HER2-negative Breast Cancer Research Articles

Abstract PO3-01-12: Clinicopathologic Factors affecting response in patients with Estrogen receptor-positive and Human Epidermal Growth Factor Receptor-negative breast cancer receiving neoadjuvant chemotherapy

Abstract Background: The evolution of Neoadjuvant chemotherapy(NAC) regimen has enabled the down-staging of locally advanced breast cancer, allowing patients to undergo breast conserving surgery. NAC is known to be effective in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. However, the role of NAC in hormone receptor-positive and HER2-negative (HR+HER2-) breast cancer patients remains unclear. In this study, we aimed to explore the utility of NAC for estrogen receptor-positive and HER2-negative (ER+HER2-) breast cancer patients. Methods: Clinical data were collected from 120 patients who were diagnosed with estrogen receptor (ER)-positive and HER2-negative breast cancer and received neoadjuvant chemotherapy between July, 2017 and April, 2023 at Seoul St Mary’s Hospital (Seoul, Korea). We analyzed the factors that affect clinical response subgroups, including pathologic complete response (pCR), partial response (PR), stable disease(SD), and progressive disease (PD), following neoadjuvant chemotherapy. The median follow-up period was 17 months. < Results: Among 120 patients after NAC, 5.8% achieved pCR, while 67.5% had a partial response. The median age at the time of surgery was 55 years at pCR group, 49 years at PR group, 47 years at SD group, and 49 years at PD group. Although the age of patients achieving pathological complete response was higher, this differences was not statistically significant. Patients achieving pCR had a higher incidence of progesterone receptor (PR) negativity (pCR 71.4% vs PR 30.9%, p=0.011) and higher levels of Ki-67 expression than those who did not achieve pCR (71.7% vs 35.6%, p=0.003). Also, there was no significant difference in Androgen receptor (AR) and HER-2 expression between the groups. Tumor size was also significantly associated with clinical response (p=0.003). However, no differences in clinical response was observed between patients with lymph node metastasis (p=0.221). Our analysis of 107 patients who were clinically N positive before NAC showed that the Ki-67 index level was the only factor found to affect nodal pCR. In addition, in the non-pCR group, patients with a Ki-67 index of less than 20% after neoadjuvant had a significantly better disease-free survival (5yr DFS, 79.8% vs 65.9%, p=0.039) Conclusion: Our analysis revealed that patients with higher levels of Ki-67 and lower level of PR expression were more likely to achieve pCR or PR. Also, decrease in Ki-67 index was confirmed to be an important prognostic factor of ER+ HER2- breast cancer. A combination of clinical and molecular factors, such as tumor size, progesterone receptor expression, and Ki-67 expression, can be used to optimize treatment plans and improve outcomes for the patient population. Citation Format: Jin Ah Lee, Young Joo Lee, Dooreh Kim, Chang Ik Yoon, Woo-Chan Park, Soo Youn Bae. Clinicopathologic Factors affecting response in patients with Estrogen receptor-positive and Human Epidermal Growth Factor Receptor-negative breast cancer receiving neoadjuvant chemotherapy [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 PO3-01-12.

Abstract PO5-04-14: Quality of Life (QoL) among metastatic hormone receptor positive, HER2 negative breast cancer patients during first line systemic treatment

Abstract Background Current international guidelines recommend endocrine therapy combined with a CDK4/6 inhibitor as the preferred first line systemic treatment in patients diagnosed with metastatic hormone receptor positive (HR), HER2 negative breast cancer (BC). Randomized controlled trials that led to the approval of these agents in the first line disease setting are derived from controlled environments and selected patients. We aimed to assess real-world patients’ characteristics, safety and health related quality of life in a non-select cohort of patients being managed in a Brazilian private Cancer Center. Methods: We performed a cross sectional study at Beneficencia Portuguesa de Sao Paulo evaluating quality of life among patients with metastatic HR+/HER2 negative treated in the first line disease setting. Inclusion criteria included patients that received the combination of a CDK4/6i with any endocrine therapy (ET) between January 2018 and April 2023. Primary endpoint was quality of life assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC QLQ-BR23, it is baseline, there is only one measurement for each patient. Results: We analyzed 72 patients who meet the inclusion criteria. Median age at diagnosis was 49 years old (ranging from 31 to 91). Approximately half of the population was premenopausal (51%). Palbociclib and abemaciclib were the most commonly used CDK4/6i, with 42 and 35% of patients, respectively. ECOG performance status was zero or one in almost the entire patient population analyzed (97%). 53% of the patients were diagnosed as de novo metastatic BC. Table 1 and 2 summarize the patients characteristics. Mean global health status was 75.4, with social and cognitive functioning scoring the highest (Mean 78.6 and 79.1, respectively). The most distressing symptom among the symptom scale was fatigue (Mean 27.2). Most symptoms and functioning scales did not meet the threshold for clinically meaningful differences between the different CDK4/6 inhibitors. Conclusion: Real-world data from our study is consistent with the historical expected health related quality of life among patients diagnosed with HR+/HER2 negative metastatic BC in the first line disease setting. Table. Citation Format: Débora Gagliato, Julio Antonio Araujo, Bianca Milena Verboski, Guilherme William Marcelino, Fabiana Nogueira Momberg, Gilmara Silveira da Silva, Rozana Mesquita Ciconelli, Antônio Buzaid. Quality of Life (QoL) among metastatic hormone receptor positive, HER2 negative breast cancer patients during first line systemic treatment [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 PO5-04-14.

Abstract PO4-16-11: De-escalation of anthracyclines during adjuvant therapy based on Oncotype RS: A single institution experience in Mexico City

Abstract Introduction: In Mexico, hormone positive HER2 negative breast cancer is the most frequent subtype, accounting for 76.6% of cases. For patients undergoing local control management through surgery; adjuvant chemotherapy is usually followed depending on different risk factors. In order to avoid overtreatment, different genomic firms have been approved aiding in a more objective decision. One of these genomic firms is the Oncotype Recurrence score. The TAILORx and RxPONDER trials have provided guidance in determining which patients are candidates for chemotherapy depending on their menopausal status. However, it has not yet been determined whether patients requiring chemotherapy can receive an anthracycline-free regimen. In the Plan B clinical trial, a non-inferiority analysis was conducted on early-stage breast cancer patients who received anthracycline-based or non-anthracycline-based chemotherapy, with the non-anthracycline regimen being non-inferior, including patients with a RS > 25. We intend to reevaluate these findings in our Mexican population. Methods: We evaluated 217 patients with early stage hormone sensitive HER2 negative breast cancer who had an Oncotype Recurrence score (RS) result. This retrospective cohort study took place by analyzing electronic records from January 2011 to December 2017 with patients treated at the National Cancer Institute in Mexico City. We included patients 18 years of age or older, any sex with an Oncotype RS ≥ 16 in premenopausal patients or ≥ 26 in postmenopausal patients who received adjuvant chemotherapy with or without anthracyclines. Our primary endpoint was iDFS comparing TC vs AC-T. Overall survival was set as a secondary endpoint. Results: Of the 217 patients with an Oncotype recurrence score, only 46 patients received adjuvant chemotherapy of which 71.7% were premenopausal with a median age of 45 years. Stage II was the most common stage with 91.3% of the population, as well as ductal carcinoma with 82.6%. All patients had positive lymph nodes, 54.3% at least 1 lymph node. Most patients received AC-T adjuvant chemotherapy (60.9%), and only 39.1% received TC. Of the 46 patients analyzed, only 19.6% (9) had a recurrence upon follow-up (Table 1). Median time of follow up was 87.5 months. Difference in Disease free survival could not be established between patients receiving AC-T with 105 months (CI 95% 94.36-117.43 months) vs TC with 94.09 months (CI 95% 83.85-104.34 months, < p.918) (Figure 1). Overall survival did not have a statistical difference between both chemotherapy regimens, p< 0.649 (Figure 2A), when comparing Oncotype RS, overall survival was better in those with Oncotype OS < 26, p< 0.023 (Figure 2B). Discusion As described previously in the Plan B trial, TC was non inferior to the conventional adjuvant regimen of AC-T in Hormone positive HER2 negative early-stage breast cancer. Our results tend to show similar results when compared to the Plan B. An important aspect to our study was that 71.7% of our patients were premenopausal, where in the Plan B trial only 35% were premenopausal, considered a higher risk group of patients. Although a statical difference couldn´t be established due to our small sample size, in DFS or OS when comparing the chemotherapy regimen. Premenopausal patients with an Oncotype RS < 26 could receive an anthracycline free regimen, without impact in their overall survival. Larger prospective studies are necessary to assure this conclusion. Figure 1 DFS (TC vs AC-T) Figure 2 A and B Overall Survival Table 1 (Baseline characteristics) Citation Format: Carlos Arturo González Núñez, Paula Cabrera-Galeana, Juan Enrique Bargalló Rocha, Rafael Vazquez-Romo, Sergio Aguilar-Villanueva, Alexandra Garcilazo, Areli Velazquez-Martinez, Andrea Maliachi, Ruben Rodriguez, Esmeralda Romero-Bañuelos. De-escalation of anthracyclines during adjuvant therapy based on Oncotype RS: A single institution experience in Mexico City [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 PO4-16-11.

Abstract PO4-20-04: A Randomized Window of Opportunity Study of Preoperative Letrozole and Simvastatin Versus Letrozole Alone in Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer

Abstract Hormone receptor positive (HR+), HER2 negative (HER2-) breast cancers are poor responders to immunotherapy. There is a need for innovative approaches to improve immune responses in these tumors. The combination of statins and aromatase inhibitors have demonstrated antiproliferative and immunomodulatory properties. However, this combination has never been studied in the preoperative setting; thus, our ongoing study represents an opportunity to investigate this approach. We designed a randomized two-arm presurgical “window of opportunity” trial to evaluate the effects of letrozole and simvastatin versus letrozole alone 14 days prior to surgery. Tissue and blood will be obtained at baseline and 14 days after completion of therapy at the time of surgery. Inflammatory markers in the blood and multiplex immunohistochemistry (IHC) in tissue will be assessed. To be eligible for the trial, participants must be postmenopausal women with histologically confirmed stage I-III HR+, HER2- invasive breast cancer with baseline ki-67 ≥10% that have not received prior chemotherapy, endocrine therapy, and/or immunotherapy within 3 months prior to trial enrollment. They should also not have received any cholesterol lowering medication within 3 months prior to trial enrollment. The primary objective is to determine if the addition of simvastatin to letrozole compared to letrozole alone will result in a decrease in geometric mean % change in ki-67 from pre-surgical baseline to 14 days following preoperative therapy. Ki-67 is a validated surrogate marker for disease-free survival in HR+, HER2- breast cancer. The main secondary objective is to determine if the addition of simvastatin to letrozole compared to letrozole alone will result in increased immune activation from pre- to post-treatment based on the evaluation of the immune subtype composition in tissue via multiplex immunofluorescence. We aim to enroll 16 patients in each arm to achieve 90% power and detect a minimum difference of 7.5% in ki-67 using a two-sided Mann-Whitney U or Wilcoxon Rank-Sum test. After accounting for a possible drop off rate of 20%, the study’s target accrual will be 40 participants. Statistical analyses will be performed using SAS 9.4. the significance level will be set at alpha = 0.1. Descriptive statistics will be applied to tissue and blood biomarkers of interest at 2 designated time points, prior to preoperative therapy and following completion of preoperative therapy. The absolute change or percentage change of those biomarkers will also be calculated and compared between the 2 arms using the nonparametric Mann-Whitney U test. The correlation among biomarkers will be described by Pearson correlation coefficient with 95% confidence interval. The p-value will be adjusted by Benjamini-Hochberg procedure to control the false discovery rate. All adverse events experienced data will be described by summary statistics and will be assessed according to CTCAE version 5.0. Currently, the study has accrued 2 participants. After completing accrual, we will assess whether the tumor-immune milieu has undergone modulation, resulting in a more immunogenic environment. If an immunogenic effect is demonstrated, this will provide rationale for a future multi-center trial assessing the combination of letrozole, simvastatin, and immunotherapy. Citation Format: Ruth Sacks, Elizabeth Haas, Jade Jones, Manali Bhave, Keerthi Gogineni, Jane Meisel, Demetria Smith-Graziani, Suchi Pakkala, Sarah Friend, Cletus Arciero, Lauren Postlewait, Clara Farley, Cathy Graham, Toncred Styblo, Monica Rizzo, Rhonda Pickett, Nicholas Crasta, Lori Brown, Xiaoxian Li, Sunil Badve, Madhav Dhodapkar, Kevin Kalinsky. A Randomized Window of Opportunity Study of Preoperative Letrozole and Simvastatin Versus Letrozole Alone in Stage I-III Hormone Receptor Positive, HER2 Negative 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 PO4-20-04.

Abstract PO4-05-02: The clinical impact of NOLUS in unresectable/metastatic hormone receptor-positive (HR+)/HER2-negative breast cancer

Abstract Background A non-luminal disease score (NOLUS) is pathology-based predictive model to identify PAM50 non-luminal disease within HR+/HER2-negative breast cancer. NOLUS is a new model, therefore, its clinical utility is not sufficiently elucidated. In this study, the clinical impact of NOLUS was investigated in unresectable/metastatic estrogen receptor (ER) positive (ER+)/HER2-negative breast cancer. Patients and Methods The total of 61 patients, who were diagnosed unresectable/metastatic ER+/HER2-negative breast cancer between 2010 and Apr 2023, were included in this study. A NOLUS status was calculated with formula:−0.45∗ER −0.28∗PR +0.27∗Ki67 + 73.02 and diagnosed as NOLUS-positive (≥51.38) and NOLUS-negative (< 51.38) according to the previous reports (Pascual T et al, Front Oncol 2019; 9:303). The relationships between NOLUS status and clinicopathological factors and the prognosis were analyzed. Results Among 61 patients, 10 patients (16.4%) were NOLUS-positive and 51 (83.6%) were NOLOS-negative. NOLUS-positivity was significantly associated with progesterone receptor (PgR)-negativity (p=0.0051) and higher histological grade (0.0234), and had tendency to have shorter recurrence free interval and liver metastasis. NOLUS-positivity was not associated with age, menopausal status and the Ki67. The proportion of the patients whose first line treatment for unresectable/metastatic was endocrine therapy with or without targeted therapy was higher in the NOLUS-negative group. NOLUS-positivity was significantly associated with shorter overall survival (OS; log-rank p=0.0012). Uni- and multivariate analysis, NOLUS-positivity was the poor prognostic factor for OS. Conclusion The prognosis in of the patients with NOLUS-positive unresectable/metastatic HR+/HER2-negative breast cancer was significantly poor. NOLUS is useful to predict the prognosis of these patients. Table. NOLUS and clinicopathological characteristics. NOLUS-positivity was significantly associated with progesterone receptor (PgR)-negativity (p=0.0051) and higher histological grade (0.0234), and had tendency to have shorter recurrence free interval and liver metastasis. NOLUS-positivity was not associated with age, menopausal status and the Ki67. Table. Univariate and multivariate analysis for OS after recurrence NOLUS-positivity was significantly associated with shorter overall survival (OS; log-rank p=0.0012). Uni- and multivariate analysis, NOLUS-positivity was the poor prognostic factor for OS. Citation Format: Wakako Tajiri, Yoshiaki Nakamura, Junji Kawasaki, Yumiko Koi, Sayuri Akiyoshi, Chinami Koga, Eriko Tokunaga. The clinical impact of NOLUS in unresectable/metastatic hormone receptor-positive (HR+)/HER2-negative 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 PO4-05-02.

Abstract PO3-19-08: A phase 2 randomized pre-operative,window of opportunity trial investigating the effect of elacestrant with/without triptorelin in premenopausal patients with HR+/HER2- breast cancer – SOLTI-2104-PremiÈRe trial

Abstract Background. Premenopausal women diagnosed with HR+/HER2- breast cancer (BC) often have a different biology and worse prognosis. The SOFT and TEXT studies demonstrated an increase diseasefree survival (DFS) with ovarian function suppression (OFS) plus tamoxifen or exemestane compared to tamoxifen alone. Of note, high-risk clinicopathologic features, adjuvant chemotherapy, or aged ≤35 years correlated with greater OFS benefit. However, adding OFS in this context has intrinsic issues as higher toxicity, which led to treatment discontinuation (20% in SOFT trial), and suboptimal OFS was found in around 25% of patients (pts) with exemestane plus monthly triptorelin (SOFT-EST sub-study). Thus, new effective ET options without OFS are needed for premenopausal patients (pts). Elacestrant is the first oral, non-steroidal, selective estrogen receptor degrader (SERD) to demonstrate improved efficacy to SOC treatments and specifically compared to fulvestrant in postmenopausal pts with HR+/HER2- metastatic BC at the phase III EMERALD trial. In menopausal patients with HR+/HER2- early BC, the window of opportunity SOLTI-1905 ELIPSE trial (NCT04797728), showed that elacestrant was associated with a 27.3% rate of Complete Cell Cycle Arrest (CCCA) and a statistically significant suppression of Ki-67. Among Luminal A tumors, the CCCA rate was 45% and the average decrease in Ki-67 was 64.6%, while no CCCA was reported and the suppression of Ki-67 was less pronounced (31.7%) in the Luminal B population. There is still a need for investigating elacestrant without OFS in the premenopausal scenario. We hypothesize that elacestrant as a single agent or in combination with triptorelin is an effective and safe treatment regimen in premenopausal pts with HR+/HER2-negative early BC capable of achieving an equivalent CCCA rate as a subrogate of effectiveness regardless the use of OFS Study design. PREMIERE is a parallel, non-comparative, two-arm, randomized 1:1, open-label, multicenter, exploratory study in premenopausal women with primary operable HR+/HER2-negative BC. The study aims to evaluate the biological effects of elacestrant with or without triptorelin. Participants must have histologically confirmed HR+ (≥ 10%) and HER2- operable early BC stage I to stage IIB >1 cm with a Ki-67 between 10-35%. The primary objective is to assess the ability of each treatment arm to induce CCCA determined by central assessment of Ki-67 (% Ki-67 ≤ 2.7%). No formal comparison between treatment arms is intended. Secondary objectives include evaluating the biological activity of elacestrant with or without OFS, antiproliferative activity, changes in gene expression including PAM50 subtype changes, and the effect of optimal vs suboptimal suppression on CCCA . Serum E2 and FSH levels will also be evaluated. Safety and tolerability will be assessed based on adverse events and clinical laboratory test results. Pts will undergo screening and randomization, with stratification by PAM50 subtype (Luminal A vs Non-luminal A). Treatment will be elacestrant 400 mg once daily or elacestrant 400 mg once daily plus triptorelin 3.75 mg days +1 and +29 for 30 (+7) days. Surgery or biopsy will be performed after treatment completion, and a post-surgery visit will mark the end of the active follow-up period. Patients will receive SOC treatment after surgery. 48 patients will be recruited in 9 sites within SOLTI Spanish network in 9 months period. This study is financially supported by Menarini-Stemline. Citation Format: Meritxell Bellet- Ezquerra, Cristina Hernando, Pablo Tolosa, Maria Vidal, Yolanda Fernández, Santiago González-Santiago, Pilar Sanchez, Susana De La Cruz, Vanesa Ortega, Xavier Gonzalez-Farré, Milana Bergamino, Alejandra Espinosa, Tomás Pascual. A phase 2 randomized pre-operative,window of opportunity trial investigating the effect of elacestrant with/without triptorelin in premenopausal patients with HR+/HER2- breast cancer – SOLTI-2104-PremiÈRe trial [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 PO3-19-08.

Abstract PO2-02-09: Pathological complete response to neoadjuvant systemic therapy and its predictive factors among early breast cancer subtypes: the emerging role of HER2

Abstract Purpose Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) for breast cancer (BC) is a prognostic factor for relapse-free and overall survival (OS). Despite recent therapeutic developments for early BC, there are still a significant proportion of patients who do not achieve pCR. In this study we established pCR rates in routine care and investigated possible predictive factors of pCR, including HER2 status. Methods We evaluated 980 stage I-III BC patients receiving NACT between 2013 and 2022. Patient characteristics, rates of pCR (ypT0-is ypN0), toxicities, treatment modifications and survival outcomes were recorded. Standard histopathological variables were recorded [with HER2-low status, defined as HER2 1+ on immunohistochemistry (IHC) or 2+ on IHC without in situ hybridization (ISH) gene amplification]. Overall survival (OS) and relapse-free survival (RFS) were calculated. Median follow-up time was 60.3 months (interquartile range 19.7-78.7). Results The mean age of the study population was 49.6 ± 11.2 years. 64% had stage II disease, 70.5% had grade 3 disease, and 90.5% had ductal histopathology. 34.6% had estrogen receptor (ER)-positive/HER2-negative, 27.1% had triple-negative (TN), and 38.3% had HER2-positive BC. 233 patients (23.8%) had HER2-low disease. pCR rate was 35.8% in the overall population, 16.8% in ER-positive/HER2 negative BC, 32.7% in TNBC and 55.2% in HER2-positive BC. pCR rate differed according to grade, histology, HER2 status, radiological and clinical response of disease (p < 0.001) and early discontinuation of NACT (p = 0.001), but not according to age, menopausal status, BRCA status, platinum use, NACT dose reduction or delays, neutrophils-to-lymphocytes, platelets-to-lymphocytes, or lymphocytes-to-monocytes ratios. OS and RFS were better following pCR [HR 0.23 (95% CI, 0.14-0.38, p < 0.001) and HR 0.27 (95% CI, 0.18-0.40, p < 0.001), respectively]. Among HER2-negative BC patients (605, 61.7% of the entire cohort), there was a trend to lower pCR rate in HER2-low compared to HER2-negative (IHC 0) BC (19.7% vs 26.3% respectively, p = 0.06). pCR rate was significantly lower in ER-positive/HER2-low compared to ER-positive/HER2-negative (IHC 0) BC (12.1% vs 20.9% respectively, p = 0.031), while no difference in pCR rates was observed in TNBC patients by HER2 status. Despite a lower rate of pCR, Kaplan-Meyer curve showed that OS was significantly better in the HER2-low BC compared to HER2-negative (IHC 0) population at 100-months follow up. Multivariable Cox-regression model in the HER2-negative BC cohort demonstrated that HER2-low status was an independent predictor of OS (HR 0.59, 95% CI, 0.39-0.89 p = 0.012). Conclusions In our real-world analysis, pCR rates are consistent with the published data. Many patients still have residual disease following NACT, predicting worse outcomes, and may benefit from further adjuvant systemic therapies. Consistent with other studies, our findings suggest a possible prognostic and predictive role of HER2-low status especially among patients with ER-positive BC. This could lay the foundations for novel therapies targeting HER2 among HER2-low cancer subtypes. Citation Format: Matilde Corianò, Nicolo M.L. Battisti, Hala Aziz, Nalinie Joharatnam Hogan, Antonino Musolino, Alistair Ring. Pathological complete response to neoadjuvant systemic therapy and its predictive factors among early breast cancer subtypes: the emerging role of HER2 [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 PO2-02-09.

Abstract PO5-09-01: Relative low body mass index (BMI) and fat quantity predicts prognosis better than absolute BMI in hormone receptor-positive, HER2-negative breast cancer

Abstract Purpose: Most existing research about obesity and prognosis in breast cancer patients primarily compares obese and non-obese individuals according to standard body mass index (BMI) categories. With a notably high percentage of Asian patients presenting with young age onset and normal weight, the prevalence of overweight and obesity based on absolute BMI values is lower in Asia (according to WHO guideline, BMI under 18.5 means underweight, and BMI over 25 means overweight). Understanding the impact of relatively low and high weight on prognosis can provide more insightful data than assessments based on absolute BMI thresholds. This study aimed to investigate the impact of relative low/high BMI on the prognosis of breast cancer and to explore the influence of body fat quantity (FQ), which is closely related to BMI. Methods: The study population consisted of 3,663 patients who received surgery for primary breast cancer at Seoul National University Hospital from 2006 to 2015. Pre-treatment BMI was divided into quartiles, defining low-BMI (Q1) as ≤ 21.33, high-BMI (Q4) as > 25.53, and mid-BMI as values between the two. Fat quantity (FQ) was derived from chest CT using the deep learning-based FDA-approved DeepCatch software. It measures the fat volume at the L1 level then divides this value by the square of the patient's height. It was then also divided into quartiles, establishing the definitions of low-, mid-, and high-FQ. The associations of BMI and FQ with distant metastasis-free survival (DMFS) and overall survival (OS) were examined. Results: The high-BMI group demonstrated older median age and higher T and N stages (p< 0.001). The high- and low-BMI groups also showed a higher prevalence of estrogen receptor positive cancer compared to the mid-BMI group. A strong correlation (Pearson correlation coefficient 0.83) was observed between BMI and FQ. In HR-positive, HER2-negative breast cancer, high-BMI patients had a 1.55 times higher risk of distant metastasis (95% CI: 1.15-2.11, p = 0.005), and a 1.78 times higher risk of mortality (95% CI: 1.22-2.58, p = 0.003) compared to mid-BMI patients, while low-BMI patients demonstrated better outcomes regarding DMFS (HR 0.67, p=0.035) and OS (HR 0.59, p=0.04). Comparison of FQ with prognosis revealed that the low-FQ patients exhibited better DMFS (HR 0.59, p=0.005) and OS (HR = 0.44, p=0.002) compared to mid-FQ patients in HR-positive, HER2-negative breast cancer. However, when adjusted for T and N stages, low-BMI patients in the HR-positive, HER2-negative group showed no difference in prognosis from mid-BMI patients but better prognosis compared to high-BMI patients. In contrast, when defined using absolute BMI, underweight patients did not show a difference in DMFS (HR 0.72 vs. normal BMI, p = 0.515) and OS (HR 0.91 vs. normal BMI, p = 0.87) compared to those with normal weight and overweight. The low-FQ group had the best prognosis regarding DMFS (HR 0.66 vs. mid-FQ, p=0.032) and OS (HR 0.50 vs. mid-FQ, p=0.008). Conclusions: Low-BMI is a favorable prognostic factor compared to high-BMI for DMFS and OS in HR-positive, HER2-negative breast cancer. The relative BMI defined according to BMI quartiles was a better prognostic factor than to absolute BMI standards. Investigations with FQ showed similar tendencies, suggesting that low BMI's favorable prognostic influence may be associated with fat. Future investigations should aim to validate these results and delve deeper into the underlying mechanisms. Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Soon Ho Yoon work as chief medical officer in MEDICALIP. This author did not involve data/statistical analysis. Other authors have no competing interest to declare. Citation Format: Eunhye Kang, Ji-Jung Jung, Ik Beom Shin, Hawjeong Lee, Jin Young Byeon, Changjin Lim, Hong-Kyu Kim, Hyeong-Gon Moon, Wonshik Han, Jong-Ho Cheun, Soon Ho Yoon, Han-Byoel Lee. Relative low body mass index (BMI) and fat quantity predicts prognosis better than absolute BMI in hormone receptor-positive, HER2-negative 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 PO5-09-01.

Abstract PO5-17-08: Real world outcomes of neoadjuvant chemotherapy in ER-positive/PR-positive, HER2-negative breast cancer

Abstract Background: Neoadjuvant chemotherapy is utilized to downstage locally-advanced estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+), HER2-negative breast cancer despite modest pathological complete response (pCR) rates. The two most commonly utilized regimens include docetaxel plus cyclophosphamide (TC) or dose-dense doxorubicin and cyclophosphamide followed by paclitaxel (ddAC-T). Given few head-to-head comparisons of neoadjuvant TC with ddAC-T in this population, we performed a real world data analysis. Methods: 148 patients with ER+/PR+, HER2-negative breast cancer were included in the analysis. The patients were divided into two groups based on the neoadjuvant chemotherapy regimen used (TC vs ddAC-T) and the clinical responses to chemotherapy were categorized as complete, partial, no response/stable, or progressive disease. We examined the differences or associations in demographics, clinical characteristics, overall survival (OS), and invasive disease-free survival (IDFS) between TC and ddAC-T neoadjuvant chemotherapy. pCR was defined as the absence of invasive carcinoma in breast and lymph nodes (ypT0/ypTis and ypN0). Partial response was defined as a decrease in either or both T and/or N stage, compared to pre-treatment evaluation; no response was defined as no change in either T or N categories; and progressive disease was defined as an increase in either the T or N staging at time of pathologic evaluation. Results: The median age of participants was 55 years (range 28-78 years). 67% had clinical stage II disease, while 26% had stage III. 130 participants received neoadjuvant ddAC-T while 18 participants received TC. The ddAC-T group had 7% patients who achieved a pCR and 37% with a partial response, compared to the TC group with 0% of patients with a pCR and 33% with a partial response. The TC group had a higher rate of progressive disease, compared to the ddAC-T group (67% versus 20%). On univariate analysis, the choice of neoadjuvant chemotherapy was not predictive of pathologic response (p = 0.3864). As expected, premenopausal status was associated with a higher likelihood of a pathologic response with an odds ratio of 2.917 (95% CI: 1.465-5.809). On multivariate analysis, chemotherapy regimen was not predictive of pathologic response (p = 0.6047), after controlling the effects of age and menopausal status. No significant difference was noted in OS or IDFS at 24 and 48 months between the ddAC-T and TC groups. On multivariate analysis, controlling for BMI, ER, PR, race, and ECOG performance status, the choice of chemotherapy was not predictive of IDFS. Non-white participants appeared to have inferior IDFS (HR = 2.956, 95% CI: 1.208, 7.238, p-value = 0.0177). Conclusion: In this single-center retrospective analysis, we show real world outcomes of the use of neoadjuvant chemotherapy regimens among patients with ER+/PR+, HER2-negative breast cancer. Both ddAC-T and TC had low pCR rates, 5.98% and 0%, respectively. However, there was no statistical difference between IDFS or OS when comparing the two chemotherapy regimens. More data are needed to optimize neoadjuvant treatment in this patient population and to determine whether anthracyclines can be avoided. Table. Pathologic responses The results (summarized by odds ratio (OR) and its 95% CI) from logistic regression on the pathological responses (complete and partial). Citation Format: Matthew Kurian, Marcus Trybula, Kanchi Patell, Gregory Guzik, Seunghee Margevicius, Pingfu Fu, Alberto Montero, James Martin. Real world outcomes of neoadjuvant chemotherapy in ER-positive/PR-positive, HER2-negative 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 PO5-17-08.

Abstract PO2-23-08: High intratumor heterogeneity induced PSME2 confers endocrine resistance via ERα PARylation in hormone receptor-positive and HER2-negative breast cancer

Abstract Background: Hormone receptor-positive and HER2-negative breast cancer, characterized by its significant intratumor heterogeneity (ITH), poses increased recurrence, metastasis risk, and endocrine resistance. A comprehensive understanding of the genomic and biological characteristics underlying ITH is crucial for the development of effective therapeutic strategies. Methods: We leveraged the multiomics data from our large cohort of 381 hormone receptor-positive and HER2-negative breast tumors, supplemented with single-cell sequencing (scRNA-seq) data from 9 individual samples, to investigate ITH and its associated molecular features. Mechanistic investigations were conducted using Stable Isotope Labeling by Amino Acids in Cell culture (SILAC) proteomics, co-immunoprecipitation (Co-IP), Chromatin Immunoprecipitation followed by quantitative PCR (ChIP-qPCR), and dual-luciferase reporter assays. We specifically focused on the role of Proteasome activator subunit beta (PSME2), a potential regulator of drug resistance and metastasis. Results: We quantified the degree of ITH at sample level using multi-omics and scRNA-seq data and observed a correlation between higher ITH levels, increased genomic instability, upregulation of the STING type-I-interferon-dependent pathway, and poor efficacy of endocrine therapy. Both bulk and single-cell data revealed an enrichment of PSME2, associated with type-I interferon, in groups exhibiting high ITH. Patients with elevated PSME2 expression manifested a poorer prognosis and diminished responsiveness to endocrine therapy. Within the context of ITH, we discovered that IFN-I transcriptionally activated PSME2 via STAT1. Further investigation revealed a complex interplay among PSME2, PARP1, and EWS, wherein PSME2-mediated degradation of EWS relieved the transcriptional repression of PARP1, resulting in its overexpression. This series of events, orchestrated by PSME2, led to ERα PARylation and promoted tamoxifen resistance. In subsequent clinical translation studies employing mouse xenograft, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models, we demonstrated that PARP1 inhibitors could effectively mitigate tamoxifen resistance induced by high PSME2 expression, providing new insights into therapeutic strategies. Conclusions: Our study highlights the importance of understanding ITH in hormone receptor-positive and HER2-negative breast cancer and identifies PSME2 as a key player in endocrine resistance and patient prognosis. The application of PARP1 inhibitors shows promise in improving treatment outcomes in tumors with elevated ITH and PSME2 expression. Working Modle Citation Format: Li-Ping Ge, Zi-Yu Wang, Xi Jin, Yi-Zhou Jiang, Zhi-Ming Shao. High intratumor heterogeneity induced PSME2 confers endocrine resistance via ERα PARylation in hormone receptor-positive and HER2-negative 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 PO2-23-08.

Abstract PO2-05-01: Famitinib, a multi-targeted receptor tyrosine kinase inhibitor, combined with dalpicilib and fulvestrant in advanced HR-positive and HER2-negative breast cancer

Abstract Background: CDK4/6 inhibitors combined with endocrinotherapy (ET) represent an essential part of the treatment for HR-positive and HER2-negative breast cancer (BC). However, the role of angiogenesis inhibitors, such as bevacizumab, in these patients (pts) is controversial. While it has been demonstrated to improve progression-free survival (PFS), it has failed to show a significant overall survival (OS) benefit in HER2-negative BC. Several preclinical studies have explored the combination of anti-angiogenesis multi-targeted receptor tyrosine kinase inhibitors (TKIs) and CDK4/6 inhibitors in other cancers, suggesting a synergistic effect. Our phase Ib/II trial (NCT05176080, ChiCTR2100053950) aims to evaluate the safety and efficacy of a novel anti-angiogenesis TKI famitinib (F) added to dalpiciclib (D) and ET in advanced HR-positive and HER2-negative BC. Here we report the results of Phase Ib. Methods: A 3+3 de-escalation design was used in this dose-exploring phase (phase Ib). Pts with HR-positive and HER2-negative BC, who had no more than two prior chemotherapies in the advanced setting, were enrolled and administered F (orally, at doses of 15 mg/d, 10 mg/d, or 15 mg qod), D (orally, at doses of 150, 125 or 100 mg/d, 21 days on and 7 days off) and fulvestrant (intramuscularly, at a fixed dose of 500 mg every four weeks) until progression, unaccepted toxicities, or withdrawal. The initial dose level (Level 1) was set as F 15 mg daily and D 150 mg/d. The primary endpoints were recommended phase 2 dose (RP2D) and safety. Results: From December 2021 to June 2022, 18 pts were enrolled, and 3, 6, 3, and 6 pts were assigned to Level 1 (F 15 mg + D 150 mg), Level 2 (F 10 mg + D 125 mg), Level 3 (F 15 mg qod + D 125 mg), and Level 4 (F 10 mg + D 100 mg), respectively. 14 (77.8%) pts had visceral metastasis, and 7 (38.9%) had prior systemic therapies in the advanced setting. 13 (72.2%) pts had received ET, and 11 (61.1%) were resistant to ET before enrolled. A total of 6 dose-limiting toxicities (DLTs) were observed, including 3 Grade 4 thrombopenia (2 in Level 1, 1 in Level 2) and 3 Grade 4 neutropenia (2 in Level 3, 1 in Level 4), 4 of which were serious adverse events (AEs). The most common (≥20%) treatment-related AEs of Grade 3 or above were neutropenia (100.0%), leukopenia (88.9%), thrombocytopenia (33.3%), anemia (27.8%), lymphopenia and hypertension (both 22.2%). No death was reported. Overall 10 pts (55.6%) achieved confirmed partial responses and 16 (88.9%) achieved clinical benefits. Confirmed objective response rates (ORRs), clinical benefit rates (CBRs), and DLTs in different dose levels were shown in Table 1. Considering the efficacy and safety profiles, Level 4 was selected as RP2D. Conclusion: The anti-angiogenesis multi-targeted receptor TKI famitinib combined with CDK4/6i and fulvestrant has shown antitumor effects in advanced HR-positive and HER2-negative BC, and no new safety signals were observed. Citation Format: Min Yan, Mengwei Zhang, Limin Niu, Huimin Lv, Zhenzhen Liu, Huiai Zeng, Shengnan Zhao, Huihui Sun, Jing Wang, Yajing Feng, Huajun Li. Famitinib, a multi-targeted receptor tyrosine kinase inhibitor, combined with dalpicilib and fulvestrant in advanced HR-positive and HER2-negative 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 PO2-05-01.

Abstract PO2-19-03: Phase 2 study of response-guided neoadjuvant sacituzumab govitecan in patients with localized breast cancer (NeoSTAR)

Abstract Background: Optimizing treatments for localized breast cancer is key to preventing metastatic recurrences and reducing mortality. Sacituzumab Govitecan (SG) is a novel antibody-drug conjugate in which the topoisomerase 1 inhibitor SN-38 (the active metabolite of irinotecan) is coupled to a humanized monoclonal antibody targeting the antigen Trop-2, which is highly expressed in triple negative breast cancer (TNBC). SG is FDA approved for patients with metastatic hormone receptor-positive (HR+) and TNBC. However, efficacy in localized BC is not known. The NeoSTAR clinical trial is evaluating SG in the neoadjuvant (NA) setting for participants with localized breast cancer. Cohort A1 evaluating NA SG monotherapy in localized TNBC is completed, and now cohorts A2 (SG + pembrolizumab (P) for TNBC), B1 (SG monotherapy for HR+ BC), and C (SG + P for HER2- inflammatory breast cancer (IBC)) are enrolling. Trial design: This is a single-arm phase II study of NA SG or SG + P with multiple cohorts across different breast cancer subtypes. In all cohorts, SG is administered via an IV infusion on days 1 and 8 of each 21-day cycle at a starting dose of 10 mg/kg for 4 cycles. For cohorts A2 and C, pembrolizumab is given on day 1 of each cycle. For A2 and B1, after 4 cycles, participants who have biopsy-proven residual disease will have the option to receive additional standard NA therapy at the discretion of the treating physician and subsequently proceed to surgery. Those with a complete response on imaging may proceed directly to surgery. If pathological complete response (pCR) is achieved after 4 cycles of SG + P, participants on A2 will remain on study and receive adjuvant weekly paclitaxel and carboplatin for 12 weeks along with continuation of P to complete a total of one year of the PD-1 inhibitor; participants on B1 will receive adjuvant therapy at the discretion of the treating physician, with the option to continue P to complete a total of one year. On cohort C, after 4 cycles of SG + P, dose-dense doxorubicin + cyclophosphamide + P for 4 cycles will be given before considering surgery. A baseline research biopsy is required for all cohorts, as well as tissue collection following treatment with SG (either at surgery or via biopsy prior to additional NA therapy). Eligibility criteria: Participants ≥ 18 years of age with previously untreated localized breast cancer as determined by the local institution will be enrolled. For A2, participants must either have a primary tumor >2 cm or be node positive. For B1, participants with anatomic clinical stage II-III breast cancer with primary tumor > 1.5 cm and high genomic risk are eligible. For the IBC cohort (C), participants with T4d and any N are eligible. An ECOG performance score of 0 or 1, and adequate bone marrow, hepatic, and renal function is required. Study Objectives: The primary objective is to assess the pCR rate in breast and lymph nodes (ypT0/isN0) with SG + P (A2), SG (B1), or SG + P followed by AC + P (C). Secondary objectives include assessment of overall response rate, evaluation of the safety and tolerability of SG or SG + P (CTCAE v5.0), event-free survival (EFS), and quality of life (EORTC QLQ-C30). Exploratory objectives include assessment of potential predictive biomarkers, including Trop-2 expression, DNA damage response markers and immunological markers, as well as changes in cell free DNA with SG. Statistical methods: The primary analysis is based on the estimated pCR rate with SG or SG + P and will be provided as a proportion (with two-sided 95% confidence interval). Each cohort will follow a Simon two-stage design. EFS will be analyzed using Kaplan-Meier methods and descriptive statistics. Target Accrual: 50 participants (A2), 56 participants (B1), 39 participants (C) Contact: Dr. Laura Spring (LSpring@mgh.harvard.edu) Clinicaltrials.gov #: NCT04230109 Citation Format: Laura Spring, Ana Garrido-Castro, Filipa Lynce, Nadine Tung, Rachel Abelman, Lianne Ryan, Megan Moran, Elizabeth Mittendorf, Leif Ellisen, Sara Tolaney, Aditya Bardia. Phase 2 study of response-guided neoadjuvant sacituzumab govitecan in patients with localized breast cancer (NeoSTAR) [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 PO2-19-03.

Abstract PO4-04-13: Impact of dose reduction of CDK4/6 inhibitors on progression-free survival in Mexican patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a retrospective single-center study

Abstract Background Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been demonstrated to prolong survival in women with hormone receptor-positive, HER-2 negative, metastatic breast cancer. However, these treatments often require dose adjustments due to adverse effects, resulting in a reduction in 30-50% of cases. There is evidence suggesting a relationship between dose intensity and progression-free survival (PFS), but data in the Hispanic population are limited. Therefore, the objective of the study was to explore the association between dose reduction of CDK4/6/i inhibitors and PFS in patients with metastatic breast cancer. Methods We conducted a retrospective single-center study involving patients diagnosed with hormone receptor-positive, HER-2 negative metastatic breast cancer (MBC) between 2020 and 2023. Eligible patients were those who received at least one cycle of palbociclib, abemaciclib, or ribociclib and had a follow-up period of more than three months since the initiation of CDK4/6 inhibitor (CDK4/6i) treatment. Patient data were collected from electronic medical records. We analyzed demographic and clinicopathological characteristics and estimated the PFS in patients who had any dose reduction within the first 12 weeks compared to those who did not, using Kaplan-Meier plots and compared the differences in survival using the log-rank test. A Cox regression analysis was performed to estimate survival hazard ratios (HR). Results Among 41 patients, the mean age at CDK4/6i initiation was 61.0 years (SD 12.9), 22 (53.7%) were postmenopausal at diagnosis, 25 (61%) had recurrent disease, and 22 (53.7%) were receiving CDK4/6i in the first-line setting. Bone metastases were present in 30 (73.2%), and visceral metastases in 22 (53.7%). Regarding type of CDK4/6i, 33 (80.5%) received palbociclib, 7 (17.1%) ribociclib, and 1 (2.4%) abemaciclib. At 12 weeks, 12 patients (29.3%) had a dose reduction (Table 1). With a median follow-up since CDK4/6i initiation of 407 days (95% confidence interval (CI) 272-542), 19 events were recorded, with a median PFS of 12.6 months (95% CI 8.0-17.3) for the overall population. Median PFS was 9.7 months (95% CI 0.6-18.8) in patients who had a dose reduction at 12 weeks and 35.2 months (95% CI 0-72.2) in those who did not (p=0.014). The univariate Cox proportional hazard model showed that dose reduction was associated with a worse PFS (hazard ratio 3.1; 95% CI: 1.20–7.80, p = 0.0019) Conclusion In this cohort of Mexican patients with hormone receptor-positive, HER2-negative metastatic breast cancer we found that dose reduction of CDK4/6 inhibitors within the first 12 weeks of treatment was associated with worse PFS. Given the retrospective nature of this analysis, we believe that these findings should be replicated in prospective studies. Table. Patient characteristics Citation Format: Andres Meraz-Brenez, Alejandro Aranda-Gutierrez, Hector Raul Gonzalez-Sanchez, Bertha Alejandra Martinez-Cannon, Leonardo Verduzco-Rodriguez, Haydee Cristina Verduzco-Aguirre. Impact of dose reduction of CDK4/6 inhibitors on progression-free survival in Mexican patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a retrospective single-center 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 PO4-04-13.

Abstract PO2-02-03: Clinical and pathological factors associated with Oncotype DX® 21-Gene recurrence score in patients diagnosed with early stage breast cancer in a low-middle income country

Abstract INTRODUCTION: Oncotype DX® recurrence score (ODX RS) is a 21-gene assay warranted to determine the the prognosis in patients with hormone receptor positive, HER-2 negative early stage breast cancer. In this context, the test is also predictive of benefit of adjuvant chemotherapy.1,2,3 OBJECTIVES: We aimed to correlate the clinical and pathological factors associated with Oncotype DX® 21-Gene in patients diagnosed with early stage Breast Cancer. Additionally, description of adjuvant treatment patterns and survival outcomes were described according to the Oncotype DX® 21-Gene result. METHODS: Data from medical records from a single center in Brazil were collected retrospectively from women over 18 years diagnosed with early breast cancer between 2012 and 2022. Included patients were diagnosed with stage T1-T2 breast cancer, hormone receptor positive, HER-2 negative, with up to three positive lymph nodes. All included patients had an Oncotype DX® test performed after definitive breast surgery. The ODX RS has been categorized into two levels according to menopausal status. Correlation between breast cancer recurrence and clinicopathological characteristics was done. The software SPSS was used for statistical analyzes with the significance of 0.05. RESULTS: From 197 patients, 20 have had breast cancer recurrence (10.15%) whom 10 were premenopausal and 10 were postmenopausal. The median ODX RS in these 20 patients was 15 (ranged from 9 to 31). The most common site of recurrence was breast and regional recurrence in 18 patients (90%). Adjuvant chemotherapy was omitted in 16 patients (80%) who have had breast cancer recurrence. Among premenopausal patients whose ODX RS was >20, 33 patients (91.66%) received adjuvant chemotherapy. Among postmenopausal patients whose ODX RS was >25, 19 (86.36%) received adjuvant chemotherapy. The probability of recurrence free survival was worse in premenopausal patients > 44-years-old compared to those with < =44 years-old (p = 0.036) and also worse in histological grade 3 tumors compared to grade 1 (p=0.0048). Tumor size >14 millimeters (mm) was correlated to worse recurrence free survival in premenopausal patients (p=0.017). Low estrogen and progesterone receptor was associated with a higher ODX RS (p=0.0035 and p< 0.0001, respectively) in premenopausal patients, but not associated with recurrence free survival. Clinicopathological characteristics and recurrence free survival correlation in postmenopausal patients were not significant. CONCLUSION: This retrospective analysis suggests that factors other than the Oncotype DX® score, such as age and grade contributed to worse survival outcomes among our patients population. Of note, age older than 44 years-old, histological grade 3 and tumor size >14 mm were associated with a higher probability of recurrence in premenopausal patients, despite the Oncotype DX® score. REFERENCES: 1. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med [Internet]. 2004;351(27):2817–26. Available from: http://dx.doi.org/10.1056/NEJMoa041588. 2. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med [Internet]. 2018;379(2):111–21. Available from: http://dx.doi.org/10.1056/NEJMoa1804710. 3. Kalinsky K, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med [Internet]. 2021;385(25):2336–47. Available from: http://dx.doi.org/10.1056/NEJMoa2108873. Table 1 – Clinical and pathological characteristics of 197 hormone receptor positive, HER-2 negative early breast cancer patients who did the Oncotype DX® 21-Gene Recurrence Score assay. Data from medical records collected retrospectively of women diagnosed with early breast cancer between 2012 and 2022 from a single center in Brazil. Figure 1 – Probability of recurrence free survival in premenopausal patients according to age <=44 (blue line) or > 44-years-old (pink line). Data from medical records collected retrospectively of women with hormone receptor positive, HER-2 negative early breast cancer who did the Oncotype DX® 21-gene assay diagnosed between 2012 and 2022 from a single center in Brazil. Figure 2 – Probability of recurrence free survival in premenopausal patients according to histological grade. Tumor with histological grade 1 (blue line) or histological grade 3 (pink line). Data from medical records collected retrospectively of women with hormone receptor positive, HER-2 negative early breast cancer who did the Oncotype DX® 21-gene assay diagnosed between 2012 and 2022 from a single center in Brazil. Citation Format: Carolina Cavalcanti Gonçalves Ferreira, Julio Araujo, Shermann Brandão Rodrigues Moreira, Antônio Buzaid, Débora Gagliato. Clinical and pathological factors associated with Oncotype DX® 21-Gene recurrence score in patients diagnosed with early stage breast cancer in a low-middle income country [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 PO2-02-03.

Abstract PO1-23-08: Exosome-based delivery of microRNAs confers adriamycin-resistance to sensitive cells through modulating the immune and metabolism-related gene PTEN in HER2-negative breast cancer

Abstract Background: Anthracycline-based chemotherapy is widely used to treat breast cancer. However, acquired drug resistance remains a challenge to successful treatment. Recently, increasing evidence has shown that changes in the tumour immune microenvironment (TIME), in addition to increasing drug resistance of tumour cells, consistently contribute to the development of chemoresistance. Methods: TIME scores and tumor-infiltrating immune cells (TICs) scores were used to investigate the prognosis, clinicopathological characteristics and gene transcriptome profiling of HER2-negative breast cancer patients who received anthracycline-based chemotherapy. Exosomes isolated from MCF/7-ADR (ADR-exos) and MCF/7-S (S-exos) cell lines were characterized. We identified dysregulated miRNAs using miRNA microarray analysis on MCF/7-ADR cells and their exosomes compared to MCF/7-S cells and their exosomes. Protein profiling was performed to identify differentially expressed proteins in up- and down-regulated miR-222 cells. The ability of ADR-exos to transfer drug-resistance mediated by miR-222 was assessed by immunofluorescence assay, flow cytometry and qRT-PCR. We optimized the conditions to load miR-222 mimic (or inhibitor) into exosomes produced by HBL-100 cells (H-exos). The influence of miR-222 inhibitor-containing exosomes (inhibitor-exos) on the downstream pathway of miR-222 and the potential therapeutic effects both in vitro and in vivo were evaluated. We also evaluated the relationship between miR-222/PTEN and drug resistance in circulating exosomes from mice after adriamycin-based chemotherapy. Results: Firstly, we discovered the complicated and heterogenous TICs subtypes and their unique biological behaviors in HER2-negative breast cancer. Then, we identified 85 differentially expressed immunologic signature gene sets and 7202 corresponding immune-related genes in three subtypes quantified by gene set variation analysis (GSVA). We identified 12 up-regulated and 13 down-regulated genes using miRNA microarray analysis in adriamycin-resistant cells and their exosomes. The TMT mass spectrometry found 45 differentially expressed proteins affected by the miR-222 level. Moreover, we successfully established miRNA mimic/inhibitor-containing exosomes to explore the solo function of exosomal miR-222 in adriamycin-resistance both in vitro and in vivo. More importantly, for the first time, we detected the levels of miR-222 and its target gene PTEN in circulating exosomes from mice after adriamycin-based chemotherapy and explored the potential clinical implications of miR-222/PTEN-containing exosomes in chemotherapy and immune suppression of breast cancer patients. Conclusions: HER2-negative breast cancer patients own unique TIME subtypes, leading to different outcomes of chemotherapy. We exhibit the potential applications of miR-222-mimic/inhibitor-containing exosomes for reversing chemo-resistance. Adriamycin-resistant cells can transmit drug-resistance to sensitive cells via delivering miR-222 by modulating the immune- and metabolism-related target gene PTEN both in vitro and in vivo without interference from other relevant drug-resistance factors in exosomes. Therefore, miR-222-containing exosomes as well as their target gene PTEN may be a promising biomarker for predicting the efficacy of chemo-resistance and tumor immunity regulation in breast cancer patients receiving anthracycline-based chemotherapy. Keywords: exosomes, breast cancer, tumor immune microenvironment, chemo-resistance, microRNAs Citation Format: Sujin Yang, Tian-cheng Cheng, Jia-hao Wu, Wei-xian Chen. Exosome-based delivery of microRNAs confers adriamycin-resistance to sensitive cells through modulating the immune and metabolism-related gene PTEN in HER2-negative 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 PO1-23-08.

Abstract PO3-03-02: Effect of Surgery on Breast Cancer-Specific Mortality in Elderly Patients with Hormone Receptor-Positive, HER2-Negative Breast Cancer

Abstract Background: The number of elderly patients with breast cancer has been increasing in Japan. Although standard treatment including surgery is desirable if the expected life expectancy is sufficient, not all elderly patients with breast cancer are eligible for surgery due to frailty and comorbidities. Endocrine therapy (ET) alone is an alternative option if surgery is not considered adequate in patients with hormone receptor-positive breast cancer. We evaluated whether ET alone was associated with inferior overall and breast cancer-specific survival compared to standard treatment including surgery in elderly patients. Methods: This study included all patients aged 75 years and over who were diagnosed with non-metastatic primary invasive hormone receptor-positive, HER2-negative breast cancer and treated at Hiraka General Hospital from July 2006 to March 2022. Patients were divided as those who received ET alone (ET alone group) and those who received surgery with other therapies (Surgery group). Survival status as on March 31, 2023 and cause of death were determined. Overall survival and breast cancer-specific survival were estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate analysis and multivariate Cox proportional hazards regression model including age, Eastern Cooperative Oncology Group performance status (PS) score, clinical stage, and treatment were used to identify survival-associated factors. Propensity score matching was used to reduce the effect of selection bias on treatment type during survival comparison of the groups. Results: The study cohort comprised 128 patients, including 33 and 95 patients in the ET alone group and Surgery group, respectively. The median ages were 84.6 and 80.4 years in the ET alone group and Surgery group, respectively (p < 0.05). Ten patients (30%) in the ET alone group had poor PS (3 or 4), and no patient in the Surgery group had poor PS (p < 0.01). Also, 24.2%, 54.5%, and 21.2% of the patients in the ET alone group and 48.4%, 43.2%, and 8.4% of the patients in the Surgery group had clinical stage I, II, and III disease at diagnosis, respectively (p < 0.05). Survival status was confirmed in all patients, and the cause of death was confirmed in 52 of the 53 patients who died (98%) during the study period, including 24 and 29 patients in the ET alone group and Surgery group, respectively. Breast cancer was the cause of death in 3 patients (13%) in the ET alone group and 5 patients (17%) in the Surgery group. By univariate analysis, overall survival was significantly better in the Surgery group than in the ET alone group (median, 12.5 vs. 4.1 years; p < 0.0001). Similarly, breast cancer-specific survival was better in the Surgery group than in the ET alone group (p < 0.05). By multivariate Cox proportional hazards regression analysis, age was associated with shorter overall survival time (hazard ratio [HR] 1.07, 95% confidence interval [CI] 1.00–1.15; p = 0.04) and surgery was associated with longer overall survival (HR 0.24, 95% CI 0.12–0.47; p < 0.001). Breast cancer-specific survival was associated with age (HR 1.18, 95% CI 1.03–1.36; p = 0.02) and clinical stage (HR 8.89, 95% CI 1.05–75.5; p < 0.05) but not with treatment (HR 0.66, 95% CI 0.73–5.85; p = 0.71). After propensity score matching, overall survival was significantly better in the Surgery group than in the ET alone group (HR 0.26, 95% CI 0.09–0.73; p = 0.01) whereas breast cancer-specific survival was not significantly different between the two groups (HR 0.82, 95% CI 0.08–8.27; p = 0.86). Conclusion: Even in elderly patients, surgery should be considered if sufficient life expectancy is expected. However, most of the deaths were not related to breast cancer in the present study cohort. Therefore, for elderly patients without sufficient life expectancy, endocrine therapy alone would be an appropriate option. Citation Format: Misako Yatsuyanagi, Tomoyuki Shimada, Yuko Takeishi, Yukiko Matsuzaka, Chika ohsawa. Effect of Surgery on Breast Cancer-Specific Mortality in Elderly Patients with Hormone Receptor-Positive, HER2-Negative 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 PO3-03-02.

Abstract PO1-03-09: Transcriptomic profiling of ER-negative and ER-low, HER2-negative breast cancer and its implications on immune regulation

Abstract Background: The recommended cut-off of < 1% positive cells to define estrogen receptor (ER) negative status in breast cancer (BC) is highly debated. Few data exist on transcriptomic features of ER-low BC, suggesting no major differences vs ER-neg. Among HER2-negative BCs, we compared gene-expression profiling (including PAM50 intrinsic subtyping) according to ER status (ER-neg: 0% vs. ER-low: 1-9%) and assessed its impact on Tumor-infiltrating lymphocytes (TILs) levels. Methods: Across two cancer centers, stage I-III HER2-negative BCs FFPE samples were reviewed for ER status. All ER-low (ER 1-9%) samples were identified and a cohort of ER-neg BC samples, matched for age and stage, was also retrieved. A small cohort of pts with intermediate ER expression (ER-int: 10-50%) was included as a control cohort. Expression of 776 BC–related genes was evaluated by nCounter® (Breast Cancer 360TM Panel) and intrinsic molecular subtyping was determined using the PAM50 subtype predictor. A False Discovery Rate (FDR) corrected unpaired two-class SAM was used to identify genes differentially expressed in different subgroups. TILs were evaluated on archival H&E slides following guidelines. Results: Of 116 stage I-III HER2-neg BC pts included, 39 had ER-neg BC, 65 had ER-low BC, and 12 had ER-int disease. PAM50 intrinsic subtype distribution was similar in ER-neg and ER-low BCs, (with an enrichment in basal-like tumors), while both subgroups differed significantly from ER-int samples (Table). As compared to ER-neg tumors, ER-low BCs showed significantly higher expression of GATA3 gene and lower expression of EDN1 and PROM1 genes by SAM analysis (FDR< 5%); however, when the analysis was limited to PAM50 basal-like tumors (N=77) we only identified two genes that were downregulated in ER-low BCs (EDN1, PROM1) as compared to ER-neg BCs. On the contrary, significant differences in transcriptomic regulation were observed between ER-low and ER-int BCs, with ER-low BCs showing significantly higher expression of 53 genes and lower expression of 398 genes, as compared to ER-int (SAM analysis FDR< 5%). We previously reported similar TIL levels in ER-low and ER-neg tumors. In both ER-low and ER-int BCs, PAM50 basal-like subtype was associated with significantly higher TILs: median TIL levels 20 (range 0-80) and 6 (range 1-40) for PAM50 Basal-like BCs versus other PAM50 subtypes respectively in ER-low samples (p< 0.001); median TIL levels 53 (range 25-80) and 5 (range 0-10) for PAM50 Basal-like BCs versus other PAM50 subtypes respectively in ER-int samples (p=0.036). No significant difference in TIL levels according to PAM50 subtyping were observed in ER-neg tumors. No significant difference in mRNA levels for PD-1 (PDCD1) and PD-L1 (CD274) genes was observed between ER-low and ER-neg tumors. Conclusions: Among patients with HER2-neg BC, gene-expression profiling is similar in ER-neg (i.e., < 1%) vs. ER-low tumors with a high prevalence of PAM50 Basal-like tumors and few differentially expressed genes. In both ER-low and ER-int HER2-neg BCs, PAM50 Basal-like subtype is also associated with higher TIL levels. Our results strongly indicate that HER2-neg/ER-low BCs and HER2-neg/ER-neg BCs are similar biological entities, thus further supporting the use of similar treatments in patients with early-stage ER-low and triple-negative BC, including immune checkpoint inhibitors. PAM50 intrinsic subtype distribution according to ER levels Citation Format: Gaia Griguolo, Claudio Vernieri, Davide Massa, Lorenzo Nicolè, Claudia Pinato, Federica Miglietta, Andrea Vingiani, Silvia Brich, Riccardo Lobefaro, Francesca Schiavi, Matteo Fassan, Giancarlo Pruneri, Valentina Guarneri, Maria Vittoria Dieci. Transcriptomic profiling of ER-negative and ER-low, HER2-negative breast cancer and its implications on immune regulation [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 PO1-03-09.

Abstract PO3-20-12: A Case Report on the Management of a Patient with Local Breast Cancer, BIA-ALCL and Radiation Induced Metastatic Angiosarcoma: A Multidisciplinary Approach

Abstract A Case Report on the Management of a Patient with Local Breast Cancer, BIA-ALCL and Radiation-Induced Metastatic Angiosarcoma: A Multidisciplinary Approach Abstract: Breast cancer recurrence presents a complex challenge in clinical practice. We present the case of a 60-year-old female with a history of stage 2A right breast cancer diagnosed on 12/1/2013. The patient underwent bilateral mastectomy and adjuvant chemotherapy, followed by breast reconstruction. The patient subsequently developed asymmetric right breast swelling, which was biopsied and was positive for T lymphocyte markers CD30, CD43, CD45, CD4 and she was diagnosed with anaplastic large cell lymphoma in 12/14/2018, which was thought to be associated with her breast implants. In May 2022, a right chest wall mass was detected, which demonstrated growth and increased vascularity on imaging. A biopsy on 5/5/22 confirmed poorly differentiated carcinoma initially thought to be a secondary intraductal carcinoma of the breast, invading the chest wall by metastasis or direct extension, negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Further workup confirmed this mass to be angiosarcoma, most likely associated with the patient’s prior radiation therapy. The patient was started on neoadjuvant carboplatin/paclitaxel/pembrolizumab on 6/9/2022, and continued with Doxorubicin/Cyclophosphamide and pembrolizumab, which was completed on 11 November 2022. Imaging studies post-treatment showed a slightly smaller mass in the right mastectomy bed, indicating a partial response to treatment. However, a subsequent PET scan revealed a recurrence of breast cancer in the right chest wall. Considering the patient's history of prior radiation therapy and the inability to administer further radiation, the treatment plan was revised. She underwent reconstructive chest wall surgery on 1/4/2023, with complete resection and negative margins. She started on adjuvant pembrolizumab planned for one year, but the patient presented on 3/3/2023 with the growth of a chest wall mass and bleeding, consistent with progression. Liquid Tempus testing was obtained but negative for an actionable target. Options such as hyperthermia, enrollment to clinical trial, and re-irradiation were discussed, and the patient was restarted on weekly paclitaxel on 3/31/2023 due to a previous response. The patient had further local disease progression on 5/26/2023, and this regimen was stopped. The patient is planning to get Tempus testing on tumor tissue and start the next line palliative regimen with either doxorubicin or gentamicin and repeat re-irradiation if no response to these regimens. This case report highlights the challenges in managing breast cancer therapy-induced adverse conditions with two secondary tumors, both associated with the patient’s prior therapy. The importance of a multidisciplinary approach, including medical oncology, surgical oncology, radiation oncology, and sarcoma specialists, is emphasized. The use of molecular testing and consideration of clinical trials may provide additional treatment options. Further research and clinical trials are warranted to optimize the management of recurrent breast cancer with transformation to rare histological subtypes such as angiosarcoma. Citation Format: Liubou Varanitskaya, Serhan Unlu, Christina Clemow. A Case Report on the Management of a Patient with Local Breast Cancer, BIA-ALCL and Radiation Induced Metastatic Angiosarcoma: A Multidisciplinary Approach [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 PO3-20-12.

Abstract RF01-06: Efficacy and safety of toripalimab plus metronomic chemotherapy in HER2 negative metastatic breast cancer: a multicenter phase II trial based on a Bayesian adaptive randomized design

Abstract Background: Combining Immune checkpoint blockade (ICB) with chemotherapy may significantly improve efficacy in patients with breast cancer. Metronomic chemotherapy is based on more frequent and low-dose drug administrations compared with conventional chemotherapy. Some clinical studies with small samples have tried the combination of metronomic chemotherapy and ICB in patients with advanced tumors. However, whether metronomic chemotherapy is more suitable for ICB than conventional chemotherapy is still unclear. Thus, we performed the first clinical trial, to our knowledge, of metronomic chemotherapy combined with PD-1 blockade comparing with the efficacy of combined conventional chemotherapy and ICB. Methods: This study is a multicenter randomized phase 2 trial using a multi-arm design with Bayesian adaptive randomization and efficacy monitoring. Eligible patients have advanced HER2 negative breast cancer, with no more than one prior line of standard chemotherapy. Patients were randomized to 5 groups: ① metronomic vinorelbine (NVB, 40 mg/day, TIW) monotherapy (the control cohort); ② NVB + Toripalimab (anti-PD1 antibody, 240 mg Q3W); ③Bevacizumab (5 mg/kg Q3W) + NVB+ Toripalimab (the BEV cohort); ④ Cisplatin (50mg/m Q3W) + NVB + Toripalimab (the DDP cohort), ⑤Cyclophosphamide (50mg/day, QD) + Capecitabine (500 mg, TID) + NVB+ Toripalimab (the VEX cohort). The primary endpoint is disease control rate (DCR), and secondary endpoints are objective response rate (ORR), progression free survival (PFS), and overall survival (OS). The safety profile has also been assessed. Mass cytometry time-of-flight (CyTOF) analyses of paired blood samples were performed to demonstrate dynamic changes in systemic immune profile. Results: A total of 103 patients were randomized. Characteristics were as expected for advanced breast cancer and balanced between cohorts. Adverse events of any grade occurred in 64 patients, with 5.2% grade >3. The rate of nausea was significantly higher in the cisplatin cohort than in the others (P< 0.001). Toripalimab was not associated with any previously unreported toxicity. Among the five treatment cohorts, the VEX cohort and the cisplatin cohort had the highest DCR, 69.7% (95% CI 51.7–85.9%) and 73.7% (95% CI 56.1–88.7%), respectively. Followed by the bevacizumab cohort, DCR is 55.7% (95% CI 37.4%–73.6%). Most objective responses were observed in the VEX cohort (ORR: 18.5%; 95% CI 5.6–34.1%), followed by cisplatin (ORR 14.5%; 95% CI 3.3–29.0%). It is worth noting that the PFS of patients in the VEX cohort was the longest, reaching 6.6 months (95% CI 4.0-5.9), followed by 4.0 months (95% CI 2.4-10.4) in patients of the bevacizumab cohort. The PFS of patients receiving the cisplatin regimen was relatively short, only 3.5 months (95% CI 2.2-5.3). Similarly, patients in the cisplatin cohort had shorter OS than those in the VEX and bevacizumab cohorts. In the TNBC subgroup, again, patients in the VEX cohort had the highest DCR (74.1%, 95%CI 47.9%-95.4%) and longest PFS (9.8 months, 95%CI 3.8-21.9). We obtained over 63 million cells in total and clustered CD45+ immune cells into 32 clusters. The systemic immune profile of patients changed dramatically over 2 cycles of PD-1 blockade. However, only the change of cluster 30 differed between responders and non-responders. This is a group of intermediate monocytes with a high expression of CD38, which decreased in responders but significantly increased in non-responders. CD38-NAD+ axis regulates the PD1+ exhausted T cell function. Meanwhile, the overall expression of CD38 in monocytes was significantly increased by DDP and BEV treatment compared with baseline, but not in the VEX groups. DDP significantly increased the expression level of CD38 on NK cells, while BEV or VEX treatment did not affect it. Conclusions: These data suggest promising clinical efficacy and evidence of cooperativity between metronomic VEX chemotherapy and PD-1 blockade. Citation Format: Hongnan Mo, Xiaoying Sun, Jingtong Zhai, Jiashu Han, Hewei Ge, Yuhan Wei, Xiuwen Guan, Haili Qian, Fei Ma. Efficacy and safety of toripalimab plus metronomic chemotherapy in HER2 negative metastatic breast cancer: a multicenter phase II trial based on a Bayesian adaptive randomized design [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 RF01-06.

Abstract PO1-04-12: Palbociclib versus ribociclib in first-line treatment of patients with hormone-receptor positive HER2 negative advanced breast cancer – real world outcome data from the German registry platform OPAL

Abstract Introduction CDK4/6 inhibitors (CDKi) plus endocrine therapy (ET) are standard of care in first-line (1L) treatment of hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (ABC). In the pivotal trials the three CDK4/6i (palbociclib, ribociclib and abemaciclib) + ET showed similar progression-free survival (PFS) benefit over ET alone. However, other than ribociclib, palbociclib failed to demonstrate overall survival (OS) benefit. As patient (pts) characteristics differed between the trials, especially in the number of pts with treatment-free interval (TFI) of < 12 months after end of adjuvant ET, head-to-head comparisons of the CDKi are of clinical interest. Here we analyze the outcome of pts treated with palbociclib + ET or ribociclib + ET with real-world data from OPAL. Methods OPAL (NCT03417115) is a prospective observational, open, longitudinal multicenter cohort study (clinical registry) in Germany. Pts with ABC and early breast cancer can be recruited at start of their first systemic treatment. There are no treatment restrictions. Sites from all medical sectors can participate in OPAL (medical and gynecologic oncologists from outpatient centers and hospitals). Details on all (sequential) treatments, patient and tumor characteristics, biomarker testing, clinical and patient-reported outcomes are collected. Follow-Up is until death or up to 5 years. Between 01/2018 and 07/2021 1049 pts with HR+ HER2- ABC were recruited by 143 sites. Database cut was on 31/08/2022. 384 pts received palbociclib + ET and 231 pts received ribociclib + ET as 1L treatment. All endocrine combination partners including switch of ET during first line therapy was allowed, whereas switch of CDK4/6i (n=25) were excluded. PFS in registries can differ from PFS in clinical trials, since the RECIST criteria are usually not applied in routine care. PFS in registries represents the time to clinically relevant progression in routine care. PFS and OS were estimated using the Kaplan-Meier method. To adjust for confounding, inverse probability of treatment weighting (IPTW) by propensity score analysis was used to compare PFS and OS between 1L palbociclib+ET and ribociclib+ET. IPTW was performed for the following variables: age, menopausal status, ECOG, any comorbidity, Charlson comorbidity index, metastatic stage, type of metastasis, number of metastatic sites, estrogen-/progesterone status, IHC status, previous chemo-/endocrine therapy, kind of endocrine combination partner, disease-free interval, and treatment-free interval. Results From 2018 to 2021, the proportion of CDK4/6i increased from 68% to 86% in 1L of HR+HER2- ABC. Overall, palbociclib was used in 44% and ribociclib in 26% of all first-line treatments in OPAL. Median age of pts receiving palbociclib/ribociclib was 66/68 years and for 77/81% of pts at least one comorbidity was documented. 37/35% of pts already had metastasis at diagnosis (M1) and 25/26% of pts had a TFI < 12 months. After IPTW, the two treatment groups were comparable for all tested characteristics. 42/46% of patients had a progression (palbociclib/ribociclib group). IPTW-adjusted median PFS was 25.1 months (95% Confidence interval (CI) 20.1 – 30.1) for the palbociclib and 27.0 months (95%-CI 21.1 – 31.6) for the ribociclib group. Hazard ratio was 0.91 (0.71 – 1.17) for palbociclib versus ribociclib. 26/29% of patients had an OS event (palbociclib/ribociclib group). IPTW-adjusted median OS was 36.7 months (95%-CI 33.0 – NA) for the palbociclib and 36.6 months (95%-CI 33.1 – NA) for the ribociclib group. Hazard ratio was 0.95 (0.69 - 1.30) for palbociclib versus ribociclib. Conclusions This analysis of real word data in the OPAL registry platform showed similar PFS and OS for palbociclib + ET compared to ribociclib + ET, when adjusted for a wide range of potential confounding variables. Further analyses will investigate whether one drug showed favorable results in certain subgroups of pts. Citation Format: Marc Thill, Mark-Oliver Zahn, Anja Welt, Arnd Nusch, Matthias Zaiss, Kathrin Engelken, Gabriele Kaltenecker, Kai Ringwald, Katja Gratzke, Lisa Kruggel, Martina Jänicke, Holger Schulz, Christoph Losem, Volker Hagen, Roland Fricker, Elmar Stickeler, Nadia Harbeck, Achim Wöckel, Thomas Decker. Palbociclib versus ribociclib in first-line treatment of patients with hormone-receptor positive HER2 negative advanced breast cancer – real world outcome data from the German registry platform OPAL [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 PO1-04-12.