bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic factors for overall survival (OS) in metastatic melanoma (MM) patients (pts) treated with immune checkpoint inhibitors: A single institution study of 696 pts.
Authors: McKean Meredith Ann , Haydu Lauren Elaine , Ma Junsheng , Bassett Roland L. , Hwu Wen-Jen , Patel Sapna Pradyuman , Diab Adi , Glitza Isabella Claudia , Tawbi Hussein Abdul-Hassan , Wong Michael K , McQuade Jennifer Leigh , Hwu Patrick , Davies Michael A. , Amaria Rodabe Navroze 
Published: September 2018

9574 Background: Limited OS data, including prognostic and predictive factors of response, is available in mm pts treated with immune checkpoint inhibitors. Methods: A single-institution retrospective review was conducted on 696 mm pts treated with single-agent anti CTLA-4 or anti PD-1 on and off clinical trial between 2011-2015. Median OS was calculated from mm diagnosis. Results:Median age at mm diagnosis was 60 years old (range 15-86) and 65.2% were male. Subtypes were 63.2% non-acral cutaneous, 17.2% unknown primary, 7.8% mucosal, 6.5% acral, and 5.3% uveal. AJCC v7 staging at diagnosis was 7.9% M1a, 16.5% M1b, 33.0% M1c, and 42.5% not staged due to unknown LDH. LDH was elevated in 18.0% (400 pts). Mutation rates were 30.0% BRAF V600E/K (636 pts tested) and 24.5% NRAS (429 pts tested). First-line therapy for BRAF V600E/K mm pts included anti CTLA-4 (24.1%), BRAF/MEK targeted therapy (21.5%) and anti PD-1 (8.9%). First-line therapy for BRAF WT mm pts included anti CTLA-4 (28.1%) and anti PD-1 (12.8%). Median OS from mm for the cohort was 36.5 months (95% CI 33.3-44.9). Elevated LDH and staging correlated with OS (p < 0.001, p < 0.001, respectively) on univariate analysis. Age, gender, subtype and mutation status were not significantly associated with OS. Compared to BRAF WT, pts with BRAF V600E/K mutation were younger (median = 53 vs 62 yrs, p < 0.001), more likely to have non-acral cutaneous mm (83.2% vs 58.0%, p < 0.001) and have a diagnosis of brain metastasis during the disease course (57.0% vs 28.8%, p < 0.001). While adjusting for stage, there was no significant difference in OS based on first or second line therapy in pts with BRAF V600E/K mm or first line therapy in BRAF WT MM; however, BRAF WT pts treated second line with anti-PD1 were observed to have improved OS compared with pts receiving anti-CTLA 4 (HR 0.43 95% CI:0.23-0.84 p = 0.012). Conclusions: This study demonstrates that LDH and stage are prognostic of OS in all mm pts treated with single agent immune therapy. Second line therapy in BRAF WT pts treated with single agent immune therapy is also prognostic of OS thus prompting further investigation to determine advantageous therapy sequencing in MM.
A toll-like receptor agonist to drive melanoma regression as a vaccination adjuvant or by direct tumor application.
Authors: Royal Richard Eldon , Vence Luis M , Wray Tara , Cormier Janice N. , Lee Jeffrey Edwin , Gershenwald Jeffrey E. , Ross Merrick I. , Wargo Jennifer Ann , Amaria Rodabe Navroze , Davies Michael A. , Diab Adi , Glitza Isabella Claudia , Hwu Wen-Jen , Patel Sapna Pradyuman , Woodman Scott Eric , Overwijk Willem W , Hwu Patrick 
Published: September 2018

9582 Background: Toll like receptor (TLR) agonists may enhance vaccination or direct immune activation at the tumor microenvironment. This trial evaluates the biologic and clinical effects of Resiquimod, a TLR 7/8 agonist that can activate both myeloid (mDC, TLR 8) and plasmacytoid (pDC, TLR 7) dendritic cells, in patients with advanced stage melanoma. Methods: Class I HLA-A0201+ subjects with in-transit melanoma metastases or high risk for recurrence were vaccinated weekly with peptide vaccination (class I restricted peptide GP100209-2m and, if HLA-DP4+, also with class II restricted peptide MAGE-3243-258). Subjects were randomized 1:1 to receive Resiquimod as an adjuvant applied to the GP100 vaccination site. Subjects with in-transit disease were thereafter treated with resiquimod topically on half of the target lesions. Results: All patients (n = 47) underwent GP100209-2m vaccination, a majority (39) also received the MAGE-3243-258 peptide. The type I interferon-inducible genes (Mx A and IRF7), IFNg, and IP-10 RNA expression were up-regulated only in vaccination sites treated with Resiquimod (each p < 0.01) , demonstrating pDC activation (Type I interferon) and possibly T and NK cell activation (IFNg and IP-10). Nineteen subjects had in-transit disease at entry into the trial. In response to peptide vaccination alone, tumor regression was more likely in patients who received Resiquimod at the vaccination site (group A) compared to those who did not (group B). (4/9 vs 0/10, p = 0.033). In group A, 5 patients continued treatment with Resiquimod topically on the tumors, and all had tumor response (4PR, 1CR). In group B, 5 continued to tumoral resiquimod and 3 had regression (3 PR). Conclusions: Resiquimod increases Type I interferon and IFNg at the peptide vaccination site by activation of pDC/mDC and increases the antitumor response sufficiently to mediate regression of in-transit melanoma metastasis. Resiquimod on in-transit melanoma, in vaccinated hosts, drives regression of metastases, regardless of previous exposure at vaccination. Clinical trial information: NCT00960752.
Clonality of T cell repertoire in the tumor (TME) and peripheral blood of regionally advanced melanoma patients (pts) treated with neoadjuvant ipilimumab (ipi) and high dose interferon-α (HDI).
Authors: Vallabhaneni Priyanka , Achkar Tala , Vignali Marissa , Benzeno Sharon , Rytlewski Julie , Tarhini Ahmad A. 
Published: September 2018

9585 Background: Pts with regionally advanced melanoma were treated with neoadjuvant ipi and HDI in a reported study ( Tarhini. J Clin Oncol suppl, 2016; abstr 9585). Pathologic complete response (pCR) was found in 32% of pts. Clonality of T cell repertoire was investigated in TME and peripheral blood mononuclear cells (PBMC). Methods: Pts were randomized to neoadjuvant ipi 3 or 10 mg/kg combined with HDI. Tumor biopsies were evaluable for testing at pretreatment (N = 20 pts) and definitive surgery (week 6-8; N = 25). When available, primary (N = 24) and relapse tumors (N = 6) were tested. PBMC: pretreatment (N = 29), 6 weeks (wk) (N = 24), then 3 (N = 23), 6 (N = 21), 12 (N = 14) months. T cell receptor beta chain (TCRB) repertoire was immunosequenced in PBMC and TME to determine repertoire clonality and T cell fraction in blood and TME (TIL; fraction of all nucleated cells identified as T cells). Results: PBMC T cell fraction when measured early on-treatment (6 wks) was significantly higher in pts who had pCR or microscopic residual disease vs. gross disease at the 6-8 wks surgery (p = 0.047). PBMC clonality was significantly lower at 12 wks (p = 0.025) for pts who continued to be relapse free (NED) long term vs. those who eventually relapsed. In TME, except for trends no significant difference in clonality was seen, but in pts with pCR TIL fraction was significantly higher when measured in primary tumors (p = 0.033). The number of tumor-associated clones that were expanded in blood post-treatment was strongly correlated with both TIL fraction (Rho 0.7299, p = 0.0003) and TIL clone diversity (Rho 0.882, p = 2.7-7). Conclusions: Higher T cell fraction and lower clonality in PBMC when measured early on-treatment, and higher TIL fraction in primary tumor constituted promising biomarkers of response. Pts with higher TIL fractions were more likely to have tumor-associated clones detectable in blood, suggesting these may be useful for tracking the immune response. These findings warrant validation in an independent cohort and exploration with other immunotherapeutics. Clinical trial information: NCT01608594.
Predictive value of neutrophil-to-lymphocyte ratio on pathological complete response in triple negative breast cancer.
Authors: Enriquez Daniel , De la Cruz Ku Gabriel Antonio , Fernandez Margiory , Eyzaguirre Eduardo , Luque Renato , Paitan David , Luján Maria , Saavedra Antonella , Valcárcel Bryan , Morante Zaida , Fuentes Hugo Alejandro , Neciosup Silvia P. , Gomez Henry Leonidas 
Published: September 2018

e12012 Background: Immune response in Triple Negative Breast Cancer (TNBC) plays a critical role in pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Therefore, neutrophil to lymphocyte ratio (NLR) could be an interesting biomarker to evaluate systemic inflammation in TNBC. Our aim was to evaluate the effect of NLR, also progression free survival (PFS) and overall survival (OS) as secondary objectives. Methods: We reviewed 338 medical records of II-III CS TNBC patients treated with NAC, in the 2000-2014 period, at Instituto Nacional de Enfermedades Neoplasicas. Patients were grouped in NLR < 3 and ≥3. Survival differences were assessed by log-rank test in the univariate analysis and prognostic factors were then investigated by Cox regression analysis. Results: Mean age was 47y [range:24-79], 54% were premenopausal, 90.9% had clinical T3-T4 tumor and 80.5% clinical nodal involvement. There were 44 and 294 pts with II and III CS, respectively. From 338 patients, 259 had NLR < 3 and 79, ≥3. No significant clinical differences were noted between these groups, except a higher mean BMI among patients with NLR < 3 (28 vs 26Kg/m2, p = 0.01). pCR rate was higher in NLR < 3 patients (22% vs 15.2%, p < 0.001) and partial response was reached on 70.7% and 62% of pts with NLR < 3 and ≥3, respectively. At 5 year median follow-up, 5-year DFS was higher among patients with NLR < 3 (47 vs 34%, HR = 0.69, 95%CI: 0.50-0.95, p = 0.02) and so was 5-year OS (55 vs 40%, HR: 0.61, CI95%: 0.43-0.85, p = 0.004). At multivariate analysis, premenopausal status, non-pCR and nodal involvement were associated with worse DFS. Otherwise, NLR < 3 (HR: 0.61, 95%CI: 0.43-0.86, p = 0.005) and pCR were predictors of better OS, nonetheless nodal involvement had negative impact on OS. Conclusions: NLR is a valuable predictive biomarker of pCR and OS in TNBC patients. We report less pCR rates due to higher stages among peruvian population.
Reducing doxorubicin cardiotoxicity in rats with mammary tumors by dantrolene.
Authors: Todorova Valentina K , Kaufmann Yihong Jiang-Cao , Kumarapeli Asangi R , Siegel Eric R , Owen Aaron , Aronson Julia H , Makhoul Issam , Wei Jeanne , Theus Sue A , Klimberg Suzanne 
Published: September 2018

e12013 Background: Doxorubicin (DOX), widely used in breast cancer, is known for its cardiotoxicity. Preventing DOX-cardiotoxicity without affecting its antitumor efficacy has not been successful. DOX-cardiotoxicity results from oxidative stress that increases intracellular calcium levels by promoting the release of Ca2+ from sarcoplasmic reticulum (SR) and impairing Ca2+ clearance in cardiomyocytes. Dantrolene (DNT), a postsynaptic muscle relaxant inhibits the release of Ca2+ from SR by inhibiting the ryanodine receptor (RYR). The aim of this study was to examine the effect of DNT on cardiotoxicity and anti-tumor efficacy of DOX in a rat model of breast cancer. Methods: Female F344 rats with implanted MatBIII breast cancer cells were randomized into 3 groups of 12 rats/group and were treated as follows: “DOX” group was injected i.p. with DOX 2x week for 3 weeks (cumulative dose 12 mg/kg); “DNT” group received daily DNT (5mg/kg/day) by oral gavage; and “DOX+DNT” group was treated with DOX 2x week for 3 weeks and daily DNT (5mg/kg). The presence of cardiac alterations was examined by echocardiography before and after the experiment. Body weight, tumor size and volume were measured at sacrifice. H&E stainings of the hearts and tumors was examined. Blood glutathione (GSH) levels were determined. Results: Mortality in the groups of rats treated with DOX alone, DNT+DOX and DNT was 40%, 16% and 0%, respectively. Histopathologic analysis of hearts of the surviving rats showed reduced DOX induced cardiotoxicity in the group treated with DOX+DNT as shown by reduced interstitial edema, cytoplasmic vacuolization and myofibrilar dysruption, compared to DOX only treated hearts. DNT significantly increased cardiac output and stroke volume, and improved the decline of left ventricle ejection fraction (LVEF) induced by DOX by 50%. Also, reduced breast tumor volumes with increased tumor necrosis was observed in rats treated with DOX+DNT compared to DOX alone. Rats treated with DNT lost less body weight and had a higher blood GSH levels. Conclusions: These data indicate that DNT is able to provide protection against DOX cardiotoxicity while maintaining its antitumor efficacy. Further preclinical studies are needed to determine the optimal dosing of DNT.
Likelihood of late relapse assessed by the Breast Cancer Index (BCI) in LN-invasive lobular compared to invasive ductal carcinoma.
Authors: Nunes Raquel , Salganik Max , Liu Junmei , Schnabel Catherine A. , Richardson Andrea Lynn 
Published: September 2018

e12025 Background: Women with HR+ breast cancer remain at risk for late distant recurrences (DR) despite optimal adjuvant therapy. Invasive lobular carcinoma (ILC) is the 2nd most common subtype of invasive breast cancer. When compared to invasive ductal carcinoma (IDC), ILC has distinguishing clinical and pathologic characteristics that may result in different response to therapy and long term prognosis. BCI is a validated gene expression-based assay for pts with early stage HR+ breast cancer that provides risk of late (5-10 y) DR and predicts likelihood of benefit of extended endocrine therapy (EET). Here, we compared BCI assay results in pts with HR+, LN- ILC vs IDC. Methods: The BCI Clinical Database for Correlative Studies is an IRB-approved de-identified database that contains >50 clinicopathologic and molecular variables from cases submitted for BCI in clinical practice (N=14,463). Molecular variables include BCI Prognostic score, HoxB13/IL17BR ratio (H/I), and molecular grade index (MGI). Clinicopathologic variables were abstracted from pathology reports (available for a subset of cases). LN- pts with available pathologic data were analyzed. Chi-squared tests were used to compare BCI results between IDC and ILC subgroups. Results: Analyses included 2554 LN- pts with available histologic subtype data (80.7% IDC; 13.7% ILC; 2.6% mixed; 2.9% other). Median age was 59.3y (range 27-89y; 74% ≥ 50y). BCI Prognostic had a broad distribution of individual risk assessment in both IDC and ILC. However, BCI Prognostic had a lower median BCI scores (P<0.0001) in ILC, and classified a smaller proportion of pts with ILC as high risk for late DR compared to IDC (36.5% vs 53.1%; P<0.0001). IDC had a higher median molecular proliferative status (MGI) compared to ILC (P<0.0001). BCI Predictive (H/I) identified a slightly decreased proportion of pts with ILC benefiting from extended endocrine therapy compared to IDC (38.2% vs 41.1%). There was no difference in quantitative ER or PR (by PCR) between groups. Conclusions: BCI identified a smaller proportion of pts with ILC at high risk of late DR compared to IDC. Further studies evaluating outcomes are warranted to further validate BCI in pts with ILC.
Feasability of contrast-enhanced CT in breast conservation surgery for invasive and non-invasive breast cancer.
Authors: Kamada Yoshihiko , Tamaki Kentaro , Uehara Kanou , Tamaki Nobumitsu 
Published: September 2018

e12084 Background: MRI imaging has become the standard for planning breast conservation surgery for breast cancer. However, due partly to lack of resources of a small clinic practice, we have been utilizing contrast enhanced CT facilitated with ultrasound for this purpose. The aim of this presentation is to assess the feasability of contrast-enhanced CT in breast conservation surgery. Methods: We used GE Brightspeed-8 CT, with HP Z440 workstation (for free line masking). 100 mld of Iopamidol contrast medium was injected at a rate of 3 ml/sec and image capture was done at the 60 or 180 second phase. Images were taken with the patient in a supine position. We evaluate a total of 2057 cases operated in a ten year period between 2005.1.1 to 2014.12.31, excluding cases receiving preoperative chemotherapy. 1,757 cases (85%) were invasive and 300 cases (15%) were non-invasive breast cancer cases. Results: Lesion localization by contrast-enhance CT was acceptable by predefined criteria in 72% of invasive carcinoma cases, and 89% non-invasive carcinoma cases. The breast conservation rate was 77% and 83% for invasive and non-invasive breast cancer cases, respectively. Surgical margins were positive “on ink” for 8 cases (0.6%), and positive within 5 mm (including DCIS) in 340 cases (25.1%) of the 1,357 invasive cancer cases treated with BCT. There were 7 completion total mastectomies and 3 partial mastectomies for the patients with positive margins (11/340 = 3.2%). Surgical margins were positive for 78 cases (31.3%) of the 249 DCIS cases undergoing BCT. There was 1 completion mastectomy and 2 partial mastectomies for the patients with positive margins (3/78 = 3.8%). Local recurrence rates for invasive and non-invasive breast cancer cases undergoing BCT were 2.6% (average observation period 65.0 months) and 2.8% (average observation period 64.4 months), respectively. Conclusions: Contrast-enhanced CT facilitated with ultrasound imaging is an effective and easy to implement modality for planning breast conservation surgery in invasive and non-invasive breast cancer, possibly in part due to imaging that corresponds closely to the breast position during surgery.
Postmastectomy radiation in women with node positive breast cancer in the Ontario population.
Authors: Latosinsky Steven , Jenkyn Krista Bray , Li Lihua , Shariff Salimah 
Published: September 2018

e12104 Background: Despite two randomized controlled trials first published in 1997 showing improvements in both locoregional control and survival, postmastectomy radiation for node positive breast cancer patients has not been universally accepted; particularly for patients with 1-3 positive nodes. Subsequent favorable meta-analyses have resulted in more recent guidelines supporting postmastectomy radiation. We examined the rate and predictors of postmastectomy radiation receipt in node positive breast cancer patients in Ontario (population 13.2 million). Methods: We used the Ontario Cancer Registry, a population-based, prospectively-collected registry, to identify all node positive female breast cancer patients in the province with a diagnosis date between April 1, 2010 and Sept 30, 2014. Patient records were linked to prospectively maintained health administrative databases. Through these databases, the universal single-payer health care system in Ontario can capture details for each patient for all health care encounters, hospitalizations, procedures (mastectomy), prescription medications, systemic cancer therapy and radiation. Logistic regression modeling using generalized estimating equations was employed to determine the association between patient, tumor and treatment characteristics and receipt of radiation, while accounting for the possible clustering effect by health regions. Results: Of the 6,535 women with node positive breast cancer who had undergone a mastectomy 73.9% received radiation. Of the 4227 women with 1-3 positive nodes, 68.7% received radiation, and of the 2308 women with > 3 positive nodes 83.4% received radiation. Receipt of radiation was positively associated with younger age ( < 70 years), increasing cancer stage and a lower Charlson comorbidity index. Conclusions: In a setting with universal healthcare, the majority of women with node positive breast cancer in Ontario received postmastectomy radiation, including women with 1-3 positive nodes. Older women, those with higher stage and those who had increased co-occurring medical conditions were less likely to receive radiation therapy.
Immune biomarkers and treatment (tx) outcome in hormone receptor-positive (HR+) breast cancer (BC) patients (pts) treated with preoperative chemotherapy (preop chemo) plus bevacizumab (bev).
Authors: Waks Adrienne Gropper , Barry William Thomas , Gjini Evisa , Dillon Deborah , Rodig Scott , Brock Jane E. , Baltay Michele , Savoie Jennifer , Stover Daniel G. , Winer Eric P. , Krop Ian E. , Tolaney Sara M. 
Published: September 2018

e12134 Background: Though preliminary study of the BC immune microenvironment suggests that HR+ tumors are less immune-active than other subtypes, immune biomarkers may have important clinical implications in HR+ BC pts. Methods: 78 HR+/HER2- BC pts were enrolled on a prospective trial of preop bev followed by bev with adriamycin/cyclophosphamide/paclitaxel dose-dense chemo. Tumor samples were collected at diagnosis and surgery (pre-tx and post-tx). PD-L1 expression (by immunohistochemistry) and tumor-infiltrating lymphocytes (TILs) were scored. Whole transcriptome sequencing and Nanostring PanCancer Immune Profiling Panel were performed. Pathologic response at surgery was assessed by Miller-Payne (MP) and residual cancer burden (RCB) scores. We calculated adjusted correlations by linear/logistic regression for RCB/dichotomized MP, respectively. Results: 55 pts who received trial tx and had >1 analyzable specimen are included. Pre-tx TILs and tumor PD-L1 (tPD-L1) scores (see table) were slightly positively correlated (Spearman rho 0.23, p=0.1). Large changes (>5%) in TILs or tPD-L1 from pre-tx to post-tx were rare: 2 pts each had large changes in TIL or tPD-L1 score (N=38 and N=31 pairs, respectively). Higher pre-tx TILs or tPD-L1 were significantly associated with more favorable RCB and MP (all Spearman p<0.01) in unadjusted analyses. After adjustment for age and tumor grade, higher pre-tx TILs and tPD-L1 were associated with more favorable RCB (p<0.01 for both), and higher pre-tx tPD-L1 correlated with more favorable MP (p=0.03). Pathologic complete response occurred in 4 pts; all 4 had high pre-tx TILs, pre-tx tPD-L1, or both. Analysis of immune-related RNA signatures is ongoing. Conclusions: High levels of tumor-immune interaction were seen in only a minority of untreated HR+ breast tumors, and did not typically change after tx with chemo plus bev. Nonetheless, TILs and tPD-L1 are significantly associated with pathologic response to preop tx in HR+ disease. [Table: see text]