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BACKGROUND: Cooperative group trials and institutional series reported the risk of MDS and/or AML after adjuvant chemotherapy for early stage breast cancer (eg, NSABP 0.21%, Smith JCO 2003; ECOG 2197 0.5%, Goldstein ASCO 2012). We examined the incidence of MDS and/or AML in breast cancer survivors that are part of the NCCN Breast Cancer Outcomes Database. METHODS: The NCCN Database prospectively identifies all incident breast cancers diagnosed at participating cancer centers, and patients that continue their care at an NCCN site are followed annually with information collected on subsequent treatment, recurrence, and new cancers. Mortality is also ascertained for all diagnosed patients every 2 years through the National Death Index. Women with stages 1-3 breast cancer (BC) diagnosed between 1997- 2008 were included in this analysis. Univariate chi square analyses were used to compare characteristics between patients with BC and BC&MDS and/or AML. Time from BC to MDS and/or AML and 5-/10-year cumulative incidence rates were analyzed using proportional subdistribution hazards regression models that account for death as a competing risk to MDS and/or AML. RESULTS: Among 21563 stage 1-3 BC patients from 8 NCCN sites, 39 (0.18%) subsequently developed MDS and/or AML. Median overall follow-up was 4.7 years and median time from BC to MDS and/or AML was 2.8 years (range, 0.6 to 8.3 years). Cumulative MDS and/or AML incidence was 0.19% at 5y and 0.27% at 10y. Overall, cancer characteristics at BC diagnosis within BC&MDS and/or AML and within BC groups were similar (Caucasian 82%v82%, AA 8% v8%; ER+ 79%v75%, HER2+ 14%v21%, TNBC 15%v14%; contralateral BC 3%v2%; pancreas or ovarian cancer 0%v1%). 13191 had adjuvant chemo (75%v67%; anthracycline 89%v91%, AC-taxane 46%v35%, dose-dense 6%v5%). Trends observed included more patients in BC&MDS and/or AML group with prior radiation (85%v70%, p = 0.06) and older age at BC diagnosis (median age 59v54 years, p = 0.09). Risk for developing MDS and/or AML after BC (adjusted for age at BC and race) was increased in those receiving any chemotherapy versus no chemotherapy (HR 2.16, 95% CI 0.98-4.77, p = 0.06), any RT versus no RT (HR 2.44, 95% CI 1.01-5.88, p = 0.04), and if chemo/RT given versus just chemo or just RT (HR 2.2, 95% CI 1.05-4.59, p = 0.04). No increased risk was observed if a taxane was added to an anthracycline regimen (HR 1.27, 95% CI 0.57-2.81, p = 0.56). CONCLUSIONS: In a large national prospective registry across NCCN sites, risk of MDS and/or AML is increased after adjuvant chemotherapy and/or adjuvant radiation therapy for stages 1-3 breast cancer, especially if both are used. Specific population subsets will be further examined. These rates are similar to those observed in clinical trials, but may underestimate actual numbers due to patients lost to follow-up. In addition, an MDS diagnosis was routinely under-reported in population databases until recently. Strategies to limit risk of subsequent cancers in patients likely to survive early stage breast cancer should be considered at the time of initial diagnosis. Predictors of MDS and/or AML in breast cancer survivors are needed. [ABSTRACT FROM AUTHOR]

Background: Near-infrared optical measurements have been recently shown to offer a promising non-invasive way for monitoring breast neoadjuvant chemotherapy (NAC) and predicting outcome. In particular, snapshots of tissue oxy and deoxy-hemoglobin concentration as well as water and lipid content have been demonstrated to be sensitive to therapy-induced changes. In this study, we extend optical measurements to capture additional hemodynamic and metabolic biomarkers revealed by dynamically imaging breast tissue during fractional mammographic compression. Using our dynamic tomographic optical breast imaging (TOBI) system we evaluate the early prediction performance of this advanced technology. Methods: We are conducting a pilot feasibility study in female patients with unilateral locally advanced breast cancer undergoing standard-of-care NAC. Pre-treatment and day 7 post-treatment TOBI scans are obtained, with additional (optional) scans on day 1 of each subsequent chemotherapy cycle. Both breasts are compressed in turn to 4-8 lbs of force, and optical images are acquired once every 2 seconds over two minutes. Time-resolved oxy-(HbO), deoxy-(HbR), and total-(HbT) hemoglobin concentration and hemoglobin oxygen saturation (SO2) are calculated. The compression-induced rate of change of HbT correlates with changes in tissue blood volume indicative of biomechanical properties. The evolution of tissue SO2 is modeled to obtain an index of the ratio of oxygen metabolism to blood flow. Therapy induced changes are quantified, and comparisons between changes in responders vs. non-responders are performed (response is defined here as >50% reduction in the largest tumor diameter). Results: We have enrolled 20 patients so far, of which 90% (N = 18) completed both the day 0 and day 7 scans. 17 patients have undergone surgery at this point. We focused our initial analysis on 5 HER2+ patients, of which two were non-responders, and three were responders according to our criteria. Four patients received taxol+herceptin+lapatinib, while the other received taxol+lapatinib only. In this small subgroup, the non-responders had an average increase of 1% in total hemoglobin concentration (HbT) from day 0 to day 7, while the responders had an average 12% decrease in HbT, respectively. We also noted different trends in the evolution of the tissue oxygen consumption to blood flow ratio, which increased 32% in non-responders from day 0 to day 7, while decreasing 11% in responders. Conclusions: The large percentage of enrolled patients that completed both initial scans demonstrates the feasibility of using dynamic optical breast tomography for breast neoadjuvant chemotherapy monitoring. Results in a small cohort of 5 HER2+ patients suggested a decreasing trend in HbT for responders as observed by previous studies. We also report for the first time an increase in the metabolic ratio of oxygen consumption to blood flow in non-responders vs. a decrease in responders. These initial results of our on- going study suggest that dynamic TOBI can detect changes due to treatment and may have predictive value for the treatment outcome and supports further studies of this non- invasive and portable tool for chemotherapy monitoring. [ABSTRACT FROM AUTHOR]

Introduction: Population based studies (eg, Hershman et al. BCRT 2006 and Lohrisch et al. JCO 2006) showed poorer survival associated with long delays in adjuvant chemotherapy (CTX) initiation following definitive surgery (DS) for women with breast cancer (BC). Delays in CTX following diagnosis (DX) have not been evaluated. The ASCO/NCCN quality measures (QMs) recommend CTX <=120 days after DX for patients with stage II/III ER/PR negative disease. We sought to examine the impact of delayed CTX on survival overall and stratified by disease-specific prognostic factors. Methods: 4,608 women with stage I-III HER2 negative breast cancer diagnosed between 2000 and 2006 at 8 NCCN centers were identified using the NCCN outcomes database. Patients with T3/4 disease or who received neoadjuvant therapy were excluded. The association between CTX timing and OS was evaluated using multivariate Cox models adjusted for CTX type, age, race, BMI, residential distance, insurance, SES, comorbidity, ER/PR, LVI, grade, T stage, and N stage. The impact of CTX timing was evaluated using a >90-day (d) DS-to-CTX threshold, based on poor outcomes observed in prior studies, and a >120d DX-to-CTX threshold, based on the ASCO/NCCN QMs. Results: Median follow-up was 7.2 years and OS at 7 years was 89%. Overall, 401 (8.7%) patients received CTX >120d after DX and 113 (2.4%) patients received CTX >90d after DS. The DX-to-CTX interval was more strongly correlated with the DX-to-DS (r = 0.74) interval than DS-to-CTX (r = 0.54) interval. A >90d DS-to-CTX interval was significantly associated with poorer survival (HR: 1.65, 95% CI 1.04-2.60, p = 0.03) in adjusted analyses. Shorter DS-to-CTX thresholds of >60d (n = 636, HR: 1.13, 95% CI: 0.89-1.43, p = 0.319) or >75d (n = 273, HR: 1.05, 95% CI 0.74-1.49, p = 0.76) were not associated with OS. The association between a >120d DX-to-CTX interval and OS was not statistically significant (HR: 1.32, 95% CI 0.99-1.76, p = 0.06). Patients who received CTX >135d(n = 231, HR1.25, 95% CI: 0.87-1.81, p = 0.22)or>150d(n = 128, HR1.15, 95% CI: 0.59-2.24, p = 0.69) after DX did not display an increased risk of death. Excluding pathological staging factors from the model had no effect on the results. In subgroup analyses stratified by ER/PR, LVI, grade, T stage or N stage, a >120d delay in CTX did not display significant associations with OS. Among ER/PR negative patients, the association between a >120d delay and OS was borderline non-significant after adjusting the p-value for multiple hypothesis testing using the false discovery rate method (HR: 1.80, 95% CI: 1.16-2.79, p = 0.09). Conclusion: Consistent with previous studies, CTX delays of >90 days following surgery were associated with poorer survival. OS was not significantly compromised in patients with DX-to-CTX intervals >120 days although this analysis may have limited power to detect small effects. More variation in the DX-to-CTX interval was attributed to pre-surgery time which may explain the differences observed between the DX-to-CTX and DS-to-CTX intervals. Among patients with ER/PR negative disease, a non-significant association between OS and a >120 day DX-to -CTX interval was observed that warrants further examination. [ABSTRACT FROM AUTHOR]

Background: The results of the ACOSOG- Z0011 trial have had potential practice changing implications for the management of patients with positive sentinel lymph node (SLN) undergoing lumpectomy and radiation for breast cancer. However, some evidence suggests a shift in axillary management even prior to the initial report of data supporting sentinel lymph node biopsy (SLNB) alone in mid-2010. We analyzed data in the National Comprehensive Cancer Network (NCCN) outcomes database from NCCN centers and the Michigan Breast Oncology Quality Initiative (MiBOQI) hospitals to examine institutional practice patterns with respect to use of completion axillary dissection (CALND) for SLN positive breast cancer in the years leading up to publication of these trial results. We hypothesized that CALND would be omitted more frequently in women treated at NCCN centers compared to those treated at MiBOQI programs. Methods: We identified 2,172 women with clinical T1/T2 N0 breast cancer who underwent breast surgery and SLNB and had a positive SLN from 2007 through 2010 at one of 12 participating NCCN centers or 12 MiBOQI sites. Patient and tumor characteristics, definitive breast procedure, year of diagnosis, and institutional affiliation were analyzed as predictors of use of SLNB alone in univariate Chi-Square and multivariable logistic regression models. Results: CALND was omitted in 314 (14.5%) of the 2,172 patients. Over time, there was a dramatic increase in the use of SLNB alone (12% in 2007 to 23% in 2010). In the univariate analyses, increased patient age, later year of diagnosis, lower T stage, and lower pathologic N stage were significant predictors of use of SLNB alone (all p < .0001). There was no association between definitive breast surgery type, hormone receptor status, Her-2 Neu status, or institutional affiliation and use of SLNB alone. In the multivariable model, older age at diagnosis, later year of diagnosis, and lower pathologic N stage remained significant independent predictors of SLNB alone. There were no significant differences in rates of omission of CALND between NCCN and MIBOQI sites. Conclusions: Omission of CALND occurred frequently in women with SLN positive breast cancer cared for in both NCCN and MiBOQI institutions in advance of reporting results of ACOSOG-Z0011. This shift was seen in management of patients undergoing lumpectomy as well as mastectomy. Further study is warranted to determine the extent of durable practice changes as well as any impact on survival and local-regional control. [ABSTRACT FROM AUTHOR]

Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing was performed of circulating tumor cells (CTC) isolated from blood samples of women with metastatic estrogen receptor (ER) + breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it contributes to acquired resistance to endocrine therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ER + breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients. Implications: This study highlights a role for the AR in breast cancer bone metastasis, and suggests that therapeutic targeting of the AR may benefit patients with metastatic breast cancer. Mol Cancer Res; 16(4); 720-7. ©2018 AACR ., (©2018 American Association for Cancer Research.)

U-71,184 is a CC-1065 analogue which is highly cytotoxic in vitro and has a broad spectrum of antitumor activity in vivo. Against B16 cells, U-71,184 was 8-fold and 253-fold more potent than Actinomycin D and Adriamycin, respectively. U-71,184 killed 90% of B16 cells at 0.01 ng/ml levels of drug in the medium, which was equivalent to an intracellular concentration of about 8 pg/10(6) cell (= 2 x 10(-8) pmol/cell). A B16 cell line resistant to U-71,184 developed after 3 months of in vitro exposure to gradually increasing concentrations of the drug. The sensitive and resistant cell lines were cloned and a B16/R clone was selected which was 60 to 100 times more resistant to U-71,184 than the cloned sensitive parent (B16/S). Cells grown in the absence of U-71,184 for 2 months retained resistance to the drug. B16/R was slightly cross-resistant only to Adriamycin but not to Actinomycin D, vinblastine, or colchicine. Among alkylating agents, it was slightly cross-resistant to Melphalan but not to 1,3-bis(2-chloroethyl)-1-nitrosourea or cisplatin. B16/R did not overexpress mdr mRNA. Therefore, this cell line does not exhibit the multidrug-resistant phenotype. Most karyotypes of B16/R had a marker chromosome which carried an aberrantly staining region apparently containing repetitive replication of the same segment. Resistance can be partly accounted for by the approximately 10-fold lesser uptake of [3H]-U-71,184 in B16/R, as compared to B16/S. B16/R was cross-resistant in varying degrees to several other CC-1065 analogues. The ratio of the 50% lethal dose of U-71,184 for B16/R, as compared to B16/S, was about 60 (i.e., R/S = 60). In comparison, the following compounds had an R/S ratio of less than 20 (i.e., modest level of cross-resistance to U-71,184): U-68,819, U-73,975, U-75,500, U-75,559, and CC-1065. In contrast, the following compounds had an R/S ratio greater than 20 (i.e., highly cross-resistant to U-71,184): U-71,184 analogues U-71,185, U-73,903, and U-75,012; U-73,975 analogues U-75,613, U-75,032, and U-73,896; and CC-1065 enantiomer U-76,915. We cannot yet explain the difference in the level of cross-resistance between these compounds in vitro. B16/S and B16/R cells were tumorigenic in mice and B16/R was resistant to U-71,184 in vivo. There was no clear indication of cross-resistance of B16/R in vivo to Adriamycin, Actinomycin D, cisplatin, or Melphalan. However, U-73,975, a compound with modest cross-resistance in vitro, was significantly cross-resistant in vivo.

CC-1065 is a potent antitumor antibiotic which is cytotoxic to P388 and L1210 leukemia cells in vitro and in vivo. CC-1065 covalently binds to calf thymus DNA preferentially to adenine-thymine regions at N3 of adenine. Here, we compare CC-1065 interaction with P388-derived chromatin, DNA, and histones as measured by electronic absorption and circular dichroism. Two CC-1065 analogues (U-71,184 and its enantiomer, U-71,185) which show different biological activities from CC-1065 were also studied. The shape and temporal behavior of the induced circular dichroism curves generated by CC-1065 or its analogues bound to chromatin were similar to CC-1065 plus DNA. This suggested that CC-1065 and its analogues bind to the minor groove of chromatin DNA in a manner similar to calf thymus DNA. However, the binding of CC-1065 and its analogues to DNA induced a more intense circular dichroism band than binding to chromatin. The order of interaction for both chromatin and DNA was CC-1065 greater than U-71,184 greater than U-71,185. In contrast to the essentially irreversible binding to DNA after 24-h incubation, binding to chromatin was primarily a reversible interaction, the degree of reversibility being U-71,185 greater than U-71,184 = CC-1065. CC-1065 binds weakly and nonspecifically to histones.

Using polyclonal antibodies raised against a rat liver nuclear envelope protein, lamin protein A, the nuclear matrix proteins of a Walker 256 rat mammary carcinoma wild-type (WS) and a selected cell line with acquired resistance to nitrogen mustards (WR) were found to possess antigenic determinants which were recognized by the antibodies. In one-dimensional immunoblotting analysis, the nuclear matrix protein fractions of both cell lines revealed a common band at Mr 75,000; however only the WS nuclear matrix protein fraction contained a broad band at approximately Mr 70,000. Two-dimensional gel blotting studies of these proteins showed that this Mr 70,000 WS protein had a pI of approximately 7.5. Immunoprecipitation analysis revealed that the altered mobility of this protein could be a function of phosphorylation. The nuclear matrix proteins from both WS and WR cells were shown to bind 3':5'-cyclic adenylic acid (cAMP), as judged by photoaffinity labeling and gel electrophoresis studies. The WS nuclear matrix proteins showed a quantitatively greater level of cAMP binding compared to WR, with predominant binding to proteins with molecular weights of 45,000, 55,000, and 70,000. In WR cells, there was no cAMP binding in the Mr 70,000 region. These data indicate that the Mr 70,000 nuclear matrix lamin proteins are antigenically similar in WS and WR but differ in that the WR protein is hypophosphorylated and does not bind cAMP.