ANG1005 for brain metastases from breast cancer: 18F-FLT-PET and MRI as complementary approaches to response assessment.

Abstract BACKGROUND: Sorafenib has demonstrated anti-tumor efficacy in breast cancer and radiosensitizing activity preclinically. [18F] 3’deoxy-3’-fluorothymidine (FLT) is a PET tracer which correlates with cellular proliferation and may improve response assessment. METHODS: A phase I trial of whole brain radiotherapy (WBRT)+sorafenib was conducted using a 3 + 3 design. Sorafenib was given daily at the start of WBRT for 21 days (dose levels: 200mg, 400mg, and 600mg). The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). Macdonald Criteria were used for response assessment. A correlative serial FLT-PET imaging study was conducted to assess radiographic changes among pts receiving WBRT +/- sorafenib, in parallel with MRI. RESULTS:13 pts in the dose escalation were evaluable for dose-limiting toxicity (DLT). DLTs were: Grade (G) 4 increased lipase at 200mg (1 pt) and G3 rash at 400mg (3 pts) level. MTD was 200mg. Six additional pts were treated in an expansion cohort without additional DLT. 14 pts were evaluable for response. The overall response rate was 71%: 4 complete + 6 partial responses. Median follow up was 14 months (range: 3–44). Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT+sorafenib and 5 WBRT) were enrolled in the FLT-PET study: all had baseline FLT-PET, 14 with follow up at 7–10 days post WBRT (FU1), and 9 with followup at 12 weeks post WBRT (FU2). 55 baseline lesions were observed and analyzed: 38 at FU1 and 15 at FU2. Decline in average SUVmax of ≥25% was seen in 9/10 (90%) of WBRT+sorafenib pts and 2/4 (50%) of WBRT only pts at FU1. CONCLUSIONS: Concurrent WBRT+sorafenib appears safe at 200mg daily dose with clinical activity. This combination should be considered for further efficacy evaluation. NCT01724606 and NCT01621906.

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A phase I trial of sorafenib with whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases and a correlative study of FLT-PET brain imaging

Breast Cancer Research and Treatment ◽

10.1007/s10549-021-06209-4 ◽

2021 ◽

Author(s):

Aki Morikawa ◽

Milan Grkovski ◽

Sujata Patil ◽

Komal L. Jhaveri ◽

Kendrick Tang ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Phase I ◽

Brain Imaging ◽

Cancer Patients ◽

Phase I Trial ◽

Whole Brain Radiotherapy ◽

Breast Cancer Patients ◽

Brain Radiotherapy ◽

Flt Pet

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Early response assessment after one cycle of neoadjuvant chemotherapy in breast cancer by FLT-PET/CT.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.e22166 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. e22166-e22166

Author(s):

Ewa Chmielowska ◽

Bogdan Malkowski ◽

Maciej Studzinski ◽

Michal Marjanski ◽

Monika Olejniczak ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Response Assessment ◽

Early Response ◽

Flt Pet ◽

Pet Ct ◽

Early Response Assessment

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ANG-1005 in Patients with Brain Metastases from Breast Cancer: Correlative Imaging with 18F-FLT-PET/CT

Annals of Oncology ◽

10.1093/annonc/mdv091.1 ◽

2015 ◽

Vol 26 ◽

pp. ii20

Author(s):

S. Bates ◽

M. Lindenberg ◽

C. Bryla ◽

N. Patronas ◽

L. Amiri-Kordestani ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Correlative Imaging ◽

Flt Pet ◽

Pet Ct

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Real-time drug testing using patient-derived organoids from resected breast cancer brain metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14003 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14003-e14003

Author(s):

Aki Morikawa ◽

Nathan Merrill ◽

Liwei Bao ◽

Xu Cheng ◽

Ruth Freedman ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Real Time ◽

Drug Testing ◽

Clinical Care ◽

Clinical Pathology ◽

Response Assessment ◽

Drug Combinations ◽

Pathology Report ◽

Sensitivity Testing

e14003 Background: Brain metastases (BrMet) remain a clinically challenge. There is an increase interest in evaluating the efficiacy of systemic therapy for BrMet. Patient-derived organoids (PDO) and xenografts (PDX) are thought to capture the tumor heterogeneity and molecular alterations of the source tumor, and may be used as ‘avatars’ for therapeutic response assessment of the source patient. PDO has an advantage over PDX with a shorter establishment time, and thus, may allow a real-time drug sensitivity testing. The objective of this study was to determine the feasibility of establishing PDO from resected breast cancer BrMet and to evaluate the drug sensitivities in a time period amenable to eventual implemention into clinical utiliity. Methods: Under an IRB-approved protocol, resected BrMet tissues were prospectively collected at the time of clinically indicated neurosurgical procedure as part of a banking program. Tumors were directly cultured as 3-D organoids. DNA and RNA were collected. Drug testing panels included standard clinical care drugs or drug combinations as well as those selected based on the molecular profiling. When clinically conducted next-generation sequencing testing reports were available, we also tested drugs (or class of drugs) that were suggested as a potential therapeutic consideration in these reports. When possible, Nanostring PanCancer Panel evaluation was conducted at the time of PDO establishment to guide the selection of drugs. Results: To date, 11 breast cancer BrMet samples have been collected. 8/11 were successfully established as ‘direct from operating room’ PDO and underwent drug panel testing. The reasons for 3 cases not drug tested include: no viable tumor (confirmed by clinical pathology report as necrosis only) and primary brain tumor (not metastasis). Of the 8 PDO, the clinical subtypes were 5HER2+, 2HR-HER2-, and 1HR+HER2- cases.The median time from collection to the drug testing results availability was 11 days (range: 7-19 days). The median number of drugs or drug combinations tested was 23 (range: 7-32). The drug testing revealed various patterns of sensitivities to chemotherapies and targeted therapies. Nanostring PanCancer testing of PDO identified potential targetable pathways for which PDO demonstrated sensitivity when the drugs were matched to the associated molecular pathway. Conclusions: While the expected number of cases has been much lower due to COVID-19 pandemic-related change in clinical practice patterns and research operations, we have successfully demonstrated that the real-time establishment of BrMet PDO is feasible and may be used as a platform for further investigations. Real-time PDO could be potentially employed to predict drug sensitives for prioritizing drug therapy options in a clinically meaningful time-frame. PDO platform may be used to investigating biomarkers and mechanisms of response and resistance to therapy.

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NCOG-08. A COMPARISON OF RESPONSE-ASSESSMENT AND DATA VISUALIZATION METHODS FOR CHARACTERIZATION OF TIME-DEPENDENT OUTCOMES FOLLOWING RADIOSURGERY (SRS) FOR BRAIN METASTASES

Neuro-Oncology ◽

10.1093/neuonc/noaa215.547 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii130-ii131

Author(s):

Tatiana Kashtanova ◽

Andrew Keller ◽

Naren Ramakrishna

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Cancer Patients ◽

Response Assessment ◽

Post Treatment ◽

Breast Cancer Patients ◽

The Impact ◽

Average State

Abstract PURPOSE We compared multiple response assessment and visualization techniques for characterization of post-SRS treatment outcomes in a cohort of breast cancer patients with long median follow-up. METHODS A retrospective IRB-approved review was completed of 75 breast cancer patients treated with SRS for 271 brain metastases with median follow up of 40 months. Tumor dimensions, brain failure events, corticosteroid use, and clinical status were analyzed utilizing RANO-BM, bidimensional product (BDP), and bidimensional sum (BDS) techniques. 46/75 patients were eligible for RANO-BM assessment. Response at each post-treatment assessment were scored as PD, SD, PR, or CR, and the concordance between techniques was determined. A scoring system-based outcome metric labelled ‘average state’ was derived to estimate fractional time/response state by each assessment method. Interactive timeline displays of outcome states were generated. RESULTS The concordance of patient response states was determined using either RANO-BM, BDP or BDS among the 46 eligible patients. The overall mean and median concordance between techniques were 0.82 and 0.83, (range 0.52 – 1). The average state for the patient population post-treatment was 1.98 by RANO-BM, 2.29 by BDP, and 2.19 by BDS. For patients excluded from RANO-BM secondary to lack of measurable disease, the average state was determined to be 2.44 by BDP and 2.35 by BDS. The average state for HER2+ vs. HER2- patients was 2.21 vs. 1.75 by RANO-BM, 2.58 vs. 2 by BDP, and 2.39 vs. 1.99 by BDS. An interactive timeline view was generated to display outcome states utilizing the 3 response assessment techniques, and the impact of inclusion of non-target lesions and variable response parameters was assessed graphically. CONCLUSIONS These results characterize the concordance and the limitations of multiple outcome assessment methodologies in a post-SRS cohort with long median follow-up. The utility of a novel ‘average state’ outcome metric is demonstrated in this cohort.

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