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Hypofractionated whole-breast radiation therapy (RT) has proved to be equivalent to conventionally fractionated RT in multiple randomized trials. There is controversy regarding its use in younger women because of their underrepresentation in trials and the concern for late toxicity. We evaluated disease control and cosmetic outcomes in patients aged50 years treated with hypofractionated RT in 4 prospective single-institutional trials.From 2003 to 2015, 1313 patients were enrolled in 4 prospective protocols investigating the use of adjuvant hypofractionated RT after breast-conserving surgery with a daily or weekly concomitant boost. We identified the records of 348 patients aged50 years at consultation for this analysis. Overall survival, disease-free survival, and local recurrence-free survival were estimated using the Kaplan-Meier method by study and across studies using meta-analytic methods. The late effects of RT, clinician-rated cosmesis, and patient-rated cosmesis were also evaluated.With a median follow-up period of 66.9 months, the overall survival rate was 99.6%, the disease-free survival rate was 96.3%, and the local recurrence-free survival rate was 97.7% at 3 years. Clinician-rated cosmesis (n = 242) was excellent or good in 93.4% of cases and fair or poor in 6.6%. Patient-rated cosmesis (n = 259) was excellent or good in 86.1% and fair or poor in 13.9%. When patients rated themselves differently than their physicians, patients more often rated themselves poorly compared with their physicians (P = .0044, Cochran-Mantel-Haenszel test).At a median follow-up of 5 years, an analysis of patients aged 50 years demonstrated that hypofractionated RT was safe and effective, with good to excellent cosmesis as assessed by both clinicians and patients.

Introduction. Prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (AHCT) remains a major challenge. The combination of methotrexate (MTX) and a calcineurin inhibitor has been the standard regimen for prophylaxis in patients receiving matched sibling donor (MSD) or matched unrelated donor (MUD) transplants for the past few decades. However, over 50% of patients undergoing AHCT still develop acute or chronic GvHD or even both, causing high rates of morbidity and mortality. Moreover, calcineurin inhibitors also have untoward toxic side effects. High dose post-transplant cyclophosphamide (PTCy), initially introduced for GvHD prevention in the setting of haploidentical transplantation, has now been studied in MSD and MUD transplants. We adopted a novel approach to prevent GvHD using a short course of PTCy and bortezomib. We hypothesized that such combination is safe and effective and omits the need for calcineurin or m-TOR inhibitors. Study Design. We report the outcomes of a prospective cohort of patients who received PTCy and bortezomib for GvHD prevention following MSD or MUD transplants. Twenty-eight patients were treated in a phase I-II trial and their clinical outcomes were previously reported (al-Homsi AS et al, BBMT 2019). Most of the remaining patients were treated on an extension trial. GvHD prevention consisted of PTCy 50 mg/kg IV on day +3 and +4, and bortezomib 1.3mg/m 2 IV 6 hours after transplant and again 72 hours after. Patients receiving MUD transplants also received rabbit ATG (thymoglobulin®) 5mg/kg total IV fractionated on day -4 to -2. All patients received peripheral blood grafts and standard supportive care as per Institutional policy. G-CSF was administered routinely until neutrophil engraftment. Results. Fifty-eight patients are included in this analysis. Median age was 60 (range 22-78) years. Fifty-three percent of patients were male. Underlying malignancies consisted of myeloid and lymphoid malignancies in 79.3% and 20.6%, respectively. Acute myeloid leukemia (50%) and myelodysplastic syndromes (24.1%) were the most common diseases. At transplant, disease risk index was low, intermediate, high and very high in 19.0%, 48.3%, 31.0% and 1.7% of patients, respectively. Median Pretransplant Assessment of Mortality Score (PAM) was 16.7 (5.4-29.4). Grafts were from MSD in 24.1% or MUD in 75.9% of patients. Recipient (R)/Donor (D) CMV status at transplant was as follows: R+/D+: 43%; R+/D-: 21%; R-/D+: 14% and R-/D-: 22%. Conditioning regimens consisted of reduced intensity fludarabine and busulfan in all but 2 patients who were conditioned with myeloablative fludarabine and busulfan. Overall, the regimen was remarkably well tolerated. Median times to neutrophil and platelet engraftment were 16 (13-28) and 26 (15-57) days respectively. No patient experienced primary graft failure. CMV and EBV reactivation rates were 46.6% and 24%. Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 35% (95% CI: 22%-47%) and 15% (95% CI: 7%-25%) at day +120, respectively. Cumulative incidence of chronic GvHD was 14% at 1 year . Overall, 34% of patients required immunosuppression with systemic steroids after day +4 either for grade III-IV acute or chronic GvHD. Disease relapse rate was 26%. One-year cumulative incidence of transplant-related mortality was 14% (95% CI: 6%-25%). Median overall survival was 30.7 (95% CI: 15.7-not yet reached) months. One-year overall survival was 72% (95% CI: 57%-82%). One-year composite GvHD (acute and chronic) free and relapse free survival (GRFS) was 41.6% (95% CI: 28.9%-54%). Conclusion. PTCy and bortezomib combination for GvHD prophylaxis following MSD and MUD transplants is well tolerated and effective. It offers an alternative regimen to calcineurin and m-TOR inhibitor-containing regimens and may be preferred in certain settings including patients with limited resources, poor medication compliance, and with impaired renal function. A comparison of this cohort to a matched control group of patients receiving methotrexate and cyclosporine for GvHD prevention is ongoing. Disclosures Abdul-Hay: Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Other: Advisory Board, Speakers Bureau; Jazz: Other: Advisory Board, Speakers Bureau; Abbvie: Consultancy; Takeda: Speakers Bureau. Al-Homsi: Celyad: Other: Advisory Board; Daichii Sanyko: Consultancy. OffLabel Disclosure: Cyclophosphamide and Bortezomib are used for GvHD prevention

Prior studies of timeliness of adjuvant chemotherapy (AC) initiation in stage III colon cancer have suggested longer time to AC at public compared with private hospitals. Few studies have explored differences in AC completion. We investigated whether timely initiation and completion of AC differed between a public and private hospital, affiliated with the same academic institution in a large, urban setting. We conducted a retrospective cohort study of stage III colon cancer patients who had surgery and AC at the same medical center between 2008 and 2015, either at its affiliated public hospital (n = 43) or private hospital (n = 79). We defined timely initiation as receiving AC within 60 days postoperatively, and completion as receiving ≥ 75% of planned AC. Univariate and stepwise multivariable logistic regressions were used to identify factors associated with AC delivery. Median number of days to AC was significantly greater among patients at the public (53, range 31–231) compared with the private hospital (43, range 25–105; p = 0.002). However, the percentage of patients with timely AC initiation did not differ substantially by hospital (74 vs 81%, p = 0.40). In multivariable analysis, age (OR 0.95/year, 95% CI 0.91–0.99) and laparoscopic versus open surgery (OR 5.65, 95% CI 1.92–16.62) were significant factors associated with timely AC initiation. Moreover, AC completion did not differ significantly between public (83.7%) and private (89.9%) hospital patients (p = 0.32). The proportions of patients with timely initiation and completion of AC were similar at a public and private hospital affiliated with a large, urban medical center. Future research should investigate how specific system-level factors help alleviate this expected difference in timely care delivery.

The LUCINDA Trial (Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer’s) is a 52 week, randomized, placebo-controlled trial of leuprolide acetate (Eligard) in women with Alzheimer’s disease (AD). Leuprolide acetate is a gonadotropin analogue commonly used for hormone-sensitive conditions such as prostate cancer and endometriosis. This repurposed drug demonstrated efficacy in a previous Phase II clinical trial in those women with AD who also received a stable dose of the acetylcholinesterase inhibitor donepezil (Bowen et al., 2015). Basic biological, epidemiological and clinical trial data suggest leuprolide acetate mediates improvement and stabilization of neuropathology and cognitive performance via the modulation of gonadotropin and/or gonadotropin-releasing hormone signaling. LUCINDA will enroll 150 women with mild-moderate AD who are receiving a stable dose of donepezil from three study sites in the United States. Cognition and function are the primary outcome measures as assessed by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale. Blood and MRI biomarkers are also measured to assess hormonal, inflammatory and AD biomarker changes. We present the protocol for LUCINDA and discuss trial innovations and challenges including changes necessitated by the covid-19 pandemic and study drug procurement issues.

4504 Background: Trimodality bladder preservation therapy (TMT) is a standard treatment option for clinically localized MIBC with curative intent. Pembro has shown activity in MIBC in the neoadjuvant setting and may combine well with TMT to improve outcomes. This trial evaluated the safety and efficacy of pembro added to TMT in MIBC. Methods: This multicenter phase 2 trial included pts with cT2 – T4aN0M0 MIBC who declined or were ineligible for cystectomy (RC), ECOG PS 0/1, eGFR > 30 cc/min, and no contraindications to pelvic RT or pembro. No perioperative chemotx for MIBC was permitted. Pts received pembro 200 mg x 1 followed 2-3 weeks by maximal TURBT and then whole bladder RT (52 Gy/20 fx; IMRT preferred) with twice wkly gem 27 mg/m2 and pembro Q3 wks x 3 treatments. 12 wks post-RT, CT/MR AP, TUR of tumor bed and cytology were performed to document response. Up to 6 pts were enrolled to a safety cohort (SC) followed by 48 pts in efficacy cohort (EC). The primary endpt is 2-yr bladder-intact disease-free survival (BIDFS: first of MIBC or regional nodal recurrence, distant metastases, or death) assessed by serial cysto/cytology and CT/MRI. EC had 85% power to detect a 20% absolute improvement in 2-yr BIDFS rate over 60% historical rate (RTOG Pooled analysis; Mak JCO 2014). Key secondary endpts were safety, 12 wks CR rate, metastases-free survival and overall survival. Tumor tissue was collected at study entry, maximal TURBT and post-treatment TUR of tumor bed with serial PBMCs for correlative analyses. Results: From 5/2016 to 10/2020, 54 pts (6 SC, 48 EC; 72% M) enrolled at 5 centers; Median age 67 (65-89) for SC and 74 (51-97) for EC. C-stage (74% cT2, 22% cT3, and 4% cT4). 39 (72%) declined RC. All 6 pts in SC and 42/48 (88%) of EC pts completed all study therapy; 1/48 (2%), 2/48 (4%), and 4/48 (8%) discontinued RT/Gem, Gem or Pembro, respectively, most often due to toxicity. As of 1/2021 (median F/U 40.9 mos (38.6-50.8) SC and 11.7 mos (0.6 – 32.2) EC), no recurrences in SC, and 12/48 EC pts had any recurrence (6 NMIBC, 0 MIBC, 2 regional and 4 distant). The estimated 1 yr BIDFS rate is 77% (95% CI: 0.60-0.87). 12 wks CR rate was 100% in SC and 83% for EC (1 PR, 3 NR, 1 Progression, 11 NE; 2 still on active study). In the EC, 35% of pts had a Gr ≥3 TEAE (Gr 3 events included UTI 8%, diarrhea 4%, colitis 4%, bladder pain/obstruction 4%, neutropenia 2%, thrombocytopenia 2%). Notable Pembro Gr ≥3 TRAE included 3 pts (6%) Gr 3 GI toxicity and 1 pt Gr 4 colonic perforation. 1 patient died due to fungemia, unrelated to study therapy. Conclusions: Pembro added to hypofractionated RT and twice weekly gem was well-tolerated with promising efficacy in this early analysis. Pembro-related toxicity was consistent with prior monotherapy trials. Selected correlative analyses from serially collected blood and tissue specimens will be presented. Clinical trial information: NCT02621151.

Purpose:Neoadjuvant therapy has been widely integrated in the treatment of locally advanced breast cancer. Over time, this strategy has been extended to include patients with earlier stage disease to allow for assessment of in vivo response to treatment. The aim of this study was to describe the national trends in neoadjuvant therapy for all invasive breast cancers with a particular focus on triple negative disease and HER2 status. Methods: The National Cancer Database (NCDB), an oncology outcomes database that collects data from more than 1500 Commission on Cancer (CoC) accredited cancer programs, was queried for all women diagnosed with invasive breast cancer from 2006-2013. Patients with unknown systemic therapy sequence were excluded. Women were classified by whether or not they received neoadjuvant systemic, chemo and/or endocrine, therapy. Results: We identified 1,221,976 cases that were eligible for this analysis. Of these, 29.7% were HER2 negative, 18.4% were classified as triple negative, and 8.9% received neoadjuvant systemic therapy. The percentage of patients receiving neoadjuvant therapy increased from 7.5% in 2006 to 9.8% in 2012 with a slight decrease to 9.5% in 2013. This increase in the use of neoadjuvant therapy over the time period was statistically significant (p Number and percent of patients who received/did not receive neoadjuvant therapy by year2006 (N=136117)2007 (N=143033)2008 (N=148888)2009 (N=154713)2010 (N=154040)2011 (N=162333)2012 (N=163395)2013 (N=159457)No Neoadjuvant Therapy | 125908 (92.5)131559 (91.98)136593 (91.74)141364 (91.37)139459 (90.53)146500 (90.25)147401 (90.21)144306 (90.5)Neoadjuvant Therapy | 10209 (7.5)11474 (8.02)12295 (8.26)13349 (8.63)14581 (9.47)15833 (9.75)15994 (9.79)15151 (9.5) Conclusions: Over the time period from 2006-2013, there has been an apparent increase in the percentage of patients who received neoadjuvant therapy. This trend is accompanied by increases in the percentage of TNBC patients and in Her2 positive patients who received neoadjuvant therapy. Other factors and the joint effects of these factors on the observed increase in the use of neoadjuvant therapy are under evaluation to elucidate the basis for this observation in the NCDB data. Citation Format: Schnabel F, Schwartz S, Hochman T, Chun J, Goldberg J. National trends in neoadjuvant therapy for breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-26.

Patients with multifocal breast cancers (MBCs) have a poorer prognosis than patients with unifocal breast cancers. Studies have attributed this to tumor size underestimation in MBC. An alternative hypothesis is that some MBCs behave in a fashion analogous to the “satellite” and “in-transit metastasis” observed in melanoma and, thereby, are more clinically aggressive. We identified 79 cases of MBC, which we classified into 2 groups: study cases defined as ≥2 morphologically similar tumor foci with ≥1 focus without in situ carcinoma (n = 21); and a control group defined as ≥2 morphologically similar or dissimilar foci with associated in situ carcinoma in all foci (n = 58). The odds of being a study case is 1.86 (95% confidence interval [CI] 1.26-2.74) times greater per unit increase in number of tumor foci (median of 4 tumor foci; P = .002). Study cases were 73.33 (95% CI = 8.91-603.16) times more likely to have lymphovascular invasion (LVI) and 14.72 (95% CI = 4.37-49.61) times more likely to have nodal metastases. Grade I/II tumors were 0.20 (95% CI = 0.07-0.59) times less likely to be study cases. There was a significant positive interaction ( P < 0.001) indicated by the relationship of LVI status and nodal status with the study case and control group. We conclude that there is a subset of MBC that presents with more numerous tumor foci and a higher rate of nodal metastasis. The aggressive behavior of these cases may be attributed to their proclivity for LVI.

INTRODUCTION Vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT represent clinically and/or preclinically validated molecular targets in vestibular schwannomas. We conducted a single institution, prospective, open-label, two-stage phase II study (ClinicalTrials.gov identifier NCT02129647) to estimate the response rate to axitinib, an oral multi-receptor tyrosine kinase inhibitor targeting VEGFR, PDGFR and c-KIT, in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannomas (VS). METHODS NF2 patients older than 5 years with at least one volumetrically measurable, progressive VS were eligible. The primary endpoint was to estimate the objective volumetric response rates to axitinib. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Response was assessed every 3 months with MRI using 3-D volumetric tumor analysis and audiograms. Volumetric response and progression were defined as ≥20% decrease or increase in VS volume, respectively. RESULTS Twelve eligible patients (ages: 14–56 years) were enrolled on this study. Seven of twelve patients completed 12 cycles (range: 2 to 12 cycles). We observed two imaging and three hearing responses. Best volumetric response was -53.9% after nine months on axitinib. All patients experienced drug-related toxicities, the most common adverse events were diarrhea, hematuria and skin toxicity, not exceeding grade 2 and hypertension, not exceeding grade 3. CONCLUSIONS While axitinib has modest anti-tumor activity in NF2 patients, it is more toxic and appears to be less effective compared to bevacizumab. Based on these findings, further clinical development of axitinib for this indication does not appear warranted.

BACKGROUND There is no effective therapy for patients (pts) with IDH-mutant gliomas that progress after RT and chemotherapy. At time of progression, these tumors have often transformed to glioblastoma (GBM) and have increased numbers of somatic mutations, i.e. have a “hypermutator phenotype”. We hypothesized that there is synergistic efficacy of Avelumab (anti-PD-L1) combined with HFRT in pts with secondarily transformed IDH-mutant GBMs. Safety-lead-in results will be presented. METHODS This is a phase II, open-label, single-arm, multicenter study of Avelumab with HFRT in adults with transformed IDH-mutant GBM who previously received RT and TMZ and/or PCV. All pts received Avelumab 10 mg/kg IV followed at Day 8 by HFRT (25 Gy in 5 daily 5-Gy fractions) and then Avelumab 10 mg/kg IV every 2 weeks. A 3 + 3 design was used for a 6-patient safety-lead-in cohort. Adverse events were recorded according to CTCAE. RESULTS Six pts (F=4, M=2) with a median age= 45.5 yrs (range 31.5–54.4 yrs) were enrolled in the safety-lead-in cohort. No DLT was observed. Grade ≥ 3 AEs included increased cerebral edema (3 pts), hyponatremia (1 pt) and worsening hemiparesis (3 pts). Grade ≤ 2 AEs included nausea, hypothyroidism, lymphopenia, thrombocytopenia, transaminase elevation, and fever/chills. Median follow-up time was 8.9 mo. Best treatment response was SD in 1 patient. At time of last follow-up all pts have discontinued treatment for PD. Median PFS was 4.2 mo (range 1.4–5.7). Median OS was 10.1 (range 6.8–21+) mo. 4 pts (67%) died, 2 pts remain alive in follow-up at 6.9 and 21.6 months after treatment initiation. The study was closed after the safety lead-in completed enrollment due to slow accrual. CONCLUSIONS Avelumab combined with HFRT was tolerable without dose-limiting toxicity in this safety-lead-in cohort of adult patients with transformed IDH-mutant GBM. Further studies are necessary to determine efficacy of this treatment regimen.

Recent whole genome melanoma sequencing studies have identified recurrent mutations in the gene encoding the catalytic subunit of serine/threonine phosphatase 6 (PPP6C/PP6C). However, the biochemical, functional, and clinical ramifications of these mutations are unknown. Sequencing PP6C from patients with melanoma (233 primary and 77 metastatic specimens) with extended prospective clinical outcome revealed a large number of hotspot mutations in patients with both primary and metastatic melanoma. Despite minimal association between stage and presence of PP6C mutations in patients with primary melanoma, a subpopulation of cells within each tumor did contain PP6C mutations, suggesting PP6C mutation is an early, but non–tumor-initiating event in melanoma. Among patients with primary melanoma with PP6C mutations, patients with stop mutations had significantly shorter recurrence-free survival compared with patients without stop mutations. In addition, PP6C mutations were independent of commonly observed BRAF and NRAS mutations. Biochemically, PP6C mutations could be classified as those that interact with PP6C regulatory subunits and those that do not. Mutations that did not bind to PP6C regulatory subunits were associated with increased phosphorylation of Aurora kinase, a PP6C substrate, and mitotic defects. However, both classes of PP6C mutations led to increased sensitivity to Aurora kinase inhibition. Together, these data support for the first time that PP6C mutations are molecularly, biochemically, and clinically heterogeneous. Implications: PP6C mutations have distinct functional and clinical consequences in melanoma, and confer sensitivity to Aurora A kinase inhibitors. Mol Cancer Res; 12(3); 433–9. ©2013 AACR.

Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers.We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m(2)/day (children18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as ≥15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients.None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules.Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic ("phase 0") study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors.

Myelofibrosis is a chronic and progressive myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating symptoms and leukemic transformation. Ruxolitinib, an oral JAK1/2 inhibitor, is highly effective in ameliorating systemic symptoms and reducing splenomegaly. Current clinical research is focused on the evaluation of agents based on pre-clinical rationale that can result in disease course modification. Panobinostat is a pan-histone deacetylase inhibitor that has demonstrated clinical activity as a single agent in early phase trials of myelofibrosis. We previously conducted a phase I trial of panobinostat monotherapy in patients with myelofibrosis and determined 25mg thrice weekly as the recommended phase II dose. We then completed an investigator initiated, Simon 2-stage, phase II trial of 22 myelofibrosis patients at our single institution. After 6 cycles of therapy, the overall response rate by IWG-MRT criteria was 36% (8/22; 95% CI: 16-56%). The median percent reduction in spleen volume was 34% (range, 1.6%-73%) in eight evaluable patients. The average reduction in JAK2V617F allele burden was 6.8% (Range; -4.0% to 20.2%) and one patient obtained a complete molecular response. Six patients remained on therapy in the extension phase for a median of 18 months (range, 7-44). Treatment discontinuation was frequent due to patient/physician perception of therapy ineffectiveness. The optimal dosing of panobinostat for the treatment of MF remains somewhat ill-defined but appears to be most effective and better tolerated when administered at lower doses over a prolonged duration of therapy.

This single-institution phase II study was performed to estimate the response rate to lapatinib in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Twenty-one eligible patients were enrolled. Brain and spine MRIs, including 3-dimensional volumetric tumor analysis, and audiograms were performed once at baseline and again every 12 weeks. The primary response end point was evaluable in 17 patients and defined as ≥15% decrease in VS volume. Hearing was evaluable as a secondary end point in 13 patients, with responses defined as an improvement in the pure tone average of at least 10 dB or a statistically significant increase in word recognition scores. Four of 17 evaluable patients experienced an objective volumetric response (23.5%; 95% confidence interval [CI], 10%–47%), with median time to response of 4.5 months (range, 3–12). In responders, reduction in VS volumes ranged from −15.7% to −23.9%. Four of 13 patients evaluable for hearing met hearing criteria for response (30.8%; 95% CI, 13%–58%). One sustained response exceeded 9 months in duration. Median time to overall progression (ie, volumetric progression or hearing loss) was 14 months. The estimated overall progression-free survival and volumetric progression-free survival at 12 months were 64.2% (95% CI, 36.9%–82.1%) and 70.6% (95% CI, 43.1%–86.6%), respectively. Toxicity was generally minor, and no permanent dose modifications were required. Lapatinib carries minor toxicity and has objective activity in NF2 patients with progressive VS, including volumetric and hearing responses. Future studies could explore combination therapy with other molecular targeted agents such as bevacizumab.

Background There are well established risk factors for breast cancer, including elements of personal and family history. Ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) have long been viewed as representing two points on the spectrum of one disease. There is limited and conflicting information in the literature regarding risk factor profiles for DCIS as compared with IDC. The purpose of this study was to investigate the relationship of established risk factors in a population of women newly diagnosed with pure DCIS and IDC. Methods The Breast Cancer Database at NYU Langone Medical Center was queried for women who were diagnosed with pure DCIS and IDC from 1/2010-3/2011. Variables of interest included: age, family history of breast cancer (FHBC), BRCA1/2 status, age at menarche and menopause, parity, age at first birth, breast feeding, body mass index (BMI), history of atypical hyperplasia or lobular carcinoma in situ (ADH, ALH, LCIS), stage, ER/PR status, and method of presentation. Wilcoxon non-parametric tests, Chi-Square tests, and Fisher's Exact Tests were used to evaluate differences among DCIS and IDC patients. Results Of the 593 women identified in this study, 140 (24%) had pure DCIS and 453 (76%) had IDC. The median age at diagnosis was 59 years. There were 9 (1.5%) BRCA1/2 mutation carriers. Of these, 7 had IDC and 2 had DCIS. The majority of patients with IDC were stage I (67%) and ER/PR+ (73%). The majority of patients with DCIS were also ER/PR+ (71%). In our cohort, the majority of DCIS (83%) was mammographically detected versus 47% of IDC cases. There were no statistically significant differences in breast cancer risk factors between the two groups. Conclusions In contrast to some previously published work, the risk factor profile in our cohort was similar for patients with IDC and DCIS. In this population, the majority of cases of DCIS were detected mammographically, underscoring the importance of mammography in early detection of breast cancer. There is increasing interest in identifying a population of women with DCIS who might never progress to invasive disease. Our data suggests that this population is unlikely to be distinguished by its risk factor profile. Genetic and molecular characteristics are more likely to provide the criteria by which this subgroup of patients is identified. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-10-08.

p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than did stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients. Cancer Res; 70(21); 8446–56. ©2010 AACR.

Background: Although the optimal timing of adjuvant chemotherapy (AC) for stage III colon cancer patients has been debated, most studies recommend initiating AC within approximately 60 days of surgery. Significant disparities in timeliness of AC initiation in colon cancer have been reported in public versus private hospitals, with longer time to AC at public hospitals. We evaluated whether timeliness of AC differed between a public and a private hospital, both affiliated with the same major academic institution in New York City. Methods: We conducted a retrospective cohort study of Stage III colon cancer patients who underwent surgery and received AC at the same institution from 2008-2015 at NYU Langone Medical Center’s affiliated public hospital (Bellevue) or its private hospital (Tisch). Patient data were obtained through review of hospital tumor registry and electronic medical records. Patient characteristics were compared by hospital. We defined timeliness as receipt of AC within 60 days postoperatively. Univariate and stepwise multivariable logistic regressions were used to identify factors associated with timely AC. Results: Forty three patients at Bellevue Hospital and 79 patients at Tisch Hospital who underwent surgery and received AC at the same institution were included. Median number of days to AC was significantly greater among patients receiving care at Bellevue (53, range 31-231) compared to Tisch (43, range 25-105; p=0.002). However, the percentage of patients who received timely AC did not differ substantially at Bellevue and Tisch (74% vs 81%, p=0.40). Individual characteristics significantly associated with timely initiation of AC were non-Hispanic ethnicity (OR: 2.71, 95% CI: 1.06-6.95), married (OR: 2.89, 95%CI: 1.15-7.30), and laparoscopic (vs open) surgery (OR: 4.30, 95%CI: 1.64-11.25). The odds of receiving timely AC at Bellevue compared to Tisch was not significant (OR: 0.68, 95% CI: 0.28-1.65). When hospital and other factors were examined jointly, only age (OR: 0.95/year, 95% CI: 0.91-0.99) and laparoscopic (vs open) surgery (OR: 5.65, 95% CI: 1.92-16.62) remained as important factors associated with receiving timely AC (Likelihood Ratio Chi-Square=14.95, p=0.0019). When hospital was omitted from multivariable analysis, age and surgery type still remained the only significant factors associated with timely AC (OR’s unchanged, Likelihood Ratio Chi-Square=14.81, p-value=0.0006). Conclusions: The proportion of patients receiving timely AC within 60 days of surgery was similar at both an affiliated public and private hospital at NYU Langone Medical Center. Age and type of surgery were significant predictors of timeliness in our population. Further research should be conducted to understand how system-level factors may promote timely receipt of care. Citation Format: Daniel Lin, Benjamin Levinson, Judith D. Goldberg, Tsivia Hochman, Lawrence P. Leichman, Heather T. Gold. Comparison of a public versus private hospital in New York City in delivering timely adjuvant chemotherapy among stage III colon cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5282. doi:10.1158/1538-7445.AM2017-5282

Recurrent pediatric low-grade astrocytoma (PLGA) represents a major clinical problem in neuro-oncology, and novel, less toxic and more effective therapies are needed.1 Recently, our increased understanding of the key molecular pathways driving PLGA growth and the increasing availability of targeted therapies for those pathways have led to great interest in exploring molecular targeted therapies for PLGA. Pilocytic astrocytoma (PA) is the most common histological subtype of PLGA. Patients with neurofibromatosis type 1 (NF1) are predisposed to developing PAs, predominantly in the optic tract (ie, optic pathway gliomas [OPGs]).2 NF1 is characterized by the loss of the NF1 gene product neurofibromin, resulting in activation of the RAS/RAF/MEK/ERK signaling pathway.3 The majority of sporadic PAs harbor a unique tandem duplication at chromosome 7q34, which produces a fusion gene between KIAA1549 and the kinase domain of BRAF that result in constitutive BRAF and ultimately MAPK activation. In recent genomic studies, almost all PAs that do not harbor KIAA-BRAF have been shown to harbor other genetic lesions that also result in constitutive MAPK pathway activation, such as activating genetic hits in FGFR1, NTRK2, and RAF1.4,5 PLGAs express pro-angiogenic factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF]), and their receptors (VEGFR and PDGFR).6–8 Bevacizumab, a VEGF inhibitor, has recently shown very encouraging activity in PLGA.9,10 Sorafenib is an oral, small-molecule multikinase inhibitor with potent in vitro activity against both wild-type and mutant (V600E) BRAF.11 Recent preclinical data showed that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with sorafenib.12 Sorafenib also exerts anti-angiogenic activity via inhibition of VEGFR-1/2/3, PDGFRβ, Flt-3, and c-kit, which has been studied in a variety of preclinical models13,14 as well as in clinical studies using dynamic, contrast-enhanced MRI.15 Because sorafenib is a potent inhibitor of several key molecular pathways that are relevant in PLGAs and encouraging preclinical data,12 we conducted this prospective phase II clinical trial to assess the objective response rate to sorafenib in patients with PLGA.

Introduction Inflammatory breast cancer (IBC) is an aggressive and rare cancer with a poor prognosis and a need for novel targeted therapeutic strategies. Preclinical IBC data showed strong activation of the phosphatidylinositide-3-kinase/mammalian target of rapamycin (mTOR) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, and expression of inflammatory cytokines and tumor-associated macrophages (TAMs). Patients and Methods Archival tumor tissue from 3 disease types (IBC treated with neoadjuvant chemotherapy [NAC], n = 45; invasive ductal carcinoma [IDC] treated with NAC [n = 24; ‘treated IDC'; and untreated IDC [n = 27; ‘untreated IDC']) was analyzed for the expression of biomarkers phospho-S6 (pS6) (mTOR), phospho-JAK2 (pJAK2), pSTAT3, interleukin (IL)-6, CD68 (monocytes, macrophages), and CD163 (TAMs). Surrounding nontumor tissue was also analyzed. Results Biomarker levels and surrogate activity according to site-specific phosphorylation were shown in the tumor tissue of all 3 disease types but were greatest in IBC and treated IDC and least in untreated IDC for pS6, pJAK2, pSTAT3, and IL-6. Of 37 IBC patients with complete biomarker data available, 100% were pS6-positive and 95% were pJAK2-positive. In nontumor tissue, biomarker levels were observed in all groups but were generally greatest in untreated IDC and least in IBC, except for JAK2 . Conclusion IBC and treated IDC display similar levels of mTOR and JAK2 biomarker activation, which suggests a potential mechanism of resistance after NAC. Biomarker levels in surrounding nontumor tissue suggested that the stroma might be activated by chemotherapy and resembles the oncogenic tumor-promoting environment. Activation of pS6 and pJAK2 in IBC might support dual targeting of the mTOR and JAK/STAT pathways, and the need for prospective studies to investigate combined targeted therapies in IBC.

Purpose: Skin metastases of breast cancer remain a therapeutic challenge. Toll-like receptor 7 agonist imiquimod is an immune response modifier and can induce immune-mediated rejection of primary skin malignancies when topically applied. Here we tested the hypothesis that topical imiquimod stimulates local antitumor immunity and induces the regression of breast cancer skin metastases. Experimental Design: A prospective clinical trial was designed to evaluate the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 d/wk for 8 weeks. Safety and immunologic correlates were secondary objectives. Results: Ten patients were enrolled and completed the study. Imiquimod treatment was well tolerated, with only grade 1 to 2 transient local and systemic side effects consistent with imiquimod's immunomodulatory effects. Two patients achieved a partial response [20%; 95% confidence interval (CI), 3%–56%]. Responders showed histologic tumor regression with evidence of an immune-mediated response, showed by changes in the tumor lymphocytic infiltrate and locally produced cytokines. Conclusion: Topical imiquimod is a beneficial treatment modality for breast cancer metastatic to skin/chest wall and is well tolerated. Importantly, imiquimod can promote a proimmunogenic tumor microenvironment in breast cancer. Preclinical data generated by our group suggest superior results with a combination of imiquimod and ionizing radiation and we are currently testing in patients whether the combination can further improve antitumor immune and clinical responses. Clin Cancer Res; 18(24); 6748–57. ©2012 AACR.

INTRODUCTION AND OBJECTIVES: Pathological grade is the most important prognostic indicator used to risk stratify and select treatment for non-invasive urothelial carcinoma (UC). The 1973 World Health Organization (WHO) grading classification has been most widely used, but suffers from unacceptably high interobserver variability. The 2004 WHO/International Society of Urological Pathology (ISUP) revision was developed to reduce variability by providing welldefined histological criteria for each grade. We compared interobserver reproducibility between the 1973 and 2004 systems and between general versus expert genitourinary pathologists. METHODS: 1 general pathologist (GP) and 2 genitourinary pathology specialists (GU1 and GU2) were blinded to patient identity and graded 98 consecutive UC specimens retrospectively using the 1973 and 2004 classifications. Kappa statistics ( ) were used to measure interobserver reproducibility. By convention, values from 0.21 – 0.4 represent “fair” agreement, from 0.41 0.6 represent “moderate” agreement, and 0.6 represent “substantial” agreement. As an example, values for prostate cancer Gleason score among genitourinary pathologists have been reported to be 0.6. RESULTS: Overall agreement was only fair for both systems and while higher for the 2004 system than the 1973, this was not significant ( : 0.38 versus 0.26, respectively). Agreement between the two specialists versus agreement between each specialist and the generalist was higher using the 1973 system ( : 0.37 vs 0.33 and 0.18) but lower using the 2004 system ( : 0.31 vs 0.46 and 0.39). The generalist had better agreement with both specialists using the 2004 system versus the 1973 system ( : 0.46 and 0.39 versus 0.33 and 0.18). These findings were not statistically significant. CONCLUSIONS: Reproducibility is not improved by the 2004 WHO/ISUP revision to the 1973 WHO grading system, even among expert genitourinary pathologists. Since management of non-invasive UC is primarily determined by its grade, this limits a clinician’s ability to risk stratify tumor and potentially alters treatment. Our findings underscore the need to identify molecular markers that can provide a more reliable risk stratification system.

Purpose Damage to heart and lung from breast radiotherapy is associated with increased cardiovascular mortality and lung cancer development. We conducted a prospective study to evaluate which position is best to spare lung and heart from radiotherapy exposure. Methods and Materials One hundred consecutive Stage 0–IIA breast cancer patients consented to participate in a research trial that required two computed tomography simulation scans for planning both supine and prone positions. The optimal position was defined as that which best covered the contoured breast and tumor bed while it minimized critical organ irradiation, as quantified by the in-field heart and lung volume. The trial was designed to plan the first 100 patients in each position to study correlations between in-field volumes of organs at risk and dose. Results Fifty-three left and 47 right breast cancer patients were consecutively accrued to the trial. In all patients, the prone position was optimal for sparing lung volume compared to the supine setup (mean lung volume reduction was 93.5 cc for right and 103.6 cc for left breast cancer patients). In 46/53 (87%) left breast cancer patients best treated prone, in-field heart volume was reduced by a mean of 12 cc and by 1.8 cc for the other 7/53 (13%) patients best treated supine. As predicted, supine-prone differences in in-field volume and mean dose of heart and lung were highly correlated (Spearman's correlation coefficient for left breast cancer patients was 0.90 for heart and 0.94 for lung and 0.92 for right breast cancer patients for lung). Conclusions Prone setup reduced the amount of irradiated lung in all patients and reduced the amount of heart volume irradiated in 87% of left breast cancer patients. In-field organ volume is a valid surrogate for predicting dose; the trial continued to the planned target of 400.

We report a comparison of the dosimetry and toxicity of three-dimensional conformal radiotherapy (3D-CRT) vs. intensity-modulated radiotherapy (IMRT) among patients treated in the prone position with the same fractionation and target of the hypofractionation arm of the Canadian/Whelan trial.An institutional review board-approved protocol identified a consecutive series of early-stage breast cancer patients treated according to the Canadian hypofractionation regimen but in the prone position. Patients underwent IMRT treatment planning and treatment if the insurance carrier approved reimbursement for IMRT; in case of refusal, a 3D-CRT plan was used. A comparison of the dosimetric and toxicity outcomes during the acute, subacute, and long-term follow-up of the two treatment groups is reported.We included 97 consecutive patients with 100 treatment plans in this study (3 patients with bilateral breast cancer); 40 patients were treated with 3D-CRT and 57 with IMRT. IMRT significantly reduced the maximum dose (Dmax median, 109.96% for 3D-CRT vs. 107.28% for IMRT; p0.0001, Wilcoxon test) and improved median dose homogeneity (median, 1.15 for 3D-CRT vs. 1.05 for IMRT; p0.0001, Wilcoxon test) when compared with 3D-CRT. Acute toxicity consisted primarily of Grade 1 to 2 dermatitis and occurred in 92% of patients. Grade 2 dermatitis occurred in 13% of patients in the 3D-CRT group and 2% in the IMRT group. IMRT moderately decreased rates of acute pruritus (p = 0.03, chi-square test) and Grade 2 to 3 subacute hyperpigmentation (p = 0.01, Fisher exact test). With a minimum of 6 months' follow-up, the treatment was similarly well tolerated in either group, including among women with large breast volumes.Hypofractionated breast radiotherapy is well tolerated when treating patients in the prone position, even among those with large breast volumes. Breast IMRT significantly improves dosimetry but yields only a modest but confirmed benefit in terms of toxicities. If a concurrent boost to the tumor bed is not required, a conformal 3D-CRT approach can adequately deliver prone whole-breast hypofractionation radiotherapy.

International audience; Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme degrading the extracellular matrix and overexpressed by many tumors. Here, we documented the presence of MMP-2-specific CD4(+) T cells in tumor-infiltrating lymphocytes (TILs) from melanoma patients. Strikingly, MMP-2-specific CD4(+) T cells displayed an inflammatory T(H)2 profile, i.e., mainly secreting TNF-α, IL-4, and IL-13 and expressing GATA-3. Furthermore, MMP-2-conditioned dendritic cells (DCs) primed naïve CD4(+) T cells to differentiate into an inflammatory T(H)2 phenotype through OX40L expression and inhibition of IL-12p70 production. MMP-2 degrades the type I IFN receptor, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production. Active MMP-2, therefore, acts as an endogenous type 2 "conditioner" and may play a role in the observed prevalence of detrimental type 2 responses in melanoma.

We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer (LABC). We now report disease-free survival (DFS) and overall survival (OS) in the context of pathologic response. 105 LABC patients (White 46%, Non-White 54%) were treated with paclitaxel (30 mg/m2 intravenously twice a week) for 10–12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2–7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of

Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multi-modality therapy results in a 5 year OS of 30%, underscoring the unmet need for targeted therapy. Our preclinical research in cell lines & xenograft tumor models has identified a role for hyper-activated PI3K/mTOR signaling in IBC. IBC cells express IL-6 and IL-8, which recruit tumor activated macrophages (TAMs) that further induce inflammatory cytokines and activate the JAK2/STAT3 pathway. We investigated the independent and combined activity of these pathways in IBC patient tissues. Methods: Archived tissue specimens of 42 IBC patients (dx 1999-2009) and 27 non-IBC patients (dx 2001-2005) with invasive ductal carcinoma (IDC) were obtained. Surrounding non-tumor normal tissue from IBC (companion controls) was also utilized. All specimens were analyzed using immunohistochemistry (IHC) and scored by 3 independent pathologists. Results were defined as 0 = negative; 1+,2+ = positive for activated mTOR (P-S6); activated JAK2/STAT3 (P-JAK2; P-STAT3); cytokine (IL-6); macrophage infiltration (CD68) and TAM (CD163). Proportions of IBC cases with positive expression were compared with non-IBC cases (Fisher's exact test) & companion controls (McNemar's test). Clinical & survival data were obtained. Results: Median age at diagnosis: 46 yrs (31-62) in early stage IBC [EIBC] (n = 37) & 41 yrs (29-57) in pts with de novo metastatic IBC [MIBC] (n = 5). In EIBC, 19/36: HER2+ (1 unk); 8/19: ER+/HER2+; 8/36: ER-/HER2-. In MIBC, all were ER- (1 unk) & 3/4 were HER2+ (1 unk). 88% were rx with neoadjuvant &/or adjuvant anthracycline & taxane w/o adjuvant trastuzumab. There were 24 pt deaths (5/5 MIBC). Median f/u for EIBC: 6.3 yrs and for MIBC: 3.4 yrs. Median OS: 81.4 mo (95% CI lower 48 mo) for EIBC & 41 mo (95% CI 8-81 mo) for MIBC. Median RFS: 18 mo (95% CI 18-79 mo) for 23 pts (13 NED; 1 unk). The non-IBC patients were all stage 2-3 with median age at diagnosis: 58 yrs (39-94). 19/27: ER+; 7/25 HER2+ (2 unk); 15/25 ER+/HER2-; 3/25 ER-/HER2-. 78% were rx with adjuvant anthracycline & taxane, 4% were rx with FEC and 18% did not receive adjuvant chemotherapy. 18% received adjuvant trastuzumab. Median f/u: 8.0 yrs. Median OS: not yet reached and median RFS: 111.3 mo (95% CI lower 34.5 mo). EIBC cases were compared with non-IBC cases & companion controls (Table 1). PS6, pJAK2 and pSTAT3 expression was significantly increased in IBC compared to non-IBC. Of the 29 EIBC patients with complete biomarker data who were PS6+, 28/29 (97%) were JAK2+, 15/29 (52%) were STAT3+, 26/29 (90%) were CD68+, 20/29 (69%) were CD163+ and 28/29 (97%) were IL6+. Conclusion: This is the first study to validate preclinical findings & show a strong co-association between hyper-activation of mTOR & JAK/STAT pathways in most IBC patient tumors when compared to surrounding non-tumor tissue and non-IBC (IDC) tumors and tissues. These findings suggest a key role for dual blockade of mTOR & JAK/STAT pathways for IBC in phase I trials. BiomarkerMcNemars p-value: Early Stage IBC vs companion controls (N = 37)Fishers p-value: Early stage IBC (N = 37)vs non-IBC (N = 27)PS6 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-6.

60 Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multi-modality Rx results in a 5 year OS of 30-50%, underscoring the unmet need for targeted Rx. Our preclinical research in cell lines and xenografts identifies a role for activated PI3K/mTOR pathway in IBC. IBC cells express IL-6 and IL-8 and recruit tumor activated macrophages (TAMs) that further induce IL-6, IL-8 and activate the JAK2/STAT3 pathway. We investigated the independent and combined activity of these pathways in IBC tissues. Methods: Archived tissues of 42 IBC pts and 13 controls (nl breast) were analyzed using IHC and scored by 3 independent pathologists. Results defined as: 0, 1+ = neg; 2+ = pos for activated mTOR (P-S6) and 0 = neg; 1+, 2+ = pos for activated nuclear JAK2/STAT3 (P-JAK2; P-STAT3), cytokine (IL-6), macrophage (mØ) infiltration (CD68) and TAM (CD163). Proportions of IBC cases with pos expression were compared with controls (Fishers exact tests). Clinical and survival data were obtained. Results: Median age at diagnosis: 46 yrs (31-62) in early-stage IBC [EIBC] (n=37) and 41 yrs (29-57) in pts with de novo metastatic IBC [MIBC] (n=5). In EIBC, 19/36: HER2+ (1 unk); 8/19: ER+/HER2+; 8/36: ER-/HER2-. In MIBC, all were ER- (1 unk) and 3/4 were HER2+ (1 unk). 88% Rx with neoadjuvant and/or adjuvant anthracycline and taxane w/o adjuvant trastuzumab. 24 pts died (5/5 MIBC). Median OS: 86 mo (95% CI lower 48 mo) for EIBC & 41 mo (95% CI 8-81 mo) for MIBC. Median RFS: 18 mo (95% CI 18-79 mo) for 23 pts (13 NED; 1 unk). All controls: neg for P-S6, JAK2, STAT3 and TAMs and 92% neg for mØ and IL-6. Proportion of IBC with pos expression when compared to controls listed in table (p

11106 Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multimodality Rx results in 5 year median OS of 30-50%, underscoring the unmet need for novel targeted strategies. Our preclinical research in cell lines and xenografts suggests a role for activated PI3K/AKT/mTOR pathway in IBC. IBC cells not only express high levels of IL-6 and IL-8 but can recruit tumor activated macrophages (TAMs), which can further induce IL-6, IL-8 and activate JAK2/STAT3 pathway. We therefore investigated independent and combined activity of these pathways. Methods: Archived tissue specimens of 42 IBC pts (1999 - 2009) and 13 controls (normal breast) were analyzed using IHC and scored by 3 independent pathologists. Results were defined as: 0, 1+ = neg; 2+ = pos for activated mTOR (phosphorylatedS6) and 0 = neg; 1+, 2+ = pos for activated nuclear JAK2/STAT3 (pJAK2; pSTAT3), cytokine (IL-6), macrophage infiltration (CD68) and TAMs (CD163). Proportion of IBC cases with pos expression were compared to proportion among controls (Fishers exact test). Clinical and survival data were obtained. Results: Median age at diagnosis - 44.5 yrs (29-64). 22 had HER2 overexpression (8 also ER+) and 9 were ER-/HER2-; ER & HER2 unknown for 1 and 2 pts respectively. Majority were Rxed with neoadjuvant anthracycline and/taxane without adjuvant trastuzumab. There were 24 deaths. Median OS: 67 mths (95% CI: lower 41). Proportions of IBC cases with pos expression when compared to controls are listed in the table (Fishers p value

36 Background: Mammographic breast density (BD) is associated with a 4- to 6-fold increased risk for developing breast cancer. A previous study has shown that background parenchymal enhancement (BPE) as measured on MRI can be correlated with breast cancer risk. Being overweight or obese is also an established risk factor for breast cancer. The purpose of this study was to evaluate the relationship between BD, BPE, FGT (assessment of fibroglandular tissue with contiguous MR images), and BMI in pre- and post-menopausal women. Methods: The Breast Cancer Database at NYU Langone Medical Center was queried and a total of 187 women had completed both screening mammograms and MRIs. Variables of interest included BD, BPE, FGT, BMI, and menopausal status. BD was defined by ACR classifications 1-4. FGT was assessed on a similar scale 1-4. BPE was categorized as minimal, mild, moderate, or marked. BMI (kg/m2) was grouped as underweight (≤18), normal (19-24), overweight (25-29), and obese (≥30). Statistical analyses were performed using Spearman Correlation Coefficients and Cochran Mantel Haenszel tests. Results: The median age in our cohort was 51 years (range 22-87 years). The majority were Caucasian (71%) with early stage breast cancers (75%). There was no correlation between BD and BPE (r=0.132) and a weak correlation between BPE and FGT (r=0.312). However, there was a strong positive correlation between BD and FGT (r=0.733). After adjusting for menopausal status, these correlations remained the same. When we stratified by BMI, we found the strongest positive association between BD and FGT among women with BMI≥25 (r=0.715). Conclusions: In our cohort of newly diagnosed breast cancer patients, BD and BPE were not correlated, even after adjusting for menopausal status. This implies that BD and BPE may represent different characteristics of breast tissue and may have different implications. We found a strong correlation between FGT and BD. This association was strongest in women who were overweight and obese. FGT is a more objective and quantitative measurement of breast density and may be more useful in quantitative breast cancer risk assessment.Further studies are necessary to determine if BPE and FGT are independent risk factors for breast cancer.

e11064 Background: We demonstrated in three prospective trials that taxane-based concurrent chemo-radiation achieves high pathological response rates that correlate with decreased recurrence rates and improved survival in locally advanced breast cancers (LABC, Adams et al, BCRT 2010). We now report the results among HER-2 positive LABC patients treated with trastuzumab and concurrent paclitaxel and radiotherapy, preoperatively. Methods: Patients with HER-2 positive LABC (stages IIB-IIIC) were prospectively treated as part of an IRB-approved neoadjuvant trastuzumab-paclitaxel-radiotherapy protocol. Paclitaxel was administered at a dose of 30 mg/m2 twice a week and trastuzumab was given weekly at a dose of 2 mg/kg (after initial loading with 4 mg/kg) for a total of 10 weeks. Radiotherapy was delivered to the breast and regional lymph nodes during weeks 2-7, daily, at 1.8 Gy per fraction to a total dose of 45 Gy. A 14 Gy boost (2 Gy per fraction) was added to the area of the originally palpable tumor site. Tumor response was assessed at definitive cancer surgery; defined as pathological complete response (pCR) in the absence of invasive cancer in breast and lymph nodes; pathological partial response (pPR) as the persistence of < 10 microscopic foci of invasive carcinoma in breast or lymph nodes. All other patients were classified as having achieved no pathologic response. Results: Twenty-one patients with HER-2 positive LABC were treated. The median age of the patients was 50 years (range 28-76). The most common toxicity was acute dermatitis; no grade IV toxicity was detected. Pathological response (pCR and pPR) after neoadjuvant trastuzumab/paclitaxel/radiation was achieved in 12 patients (57%, 95% CI: 37% - 76%). Responses were observed in 8/12 patients with hormone receptor (HR)-negative (7 pCR, 1 pPR) and in 4/9 patients with HR-positive cancers (3 pCR, 1 pPR). Conclusions: In HER-2 positive LABC, neoadjuvant trastuzumab during paclitaxel and concurrent radiotherapy resulted in a 57% pathological response rate, independently of HR status.

e11010 Background: We originally reported that p27 loss in T1a/b breast carcinomas was associated with lack of estrogen and progesterone (ER/PR) hormone receptors, but not in T1c node negative tumors (Mirchandani et al, Anticancer Research 2011). The current study explored the association of p27 expression with lymph node (N) status. Methods: 217 consecutive patients with T1 tumors were identified from 2001-2003. All patients underwent sentinel node biopsy (and complete lymphadenectomy when positive on frozen section): 111 were N0 and 106 were N+. Immunohistochemistry was performed for ER/PR, Her2, and nuclear p27 (low vs normal) and tumors were graded (well, moderate, and poorly differentiated). Analysis was conducted to define associations between standard variables and p27 expression among node positive and node negative tumor carriers (Table). Results: Low p27 expression was found in 21% of N0 and 36% of N+ T1 breast cancer patients (Chi-square=6.14, p-value=0.01). However from a series of multivariable analyses, only tumor size was significantly associated with node positivity. Conclusions: Poorly differentiated tumors, T1c tumors, and low p27 expression were associated with lymph node positivity, but only tumor size was significant in multivariable analysis. Contrary to our prior report, the relationship between low p27 and ER/PR- is strongest in the T1c subset (data not shown). Future studies will expand study cohorts to explore whether low p27 expression is a biomarker of poor outcome at 10 years in patients with T1 tumors treated with antiestrogens. [Table: see text]

589 Background: The association of hormone receptor (HR) status of the original tumor with pathologic response and correlation with DFS and OS from a multi-institutional trial of concurrent paclitaxel (P) and radiation (RT) are reported. Methods: 105 LABC patients were treated with neoadjuvant concurrent P and RT (P: 30 mg/m2 2x/week for 10-12 weeks; RT: 1.8 Gy daily to breast, axillary and supraclavicular LN weeks 2-7 to total of 45 Gy followed by a tumor boost of 14 Gy at 2 Gy/fraction). Pathologic response was defined as absence of invasive cancer in breast and LN (pCR) or persistence of less than 10 microscopic foci of invasive cancer in breast or LN (pPR). Logistic regression methods were used to predict response status, logrank tests and Cox proportional hazards methods to evaluate DFS and OS in relation to HR status and pathologic response. Results: Pathologic response (pCR+pPR) for the entire cohort was achieved in 36/105 patients (34%, 95% CI: 25-44%). For all patients, lack of a pathologic respo...

Purpose: A prospective trial of preoperative concurrent paclitaxel and radiation for patients with LABC was conducted at three academic institutions. Five-year local and systemic control rates are reported. Patients and Methods: 105 patients with LABC were treated with concurrent neoadjuvant paclitaxel and radiation. Paclitaxel was administered at 30 mg/m2 intravenously twice a week for 10-12 weeks. Daily radiotherapy was delivered to the breast, axillary and supraclavicular lymph nodes during weeks 2-7, at 1.8 Gy per fraction to a total dose of 45 Gy followed by a boost of 14 Gy at 2 Gy per fraction to the originally palpable tumor. Weekly trastuzumab (2mg/kg) was added for 8 more recent patients whose tumor over-expressed Her-2/neu. At one of the three institutions preoperative paclitaxel (3 cycles of 175 mg/m2 q 3 weeks) was also administered prior to chemo-radiation to 36 patients. Pathologic response was defined as complete response (pCR) in the absence of invasive cancer in breast or lymph nodes; partial response (pPR) as the persistence of < 10 microscopic foci of invasive carcinoma in breast or lymph nodes. After surgery additional systemic therapy was left to the discretion of the treating physician. Results: Pathological response (pCR and pPR) after neoadjuvant chemo-radiation was achieved in 36/105 patients (34.3%, 95% confidence interval: 25.3% - 44.2%). 30/105 patients underwent breast-conserving surgery after neoadjuvant chemo-radiation (28.6%), while 74 underwent mastectomy. One patient progressed during therapy and did not undergo surgery. With a median follow up of 60 months and a maximum of 137 months, the median survival has not been reached. The estimated 5-year overall cumulative survival (OS) is 71.6% (95% confidence interval: 60.5% - 80.1%). Local recurrence occurred in 4/105 patients (3.8%): in 3/4 synchronously with or following systemic recurrence. Five patients (4.8%) developed contra-lateral breast cancer. Patients without a pathologic response had a higher risk of recurrence or death than patients who had a pathologic response (hazard ratio = 2.86, logrank p-value=0.009); similarly, survival was shorter (hazard ratio = 4.28, logrank p-value=0.003). The 5-year estimated OS for non-responders was 61.6% compared with 87.9% for responders. A separate analysis of patients who received additional preoperative paclitaxel before chemo-radiation showed a pathologic response rate of 41.7% (15/36 patients, 95% confidence interval: 25.5% to 59.2%); with an estimated 5-year OS of 63.9% (95% confidence interval: 46.1% - 77.2%). Conclusion: This series of 105 patients with LABC treated with concurrent paclitaxel and radiation demonstrated a 71.6% 5-year OS and 96% local control rate. Pathological response to concurrent paclitaxel and radiation was associated with a significantly better 5-year survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5639.