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Purpose Adjuvant chemotherapy reduces recurrence in early-stage triple-negative breast cancer (TNBC). However, data are lacking evaluating anthracycline + taxane (ATAX) versus taxane-based (TAX) chemotherapy in older women with node-negative TNBC, as they are often excluded from trials. The purpose of this study was to evaluate the effect of adjuvant ATAX versus TAX on cancer-specific (CSS) and overall survival (OS) in older patients with node-negative TNBC. Patients and methods Using the SEER-Medicare database, we selected patients aged ≥ 66 years diagnosed with Stage T1-4N0M0 TNBC between 2010 and 2015 (N = 3348). Kaplan–Meier survival curves and adjusted Cox proportional hazards models were used to estimate 3-year OS and CSS. Multivariant Cox regression analysis was used to identify independent factors associated with use of ATAX compared to TAX. Results Approximately half (N = 1679) of patients identified received chemotherapy and of these, 58.6% (N = 984) received TAX, 25.0% (N = 420) received ATAX, and 16.4% (N = 275) received another regimen. Three-year CSS and OS was improved with any adjuvant chemotherapy from 88.9 to 92.2% (p = 0.0018) for CSS and 77.2% to 88.6% for OS (p p = 0.048) for ATAX and OS was 91.0% for TAX and 86.4% for ATAX (p = 0.032). Conclusion While adjuvant chemotherapy was associated with improved clinical outcomes, the administration of ATAX compared to TAX was associated with inferior 3-year OS and CSS in older women with node-negative TNBC. The use of adjuvant ATAX should be considered carefully in this patient population.

PURPOSE OF REVIEW: In this review, we discuss targets of interest in Triple-negative breast cancer (TNBC), approved targeted agents and the results of the clinical trials that led to their approval. Additionally, we review ongoing clinical trials evaluating the use of novel targeted agents in the treatment of TNBC. RECENT FINDINGS: TNBC accounts for 15–20% of all breast cancer cases and is associated with worse clinical outcomes. Patients have a higher risk of metastatic recurrence and inferior overall survival compared to other breast cancer subtypes. Cytotoxic chemotherapy has historically been the mainstay of treatment for TNBC. In recent years, we have seen a surge in clinical trials investigating the use of targeted agents in TNBC and now have approval for targeted therapies in select patients. Inhibitors of PARP (olaparib and talazoparib), PD-L1 (atezolizumab) and an antibody drug conjugate targeting Trop-2 (sacituzumab govitecan-hziy) are now approved for the use in select groups of patients with TNBC. SUMMARY: Various novel targeted agents as monotherapy, dual targeted combinations, and chemotherapy combinations are currently under investigation. The results are promising and may significantly improve patient outcomes in TNBC.

Paraneoplastic neurologic diseases (PND) are rare but can occur in patients with common malignancies including breast cancer. In patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive breast cancer, PND have been reported in association with anti-Yo antibodies and with clinical presentation of paraneoplastic cerebellar degeneration. We describe the case of a woman with progressively altered mental status and seizures, ultimately requiring admission. Based on her clinical presentation, imaging findings, and evidence of neural-directed antibodies in her serum and cerebrospinal fluid, she was diagnosed with paraneoplastic limbic encephalitis (LE) due to an underlying HR-negative, HER2-positive breast cancer. She showed a transient response to immunosuppression but had more significant improvement after surgical resection and initiation of chemotherapy along with HER2-directed therapy. To the best of our knowledge, this is the first documented case of paraneoplastic LE in a patient with HR-negative, HER2-positive breast cancer likely caused by the production of an unclassified anti-neuronal antibody.

Patients with metastatic breast cancer (MBC) refractory to standard of care therapies have a poor prognosis. The purpose of this study was to assess patient characteristics and clinical outcomes for patients with MBC treated on phase I clinical trials. We performed a retrospective review of all patients with MBC who were enrolled in phase I clinical trials at the University of Colorado Cancer Center from January 2012 to June 2018. A total of 208 patients were identified. Patients had a mean age of 57 years and received on average 2.1 (range 0‐10) prior lines of chemotherapy. The majority of patients had hormone receptor‐positive/HER2‐negative breast cancer (58.6%) and 30.3% had triple‐negative breast cancer. The median progression free survival (PFS) was 2.8 months (95% CI, 2.3‐3.9) and median overall survival (OS) was 11.5 months (95% CI, 9.6‐13.2). Independent factors associated with longer PFS in multivariable analysis were treatment in a breast cancer‐selective trial or cohort (p = 0.016), age >50 years (p = 0.002), and ≤2 prior lines of chemotherapy in the metastatic setting (p = 0.025). Phase I clinical trials remain a valuable option for select patients with MBC and enrollment should be encouraged when available., We performed a retrospective review of all patients with metastatic breast cancer (MBC) who were enrolled in phase I clinical trials at the University of Colorado Cancer Center. Independent factors associated with longer PFS in multivariable analysis were treatment in a breast cancer‐selective trial or cohort, age >50 years, and ≤2 prior lines of chemotherapy in the metastatic setting. Phase I clinical trials remain a valuable option for selecting patients with MBC and enrollment should be encouraged when available.

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.

Purpose Adjuvant pertuzumab and neratinib are independently FDA-approved for treatment of early-stage HER2-positive breast cancer in combination with or following trastuzumab for one year, respectively. Both agents reduce the risk of recurrence; however, the absolute benefit is modest for many patients with added risk of adverse effects. The purpose of this study was to evaluate the clinical use of adjuvant pertuzumab and neratinib in patients with early-stage HER2-positive breast cancer. Methods Patients diagnosed with stage I–III HER2-positive breast cancer treated with trastuzumab at four University of Colorado Health hospitals between July 2016 and April 2019 were identified. Patient demographics, cancer stage, treatment, and administration of pertuzumab and/or neratinib were obtained. Results We identified a total of 350 patients who received adjuvant trastuzumab for stage I–III HER2-positive breast cancer; 253 (73.1%) had tumors that were ≥ T2 or node-positive disease. The rate of adjuvant pertuzumab use increased following FDA approval; pertuzumab was administered to the majority of patients with node-positive HER2-positive breast cancer. The use of adjuvant pertuzumab was associated with younger age, premenopausal status, and node-positive disease. Rates of administration of adjuvant neratinib were lower, with only 15.2% of patients receiving this therapy within 3 months of completing adjuvant trastuzumab. Conclusion In our cohort of patients treated within a diverse healthcare network, the majority of patients with node-positive HER2-positive breast cancer received adjuvant pertuzumab following FDA approval. The use of adjuvant neratinib was less common, potentially as a result of adverse effects, prolongation of therapy, previous administration of adjuvant pertuzumab, and modest benefit.

INTRODUCTION: Breast cancer is the most common malignancy in women in the United States and triple-negative breast cancer (TNBC) accounts for 15–20%. The standard of care for metastatic TNBC has been limited to cytotoxic chemotherapy with modest efficacy. TNBC is associated with high levels of tumor-infiltrating lymphocytes and PD-L1 expression, supporting the investigation of immune checkpoint inhibitors in this breast cancer subtype. AREAS COVERED: This review summarizes the clinical data supporting the use of atezolizumab and nab-paclitaxel in the treatment of metastatic PD-L1-positive TNBC. It examines the pharmacology and toxicity profile of the combination in patients with metastatic TNBC. EXPERT OPINION: The addition of atezolizumab to nab-paclitaxel prolonged progression-free survival in both the intention-to-treat and PD-L1-positive subgroups in the first line setting in patients with metastatic TNBC. The IMpassion 130 trial led to FDA-approval of this combination in patients with PD-L1-positive, metastatic TNBC and represents the first approval of immunotherapy for TNBC. This work supports ongoing investigations of other immunotherapy combinations in TNBC, predictive biomarker development and immunotherapy in patients with early stage TNBC. Immunotherapy combinations in TNBC have the potential to lead to improved survival in this group of patients with high risk disease.

3075 Background: OKI-179 is a novel, oral pro-drug analog of largazole, a compound in the romidepsin-depsipeptide class of natural products. OKI-006, the active metabolite of OKI-179, inhibits HDAC 1,2,3 (IC50 = 1.2, 2.4, 2.0 nM, respectively), with no significant inhibition of Class IIa HDACs and has shown promising activity in preclinical models of solid tumors. We conducted a first-in-human dose escalation study of OKI-179 in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, ECOG ≤1, normal QTc, and disease refractory to or with no available standard therapy options were treated with OKI-179 with either intermittent dosing (once daily for 4 days on 3 days off) or continuous dosing (once daily). Dose escalation was conducted using a standard 3+3 design. Pharmacokinetic (PK) and pharmacodynamic (PD) testing was performed at various time points after dosing. Results: As of Feb 4, 2021, 26 patients (19 female, 7 male) were enrolled with mean age of 63 (range 41-83). Patients received a median of 5 (range 1-11) prior lines of therapy and most common tumor types included pancreatic (N = 5), breast (N = 4), lung (N = 4), and ovarian cancer (N = 4). Twenty patients were treated in intermittent dosing cohorts from 30-450 mg. One DLT (Grade 2 [G2] thrombocytopenia) occurred in the 450 mg cohort which was expanded to 6 patients without subsequent DLTs. Six patients were treated in 2 continuous dosing cohorts of 200 mg and 300 mg. Two of 3 patients in the 300 mg cohort had DLTs of G3-4 thrombocytopenia and no DLTs were observed in 3 patients treated at 200 mg PO daily. The most common adverse events (AEs) were nausea (62%), fatigue (42%), anemia (39%), anorexia (27%), and vomiting (23%). These AE’s were G1-2 except for G3 anemia (12%), G3 fatigue (12%), and G3 anorexia (4%). No other G4-5 treatment-related AEs occurred. Median time on study was 79 days and best response was stable disease (SD) in 10 of 24 patients evaluable for efficacy (42%). Prolonged SD was observed in patients with platinum-resistant serous ovarian cancer (446 days) and adenoid cystic nasopharyngeal carcinoma (256 days). OKI-006 achieved consistent exposure with Cmax > 2,000 ng/ml and AUC > 8,000 hr*ng/ml, well above the targeted exposure for efficacy based on pre-clinical studies in murine models. Tmax was 2 hours and T1/2 was 6-8 hours. OKI-179 treatment resulted in > 3X increased T cell histone H3K9 and H3K27 acetylation within circulating PBMCs at doses of 180 - 450 mg. Conclusions: OKI-179 has a manageable safety profile, with thrombocytopenia being the on-target DLT. It has a favorable PK profile and demonstrated on-target PD effects at tolerable doses. The MTD and RP2D for OKI-179 was 450 mg daily for intermittent dosing and 200 mg daily for continuous dosing. Phase 2 studies are being designed, with a focus on combination with endocrine therapy in ER+ breast cancer and in NRAS-mutant melanoma. Clinical trial information: NCT03931681.

e12517 Background: HER2-positive breast cancers have a higher risk of recurrence, though systemic chemotherapy in combination with HER2-targeted agents significantly reduces this risk. Neratinib (N) is a small molecule inhibitor of HER2 that was shown in the ExteNET trial to improve invasive disease-free survival in patients with stage II-III breast cancer. The purpose of this study was to investigate factors associated with the use of adjuvant N in patients with HER2-positive breast cancer treated in the University of Colorado Health system (UCH). Methods: We performed a retrospective chart review of women diagnosed with stage I-III breast cancer who received adjuvant trastuzumab (T) between July 2016 and April 2019 at UCH to coincide with the approval of N in July 2017. We collected patient demographics, baseline characteristics, and cancer treatments. Results: A total of 350 patients were identified who received adjuvant T for treatment of stage I-III HER2-positive breast cancer within the inclusion timeframe. 234 patients (74.1%) were either ≥ T2 and/or node-positive at diagnosis as in the inclusion criteria of ExteNET. Of these, only 31 (13.3%) were prescribed adjuvant N within 2 months of completing adjuvant T. 81 (34.6%) received adjuvant pertuzumab (P) in addition to T. Of those who received N, 78.8% were ≥ T2 and 78.8% were node-positive. The average age of those receiving N was 49.3 versus 54.9 years in those not receiving N. Hormone receptor (HR)-positive disease was noted in 72.7% of those receiving N and 68.6% in those who did not (P = 0.624). The vast majority (97.0%) of patients were prescribed diarrheal prophylaxis with N. Patients receiving adjuvant N were less likely to have had a pathologic complete response (pCR) following neoadjuvant chemotherapy than those who did not receive N (23.1% versus 51.0%, P = 0.008). Of those who received N, 18 (54.5%) were treated at an academic hospital, where 34.2% of the total studied patient population was treated. Conclusions: The use of adjuvant N in patients with ≥ T2 or node-positive HER2-positive breast cancer in our patient population was low. Patients who did receive adjuvant N were more likely to have residual disease following adjuvant chemotherapy and be treated at an academic hospital. Despite the greater benefit of adjuvant N in HR-positive HER2-positive breast cancer in ExteNET, HR status did not correlate with the use of adjuvant N in our study. Trials assessing the additional benefit of adjuvant N in patients receiving adjuvant P or trastuzumab emtansine will likely be required prior to widespread use of adjuvant N.

e12505 Background: TNBC is an aggressive breast cancer subtype comprising approximately 15% of breast cancers. Adjuvant chemotherapy reduces the risk of recurrence, particularly in patients with tumors > 1 cm or node positive disease. Anthracycline (A) + taxane (T)-containing regimens are more efficacious than T-based regimens, however, the risk of cardiac toxicity is greater in older patients. We investigated the use of AT and T-containing regimens in patients ≥ 66 years old with node negative TNBC and evaluated clinical outcomes and cardiac risk factors. Methods: We identified female patients ≥ 66 diagnosed between 2010-2015 with TNBC node negative disease in the Surveillance, Epidemiology, and End Results (SEER) Medicare database. Baseline characteristics, including age, tumor size, cardiac history, and adjuvant chemotherapy administration (AT vs. T) were collected. A logistic regression analysis was performed to estimate independent predictors of AT vs. T chemotherapy. Overall survival (OS) was estimated at 3 years. Results: We identified 3348 patients, including 1679 (50.2%) who received chemotherapy for T1a/bN0 (32.5%), T1cN0 (55.5%), T2N0 (57.0%) and T3/T4N0 (49.6%) disease. Of those, 984 (58.6%) received T, 420 (25.0%) received AT and 275 (16.4%) received other chemotherapy. AT use was associated with larger tumor size; T1a/bN0 (13.6%), T1cN0 (21.3%), T2N0 (31.6%) and T3/T4N0 (34.9%). In a multivariate analysis, independent predictors of AT vs. T were age, region treated in the USA, tumor size and presence of prior cardiac risk factors or pre-existing cardiac disease. OS at 3 years was 91% for T and 86% for AT (p 0.03). Conclusions: Approximately half of older patients diagnosed with node negative TNBC received adjuvant chemotherapy. T-based regimens were more commonly used than AT regimens. Younger age, higher stage and lack of cardiac comorbidities correlated with use of AT compared to T. Continued investigation of the benefit of adjuvant chemotherapy in older patients may assist in clinical decision making.

Background: Immuno-oncology (IO) agents have demonstrated exceptional clinical benefit in patients with many tumor types, including melanoma and lung cancer. The PD-L1 inhibitor, atezolizumab, was recently FDA approved in combination with nab-paclitaxel for patients with PD-L1 positive triple-negative breast cancer (TNBC); however, single-agent PD-1/PD-L1 inhibitors demonstrate modest efficacy in breast cancer. The purpose of this study was to investigate the efficacy of IO agents in patients with metastatic breast cancer treated in phase I clinical trials. Methods: We performed a retrospective analysis using a database of patients with metastatic breast cancer who received treatment with IO agents in phase I/Ib clinical trials at the University of Colorado Anschutz Medical Campus from January 1, 2012 to July 1, 2018. Abstracted data included patient demographics, baseline characteristics, and clinical outcomes. Results: 208 patients with metastatic breast cancer were treated in phase I/Ib clinical trials; 43 were treated with an IO agent. The average age was 53 years old and 55.8% had hormone receptor-positive/HER2-negative breast cancer, 39.5% TNBC, and 4.6% HER2-positive disease. On average, patients received two prior lines of chemotherapy (range 0-7) in the metastatic setting. 31/43 patients (72.1%) received single agent or combination IO, and 12/43 (27.9%) received IO + chemotherapy. Median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 12.1 months in all patients. 9/43 (21%) of patients remained on study > 6 months and had a median PFS of 8.6 months. Patients remaining on study > 6 months were more likely to be treated with IO + chemotherapy compared to patients with a PFS < 6 months (77.8% v. 14.7%, p=0.0007). There was no difference in sites of metastasis, prior lines of chemotherapy, breast cancer subtype, absolute lymphocyte count, or LDH between patients with a PFS > 6 months compared to < 6 months. Conclusions: A subset of patients with metastatic breast cancer treated in phase I clinical trials at our center with an IO agent had derived prolonged clinical benefit. The benefit was not limited to patients with TNBC and was associated with receipt of chemotherapy in combination with IO. Predictors of response to immunotherapy in breast cancer beyond PD-L1 expression remain uncharacterized, and further research is needed to identify these factors. Citation Format: Jodi A. Kagihara, Jennifer A. Weiss, Andrew Nicklawsky, Dexiang Gao, Virginia F. Borges, Peter Kabos, Antonio Jimeno, Jennifer R. Diamond. Efficacy of immunotherapy agents in patients with metastatic breast cancer treated in phase I clinical trials [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A76.

Invasive plants such as Castor bean (Ricinus communis) are known to threaten ecosystems due to their competition for resources. The Ballona Wetlands and Temescal Canyon managers employ different techniques to manage the spread of R. communis, potentially resulting in differences in plant survivorship. To investigate this possibility, height of the stems of individual R. communis plants at each site were recorded in order to assign them to cohort groups. Based on the hypothesis predicted that R. communis would have a similar cohort structure at both sites but would exhibit higher survivorship at Temescal Canyon, where R. communis are removed less frequently than at the Ballona Wetlands. However, results indicate that management does not affect cohort structure or stability at either site, but rather, it may have contributed to the significantly higher overall survivorship of R. communis at Temescal Canyon.

In the green lynx spider Peucetia viridans (Hentz 1832), the two openings of a mated female's epigynum are often sealed by copulatory plugs, sometimes with the two-pronged distal portion of the paracybium of a male palpus inserted in each opening and embedded in the plugs. The presence of copulatory plugs and paracymbia may prevent further mating by the female. However, not all mated females exhibit these structures, perhaps allowing some P. viridans females to mate with more than one male, despite the assertion of Whitcomb & Eason (1965) that females only mate once. We investigated this possibility by surveying the extent of multiple paternity in field-collected P. viridans broods from southern California. For adult females and their egg sacs, we determined the aspartate aminotransferase genotype for each mother and her spiderlings using allozyme electrophoresis in order to assess whether the progeny data best fit with a single male as the father. Two broods exhibited clear evidence of multiple ...