, which justifies the need for developing patient navigation programs. [Table: see text]

Analysis of the nischarin expression across human tumor types reveals its context-dependent role and a potential as a target for drug repurposing in oncology.

Nischarin was reported to be a tumor suppressor that plays a critical role in breast cancer initiation and progression, and a positive prognostic marker in breast, ovarian and lung cancers. Our group has found that nischarin had positive prognostic value in female melanoma patients, but negative in males. This opened up a question whether nischarin has tumor type-specific and sex-dependent roles in cancer progression. In this study, we systematically examined in the public databases the prognostic value of nischarin in solid tumors, regulation of its expression and associated signaling pathways. We also tested the effects of a nischarin agonist rilmenidine on cancer cell viability in vitro. Nischarin expression was decreased in tumors compared to the respective healthy tissues, most commonly due to the deletions of the nischarin gene and promoter methylation. Unlike in healthy tissues where it was located in the cytoplasm and at the membrane, in tumor tissues nischarin could also be observed in the nuclei, implying that nuclear translocation may also account for its cancer-specific role. Surprisingly, in several cancer types high nischarin expression was a negative prognostic marker. Gene set enrichment analysis showed that in tumors in which high nischarin expression was a negative prognostic marker, signaling pathways that regulate stemness were enriched. In concordance with the findings that nischarin expression was negatively associated with pathways that control cancer growth and progression, nischarin agonist rilmenidine decreased the viability of cancer cells in vitro. Taken together, our study lays a ground for functional studies of nischarin in a context-dependent manner and, given that nischarin has several clinically approved agonists, provides rationale for their repurposing, at least in tumors in which nischarin is predicted to be a positive prognostic marker.

Beyond blood pressure, fluid and electrolyte homeostasis - Role of the renin angiotensin aldosterone system in the interplay between metabolic diseases and breast cancer.

The classical renin angiotensin aldosterone system (RAAS), as well as the recently described counter-regulatory or non-canonical RAAS have been well characterized for their role in cardiovascular homeostasis. Moreover, extensive research has been conducted over the past decades on both paracrine and the endocrine roles of local RAAS in various metabolic regulations and in chronic diseases. Clinical evidence from patients on RAAS blockers as well as pre-clinical studies using rodent models of genetic manipulations of RAAS genes documented that this system may play important roles in the interplay between metabolic diseases and cancer, namely breast cancer. Some of these studies suggest potential therapeutic applications and repurposing of RAAS inhibitors for these diseases. In this review, we discuss the mechanisms by which RAAS is involved in the pathogenesis of metabolic diseases such as obesity and type-2 diabetes as well as the role of this system in the initiation, expansion and/or progression of breast cancer, especially in the context of metabolic diseases.

Behavioral Interventions to Improve Breast Cancer Screening Outreach

Despite public health efforts, breast cancer screening rates remain below national goals. To evaluate whether bulk ordering, text messaging, and clinician endorsement increase breast cancer screening rates. Two concurrent, pragmatic, randomized clinical trials, each with a 2-by-2 factorial design, were conducted between October 25, 2021, and April 25, 2022, in 2 primary care regions of an academic health system. The trials included women aged 40 to 74 years with at least 1 primary care visit in the past 2 years who were eligible for breast cancer screening. Patients in trial A were randomized in a 1:1 ratio to receive a signed bulk order for mammogram or no order; in a factorial design, patients were concurrently randomized in a 1:1 ratio to receive or not receive text message reminders. Patients in trial B were randomized in a 1:1 ratio to receive a message signed by their primary care clinician (clinician endorsement) or from the organization (standard messaging); in a factorial design, patients were concurrently randomized in a 1:1 ratio to receive or not receive text message reminders. The primary outcome was the proportion of patients who completed a screening mammogram within 3 months. Among 24 632 patients included, the mean (SD) age was 60.4 (7.5) years. In trial A, at 3 months, 15.4% (95% CI, 14.6%-16.1%) of patients in the bulk order arm and 12.7% (95% CI, 12.1%-13.4%) in the no order arm completed a mammogram, showing a significant increase (absolute difference, 2.7%; 95% CI, 1.6%-3.6%; P < .001). In the text messaging comparison arms, 15.1% (95% CI, 14.3%-15.8%) of patients receiving a text message completed a mammogram compared with 13.0% (95% CI, 12.4%-13.7%) of those in the no text messaging arm, a significant increase (absolute difference of 2.1%; 95% CI, 1.0%-3.0%; P < .001). In trial B, at 3 months, 12.5% (95% CI, 11.3%-13.7%) of patients in the clinician endorsement arm completed a mammogram compared with 11.4% (95% CI, 10.3%-12.5%) of those in the standard messaging arm, which was not significant (absolute difference, 1.1%; 95% CI, -0.5% to 2.7%; P = .18). In the text messaging comparison arms, 13.2% (95% CI, 12.0%-14.4%) of patients receiving a text message completed a mammogram compared with 10.7% (95% CI, 9.7%-11.8%) of those in the no text messaging arm, a significant increase (absolute difference, 2.5%; 95% CI, 0.8%-4.0%; P = .003). These findings show that text messaging women after initial breast cancer screening outreach via either electronic portal or mailings, as well as bulk ordering with or without text messaging, can increase mammogram completion rates. ClinicalTrials.gov Identifier: NCT05089903.

Abstract PO1-24-07: LYSOSOMAL-ASSOCIATED TRANSMENBRANE 4B (LAPTM4B) AS POTENTIAL BIOMARKER IN BREAST CANCER

Abstract LAPTM4B is a transmembrane that promotes autophagy and renders tumor cells resistant to metabolic and genotoxic stress. Increased expression of LAPTM4B has been found in breast, liver, lung, ovarian, uterine and gastric cancers. Overexpression of LAPTM4B contributes to chemotherapy resistance, proliferation and metastases. We analyze the expression of LAPTM4B in serum by ELISA method in a series of breast cancer patients in different clinical situations to assess its possible potential as a biomarker. A total of 135 patients were analyzed, 95 patients were in early breast cancer and 50 in metastatic disease. Of the 95 patients with early disease, 52 had a luminal A phenotype, 19 luminal B, 15 HER2 positive and 9 triple negative. And of the other 50 they were luminal in 34, HER2 positive in 11 and triple negative in 5. The attached table specifies the values of the LAPTM4B expression in the different clinical situations. GLOBAL LUMINAL A LUMNAL B HER2 TRIPLE NEGATIVE SITUATIONS Laptm4b n Laptm4b n Laptm4b n Laptm4b n Laptm4b n EARLY 9,6 ng/ml 95 7,7 ng/ml 52 12,8 ng/ml 19 13,4 ng/ml 15 7,1 ng/ml 9 METASTATIC 16,8 ng/ml 50 13,7 ng/ml 34 7,2 ng/ml 11 58,9 ng/ml 5 We found a statistic difference in the expression of LAPTM4B in patients with early and metastatic disease (ANOVA test p:0,028 ). LAPTM4B was higher in the luminal B and HER2 subtypes in early breast cancer while in metastatic disease was overexpressed in triple negative. An interesting finding was that in metastatic disease, LAPTM4B was overexpressed in patients with progression compared to patients in response. 30 ng/ml vs 10 ng/ml (ANOVA test p:0,011) LAPTM4B expression may be a potential biomarker in breast cancer since its expression is statistically different in early and metastatic disease (9,6 vs 16,8 ng/ml).In addition, patients with metastatic breast cancer who re in response also have lower levels of LAPTM4B compared with patients in progression. Monitoring the levels of LAPTM4B in serum can help us to predict the treatment response. Citation Format: Serafin Morales Murillo, Ariadna Gasol Cudós, Noemí Tuset Der-Abrain, Izaskun Urdanibia, Ana Velasco Sánchez. LYSOSOMAL-ASSOCIATED TRANSMENBRANE 4B (LAPTM4B) AS POTENTIAL BIOMARKER IN BREAST CANCER [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-24-07.

Abstract PO3-28-02: BODY-IMAGE DISTRESS IN BREAST CANCER SURVIVORS AND THEIR EVALUATION OF MEDICAL TATTOOING FOLLOWING SURGERY

Abstract A review of the literature reveals a high incidence of body-image distress among breast cancer survivors who have undergone surgery, which is a natural response to the significant changes in their appearance. Reconstructive surgery, utilizing implants or flaps, may be employed to restore breast size and shape. Medical tattooing can recreate the nipple-areola complex and decorative appliques can conceal scars and skin color variations. Both reconstructive surgery and medical tattoos are associated with patient-reported satisfaction, yet further research is necessary to understand their combined impact on body-image distress. To investigate this, a survey was distributed among national breast cancer support groups and advocacy organizations, yielding 207 responses from individuals meeting the study's criteria. The participants were categorized into two groups: those who received post-surgical medical tattoos (n = 61) and those who did not (n = 146). The study also examined how participants evaluated the cosmetic and decision satisfaction of patients who made various surgical and cosmetic intervention choices. This was accomplished by having participants rate images of patients who had received three types of intervention: mastectomy and reconstruction only, mastectomy and medical tattooing only, and mastectomy, reconstruction, and medical tattooing. Using linear regression and multilevel modeling that controlled for demographic and clinical factors associated with body-image distress, the findings demonstrated that participants with medical tattoos reported significantly lower levels of body-image distress, depressive symptoms, and perceived stress compared to those without medical tattoos. Furthermore, participants rated images of patients who underwent both reconstruction and medical tattooing post-mastectomy as having significantly higher cosmetic and decision satisfaction ratings than images of patients who received reconstruction or medical tattooing alone. This research expands on our understanding of body-image distress in survivors as a multidimensional construct and may serve to indicate potential means for intervention. Enhancing our understanding of how breast cancer treatment and surgery affects survivors' body-image distress may aid healthcare professionals in offering additional psychoeducation and recommendations. Furthermore, presenting information about medical tattooing as a complementary cosmetic option early in the treatment process allows patients the opportunity to consider it within the context of their overall treatment plan. Table. Linear regression results using BIBCQ as the outcome variable and medical tattoo group as the predictor variable with covariates included. Note. PHQ9 = Patient Health Questionnaire-9. PSS = Perceived Stress Scale. Citation Format: Miranda Proctor, Jeffrey Cassisi. BODY-IMAGE DISTRESS IN BREAST CANCER SURVIVORS AND THEIR EVALUATION OF MEDICAL TATTOOING FOLLOWING SURGERY [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-02.

Abstract PO5-06-05: DISCORDANCE BETWEEN HORMONE RECEPTORS AND HER2 STATUS IN BREAST CANCER PATIENTS RELAPSE

Abstract Introduction: Breast cancer (BC) is a heterogeneous disease, and during its progression, the tumor phenotype can undergo changes that are often associated with a poor prognosis. In this study, we aim to compare the discordance in estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 expression between primary and recurrent/metastatic lesions. Methods: This study is a retrospective analysis of 132 non-advanced breast cancer patients who experienced confirmed recurrence/metastasis at the Instituto Nacional de Enfermedades Neoplasicas between 2011 and 2022. Descriptive analysis was conducted to assess the expressions of ER, PgR, HER-2, and Ki-67 in primary and metastatic breast cancer, as well as clinical variables. Normality tests, including Kolmogorov-Smirnov and Shapiro-Wilk, were performed. The paired samples Wilcoxon test was used to determine significant differences between primary and recurrent/metastatic tumors. Additionally, Spearman's rank correlation coefficient was employed to evaluate the relationships of expression discordance. Results: Fifty-nine percent of patients presented locoregional recurrence, while 41% presented visceral metastasis. In the primary tumor, ER and PR expression were found in 63.6% and 55.3% of cases, respectively. HER2 status was determined as 0 (36.3%), +1 (22%), +2 (14.4%), +3 (26.5%), and not determined (0.8%) by IHC. For the recurrent/metastatic tumor, ER and PR expression were found in 59% and 34% of cases, respectively. HER2 status was determined as 0 (27.3%), +1 (19.7%), +2 (25%), +3 (25%), and not determined (3%). The median Ki-67 levels were 37% in the primary tumor and 40% in the recurrent/metastatic tumor. Significant differences were found for ER (p=0.014), PR (p&amp;lt; 0.001), and HER2 (p=0.019), but not for Ki-67 percentage (p=0.139). The discordance rates of ER, PR, HER2, and Ki-67 expression were 27.9%, 47.7%, and 26.3%, respectively. Conclussions: Discordance in hormone receptor expression between primary and recurrent/metastatic tumors is a common phenomenon, with ER showing a discordance rate of 27.9% and PR showing a higher rate of 47.7%. HER2 status also displayed significant discordance, with a 26.3% rate of discordant expression between primary and recurrent/metastatic tumors. The findings from this study emphasize the dynamic nature of breast cancer and the importance of comprehensive evaluation of biomarker expression in both primary and recurrent/metastatic tumors, to choose the best treatment options. Citation Format: Katia Roque, Iris Otoya, Natalia Valdivieso, Zaida Morante, Hugo Fuentes, Silvia Neciosup, Henry Gómez, Jorge Cotito, Gonzalo Ziegler, Estefania Peña, Tatiana Vidaurre, Ramon Andrade de Mello, Carlos Castañeda. DISCORDANCE BETWEEN HORMONE RECEPTORS AND HER2 STATUS IN BREAST CANCER PATIENTS RELAPSE [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-05.

Abstract PO3-19-07: AC699-001, a first in human Phase 1 trial utilizing a novel estrogen receptor chimeric degrader in patients with advanced or metastatic breast cancer

Abstract Background Estrogen receptors (ER) are hormone-regulated transcription factors that play a critical role in breast cancer initiation and proliferation. Modulation of estrogen activity with therapeutics such as tamoxifen and aromatase inhibitors have been the mainstay therapeutic strategy for ER-positive breast cancer. Several ER-directed therapies have been developed to antagonize the oncogenic ER function, including Selective ER Degraders (SERDs) such as fulvestrant which is approved to treat patients with advanced or metastatic breast cancer. However, it requires intramuscular injection and has poor solubility, thereby limiting its administered dose and therefore its efficacy. In addition to SERDs, a newly emerging technology, E3 ligase-engaged chimeric degraders, has been used to induce potent and deeper ER degradation. Empowered by Accutar's proprietary Protein-Protein Interaction Targeting Chimeras (PPI-TAC) platform, AC699 was meticulously designed as a chimeric degrader to target and degrade the protein of interest, ERα. By effectively linking an ER ligand to an E3-ligase recruiting ligand, AC699 brings ERα in proximity to an E3 ligase, thereby inducing subsequent ubiquitination and degradation of ERα. Notably, chimeric ER degraders possess the unique advantage of degrading the ER protein without the inherent risk of activating an ER signal. Moreover, these molecules are not degraded alongside the target protein allowing for their efficient recycling within the cell. This direct mechanism enables chimeric ER degraders to achieve potent ER degradation with increased specificity, thereby potentially providing a higher therapeutic index compared to SERDs. This abstract describes a first-in-human Phase 1 trial of AC699, a novel ER degrader. Study Description The AC699-001 Phase 1 dose escalation study will enroll up to 60 patients with locally advanced or metastatic ER-positive, human epidermal growth factor receptor 2-negative, breast cancer. Patients must have progressed on standard treatment including at least two prior endocrine regimens or at least one prior line of therapy if combined with a CDK4/6 inhibitor. Prior chemotherapy is not required but must not exceed three prior cytotoxic regimens. Patients must have at least one measurable lesion or at least one predominantly lytic bone lesion. AC699 is given orally, once daily, with doses ranging from 100 mg to 600 mg in a standard 3+3 dose escalation design. The primary objective is to evaluate the safety and tolerability of AC699 using CTCAE 5.0. Secondary objectives include assessing preliminary anti-tumor activity according to RECIST 1.1 and characterizing the pharmacokinetic profile of single and multiple doses of AC699. Enrollment began in December 2022 with five sites in the United States planned. NCT05654532. Citation Format: Manish R Patel, Rachel Layman, Joy Nolte Fong, Hui Zhang, Su Kim, Erika Hamilton. AC699-001, a first in human Phase 1 trial utilizing a novel estrogen receptor chimeric degrader in patients with advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-07.

Abstract PO4-01-11: Ovarian function suppression (OFS) use beyond five years?: Young breast cancer patient preferences

Abstract Background. Breast cancer (BC) is the leading cause of cancer-related death in young women worldwide, and late recurrence of hormone receptor-positive disease plays a substantial role. Adjuvant endocrine therapy with 5 years of ovarian function suppression (OFS) and an aromatase inhibitor or tamoxifen is recommended for many young patients with high risk hormone receptor-positive BC. Data are limited regarding extended endocrine therapy among premenopausal BC survivors, and non-existent to inform treatment decisions regarding extending OFS beyond 5 years. We sought to evaluate young BC survivors’ perceptions and preferences regarding extending OFS beyond 5 years, and consideration of a potential future study to assess the role of extended OFS. Methods. From January-April 2023, email invites were sent to the Young Survival Coalition (YSC) listserv (N=14,291) specifically asking members with a history of invasive BC (≤45 years at diagnosis; stage I-III without metastatic recurrence) receiving OFS injections for adjuvant endocrine treatment to complete a one-time anonymous online survey. The survey was designed to capture information regarding current endocrine therapy use, patient-provider communication regarding extended endocrine therapy including OFS, OFS-related concerns (rating 0-5 [low: 0-1, moderate: 2-3, severe: 4-5]), and interest in a potential future clinical trial utilizing OFS beyond 5 years. Descriptive statistics were utilized to summarize responses, and two-sided Fishers exact tests and chi-square analyses were used for comparisons. Results. A total of 1,030 YSC members completed the survey, and 615 were analyzed due to eligibility and completeness of data. The majority were from the United States (n=579, 94.1%) or Canada (n=8, 1.3%), were non-Hispanic white (n=452, 73.5%), non-Hispanic Black (n=46, 7.5%), or Hispanic (n=43, 7.0%), and had been diagnosed with stage II BC (n=316, 51.4%). The average age at survey was 38.1 years (SD=5.15, range=22-54) and at initial BC diagnosis was 34.6 years (SD=4.96, range=20-49). Most (n=510, 83.0%) were within their first 5 years of OFS treatment while 14.5% (n=89) had already been receiving OFS for more than 5 years. Many respondents (n=344, 55.9%) reported discussing OFS use beyond 5 years with their provider, of whom 39.8% (n=245) reported their provider recommending they continue OFS for more than 5 years. Despite reporting moderate and severe concerns regarding OFS side effects (n=476, 77.4%), inconvenience of injection visits (n=272, 44.2%), and high cost of medication (n=223, 36.3%), most respondents (n=396, 64.4%) would consider continuing OFS beyond 5 years if it would reduce risk of BC recurrence. For nearly half of respondents (n=289, 47.0%) a risk reduction of at least 5% would be required for extended OFS to be worthwhile compared to the remaining 46.3% (n=285) who indicated interest for &amp;lt; 5% risk reduction. When asked hypothetically if they would take part in a clinical trial to determine efficacy of OFS use beyond 5 years, the majority were interested (n=357, 58.0%). Respondents who were interested were less likely to be concerned about the high cost of medication (p=0.003) however they were also less likely to take OFS beyond 5 years if it only led to 1-2% BC risk reduction (p=0.006) compared to those who were not interested. There were no other proportional differences on any other outcome. Conclusion. Many BC survivors and providers are already considering incorporation of OFS beyond 5 years into adjuvant endocrine therapy despite harboring concerns and lack of data. Efforts to determine the efficacy and benefits of extended OFS are necessary given the risk of late recurrence in this population as well as the potential for significant short- and long-term toxicities. The results from this survey study suggest that future clinical trials evaluating potential benefits and risks of long-term OFS use among young BC survivors are needed and likely feasible. Citation Format: Kate Dibble, Tal Sella, Kathryn Ruddy, Craig Snow, Amanda Nixon, Patricia Spears, Karla Ballman, Lisa Carey, Ann Partridge. Ovarian function suppression (OFS) use beyond five years?: Young breast cancer patient preferences [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-01-11.

Abstract PO5-10-07: Risk factors associated with secondary cancers in AYA patients with breast cancer. A SEER database study

Abstract Background Adolescents and young adults (AYA) diagnosed with breast cancer face unique challenges and have distinct characteristics compared to older patients. While primary breast cancer remains a significant concern, the risk of developing secondary cancers in this population is also of great importance. This study aimed to identify these risk factors by analyzing a large cohort of AYA breast cancer patients using SEER (Surveillance Epidemiology and End Result) Database. Methods Patients were identified from SEER Research Data 17, from 2000 to 2019. Patients aged 18-39 years with breast cancer and at least 1 year of survival were identified. Secondary cancers were then identified and included any disease site. Patient demographic and clinical characteristics were summarized by secondary cancer status using Mann-Whitney U and Fisher’s exact tests. Overall survival from the initial breast cancer diagnosis was summarized by secondary cancer status using standard Kaplan-Meier methods, where the median and 3/5-year rates were estimated with 95% confidence intervals. Comparisons were made using the log-rank test. SAS v9.4 (Cary, NC) was used at a significance level of 0.05. Results A total of 47,912 AYA breast cancer patients were identified, of which 2,886 (6.0%) developed a secondary cancer at least 1 year after the initial breast cancer diagnosis. When comparing patients with and without secondary cancers, we observed significant differences with respect to age at initial breast cancer diagnosis, race, stage, nodal status, surgical procedure, ER status, PR status, Her2 status, and sub-type (Table 1). The analysis of overall survival showed that, from the time of breast cancer diagnosis, there was no statistically significant difference between patients with and without secondary cancers. However, this may be due to an immortal time bias. Breast was the most common site of secondary cancer (67%) followed by gynecological (7%), colorectal (3.7%), skin (3.4%) lung and hematologic (2.7%) Compared to other subtypes, TNBC patients were found to have much shorter time to secondary cancer development of 38 months compared to Her2+ and ER/PR+ (40 and 45 months respectively, P&amp;lt; 0.001). Black and Hispanic individuals were found to have higher rates (7.4% and 6.3%) and earlier development of secondary cancer (76 months and 74 months) as compared to whites and Asians (5.9% and 5%, 88 months and 81 months, P&amp;lt; 0.001 and P&amp;lt; 0.002 respectively). Conclusion This study identified several risk factors associated with the development of secondary cancers in AYA breast cancer patients such as age at initial breast cancer diagnosis, race, stage, nodal status, surgical procedure and sub-type. Higher rates and early development of secondary cancer were observed among TNBC subtype and Black and Hispanic races that calls for further investigation and tailored interventions to improve outcomes in specific patient populations. Table 1 showing significant differences in characteristics AYA breast cancer patients who developed secondary breast cancer compared to those who did not Citation Format: Sheeba Ba Aqeel, Alankrita Taneja, Shipra Gandhi. Risk factors associated with secondary cancers in AYA patients with breast cancer. A SEER database study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-10-07.

Abstract PO4-17-01: Patient Perception and Decision-Making in HER2+ Early Breast Cancer Management: Insights from the ASKHER2 European Survey

Abstract Background Breast cancer remains the most prevalent cancer in women globally, with Human Epidermal Growth Factor Receptor 2 positivity (HER2+) observed in 15-30% of initial breast cancer cases. Adjuvant treatment for HER2+ early breast cancer has notably reduced mortality and recurrence rates. However, the heterogeneity of the disease and in conveying risk information by healthcare providers (HCPs) leaves many women uncertain about their individual risk of recurrence and potential treatment (tx) options. Evidence shows that fear of recurrence, uncertainty about prognosis, and inadequate risk/benefit information can affect patients' decisions during their tx phase. Therefore, it is important to better understand the perceptions, attitudes, and behaviors regarding the risk of recurrence in women with HER2+ early breast cancer. Methods A protocol-driven, direct-to-patient online survey (30 questions total) was administered in France, Germany, Italy, Portugal, Spain, and Sweden via patient advocacy groups and panels. Women aged 18 years and above with either early-stage (eBC) (stages I-III) or metastatic (mBC) (stage IV) as the result of recurrence from an initial diagnosis of locally advanced HER2+ breast cancer were eligible to participate. The implementation of soft quotas ensured a representative sample size. This abstract presents the results of the survey. Results A total of 622 participants completed the survey between July 2022 and February 2023. Majority of participants (70%) were between 40 and 65 years of age. Almost 85% had eBC (N=527), 62% had been diagnosed with HER2+ eBC for ≥ 2 years, and 68% were undergoing breast cancer tx at the time of the survey. The main worries and concerns that were reported by participants when asked about their tx plan were risk of recurrence (27%), fear of dying (22%) and risk of tx failure (14%). Among eBC participants, 40% perceived their personal risk of recurrence to be moderate, 18% perceived it to be high, while 21% did not know their personal risk. Most eBC participants (72%) preferred short and simple explanations from the medical team about the risk of cancer recurrence, while 4% preferred not to receive this information. Overall, 30% of participants said they had fully discussed the risk of recurrence with their doctor, while 20% had no discussion. Almost all participants (97%) wanted to be involved in their tx decision, 49% completely and 48% partially. To reduce this risk of recurrence, participants with eBC were willing to change their diet habits (77%), exercise more frequently (74%), take additional tx (65%) or undergo surgery (60%). Most participants (69%) were willing to take additional tx even if it would reduce their risk of recurrence by less than 50%. Participants were most willing to tolerate fatigue (53%), followed by hot flashes (51%) and joint pain (44%), as the most acceptable side effects if they had to take additional treatments with the potential benefit of reducing risk of recurrence. Conclusion The multinational large direct-to-patient ASKHER2 survey reflects participants’ experience and highlights concerns of patients with HER2+ breast cancer, notably on their recurrence risk. To mitigate this risk, patients exhibited a willingness to modify lifestyle habits and consider additional tx. A fraction of participants considered they had thoroughly discussed these risks with their HCPs, while the vast majority desired active involvement in their treatment decisions. These results underscore the ongoing need for HCPs to discuss the risk of recurrence in a clear way, addressing the full potential of treatment options in eBC and mBC, to enable patients to participate in this patient-centered approach of the decision-making process. Citation Format: Matteo Lambertini, Christian Jackisch, Olivier Trédan, Maria Vidal, Mário Fontes-Sousa, Antonios Valachis, Rosanna D’Antona, Marcelo Ruz, Eugenia Krone, Miriam Brice, Erwan Berjonneau, Soraia Matos, Olivia Dialla, Laure Guéroult-Accolas. Patient Perception and Decision-Making in HER2+ Early Breast Cancer Management: Insights from the ASKHER2 European Survey [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-01.

Abstract PO3-22-02: Concurrent chemotherapy with adjuvant radiation for patients with high-risk locally advanced breast cancer: safety and outcomes

Abstract Background: Patients with locally advanced breast cancer are at high risk for locoregional and distant recurrence and novel strategies are needed to enhance the efficacy of adjuvant radiation therapy. Selected chemotherapies act synergistically to safely radiosensitize residual disease to radiation therapy and may improve locoregional control when given concurrently. We report our institutional experience using concurrent chemotherapy with adjuvant radiotherapy for high-risk breast cancer patients. Methods: We conducted a retrospective study of breast cancer patients treated definitively with chemotherapy, surgery, and concurrent chemo-radiation (chemo-XRT) in the adjuvant setting between May 2006 and April 2019. The decision to combine chemotherapy with adjuvant conventionally fractionated radiation was based on provider discretion regarding patient’s risk of recurrence. The primary outcome was risk of locoregional recurrence (LRR). Secondary outcomes included disease free survival (DFS), overall survival (OS), and toxicity. The cumulative incidence of local recurrence was estimated with distant recurrence and death as competing risks. DFS and OS was estimated using the Kaplan-Meier method. Results: A total of 42 patients met inclusion criteria; of these 35 (83%) patients were receiving treatment for their initial breast cancer diagnosis and 7 (17%) patients were receiving treatment for a locoregional recurrence. Of the 35 patients treated in the primary setting, the majority had stage III disease (91%). Twenty-nine patients (83%) received neoadjuvant chemotherapy (NAC) all of which had residual disease after NAC and 6 patients (17%) received upfront primary surgery. Overall median total radiation dose was 57 Gy (range 45-68 Gy) with a majority receiving comprehensive regional nodal irradiation (25, 60%). Chemotherapy agents used for chemo-XRT included capecitabine (29, 69%), paclitaxel (8, 19%), and cisplatin (5, 12%). Median follow-up was 5 years after surgery (range: 4 months-16 years). At 5 years, the cumulative risk of LRR was 7% (95% CI: 2-21%). DFS was 47% (95% CI: 34-65%) and OS was 56% (95% CI: 42-74%). Of note, there were multiple exceptional responders, with OS of 51% at 10 years and 45% at 15 years. Chemo-XRT was well tolerated with 7% grade 3 toxicity (dermatitis), no grade 4 toxicity, and no new toxicity signals observed. Conclusions: Concurrent chemo-XRT for breast cancer patients with high risk locally advanced disease was safe and well tolerated. Chemo-XRT showed promise as a method to decrease risk of locoregional recurrence: the studied patient population was at very high risk, but only 7% of patients had a locoregional recurrence at 5 years. Further prospective evaluation of concurrent chemo-XRT is needed. Table 1. Patient characteristics and outcomes (N = 42) XX- XX Citation Format: Lynn Symonds, Sasha Swenson, Macklin Nguyen, Daniel Hippe, Hannah Linden, Jennifer M. Specht, WIlliam Gwin, Janice Kim. Concurrent chemotherapy with adjuvant radiation for patients with high-risk locally advanced breast cancer: safety and outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-22-02.

Abstract PO4-16-12: Patient initiated centricity towards improved communication, side effect management and follow-up care by Real World Evidence Survey from patients for patients – Preview of the Breast BRIDGister Platform

Abstract Background Treatment adherence is crucial for outcome improvement. Still up to 50% of patients interrupt e.g. endocrine treatment or other effective treatment choices due to side effects or miscommunication. Reasons may include limited time spent for patient information in daily routine and the intrinsic barriers to frankly tell the truth to the attending physicians. Therefore, a patient initiated survey has been compiled to comprehensively address all clinical, diagnostic and critical aspects of importance for patients by decentral data capture from patients at home via smart devices in a pseudonymized &amp; interactive fashion to refocus on challenges regarding patients needs, fears and wishes to support evidence based statistical analysis of Real World Data. Materials and Methods Establishing a cloud-based IT Platform enabling nationwide, decentral data entry using Climedo clinical trial software tools without the need of any commercial app utilities and therefore obeying GDPR conform standards to create an interconnected online platform integrating 36 interconnected surveys comprising &amp;gt;1.200 singular questions has been set up between 2020 and 2022 based on patients content elaboration &amp; wishes. The questionnaires address all Real World experiences e.g. at initial diagnosis, during primary treatment and all subsequent lines as well as side effect management with complementary medicine and follow up care realities. After 100 patients a preplanned statistical analysis has been performed to evaluate the feasibility of the patient oriented ePRO approach and demonstrate relevance of proof-of-concept results before entering international trial expansion. Descriptive analysis by Excel as well as Correlation analysis; Chi square and Partitioning tests using the SAS JMP® 9.0.0 software were performed. Results Despite in depth complexity &amp;gt; 85% of patients completed the whole survey. Age distribution of the pilot cohort revealed comparably younger patient age (28% between 30-39 years, 40% between 40-49 years, 24% between 50-59 and 10% being above 60 years) and dominance of Triple Negative Patients (~39%) participating the online survey in the pilot cohort. 97% of patients were treated in certified breast centers (50% in larger centers of bigger towns,15% in central clinics, 23% in university sites, 5% in local hospitals and 7% at office based doctors). Interestingly, 25% of patients did not or only partially understand their diagnosis and upcoming treatment. Time spent for communicating initial breast cancer diagnosis was less than 10 minutes for 25% of patients, while 13% did not remember. Exclusively one treatment option was discussed with 86% of patients. 78% have been informed about their initial breast cancer diagnosis in personal meetings, while 21% were informed by phone calls. 37% of patients had been informed about their patient rights. At preplanned interim analysis 38% of patients were lymphnode positive and 6% metastasized at initial diagnosis. 56% of patients were satisfied with their guideline conform follow-up-care, while 42% did pay for additional follow up care on their own. 85% of patients wished to have a risk-adopted, more individualized follow-up care. Conclusion Despite complexity and lengthiness &amp;gt; 85% of patients did complete the survey. There is an apparent need to have more time for initial confrontation with diagnosis and treatment options. Patients are frequently not informed about alternative treatment options as well as patient rights. Patients frequently feel under pressure in their life threatening situation and suffer substantial lack of information as well as appropriate personal communication. Patient centricity should focus on elaborated communication and information systems that support treatment decision acceptance and adherence. Further details analysis will become available in upcoming subanalysis of the Breast BRIDGister platform survey. Citation Format: Cornelia Stuewe, Ralph Wirtz, Christa Gress, Lena Schmidt, Veronika Schweighart, Sebastian Eidt, Claudia Schumacher, Julia Habraschka, Heidi Lehmann, Katrin Schuere. Patient initiated centricity towards improved communication, side effect management and follow-up care by Real World Evidence Survey from patients for patients – Preview of the Breast BRIDGister Platform [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-16-12.

Abstract PO5-07-07: The biological basis of breast MRI background parenchymal enhancement in women with high breast cancer risk

Abstract Introduction: The amount and degree of the fibroglandular tissue (FGT) enhancement on breast MRI, known as background parenchymal enhancement (BPE), is an emerging marker of breast cancer risk. Higher qualitative and quantitative BPE levels have been shown to correlate with both future risk of initial breast cancer diagnosis and breast cancer recurrence after treatment. Furthermore, adjuvant and preventative therapies such as radiation and endocrine therapy have been shown to lower BPE in many women, potentially serving as a marker of treatment efficacy. However, the biological basis of BPE remains unclear and elucidation of this mechanism could identify novel targeted prevention strategies. The goal of this study was to assess the association of BPE levels with markers of inflammation, vascularity, proliferation, and estrogen sensitivity in a cohort of high-risk women. Materials and Methods: In this IRB-approved retrospective study, we identified asymptomatic high-risk women who underwent at least one dynamic contrast-enhanced (DCE) breast MRI within one year of prophylactic bilateral mastectomy. Qualitative BPE assessments were obtained from clinical reports. Quantitative BPE measures were obtained using in-house semi-automated software: whole breast FGT was first segmented on pre-contrast images, percent enhancement (PE) was calculated for each voxel as (S1-S0)/S0 × 100%, where S0 and S1 are pre- and early post-contrast signal intensity, respectively, and quantitative BPE was then defined as the mean PE of the FGT. Additionally, the BPE volume ratio was calculated as the fraction of FGT that had a PE &amp;gt;50%. Histopathology markers of inflammation (COX-2), vascularity (VEGF), proliferation (Ki-67), and estrogen receptor status (ER) were prospectively measured on archived mastectomy specimens of each breast. BPE metrics were correlated with histopathological markers using Spearman’s rank correlation, with and without adjustment by menopausal status of the patient. All tests were based on generalized estimating equations models to account for the non-independence of the two breasts per patient. A p-value &amp;lt; 0.05 was considered significant. Results: We identified 56 women (median age: 39; range: 26-63 years) for this study, of which 39% were post-menopausal (N=22). Distribution of qualitative BPE levels were 41% minimal (N=23), 29% mild (N=16), 18% moderate (N=10), and 12% marked (N=7). Qualitative BPE and quantitative BPE markers were moderately positively correlated (r=0.37-0.54, p&amp;lt; 0.01). Table 1 lists the correlations between BPE metrics and histopathology markers. After adjusting for menopausal status, qualitative BPE was positively associated with ER (r=0.27, p=0.02) and VEGF (r=0.24, p&amp;lt; 0.01; r=0.21, p=0.02 adjusted). Quantitative BPE and BPE volume ratio were both positively correlated with VEGF (p&amp;lt; 0.04) and negatively correlated with COX2 (p&amp;lt; 0.05). No significant associations were observed between BPE and Ki-67. Discussion: Our study suggests that increased BPE on MRI positively correlates with increased vascularity and higher estrogen receptor expression but not inflammation or proliferation within normal breast tissue in high-risk women. These findings, along with established associations between BPE and cancer risk, could be useful to select and assess efficacy of targeted preventative treatments. Table. Spearman rank correlations between BPE metrics and histopathological markers. Citation Format: Pegah Khoshpouri, Anum Kazerouni, Sana Parsian, Daniel Hippe, Olivia Walsh, Lisa Koch, Savannah Partridge, Habib Rahbar. The biological basis of breast MRI background parenchymal enhancement in women with high breast cancer risk [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-07-07.

Why does hormonal contraception and menopausal hormonal treatment have such a small effect on breast cancer risk?

Oestrogen is considered by many to be a major cause of breast cancer, and yet hormonal contraception and menopausal hormonal therapy have a paradoxically small effect on breast cancer risk. Also, in the oestrogen-only arm of the Women's Health Initiative, subjects given oestrogen had a reduced risk of breast cancer compared to controls. Initiation of breast cancer likely begins early in life, in the long-lived ER-PR- breast stem cell. The main mitogen of ER+PR+ breast cancers is oestrogen derived from local breast fat and the tumour itself, rather than circulating oestrogens. Progesterone is relatively breast neutral, but progestins in the laboratory have been shown to expand malignant breast stem cell number.