Selection Of Patients For Therapy Research Articles

TP53 mutation and BUBR1 overexpression characterize the DNA aneuploidy of gastric cancer.

e15039 Background: Gastric cancers show a high frequency of DNA aneuploidy, which is a phenotype of chromosomal instability. Gastric carcinomas with aneuploidy have been shown to have higher proliferative activity and metastatic or invasive potential than diploid tumors, which leads to a poor prognosis. It has been suggested that an abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. In this study, we focused on the TP53 gene and BUBR1 protein in gastric cancer to elucidate their relation with the features of DNA aneuploidy. Methods: The study included 178 unselected Japanese patients with primary gastric cancer who underwent gastrectomy between 1994 and 2006 at Kyushu University Hospital, Fukuoka. DNA ploidy status, TP53 gene status, and BUBR1 expression were analyzed. Nuclear DNA content was measured using laser scanning cytometry. The TP53 gene was amplified from exon 5 to exon 9, including exon-intron junctions, by PCR using p53 primers (Nippon Gene, Tokyo, Japan) and Ex Taq DNA polymerase (TaKaRa Bio Inc., Tokyo, Japan). Results: DNA aneuploidy was identified in 108 cases, and TP53 gene mutation was seen in 28 of 143 cases. Both DNA aneuploidy and TP53-mutated tumors correlated with high age and differentiated type tumors. BUBR1 aberrant expression, investigated using immunohistochemistry, was seen in 89 cases, and it correlated with malignant features such as deep invasion, and lymph node and liver metastases. DNA aneuploidy was significantly related to high BUBR1 expression (P = 0.0055), and a more significant relation was found between DNA aneuploidy and TP53mutation (P = 0.0032). Tumors with high BUBR1 expression showed poor prognosis. Conclusions: DNA aneuploidy is associated with the carcinogenesis and prognosis of gastric cancer. Therefore, there has been considerable interest in targeting cell cycle checkpoints, particularly in emerging and alternative anticancer strategies. The development of selection markers to aid in the selection of appropriate therapies for patients will be the primary focus of future research. TP53 mutation and BUBR1 expression may provide clinically useful diagnostic, therapeutic, and prognostic information.

Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology

To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Three unbiased literature searches of electronic databases were performed to capture published articles from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. EVIDENCE was formally graded for each recommendation. Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.

Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis – implications for cardiovascular safety

This study sought to examine the effects and underlying mechanisms of systemic VEGF inhibition in experimental atherosclerosis and aortic endothelial cells. Pharmacological inhibition of vascular endothelial growth factor (VEGF), a major mediator of angiogenesis, has become a widely applied treatment of certain cancers and multiple ocular diseases including age-related macular degeneration. However, recent clinical trials raise concern for systemic vascular adverse effects, prompting the Food and Drug Administration to revoke the approval of bevacizumab for metastatic breast cancer. Eight-week old apolipoprotein E knockout mice received a high-cholesterol diet (1.25% cholesterol) for 24 weeks and were exposed to a systemic pan-VEGF receptor inhibitor (PTK787/ZK222584, 50mg/kg/d) or placebo (gavage) for the last 10 weeks. Atherosclerotic lesions were characterized in thoraco-abdominal aortae and aortic arches. Mechanistic analyses were performed in cultured human aortic endothelial cells. Systemic VEGF inhibition increased atherosclerotic lesions by 33% whereas features of plaque vulnerability (i.e. necrotic core size, fibrous cap thickness) remained unchanged compared with controls. Aortic eNOS expression was decreased (trend). In human endothelial cells VEGF inhibition induced a dose-dependent increase in mitochondrial superoxide generation with an uncoupling of eNOS, resulting in reduced NO availability and decreased proliferation. Systemic VEGF inhibition disrupts endothelial homeostasis and accelerates atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies. Cardiovascular safety profiles of currently applied anti-angiogenic regimens should be determined to improve patient selection for therapy and allow close monitoring of patients at increased cardiovascular risk.

ERCC1 and XRCC1 expression predicts survival in bladder cancer patients receiving combined trimodality therapy

Combined trimodality therapy, including transurethral resection and platinum-based chemoradiotherapy, has shown promising results for muscle-invasive bladder cancer. However, this type of treatment may decrease survival as a result of delayed cystectomy in patients with non-responding tumors. DNA repair proteins may affect survival of bladder cancer patients receiving combined trimodality therapy, by affecting the perioperative nature of the tumor cells or by repairing DNA damaged by platinum agents and radiation. We investigated the associations of excision repair cross-complementing group 1 (ERCC1), X-ray repair cross-complementing group 1 (XRCC1) and apurinic/apyrimidinic endonuclease 1 (APE1) expression with response and survival in 157 locally advanced bladder cancer patients receiving combined trimodality therapy, in order to determine the predictive value of the expression of these proteins in patient selection for therapy. We examined ERCC1, XRCC1 and APE1 expression in tumor specimens using immunohistochemistry. Patients positive for ERCC1, positive for XRCC1 and positive for either ERCC1 or XRCC1, exhibited significantly improved disease-specific survival rates (P=0.023, 0.025 and 0.0091, respectively). In multivariate analysis, combined ERCC1 and XRCC1 expression was independently associated with disease-specific mortality [risk ratio (RR): 0.64; 95% confidence interval (CI), 0.43-0.94 and P=0.024]. Thus, combined ERCC1 and XRCC1 expression may serve as an independent prognostic marker for survival in bladder cancer patients receiving combined trimodality therapy. Prospective studies with a larger sample size are required to confirm these results.

Role of CYP450 in Antiplatelet Therapy: Considerations for Patients at Risk for Further Cardiovascular or Cerebrovascular Problems

Objective: To determine how interactions with cytochrome P450 ( CYP450) isoenzyme pathways may influence the selection of antiplatelet therapy in patients with cardiovascular and cerebrovascular disease. Data Sources: A MEDLINE search (1966-September 2012) was performed using the following MeSH search terms: clopidogrel, prasugrel, ticagrelor, aspirin, dipyridamole, drug interactions, polymorphism, cytochrome P450, platelets, platelet reactivity testing, and platelet function. In addition, reference citations were reviewed. Study Selection and Data Extraction: Selected studies analyzed the effects of CYP450 isoenzymes on the efficacy of antiplatelet therapy and potential drug-drug interactions. Data Synthesis: Antiplatelet therapy is pivotal in reducing the risk of acute coronary syndromes. Thienopyridines are commonly prescribed for antiplatelet drug therapy; however, a multitude of factors can influence their efficacy, given that thienopyridines require activation through CYP450 isoenzymes. Genetic polymorphisms in CYP450 isoenzymes and the susceptibility of drug-drug interactions mediated through the CYP450 system have led to variability in antiplatelet response. Two factors in particular have been prime targets in elucidating the role of CYP450 isoenzymes on thienopyridine activity and bioavailability: CYP2C19*2 polymorphisms and drug interactions with proton pump inhibitors. Additionally, many studies have surfaced in an attempt to quantify a patient's response to antiplatelet therapy but, to date, none has determined whether platelet reactivity testing is mandatory prior to initiation of therapy or whether it correlates with clinical efficacy. This review spotlights the pharmacokinetic and pharmacodynamic influences that CYP450 isoenzymes exert on antiplatelet therapies and attempts to categorize the role of platelet reactivity testing in determining the clinical significance of drug interactions. Conclusions: Suboptimal responses to antiplatelet therapy may occur because of interactions with CYP450 isoenzyme pathways. Further studies are warranted to clarify the impact of genetic polymorphisms and drug-drug interactions on clinical outcomes in patients with cardiovascular/cerebrovascular disease.

Prognostic value of bcl-2 expression among women with breast cancer in Libya

We studied the association of the immunohistochemical bcl-2 expression in Libyan breast cancer with clinicopathological variables and patient outcome. Histological samples from 170 previously untreated primary Libyan breast carcinoma patients were examined. In immunohistochemistry, the NCL-L-bcl-2-486 monoclonal antibody was used. Positive expression of bcl-2 was found in 106 patients (62.4 %). The bcl-2 expression was significantly associated with estrogen receptor (p<0.0001) and progesterone receptor positive tumors (p=0.002), small tumor size (p<0.0001), low tumor grade (p<0.0001), negative axillary lymph nodes (p<0.0001), early stages (p=0.001), and low risk of metastasis (p<0.0001). Positive expression was also associated with older patients (>50 years; p=0.04). Histological subtypes and family history of breast cancer did not have significant relationship with bcl-2. Patients with positive expression of bcl-2 had lower recurrence rate than bcl-2-negative patients and better survival after median follow-up of 47 months. Patients with high bcl-2 staining were associated with the best survival. The role of bcl-2 as an independent predictor of disease-specific survival was assessed in a multivariate survival (Cox) analysis, including age, hormonal status, recurrence, histological grade, and clinical stage variables. Bcl-2 (p<0.0001) and clinical stage (p=0.016) were independent predicators of disease-specific survival. For analysis of disease-free survival, the same variables were entered to the model and only bcl-2 proved to be an independent predictor (p=0.002). Patients with positive expression of bcl-2 were associated with low grade of malignancy, with lower recurrence rate, with lower rate of death, and with longer survival time. Bcl-2 is an independent predictor of breast cancer outcome, and it provides useful prognostic information in Libyan breast cancer. Thus, it could be used with classical clinicopathological factors to improve patient selection for therapy.

Abstract P3-06-11: Response and long-term outcomes after neo-adjuvant chemotherapy: Pooled dataset of patients stratified by molecular subtyping using MammaPrint and BluePrint

Abstract Background: Classification into molecular subtypes may increasingly be important for the selection of therapy for patients with early-stage breast cancer. Previous analyses had shown that breast cancer subtypes have distinct clinical outcome [Sorlie et al. PNAS 2001; Esserman et al. BCRT 2011]. In our study, we analyzed the response to neo-adjuvant chemotherapy and long-term outcomes using the 70-gene profile (MammaPrint) together with an 80-gene molecular subtyping profile (BluePrint). Methods: This analysis was performed on data from 421 patients: 141 patients from the I-SPY I trial; 230 patients from the biomarker discovery program at MD Anderson (131 and 99 respectively; Hess et al. JCO 2006; Iwamoto et al. BCRT 2011]; and 50 patients from the City of Hope [Somlo et al. ASCO 2010]. All patients were treated in the neo-adjuvant setting with chemotherapy. MammaPrint and BluePrint outcomes were determined from either 44K Agilent arrays run at Agendia or available through the I-SPY I data portal, or from Affymetrix U133A arrays. The combination of MammaPrint and BluePrint resulted in four distinct molecular groups: Luminal A (MammaPrint Low Risk/Luminal-type), Luminal B (MammaPrint High Risk/ Luminal-type), Basal-type and HER2-type. Results: The overall pCR of this patient cohort was 22% but differed substantially among the defined BluePrint molecular subgroups. pCR was observed in 3% of the Luminal A and 12% of Luminal B, in 38% of the HER2-type and in 42% of the Basal-type samples. 42% of patients with clinical HER2-positive phenotype are classified as Luminal-type by BluePrint: eight patients as Luminal A and 34 patients as Luminal B. 5-year distant metastases-free survival (DMFS) of patients with HER2-type by BluePrint who achieve pCR is 87%, compared with 78% for clinical HER2+ patients with pCR. These data are in line with a recent retrospective analysis of a large cohort of patients, which showed that pCR rate is not a suitable surrogate for clinical HER2+/Hormone Receptor-positive patients and is not associated with outcome [von Minckwitz et al. JCO 2012]. BluePrint classifies more patients as Basal-type (n = 120) with higher pCR rate (42%), compared with clinical subtyping (triple negative, n=93) with a pCR rate of 31%. Despite including eight clinical HER2+ and 11 triple-negative patients, those with BluePrint Luminal A subtype (n = 88) have excellent 5-year DMFS of 94% and appear to have no benefit from chemotherapy (low pCR rate). Conclusions: Molecular subtyping using BluePrint with MammaPrint can help to improve outcomes of patients in the neo-adjuvant setting over clinical subtyping. We observed differences in pCR and DMFS following neo-adjuvant treatment in groups stratified by MammaPrint and BluePrint; for example, patients with Luminal A breast cancer (assessed with MammaPrint and BluePrint) have a good baseline prognosis with excellent survival and may not benefit from chemotherapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-11.

Abstract P6-14-05: Impact of breast cancer CME: Physician practice pattern, knowledge, and competence assessments

Abstract Background: Several scientific advances for women with breast cancer have taken place in the last decade. The National Cancer Institute reports that approximately 2.5 million women with a history of breast cancer are alive today due to advances in screening, detection, treatment, and supportive care. Due to the volume and pace of scientific advances within the specialty of oncology, the timely dissemination of clinical trial results and discussions regarding the appropriate incorporation of advances into therapeutic strategy is necessary to provide the highest quality patient care. Furthermore, increasing awareness in the breast cancer community on similarities and differences amongst practice management strategies helps to identify individual practice patterns and benchmark individual knowledge and competence against one's professional peers. Methods: Between November 2011 and November 2012, educational outcomes assessments were gathered during 95 independent continuing medical education (CME) activities held within community and academic institutions and practices across the United States. The activities educated oncology healthcare providers on recent updates to the development and integration of new therapies in the management of ER+, HER2+ and/or HER2− breast cancer. Participants were asked a series of case-based questions via an audience response system to assess baseline knowledge, competence, and identify practice patterns. Assessments were repeated post a 1-hour independent CME certified activity, with an additional 6-week electronic follow-up. Barriers to implementing the information learned were captured at 6-week follow-up. Educational gaps were identified through documentation and comparison of current best practices versus actual participant responses. Results: To date, a total of 568 healthcare providers have participated in the initiative of which 326 (57%) were physicians. Number of years in practice included &amp;lt; 10 years (22%), 10–20 years (50%), 21–30 years (13%), &amp;gt; 30 years (15%). The number of breast cancer patients seen per month included ≤ 10 (45%), 11–20 (17%), 21–30 (15%), 31–40 (8%), and &amp;gt; 40 (15%). This represents a potential impact of 3,706 patient lives. Provider competency in applying recent literature to the patient care setting was both assessed and measured. Results of patient therapy selection in the first-line and relapsed MBC setting will be reported. Knowledge and awareness regarding recent clinical trials as well as self-reported competence in discussing the mechanism of action, efficacy, and safety data from recent clinical trials will be presented. Participants reported a number of barriers to applying data learned at the activities into clinical practice. Responses included lack of reimbursement (24%), treatment side effects (24%), newness of treatment data (40%), perceived efficacy (8%) and treatment not commercially available (4%). Conclusion: The results suggest the education of providers on the most currently available clinical trial results and peer discussion of how to optimize translation of this information into patient care increases breast cancer provider knowledge and competence. Breast cancer CME plays an important role in improving the care of patients and practice of medicine. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-14-05.

The assessment of data mining for the prediction of therapeutic outcome in 3719 Egyptian patients with chronic hepatitis C

Decision-tree analysis; a core component of data mining analysis can build predictive models for the therapeutic outcome to antiviral therapy in chronic hepatitis C virus (HCV) patients. To develop a prediction model for the end virological response (ETR) to pegylated interferon PEG-IFN plus ribavirin (RBV) therapy in chronic HCV patients using routine clinical, laboratory, and histopathological data. Retrospective initial data (19 attributes) from 3719 Egyptian patients with chronic HCV presumably genotype-4 was assigned to model building using the J48 decision tree-inducing algorithm (Weka implementation of C4.5). All patients received PEG-IFN plus RBV at Cairo-Fatemia Hospital, Cairo, Egypt in the context of the national treatment program. Factors predictive of ETR were explored and patients were classified into seven subgroups according to the different rates of ETR. The universality of the decision-tree model was subjected to a 10-fold cross-internal validation in addition to external validation using an independent dataset collected of 200 chronic HCV patients. At week 48, overall ETR was 54% according to intention to treat protocol. The decision-tree model included AFP level (<8.08 ng/ml) which was associated with high probability of ETR (73%) followed by stages of fibrosis and Hb levels according to the patients' gender followed by the age of patients. In a decision-tree model for the prediction for antiviral therapy in chronic HCV patients, AFP level was the initial split variable at a cutoff of 8.08 ng/ml. This model could represent a potential tool to identify patients' likelihood of response among difficult-to-treat presumably genotype-4 chronic HCV patients and could support clinical decisions regarding the proper selection of patients for therapy without imposing any additional costs.

Response and long-term outcomes after neoadjuvant chemotherapy: Pooled dataset of patients stratified by molecular subtyping by MammaPrint and BluePrint.

10 Background: Classification of breast cancers into molecular subtypes may be important for the proper selection of therapy for patients with early breast cancer. Previous analyses had shown that breast cancer subtypes have distinct clinical outcome (Sorlie, PNAS, 2001; Esserman, BCRT, 2011). Herein, we analyze using MammaPrint together with an 80-gene molecular subtyping profile (BluePrint) the response to neo-adjuvant chemotherapy and long term outcomes. Methods: This study was carried out on data from 144 patients from the I-SPY I trial; 232 patients from biomarker discovery program at MD Anderson (133 and 99 respectively; Hess, 2006, JCO; Iwamoto, 2011, BCRT); and 68 patients from City of Hope (Somlo, ASCO, 2010). All patients were treated in the neo-adjuvant setting with standard chemotherapy. MammaPrint and BluePrint were determined on 44K Agilent arrays run at Agendia or available through the I-SPY 1 data portal, or from Affymetrix U133A arrays. MammaPrint and BluePrint resulted in 4 distinct molecular groups: Luminal A (MammaPrint Low-risk/Luminal-type), Luminal B (MammaPrint High-risk/Luminal-type), Basal-type and HER2-type. Results: The overall pCR of this patient cohort was 22% but differed substantially among the subgroups. pCR was observed in 5% of the Luminal-A samples and 10% of Luminal-B, in 39% of the HER2-type samples and in 33% of the Basal-type samples. Patients with Basal-type tumors had a 5-year DFS of 71%; HER2-type had a 5-year DFS of 67% (n=71); 69% in HER2-type subgroup not treated with HER2-targeted therapy (n=45); Luminal-B type had a 5-year DFS of 77% and Luminal-A type showed 5-year DFS of 95%. Conclusions: We observed marked differences in response and DFS to neo-adjuvant treatment in groups stratified by MammaPrint and BluePrint. These findings confirm differences in chemotherapy response among molecular subgroups and indicate that the BluePrint and MP profile used for this analysis helps to further establish a clinical correlation between molecular subtyping and treatment outcomes.

Response and long-term outcomes after neoadjuvant chemotherapy: Pooled dataset of patients stratified by molecular subtyping by MammaPrint and BluePrint.

10597 Background: Classification of breast cancers into molecular subtypes may be important for the proper selection of therapy for patients with early breast cancer. Previous analyses had shown that breast cancer subtypes have distinct clinical outcome (Sorlie, PNAS, 2001; Esserman, BCRT, 2011). Herein, we analyze using MammaPrint together with an 80-gene molecular subtyping profile (BluePrint) the response to neo-adjuvant chemotherapy and long term outcomes. Methods: This study was carried out on data from 144 patients from the I-SPY I trial; 232 patients from biomarker discovery program at MD Anderson (133 and 99 respectively; Hess, 2006, JCO; Iwamoto, 2011, BCRT); and 68 patients from City of Hope (Somlo, ASCO, 2010). All patients were treated in the neo-adjuvant setting with standard chemotherapy. MammaPrint and BluePrint were determined on 44K Agilent arrays run at Agendia or available through the I-SPY 1 data portal, or from Affymetrix U133A arrays. MammaPrint and BluePrint resulted in 4 distinct molecular groups: Luminal A (MammaPrint Low-risk/Luminal-type), Luminal B (MammaPrint High-risk/Luminal-type), Basal-type and HER2-type. Results: The overall pCR of this patient cohort was 22% but differed substantially among the subgroups. pCR was observed in 5% of the Luminal-A samples and 10% of Luminal-B, in 39% of the HER2-type samples and in 33% of the Basal-type samples. Patients with Basal-type tumors had a 5-year DFS of 71%; HER2-type had a 5-year DFS of 67%(n=71); 69% in HER2-type subgroup not treated with HER2-targeted therapy (n=45); Luminal-B type had a 5-year DFS of 77% and Luminal-A type showed 5-year DFS of 95%. Conclusions: We observed marked differences in response and DFS to neo-adjuvant treatment in groups stratified by MammaPrint and BluePrint. These findings confirm differences in chemotherapy response among molecular subgroups and indicate that the BluePrint and MP profile used for this analysis helps to further establish a clinical correlation between molecular subtyping and treatment outcomes.

32P Ageing Biomarkers in an Elderly Breast Cancer Population: Correlation with Comprehensive Geriatric Assessment (CGA)

ABSTRACT Introduction With increasing life expectancy in the western population, the field of geriatric oncology has been expanding rapidly over the last years. The concept that treatment of cancer in the older person is possible, and can be beneficial even at high age, has been confirmed. However, potential benefit of treatment must be balanced against risks of toxicity and decline in functionality and quality of life. This balance is influenced by the patient’s biological age and life expectancy. CGA can reflect biological age to a certain extent, but with potential limitations in terms of validity, sensitivity and reliability. Better ageing markers are therefore needed, to refine selection of patients for therapy. Methods We retrospectively analyzed a panel of potential ageing biomarkers in blood samples collected at diagnosis from 162 breast cancer patients (≥70 years of age) for whom CGA at the same time point was also available. Patients were divided into 3 categories (Fit-Vulnerable-Frail) on the basis of CGA, using Balducci’s definition. Analyzed biomarkers were circulating levels of IL-6, MCP-1 (CCL2), RANTES (CCL5) and mean leukocyte telomere length. The first three markers were determined by ELISA on serum/plasma, telomere length was determined by RT-PCR on leukocyte DNA. Results Mean levels of circulating IL-6 correlated with levels of frailty (Mean for Fit: 4,40 pg/mL, SEM 1.96 versus Mean for Frail 7.02, SEM 1.77; p = 0.018). Mean telomere length decreased with increasing frailty, although not statistically significant (Mean T/S ratio for Fit: 1.15, SEM 0.14 versus Mean T/S ratio for Frail: 0.92, SEM 0.05; p = 0.99). No correlation between frailty and mean circulating levels of MCP-1 or RANTES could be demonstrated. Conclusion Plasma levels of circulating IL-6 are correlated significantly with the level of frailty determined by CGA in older breast cancer patients. We also saw a decrease of telomere length with increasing frailty, although not statistically significant. IL-6 and telomere length mandate further investigation as markers of biological age in cancer patients, and also as predictors for treatment toxicity and outcome, in order to improve appropriate treatment selection. Disclosure All authors have declared no conflicts of interest.

P1-06-20: Response to Neo-Adjuvant Chemotherapy and Outcomes for I-SPY 1 Patients Stratified by the 70-Gene Prognosis Signature (MammaPrint) and Molecular Subtyping (BluePrint).

Abstract Background Classification of breast cancers into molecular subtypes may be important for the proper selection of therapy for patients as tumors with seemingly similar biology can have strikingly different clinical outcomes. We analyzed response to neo-adjuvant chemotherapy as a function of molecular sub-types and show patient survival from the multi-center neo adjuvant trial, I-SPY I (CALGB 150007/150012; ACRIN 6657). Previous analyses had shown that breast cancer subtypes as identified by immunohistochemistry or molecular analyses, have distinct clinical outcome (Esserman, ASCO 2009). Here, we analyze how the 70-gene signature (MammaPrint) together with an 80-gene molecular subtyping profile (BluePrint=Basal-type, Luminal-type, ERBB2-type; de Snoo, ASCO, 2010 and manuscript under review) can sub-classify patients. Materials: This study was carried out on genomics data of core needle biopsies from 149 out of 221 patients enrolled in the I-SPY I trial, a multi-center trial designed to identify predictive markers of pathological complete response (pCR) and disease-free survival (DFS) in women with locally advanced breast cancer (3 cm or greater). All women received neoadjuvant Doxorubicin &amp; Cytoxan followed by paclitaxel chemotherapy. The 70-gene and the subtyping signatures, Basal, Luminal and ERBB2-type were determined on 44K Agilent arrays available through the I-SPY 1 data portal (Esserman, ASCO, 2009 and manuscript under review). Results: The 70-gene signature classified 9% of patients (13/149) as Low Risk, of whom one patient was ERBB2-type, and the other 12 were Luminal-type. None of these patients experienced a pCR. The remaining 136 were classified as 70-gene High Risk (91%), of whom 47% were classified as Luminal-type with a pCR rate of 13%, 41% were Basal-type with a pCR rate of 34%, and 12% were ERBB2-type with a pCR rate of 56%. Patients with BluePrint Basal-type tumors had a 5-year DFS of 61%; ERBB2-type had a 5-year DFS of 78%; 70-gene High Risk/Luminal-type had a 5-year DFS of 73% and 70-gene Low Risk/Luminal-type showed 5-year DFS of 100%. The molecular subtype classification shows significant association to clinically assessed receptor status. However, clinically assessed HER2+ patients were distributed across all molecular subtypes, where ER+HER+ are predominantly classified as Luminal-type. Conclusion: This study was performed with the I-SPY I dataset, which provides a platform to compare, contrast &amp; combine marker signatures to tailor therapy. We show how combining BluePrint, with MammaPrint risk-classification can detect specific groups of patients who are at high risk of recurrence and who would have a higher likelihood to benefit from chemotherapy. Furthermore, MammaPrint Low Risk patients do not benefit from neo-adjuvant therapy, though have excellent survival rates, suggesting that the Low Risk Luminal-type patients could be managed conservatively. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-20.

Selection of Therapies in Patients with Psoriasis and Psoriatic Arthritis

Background Psoriatic arthritis is a chronic and debilitating condition. The biologic therapies are targeted therapeutic options that have shown promise; notably, there are substantial data supporting the use of the anti–tumor necrosis factor (TNF) agents in the treatment of psoriatic arthritis and in the prevention of radiographic progression of joint destruction. We report three cases that demonstrate the selective benefits of ustekinumab and of TNF blockers, depending on the relative severities of joint and cutaneous symptoms. Observations We describe three cases of psoriatic arthritis and psoriasis in patients being treated with anti-TNF agents who, after switching to ustekinumab from TNF blockers, complained of worsening joint pain, although their cutaneous findings improved. Two of these patients opted to discontinue their therapy with ustekinumab and restart anti-TNF therapy; they prioritized control of their joint pain over the skin clearing they had while taking ustekinumab. Conclusions Ustekinumab may not be as efficacious as agents that block TNF for the treatment of psoriatic arthritis. Further study is needed to assess its efficacy in psoriatic arthritis.

Effect of Obesity on Outcomes after Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Obesity has implications for chemotherapy dosing and selection of patients for therapy. Autologous hematopoietic stem cell transplant (AutoHCT) improves outcomes for patients with multiple myeloma, but optimal chemotherapy dosing for obese patients is poorly defined. We analyzed the outcomes of 1087 recipients of AutoHCT for myeloma reported to the CIBMTR between 1995 and 2003 who received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal, overweight, obese, or severely obese. There was no overall effect of BMI on progression-free survival (PFS), overall survival (OS), progression, or nonrelapse mortality (NRM). In patients receiving melphalan and TBI conditioning, obese and severely obese patients had superior PFS and OS compared with normal and overweight patients, but the clinical significance of this finding is unclear. More obese patients were more likely to receive a reduced dose of melphalan, but there was no evidence that melphalan or TBI dosing variability affected PFS. Therefore, current common strategies of dosing melphalan do not impair outcomes for obese patients, and obesity should not exclude patients from consideration of autologous transplantation. Further research is necessary to optimize dosing of both chemotherapy and radiation in obese patients.

Abstract 5112: Proteomic investigation of melphalan resistance in multiple myeloma to support selection of combination therapy

Abstract Introduction: Proteomic analyses using iTRAQ and reaction monitoring mass spectrometry are used to examine the mechanism of melphalan resistance and build an assessment platform to enable future selection of combination therapy in patients. Experimental Procedures: Drug IC50 values and interactions are assessed using cell viability measurements. Protein expression analysis using isobaric tags for relative and absolute quantification (iTRAQ) was used to compare melphalan resistant cell lines (8226/LR5 and U266/LR6) to their isogenic, naïve counterparts (RPMI-8226, U266). In this study, iTRAQ was used to identify proteins that have changed in expression level during the development of melphalan resistance in multiple myeloma (MM). In addition to manual selection of differentially expressed proteins, the resulting quantitative data were coalesced into pathway models using Metacore, GeneGO for further analysis. For targeted protein detection and quantification, liquid chromatography coupled to multiple reaction monitoring mass spectrometry (LC-MRM) assays are developed and implemented. Data Summary: Melphalan resistant cells are more susceptible to other chemotherapy agents, including steroids, proteasome inhibitors, and geldanamycin derivatives, than their isogenic, naïve counterparts. To investigate the differences, iTRAQ showed numerous changes in protein expression, including redox stress components, mitochondrial proteins, and heat shock proteins (HSPs). LC-MRM assays were developed for proteins detected in the iTRAQ experiments that are current chemotherapy targets, e.g. HSPs and proteasome components. Furthermore, assays have also been developed for additional protein targets of other chemotherapy agents, e.g. topoisomerases and the glucocorticoid receptor, that were not detected in the iTRAQ results. LC-MRM was then used to examine the expression of these proteins in the four model cell lines listed above and in the naïve cells following the onset of drug treatment. Endogenous proteins were quantified in less than 10,000 cells. These assays can be combined to develop an assessment tool to help elucidate the mechanisms of drug resistance and enable the assessment of myeloma cells from patients’ bone marrow aspirates. Conclusions: Quantification of the proteomes of myeloma cell lines using iTRAQ provided insights into the mechanism of melphalan resistance in multiple myeloma. Investigation of the expression of these proteins and other drug targets in myeloma cell lines has produced an LC-MRM platform that can be translated for patient assessment to assist in selection of chemotherapy combinations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5112. doi:10.1158/1538-7445.AM2011-5112

Predictors of Response to a Nasal Expiratory Resistor Device and Its Potential Mechanisms of Action for Treatment of Obstructive Sleep Apnea

A one-way nasal resistor has recently been shown to reduce sleep disordered breathing (SDB) in a subset of patients with Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS). The purpose of this study was to examine characteristics predictive of therapeutic response to the device and provide pilot data as to its potential mechanisms of action. PATIENTS, INTERVENTIONS, AND MEASUREMENTS: 20 subjects (15M/5F, age 54 ± 12 years, BMI 33.5 ± 5.6 kg/m²) with OSAHS underwent 3 nocturnal polysomnograms (NPSG) including diagnostic, therapeutic (with a Provent® nasal valve device), and CPAP. Additional measurements included intranasal pressures and PCO₂, closing pressures (Pcrit), and awake lung volumes in different body positions. In 19/20 patients who slept with the device, RDI was significantly reduced with the nasal valve device compared to the diagnostic NPSG (27 ± 29/h vs 49 ± 28/h), with 50% of patients having an acceptable therapeutic response. Among demographic, lung volume, or diagnostic NPSG measures or markers of collapsibility, no significant predictors of therapeutic response were found. There was a suggestion that patients with position-dependent SDB (supine RDI > lateral RDI) were more likely to have an acceptable therapeutic response to the device. Successful elimination of SDB was associated with generation and maintenance of an elevated end expiratory pressure. No single definitive mechanism of action was elucidated. The present study shows that the nasal valve device can alter SDB across the full spectrum of SDB severity. There was a suggestion that subjects with positional or milder SDB in the lateral position were those most likely to respond.

Molecular assays in breast cancer pathology

Recent advances in understanding the molecular pathology of breast cancer offer significant potential to identify patients who may benefit from adjuvant therapies. To date, few of these advances are utilised in a routine setting. We review molecular assays that are currently in use or are in the advanced stages of development, which may be used as predictive or prognostic biomarkers in breast cancer.The only widely used breast cancer molecular assay is in situ hybridisation (ISH) for human epidermal growth factor receptor 2 (HER2) gene amplification and we highlight key issues with the interpretation of this assay, with particular attention to the difficulties of the equivocal category. New molecular assays such as ISH for the topoisomerase II alpha (TOP2A) gene and for the aberrations in the copy number of the centromeric region of chromosome 17 are readily performed in a standard histopathology laboratory, but to date there are insufficient data to support their routine use. We also review the current data on two commercially available multigene expression assays, Oncotype DX and MammaPrint and discuss their potential use. Overall, while new molecular assays have significant potential to improve patient selection for therapy, well-performed histopathology with reliable interpretation of standard hormone and HER2 assays provides the most important predictive and prognostic information in early breast cancer.

Metalloprobes for functional monitoring of tumour multidrug resistance by nuclear imaging

Cancer chemotherapy has been used since the early 1950s and still remains one the major therapeutic options for many malignant tumours. A major obstacle to successful cancer chemotherapy is drug resistance. Frequently resistance is intrinsic to the cancer, but as therapy becomes more effective, acquired resistance has also become more frequent. One form of resistance, named multidrug resistance (MDR), is responsible for the failure of tumours to respond to a wide spectrum of chemotherapeutic agents. The in vivo monitoring of MDR could assist in the selection of patients for therapy and can avoid ineffective and potentially toxic treatments. Therefore, methods for functionally interrogating MDR transport activity have been sought, namely single photon emission computed tomography (SPECT) and positron emission tomography (PET). Cationic radiotracers originally developed as SPECT myocardial imaging agents, such as [(99m)Tc(MIBI)(6)](+) and [(99m)Tc(tetrofosmin)(2)O(2)](+), are used for both early cancer detection and non-invasive monitoring of the tumour MDR transport function. With the ultimate goal of obtaining better performing radioprobes for MDR imaging, other metal-based complexes and/or small molecules have also been synthesized and biologically evaluated. In this perspective we will report on the chemical efforts made to find metalloprobes for in vivo monitoring of MDR by nuclear imaging techniques. The current knowledge on the biological mechanisms and proteins involved in tumour MDR will be also briefly presented, as its understanding is invaluable for the rational design and biological evaluation of new radioprobes.

Small Intracerebral Haemorrhages are Associated with Less Haematoma Expansion and Better Outcomes

Haematoma expansion following intracerebral haemorrhage is a major determinant of early neurological worsening and poor clinical outcome. This has created interest in improving patient selection for therapies targeting haematoma expansion. Based on prior observations, we hypothesised that intracerebral haemorrhage volumes under 10 ml would be less likely to expand. We additionally sought to define a baseline haematoma volume below which significant growth was not observed. Patient data were obtained from the Virtual International Stroke Trials Archive. Patients with intracerebral haemorrhage presented within six-hours of symptom onset had baseline clinical, radiological and laboratory data, and computed tomographic scan at 72 h and three-month follow-up. The predictor of interest was baseline haematoma volume. Primary outcomes were absolute and relative haematoma growth. Secondary outcomes were early neurological worsening, good functional outcome, and 90-day mortality. The final dataset consisted of 496 patients. Baseline haematoma volumes under 10 ml were associated with much lower odds of absolute expansion compared to larger haematomas. Smaller haematomas were associated with significantly decreased odds of early neurological worsening and three-month mortality, and increased odds of good functional outcome. The smallest haematoma to double in size was 3·97 ml. Among the 34 subjects with very small haematomas (<3 ml), none had early neurological worsening and most had good three-month outcome (73·5%, mRS≤3). This study provides observational evidence that very small haematomas are unlikely to expand, by commonly used absolute growth definitions, and may represent a subgroup of patients with intracerebral haemorrhage destined towards good clinical outcomes.