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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 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.

Background:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, disproportionally affecting African American and Hispanic patients, and germline BRCA1/2 mutation carriers. Prognosis of relapsed, metastatic disease is extremely poor and effective well-tolerated therapies are urgently needed. Our collaborators have discovered that TNBCs often lose feedback control of receptor tyrosine kinases (RTKs) including PDGFR and MET, locking these receptors in a chronically active state. These receptors share a common negative regulator called Protein Tyrosine Phosphatase, Non-Receptor Type 12 (PTPN12). Baylor investigators have shown that PTPN12- deficient TNBCs may be responsive to combined RTK inhibition. Sitravatinib is a spectrum selective RTK inhibitor that has shown strong antitumor activity in patient derived xenografts (PDXs) of TNBC with low levels of PTPN12. We have therefore designed a phase II, multi-institution, two cohort trials to evaluate the efficacy of sitravatinib in patients with metastatic TNBC (mTNBC). Methods: Patients with diagnosis of mTNBC who have received at least one line of chemotherapy +/- atezolizumab for advanced disease would be considered for enrollment. Patients would need to have tissue from metastatic site available for evaluation or agree to undergo biopsy if banked tumor tissue is not available. Sitravatinib at 100 mg daily, the recommended phase 2 dose for sitravatinib monotherapy, will be started at the initiation of the study and continued until progression or unacceptable toxicity. The study will employ a modified optimal Simon’s two stage design. Patients will be recruited into two cohorts: PTPN12 low or PTPN12 high/normal cohorts simultaneously and independently. Seven patients will be enrolled to each arm during the first stage. After the first stage, depending on the observed number of responses, the study will proceed to the 2nd stage. The primary endpoint is progression-free survival status at 24 weeks (PFS24). Current Trial status: The trial is funded by Mirati Therapeutics and opened to enrollment at Dan L Duncan Comprehensive Cancer Center (DLDCCC) clinics as of 6/8/21. Trial is due to open at UT Southwestern Dallas by 11/2021. The correlative science is funded by an institutional SPORE grant. Conclusion: This trial aims to show that sitravatinib is safe and to investigate whether it could be a treatment option in mTNBC. Citation Format: Maryam Nemati Shafaee, Kristen Otte, Nicholas J Neill, Kent C Osborne, Thomas F Westbrook, Susan Hilseneck, Matthew J Ellis. A phase 2 study of sitravatinib in metastatic, pre-treated, triple negative breast cancer, NCT # 04123704 [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 OT2-28-01.

Introduction: There are no robust molecular predictors for response of TNBC to chemotherapy. Microscaled proteogenomics (PMC6985126) was therefore applied to biopsies from TNBC patients undergoing neoadjuvant carboplatin/docetaxel. Approach: Sufficient tumor-rich tumor core biopsies were accrued from 59 patients. A second biopsy was collected from 16 patients on day 3. Study endpoints were pathological complete response (pCR) and residual cancer burden (RCB). Analyses included exome-based mutational signatures, RNA-based TNBC subtyping, immune cell infiltrate scores, and multi-gene proliferation scores, protein and phosphoprotein-based stimulatory and inhibitory immunomodulators. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used for gene set and pathway scoring. Non-parametric tests and outlier analyses were applied to identify differential genes, proteins and pathways. Results: Most cases were PAM50 basal-like and all Lehmann TNBC subtypes were represented. BRCA1/2 and PALB2 homologous recombination (HRD) mutations were observed in 7 cases. Neither subtype, HRD mutation nor HRD mutation signature associated with pCR, but higher mismatch repair defect signature associated with higher RCB. Comparison of baseline pCR vs non-pCR cases showed higher ssGSEA scores for metabolic pathways including oxidative phosphorylation, fatty-acid metabolism, and glycolysis in the non-pCR cases at the protein but not at mRNA level. Non-pCR cases were associated with chromosomal deletions in chemokine receptors, JAK2, and PD-L1, lower PD-L1 protein levels, and lower immune activation. Consistently, ssGSEA scores for interferon alpha and gamma response pathways were higher in pCR cases. Phospho-PD-L1 levels were anti-correlated with developmental pathways. Matched comparisons of baseline and on-treatment samples revealed increase in proteins involved in cell cycle, DNA replication, and mismatch repair following treatment. Metabolic proteins were also upregulated following treatment, while complement activation, immune, and cell adhesion-related proteins were downregulated. Conclusion: Microscaled proteogenomic analysis revealed a wealth of biological features associated with chemotherapy resistance beyond immune response markers, including metabolic features that are only present at the protein level. These data suggests that the development of a microscaled proteogenomic chemotherapy response predictor is a feasible objective for future studies. Citation Format: Meenakshi Anurag, Eric Jaehnig, Shankha Satpathy, Karsten krug, Jonathan T. Lei, Yongchao Dou, Beom-Jun Kim, Cathy M. Sullivan, D. R. Mani, Erik J. Bergstrom, Gloria V. Echeverria, Ian S. Hagemann, Kristen Otte, Henry Rodriguez, Ana I. Robles, Michael T. Lewis, Michael Gillette, Bing Zhang, Mothaffar F. Rimawi, Steven Carr, Foluso O. Ademuyiwa, Matthew J. Ellis. Molecular dissection of chemotherapy response in triple negative breast cancer (TNBC) using microscaled proteogenomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 18.

Introduction: Cytotoxic chemotherapy for sporadic Triple Negative Breast Cancer (TNBC) remains the standard of care and the recent approval for adjuvant PD1 therapy is not biomarker guided. Pathological complete response (pCR) is often not achieved and portends poor survival. Predictive markers for individual drugs have proven elusive. Approach: Microscaled proteogenomics (MPG) was applied to snap-frozen TNBC clinical trial core needle biopsies obtained before treatment with carboplatin and docetaxel (WashU: NCT201404107 and BCM: NCT02544987). Clinical endpoints for discovery analysis were pathological complete response (pCR) and residual cancer burden (RCB). Standard non-parametric statistical tests were employed to identify proteogenomic features associated with these endpoints. Results: Copy number aberrations (CNA) are a recurrent feature of TNBC and a potential driver of chemotherapy sensitivity. We therefore sought CNA with concordant changes at the mRNA and protein levels that also associate with pCR status. Genes located within a recurrent interstitial deletion at chromosomal location 19q13.3 were the most significantly down-regulated at mRNA and protein level in chemotherapy resistant cases. 19q13.3 encodes multiple DNA damage response (DDR) genes; however, only LIG1, a DNA ligase required for lagging strand synthesis and DNA repair, showed concordant changes at both the mRNA and protein level. In multiple independent TNBC data sets, LIG1 deletion was associated lack of pCR and poor metastasis-free survival. Additionally in the BrighTNess TNBC trial lower LIG1 mRNA levels were associated with increased chemotherapy resistance in the carboplatin containing arms (no pCR and residual cancer burden I-III; p=0.0008 and 0.003 respectively). In PDX-derived short-term cultures and PDXs treated with docetaxel or carboplatin, a specific association of carboplatin resistance with LIG1 deletion was observed. LIG1 depleted-tumors did not harbor elevated scores for homologous recombination defect signature, suggesting LIG1 loss is an orthogonal pathway for TNBC pathogenesis The high chromosomal instability index in LIG1 deletion tumors in our TNBC study was robustly reproduced in multiple datasets (including TCGA-BRCA ; Metastatic breast cancer project). LIG1 copy number deletion was also associated with poor progression free survival, and high chromosomal instability in multiple other cancers (including TCGA-​UCEC HR=2.23, TCGA-HNSC HR=1.46, TCGA-PRAD HR=2.07, TCGA- COAD HR=1.75 and TCGA-KIRP HR=4.00). Conclusion: Deletion of LIG1 is associated with chromosomal instability in TNBC and occurs in tumors without genomic evidence for defects in homologous recombination. Other clinical features of LIG1 deleted TNBC and how LIG1 loss may cause chromosomal instability and tumorigenesis will be discussed. Citation Format: Meenakshi Anurag, Eric Jaehnig, Jonathan Lei, Beom-Jun Kim, Anh Minh Tran Huynh, Yongchao Dou, Tanmayi Vashist, Erik Bergstrom, Xuxu Gou, Viktoriya Korchina, Donna Marie Muzny, Kristen Otte, Harshavardhan Doddapaneni, Lacey Dobrolecki, Gloria Vittone Echeverria, Bora Lim, Mothaffar Rimawi, Karsten Krug, Ian Hageman, Henry Rodriguez, Ana I. Robles, Tara Hiltke, Kent Osborne, Michael Gillette, George Miles, Steven Carr, Michael T Lewis, Bing Zhang, Foluso Ademuyiwa, Shankha Satpathy, Matthew J. Ellis. LIG1 deletion predicts chemotherapy resistance, chromosomal instability, and poor prognosis in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1010.

Chemotherapy may induce alopecia. Although scalp cooling devices have been used to prevent this alopecia, efficacy has not been assessed in a randomized clinical trial.To assess whether a scalp cooling device is effective at reducing chemotherapy-induced alopecia and to assess adverse treatment effects.Multicenter randomized clinical trial of women with breast cancer undergoing chemotherapy. Patients were enrolled from December 9, 2013, to September 30, 2016. One interim analysis was planned to allow the study to stop early for efficacy. Data reported are from the interim analysis. This study was conducted at 7 sites in the United States, and 182 women with breast cancer requiring chemotherapy were enrolled and randomized.Participants were randomized to scalp cooling (n = 119) or control (n = 63). Scalp cooling was done using a scalp cooling device.The primary efficacy end points were successful hair preservation assessed using the Common Terminology Criteria for Adverse Events version 4.0 scale (grade 0 [no hair loss] or grade 1 [50% hair loss not requiring a wig] were considered to have hair preservation) at the end of 4 cycles of chemotherapy by a clinician unaware of treatment assignment, and device safety. Secondary end points included wig use and scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Hospital Anxiety and Depression Scale, and a summary scale of the Body Image Scale.At the time of the interim analysis, 142 participants were evaluable. The mean (SD) age of the patients was 52.6 (10.1) years; 36% (n = 51) received anthracycline-based chemotherapy and 64% (n = 91) received taxane-based chemotherapy. Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%-60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%-7.6%) (success rate difference, 50.5%; 95% CI, 40.5%-60.6%). Because the 1-tailed P value from the Fisher exact test was.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events.Among women with stage I to II breast cancer receiving chemotherapy with a taxane, anthracycline, or both, those who underwent scalp cooling were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling. Further research is needed to assess longer-term efficacy and adverse effects.clinicaltrials.gov Identifier: NCT01986140.

10088 Background: Adjuvant chemotherapy decreases the risk of recurrence. However, it has distressing side effects, including alopecia. There are no randomized trials assessing modern scalp cooling to prevent alopecia, and success rates in non-randomized trials have varied. Methods: We conducted a multi-center randomized trial to evaluate the safety and efficacy of the Orbis Paxman Hair Loss Prevention System (OPHLPS) in reducing chemotherapy-induced alopecia. Women with stage I-II breast cancer planned to receive anthracycline- or taxane- based chemotherapy for at least four cycles were eligible and randomized in a 2:1 ratio to scalp-cooling or control. Scalp-cooling was done with the OPHLPS 30 minutes prior to, during and 90 minutes after each chemotherapy. The primary efficacy endpoints were hair preservation and device safety. We planned to enroll 235 subjects to provide 85% power to detect a 20% difference in hair preservation. Secondary endpoints included wig/scarf use and quality of life assessed by the EORTC QLQ-30, HADS and BIS. Subjects will be followed for 5 years for recurrence, overall survival, and site of recurrence. One interim analysis was planned to allow the study to stop early for efficacy after 142 subjects were enrolled and evaluable for the primary endpoint. To maintain the overall type 1 error rate, an O’Brien-Fleming spending function was used (interim boundary p = 0.0061). Results: This is the first randomized trial with modern scalp cooling in the world. For the interim analysis, 142 subjects were evaluable. Among them, 48 (50.5%) out of 95 in the cooling group and 0 (0%) out of 47 in the control group had hair preservation. The one-tailed p-value from the Fisher’s exact test is < 0.0001, which crosses the superiority boundary (p = 0.0061). Thus on 9/26/2016 the DSMB stopped the study early. The interim analysis was presented at SABCS 2016. There are 195 subjects enrolled on this clinical trial, and the final subject will be evaluable for the primary outcome February 2017. The final analysis will be presented. Conclusions: Our trial showed that scalp cooling using OPHLPS is highly effective in hair retention. Paxman Coolers has applied for FDA clearance for the OPHLPS based on the results of the interim analysis. Clinical trial information: NCT01986140.