Preservation of quality of life in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer treated with tucatinib or placebo when added to trastuzumab and capecitabine (HER2CLIMB trial).

AIMS: In HER2CLIMB, tucatinib significantly improved progression-free and overall survival in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer. We evaluated the impact of tucatinib on health-related quality of life (HR-QoL) in HER2CLIMB. METHODS: Patients were randomised 2:1 to tucatinib or placebo combined with trastuzumab and capecitabine. Starting with protocol version 7, the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS) were administered at day 1 of cycle 1, every two cycles during cycles 3-9, every three cycles during cycle 12 and thereafter and at each patient's 30-day follow-up visit. RESULTS: Among 364 patients eligible for HR-QoL assessment, 331 (91%) completed ≥1 assessment. EQ-VAS scores were similar for both arms at baseline and maintained throughout treatment. EQ-5D-5L scores were similar between the treatment arms, stable throughout therapy and worsened after discontinuing treatment. Risk of meaningful deterioration (≥7 points) on EQ-VAS was reduced 19% in the tucatinib vs. placebo arm (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.55, 1.18); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.8 months (4.3, -) in the placebo arm. Among patients with brain metastases (n = 164), risk of meaningful deterioration on EQ-VAS was reduced 49% in the tucatinib arm (HR: 0.51; 95% CI: 0.28, 0.93); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.5 months (4.2, -) in the placebo arm. CONCLUSIONS: HR-QoL was preserved for patients with HER2+ metastatic breast cancer who were treated with tucatinib added to trastuzumab and capecitabine and maintained longer with tucatinib therapy than without it among those with brain metastases. CLINICAL TRIAL REGISTRATION: NCT02614794.

Expression of trefoil factor 3 is decreased in colorectal cancer.

In colorectal cancer (CRC), high expression of trefoil factor 3 (TFF3) is associated with tumor progression and reduced patient survival; however, bioinformatics analyses of public 'omics' databases show low TFF3 expression in CRCs as compared to normal tissues. Thus, we examined TFF3 expression in CRCs and matching normal tissues to evaluate its role in CRC progression. TFF3 gene expression was characterized using the bioinformatics portal UALCAN (http://ualcan.path.uab.edu). Tissue microarrays (TMAs) of archival CRC specimens (n=96) were immunostained with anti­human TFF3 antibodies. Immunohistochemical (IHC) staining intensity was semi­quantitatively scored. For this cohort, the median follow­up was 5.4 years. Associations between clinical and pathological variables were determined using Chi­square or Fisher's exact tests. Univariate disease­free survival was estimated by the Kaplan­Meier method. Omics data analyses by UALCAN showed downregulation of TFF3 expression in CRC relative to normal tissue at protein (χ2, P<0.0001) levels. There was a similar decreasing trend of TFF3 expression in the pathologic stages of the CRCs (RNA, χ2, P=0.88 and protein, χ2 P<0.0001). UALCAN data analysis showed that TFF3 exhibited 27% lower mRNA expression in tumors with mutant TP53 (P=0.007). Confirming the findings of omics analyses, IHC analysis of TMAs exhibited lower TFF3 expression in 95.6% (65 of 68) of the available normal­tumor matching pairs (χ2, P<0.0001). There was no statistically significant association of tumor TFF3 expression with patient sex, race/ethnicity, tumor location within the colorectum, Tumor, Node, Metastasis (TNM) stage, lymph node metastasis, or surgical margins. However, low TFF3 IHC staining in tumor tissue was associated with histological grade (P=0.026). Kaplan­Meier survival analysis showed no prognostic value of low TFF3 expression relative to those with high expression (log­rank, P=0.605). Our findings demonstrate low expression of TFF3 in CRCs. Association between low TFF3 and histopathological features suggests involvement of this molecule in progression of CRC.

Resistin: An inflammatory cytokine with multi-faceted roles in cancer.

Systemic and organ-confined inflammation has been associated with cancer development and progression. Resistin, initially described as an adipocyte-derived cytokine in mice, is mostly expressed by the macrophages in humans. It has potent pro-inflammatory properties, and its elevated serum levels are detected in cancer patients. Aberrant expression of resistin receptors is also reported in several malignancies and associated with aggressive clinicopathological features. Several lines of evidence demonstrate that resistin, acting through its different receptors, promotes tumor growth, metastasis, and chemoresistance by influencing a variety of cellular phenotypes as well as by modulating the tumor microenvironment. Racially disparate expression of resistin has also attracted much interest, considering prevalent cancer health disparities. This review discusses the aberrant expression of resistin and its receptors, its diverse downstream signaling and impact on tumor growth, metastasis, angiogenesis, and therapy resistance to support its clinical exploitation in biomarker and therapeutic development.

Inflammation, immunosuppressive microenvironment and breast cancer: opportunities for cancer prevention and therapy.

Breast cancer is the most commonly diagnosed malignancy and a leading cause of cancer-related death in women worldwide. It also exhibits pronounced racial disparities in terms of incidence and clinical outcomes. There has been a growing interest in research community to better understand the role of the microenvironment in cancer. Several lines of evidence have highlighted the significance of chronic inflammation at the local and/or systemic level in breast tumor pathobiology. Inflammation can influence breast cancer progression, metastasis and therapeutic outcome by establishing a tumor supportive immune microenvironment. These processes are mediated through a variety of cytokines and hormones that exert their biological actions either locally or distantly via systemic circulation. Targeting of immune and inflammatory pathways has met tremendous success in some cancers underscoring the importance of research to further our understanding of these systems in breast cancer. This knowledge can be helpful not only in the development of novel prevention and therapeutic strategies, but also help in better prediction of therapeutic responses in patients. This review summarizes some of the significant findings on the role of inflammation in breast cancer to gain collective molecular and mechanistic insights. We also discuss ongoing efforts and future outlook to exploit the existing knowledge for improved breast cancer management.

Genetic Mutations in B-Acute Lymphoblastic Leukemia Among African American and European American Children.

BACKGROUND: The survival of patients with B-acute lymphoblastic leukemia (B-ALL) is significantly lower in African American (AA) children compared with European American children (EA). Here, we present a whole exome sequencing (WES) study showing race-specific genetic variations that may play a role on the disparate outcomes among AA and EA children with B-ALL. PATIENTS AND METHODS: Five AA and 15 EA patients ranging in age from 1 to 18 years were enrolled. The median blast percentage was 94.8% (range, 64.5%-99.9%). Frozen bone marrow aspirate was used to extract DNA, and WES was performed, focusing on race and B-ALL-specific germline mutations. RESULTS: Most genetic variants (n = 339) were shared between AA and EA children. Some genetic aberrations were only uniquely identified in AA (n = 58) and others in EA (n = 52) In AA, the genetic aberrations clustered in canonical pathways related to telomerase signaling and cancer signaling. In EA, the unique genetic aberration clustered in pathways related to stem cell pluripotency and hereditary cancer. CONCLUSIONS: Our study revealed aberrant genetic aberrations in signaling networks that may contribute to race-specific aspects of leukemogenesis. Our results suggest the value of WES as a tool for development of individual gene signatures and gene scores for AA and EA children afflicted by B-ALL. These findings may ultimately impact disease management and contribute to the elimination of disparate outcomes in AA children with B-ALL.

An Abundance of Polyps: An Intriguing Case of Lymphomatous Polyposis.

Multiple lymphomatous polyposis (MLP) is a rare condition in which non-Hodgkin lymphoma (NHL), typically mantle cell lymphoma, presents as multiple mucosal polyps of the intestine. We present the case of a 66-year-old man who presented with newly acquired polyps throughout the colon, detected by endoscopy. Endoscopic biopsies confirmed the diagnosis of mantle cell lymphoma. The patient underwent treatment on a research protocol. Our case illustrates the importance of considering MLP or other forms of NHL in elderly patients found to have multiple gastrointestinal polyps, especially those who have a history of clear colonoscopy within the previous one to two years.