Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes.

Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.

Factors Associated with Interest in Gene-Panel Testing and Risk Communication Preferences in Women from BRCA1/2 Negative Families.

Scientific advances have allowed the development of multiplex gene-panels to assess many genes simultaneously in women who have tested negative for BRCA1/2. We examined correlates of interest in testing for genes that confer modest and moderate breast cancer risk and risk communication preferences for women from BRCA negative families. Female first-degree relatives of breast cancer patients who tested negative for BRCA1/2 mutations (N = 149) completed a survey assessing multiplex genetic testing interest and risk communication preferences. Interest in testing was high (70 %) and even higher if results could guide risk-reducing behavior changes such as taking medications (79 %). Participants preferred to receive genomic risk communications from a variety of sources including: primary care physicians (83 %), genetic counselors (78 %), printed materials (71 %) and the web (60 %). Factors that were independently associated with testing interest were: perceived lifetime risk of developing cancer (odds ratio (OR) = 1.67: 95 % confidence interval (CI) 1.06-2.65) and high cancer worry (OR = 3.12: CI 1.28-7.60). Findings suggest that women from BRCA1/2 negative families are a unique population and may be primed for behavior change. Findings also provide guidance for clinicians who can help develop genomic risk communications, promote informed decision making and customize behavioral interventions.

Introduction of D-phenylalanine enhanced the receptor binding affinities of gonadotropin-releasing hormone peptides.

The purpose of this study was to examine whether the introduction of D-Phe could improve the GnRH receptor binding affinities of DOTA-conjugated D-Lys(6)-GnRH peptides. Building upon the construct of DOTA-Ahx-(D-Lys(6)-GnRH1) we previously reported, an aromatic amino acid of D-Phe was inserted either between the DOTA and Ahx or between the Ahx and D-Lys(6) to generate new DOTA-D-Phe-Ahx-(D-Lys(6)-GnRH) or DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) peptides. Compared to DOTA-Ahx-(D-Lys(6)-GnRH1) (36.1 nM), the introduction of D-Phe improved the GnRH receptor binding affinities of DOTA-D-Phe-Ahx-(D-Lys(6)-GnRH) (16.3 nM) and DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) (7.6 nM). The tumor targeting and pharmacokinetic properties of (111)In-DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) was determined in MDA-MB-231 human breast cancer-xenografted nude mice. Compared to (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1), (111)In-DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) exhibited comparable tumor uptake with faster renal and liver clearance. The MDA-MB-231 human breast cancer-xenografted tumors were clearly visualized by single photon emission computed tomography (SPECT) using (111)In-DOTA-Ahx-D-Phe-(D-Lys(6)-GnRH) as an imaging probe, providing a new insight into the design of new GnRH peptides in the future.

Influences of hydrocarbon linkers on the receptor binding affinities of gonadotropin-releasing hormone peptides.

Three new DOTA-conjugated GnRH peptides with various hydrocarbon linkers were synthesized to evaluate the influences of the linkers on their receptor binding affinities. The hydrocarbon linker displayed a profound impact on the receptor binding affinities of DOTA-conjugated GnRH peptides. The Aun linker was better than Gaba, Ahx and Aoc linkers in retaining strong receptor binding affinity of the GnRH peptide. DOTA-Aun-(D-Lys(6)-GnRH) displayed 22.8 nM GnRH receptor binding affinity. (111)In-DOTA-Aun-(D-Lys(6)-GnRH) exhibited fast tumor uptake and urinary clearance in MDA-MB-231 human breast cancer-xenografted nude mice. The cellular and biological results provided an insight into the design of new GnRH peptides in the future.

The role of antiresorptive therapies in improving patient care in early and metastatic breast cancer.

Breast cancer is the second most common cancer among American women and has a high rate of metastasis to bone. Patients regularly undergo adjuvant therapy (chemotherapy or hormonal therapy) following surgical resection of the tumor. In addition to potential direct effects on bone cells, both chemotherapy and hormonal therapy induce ovarian dysfunction and dramatically decrease estrogen levels in both pre- and postmenopausal women. This leads to decreased bone mineral density and increased fracture risk. Antiresorptive therapies (e.g, zoledronic acid and denosumab) have demonstrated efficacy in preventing cancer therapy-induced bone loss in patients with breast cancer and are approved for the prevention of skeletal-related events in patients with bone metastases from breast cancer. This review will focus on the evolving role of these antiresorptive therapies in the care of women with early or metastatic breast cancer.

SWOG S0215: a phase II study of docetaxel and vinorelbine plus filgrastim with weekly trastuzumab for HER2-positive, stage IV breast cancer.

SWOG trial S0102 showed significant activity of the combination of docetaxel and vinorelbine in HER2-negative metastatic breast cancer (MBC). For HER2-positive patients, additional benefit may occur with the addition of trastuzumab due to its synergy with docetaxel and vinorelbine. Patients with HER2-positive MBC, but without prior chemotherapy for MBC or adjuvant taxane, were eligible. Docetaxel (60 mg/m²) was given intravenously on Day 1, vinorelbine (27.5 mg/m²) intravenously on Days 8 and 15, and filgrastim (5 µg/kg) on Days 2-21 of a 21-day cycle. In addition, patients received weekly infusions of trastuzumab (2 mg/kg) after an initial bolus of 4 mg/kg. The primary outcome was 1 year overall survival (OS), with secondary outcomes of progression-free survival (PFS), response rate, and toxicity. Due to slow accrual (February 2003-December 2006), enrollment was stopped after 76 of 90 planned patients. There have been 32 deaths and 51 progressions among the 74 eligible patients who received treatment. The estimated 1 year OS was 93% (95% CI 84-97%) with a median of 48 months. One-year PFS was 70% (95% CI 58-79%) with a median of 20 months. Response rate for measurable disease was 84%. No deaths were attributed to treatment. Grade 4 toxicities were reported for 19% with neutropenia the most common (15%). The most common grade 3 toxicities (33%) were leucopenia (14%) and fatigue (10%). The combination of trastuzumab, docetaxel, and vinorelbine is effective as first-line chemotherapy in HER2-positive MBC with minimal toxicity. One-year survival estimates are among the highest reported in this population.

Synthesis and evaluation of novel gonadotropin-releasing hormone receptor-targeting peptides.

The purpose of this study was to develop novel radiolabeled gonadotropin-releasing hormone (GnRH) receptor-targeting peptides for breast cancer imaging. Three novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated GnRH peptides were designed and synthesized. The radiometal chelator DOTA was conjugated to the epsilon or alpha amino group of D-lysine, or the epsilon amino group of L-lysine via an Ahx {aminohexanoic acid} linker to generate DOTA-Ahx-(D-Lys(6)-GnRH1), DOTA-Ahx-(D-Lys(6)-GnRH2) and DOTA-Ahx-(L-Lys(6)-GnRH3), respectively. The conjugation of the DOTA to the epsilon amino group of D-lysine (rather than alpha amino group of D-lysine nor epsilon amino group of L-lysine) maintained the nanomolar GnRH receptor binding affinity. The IC(50) values of DOTA-Ahx-(D-Lys(6)-GnRH1), DOTA-Ahx-(D-Lys(6)-GnRH2) and DOTA-Ahx-(L-Lys(6)-GnRH3) were 36.1 nM, 10.6 mM and 4.3 mM, respectively. Since only DOTA-Ahx-(D-Lys(6)-GnRH1) displayed nanomolar receptor binding affinity, the specific GnRH receptor binding of (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1) was determined in human GnRH receptor membrane preparations. Furthermore, the biodistribution and tumor imaging properties of (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1) were examined in MDA-MB-231 human breast cancer-xenografted nude mice. (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1) exhibited specific GnRH receptor binding and rapid tumor uptake (1.76 ± 0.58% ID/g at 0.5 h postinjection) coupled with fast whole-body clearance through the urinary system. The MDA-MB-231 human breast cancer-xenografted tumor lesions were clearly visualized by single photon emission computed tomography (SPECT)/CT at 1 h postinjection of (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1). The profound impact of DOTA position on the binding affinity of the GnRH peptide provided a new insight into the design of novel radiolabeled GnRH peptides. The successful imaging of MDA-MB-231 human breast cancer-xenografted tumor lesions using (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1) suggested its potential as a novel imaging probe for human breast cancer imaging.

E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group.

PURPOSE: Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. PATIENTS AND METHODS: E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. RESULTS: Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. CONCLUSION: The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.

The effect of adjuvant radiotherapy on mortality differs according to primary tumor location in women with node-positive breast cancer.

PURPOSE: To evaluate the prognostic significance of primary tumor location and to examine whether the effect of adjuvant radiotherapy on survival varies according to tumor location in women with axillary node-positive (ALN+) breast cancer (BC). PATIENTS AND METHODS: Data were abstracted from the SEER database for 24,410 women aged 25-95 years, diagnosed between 1988-1997 with nonmetastatic T1-T2, ALN+ BC. Subgroup analyses were performed using interactions within proportional hazards models. Event was defined as death from any cause. Prognostic variables were selected using Akaike Information Criteria. Joint significances of subgroups were evaluated with Wald test. RESULTS: Median follow-up was 10 years. In joint models, statistically significant interactions were found between tumor location, nodal involvement, type of surgery, and radiotherapy. Factorial presentation of interactions showed consistent 13% proportional reduction of mortality in all subgroups, except in women with medial tumors with > or = 4 ALN+ treated with mastectomy. In this subgroup, use of radiotherapy was associated with a 16% proportional increase in mortality. CONCLUSION: Medial tumor location is a significant adverse prognostic factor that should be considered in treatment decision- making for women with ALN+ BC. Improved survival was observed with radiotherapy use in all subgroups, except in women with medial tumors with > or = 4 ALN+ treated with postmastectomy radiotherapy. These findings raise concern that the favorable effect of radiotherapy may be offset by excess toxicities in the latter subgroup.

Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial.

Importance: Pathologic complete response rate (pCR), the primary end point of the ACOSOG (American College of Surgeons Oncology Group) Z1041 (Alliance) trial, and disease-free survival (DFS) and overall survival (OS) in women with operable HER2-positive breast cancer are similar between treatment regimens. Objective: To assess DFS and OS for patients treated with sequential vs concurrent anthracycline plus trastuzumab. Design, Setting, and Participants: Phase 3 randomized clinical trial conducted at 36 centers in the continental United States and Puerto Rico. Women 18 years or older with invasive operable HER2-positive breast cancer were enrolled from September 15, 2007, to December 15, 2011, and randomized to 1 of 2 treatment arms. The analysis data set was locked on October 15, 2017, and analysis was completed on December 15, 2017. Interventions: Patients randomized to arm 1 received 500 mg/m2 of fluorouracil, 75 mg/m2 of epirubicin, and 500 mg/m2 of cyclophosphamide (FEC) every 3 weeks for 12 weeks followed by the combination of 80 mg/m2 of paclitaxel and 2 mg/kg (except initial dose of 4 mg/kg) of trastuzumab weekly for 12 weeks. Patients randomized to arm 2 received the same combination of paclitaxel with trastuzumab weekly for 12 weeks followed by FEC every 3 weeks with weekly trastuzumab for 12 weeks. Women with hormone receptor-positive disease received endocrine therapy, and radiotherapy was delivered at physician discretion. Main Outcomes and Measures: The primary outcomes were DFS and OS and pCR in the breast and nodes. Results: Two hundred eighty-two women with HER2-positive breast cancer were enrolled in the trial, and 2 withdrew consent before treatment. Among the remaining 280 women, the median age was 50 years (range, 28-76 years), 232 (82.9%) were white, 29 (10.3%) were black, 8 (2.9%) were Asian, 4 (1.4%) were American Indian or Alaskan Native, and 7 (2.5%) did not report race/ethnicity. There were 22 disease events in arm 1 and 27 in arm 2. Disease-free survival rates did not differ with respect to treatment arm (stratified log-rank P = .96; stratified hazard ratio [HR] [arm 2 to arm 1], 1.02; 95% CI, 0.56-1.83). Overall survival did not differ with respect to treatment arm (stratified log-rank P = .73; stratified HR [arm 2 to arm 1], 1.17; 95% CI, 0.48-2.88). Conclusions and Relevance: Across a median follow-up of 5.1 years (range, 26 days to 6.2 years), pCR, DFS, and OS did not differ with respect to sequential or concurrent administration of FEC with trastuzumab. Trial Registration: ClinicalTrials.gov identifier: NCT00513292.

Breast disease: benign and malignant.

Breast diseases, both benign and malignant, are common. Typically, young women present with more benign pathologies; however, breast malignancies can occur in young women, especially in those harboring mutations in the BRCA genes, other inherited genetic syndromes associated with increased risk of breast cancer, or familial predisposition for breast cancer. In all women aged 40 and over presenting with abnormalities of the breast, a primary breast cancer should be ruled out because it is the leading cancer among women in developed countries.

The rs4646 and rs12592697 Polymorphisms in CYP19A1 Are Associated with Disease Progression among Patients with Breast Cancer from Different Racial/Ethnic Backgrounds.

Given the racial/ethnic disparities in breast cancer, we evaluated the association between CYP19A1 single nucleotide polymorphisms (SNPs) on disease progression in women with breast cancer from different racial/ethnic backgrounds. This is a cross-sectional analysis of data from 327 women with breast cancer in the Expanded Breast Cancer Registry program of the University of New Mexico. Stored DNA samples were analyzed for CYP19A1 SNPs using a custom designed microarray panel. Genotype-phenotype correlations were analyzed. Of the 384 SNPs, 2 were associated with clinically significant outcomes, the rs4646 and rs12592697. The T allele for the rs4646 was associated with advanced stage of the disease at the time of presentation (odds ratio [OR]:1.8, confidence intervals [CI]: 1.05-3.13, p < 0.05) and a more progressive disease (OR: 2.1 [CI: 1.1-4.0], p = 0.04). For the rs12592697, the variant T allele was more frequent in Hispanic women and associated with a more progressive disease (OR: 2.05 [CI: 1.0-4.0], p = 0.04). However, further analysis according to menopausal status showed that the association between these 2 SNPs with disease progression or the stage at diagnosis are confined only to postmenopausal women. The odds ratios of disease progression among postmenopausal women carrying the T allele for the rs4646 and rs12592697 are 3.05 (1.21, 7.74, p = 0.02) and 3.80 (1.24, 11.6, p = 0.02), respectively. Regardless, differences in disease progression among the different genotypes for both SNPs disappeared after adjustment for treatment. In summary, the rs4646 and the rs12592697 SNPs in CYP19A1 are associated with differences in disease progression in postmenopausal women. However, treatment appears to mitigate the differences in genetic risk.

Everolimus in the Treatment of Metastatic Breast Cancer.

The discovery of the mammalian target of rapamycin (mTOR) molecular pathway has brought insight into its vital role in breast cancer pathogenesis. Several clinical trials have shown that the mTOR inhibitor everolimus could improve patient outcomes in several subtypes of breast cancer, including hormone receptor-positive, human epidermal growth factor receptor-negative metastatic disease that has progressed after prior endocrine therapy. This review summarizes findings from clinical trials that have demonstrated the benefit of everolimus in metastatic breast cancer and highlights some new research directions utilizing everolimus.

Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012.

PURPOSE: Patients with inflammatory breast cancer (IBC) or locally advanced breast cancer (LABC) were randomly assigned to 21-day doxorubicin and cyclophosphamide administered for five cycles (standard arm) versus weekly doxorubicin and daily oral cyclophosphamide administered with granulocyte colony-stimulating factor support for 15 weeks (continuous arm). All patients had subsequent weekly paclitaxel for 12 weeks before surgery. PATIENTS AND METHODS: Patients (n = 372) were randomly assigned to the standard arm (n = 186) or the continuous arm (n = 186) stratified by disease type (LABC, n = 256; IBC, n = 116). The primary outcome was microscopic pathologic complete response (pCR) at surgery. Secondary outcomes included disease-free survival, overall survival, and toxicity. RESULTS: More patients in the standard arm had grade 3 to 4 leukopenia and neutropenia, but there were more instances of stomatitis/pharyngitis and hand-foot skin reaction in the continuous arm. Assessed among 356 eligible patients, pCR was not different between the treatment groups stratified by disease type (P = .42). In subset analysis, higher pCR rates were observed in the continuous arm versus the standard arm only for stage IIIB disease (P = .0057) and in IBC (P = .06). Comparison of overall survival and disease-free survival showed no difference between treatment groups (P = .37 and P = .87, respectively). CONCLUSION: No significant clinical benefit was seen for the investigational arm in this trial overall.

Method of detection and breast cancer survival disparities in Hispanic women.

BACKGROUND: Hispanic women in New Mexico (NM) are more likely than non-Hispanic women to die of breast cancer-related causes. We determined whether survival differences between Hispanic and non-Hispanic women might be attributable to the method of detection, an independent breast cancer prognostic factor in previous studies. METHODS: White women diagnosed with invasive breast cancer from 1995 through 2004 were identified from NM Surveillance Epidemiology End Results (SEER) files (n = 5,067) and matched to NM Mammography Project records. Method of cancer detection was categorized as "symptomatic" or "screen-detected." The proportion of Hispanic survival disparity accounted for by included variables was assessed using Cox models. RESULTS: In the median follow-up of 87 months, 490 breast cancer deaths occurred. Symptomatic versus screen-detection was classifiable for 3,891 women (76.8%), and was independently related to breast cancer-specific survival [hazard ratio (HR), 1.6; 95% confidence interval (95% CI), 1.3-2.0]. Hispanic women had a 1.5-fold increased risk of breast cancer-related death, relative to non-Hispanic women (95% CI, 1.2-1.8). After adjustment for detection method, the Hispanic HR declined from 1.50 to 1.45 (10%), but after inclusion of other prognostic indicators the Hispanic HR equaled 1.23 (95% CI, 1.01-1.48). CONCLUSIONS: Although the Hispanic HR declined 50% after adjustment, the decrease was largely due to adverse tumor prognostic characteristics. IMPACT: Reduction of disparate survival in Hispanic women may rely not only on increased detection of tumors when asymptomatic but on the development of greater understanding of biological factors that predispose to poor prognosis tumors.

Modeling the effect of tumor size in early breast cancer.

SUMMARY BACKGROUND DATA: The purpose of this study was to determine the type of relationship between tumor size and mortality in early breast carcinoma. METHODS: The data was abstracted from 83,686 cases registered in the Surveillance, Epidemiology, and End Results Program of women diagnosed with primary breast carcinoma between 1988 and 1997 presenting with a T1-T2 lesion and no metastasis in whom axillary node dissection was performed: 58,070 women were node-negative (N0) and 25,616 were node-positive (N+). End point was death from any cause. Tumor size was modeled as a continuous variable by proportional hazards using a generalized additive models procedure. RESULTS: Functionally, a Gompertzian expression exp(-exp(-(size-15)/10)) provided a good fit to the effect of tumor size (in millimeters) on mortality, irrespective of nodal status. Quantitatively, for tumor size between 3 and 50 mm, the increase of crude cumulative death rate (number of observed deaths divided by the number of patients at risk) increased with size from 10% to 25% for N0 and from 20% to 40% for N+. CONCLUSIONS: The functional relationship of tumor size with mortality is concordant with current knowledge of tumor growth. However, its qualitative and quantitative independence of nodal status is in contradiction with the prevailing concept of sequential disease progression from primary tumor to regional nodes. This argues against the perception that nodal metastases are caused by the primary tumor.

A phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for five days every three weeks to patients with metastatic adenocarcinoma of the colon or rectum.

BACKGROUND: To evaluate the antitumor activity, toxicities, and pharmacokinetics (PK) of DX-8951f administered as a 30-min infusion daily for 5 days every 3 weeks in patients with fluorouracil-resistant metastatic colorectal carcinoma. PATIENTS AND METHODS: Sixteen patients were enrolled. All had metastatic colorectal carcinoma resistant to or progressing after chemotherapy containing 5-fluorouracil and no prior chemotherapy with camptothecin derivatives. DX-8951f was administered until disease progression or unacceptable toxicity. Responses were assessed after every two courses. RESULTS: Fifteen patients were evaluable. Fifty-one courses of therapy were delivered (median 2). Responses were one minor response, six stable disease, and eight progressive disease. The principal adverse event was neutropenia, with grade 3 and 4 toxicities in three and eight patients, respectively. Non-hematologic toxicities were mild to moderate; the most common were fatigue, nausea, and diarrhea. Plasma concentrations of DX-8951 were well described using a linear two-compartment PK model. There was no evidence of nonlinearity in the elimination of PK or auto-inhibition or induction of DX-8951 clearance over the 5 days of administration. CONCLUSIONS: DX-8951f at this dose and schedule had no significant activity in this patient population. The toxicity profile, mainly hematologic, was consistent with previous reports. The clearance and volume of distribution were not different from those previously reported.

STK15/Aurora-A expression in primary breast tumors is correlated with nuclear grade but not with prognosis.

BACKGROUND: DNA amplification on chromosome 20q13 is commonly detected in breast carcinoma and is correlated with poor prognosis. STK15 maps to this amplicon. The objective of the current study was to use immunohistochemistry to determine STK15 expression in primary breast tumors. The authors also explored whether STK15 was a prognostic factor for breast carcinoma by comparing the level of STK15 gene expression with clinical parameters that are known prognostic factors for the disease. METHODS: Archival mastectomy and lumpectomy specimens, randomly selected, were immunohistochemically stained to determine the STK15 gene expression level. The clinical parameters of these same patients were reviewed retrospectively and analyzed for correlations with STK15 expression level, based on a positive-versus-negative scoring system. RESULTS: Of the 112 human breast tumor specimens analyzed, 26% stained positively for STK15 by immunohistochemistry. Of the tumors, that stained positively 62.1% had a well-to-moderately differentiated nuclear grade. The correlation between STK15 staining and nuclear grade was nearly statistically significant (P = 0.05). No association was found between STK15 staining and tumor size, lymph node status, or hormone receptor status. Analysis of recurrence-free survival and overall survival rates also failed to reveal a statistically significant difference between the two groups. CONCLUSIONS: STK15 expression by immunohistochemistry was noted in approximately one-fourth of primary breast tumors. STK15 expression was associated with nuclear grade, but no correlation was found between the other clinical parameters evaluated. Furthermore, no differences were found in survival rates when they were analyzed by level of STK15 staining.