Loss of Chromosome 8p Governs Tumor Progression and Drug Response by Altering Lipid Metabolism

Publication date: 9 May 2016
Source:Cancer Cell, Volume 29, Issue 5
Author(s): Yanyan Cai, Jonathan Crowther, Tibor Pastor, Layka Abbasi Asbagh, Maria Francesca Baietti, Magdalena De Troyer, Iria Vazquez, Ali Talebi, Fabrizio Renzi, Jonas Dehairs, Johannes V. Swinnen, Anna A. Sablina
Large-scale heterozygous deletions are a hallmark of cancer genomes. The concomitant loss of multiple genes creates vulnerabilities that are impossible to reveal through the study of individual genes. To delineate the functional outcome of chromosome 8p loss of heterozygosity (LOH), a common aberration in breast cancer, we modeled 8p LOH using TALEN-based genomic engineering. 8p LOH alters fatty acid and ceramide metabolism. The shift in lipid metabolism triggers invasiveness and confers tumor growth under stress conditions due to increased autophagy. The resistance of 8p-deleted cells to chemotherapeutic drugs concurs with poorer survival rates of breast cancer patients harboring an 8p LOH. The autophagy dependency of 8p-deleted cells provides the rational basis for treatment of 8p LOH tumors with autophagy inhibitors.

Graphical abstract

Teaser

Cai et al. examine the effect of chromosome 8p deletion, which is common in carcinomas. While 8p loss is insufficient to transform cells, it alters fatty acid and ceramide metabolism, leading to increased invasiveness and enhanced autophagy that allow tumors to grow under stress conditions.


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A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity

Publication date: 9 May 2016
Source:Cancer Cell, Volume 29, Issue 5
Author(s): Hui Jing, Jing Hu, Bin He, Yashira L. Negrón Abril, Jack Stupinski, Keren Weiser, Marisa Carbonaro, Ying-Ling Chiang, Teresa Southard, Paraskevi Giannakakou, Robert S. Weiss, Hening Lin




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Association of TP53 mutations with TP53 codon 72 polymorphism and outcome in triple-negative breast cancer

Abstract

Despite recent improvements, triple-negative breast cancer (TNBC) remains a breast cancer subtype with poor prognosis. TP53 mutations are commonly associated with TNBC, suggesting a role in breast cancer carcinogenesis. In addition to mutations, several reports focused on TP53 polymorphisms and their association with breast cancer risk and outcome. TP53 codon Pro72Arg polymorphism may predict response to anti-cancer therapy as Pro72 is apparently less effective in the induction of apoptosis.

Here, we investigated a potential association of TP53 mutations with TP53 codon 72 polymorphism and clinical outcome in a homogeneous cohort of TNBC patients.

DNA isolated from formalin-fixed paraffin-embedded tissue of 35 consecutive TNBC patients was investigated for TP53 mutation and TP53 codon 72 polymorphic status by Sanger sequencing.

The kind of TP53 mutations were associated with particular polymorphic Pro72Arg genotypes. Frameshift mutations were significantly correlated with Pro/Pro carriers, nonsense mutations showed a trend for Pro/Arg carriers. Despite this observation no association with clinical outcome was observed.

Further studies with larger and more homogeneous cohorts are warranted in order to elucidate a potential association of TP53 Pro72Arg polymorphism and particular TP53 mutations with TNBC carcinogenesis and outcome.

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Membrane Localization of Human Equilibrative Nucleoside Transporter 1 in Tumor Cells May Predict Response to Adjuvant Gemcitabine in Resected Cholangiocarcinoma Patients

Background.

The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine.

Methods.

Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazard ratios (HRs) of relapse and associated 95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score.

Results.

Twenty-three (32.4%) cases were negative for hENT-1, 22 (31.0%) were positive in the cytoplasm only, and 26 (36.6%) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95% CI 0.24–0.99, p = .046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95% CI 0.34–2.68; three to four cycles: HR 0.99, 95% CI 0.34–2.90; five to six cycles: HR 0.27, 95% CI 0.10–0.77).

Conclusion.

hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting.

Implications for Practice:

Gemcitabine is becoming an increasingly used adjuvant modality in cholangiocarcinoma (CC), but limited data are available on predictive biomarkers of response. In this study, patients receiving more than four cycles of adjuvant gemcitabine and harboring Human equilibrative nucleoside transporter 1 (hENT-1, the major transporter involved in gemcitabine intracellular uptake) on tumor cell membrane had a longer disease-free survival compared with patients negative or positive for hENT-1 only in the cytoplasm of tumor cells. Overall these results may lay the basis for further prospective randomized trials based on a larger population of patients and may prove useful for tailoring appropriate gemcitabine-based chemotherapy for CC patients in the adjuvant setting.

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Targeting Prolactin Receptor (PRLR) Signaling in PRLR-Positive Breast and Prostate Cancer

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Benign and Malignant Breast Disease at Rwandas First Public Cancer Referral Center

Background.

Breast cancer incidence is rising in low- and middle-income countries. Understanding the distribution of breast disease seen in clinical practice in such settings can guide early detection efforts and clinical algorithms, as well as support future monitoring of cancer detection rates and stage.

Patients and Methods.

We conducted a retrospective medical record review of 353 patients who presented to Butaro Cancer Center of Excellence in Rwanda with an undiagnosed breast concern during the first 18 months of the cancer program.

Results.

Eighty-two percent of patients presented with a breast mass. Of these, 55% were diagnosed with breast cancer and 36% were diagnosed with benign disease. Cancer rates were highest among women 50 years and older. Among all patients diagnosed with breast cancer, 20% had stage I or II disease at diagnosis, 46% had locally advanced (stage III) disease, and 31% had metastatic disease.

Conclusion.

After the launch of Rwanda's first public cancer referral center and breast clinic, cancer detection rates were high among patients presenting with an undiagnosed breast concern. These findings will provide initial data to allow monitoring of changes in the distribution of benign and malignant disease and of cancer stage as cancer awareness and services expand nationally.

Implications for Practice:

The numbers of cases and deaths from breast cancer are rising in low-income countries. In many of these settings, health care systems to address breast problems and efficiently refer patients with symptoms concerning for cancer are rudimentary. Understanding the distribution of breast disease seen in such settings can guide early detection efforts and clinical algorithms. This study describes the characteristics of patients who came with a breast concern to Rwanda's first public cancer referral center during its first 18 months. More than half of patients with a breast mass were diagnosed with cancer; most had late-stage disease. Monitoring changes in the types of breast disease and cancer stages seen in Rwanda will be critical as breast cancer awareness and services grow.

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Into the Clinic With Nivolumab and Pembrolizumab

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FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy

On October 9, 2015, the U.S. Food and Drug Administration expanded the nivolumab metastatic non-small cell lung cancer (NSCLC) indication to include patients with nonsquamous NSCLC after a 3.25-month review timeline. Approval was based on demonstration of an improvement in overall survival (OS) in an international, multicenter, open-label, randomized trial comparing nivolumab to docetaxel in patients with metastatic nonsquamous NSCLC with progression on or after platinum-based chemotherapy. The CheckMate 057 trial enrolled 582 patients who were randomized (1:1) to receive nivolumab or docetaxel. Nivolumab demonstrated improved OS compared with docetaxel at the prespecified interim analysis with a hazard ratio (HR) of 0.73 (p = .0015), and a median OS of 12.2 months (95% CI: 9.7–15.0 months) in patients treated with nivolumab compared with 9.4 months (95% CI: 8.0–10.7 months) in patients treated with docetaxel. A statistically significant improvement in objective response rate (ORR) was also observed, with an ORR of 19% (95% CI: 15%–24%) in the nivolumab arm and 12% (95% CI: 9%–17%) in the docetaxel arm. The median duration of response was 17 months in the nivolumab arm and 6 months in the docetaxel arm. Progression-free survival was not statistically different between arms. A prespecified retrospective subgroup analysis suggested that patients with programmed cell death ligand 1-negative tumors treated with nivolumab had similar OS to those treated with docetaxel. The toxicity profile of nivolumab was consistent with the known immune-mediated adverse event profile except for 1 case of grade 5 limbic encephalitis, which led to a postmarketing requirement study to better characterize immune-mediated encephalitis.

Implications for Practice:

Based on the results from the CheckMate 057 clinical trial, nivolumab represents a new treatment option for patients requiring second-line treatment for metastatic non-small cell lung cancer. The role of nivolumab in patients with sensitizing epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations is less clear. Until dedicated studies are performed to better characterize the role and sequence of programmed cell death 1 (PD-1) therapy, patients with EGFR or ALK alterations should have progressed on appropriate targeted therapy before initiating PD-1 inhibitor therapy. Some patients whose tumors lack programmed cell death ligand 1 (PD-L1) expression also appear to have durable responses. The U.S. Food and Drug Administration granted approval to Dako's PD-L1 test, PD-L1 IHC 28-8 pharmDx, which the applicant claimed as a nonessential complementary diagnostic for nivolumab use.

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Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer: Where Do We Go From Here?

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Clinical Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer is characterized by genomic instability, with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Given the action of poly(ADP-ribose) polymerase (PARP) inhibitors in targeting tumors with deficiencies in this repair pathway by loss of BRCA1/2, ovarian tumors could be an attractive population for clinical application of this therapy. PARP inhibitors have moved into clinical practice in the past few years, with approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past 2 years. The U.S. FDA approval of olaparib applies to fourth line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval to olaparib maintenance in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. In order to widen the ovarian cancer patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. Additionally, a better understanding of the toxicity profile is needed if PARP inhibitors are to be used in the curative, rather than the palliative, setting. We reviewed the development of PARP inhibitors in phase I–III clinical trials, including combination trials of PARP inhibitors and chemotherapy/antiangiogenics, the approval for these agents, the mechanisms of resistance, and the outstanding issues, including the development of biomarkers and the rate of long-term hematologic toxicities with these agents.

Implications for Practice:

The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has recently received approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA), with a second agent (rucaparib) likely to be approved in the near future. However, the patient population with potential benefit from PARP inhibitors is likely wider than that of germline BRCA mutation-associated disease, and biomarkers are in development to enable the selection of patients with the potential for clinical benefit from these agents. Questions remain regarding the toxicities of PARP inhibitors, limiting the use of these agents in the prophylactic or adjuvant setting until more information is available. The indications for olaparib as indicated by the FDA and EMA are reviewed.

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Cytoreductive Surgery Plus Platinum-Based Hyperthermic Intraperitoneal Chemotherapy in Epithelial Ovarian Cancer: A Promising Integrated Approach to Improve Locoregional Control

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The Impact of Mismatch Repair Status in Colorectal Cancer on the Decision to Treat With Adjuvant Chemotherapy: An Australian Population-Based Multicenter Study

Background.

Testing for mismatch repair (MMR) status in colorectal cancer (CRC) may provide useful prognostic and predictive information. We evaluated the impact of such testing on real-world practice regarding adjuvant chemotherapy for patients with resected CRC.

Patients and Methods.

A total of 175 patients with stage II and III mismatch repair-deficient (MMRD) CRC were identified from an Australian population-based study of incident CRCs. Their treatment decisions were compared with those for a cohort of 773 stage-matched patients with mismatch repair-proficient (MMRP) CRCs. The effect of MMR status, age, and pathologic characteristics on treatment decisions was determined using multiple regression analysis.

Results.

Overall, 32% of patients in stage II and 71% of patients in stage III received adjuvant chemotherapy. Among the stage II patients, those with MMRD cancer were less likely to receive chemotherapy than were MMRP cases (15% vs. 38%; p < .0001). In this group, the treatment decision was influenced by age, tumor location, and T stage. MMR status influenced the treatment decision such that its impact diminished with increasing patient age. Among patients with stage III tumors, no difference was found in the chemotherapy rates between the MMRD and MMRP cases. In this group, age was the only significant predictor of the treatment decision.

Conclusion.

The findings of this study suggest that knowledge of the MMR status of sporadic CRC influences treatment decisions for stage II patients, in an era when clear recommendations as to how these findings should influence practice are lacking.

Implications for Practice:

Microsatellite instability (MSI) is a molecular marker of defective DNA mismatch repair found in 15% of sporadic colorectal cancers. Until recently, expert guidelines on the role of MSI as a valid biomarker in the selection of stage II patients for adjuvant chemotherapy were lacking. Conducted at a time when the clinical utility of routine MSI testing was unclear, this study found that clinicians were influenced by MSI status in selecting stage II patients for chemotherapy. Furthermore, the impact of MSI on treatment decisions was greatest in younger patients and declined progressively until age 80 years, when no effect was found.

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Phase I Study of the Prolactin Receptor Antagonist LFA102 in Metastatic Breast and Castration-Resistant Prostate Cancer

Lessons Learned

Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.

Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.

Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.

Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.

Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels.

Background.

Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity.

Methods.

Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3–60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.

Results.

A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected.

Conclusion.

Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested.

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Vision for the Global Health and Cancer Section

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Cisplatin/Tegafur/Uracil/Irinotecan Triple Combination Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma: A Phase I/II Clinical Study

Lessons Learned

Cisplatin/tegafur/uracil/irinotecan triple combination therapy shows moderate response, especially in patients without previous chemoradiotherapy within the 6 months before this combination therapy.

Toxicity is tolerable, and quality of life is improved in responders.

Background.

The prognosis is poor in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Triple combination therapy may increase tumor response.

Methods.

This phase I/II prospective trial first determined the dose-limiting toxicity and recommended dose of irinotecan with cisplatin and tegafur/uracil (UFUR) in phase I. Irinotecan was supplied at doses of 40, 50, 60, and 70 mg/m² by using a standard 3+3 design. Doses of cisplatin and UFUR were held stable. In phase II, the recommended dose of irinotecan was administered intravenously (i.v.) over 90 min on day 1, with cisplatin 50 mg/m² i.v. over 60 min also on day 1, and oral UFUR 200 mg twice a day for 5 days every 2 weeks a cycle.

Results.

In the phase I portion, 14 patients were enrolled, and the dose level of irinotecan at 60 mg/m² was defined as the recommended dose for the phase II portion of the study. Among 43 patients enrolled in the phase II portion, complete response was seen in 2 patients (4.7%) and partial response in 10 patients (23.3%), and the disease control rate was 39.5%. In a subgroup analysis of patients whose prior chemoradiotherapy was more than 6 months earlier, a response rate of 40.7% and disease control rate of 59.3% were observed.

Conclusion.

Cisplatin/UFUR/irinotecan triple combination therapy is tolerated and effective for selected patients. Individualized choice of treatment will influence prognosis and quality of life in R/M HNSCC patients.

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Clinical Trials of Antiangiogenesis Therapy in Recurrent/Persistent and Metastatic Cervical Cancer

Background.

Treatment options for women with metastatic, persistent, or recurrent cervical cancer are limited and thus the disease portends a poor prognosis. It is critical to understand the pathophysiology of cervical cancer to better delineate therapeutic targets. The development of antiangiogenic therapies and their subsequent analysis in rigorous therapeutic trials have redefined current management strategies and is an exciting area of current exploration.

Results.

Translational trials have furthered the understanding of molecular determinants of angiogenesis. Phase II trials have shown promising trends with developing antiangiogenic therapies. A practice-changing phase III trial has recently been published. Given the potential benefits and different toxicity spectrum compared with standard cytotoxic chemotherapy, antiangiogenic options are under active investigation for this vulnerable patient population. Emerging data are promising for other antiangiogenic-directed therapeutics, as well as cervical cancer molecular biomarkers to guide diagnosis and treatment.

Conclusion.

Antiangiogenic therapies have evolved during the past 20 years and remain an exciting area of current exploration.

Implications for Practice:

Understanding of the angiogenic microenvironment has furthered understanding of tumor biology and management. Antiangiogenic therapies show promise for women with advanced cervical cancer. A review of the evolution of these biologic agents shows them to be an effective and tolerable management strategy for many patients in this vulnerable population, with exciting future potential.

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Patient-Reported Outcomes and Early Discontinuation in Aromatase Inhibitor-Treated Postmenopausal Women With Early Stage Breast Cancer

Background.

Early discontinuation of aromatase inhibitors (AIs) is common and leads to poor outcomes but is challenging to predict. In the Exemestane and Letrozole Pharmacogenetics trial, a high rate of early discontinuation due to intolerance was observed. We hypothesized that early changes in patient-reported outcomes (PROs) predict AI discontinuation and that biochemical factors are associated with changes in PROs.

Patients and Methods.

Postmenopausal women with early-stage breast cancer enrolled in a prospective randomized trial of exemestane versus letrozole completed questionnaires at baseline and serially over 24 months to assess overall quality of life (EuroQOL Visual Analog Scale [VAS]); mood; and multiple symptoms, including a musculoskeletal symptom cluster. A joint mixed-effects/survival model was used to estimate the effect of the change in PROs on AI discontinuation. Associations between biochemical factors and change in PROs were examined.

Results.

A total of 490 patients were analyzed. Worsening of EuroQOL VAS and the musculoskeletal cluster were associated with the highest risk for early discontinuation (hazard ratio [HR], 2.77 [95% confidence interval (CI), 2.72–2.81; p = .015]; HR, 4.39 [95% CI, 2.40–8.02; p < .0001], respectively). Pharmacokinetics and estrogen metabolism were not consistently associated with change in PRO measures. No clinically significant differences in any PRO between AIs were observed.

Conclusion.

Changes in PROs early during AI therapy were associated with treatment discontinuation. Identification of these changes could be used to target interventions in patients at high risk for early discontinuation.

Implications for Practice:

Early changes in patient-reported outcomes (PROs) can predict nonpersistence to aromatase inhibitor therapy. If used in clinical practice, PROs might identify women at highest risk for early discontinuation and allow for interventions to improve tolerance before significant toxicities develop. Further research is needed to improve capturing PROs in routine clinical practice.

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Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise

Background.

Challenges in the diagnosis and classification of cholangiocarcinoma have made it difficult to quantify the true incidence of this highly aggressive malignancy.

Methods.

We analyzed the Surveillance, Epidemiology, and End Results data to assess long-term trends in the age-standardized incidence of intrahepatic and extrahepatic cholangiocarcinoma between 1973 and 2012, correcting for systematic coding errors. Because intrahepatic cholangiocarcinoma (ICC) may frequently be misdiagnosed as cancer of unknown primary (CUP), we also analyzed trends in the incidence of CUP.

Results.

Between 1973 and 2012, the reported U.S. incidence of ICC increased from 0.44 to 1.18 cases per 100,000, representing an annual percentage change (APC) of 2.30%; this trend has accelerated during the past decade to an APC of 4.36%. The incidence of extrahepatic cholangiocarcinoma increased modestly from 0.95 to 1.02 per 100,000 during the 40-year period (APC, 0.14%). The incidence of CUP with histologic features potentially consistent with cholangiocarcinoma decreased by 51% between 1973 and 2012 (APC, –1.87%), whereas the incidence of CUP with squamous or nonepithelial histologic features increased modestly (APC, 0.42%).

Conclusion.

The recognized incidence of ICC in the U.S. continues to rise, whereas the incidence of ECC is stable. The incidence of CUP has fallen dramatically during the same time period.

Implications for Practice:

Clinical distinctions between cholangiocarcinoma (particularly intrahepatic cholangiocarcinoma [ICC]) and cancer of unknown primary (CUP) can be challenging. Recent discoveries have identified recurrent and potentially targetable genomic abnormalities in ICC, highlighting the importance of improving diagnosis. This study demonstrates that the incidence of ICC is increasing in the U.S., whereas the incidence of extrahepatic cholangiocarcinoma is stable. Concomitantly, the incidence of CUP has declined dramatically, suggesting that improved distinction between ICC and CUP may be a major driver of the increasing recognized incidence of ICC. The increasing incidence of ICC warrants further study of prevention and treatment approaches.

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Risk of Congestive Heart Failure in Early Breast Cancer Patients Undergoing Adjuvant Treatment With Trastuzumab: A Meta-Analysis

Background.

The use of trastuzumab has proven to be a successful strategy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer; however, it is associated with an increased risk of cardiac dysfunction. We performed an up-to-date, comprehensive meta-analysis to clarify the risk of congestive heart failure (CHF) in patients with early breast cancer receiving different durations of adjuvant trastuzumab with the longest-term follow-up.

Methods.

Eligible studies included randomized control trials of HER2-positive early breast cancer patients with or without trastuzumab in adjuvant chemotherapy. Adequate reporting of CHF data were required for inclusion. Statistical analyses were conducted to calculate the overall incidence, relative risk (RR), and 95% confidence interval (CI) by use of a fixed-effects model.

Results.

Six randomized control trials including 18,111 patients were identified. The overall incidence of high-grade CHF in patients treated with trastuzumab versus placebo was 1.44% (95% CI, 0.79%–2.64%) and the RR was 3.19 (95% CI, 2.03–5.02; p < .00001). In subgroup analysis, the difference in CHF incidence failed to achieve significance. The RR for 8 mg/kg trastuzumab (high dose) was greater than that for 4 mg/kg (low dose) (RR, 6.79, 95% CI, 2.03–22.72, p = .0001; versus RR, 2.64; 95% CI, 1.61–4.32; p = .002). Additionally, higher RRs were observed for patients receiving trastuzumab for 1 year (RR, 3.29; 95% CI, 2.07–5.25) and 2 years (RR, 9.54; 95%CI, 2.19–41.43), but not 9 weeks (RR, 0.50; 95% CI, 0.05–5.49) compared with control groups. No evidence of publication bias was observed.

Conclusion.

Adjuvant trastuzumab therapy was strongly associated with an increased risk of significant CHF in patients with early breast cancer, particularly in 2-year use.

Implications for Practice:

This comprehensive meta-analysis evaluated the risk of congestive heart failure with a usage profile of adjuvant trastuzumab in patients with early breast cancer. Before initiating treatment with trastuzumab, a risk-benefit analysis for individual patients should be critically evaluated, considering that the prognosis is closely related to drug dose and duration of use. Cardiac function should be monitored throughout the treatment period and also during follow-up. Thus, early identification of trastuzumab-related cardiac dysfunction can allow effective medical intervention, elimination of symptoms, recovery of function, and continuation of trastuzumab therapy.

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Chimeric Antigen Receptor T-Cell Therapy for the Community Oncologist

The field of cancer immunotherapy has rapidly progressed in the past decade as several therapeutic modalities have entered into the clinic. One such immunotherapy that has shown promise in the treatment of cancer is the use of chimeric antigen receptor (CAR)-modified T lymphocytes. CARs are engineered receptors constructed from antigen recognition regions of antibodies fused to T-cell signaling and costimulatory domains that can be used to reprogram a patient's T cells to specifically target tumor cells. CAR T-cell therapy has demonstrated sustained complete responses for some patients with advanced leukemia, and a number of CAR therapies are being evaluated in clinical studies. CAR T-cell therapy-associated toxicities, including cytokine release syndrome, macrophage activation syndrome, and tumor lysis syndrome, have been observed and effectively managed in the clinic. In patients with significant clinical responses, sustained B-cell aplasia has also been observed and is a marker of CAR T-cell persistence that might provide long-term disease control. Education on CAR T-cell therapy efficacy and safety management is critical for clinicians and patients who are considering this novel type of treatment. In the present report, the current landscape of CAR T-cell therapy, the effective management of patients undergoing treatment, and which patients are the most suitable candidates for current trials are discussed.

Implications for Practice:

The present report describes the current status of chimeric antigen receptor (CAR) T lymphocytes as an immunotherapy for patients with relapsed or refractory B-cell malignancies. CAR T cells targeting CD19, a protein expressed on many B-cell malignancies, typically induce high complete response rates in patients with B-cell leukemia or lymphoma who have very limited therapeutic options. Recent clinical trial results of CD19 CAR T-cell therapies and the management of CAR T-cell-associated adverse events are discussed. The present report will therefore inform physicians regarding the efficacy and safety of CAR T cells as a therapy for B-cell malignancies.

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Cardiotoxicity and Cardiac Monitoring During Adjuvant Trastuzumab in Daily Dutch Practice: A Study of the Southeast Netherlands Breast Cancer Consortium

Introduction.

We assessed the incidence and timing of first cardiac events, impact on trastuzumab prescription, and role of left ventricular ejection fraction (LVEF) monitoring in daily practice of trastuzumab-treated patients with human epidermal growth receptor 2 (HER2)-positive early breast cancer.

Methods.

We included all patients with stage I–III breast cancer diagnosed in the early years (2005–2007) after the introduction of adjuvant trastuzumab in five hospitals in Southeast Netherlands. We studied the incidence and timing of cardiotoxicity in patients treated with adjuvant trastuzumab, using similar cardiac endpoints as in the Herceptin Adjuvant (HERA) trial.

Results.

Of 2,684 included patients, 476 (17.7%) had a HER2-positive tumor. Of these, 269 (56.9%) were treated with adjuvant chemotherapy, and of these, 230 (85.5%) also received trastuzumab. Cardiotoxicity was observed in 29 of 230 patients (12.6%). Twenty of the 230 patients (8.7%) had symptomatic cardiotoxicity, defined as a drop in LVEF of at least 10 percentage points and to below 50%, accompanied by symptoms of congestive heart failure. Trastuzumab was definitely discontinued because of supposed cardiotoxicity in 36 patients (15.6%), of whom only 15 (6.5%) had a significant LVEF drop. Of the 36 patients who prematurely discontinued trastuzumab (including the 29 in whom cardiotoxicity was observed), 84.8% stopped in the first 6 months. No cardiac deaths were seen.

Conclusion.

In the first years after implementation of trastuzumab for treatment of early breast cancer, physicians frequently based their decision to discontinue treatment on patient symptoms apart from LVEF outcome. We suggest that focusing LVEF monitoring on the first 6 months might be more cost-effective without compromising patient safety. Nonetheless, further research is needed.

Implications for Practice:

Knowledge of when cardiotoxicity occurs in daily practice will help shape the best follow-up method for cardiac monitoring in trastuzumab-treated patients with human epidermal growth receptor 2-positive early breast cancer. In the first years after implementation of trastuzumab for treatment of early breast cancer, physicians frequently based their decision to discontinue treatment on patient symptoms apart from left ventricular ejection fraction (LVEF) outcome. When cardiotoxicity was found in daily practice, it occurred mainly in the first 6 months after start of trastuzumab. This study suggests that focusing LVEF monitoring on the first 6 months might be more cost-effective without compromising patient safety. This insight stresses the relevance of performing real-world analyses.

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Best Practices in Chronic Myeloid Leukemia Monitoring and Management

Optimal use of current therapeutic opportunities for chronic myeloid leukemia patients requires integration of clinical and laboratory monitoring. Assessment of molecular response (MR) by real-time quantitative polymerase chain reaction is the most sensitive way to monitor tyrosine kinase inhibitor (TKI) treatment efficacy. Besides major molecular response, which has emerged as a safe haven for survival since the initial studies of first-line imatinib treatment, two additional MR milestones have recently been defined: early molecular response and deep molecular response. The achievement of such MR milestones within defined time points during therapy is thought to draw the ideal trajectory toward optimal long-term outcome and, possibly, successful treatment discontinuation. Sensitive and reproducible MR measurement and proper interpretation of MR results are therefore critical to correctly inform therapeutic decisions. In patients who do not achieve an optimal response to TKI therapy, BCR-ABL1 mutation screening should also be performed, because it may deliver useful information for TKI choice. This review aims to help clinicians apply and translate the latest response definitions and clinical recommendations into practice. We provide a critical update on how these recommendations have incorporated MR levels in the clinical decision algorithms and how detection of BCR-ABL1 mutations should be interpreted. We also include a practical guide for pathologists and molecular biologists to best perform molecular testing and for hematologists and oncologists to best integrate it into routine practice.

Implications for Practice:

Ever-more-potent therapeutic strategies have been developed for chronic myeloid leukemia (CML) in parallel with the evolution of therapeutic goals and the refinement of response definitions and monitoring schemes and procedures. Terminology and methodology continue to evolve rapidly, making it difficult for busy hematology/oncology professionals to keep abreast of the newest developments. Optimal CML patient management results from the timely and rational use of molecular testing, the critical assessment of the power and pitfalls of current technology, and the appropriate interpretation and contextualization of results.

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The Treatment of Colorectal Cancer During Pregnancy: Cytotoxic Chemotherapy and Targeted Therapy Challenges

Cancer diagnosed during pregnancy has increased because of delayed child-bearing and the known occurrence of age-dependent malignancies. Cases of colorectal cancer (CRC) in pregnancy have recently been reported. With the expected rise in CRC diagnosed in young adults coupled with the current trend of delayed child-bearing, CRC during pregnancy is likely to increase. Treating pregnant women with CRC by using antineoplastics presents a dilemma because there are many unknowns to guide treatment decisions. We review the issues regarding the use of 10 CRC-approved agents in pregnancy.

Implications for Practice:

Colorectal cancer (CRC) in pregnancy is likely to become more common because of the current population trend in delayed child-bearing and the increase in CRC incidence expected among young adults. Practitioners should become familiar with the challenges associated with systemic treatment of a pregnant patient with CRC. This review addresses concerns surrounding the 10 systemic agents approved for CRC to help provide treatment guidance when such a case arises.

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Erratum to: PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment

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Resection of pituitary tumors: endoscopic versus microscopic

Abstract

Transsphenoidal microscopic pituitary surgery has long been considered the gold standard in surgical treatment of pituitary tumors. Endonasal endoscopic pituitary surgery has come into prominence over the last two decades as an alternative to microscopic surgery. In this review, we use recent literature to discuss the advantages and disadvantages of each approach. Our review shows that for small intrasellar tumors, both approaches appear equally effective in experienced hands. For larger tumors with extrasellar extension, the endoscopic approach offers several advantages and may improve outcomes associated with the extent of resection and postoperative complications.

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Surgery of insular and paralimbic diffuse low-grade gliomas: technical considerations

Abstract

Once considered a "no man's land" especially when invaded by a diffuse low grade glioma (DLGG), the insula remains to this day a surgical challenge. Surgery for insular DLGG involves consideration of its hidden location under the potentially eloquent operculae, the proximity to vascular tree and high density of functions not only in the insular cortex but also in the white fiber pathways passing under the insular lobe. The natural history of DLGG and the potential benefits and consequences of the surgical approach also need a close look. In the last decade, a better knowledge of the functional anatomy and connectivity of this region, as well as an improvement in surgical techniques as direct stimulation mapping, combined with an increasing literature showing a favorable impact of maximal resection for DLGG, were deciding factors in the paradigmatic shift from expectative treatment to early surgical management. Here, our goal is to discuss the structural and functional aspects of the insula, the specificities of insular and paralimbic DLGG by emphasizing the technical considerations of surgery in this region, as well as its oncological and functional outcomes. In summary, this new strategy based upon early maximal safe surgical resection showed both oncological benefit and preservation of quality of life—or even an improvement thanks to epilepsy relief.

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Issue Information

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Hyperfibrinogenemia is associated with inflammatory mediators and poor prognosis in patients with gastric cancer

Abstract

Purpose

Hyperfibrinogenemia is associated with poor prognosis in various cancers; however, its clinical relevance in gastric cancer has not been well analyzed. We conducted this study to assess the clinicopathological significance and prognostic value of hyperfibrinogenemia in patients with gastric cancer.

Methods

Plasma fibrinogen levels were measured preoperatively in 315 patients undergoing surgery for gastric cancer. We then evaluated the clinicopathological significance of hyperfibrinogenemia and its relationship with several biomarkers, including white blood cell (WBC), C-reactive protein (CRP), platelet count, prothrombin time (PT) and activated partial thromboplastin time (APTT). Postoperative plasma levels were compared with preoperative levels. The multivariate prognostic value of hyperfibrinogenemia was calculated using the Cox proportional hazards model.

Results

Tumor progression was significantly associated with hyperfibrinogenemia, as were the CRP level and platelet counts. Plasma fibrinogen levels decreased significantly after radical surgery. Adjusting for TNM factors, multivariate analysis indicated that hyperfibrinogenemia was an independent prognostic factor for poor survival (hazard ratio = 2.607, 95 % confidence interval = 1.180–5.761, P = 0.018).

Conclusion

Preoperative hyperfibrinogenemia was associated with tumor progression, inflammatory mediators, and poor overall survival in patients with gastric cancer.

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Fine-needle aspiration of soft tissue perineurioma: A comparative analysis of cytomorphology and immunohistochemistry with benign and malignant mimics

Abstract

BACKGROUND

Soft tissue perineurioma (STP) is a benign peripheral nerve sheath tumor demonstrating uniform perineurial cell differentiation. To the authors' knowledge, the cytomorphologic features of STP remain incompletely characterized, and the distinction between STP and its benign (intramuscular/cellular myxoma) and malignant (low-grade fibromyxoid sarcoma [LGFMS]) mimics is challenging.

METHODS

Fine-needle aspiration (FNA)/core needle biopsies of 25 low-grade myxoid spindle cell neoplasm cases including STP (5 cases), intramuscular/cellular myxoma (16 cases), and LGFMS (4 cases) were reviewed retrospectively for cytomorphologic and immunophenotypic comparison.

RESULTS

FNA smears of STP were hypocellular with scattered clusters of spindle cells with bland, slender nuclei; bipolar cytoplasmic processes; and scant myxoid to collagenous matrix. STP commonly lacked the abundant granular myxoid matrix material present in intramuscular/cellular myxoma (20% in STP vs 75% in intramuscular/cellular myxoma; P <.05), but these tumors were otherwise remarkably found to be similar on FNA smears. All STP and intramuscular/cellular myxoma cases lacked cytologic atypia, whereas 50% of LGFMS cases demonstrated mild nuclear atypia. EMA was positive in all STPs, but also was found to be at least focally positive in 60% of intramuscular/cellular myxoma cases (9 of 15 cases) and 75% of LGFMS cases (3 of 4 cases). MUC4 was found to be negative in all 15 intramuscular/cellular myxoma and 5 STP cases, but was positive in all 4 LGFMS cases.

CONCLUSIONS

STP, intramuscular/cellular myxoma, and LGFMS have significant cytomorphologic overlap. Immunohistochemical staining with EMA is not beneficial due to a lack of specificity. Negative MUC4 staining reliably excludes LGFMS. Therefore, a clinically meaningful approach to the FNA biopsy evaluation of a low-grade myxoid spindle cell neoplasm is to provide a differential diagnosis and to exclude a low-grade sarcoma. Cancer Cytopathol 2016. © 2016 American Cancer Society.

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Morphologists overestimate the nuclear-to-cytoplasmic ratio

BACKGROUND

The Paris System for Reporting Urinary Cytology (TPS) has defined nuclear-to-cytoplasmic (N:C) ratio cutoff values for several of its risk-stratified diagnostic categories. However, because pathologists are not trained to recognize strict N:C ratio cutoff values, a previously designed survey was used to determine whether pathologists could accurately identify N:C ratios according to TPS standards.

METHODS

Participants were instructed to estimate the N:C ratio of ideal (line drawing) and real (cell photograph) images presented via an online survey. Actual N:C ratios ranged from 0.3 to 0.8, and 3 answer choices were available: < 0.5, ≥ 0.5 and <0.7, and ≥0.7. The resulting data were analyzed to determine the accuracy and performance of the subgroups.

RESULTS

A total of 137 individuals completed the survey. Approximately 24.1% were cytopathologists, 18.2% were pathologists without formal cytopathology training, 18.2% were cytotechnologists, 24.1% were pathology residents, and 15.3% were nonmorphologists. Overall, 70.0%, 67.6%, and 93.3% of responses, respectively, were correct for images with an N:C ratio of < 0.5, ≥0.5 and < 0.7, and ≥0.7. For images with an actual N:C ratio < 0.5 and ≥0.5 and < 0.7, 30.0% and 25.0% of responses, respectively, overestimated the N:C ratio. Furthermore, for images with an N:C ratio of 0.4 and 0.6, > 40.0% of responses overestimated the N:C ratio. As a whole, morphologists were significantly more accurate than nonmorphologists (P = .030).

CONCLUSIONS

Morphologists tended to overestimate the N:C ratio, particularly at ratios close to TPS-recommended cutoff values. Additional training regarding N:C ratio estimation may help pathologists to adapt to this new system. Cancer Cytopathol 2016. © 2016 American Cancer Society.

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Correspondence

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Quality Indicators to Assure and Improve Cancer Care in Spain Using the Delphi Technique

Background: The quality of cancer care has become a priority for health care systems. The goal of this research was to develop a set of evidence-based quality indicators (QIs) for organization, palliative care, and colorectal, breast, and lung cancers for introducing a system of benchmarking in Spain. Methods: A comprehensive evidence-based literature search was performed to identify potential QIs. An expert panel (the health care quality promotion group) of 9 oncologists identified indicators and evaluated them. A Delphi process involving 58 physicians was used to rank QIs by clinical relevance (validity). The expert panel then evaluated the selected indicators in terms of the feasibility of measuring them in Spanish hospitals, their usefulness for comparisons, their degree of clinical relevance, and their sensitivity to the impact of health care improvements. Results: From the literature review, 99 potential QIs were identified. The Delphi process shortened the list to 72 QIs. A final set of 57 QIs was established by the health care quality promotion group: 12 related to organizational issues, 11 to colorectal cancer, 11 to breast cancer, 12 to lung cancer, and 11 to palliative care. This final set included structure (n=2), process (n=36), and outcome (n=19) indicators. Conclusions: A set of QIs has been developed using a validated Delphi method, meaning that we can be confident of their validity, feasibility, sensitivity, and acceptability. These QIs are to serve as the basis of a strategy for benchmarking across oncology services in Spanish hospitals and should enable us to assure and improve the quality of cancer care.

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Oncology Research Program

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Fine-Needle Aspiration Biopsy of Palpable Breast Masses: Patterns of Clinical Use and Patient Experience

Background: Timeliness is an important and recognized measure of health care quality. Multiple health organizations worldwide have published timeliness targets for breast cancer care. We performed the first comparison of patient wait times and utilization patterns for palpable breast mass diagnosis and treatment with regard to biopsy method. Patients and Methods: Palpable breast masses in women biopsied via a fine-needle aspiration (FNA) or core biopsy at 2 affiliated academic medical centers in 2009 were analyzed if subsequently treated with excision or neoadjuvant therapy. Patient demographics, mass size and radiologic features, pathology diagnoses, and wait times to diagnosis and treatment were recorded. Results: Patients diagnosed by FNA biopsy received their biopsy diagnosis more than 8 days sooner than those diagnosed by core biopsy. Most FNA biopsies occurred the same day the patient clinically presented. Time to treatment did not differ significantly between groups. Both biopsy methods demonstrated comparable diagnostic accuracy. Breast masses diagnosed by FNA biopsy had Breast Imaging Reporting and Data System (BI-RADS) scores ranging from 1 through 5, whereas nearly all core biopsy cases had a BI-RADS score of 4 or greater. All patient groups were demographically comparable and presented with similar breast mass sizes. Conclusions: Wait times for breast biopsies were significantly shorter for patients diagnosed by FNA compared with core biopsy. FNA biopsy was often used to evaluate breast masses of low clinical suspicion. In light of health care goals for practice improvement and cost containment, breast FNA biopsy may be an underused resource.

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NCCN News

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Basal Cell Skin Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology

Basal cell carcinoma (BCC) of the skin is the most common cancer, with a higher incidence than all other malignancies combined. Although it is rare to metastasize, patients with multiple or frequently recurring BCC can suffer substantial comorbidity and be difficult to manage. Assessment of risk is a key element of management needed to inform treatment selection. The overall management of BCC primarily consists of surgical approaches, with radiation therapy as an alternate or adjuvant option. Many superficial therapies for BCC have been explored and continue to be developed, including topicals, cryosurgery, and photodynamic therapy. Two hedgehog pathway inhibitors were recently approved by the FDA for systemic treatment of advanced and metastatic BCC, and others are in development. The NCCN Guidelines for Basal Cell Skin Cancer, published in full herein, include recommendations for selecting among the various surgical approaches based on patient-, lesion-, and disease-specific factors, as well as guidance on when to use radiation therapy, superficial therapies, and hedgehog pathway inhibitors.

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Closely Guarded Secrets

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NCCN Guidelines Insights: Prostate Cancer Early Detection, Version 2.2016

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer Early Detection provide recommendations for prostate cancer screening in healthy men who have elected to participate in an early detection program. The NCCN Guidelines focus on minimizing unnecessary procedures and limiting the detection of indolent disease. These NCCN Guidelines Insights summarize the NCCN Prostate Cancer Early Detection Panel's most significant discussions for the 2016 guideline update, which included issues surrounding screening in high-risk populations (ie, African Americans, BRCA1/2 mutation carriers), approaches to refine patient selection for initial and repeat biopsies, and approaches to improve biopsy specificity.

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The Rapid Evolution of Novel Therapies in Multiple Myeloma

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Refusal of Recommended Chemotherapy for Ovarian Cancer: Risk Factors and Outcomes; a National Cancer Data Base Study

Objective: To identify risk factors associated with refusal of recommended chemotherapy and its impact on patients with epithelial ovarian cancer (EOC). Methods: We identified patients in the National Cancer Data Base diagnosed with EOC from January 1998 to December 2011. Patients who refused chemotherapy were identified and compared with those who received recommended, multiagent chemotherapy. Univariate and multivariable analyses were performed using chi-square test with Bonferroni correction, binary logistic regression, log-rank test, and Cox proportional hazards modeling. The threshold for statistical significance was set at a P value of less than 0.05. Results: From a cohort of 147,713 eligible patients, 2,707 refused chemotherapy. These patients were compared with 92,212 patients who received recommended multiagent chemotherapy. Older age, more medical comorbidities, not having insurance, and later year of diagnosis were directly and significantly associated with chemotherapy refusal when analyzed using multivariable logistic regression. In addition, lower-than-expected facility adherence to NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Ovarian Cancer, treatment at low-volume center, lower grade, and higher stage were all significantly and independently associated with chemotherapy refusal. Median overall survival of patients who received multiagent chemotherapy was significantly longer than that of those who refused chemotherapy (43 vs 4.8 months; P<.0005). After controlling for known patient, facility, and disease prognostic factors, chemotherapy refusal is significantly associated with increased risk of death. Conclusions: Refusal of recommended chemotherapy carries significant risk of early death from ovarian cancer. Our data demonstrate that the decision to refuse chemotherapy is multifactorial and, in addition to unalterable factors (eg, stage/grade, age), involves factors that can be changed, including facility type and payor. Efforts at addressing these discrepancies in care can improve compliance with chemotherapy recommendations in the NCCN Guidelines for Ovarian Cancer and outcomes.

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Antitumor Response of VEGFR2- and VEGFR3-Amplified Angiosarcoma to Pazopanib

Background: Angiosarcoma is a malignant neoplastic disease originating from or differentiating toward vascular endothelium, for which systemic pharmacologic treatment has limited durability. The molecular oncogenesis of angiosarcoma is often linked to inappropriate activations of vascular endothelial growth factor receptor (VEGFR) family members, which presents an opportunity for the use of therapy that selectively targets the machinery of vascular signaling. Methods: Hybridization capture of 3,320 exons of 182 cancer-related genes and the introns of 14 genes frequently rearranged in cancer was applied to more than 50 ng of DNA extracted from a formalin-fixed, paraffin-embedded biopsy of recurrent angiosarcoma and was sequenced to high, uniform coverage of 939x. Results: The angiosarcoma harbored amplifications of VEGFR2 (KDR) of 8 copies and VEGFR3 (FLT4) of 16 copies. The patient was initially treated with sorafenib, an inhibitor of VEGFR2, and developed progressive disease. The patient then received pazopanib, an inhibitor of VEGFR2 and VEGFR3 and experienced a potent antitumor response resulting in clinically stable disease for 6 months. Conclusions: This exceptional response to pazopanib treatment suggests that a subset of patients with angiosarcoma with genomic alterations in vascular signaling genes may respond well to pazopanib.

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Development and Validation of a Clinical Trial Accrual Predictive Regression Model at a Single NCI-Designated Comprehensive Cancer Center

Background: Clinical study sites often do not achieve anticipated accrual to clinical trials, wasting critical patient, material, and human resources. The expensive and extensive process to bring a drug to approval highlights the need to streamline clinical pipeline processes. We sought to create a predictive accrual model to be used when considering clinical trial activation at the level of the individual site. Materials and Methods: This retrospective cohort study used 7 years of registry data from treatment and supportive care interventional studies at a single academic cancer center to build a negative binomial regression model with local and protocol variables known prestudy. Actual, team-predicted, and model-predicted accrual and sensitivity/specificity were calculated. Results: To build the model, 207 trials were used. Investigational drug application, disease team, number of national sites, local Institutional Review Board use, total national accrual time, accrual completed, and national enrollment goal were independently and significantly associated with accrual. Predicted accrual was 94% of actual, maintaining predictive value at multiple cutoff values. Validation included 61 trials. The model correctly predicted whether a study would accrue at least 4 subjects 75% of the time. Correlation at the category level was 44.3%, and model sensitivity and specificity are 70% and 78%, respectively. Conclusions: We identified and validated national and local key factors associated with accrual at our site. This methodology has not been previously validated broadly with the intent of trial feasibility. Model validation shows it to be an accurate and quick metric in anticipating accrual success that can be used for resource allocation.

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Therapeutically Induced Changes in HER2, HER3, and EGFR Protein Expression for Treatment Guidance

Protein-targeted therapies are expected to selectively kill tumor cells that express the targeted protein biomarker. Although a tumor mass may initially respond to targeted therapies based on expression of the targeted protein, all cells within a tumor may not express the targeted protein above a critical threshold level; therefore, those cells that do not express, or that downregulate expression of, the targeted protein may not be responsive to therapy. The ability to monitor the dynamic expression of these protein biomarkers throughout the course of therapy may allow for treatment to be personalized in real-time in response to the evolving nature of the tumor. This report demonstrates, by monitoring a single patient through multiple therapies, how targeted mass spectrometry is an effective, quantitative method that provides real-time analysis of multiple therapeutically associated targeted proteins that can be used to personalize a patient's treatment strategy throughout the course of care.

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Fine-Needle Aspiration for Breast Cancer Diagnosis: One Size Does Not Fit All

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[KRAS mutation does not influence oxaliplatin or irinotecan efficacy, in association with bevacizumab, in first line treatment of metastatic colorectal cancer].

Related Articles

[KRAS mutation does not influence oxaliplatin or irinotecan efficacy, in association with bevacizumab, in first line treatment of metastatic colorectal cancer].

Bull Cancer. 2016 May 4;

Authors: Cabart M, Frénel JS, Campion L, Ramée JF, Dupuis O, Senellart H, Hiret S, Douillard JY, Bennouna J

Abstract
INTRODUCTION: The identification of RAS status (KRAS and NRAS) has changed the management of metastatic colorectal cancer (mCRC). The impact of the RAS mutation on cytotoxic chemotherapy efficacy has not yet been determined. Nevertheless, several retrospective studies suggest a greater efficacy of oxaliplatin in mCRC with KRAS mutation.
METHODS: We analyzed retrospectively the progression free survival (PFS) and overall survival (OS) in 216 patients with mCRC receiving first line treatment between 2008 and 2010 according to KRAS status and chemotherapy regimen used (oxaliplatin- or irinotecan-based, in association with fluoropyrimidine and bevacizumab).
RESULTS: In KRAS mutated tumors, median OS was 23.4 months with oxaliplatin-based regimen, and 23.6 months with irinotecan-based regimen, with no significant difference (HR 1.30; 95 % CI 0.81-2.09; P=0.27). In KRAS wild-type tumors, median OS was 30.3 months with oxaliplatin-based regimen, and 25.4 months with irinotecan-based regimen, with no significant difference (HR 0.81; 95 % CI 0.52-1.24; P=0.33). Similarly, KRAS mutational status had no significant effect on efficacy of oxaliplatin or irinotecan regarding PFS.
DISCUSSION: In this retrospective study, KRAS mutational status does not influence the efficacy of first line cytotoxic chemotherapy in association with bevacizumab.

PMID: 27155924 [PubMed - as supplied by publisher]

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Is it my cancer or am i just getting older?: Impact of cancer on age-related health conditions of older cancer survivors

BACKGROUND

The extent to which cancer exacerbates or creates new health conditions is a long-standing, unanswered question. The current prospective study examined the short-term impact of cancer on the functioning, development of, and worsening of age-related health conditions among older adults who develop cancer compared with age-matched controls.

METHODS

Surveillance, Epidemiology, and End Results registry data were linked with Medicare Health Outcomes Survey (MHOS) data. A total of 921 eligible cases were Medicare beneficiaries with diagnosis of breast, colorectal, lung, or prostate cancer made between their baseline and follow-up MHOS. Using propensity score matching, 4605 controls without cancer were matched from the MHOS. Analysis of covariance and logistic regression were used to examine changes in physical functioning, activities of daily living, age-related conditions, and exacerbation of preexisting conditions for cases compared with controls.

RESULTS

Cancer groups demonstrated greater declines in activities of daily living and physical function compared with controls (mean, -1.53 [standard error, 0.14]), with the greatest change noted for patients with lung cancer (mean, -6.72 [standard error, 0.94]). Having a cancer diagnosis increased the risk of depression but did not increase the odds of developing arthritis in the hand and/or hip, urinary incontinence (except for prostate cancer), or vision and/or hearing problems. Having a cancer diagnosis also did not exacerbate the severity of arthritis or foot neuropathy.

CONCLUSIONS

The findings of the current study suggest that cancer is a stronger driver for declines in physical functioning and an increased risk of depression in older adults. Interventions are needed to decrease these risks. Clinicians need to prepare patients and families for changes in functioning levels and interventions that limit the declines for older patients with cancer are needed. Cancer 2016. © 2016 American Cancer Society.

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Metastasectomy, intralesional resection, or stabilization only in the treatment of bone metastases from renal cell carcinoma

Background

The mainstay of treatment for bone metastases from renal cell carcinoma is surgery. We assessed if there was a difference in local recurrence, reoperation, and survival between patients who underwent metastasectomy, intralesional curettage, or stabilization only for renal cell carcinoma metastasis to the appendicular skeleton, and if there was a difference in these outcomes based on margin status.

Methods

This retrospective study included 183 patients; 48% underwent metastasectomy (n = 88, margins: 64 negative; 20 positive; 4 unclear), 30% intralesional curettage (n = 54), and 22% stabilization only (n = 41).

Results

The recurrence rate differed and was highest after stabilization only (39%), followed by intralesional curettage (22%), and metastasectomy (12%) (P = 0.003). However, we found no difference in reoperation rate (P = 0.847). Survival was better in patients who underwent metastasectomy (P = 0.020). The recurrence rate was lower in patients who had a negative margin (5%) as compared to those with a positive margin (26%) (P < 0.001). However, we found no difference in reoperation rate (P = 0.97). Negative margins showed better survival (P < 0.001).

Conclusions

Our findings emphasize the importance of obtaining negative margins in patients with a good life expectancy, as lower recurrence rate can be attained at a not significant additional risk for reoperation, with a potential impact on survival. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Local treatment with electrochemotherapy of superficial angiosarcomas: Efficacy and safety results from a multi-institutional retrospective study

Background

Angiosarcoma is an aggressive vascular neoplasm with a high propensity for local recurrence. Electrochemotherapy is an emerging skin-directed therapy, exerting prominent cytotoxic activity, and antivascular effects. Its efficacy in angiosarcoma has not been investigated.

Methods

This multicenter retrospective analysis reviewed patients who underwent electrochemotherapy from 2007 to 2014 for superficial advanced angiosarcomas. Bleomycin was administered intravenously and delivered within tumors by means of percutaneously applied electric pulses, according to the European Standard Operating Procedures for Electrochemotherapy. Tumor assessment was performed using RECIST (version 1.1). Toxicity (CTCAE, v4.0) and local progression-free survival (LPFS) were also evaluated.

Results

Nineteen patients (13 with locally advanced and 6 with metastatic angiosarcomas) were treated. Tumor sites were: scalp (n = 5), breast (n = 8), other skin sites (n = 3), and soft tissue (n = 3). Target lesions (n = 54) ranged in size from 1.5 to 2.5 cm (median, 2 cm). Treatment was well tolerated. After 2 months, an objective response was observed in 12/19 (63%) patients, complete in 8 (42%). One-year LPFS within treatment field was 68%. Local symptom improvement included palliation of bleeding (5/19 patients) and pain relief (6/19 patients).

Conclusions

Electrochemotherapy may represent a new locoregional treatment for selected patients with superficial angiosarcomas. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Clinicopathologic and survival analysis of resected ampullary adenocarcinoma

Introduction

Ampullary adenocarcinoma (AAC) is a rare neoplasm. We sought to determine the clinicopathologic factors contributing to the overall survival (OS) and recurrence-free (RFS) survival.

Methods

Patients (pts) with resected AAC were identified from 1996 to 2015 and reviewed for clinicopathologic factors and correlated with outcome.

Results

We identified and evaluated 106 pts diagnosed with AAC. The median age was 70.2 years (range 41–86) and 60 (56.6%) were male. Overall, 105 pts (99.1%) had a pancreaticoduodenectomy. An R0 resection was achieved in 101 (95%) pts. Median follow-up was 19 months with a median OS of 49.3 months. Lymph node metastasis and poorly differentiated tumors adversely affected OS on multivariate analysis (MVA). Twenty patients (18.9%) developed recurrence. The median RFS was 27 months. RFS was adversely affected by lymph node count and metastasis, tumor differentiation, and histological subtype on MVA. Survival was not affected by the addition of adjuvant therapy. Retrieval of ≤12 lymph nodes and lymph node ratio ≥0.10 resulted in worse OS on Kaplan–Meier analysis.

Conclusions

Our data show retrieval of ≤12 nodes, involvement of nodes with AAC, moderately or poorly differentiated tumors, and pancreaticobiliary subtype adversely affected survival, while the use of adjuvant therapy demonstrated no significant benefit. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Anastomotic recurrence of colon cancer: Genetic analysis challenges the widely held theories of cancerous cells’ intraluminal implantation and metachronous carcinogenesis

Background and Objectives

Anastomotic recurrence (AR), whose etiopathogenesis is attributed to intraluminal implantation of cancerous cells or metachronous carcinogenesis, is a major issue for patients undergoing colon cancer (CC) resection. The objective of the study is to throw some light on AR etiopathogenesis and to identify risk factors of AR in selecting patients to undergo early endoscopy.

Methods

An analysis of clinical and histopathological parameters, including MSI and LOH of seven sites (Myc-L, BAT26, BAT40, D5S346, D18S452, D18S64, D16S402) was performed in primary CC and AR of 18 patients. They were then compared to 36 controls not developing AR.

Results

A genetic instability was present in 16/18 patients, with distinct genetic patterns between primaries and ARs. LOH at 5q21 and/or 18p11.23 were found in both primary and AR in >50% of cases, but this rate was no different from control population. CEA resulted as associated with AR (P = 0.03), whereas N status presented a borderline result (P = 0.08).

Conclusions

Our findings challenge present theories about AR development. No "genetic marker" has been found. CEA and, to a lesser extent, N status, appear associated with AR. Rectal washout is seemingly meaningless. Iterative resection should be recommended since a long survival may be expected. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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