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Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial.

The presence of tumor-infiltrating lymphocytes (TILs) is associated with improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer treated with adjuvant trastuzumab and chemotherapy. The prognostic associations in the neoadjuvant setting of other anti-HER2 agents and combinations are unknown.
To determine associations between presence of TILs, pathological complete response (pCR), and event-free survival (EFS) end points in patients with early breast cancer treated with trastuzumab, lapatinib, or the combination.
The NeoALTTO trial (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) randomly assigned 455 women with HER2-positive early-stage breast cancer between January 5, 2008, and May 27, 2010, to 1 of 3 neoadjuvant treatment arms: trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The primary end point used in this study was pCR in the breast and lymph nodes, with a secondary end point of EFS. We evaluated levels of percentage of TILs using hematoxylin-eosin-stained core biopsy sections taken at diagnosis (prior to treatment) in a prospectively defined retrospective analysis.
Levels of TILs were examined for their associations with efficacy end points adjusted for prognostic clinicopathological factors including PIK3CA genotype.
Of the 455 patients, 387 (85.1%) tumor samples were used for the present analysis. The median (interquartile range [IQR]) level of TILs was 12.5% (5.0%-30.0%), with levels lower in hormone receptor-positive (10.0% [5.0%-22.5%]) vs hormone receptor-negative (12.5% [3.0%-35.0%]) samples (P = .02). For the pCR end point, levels of TILs greater than 5% were associated with higher pCR rates independent of treatment group (adjusted odds ratio, 2.60 [95% CI, 1.26-5.39]; P = .01). With a median (IQR) follow-up time of 3.77 (3.50-4.22) years, every 1% increase in TILs was associated with a 3% decrease in the rate of an event (adjusted hazard ratio, 0.97 [95% CI, 0.95-0.99]; P = .002) across all treatment groups.
The presence of TILs at diagnosis is an independent, positive, prognostic marker in HER2-positive early breast cancer treated with neoadjuvant anti-HER2 agents and chemotherapy for both pCR and EFS end points.
clinicaltrials.gov Identifier: NCT00553358.

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SUMO deconjugation is required for arsenic-triggered ubiquitylation of PML.

Acute promyelocytic leukemia is characterized by a chromosomal translocation that produces an oncogenic fusion protein of the retinoic acid receptor α (RARα) and promyelocytic leukemia protein (PML). Arsenic trioxide chemotherapy of this cancer induces the PML moiety to organize nuclear bodies, where the oncoprotein is degraded. This process requires the participation of two SUMO paralogs (SUMO1 and SUMO2) to promote PML ubiquitylation mediated by the ubiquitin E3 ligase RNF4 and reorganization of PML nuclear bodies. We demonstrated that the ubiquitylation of PML required the SUMO deconjugation machinery, primarily the deconjugating enzyme SENP1, and was suppressed by expression of non-deconjugatable SUMO2. We hypothesized that constitutive SUMO2 conjugation and deconjugation occurred basally and that arsenic trioxide treatment caused the exchange of SUMO2 for SUMO1 on a fraction of Lys(65) in PML. On the basis of data obtained with mutational analysis and quantitative proteomics, we propose that the SUMO switch at Lys(65) of PML enhanced nuclear body formation, subsequent SUMO2 conjugation to Lys(160), and consequent RNF4-dependent ubiquitylation of PML. Our work provides insights into how the SUMO system achieves selective SUMO paralog modification and highlights the crucial role of SENPs in defining the specificity of SUMO signaling.
Copyright © 2015, American Association for the Advancement of Science.

Qualitative Development and Content Validity of the Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ), A Patient-Reported Outcome Instrument.

The purpose of this article was to describe the process and results of the preliminary qualitative development of a new symptoms-based patient-reported outcome (PRO) measure intended for assessing treatment benefit in clinical trials of advanced non-small cell lung cancer (NSCLC).
Individual qualitative interviews were conducted in adults with NSCLC (Stages I-IV) in the United States. Experienced interviewers conducted concept-elicitation (CE) and cognitive interviews using semistructured interview guides. The CE interview guide was used for eliciting spontaneous reports of symptom experiences along with probing to further explore and confirm concepts. Interview transcripts were coded and analyzed by professional qualitative coders, and were summarized by like content using an iterative coding framework. Data from the CE interviews were considered alongside existing literature and clinical expert opinion during an item-generation process, leading to the development of a preliminary version of the NSCLC Symptom Assessment Questionnaire (SAQ). Three waves of cognitive interviews were conducted to evaluate concept relevance, item interpretability, and structure of the draft items and to facilitate further instrument refinement.
Fifty-one subjects (mean [SD] age, 64.9 [11.2] years; 51.0% women) participated in the CE interviews. A total of 1897 expressions of NSCLC-related symptoms were identified and coded in interview transcripts, representing ~42 distinct symptom concepts. A 9-item initial-draft instrument was developed for testing in 3 waves of cognitive interviews with additional subjects with NSCLC (n = 20), during which both paper and electronic versions of the instrument were evaluated and refined. Participant responses and feedback during cognitive interviews led to the removal of 2 items and substantial modifications to others.
The NSCLC-SAQ is a 7-item PRO measure intended for use in advanced NSCLC clinical trials to support medical product labelling. The NSCLC-SAQ uses a 7-day recall period and verbal rating scales. It was developed in accordance with the US Food and Drug Administration’s PRO Guidance and scientific best practices, and the resulting qualitative interview data provide evidence of content validity. The NSCLC-SAQ has been prepared in both paper and electronic administration formats and a tablet computer-based version is currently undergoing quantitative testing to confirm its measurement properties and support US Food and Drug Administration qualification.
Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Metastatic Pancreatic Adenocarcinoma Treatment Patterns, Health Care Resource Use, and Outcomes in France and the United Kingdom Between 2009 and 2012: A Retrospective Study.

In Europe, pancreatic cancer (PC) accounts for approximately 2.6% of all new cancer cases and is the fourth leading cause of cancer-related death. Despite substantial morbidity and mortality, limited data are available describing real-world treatment patterns and health care resource use in any European country. We evaluated PC-related treatment patterns and associated health care resource use among patients with metastatic PC in the United Kingdom and France.
One hundred three oncology specialists (53 in France and 50 in the United Kingdom) abstracted data from medical records of 400 patients whom they treated for metastatic PC. Eligible patients had a diagnosis of metastatic PC at age 18 years or older between January 1, 2009, and December 31, 2012; had ≥3 months of follow-up time beginning at metastatic diagnosis; and received at least 1 cancer-directed therapy for metastatic disease. Information on patient demographics, Eastern Cooperative Oncology Group performance status, location of primary tumor, presence of comorbidities, adverse events, and complications were collected. Data on cancer-directed treatments and supportive care measures were evaluated. All analyses were descriptive.
Approximately two thirds of patients were men, and median age at metastatic disease diagnosis was 62.2 years. Nearly all patients (97.3%) received chemotherapy to treat metastatic disease, 9.3% received radiation therapy, and 7.8% received a targeted therapy. Overall, the most frequently administered first-line regimens for metastatic disease were gemcitabine alone (46.0%), a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX; 20.1%); gemcitabine/capecitabine (10.8%); and gemcitabine/oxaliplatin (9.5%). Approximately 40% of patients in France and 15% of patients in the United Kingdom received second-line systemic therapy, whereas 20% of patients in France and 3.4% of patients in the United Kingdom received third-line systemic therapy for metastatic disease. Overall, 52.5% of patients experienced at least one complication of PC. More than two thirds of patients had ≥1 office visit unrelated to chemotherapy administration, 54.0% had ≥1 inpatient hospitalization, 36.8% had ≥1 emergency department visit, and 25.3% had ≥1 pain management clinic visit. A total of 26.5% of patients in France and 42.5% in the United Kingdom entered hospice or long-term care.
This study provides new, detailed information for patients with metastatic PC in real-world settings in 2 European countries. A small proportion of patients received &gt;1 line of systemic therapy for metastatic disease, which is likely due to the aggressiveness of this disease and the lack of effective therapeutic options.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein.

Prevention efforts for respiratory syncytial virus (RSV) have been advanced due to the recent isolation and characterization of antibodies that specifically recognize the prefusion conformation of the RSV fusion (F) glycoprotein. These potently neutralizing antibodies are in clinical development for passive prophylaxis and have also aided the design of vaccine antigens that display prefusion-specific epitopes. To date, prefusion-specific antibodies have been shown to target two antigenic sites on RSV F, but both of these sites are also present on monomeric forms of F. Here we present a structural and functional characterization of human antibody AM14, which potently neutralized laboratory strains and clinical isolates of RSV from both A and B subtypes. The crystal structure and location of escape mutations revealed that AM14 recognizes a quaternary epitope that spans two protomers and includes a region that undergoes extensive conformational changes in the pre- to postfusion F transition. Binding assays demonstrated that AM14 is unique in its specific recognition of trimeric furin-cleaved prefusion F, which is the mature form of F on infectious virions. These results demonstrate that the prefusion F trimer contains potent neutralizing epitopes not present on monomers and that AM14 should be particularly useful for characterizing the conformational state of RSV F-based vaccine antigens.