Background: Metastatic breast cancer (MBC) which causes significant morbidity and mortality worldwide is in need of more effective treatment regimens. In combination with chemotherapy, anti-PD1 antibody pembrolizumab has been shown to prolong progression-free survival (PFS) of patients with triple-negative subtype MBC (TN-MBC), however, its efficacy remains low for the other 80% of patients with MBC. MBC’s heterogenous pattern of immune infiltration and expression make it challenging to treat with single immunotherapeutic agents such as pembrolizumab and successful immunotherapy must therefore target multiple pathways. To augment antitumor host immune responses during treatment, studies have examined adjunct agents such as “oncolytic” adenovirus (OAds), which are vectors that preferentially replicate in and lyse tumor cells leading to the activation of host immunity. OAds have been tested in a myriad of clinical trials with the hope to enhance host immune activation but those trials have shown limited successes. Methods: To overcome the multiple immunogenic barriers in solid tumors, our group developed a binary oncolytic/helper-dependent adeno-immunotherapy (CAdVEC). The first generation CAdVEC (CAdTrio) contains an OAd and a “helper-dependent” adenovirus (HDAd) that produces immunostimulant molecules including interleukin (IL)-12p70 and anti-PD-L1 antibody. Based on successful results using animal models, a first-in-human Phase 1 study with CAdTrio was conducted among patients with all solid tumors (NCT03740256). Four patients with MBC were enrolled in the virus dose-escalation phase of the trial and received an intra-tumor injection of CAdTrio. Given the novelty of this binary agent, starting dose of CAdTrio was more than 2-logs lower than that used in other OAd trials. Three patients received dose level (DL) 1 and one patient received DL2. All patients also received pembrolizumab 6 weeks after the virus injection. The primary endpoint for this phase I dose escalation was dose-limiting toxicities (DLT). Secondary outcomes included overall response rates (ORR), disease control rate (DCR), PFS, overall survival (OS), and treatment-related adverse events. Results: No patients developed DLT. The most common toxicities were fever, fatigue and pain around the injection site, but none were greater than grade 2. No significant elevation in liver enzymes were observed. Three of the four patients had partial response (PR). One patient progressed after ten weeks of stable disease and passed away. The three patients with PR received pembrolizumab within 7 weeks of CAdVEC injection. Analysis of injected tissues prior to pembrolizumab treatment showed that CAdTrio repolarized the tumor microenvironment toward immune activity by increasing the number of infiltrating Th1 immune cells, leading to responses in some treated tumors and even in one distant metastasis, demonstrating the potent systemic immune response to local CAdTrio treatment in patients with MBC. Conclusions: Our study demonstrated that intra-tumor injection with CAdTrio was safe and effective in patients with MBC but the significance of the results was limited by the small sample size. An MBC dedicated phase II trial is planned to be conducted to fully evaluate the efficacy and safety of CAdVEC treatment and to further elucidate mechanisms of resistance/sensitivity among patients with MBC. Citation Format: Natalie Chen, Daniel Wang, Caroline E. Porter, Amanda Rosewell Shaw, Catherine R. Robertson, Mae L. Woods, Ya Xu, Greyson Biegert, Alphi Kuriakose, Tao Wang, Bambi J. Grilley, Helen Heslop, Malcolm K. Brenner, Masataka Suzuki, Bora Lim. Treatment of Metastatic Breast Cancer with Multipotent Oncolytic/Helper Adenovirus CAdVEC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-04.

Breast cancer is a highly heterogeneous group of diseases posing a significant challenge in biomarker-driven research and the development of effective targeted therapies. Especially the treatment of metastatic breast cancer poses even more challenges, as we still lose more than 42,000 women and men each year in the United States alone. New biological insight helps to improve breast cancer treatment through early detection, adaptation to chemotherapy resistance, and tailoring to find the right size of care. This review focuses on existing and new areas of predictive biomarkers under development to tailor the management of breast cancer and the application of integrative approaches that have resulted in the promising candidate biomarker discovery. Furthermore, we review new methods to detect metastatic progression using imaging, and blood-based assays. We hope to increase the attention and awareness of a new generation of therapeutic development strategies in metastatic breast cancer.

Authors: Maria Luisa Machado Heredia1,2 Alphi Kuriakose1,2 Huma Javaid1,3 Brian Menegaz 1,3 Alastair Thompson1,2,3 Bora Lim1,2 Affiliation 1Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030 2 Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030 3 Department of Surgery, Baylor College of Medicine, Houston, TX 77030 Background and Purpose Increasing research data support the existence of barriers and discrepancies to oncology interventional clinical trial enrollment rate based on patients’ social-economic status. However, few studies examined if such discrepancy exists in observational trials. We hypothesize the enrollment discrepancy remains the same in specimen collection only protocols, and several factors including health literacy and religious belief contribute to such discrepancy. Methods Data was collected from March 1st, 2022, to July 7th, 2022, as part of an ongoing pilot study examining circulating tumor DNA (ctDNA) from patients diagnosed with stage IV metastatic breast cancer starting a new line of therapy treatment (BCM protocol number H- 48751). This study was selected as specimen collected is part of normally scheduled standard of care clinical labs and beyond informed consent does not require any additional patient commitment for participation. This study was performed across both county and private practice sites:1) Smith Clinic-Harris Health System 2) Baylor Saint Luke’s Medical center (BSLMC); respectively. Correlations for independent variables potentially affecting enrollment were assessed to estimate the association between patient participation and socio-economic factors like religious affiliation and level of formal education received. Free-form text responses were collected from patients who declined study participation. Results Fourteen eligible candidates were asked to participate in the observational trial to determine whether serial changes in ctDNA ratio correlate with the results of first monitoring patients via imaging at three months. Out of 14 patients approached, 5 patients (36%) declined. Interestingly, all five patients who declined were from Smith Clinic- Harris Health System, while all BSLMC patients agreed to enroll. Based on the free-text response of why patients declined the ctDNA study, we identified a total of 4 different categories: Language barriers, low health literacy, religious objection, and disinterest in research. Using these four categories, we continue to collect data to improve our understanding of barriers in observational trial enrollment. Conclusion Low literacy and other socioeconomic factors serve as barriers to enrollment in observational trials for patients who suffer from stage IV breast cancers. In our preliminary data, we also noted that these barriers are only relevant for patients who are treated at the county hospital. An investigation to recognize low literacy and religious affiliation as barriers to poor trial accrual is ongoing. Reasons to declining participation in observational trial. Citation Format: Maria L. Machado Heredia, Alphi Kuriakose, Brian A. Menegaz, Alastair M. Thompson, Bora Lim, Huma Javaid. Barriers to enrolling in observational trials for patients with stage IV breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-08-03.

Background: Patients with higher socioeconomic status (SES) are overrepresented in NCI-sponsored cancer clinical trials (CCT). Inadequate access, social and cultural barriers have been described as reasons for poor accrual of patients with low SES into clinical trials. Racial minorities including African Americans (AA) and Hispanics are underrepresented in CCT and often experience issues related to lack of access. On the other hand, survey studies throughout United States suggest equal willingness for participation in CCT among all racial categories. When access to CCT is not a barrier to enrollment, the rate of CCT participation by Racial and Ethnic minorities with low SES is not well studied. Methods: We performed a retrospective review of the database of new patients screened for breast CCT at Dan L Duncan Comprehensive Cancer Center (DLDCCC). DLDCCC is an ideal venue for studies on clinical trial diversity because it provides cancer care to two very different patient demographics: 1) Smith Clinic is a Harris Health System (HHS) cancer clinic where a majority of the patients are of low SES; half of our patients earn less than $25,000 annually, 60% are uninsured using a county financial assistance program called “Gold Card”, 65% are unable to speak proficient English, and 52% are Hispanic, 25% AA, 9% Caucasian and 5% Asian, 2) Baylor St Luke’s Medical Center (BSLMC) serves predominantly Caucasian patients with >95% of the patients having federal or commercial insurance. Cancer clinical trials are available at both sites, and all patients across the two clinics have equal opportunity for enrollment. The database dates back to 5/2015 and includes 3,084 patients. Using the chi-squared test, we compared the rate of trial availability, trial eligibility and enrollment for breast CCT between two patient populations receiving care at Smith clinic vs. BSLMC. We tabulated the rate of trial participation decline at each clinic per year from 5/2015 to 6/2021. The study had IRB approval from Baylor College of Medicine.Results: Among the 3,084 new-to-practice patients, 1,664 patients were seen at BSLMC and 1,420 were seen at Smith Clinic. Clinical trials were available for 758 (53.4%) patients at Smith clinic and 742 (44.6%) patients at BSLMC, p<0.001. Patients were eligible for clinical trials at a similar rate at each site: 193 (25.5%) at Smith Clinic and 182 (24.5%) at BSLMC clinic. Patients at Smith Clinic were more likely to decline clinical trial enrollment compared to BSLMC (62.2% vs. 41.8%, P<0.001). The rate of CCT participation decline was consistent across the years, 2015-2021. Conclusion: While access to clinical trials has been considered a major rate limiting step towards improving diversity in clinical trials, our experience at DLDCCC Breast Clinics suggests that patients with low SES more frequently refuse trial enrollment even when they have access and are trial eligible. Factors underlying our population’s excess reluctance for enrollment onto CCT at Smith clinic compared to BSLMC is currently under investigation, to be reported at the SABCS. Citation Format: Maryam Nemati Shafaee, Emily L Podany, Katherine Sanchez, Nicole Higashiyama, Valentina Hoyos, Liz Binu Micheal, Kristen Otte, Anne Pavlick, Julie Nangia, Alphi Kuriakose, Kent C Osborne, Maria Jibaja-Weiss, Matthew J Ellis, Shaun Bulsara, Mothaffar Rimawi. Breast cancer clinical trial participation rate among patients of low socioeconomic status at a comprehensive cancer center [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-14-02.