Abstract P2-09-05: LCCC 1525: A phase II study of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer (mTNBC)

Background: Advanced triple negative breast cancer (TNBC) has a poor prognosis, with a median survival of approximately 12 months. Due to a lack of receptor targets, chemotherapy remains the mainstay of treatment. A subset of TNBC has defects in homologous recombination (HR) DNA repair due to germline BRCA mutations. Poly(ADP-ribose) polymerase (PARP) inhibitors have been shown to be an effective therapy in this subgroup. The phosphoinositide-3-kinase (PI3K) pathway inhibitors are also active in some breast cancers, lowering nucleotide pools required for DNA synthesis and S-phase progression. Preclinical studies suggest that PI3K stabilizes and preserves double strand break repair by interacting with the HR complex. Inhibition of PI3K/mTOR could impede PI3K interaction with the HR complex, thereby increasing dependency on PARP enzymes for DNA repair, and making this dual inhibition a rational combination. This trial is studying the safety and efficacy of combining the PI3K/mTOR inhibitor, gedatolisib, and the PARP inhibitor, talazoparib. Single-agent talazoparib is currently approved in advanced HER2 negative breast cancer with a germline BRCA 1/2 mutation. Trial design: This trial is designed with a safety run-in to determine the recommended phase 2 doses (RP2D) of the talazoparib and gedatolisib combination. The safety run-in will be followed by a phase II single-arm study of the combination, with 2 patient cohorts. Cohort A will be comprised of patients with advanced TNBC with negative or unknown germline BRCA1/2 status. Cohort B will be used for an exploratory analysis, comprised of patients with advanced HER2 negative breast cancer and a germline BRCA1/2 mutation. Eligibility Criteria: For the safety run-in phase, patients ≥18 of age with advanced breast cancer (defined as metastatic or unresectable) are eligible if they meet criteria for either cohort A or cohort B. For cohort A, all patients are required to have at least one line of prior systemic therapy for advanced breast cancer but no more than 2 lines of prior chemotherapy are allowed. For cohort B, no more than 2 lines of prior chemotherapy are allowed, with no limit on prior endocrine or targeted therapies. Patients with type I or poorly controlled diabetes are excluded due to the common side effect of hyperglycemia with gedatolisib. Specific aims: Primary objective of the safety run-in: Determine the RP2D of talazoparib in combination with gedatolisib in patients with advanced HER2 negative (triple negative or BRCA1/2 deficient) breast cancer. Primary objective of the phase II study: Estimate the objective response rate (ORR) in patients with BRCA1/2 negative, or unknown, advanced TNBC - Cohort A. Correlative analysis will include correlating the HR deficiency (HRD) score with clinical response in patients with TNBC. Statistical Methods: In the safety run-in, a 3+3 design will be used for dose escalation. Maximum tolerated dose (MTD) is decided when 6 patients are treated at a dose level with < 2 DLTs. The MTD will be the RP2D. The safety run-in (dose escalation) component will require 9-18 subjects. In the Phase II study, the primary endpoint for sample size justification is ORR for cohort A (TNBC). The null response rate of 5% will be compared to the alternative hypothesis of 20% ORR with a 1-sided alpha level of 0.1. Based on the exact binomial test, we propose 21 subjects to target a power level of 80%. ORR in cohort B is a secondary endpoint. Target Accrual: Our target accrual for the safety run-in is 9-18 participants. Assuming 10% of subjects will be not be evaluable for the primary outcomes, then the number of patients accrued to cohort A will be 24. Cohort B will remain at 12 since it is exploratory. Contact information: The study is being administered through the Big Ten Cancer Research Consortium and can be identified as BTCRC-BRE18-337. Citation Format: Sneha Phadke, Menggang Yu, Kathy Miller, Ami Shah, Oana Danciu, Kari Wisinski. Phase 2 trial with safety-run in of gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive HER2 negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-06-02.

The role of VEGF in triple-negative breast cancer: where do we go from here?

Background: Circulating Tumor cells (CTCs) are prognostic at baseline and first follow-up in patients with metastatic breast cancer (MBC). Using the most commonly used assay (CellSearch®), we have previously reported the ability to detect apoptotic vs. non-apoptotic CTCs in patients with MBC. However, there has been concern regarding the performance of the CellSearch® assay in patients with triple negative (TN) MBC. We hypothesized that CellSearch® is an effective assay in patients with TN MBC, and that CTC-apoptosis might further separate prognosis. Therefore, we studied CTCs in patients with TN MBC who participated in a prospective randomized phase II trial testing for activity of tigatuzumab (TIG) in combination with nanoparticle albumin-bound paclitaxel (nab-PAC) conducted by the Translational Breast Cancer Research Consortium (overall results reported by Forero A., et al, ASCO 2013). Methods: Whole blood (WB) was drawn into a CellSave tube at baseline, day 15, and day 29 and CTC counts were determined using the CXC CellSearch® kit. Apoptosis was characterized by staining with a monoclonal antibody that detects a neo-epitope on fragmented cytokeratin (M-30) and independently by visual inspection (nucleic condensation and/or fragmentation, as well as granular cytokeratin). Association between levels of CTCs and CTC-apoptosis with the overall response rate (ORR) and progression free survival (PFS) at baseline, day 15, and day 29 was assessed using logistic regression, Kaplan Meier curves, and Cox proportional hazards modeling. Results: Of the 60 patients entered into the trial, 52 were evaluable for CTCs. Of these, 19/52 (36.5%), 14/52 (26.9%), and 13/49 (26.5%) had elevated CTCs (≥5CTC/7.5 ml WB) at baseline, day 15, and day 29, respectively. Patients with elevated CTCs at each time point had worse PFS than patients with low or no CTCs. Hazard rates (HR) at baseline, day 15, and day 29 were 2.38 (95% CI: 1.27-4.45, p = 0.007), 2.87 (95% CI: 1.46-5.66, p = 0.002), and 3.40 (95% CI: 1.68-6.89, p = 0.001), respectively. The odds of overall response for those who had elevated CTCs compared to those who did not at baseline, day 15, and day 29, were 0.25 (95% CI: 0.073-0.81, p = 0.024), 0.18 (95% CI: 0.04-0.67, p = 0.014), and 0.06 (95% CI: 0.01-0.28, p = 0.001), respectively. There was no apparent prognostic effect comparing the degree of CTC-apoptosis vs. non-apoptosis. Conclusions: Similar to observations in other intrinsic subgroups, CTCs were detected in a large fraction of TN MBC patients at baseline using CellSearch® assay, and reductions in CTC levels reflected response. In these homogenously prospectively enrolled TN MBC patients, regardless of treatment, CTCs are prognostic at baseline, day 15, and day 29. It does not appear that analysis of CTC-apoptosis is prognostic. Supported by Susan G. Komen for the Cure, Veridex, LLC, Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale™ (DFH), Associazione Sandro Pitigliani and by a studentship from FIRC (CP), Triple Negative Breast Cancer Foundation, The AVON Foundation, and The Breast Cancer Research Foundation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-04-01.

Rationale and purpose: Triple negative breast cancers (TNBCs), characterized by lack of hormone receptors' expression in absence of HER2 amplification, partially overlap with the basal-like subtype, with frequent occurrence in BRCA1 mutation carriers (BRCA1+). TNBCs are often associated with earlier onset, interval cancer diagnosis, larger size and aggressive clinical course with peak risk of recurrence at 1-3 years and increased mortality rate in the first 5 years. Thus, when screening women at high risk of breast cancer, special attention should be paid to patient outcome for TNBCs in comparison with non-TNBCs. Our aim was to compare TNBCs and non-TNBCs diagnosed during a prospective, non-randomized, multimodality screening study – including clinical breast examination (CBE), mammography, ultrasound (US) and magnetic resonance imaging (MRI) – on women at familial/genetic high risk of breast cancer conducted in 18 centres from June 2000 to March 2008 (ISS-HIBCRIT-1; Sardanelli F et al, Invest Radiol 2011). Methods: Comparisons were performed using Mann-Whitney U, Fisher exact and χ2 tests. Results: Among the 44 patients diagnosed with invasive cancers, 14 (31%) were TNBCs and 30 (69%) non-TNBCs, the former being 13 invasive ductal (IDC) and 1 atypical medullary carcinoma, the latter also including 15/30 lobular subtypes and/or DCIS component (p=0.005). Of the 14 TNBCs, 10 (71%) were found in BRCA1+, 2 (14%) in BRCA2+ and 2 (14%) in BRCA-untested women with strong family history of breast/ovarian cancer; the same data for 30 non-TNBCs were 9 (30%), 6 (20%) and 15 (50%) respectively (p=0.028). We had only three interval cancers, all TNBCs. The median age at diagnosis was 49 years (range 36-62) for TNBCs and 53 years (range 35-72) for non-TNBCs (p=n.s). TNBCs presented a higher rate (11/14, 79%) of pathological grade 3 IDCs compared with non-TNBCs (8/30, 27%) (p=0.002). The mean tumor size was 1.6 cm for TNBCs and 1.2 cm for non-TNBCs (p=n.s). Nodal status was negative in 12/14 (86%) TNBCs and in only 16/30 (53%) non-TNBCs (p=0.038). MRI similarly outperformed CBE, mammography and US in both TNBCs and non-TNBCs. Clinical course and survival could be monitored for 40/44 patients (91%), 13 TNBCs and 27 non-TNBCs, with a follow-up of 5.8 and 6.3 years (p=n.s) respectively. The rate of disease-free patients for over 5 years was 8/13 (62%; mean disease-free interval 7.0 years, range 5.0-8.0) for TNBCs and 17/27 (63%; mean 7.2 years, range 5.2-9.9) for non-TNBCs. Death due to BC occurred for 2/13 TNBC (15%, at 3.5 and 4.2 years) and 3/27 non-TNBC patients (11%; at 2.0, 4.9 and 5.7 years). The rate of locoregional relapse was 1/13 (8%, at 4.4 years) and 5/27 (19%; mean time of 5.0 years, range 2.4-7.0) respectively. Distant recurrence was reported for only 2 non-TNBC patients. Conclusion: TNBCs showed stronger association with BRCA1+ status, lower rate of lobular subtypes or DCIS component, and less frequent nodal involvement. Despite a more frequent pathological grade 3 and the tendency to be diagnosed as interval cancers, under the current treatment protocols TNBCs showed relapse and BC-related death rates and over-5-year disease-free intervals similar to those of non-TNBCs. These data provide outcome evidence supporting the value of entering women at high risk of TNBC (in particular BRCA1+) in intensive screening programs including MRI. Citation Format: Franca Podo, Filippo Santoro, Siranoush Manoukian, Clelia de Giacomi, Laura Cortesi, Lorenzo Preda, Stefano Corcione, Francesco Sardanelli. High-risk patients found affected with breast cancer during a multimodality screening program: Triple negative versus non-triple negative breast cancers. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B13.

Introduction: Sacituzumab govitecan (SG) is FDA-approved for the treatment of both metastatic triple negative breast cancer (mTNBC) and hormone receptor positive (HR+)/HER2- metastatic breast cancer (MBC). In phase III clinical trials, SG caused grade 3 neutropenia in ∼50% of patients. However, the real-world incidence of SG-induced neutropenia and the practice patterns regarding the use of adjuvant growth factor use are not well characterized. Methods: In this single retrospective cohort study, we identified patients with HR+/HER2- or TNBC MBC who received SG between 2020-2024 per standard of care. We used manual review of electronic health records to identify key clinical characteristics, treatment history, safety parameters, and documented use of growth factor support via granulocyte colony stimulating factor (GCSF, either filgrastim or pegfilgrastim) while on treatment with SG. Results: We identified 74 patients with MBC who were treated with SG, including 45 patients with mTNBC (60.8%), 27 patients with HR+/HER2- MBC (36.5%), and 2 patients with heterogenous expression who were categorized as HR+/HER2+ MBC (2.7%). Median age was 56.5 years (range 28.4 - 81.1 years). Patients with mTNBC received a median of 2 prior lines of chemotherapy (range 0-5) and patients with HR+/HER2- disease received a median of 8 lines of prior therapy including 4 prior lines of chemotherapy (range 2-14 total lines, 0-8 lines of chemotherapy). Median time on SG was 4.4 months (range 0.26-39.8 months) for patients with mTNBC and 1.9 months (range 0.26-15.6 months) for patients with HR+/HER2- MBC. Most patients experienced any grade neutropenia while on SG (n=60, 81.1%), including most patients with mTNBC (n=37, 82.2%) and HR+/HER2- MBC (n=21, 77.8%). Grade 3 neutropenia was common during SG (n=39, 52.7%), with similar rates among patients with mTNBC (n=25, 55.6%) and HR+/HER2- MBC (n=12, 44.4%). Rates of neutropenic fever were low: in total 5/74 (6.8%), of whom 4/45 (8.9%) were mTNBC. A total of 8/74 (10.8%) patients were hospitalized for SG-related neutropenia with median length of stay 3.5 (range 1-10) days. Dose delays for any reason occurred in patients with mTNBC (n=18, 40.0%) and HR+/HER2- MBC (n=8, 29.6%), about half of which were due to neutropenia (for mTNBC n=7, 15.6%, HR+/HER2- MBC n=4, 14.8%). Dose reductions for any reason were also common among patients with mTNBC (n=21, 46.7%) and HR+/HER2- MBC (n=18, 66.7%), including some due to neutropenia (for mTNBC n=7, 15.6%, for HR+/HER2- n=4, 14.8%). Most patients discontinued SG due to disease progression for both mTNBC (n=43, 95.6%) and HR+/HER2- MBC (n=24, 88.9%). Two patients with HR+/HER2- MBC (7.4%) discontinued therapy due to toxicity. The remaining patients are still on therapy or discontinued for unrelated reasons. Most patients received GCSF during treatment with SG (n=64, 86.5%), most of whom received filgrastim (n=62, 83.8%) and a minority of whom received peg-filgrastim (n=7, 9.5%). In total 34/74 (45.9%) patients received primary GCSF prophylaxis and 24/74 (32.4%) patients received secondary GCSF prophylaxis. Rates of primary and secondary prophylaxis varied by subtype for mTNBC and HR+/HER2- respectively (primary: 37.8% and 55.6%; secondary: 40.0% and 22.2% respectively). Conclusion: In this single center retrospective study, >80% patients with mTNBC and HR+/HER2- MBC on SG experienced any grade neutropenia. Similar to published trials, nearly half of patients in both subgroups experienced grade 3 neutropenia but rates of hospitalizations and neutropenic fever were <10% in this heavily pre-treated, real-world cohort. Rates of SG dose reduction occurred in ∼50% of patients, but rates of discontinuation due to toxicity were low. GCSF prophylaxis, either primary or secondary, was used in ∼80% of patients. Additional studies are needed to clarify which patients may be at highest risk for SG-induced neutropenia and the optimal growth factor regimens to improve outcomes. Citation Format: Samantha Fisch, Joshua Chin, Laura Quintal, Melanie Majure, Michelle Melisko, Jo Chien, Hope S. Rugo, Laura A. Huppert. Single-center retrospective cohort study evaluating neutropenia and growth factor use with sacituzumab govitecan in patients with HR+/HER2- and triple negative metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-12-25.

PurposeTriple negative breast cancer (TNBC) is characterized by the presence of immune cells in the tumor microenvironment, however, the response to single-agent immune checkpoint inhibitor (ICI) therapy is modest. Preclinical...

Immune checkpoint blockade (ICB) monotherapy has produced limited benefit in breast cancer (BC) with response rates (RR) ranging from 5 to 23%. Combination ICB improved RR and progression free survival (PFS) resulting in atezolizumab + nab-paclitaxel receiving FDA accelerated approval for programmed cell death ligand 1 (PD-L1) positive, triple negative breast cancers (TNBC). BC has historically been considered immunologically quiet with most having a low mutational burden, low PD-L1 expression, defective antigen presentation machinery, and immuosuppressive signals in the tumor microenvironment (TME). An approach using a combination of immuno-oncology (IO) agents including ICB, immunomodulators and vaccines may shift the TME to allow for improved antigen presentation, the release of immunostimulatory cytokines, more immunogenic cell death and increased PD-L1 expression. The transcription factor brachyury plays an important role in breast tumor plasticity. High brachyury expression is associated with treatment resistance and a worse prognosis. Entinostat is a histone deacetylase inhibitor that has activity in multiple breast cancer subtypes. Preclinical data demonstrates entinostat upregulates MHC, enhances immune-mediated lysis and upregulates PD-L1 expression through epigenetic modification. Bintrafusp alfa is a bifunctional protein composed of the extracellular domain of the TGF-βRII receptor (TGF-β“trap”) fused to a human IgG1. Preclinical data shows bintrafusp alpha treatment increases T-cell trafficking, antigen-specific CD8+ T-cell lysis and NK cell activation. Monotherapy clinical studies with these agents have produced modest results in solid tumors, including BC. Preclinical data evaluating combinations of these agents shows a reduction in in tumor size, improved antigen-specific T-cell responses, reduced regulatory T cells, increased CD8+T-cells, and increased PD-L1 expression. We propose the stepwise addition of BN-Brachyury, Bintrafusp alfa, T-DM1 and Entinostat in advanced BC. This phase Ib study will assess efficacy and safety of the regimen and has three cohorts: Cohort 1(TNBC) will receive BN-Brachyury + Bintrafusp alfa. Cohort 2 (HER2+) will receive T-DM1 + BN-Brachyury + Bintrafusp alfa +/- entinostat. After safety is established in Cohort 2, patients in Cohort 3 (HER2+) will be assigned to receive T-DM1 + BN-Brachyury + Bintrafusp alfa +/- entinostat. Responses are evaluated every 2 cycles (6 weeks). Patients in Cohorts 2 and 3 will undergo research biopsies -baseline and after 2 cycles to evaluate changes within TME. Peripheral immune responses will be evaluated at selected time points. All patients must have measurable disease and HER2+ patients must have biopsiable disease. >1 prior treatment is required. Asymptomatic or brain metastases treated > 6 weeks are allowed. Well controlled HIV, HBV or treated HCV is allowed. Exclusion criteria include symptomatic brain metastases or clinically significant bleeding (<3 months from study entry). Co-primary objectives are RR and safety. Secondary objectives include PFS and changes in tumor infiltrating lymphocytes (Cohorts 2 and 3). Exploratory analyses include changes in immune cells and cytokines in the peripheral blood. Analyses performed will be descriptive, reporting the outcome measure for each treatment arm indicated along with two-tailed 80% and 95% confidence intervals. All cohorts employ a safety assessment in the initial 6 patients and a Simon minimax 2-stage design for clinical efficacy. We plan to recruit 51 patients: 13 patients with TNBC, 38 patients with HER2+BC. This trial will open Fall 2019 at the National Institutes of Health (Bethesda, MD). For more information contact the PI, Margaret.gatti-mays@nih.gov. Citation Format: Margaret E Gatti-Mays, Claudia Palena, Sofia R Gameiro, Renee N Donahue, Caroline Jochems, Seth Steinberg, Stan Lipkowitz, Alexandra Zimmer, Deneise Francis, Julius Strauss, Houssein Abdul Sater, Lisa Cordes, Jason Redman, Fatima Karzai, Marijo Bilusic, Ravi A Madan, James L Gulley, Jeffrey Schlom. A phase Ib trial of sequential combinations of BN-brachyury, entinostat, ado-trastuzumab emtansine (T-DM1) and bintrafusp alfa (M7824) in advanced stage breast cancer (BrEAsT) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-01.

LAG-3: another brake to release in breast cancer?

Background PARP inhibitors have proven efficacy in breast cancer patients with germline BRCA1 or BRCA2 mutations (gBRCAmt) but also have potential to be effective in cancers with defects in homologous recombination (HR) DNA repair. Moreover, synergy between PARP inhibition and immune checkpoint blockade is expected based on increased mutation burden, neoantigen expression, and immunogenic cell death. Triple negative breast cancer (TNBC) or low estrogen receptor (ER)-positive breast cancers may have diverse defects in HR repair. Methods This is a window of opportunity, serial biopsy trial of olaparib and durvalumab before standard neoadjuvant chemotherapy for TNBC or low ER+ breast cancer (NCT03594396). Patients had clinical stage II/III TNBC or low ER+ HER2- breast cancers where ER was expressed in 10% or lower in tumor cells. Olaparib 300mg bid was given for 4 weeks without rest. One dose of durvalumab 1500mg was given on day 15. Study tumor biopsy and blood sample were taken before the study treatment, after 2 weeks of olaparib before durvalumab, and 2 weeks after durvalumab at the completion of 4 weeks of olaparib. FDG-PET/MRI was taken at baseline, after 2 weeks, after 4 weeks of study treatment, and computed tomography (CT) scan at baseline and after 4 weeks. After the study treatment, standard neoadjuvant chemotherapy with 4 cycles of doxorubicin+cyclophosphamide followed by 4 cycles of docetaxel was given. Primary endpoint was the changes of tumor biology detected by serial tumor biopsy. Secondary endpoints were pathological complete response (pCR) rate, response rate, prediction of early metabolic response by functional HR status, and safety. Functional HR deficiency was assessed by counting RAD51 foci as a marker for HR repair in the baseline tumor tissues before and after 30Gy irradiation to induce DNA damage. Results Fifty-four female patients were enrolled (median age 40 years, range 24-68). ER was negative (TNBC) in 43 patients and low-positive in 11 patients. Clinical stage was II in 25 patients and III in 29 patients, and axillary lymph node involvement was in 47 patients. gBRCAmt was assessed in 53 patients and 16 (30.1%) harbored pathogenic mutations. Functional HR status as measured by RAD51 foci formation was deficient in 27 (50%) patients and proficient in 27 (50%) patients. Functional HR deficiency was related with early metabolic response by FDG-PET after 2 weeks of olaparib (response in 17/27 HR-deficient tumors [63.0%] vs. 7/27 HR-proficient tumors [25.9%]; p=.006). After 4 weeks of olaparib and durvalumab, HR-deficiency was still related to metabolic response (23/27 vs. 17/27, respectively; p=.062) but HR-proficient tumors also showed metabolic decline. Moreover, HR deficiency was also related with RECIST response measured by CT after 4 weeks (17/27 vs. 9/27; p=.029). As of June 2021, 40 patients completed the neoadjuvant treatment and surgery; among those, 30 achieved pCR (pCR rate 75%). Among 13 patients with gBRCAmt who underwent surgery, 11 achieved pCR (84.6%). Updated results on pCR will be presented. Conclusions Olaparib and durvalumab followed by standard neoadjuvant chemotherapy shows very high pCR rate in TNBC or low ER+ stage II/III breast cancer. Functional HR status as measured by RAD51 foci formation was predictive of early metabolic response to olaparib. Genomic and transcriptomic analyses are underway in the samples before, during, and after olaparib and durvalumab. Citation Format: Seock-Ah Im, Kyung-Hun Lee, Ahrum Min, Daewon Lee, Tae Yong Kim, Han Suk Ryu, Jiwon Koh, Gi-Jeong Cheon, Yoon-Jung Shin, Yujin Kim, Hyeong-Gon Moon, Wonshik Han, Han-Byoel Lee, Morgan Diolaiti, David Quigley, Alan Ashworth, Nariya Cho. Window of opportunity trial of neoadjuvant olaparib and durvalumab for triple negative or low ER-positive breast cancer [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 PD15-08.

Background: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. In recent years, major progress has been made in the treatment of metastatic breast cancer (MBC), especially for hormone receptor (HR) positive and HER2 positive MBC. In contrast, for most TNBC patients no targeted treatment options are available. Population-based data on overall survival (OS) of triple negative MBC are scarce and were totally missing for the Austrian population. Here, we present the overall survival (OS) results of triple-negative breast cancer patients included the MBC registry of the Austrian Study Group for Medical Tumor Therapy (AGMT). Patients and methods: The AGMT_MBC-Registry is a multicenter nationwide ongoing retrospective and prospective registry for MBC patients in Austria. Unadjusted, univariate survival probabilities of OS were calculated by the Kaplan-Meier method and multivariate hazard ratios (HR) were estimated by Cox regression models. In this analysis only patients with triple-negative MBC with available survival data were included. Results: As of 31/01/2019, 1,253 patients were included in the AGMT-MBC-Registry. Out of 1,219 evaluable patients with available survival data, 192 (17.8%) were triple-negative. Mean age at diagnosis of MBC was 59 (range 27-89), 44 patients (22.9%) were diagnosed with de novometastatic disease, 89 patients (46.4%) with metachronous MBC had a disease free survival (DFS) < 24 months, 134 (69.8%) were treated with (neo)adjuvant therapy, 114 (59.4%) had visceral disease at diagnosis of MBC, and number of involved metastatic sites at diagnosis was 1 in 102 (53.1%), 2 in 49 (25.5%), 3 in 24 (12.5%) and > 3 sites in 17 (8.9%) patients. Fifty-nine patients (49.5%) received at least one treatment-line which included bevacizumab. Bevacizuamb was combined with capecitabine, paclitaxel and gemcitabine in 38, 68 and 5 patients, respectively. Median OS of TNBC was 15.2 months (95% CI 11.4-18.9), compared to 32.9 months (95% CI 29.7-35.7) in the overall cohort. In multivariate analysis including established risk factors and clinically relevant variables, only three variables were significantly associated with OS in TNBC patients: disease free survival (<24 months vs ≥ 24 months or de novo MBC: HR 1.80 [95% CI 1.29-2.51]), visceral disease (yes vs no: HR 1.75 [95% CI 1.22-2.52]), and number of metastatic sites at initial diagnosis (2-3 vs 1: HR 1.81 [95% CI 1.26-2.60], > 3 vs 1: HR 3.05 [95% CI 1.66-5.61]). Conclusion: The poor prognosis of TNBC was confirmed in this population-based analysis. Besides known prognostic factors like de novo metastatic disease, DFS and visceral disease, the number of metastatic sites at initial diagnosis was identified as a novel independent prognostic factor in TNBC. Citation Format: Gabriel Rinnerthaler, Simon P Gampenrieder, Andreas Petzer, Christoph Tinchon, David Fuchs, Marija Balic, Sonja Heibl, Holger Rumpold, Daniel Egle, August F Zabernigg, Christian F Singer, Johannes Andel, Michael Hubalek, Michael Knauer, Richard Greil. Prognosis of triple negative metastatic breast cancer (MBC): Results from the AGMT_MBC-Registry [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-29.

Abstract: Trials in progress Authors: Dr Rachel Dear, A/Prof Christine Chaffer, Dr Beatriz Perez San Juan Title: 4CAST: A Phase 1b dose exploration and dose expansion, open-label study evaluating the safety and efficacy of INO-464 in combination with Chemotherapy in patients with metASTatic breast cancer. Problem statement: Metastatic triple negative breast cancer (mTNBC) has poor outcomes, with rapid progression and a median overall survival of 16 months. Standard treatment includes chemotherapy, with a possible role for immunotherapy. The antibody-drug conjugate sacituzumab govitecan was been granted recent approval. The development of new targeted treatments remains an unmet need. The androgen receptor is a mediator of chemotherapy-resistance in triple-negative breast cancer. Taxane and platinum-based chemotherapy induces cell plasticity and the emergence of chemotherapy-resistance. The androgen receptor (AR) antagonist, INO-464, but not abiraterone or enzalutamide, blocks chemotherapy induced cell plasticity to inhibit and primary and metastatic tumour growth. Three early-phase prospective clinical studies investigating anti-androgen therapy have demonstrated clinical benefit of single-agent AR-targeted agents in women with metastatic AR positive TNBC. The 450 mg daily start dose of INO-464 was well-tolerated and declared the recommended phase 2 dose. Preliminary laboratory data demonstrates an increase in survival and suppression of metastatic TNBC when INO-464 is used in combination with docetaxel. Methods: To determine the feasibility, safety and efficacy of INO-464 in combination with chemotherapy for the treatment of metastatic breast cancer. In Part 1 (dose exploration) of the trial we aim to establish the tolerability and safety and determine the recommended phase 2 dose of INO-464 when used in combination with docetaxel. Part 1 will recruit 6-18 females or males with locally advanced or metastatic breast cancer ie hormone receptor positive, HER2-positive or triple-negative breast cancer. In Part 2 (dose expansion) the clinical activity INO-464 and docetaxel in participants with metastatic triple negative breast cancer will be assessed. Results: Ethics approval for Part 1 of the trial was granted in May 2021. The trial received governance approval from St Vincent’s Hospital governance in June 2022. Recruitment commenced on the 1 July 2022. The trial has received 40 enquiries, of which three patients were eligible and one patient has consented to the trial and will be ready to start in the next two weeks. Conclusion: This investigator-initiated trial is an example of a collaborative effort between the Garvan Institute of Medical Research and the Kinghorn Cancer Centre at St Vincent’s Hospital. If the combination of INO-464 and docetaxel is shown to be safe we look forward to recruiting to the part 2 dose expansion phase across multiple Australian sites. This is study is registered with ClinicalTrials.gov NCT04947189. Disclosure of interests: A/Prof Christine Chaffer is the Managing Director of Kembi Therapeutics that is providing the investigational product for the clinical trial. Citation Format: Rachel F. Dear, Kathleen Batty, Beatriz Perez, Christine Chaffer. 4CAST: A Phase 1b dose exploration and dose expansion, open-label study evaluating the safety and efficacy of INO-464 in combination with Chemotherapy in patients with metASTatic 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 OT1-02-01.

BackgroundImmuno-oncology (IO) agents have demonstrated efficacy across many tumor types and have led to change in standard of care. In breast cancer, atezolizumab and pembrolizumab were recently FDA-approved in combination with chemotherapy specifically for patients with PD-L1-positive metastatic triple-negative breast cancer (TNBC). However, the single agent PD-1/PD-L1 inhibitors demonstrate only modest single agent efficacy in breast cancer. The purpose of this study was to investigate the efficacy of novel IO agents in patients with metastatic breast cancer (MBC), beyond TNBC, treated in phase I clinical trials at the University of Colorado.MethodsWe performed a retrospective analysis using a database of patients with MBC who received treatment with IO agents in phase I/Ib clinical trials at the University of Colorado Hospital from January 1, 2012 to July 1, 2018. Patient demographics, treatments and clinical outcomes were obtained.ResultsWe identified 43 patients treated with an IO agent either as a single agent or in combination. The average age was 53 years; 55.8% had hormone receptor-positive/HER2-negative breast cancer, 39.5% TNBC and 4.7% HER2-positive. Patients received an average of 2 prior lines of chemotherapy (range 0-7) in the metastatic setting. Most patients (72.1%) received IO alone and 27.9% received IO plus chemotherapy. Median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 12.1 months. Patients remaining on study ≥ 6 months (20.9%) were more likely to be treated with chemotherapy plus IO compared to patients with a PFS < 6 months (77.8% v. 14.7%). No differences in number of metastatic sites, prior lines of chemotherapy, breast cancer subtype, absolute lymphocyte count, or LDH were identified between patients with a PFS ≥ 6 months vs. < 6 months.ConclusionsOur phase I experience demonstrates benefit from IO therapy that was not limited to patients with TNBC and confirms improved efficacy from IO agents in combination with chemotherapy. A subset of patients with MBC treated in phase I clinical trials with an IO agent derived prolonged clinical benefit. Predictors of response to immunotherapy in breast cancer remain uncharacterized and further research is needed to identify these factors.

1086 Background: Patients with triple negative (ER, PR, Her2 negative) breast cancers do not derive benefit from Herceptin or hormonal agents. For them, conventional chemotherapy remains the only option. Recent data suggests that triple negative breast cancers (TNBC) have increased sensitivity to platinum agents. We conducted a retrospective analysis to determine the response rates of such patients treated with paclitaxel and carboplatin (TC) chemotherapy. Methods: Patients with metastatic/recurrent TNBC were included in our study. Chemotherapy administered at weekly (paclitaxel 80mg/m2 and carboplatin AUC2 on D1, D8, D15) or 3 weekly intervals (paclitaxel 175mg/m2 and Carboplatin AUC 5 on D1). ER and PR status was defined using IHC. Her 2 positive was defined by a positive FISH or 3+ IHC staining. Results: 101 patients with TNBC were diagnosed at our centre from 2002 to 2005 and of these only 23 patients had metastatic/ recurrent disease. 14 patients were treated with TC and therefore included in our analysis. Median age of patients was 53 yrs (range 36 to 68yrs). 3 patients had metastatic disease at diagnosis and 11 patients were treated for recurrent disease. Median time to recurrence for this subgroup was 20 months (range 8 to 224mths). 4 and 6 patients had prior adjuvant exposure to taxanes and anthracyclines respectively. Median prior lines of chemotherapy was 1 (range 0–4). Median number of disease sites in patients was 4. Eight patients (57%) experience a partial response (PR) with TC. 2 patients had stable disease and 4 progressive disease. Although no patients experienced complete response, 3 patients had good PR. One patient with metastatic disease had complete resolution of a large, 9cm locally invasive breast tumor after 3 cycles of TC. The second had a 90% reduction in volume of a large chest wall recurrence after 2 cycles TC. Patients who had 2 or 3 prior lines of chemotherapy also continued to show response. The median time to tumor progression was 16 weeks (range 4–28 wks). Conclusions: TC gives a high response rate in patients with metastatic/ recurrent TNBC. Patients with prior exposure to taxanes and those with large volume disease showed good response. Randomised trials are underway to compare the TC regimen with non-platinum containing doublets. No significant financial relationships to disclose.

Up to 40% of breast cancers have been shown to express the glucocorticoid receptor (GR), and activation of the GR is associated with poor prognosis in ER-negative breast cancer. We hypothesize that GR activation in breast cancer cells initiates anti-apoptotic signaling contributing to chemotherapy resistance. Based on our compelling preclinical data demonstrating that GR antagonism with mifepristone (mif) increases paclitaxel (pac) induced breast cancer cell death in vitro and in vivo, we conducted the first clinical trial of the combination of anti-GR therapy and chemotherapy in patients (pts) with metastatic breast cancer (MBC). Because the combination of mif and nab-paclitaxel (nab) had not previously been administered to pts, and because nab can result in cumulative neurotoxicity, a randomized, placebo-controlled, phase I design was used. Mif is known to inhibit CYP2C8, an enzyme involved in the metabolism of pac, thus plasma pac levels were monitored to evaluate for significant changes in clearance. A 3+3 dose escalation scheme was planned, with an initial nab dose of 100mg/m2 weekly and a mif dose of 300 mg/d for 2 days (day prior to and of nab infusion). For each dose level (DL), patients were randomized 3:2 to mif:placebo (p) for cycle 1 (C1). After C1, pts randomized to p were crossed over to receive mif at their assigned DL for the duration of study treatment. DL1 was deemed intolerable due to neutropenia, so the nab dose was decreased to 80 mg/m2 for DL2, and dose escalation of mif beyond 300 mg was halted. Serum cortisol and ACTH levels—biomarkers of effective GR blockade—were measured before and after mif treatment. Archival tumor was collected to determine tumor GR expression, and peripheral blood lymphocytes (PBLs) were collected to evaluate GR-target gene expression after mif. 9 pts were enrolled. Median age was 56 yrs (range 47-74). Median number of prior therapies for MBC was 2 (range 0-3). 8 pts had triple-negative breast cancer (TNBC), and 1 had ER+ disease. 8 of 9 pts had recurred after taxane-based therapy. 1 pt had a CR, 4 pts a PR, and 4 pts POD. 4 of 5 pts who responded to nab plus mif had previously relapsed after taxane-based therapy. 4 pts were treated at DL1 (2 mif, 2 p). Both pts randomized to mif experienced a dose-limiting toxicity (DLT) of neutropenia during C1. 5 pts were treated at DL2 (3 mif, 2 p), and 2 of the 3 pts randomized to mif for C1 experienced a DLT (neutropenia). Plasma pac levels were consistent with delayed clearance of nab when co-administered with mif for most pts. All pts were found to have a 2-fold or greater rise in their serum cortisol levels, demonstrating effective adrenal GR inhibition. Mif delays clearance of nab in most pts, and results in DLT. Given the inter-patient variability in delay of nab clearance by mif, co-administration produces unpredictable toxicity. However, given the responses seen in taxane-pretreated TNBC pts, GR antagonism is a promising approach for treating aggressive TNBCs. As neither carboplatin nor gemcitabine are metabolized, mif is unlikely to affect clearance of these agents. As they are widely used for advanced TNBC, both agents represent attractive chemotherapy partners for future clinical investigation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-21.

1024 Background: The plasmaMATCH trial was an open label platform trial, consisting of circulating tumour DNA (ctDNA) testing in ̃1000 patients with advanced breast cancer (ABC) linked to parallel treatment cohorts with therapies matched to mutations identified in ctDNA. Cohorts A-D have already reported (Turner N et al, Lancet Oncol 2020). Cohort E recruited patients with triple negative breast cancer (TNBC) without a targetable mutation identified at ctDNA screening, treating with olaparib (PARP inhibitor) plus ceralasertib (ATR inhibitor). Methods: Patients with TNBC who had received 1 or 2 lines of chemotherapy for advanced disease or relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300mg b.i.d continuously and ceralasertib 160mg qd on days 1–7 on a 28 day cycle, until disease progression. The primary endpoint was confirmed objective response rate by RECIST v1.1. Secondary endpoints included clinical benefit rate, progression-free survival (PFS) and safety. Biomarker analysis included response according to BRCA and somatic DNA repair gene status and ATM loss. Using a two-stage design with a target response rate of 25%, unacceptable response rate of 10%, alpha=2% and power=90%, ≥13 responses out of 69 evaluable stage 2 patients were required to infer efficacy (5/37 stage 1). Results: Between 17/09/18 and 5/10/20 75 patients enrolled in Cohort E of whom 70 were evaluable for response. The median age was 55.6 years. 42 (56%) patients had 1 and 13 (17.3%) had 2 prior line(s) of chemotherapy for metastatic disease. Efficacy is shown in Table. The most common grade ≥3 adverse events were: hypertension 12 (17%) and anaemia 9 (13%). Dose reductions and interruptions occurred in 19 (26.4%) and 34 (47.2%) patients respectively. Conclusions: The response rate to olaparib and ceralasertib did not meet pre-specified criteria for efficacy in the overall evaluable population. Responses were observed in patients without germline or somatic BRCA1/2 mutations. Translational analyses are underway to identify potential biomarkers of response in this population and will be presented at the meeting. Clinical trial information: ISRCTN16945804. [Table: see text]