Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that plays a key role in the normal regulation of peripheral immune tolerance. Tumors also employ this mechanism to induce a state of immunosuppression, evading immune mediated destruction. Indoximod (D-1-methyltryptophan) is a broad IDO pathway inhibitor as it has been shown to potentially interfere with multiple targets within the IDO pathway. Preclinical studies in MMTV-neu mouse models have demonstrated that combining indoximod with cytotoxic chemotherapy had a greater in-vivo anti-tumor effect than either agent alone. A phase 1 trial combining docetaxel and indoximod demonstrated safety and responses in metastatic breast cancer (mBC) patients. Based on these data a phase 2 trial evaluating indoximod in combination with taxane chemotherapy as first line therapy in patients with metastatic breast cancer was initiated. Methods: The study is a 1:1 randomized, placebo controlled, four arm phase 2 trial. The study treatment is docetaxel 75mg/m2 IV D8 plus indoximod 1200mg PO BID D1-14 every 21 days or matching placebo in study arms 1A and 2A or paclitaxel 80 mg/m2 IV weekly 3 out of 4 weeks with indoximod or matching placebo given BID Days 1-14 in arms 1B and 2B. The primary endpoint is progression free survival. Secondary endpoints include overall survival, response rate, safety, and immune response correlative assays. Patients with measurable, histologically confirmed mBC, no prior chemotherapies (hormonal therapies allowed) in the metastatic setting, ER+ or ER –, HER2 -, ECOG PS 0-1, no active CNS disease, no active autoimmune disease are eligible. Target enrollment is 154 patients. Results: At submission, 65 patients have evaluable safety data on trial. The pooled, blinded data was evaluated for any safety signals. Patient demographics include median age 58 years, 95% female, 17% African American, 25% triple-negative disease, and 82% with multiple sites of metastatic disease. 28% of patients had at least one Grade 3 or 4 adverse event. Those occurring in multiple patients include dyspnea 5%, pleural effusion 3%, non-cardiac chest pain 3%, and febrile neutropenia 3%. Most patients had at least one adverse event (86%). The most common were anemia 14%, tearing 11%, constipation 19%, diarrhea34%, nausea 44%, vomiting 22%, fatigue 48%, peripheral edema 17%, increased liver function tests 10%, lymphopenia 17%, hyperglycemia 15%, myalgia 14%, dizziness 14%, dysguesia 16%, headache 20%, peripheral neuropathy 12%, dyspnea 19%, alopecia 34%, and rash 14%, all compatible with the side effect profile of single agent taxanes. No immune specific serious advents were reported. No treatment related deaths have been reported. Conclusion: The aggregate safety data for these 65 patient are similar to what is typically observed with docetaxel and paclitaxel. No unexpected serious immune linked adverse events were reported. The trial is currently open at multiple clinical sites in the US and Europe and actively enrolling patients. Updated data will be presented. NCT01191216. Citation Format: Tang S-C, Montero A, Munn D, Link C, Vahanian N, Kennedy E, Soliman H. A phase 2 randomized trial of the IDO pathway inhibitor indoximod in combination with taxane based chemotherapy for metastatic breast cancer: Preliminary data. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-09.

Background: The host anti-tumor immune response plays an important role in determining natural history and therapy response for early stage breast cancer. Tumors with high levels of lymphocytic infiltration appear to have a superior prognosis and response rate to neoadjuvant chemotherapy. However, these tumors are in the minority so methods to enhance tumor lymphocyte infiltration should be identified. The oncolytic virus, talimogene laherparpvec (TVEC) is a genetically modified HSV1 virus which selectively replicates in transformed cells while sparing normal tissue. This leads to lysis of infected tumor cells along with co-expression of GM-CSF to elicit an enhanced anti-tumor immune response. Prior data has shown TVEC can be safely combined with chemotherapy in other indications, so we launched an investigator initiated study to determine the safety and efficacy of combining TVEC with neoadjuvant dose dense chemotherapy in stage II-III TNBC. Study design: The study is a phase 1 (2 dose levels of TVEC, 3+3 design) and phase 2 single arm Simon two stage combination trial. Primary endpoints of phase 1 is safety of intratumoral TVEC (DL1=106 PFU x 5 injections, DL2=106 PFU x 1 then 108 PFU x 4 injections) administered q2-3 weeks concurrently with weekly paclitaxel followed by standard dose dense AC x 4 and local therapy as indicated. Phase 2 primary endpoint is pCR rate of the study treatment, secondary endpoints include DFS, OS, immune correlates in resected tumor specimens. Eligibility criteria includes females >17 years old, newly diagnosed T2-3N0-3 TNBC, adequate organ function, primary tumor amenable to injection with TVEC, no immunosuppressive or autoimmune conditions, no inflammatory or bilateral/multifocal disease. Sample size is up to 49 patients (12 phase 1, 37 phase 2) with 80% power to detect increase in pCR rate from 30% to 50% with one sided p=.1 in phase 2. Study status: This novel Amgen supported investigator initiated study activated to accrual 3/2017 and first patient on study was on 5/2017. The study is currently open only at the Moffitt Cancer Center. Target study completion date 8/2021. (NCT02779855) Citation Format: Soliman HH, Hogue D, Han H, Lee C, Ismail-Khan R, Khong H, Niell B, Czerniecki B. Phase 1/2 trial of the oncolytic virus, talimogene laherparpvec, in combination with neoadjuvant chemotherapy in stage II/III triple negative breast cancer [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 OT2-07-01.

Background The standard regimen of radiotherapy following lumpectomy consists of whole breast irradiation (WBI) to the entire breast including the lumpectomy cavity and all the surrounding normal breast tissue. Recently, there has been increased interest in partial breast irradiation (PBI) as an alternative to WBI. However, the preferences of patients with early breast cancer as to what type of radiotherapy regimen post lumpectomy they would prefer and why is unclear in the literature. This study was conducted to determine whether patients with early stage breast cancer would prefer PBI or WBI and to identify important factors for patients when making their treatment decision. Methods Based on our previous study of early stage breast cancer patient information needs, the relevant literature and the ASTRO consensus statement guidelines, an educational tool and questionnaire were developed. New patients with early breast cancer who were referred for adjuvant radiotherapy at the large academic cancer center were invited to participate. Women >40 years of age with a new histological diagnosis of ductal carcinoma in-situ or invasive breast carcinoma treated with breast conserving surgery showing clear margins for non-invasive and invasive disease and negative axillary nodes were eligible. Descriptive statistics were calculated for all variables of interest. Survey question responses were compared between those preferring WBI or PBI using chi-square analyses or Fisher's exact tests. Results Ninety /126 patients who were approached about this study completed the survey, 27(30%) preferred PBI and 55(62%) preferred WBI. Four patients (4%) required more information to choose between WBIvsPBI, and 3 patients (3%) had no preferences. From patients who choose WBI,32(58%)patients preferred hypofractionated RTvs 14 (25%)conventional RTregimen,Factors rated as important by patients in making their decision included convenience [PBI=18/26(69%), WBI=36/54(67%)], financial factors [PBI=14/26(53%), WBI=21/55(38%)], radiation dose to the breast [PBI=20/26(80%), WBI=46/55(83%)], invasiveness [PBI=18/26(69%), WBI=43/53(81%),, recurrence rate [PBI=26/26(100%), WBI=55/55(100%)], survival [PBI=26/26(100%),WBI=54/55(98%)], side effects PBI 21/26 (81%) WBI 47/55(85%) effectiveness [PBI=25/26(96%),WBI=54/54(100%)], standard method of treatment [PBI=16/26(61%), WBI=52/54(96%), p=0.001] and radiation dose to surrounding organs [PBI=23/26(88%), WBI=52/54(95%)]. Conclusions Our study shows that patients with early breast cancer prefer WBI as an adjuvant treatment post lumpectomy. There is significant association between preference of treatment and importance of standard treatment. Patients preferring WBRT were more likely to consider standard treatment as more important than those preferring PBI.There was a marginally significant association between marital status and preference of radiotherapy(p=0.0773) and employment (p=0.0667).Those currently not employed were marginally more likely to prefer WBI than those currently employed. A detailed analysis of all decisional preferences between WBI and PBI will be presented at the meeting. Citation Format: Szumacher EF, McGuffin M, Presutti R, Pignol IP, Harth T, Mesci A, Feldman-Stewart D, Chow E, DiProspero L, Vesprini D, Rakovitch E, Lee J, Doherty M, Soliman H, Ackerman I, Cao X, Kiss A. Breast cancer patients' preferences for adjuvant radiotherapy post-lumpectomy: Whole breast irradiation versus partial breast irradiation-single institutional study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-10.

Background: Cancer immunotherapy is increasingly important in many malignancies. Breast cancers with greater numbers of tumor-infiltrating lymphocytes (TILs) exhibit better responses to neoadjuvant therapy. Additionally, increased CD8+ TILs in the breast tumor microenvironment have better outcomes. The Total Cancer Care (TCC) biorepository at Moffitt Cancer Center allows for the collection of all clinical patient data and tissue for analysis of novel biomarkers with prognostic and predictive abilities. Using TCC consented patients, we sought to determine if an immune based signature score derived from gene expression profile data would have a significant prognostic ability, and determine if this signature is differentially expressed within different PAM50 molecular subtypes. Methods: Tumors were arrayed on Affymetrix HuRSTA-2a520709 GeneChips (Affymetrix, Santa Clara, CA). The chips contain ∼60,000 probe sets representing ∼25,037 unique genes (Affymetrix HuRSTA-2a520709). Gene expression data was normalized using iterative rank-order normalization and de-batched using Principal Component Analysis (PCA). The immune score for each tumor was derived using the first component from a PCA model based on all immune related genes in breast primary tumor samples. Mean immune score between molecular subtypes was compared using one way ANOVA. Results: A total sample of 310 non-metastatic patients with full clinical and gene expression data were available for the analysis. Mean age was 55. Staging breakdown was Stage I: 26%, stage II: 46%, and stage III: 17%. For tumor grades, 10% were well differentiated, 45% poorly or undifferentiated, 41% moderately differentiated, and 3% missing. Mean follow up for overall survival (OS) was 6.84 years and 6.10 years for recurrence free survival (RFS). For IHC subtypes 62% were hormone receptor positive, 18% triple negative, and 20% HER2 positive. The mean immune score across the whole population was 0.05 (range -2.22 to 2.27). Mean scores were higher in PAM50 basal (.379, 95% CI .143 to .615) and HER2 enriched (.316, 95% CI .143 to .6155) vs. luminal A (-.215, 95% CI -.34 to -.09)/B (-.168, 95% CI -.332 to -.004) subtypes. Immune score was not prognostic for OS hazard ratio (HR) 1.11 (95% CI: 0.91-1.36) p=.30, but was for RFS HR=0.71 (95% CI: 0.53-0.96) p=.02 in a multivariate analysis controlling for age, race, stage, grade, adjuvant treatment, and molecular subtype. Conclusions: The mean immune score is higher in basal and HER2 enriched tumors, suggesting we can potentially identify immune infiltrate enriched patients for immunotherapy trials using existing gene expression profiling data routinely obtained on breast cancer primary tumors. Correlation between score and lymphocyte infiltrate on histology is ongoing and will be presented. A higher score also appears to be an independent predictor of RFS which will need to be confirmed in additional independent well annotated datasets. Citation Format: Sheen MA, Connor CG, Berglund AE, Prabhakaran S, Rizk VT, Soliman HH. Evaluation of a prognostic immune gene expression signature in different breast cancer molecular subtypes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-17.

Background:The current treatment for pseudomyxoma peritonei (PMP) consists of radical cytoreductive surgery (CRS) followed by hyperthermic intra-peritoneal chemotherapy (HIPEC). Aim:To assess PMP patients regarding the clinical and pathological characteristics, the treatment including surgery (CRS) and chemotherapy either HIPEC type or post-operative systemic chemotherapy aiming to evaluate end results regarding recurrence and survival.