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Current methods of recording and reporting financial conflicts of interest are flawed and often result in inaccurate and inconsistent reporting by well‐intentioned individuals. To that end, this editorial identifies a number of specific current challenges for conflict‐of‐interest reporting along with potential solutions. [ABSTRACT FROM AUTHOR]

The author reflects on adjuvant hormonal therapy for treating premenopausal women with breast cancer. Topics include the prevalence of breast cancer cases in the U.S. in 2014 according to the American Cancer Society, the challenge of treating this type of cancer with tamoxifen and the role of aromatase inhibitors. Also discussed is chemotherapy induced amenorrhea.

Obesity is a leading modifiable risk factor for the development of several epithelial malignancies. In addition to increasing risk, obesity also confers worse prognosis for many cancers. Obesity represents an overall state of energy imbalance frequendy associated with systemic effects including insulin resistance, altered hormone signaling, and high circulating levels of proinflammatory mediators. In addition to its systemic effects, obesity causes subclinical white adipose inflammation including increased tissue levels of proinflammatory mediators. Both local and systemic effects are likely to contribute to the development and progression of cancer. An understanding of the interplay between local and systemic alterations involved in the obesity-cancer link provides the basis for developing interventions aimed at mitigating the protumorigenic effects. [ABSTRACT FROM AUTHOR]

Dose-dense chemotherapy has made a significant contribution to the adjuvant treatment of breast cancer. One way of achieving dose-density is through the use of sequential therapy with noncross resistant therapies to cause cell kill in tumors composed of heterogeneous cells. Another way to achieve this is to shorten the inter-treatment interval to minimize the re-growth of tumor cells, thus allowing for more effective cell killing. Several trials have tested this concept with the majority demonstrating improved efficacy with a dose-density when compared with the traditional schedule. One such notable trial was CALGB 9741 that showed that when dose size and cycle numbers were kept constant, shortening the interval between each chemotherapy dose, with granulocyte-colony stimulating factor support, significantly improved disease-free and overall survival. This important and practice-changing trial led to the wide adoption of dose-dense chemotherapy and formed the basis of many subsequent studies, including allowing for the addition of biologic and targeted agents with excellent safety profile. [ABSTRACT FROM AUTHOR]

The article discusses what a learning health care system looks like and the key features of a learning health care system in oncology. The efforts undertaken by the American Society of Clinical Oncology (ASCO) volunteers, led by an Advisory Committee and supported by expert staff and outside consultants, to build CancerLinQ, a learning information network for quality, are described. The need is to fully embrace the Institute of Management's (IOM's) vision for a learning health care system.

Cytochrome P450 aromatase (aromatase), a product of the CYP19 gene, catalyzes the synthesis of estrogens from androgens. Because aromatase-dependent estrogen biosynthesis has been linked to hormone-dependent breast carcinogenesis, it is important to elucidate the mechanisms that regulate CYP19 gene expression. The main objective of this study was to identify the receptors (EP) for prostaglandin E2 (PGE2) that mediate the induction of CYP19 transcription in human adipocytes and breast cancer cells. Treatment with PGE2 induced aromatase, an effect that was mimicked by either EP2 or EP4 agonists. Antagonists of EP2 or EP4 or small interference RNA-mediated down-regulation of these receptors suppressed PGE2-mediated induction of aromatase. PGE2 via EP2 and EP4 stimulated the cAMP->protein kinase A pathway resulting in enhanced interaction between P-CREB, p300, and the aromatase promoter I.3/II. Overexpressing a mutant form of p300 that lacks histone acetyltransferase activity suppressed PGE2-mediated induction of aromatase promoter activity. PGE2 via EP2 and EP4 also caused a reduction in both the amounts of BRCA1 and the interaction between BRCA1 and the aromatase promoter I.3/II. Activation of the aromatase promoter by PGE2 was suppressed by overexpressing wild-type BRCA1. Silencing of EP2 or EP4 also blocked PGE2-mediated induction of the progesterone receptor, a prototypic estrogen-response gene. In a mouse model, overexpressing COX-2 in the mammary gland, a known inducer of PGE2 synthesis, led to increased aromatase mRNA and activity and reduced amounts of BRCA1; these effects were reversed by knocking out EP2. Taken together, these results suggest that PGE2 via EP2 and EP4 activates the cAMP->PKA->CREB pathway leading to enhanced CYP19 transcription and increased aromatase activity. Reciprocal changes in the interaction between BRCA1, p300, and the aromatase promoter I.3/II contributed to the inductive effects of PGE2. [ABSTRACT FROM AUTHOR]

This article presents a review of the breast cancer medication trastuzumab, its mechanism of action and clinical value. In general, patients with breast-cancer cells that overexpress human epidermal growth factor receptor type 2 (HER2) have decreased overall survival and may have differential responses to treatment. Trastuzumab works by binding to the domain of HER2 and inhibiting the proliferation and survival of HER2-dependent tumors. Many studies of the drug are outlined. The most pivotal of all showed that the activity of trastuzumab in combination with chemotherapy was more effective than chemotherapy alone.

Taxanes are now routinely used in conjunction with radiation therapy (RT) as adjuvant therapy for breast cancer. Recent publications have reported several cases of radiation pneumonitis (RP) in patients receiving RT and taxane chemotherapy, thus raising concern as to the safety of this combination. To decrease the potential risk of RP, we sequenced RT after taxane chemotherapy with a target interval of 3–4 weeks in two consecutive institutional breast protocols. Forty patients were treated on two adjuvant systemic protocols consisting of modified radical mastectomy ( n = 9) or breast-conserving surgery ( n = 31), followed by adjuvant doxorubicin, cyclophosphamide, and a sequential taxane (ACT), followed by RT. All patients had either node-positive or high-risk node-negative breast cancer and were treated between October 2000 and September 2002. Postmastectomy, a median dose of 5040 cGy was delivered to the chest wall. After breast-conserving surgery, a median dose of 4680 cGy was delivered to the breast plus a 1400 cGy boost to the surgical cavity. Information regarding RP was gathered retrospectively by reviewing patient records. With a median follow-up of 28 months (range 6–42 months), no cases of clinical RP were identified and no local failures had occurred. The median time interval for all patients between the completion of chemotherapy and the initiation of RT was 34 days (range 5–70 days). At the latest follow-up, 2 patients were diagnosed with metastatic disease and 38 patients were without evidence of disease. Sequencing of RT after taxane therapy with a target interval of 3–4 weeks does not appear to result in increased pulmonary toxicity and is associated with good local control. [ABSTRACT FROM AUTHOR]

This article focuses on adjuvant breast cancer therapy. Increased early detection and improved treatment have made clinical cure possible for more patients with breast cancer than ever before. The medical oncologist contributes to this outcome through participation in the multidisciplinary care of patients with early stage disease and by providing systemic adjuvant therapy designed to treat undetectable metastatic foci of disease. The article reviews the metaanalyses performed every fifth year at Oxford University to provide a foundation for clinical practice, and clinical trials.

High-dose chemotherapy is based on the scientific hypothesis that escalating the dose of drug will overcome drug resistance and improve outcome. Autologous bone marrow transplantation and, more recently, peripheral stem cell transplantation used as a means to restore marrow, made this a viable treatment for patients with selected tumours such as haematological malignancies. The role in breast cancer is less certain. Given the known as well as the potential toxicities, the objective of high-dose chemotherapy should be cure as opposed to palliation. However, the natural history of breast cancer can be protracted, with relapses occurring 15–20 years after treatment or within months of curative surgery. In breast cancer there is a positive correlation between recurrence-free and long-term survival. Therefore, the recurrence-free survival can be considered a surrogate endpoint in clinical trials. In patients with metastatic disease where cure is rare, at best, duration of a disease-free state may be a surrogate for overall benefit. Alternatively, time to progression may be another endpoint in the evaluation of treatment for metastatic disease. This is based on the assumption that quality of life is enhanced without progression of disease. Toxicity is the significant issue in the use of high-dose chemotherapy. The most common toxicity is myeloablation, potentially requiring prolonged hospitalisation. The only justification for these toxicities would be evidence of significant and meaningful benefit. A clinically relevant benefit with high-dose chemotherapy has not been seen in major randomised clinical trials of breast cancer in both the adjuvant and metastatic setting. In patients with advanced breast cancer, a small percentage may achieve long-term, disease-free survival, although there is no improvement in overall survival. Nonetheless, some investigators believe that high-dose chemotherapy holds promise, although currently this treatment is not recommended outside of a well designed prospective trial. These studies have provided useful information regarding cancer treatment. However, ongoing study of drug administration intervals, that is, dose-dense therapies, may lead to an approach that allows superior and less toxic treatment for breast cancer. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignancy in women, affecting thousands of people each year. The majority of women are diagnosed with early stage breast cancer, which is curable. The follow-up care of the breast cancer survivor requires an understanding of the goals of follow-up and the short and long term side effects of breast cancer treatment. In this article, we will discuss the principles of follow-up care of the breast cancer survivor. [Copyright &y& Elsevier]

The author presents a commentary on a paper which reported that an erythropoiesis stimulation agent (ESA) can safely treat chemotherapy-induced anemia in patients with breast cancer receiving adjuvant therapy. A second randomization among patients in the intense dose-dense (IDD) arm to receive epoetin alfa (Epo) or not. The author highlights the insufficiency of the data provided by the research in support of the routine use of ESAs.

The article comments on studies on the use of taxanes to treat breast cancer and other solid tumors, including a study by M. Martin and colleagues on the use of adjuvant docetaxel for node-positive breast cancer. Martin's team compared the effectiveness of an anthracycline-containing regimen against a sequence of fluorouracil, epirubicin and cyclophoshphamide (FEC). The effects of the uses of paclitaxel and docetaxel are also discussed.

This article comments on preoperative chemotherapy for the treatment of breast cancer. Preoperative therapy has been shown to increase survival and control of the cancer in breast cancer but not in all forms of it. There are 3 subsets of patients for whom preoperative therapy is beneficial, including patients with inoperable breast cancer and those who are poor candidates for breast conservation because of the size of the tumor.

A reply by Clifford A. Hudis to letters to the editor about his article “Trastuzumab — mechanism of action and use in clinical practice” in the July 5, 2007 issue is presented.

The article reflects on the MINDACT trial which examined whether the 70-gene signature would reduce the use of adjuvant chemotherapy for breast cancer. It states that a high bar or a randomized design for the trial would be required to convince clinicians and patients that chemotherapy is not needed in healthy younger patients. It concludes that a team of well-coordinated and highly collaborative team of investigators can efficiently carry out a potentially practice-changing study.

Building on a foundation of clinical and laboratory observations, translational research, broad collaborations, and global education, adjuvant therapy for early-stage breast cancer has been an effective public health intervention. Standardization and even a one-size-fits-all philosophy were supported by individual trials and the worldwide overviews that showed proportional reductions in risk with chemotherapy in particular. Because higher risk, identified anatomically on the basis of tumor size or the presence of ipsilateral axillary nodal metastases, was associated with greater absolute therapeutic benefit, many clinical groups set risk thresholds, defined as a tumor size of 1 cm in the greatest dimension or any . . . [ABSTRACT FROM AUTHOR]

Background Bevacizumab is a humanised monoclonal antibody which blocks the binding of circulating vascular endothelial growth factor to its receptors. To date, the Food and Drug Administration has approved bevacizumab for the treatment of several solid tumours. To assess the impact of bevacizumab-based regimens on outcome in these advanced solid tumour types, we performed a meta-analysis. We included all of the randomised trials (phase II or III) where bevacizumab was tested in the first line setting compared with a control arm, including chemotherapy, placebo or other anti-neoplastic agents. Methods A literature-based meta-analysis of randomised controlled trials (RCTs) in accordance with the preferences for reported items in systematic reviews and meta-analyses guidelines were undertaken. The primary end-point considered was overall survival (OS). The secondary end-points were progression-free survival (PFS) time, response rate and safety. A subgroup analysis was performed to highlight any differences between studies in different tumour types for all end-points. Results The pooled analysis from RCTs on bevacizumab-based regimens revealed significantly increased OS (hazard ratio [HR] for death 0.92, 95% confidence interval [CI]: 0.88–0.95; P < 0.0001), PFS (HR: 0.72, 95% CI: 0.67–0.78; P < 0.00001) and response rate (risk ratio: 1.38, 95% CI: 1.27–1.50; P < 0.00001) compared to control arm in solid tumours overall and in colorectal, lung, ovarian and renal cancer as single indications. However, notably, no effect on survival was seen in breast cancer. Conclusion This study confirmed that bevacizumab-based regimens result in a significant effect on survival and response in advanced colorectal, lung, ovarian and kidney cancer. In cancers where bevacizumab failed overall as in breast cancer, a dedicated biomarkers analysis is warranted to select the proper subgroup of patient that might have the adequate clinical benefit. [ABSTRACT FROM AUTHOR]

A response by the author to a letter to the editor about his article "Health Care in the Age of Genetic Medicine," from the December 12, 2007 issue is presented.

Cyclooxygenase-2 (COX-2) and Id-1 are overexpressed in avariety of human malignancies. Recently, each of these genes was found to play a role in mediating breast cancer metastasis to the lungs, but their potential interdependence was not evaluated. Hence, the main objective of the current study was to determine whether COX-2-derived prostaglandin (PGE2) activated Id-1 transcription, leading in turn to increased invasiveness of mammary epithelial cells. In MDA-MB-231 cells, treatment with PGE2 induced Id-1, an effect that was mimicked by an EP4 agonist. PGE2 via EP4 activated the epidermal growth factor receptor (EGFR) → ERK1/2 pathway, which led to increased expression of Egr-1. PGE2 stimulated EGFR signaling by inducing the release of amphiregulin, an EGFR ligand. The ability of PGE2 to activate Id-1 transcription was mediated by enhanced binding of Egr-1 to the Id-1 promoter. Silencing of COX-2 or pharmacological inhibition of COX-2 led to reduced PGE2 production, decreased Id-1 expression, and reduced migration of cells through extracellular matrix. A similar decrease in cell migration was found when Id-1 was silenced. The interrelationship between COX-2, PGE2, Id-1, and cell invasiveness was also compared in nontumorigenic SCp2 and tumorigenic SCg6 mammary epithelial cells. Consistent with the findings in MDA-MB-231 cells, COX-2-derived PGE2 induced Id-1, leading in turn to increased cell invasiveness. Taken together, these results suggest that PGE2 via EP4 activated the EGFR → ERK1/2 → Egr-1 pathway, leading to increased Id-1 transcription and cell invasion. These findings provide new insights into the relationship between COX-2 and Id-1 and their potential role in metastasis. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To report on the longitudinal cognitive functioning of older women receiving adjuvant chemotherapy for breast cancer. DESIGN: Neuropsychological and functional status testing were performed before chemotherapy and 6 months after chemotherapy. SETTING: Cancer center. PARTICIPANTS: Thirty-one patients aged 65 and older with Stage I to III breast cancer. Of the 31 patients enrolled, three refused posttesting, and 28 were evaluable. MEASUREMENTS: The following domains of cognitive function were examined: attention; verbal memory; visual memory; and verbal, spatial, psychomotor, and executive functions. RESULTS: Participants had a mean age of 71 (range 65–84): 39% Stage I, 50% Stage II, and 11% Stage III. The number of scores 2 standard deviations (SDs) below the norm were calculated for each patient before and 6 months after chemotherapy; 14 (50%) had no change, 11 (39%) worsened, and three (11%) improved ( P=.05). Seven patients (25%) experienced a decline in cognitive function, defined as a 1-SD decline from pre- to posttesting in two or more neuropsychological domains. Exploratory analyses revealed no significant difference between functional status, comorbidity, and depression scale scores and change in overall quality-of-life scores before and after chemotherapy. CONCLUSION: In this cohort of older women receiving adjuvant chemotherapy, a subset experienced a decline in cognitive function from before chemotherapy to 6 months after chemotherapy. Further prospective study is needed to confirm these observations and to identify the subgroup at special risk. [ABSTRACT FROM AUTHOR]

Background: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.Methods: Serial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS.Results: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.Conclusions: We identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC. [ABSTRACT FROM AUTHOR]

Chemotherapy‐induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient‐reported outcome and (2) propose a dose‐adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose‐neuropathy model was developed using dosing and patient‐reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin–bound paclitaxel or ixabepilone as first‐line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose‐adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin–bound paclitaxel, and ixabepilone, simulations with the proposed dose‐adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient‐reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies. [ABSTRACT FROM AUTHOR]

A response by Jennifer A. Ligibel and colleagues to a letter to the editor about their article "Body Mass Index, PAM50 Subtype, and Outcomes in Node-Positive Breast Cancer: CALGB 9741," published in a previous issue is presented.

Microcalcifications (MCs) are routinely used to detect breast cancer in mammography. Little is known, however, about their materials properties and associated organic matrix, or their correlation to breast cancer prognosis. We combine histopathology, Raman microscopy, and electron microscopy to image MCs within snap-frozen human breast tissue and generate micron-scale resolution correlative maps of crystalline phase, trace metals, particle morphology, and organic matrix chemical signatures within high grade ductal carcinoma in situ (DCIS) and invasive cancer. We reveal the heterogeneity of mineral-matrix pairings, including punctate apatitic particles (<2 µm) with associated trace elements (e.g., F, Na, and unexpectedly Al) distributed within the necrotic cores of DCIS, and both apatite and spheroidal whitlockite particles in invasive cancer within a matrix containing spectroscopic signatures of collagen, non-collagen proteins, cholesterol, carotenoids, and DNA. Among the three DCIS samples, we identify key similarities in MC morphology and distribution, supporting a dystrophic mineralization pathway. This multimodal methodology lays the groundwork for establishing MC heterogeneity in the context of breast cancer biology, and could dramatically improve current prognostic models. [ABSTRACT FROM AUTHOR]

Background: The 21-gene recurrence score (RS) assay determines the benefit of adding chemotherapy to endocrine therapy for patients with early stage, estrogen receptor (ER)-positive, HER2-negative breast cancer. The RS risk groups predict the likelihood of distant recurrence and have recently been associated with an increased risk of locoregional recurrence (LRR). This study analyzed clinicopathologic features of patients with low RS and LRR.Methods: In our institutional database, we identified 1396 consecutive female patients with lymph node negative, ER+/HER2- invasive breast carcinoma and low RS (<18) results, treated at our center from 2008 to 2013. We collected data on clinicopathologic features, treatment and outcome.Results: The median patient age was 57 years (range 22-90). The median tumor size was 1.2 cm (range 0.3-5.8). Overall, 66.6% (930/1396) women were treated with breast conserving surgery (BCS) and radiation therapy, 3.4% (48/1396) with BCS alone, 29.7% (414/1396) with total mastectomy, and 0.3% (4/1396) with total mastectomy and radiation therapy. Most patients (84.8%; 1184/1396) received endocrine therapy alone, 12.1% (169/1396) were treated with chemotherapy plus endocrine therapy, and only 3.1% (43/1396) received no systemic therapy. At a median follow-up of 52 months, 0.9% (13/1396) of patients developed LRR. Sites of LRR included the ipsilateral breast (n = 8), chest wall (n = 3), axillary node (n = 1), and internal mammary node (n = 1). All patients with LRR had negative resection margins at the initial surgery. The rate of LRR in patients treated with adjuvant endocrine therapy alone was 0.7% (8/1184). All eight patients received standard local treatment. Three patients had lymphovascular invasion but no other significant risk factors for LRR were identified.Conclusions: Our study of node negative, ER+/HER2- breast cancer patients with low RS observed extremely low rates of LRR: 0.9% (13/1396) in the whole cohort and 0.7% (8/1184) in patients treated with endocrine therapy alone. As the largest series to date, we report detailed clinicopathologic data and clinical outcomes of this cohort and provide a comprehensive characterization of patients who developed LRR. [ABSTRACT FROM AUTHOR]

Background: Management of the axilla in stage II/III breast cancer undergoing neoadjuvant systemic therapy (NST) is controversial. To understand current patterns of care, we collected axillary data from 2 NST trials: HER2-positive (Cancer and Leukemia Group B [CALGB] 40601) and triple-negative (CALGB 40603).Study Design: Axillary evaluation pre- and post-NST was per the treating surgeon and could include sentinel node biopsy. Post-NST, node-positive patients were recommended to undergo axillary lymph node dissection (ALND). We report pre-NST histopathologic nodal evaluation and post-NST axillary surgical procedures with correlation to clinical and pathologic nodal status.Results: Seven hundred and forty-two patients were treated, 704 had complete nodal data pre-NST and post-NST. Pre-NST, 422 (60%) of 704 patients underwent at least 1 procedure for axillary node evaluation (total of 468 procedures): fine needle aspiration (n = 234; 74% positive), core needle biopsy (n = 138; 72% positive), and sentinel node biopsy (n = 96; 33% positive). Pre-NST, 304 patients were considered node-positive. Post-NST, 304 of 704 patients (43%) underwent sentinel node biopsy; 44 were positive and 259 were negative (29 and 36 patients, respectively, had subsequent ALND). Three hundred and ninety-one (56%) patients went directly to post-NST ALND and 9 (1%) pre-NST node-positive patients had no post-NST axillary procedure. Post-NST, 170 (24%) of the 704 patients had residual axillary disease. Agreement between post-NST clinical and radiologic staging and post-NST histologic staging was strongest for node-negative (81%) and weaker for node-positive (N1 31%, N2 29%), with more than half of the clinically node-positive patients found to be pathologic negative (p < 0.001).Conclusions: Our results suggest there is no widely accepted standard for axillary nodal evaluation pre-NST. Post-NST staging was highly concordant in patients with N0 disease, but poorly so in node-positive disease. Accurate methods are needed to identify post-NST patients without residual axillary disease to potentially spare ALND. [ABSTRACT FROM AUTHOR]

BACKGROUND A 21-gene expression assay (Oncotype DX recurrence score [RS]) that uses reverse transcriptase-polymerase chain reaction is used clinically in patients with early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinoma (ER+/HER2- BC) to determine both prognosis with tamoxifen therapy and the usefulness of adding adjuvant chemotherapy. Use of the assay is associated with reductions in overall chemotherapy use. The current study examined the treatments and outcomes in patients with low RS. METHODS The authors reviewed the institutional database to identify patients with lymph node-negative, ER+/HER2- BC who were treated at the study institution between September 2008 and August 2013 and their 21-gene RS results. RESULTS A total of 1406 consecutive patients with lymph node-negative ER+/HER2- BC and a low RS were identified (510 patients had an RS of 0-10 and 896 patients had an RS of 11-17). The median age at the time of diagnosis of BC was 56 years; 63 patients (4%) were aged <40 years. Overall, 1361 patients (97%) received endocrine therapy and 170 patients (12%) received chemotherapy. The median follow-up was 46 months. Six patients (0.4%) developed distant metastases (1 patient with an RS of 5 and 5 patients with an RS of 11-17). In the cohorts of patients with an RS of 11 to 17, the absolute rate of distant metastasis among patients aged <40 years was 7.1% (3 of 42 patients) versus 0.2% among patients aged ≥40 years (2 of 854 patients). CONCLUSIONS The data from the current study document a 0.4% rate of distant metastasis within 5 years of BC diagnosis among patients with lymph node-negative ER+/HER2- BC with an RS <18. Patients aged <40 years at the time of BC diagnosis were observed to have a higher rate of distant metastases. Analysis of data from other studies is necessary to validate this observation further. Cancer 2017;131-137. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with increased adipose tissue in the tongue. Chronic white adipose tissue (WAT) inflammation commonly occurs in the obese. We investigated whether WAT inflammation in the tongue impacts survival in patients with squamous cell carcinoma (SCC) of the oral tongue.Methods: In a retrospective cohort study, patients with T1 and T2 SCC of the oral tongue who underwent curative-intent resection were included. Tongue WAT inflammation was defined by the presence of dead or dying adipocytes surrounded by macrophages forming crown-like structures. The primary and secondary endpoints were disease-specific survival (DSS) and overall survival (OS), respectively. Subgroup analyses were carried out in patients without lymph node involvement for whom adjuvant therapies were not indicated.Results: Archived tissue was available from 125 patients. The median follow-up was 55 months (range, 3-156 months). Overall, 49 of 125 patients (39%) had tongue WAT inflammation, which was associated with higher body mass index, increased tumor thickness, and vascular invasion (P < .05). The 3-year DSS rate for patients with tongue WAT inflammation was 59% (95% confidence interval [CI], 46%-76%) versus 82% (95% CI, 73%-92%) for those without inflammation. For patients without lymph node involvement for whom adjuvant therapy was not indicated (N = 70), tongue WAT inflammation was associated with shortened DSS and OS (P < .05). When adjusted for body mass index and potential prognostic covariates, the hazard ratio for DSS and OS was 5.40 (95% CI, 1.20-24.26) and 2.97 (95% CI, 1.02-8.65), respectively.Conclusions: Tongue WAT inflammation is associated with worse DSS and OS in patients who have early stage SCC of the oral tongue. Cancer 2016;122:3794-3802. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Ixabepilone (Ixempra; Bristol-Myers Squibb), a cytotoxic microtubule inhibitor, was approved by the US FDA for the treatment of metastatic breast cancer in October 2007. It is the first member of the epothilone family of anticancer agents to be approved. [ABSTRACT FROM AUTHOR]

Background: Biological differences between BRCA-associated breast cancer and sporadic breast cancer may warrant different adjuvant chemotherapy (ACRx) recommendations despite similar phenotypic features. A 21-gene expression profile (Oncotype DX) generates a prognostic recurrence score (RS) that predicts the ACRx benefit in patients with hormone receptor-positive breast cancer. No reports describe assay results for BRCA-associated breast cancer.Methods: A review of Memorial Sloan Kettering Cancer Center databases identified 4908 patients with hormone receptor-positive, node-negative breast cancer who underwent Oncotype DX testing between July 2006 and March 2014. BRCA1/BRCA2 carriers (cases) were identified and matched (1:2) by age at diagnosis and tumor size to noncarrier controls. Two-sample nonparametric tests were used to compare the baseline characteristics, RSs, and risk stratification between BRCA1 and BRCA2 patients. Conditional logistic regression was used to assess these differences by mutational status.Results: Fifty mutation-associated cases (19 BRCA1 cases and 31 BRCA2 cases) and 100 controls who were well matched for age (P = .9) and tumor size (P = .6) were included. BRCA1 and BRCA2 carriers had similar median RSs (P = .6) and risk category stratification (P = .3). The median RS was higher for cases versus controls (24 vs 16; P < .0001). Risk stratification also differed by mutational status (P = .0002). Cases had more high-risk disease (28% vs 7%) and intermediate-risk disease (56% vs 36%) and less low-risk disease (16% vs 57%). Cases were more likely than controls to receive ACRx (74% vs 46%; P = .002).Conclusions: Germline BRCA-associated hormone receptor-positive breast cancer may be associated with intrinsically less favorable biology. Few affected carriers have RS indicating a clear absence of benefit from ACRx. The increased use of ACRx and benefit from ACRx in BRCA carriers may mitigate otherwise inferior outcomes. [ABSTRACT FROM AUTHOR]

White adipose tissue inflammation (WATi) has been linked to the pathogenesis of obesity-related diseases, including type 2 diabetes, cardiovascular disease, and cancer. In addition to the obese, a substantial number of normal and overweight individuals harbor WATi, putting them at increased risk for disease. We report the first technique that has the potential to detect WATi noninvasively. Here, we used Raman spectroscopy to detect WATi with excellent accuracy in both murine and human tissues. This is a potentially significant advance over current histopathological techniques for the detection of WATi, which rely on tissue excision and, therefore, are not practical for assessing disease risk in the absence of other identifying factors. Importantly, we show that noninvasive Raman spectroscopy can diagnose WATi in mice. Taken together, these results demonstrate the potential of Raman spectroscopy to provide objective risk assessment for future cardiometabolic complications in both normal weight and overweight/obese individuals. [ABSTRACT FROM AUTHOR]

Purpose: To determine if the histology of a breast malignancy influences the appearance of untreated osseous metastases on FDG PET/CT. Methods: This retrospective study was performed under IRB waiver. Our Hospital Information System was screened for breast cancer patients who presented with osseous metastases, who underwent FDG PET/CT prior to systemic therapy or radiotherapy from 2009 to 2012. Patients with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), or mixed ductal/lobular (MDL) histology were included. Patients with a history of other malignancies were excluded. PET/CT was evaluated, blinded to histology, to classify osseous metastases on a per-patient basis as sclerotic, lytic, mixed lytic/sclerotic, or occult on CT, and to record SUVmax for osseous metastases on PET. Results: Following screening, 95 patients who met the inclusion criteria (74 IDC, 13 ILC, and 8 MDL) were included. ILC osseous metastases were more commonly sclerotic and demonstrated lower SUVmax than IDC metastases. In all IDC and MDL patients with osseous metastases, at least one was FDG-avid. For ILC, all patients with lytic or mixed osseous metastases demonstrated at least one FDG-avid metastasis; however, in only three of seven patients were sclerotic osseous metastases apparent on FDG PET. Conclusion: The histologic subtype of breast cancer affects the appearance of untreated osseous metastases on FDG PET/CT. In particular, non-FDG-avid sclerotic osseous metastases were more common in patients with ILC than in patients with IDC. Breast cancer histology should be considered when interpreting non-FDG-avid sclerotic osseous lesions on PET/CT, which may be more suspicious for metastases (rather than benign lesions) in patients with ILC. [ABSTRACT FROM AUTHOR]

Background: Obesity at diagnosis is associated with poor prognosis in women with breast cancer, but few reports have been adjusted for treatment factors.Methods: CALGB 9741 was a randomized trial of dose density and sequence of chemotherapy for node-positive breast cancer. All patients received doxorubicin, cyclophosphamide, and paclitaxel, dosed by actual body weight. Height and weight at diagnosis were abstracted from patient records, and the PAM50 assay was performed from archived specimens using the NanoString platform. Relationships between body mass index (BMI), PAM50, and recurrence-free and overall survival (RFS and OS) were evaluated using proportional hazards regression, adjusting for number of involved nodes, estrogen receptor (ER) status, tumor size, menopausal status, drug sequence, and dose density. All statistical tests were two-sided.Results: Baseline height and weight were available for 1909 of 2005 enrolled patients; 1272 additionally had subtype determination by PAM50. Median baseline BMI was 27.4kg/m(2). After 11 years of median follow-up, there were 619 RFS events and 543 deaths. Baseline BMI was a statistically significant predictor of RFS (adjusted hazard ratio [HR] for each five-unit increase in BMI = 1.08, 95% confidence interval [CI] = 1.02 to 1.14, P = .01) and OS (adjusted HR = 1.08, 95% CI = 1.01 to 1.14, P = .02) BMI and molecular phenotypes were independent prognostic factors for RFS, with no statistically significant interactions detected.Conclusions: BMI at diagnosis was a statistically significant prognostic factor in a group of patients receiving optimally dosed chemotherapy. Additional research is needed to determine the impact of weight loss on breast cancer outcomes and to evaluate whether this impact is maintained across tumor subtypes. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the treatment of human epidermal growth factor receptor type 2 (HER2)-positive breast cancer using adjuvant paclitaxel and trastuzumab. Topics discussed include the risk of early cancer recurrence, effectiveness and adverse events associated with the adjuvant therapy, and the rate of survival free from the disease.

Background In breast cancer studies, many different endpoints are used. Definitions are often not provided or vary between studies. For instance, "local recurrence" may include different components in similar studies.This limits transparency and comparability of results.This project aimed to reach consensus on the definitions of local event, second primary breast cancer, regional and distant event for breast cancer studies. Methods The RAND-UCLA Appropriateness method (modified Delphi method) was used. A Consensus Group of international breast cancer experts was formed, including representatives of all involved clinical disciplines. Consensus was reached in two rounds of online questionnaires and one meeting. Results Twenty-four international breast cancer experts participated. Consensus was reached on 134 items in four categories. Local event is defined as any epithelial breast cancer or ductal carcinoma in situ (DCIS) in the ipsilateral breast, or skin and subcutaneous tissue on the ipsilateral thoracic wall. Second primary breast cancer is defined as epithelial breast cancer in the contralateral breast. Regional events are breast cancer in ipsilateral lymph nodes. A distant event is breast cancer in any other location. Therefore, this includes metastasis in contralateral lymph nodes and breast cancer involving the sternal bone. If feasible, tissue sampling of a first, solitary, lesion suspected for metastasis is highly recommended. Conclusion This project resulted in consensus-based event definitions for classification of recurrence in breast cancer research. Future breast cancer research projects should adopt these definitions to increase transparency. This should facilitate comparison of results and conducting reviews as well as meta-analysis. [ABSTRACT FROM AUTHOR]

Background In breast cancer studies, many different endpoints are used. Definitions are often not provided or vary between studies. For instance, "local recurrence" may include different components in similar studies. This limits transparency and comparability of results. This project aimed to reach consensus on the definitions of local event, second primary breast cancer, regional and distant event for breast cancer studies. Methods The RAND-UCLA Appropriateness method (modified Delphi method) was used. A Consensus Group of international breast cancer experts was formed, including representatives of all involved clinical disciplines. Consensus was reached in two rounds of online questionnaires and one meeting. Results Twenty-four international breast cancer experts participated. Consensus was reached on 134 items in four categories. Local event is defined as any epithelial breast cancer or ductal carcinoma in situ (DCIS) in the ipsilateral breast, or skin and subcutaneous tissue on the ipsilateral thoracic wall. Second primary breast cancer is defined as epithelial breast cancer in the contralateral breast. Regional events are breast cancer in ipsilateral lymph nodes. A distant event is breast cancer in any other location. Therefore, this includes metastasis in contralateral lymph nodes and breast cancer involving the sternal bone. If feasible, tissue sampling of a first, solitary, lesion suspected for metastasis is highly recommended. Conclusion This project resulted in consensus-based event definitions for classification of recurrence in breast cancer research. Future breast cancer research projects should adopt these definitions to increase transparency. This should facilitate comparison of results and conducting reviews as well as meta-analysis. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated associations among comorbidity, toxicity, time to relapse (TTR), and overall survival (OS) in older women with early-stage breast cancer receiving adjuvant chemotherapy. Methods: Cancer and Leukemia Group B 49907 (Alliance) randomly assigned women 65 years old with stages I-III breast cancer to standard adjuvant chemotherapy or capecitabine. We reviewed data from 329 women who participated in the quality of life companion study CALGB 70103 and completed the Physical Health Subscale of the Older American Resources and Services Questionnaire. This questionnaire captures data on 14 comorbid conditions and the degree to which each interferes with daily activities. A comorbidity burden score was computed by multiplying the total number of conditions by each condition's level of interference with function. Outcomes were grade 3 to 5 toxicity, TTR, and OS. Logistic regression was used to evaluate associations between comorbidity and toxicity, and Cox proportional hazards models for TTR and survival. Results: Number of comorbidities ranged from 0 to 10 (median 2); the comorbidity burden score ranged from 0 to 25 (median 3). The most common conditions were arthritis (58%) and hypertension (55%). Comorbidity was associated with shorter OS, but not with toxicity or TTR. The hazard of death increased by 18% for each comorbidity (hazard ratio [HR]=1.18, 95% CI=1.06 to 1.33) after adjusting for age, tumor size, treatment, node and receptor status. Comorbidity burden score was similarly associated with OS (HR=1.08; 95% CI, 1.03 to 1.14). Conclusions: Among older women enrolled onto a clinical trial, comorbidity was associated with shorter OS, but not toxicity or relapse. [ABSTRACT FROM AUTHOR]

Aims Radiation Therapy Oncology Group 98-04 sought to identify women with 'good risk' ductal carcinoma in situ (DCIS) who receive no significant benefit from radiation. Enrolment criteria excluded close or positive margins and grade 3 disease. To ensure reproducibility in identifying good risk pathology, an optional web based teaching tool was developed and a random sampling of 10% of submitted slides were reviewed by a central pathologist. Methods Submitting pathologists were asked to use the web based teaching tool and submit an assessment of the tool along with the pathology specimen form and DCIS H&E stained slide. Per protocol pathology was centrally reviewed for 10% of the cases. Results Of the 55 DCIS cases reviewed, three had close or positive margins and three were assessed to include grade 3 DCIS, therefore 95% of DCIS cases reviewed were correctly graded, and 89% reviewed were pathologically appropriate for enrolment. Regarding the teaching tool, 13% of DCIS cases included forms that indicated the website was used. One of these seven who used the website submitted DCIS of grade 3. Conclusions Central review demonstrates high pathological concordance with enrolment eligibility, particularly with regard to accurate grading. The teaching tool appeared to be underused. [ABSTRACT FROM AUTHOR]

BACKGROUND Although obesity increases risk and negatively affects survival for many malignancies, the prognostic implications in squamous cell carcinoma (SCC) of the oral tongue, a disease often associated with prediagnosis weight loss, are unknown. METHODS Patients with T1-T2 oral tongue SCC underwent curative-intent resection in this single-institution study. All patients underwent nutritional assessment prior to surgery. Body mass index (BMI) was calculated from measured height and weight and categorized as obese (≥ 30 kg/m2), overweight (25-29.9 kg/m2), or normal (18.5-24.9 kg/m2). Clinical outcomes, including disease-specific survival, recurrence-free survival, and overall survival, were compared by BMI group using Cox regression. RESULTS From 2000 to 2009, 155 patients (90 men, 65 women) of median age 57 years (range, 18-86 years) were included. Baseline characteristics were similar by BMI group. Obesity was significantly associated with adverse disease-specific survival compared with normal weight in univariable (hazard ratio [HR] = 2.65, 95% confidence interval [CI] = 1.07-6.59; P = .04) and multivariable analyses (HR = 5.01; 95% CI = 1.69-14.81; P = .004). A consistent association was seen between obesity and worse recurrence-free survival (HR = 1.87; 95% CI = 0.90-3.88) and between obesity and worse overall survival (HR = 2.03; 95% CI = 0.88-4.65) though without reaching statistical significance ( P = .09 and P = .10, respectively) in multivariable analyses. CONCLUSIONS In this retrospective study, obesity was an adverse independent prognostic variable. This association may not have been previously appreciated due to confounding by multiple factors including prediagnosis weight loss. Cancer 2014;120:983-991. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Seventy percent of breast cancers express estrogen receptor (ER), and most of these are sensitive to ER inhibition. However, many such tumors for unknown reasons become refractory to inhibition of estrogen action in the metastatic setting. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases. These included highly recurrent mutations encoding p.Tyr537Ser, p.Tyr537Asn and p.Asp538Gly alterations. Molecular dynamics simulations suggest that the structures of the Tyr537Ser and Asp538Gly mutants involve hydrogen bonding of the mutant amino acids with Asp351, thus favoring the agonist conformation of the receptor. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists. These data implicate LBD-mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may be of substantial therapeutic benefit. [ABSTRACT FROM AUTHOR]

BACKGROUND The authors have previously reported 2 consecutive phase 2 trials in patients with early breast cancer that overexpresses human epidermal growth factor receptor 2 ( HER2) to assess the feasibility of incorporating anti-HER2 therapies into dose-dense (dd) chemotherapy regimens. The incidence of congestive heart failure (CHF) at a median follow-up of 2 years was 1.4% and 3.2%, respectively. METHODS In trial A, patients received dd doxorubicin and cyclophosphamide (AC)→paclitaxel (T) (each given every 2 weeks) × 4 with trastuzumab (H) given × 1 year. In trial B, weekly T (weekly × 12) was substituted for ddT and lapatinib × 1 year was added. Herein, the authors report the longer-term incidence of CHF and distant disease-free survival (DDFS). RESULTS From January 2005 to May 2008, 165 patients enrolled (median age, 46 years, with a median left ventricular ejection fraction of 68% [range, 52%-81%]), 17%of whom had previous hypertension. With a median follow-up of 84 months (trial A) and 57 months (trial B), 1 additional patient developed CHF. Therefore, the cumulative incidence of CHF was 1.4% (95% confidence interval [95% CI], 1.36%-7.7%) for trial A and 4.2% (95% CI, 4.2%-10.4%) for trial B. The 5-year DDFS for trials A and B was 92% (95% CI, 83%-97%) and 89% (95% CI, 81%-94%), respectively. CONCLUSIONS Longer follow-up of these 2 studies has demonstrated that ddAC→TH only or with lapatinib is associated with a low risk of CHF and promising DDFS in patients with early breast cancer. Cancer 2013;119:3943-3951. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Highlights: [•] Knocking out mPGES-1 suppresses mouse mammary tumor growth. [•] Angiogenesis is reduced by genetic ablation of mPGES-1. [•] Aromatase activity is substantially reduced in mPGES-1-deficient mammary glands. [ABSTRACT FROM AUTHOR]

Background: Sorafenib is an oral multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized phase 2b screening trial in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer demonstrated a significant improvement in progression-free survival (PFS) when sorafenib was added to capecitabine versus placebo (median 6.4 versus 4.1 months; hazard ratio = 0.58; P = 0.001). Most drug-related adverse events were Grade 1/2 in severity with the exception of Grade 3 hand-foot skin reaction/syndrome (44% versus 14%, respectively). These results suggest a role for the combination of sorafenib and capecitabine in breast cancer and supported a phase 3 confirmatory trial. Here we describe RESILIENCE - a multinational, double-blind, randomized, placebo-controlled, phase 3 trial - assessing the addition of sorafenib to first- or second-line capecitabine in advanced HER2-negative breast cancer. Methods/design: Eligibility criteria include ⩾18 years of age, ⩽1 prior chemotherapy regimen for metastatic disease, and resistant to/failed taxane and anthracycline or no indication for further anthracycline. Prior treatment with a vascular endothelial growth factor inhibitor is not allowed. Patients with significant cardiovascular disease or active brain metastases are not eligible. Patients are stratified by hormone-receptor status, geographic region, and prior metastatic chemotherapy status and randomized (1:1) to capecitabine (1000 mg/m2 orally twice daily (BID), days 1 to 14 of 21) in combination with sorafenib (orally BID, days 1 to 21, total dose 600 mg/day) or matching placebo. Capecitabine and sorafenib/placebo doses can be escalated to 1250 mg/m2 BID and 400 mg BID, respectively, as tolerated, or reduced to manage toxicity. Dose re-escalation after a reduction is allowed for sorafenib/placebo but not for capecitabine. This dosing algorithm was designed to mitigate dermatologic and other toxicity, in addition to detailed guidelines for prophylactic and symptomatic treatment. Radiographic assessment is every 6 weeks for 36 weeks, and every 9 weeks thereafter. The primary endpoint is PFS by blinded independent central review (Response Evaluation Criteria in Solid Tumors 1.1 criteria). Secondary endpoints include overall survival, time to progression, overall response rate, duration of response, and safety. Enrollment began in November 2010 with a target of approximately 519 patients Discussion: RESILIENCE will provide definitive PFS data for the combination of sorafenib and capecitabine in advanced HER2-negative breast cancer and better characterize the benefit-to-risk profile. Trial registration: Clinicaltrials.gov, NCT01234337 [ABSTRACT FROM AUTHOR]

Background: Current treatments for lymphedema after breast cancer treatment are expensive and require ongoing intervention. Clinical experience and our preliminary published results suggest that acupuncture is safe and potentially useful. This study evaluates the safety and potential efficacy of acupuncture on upper-limb circumference in women with lymphedema.Methods: Women with a clinical diagnosis of breast cancer-related lymphedema (BCRL) for 0.5-5 years and with affected arm circumference ≥2 cm larger than unaffected arm received acupuncture treatment twice weekly for 4 weeks. Affected and unaffected arm circumferences were measured before and after each acupuncture treatment. Response, defined as ≥30% reduction in circumference difference between affected/unaffected arms, was assessed. Monthly follow-up calls for 6 months thereafter were made to document any complications and self-reported lymphedema status.Results: Among 37 enrolled patients, 33 were evaluated; 4 discontinued due to time constraints. Mean reduction in arm circumference difference was 0.90 cm (95% CI, 0.72-1.07; P < .0005). Eleven patients (33%) exhibited a reduction of ≥30% after acupuncture treatment. Seventy-six percent of patients received all treatments; 21% missed 1 treatment, and another patient missed 2 treatments. During the treatment period, 14 of the 33 patients reported minor complaints, including mild local bruising or pain/tingling. There were no serious adverse events and no infections or severe exacerbations after 255 treatment sessions and 6 months of follow-up interviews.Conclusions: Acupuncture for BCRL appears safe and may reduce arm circumference. Although these results await confirmation in a randomized trial, acupuncture can be considered for women with no other options for sustained arm circumference reduction. [ABSTRACT FROM AUTHOR]