Treatment of triple‐negative breast cancer (TNBC) remains challenging due to the underlying heterogeneity of this disease coupled with the lack of predictive biomarkers and effective targeted therapies. Intratumoral heterogeneity, particularly enrichment for breast cancer stem cell‐like subpopulations, has emerged as a leading hypothesis for systemic therapy resistance and clinically aggressive course of poor prognosis TNBC. A growing body of literature supports the role of the stem cell renewal Hedgehog (Hh) pathway in breast cancer. Emerging preclinical data also implicate Hh signaling in TNBC pathogenesis. Herein, we review the evidence for a pathophysiologic role of Hh signaling in TNBC and explore mechanisms of crosstalk between the Hh pathway and other key signaling networks as well as their potential implications for Hh‐targeted interventions in TNBC.

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3564 Background: Autologous stem cell transplant (ASCT) with high-dose therapy (HDT) is an effective treatment modality for multiple myeloma (MM). MM is the leading indication for ASCT in North America. It was shown in a recent meta-analysis that a strategy of using ASCT early in the course of myeloma improves progression free survival (PFS) and quality of life. However, this study addressed only patients who had received conventional chemotherapy. Over the last decade, novel agents (thalidomide, bortezomib, and lenalidomide) have replaced conventional chemotherapy for induction in myeloma. These agents have demonstrated superior response rates when compared to conventional chemotherapy, and there is some indication that using novel therapies for induction before ASCT improves the duration of response and overall survival (OS). However, the question of whether early ASCT is the best strategy in the era of novel agents remains unanswered. We performed a retrospective analysis in order to compare the outcomes of patients with newly diagnosed MM treated with novel agents who received an early versus late ASCT. Methods: 179 newly diagnosed MM patients were treated or referred to The Ohio State University for ASCT between October 2006 and December 2009. All patients in the analysis received either thalidomide, bortezomib, or lenalidomide as part of their induction regimen and went on to receive HDT and ASCT. We compared the outcomes of patients who received ASCT within 12 months of diagnosis (early group, N=134) to those who received ASCT at a later date (late group, N=45). All patients received melphalan 140mg/m2 or 200mg/m2 as preparative regimen. Kaplan-Meier estimates were used to compare PFS and OS. Result: In our sample of 179 subjects there were no statistically significant differences in age, sex, race, performance status, comorbidity index score, disease stage at diagnosis, genetic risk and preparative regimen dose between the two groups. The median time from diagnosis to transplant was 7.2 months in the early group (N=134) and 17.7 months in the late group (N=45). In the early group, 81% of patients had received one line of treatment before transplant vs. 49% in the late group (p < 0.001). The overall response rate (ORR) prior to transplant was 90% (9% complete (CR), 31% very good (VGPR), 45% partial (PR)) in the early group, and 83% (9% CR, 22% VGPR, 47% PR) in the late group (p = 0.277). The ORR post transplant was 92% in the early group and 82% in the late group (p = 0.082), with a statistically significant proportion of patients in the early group obtaining CR (52% vs. 27%, p = 0.003). One year non-relapse mortality was 2% for both groups. At a median follow up of 22 months, 36% vs. 47% of patients had progressed (p = 0.29) and 7.5% vs. 24% had died due to disease progression (p = 0.005) in the early vs. late group. Median PFS was 30 months vs. 27 months with 1 year and 3 years PFS of 83% vs. 75% and 64% vs. 55% in the early vs. late group respectively (p = 0.851, Fig. 1). Of patients who had only one therapy pre transplant, results trended toward equivalent PFS in the two groups (p = 0.090), however more than 1 line of therapy and late transplant resulted in a progression hazard ratio of 2.43 (p = 0.050). OS was significantly better in the early group vs. the late group (p = 0.005, Fig. 2). On Cox regression analysis, a late ASCT resulted in a mortality hazard ratio of 3.30. Conclusion: An early ASCT in newly diagnosed MM patients receiving novel agents for induction resulted in an improved OS but not PFS. Patients who are responding well to their first line treatment may have equivalent PFS regardless of time to ASCT. Patients who have had ≥ 2 lines of treatment and underwent ASCT within 12 months had significantly improved PFS compared to those who received ≥ 2 lines of treatment but were transplanted later. Therefore, patients who have not responded to their first line regimen and are within 12 months of diagnosis may have the greatest benefit from ASCT. An extended analysis will be presented at the meeting. A multicenter randomized study comparing early vs. late transplant is underway. Disclosures: Phillips: NCI/NIH: Research Funding; NCCM Grant: Research Funding; ARRA RC2 Grant: Research Funding. Byrd:Genzyme Corporation: Research Funding.

17 Background: The UVB-vitamin D-breast cancer (BC) hypothesis is supported by ecological studies demonstrating an inverse correlation between sunlight exposure and BC incidence and mortality. Observational studies also favor an inverse association between vitamin D status and BC risk, recurrence and mortality. Yet controversies remain regarding the role of vitamin D in BC. We examined associations between vitamin D levels, geographic location, clinical, and pathologic characteristics of BC patients (pts). Methods: This was a retrospective analysis from the electronic health record database of pts diagnosed with BC between 1/2007 and 5/2013 across US Oncology Network practices categorized based on their geographic location into: northern (> 40° N), central (35 to 40°N) and southern (< 35°N) latitude. We collected age at diagnosis, BMI, smoking history, stage, estrogen receptor (ER), progesterone receptor (PR), HER2 status, and the first documented serum 25-hydroxyvitamin D (25-(OH)D) level, categorized as 30 optimal. Statistical comparison was performed using Chi-squared tests for categorical variables and Kruskal-Wallis tests for continuous variables. Logistic regression was used to predict the likelihood of vitamin D deficiency. Results: 20,338 BC pts with a documented vitamin D level were identified. Mean age at diagnosis was 58. Stage and receptor status distribution were: 8%, 41%, 32%, 11% and 4% for stage 0, I, II,III, and IV respectively; 63%, 13%, and 10% for ER+/HER-2-, HER-2+ and TNBC, respectively. 17.6% and 27.8% of pts had deficient or suboptimal vitamin D levels. The covariates of age < 60 years (OR 1.24), advanced stage (OR 1.32 stage II, OR 1.51 stage III, and OR 1.81 stage IV), TNBC (OR 1.45), BMI ≥ 25 (OR 2.02), current smoker (OR 2.11), and lower latitudes (OR 1.36 and 1.19 for central and southern latitude respectively) were independent predictors of a first documented vitamin D deficiency in a multivariate model. Conclusions: Vitamin D deficiency may be associated with TNBC and central and southern latitudes. The possible influences of differential vitamin D supplementation and timing of testing require further investigation.

IntroductionBreast cancer arising in young women is relatively uncommon constituting around 5-7 % of women diagnosed in the Western World [ 1 , 2 ]. The prevalence is higher in the developing world, with up to 20 % of patients diagnosed below the age of 40 in Africa and the Middle East [ 3 , 4 ].Breast cancer in young women differs in several aspects from tumors diagnosed in older patients. Women ≤40 tend to have advanced disease at diagnosis, typically presenting with large palpable, often multifocal tumors and exhibiting higher prevalence of lymphatic involvement and nodal spread [ 1 , 5 , 6 ]. Moreover, young age at breast cancer diagnosis has consistently been shown to be an independent predictor of worse outcome in both early and late stage disease [ 1 , 6 -10 ]. This likely provides an explanation for the trends observed in clinical practice favoring mastectomy and adjuvant chemotherapy use in this patient population despite lack of proven recurrence or survival benefi t justifying a more aggressive treatment approach [ 11 -18 ].It is unclear whether the adverse clinical and histologic features of breast cancer in young patients can entirely account for their increased risk of relapse and diseaserelated mortality. Despite lack of differences in stage-adjusted short-term survival in younger compared to older women [ 19 ], studies with long-term follow-up have revealed that survival disparities are more prominent in early rather than late stage disease [ 1 , 20 ], emphasizing the precedence of tumor biology over clinical stage as predictor of outcome in this disease [ 21 ].Higher rates of hormone-receptor negative and HER2-overexpressing tumors occur in younger patients [ 1 , 3 ]. Other adverse histologic features seen in this patient population include high tumor grade, poor differentiation, and