On the basis of the paucity of high-quality, consistent evidence, there are no agents recommended for the prevention of CIPN. With regard to the treatment of existing CIPN, the best available data support a moderate recommendation for treatment with duloxetine. Although the CIPN trials are inconclusive regarding tricyclic antidepressants (such as nortriptyline), gabapentin, and a compounded topical gel containing baclofen, amitriptyline HCL, and ketamine, these agents may be offered on the basis of data supporting their utility in other neuropathic pain conditions given the limited other CIPN treatment options. Further research on these agents is warranted.

PURPOSE To update the ASCO guideline on the recommended prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer survivors. METHODS An Expert Panel conducted targeted systematic literature reviews to identify new studies. RESULTS The search strategy identified 257 new references, which led to a full-text review of 87 manuscripts. A total of 3 systematic reviews, 2 with meta-analyses, and 28 primary trials for prevention of CIPN in addition to 14 primary trials related to treatment of established CIPN, are included in this update. RECOMMENDATIONS The identified data reconfirmed that no agents are recommended for the prevention of CIPN. The use of acetyl-l-carnitine for the prevention of CIPN in patients with cancer should be discouraged. Furthermore, clinicians should assess the appropriateness of dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment. Duloxetine is the only agent that has appropriate evidence to support its use for patients with established painful CIPN. Nonetheless, the amount of benefit from duloxetine is limited. Additional information is available at www.asco.org/survivorship-guidelines .

A B S T R A C T PurposeNo biomarkers have been identified to predict outcome with the use of an antiangiogenesis agent for cancer. Vascular endothelial growth factor (VEGF) genetic variability has been associated with altered risk of breast cancer and variable promoter activity. Therefore, we evaluated the association of VEGF genotype with efficacy and toxicity in E2100, a phase III study comparing paclitaxel versus paclitaxel plus bevacizumab as initial chemotherapy for metastatic breast cancer. Patients and MethodsDNA was extracted from tumor blocks of patients from E2100. Three hundred sixty-three samples were available to evaluate associations between genotype and outcome. Genotyping was performed for selected polymorphisms in VEGF and VEGF receptor 2. Testing for associations between each polymorphism and efficacy and toxicity was performed. ResultsThe VEGF-2578 AA genotype was associated with a superior median overall survival (OS) in the combination arm when compared with the alternate genotypes combined (hazard ratio ϭ 0.58; 95% CI, 0.36 to 0.93; P ϭ .023). The VEGF-1154 A allele also demonstrated a superior median OS with an additive effect of each active allele in the combination arm but not the control arm (hazard ratio ϭ 0.62; 95% CI, 0.46 to 0.83; P ϭ .001). Two additional genotypes, VEGF-634 CC and VEGF-1498 TT, were associated with significantly less grade 3 or 4 hypertension in the combination arm when compared with the alternate genotypes combined (P ϭ .005 and P ϭ .022, respectively). ConclusionOur data support an association between VEGF genotype and median OS as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer.

Triple-negative breast cancer has recently been recognized as an important subgroup of breast cancer with a distinct outcome and therapeutic approach when compared with other subgroups of breast cancer. Triple-negative breast cancer comprises primarily, but not exclusively, a molecularly distinct subtype of breast cancer, the basal-like subtype. We do not yet have an assay to identify basal-like breast cancer in clinical samples, so triple-negative breast cancer has become a commonly used proxy for this subtype. The molecular biology and pathophysiology of triplenegative breast cancer are not completely understood, but understanding is improving rapidly with the advent of sophisticated molecular biology platforms. Moreover, the established risk factors of breast cancer as a whole may not apply to this unique subgroup of patients. Finally, because triple-negative breast cancer is defined by the absence of a target, there are currently limitations to using a tailored therapeutic approach, leaving conventional cytotoxic therapies as the mainstay. Active preclinical and clinical research programs focus on defining the clinical behavior, delineating the risk factors, and more completely understanding the molecular biology of triple-negative breast cancer to improve prevention, optimize conventional agents, and unveil novel therapeutic targets. This CCR focus article will review the current state of the art on triplenegative breast cancer.Triple-negative breast cancer [estrogen receptor negative, progesterone receptor negative, human epidermal growth factor receptor 2 (HER2) negative] remains a major challenge to physicians and patients, and a source of great interest to laboratory investigators. Although triple-negative breast cancer accounts for a relatively small minority of breast cancer cases, it is responsible for a disproportionate number of breast cancer deaths. Moreover, there have been fewer advances in the treatment of triple-negative breast cancer than have been seen with other subtypes. For these reasons, new research initiatives for triple-negative breast cancer are critical. The investigation of triple-negative breast cancer is one facet of an emerging effort that regards breast cancer as a collection of separate diseases rather than a single heterogeneous entity, an important step toward the individualization of therapy (1). Here we attempt to (a) define triple-negative breast cancer and compare and contrast it with basal-like disease (a term frequently used interchangeably with triple-negative disease); (b) outline established and proposed risk factors; (c) review the molecular, pathologic, and clinical features of triple-negative disease; (d) provide an overview of ongoing therapeutic trials; and (e) suggest possible avenues for future research.Triple-Negative or Basal-like Breast Cancer: Which Is It?Triple-negative breast cancer has become a commonly used descriptor for malignancies that are estrogen receptor, progesterone receptor, and HER2 negative. The recent focus on this subgroup of...

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PURPOSE The Adjuvant Paclitaxel and Trastuzumab trial was designed to address treatment of patients with small human epidermal growth factor receptor 2 (HER2)–positive breast cancer. The primary analysis of the Adjuvant Paclitaxel and Trastuzumab trial demonstrated a 3-year disease-free survival (DFS) of 98.7%. In this planned secondary analysis, we report longer-term outcomes and exploratory results to characterize the biology of small HER2-positive tumors and genetic factors that may predispose to paclitaxel-induced peripheral neuropathy (TIPN). PATIENTS AND METHODS In this phase II study, patients with HER2-positive breast cancer with tumors 3 cm or smaller and negative nodes received paclitaxel (80 mg/m2) with trastuzumab for 12 weeks, followed by trastuzumab for 9 months. The primary end point was DFS. Recurrence-free interval (RFI), breast cancer–specific survival, and overall survival (OS) were also analyzed. In an exploratory analysis, intrinsic subtyping by PAM50 (Prosigna) and calculation of the risk of recurrence score were performed on the nCounter analysis system on archival tissue. Genotyping was performed to investigate TIPN. RESULTS A total of 410 patients were enrolled from October 2007 to September 2010. After a median follow-up of 6.5 years, there were 23 DFS events. The 7-year DFS was 93% (95% CI, 90.4 to 96.2) with four (1.0%) distant recurrences, 7-year OS was 95% (95% CI, 92.4 to 97.7), and 7-year RFI was 97.5% (95% CI, 95.9 to 99.1). PAM50 analyses (n = 278) showed that most tumors were HER2-enriched (66%), followed by luminal B (14%), luminal A (13%), and basal-like (8%). Genotyping (n = 230) identified one single-nucleotide polymorphism, rs3012437, associated with an increased risk of TIPN in patients with grade 2 or greater TIPN (10.4%). CONCLUSION With longer follow-up, adjuvant paclitaxel and trastuzumab is associated with excellent long-term outcomes. Distribution of PAM50 intrinsic subtypes in small HER2-positive tumors is similar to that previously reported for larger tumors.

Purpose Population-based studies have shown improved survival for patients diagnosed with metastatic breast cancer (MBC) over time, presumably due to the availability of new and more effective therapies. The objective of this analysis was to determine if survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy. Methods Adjuvant chemotherapy trials coordinated by the Eastern Cooperative Oncology Group (ECOG) that accrued patients between 1978–2002 were reviewed. Survival following distant recurrence was estimated for progressive time periods, and adjusted for baseline covariates in a Cox proportional hazards model. Results Of the 13,785 patients who received adjuvant chemotherapy in 11 trials, 3447 (24.4%) developed distant recurrence; median survival following recurrence was 20 months (95% confidence intervals: 19, 21). Factors associated with inferior survival included shorter distant recurrence free interval (DRFI), ER- and PR-negative disease number of positive axillary nodes at diagnosis and black race (p<0.0001 for all). When time-period of recurrence was added to the model, it was not significantly associated with survival for the general population with recurrence. Survival improved over time only in hormone-receptor negative patients with a DRFI ≤ 3 years, both among the 5 recent and entire trial datasets (p=0.01 and p=0.05 respectively). Conclusions In contrast to reports from population-based studies, we did not observe general improvement in survival over the last three decades for patients who developed distant recurrence after adjuvant chemotherapy after adjusting for DRFI. Improved survival for hormone-receptor negative patients with a short DRFI suggests benefit from trastuzumab.

The purpose of this study was to evaluate the preliminary efficacy and satisfaction/acceptability of training in memory or speed of processing versus wait-list control for improving cognitive function in breast cancer survivors. 82 breast cancer survivors completed a three-group randomized, controlled trial. Primary outcomes were objective neuropsychological tests of memory and speed of processing. Secondary outcomes were perceived cognitive functioning, symptom distress (mood disturbance, anxiety, and fatigue), quality of life, and intervention satisfaction/acceptability. Data were collected at baseline, post-intervention, and 2-month follow-up. Using repeated-measures mixed-linear ANCOVA models, each intervention was compared to wait-list control while adjusting for age, education, and baseline measures. The effect sizes for differences in means and the reliable improvement percentage were reported. The results show that domain-specific effects were seen for both interventions: memory training improved memory performance at 2-month follow-up (p = 0.036, d = 0.59); speed of processing training improved processing speed post-intervention (p = 0.040, d = 0.55) and 2-month follow-up (p = 0.016; d = 0.67). Transfer effects to non-trained domains were seen for speed of processing training with improved memory post-intervention (p = 0.007, d = 0.75) and 2-month follow-up (p = 0.004, d = 0.82). Both interventions were associated with improvements in perceived cognitive functioning, symptom distress, and quality of life. Ratings of satisfaction/acceptability were high for both interventions. It was concluded that while both interventions appeared promising, speed of processing training resulted in immediate and durable improvements in objective measures of processing speed and verbal memory. Speed of processing training may have broader benefits in this clinical population.