Gary N. Schwartz

Longitudinal Assessment of Cognitive Changes Associated With Adjuvant Treatment for Breast Cancer: Impact of Age and Cognitive Reserve

PURPOSE To examine the impact of age and cognitive reserve on cognitive functioning in patients with breast cancer who are receiving adjuvant treatments. PATIENTS AND METHODS Patients with breast cancer exposed to chemotherapy (n = 60; mean age, 51.7 years) were evaluated with a battery of neuropsychological and psychological tests before treatment and at 1, 6, and 18 months after treatment. Patients not exposed to chemotherapy (n = 72; mean age, 56.6 years) and healthy controls (n = 45; mean age, 52.9 years) were assessed at matched intervals. RESULTS Mixed-effects modeling revealed significant effects for the Processing Speed and Verbal Ability domains. For Processing Speed, a three-way interaction among treatment group, age, and baseline cognitive reserve (P < .001) revealed that older patients with lower baseline cognitive reserve who were exposed to chemotherapy had lower performance on Processing Speed compared with patients not exposed to chemotherapy (P = .003) and controls (P < .001). A significant group by time interaction for Verbal Ability (P = .01) suggested that the healthy controls and no chemotherapy groups improved over time. The chemotherapy group failed to improve at 1 month after treatment but improved during the last two follow-up assessments. Exploratory analyses suggested a negative effect of tamoxifen on Processing Speed (P = .036) and Verbal Memory (P = .05) in the no-chemotherapy group. CONCLUSION These data demonstrated that age and pretreatment cognitive reserve were related to post-treatment decline in Processing Speed in women exposed to chemotherapy and that chemotherapy had a short-term impact on Verbal Ability. Exploratory analysis of the impact of tamoxifen suggests that this pattern of results may be due to a combination of chemotherapy and tamoxifen.

Evaluation of Breast Tumor Response to Neoadjuvant Chemotherapy with Tomographic Diffuse Optical Spectroscopy: Case Studies of Tumor Region-of-Interest Changes

PURPOSE To evaluate two methods of summarizing tomographic diffuse optical spectroscopic (DOS) data through region-of-interest (ROI) analysis to differentiate complete from incomplete responses in patients with locally advanced breast cancer undergoing neoadjuvant treatment and to estimate the standard deviations of these methods for power analysis of larger study designs in the future. MATERIALS AND METHODS Subjects participating in the HIPAA-compliant imaging study, approved by the institutional review board, provided written informed consent and were compensated for their examination participation. Seven of 16 cases in women with complete study data were analyzed by using both fixed- and variable-size (full-width-at-half-maximum) ROI measures of the DOS total hemoglobin concentration (Hb(T)), blood oxygen saturation, water fraction, optical scattering amplitude, and scattering power in the ipsilateral and contralateral breasts. Postsurgical histopathologic analysis was used to categorize patients as having a complete or incomplete treatment response. RESULTS Average normalized change in Hb(T) was the only DOS parameter to show significant differences (P < or = .05) in the pathologic complete response (pCR) and pathologic incomplete response (pIR) outcomes in seven patients. Mean values of the changes for fixed-size ROIs were -64.2% +/- 50.8 (standard deviation) and 16.9% +/- 38.2 for the pCR and pIR groups, respectively, and those for variable-size ROIs were -96.7% +/- 91.8, and 14.1% +/- 26.7 for the pCR and pIR groups, respectively. CONCLUSION Tomographic DOS may provide findings predictive of therapeutic response, which could lead to superior individualized patient treatment. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/2522081202/DC1.

Microwave imaging for neoadjuvant chemotherapy monitoring: initial clinical experience

IntroductionMicrowave tomography recovers images of tissue dielectric properties, which appear to be specific for breast cancer, with low-cost technology that does not present an exposure risk, suggesting the modality may be a good candidate for monitoring neoadjuvant chemotherapy.MethodsEight patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer were imaged longitudinally five to eight times during the course of treatment. At the start of therapy, regions of interest (ROIs) were identified from contrast-enhanced magnetic resonance imaging studies. During subsequent microwave examinations, subjects were positioned with their breasts pendant in a coupling fluid and surrounded by an immersed antenna array. Microwave property values were extracted from the ROIs through an automated procedure and statistical analyses were performed to assess short term (30 days) and longer term (four to six months) dielectric property changes.ResultsTwo patient cases (one complete and one partial response) are presented in detail and demonstrate changes in microwave properties commensurate with the degree of treatment response observed pathologically. Normalized mean conductivity in ROIs from patients with complete pathological responses was significantly different from that of partial responders (P value = 0.004). In addition, the normalized conductivity measure also correlated well with complete pathological response at 30 days (P value = 0.002).ConclusionsThese preliminary findings suggest that both early and late conductivity property changes correlate well with overall treatment response to neoadjuvant therapy in locally advanced breast cancer. This result is consistent with earlier clinical outcomes that lesion conductivity is specific to differentiating breast cancer from benign lesions and normal tissue.

Expression of "Spot 14" (THRSP) predicts disease free survival in invasive breast cancer: immunohistochemical analysis of a new molecular marker.

SummaryMost breast cancers are “lipogenic”, defined by high fatty acid synthase (FAS) content and dependence on fatty acid synthesis for growth and survival. S14 (Spot 14; THRSP) is a nuclear protein that activates genes required for fatty acid synthesis. The S14 gene is amplified in ~15% of breast cancers, but clinical correlates of its expression were unknown. We analyzed 131 breast cancers by immunohistochemistry for S14 and FAS. Staining was graded 0, 1, or 2+, and scores were correlated with traditional tumor markers, histological features, and outcome. S14 and FAS staining were related to tumor size (p=0.05 for S14, p=0.038 for FAS), but not to stage. S14 but not FAS scores correlated with tumor grade in both DCIS (p=0.003) and invasive cases (p<0.001). Invasive cases (pooled node − and +) with weak S14 staining (n=21) showed no recurrence over 3000 d follow-up, including 10 cases with lymph node involvement, whereas 32% of 67 strongly-staining tumors recurred (log rank p<0.0001). S14 scores did not cosegregate with sex steroid receptors, Her2/neu, or cyclin D1. Low level S14 expression is associated with prolonged disease-free survival in invasive cases, including those with nodal metastasis. High-level expression of S14 identifies a subset of high-risk breast cancers that is not specified by analysis of sex steroid receptors, Her2/neu, or cyclin D1, and provides a molecular correlate to histologic features that predict recurrence.

Quality of life among patients with stage II and III breast carcinoma randomized to receive high-dose chemotherapy with autologous bone marrow support or intermediate-dose chemotherapy : Results from cancer and leukemia group B 9066

The objective of this study was to compare the quality of life (QOL) after treatment among patients who had breast carcinoma with multiple positive lymph nodes. The patients were randomized to receive either high‐dose chemotherapy with autologous stem cell support (HDC) or intermediate‐dose chemotherapy (IDC) in the adjuvant setting.

ΔNp63α-Mediated Activation of Bone Morphogenetic Protein Signaling Governs Stem Cell Activity and Plasticity in Normal and Malignant Mammary Epithelial Cells

Genetic analysis of TP63 indicates that ΔNp63 isoforms are required for preservation of regenerative stasis within diverse epithelial tissues. In squamous carcinomas, TP63 is commonly amplified, and ΔNp63α confers a potent survival advantage. Genome-wide occupancy studies show that ΔNp63 promotes bidirectional target gene regulation by binding more than 5,000 sites throughout the genome; however, the subset of targets mediating discreet activities of TP63 remains unclear. We report that ΔNp63α activates bone morphogenic proteins (BMP) signaling by inducing the expression of BMP7. Immunohistochemical analysis indicates that hyperactivation of BMP signaling is common in human breast cancers, most notably in the basal molecular subtype, as well as in several mouse models of breast cancer. Suppression of BMP signaling in vitro with LDN193189, a small-molecule inhibitor of BMP type I receptor kinases, represses clonogenicity and diminishes the cancer stem cell-enriched ALDH1(+) population. Importantly, LDN193189 blocks reconstitution of mixed ALDH1(+)/ALDH1(-) cultures indicating that BMP signaling may govern aspects of cellular plasticity within tumor hierarchies. These results show that BMP signaling enables reversion of committed populations to a stem-like state, potentially supporting progression and maintenance of tumorigenesis. Treatment of a mouse model of breast cancer with LDN193189 caused reduced expression of markers associated with epithelial-to-mesenchymal transition (EMT). Furthermore, in vivo limiting dilution analysis assays revealed that LDN193189 treatment suppressed tumor-initiating capacity and increased tumor latency. These studies support a model in which ΔNp63α-mediated activation of BMP signaling governs epithelial cell plasticity, EMT, and tumorigenicity during breast cancer initiation and progression.

Personalized therapy for breast cancer.

Breast cancer is a complex disease characterized by many morphological, clinical and molecular features. For many years, this disease has been classified according to histopathologic criteria, known as the tumor, node and metastasis (TNM) staging system. Clinical criteria that include immunohistochemical markers, such as the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2), provide a classification of breast cancer and dictates the optimal therapeutic approach for treatment. With genomic techniques, such as real‐time reverse transcriptase PCR (RT‐PCR), microarrays, next‐generation sequencing, and whole‐exome sequencing, breast cancer diagnostics is going through a significant evolution. Genomic and transcriptomic technologies make the analysis of gene expression signatures and mutation status possible so that tumors may now be classified more accurately with respect to diagnosis and prognosis. The ‐omic era has also made the possible identification of new biomarkers involved in breast cancer development, survival and invasion that can be gradually incorporated either into clinical testing or clinical trials. Together, clinical and molecular criteria can contribute to a more personalized management of the breast cancer patient. This article will present the progress made in the diagnosis and management of breast cancer using molecular information provided by genomic and transcriptomic technologies.

Clinical and Translational Results of a Phase II, Randomized Trial of an AntiIGF-1R (Cixutumumab) in Women with Breast Cancer That Progressed on Endocrine Therapy

Purpose: This phase II trial evaluated the efficacy and safety of cixutumumab, a human anti–insulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor–positive breast cancer. Experimental Design: Patients with hormone receptor–positive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored. Results: Ninety-three patients were randomized (arm A, n = 62; arm B, n = 31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)]. Conclusions: Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1R–targeted therapies requires further validation. Clin Cancer Res; 22(2); 301–9. ©2015 AACR.

Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: the impact of APOE and smoking.

This study examined the association of post‐treatment changes in cognitive performance, apolipoprotein E (APOE), and smoking in breast cancer patients treated with adjuvant therapy.

Stromal Expression of miR-21 Identifies High-Risk Group in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Expression of miR-21, an oncomiR, is frequently altered and may be distinctly expressed in the tumor stroma. Because tumor lesions are a complex mixture of cell types, we hypothesized that analysis of miR-21 expression at single-cell resolution could provide more accurate information to assess disease recurrence risk and BC-related death. We implemented a fully automated, tissue slide-based assay to detect miR-21 expression in 988 patients with BC. The miR-21(High) group exhibited shorter recurrence-free survival [hazard ratio (HR), 1.71; P < 0.001] and BC-specific survival (HR, 1.96; P < 0.001) in multivariate regression analyses. When tumor compartment and levels of miR-21 expression were considered, significant associations with poor clinical outcome were detected exclusively in tumor epithelia from estrogen receptor- and/or progesterone receptor-positive human epidermal growth factor receptor 2-negative cases [recurrence-free survival: HR, 3.67 (P = 0.006); BC-specific survival: HR, 5.13 (P = 0.002)] and in tumor stroma from TNBC cases [recurrence-free survival: HR, 2.59 (P = 0.013); BC-specific survival: HR, 3.37 (P = 0.003)]. These findings suggest that the context of altered miR-21 expression provides clinically relevant information. Importantly, miR-21 expression was predominantly up-regulated and potentially prognostic in the tumor stroma of TNBC.