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Brock, Jane

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Brock

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Brock, Jane
Author's Publications: search.filters.isAuthorOfPublication.9ab6fa0b-130d-4cba-b2ad-11ef9ca574ac

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    Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry
    (Public Library of Science, 2013) Kluk, Michael J.; Ashworth, Todd; Wang, Hongfang; Knoechel, Birgit; Mason, Emily F.; Morgan, Elizabeth; Dorfman, David; Pinkus, Geraldine; Weigert, Oliver; Hornick, Jason; Chirieac, Lucian; Hirsch, Michelle; Oh, David J.; South, Andrew P.; Leigh, Irene M.; Pourreyron, Celine; Cassidy, Andrew J.; DeAngelo, Daniel J.; Weinstock, David M.; Krop, Ian E.; Dillon, Deborah; Brock, Jane; Lazar, Alexander J. F.; Peto, Myron; Cho, Raymond J.; Stoeck, Alexander; Haines, Brian B.; Sathayanrayanan, Sriram; Rodig, Scott; Aster, Jon
    Fixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical trials.
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    Clinical practice patterns and cost effectiveness of human epidermal growth receptor 2 testing strategies in breast cancer patients
    (Wiley-Blackwell, 2009) Phillips, Kathryn A.; Marshall, Deborah A.; Haas, Jennifer; Elkin, Elena B.; Liang, Su-Ying; Hassett, Michael; Ferrusi, Ilia; Brock, Jane; Van Bebber, Stephanie L.
    BACKGROUND: Testing technologies are increasingly used to target cancer therapies. Human epidermal growth factor receptor 2 (HER2) testing to target trastuzumab for patients with breast cancer provides insights into the evidence needed for emerging testing technologies. METHODS: The authors reviewed literature on HER2 test utilization and cost effectiveness of HER2 testing for patients with breast cancer. They examined available evidence on: percentage of eligible patients tested for HER2; test methods used; concordance of test results between community and central/reference laboratories; use of trastuzumab by HER2 test result; and cost effectiveness of testing strategies. RESULTS: Little evidence was available to determine whether all eligible patients are tested, how many are retested to confirm results, and how many with negative HER2 test results still receive trastuzumab. Studies suggested that up to 66% of eligible patients had no documentation of testing in claims records, up to 20% of patients receiving trastuzumab were not tested or had no documentation of a positive test, and 20% of HER2 results may be incorrect. Few cost-effectiveness analyses of trastuzumab explicitly considered the economic implications of various testing strategies. CONCLUSIONS: There was little information about the actual use of HER2 testing in clinical practice, but evidence suggested important variations in testing practices and key gaps in knowledge exist. Given the increasing use of targeted therapies, it is critical to build an evidence base that supports informed decision making on emerging testing technologies in cancer care.
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    Phase II study of tivantinib (ARQ 197) in patients with metastatic triple-negative breast cancer
    (Springer US, 2015) Tolaney, Sara M.; Tan, Sally; Guo, Hao; Barry, William; Van Allen, Eliezer; Wagle, Nikhil; Brock, Jane; Larrabee, Katherine; Paweletz, Cloud; Ivanova, Elena; Janne, Pasi; Overmoyer, Beth; Wright, John J.; Shapiro, Geoffrey I.; Winer, Eric P.; Krop, Ian E.
    Summary Background: MET expression and activation appear to be important for initiation and progression of triple-negative breast cancer. Tivantinib (ARQ 197) is an orally administered agent that targets MET, although recent preclinical data suggests the agent may have mechanisms of action that are independent of MET signaling. We conducted a phase 2 study of tivantinib monotherapy in patients with metastatic triple-negative breast cancer. Methods: Patients with metastatic triple-negative breast cancer who had received 1 to 3 prior lines of chemotherapy in the metastatic setting were enrolled into this two-stage, single arm phase 2 study. Treatment consisted of twice daily oral dosing of tivantinib (360 mg po bid) during a 21-day cycle. Patients underwent restaging scans at 6 weeks, and then every 9 weeks. Tumor biomarkers that might predict response to tivantinib were explored. Results: 22 patients were enrolled. The overall response rate was 5 % (95 % CI 0–25 %) and the 6-month progression-free survival (PFS) was 5 % (95 % CI 0–25 %), with one patient achieving a partial response (PR). Toxicity was minimal with only 5 grade ≥3 adverse events (one grade 3 anemia, one grade 3 fatigue, and 3 patients with grade 3/4 neutropenia). Conclusion: This study represents the first evaluation of tivantinib for the treatment of metastatic triple-negative breast cancer. These results suggest that single agent tivantinib is well tolerated, but did not meet prespecified statistical targets for efficacy.
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    Prevalence and Predictors of Loss of Wild Type BRCA1 in Estrogen Receptor Positive and Negative BRCA1-Associated Breast Cancers
    (BioMed Central, 2010) Fetten, Katharina; Yassin, Yosuf; Buraimoh, Ayodele; Kim, Ji-Young; Legare, Robert D; Tung, Nadine; Miron, A; Schnitt, Stuart; Gautam, Shiva; Kaplan, Jennifer; Szasz, Attila M.; Tian, R; Wang, Zhigang C.; Collins, Laura; Brock, Jane; Krag, Karen; Sgroi, Dennis; Ryan, Paula D.; Silver, Daniel P.; Garber, Judy; Richardson, Andrea
    Introduction: The majority of breast cancers that occur in BRCA1 mutation carriers (BRCA1 carriers) are estrogen receptor-negative (ER-). Therefore, it has been suggested that ER negativity is intrinsic to BRCA1 cancers and reflects the cell of origin of these tumors. However, approximately 20% of breast cancers that develop in BRCA1 carriers are ER-positive (ER+); these cancers are more likely to develop as BRCA1 carriers age, suggesting that they may be incidental and unrelated to BRCA1 deficiency. The purpose of this study was to compare the prevalence of loss of heterozygosity due to loss of wild type (wt) BRCA1 in ER+ and ER- breast cancers that have occurred in BRCA1 carriers and to determine whether age at diagnosis or any pathologic features or biomarkers predict for loss of wt BRCA1 in these breast cancers. Methods: Relative amounts of mutated and wt BRCA1 DNA were measured by quantitative polymerase chain reaction performed on laser capture microdissected cancer cells from 42 ER+ and 35 ER- invasive breast cancers that developed in BRCA1 carriers. BRCA1 gene methylation was determined on all cancers in which sufficient DNA was available. Immunostains for cytokeratins (CK) 5/6, 14, 8 and 18, epidermal growth factor receptor and p53 were performed on paraffin sections from tissue microarrays containing these cancers. Results: Loss of wt BRCA1 was equally frequent in ER+ and ER- BRCA1-associated cancers (81.0% vs 88.6%, respectively; P = 0.53). One of nine cancers tested that retained wt BRCA1 demonstrated BRCA1 gene methylation. Age at diagnosis was not significantly different between first invasive ER+ BRCA1 breast cancers with and without loss of wt BRCA1 (mean age 45.2 years vs 50.1 years, respectively; P = 0.51). ER+ BRCA1 cancers that retained wt BRCA1 were significantly more likely than those that lost wt BRCA1 to have a low mitotic rate (odds ratio (OR), 5.16; 95% CI, 1.91 to ∞). BRCA1 cancers with loss of wt BRCA1 were more likely to express basal cytokeratins CK 5/6 or 14 (OR 4.7; 95% CI, 1.85 to ∞). Conclusions: We found no difference in the prevalence of loss of wt BRCA1 between ER+ and ER- invasive BRCA1-associated breast cancers. Our findings suggest that many of the newer therapies for BRCA1 breast cancers designed to exploit the BRCA1 deficiency in these cancers may also be effective in ER+ cancers that develop in this population.