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.

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Objective: The primary purpose of the study is to determine the local and systemic antitumor efficacy of talimogene laherparepvec in locally recurrent breast cancer patients with or without distant metastases, as evidenced by improved overall response rates. This will be the first study to use biopsy of distant disease to demonstrate whether systemic immune modulation has antitumor efficacy in breast cancer patients. BACKGROUND: Patients with locally recurrent breast disease frequently undergo multimodal treatment at the first occurrence of breast cancer, and because local treatment modalities such as surgical intervention and radiation are difficult to add, they subsequently receive systemic therapy. Talimogene laherparepvec (T-VEC) was developed to eliminate solid tumors and has since been considered as a potential treatment option for body surface tumors. In addition to T-VECinjected area, this agent is capable of modifying the immune response with the potential of inhibiting distant metastases. Hence, locally recurrent breast disease could benefit from T-VECregardless of concomitant distant metastases, and may offer a new local treatment option. Study Design and Treatment Plan: This is a single agent phase II study. Patients with breast cancer who have recurrence of chest wall disease with or without distant metastasis, have at least 1 injectable lesion ≥5 mm in longest diameter or multiple injectable lesions that in aggregate have a longest diameter of ≥ 5 mm, and meet inclusion and exclusion criteria will be eligible to participate in the study. Patient will receive T-VEC via intra-tumoral injection every 2 weeks after the first initial injection (3 weeks). STATISTICAL METHODS: Up to 35 patients will be enrolled in the study. The trial will be conducted using a two-stage design and the overall response rate will be estimated accordingly. It is assumed that the talimogene laherparepvec single agent will have a response rate of 20%. A response rate of 5% or lower will be considered treatment failure and the regimen will be rejected under this circumstance. Status of the study: Activation Date: Aug 2016. 6 patients have been treated. Enrollment continues. Sponsor: Amgen State of Texas appropriation for rare and aggressive breast cancer research. Citation Format: Willey JS, Marx AN, Lim B, Ibrahim NK, Valero V, Mittendorf EA, Reuben JM, Le-Petross HT, Whitman GJ, Krishnamurthy S, Woodward WA, Lucci A, Liu DD, Shen Y, Ueno NT. A phase II study using talimogene laherparepvec as a single agent for inflammatory breast cancer or non-inflammatory breast cancer patients with inoperable local recurrence [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 OT1-01-05.

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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.

Despite the fact that cervical cancer is one of the leading causes of death in women worldwide, research has yet to elucidate why some HPV-infected women develop cancerous lesions while others are able to clear the infection. Previous studies have shown that HPV integration status may be associated with cervical cancer development, and yet, host genetic factors that may be involved in the viral integration process have not yet been identified. The purpose of this study was to examine the association between both HPV 18 viral integration status and single nucleotide polymorphisms (SNPs) in non-homologous end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia. Specifically, we sought to compare women with no dysplasia to those with low-grade or high-grade squamous intraepithelial lesions. METHODS: A total of 765 women were selected from two large trials designed to evaluate optical technologies for cervical cancer. Genotyping was performed using the Illumina Golden Gate platform. HPV 18 integration status was determined using a previously established protocol. Chi-square tests were conducted to determine which SNPs were associated with normal cytology, low-grade, or high-grade lesions. Among participants with cervical dysplasia, polytomous logistic regression models were used to evaluate the effect of each polymorphism on viral integration status. An additive genetic model was used for all tests. P-values were adjusted using the false discovery rate method. RESULTS: Women with high-grade lesions were significantly younger than women with low-grade or no lesions. Tag-SNPs in 13 DNA repair genes, including MRE11A, ATM, and XRCC4, were significantly associated with cervical dysplasia. Most participants had a mix of both episomal and integrated HPV 18. Tag-SNPs in the XRCC4, PRKCH, and MRE11A genes were found to be significantly associated with HPV 18 integration status. CONCLUSION: Our study indicates that host genetic variation in NHEJ DNA repair pathway genes, including MRE11A and XRCC4, are significantly associated with HPV 18 integration, and that these genes may play a key role in determining cervical cancer development and progression. This is the first study to examine host genetic variation in association with the viral integration event. Predictors of Cancer Survivors' Receptivity to Lifestyle Behavior Change InterventionsBasen-Engquist K, Carmack C, Blalock J, Baum G, Rahming W, Demark-Wahnefried W Purpose: To assess cancer survivors' interest in lifestyle behavior change interventions, and to identify predictors of interest.Methods: Mailed surveys were sent to a stratified random sample of breast, colorectal, and prostate cancer survivors ascertained from the MD Anderson tumor registry and departmental databases. Surveys queried survivors about their diet, exercise, and smoking behaviors; symptoms; and their interest in interventions.Results: Surveys were received from 1053 cancer survivors. Roughly half of the sample were very/extremely interested in programs to help them get in shape (45%), e...

Purpose: To report preliminary data in a pilot study evaluating the ability of Tc99m sestamibi Molecular Breast Imaging (MBI) to predict response and assess residual disease at the completion of neoadjuvant chemotherapy (NAC) in breast cancer patients. Materials and Methods: Patients with localized, invasive breast cancer (T1-T4, N0-N3, M0) planned for NAC were enrolled in this prospective IRB approved clinical trial. All patients had digital mammography (DM), ultrasound (US), and MBI at baseline (T0), after 2 NAC cycles (T1), and at after NAC completion (T2). Tumor size and volume changes were compared with residual disease at surgery. MBI images were corrected for scatter and attenuation using a novel approach and regions of interest (ROI) were drawn over tumors to compute three quantitative MBI uptake metrics for correlation with pathologic response: tumor to background ratio (TBR), fractional activity uptake (FAU), and MBI-specific standardized uptake value (SUV). ROC analysis was performed. Results: Patients (n=25) who completed NAC, had 75 imaging time points and had surgery, were included in this analysis. Median age was 49 years (range 31 -77). Eleven patients (11/25, 44%) had complete pathologic response (pCR). Absolute TBR values after 2 cycles (T1) and before surgery (T2) had highest correlation with pCR (AUC 0.81; 95% CI 0.63 to 0.99, p=0.01, and AUC 0.78; 95% CI 0.59 to 0.97, p=0.015, respectively). Change in SUV after 2 cycles, Δ SUV1 (T1-T0), (AUC 0.84; 95% CI 0.66 to 1.00, p=0.01) and change in SUV prior to surgery, Δ SUV2 (T2-T0) (AUC 0.80; 95% CI 0.60 to 1.00, p=0.02), were most predictive of pCR. Tumor size and volume showed modest specificity for detecting residual disease, and was highest for MBI (79%), followed by MMG (64%), and lowest for US (55%). Conclusion: Quantitative MBI metrics show promise for the prediction of pCR in breast cancer patients undergoing NAC. Establishment of quantitative metrics for the early prediction of tumor response during NAC of breast cancer patients may provide an alternate to influencing NAC choice early in the management algorithm. Further investigation with a larger sample size is warranted. Citation Format: Rauch GM, Adrada BE, Kappadath C, Candelaria RP, Huang ML, Santiago L, Moseley T, Scoggins ME, Knudtson JD, Lopez BP, Hess KR, Krishnamurthy S, Moulder S, Valero V, Yang W. Quantitative assessment of tumor response to neoadjuvant chemotherapy in women with locoregional invasive breast cancer using Tc99m sestamibi molecular breast imaging - preliminary results [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 P5-01-02.