Many anticancer drugs induce apoptosis by molecular mechanisms mediated through mitochondrial dysfunction [ 24 — 26 ]. Release of cytochrome c from the internal part of the mitochondrial membrane into the cytosol results in the activation of caspase cascades, in particular caspase 9, caspase 3, caspase 6, and caspase 7. Because caspase 3 is the main executioner of apoptosis, immunohistochemical analysis to the active form of caspase 3, known as cleaved caspase 3 CC3 , has been used as an indicator of apoptosis in paraffin sections from various tissue sites [ 27 — 30 ].
Compared to the traditional TUNEL assay, whose interpretation and specificity have been reported as being difficult and controversial, CC3 immunohistochemistry is an easy, sensitive, and reliable method for detecting and quantifying apoptosis in tissues, with good correlation reported between it and the TUNEL assay [ 29 ].
Few studies have used it as a marker of response to treatment in breast cancer. While the results may be counterintuitive in that CC3 and therefore apoptosis declined with anastrozole treatment, and a greater reduction was seen with longer duration of treatment, these results mirror what has been demonstrated with the TUNEL assay in anastrozole treated patients [ 20 , 31 , 32 ].
Unlike what is observed with cytotoxic chemotherapy, patients in the IMPACT study and others have demonstrated a decrease in apoptosis with endocrine therapy [ 20 , 32 ]. It is possible that the capacity of breast cancer cells to pass into apoptosis is retarded by the profound antiproliferative effects of antiestrogenic therapy. It has been observed that c-Myc is a determinant of both proliferation and apoptosis [ 20 ], and its expression is enhanced by estrogen and suppressed by antiestrogens.
This data suggests that estrogen may not be important for cell survival in breast cancers. There remain a number of limitations to the current study. It was single center and single arm with a small sample size. Additional logistical and practical issues would be present in a multicenter or multiarm trial. Further difficulties may additionally be encountered if a novel agent with no known therapeutic benefit was used instead of anastrozole or if the biomarker was experimental and pathologists had little prior experience with measuring it.
Additionally, the authors of this paper acknowledge that the involvement of a single dedicated surgeon and few medical oncologists would have potentially allowed for greater accrual. The success of the accrual may be less generalizable to larger group practices where it may be more difficult to overcome logistical hurdles.
The main objective of our study was to assess feasibility of such window trials at our institution. In summary, this study demonstrates that accrual to nontherapeutic protocols is feasible in a single large academic cancer center and is acceptable to patients.
The success achieved with this trial has been used as a strategy to convince other surgeons and patients to be involved in future research NCT The authors declare that there is no conflict of interests regarding the publication of this paper. This trial was supported by the University of Ottawa Department of Surgery research grant. Special thanks are due to Nancy Page for her assistance with REB and Health Canada approval and for overseeing the administrative aspects of the study.
The authors are grateful to Luisa Ianni for her assistance in recruiting participants and for data collection. They would also like to thank Emily Desormeaux and Joelle Levac who assisted with all the immunohistochemistry performed. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors.
Read the winning articles. Journal overview. Special Issues. Pond, 5 Christina L. Academic Editor: Kefah Mokbel. Received 23 Aug Accepted 26 Dec Published 20 Jan Abstract Background. Introduction Window of opportunity also called phase 0 trials can provide insight into biological effects and potential therapeutic efficacy of novel therapeutic strategies [ 1 — 4 ]. Methods 2. Study Participants and Eligibility This study was a single center, single arm, prospective study to assess the feasibility of performing a window of opportunity study at our center.
Study Procedures All potential study patients with a core biopsy confirmed invasive breast cancer were evaluated at initial consultation by one surgeon AA. Figure 1. Figure 2. Table 1. Clinical and pathological characteristics of patients who enrolled in the study.
Table 2. Figure 3. Ki67 labelling index a and cleaved caspase 3 CC3 b at baseline and after anastrozole treatment at surgery. Table 3. Association between Ki67 labelling index and cleaved caspase 3 CC3 values at baseline before anastrozole and surgery after anastrozole using the Spearman value for associations. References I.
Kalinsky and D. Wisinski, A. Faerber, S. Wagner et al. Glimelius and M. Hilton, A. Arnaout, and M. Arnaout, J. Boileau, and M. Wright, J. Zubovits, S. Gardner et al.
Lemieux, M. Clemons, L. Provencher et al. View at: Google Scholar H. Al-Husaini, E. Amir, B. Fitzgerald et al. Goodwin, V. Stambolic, J. Lemieux et al. Freedman, S. Verma, and M. Singletary, R. Lieberman, N. Atkinson et al. Medical history of clinically significant lung diseases or who are suspected to have these diseases by imaging at the screening period. Clinically significant corneal disease. Known hypersensitivity to either the drug substance components or inactive ingredients in the drug product or history of severe hypersensitivity reactions to other monoclonal antibodies.
Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder and any autoimmune, connective tissue, or inflammatory disorders with potential pulmonary involvement or prior pneumonectomy.
Table 2 Primary and secondary objectives and endpoints. Primary objective Primary endpoint To evaluate if one dose of U increases the value of the CelTIL score between baseline and post-treatment samples in all included patients with early breast cancer. This unscaled CelTIL score will then be scaled to reflect a range from 0 to points.
Secondary objectives Secondary endpoints To identify a significant increase in the CelTIL score after one dose of U between baseline and post-treatment samples within each of the four ERBB3 cohorts. To evaluate the antiproliferative activity of one dose of U between baseline and post-treatment samples. Correlation coefficients between both biomarkers. To evaluate the changes of HER3 expression.
To describe the safety and tolerability of U Figure 2. Evaluating ERBB3 Expression in Independent Datasets In order to examine the consistency of the cutoff points, results from the in-house nCounter dataset were compared to two independent cohorts i.
Figure 3. Footnotes Funding. References 1. HER3 overexpression and survival in solid tumors: a meta-analysis. HER3 comes of age: new insights into its functions and role in signaling, tumor biology, and cancer therapy. Clin Cancer Res. Breast Cancer Res Treat. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. A novel HER3-targeting antibody—drug conjugate, U, exhibits potent therapeutic efficacy through the delivery of cytotoxic payload by efficient internalization.
Abstract U, a novel HER3-targeting antibody-drug conjugate, exhibits in vitro antitumor activity against breast cancer cells expressing HER3 mutations without dependence on HER2 overexpression. Cancer Res. J Clin Invest. Ann Oncol. HER3 status by immunohistochemistry is correlated with poor prognosis in hormone receptor-negative breast cancer patients.
BMC Cancer. Combined HER3-EGFR score in triple-negative breast cancer provides prognostic and predictive significance superior to individual biomarkers. Sci Rep. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of patients treated with neoadjuvant therapy. Lancet Oncol. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG J Clin Oncol.
Prediction of survival after neoadjuvant chemotherapy for breast cancer by evaluation of tumor-infiltrating lymphocytes and residual cancer burden. De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 HER2 —positive early breast cancer BC : final analysis of the West German study group adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor—positive phase ii randomized trial—efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy ET versus trastuzumab plus ET.
A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes CelTIL in HER2-positive breast cancer treated with chemo-free dual HER2 blockade. Neoadjuvant management of early breast cancer: a clinical and investigational position statement. Future Oncol. Steps forward for cancer precision medicine. Nat Rev Drug Discov. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer PAMELA : an open-label, single-group, multicentre, phase 2 trial.
Purpose: Epidemiologic and preclinical data suggest a potential role for vitamin D in breast cancer treatment and prevention. However, results of prospective randomized trials are inconsistent. The objective of this study was to assess the effects of high-dose cholecalciferol vitamin D3 on breast tumour proliferation and apoptosis.
Methods: We conducted a prospective, randomized, phase 2, double-blinded pre-surgical window of opportunity trial. Newly diagnosed breast cancer patients were randomized to receive 40, IU of vitamin D3 per day or placebo for 2 to 6 weeks prior to breast surgery.
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