Breast Cancer Outcomes Research Articles

Abstract PO3-05-09: The impact of body mass index on CDK4/6 inhibitor treatment survival outcomes in metastatic breast cancer

Abstract Introduction: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are important in the treatment of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC). Previous studies have shown that CDK4/6is affect metabolic processes and cell metabolism, including adipogenesis, lipid synthesis, and glucose regulation. Obesity has been associated with worse survival in breast cancer. We aimed to assess the effect of body mass index (BMI) on survival outcomes in patients treated with CDK4/6is for MBC. Methods: Patients diagnosed with metastatic HR+/HER2-negative BC and who were treated with palbociclib, ribociclib, or abemaciclib from 6/10/2015 to 12/28/2022 were selected from the Montefiore Health system database and followed until 3/24/2023. The patients were divided into three groups according to BMI level as follows; normal: 18.5-24.9 kg/m2, overweight: 25-29.9 kg/m2 and obese: ≥ 30 kg/m2. Patients were also stratified by BMI measured after 3 months of therapy. Characteristics of the patients and tumors in the subgroups were compared using chi-squared/Fisher’s exact test for categorical data and Kruskal-Wallis/Wilcox signed rank tests for continuous data. Kaplan-Meier and Cox proportional hazards analysis were used to compare overall survival (OS) and progression free survival (PFS). Results: Among 221 patients, 66 were normal weight, 78 were overweight, and 77 were obese. There was no statistically significant difference in clinicopathological characteristics among the cohorts. Neither BMI measured at baseline nor after 3 months of therapy had any association with OS (P = 0.8 at baseline and P = 0.1 after 3 months) or PFS (P = 0.4 at baseline and P = 0.6 after 3 months). Multivariable analysis showed no statistically significant association between BMI and worse OS (HR: 1.1 for overweight, P = 0.7; and 0.96 for obese, P = 0.9) or worse PFS (HR: 0.9 for overweight, P = 0.8; and 0.76 for obese, P = 0.5). Multivariate analysis revealed a significant effect of obese BMI after 3 months of treatment on OS (HR: 0.48, P = 0.035) but not on PFS (HR: 0.88, P = 0.8). Overweight BMI after 3 months of treatment was not found to have a significant effect on OS (HR: 0.49, P = 0.063) or PFS (HR: 0.89, P = 0.9). Conclusion: The clinical effectiveness of CDK4/6is was not found to be influenced by BMI measured prior to therapy; however, there may be an association between improved OS and obese BMI after 3 months of treatment. Median OS and PFS in patients with MBC comparing different BMI groups (normal, overweight, and obese) at baseline prior to therapy and after 3 months of therapy. Table 1 Baseline characteristics of patients with MBC comparing different BMI groups (normal, overweight, and obese) at baseline prior to therapy and after 3 months of therapy. Table 2 Table 3 Multivariable analysis of OS and PFS for patients with MBC comparing different BMI groups (normal, overweight, and obese) at baseline prior to therapy and after 3 months of therapy. Citation Format: Frank Zhang, Jesus Anampa Mesias. The impact of body mass index on CDK4/6 inhibitor treatment survival outcomes in metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-09.

Abstract PO1-16-11: Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) study

Abstract Background: BC is the most incident cancer worldwide in < 40 years old (y) women. Increasing body mass index and changes in reproductive history contribute to the growing incidence of premenopausal BC. A higher proportion of luminal B-like and estrogen receptor negative (ER─) tumors, an increased risk of early relapse, and more unfavorable longer-term outcomes for young women with ER+ tumors when compared to older women, have been reported. In this analysis, we focus on age-specific BC characterization from a real-world population-based perspective. Methods: Pts were enrolled in the non-interventional and ambispective RegistEM study in ABC diagnosed between 2016 and 2019. We describe the features and outcomes of < 50 y pts at their initial BC diagnosis according to their BC subtype. BC subtypes were based on the most recent tumor tissue sample (distant metastasis, and in its absence, primary BC). Comparisons between < 40 and ≥ 50 y groups were performed. Results: Pts < 50 y represent 39% (n=685) of total pts with available data (n=1739, any age group) in the registry. By age, 12% (n=212) were < 40y, and 27% (n=473) 40-49y. At first BC diagnosis, 75% and 25% pts had early BC (EBC) and de novo metastatic BC (MBC), respectively. In EBC pts, stage II (50%) and III (28%) were the most frequent at diagnosis; invasive non-special type carcinoma was the predominant morphology, and grade 2 was the most common histological grade, but grade 3 was predominant in TN pts and HER2+ < 40y pts. The median time to recurrence was < 2y in TN pts, 3y in HER2+ pts, and 6y in luminal HER2─ pts. At ABC diagnosis, the median age was 47y, all pts were female but one, 98% white, and 60% premenopausal (94% were premenopausal at EBC diagnosis). A family history of BC and/or ovarian cancer was reported in 34% pts, and a hereditary-risk genetic test was performed in 39% (254 of 652) pts; 12% (n=30) had BRCA1/2 mutations, with a proportion higher in TN pts (9 of 33, 27%) vs. luminal HER2─ (21 of 183, 12%) and HER2+ (0 of 38) pts. Visceral disease was the most frequent in all subgroups, highlighting statistical differences (p=0.022) between age groups ( < 40y 55% vs. ≥50y 71%) only in TN pts. 60% had ≤ 2 locations involved, similarly in all subgroups. The presence of >2 metastatic locations was statistically higher in HER2+ pts ≥50y (54%) vs both < 40y (32%) and 40-49y (48%). Brain disease was more present at ABC diagnosis in TN (9%) and HER2+ (7%) than in luminal HER2─ (3%). Median no. of treatment lines (L) was 3 (range 0-11), and median follow-up 44 mo (95% CI: 41-44). 99% pts received 1L, the distribution of treatments by BC subtype within each age subgroup was similar; median duration of 1L was 21 months (mo) in luminal HER2─, 17 mo in HER2+, and 5 mo in TN pts. 68% of pts who received 1L, reached 2L. Duration of 2L dropped dramatically: 8 mo in luminal HER2─, 6 mo in HER2+, and 2 mo in TN pts. No differences between ≥50y and the rest of pts were observed in PFS for any treatment line. 49% pts had died at the database cut-off date (05-April-23), with no differences between age groups, but TN pts had the highest death rate (80%). Additional data according to BC subtypes and age groups are in the table. Conclusions: Luminal HER2─ was the predominant BC subtype in all age subgroups. Visceral disease was more prevalent in young TN pts compared to older pts. TNBC pts experienced a shorter median time to recurrence and the highest mortality rate regardless of age, compared to HER2+ and luminal HER2- pts, indicating the need for targeted interventions in this subgroup. Citation Format: Sara López-Tarruella, Angel Guerrero, Isabel Álvarez, Silvia Antolin Novoa, Ariadna Tibau, Josefina Cruz, César A Rodríguez, Purificación Martínez, J. Ignacio Chacón, María Hernández, Mireia Margelí, Encarna Adrover, Catalina Falo, Iria González, Álvaro Rodríguez-Lescure, María Marín, César Gómez, Juan de la Haba-Rodríguez, J. José Illaramendi, Raquel Andrés, Andrea Blasco, Mª José Escudero, Susana Bezares, Federico Rojo. Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) 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 PO1-16-11.

Abstract PO1-09-11: Racial Differences in Pathologic Complete Response Rate and Overall Survival Following Neoadjuvant Chemotherapy for Breast Cancer

Abstract Background: Neoadjuvant chemotherapy (NAC) is increasingly used in the treatment of breast cancer and has been utilized in multiple clinical trials assessing the efficacy of novel therapies. Pathologic complete response (pCR) following NAC is associated with improved survival outcomes in breast cancer and pCR is a commonly used endpoint in clinical trials. Despite improvements in breast cancer survival using modern treatment regimens, Black women continue to experience worse survival outcomes as compared to White women. The objective of this study was to evaluate the association between race and clinical outcomes, specifically pCR rate, recurrence free survival and overall survival, in patients undergoing neoadjuvant chemotherapy at our institution. Methods: We conducted a retrospective review of patients who completed at least 75% of the recommended cycles of neoadjuvant chemotherapy for breast cancer between 2010 and 2016 and underwent surgery. Receptor subtypes were defined as HR+/HER2-negative, HER2+ or triple-negative. The association between race and pCR, defined as ypT0/ypTis ypN0, and survival endpoints of overall survival and recurrence free survival were analyzed using multivariable logistic regression and Cox proportional hazard models. Results: A total of 532 women met the inclusion criteria, 323 (60.7%) were White, 188 (35.3%) were Black and 21 (3.9%) were other/unknown. Median follow-up was 65 months. The receptor subgroups consisted of 195 (36.7%) HR+/HER2-negative cancers, 193 (36.3%) HER2+ cancers and 144 (27.1%) triple-negative cancers. No significant association between race and receptor subtype (p=0.55) or pre-treatment clinical stage (p=0.96) was observed. The overall observed pCR rate was 19% for Black patients and 27% for White patients, demonstrating a significantly different pCR rate by race in multivariate analysis (odds ratio of pCR White vs Black of 1.75; p=0.02). The largest discrepancy in pCR rate between White and Black patients was within subjects with triple-negative disease (pCR rate 44% White patients vs 27% Black patients, p=0.03). There was no association between recurrence free survival and race in univariate analysis (p=0.15). A significant difference in overall survival by race was observed using multivariable Cox proportions hazard model (hazard ratio Black vs White 1.77; p=0.03). Conclusions: In this retrospective analysis of patients receiving neoadjuvant chemotherapy, Black patients experienced a significantly lower pCR rate compared to White patients, with the biggest gap identified within triple-negative breast cancers. During the study period, Black patients also experienced a lower overall survival rate compared to White patients. Differences in the ability to achieve a pCR may be a contributing factor to the worse survival outcomes of Black patients. Citation Format: Chad Livasy, Erin Donahue, Brittany Neelands, Lejla Hadzikadic-Gusic, Terry Sarantou, Mckenzie Needham, Alicia Patrick, Arielle Heeke, Antoinette Tan, Richard White. Racial Differences in Pathologic Complete Response Rate and Overall Survival Following Neoadjuvant Chemotherapy for 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 PO1-09-11.

Abstract PO5-27-10: Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing

Abstract Background: ADCs have had tremendous impact on patient outcomes in breast cancer and are rapidly moving towards second line use. However, many patients fail to respond or relapse after treatment with ADC therapies due to tumor heterogeneity and resistance to ADC payloads. Method: CatenaBio has developed a novel Multi-Payload-Conjugate (MPC) system capable of attaching distinct payloads at different sites to the same antibody, enabling the production of single-molecule targeted combination therapies with defined DAR. Results: We screened combinations of different payloads targeting several different mechanisms attached to trastuzumab at different drug-antibody ratios to optimize tumor cell killing. These targeted combination ADCs demonstrated robust killing in both HER2 high and low tumor cell lines. Conclusion: Antibody Drug Conjugates have revolutionized the treatment of high HER2 positive breast cancer. More recently advances have been made in the design of ADCs to expand indications to include HER2 low as well as HER2 negative patients. These constructs offer the next step in ADC design and allow for the combination of multiple mechanisms of action in a single MPC that are highly effective across multiple breast cancer cell lines. These molecules offer the potential to circumvent tumor resistance pathways and deliver deeper and more durable responses. Disclosures: Marco Lobba, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Chanez Symister, Andrew Lau, Richard Kendall, and Saurabh Johri are employed by Catena Biosciences. Matthew Francis is a co-founder and advisor to Catena Biosciences. Citation Format: Marco Lobba, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Chanez Symister, Andrew Lau, Richard Kendall, Saurabh Johri, Matthew Francis. Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing [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 PO5-27-10.

Abstract PS13-04: Frequent Intra-Tumoral Hypoxia in Pregnancy-Associated Breast Cancer

Abstract Rationale: Breast cancer is the most common malignancy in pregnant women, occurring in approximately 1:3000 pregnancies. Breast cancer diagnosed during pregnancy or after childbirth is also known as Pregnancy-Associated Breast Cancer (PABC). PABC is known for exhibiting several unfavorable prognostic tumor characteristics, such as an advanced tumor stage at diagnosis, high histologic grade and frequent hormone receptor negativity. Most probably, several interplaying mechanisms may promote the tumor progression and adverse clinical outcome of PABC. One of these mechanisms may be the presence of hypoxia, a relative state of low intra-tumoral oxygen levels which is a known marker of adverse outcome in breast cancer. However, the occurrence and prognostic consequences of the presence of intra-tumoral hypoxia in PABC have not been studied yet. Methods: We constructed a cohort with histopathological, clinical, and outcome data of patients diagnosed with breast cancer during pregnancy (PrBC) or within one year after childbirth (PPBC) in the Netherlands between 1988 and 2022. Next, tissue blocks of all patients were collected from the participating Dutch pathology laboratories. Using H&E stained slides of the tumor tissue blocks, we selected suitable donor sites for a tissue micro array (TMA). Slides from these TMAs were stained for three important hypoxia-associated proteins: glucose transporter-1 (Glut-1), carbonic anhydrase IX (CAIX) and hypoxia-inducible factor-1α (HIF-1α). Expression was scored by an expert breast pathologist blinded by clinicopathologic data. Results: For a total of 195 PrBC and PPBC patients, we were able to assess the expression of Glut-1, CAIX and HIF-1α on tumor cells. Patients had a median age of 33 years at diagnosis, whilst a large majority had a Bloom & Richardson grade III tumor (76%) with frequent hormone receptor negativity (50%). Expression of hypoxia-associated proteins was frequent, with 61% of the tumors expressing Glut-1, 30% expressing CAIX and 56% expressing HIF-1α. In total, 153 (78%) of the tumors expressed at least one of the hypoxia-associated proteins. We observed a significantly worse 5-year overall survival for patients with intra-tumoral hypoxia in comparison to patients without intra-tumoral hypoxia (70% vs. 90%, p=0.046). Conclusions: We show that the presence of intra-tumoral hypoxia in PABC is common, with 78% of tumors expressing at least one of the studied hypoxia-associated proteins. Importantly, patients with tumors overexpressing hypoxia-markers have a significantly worse survival. This shows that intra-tumoral hypoxia may be an important underlying carcinogenic mechanism in PABC, and might be a promising novel therapeutic target in this patient group. Citation Format: Carsten Bakhuis, Carmen Van Dooijeweert, Britt Suelmann, Pieter Westenend, Sabine Linn, Elsken Van der Wall, Paul Van Diest. Frequent Intra-Tumoral Hypoxia in Pregnancy-Associated 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 PS13-04.

Abstract PO3-24-09: May ESR1 mutant breast cancer cells influence fibroblast phenotype?

Abstract For almost 50 years, it has been postulated that carcinogenesis relies on the intrinsic genetic abnormalities of tumor cells, but in the last decades, it has been reported that their functional interactions with the tumor microenvironment (TME) might affect therapy response and contribute to the disease progression. Based on these observations, the aim of the present study was to investigate the functional interactions between one of the essential components of TME, the fibroblasts, and breast cancer (BC) cells, expressing mutations in the hormone-binding domain (HBD) of the gene encoding for the estrogen receptor alpha (ESR1). Thus, we employed estrogen receptor-positive MCF-7 BC cells CRISPR engineered to express the Y537S-HBD mutation. Y537S is the most commonly detected mutation harbored in HBD-ESR1 and is a major contributor to endocrine therapy resistance and poor clinical outcome in BC. We collected conditioned media (CM) from BC cells and fibroblasts isolated from primary human tissues (normal fibroblasts, NFs, and cancer-associated fibroblasts, CAFs) in order to assess in vitro co-culture systems that can mimic the complex in vivo TME. It was interesting to observe that CAFs displayed a significant increase in their proliferation and migration when exposed to CM of mutant BC cells with respect to the parental ones. These latter findings fit with the immunofluorescence analysis showing a more evident formation of actin stress fibers. However, proteomic analysis demonstrated, in the same circumstances, more significant changes in NFs than in CAFs. Among the up-regulated proteins revealed by NFs upon Y537S-CM exposure, most of them overlap the up-regulated proteins featuring the intrinsic phenotype of CAFs, mainly involved in the cellular ultrastructural organization (i.e. cytoskeleton, focal adhesion, vesicle, and organelle) as evidenced by Metacore functional analysis. On the other side, we demonstrated that mutant clones showed more aggressive behavior in terms of proliferation, growth, migration, and invasion, compared to the parental counterpart upon exposure to the CM-derived from NFs and CAFs. This led us to further investigate the intrinsic properties of the mutated clones through their genomic and proteomic profiles that evidenced, by using Metacore software, an enrichment of insulin-like growth factor 1 receptor (IGF1R) pathway. The relevance of the latter datum was confirmed by the higher content of the IGF-1 ligand found in the secretome of mutant cells. Thus, the short autocrine loop maintaining IGF1/IGF1R signaling activation in mutant clones might reasonably play an important role in mediating the autocrine and paracrine effects between mutant cells and fibroblasts. For instance, the pharmacological blockade of IGF1R signaling interfered with the reciprocal interactions between fibroblasts and BC cells that sustained tumor growth and progression as evidenced in both “in vitro” and “in vivo” experiments. In conclusion, our study addressed the IGF1R pathway as a potential druggable target helpful to disconnect mutant breast cancer cell-fibroblast crosstalk that potentiates breast tumor growth and progression. Citation Format: Luca Gelsomino, Amanda Caruso, Rocco Malivindi, Adel Elisabetta Leonetti, Emine Tasan, Salvatore Panza, Giuseppina Daniela Naimo, Ines Barone, Cinzia Giordano, Daniela Bonofiglio, Loredana Mauro, Guowei Gu, Suzanne Fuqua, Stefania Catalano, Sebastiano Andò. May ESR1 mutant breast cancer cells influence fibroblast phenotype? [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 PO3-24-09.

Abstract PO2-11-12: The power of storytelling to heal, build community, and understand the experiences of Black breast cancer survivors

Abstract Background: The BRIDGE community focus group was designed to support and empower current and former Black breast cancer patients. The overarching goals of the focus group were to provide a mechanism for participants to amplify their voices through storytelling, foster healing, and establish a supportive community. Additionally, the research team aimed to gather qualitative data on social support, treatment adherence barriers, interactions with medical providers, and experiences with race and racism within and outside of the healthcare system. Approach: The focus group consisted of six sessions, each with a specific agenda and activities. Participants were encouraged to keep journals throughout the program. Each session began with an icebreaker and journal discussion. Session-specific activities were designed to encourage self-reflection, exploration of personal identities, and discussion of fears. These topics were explored through creative outlets such as role-play, storyboards, and jewelry-making. Each session ended with a unifying affirmation and opportunity for fellowship. Results: We enrolled 10 Black women previously diagnosed with breast cancer and provided a safe space for them to reflect on their breast cancer journey, associated fears, and the role of race in their healthcare experience. Participants discussed positive and negative experiences with healthcare providers, highlighting the knowledge and access gaps that often exist in marginalized communities. The program also provided insights into the multi-level concept of support and its impact on breast cancer outcomes. Participants discussed the positive aspects of familial and community support but identified several areas where system and structural supports may have improved their outcomes. After completing all six sessions, women reported an improvement in their overall self-actualization and purpose—with several describing their time in the program as ‘life-changing’. Notably, the focus group facilitated deep connection and friendship among participants and improved general wellness and satisfaction. Discussion: Through the sharing of personal narratives and supportive discussions, the focus group created a safe environment where participants felt empowered to express their emotions, address challenges, and dismantle fears related to breast cancer mortality. The BRIDGE research team will summarize the themes that emerged across sessions to share with scientific, clinical, and community stakeholders. In parallel, they will explore opportunities for continued community building and support for participants beyond the focus group sessions. Overall, this storytelling focus group showcased the significance of amplifying the voices of historically marginalized groups, providing support, and fostering community. The insights gained have the potential to inform future interventions and support services for Black breast cancer survivors, addressing their unique needs and challenges and ultimately improving cancer health equity. Citation Format: Lauren McCullough, Cynthia Young, Chava Bowden, Madison Gardner, Breanna Berry, Alexix Smith, Jacquelyn Anthony Bryant. The power of storytelling to heal, build community, and understand the experiences of Black breast cancer survivors [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 PO2-11-12.

Abstract PO4-19-12: Trial in progress: An Observational Study to Examine Changes in Metabolic Syndrome Components in Patients With Breast Cancer Receiving (Neo)Adjuvant Aromatase Inhibitors

Abstract Background: (Neo) adjuvant systemic therapy has been shown to adversely impact metabolic health manifested as weight gain, dyslipidemia, and insulin resistance, which ultimately lead to the development of metabolic syndrome (MetS). MetS increases the risk of development for type 2 diabetes mellitus and cardiovascular disease and is associated with an increased risk of breast cancer recurrence, death due to breast cancer, and all-cause mortality. We have previously reported that 76% of metabolically healthy women receiving (neo) adjuvant chemotherapy will develop MetS at a median of 15 weeks. The impact of aromatase inhibitors (AIs) on metabolic health has not been systematically assessed in a longitudinal study. We hypothesize that AIs in the (neo) adjuvant setting will alter metabolic parameters and have embarked on a clinical trial to study this. Methods: This is a prospective observational study that will include: postmenopausal patients with newly diagnosed, early-stage hormone receptor (HR)-positive breast cancer with planned (neo)adjuvant treatment with an AI. Participants will be excluded if they have received or have planned treatment with (neo)adjuvant chemotherapy or are currently receiving antidiabetic medications or cholesterol-lowering agents. All patients will undergo a baseline assessment that includes: BMI, physical exam inclusive of blood pressure, waist circumference, assessment of body fat, lipid profile, insulin, metabolic biomarkers, and completion of the Functional Assessment of Cancer Therapy – Endocrine Symptoms (FACT-ES). Following institution of an AI, reassessment of the aforementioned tests will be repeated after 4 months and 12 months of therapy. The primary endpoint is the change in insulin resistance (as measured by HOMA-IR, homeostatic model assessment for insulin resistance) at 4 months. Secondary endpoints include the change in HOMA-IR at 12 months and the change in individual MetS components, metabolic biomarkers, anthropometric measurements, as well as FACT-ES scores from baseline to 4- and 12-months of AI treatment. The mean paired differences will be calculated for HOMA-IR measurements as well as for the secondary endpoints, and the 1-sided paired t-test will be used to test for statistical significance. One-way analysis of covariance will be used to compare means while adjusting for age, race/ethnicity, and BMI. Using a 1-sided paired t-test for the mean difference in HOMA-IR measurements from baseline to 4 months, we will have 80% power to detect an effect size of 0.405 with 40 patients (α = 0.05). Enrollment began in April 2023 and is ongoing. Contact alevee@coh.org for more information. Given the increased recognition of the importance of metabolic health in breast cancer outcomes, this data will inform future trials that focus on maintaining metabolic health in breast cancer survivors. Citation Format: Alexis LeVee, Nora Ruel, Victoria Seewaldt, Joanne Mortimer. Trial in progress: An Observational Study to Examine Changes in Metabolic Syndrome Components in Patients With Breast Cancer Receiving (Neo)Adjuvant Aromatase Inhibitors [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 PO4-19-12.

Abstract PO5-10-06: A Pilot Study for Clinical Research Nurse Navigation at an Urban NCI-Designated Comprehensive Cancer Center

Abstract Background: Breast cancer is now the leading cause of cancer death for non-Hispanic Black women in Georgia with non-Hispanic Black women 40% more likely to die of breast cancer compared to White women. Inadequate representation of patients in clinical trials may contribute to health care inequity, though prior work has also shown disparate outcomes on similar clinical trials at Emory, suggesting differences in tumor biology may also be contributing to the disparity. Improving diversity in trial participation is imperative to better understand these differences, particularly with newer molecularly targeted therapies. We aimed to utilize Clinical Trials Nurse Navigation to increase clinical trial enrollment at an urban NCI-designated comprehensive care center in Atlanta, Georgia. Methods: A prospective pilot study was conducted investigating the role of a Clinical Research Nurse as a dedicated Clinical Trials Nurse Navigator to identify, pre-screen, and refer potential patients to both breast and next generation sequencing (NGS)-driven basket clinical trials at the Winship Cancer Institute at Emory University. The role also included centralizing all molecular data from patients with stage IV breast cancer into a database as a tool to refer patients to NGS-driven clinical trials. This role expands upon the Institute’s current research nursing scope to better meet the needs of our diverse patient population. Our catchment area is 35% non-Hispanic Black or African American. The nurse prescreened patients with stage IV breast cancer from breast oncology clinic templates and the breast NGS database to match them with clinical trials, with a particular emphasis on patients with stage IV triple negative breast cancer. The study began in January 2022 and is currently ongoing. Results: Since study initiation in January 2022, there has been a 27% increase in breast cancer clinical trial enrollment over a 12-month period. Over the last 6 months from January 2023, this has increased even further with 57 patients enrolled onto breast cancer clinical trials compared to a total enrollment of 70 patients onto breast cancer clinical trials in 2022 (Table 1). Of these patients, 11% enrolled in NGS-driven clinical trials in 2022 to present compared to 0% in 2021. Twenty-two (31.4%) non-Hispanic Black women enrolled onto breast cancer clinical trials in 2022 with another 21 (36.8%) non-Hispanic Black women enrolled thus far in 2023 (Table 1). Conclusion: Disparities in clinical trial enrollment may contribute to racial inequities in breast cancer outcomes. Implementation of clinical research nurse navigation has successfully improved clinical trial enrollment and diversity in clinical trial enrollment at our urban cancer center. Through increasing clinical trial prescreening, centralizing an NGS database, and dedicated nurse support to allow patients to navigate onto clinical trials, we achieved a 21% improvement in clinical trial enrollment from 2021 to 2022 and are on track to increase enrollment by 200% by the end of 2023. Clinical trials nurse navigators serve as an essential link between clinical trial patients and their providers, and should strongly be considered a key component of all clinical trials programs. Table 1 Breast Working Group Patient Enrollment by Race and Ethnicity, 2019-2023 Citation Format: Lizzie Huckaby, Maisey Ratcliffe, Madison Canning, Demetria Smith-Graziani, Kevin Kalinsky, Manali Bhave. A Pilot Study for Clinical Research Nurse Navigation at an Urban NCI-Designated Comprehensive Cancer Center [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-10-06.

Abstract PO1-09-05: Reversing Rural Disparity Through Increased Access to Breast Care Using Model of Academic-Community Collaboration

Abstract Background: Rural disparity in Breast Cancer (BC) often relates to poor geographic access. We are small county in rural North Carolina with historically poor outcomes, including more advanced stages of BC at presentation, higher mastectomy rates, and higher BC-specific mortality rates than elsewhere. Beginning in 2002 we increased access to care by construction of a 19-bed Critical Access Hospital. With a higher median age population (10 years older), and cancer as the number one cause of death (30% of all deaths), we began to increase access to services with focus on cancer. Two decades later, we still do not provide all aspects of care locally, but through a model of collaboration we have increased access to all aspects of cancer care. Breast Cancer is the most common, and this report details the reversal in disparity seen rurally based on our model of collaboration with both a regional community cancer program and academic cancer program. Methods: We partnered with academic and community cancer centers in nearby counties to increase access to imaging, cancer specialists, radiation therapy and chemotherapy services, and support services for breast care. When we could not provide these services locally, we helped navigate patients to these other facilities to improve access. We invited dedicated breast surgeon from community cancer program to attend clinic weekly in our area. We created virtual breast-specific tumor boards to discuss 100% of cases prospectively, with improved access to pathologists, geneticists, fellowship-trained imaging specialists, breast surgeons and other multi-disciplinary care members (reconstructive surgery, PT/OT, integrative medicine, GYN). We became cancer accredited with both COC and NAPBC. We compare metrics pre/post-improvements. Results: Baseline: 1. Mortality rates: (2002-2006) 5-year BC mortality rates in our region averaged 32.3/100,000 population which was in the top quartile for the state, 30% higher than the state average. 2. Stages at presentation: 47% of BC stages were early (stages 0/1) in our service region compared to 62% elsewhere (NCDB data). Stage IV represented 6% in our region versus 4% elsewhere. 2500 mammograms/year at hospital at baseline. 3. Surgery/Radiation Therapy: Mastectomy rates averaged >50% in region, with correspondingly lower breast conserving rates than elsewhere due to lack of access to breast surgeons and radiation therapy services locally. Closest RT facility 80 miles. 4. Distances to high quality breast care averaged 150 miles. Closest Academic/Community Cancer Program 2-hour drive (one way). Post Collaboration: 1. Mortality rates: (2015-2019), 5-year BC mortality rates in our region averaged 16.3/100,000 population which is in the lowest quartile, 20% lower than the state average. 2. Stages at presentation: 74% of BC stages are early (stages 0/I) in our region versus 68% elsewhere. Stage IV now below parity with 3% locally versus 4% nationally. More than 5100 mammograms/year done currently at local hospital. 3. Surgery/Radiation Therapy: Mastectomy rates average 21%, with partial mastectomy rates of 79% in our area versus 70% elsewhere (NAPBC data) with RT services available locally. 4. Distances to quality breast care average 20 miles, and we are nationally accredited program in breast care as a critical access hospital. Analytic case load is now triple baseline numbers. Conclusion: We reversed the trend in rural disparity in breast cancer outcomes through model of collaboration. We increased screening rates locally, doubling the number of screening/diagnostic exams, increased the percentage of early stage at diagnosis, halved our mastectomy rates, and reduced BC-specific mortality 50% relative to baseline (and now 20% lower than state). We are now at parity with most BC-specific quality metrics reflecting a huge shift in rural disparity, which could only be achieved rurally through collaboration. Reversing Rural Disparity Through Increased Access to Breast Care Using Model of Academic-Community Collaboration This table depicts the changes in our region over time, which have brought us to parity with Breast Care nationally. Citation Format: Charles Shelton, Antonio Ruiz. Reversing Rural Disparity Through Increased Access to Breast Care Using Model of Academic-Community Collaboration [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 PO1-09-05.

Abstract PO5-04-12: Comparison of chemotherapy efficacy in metastatic lobular vs. ductal breast cancer

Abstract Comparison of chemotherapy efficacy in metastatic lobular vs. ductal breast cancer Background: Invasive lobular carcinomas (ILC) are thought to be less chemo-sensitive than invasive ductal carcinomas (IDC), as reflected by lower rates of pathological complete response following neoadjuvant therapy. In the metastatic setting, evidence regarding chemotherapy (Cx) efficacy is limited. Methods: A retrospective review of prospectively collected data for consecutive patients (pts) with metastatic ILC (mILC) treated at a single institution between 2000 and 2023 was included. Pts with mILC were matched on a 1:2 ratio with a cohort of pts with metastatic IDC (mIDC) by age, era of diagnosis and initial metastatic burden. Primary outcome was efficacy of Cx in mILC vs. mIDC pts as measured by time to next treatment - TTNTc (months (m) between start date of first & second Cx). Key secondary endpoints included differences in efficacy of endocrine therapy between the two groups (as measured by TTNT and outcomes in pts with endocrine resistance (EnR) as defined by ESMO consensus guideline) and overall survival (time from diagnosis of metastatic breast cancer (BC) to death or last follow-up [OS]). Results: 376 pts were included, mILC (122) and mIDC (254) with median age 64y and 62y, respectively. A significantly higher proportion of mILC pts had hormone receptor positive/HER2 negative or lower proportion of triple negative disease (p< 0.0001). Compared to mIDC, mILC pts were more likely to have de novo disease (29% vs. 18%; p=0.02), lower grade (p< 0.0001), received endocrine therapy only (p=0.03) and were less likely to have visceral disease at diagnosis or any time after metastatic diagnosis (20% vs. 45% p< 0.0001, 35% vs. 51% < 0.0004, respectively). Median time to commencing chemotherapy from metastatic diagnosis was longer in mILC pts (5.8 v 2.0 m, p=0.03). There was no significant differences in TTNTc for patients with mILC and mIDC except for those with visceral disease at diagnosis (Table 1). There was no significant difference in TTNTc by histological subtype of mILC (p=0.46) or by choice of first line chemotherapy used (p=0.91). In the entire population, no significant OS difference observed in mILC and mIDC (Table 1). BC outcome was assessed in pts receiving endocrine therapy as first-line treatment (mILC 65, mIDC 102). There was no difference in TTNT (mILC 14.6m vs. mIDC 14.8m). There were no differences in incidence of EnR between the groups. OS was shorter in mILC pts with primary EnR. The presence of primary, secondary or no resistance within each histological group was significantly associated with OS (Table 1). Conclusion: Pts with mILC have a longer time to commencing chemotherapy, but efficacy of chemotherapy is similar to pts with mIDC; irrespective of lobular histologic subtype, first line chemotherapy regimen used and sites of disease, except for those mILC with visceral disease. There was no significant difference in OS between mILC and mIDC pts treated in this single centre study. Efficacy of endocrine treatment when given as first line treatment was similar in both groups with no significant difference when pts were evaluated by presence or absence of endocrine resistance, except for primary EnR, but pt numbers were small in this group. Our results demonstrate equivalent chemotherapy efficacy in pts with mILC as compared to mIDC.

Abstract PO4-09-06: Area Deprivation Index (ADI) among Patients with Breast Cancer in Buffalo

Abstract Introduction: Socioeconomic and racial disparities can limit access to health care. Prior studies suggest that living in a disadvantaged neighborhood results in poorer outcomes in several malignancies. ADI is an index that categorizes areas based on socioeconomic variables. In this observational study, we aimed to investigate the ADI among patients (pts) with breast cancer (BC) seen at Roswell Park Comprehensive Cancer Center in Buffalo, New York, and study its association with clinical outcomes to identify the areas with the highest unmet need for possible intervention strategies. Methods: We reviewed data of 187 pts diagnosed with stages 1-3 and de-novo stage 4 BC between 2014 to 2018. We obtained information on ADI using pts’ home addresses via Neighborhood Atlas tool www.neighborhoodatlas.medicine.wisc.edu. ADI values were categorized into four quartiles Q1(80-100%), Q2(60-79%), Q3(40- 59%), and Q4(0-39%) from highest deprivation/poor social economic status areas to least disadvantaged areas, respectively. Demographic and clinicopathological characteristics including age, race, comorbidities, stage, type of insurance, duration on treatment were compared by ADI. Kruskal-Wallis and Chi-square was used for comparing continuous and categorical variables, respectively. Recurrence free survival (RFS), time to next treatment (TNT), and overall survival (OS) were estimated using Kaplan Meier method. Multivariate Cox regression model was used to analyze outcomes for pts with stage 4 in the most disadvantaged areas (ADI ≥60%) adjusting for relevant covariates. Analyses were performed using SAS v9.4 at a significance level of < 0.05. Results: 98% pts (183/187) were females, 85% (160/187) Whites, 9% (17/187) African Americans, and 3% (6/187) Asians. 62% (116/187) lived in the most disadvantaged areas: 37% (70/187) in Q1, and 24% (46/187) in Q2, while 27% (51/187) lived in Q3, and 11% (n=20/187) in Q4. 80% (150/187) pts were diagnosed with hormone receptor positive BC, 18% (34/187) HER2 positive, and 15% (28/187) triple negative BC. 45% of pts (83/187) had de novo stage 4, the rest were diagnosed with stages 1-3. There was no difference in the distribution of age, race, employment, insurance, comorbidities, substance use, smoking, access to contraception, screening mammogram, or adherence to anti-estrogen and radiation therapy by ADI. There was a significant difference in adherence to chemotherapy/anti HER2 therapy: 92% (36/39) in Q1,100% (24/24) in Q2 vs. 85% (24/28) in Q3 and 67% (6/9) in Q4, p=0.029. Among pts with stages 1-3, there was no difference in RFS (p= 0.700) or OS (p= 0.400) by ADI. Among stage 4 patients, there was an association between TNT and ADI, where patients living where there was a trend towards worse survival with increasingly disadvantaged neighborhoods, p=0.008 (Table 1). Moreover, there was a significant difference in OS by ADI, p=0.03 (Table 2). There was a significant association between ADI and both TNT and OS, even after adjusting to age, race, BC subtypes p= 0.004 and p= 0.034 respectively (Table 3). Conclusion: Our study in the Western New York region showed that BC pts living in disadvantaged areas had worse survival and shorter TNT despite being more adherent to chemotherapy/anti HER2 therapy. Our study validates prior studies showing that ADI is an important factor impacting BC outcomes. These data will help guide our future efforts to maximize resource allocation towards these disadvantaged areas to improve BC outcomes. Table 1 Table 2 Table 3 Citation Format: Malak Alharbi, Arya Mariam Roy, Archit Patel, Kayla Catalfamo, Kristopher Attwood, Angela Omilian, Elizabeth Bouchard, Ellis Levine, Tracey O'Connor, Amy Early, Shipra Gandhi. Area Deprivation Index (ADI) among Patients with Breast Cancer in Buffalo [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 PO4-09-06.

Abstract PS09-01: Individual patient data meta-analysis of clinical and translational biomarkers for prediction of pathological complete response (pCR) after de-escalated therapy in HER2+ breast cancer in four trials of the West German Study Group

Abstract Background Introduction of anti-HER2 therapies substantially improved outcomes for HER2-positive early breast cancer (HER2+ eBC). However, a considerable proportion of patients (pts) may still be overtreated with systemic chemotherapy (CTx) combinations. Establishing safe de-escalation strategies to avoid toxicities requires precise patient selection. Therefore, we set out to determine predictors for efficacy and survival in the unique setting of four de-escalation trials investigating short (12-week) neoadjuvant treatments (NAT) in HER2+ eBC. We investigated the prognostic ability of clinical and translational biomarkers for pCR to identify pts with the best prognosis after de-escalated systemic CTx-free NAT. Methods 756 pts who received de-escalated NAT were analyzed: trastuzumab + pertuzumab (T + P, n=92) and T + P + paclitaxel (pac, n=42) in ADAPT-HR-/HER2+ (NCT01817452); trastuzumab emtansine (T-DM1, n=118), T-DM1 + endocrine therapy (ET, n=125), and T + ET (n=129) in ADAPT-HR+/HER2+ (NCT01779206), T + P + pac (n=107) and T + P + ET (n=100) in TP-II (NCT03272477); and T + P + pembrolizumab (n=43) in Keyriched-1 (NCT03988036) in HER2-enriched (HER2-E) subtype by PAM50. The primary endpoint of each trial was pCR (ypT0/is ypN0). Survival was a secondary endpoint in all trials but Keyriched-1; survival data for TP-II are pending. Baseline gene expression was analyzed by BC360 assay; intrinsic molecular subtypes were determined using the PAM50 predictor. Stromal tumor infiltrating lymphocytes (sTILs) were evaluated at baseline and at week 3 of NAT. sTILs were categorized using a 30% threshold and the low cellularity category ( < 500 invasive tumor cells) at week 3. Prognostic markers for pCR were identified with univariate and multivariable logistic regression models with backstep algorithm excluding variables with p≥0.1; considered variables included age, sTILs (baseline, 3-weeks), cT, cN, grade, hormone receptor and HER2 status, intrinsic subtype, and standardized ERBB2 and ESR1 gene expression. These analyses were performed separately for NAT involving systemic CTx (i.e. containing pac, n=149) and systemic CTx-free NAT (n=607). Results Overall pCR rate was 39.1% (CTx: 66.4%; CTx-free: 32.5%). Multivariable analysis identified predictors of pCR after CTx-free NAT: low cellularity at week 3 (vs < 30% sTILs: OR 3.21, 95%CI 1.85-5.57), ERBB2 (OR 1.90, 95%CI 1.41-2.55), HER2 3+ (vs 1+/2+ and ISH+: OR 8.01, 95%CI 1.65-38.99), LumA/LumB/Basal subtype (vs HER2-E: OR 0.57, 95%CI 0.34-0.97), cT2 (vs 1: OR 0.54, 95%CI 0.33-0.89), and cN1-3 (vs 0, OR 0.46, 95%CI 0.27-0.78). In CTx-containing NAT, only ERBB2 (OR 2.08, 95%CI 1.28-3.40) and additionally ESR1 (OR 0.38, 95%CI 0.23-0.61) were prognostic for pCR. Updated analysis including expanded gene expression data from ADAPT-HR+/HER2+ and a prognostic score for pCR after CTx-free NAT developed using machine learning methods will be presented at the meeting. Conclusions This pooled analysis demonstrated a 66% pCR rate after a short (12-week) de-escalated NAT in HER2+ eBC. In one-third of patients (with mainly stage I cancer, higher HER2 expression by immunohistochemistry and gene expression analysis, and low cellularity at 3 weeks), pCR can be achieved without systemic CTx. Identified biomarkers could pave the way for developing new patient selection strategies to spare CTx-associated acute and late toxicities in a clinically meaningful number of patients. Citation Format: Monika Graeser, Oleg Gluz, Christine zu Eulenburg, Sherko Küemmel, Raquel von Schumann, Matthias Christgen, Rachel Wuerstlein, Enrico Pelz, Hans-Heinrich Kreipe, Peter Schmid, Marc Thill, Michael Braun, Jochem Potenberg, Claudia Schumacher, Joke Tio, Andreas Hartkopf, Marianne Just, Christian Schem, Kerstin Lüdtke-Heckenkamp, Eva-Maria Grischke, Felix Hilpert, Angela Kentsch, Ronald Kates, Ulrike Nitz, Nadia Harbeck. Individual patient data meta-analysis of clinical and translational biomarkers for prediction of pathological complete response (pCR) after de-escalated therapy in HER2+ breast cancer in four trials of the West German Study Group [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 PS09-01.

Abstract PO3-06-14: Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer

Abstract Background: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). This trial evaluated the efficacy of pembrolizumab in combination with binimetinib, a MEK inhibitor. Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were enrolled. Treatment includes a 2-week run-in with binimetinib followed by pembrolizumab. There were 2 dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1. A standard 3+3 design was used in Phase I, and Simon’s two-stage Optimal design was used in Phase II. PD-L1 22C3 was performed in archival samples with CPS ≥ 10 considered as positive (PD-L1+). Tumor-infiltrating lymphocytes (TILs) were quantified into 0, 1, 2, and 3+. Circulating tumor cells (CTC) and circulating cancer-associated macrophage-like cells (CAML) were isolated using CellSieve microfilters and immunofluorescently labeled with PD-L1 and p-ERK. Wilcoxon rank sum test, Chi-square test, Cox regression model, and Spearman correlation were used for analysis. Results: 22 patients were enrolled with a median age of 58 years old. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0, with grade 3 ALT abnormality, flank pain, and nausea. In the next 6 patients in DL -1, there was 1 DLT with grade 3 AST/ALT abnormality. There were 17 patients treated with DL -1 and were evaluable for response. The objective response rate (ORR) was 29.41% (95% CI: 10.31-55.9) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR ≥ 24 weeks) was 35.29% (95% CI: 14.21-61.67). ORR in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30) and CBR was 66.67% (95% CI: 29.93-92.51). No response was observed in all 5 patients with liver metastases. There were 40.9% of patients with PD-L1 CPS ≥ 10. ORR in patients with PD-L1+ was 80%. However, 11.1% of patients with PD-L1 negative tumors also had an objective response and 44.4% of patients had clinical benefit ≥ 24 weeks. PD-L1 expression in archival tissue was associated with ORR (p 0.032) but not CBR (p 0.198), progression-free survival (PFS, p 0.373), and overall survival (p 0.348). TILs in archival tissue were also not associated with CBR (p 0.155) and PFS (p 0.157). One patient with TILs 0 had a stable disease ≥ 24 weeks and 2 patients TILs 1+ also had an objective response. We further evaluated blood-based biomarkers with CTC and CAML. Baseline PD-L1 in CAML (p 0.04) and decline in CAML size (p 0.02) after 1 cycle was significantly associated with CBR. However, baseline CTC count, CAML count (p 0.64), CAML size (p 0.46), p-ERK in CAML (p 0.23), and changes in CTC count, CAML count (p 0.83), p-ERK (p 0.07), and PD-L1 (p 0.08) in CAML were not significantly associated with responses. Using Cox regression analysis, a reduction in CAML count (p 0.02), CAML size (p 0.01), and PD-L1 in CAML (p 0.03) were associated with significant improvement in overall survival but not the reduction in p-ERK (p 0.6). However, PD-L1 expression in CAML is not associated with PD-L1 expression in archival tissue (Spearman correlation 0.13). Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Consistent with the preclinical data that MEKi can restore T cell function, promising activity was observed even in patients with low TILs and PD-L1 negative, particularly in patients without liver metastases. PD-L1 expression in peripheral blood CAML rather than archival tumor tissue may serve as a better biomarker to predict the clinical benefit of this combination. Early reductions in CAML count and size, were also significantly associated with responses. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination. Citation Format: Saranya Chumsri, Joseph Larson, Daniel Adams, Kathleen Tenner, Cha-Mei Tang, Morgan Weidner, Amanda Arnold, Dana Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Edith Perez, Keith Knutson. Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-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 PO3-06-14.

Abstract PO1-07-04: Multiomics analysis reveals the landscape of PD-L1 expression in triple-negative breast cancer

Abstract Background: Tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) remain controversial in predicting clinical outcomes of triple-negative breast cancer (TNBC), as outcomes do not always correlate with the expression of these biomarkers. Genomic and transcriptomic alterations that might contribute to the expression of these biomarkers remain incompletely uncovered. Methods: We evaluated PD-L1 immunohistochemistry (IHC) scores (SP142 and 28-8) and TILs in our TNBC multiomics dataset and two immunotherapy clinical trial cohorts. Then, we analyzed genomic and transcriptomic alterations correlated with TILs, PD-L1 expression and patient outcomes. Results: Despite TILs serving as a decent predictor for TNBC clinical outcomes, there remained exceptions. Our study revealed that several genomic alterations were correlated with unexpected events. Particularly, PD-L1 expression may cause a paradoxical relationship between TILs and prognosis in certain patients. Consequently, we classified TNBCs into four groups based on PD-L1 and TIL levels. The TIL-PD-L1+ and TIL+PD-L1- groups were not typical “hot” tumors; both were associated with worse prognoses and lower immunotherapy efficacy than TIL+PD-L1+ tumors. Copy number variation of PD-L1 and oncogenic signaling activation were correlated with PD-L1 expression in the TIL-PD-L1+ group, whereas GSK3B-induced degradation might cause undetectable PD-L1 expression in the TIL+PD-L1- group. These factors have the potential to affect the predictive function of both PD-L1 and TILs. Conclusions: Several genomic and transcriptomic alterations may cause paradoxical effects among TILs, PD-L1 expression and prognosis in TNBC. Investigating and targeting these factors will advance precision immunotherapy for TNBC patients. Keywords: Triple-negative breast cancer, PD-L1 expression, Tumor-infiltrating lymphocytes, Multiomics, Immunotherapy Citation Format: Han Wang, Xiao-Hong Ding, Cheng-Lin Liu, Yi Xiao, Ruo-Hong Shui, Yan-Ping Li, Chen Chen, Wen-Tao Yang, Zhi-Ming Shao, Yi-Zhou Jiang. Multiomics analysis reveals the landscape of PD-L1 expression in triple-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 PO1-07-04.

Abstract PS16-06: Tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: A single-center real-world study

Abstract Background Previous studies have presented compelling evidence suggesting that the inclusion of platinum agents alongside anthracyclines and taxanes could potentially enhance treatment outcomes in high-risk triple-negative breast cancer (TNBC). Moreover, pembrolizumab has been integrated into clinical practice as a part of standard-of-care for non-metastatic TNBC with high risk. In light of these findings, we undertook a real-world study to investigate the impact of incorporating platinum agents and pembrolizumab on achieving pathologic complete response (pCR) in TNBC patients undergoing neoadjuvant chemotherapy (NAC). Furthermore, we specifically examined the influence of tumor-infiltrating lymphocytes (TILs) on the treatment outcomes. Patients and Methods In this real-world study conducted at Gangnam Severance Hospital, Seoul, Republic of Korea, we analyzed a cohort of 398 patients with TNBC who underwent surgery following NAC between March 2007 and November 2022. Among them, 247 patients received an anthracycline-taxanes (A-T), 120 received a carboplatin regimen including A-T, and 31 received a pembrolizumab regimen including A-T-carboplatin as part of their neoadjuvant chemotherapy treatment. TIL was evaluated in biopsied samples prior to NAC according to the guideline of TIL international working group. The high TIL was defined with a cutoff of 50%. Results Among the 398 patients analyzed, 87 (21.9%) had high TIL tumors. The pCR rates were 32% in the anthracycline-taxane (A-T) regimen group, 57% in the A-T-carboplatin regimen group, and 68% in the pembrolizumab with A-T-carboplatin regimen group. Within the high TIL group, the pCR rate did not increase with the addition of carboplatin (51.8% in the A-T group and 41.7% in the A-T-carboplatin group), but reached 85.7% with the addition of pembrolizumab and carboplatin. Among the low TIL group, the pCR rate increased from 26.7% to 61.1% with the addition of carboplatin, but there was no difference in the pCR rate between the carboplatin and pembrolizumab groups (61.1% and 60.9%, respectively). In clinically node-positive patients, the pCR rate significantly increased with pembrolizumab in the high TIL group (40.9% versus 100%, p=0.035). However, in low TIL patients, the addition of carboplatin alone significantly increased the pCR rate to 62.3%, whereas the addition of pembrolizumab did not show the same effect. Conclusions Our real-world data consistently demonstrates an increased pCR rate with the addition of carboplatin and pembrolizumab. Among patients with high TIL, the addition of carboplatin did not result in an elevated pCR rate. However, the addition of pembrolizumab tended to maximize the pCR rate, surpassing 80%. On the other hand, among patients with low TIL, the addition of carboplatin significantly increased the pCR rate, while the addition of pembrolizumab did not have the same effect. Efforts should be made to improve the response to pembrolizumab-containing regimens for patients with low baseline TIL levels. Citation Format: Min Ji Kim, Yoonwon Kook, Seung Ho Baek, Junghyun Kim, Sohyun Moon, Seung Eun Lee, Jee Hung Kim, Soong June Bae, Sung Gwe Ahn, Joon Jeong. Tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: A single-center real-world 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 PS16-06.

Abstract PO5-02-10: Favorable effect of HER2-low expression on prognosis for breast cancers after neoadjuvant chemotherapy

Abstract [Background] The clinicopathological characteristics, pathological complete response and survival outcomes of HER2-low, HER2-zero and HER2-positive breast cancers are yet to be elucidated in Chinese patients especially those administered neoadjuvant chemotherapy. [Methods] We retrospectively identified 259 patients with different HER2 statuses (zero, low and positive) who underwent surgery as planned after neoadjuvant chemotherapy from a prospectively maintained institutional cohort database in Renji Hospital, School of Medicine, Shanghai Jiao Tong University between 2014 and 2019. Overall survival (OS) denoted the time from surgery to death, irrespective of cause. Locoregional relapse-free survival (LRFS) was estimated from surgery to first occurrence of locoregional, ipsilateral relapse, or death, irrespective of cause. We defined pathologic complete response (pCR) as ypT0 ypN0 (absence of cancer in the breast and axillary nodes). The definition of ypT0/is ypN0 (absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ) was evaluated as an additional endpoint. [Results] A total of 89 (34.36%), 66 (25.48%) and 104 (40.16%) HER2-low, HER2-zero and HER2-positive breast cancers were enrolled in this analysis, respectively. The median follow-up interval was 5.74 years. Hormone receptor(HR) expression was numerically more common in HER2-low breast cancers than the other two subgroups (83.15% in HER2-low vs 72.73% in HER2-zero vs 77.88% in HER2-positive, P >0.05). The level of Ki-67 index was significantly lower in the HER2-low tumors than that of HER2-zero tumors (P=0.023). HER2-positive tumors had the highest proportion of histological grade III (P=0.005). The HER2-low breast cancers showed significantly better OS (P=0.0056) and LRFS (P=0.002) than HER2-zero counterparts. Subgroup analysis revealed the similar benefit in LRFS (P=0.018) rather than OS (P=0.055) for patients with HR positive/HER2-negative tumors. When the HER2-positive tumors was combined together for comparison, the OS (P=0.016) and LRFS (P=0.0062) also significantly differed among patients with HER2-low, HER2-zero, and HER2-positive tumors. Additionally, the HR negative patients had analogous OS outcome to the entire population according to different HER2 status (P=0.041). Multivariable Cox-regression analysis and external validation in the TCGA database as well as Kaplan-Meier plotter database supported that HER2-low tumors and HER2-positive tumors treated with HER2-directed therapy may have similar survival outcomes, while HER2-zero peers may have the worst outcome compared with the above two groups. There were no remarkable differences in pCR rates between HER2-low and HER2-zero tumors after neoadjuvant chemotherapy (ypT0ypN0 and ypT0/isypN0, P=0.452 and P=0.777, respectively). HER2-positive tumors had a significantly higher pCR rate, especially compared to HER2-low tumors in the entire population (both P< 0.001) as well as in the HR positive subgroup (both P< 0.0001). The pCR status affected survival outcomes for breast cancers with different HER2 status. As for those without pCR, the HER2-low subgroup showed a remarkably better performance compared with HER2-zero patients in terms of OS (P=0.018) and LRFS (P=0.005), while little difference was found for patients who achieved pCR. [Conclusion] Our study demonstrated that HER2-low breast cancer may be a different entity from HER2-zero or HER2-positive tumors, which provide illuminating evidence in view of patients receiving neoadjuvant treatment. Citation Format: Yingying Zhao, Wenjin Yin, Xinru Chen, Jingsong Lu. Favorable effect of HER2-low expression on prognosis for breast cancers after 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 PO5-02-10.

Abstract PO5-17-12: Impact of HER2-low status on axillary response and surgical management after neoadjuvant chemotherapy in early breast cancer

Abstract Background: Breast cancer (BC) with low expression of HER2 (HER2-low) might constitute a group of tumors with unique clinical and biological characteristics. Little is known about axillary downstaging and nodal surgical outcomes in HER2-low BC after neoadjuvant chemotherapy (NACT). The aim of this study was to evaluate axillary response and surgical management of the axilla in HER2-low BC patients submitted to NACT. Methods: In this cross-sectional single center study, we consecutively included all patients diagnosed with early HER2-negative BC between 2017 to 2021 that were treated with NACT. Patients must have biopsy-confirmed stage II-III BC, submitted to breast surgery after NACT. Clinical and pathological response in the axilla, type of axillary surgery, and surgical outcomes data were collected. HER2-low was defined by IHC score 1+, or 2+ ISH non-amplified; HER2-zero was defined by IHC score 0. Pathological response was determined locally. Results: At diagnosis, 291 patients had clinically involved axillary nodes (cN1: 69.4%; cN2: 25.1%; cN3: 5.5%). Among 136 patients eligible for SLN biopsy after NACT, 77 (26.5%) had pathologically negative SLN. Of those submitted to upfront axillary dissection (n=154), 52 (33.7%) had pN0 disease. In total, 129 (44.3%) patients with clinically involved axillary lymph nodes at diagnosis were converted to cN0 after NACT. There was no difference in the rate of axillary downstaging between HER2-low and HER2-zero tumors, 17.8% vs 26.5%, respectively (p=0.0026). 236 patients were submitted to sentinel lymph node biopsy (SLN), of whom 214 (81.4%) with blue dye-only, 40 (15.2%) with radioactive isotope, and 7 (2.7%) with dual tracer. SLN detection failure were reported for 12 patients (0.046%). Mean number of lymph nodes retrieved were 2.7. Most patients had a negative SLN biopsy (180/263; 68.4%), of whom 91 (50.6%) were HER2-low and 89 (49.4%) were HER2-zero. Positive SLN biopsy were reported in 83 patients (isolated tumor cells: 20,5%; micrometastasis: 24.1%; macrometastasis: 55.4%), with capsular extravasation in 25.3%. A positive SLN biopsy occurred in 61.4% of patients with HER2-low tumors, and in 38.5% of patients with HER2-zero tumors. Among patients with a positive SLN biopsy (n=83), 67 were submitted to axillary dissection, of whom 39 (58.2%) had no additional nodes involved (HER2-low: 61.5%; HER2-zero: 38.4%). Considering N0 tumors at diagnosis, 127 patients were submitted to SNL, and only 18.9% had a positive result (HER2-low: 66.6%; HER2-zero: 33.3%). In the subgroup of initially cN+ disease, 136 (46.7%) underwent SLN biopsy, with 59 (43.4%) with a positive result (HER2-low: 59.3%; HER2-zero: 40.7%). Conclusions: Our results showed that HER2-low BC patients had a statistically significant lower frequency of axillary downstaging after NACT. More than 40% of patients with cN+ at diagnosis were downstaged to cN0 and were submitted to SNL biopsy. Axillary dissection were avoided in roughly 25% of patients with cN+ BC at initial staging. Citation Format: Leonardo Roberto da Silva, Guilherme Sartori, Susana Ramalho, Tomás Reinert, Mahira Lopes Da Rosa, Grazielle Morais Tavares, Higor Mantovani, Vivian Vasconcelos, Ana Elisa Ribeiro Da Silva Cabello, Guilherme Coelho, Jovana Mandelli, Facundo Zaffaroni, Carlos Barrios, Marcia Silveira Graudenz, César Cabello. Impact of HER2-low status on axillary response and surgical management after neoadjuvant chemotherapy in early 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 PO5-17-12.

Abstract PO4-02-09: Clinical outcomes of neoadjuvant chemotherapy in HER2-low early breast cancer

Abstract BACKGROUND: According to immunohistochemistry (IHC) expression of HER2 receptor, breast cancer (BC) can be classified as either IHC score 0, 1+, 2+ or 3+. Until recently, two distinct BC subtypes were recognized depending on the HER2 IHC expression and in situ hybridization (ISH) score: HER2 positive (IHC 3+ or IHC 2+ ISH-amplified) and HER2 negative (IHC 0, 1+ or 2+ ISH negative). More recently a new BC entity termed HER2-low was acknowledged, defined as either HER2 IHC 1+ or 2+ ISH-negative. Given that no treatment benefit was observed in HER2-low group of patients in the pivotal trastuzumab studies, many years had to pass before the discovery of antibody-drug conjugates such as trastuzumab deruxtecan, that led to a significant improvement in the clinical outcome of HER2-low BC, compared to standard therapy options. It is still debated whether HER2-low BC represents a distinct biological subtype. The aim of this study was to determine whether there is an impact of HER2-low status on the effect of neoadjuvant chemotherapy (NACT) and its primary indicator - the rate of the pathologic complete response (pCR). METHODS: A retrospective study of 363 BC cases who received NACT between January 2020 and December 2022 at University Hospital Centre Zagreb, Croatia, was conducted with prior Ethics Committee approval. Histopathological characteristics of tumours available from the hospital information system (BIS), including hormone receptor status (ER, PR), HER2 status and Ki-67 at the time of diagnosis and after neoadjuvant treatment, as well as pCR rates, were analysed. pCR rates were calculated for HER2-low and HER2 0 cases. Chi square test was used to analyse association between pCR rate and HER2 status. RESULTS: After exclusion of HER2 positive BC cases, as well as cases with missing data, a total of 215 patients were included in the analysis. Of those, 101 (47%) were HER2-low, and 114 (53%) were HER2 negative. The majority of patients (N=151, 70.2%) had luminal BC, while 64 (29.8%) patients had triple negative BC (TNBC). In the luminal group, 86 cases (57%) were HER2-low, and 65 (43%) were HER2 0. In the TNBC group, 15 cases (23.4%) were HER2-low and 49 (76.6%) were HER2 0. The rate of pCR among luminal subtypes was 6.2% for HER2-low tumours, and 15.4% for HER2 0 tumours (p=.051559), approaching statistical significance. In the TNBC group, the pCR rate for HER2-low group was 60%, compared to 40% in the HER2 0 group, trending towards, but not reaching statistical significance (p=.191564). CONCLUSION: A trend toward higher pCR rates after neoadjuvant chemotherapy was observed in the luminal HER2 0 group compared to HER2-low luminal BC, almost reaching statistical significance. Interestingly, in TNBC there was a trend towards higher pCR rates among the HER2-low group, although a small number of patients precludes any definitive conclusions. Further trials that include novel targeted therapies are needed, as that might lead to significant changes in therapeutic approach, as well as clinical outcome of HER2-low BC patients. Citation Format: Dora Gudelj, Katarina Čular, Lea Toula, Marija Križić, Marina Popović, Natalija Dedić Plavetić, Ana Kelečić, Gordana Ivanac, Majana Soče, Iva Kukal Gjergjaj, Tajana Silovski. Clinical outcomes of neoadjuvant chemotherapy in HER2-low early 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 PO4-02-09.

Abstract PO2-17-09: Overall survival differences between HER2 Low and other breast cancer subtypes in a reference center in Brazil

Abstract Background: Breast cancer (BC) is a heterogeneous disease, and its subtypes have different prognosis and diverse responses to endocrine therapy and chemotherapy. In clinical practice, immunohistochemical markers are often used to classify BC into subtypes according to the presence of hormone receptors, human epidermal growth factor receptor 2 (HER2) and evaluation of proliferation measured by Ki67. Recently, there has been a suggestion for a possible alternative terminology for situations involving IHC 1+ or 2+ with negative ISH, this proposed term is referred to as HER2-low and represents about 50 to 55% of all primary BC. There are relevant gaps regarding the outcomes of HER2-low BC. Considering the new emerging therapies for HER2-low, a better description of the epidemiology, response to treatment and results of this population is extremely relevant. Objective: The purpose of this study was to use real-world data in order to investigate the Brazilian patients with BC treated in a Reference Center and evaluate the survival outcomes in different subtypes identified by molecular immunohistochemistry including HER2-Low and evaluate the survival in subtypes by stage. Methods: This retrospective cohort study included women, age > 18 years with breast cancer treated between 2010 and 2019 at Perola Byington Hospital in the city of São Paulo, Brazil. After the diagnose, the included patients were submitted to an immunohistochemical analysis to identify the subtype of the BC. Institutional Review Board of Pérola Byington Hospital approved the use of patients' data before the beginning of the study, under the reference number CAAE 7238317.6.0000.0069). An informed consent was dismissed, and this study was carried out according to the Declaration of Helsinki, including protection of patients' confidentiality. The primary outcome measure was overall survival (OS), which was defined as the length of time (in months) from the date of diagnosis to the date of death (from any cause). The secondary outcome measure was disease-free survival (DFS), which was defined as the length of time after the end of the primary cancer treatment in which the patient survives without any signs or symptoms of cancer. Continuous variables were summarized using their mean. Qualitative variables were summarized for the general population and by HCI subgroups using counts, percentages, and absolute numbers. The Kaplan-Meier method was used to estimate survival rates and mean survival times in the general population and by groups. All statistical tests were bilateral and p< 0.05 was considered significant. Statistical analyses were performed using the Python programming language version 3.8. Results: Between January 2010 and December 2019, 1,826 women were diagnosed with breast cancer and classified as a HER2-low subtype, among the 9,278 participants included in the study (19,68%). Regarding the OS analysis, patients with the "Luminal A" subtype had better survival (106 months) results when compared with the other subtypes and women with triple negative disease had the worse prognosis with OS of 96 months. The median survival in HER2-low with hormonal receptor positive was 101 months and statistically significant when compared with 90 months in HER2-low hormonal receptor negative (p < 0,01). When looking for stage IV HER2-low and HER2+ have better overall survival rates compared to other subtypes. Conclusion: This real-world data study shows difference in the prevalence of the HER2-low subtype. In addition, there is a difference in OS between tumor subtypes and when evaluating the HER2-low subtype with or without the presence of receptors, this difference is marked. Citation Format: Andre Mattar, Andressa Amorim, Marina Diogenes, Marcelo Antonini, Francisco Pimentel Cavalcante, Luiz Henrique Gebrim. Overall survival differences between HER2 Low and other breast cancer subtypes in a reference center in Brazil [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 PO2-17-09.