Allo-SCT using unrelated donors is a curative treatment for patients with hematological disorders. The best donor is one matched for 10/10 HLA alleles, however studies have shown an additional survival benefit when considering other genetic factors. It has been shown that a six-nucleotide insertion/deletion polymorphism in the CASP8 gene promoter results in reduced susceptibility of T lymphocytes to undergo apoptosis. In 186 SCT recipients, we found a significantly better OS in those who received a transplant from a WT/WT donor compared with donors with a deletion (3 years: 52 vs 34%; P = 0.03; multivariate analysis; RR 0.61; 95% CI 0.38-0.98, P = 0.04). This was more marked when both the patient and the donor had a deletion (3 years OS: 62% compared with 36%, P = 0.01). As the majority of these patients received Alemtuzumab during conditioning, we went on to analyze the in vitro effect of the polymorphism on Alemtuzumab-induced apoptosis. We showed statistically significantly higher percentages of apoptotic naïve CD4 (P o 0.0005) and CD8 (P o 0.0005) T cells in WT/WT donors in comparison with donors with a deletion. These data imply an unrecognized role for the CASP8 promoter polymorphism on survival following unrelated SCT particularly in the context of T-cell depletion with Alemtuzumab.
Background: Inflammatory breast cancer (IBC) is a rare form of aggressive breast cancer with no existing identifiers for screening or prevention strategies. Women with triple-negative (TNBC, ER–, PR–, Her2–) non-inflammatory breast cancer are less likely to breastfeed, and we have shown in adjacent normal breast tissue that this tissue has more foci of stem cells compared to non-TNBC cancers. A disproportionately higher percentage of women with IBC have TNBC relative to women with non-IBC. We hypothesized that adjacent normal tissue in TNBC IBC vs. TN non-IBC may also display unique biological features based on epidemiologic characteristics. Methods: We examined epidemiologic factors by breast cancer receptor subtype in 144 patients diagnosed with IBC in 1991–2011 at MD Anderson Cancer Center. Breast cancer risk factors including parity and breastfeeding were compared between patients with TN and non-TN IBC with chi-square or Wilcoxon rank sum tests. Normal adjacent tissues were stained for stem cell markers CD44+CD49f+CD133/2+ and macrophage marker CD68. Results: The mean age at diagnosis was 52.3 years (range = 23–80) and 83% of patients were non-Hispanic white, 80% were overweight or obese (BMI >25), and 36% were TN IBC. Patients with TN IBC had significantly lower frequency of breastfeeding compared with non-TN IBC, 28% vs. 55%, (p = 0.01). No differences were found in the frequency of other breast cancer risk factors. All 8 IBC adjacent tissue samples showed a distinct spatial distribution of stem cell staining, not limited to the triple negative patients. Compared with 0/60 non-IBC cases, 0/8 triple negative non-IBC, (p = 0.001 Pearson chi-square). Given the high BMI among IBC patients, we further examined normal tissues for the presence of CD68+ cells distributed individually or as clusters exhibiting a “crown-like” pattern (multiple CD 68+ macrophages found around dead adipocytes), and found that 7 of the 8 IBC adjacent tissues were CD68+. Benign biopsies collected from 2 patients at 10 years before diagnosis displayed similar staining, including both stem cell and CD68 staining. Compared with 12/60 non-IBC adjacent tissues were positive for CD68, with 1/8 TN non-IBC, (p = 0.001 Pearson chi-square). Conclusion: We describe for the first time a stem-cell staining pattern unique to IBC present in all IBC tissues examined, including pre-cancer biopsies. Tissue samples from additional patients will be examined to further explore the relationship between stem cells and CD68 positivity with IBC subtypes. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-10-01.
Primary Objective: To assess the efficacy of MK-3475 as a single agent in patients with MIBC and non-IBC TNBC. The primary endpoint is disease control rate at the end of 4 months after receiving the treatment. We will also investigate the association between biomarkers in the peripheral blood and tumor tissue, safety and efficacy. Background: The extensive invasion of lymphatic vessels by tumor emboli in patients with IBC suggests that the host immune surveillance system is suboptimal or that the tumor cells have decreased immunogenicity through immune editing to avoid detection by the host. In the immune-competent host, tumor cells must overcome both innate and adaptive immunologic defenses of the host. The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. MK-3475 is a potent and highly selective humanized mAb designed to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. MK-3475 strongly enhances T lymphocyte immune responses in cultured blood cells from healthy human donors, cancer patients, and primates. Mouse anti-PD-1, as a monotherapy, demonstrated efficacy in several syngeneic mouse tumor models. To date, no specific targeted therapeutic options exist for the treatment of MIBC and TNBC. After patients achieving a clinical response to systemic therapy, the maintenance of disease control is not guaranteed. Further, our recent publication suggests that IBC has immune dysfunction. Chemotherapies can debulk the disease volume but cannot be used for maintenance due to their toxicities. Using an anti PD-1 monoclonal antibody is a promising approach for this patient population. Study Design and Treatment Plan: This is a single arm phase II study. Up to 35 patients with HER2 negative MIBC or metastatic TN-IBC (MTNBC) who have achieved clinical response or stable disease after receiving any prior systemic therapy for metastatic/recurrent disease, and meet all other criteria will be eligible. Patients will receive MK-3475 200 mg IV every 3 weeks for up to 2 years. Statistical Considerations: The trial will be conducted using Simon's optimal two-stage design and the rate of disease control will be estimated accordingly. It is assumed that the MK-3475 single agent will have a disease control rate of 30%. A disease control rate of 10% or lower will be considered treatment failure and the regimen will be rejected under this circumstance. Status of the study: Activation Date: June 2015. 13 patients have been enrolled. Enrollment continues. Sponsor: Merck Sharp & Dohme Corp. State of Texas appropriation for rare and aggressive breast cancer research. Citation Format: Willey JS, Parker CA, Valero V, Lim B, Reuben JM, Krishnamurthy S, Gong Y, Scoggins ME, Dryden MJ, Liu DD, Woodward WA, Ueno NT. A phase II study of anti-PD-1 (MK-3475) therapy in patients with metastatic inflammatory breast cancer (MIBC) or non-IBC triple negative breast cancer (non-IBC TNBC) who have achieved clinical response or stable disease to prior chemotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-02-01.
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