The GLI1 oncogene and p53 tumor suppressor gene function in an inhibitory loop that controls stem cell and tumor cell numbers. Since GLI1 and p53 both interact with the coactivator TATA Binding Protein Associated Factor 9 (TAF9), we hypothesized that competition between these transcription factors for TAF9 in cancer cells may contribute to the inhibitory loop and directly affect GLI1 function and cellular phenotype. We showed that TAF9 interacts with the oncogenic GLI family members GLI1 and GLI2 but not GLI3 in cell-free pull-down assays and with GLI1 in rhabdomyosarcoma and osteosarcoma cell lines. Removal of the TAF9-binding acidic alpha helical transactivation domain of GLI1 produced a significant reduction in the ability of GLI1 to transform cells. We then introduced a point mutation into GLI1 (L1052I) that eliminates TAF9 binding and a point mutation into GLI3 (I1510L) that establishes binding. Wild-type and mutant GLI proteins that bind TAF9 showed enhanced transactivating and cell transforming activity compared with those that did not. Therefore, GLI-TAF9 binding appears important for oncogenic activity. We then determined whether wild-type p53 down-regulates GLI function by sequestering TAF9. We showed that p53 binds TAF9 with greater affinity than does GLI1 and that co-expression of p53 with GLI1 or GLI2 down-regulated GLI-induced transactivation, which could be abrogated using mutant forms of GLI1 or p53. This suggests that p53 sequesters TAF9 from GLI1, which may contribute to inhibition of GLI1 activity by p53 and potentially impact therapeutic success of agents targeting GLI-TAF9 interactions in cancer.

Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are now widely applied across numerous malignancies. Pembrolizumab has two breast-specific indications in triple-negative disease. Currently, programmed death ligand-1 (PD-L1) expression on tumor and surrounding immune cells is the only validated predictive biomarker for immune checkpoint inhibitors (ICIs) in breast cancer; however, it can be imprecise. Additional biomarkers are needed to identify the patient population who will derive the most benefit from these therapies. The tumor immune microenvironment contains many biomarker candidates. In tumor cells, tumor mutational burden has emerged as a robust biomarker across malignancies in general, with higher burden cancers demonstrating improved response, but will need further refinement for less mutated cancers. Preliminary studies suggest that mutations in breast cancer gene 2 (BRCA-2) are associated with increased immune infiltration and response to ICI therapy. Other genomic alterations are also being investigated as potential predictive biomarkers. In immune cells, increased quantity of tumor-infiltrating lymphocytes and CD8+ cytotoxic T cells have correlated with response to immunotherapy treatment. The role of other immune cell phenotypes is being investigated. Peripherally, many liquid-based biomarker strategies such as PD-L1 expression on circulating tumor cells and peripheral immune cell quantification are being studied; however, these strategies require further standardization and refinement prior to large-scale testing. Ultimately, multiple biomarkers utilized together may be needed to best identify the appropriate patients for these treatments.

Trastuzumab deruxtecan has been shown to have responses in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, the safety of this medication in patients with severe liver dysfunction and untreated or symptomatic central nervous system metastases is unknown. We describe a patient with metastatic HER2-positive breast cancer with liver failure and leptomeningeal metastases who was treated with dose-reduced trastuzumab deruxtecan. With treatment, the patient’s hyperbilirubinemia resolved and she demonstrated a response on imaging. She was dose-escalated to full dose with minimal adverse events.

Background: Highly penetrant pathogenic variants causing hereditary breast and ovarian cancer syndrome occur among patients of racial/ethnic minorities at least as frequently as they do among non-Ashkenazi Jewish, non-Hispanic White patients. However, studies suggest that disparities persist in genetic counseling and testing in these populations. It is critical that we reduce the testing gap to better understand genetic susceptibility in minority patients and identify individuals who may benefit from preventive and therapeutic interventions. We explore genetic counseling and testing outcomes in a safety net system with significant support from financial assistance programs that minimizes typical financial and insurance barriers. Methods: This is a retrospective study of adult patients evaluated by a genetic counselor for hereditary breast/ovarian cancer syndrome between October 1, 2009 and September 30, 2019 in Smith Clinic, which is part of a large, county hospital system serving predominantly racial/ethnic minority and uninsured or under-insured patients, and affiliated with the Dan L Duncan Comprehensive Cancer Center. All patients between October 1, 2009 and February 28, 2013 underwent genetic testing, whereas all patients after March 1, 2013 were evaluated by a genetic counselor but may not have completed testing. Patient clinical data was summarized using descriptive statistics. Results: 1,682 patients (mean age at time of counseling/testing 48.2 years) were evaluated by a genetic counselor. Patient-reported race/ethnicity was 58.7% Hispanic, 25.2% non-Hispanic Black (NHB), 8.8% non-Hispanic White (NHW), 4.6% Asian, and 2.7% other with 2.6% having some Native American and 0.6% having any Ashkenazi Jewish genealogic ancestry. Among the 1,397 patients who completed genetic testing, 76.2% received financial assistance. The majority were tested with a multigene panel (70.4%) with the remaining primarily undergoing BRCA sequencing or BRCA large rearrangement test (multigene panels not available until April 2014). More than three-quarters of patients who did not complete testing (n=285, 20.6% of those evaluated after March 1, 2013) did not meet guideline-based criteria or had a relative who was a more appropriate candidate for testing. Only 10.2% declined testing with rates of decline highest among NHB patients. A pathogenic mutation was found in 15.4% of individuals tested: BRCA1 (n=108), BRCA2 (n=57), PALB2 (n=26), ATM (n=8), other (n=18). Rates of pathogenic mutations were higher among NHW and Hispanic patients (NHW 14.9%, Hispanic 17.4%, NHB 11.3%, Asian 9.0%, Other 17.1%). The relatively high percentages of identified pathogenic mutations was likely related to the fact that 84.1% of patients were referred for a personal history of breast and/or ovarian cancer with 6.1% of NHW and 5.7% of Hispanic patients referred for a relative with or personal history of a known pathogenic mutation. Among those with BRCA1/2 or PALB2 mutations, risk-reducing procedures were frequent among all races except those classified as other (mastectomies: NHW 50%, NHB 45.5%, Hispanic 51.9%, Asian 40%, other 16.7%; salpingo-oophorectomies or salpingectomies: NHW 35.7%, NHB 45.5%, Hispanic 56.4%, Asian 60%, other 16.7%). Conclusions: In a racially/ethnically diverse, low-income population, genetic testing uptake is high when supported by financial assistance programs and an on-site genetic counselor. Regardless, reasons for declining testing warrant further exploration, particularly among non-Hispanic Black patients, to further reduce disparities in testing. Prompt referral of patients who meet testing guidelines for genetic evaluation is also critical since pathogenic mutations were frequently identified in all racial/ethnic subgroups and nearly half underwent a risk-reducing procedure. Citation Format: Nicole Higashiyama, Shaun Bulsara, Susan Hilsenbeck, Tiffaney Tran, Ria Brown, Mary Fang, Cathy Sullivan, Georgiann Garza, Maryam Nemati Shafaee, C. Kent Osborne, Mothaffar Rimawi, Julie Nangia. Genetic assessment of hereditary breast and ovarian cancer in the Smith Clinic: A 10-year, single center experience [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 P2-09-09.

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.