TPS618 Background: It is unclear whether the clinical benefit of cytotoxic adjuvant chemotherapy (CT) could be replaced by ovarian-function suppression (OFS) in premenopausal, estrogen receptor (ER)+HER2- breast cancer patients who have high clinical risk score and low genomic risk assessed by multigene assays. The TAILORx trial included a subgroup of premenopausal women with high clinical risk scores and midrange RS scores and found that CT, in addition to endocrine treatment (ET), offered clear benefits in terms of invasive disease-free survival (iDFS) and distant-recurrence-free survival (DRFS) compared to ET alone. However, a majority of the patients did not receive OFS, and the use of OFS as an alternative to chemotherapy in this population is still an area of ongoing research and debate. In addition, in premenopausal women of the RxPonder trial, which enrolled node-positive disease, it is noted that the addition of OFS to ET for at least 12 months improved iDFS numerically in the ET-alone arm, although this improvement did not reach statistical significance. We hypothesized that a favorable DRFS could be achieved by OFS plus ET without CT in premenopausal, pN1, ER+HER2- breast cancer with low genomic risk identified by an NGS-based multigene assay, the OncoFREE. Methods: The INTERSTELLAR trial is a prospective, multicenter, single-arm, non-inferiority clinical study. Premenopausal women aged ≤50 years with pT1-2 ER+HER2- breast cancer and 1-3 lymph node metastasis will be enrolled. They will be tested with OncoFREE, an NGS-based breast cancer prognosis multigene assay developed and available in South Korea, where a higher portion of the patients is premenopausal. Patients with low genomic risk (Decision Index≤20) are administered OFS plus tamoxifen or an aromatase inhibitor for five years. We hypothesize that the 5-year DRFS of the single arm treated with OFS plus ET would be not inferior to 96.1%, which is observed in the chemo-ET arm from the premenopausal subgroup of the RxPonder trial. The one-sided test with a non-inferiority margin of 3% and statistical power of 80% at a significance level of 0.05 resulted in a sample size of 380 patients with low genomic risk. Considering a 70% designation to low genomic risk by OncoFREE and a 10% drop-out rate, 604 patients will be enrolled from 15 tertiary care hospitals in South Korea. The primary endpoint will be tested in the 380 patients with low genomic risk. The patients with high genomic risk will receive CT followed by ET and will be followed for survival analysis as a secondary end-point. The trial has not enrolled its first patient yet at the time of submission. Clinical trial information: NCT05333328 .

BACKGROUND:The NAUTILUS trial randomized cT1-2/N0 breast cancer patients to evaluate the non-inferiority of omitting SLNB. We report the clinicopathologic characteristics and axillary lymph node (ALN) status of the patients enrolled in the NAUTILUS trial and suggest expectations based on the results of this trial, which are relevant in the context of the SOUND and INSEMA trials, where the majority of participants were aged 50 years or older. METHODS:The NAUTILUS trial randomized 1734 subjects into SLNB or no-SLNB arms. Axillary ultrasonography was mandatory to determine clinical N0. Clinicopathologic variables and ALN status in the SLNB arm were analyzed to determine expectations for the NAUTILUS trial results compared to other clinical trials. RESULTS:Among 1734 patients, 1664 subjects were available for clinicopathologic analysis; 50.4% were in the SLNB arm and 49.6% were in the no-SLNB arm. Median age was 55 (range, 29-92) years, and 40.1% were premenopausal. Overall, 1.7%, 83.9%, and 14.0% subjects were pTmic, pT1, and pT2, respectively, with a median tumor size of 1.3 cm (range, 0.1-6.0). In the SLNB arm, 11.2% had ALN metastasis, comprising 1.1%, 9.4%, and 0.6% with pN1mic, pN1, and pN2-3, respectively. ALN metastasis rates according to tumor size were 7.0%, 12.8%, and 17.2% for sizes ≤1.0 cm, >1.0 cm & ≤ 2.0 cm, and >2.0 cm & ≤ 5.0 cm, respectively. CONCLUSIONS:The NAUTILUS trial completed enrollment, with included 14.0% pT2 and 40.1% premenopausal subjects and is expected to show the impact of SLNB omission in these subgroups. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04303715.

Metastasis and stem cell-like traits are major contributors to breast cancer lethality, yet the transcriptional mechanisms driving these processes remain poorly understood. Nuclear factor of activated T-cells 5 (NFAT5), is originally characterized as an osmoregulatory transcription factor implicated in cellular adaptation to hypertonic stress, has recently been implicated in cancer progression and invasion. However, the precise mechanisms by which NFAT5 contributes to breast cancer progression remain unclear. In this study, we investigated the role of NFAT5 in epithelial–mesenchymal transition (EMT) and stemness-associated phenotype in breast cancer cells. NFAT5 overexpression in MCF7 cells promoted EMT and mammosphere formation, whereas NFAT5 knockdown ameliorated transforming growth factor-β (TGF-β)-induced EMT, migration, and invasion. Disruption of the nuclear localization signal (NLS) in NFAT5 also inhibited TGF-β-induced EMT and reduced β-catenin nuclear accumulation. Mechanistically, TGF-β promoted NFAT5 nuclear localization and facilitated the formation of an intranuclear NFAT5/β-catenin complex. This complex enhanced NFAT5 occupancy at the E-cadherin promoter and was associated with reduced E-cadherin transcription. β-catenin depletion attenuated NFAT5 enrichment at the E-cadherin promoter and reduced nuclear NFAT5 accumulation, suggesting that β-catenin contributes to NFAT5 nuclear localization and promoter engagement during TGF-β-induced EMT. NFAT5 knockdown also reduced xenograft tumor growth and altered stemness-associated marker expression in vivo. In human breast cancer tissues, NFAT5 expression was significantly elevated and predominantly localized in the nucleus compared with adjacent normal tissues. Gene set enrichment analysis (GSEA) further showed enrichment of EMT-, stemness-, and Wnt/β-catenin-related gene signatures in NFAT5-high breast tumors. Together, these findings identify NFAT5 as a contributor to TGF-β-induced EMT and stemness-associated breast cancer progression through its interaction with β-catenin, highlighting NFAT5-associated transcriptional regulation as a potential therapeutic target in aggressive breast cancer.

BACKGROUND:The Clinical Treatment Score post-5 years (CTS5), a prognostic tool for late distant recurrence, was validated in postmenopausal patients, but its value in premenopausal women remains unclear. Using 8-year ASTRRA data, we evaluated the prognostic performance of CTS5 in premenopausal breast cancer patients. METHODS:Patients without any event within the first 5 years were included in this analysis and were categorized into three risk groups based on CTS5 cutoff values. Late distant metastasis-free survival (DMFS) and overall survival were analyzed. Subgroup analyses were conducted to compare outcomes between the tamoxifen (TAM)-only and TAM + ovarian function suppression (OFS) groups. RESULTS:Of the 1028 included premenopausal patients, late distant metastasis rates were 3.43% (low-risk, n = 466), 2.56% (intermediate-risk, n = 312), and 9.63% (high-risk, n = 270). The high-risk group showed a significantly higher risk of late DMFS compared to the low-risk group (HR = 3.32; 95% CI: 1.73-6.37; p < 0.001). The intermediate-risk group showed no significant difference (HR = 1.06; p = 0.876). When combining the low/intermediate-risk groups, the high-risk group maintained a significantly elevated risk (HR = 3.16; p = 0.015). OS results were consistent. Subgroup analysis confirmed that CTS5's prognostic ability was maintained in both the TAM-only (HR = 3.23; 0 = 0.004) and TAM + OFS groups (HR = 3.49; p = 0.029), consistently identifying high-risk patients. CONCLUSION:In this randomized trial, unmodified CTS5 identifies high-risk patients but exhibits threshold inversions, making it unreliable for premenopausal extended therapy.

Background The prognostic role of age in metastatic breast cancer (MBC) remains unclear and may vary according to tumor biology. We investigated whether the impact of age on survival differs by estrogen receptor (ER) status in metastatic breast cancer. Methods We conducted a retrospective cohort study of 657 patients with MBC treated at a single tertiary center between 2000 and 2022. Patients were stratified by ER status (ER-positive, n = 419; ER-negative, n = 238) and categorized into three age groups: young (< 35 years), middle-aged (35–50 years), and older (> 50 years). Overall survival (OS) was analyzed using Kaplan–Meier estimates and multivariable Cox proportional hazards models, with a sensitivity analysis using multiple imputation to evaluate the impact of Ki-67 adjustment. Results In ER-positive MBC, age was not associated with OS (log-rank p = 0.91); bone metastasis differed across age groups (46.2%, 51.8%, 36.0% for young, middle-aged, older; p = 0.007) without affecting survival. In ER-negative MBC, age was significantly associated with OS (log-rank p = 0.02), with young and middle-aged patients showing aggressive features including high Ki-67 and early relapse (6–24 months: 77.8%, 55.1%, 36.1%, respectively; p = 0.003). In multivariable analysis, middle-aged patients had higher risk of death than older patients (hazard ratio 1.77, 95% CI 1.12–2.81; p = 0.015), which persisted after Ki-67 adjustment (1.76, 95% CI 1.11–2.81; p = 0.017), whereas Ki-67 itself was not independently prognostic. Conclusions The prognostic impact of age in MBC strongly depends on ER status. While age lacks prognostic significance in ER-positive disease, it independently predicts survival in ER-negative MBC, with the highest risk among middle-aged patients. Robust to Ki-67 adjustment, age may be an integrative marker reflecting tumor biology beyond proliferation indices.

Introduction: In the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC), the current guidelines recommend endocrine therapy combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors as the preferred first-line treatment to preserve quality of life. Ribociclib is a CDK4/6 inhibitor that has been used in combination with aromatase inhibitors or fulvestrant in patients with HR+, HER2- metastatic breast cancer. Various adverse drug reactions associated with ribociclib have been reported, including cutaneous reactions, hepatotoxicity, and hematologic toxicity. In this study, we aimed to evaluate the clinical manifestations and risk factors of dermatologic toxicities in patients with metastatic breast cancer treated with ribociclib. Methods: This retrospective study included patients with metastatic/recurrent breast cancer who were prescribed ribociclib from April 2021 to December 2024 at a single institution. We retrospectively reviewed the medical records of these patients to identify the frequency of cutaneous adverse events, the time of onset, and the clinical characteristics of skin reactions. Logistic regression analysis was performed on several clinical factors, including body surface area (BSA) and concomitant medications, to identify risk factors associated with the occurrence of cutaneous adverse events. Results: A total of 110 patients with MBC were enrolled during the study period. The median age was 53 years (range, 28-82); all 110 patients (100.0%) were female; the median BSA was 1.56 m2 (range, 1.29-2.07); and 32 patients (29.1%) were premenopausal. Ribociclib plus letrozole was administered in 48 patients (43.6%) and ribociclib plus fulvestrant in 29 patients (26.4%). An additional 33 patients (30.0%) received ribociclib plus letrozole with a gonadotropin-releasing hormone (GnRH) agonist. Cutaneous adverse events occurred in 29 patients (26.4%), and the median time to onset was 84 days (range, 3-498). The cutaneous adverse event patterns included pruritus, erythematous macular rash, eczematous rash/contact dermatitis, vitiligo, urticarial reactions, polymorphous light eruption, toxic epidermal necrolysis (TEN), and desquamation. Grade 1 or 2 cutaneous adverse events occurred in 93.1% of patients; Grade 3 toxicity occurred in one patient; and Grade 4 toxicity, namely toxic epidermal necrolysis (TEN), was reported in one patient. Dose reduction was required in three patients (10.3%), and permanent discontinuation of ribociclib occurred in one patient. Clinical improvement was achieved in the majority of patients (86.2%) with cutaneous adverse events following supportive care. Logistic regression analysis revealed that age, Eastern Cooperative Oncology Group (ECOG) performance status, body surface area (BSA), treatment regimen, and use of cholesterol-lowering medications were not independently associated with the development of cutaneous adverse events. Conclusion: CDK4/6 inhibitors represent one of the most important treatment options for HR+/HER2- metastatic breast cancer. Regardless of their clinical efficacy, cutaneous adverse events remain a common source of patient discomfort. Therefore, careful clinical attention and appropriate supportive care are essential to improve patients' quality of life.

Purpose: In the treatment of hormonal receptor positive(HR+) metastatic breast cancer(MBC), various guidelines recommend endocrine therapy as the first-line drug for quality of life if there is no visceral crisis, and recommend an endocrine approach for subsequent therapy as well. However, cases with low hormonal expression have poor endocrine responses even if they are HR+ metastatic breast cancer by definition. In this study, we aimed to compare the survival outcomes of such low HR+ metastatic breast cancer patients. Method: This study included the patients with metastatic/recurrent breast cancer who has been diagnosed from January 2000 to December 2022 in our institution. Patients were classified according to the level or percentage of estrogen receptor (ER) and progesterone receptor(PR) expression in tumor tissue using immunohistochemistry. Low HR+ was defined with Allred score 3∼4 or 1%∼10% of ER and PR expression. We classified HER2 negative patients into HR negative, HR low, and HR high groups and retrospectively analyzed their clinical characteristics and survival outcomes. Patient characteristics were compared among the patient groups using Pearson’s chi-square test and Kruskall-Wallis tests. The statistical analysis was performed using Kaplan-Meier survival analysis. Result: A total of 679 MBC patients were enrolled during the period, of which HER2- patients were 455 (67.0%), and of whom HR-, HR low, HR high and unknown were 134 (29.5%), 27 (5.9%), 274 (60.2%) and 20(4.4%), respectively. Median age of HER2-/confirmed HR status 435 patients was 47 years-old (40-55), 430 patients (98.9%) were female and 280 patients (64.4%) showed pre-menopausal status. There were 130 patients (29.9%) with visceral metastasis, 79 (20.3%) were overweight, and 132 (33.8%) were obese. During a median follow-up of 45.7 months, the median overall survival (OS) of the HR low subgroup was 47.9 (95% CI 2.5-93.4), which was lower than that of the HR high group (71.3 months, 95% CI 57.2-85.5), (Log rank p=0.134), and higher than that of the HR- group 28.9 (95% CI 15.7-42.0), (Log rank p=0.390). Median progression-free survival (PFS) for first-line endocrine therapy in the metastatic setting was lower in the HR low group than in the HR high group, but there was no statistical significance (6.0 vs. 16.5 months, Log rank p=0.234). Conclusion: Endocrine therapy is an important means in HR positive MBC, but oncologic outcomes may be worse for HR low patients than for HR high patients. Therefore, it is necessary to identify clinical and biologic factors that can guide endocrine therapy and subsequent therapies in HR low MBC patients. Citation Format: Ahrong Ham, Sewon Lee, Jungmin Jo, Soo Ji Hong, Ji Eun Lee, Haena Lee, Sungchan Gwark, Jeongshin An, Hyun Goo Kim, Jun Woo Lee, Joohyun Woo, Woosung Lim, Byung-In Moon, Sei Hyun Ahn, Hye Ah Lee. Survival outcome in patients with metastatic breast cancer with low hormonal receptor expression [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-08-07.

506 Background: The ASTRRA trial previously demonstrated that adding ovarian function suppression (OFS) to tamoxifen (TAM) showed consistent disease free survival (DFS) benefit at 8-yr follow-up analysis in premenopausal women with hormone-receptor (HR)–positive breast cancer who remain premenopausal or resume menstruation after chemotherapy. Here, we aimed to update the survival outcomes and identify patients most likely to benefit from OFS to tailor clinical decision-making. Methods: A total of 1,282 premenopausal women were randomized 1:1 to receive either 5 years of TAM alone (TAM-only) or 5 years of TAM with OFS for 2 years (TAM + OFS). The primary endpoint was DFS, and the secondary endpoint was overall survival (OS). For the HER2-negative cohort, a composite risk score (range: 0–5) for breast cancer-free interval (BCFI) was calculated based on tumor size, nodal status, and tumor grade using a Cox regression model. The impact of OFS was analyzed by composite risk score and stratified by age. The events for BCFI were defined as local, regional, or distant recurrence; invasive contralateral breast cancer; or death resulting from breast cancer as the first event. Results: With a median follow-up of 117.6 months, the 10-year DFS rate was 83.7% in the TAM + OFS group compared to 75.9% in the TAM-only group (hazard ratio [HR], 0.68; 95% CI, 0.53-0.87). Meanwhile, there were no significant differences in 10-year OS: 94.6% in the TAM + OFS vs. 93.2% in the TAM-only group (HR, 0.79; 95% CI, 0.50-1.27). In the 776 patients with HER2-negative breast cancer, there were no significant differences in the distribution of age group ( P = .320), tumor size ( P = .572), lymph node status ( P = .577), or histologic grade ( P = .249) between TAM + OFS and TAM-only groups. Worse 10-year BCFI was significantly associated with younger age ( < 40 vs. 40-45 years, P = .026), larger tumor size (≥ 2cm vs. < 2cm, P < .001), lymph node positivity (positive vs. negative, P < .001), and aggressive histologic grade (III vs. II vs. I, P = .006), respectively. Among patients with a high composite risk score (4–5, n = 282, 36.3% of the HER2-negative cohort), the 10-year BCFI was significantly improved with OFS: 76.6% in the TAM + OFS group vs. 65.7% in the TAM-only group (HR, 0.62; 95% CI, 0.40–0.98). This benefit was particularly pronounced in patients aged 40–45 years. Conclusions: We demonstrated the consistent benefit of adding OFS for 2 years to TAM in improving 10-year DFS. In patients with HR-positive/HER2-negative breast cancer and a high composite risk score, the addition of TAM plus OFS resulted in a 10.9% improvement in the 10-year BCFI, suggesting this approach may be beneficial, especially for those aged 40-45 years. Clinical trial information: NCT00912548 .

[This corrects the article DOI: 10.3389/fonc.2025.1465256.].

Abstract Purpose: Metastatic/recurrent breast cancer has a relatively long survival compared to other cancers and depending on the biologic subtype, the treatment outcome is different. In general, obesity or overweight is associated with poor prognosis of breast cancer, but the relationship between body mass index (BMI) and prognosis in metastatic cases is not clear. The aim of this study is investigating the effect of BMI on survival outcome through long-term follow-up in single institution, retrospectively. Method: This study included the patients with metastatic/recurrent breast cancer who has been diagnosed from January 2000 to December 2022 in an institution. BMI was calculated based on weight at diagnosis of metastatic disease, divided into 4 groups according to Asian-Pacific classification, and clinical characteristics including biologic subtype and overall survival (OS) were retrospectively reviewed. The statistical analysis was performed using Kaplan-Meier survival analysis and Cox proportional hazard model. Result: A total of 679 patients were enrolled. Median age was 51 years-old (25~89), 672 patients (99.0%) were female and 425 patients (62.6%) showed pre-menopausal status. The frequencies of HR+, HER2, and TNBC subtype were 335 (50.7%), 191 (28.9%), and 135 (20.4%), respectively and the BMI classification was 33 (5.5%), 251 (41.6%), 124 (20.5%), 196 (32.4%) for underweight, normal, overweight, and obesity, respectively. During a median follow-up of 33.8 months, the median OS in each of the HR+, HER2+, and TNBC subgroups was 54.9 (95% CI 38.7-71.1), 62.8 (95% CI 47.8-77.8), and 20.8 months (95% CI 12.0-29.7). In univariate analysis, there was no statistically significant difference in OS according to BMI in whole patients, however, in the HER2-positive group, the underweight BMI group showed poor OS (p=0.045). In multivariate analysis, the factors affecting OS were age (HR 0.59, 95% CI 0.41-0.87, p=0.008), poor ECOG PS (HR 8.35, 95% CI 2.54-27.49, p< 0.001), TNBC subtype (HR 2.14, 95% CI 1.56-2.94, p< 0.001), visceral metastasis (HR 2.13, 95% CI 1.63-2.79, p< 0.001), 5% or more weight loss during treatment (HR 1.46, 95% CI 1.09-1.97, p=0.012) and obesity BMI group (HR 0.69, 95% CI 0.51-0.94, p=0.019). Conclusion: In the case of patients with metastatic/recurrent breast cancer, there is concern about an increase in body weight, a known risk factor for breast cancer, while receiving palliative aim treatment. For the past 20 years, the mainstay of treatment for metastatic/recurrent breast cancer has been cytotoxic chemotherapy or anti-HER2 agents, and in this case, the higher BMI group patients showed better treatment outcomes compared with normal BMI patients. Citation Format: Kyoung Eun Lee, Ahrong Ham, Sewon Lee, Jungmin Jo, Soo Ji Hong, Ji Eun Lee, Haena Lee, Sungchan Gwark, Jeongshin An, Hyun-Goo Kim, Jun Woo Lee, Joohyun Woo, Woosung Lim, Byung-In Moon, Sei Hyun Ahn, Hye Ah Lee. Effects of body mass index on the treatment outcome of patients with metastatic breast cancer in the real world [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 PO4-05-11.

Abstract Background With the positive outcomes associated with Ovarian Function Suppression (OFS) treatment as reported in the ASTRRA study, which compare two therapeutic strategies, tamoxifen alone and ovarian function suppression (OFS) in premenopausal patients after chemotherapy, the role of OFS has getting important. However, considering the increased risk of bone density reduction associated with postmenopause in women, the understanding these effects is crucial in devising strategies that not only effectively combat the cancer but also concurrently safeguard the patients’ bone health. This study aimed to compare the impacts of two therapeutic strategies, tamoxifen alone and OFS on bone mineral density (BMD) in premenopausal patients after chemotherapy. Methods Of the 1483 premenopausal enrolled in ASTRRA study, we focused on a subset of 522 patients who had undergone BMD examinations at diagnosis, 3 years and 5 years after diagnosis. Patients were stratified into three categories: normal, osteopenia, osteoporosis, and we examined the changes in their classifications over the 3-year and 5-year periods from baseline to identify any deterioration in bone density. Also, Patients were examined ovarian function every 6 months for 2 years and have different randomization times. Further categorization was carried out according to the time of randomization, which means starting time of OFS after recovery of ovary function. Lastly, we conducted a subset analysis using data from the Asan Medical Center (AMC), specially focused on the absolute value of one density measured in g/cm3. Results The median age of 522 patients was 41.1 and at baseline, a higher incidence of osteopenia was observed in the OFS addition group (p=0.028). Both analysis of change in BMD categories of from baseline to 3-year and baseline to 5-year period showed no significant differences between TAM only and TAM+OFS group (3-year: p=0.567, 5-year: p=0.600). However, there was a significant increased risk of bone density deterioration in the OFS addition group, when randomization occurred at the first visit (HR= 2.970, p=0.008). Within the AMC subset, statistically significant decrease in BMD were observed in the OFS addition group at the spine (p=0.023) and femur (p=0.040) over a baseline to 3-year period. Although a decrease in BMD was also observed over a baseline to 5-year period at both the spine and femur, this change was not statistically significant. Conclusion This study revealed a deleterious impact on bone density associated with the addition of OFS, compared to tamoxifen-only treatment. Remarkably, our findings also indicated that early suppression of ovarian function exerts even more detrimental influence on bone health in premenopausal, estrogen receptor-positive breast cancer patients, who have recovered ovarian function. Change between baseline to 5 years according to randomization time interval The table shows the risk associated with bone health deterioration according to the duration of randomization, thus specifying the time interval between the recovery and suppression of ovarian function. Citation Format: Eunju Shin, Seung Il Kim, Min-ho Park, Hyun-Ah Kim, Yongsik Jung, Jai Min Ryu, Eun Hwa Park, Sung Yong Kim, Eun-Gyeong Lee, Min Hyuk Lee, Jung Ho Park, Seock-Ah Im, Soong June Bae, Su Hwan Kang, Woosung Lim, Hyun Jo Youn, Heung Kyu Park, Kyong Hwa Park, Tae-Hyun Kim, Shin-Young Park, Cheol wan Lim, Geum-Hee Kwak, Chanheun Park, Hyuk-Jae Shin, Young Bum Yoo, Sun Hee Kang, Bong Kyun Kim, Hee Jeong Kim. Comparative Study on Bone Mineral Density in Premenopausal Patients with Estrogen Receptor-Positive Breast cancer in ASTRRA study: a 5-year follow-up 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 PO2-12-06.

Abstract Analysis of clinical benefit in the real world of HER2-positive metastatic breast cancer following the development of anti-HER2 therapeutics over the past 20 years Ahrong Ham1, Sewon Lee1, Jungmin Jo1, Soo Ji Hong2, Ji Eun Lee2, Haena Lee2, Sungchan Gwark2, Jeongshin An2, Hyun Goo Kim2, Jun Woo Lee2, Joohyun Woo2, Woosung Lim2, Byung-In Moon2, Sei Hyun Ahn2, Hye Ah Lee3, Kyoung Eun Lee1 1 Division of Hematology and Oncology, Department of Internal Medicine, Ewha Womans University Mokdong hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea 2 Department of Surgery, Ewha Womans University Mokdong hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea 3 Clinical Trial Center, Ewha Womans University Mokdong hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea Purpose: Over the last two decades, treatment landscapes for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) have shown remarkable growth with the development of drugs targeting HER2. The standard of care for HER2+ MBC has continued to change with the ongoing development of new anti-HER2 therapies. We aimed to provide a comprehensive analysis of HER2-targeted therapies, clinical characteristics, and treatment outcomes in real-world practice of HER2+ MBC patients over the past 20 years. Methods: Patients who received palliative chemotherapy with HER2+ MBC between 2000 and 2022 were analyzed. We derived cohorts of two groups with or without anti-HER2 containing therapies. Patients receiving multiple anti-HER2 therapies throughout the entire period of treatment were further analyzed according to treatment regimen. The progression-free survival for palliative first-line (PFS1), and overall survival (OS) were compared between groups. A multivariate Cox regression model was used to investigate predictors of survival outcome in HER2+ MBC. Results: A total of 185 patients were analyzed. Median age was 49 years (IQR, 42-56 years). 47 patients (25.4%) were initially diagnosed with de novo stage IV disease. Visceral metastases were found in 95 patients (51.4%). The median PFS1 was 3.9 months (without anti-HER2 therapy) versus 15.6 months (with anti-HER2 therapy) between two groups (P< 0.001). Likewise, the median OS was significantly improved in anti-HER2 therapy group (34.0 months vs. 70.5 months, P=0.010). As a result of confirming the difference in OS according to the type of anti-HER2 therapies during the entire period of treatment by correspondence analysis, significant improvement was found when two or three types of anti-HER2 were used (without anti-HER2 vs. 2 types of anti-HER2, P=0.009; without anti-HER2 vs. 3 types of anti-HER2, P=0.010). Interestingly, when analyzed by treatment regimen, trastuzumab (H) + pertuzumab (P), HP + TDM-1, and H + TDM-1 significantly improved OS over regimens without anti-HER2 (without anti-HER2 vs. HP, P=0.009; without anti-HER2 vs. HP + TDM-1, P=0.013; without anti-HER2 vs. H + TDM-1, P=0.028, respectively). HP + TDM-1 therapies significantly improved survival rate compared to H single containing regimen (P=0.029). Based on our multiple Cox regression model, visceral metastasis was a significant poor OS prognostic factor and two and three types of anti-HER2 therapies were associated better OS prognosis (visceral metastasis: HR=2.40, P=0.003; 2 types of ant-HER2: HR=0.29, P=0.001; 3 types of anti-HER2: HR=0.22, P=0.018, respectively). Conclusions: Anti-HER2 therapies significantly improved PFS1 and OS. Continuing treatment by changing anti-HER2 therapies may act as a better prognostic factor. Further prospective studies are required. Citation Format: Ahrong Ham, Sewon Lee, Jungmin Jo, Soo Ji Hong, Ji Eun Lee, Haena Lee, Sungchan Gwark, Jeongshin An, Hyun-Goo Kim, Jun Woo Lee, Joohyun Woo, Woosung Lim, Byung-In Moon, Sei Hyun Ahn, Hye Ah Lee, Kyoung Eun Lee. Analysis of clinical benefit in the real world of HER2-positive metastatic breast cancer following the development of anti-HER2 therapeutics over the past 20 years [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 PO3-17-02.

Abstract Background: Young age is associated with poor prognosis and aggressive biology in early breast cancer, especially in luminal subtypes. But the prognostic impact of age in metastatic breast cancer (MBC) is unclear. Also it is known that chemotherapy is more effective in estrogen receptor (ER)-negative tumors than in ER-positive tumors and young patients respond better to chemotherapy. The authors tried to evaluate the impact of age on disease outcome according to ER status. Methods: We collected individual patient data from January 2000 to December 2022 from the Ewha Womans University Mokdong Hospital. Total 419 ER-positive and 238 ER-negative patients who had been treated for MBC were included for analysis. We compared clinical characteristics and overall survival (OS) of patients among three age groups (< 35, 35 to 50 and >50 years) at MBC diagnosis in ER-positive and -negative tumors. Results: The proportion of patients aged < 35, 35-50 and > 50 years was 3.1%, 46.6% and 32.3% in ER-positive tumors, and 2.7%, 14.8% and 18.4% in ER-negative tumors. Although most characteristics of tumors according to age were comparable, bone metastasis was more common in patients aged 35-50 years than the other age groups in ER-positive (51.8% vs. 36.0% in >50 years, P=0.006) and time to first metastasis was shorter in younger patients in ER-negative tumors (72.2% between 6 and 24 months vs. 31.1% in patients >50 years, P=0.003). The median follow-up time was 65 months. Overall survival rate was not different according to age in ER-positive tumors (P=0.909). On the other hands, younger patients had a higher risk of death in ER-negative tumors (P=0.015). In multivariate analysis, young age at MBC diagnosis (< 35years) with short time to metastasis (6 to 24 months), visceral metastasis, triple negative breast cancer was correlated with poor overall survival in ER-negative tumors (P=0.014, HR 1.77). Conclusions: Young age at MBC diagnosis was associated with a higher risk of death in ER-negative tumors, not in ER-positive tumors. These observations may suggest that physicians should consider the impact of age at diagnosis of metastasis and time course of disease in evaluating survival potential and determining a treatment strategy in metastatic breast cancers. Citation Format: Joohyun Woo, Ahrong Ham, Sewon Lee, Ji Eun Lee, Soo Ji Hong, Haena Lee, Sungchan Gwark, Jun Woo Lee, Hyun Goo Kim, Jungmin Jo, Woosung Lim, Byung-In Moon, Sei Hyun Ahn, Hye Ah Lee, Kyoung Eun Lee. The prognostic impact of age at diagnosis of metastatic breast cancer according to estrogen receptor status: a single-center, retrospective 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 PO4-06-05.

BackgroundDoxorubicin is a highly effective anti-cancer drug that causes left ventricular (LV) dysfunction and induces late-onset cardiomyopathy. However, an effective and clinically applicable preventive treatment is yet to be discovered.ObjectiveCardiac-Extracorporeal shockwave therapy (C-ESWT) has been suggested to treat inflammatory and ischemic diseases and protect cardiomyocytes from doxorubicin-induced cardiomyopathy. This study aims to assess the safety and efficacy of C-ESWT in the prevention of subclinical cardiotoxicity.MethodsWe enrolled 64 breast cancer patients. C-ESWT group 33 patients were treated with our C-ESWT (200 shots/spot at 0.09 mJ/mm2 for 20 spots, 3 times every six weeks). The efficacy endpoints were the difference in left ventricular global longitudinal strain (LVGLS) change by 2D speckle tracking echocardiography and chemotherapy-related cardiac dysfunction (CTRCD). Echocardiography was performed on the baseline line and every 4 cycles of chemotherapy, followed by a follow-up 3,6 months after chemotherapy to compare the incidence of cardiomyopathy of subclinical LV dysfunction due to chemotherapy between the two groups.ResultsParticipants averaged 50 ± 9 years in age, 100% female. In the results of follow-up 6 months after the end of chemotherapy, there was a significant difference in delta LVGLS between the C-ESWT group and the control group (LVGLS; −1.1 ± 10.9% vs. −11.5 ± 11.6% p-value; <0.001). A total of 23% (15 patients) of patients developed CTRCD (Control group; 13 vs. C-ESWT group; (2). C-ESWT was performed safely without any serious adverse events.ConclusionIn this prospective study, C-ESWT established efficacy in preventing subclinical cardiotoxicity, especially in breast cancer patients using doxorubicin chemotherapy, and the safety of C-ESWT.Clinical Trial RegistrationClinicalTrials.gov, identifier (NCT05584163).

Purpose: A single-center, randomized, prospective exploratory clinical trial to assess the clinical efficacy of augmented reality(AR)-based breast cancer localization medical imaging solution in patients with breast cancer Methods: This prospective exploratory clinical trial enrolled 20 women who were diagnosed with invasive breast cancer between the ages of 19 and 70, had a single lesion or multifocal lesion with a lesion size of 5mm or more and 30mm or less, had no metastasis to other organs, and had not received prior chemotherapy. All patients underwent mammography, ultrasound, CT, and MRI for preoperative assessment. Patients were randomly assigned to US-guided skin marking (control) and SKIA-breast (AR localization) groups of 10 each. Result: Two surgeons performed breast-conserving surgery on twenty patients. Pathologic evaluation of all patients confirmed negative margins. Two independent pathologists evaluated marginal distance, and neither the two reader's estimates (R1, 6.20±4.37 vs. 5.04±3.47, p=0.519; R2, 5.10±4.31 vs. 4.10±2.38, p= 0.970) nor the two reader's average values (5.65±4.19 vs. 4.57±2.84, p= 0.509) showed any difference between the two groups. In comparing the tumor plane area ratio, there was no statistically significant difference between the two groups for the two readers (R1, 15.90±9.52 vs. 19.38±14.05, p=0.525; R2, 15.32±9.48 vs. 20.83±12.85, p=0.290) and the two reader's mean values (15.56±9.11 vs. 20.09±13.38, p=0.388). Based on the two surgeons' responses, convenience, safety, satisfaction, and reusability were all superior in the AR localization group (p=0.000). Conclusion: AR localization is an acceptable alternative to US-guided skin marking with no significant differences in surgical outcomes. Citation Format: Minah Lee, Jun Woo Lee, Woosung Lim, Joohyun Woo, Hyun-Goo Kim, Se Hyun Paek, SangHui Park, Ji Min Kim, Jin Chung, Jee Eun Lee, Jeoung Hyun Kim. Exploratory clinical trial of preoperative non-invasive localization before surgery in breast cancer patients using augmented reality technology [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 PO1-23-05.

PURPOSE:Advances in chemotherapeutic and targeted agents have increased pathologic complete response (pCR) rates after neoadjuvant systemic therapy (NST). Vacuum-assisted biopsy (VAB) has been suggested to accurately evaluate pCR. This study aims to confirm the non-inferiority of the 5-year disease-free survival of patients who omitted breast surgery when predicted to have a pCR based on breast magnetic resonance imaging (MRI) and VAB after NST, compared with patients with a pCR who had undergone breast surgery in previous studies. METHODS:The Omission of breast surgery for PredicTed pCR patients wIth MRI and vacuum-assisted bIopsy in breaST cancer after neoadjuvant systemic therapy (OPTIMIST) trial is a prospective, multicenter, single-arm, non-inferiority study enrolling in 17 tertiary care hospitals in the Republic of Korea. Eligible patients must have a clip marker placed in the tumor and meet the MRI criteria suggesting complete clinical response (post-NST MRI size ≤ 1 cm and lesion-to-background signal enhancement ratio ≤ 1.6) after NST. Patients will undergo VAB, and breast surgery will be omitted for those with no residual tumor. Axillary surgery can also be omitted if the patient was clinically node-negative before and after NST and met the stringent criteria of MRI size ≤ 0.5 cm. Survival and efficacy outcomes are evaluated over five years. DISCUSSION:This study seeks to establish evidence for the safe omission of breast surgery in exceptional responders to NST while minimizing patient burden. The trial will address concerns about potential undertreatment due to false-negative results and recurrence as well as improved patient-reported quality of life issues from the omission of surgery. Successful completion of this trial may reshape clinical practice for certain breast cancer subtypes and lead to a safe and less invasive approach for selected patients. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT05505357. Registered on August 17, 2022. Clinical Research Information Service Identifier: KCT0007638. Registered on July 25, 2022.

Abstract Purpose: The primary role of sentinel lymph node biopsy (SLNB) for early breast cancer (BC) is axillary staging. In terms of clearance of axillary disease or prevention of recurrence, its role may be limited considering the low axillary recurrence rate of less than 2% even though false-negative rates are 5-10% and the 25% additional axillary lymph node (ALN) detection in the ALND arms of the ACOSOG Z0011 and AMAROS trials. The NAUTILUS trial (NCT04303715) randomized cT1-2/N0 BC patients planned for breast-conserving surgery to evaluate the non-inferiority of omitting SLNB regarding 5-year invasive disease-free survival. The secondary endpoints are overall survival, distant metastasis-free survival, axillary recurrence rate, and quality of life of the patients. We aimed to investigate the clinicopathologic characteristics and ALN status of the subjects enrolled in the NAUTILUS trial. Methods: NAUTILUS trial randomized 1,734 subjects into SLNB or no-SLNB arms from September 2020 to October 2022. Axillary ultrasonography was mandatory to determine clinical N0, defined as no suspicious ALN or no tumor on ultrasound-guided biopsy of suspicious ALN. Clinicopathologic variables and the ALN status of the SLNB arm were analyzed. Results: Among 1,734 enrolled subjects, 828 (50.3%) and 818 (49.7%) subjects in the SLNB and no-SLNB arms, respectively, were included for analysis. Clinical and pathologic T stage, hormonal receptor/HER2 status, histologic grade, age, menopausal status, and Ki-67 were evenly distributed between the two groups (p = 0.554, 0.350, 0.056, 0.369, 0.623, 0.725 and 0.214, respectively). Median age was 55.3 (range, 48.0-62.0) years, and 661 (40.2%) were premenopausal. Overall, 30 (1.8%), 1,382 (84.0%), and 229 (13.9%) subjects were pTmic, pT1, and pT2, respectively, and median tumor size was 1.3 cm (range, 0.1-5.0). In the SLNB group, 94 (11.4%) had ALN metastasis, of which 9 (1.1%), 78 (9.4%), and 5 (0.6%) were pN1mic, pN1, and pN2-3, respectively (Table 1). According to pathologic tumor size, 5.8% (16/279), 11.4% (48/421), and 23.8% (30/126) were ALN positive for ≤ 1.0 cm, >1.0cm & ≤ 2.0 cm, and > 2.0 & ≤ 5.0 cm, respectively. The clinical and pathologic tumor size distribution among subjects with ALN metastasis were 23 (24.5%), 43 (45.7%), 9 (9.6%) and 16 (17.0%), 48 (51.1%), 30 (31.9%), respectively, for ≤ 1.0 cm, >1.0cm & ≤ 2.0 cm, and > 2.0 & ≤ 5.0 cm (Table 2). Among them, 12 (12.8%) received subsequent ALND. There was no difference in ALN metastasis rate according to molecular subtype, histologic grade, age, menopausal status, and Ki-67 (p= 0.812, 0.204, 0.671, and 0.101, respectively). Conclusions: The NAUTILUS trial completed enrollment of 1,734 subjects, among which 1,646 are available to analyze basic clinicopathologic characteristics. The trial included 229 (13.9%) pT2 and 661 (40.2%) premenopausal subjects and is expected to show the impact of SLNB omission in these subgroups. Data lock is expected in October 2027. Patients characteristics SLNB, sentinel lymph node biopsy; LVI, lymphovascular invasion; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; HER2, anti-human epidermal growth factor-2; BCS, breast conserving surgery; TM, total mastectomy; ALND, axillary lymph node dissection Basic characteristics for sentinel lymph node biopsy group a revealed no lymph node metastasis by fine needle aspiration or gun biopsy ALN, axillary lymph node; LN, lymph node Citation Format: Jai Min Ryu, Han-Byoel Lee, Sei Hyun Ahn, Il-Yong Chung, Seeyoun Lee, Seho Park, Woosung Lim, Joon Jeong, Jeong Eon Lee, Eunhye Kang, Ji Hyun Chang, Jung Min Chang, Woo Kyung Moon, Wonshik Han, Eun-Kyu Kim. What to expect from the No axillary surgical treatment for lymph node-negative patients after ultra-sonography [NAUTILUS] trial (KBCSG-21): Clinicopathologic characteristics and axillary lymph node status of enrolled patients [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 PS01-03.