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  • 1
    Online Resource
    Online Resource
    A Single-Arm Phase II Trial of Sitravatinib in Advanced Well-Differentiated/Dedifferentiated Liposarcoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 6 ( 2023-03-14), p. 1031-1039
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 6 ( 2023-03-14), p. 1031-1039
    Abstract: To evaluate sitravatinib, an inhibitor of multiple receptor tyrosine kinases (RTK), for the treatment of well-differentiated/dedifferentiated liposarcoma (WD/DD LPS). Patients and Methods: This multicenter, open-label, Phase II trial enrolled patients with advanced WD/DD LPS who had received at least one prior systemic regimen and had progression within 12 weeks of enrollment. Patients received sitravatinib 150 mg (later amended to 120 mg) orally daily. A Simon two-stage design was used to evaluate for an improvement in the primary endpoint, progression-free rate at 12 weeks (PFR12), from 20% to 40%. Secondary endpoints included antitumor activity and safety. A subset of patients underwent paired biopsies analyzed using reverse-phase protein array. Results: Twenty-nine patients enrolled. Median age was 62 years and 31% had received 3 or more prior lines. Most patients (93%) had DDLPS or mixed WD/DD LPS. Overall, 12 of 29 patients (41%) were alive and progression-free at 12 weeks and the study met the primary endpoint. There were no confirmed responses. Median progression-free survival was 11.7 weeks [95% confidence interval (CI): 5.9–35.9] and median overall survival was 31.7 weeks (95% CI: 18.1–90.1). The most common treatment-related adverse events were diarrhea (59%), hypertension (52%), hoarseness (41%), mucositis (31%), and nausea (31%). Baseline expression of phosph o-RTKs was not significantly different between patients with and without clinical benefit from sitravatinib, but the number of samples was small. Conclusions: Sitravatinib provided a PFR12 of 41% and meaningful disease control in a subset of patients with advanced, progressive WD/DD LPS.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-3351
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 2
    Online Resource
    Online Resource
    Proteomic quantification of HER-2 abundance and activation in pancreatic ductal adenocarcinoma tumor specimens using reverse phase protein array.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e16299-e16299
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e16299-e16299
    Abstract: e16299 Background: Pancreatic adenocarcinoma (PDAC) is associated with poor survival and low response rates to available therapies, warranting a critical need for new treatment paradigms. Enrichment of tumor epithelium via laser microdissection (LMD) prior to reverse phase protein array (RPPA) analysis allows for the quantitative measurement and functional assessment of the activation state of protein drug targets. As part of an IRB-approved Molecular Tumor Board study at Inova Schar Cancer Institute, we harvested enriched tumor epithelium using LMD to support CLIA-based RPPA analysis of patients with pancreatic, breast, and other solid tumor malignancies to examine quantitative expression and activation (phosphorylation) of HER-2/3 and other known cancer-related pathways. Methods: Formalin fixed paraffin embedded (FFPE) primary and/or metastatic tumor biopsy specimens were obtained from 14 patients with PDAC, 14 patients with breast cancer, and 40 patients with other solid tumor malignancies. Tumor epithelium (5-10 µm 2 ) was enriched via LMD prior to RPPA analysis for quantification of HER-2 Total and phosphorylated (p)HER-2 Y1248 and (p)HER-3 Y1289 abundances as part of a 32-marker, CLIA-based RPPA panel examining the total and phosphoprotein abundances of targets with known relevance in solid tumors. Next generation sequencing (NGS; DNA-seq and RNA-seq) was performed on remaining tissue from each specimen. Fisher’s Exact test was used to compare activated HER2 Total , pHER2 Y1248 and pHER3 Y1289 . Results: RPPA analysis of LMD enriched tumor samples revealed significant HER-2 Total expression in patients with PDAC vs other solid tumors (p=0.0112), with HER-2 Total levels comparable to those measured in patients with breast cancer (p=0.0962). The mean HER-2 Total abundances in PDAC, breast, and all other solid tumor malignancies were 1.6, 1.3, and 0.9, respectively. Activated pHER-2 Y1248 and pHER-3 Y1289 abundances did not differ between patients with PDAC vs all other solid tumors or between patients with PDAC vs breast cancer (p 〉 0.05). RNA-seq analysis revealed ERBB2 overexpression in four of the 14 PDAC patients, while ERBB2 amplification by DNA-seq was not observed in any of the PDAC cases. Conclusions: HER-2 expression is not routinely evaluated in clinical practice in PDAC, but our results show higher median expression in PDAC than our solid tumor cohort, with nearly 50% of PDAC cases having total HER2 expression of 2+ or above. Our results may have clinical implications, especially as new classes of HER2 antibody drug conjugates are considered for patients with HER2 non amplified tumors across organ sites, and justify further investigation in a larger cohort. Clinical trial information: U20-11-4308 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e16299
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    detail.hit.zdb_id: 604914-X
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  • 3
    Online Resource
    Online Resource
    Use of CLIA accredited multi-omic platforms to correlate clinical significance of WES/WTS testing with functional protein/phosphoprotein drug target activity.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e15150-e15150
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e15150-e15150
    Abstract: e15150 Background: Targeted cancer therapies almost exclusively disrupt protein function and phosphorylation, but genomics-based biomarkers underpin the vast majority of oncology molecular profiling. The reverse phase protein array (RPPA) technology has been used in the clinical setting to identify potential drug targets and to monitor the effects of treatment on protein expression and phosphorylation. Here, we investigated the Theralink RPPA assay, a highly sensitive CAP/CLIA accredited protein/phosphoprotein profiling technology, across a pan-tumor cohort of 188 samples which had undergone whole exome sequencing and transcriptomics. Methods: Using the Theralink RPPA assay, 32 key protein and phosphoprotein cancer therapy targets were quantified from formalin-fixed, laser capture microdissected (LCM) tumor epithelium across a pan-tumor cohort of 188 cancer cases. All samples had concomitant CLIA-based whole exome and whole transcriptome analysis performed. Most of these tumors were head and neck cancer (34%), uterine cancer (23%), and ovarian/fallopian tube cancer (17%), with the remaining 26% made up of various cancer types, including skin, breast, lung, brain, and other cancers. Results: Of the pan-tumor cohort, 95% of cases had at least one actionable protein target identified, compared to 86% of cases with clinically relevant genomic alterations. Altered genes and Theralink RPPA assay protein targets were broadly classified into 10 biological pathways. The pathway most frequently identified as actionable via Theralink’s RPPA assay was HER-family protein signaling (85% of cases) with concurrent genomic alterations in HER-family genes found for 9% of cases. In contrast, mTOR signaling was found to be the most frequent clinically relevant genomically altered pathway (48% of cases). When using a clinical breast cancer reference for HER2 protein/phosphorylation levels that is guiding HER2-targeted therapy in the unamplified setting, actionable total and phospho-HER2 levels were found in 82% of the pan-tumor cases, overlapping with ERBB2 genomic alterations in 4% of cases. The gene found to be altered the most was TP53 (101 cases; 54%), which was not part of the targeted Theralink RPPA assay. Conclusions: Our data suggest that quantification of key cancer proteins and phosphoproteins using RPPA extend the identification of actionable drug targets beyond what was found with WES/WTS testing alone. Especially the quantification of total and phospho-HER2 identified a significant pan-tumor subpopulation that may benefit from HER2-targeted therapies, including trastuzumab deruxtecan (T-Dxd).
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e15150
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    detail.hit.zdb_id: 604914-X
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Interim analysis examining the feasibility of incorporating laser microdissection enrichment of tumor specimens and reverse phase protein array analysis with next generation sequencing into a molecular tumor board.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e15068-e15068
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e15068-e15068
    Abstract: e15068 Background: Since next generation sequencing (NGS) based profiling does not provide measures of protein abundance or activation state, clinical integration of reverse phase protein array (RPPA) with NGS could be useful for improving selection of targeted cancer therapy. We incorporated biopsy testing and proteogenomic analyses in an institutional Molecular Tumor Board (MTB) for cancer patients using CLIA-certified commercially available multi-omic platforms, including a commercially available CLIA RPPA functional protein drug target activation mapping platform. We present an interim analysis of our experience integrating functional phosphoprotein/protein based drug target activity data with NGS from 117 patients with metastatic solid tumors. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor biopsy specimens (n = 166) were obtained prospectively from patients as part of an IRB approved MTB. A representative H & E-stained tissue section for each specimen was reviewed by a board-certified surgical pathologist. Specimens with sufficient total tumor cellularity to achieve protein lysate input requirements for RPPA were thin sectioned onto laser microdissection (LMD) membrane slides for selective harvest of tumor epithelium by LMD and RPPA analysis. In parallel, specimens from each case were also submitted for NGS analysis. The multi-omic data for each patient was reviewed by a panel of clinicians and scientists as part of the Inova Institutional MTB for clinical decision-making. Results: Patient tissue specimens (median = 1 per patient; range 1-5) were reviewed to assess feasibility of enriching tumor areas via LMD prior to RPPA analysis. Specimens from 64/117 patients were used for LMD, RPPA, and NGS. 48/117 patients were dropped due to inadequate tumor cellularity, patient death, or referral cases with inadequate specimen. At this time, 7/117 patients remained in the consenting-LMD-RPPA workflow. The median time from patient consent to RPPA analysis completion was 47.4 days. During this period, specimens were outside of the standard hospital-NGS workflow (ie, utilized for sectioning and review for LMD-RPPA) for ~10 days (median). Integrated review of the RPPA and NGS data by the MTB supported a clinical recommendation change for 34/64 patients (53%) overall, with some dependency by primary disease site. Clinical trial information: U20-11-4308.Conclusions: Incorporation of RPPA analysis of LMD enriched tumor samples with NGS was feasible in this pan-cancer cohort, with the mean time to results being less than 7 weeks. RPPA data provided additional treatment considerations for 59% of patients, the outcomes for whom continue to be monitored. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e15068
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    detail.hit.zdb_id: 604914-X
    Location Call Number Limitation Availability
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