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Background. Patients (pts) with early triple negative breast cancer (eTNBC) are at increased risk of breast cancer recurrence and death. Recent studies have focused on escalation of therapy, with current treatment standard of at least five drugs – and associated toxicities - for eTNBC. Though presence of residual disease after neoadjuvant therapy (NAT) as measured by residual cancer burden (RCB) helps guide addition of adjuvant treatment, more effective tools to tailor therapy are limited. Persistence of circulating tumor DNA (ctDNA) in the setting of residual disease is associated with high risk of distant recurrence. However, more sensitive minimal residual disease (MRD) assays are needed to potentially guide optimization of systemic therapy. Methods. TBCRC 030 is a phase II randomized study of 12 weeks of NAT single agent cisplatin or paclitaxel for stage II-III TNBC, followed by surgery. The primary objective of the parent study was to correlate baseline biomarker for homologous recombination deficiency and RCB by study arm. From this group, responders (RCB 0/1) and non-responders (RCB 2/3) from both study arms who did not receive additional NAT prior to surgery were selected for analysis from the study cohort, matched on baseline nodal status and tumor size. As a post hoc study amendment, available pts were followed for event free survival (EFS). Plasma samples were collected prior to treatment initiation (W0), at three weeks (W3), and at twelve weeks, prior to surgery (W12). Whole genome sequencing (WGS) was performed on primary tumor tissue to identify somatic mutations and design for each pt a tumor-informed, ctDNA assay tracking up to 1000 mutations to detect MRD. Detection limit was computed for each tested sample as previously described. For each sample assayed, we report tumor fraction (TFx) when MRD was detected and the detection limit at 90% power when MRD was not detected. Results. Of 139 study pts, 68 had complete tissue and plasma samples and no receipt of additional NAT. Of these, 22 were responders. These responders, and 22 matched non-responders were identified for analysis. Data from 22 pts – 11 responders, 11 non-responders - are described here; full analysis on all 44 pts will be presented at the meeting. Personalized ctDNA assays were designed targeting 434 to 1000 variants (median 1000) and applied to 66 plasma samples. At W0, 100% (22/22) were positive for ctDNA; 73% (16/22) and 55% (12/22) were positive at W3, and W12, respectively. In pts with T1-T2 tumors median TFx was 4.1e-3(7.8e-6, 3.4e-2) and 4.7e-1(4.3e-2, 9.0e-1) in pts with T3-T4 tumors. TFx decreased from W0 to W3 and from W0 to W12 in responders (Table 1). By W12, ctDNA had cleared in 7/8 pts with RCB 0, 1/3 with RCB 1, 2/8 with RCB 2, and 0/3 with RCB 3. Overall, ctDNA levels were broad with median TFx of 1.5e-3 (range 2.9e-6 to 0.90). Detection limit at 90% power for all tested samples was a median of 8.8e-6 (range 9.9e-7 to 6.8e-3). To investigate whether ctDNA persistence after NAT was associated with BC recurrence, we analyzed a separate group of all 8 pts with known recurrence and with complete data and samples. All pts had persistent ctDNA at W12 (median TFx 6.8e-3, [2.9e-6 to 6.6e-2]). Conclusions. After 3 weeks of NAT for eTNBC, ctDNA TFx decreased, with a 3900-fold change in responders and 18-fold change in non-responders. By W3, TFx for most pts with RCB 0/1 were below the 1 in 10,000 limit of detection for many currently available assays, emphasizing the need for sensitive tests to potentially guide therapy. Additional studies will determine if ctDNA-guided approaches in eTNBC can improve pt outcomes. Table 1: Tumer Fraction and Tumer Fraction Fold Change by Response to Neoadjuvant Therapy Citation Format: Heather A. Parsons, Timothy Blewett, Xiangying Chu, Sainetra Sridhar, Katheryn Santos, Kan Xiong, Vandana Abramson, Ashka Patel, Ju Cheng, Adam M. Brufsky, Justin Rhoades, Jeremy Force, Ruolin Liu, Tiffany A. Traina, Lisa Carey, Mothaffar Rimawi, Ahmed Elkhanany, Vered Stearns, Jennifer M. Specht, Harold Burstein, Antonio C. Wolff, Eric Winer, Nabihah Tayob, Ian Krop, Todd Golub, Erica L. Mayer, Viktor Adalsteinsson. PD11-06 Circulating tumor DNA association with residual cancer burden after neoadjuvant therapy in triple negative breast cancer in TBCRC 030 [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 PD11-06.

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Background: Addition of PI3K/mTOR inhibitor after progression on CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) can potentially restore sensitivity to CDK4/6i and prevent adaptive activation of the PI3K/mTOR pathway. To evaluate this hypothesis, we conducted a Phase Ib study of gedatolisib (G), a dual inhibitor of PI3K/mTOR, palbociclib (P) a CDK4/6i, and ET (with letrozole [LET] or fulvestrant [FUL]) in women with hormone receptor positive (HR+)/HER2- advanced breast cancer (ABC). Manageable toxicity and preliminary antitumor activity were observed in 35 patients(pts) enrolled in the dose escalation portion of the study (Forero-Torres, ASCO 2018) and 103 pts enrolled in the expansion portion of the study (Layman, SABCS 2021). Here, we report updated efficacy and safety data and sub-group analysis by PIK3CA mutation status in the four expansion study arms with a March 3, 2022, data cut-off. Methods: Pts with HR+/HER2- ABC were treated in four expansion arms: A) G+P+LET as first-line treatment, B) G+P+FUL as 2nd line treatment in pts without prior CDK4/6i; C & D) G+P+FUL as 2nd or 3rd line therapy in pts with prior CDK4/6i. P, LET, and FUL were administered at standard doses. G 180 mg was intravenously administered weekly in Arms A, B, and C and three weeks on/one week off in Arm D. The primary endpoint was investigator assessed objective response rate (ORR). Secondary endpoints included safety, duration of response and progression free survival (PFS). Results: Of the 103 pts treated with G+P+ ET in the expansion arms (A-D), 100% had measurable disease at baseline, 71% (73/103) lacked PIK3CA mutations (wild type; WT), 27% (28/103) had PIK3CA-mutations (MT), 70% (72/103) had evidence of bone metastases, and 59% (61/103) had liver metastases. The most frequent grade 3 and 4 treatment related AEs (TRAE) with G+P+ET included neutropenia (63%), stomatitis (27%), rash (20%), fatigue (11%) and hyperglycemia (7%). Treatment discontinuation due to TRAEs was 6.5% in Arm A, 15.4% in Arm B, 9.4% in Arm C and 3.7% in Arm D. Efficacy data for each arm is presented in Table 1. Promising ORR and PFS were seen in all arms regardless of PIK3CA mutation status. In Arm D, ORR was 63% overall, 73% in PIK3CA-MT pts, and 60% in PIK3CA-WT pts. Median PFS in Arm D was 12.9 months with a median follow up of 29 months. 60% and 48% of pts in the PIK3CA-MT and PIK3CA-WT Arm D sub-groups, respectively, were progression free at 12 months. Conclusions: These preliminary data demonstrate promising activity of G+P+ET combination in pts who were CDK4/6i-naïve and in those whose disease progressed on or after CDK4/6i therapy regardless of PIK3CA mutation status. Encouraging results in CDK4/6i treatment naïve patients warrant further evaluation of gedatolisib in combination with CDK4/6i treatment in the front-line setting. Arm D results provide a strong basis for the initiated Phase 3 study (VIKTORIA-1) in pts whose disease progressed on or after CDK4/6i therapy. Table 1. Efficacy Data by Expansion Arms Citation Format: Robert Wesolowski, Hope Rugo, Erica Stringer-Reasor, Hyo S. Han, Jennifer M. Specht, E. Claire Dees, Peter Kabos, Ulka Vaishampayan, Seth A. Wander, Janice Lu, Keerthi Gogineni, Alexander I. Spira, Anne F. Schott, Maysa Abu-Khalaf, Pratima Nayak, Brian F. Sullivan, Igor Gorbatchevsky, AND Rachel M. Layman. PD13-05 Updated results of a Phase 1b study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer: Subgroup analysis by PIK3CA mutation status [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 PD13-05.

Gastrointestinal symptoms are commonly reported as adverse effects of selective serotonin reuptake inhibitors (SSRIs), the first-line pharmacologic treatment for pediatric anxiety disorders; however, the temporal course of these symptoms during treatment, although believed to be transient, has never been prospectively evaluated. Additionally, rates of gastrointestinal symptoms and functional gastrointestinal syndromes in anxious youth are poorly understood. We examined gastrointestinal symptoms in youth with anxiety disorders during a double-blind, placebo-controlled trial of escitalopram (n = 51). Then, in a separate sample of prospectively treated children and adolescents with generalized, social and/or separation anxiety disorders (n = 56), we examined the frequency of gastrointestinal symptoms based on the Questionnaire on Pediatric Gastrointestinal Symptoms (QPGS) and ROME III criteria and the association of these symptoms with clinical and demographic characteristics using logistic regression. The frequency/severity of abdominal pain, diarrhea, bloating constipation or total gastrointestinal symptoms did not differ between patients receiving placebo (n = 25) or escitalopram (n = 26). However, escitalopram-treated youth had transient improvement in nausea/vomiting and total upper gastrointestinal symptoms during the first two weeks of treatment. ROME III criteria for functional gastrointestinal syndromes were present in 12/56 patients (21.4%). QPGS-related functional gastrointestinal syndromes and symptoms were unrelated to treatment, treatment type, or clinical or demographic variables. Gastrointestinal symptoms are common in youth with anxiety and SSRIs produce transient—rather than sustained—gastrointestinal symptoms. Assessing gastrointestinal symptoms prior to pharmacotherapy and discussing factors that increase (or decrease) the likelihood of transient SSRI-related symptoms in youth may decrease patient uncertainty related to side effects and decrease medication-related anxiety.

INTRODUCTION Neoadjuvant chemotherapy is standard treatment for locally advanced (LABC) or inflammatory breast cancer (IBC). We hypothesized adding sunitinib, a tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2 negative LABC or IBC. PATIENTS AND METHODS We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2 negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly x12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the Clinical-pathologic scoring + estrogen receptor (ER) and grade (CPS+EG) score. RESULTS Seventy patients enrolled and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple negative disease). When defining response as pCR and/or CPS+EG score ≤ 2, 47% were responders. In ER+ patients, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue. CONCLUSIONS Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR. However, 47% were responders using pCR and/or CPS+EG score ≤2. ER+ patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for ER+ patients.

PDF file - 103 KB, Figure S2A. Progression-free survival (PFS) for all patients treated on study (Kaplan- Meier estimates) Figure S2B. Progression-free survival (PFS) for patients treated at the MTD (DL3a) on study (Kaplan-Meier estimates) Figure S2C. Progression-free survival (PFS) for patients with hormone-receptor positive tumors treated on study (Kaplan-Meier estimates)

Purpose: Dasatinib is an Src family kinase inhibitor with modest activity in advanced breast cancer. We aimed to assess toxicity and maximum tolerated dose (MTD) for dasatinib plus capecitabine, estimate efficacy, and explore effects on angiogenesis.Experimental Design: Dose levels (DL) were dasatinib 50 mg twice daily (DL1), 70 mg twice daily (DL2 and DL3), or 100 mg daily (DL3a); plus capecitabine on days 1 to 14 of a 21-day cycle, at 825 mg/m2 twice daily (DL1 and DL2) or 1,000 mg/m2 twice daily [DL3 and DL3a (MTD)]. DL3a was expanded to evaluate safety/efficacy. Plasma samples were collected for biomarker analysis.Results: Thirty-one and 21 patients were treated in the escalation and expansion phases. Sixty percent of tumors were hormone receptor–positive. Most common adverse events (AE) were any grade nausea (58%), hand–foot syndrome (44%), diarrhea (33%), fatigue (33%), vomiting (31%), and asthenia (31%). Most common grade 3/4 AEs were hand–foot syndrome (12%), diarrhea (8%), fatigue (8%), pleural effusion (8%), and vomiting (6%). The MTD was defined at DL3a (capecitabine 1,000 mg/m2 twice daily and dasatinib 100 mg daily). Of 25 response-evaluable patients treated at DL3a, confirmed partial response was noted in 24% and stable disease in an additional 32%; median progression-free survival was 14.4 weeks. Significant decreases in plasma VEGF-A and increases in VEGFR-2 and collagen-IV were observed.Conclusions: Dasatinib 100 mg once daily plus capecitabine 1,000 mg/m2 twice daily were tolerable and were associated with clinical benefit in 56% of response-evaluable patients. Biomarker changes were consistent with an antiangiogenic effect. Clin Cancer Res; 19(7); 1884–93. ©2013 AACR.

Purpose: To determine, by molecular imaging, how in vivo pharmacodynamics of estrogen-estrogen receptor (ER) binding differ between types of standard endocrine therapy.Experimental Design: The ER has been a highly successful target for breast cancer treatment. ER-directed treatments include lowering ligand concentration by using aromatase inhibitors (AI) and blocking the receptor with agents like tamoxifen (TAM) or fulvestrant (FUL). We measured regional estrogen-ER binding by using positron emission tomography with 18F-fluoroestradiol (FES PET) prior to and during treatment with AI, TAM, or FUL in a series of 30 metastatic breast cancer patients. FES PET measured in vivo estrogen binding at all tumor sites in heavily pretreated women with metastatic bone soft tissue–dominant breast cancer. In patients with uterus (n = 16) changes in uterine FES uptake were also measured.Results: As expected, tumor FES uptake declined more markedly on ER blockers (TAM and FUL, average 54% decline) compared with a less than 15% average decline on estrogen-depleting AIs (P < 0.001). The rate of complete tumor blockade [FES standardized uptake value (SUV) ≤1.5] following TAM (5/5 patients) was greater than the blockade rate following FUL (4/11; 2-sided mid P = 0.019). Percent FES SUV change in the uterus showed a strong association with tumoral change (ρ = 0.63, P = 0.01).Conclusions: FES PET can assess the in vivo pharmacodynamics of ER-targeted agents and may give insight into the activity of established therapeutic agents. Imaging revealed significant differences between agents, including differences in the efficacy of blockade by different ER antagonists in current clinical use. Clin Cancer Res; 17(14); 4799–805. ©2011 AACR.

Purpose: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation–associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine.Experimental Design: A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response.Results: Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1–6.7).Conclusions: Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib's contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation–associated breast cancer. Clin Cancer Res; 22(12); 2855–64. ©2016 AACR.

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Although tightly coupled in most normal tissues, blood flow and metabolism are often not well matched in tumors. A flow-metabolism mismatch, specifically, high metabolism relative to blood flow, can be recognized in tumors by functional and molecular imaging and is associated with poor response to treatment and early relapse or disease progression. (Clin Cancer Res 2009;15(17):5294–6)

Table S1: Schedule of pharmacokinetic analysis; Table S2: Overview of study dose levels (N=50); Table S3. Adverse events reported at any time during study therapy: grade 3-4 adverse events; Table S4: Veliparib pharmacokinetic (PK) parameters by cohort; Table S5: Total and ultrafilterable platinum pharmacokinetic parameters by cohort; Table S6: Immunohistochemistry results for 28 pre-therapy samples; Figure S1: Veliparib Cmax (ng/mL, panel A) and veliparib AUC0-6 (hr*ng/mL, panel B) by dose Cohort; Figure S2: Veliparib pharmacokinetic parameters (A) Cmax and (B) AUC0-6 at cycles 1 and 4 by cohort; Figure S3: Ultrafilterable platinum pharmacokinetic parameters Cmax and AUC0-24 at cycles 1 and 4 by cohort; Figure S4: Consort 2010 flow diagram for exploratory efficacy analysis comparing germline BRCA mutation positive to wild type; Figure S5: PAR assay results (pg/mL) for 14 patients in dose cohorts 6-8 (120-200 mg)

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PDF file - 212 KB, Figure S1A. Proportion of cell growth inhibition with the combination of dasatinib and 5- fluorouracil (5FU) in KPL4 breast cancer carcinoma cells in vitro Figure S1B. Proportion of cell growth inhibition with the combination of Dasatinib and 5- FU in HCC70 breast carcinoma cells in vitro Figure S3A. VEGFA changes by patients over baseline who were treated with Dasatinib and 5-FU (current study: CA18004; NCT00452673) Figure S3B. VEGFR2 changes by patients over baseline who were treated with Dasatinib and 5-FU (current study: CA18004; NCT00452673) Figure S3C. Collagen IV (Col-IV ) changes by patients over baseline who were treated with Dasatinib and 5-FU (current study: CA18004; NCT00452673) Figure S3D. VEGFR2 changes in value by patients over baseline (prior single dasatinib studies: CA180059 / NCT00371254 and CA180088/NCT00371345) Figure S3E. Collagen IV (Col-IV ) changes in value by patients over baseline (prior single dasatinib studies: CA180059 / NCT00371254 and CA180088/NCT00371345) Figure S3F. VEGFR2 changes in percentage over baseline (prior single dasatinib studies: CA180059 / NCT00371254 and CA180088/NCT00371345) Figure S3G. Collagen IV (Col-IV ) changes in percentage over baseline (prior single dasatinib studies: CA180059 / NCT00371254 and CA180088/NCT00371345)

PDF file - 25 KB, Table S3C . Changes in biomarkers in patients treated with single agent dasatinib on trials CA180059 + CA180088

Related Article from Blood Flow-Metabolism Mismatch: Good for the Tumor, Bad for the Patient

Arbeitsstress, der als ursachlich fur Burnout betrachtet wird, kann zu einem erhohten kognitiven und emotionalen Hyperarousal fuhren. Dieses Hyperarousal ist einer der Schwerpunkte des „Teufelskreis-Modells der chronischen Insomnie“, wodurch der Zusammenhang zu Schlafstorungen unter Arbeitsstress und Burnout deutlich wird. In dieser Ubersichtsarbeit werden Originalstudien zum Thema Schlaf und Burnout zusammengefasst und Limitationen bisheriger Forschung beschrieben. Es zeigt sich ein vielfach bestatigter querschnittlicher negativer Zusammenhang zwischen Schlafqualitat und Burnout. Obwohl es eine Vielzahl an querschnittlichen Studien gibt, wird die Generalisierbarkeit der Befunde aufgrund des starken Fokus auf gesundheitsbezogene Berufe eingeschrankt. Inkonsistent sind jedoch die wenigen Befunde zu langsschnittlichen Zusammenhangen zwischen Schlafqualitat oder Schlafstorungen und Burnout. Es bleibt vor allem offen, ob geringe Schlafqualitat oder Schlafstorungen ein Burnout vorhersagen konnen. Gleichwohl gibt es einen starken negativen Zusammenhang zwischen Schlafqualitat und Burnout, der im therapeutischen Setting mitberucksichtigt werden sollte. Neben psychoedukativen Masnahmen wird auch die kognitive Verhaltenstherapie fur Insomnie bei Burnout mit Schlafstorungen sowie generell die Reduktion des arbeitsplatzbezogenen Stressniveaus durch konkrete kurzfristige und langfristige Strategien empfohlen.

Background: 18F-Fluorodeoxyglucose (FDG) has long been used for measuring tumor glycolytic activity in clinical PET imaging. The FDA recently approved 18F-Fluoroestradiol (FES) (Cerianna) as a PET imaging tracer for characterizing disease in patients with estrogen-receptor positive (ER+) breast cancer. As FES PET enters clinical practice it is important to establish its utility in the full population of hormone-receptor positive patients, including for patients with human epidermal growth factor 2 (HER2)-overexpressing tumors. Patients with HER2-positive metastatic breast cancer have historically been treated with combination cytotoxic and HER2-directed therapy, with the understanding that HER2 is the primary driver in this disease state. This retrospective study examined uptake in matched lesions for both FES and FDG PET and compared activity in patients with HER2 positive versus HER2 negative metastatic breast cancer. Methods: Patients were selected from the UW research database who had a history of biopsy-proven primary ER+ breast cancer as well as FES and FDG PET scans within 30 days. We examined FDG and FES scans and recorded SUVmax in up to 16 matched lesions between the two scans. Patients were also divided by HER2 status (+/-). In addition, a subset of patients who underwent at least 2 paired FDG and FES scans were reviewed. Results: 270 matched FDG and FES scans were analyzed in 216 patients with history of ER+, and HER2+ or HER2- breast cancer who were not part of an ongoing clinical trial. 158 (73%) had ductal disease, 38 (18%) had lobular disease. 183 (85%) had HER2- breast cancer. Of the 33 patients who had HER2+ breast cancer, 28 (85%) had ductal carcinoma. 40 patients underwent serial scans, allowing tracking over multiple timepoints. A total of 1323 metastatic sites were recorded (average = 5/scan (range 1,16)), with the majority (71%) representing bony lesions. No difference in quantitative FES or FDG avidity was observed between soft tissue and osseous sites. FES and FDG SUVmax were similar among patients with either HER2- or HER2+ breast cancer (Table 1). Among 40 patients with multiple paired FDG and FES scans, 26 (65%) had 2 scans while the remaining 14 had 3, with FES avidity remaining stable over time. There was no correlation between FES or FDG scans and HER2 status. Conclusion: In a cohort of ER+, HER2+ and HER2- patients undergoing concurrent FDG and FES PET scans, FDG and FES activity was similar regardless of HER2 status. FES uptake in both HER2- and HER2+ patients and stability over time in serial scans suggest that HER2 does not affect ER density. This suggests that in many patients with so-called “triple positive” disease, endocrine therapy may offer a powerful primary rather than ancillary tool in select patients. FES combined with FDG PET may offer utility in predicting and assessing response to therapy in this patient population. Table 1. FES and FDG uptake in patients with HER2- or HER2+ disease Citation Format: Natasha Hunter, Lanell M. Peterson, David A. Mankoff, Mark Muzi, Delphine Chen, William R. Gwin, Shaveta Vinayak, Nancy E Davidson, Jennifer M. Specht, Hannah Linden. Fluoroestradiol (FES) and Fluorodeoxyglucose (FDG) PET imaging in patients with ER+, HER2+ or HER2- 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 P2-03-17.

Background: 18F-FES is an FDA-approved estrogen analogue PET imaging tracer (Cerianna) which measures tumor estrogen receptor (ER) expression at multiple tumor sites simultaneously and predicts response to endocrine therapy. 18F-FDG is a commonly used glucose PET imaging tracer which measures glycolytic metabolic activity in tumors. Elevated plasma ctDNA has been associated with an increased risk of relapse and can identify actionable genomic alterations. This pilot research study explored the relationship between somatic copy-number variants (CNVs) and cell-free DNA mass using low-pass-whole-genome (LPWG) ctDNA in the blood to FES and FDG PET/CT findings with both qualitative and quantitative image analysis in metastatic breast cancer patients. Methods: Two(2) 10ml Streck tubes were collected from 20 patients with metastatic ER+ breast cancer +/-30 days of their FDG-PET/CT scan (n=19) or their FES-PET/CT scan (n=9). 8 patients had both scans. Somatic mutations were assessed using comprehensive genomic profiling of tissue samples from 19 patients using the clinically validated UW-Oncoplex assay. Qualitative analysis included detection of LPWG ctDNA, presence of PIK3A mutations in tissue, and intensity of uptake in PET/CT imaging. LPWG ctDNA of blood samples evaluated ctDNA mass and CNVs that comprised at least 8% of total ctDNA. Total lesion glycolysis (TLG) in FDG scans and total lesion estrogen receptors (TLER) in FES scans were calculated using a dedicated workflow in MiM software (MiM Software Inc. Cleveland OH). Quantitative analysis included the circulating fraction (ctDNA), PET/CT SUVmax of the index lesion, number of lesions, TLG and TLER. For TLG, the threshold for determining measurable lesions was calculated using liver SULmean + 1.5*SD. The threshold for TLER was calculated using SUVmean of the mediastinal blood pool. The ctDNA fraction and the number of lesions for both FDG and FES were each ranked into 3 categories. FDG and FES data (SUVmax of index lesion, # of lesions, and TLG or TLER) were correlated to the calculated ctDNA fraction values. TLG and TLER were also correlated to each other. Results: ctDNA was classified as no ctDNA present (n=9), ctDNA present (n=8) and indeterminate (n=3). Average neoplastic ctDNA fraction was 0.114 (range 0.03-0.423). PIKC3A mutations were: 10 absent and 9 present. Ranked categories for ctDNA fraction, FDG TLG and FES TLER are shown in Table 1. Table 2 shows results of FDG and FES analysis and correlation with ctDNA. Ranked ctDNA findings correlated with both the FDG number of lesions (R2=0.69) and TLG (R2=0.83), but not the SUVmax of the index lesion (R2=0.29). Correlation decreased for ctDNA versus FES number of lesions (R2=0.51), TLER (R2=0.61), and SUVmax of index lesion (R2=0.16). TLG and TLER significantly correlated with the 8 patients that had both an FDG and FES PET/CT scan (R2=0.77). Conclusions: In this pilot study, FDG TLG showed a significant correlation with ctDNA. There is an encouraging association with ctDNA fraction and number of FDG lesions and with ctDNA fraction and extent of FES avid disease (TLER) in the 9 patients that had FES. Research Support: RG1005258 Table 1. Categorical rankings for qualitative analysis of ctDNA, TLG and TLER Table 2. FDG and FES imaging results and correlation with ctDNA Citation Format: Natasha Hunter, Lanell M. Peterson, Mark Muzi, Eric Q. Konnick, Jonathan Reichel, Paul Kinahan, Jennifer M. Specht, Rachel Yung, William R. Gwin, Hannah Linden, Christina Tran. Pilot study to evaluate circulating tumor DNA (ctDNA) to PET/CT imaging using 18F-Fluorodeoxyglucose (FDG) and 18F-Fluoroestradiol (FES) PET/CT imaging as biomarkers 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 P2-03-25.

In the past 5 years, the treatment options available to patients with HER2+ breast cancer brain metastasis (BCBM) have expanded. The longer survival of patients with HER2+ BCBM renders understanding the toxicities of local therapies even more important to consider. After reviewing the available literature for HER2 targeted systemic therapies as well as local therapies, we present a simplified algorithm for when to prioritize systemic therapies over local therapies in patients with HER2+ BCBM.

Background Treatment options for metastatic breast cancer (MBC) refractory to anthracyclines and taxanes are limited. In a phase III trial, eribulin demonstrated a significant improvement in overall survival compared to treatment of physician’s choice, but had limited tolerability because of neutropenia and peripheral neuropathy. Based on prior studies of alternative treatment schedules with other therapies, we hypothesized that a low-dose metronomic schedule of eribulin would permit patients to remain on treatment more consistently without treatment delays, resulting in longer time to progression, and improved toxicity profile. Methods We conducted a multi-site single arm, phase II trial patients with MBC. All patients were treated with metronomic eribulin (0.9 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle.) Treatment was continued until the patient developed disease progression, unacceptable toxicity, or chose to stop the study. Patients must have had prior taxane exposure. The primary endpoint was progression-free survival. Secondary end points were overall survival, response rate, and clinical benefit rate. Exploratory biomarkers were performed to analyze change in levels of circulating endothelial cells (CECs), circulating endothelial precursors, and carbonic anhydrase IX (CAIX) with response to therapy. Findings We consented 86 patients and 59 were evaluable for final analysis. Median age was 59 years; 78% had HER2 negative tumors. The median progression-free survival (PFS) was 3.5 months with overall survival (OS) of 14.3 months. Objective response rate was 15% with clinical benefit rate of 48%. Reported grade 3 neutropenia and peripheral neuropathy were 18% and 5%, respectively. Treatment discontinuation due to toxicity was seen in 3% of patients. Interpretation Metronomic weekly low-dose eribulin is an active and tolerable regimen with significantly less myelosuppression, alopecia, and peripheral neuropathy than is seen with the approved dose and schedule, allowing longer duration of use and disease control, with similar outcomes compared to the standard dose regimen.

Being installed as close as 5.5 mm to the beam axis, the Micro Vertex Detector (mvd) of the cbm experiment will be exposed to a sizable flow of heavy beam ions and nuclear fragments. The cmos Monolithic Active Pixel Sensor for the mvd, mimosis, must resist the related heavy ion impacts without permanent damage or frequent interrupt of operation as caused by single event effects (see). We motivate the requirements on the sensor and introduce our concept for protecting the device against sees. Moreover, we report the results of a related test campaign carried out with the first full size sensor prototype, mimosis-1, and different heavy ion beams at gsi.

huMNC2-CAR44 is a second generation CAR that recognizes the growth factor receptor form, MUC1*, does not bind to full-length MUC1, hits a wide range of cancers and shows to little or no binding to normal tissues and is the first therapeutic tested in humans targeting the MUC1 transmembrane cleavage product called MUC1*. A 1st-in-human clinical trial of huMNC2-CAR44, NCT04020575, for metastatic breast cancers is underway at the Fred Hutchinson Cancer Research Center. MUC1 biology has historically been poorly understood. Several flawed reports are still widely cited in the literature. We will present data that de-bunks current MUC1 dogma. Namely, we will demonstrate that full-length MUC1 plays no role in tumorigenesis. The cleaved tandem repeat domain does not form a heterodimer with the remaining transmembrane portion. We demonstrate that elimination of full-length MUC1 greatly accelerates tumor growth in vitro and in vivo. MUC1* is a Class I growth factor receptor that is activated by ligand-induced dimerization of its truncated extra cellular domain, which activates the MAP kinase signaling pathway as well as survival pathways. Onco-embryonic growth factor NME7AB binds to an ectopic site on MUC1* that is only unmasked after MUC1 is cleaved and the tandem repeat domain is shed from the cell surface. NME7AB looks like a single chain dimer of pseudo-identical domains that each can bind to a MUC1* extra cellular domain. Because it can dimerize MUC1* as a monomer, it renders the MUC1* growth factor receptor constitutively active. Adult forms of NME7AB limit self-replication by changing multimerization state from the active dimer to the inactive hexamer. Antibodies such as 5E5 and SM3 bind to aberrant, trapped glycans on O-linked glycosylation sites that are only in the tandem repeat domain, which is shed from the tumor after MUC1 cleavage. Unlike full-length MUC1, MUC1* has no sites for O-linked glycosylation, so MUC1* is missed by antibodies that target aberrant glycans. Importantly, therapeutics that target full-length MUC1 could increase tumorigenesis by enriching for cells expressing the tumorigenic MUC1* growth factor receptor. Minerva’s anti-MUC1* antibody, huMNC2, binds to the conformational epitope that is unmasked when MUC1 is cleaved to MUC1*. MMP9, which has been linked to poor prognosis and metastasis, cleaves MUC1 to a tumor-associated growth factor receptor form of MUC1*. huMNC2 and onco-embryonic growth factor NME7AB compete for binding to the same conformational epitope created when MUC1 is cleaved to MUC1* by MMP9. Neither huMNC2 nor NME7AB binds to full-length MUC1. IHC studies of thousands of human tissues – both normal and cancerous – show that the tumor associated antigen is MUC1* and not full-length MUC1. Patient-match primary and metastases show that as cancer stage progresses the amount of MUC1* increases. huMNC2-scFv bound robustly to 95% of the breast cancers, 83% ovarian, 78% pancreatic and 71% of lung cancer tissues (specimens n>2,800). There was minimal staining of normal tissues, primarily on apical surfaces which are expected to be less accessible to immune cells. In vivo, huMNC2-CAR44 T cells inhibited or completely obliterated a variety of MUC1* positive solid tumors in NSG mice (n>500). Minerva has developed next-gen CARs designed to increase persistence, and intends to file for additional INDs. Conclusions: MUC1* is the predominant form of MUC1 on cancerous tissues. Antibodies that target a conformational epitope in the membrane-proximal MUC1* extra cellular domain are tumor selective. CAR T cells targeting MUC1* extra cellular domain are highly effective against solid tumors in animals. Robust staining of cancerous tissues and minimal staining of normal tissues predicts a promising therapeutic window for huMNC2-CAR44 T cell dosing. Citation Format: Cynthia Bamdad, Andrew K Stewart, Pengyu Huang, Benoit J Smagghe, Scott T Moe, Tyler E Swanson, Thomas G Jeon, Danica M Page, Trevor J Grant, Jennifer M Specht. First-in-human chimeric antigen receptor t cells target muc1 transmembrane cleavage product [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-36.

Background: The histology and pattern of spread in lobular breast cancer has presented challenges in estimating extent of disease by traditional imaging methods. 18F-FES is an estrogen analogue PET imaging tracer which measures tumor ER expression at multiple tumor sites simultaneously. It is FDA approved in the US and will be available in 2021, pressing clinicians to define the role of FES in patients with breast cancer before use in practice. We compared quantitative FES-PET and clinical FDG-PET SUV uptake between patients with metastatic lobular carcinoma. Methods: Metastatic lesions in patients with primary ER+ lobular breast cancer were retrospectively evaluated with FES- and FDG-PET. SUV uptake was calculated in 38 patients enrolled in various studies at our institution. Up to ten matched lesions in each patient were assessed for a total of 192 lesions. Pairwise t-tests were performed to measure the difference between paired FES and FDG lesions. Results: Among metastatic breast cancer patients with lobular histology, 87% of patients had a positive FES scan. The majority of positive scans demonstrated uptake in all sites, with only a small percentage (6%) lacking FES uptake in at least one lesion. Uptake was noted in various metastatic tumor sites including bone (78%), soft tissue/lymph node (17%), breast (8%) and lung (1%). Mean (range) SUVmax in FES and FDG respectively was 3.38 (0.88, 9.08) and 4.14 (1.25, 9.49). Paired lesion analysis showed concordance between the two imaging modalities in lesions with low SUV uptake. FES and FDG uptake, however, could be discordant in both directions (FES > FDG, and FDG > FES) when there is higher level of uptake in at least one of the tracers. This was specifically seen in the 150 bone lesions, possibly indicating differences in lesion phenotype or response to therapy. Conclusions: FES and FDG scans demonstrate similar average SUV uptake in metastatic lobular breast cancer, suggesting that both scans have utility in detecting lobular histology. Our data suggests that at higher SUV values, FES may provide additional information to FDG. Discordance between FES and FDG SUV uptake in the same lesions, especially in bone, has important implications for staging and assessing response to therapy. Large prospective trials are needed to define the clinical utility of FES-PET in metastatic lobular breast cancer. Research Support: P01CA42045, R01CA72064, U01CA148131, DOD W81XWH-04-01-0675 Citation Format: Poorni Manohar, Lanell Peterson, Vicky Wu, Isaac Jenkins, Mark Muzi, Jennifer Specht, Delphine Chen, Jeanne Link, Kenneth Krohn, Paul Kinahan, David Mankoff, Hannah Linden. 18F-fluoroestradiol (fes) and 18f-fluorodeoxyglucose (fdg) pet imaging in metastatic lobular breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD6-10.

Background: The COVID-19 pandemic is negatively affecting patient enrollment, therapy administration, and patient visits in breast cancer clinical trials worldwide. COVID-19 may have a lasting impact on how clinical trials are conducted, and guidelines are necessary to inform trial design and patient safety. While many groups and journals have recently published guidelines, including NCCN, ESMO, IQVIA, and Lancet Oncology, there is no consensus on how to treat patients in the current environment. Understanding and quantifying the impact of the pandemic on clinical study sites will help inform the rational development of a consensus approach. The goal of this survey was to gather site-level data on the impact of COVID-19 from clinical sites participating in the POLARIS study (NCT03280303), an ongoing, prospective, real-world, noninterventional study in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer receiving palbociclib plus endocrine therapy. Methods: Two rounds of questionnaires were sent to investigators at POLARIS study sites: 1 via email March 26-27, 2020, and 1 via telephone from April 30-May 20, 2020. The questions on COVID-19 impact and management are shown in the Table. Results: Eighty of 122 POLARIS study sites contacted responded to the March questionnaire, and 86 responded to the April-May questionnaire. In March, 33% (26/80) of the surveyed population were working predominantly remotely, 26% (21/80) were working both onsite and remotely, and 31% (25/80) were working onsite. Approximately 24% of sites reported delayed data entry. The option of telemedicine or office visits was offered to subjects at approximately 73% (58/80) of sites, and 11% (9/80) of sites were restricted to telemedicine visits. In April-May, 36% (31/86) of respondents reported an impact on study management and 64% (55/86) reported no impact. Approximately 94% (81/86) of surveyed sites felt they were able to maintain clinical studies despite the challenges due to COVID-19, and 79% (68/86) of sites had the option for telemedicine and/or office visits, while 18% (16/86) had no telemedicine alternative. In April-May, 38% of sites reported an impact on patient visits. Conclusion: Although these findings must be interpreted with caution due to the limitations of survey studies, the results suggest that approximately 1/3 of the study sites will experience an impact on their responsiveness to correspondence, timely data entry, and subject management due to the COVID-19 pandemic. Telemedicine may be used to mitigate the effect of the pandemic on clinical trial execution. Pfizer (NCT03280303) Table. Survey QuestionsMarch Questionnaire (March 26-27, 2020)QuestionResponsesWorking onsite or remotely?26 sites are predominately working remotely21 sites are working a combination of onsite and remotely25 sites are working onsite7 sites provided inconclusive responsesSubject visits in office, by phone, by video, or a combination of 3 options?50 sites are using a combination of onsite and telemedicine8 sites have onsite visits9 sites have telemedicine visits only8 sites provided inconclusive responses4 instances where question was inapplicable due to no active subjectsIs data entry delayed?19 sites responded Yes54 sites responded No6 sites provided inconclusive responsesIs collection of biomarker blood samples impacted?11 sites indicated there will be impact to biomarker collection28 sites indicated there will be no impact to biomarker collection40 instances where question was inapplicable due to no subjects participating in collectionWhat other study areas are impacted?20 sites indicated impact due to financial challenges or limited abilities while working remotelyRemaining sites did not note any additional areas of impactPatient-reported outcome questionnaire issues?Most sites had not experienced any issues, but an overwhelming majority inquired about the ability to do them via phone or mail. Many sites and subjects expressed preference for the paper questionnaire instead of the electronic version.May Questionnaire (April 30-May 20, 2020)QuestionResponsesHas COVID-19 impacted your site’s ability to execute a study?55 sites responded No• Clarify impact on your site31 sites responded Yes• Subject visits impacted (limited onsite visits): 24• Institutional restrictions/limited staff: 7Is there any impact on scheduled onsite standard of care patient visits?53 sites responded No33 sites responded YesPlease indicate which if any of the following apply to your site:67 sites responded that telemedicine is in place for subject visitsProcess in place for remote patient study visits16 sites responded that there is no alternative for telemedicineProcess is used for remote patient study visits1 site noted that they have no active subjectsAlternative methods are available to deliver drug1 site noted that subjects are attending on site visitsOther1 site did not respond to questionHow able are you to maintain ongoing studies at this time?27 sites are extremely able to do so42 sites are very able to do soExtremely able to do so12 sites are moderately able to do soVery able to do so5 sites are able to do so only a littleModerately able to do so• COVID impact is felt more profoundly at 4 sitesA little able to do so• Financial barrier has limited one site’s time on studyNot at all able to do so0 Sites unable to do so at all Citation Format: Debu Tripathy, Joanne L Blum, Gabrielle Rocque, J. Daniel Cuevas, Jennifer Specht, Steven Corso, Jawad E Francis, Stephanie Mendez, Veneta Pope, Joseph Cappelleri, Yao Wang. Impact of COVID-19 on study sites: Survey analysis from the noninterventional POLARIS study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SS2-10.

PURPOSE: Women with personal history of breast cancer (PHBC) are currently recommended to receive annual mammography for surveillance of breast cancer recurrence or new primary. However, given issues in accuracy with mammography, there is a need for evolving evidence-based surveillance recommendations with supplemental imaging. In this systematic review, we compiled and compared existing studies that describe the test performance of surveillance breast MRI among women with PHBC. METHODS: We searched PubMed and EMBASE using MeSH terms for studies (2000–2019) that described the diagnostic characteristics of breast MRI in women with PHBC. Search results were reviewed and included based on PICOTS criteria; quality of included articles was assessed using QUADAS-2. Meta-analysis of single proportions was conducted for diagnostic characteristics of breast MRI, including tests of heterogeneity. RESULTS: Our review included 11 articles in which unique cohorts were studied, comprised of a total of 8338 women with PHBC and 12,335 breast MRI done for the purpose of surveillance. We predict intervals (PI) for cancer detection rate per 1000 examinations (PI 9–15; I(2) = 10%), recall rate (PI 5–31%; I(2) = 97%), sensitivity (PI 58–95%; I(2) = 47%), specificity (PI 76–97%; I(2) = 97%), and PPV3 (PI 16–40%; I(2) = 44%). CONCLUSIONS: Studies addressing performance of breast MRI are variable and limited in population-based studies. The summary of evidence to date is insufficient to recommend for or against use of breast MRI for surveillance among women with PHBC.

Background: Palbociclib (PAL) is a cyclin-dependent kinase 4/6 inhibitor indicated for the treatment of HR+/HER2– advanced breast cancer (ABC) in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy or with fulvestrant (FUL) in patients whose disease progressed on prior endocrine therapy (ET). Neutropenia was the most commonly reported adverse event in clinical trials. Per the prescribing information for PAL, complete blood counts (CBCs) should be monitored before initiation of PAL (Cycle 1, Day 1 [C1D1]), at the beginning of each subsequent cycle, on Day 15 of the first 2 cycles, and as clinically indicated for at least the first 6 cycles. Methods: POLARIS is a prospective, observational, multicenter, real-world study of patients with HR+/HER2‒ ABC who received PAL as deemed appropriate by the treating physician. CBC collected at baseline, anytime during the first 3 cycles, then on Day 1 (or before the start of a new cycle) of subsequent cycles as per standard of care were recorded. We analyzed the frequency of laboratory monitoring for patients with HR+/HER2– ABC receiving PAL in routine clinical practice. Lab collections outside these windows were also obtained (data not shown). Results: At data cutoff (March 30, 2022), 1242 patients were treated with PAL + ET; 902 patients as first-line (1L) and 340 as second-line or later (≥2L) therapies for ABC; 90% of all patients received 125 mg of PAL in the first cycle. The frequency of laboratory collection, overall and by site category (academic vs. community), within the first 6 months of treatment is reported in the Table. CBC collection reported by investigators and analyzed within the defined window of day 1 of each cycle (C1–C6). Day 1 CBC collection was 87% at C1D1, 69.4% at C2D1, 66.5% at C3D1, 63.2% at C4D1, 61.4% at C5D1, to 59.9% at C6D1. Reports of CBC collection on Day 15 for the first two cycles was 37.3% (C1D15) and 31.2% (C2D15). CBC collection pattern was comparable across the community and academic sites. Conclusions: In this real-world CBC monitoring data set analyzed in a defined cycle window, most sites reported CBC collection prior to PAL initiation, and over two thirds of sites in the subsequent cycles. Day 15 of Cycles 1 and 2 monitoring was conducted in one third of the patients. These results suggest that CBC collections in real-world clinical practice are performed less frequently than in clinical trials, which may reflect the sites’ desire to reduce patient and/or clinic procedural burden, and treating physician’s familiarity with PAL safety profile and their comfort level of managing patients in clinical practice. Clinical trial identification: Pfizer; NCT03280303 Table 1 Citation Format: Gabrielle B. Rocque, Joanne L. Blum, Jennifer M. Specht, Carrie Dul, Steven Corso, Daniel Cuevas, Eric Gauthier, Monica Z. Montelongo, Zhe Zhang, Yao Wang, Debu Tripathy. Laboratory monitoring in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) advanced breast cancer treated with palbociclib in a real-world setting: Results from POLARIS [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 P3-01-05.

When Roentgen discovered the X-rays 125 years ago, his finding was soon recognized as a breakthrough in research and awarded with the Nobel Prize. Today X-rays are widely used in natural and applied sciences and even art. In medicine, X-rays have made an impressive impact far beyond their original domain of diagnostic imaging. In cancer treatment, X-rays are indispensable for reaching the goal of uncomplicated and lasting tumor control. Using the possibilities of modern technology and the innovative mind of physicians and physicists, definitive cancer cure cannot only be achieved by combination of surgery and radiation, but also by radiotherapy alone. One prominent example is the application of single high radiation doses with optimal geometrical precision through image-guided stereotactic radiotherapy. The article aims to highlight past, current, and future sustainable developments in oncology in general, but in radiation oncology, especially. We discuss the very complex challenge of generating evidence by clinical research. In this context, the tumor registries play a very important role. The data of tumor registries and the results of clinical studies demonstrate the benefit for cancer patients who experienced individualized radiotherapy. For cancer cure, it is most important to treat in an early, localized stage of the disease.

PurposeThis study evaluated the ability of18F-Fluorodeoxyglucose (FDG) and18F-Fluorothymidine (FLT) imaging with positron emission tomography (PET) to measure early response to endocrine therapy from baseline to just prior to surgical resection in estrogen receptor positive (ER+) breast tumors.MethodsIn two separate studies, women with early stage ER+ breast cancer underwent either paired FDG-PET (n = 22) or FLT-PET (n = 27) scans prior to endocrine therapy and again in the pre-operative setting. Tissue samples for Ki-67 were taken for all patients both prior to treatment and at the time of surgery.ResultsFDG maximum standardized uptake value (SUVmax) declined in 19 of 22 lesions (mean 17% (range −45 to 28%)). FLT SUVmax declined in 24 of 27 lesions (mean 26% (range −77 to 7%)). The Ki-67 index declined in both studies, from pre-therapy (mean 23% (range 1 to 73%)) to surgery [mean 8% (range ConclusionsA window-of-opportunity approach using PET imaging to assess early response of breast cancer therapy is feasible. FDG and FLT-PET imaging following a short course of neoadjuvant endocrine therapy demonstrated measurable changes in SUVmax in early stage ER+ positive breast cancers. The percentage change in FDG and FLT-PET uptake did not correlate with changes in Ki-67; post-therapy SUVmax for both tracers was significantly associated with post-therapy Ki-67, an established predictor of endocrine therapy response.

PURPOSE Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake values corrected for lean body mass (SULmax) on [18F]fluorodeoxyglucose positron emission tomography/computed tomography would predict pathologic complete response (pCR) to neoadjuvant pertuzumab and trastuzumab (PT). PATIENTS AND METHODS Patients with stage II/III, estrogen receptor–negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. [18F]Fluorodeoxyglucose positron emission tomography/computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percentage of change in SULmax by C1D15 predicting pCR is less than or equal to 0.65, with a one-sided type I error rate of 10%. RESULTS Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 34%. Receiver operating characteristic analysis yielded an area under the curve of 0.76 (90% CI, 0.67 to 0.85), which rejected the null hypothesis. Between patients who obtained pCR versus not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 33.5%; P < .001), an SULmax reduction greater than or equal to 40% was more prevalent (86% v 46%; P < .001; negative predictive value, 88%; positive predictive value, 49%), and a significant difference in median C1D15 SULmax (1.6 v 3.9; P < .001) and higher proportion of C1D15 SULmax less than or equal to 3 (93% v 38%; P < .001; negative predictive value, 94%; positive predictive value, 55%) were observed. CONCLUSION Early changes in SULmax predict response to four cycles of PT in estrogen receptor–negative, HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate a more tailored approach to therapy in this setting.

BACKGROUND: ROR1 is a type 1 transmembrane tyrosine kinase receptor that plays a critical role in embryonic and fetal development. ROR1 has been described as a possible oncogene and is expressed in numerous malignancies including TNBC and non-small cell lung cancer (NSCLC). We are conducting a first-in-human trial targeting ROR1 with CAR-T cells in patients with advanced TNBC and NSCLC. The cellular construct employed targets the Ig/Fz portion of the extracellular domain of ROR1 and contains 4-1BB/CD3ζ intracellular signaling domain. The manufacturing process utilizes autologous peripheral blood lymphocytes, separated into CD4 and CD8 subsets, which are independently cultured with anti-CD3/anti-CD28 beads and IL-2, then transduced with a lentiviral vector encoding the ROR1 CAR. The CAR-T cell product is formulated in a 1:1 ratio of CD4+ and CD8+ CAR-T cells. METHODS: This ongoing phase I trial (NCT02706392) is evaluating the safety of administering ROR1 CAR-T cells in escalating doses (3.3x105, 1x106, 3.3x106 and 1x107 cells/kg) following lymphodepletion with cyclophosphamide-containing regimens using a continual reassessment method (CRM) for dose escalation. TNBC patients with adequate organ function and performance status, measurable disease, and tumors expressing ROR1 (>20% by IHC) are eligible for enrollment. Persistence of CAR-T cells in blood, cytokine levels, measures of immunogenicity and multi-parametric flow cytometry are being evaluated at multiple time points. Imaging assessments by RECIST 1.1 are performed day 28 - 90, then at 6 and 12 months, and every 6 months as clinically indicated to estimate efficacy. RESULTS: To date, 4 TNBC patients (age range 38-67) have been enrolled, treated and are evaluable for response. Patients had received prior therapies for metastatic disease (range 3-11). 3 of 4 had visceral metastases. No dose-limiting toxicities, severe neurotoxicity or severe cytokine release syndrome (sCRS) were observed at dose levels 1 and 2. Two patients experienced grade 1 CRS. 2 of 4 patients had evidence of CAR-T cell expansion between days 14 and 20, with peak CD8+ CAR-T up to 232.1 cells/uL. Analysis of surface phenotype revealed upregulation of inhibitory receptors on CAR-T cells at the peak of expansion, confirmed by RNA seq. Post-treatment tumor biopsy in patient with partial response revealed an influx of CD3+ T cells and macrophages suggesting ROR1 CAR-T cell trafficking. Two patients received 2 CAR-T cell infusions. Two patients had confirmed stable disease at 15 weeks and 19 weeks, respectively. One patient has stable disease after 1st CAR-T cell infusion, then confirmed partial response after 2nd CAR-T cell infusion which has persisted for 14 weeks. Results will be updated. CONCLUSIONS: ROR1+ CAR-T cells can be safely transferred, expand in vivo in patients with TNBC. Current efforts are directed at understanding and overcoming the mechanisms that limit homing, persistence, and/or function at tumor sites. The trial is continuing with dose-escalation. Funding provided by 8RO1 CA114536-11 and Juno Therapeutics. Citation Format: Specht JM, Lee SM, Turtle C, Berger C, Balakrishnan A, Srivastava S, Viollet V, Veatch J, Gooley T, Mullane E, Chaney CN, Rader C, Pierce RH, Gottardo R, Maloney DG, Riddell SR. A phase I study of adoptive immunotherapy for ROR1+ advanced triple negative breast cancer (TNBC) with defined subsets of autologous T cells expressing a ROR1-specific chimeric antigen receptor (ROR1-CAR) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-13.

Background: Eribulin mesylate is a non-taxane microtubule dynamics inhibitor approved by FDA in treatment of metastatic breast cancer (MBC) based on improvements in overall survival in the pivotal EMBRACE trial. Eribulin is approved at 1.4mg/m2 administered D1,8 of q21d cycle. However, this dose and schedule may have significant myelosuppression and peripheral neuropathy requiring dose reductions and treatment delays for some patients. We hypothesized that a low dose metronomic schedule will allow responding patients to remain on treatment, resulting in longer TTP (time to progression) and decreased incidence of toxicities and treatment-related discontinuations. Methods: A multi-site prospective open-label phase II trial of metronomic dosing of eribulin in patients with MBC has completed accrual of 60 patients, outcomes will be updated at presentation. Patients whose disease had progressed following 1-6 prior regimens with prior exposure to a taxane, ECOG performance status of 0 – 2, measurable disease per RECIST 1.1, with normal marrow and organ function were eligible. Eribulin was administered at 0.9mg/m2 weekly for 3 out of 4 weeks. For patients with HER2 positive disease, concurrent trastuzumab administration was allowed. Concurrent denosumab or bisphosphonates were allowed for patients with bone disease. Results: 60 patients were enrolled, average age 58 (range 34-83). Majority were postmenopausal Caucasian females, but the study included African American, Hispanic, native American, male patients. The majority of tumors were ER+, infiltrating ductal, but the study included 13 HER2+, and 12 TN tumors, with 5 ILC, and 5 mixed ILC/IDC. Nearly half of the enrolled patients had clinical benefit from the regimen, remaining on therapy for 6 months or longer, with stable disease or response; 50% had progression PD at 3 months 32% had stable disease and 18% had a partial or complete response (1, long term). Overall Survival, OS, for the entire group of heavily pre-treated patients was 1.2 years, with TN and HER2 positive patients faring better than ER+ in this small study. One HER2+ patient remains in long-term remission, off chemotherapy. The regimen was extremely well tolerated. The majority of the patients experienced grade 0 or 1 toxicity for alopecia (48/60) and peripheral neuropathy (7 with grade 2 neuropathy, 5 pre-existing, 2 with grade 3 neuropathy). There were few dose reductions (n=15), thrombocytopenia (11 grade 1 only), or use of G-CSF (14). Conclusions: Metronomic weekly low dose eribulin appears to be an active and tolerable regimen with less myelosuppression, alopecia and peripheral neuropathy than is seen with approved dose, allowing longer duration of use and disease control, with similar outcomes compared to the standard dose regimen. Outcomes will be updated at presentation. Citation Format: Chalasani P, Liu AJ, Khanjian JA, Peha M, Buening BJ, Gadi VK, Specht JM, Salazar L, Linden HM. A phase 2 study of low dose metronomic eribulin in metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-14-02.

Background: The histology and pattern of spread in lobular breast cancer has presented challenges in estimating extent of disease and identifying treatment options. 18F-FES is an estrogen analogue PET imaging tracer which measures tumor ER expression at multiple tumor sites simultaneously and predicts response to endocrine therapy. We analyzed FES-PET and FDG-PET SUV uptake in patients with metastatic lobular and ductal carcinoma to identify sites of tumor and responsiveness to therapy. Methods: We retrospectively reviewed FES and FDG SUV uptake between ER+ lobular (n = 36) and ductal (n= 173, including 6 men) metastatic breast cancer patients enrolled in various institutional studies. Up to 3 lesions in each patient were evaluated by FES SUVmax and/or FDG SUVmax for a total of 475 lesions in FES images and 462 lesions in FDG images. Classification into three categories (low FDG, high FDG/high FES, and high FDG/low FES) was generated using recursive portioning with 5-fold internal cross validation. Using a Pearson Chi-squared test, we compared degree of uptake in FES and FDG between lobular and ductal carcinomas. We used linear mixed effects model to assess association of FES SULmean3 (Lean body mass adjusted SUV) and FDG SULmean3 with histology. Overall survival (OS), from time of FES-PET scan to death, and progression free survival (PFS) was evaluated between classification groups in both histologies using Kaplan-Meier curves and Cox model. Results: In patients with metastatic breast cancer, 72 patients had low FDG, 96 had high FES/high FDG, and 41 with high FES/low FDG. Lobular lesions tended to have a higher proportion of patients in the risk group with lower FDG (42% vs 33%) and a lower proportion in the risk group with high FDG/low FES (11% vs 21%) but the difference was not statistically significant (p = 0.32). Mean (range) FES SULmean3 and FDG SULmax3 respectively for ductal was 1.38 (0.10, 6.7) and 3.17 (0.88, 12.26) and for lobular was 1.42 (0.34, 3.43) and 3.13 (1.04, 13.87). There was no significant difference between in FES SULmean3 and FDG SULmax3 between histologies. Following FES-PET imaging, patients with lobular carcinomas and low FDG demonstrated a higher median survival time (7.7 years) compared to high FDG/low FES (4.3 years) and high FDG/high FES (2.6 years). Similarly, patients with ductal carcinomas and low FDG had an improved median survival time (5.6 years) compared to both high FDG/high FES (2.9 years) and high FDG/low FES (2.5 years). However, the interaction between histology and the FDG/FES classifications was not significant (p = 0.86). Across a variety of tumor sites, lobular histology can be detected by both FES and FDG with no difference between the imaging modalities. Conclusions: In the metastatic setting, quantitative FES and FDG can be used to discriminate indolent and aggressive phenotypes in both lobular and ductal breast cancer. A greater proportion of lobular carcinoma lesions had higher FES/lower FDG and would be anticipated to be more sensitive to endocrine therapy. Further prospective trials are needed to confirm the utility of FES to stage extent of disease in metastatic breast cancer. Citation Format: Manohar PM, Peterson LM, Wu V, Jenkins IC, Novakova-Jiresova A, Specht JM, Link JM, Krohn KA, Kinahan PE, Mankoff DA, Linden HM. 18F-fluoroestradiol (FES) and 18F-fluorodeoxyglucose (FDG) PET imaging in staging extent of disease in metastatic lobular breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-10.

Data of thoracic in-field reirradiation with two courses of stereotactic body radiotherapy (SBRT) is scarce. Aim of this study is to investigate feasibility and safety of this approach. Patients with a second course of thoracic SBRT and planning target volume (PTV) overlap were analyzed in this retrospective, multicenter study. All plans and clinical data were centrally collected. 27 patients from 8 centers have been amenable for evaluation: 12 with non-small-cell lung cancer, 16 with metastases, treated from 2009 (oldest first course) to 2020 (latest second course). A median dose of 38.5 Gy to the 65%-isodose over a median of 5 fractions was prescribed in the first course and 40 Gy in 5 fractions for the second SBRT-course. Median PTV of the second SBRT was 29.5 cm3, median PTV overlap 22 cm3. With a median interval of 20.2 months between the two SBRT-courses, 1-year OS, and -LCR were 78.3% and 70.3% respectively. 3 patients developed grade 1 and one grade 2 pneumonitis. No grade > 2 toxicity was observed. Peripheral location and dose were the only factors correlating with tumor control. A second SBRT-course with PTV overlap appears safe and achieves reasonable local control.

Histone deacetylase inhibitors (HDACIs) may overcome endocrine resistance in estrogen receptor–positive (ER+) metastatic breast cancer. We tested whether (18)F-fluoroestradiol PET imaging would elucidate the pharmacodynamics of combination HDACIs and endocrine therapy. Methods: Patients with ER+/human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer with prior clinical benefit from endocrine therapy but later progression on aromatase inhibitor (AI) therapy were given vorinostat (400 mg daily) sequentially or simultaneously with AI. (18)F-fluoroestradiol PET and (18)F-FDG PET scans were performed at baseline, week 2, and week 8. Results: Eight patients were treated sequentially, and then 15 simultaneously. Eight patients had stable disease at week 8, and 6 of these 8 patients had more than 6 mo of stable disease. Higher baseline (18)F-fluoroestradiol uptake was associated with longer progression-free survival. (18)F-fluoroestradiol uptake did not systematically increase with vorinostat exposure, indicating no change in regional ER estradiol binding, and (18)F-FDG uptake did not show a significant decrease, as would have been expected with tumor regression. Conclusion: Simultaneous HDACIs and AI dosing in patients with cancer resistant to AI alone showed clinical benefit (6 or more months without progression) in 4 of 10 evaluable patients. Higher (18)F-fluoroestradiol PET uptake identified patients likely to benefit from combination therapy, but vorinostat did not change ER expression at the level of detection of (18)F-fluoroestradiol PET.