Cancer Research Consortium Research Articles

Evaluation of Radiation Pneumonitis in a Phase II Study of Consolidation Immunotherapy with Nivolumab and Ipilimumab or Nivolumab Alone Following Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-Small Cell Lung Cancer (NSCLC): Big Ten Cancer Research Consortium BTCRC-LUN16-081

Purpose/Objective(s)The addition of immunotherapy (IO) after concurrent chemoradiation (CCRT) for unresectable non-small cell lung cancer (NSCLC) has become common practice in eligible patients. Approaches to further improve outcomes and reduce treatment-related toxicity for these patients are needed. This study evaluates the risk of radiation pneumonitis after CCRT and its correlation with the radiation dose distribution, immunotherapy regimen (nivolumab vs nivolumab plus ipilimumab), and patient demographics across BTCRC-LUN16-081. Materials/MethodsPatients with unresectable stage III NSCLC after completion of CCRT were enrolled on BTCRC-LUN16-081, a randomized phase II trial to assess efficacy and tolerability of consolidative nivolumab versus nivolumab plus ipilimumab for six months. Radiation dose parameters, patient demographics, and toxicity events were evaluated among treatment arms for risk and severity of pneumonitis. ResultsOne-hundred and five patients were enrolled into two treatment arms, 54 patients received nivolumab alone and 51 patients received nivolumab plus ipilimumab. Of these, 104 patients had dose volume histogram (DVH) information available. Within this cohort, 65 patients (62.5%) had stage IIIA and 39 patients (37.5%) had stage IIIB NSCLC disease per AJCC 7th edition. During the study, 29 patients (27.9%) were diagnosed with grade 2 or greater pneumonitis. Utilizing logistic regression and evaluating different cut-offs for lung V20, patients with V20 >23% demonstrated significantly higher grade 2 or greater pneumonitis rates (37.1% vs. 16.2%, P = .031). No significant difference in rates of pneumonitis between arms were identified. Traditional lung DVH cut-offs (V5 of >65%, V20 of >35%, mean >20 Gy) were not associated with pneumonitis. ConclusionIn patients receiving nivolumab or nivolumab plus ipilimumab after definitive CCRT, lung V20 of >23% was associated with an increased risk of grade 2 or greater pneumonitis. Radiation dose constraints for lungs in patients receiving consolidative IO after CCRT should continue to be evaluated and optimized when feasible.

Phase I/II trial of plinabulin in combination with nivolumab and ipilimumab in patients with recurrent small cell lung cancer (SCLC): Big ten cancer research consortium (BTCRC-LUN17-127) study

BackgroundPlinabulin is a GEF-H1 releasing agent with an immune-enhancing function. We report results from a multicenter Phase I/II study (NCT03575793) assessing plinabulin in combination with nivolumab and ipilimumab for the treatment of recurrent SCLC. MethodsIn Phase I, patients were enrolled using a 3 + 3 design to determine dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg), and plinabulin (in escalating doses) on day 1 of each 21-day cycle for 4 cycles followed by maintenance with plinabulin and nivolumab. In phase II, patients with recurrent PD(L)1 inhibitor resistant SCLC were enrolled. The primary objective was median progression-free survival (PFS). ResultsBetween 9/2018 and 2/2023, 39 patients were enrolled, and 36 patients received study treatment and were evaluable for safety (16 in Phase I; 20 in Phase II). In the phase I dose-escalation, there were 2 DLTs; grade 3 altered mental status lasting <24 h and grade 3 infusion reaction. The Plinabulin RP2D was determined to be 30 mg/m2. Common TRAEs were vomiting (44 %), nausea (42 %), and infusion reaction (36 %); 6 % of patients had a ≥grade 3 TRAE. Five patients (14 %) had ≥grade 3 irAEs; there were no cases of immune-related pneumonitis. In the efficacy analysis in 27 patients, the median PFS was 1.6 months (95 % CI 1.2 to 2.7) and the trial did not meet the pre-specified target median PFS of 3.5 months. Four patients treated at 30 mg/m2 had PR (confirmed 1, unconfirmed 3); 5 patients had SD with a CBR of 33 %. Two of 8 patients treated in phase I at the lower 20 mg/m2 dose had confirmed PR, with 1 patient on the drug regimen for >90 cycles. The median OS and follow-up time were 5.5 months and 2.5 months respectively. ConclusionsPlinabulin in combination with nivolumab and ipilimumab was tolerable at the dose of 30 mg/m2. While the clinical responses in PD-1 resistant SCLC were limited, some patients had a long duration of response. The number of ≥grade 3 irAE with the combination were lower than expected.

Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022

Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

QUIC: Phase 2 study of gemcitabine, cisplatin, quemliclustat (AB680), and zimberelimab (AB122) during first-line treatment of advanced biliary tract cancers (BTC)—Big Ten Cancer Research Consortium study BTCRC-GI22-564.

TPS4195 Background: Despite recent approvals of immune checkpoint inhibitors with chemotherapy in the first-line setting, the median overall survival (mOS) for patients with advanced biliary tract cancer (BTC) remains less than 15 months. CD73 is a key enzyme responsible for the conversion of extracellular adenosine 5’-monophosphate into adenosine and may play an important role in creating an immunosuppressed tumor microenvironment. High expression of CD73 in BTC is associated with decreased OS. Quemliclustat (Q) is a potent, selective, reversible inhibitor of CD73. Q in combination with chemotherapy has demonstrated promising activity in patients with advanced pancreatic cancer without significant increase in adverse events. The BTCRC-GI22-564 study evaluates safety and preliminary efficacy of Q in combination with zimberelimab (Z), a monoclonal antibody targeting human PD-1, with gemcitabine and cisplatin (GC) as first-line therapy for patients with advanced BTC, QUIC (Q and Immunotherapy in Cholangiocarcinoma). Methods: This is an open label, single arm, phase II multi-site trial, evaluating Q and Z in combination with GC in patients with advanced BTC who have not received systemic treatment for advanced disease or who completed adjuvant therapy &gt; 6 months prior to development of recurrent disease. Chemotherapy is given on days 1, 8, 22 and 29 of each 42-day cycle as per local standards. Z is administered at a fixed dose of 360 mg via IV infusion every 3 weeks. Q is administered via IV infusion on days 1, 15, and 29. A safety run-in portion built into the study is planned to enroll 6 subjects to ensure there are no dose limiting toxicities (DLT). If a study defined DLT is observed, Q, gemcitabine and cisplatin will be reduced by 1 dose level, and an additional 6 subjects will be enrolled in the safety run-in portion. The primary efficacy endpoint is median progression free survival (mPFS) with null and alternative survival of 6.0 and 10.0 months, respectively. Based on an accrual rate of 3 patients per month, we expect to accrue 33-39 patients which will provide at least 83% power with a one-sided alpha of 0.1. Secondary endpoints include mOS, disease control rate, overall response rate, and duration of response. Correlative endpoints will assess clinical outcomes with immune infiltration within tumor microenvironment, CD73 and PD-L1 expression. The QUIC study is currently open to enrollment through BTCRC. Clinical trial information: NCT06048133 .

A randomized phase II trial of adjuvant pembrolizumab versus observation following curative resection for stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm: Big Ten Cancer Research Consortium BTCRC-LUN18-153.

TPS8118 Background: Each year, approximately 35,000 patients are diagnosed with stage I lung cancer in the United States. Despite early detection, the 5-year overall survival for this population remains disappointing, ranging between 73-86% with recurrence rates from 18-38%. The current standard of care for stage I NSCLC is surgery alone followed by observation as prior trials of adjuvant chemotherapy in this subgroup have failed to show benefit. More modern therapies such as programmed death-1 (PD-1) inhibitors have not been evaluated in the stage I setting but have demonstrated significant improvements in pathologic complete response, event free survival, and overall survival when added to chemotherapy for patients with fully resected stage II and III disease. The use of PD-(L)1 inhibition has also demonstrated clinically and statistically significant improvements in OS in both unresectable stage III NSCLC following chemoradiation and in the metastatic setting. Given the activity of PD-(L)1 inhibition in nearly every other subset of NSCLC patients, we aimed to evaluate this therapy following resection in stage I NSCLC patients. Methods: This study is a randomized phase II multicenter trial of adjuvant Pembrolizumab versus observation alone following complete resection of stage I NSCLC with tumors between 1-4cm. The trial randomizes patients 1:1 to either Pembrolizumab 400mg IV every 6 weeks for up to 9 cycles or observation alone. Patients are stratified by PD-L1 score (PD-L1 ≥50% vs. &lt; 50%) and tumor size (1-2cm vs. &gt; 2-4cm), and they undergo repeat CT imaging every 12 weeks. The study is being conducted through the Big Ten Cancer Research Consortium, and there are currently 11 sites open to accrual with one additional site pending activation. The primary endpoint is disease free survival with secondary endpoints including OS, DFS at multiple timepoints (1-, 2-, and 3-years), and safety. The trial initially opened to accrual at the lead site, Indiana University, in May 2020, and enrollment is currently at 95 patients with a planned enrollment of 244. (NCT04317534) Clinical trial information: NCT04317534 .

ETHAN: A phase II study comparing different endocrine therapies for male breast cancer.

TPS632 Background: Male breast cancer is a rare disease, and most cases are hormone receptor-positive (HR+). Due to a lack of clinical trials, male breast cancer has historically been treated based on data extrapolated from women. However, there are substantial knowledge gaps in the comparative efficacy, safety, and patient-reported outcomes of endocrine therapies for male breast cancer. While tamoxifen is the current standard of care, additional data are warranted for aromatase inhibitors (AI), gonadal suppression, and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Methods: This is an open-label, multicenter, randomized, phase II trial designed to evaluate different endocrine therapies in men with HR+ and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. A total of 60 men will be enrolled across nine (9) sites within the Translational Breast Cancer Research Consortium (TBCRC). Key eligibility criteria include male sex and stage I, II, or III HR+/HER2- breast cancer before surgical resection of the primary tumor and axillary nodes. Key exclusion criteria include prior anti-cancer therapy for the current breast cancer or any other malignancy within the past 12 months, and inflammatory breast cancer. The trial has two phases. The first phase is a window of opportunity component in which newly diagnosed men are randomized 1:1:1 to either tamoxifen (Arm A), anastrozole (Arm B), or anastrozole plus degarelix (Arm C) given for three weeks. The primary endpoint for the window phase is Ki-67 reduction from the baseline diagnostic biopsy to the research biopsy at the end of the window phase. The second phase consists of neoadjuvant treatment, in which the tamoxifen group is randomized 1:1 to tamoxifen (Arm D) versus tamoxifen plus abemaciclib (Arm E), and the anastrozole alone (Arm B) and anastrozole plus degarelix (Arm C) groups are merged and then randomized 1:1 to anastrozole plus degarelix (Arm F) versus anastrozole plus degarelix plus abemaciclib (Arm G). The duration of the neoadjuvant phase is four (4) months, and the primary endpoint of this phase is residual cancer burden (RCB) index at time of surgery. The trial is powered for the RCB endpoint in a 2 x 2 factorial design to detect a 0.6 unit decrease in RCB index with 80% power and alpha=10%. For the Ki-67 endpoint, we assume an approximately 50% reduction in Arms A and B; Arm C will be of interest if it leads to ≥80% reduction in Ki-67. Secondary endpoints include: estradiol and testosterone levels at baseline, end of window, and during neoadjuvant phase; preoperative endocrine prognostic index (PEPI) score at surgery; adverse events; and patient-reported outcomes (including quality of life). Tumor tissue will be collected for correlative analyses. The study opened to enrollment at Dana-Farber in October 2023, and additional sites will open in 2024. Clinical trial information: NCT05501704 .

Abstract PO2-20-01: The STOP-HER2 Trial: A Phase 2 Study of Stopping Trastuzumab - Outcomes in Patients with HER2+ Metastatic Breast Cancer (TBCRC 062)

Abstract BACKGROUND: Anti-HER2 therapies have transformed the trajectory for patients with HER2-positive (HER2+) MBC. A subset of patients with HER2+ MBC do exceptionally well and remain on maintenance anti-HER2 therapy for many years. However, current therapy is non-curative and patients are treated indefinitely. While these therapies often are well-tolerated, they may cause significant toxicities, are expensive, and typically require frequent infusion and provider visits. Case reports and retrospective series demonstrate that some patients may do well after stopping anti-HER2 treatment. We currently lack prospective data on the likelihood of clinical impact of successful treatment discontinuation, outcomes among patients who progress and restart HER2-directed therapy, and tools to predict who may safely stop therapy. In this study, we will enroll pts with an exceptional response to anti-HER2 therapy. Pts may elect to either continue or stop anti-HER2 therapy and will be followed clinically and radiographically on a protocol-specified schedule. Considering the central role of patients in choosing the study intervention arm, and the unique nature of stopping therapy as a treatment intervention, patient advocates have been deeply involved in the study design to ensure patient concerns are being heard and addressed. We will retrospectively assess minimal residual disease (MRD), measured in plasma, as a biomarker of ongoing response, in a step toward shifting the treatment paradigm for pts with HER2+ MBC. METHODS: STOP-HER2 is a prospective, non-randomized, phase II, multicenter study of either continuation (cohort 1) or cessation (cohort 2) of anti-HER2 therapy in exceptional responders with HER2+ MBC. Eligible patients must have biopsy-proven HER2+ MBC by ASCO/CAP guidelines and must have been receiving first-line anti-HER2 therapy for MBC for at least 3 years without evidence of progressive disease (PD) as determined by the treating investigator. Patients with prior brain-only PD or oligo-PD outside the brain are eligible at least 2 years after local treatment to the central nervous system (CNS) and in absence of subsequent PD. Up to fifty-two participants will be enrolled into cohort 2, and an additional thirty participants enrolled into the cohort 1, at 10 US sites within the Translational Breast Cancer Research Consortium. Co-primary endpoints are the 1-year progression-free survival (PFS) in cohorts 2 and 1, separately. Secondary endpoints include the clinical benefit rate upon re-initiation of anti-HER2 therapy for patients in cohort 2 experiencing PD after treatment discontinuation; and 3-year overall survival in both cohorts. Correlative endpoints include MRD status at baseline and the correlation between MRD dynamics and outcomes. Patient-reported outcomes will be collected and analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, and decision regret. The study will use a two-stage design to assess the primary objective of estimating the rate of participants who are free of progression at one year after discontinuing anti-HER2 therapy. If 50% or less are free of progression at one year, stopping HER2 therapy would not be considered a viable treatment plan (null hypothesis). The study is designed to have 80% power to reject the null hypothesis at the 10% type I error rate when 68% of exceptional responders are free of progression at one year after stopping HER2 therapy. STOP-HER2 began enrollment in Q2 2023 (NCT05721248). Citation Format: Heather Parsons, Kathryn Ruddy, Stefania Morganti, Karen Smith, Victoria Attaya, Eliza Kallfelz, Michelle DeMeo, Jamie LaScala, Shirley Mertz, Teri Pollastro, Patricia Spears, Adam Brufsky, Chau Dang, Susan Dent, Ahmed Elkhanany, WIlliam Gwin, Ciara O'Sullivan, Kathy Miller, Sara Nunnery, Elaine Walsh, Anna Maria Storniolo, Sara Tolaney, Nabihah Tayob, Antonio Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy Lin. The STOP-HER2 Trial: A Phase 2 Study of Stopping Trastuzumab - Outcomes in Patients with HER2+ Metastatic Breast Cancer (TBCRC 062) [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 PO2-20-01.

Abstract PS03-07: Morphometric signature identifies ductal carcinoma in situ of the breast with low risk of progression to invasive breast cancer

Abstract Background. Ductal carcinoma in situ (DCIS) is a frequently found precursor of invasive breast cancer (IBC). However, the majority of DCIS will never progress to IBC. As we cannot distinguish yet which DCIS will remain indolent (‘harmless’) from those that might progress in the future to IBC, almost all women with DCIS are intensively treated by surgery, often followed by radiotherapy. This brings an urgent clinical need to learn distinguishing harmless from potentially progressive DCIS to save many women with indolent DCIS the burden of unnecessary overtreatment. Aim. We aimed to investigate if the geometry and spatial configuration of DCIS ducts in Hematoxylin-Eosin (H&amp;E) stained tissue sections are related to the risk of progression of DCIS to ipsilateral IBC (iIBC). Methods. We obtained data from a population-based cohort of women diagnosed with primary DCIS between 1989 and 2004 in the Netherlands, treated with breast conserving surgery (BCS) only and a median follow-up time of 12 years. A nested case-control study (n=689) was designed in which patients diagnosed with iIBC recurrences during follow-up were considered as “cases” (n= 226) and those with no subsequent iIBC as “controls” (n=463). The DCIS and stroma regions were digitally annotated on H&amp;E-stained whole slide images (WSIs) by a pathologist as ground truth for the deep learning neural network of HALO AI module (IndicaLabs). We developed a computational pipeline to automatically detect and measure stroma areas, DCIS ducts, and the nucleus of their cells. We validated the accuracy of DCIS detection in H&amp;Es WSIs from an external study, in which DCIS regions were digitally annotated by an independent pathologist (Translational Breast Cancer Research Consortium, TBCRC). We classified cases and controls according to morphological measurements using logistic ridge regression with double-loop cross-validation, followed by hierarchical clustering. The risk of subsequent iIBC after primary DCIS diagnosis was evaluated by multivariate Cox proportional hazards models. Results. The accuracy of DCIS detection performed by the computational pipeline was compared with pathologist annotations in 20 slides from the TBCRC study. Results showed a satisfactory DCIS overlap area agreement of 0.76 (0.68 – 0.83). We applied the DCIS computational pipeline on the case-control series. We obtained 15 morphological measurements for each DCIS duct, such as duct area, cell density, distance between ducts, average nucleus area, etc. We calculated 8 distribution parameters from each measurement in each WSI, including median and range. After leaving out redundant variables, 55 unique morphometric variables were obtained, representing the heterogeneity of DCIS ducts per WSI. The c lassifier revealed a median area-under the curve (AUC) of 0.66 (0.55-0.77) to predict 5-years free of iIBC, 0.59 (0.50-0.67) to predict 10-years and 0.60 (0.52-0.68) to predict 15-years. The 30 variables with the highest association with outcome were used to build four morphometric signatures. Signature number 1, which is characterized by lesions with small-sized ducts, a lower number of cells and a lower DCIS/stroma area ratio, showed a significant lower risk of developing iIBC compared to the other three signatures in a multivariate Cox regression model including grade, ER, COX-2 and HER2 expression: HR = 0.56 (0.28-0.78 95%CI). Conclusion. We developed a computational pipeline able to detect and measure DCIS ducts in H&amp;E WSIs with high accuracy and reproducibility. DCIS lesions presenting the morphometric signature of small-sized DCIS ducts have a very low chance to progress to invasive breast cancer. After successful validation, our morphometric method will serve as a robust and easy to implement biomarker for de-escalation strategies in DCIS, and as such, could limit unnecessary overtreatment in the near future. Citation Format: Marcelo Sobral-Leite, Simon Castillo, Shiva Vonk, Xenia Melillo, Noomie Lam, Brandi de Bruijn, Yeman Hagos, Joyce Sanders, Mathilde Almekinders, Lindy Visser, Emilie Groen, Carolien Van der Borden, Petra Kristel, Ercan Caner, Leyla Azarang, Yinyin Yuan, Renee Menezes, Esther Lips, Jelle Wesseling, Grand Challenge PRECISION Consortium. Morphometric signature identifies ductal carcinoma in situ of the breast with low risk of progression to invasive 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 PS03-07.

Abstract PO5-26-11: The Breast Cancer Research Foundation Drug Research Collaborative – A unique and innovative model for industry-funded, academically driven research to advance the field of breast cancer

Abstract The Breast Cancer Research Foundation (BCRF) is committed to preventing and curing breast cancer through groundbreaking research. In pursuit of this mission, the BCRF launched the Drug Research Collaborative (DRC) in 2016—a pioneering program designed to bridge the gap between academic investigators and access to investigational therapies, thereby fostering greater academic-driven research in breast cancer. The DRC's primary objective is to fund independent, innovative, and high-quality investigator-initiated trials (IITs) and pre-clinical/translational research projects. In conventional drug development, industry-sponsored registration trials play a crucial role, leaving limited resources and scope for exploratory and translational IITs that fall outside the industry's drug approval strategy. Additionally, industry-funded IIT research faces challenges such as reputational risks, perceived influence during internal review processes, intellectual property (IP) concerns, and logistics/program management burdens. The BCRF-DRC program addresses these challenges by issuing requests for proposals to generate creative and unbiased ideas, which are then vetted through an academic review process involving leading breast cancer experts. The most promising research projects are selected for further advancement. The BCRF-DRC program is facilitated by the BCRF research staff, providing project management, while the Translational Breast Cancer Research Consortium (TBCRC), founded by the BCRF and also supported by Susan G. Komen, supports the clinical trial aspects of the program. Since its inception, the BCRF-DRC has expanded from one to three industry partners, securing a total funding of $25 million for 15 projects, including seven clinical trials and eight pre-clinical projects. This abstract reports on the ongoing progress and outcomes achieved by these three programs. The BCRF-DRC represents a revolutionary paradigm in research funding and collaboration by harnessing the collective power of industry partners, philanthropic organizations, and academic institutions. Through this collaborative effort, the BCRF-DRC provides a unique platform for researchers to accelerate the translation of scientific discoveries into effective clinical interventions, thus making significant strides in the field of breast cancer in the coming decades. By empowering academic investigators, fostering unbiased research, and addressing the limitations of industry-funded IITs, the BCRF-DRC is revolutionizing breast cancer research and driving the development of novel interventions. This abstract highlights the transformative potential of the BCRF-DRC program and its contribution to advancing breast cancer treatments and ultimately improving patient outcomes. The success of this collaborative model serves as a testament to the power of multi-sector partnerships and the pivotal role they play in shaping the future of breast cancer research. Citation Format: Unnati Jariwala, Dorraya El-Ashry, Judy Garber, Larry Norton. The Breast Cancer Research Foundation Drug Research Collaborative – A unique and innovative model for industry-funded, academically driven research to advance the field of 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 PO5-26-11.

Abstract PO1-06-09: Phase 2 Trial with Safety Run-In of Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast CancersBig Ten Cancer Research Consortium BTCRC-BRE18-337

Abstract Up to 2/3 of triple negative breast cancers (TNBC) have acquired defects in homologous recombination (HR) DNA repair, yet poly (ADP-ribose) polymerase inhibitor (PARPi) monotherapy has been largely ineffective in the absence of a germline BRCA 1/2 mutation (gBRCA1/2). Phosphoinositide-3-kinase (PI3K)/mTOR pathway alterations are also common in breast cancers. Preclinical data suggest that PI3K/mTOR inhibition may disrupt normal function of the HR complex and increase dependency on PARP enzymes for HR DNA repair. Thus, combining a PI3K/mTOR inhibitor with a PARPi may result in a synergistic anti-neoplastic effect. The run-in portion of this study evaluated the safety of weekly IV gedatolisib (PI3K/mTORi) and continuous daily talazoparib to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). A 3+3 design for dose escalation explored two dose levels. The phase II study began once the MTD and R2PD were confirmed. Eligibility required age ≥ 18, 1-2 prior lines of therapy (protocol later amended to allow up to 3 lines), and advanced TNBC or advanced HER2-negative BC with gBRCA1/2 mutation. The sample size for the phase II study was determined based on a 1-sided binomial test under the null and alternative ORR of 5% vs 20% with a type I error rate of 0.1 and power level of 80%. The primary endpoint was overall response rate (ORR) in TNBC without known gBRCA1/2 with secondary endpoints of progression-free survival (PFS) and overall survival (OS). Patients with a gBRCA1/2 mutation were not included in the primary endpoint analysis. Correlative studies are planned to evaluate HR deficiency mutations, PIK3CA mutations, and other exploratory genomics. A total of 33 patients were enrolled: 14 in the safety run-in phase of the trial and 19 in the phase II study (17 TNBC, 2 with gBRCA2 mutation). In the safety run-in, 6 patients were enrolled at dose level 1 (0.75 mg talazoparib po daily and 180 mg gedatolisib IV weekly) and 8 at dose level 2 (1 mg talazoparib po daily and 180 mg gedatolisib IV weekly). 42% of the cohort developed hyperglycemia, which was mostly grade 1. There was 1 DLT of grade 3 neutropenia at dose level 1. There were 3 patients who experienced grade 4 AEs, thrombocytopenia (2) and lymphopenia (1) which were outside of the DLT window. The MTD was 1 mg of talazoparib daily and 180 mg of gedatolisib weekly, and this was selected as the RP2D. A protocol amendment was made during the phase II portion to allow for a 3 week on/1 week off schedule for gedatolisib due to emerging data showing a more favorable safety profile and enhanced antitumor activity with this dosing schedule. In the 17 patients with TNBC and no gBRCA mutation in the phase II cohort, the ORR was 12%. Best response was partial response (PR) in 2 patients (12%), stable disease (SD) in 7 patients (41%), and progressive disease (PD) in 8 patients (47%). The clinical benefit rate (ORR+SD) at 16 weeks was 23.5%. The most common adverse events (AEs) in all 33 patients were anemia (70%), fatigue (67%), oral mucositis (64%), nausea (60%), neutropenia (45%) and anorexia (45%). Of these, most were grade 1-2 other than anemia (35% grade 3), neutropenia (20% grade 3), fatigue (18% grade 3), and oral mucositis (10% grade 3). There were no grade 4 AEs in the phase II study. Median PFS was approximately 3 months and median OS was approximately 6.4 months. Although this study did not meet its primary endpoint, there were 2 TNBC patients without a gBRCA1/2 mutation who achieved a partial response to this non-chemotherapy regimen. Future biomarker testing may help elucidate these findings and possible predictors of response. Citation Format: Sneha Phadke, Kari Wisinski, Oana Danciu, Ami Shah, Menggang Yu, Yi Chen, Kathy Miller, Mark Burkard. Phase 2 Trial with Safety Run-In of Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast CancersBig Ten Cancer Research Consortium BTCRC-BRE18-337 [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 PO1-06-09.

Abstract 3929: Comparative genomics of breast cancer in indigenous African and western populations first results from the E-Predict study

Abstract Breast cancer (BC) stands as the foremost female malignancy globally and is the most prevalent cancer in numerous developing countries, particularly in sub-Saharan Africa (SSA). Over the past decade, significant strides in comprehending the pathobiology of the disease and tumour dynamics have greatly enhanced treatment options, particularly in industrialized nations. Regrettably, SSA countries have witnessed only marginal, if any, improvements, with mortality rates surpassing incidence rates. Unfavourable outcome, early onset and high-grade tumours are predominant in SSA. Despite these challenging clinical phenotypes, there is currently a limited understanding of the primary molecular drivers, primarily due to a dearth of reliable data. Furthermore, there is a paucity of research conducted in, and pertinent to, the challenges of the disease in low-income countries (LICs), despite a rising incidence and higher mortality-to-incidence ratios. We thus established an international translational cancer research consortium in five distinct African countries. This initiative has contributed to the creation of a high-quality repository of biomaterials. Additionally, we have conducted whole exome sequencing on the initial 100 cases of breast cancer, comparing the molecular architecture of these tumors with data from The Cancer Genome Atlas (TCGA). We examining and compared the clinical disease phenotypes between indigenous African women and Western patients. A higher proportion of grade III tumors was observed in African patients aged between 30 to 59 years as compared to other patients within the same age group. In comparative molecular analyses, we found a significantly elevated tumor mutational burden in African patients (median of &amp;gt;15/MB) in contrast to other populations within the TCGA (median ~ 0.7/MB). Gene sets featuring co-occurring mutations, predicted to be associated with survival using the TCGA dataset, showed high mutation rates in the African cohort. Notably, co-occurring mutations between PIK3CA and genes linked to genomic instability, such as BIRC6 (HR: 11.7, p = 2.7e-05), KMT2C (HR: 4.7, p = 4.01e-04), NEB (HR: 3.84, p = 0.48), and PCLO (HR: 4.9, p = 0.016), among others, strongly correlated with poor overall survival and were highly mutated within the African cohort. Interestingly, within the TCGA, patients with early breast cancer onset exhibit twice as many mutations in KMT2C, a gene known for its association with DNA damage repair, genomic instability, and showed an improved response to immune checkpoint inhibition. These initial findings suggest that breast cancer genomics in indigenous African populations may exhibit substantial differences, potentially warranting consideration for distinct therapeutic modalities for these patients. Citation Format: Smiths Sengkwawoh Lueong, Pamela Derliche Tonouo Derliche Tonouo, Arnol Auvaker Tiofack, Rovaldo Nguims Kenfack, Jules Roger Kuiate, Esther Dina Mbassi, Sidonie Noa Ananga, Etienne Okobalemba Atenguena, Gustave Simo, Abdel Jelil Njouendou, Walters Ndaka, Zacharie Sando, Emmanuella Mayemi, Rachel Tayou, Gilles Gael Aghoagni, Anne Sango, Benjamin Pokam, Augustin Tozoula Bambara, Jens T. Siveke. Comparative genomics of breast cancer in indigenous African and western populations first results from the E-Predict study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3929.

Efficacy and safety of caspofungin for the treatment of invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease.

We assessed the efficacy of a 3-week primary or salvage caspofungin regimen in patients with chronic obstructive pulmonary disease (COPD) and concomitant proven or suspected invasive pulmonary aspergillosis (IPA). Forty-four patients were treated with an initial loading caspofungin dose of 70 mg, followed by a daily dose of 50 mg for 20 days. The main efficacy endpoint was clinical effectiveness. Secondary endpoints included the clinical efficacy of caspofungin after 1 week, therapeutic efficacy based on the European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, the sensitivity of different Aspergillus strains to caspofungin in vitro, and the safety of caspofungin. An assessment of 42 patients in the intention-to-treat group revealed efficacy rates of 33.33% within 1 week and 38.10% within 3 weeks. According to the EORTC/MSG criteria, the treatment success rate was 38.10%. The success rate of first-line treatment was 54.76%, whereas salvage treatment had a success rate of 45.24%. No adverse events were reported among the participants. Caspofungin is effective and safe as an initial or salvage treatment for patients with IPA and COPD.

Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial

BackgroundChildren with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real‑time treatment decisions for children with relapsed/refractory solid tumors.MethodsSubjects were divided into three strata: stratum 1—relapsed/refractory neuroblastoma; stratum 2—relapsed/refractory CNS tumors; and stratum 3—relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make real‑time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every two cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient clinical benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of complete response (CR), partial response (PR), stable disease (SD), no evidence of disease (NED), and progressive disease (PD) subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation.ResultsA total of 186 eligible patients were enrolled with 144 evaluable for safety and 124 evaluable for response. The average number of days from biopsy to initiation of the MTB-recommended combination therapy was 38 days. Patient benefit was exhibited in 65% of all subjects, 67% of neuroblastoma subjects, 73% of CNS tumor subjects, and 60% of rare tumor subjects. There was little associated toxicity above that expected for the MGT drugs used during this trial, suggestive of the safety of utilizing this method of selecting combination targeted therapy.ConclusionsThis trial demonstrated the feasibility, safety, and efficacy of a comprehensive sequencing model to guide personalized therapy for patients with any relapsed/refractory solid malignancy. Personalized therapy was well tolerated, and the clinical benefit rate of 65% in these heavily pretreated populations suggests that this treatment strategy could be an effective option for relapsed and refractory pediatric cancers.Trial registrationClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014.

Real-world outcomes of patients with operable renal cell carcinoma from the German translational cancer research consortium (DKTK) network.

394 Background: Nephrectomy and risk-adapted adjuvant pembrolizumab are standard treatments in localized renal cell carcinoma (RCC). Risk of recurrence from clinical trials is utilized to council patients. However, recurrence and survival in real-world practice may differ. We report real-world outcome data of patients with RCC from the German Cancer Consortium’s Clinical Communication Platform, a federated data warehouse infrastructure for oncological real-world evidence. Methods: Adult patients from routine care and nephron sparing surgery (NSS) or nephrectomy (Nx) for non-metastatic RCC between 2013-2022 at tertiary German cancer centers were retrospectively analyzed. Clear cell (cc), papillary (p) or NOS histologies were eligible. Kaplan-Meier-analyses were conducted stratified by pathological stage for DFS (Disease-Free-Survival) and OS (overall Survival). Results: 1,291 patients received NSS/Nx. 1,271 (98.5%) were R0/1. Median follow-up: 37.8 mo. (IQR 13.08; 65,74). 754 patients had ccRCC with a mean age of 63.5 y (SD: 12.1), 40% were female. 221 had pRCC, mean age was 62.1 (SD 12.6) and 36.8% were female. 165 had NOS, mean age was 63.3 (SD 12.4) and 36.8% were female. 151 patients had other histologies. Survival outcomes are reported in table 1. Conclusions: Morphologic RCC types and T-stages inform on recurrence and prognosis. Our study advises on real-world recurrence and survival rates in patients with different RCC types, which may be used to counsel patients with regards to adjuvant therapy in the clinic. A major limitation is the retrospective nature of the analysis. [Table: see text]

Patient involvement in research within the Gynecological Cancer InterGroup: A call to action for a systematic approach: Results from a survey.

Involving patients in research, not only as trial subjects, is not a newly established practice. Over the last two decades, patient roles have gradually expanded to become active research contributors, creating a more patient-centered research landscape. Our survey has explored the scope of patient involvement within the Gynecologic Cancer InterGroup (GCIG), an International Gynecologic Cancer Research Consortium, and identified challenges in developing a systematic, meaningful and sustainable level of patient involvement. In late 2019, the GCIG Harmonisation Operations Committee conducted an online survey across 26 national and/or international research cooperative groups, aiming to identify current patient involvement practices implemented by each group. Twelve questions were asked. The results have been generated to support a systematic strategic planning process to increase patient involvement into clinical research projects. More than half of the 26 participating groups have either already involved (15, [58%]) or are planning (6, [23%]) to involve patients in their research activities. Gaining patient support in raising public awareness around clinical trials appears to be one of the most desired benefits (21, [81%]). Ten respondents managed to integrate patient involvement into their standard practice. When involving patients in research the groups mostly consider that patients bring added value to the study (19, [73%]), although only eight groups (40%) have a well-organized process in doing so. Even though patient involvement is considered a significant added value to clinical research, its application within GCIG groups is not considered on a regular basis and is predominantly limited to operational aspects of research activities. The lack of resources and expertize, as well as the missing well-organized and structured process of some groups, combined with their ability to ensure process sustainability, are among the main factors affecting implementation and adoption of patient involvement within GCIG research activities.

Phase 1b/2 trial of Ipilimumab, Nivolumab, and Ciforadenant (INC) (adenosine A2a receptor antagonist) in first-line advanced renal cell carcinoma

Abstract Background Ciforadenant is an investigational immunotherapeutic small molecule that selectively and reversibly binds adenosine2A receptors (A2ARs) on T lymphocytes and other cells of the immune system. RCC metabolism is known to be highly glycolytic with a need to export adenosine triphosphate (ATP) to allow for continued proliferation of cancer cells. In the tumor microenvironment (TME) ATP is hydrolyzed to adenosine by CD39/CD73. Adenosine has immune suppressive effects on the TME through the A2 adenosine receptor (A2AR) including decreased T cell activation and proliferation (Ohta et al., 2009). Blocking A2AR on tumor associated myeloid cells such as macrophages, dendritic cells, and myeloid derived suppressor cells in preclinical mouse models have shown enhanced tumor killing (Cekic et al 2014). Preclinical studies show that the addition of ciforadenant to CTLA4 and PD1 blockade shows enhanced efficacy and in some cases elimination of the established tumors (Willingham et al., 2018). Recently, in a first in human study, the A2AR antagonist ciforadenant was found to be safe and showed activity as monotherapy in RCC patients with refractory disease following multiple lines of therapy showing a median progression free survival (mPFS) of 4.1 months (Fong et al., 2019). In the same study, the addition of ciforadenant to PD-L1 blockade with atezolizumab was shown to be safe and demonstrate activity with mPFS of 5.8 months and OS probability at 25 months of 90%. We hypothesize that the addition of the A2aR antagonist, ciforadenant, to the combination of ipilimumab and nivolumab will favorably modulate metabolic adenosine signaling and the myeloid compartment to enhance patient response by reducing immunosuppression. Methods INC is a Phase 1b/2 single-arm, multicenter study to assess safety and efficacy of the combination of ipilimumab, nivolumab, and ciforadenant in the frontline treatment of patients with advance clear cell renal cell carcinoma. This study is being conducted through the Kidney Cancer Clinical Trial Consortium. Eligibility criteria include untreated advanced clear cell RCC, ECOG PS 0 or 1, measurable disease by RECIST 1.1 and adequate organ function and excludes patients who have previously received immunotherapy. The study will include a lead-in safety phase 1b portion with enrollment of four to eight patients treated with ciforadenant 100 mg BID, nivolumab 3 mg/kg and ipilimumab 1 mg/kg (IV) q3 weeks. If the rate of patients with a dose limiting toxicity is more than 45% another four patients will be enrolled at reduced dose of ciforadenant 50 mg BID, nivolumab 3 mg/kg and ipilimumab 1 mg/kg IV q3 weeks. If continuing on trial, patients will receive nivolumab 480 mg infusion and ciforadenant beginning Cycle 2, Day 1 q4 weeks. In the Phase 2 dose-expansion portion of the study, 42 additional patients (total 50) patients consisting of untreated advanced clear cell renal cell carcinoma will be treated at the RCD determined in the Phase 1b portion of the study. The primary objective is to determine the safety and tolerability and to assess the depth of response (&amp;gt;50% by RECIST 1.1 Eisenhaur, 2009) based on a Bayesian design in patients with advanced RCC treated with ipilimumab, nivolumab, and ciforadenant. Secondary objectives will estimate the objective response rate (ORR), duration of response (DOR) progression free survival (PFS), progressive disease (PD) rate, and irAE rate of ipilimumab, nivolumab, and ciforadenant combination in untreated advanced RCC. Exploratory objectives include assessing gene expression signatures and pharmacodynamic parameters with outcome. This study is open to enrollment with six patients on trial anticipating lead-in safety analysis to be completed shortly for identification of randomized phase 2 dosing and opening the expansion cohorts. The trial will be open through the Kidney Cancer Research Consortium at MD Anderson, Vanderbilt University Medical Center, Duke University, and University of Pennsylvania. CDMRP DOD Funding: yes

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma

IntroductionOnly a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation...

Microbial regulation of anti-tumor immunity in colorectal cancer

Abstract Colorectal cancer (CRC) is one of the most common and deadly types of cancer. Although recent advances in early detection and revolutionary therapies such as checkpoint blockade immunotherapy resulted in improved outcomes in CRC, a large fraction of CRC patients, particularly with metastasis, do not respond well to existing immunotherapy modalities. This necessitates a better mechanistic understanding on tumor – immune cell interactions in the context of CRC. Microbiome influences multiple biological aspects of the host including immune responses against cancers. We recently defined a causal role for microbiome in regulating epithelial stem cell MHC-II expression and tumor initiation in the intestine. Here we expound on the significance of microbiome - MHC-II axis in CRC progression and metastasis. We found that colonization of microbes that correlate epithelial MHC-II expression in the intestine restricts CRC progression and improves overall survival in three different clinically-relevant orthotopic CRC models across mice strains. Notably, microbiome-induced anti-tumor effects are dependent on T cells. Finally, genetic inactivation of MHC-II in cancer cells diminished tumor preventing effects of microbes. These results underscore a causal role for microbe - MHC-II axis in regulating anti-tumor immunity during tumor progression. Microbes that boost MHC-II expression promote anti-tumor immunity in the colon, which may synergize with therapeutic approaches such as immunotherapy. NIH (P30CA045508-33 to S.B.), the Oliver S. and Jennie R. Donaldson Charitable Trust (S.B.), The Harold and Leila Y. Mathers Charitable Foundation (S.B), The Mark Foundation for Cancer Research (20-028-EDV to S.B.) and STARR Cancer Consortium (I13-0052 to S.B.), Chan Zuckerberg Initiative / Silicon Valley Community Foundation (2021-239862)

Abstract CT089: Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial

Abstract Background: Children with relapsed CNS tumors, neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. Here we describe a study to determine the feasibility of leveraging genomic profiling results within a molecular tumor board (MTB) to make real-time treatment decisions for children with relapsed/refractory solid tumors. Methods: Subjects were divided to 3 strata: Strata 1: Relapsed/refractory neuroblastoma, Strata 2: Relapsed/refractory CNS tumors, and Strata 3: Relapsed/refractory rare solid tumors. Samples were sent for tumor/normal whole exome (WES) and tumor whole transcriptome sequencing, and the genomic data were used in a MTB to make real-time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every 2 cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of CR, PR, SD, NED, and PD subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation. Results: 144 eligible subjects were enrolled with 144 evaluable for safety and 124 evaluable for response. Tumor types included neuroblastoma (n=31), CNS tumors (n=41), and rare tumors (n=72). Sarcomas (n=40) were the most common tumor type in the rare tumor stratum. The average time from biopsy to completion of DNA/RNA sequencing was 10 days (range 2-31 days); to completed analysis and drug prediction report, 17 days (8-41); 23 days (10-66) to MTB decisions; and 38 days (18-146) to initiation of the 4-drug combination agreed upon by the MTB. Treatments were selected on DNA and RNA findings in 19.5% of cases and in 80.5% on RNA alone. Patient benefit was exhibited in 70% of all subjects, 85% of neuroblastoma subjects, 73% of CNS tumor subjects, and 62% of rare tumor subjects. AEs occurred in &amp;lt;1% of the subject cohort. Grade 3 leukopenia was the only unexpected hematologic AE. There were 7 occurrences of unexpected non-hematologic AEs: grade 4 elevated ALT (1), grade 3 elevated AST (1), grade 3 dehydration (1), grade 3 infection (2), grade 3 oral mucositis (1), and grade 3 pancreatitis (1). Conclusions: It has been well-established that comprehensive genomic sequencing is the future of precision medicine. Here, we have demonstrated the feasibility, efficacy, and safety of a comprehensive sequencing model to guide targeted therapy for patients with any relapsed/refractory solid malignancies. Targeted therapy was well tolerated, and the response benefit rate of 70% in these heavily pretreated populations suggests that this treatment could be an effective option for relapsed and refractory pediatric cancers. Citation Format: Giselle L. Saulner Sholler, Jacqueline Kraveka, Genevieve Bergendahl, Elizabeth Lewis, William Ferguson, Abhinav Nagulapally, Karl Dykema, Valerie Brown, Michael Isakoff, Joseph Junewick, Deanna Mitchell, Don Eslin, Virginia Harrod, William Roberts, Javier Oesterheld, Randy Wada, Jawhar Rawwas, Devang Pastakia, Kevin Ginn, Raya Saab, Kevin Bielamowicz, Jason Glover, Eugenia Chang, Gina Hanna, Daniel Enriquez, Tyler Izatt, Rebecca Halperin, Sara Byron, William Hendricks, Jeffrey Trent. Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT089.

Abstract 1968: A multiomic spatial atlas of breast cancer in women of African ancestry

Abstract The US Black population consists of both US-born Black and immigrant Black populations from the Caribbean and Africa. Normal tissues in Black individuals, independent of their country of birth or residence, are woefully understudied. Yet, Black individuals disproportionately develop aggressive pathologic diseases and are treatment refractory or resistant, thus leaing to premature deaths. In women, breast cancer is more common among US Black women, and the most common non-viral driven cancer in African and Caribbean countries. Furthermore, Black women develop this disease younger than other ancestral groups and have a higher incidence aggressive pathologies, such as metaplastic and triple-negative breast cancer. With the African-Caribbean Cancer Consortium (AC3) and Transatlantic Gynecologic Cancer Research Consortium, we have created a multiomic spatial atlas of triple-negative and other breast cancers across Africa, the Caribbean, and among US-Black individuals. We performed ultrahigh-plex RNA and protein spatial phenotyping on the PhenoCycler-Fusion (PCF). The PCF is a fast end-to-end spatial biology platform that enables whole-slide spatial readouts of RNA and protein moieties at single-cell resolution. Multiomic spatial phenotyping of tissues allowed for the detection of novel cell populations associated with a given African ancestry linking unique immune/stromal cell types to the outcome and severity of breast cancer. Here, we aim to develop a benchmark that confidently measures and interprets ancestral genomic differences at the cellular level. Deciphering the relationship between African ancestry, aggressive disease biology, and early onset will enable the characterization of the tissue composition and the proportion of cell sub-populations implicated in tumorigenesis and the interplay with germline genetics. Citation Format: Jasmine T. Plummer, Nadezhda Nikulina, Ayodele Omotoso, Destiny Burnett, Priscilla Coelho, Simone Badal, Judith Hurley, Carmen Gomez, Ha Yeun Ji, Maycon Marcao, Felipe Dezem Segato, Oliver Braubach, Sophia George. A multiomic spatial atlas of breast cancer in women of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1968.