Showing papers by "Gabriel N. Hortobagyi published in 2009"
TL;DR: Demographic changes in the United States will result in a marked increase in the number of cancer diagnoses over the next 20 years, and continued efforts are needed to improve cancer care for older adults and minorities.
Abstract: Purpose By 2030, the United States' population will increase to approximately 365 million, including 72 million older adults (age ≥ 65 years) and 157 million minority individuals. Although cancer incidence varies by age and race, the impact of demographic changes on cancer incidence has not been fully characterized. We sought to estimate the number of cancer patients diagnosed in the United States through 2030 by age and race. Methods Current demographic-specific cancer incidence rates were calculated using the Surveillance Epidemiology and End Results database. Population projections from the Census Bureau were used to project future cancer incidence through 2030. Results From 2010 to 2030, the total projected cancer incidence will increase by approximately 45%, from 1.6 million in 2010 to 2.3 million in 2030. This increase is driven by cancer diagnosed in older adults and minorities. A 67% increase in cancer incidence is anticipated for older adults, compared with an 11% increase for younger adults. A 9...
1,484 citations
TL;DR: The review concludes with a consideration of HER-2 status in the prediction of response to non-HER-2 targeted treatments including hormonal therapy, anthracyclines, and taxanes.
Abstract: The human epidermal growth factor receptor (HER-2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER-2 gene amplification and protein overexpression in the absence of anti-HER-2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER-2-positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER-2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER-2-positive disease. The major marketed slide-based HER-2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ hybridization, are presented and contrasted in detail against the background of the published American Society of Clinical Oncology-College of American Pathologists guidelines for HER-2 testing. Testing issues, such as the impact of chromosome 17 polysomy and local versus central HER-2 testing, are also discussed. Emerging novel HER-2 testing techniques, including mRNA-based testing by real-time polymerase chain reaction and DNA microarray methods, HER-2 receptor dimerization, phosphorylated HER-2 receptors, and HER-2 status in circulating tumor cells, are also considered. A series of biomarkers potentially associated with resistance to trastuzumab is discussed with emphasis on the phosphatase and tensin homologue deleted on chromosome ten/Akt and insulin-like growth factor receptor pathways. The efficacy results for the more recently approved small molecule HER-1/HER-2 kinase inhibitor lapatinib are also presented along with a more limited review of markers of resistance for this agent. Additional topics in this section include combinations of both anti-HER-2 targeted therapies together as well as with novel agents including bevacizumab, everolimus, and tenespimycin. A series of novel HER-2-targeting agents is also presented, including pertuzumab, ertumaxomab, HER-2 vaccines, and recently discovered tyrosine kinase inhibitors. Biomarkers predictive of HER-2 targeted therapy toxicity are included, and the review concludes with a consideration of HER-2 status in the prediction of response to non-HER-2 targeted treatments including hormonal therapy, anthracyclines, and taxanes.
1,092 citations
TL;DR: Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving meetformin, and additional studies to evaluate the potential of met formin as an antitumor agent are warranted.
Abstract: Purpose Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this. Our purpose was to determine whether metformin use was associated with a change in pathologic complete response (pCR) rates in diabetic patients with breast cancer receiving neoadjuvant chemotherapy. Patients and Methods We identified 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. Patients were compared by groups: 68 diabetic patients taking metformin, 87 diabetic patients not taking metformin, and 2,374 nondiabetic patients. pCR rates were compared between the three groups using 2 tests of independence and compared pairwise using a binomial test of proportions. Factors predictive of pCR were assessed using a multivariate logistic regression model. Results The rate of pCR was 24% in the metformin group, 8.0% in the nonmetformin group, and 16% in the nondiabetic group (P .02). Pairwise comparisons between the metformin and nonmetformin groups (P .007) and the nonmetformin and nondiabetic groups (P .04) were significant. Comparison of the pCR rates between the metformin and nondiabetic groups trended toward but did not meet significance (P .10). Metformin use was independently predictive of pCR (odds ratio, 2.95; P .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use. Conclusion Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.
838 citations
TL;DR: Metaplastic breast cancers (MBCs) are aggressive, chemoresistant tumors characterized by lineage plasticity as discussed by the authors, and they have unique DNA copy number aberrations compared with common breast cancers.
Abstract: Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a "tumorigenic" signature defined using CD44(+)/CD24(-) breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets.
822 citations
TL;DR: Dysregulated genes that could classify breast cancer and may represent novel therapeutic targets for molecular subsets of cancers are identified.
Abstract: Purpose: We used high-resolution oligonucleotide comparative genomic hybridization (CGH) arrays and matching gene expression array data to identify dysregulated genes and to classify breast cancers according to gene copy number anomalies. Experimental Design: DNA was extracted from 106 pretreatment fine needle aspirations of stage II-III breast cancers that received preoperative chemotherapy. CGH was done using Agilent Human 4 × 44K arrays. Gene expression data generated with Affymetrix U133A gene chips was also available on 103 patients. All P values were adjusted for multiple comparisons. Results: The average number of copy number abnormalities in individual tumors was 76 (range 1-318). Eleven and 37 distinct minimal common regions were gained or lost in >20% of samples, respectively. Several potential therapeutic targets were identified, including FGFR1 that showed high-level amplification in 10% of cases. Close correlation between DNA copy number and mRNA expression levels was detected. Nonnegative matrix factorization (NMF) clustering of DNA copy number aberrations revealed three distinct molecular classes in this data set. NMF class I was characterized by a high rate of triple-negative cancers (64%) and gains of 6p21. VEGFA, E2F3 , and NOTCH4 were also gained in 29% to 34% of triple-negative tumors. A gain of ERBB2 gene was observed in 52% of NMF class II and class III was characterized by a high rate of estrogen receptor–positive tumors (73%) and a low rate of pathologic complete response to preoperative chemotherapy (3%). Conclusion: The present study identified dysregulated genes that could classify breast cancer and may represent novel therapeutic targets for molecular subsets of cancers.
331 citations
TL;DR: Concordance of quantitative hormone receptor measurements between primary and recurrent tumors is modest consistent with suboptimal reproducibility of measurement methods, particularly for IHC.
276 citations
TL;DR: High pCR rates are achieved in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab in combination with anthracyclines and taxanes, and novel adjuvant therapy strategies need to be studied in this population.
Abstract: Purpose: To evaluate HER2 status in residual tumor identified at the time of surgery in patients not achieving a pathologic complete response (pCR) and to determine the effect of alterations in HER2 status on recurrence-free survival (RFS). Experimental Design: Clinicopathologic data for patients with HER2-overexpressing breast cancer receiving neoadjuvant therapy with a taxane, anthracycline, and concomitant trastuzumab between 2004 and 2007 were reviewed. Surgical specimens for patients achieving less than a pCR were assessed to determine if there was enough residual tissue to evaluate posttreatment HER2 status. RFS was determined using the Kaplan-Meier method and compared by the log-rank statistic. Results: A pCR was achieved in 72 of the 142 (50.7%) patients. Residual tumor was sufficient to assess posttreatment HER2 status in 25 patients. Fluorescence in situ hybridization done on pretreatment specimens confirmed HER2 amplification before beginning therapy. Eight (32.0%) posttreatment tumors were found to be HER2 -negative by fluorescence in situ hybridization. At a median follow-up of 37 months (range, 8-56 months), the RFS was significantly better for patients with tumors that retained HER2 amplification (87.5% versus 50%, P = 0.04). Conclusion: High pCR rates are achieved in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab in combination with anthracyclines and taxanes. One third of patients with significant residual disease loses HER2 amplification, and this change is associated with poor RFS. Residual tumor identified at the time of surgery should be reassessed for HER2 status, and novel adjuvant therapy strategies need to be studied in this population. (Clin Cancer Res 2009;15(23):OF1–8)
267 citations
TL;DR: There is a critical need for a concerted international effort among patients with DCIS, clinicians, and basic scientists to conduct the research necessary to improve fundamental understanding of the biology and clinical behavior of DCIS and prevent development of invasive breast cancer.
Abstract: Purpose Ductal carcinoma in situ (DCIS) is the fourth leading cancer for women in the United States. Understanding of the biology and clinical behavior of DCIS is imperfect. This article highlights the current knowledge base and the scientific roadmap needed to advance the field. Methods This article is based on work done by and consultations obtained from leading experts in the field over a 6-month period that culminated in a full-day symposium designed to systematically review the most pertinent MEDLINE published reports and develop a roadmap to elucidate the molecular steps of carcinogenesis, reduce the extent or prevent the need for therapies, eliminate recurrences, and reduce morbidity. Results Expression profiling of pure DCIS will help elucidate the molecular characteristics that distinguish high-risk lesions from clinically irrelevant lesions. The development of new methods of extracting RNA from processed tissues may provide opportunities for research. Mammography often underestimates the patholo...
243 citations
TL;DR: Despite exciting progress in the understanding of breast cancer development and progression, and in the development of novel therapeutic strategies, breast cancer remains the second leading cause of cancer-related death in women.
Abstract: Despite exciting progress in the understanding of breast cancer development and progression, and in the development of novel therapeutic strategies, breast cancer remains the second leading cause of cancer-related death in women, with a yearly toll of more than 40,000 deaths in the United States
211 citations
TL;DR: High GGI is associated with increased sensitivity to neoadjuvant paclitaxel plus fluorouracil, adriamycin, and cyclophosphamide chemotherapy in both ER-negative and ER- positive patients, but it remains a predictor of worse survival in ER-positive patients.
Abstract: PURPOSE The genomic grade index (GGI) is a 97-gene measure of histological tumor grade. High GGI is associated with decreased relapse-free survival in patients receiving either endocrine or no systemic adjuvant therapy. Herein we examined whether GGI predicts pathologic response to neoadjuvant chemotherapy in patients with HER-2-normal breast cancer. METHODS Gene expression data (gene chips) was generated from fine-needle aspiration biopsies (n = 229) prospectively collected before neoadjuvant paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Pathologic response was quantified using the residual cancer burden (RCB) method. The association between the GGI and pathologic response was assessed in univariate and multivariate analyses. The performance of a response predictor combining clinical variables and GGI was evaluated under cross-validation. Results Eighty-five percent of grade 1 tumors had low GGI, 89% of grade 3 tumors had high GGI, and 63% of grade 2 tumors had low GGI. Among both estrogen receptor (ER)-positive and -negative cancers, high GGI score was associated with pathologic complete response (RCB-0) or minimal residual disease (RCB-1). A multivariate model combining GGI and clinical parameters had an overall accuracy of 71%, compared with 58% for the GGI alone, for prediction of pathologic response. However, high GGI score was also associated with significantly worse distant relapse-free survival in patients with ER-positive cancer (P = .005), and was not associated with survival in patients with ER-negative cancer. CONCLUSION High GGI is associated with increased sensitivity to neoadjuvant paclitaxel plus fluorouracil, adriamycin, and cyclophosphamide chemotherapy in both ER-negative and ER-positive patients, but it remains a predictor of worse survival in ER-positive patients.
180 citations
TL;DR: Patients who have breast cancer and diabetes are at increased risk of chemotherapy-related toxicities compared with nondiabetic patients who are receiving chemotherapy and have higher all-cause mortality.
Abstract: Purpose To evaluate whether diabetes affects patterns of adjuvant chemotherapy use, toxic effects of chemotherapy, and breast cancer outcomes. Patients and Methods By using the Surveillance, Epidemiology, and End Results–Medicare database, we identified patients aged 66 years or older who had stages I through III breast cancer that was diagnosed between 1992 and 2002. Multivariable regression analyses were performed to determine the effect of diabetes on use of chemotherapy, toxicities, and outcomes. The risks of all-cause mortality and breast cancer–specific (BCS) mortality were estimated with the Kaplan-Meier method. Results Our cohort had 70,781 men and women, of whom 14,414 (20.36%) had diabetes. Among people who received chemotherapy (n = 11,826), 21.0% were diabetics. In this group, diabetics had lower odds of receiving anthracyclines (odds ratio [OR], 0.78; 95% CI, 0.71 to 0.87) and taxanes (OR, 0.86; 95% CI, 0.75 to 0.99). Diabetes was associated with increased odds of being hospitalized for any c...
TL;DR: Recent innovations in bone imaging are discussed and algorithms are presented, based on the strengths and weaknesses of each technique, to facilitate the most successful and cost-effective choice of imaging studies for the detection of osseous metastases.
Abstract: Summary Bone is the most common site of distant metastases from breast carcinoma. The presence of bone metastases affects a patient's prognosis, quality of life, and the planning of their treatment. We discuss recent innovations in bone imaging and present algorithms, based on the strengths and weaknesses of each technique, to facilitate the most successful and cost-effective choice of imaging studies for the detection of osseous metastases. Skeletal scintigraphy (bone scan) is very sensitive in the detection of osseous metastases and is recommended as the first imaging study in patients who are asymptomatic. Radiographs are recommended for the assessment of abnormal radionuclide uptake or the risk of pathological fracture and as initial imaging studies in patients with bone pain. MRI or PET–CT can be considered for cases of abnormal radionuclide uptake that are not addressed by radiography. Osseous metastases can lead to emergent situations, such as spinal-cord compression or impending fracture of a weight-bearing bone, and imaging guidelines are essential for early detection and initiation of appropriate therapy. The imaging method used in non-emergent situations, such as assessment of the ribs, sternum, pelvis, hips, and joints, should be guided by the strengths and limitations of each technique.
TL;DR: Patients with nonmetastatic triple receptor-negative breast tumors have a high early incidence of brain metastases associated with poor survival and maybe an ideal cohort to target brain metastase preventive strategies, according to this single-institutional study.
TL;DR: In this paper, the authors compared the prognostic value of CTC and FDG-PET/CT monitoring during systemic therapy for metastatic breast cancer (MBC) patients, and categorized patients according to mid-therapy CTC counts as favorable (i.e., 41 months).
Abstract: Purpose Circulating tumor cells (CTCs) and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) are two new promising tools for therapeutic monitoring. In this study, we compared the prognostic value of CTC and FDG-PET/CT monitoring during systemic therapy for metastatic breast cancer (MBC). Patients and Methods A retrospective analyses of 115 MBC patients who started a new line of therapy and who had CTC counts and FDG-PET/CT scans performed at baseline and at 9 to 12 weeks during therapy (midtherapy) was performed. Patients were categorized according to midtherapy CTC counts as favorable (ie, 41 months). Midtherapy CTC levels correl...
TL;DR: The EGFR pathway is involved in tumor growth and metastasis of IBC, and targeting EGFR through the ERK pathway may represent an effective therapeutic approach to suppress tumorigenicity and prevent metastasis in EGFR-expressing IBC.
Abstract: Purpose: Inflammatory breast cancer (IBC) is a rare but aggressive type of advanced breast cancer. Epidermal growth factor receptor (EGFR) expression is an independent poor prognostic factor in IBC. The purpose of this study was to determine the effect on IBC tumorigenicity and metastasis of blocking the EGFR pathway. Experimental Design: IBC cell lines, which express high level of EGFR, were treated with EGFR small interfering RNA and with the EGFR tyrosine kinase inhibitor erlotinib. The role of EGFR in IBC cell proliferation, motility, invasiveness, and change of the expression levels of epithelial-mesenchymal transition markers was examined. The role of extracellular signal-regulated kinase (ERK)-1/2 in erlotinib activity was also stud- ied. The activity of erlotinib in tumor growth and metastasis was examined in an ortho- topic xenograft model of IBC. Results: Erlotinib inhibited proliferation and anchorage-independent growth of IBC cells, and this inhibition was ERK dependent. Erlotinib inhibited cell motility and invasiveness and reversed the mesenchymal phenotype of IBC cells to epithelial phe- notype in three-dimensional culture. Erlotinib dramatically inhibited IBC tumor growth in a xenograft model. Interestingly, erlotinib inhibited spontaneous lung metastasis, even at a low dose that had no significant effect on primary tumor growth. These erlotinib-treated tumors were converted to epithelial phenotype from mesenchymal phenotype. Conclusions: The EGFR pathway is involved in tumor growth and metastasis of IBC. Targeting EGFR through the ERK pathway may represent an effective therapeutic approach to suppress tumorigenicity and prevent metastasis in EGFR-expressing IBC. (Clin Cancer Res 2009;15(21):6639-48)
TL;DR: There are insufficient data to recommend replacing anthracyclines in the adjuvant treatment of breast cancer, and there is no validated test that can determine whether anthrACYclines can be of greater benefit than other agents for individual patients.
Abstract: Purpose To review data relating to anthracyclines in the adjuvant treatment of early breast cancer. Design This is a report from a seminar in which the future of anthracyclines in the adjuvant treatment of breast cancer was considered. In particular, the question of whether anthracyclines should now be discarded and replaced by taxanes was addressed. Results Accumulating data from large randomized trials indicate that genetic markers may have a role in predicting sensitivity to cytotoxic drugs. However, no reliable, validated test is available for predicting sensitivity to anthracyclines in particular. Topoisomerase IIα amplification and/or deletion, especially in conjunction with human epidermal growth factor receptor-2 amplification, has been proposed to fulfill this role but more data are needed. Currently, only one published trial has shown that a taxane-based regimen may be superior to an anthracycline-based regimen, but several trials indicate that combinations including both anthracyclines and taxa...
TL;DR: High Tau protein expression is associated with better prognosis in patients treated with adjuvant anthracycline and paclitaxel chemotherapy and endocrine therapy, but there was no significant interaction between Tau expression and pac litaxel benefit.
Abstract: Purpose We assessed Tau protein expression in primary breast cancer specimens of patients included in the National Surgical Breast and Bowel Project (NSABP) -B 28 clinical trial. Expression levels were correlated with disease-free survival (DFS) and overall survival (OS). Interaction between this marker and paclitaxel efficacy was also examined. Methods Tissue microarrays were available for 1,942 patients (63% of all trial participants) who were randomly assigned to receive either four courses of doxorubicin and cyclophosphamide (AC) or AC followed by four courses of adjuvant paclitaxel chemotherapy. All patients who were hormone receptor positive received adjuvant endocrine therapy. Immunohistochemistry was used to measure Tau expression at M. D. Anderson Cancer Center blinded to clinical outcome. Correlation between Tau and OS and DFS was performed by the NSABP Biostatistical Center. Results Forty-three percent of patients were Tau positive. Tau positivity correlated with estrogen receptor (ER) -positiv...
TL;DR: In this paper, the authors evaluated estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as predictors of locoregional recurrence in patients with lymph node-negative disease and tumors ≤ 1cm.
Abstract: Purpose Data have suggested that the molecular features of breast cancer are important determinants of outcome; however, few studies have correlated these features with locoregional recurrence (LRR). In the present study, we evaluated estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as predictors of LRR in patients with lymph node-negative disease and tumors ≤1cm, because these patients often do not receive adjuvant chemotherapy or trastuzumab. Methods and Materials The data from 911 patients with stage T1a,bN0 breast cancer who had received definitive treatment at our institution between 1997 and 2002 were retrospectively reviewed. We prospectively analyzed ER/PR/HER2 expression from the archival tissue blocks of 756 patients. These 756 patients represented the cohort for the present study. Results With a median follow-up of 6.0 years, the 5- and 8-year Kaplan-Meier LRR rate was 1.6% and 5.9%, respectively, with no difference noted in those who underwent breast conservation therapy vs. mastectomy ( p =.347). The 8-year LRR rates were greater in the patients with ER-negative (10.6% vs. 4.2%, p =.016), PR-negative (9.0% vs. 4.2%, p =.009), or HER2-positive (17.5% vs. 3.9%, p =0.009) tumors. On multivariate analysis, ER-negative and PR-negative disease (hazard ratio, 2.37; p =.046) and HER2-positive disease (hazard ratio, 3.13, p =.016) independently predicted for LRR. Conclusion Patients with ER/PR-negative or HER2-positive T1a,bN0 breast cancer had a greater risk of LRR. Therapeutic strategies, such as the use of chemotherapy and/or anti-HER2 therapies, should be considered for future clinical trials for these patients.
TL;DR: Results indicate that CXCR4 can contribute to the homing of breast cancer cells to the bone, which might have important clinical implications since patients with metastatic bone disease may achieve the highest benefit from a CX CR4-targeted therapy.
TL;DR: Currently, more than half of older women across the US diagnosed with nonmetastatic invasive breast cancer treated surgically receive BCS, representing a substantial increased use compared with historical data.
Abstract: Background Breast-conserving surgery (BCS) followed by radiotherapy is as effective as mastectomy for treatment of early invasive breast cancer. But earlier studies report low BCS use rates of 12% to 43% nationally, especially in older patients. We sought to determine current patterns and predictors of BCS use. Study Design In a national Medicare database of all beneficiaries (age greater than 65 years) with incident invasive breast cancer treated with operation in 2003, claims codes identified BCS versus mastectomy and demographic, treatment, and geographic region covariates. The 2003 Area Resource File provided socioeconomic covariates. Logistic regression modeled predictors of BCS. Results In 56,725 women, 59% were treated with BCS versus 41% with mastectomy. BCS was more likely in women who were younger than 70 years (odds ratio [OR], 1.37; 95% CI, 1.31 to 1.44; p Conclusions Currently, more than half of older women across the US diagnosed with nonmetastatic invasive breast cancer treated surgically receive BCS, representing a substantial increased use compared with historical data. Lack of BCS use appears in part associated with socioeconomic disadvantage, suggesting that persistent barriers to breast conservation exist.
TL;DR: Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting paclitaxel sensitivity.
Abstract: Paclitaxel is used widely in the treatment of breast cancer. Not all tumors respond to this drug, however, and the characteristics that distinguish resistant tumors from sensitive tumors are not well defined. Activation of the spindle assembly checkpoint is required for paclitaxel-induced cell death. We hypothesized that cyclin-dependent kinase (CDK) 1 activity and CDK2 activity in cancer cells, which reflect the activation state of the spindle assembly checkpoint and the growth state, respectively, predict sensitivity to paclitaxel. Cell viability assays and DNA and chromatin morphology analyses were performed in human breast cancer cell lines to evaluate sensitivity to paclitaxel and the cell cycle response to paclitaxel. We then examined the specific activities of CDK1 and CDK2 in these cell lines and in xenograft models of human breast cancer before and after paclitaxel treatment. Protein expression and kinase activity of CDKs and cyclins were analyzed using a newly developed assay system. In the cell lines, biological response to paclitaxel in vitro did not accurately predict sensitivity to paclitaxel in vivo. Among the breast cancer xenograft tumors, however, tumors with significantly increased CDK1 specific activity after paclitaxel treatment were sensitive to paclitaxel in vivo, whereas tumors without such an increase were resistant to paclitaxel in vivo. Baseline CDK2 specific activity was higher in tumors that were sensitive to paclitaxel than in tumors that were resistant to paclitaxel. The change in CDK1 specific activity of xenograft tumors after paclitaxel treatment and the CDK2 specific activity before paclitaxel treatment are both associated with the drug sensitivity in vivo. Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting paclitaxel sensitivity.
TL;DR: This study suggests that expression of CXCR4 in primary breast tumors is associated with a higher likelihood of developing bone metastases, which could open new avenues for the development of novel adjuvant strategies, including bone-targeting agents.
Abstract: Background. Chemokine receptor 4 (CXCR4) has been demonstrated to have a critical role in the early metastatic process. The aim of this study was to eval
TL;DR: The potential application of the nodal ratio to breast cancer staging and prognostication, its role in the context of modern surgical techniques such as sentinel node biopsy, and its potential correlations with new biologic markers such as circulating tumor cells and breast cancer stem cells are discussed.
Abstract: The number of positive axillary nodes is a strong prognostic factor in breast cancer, but is affected by variability in nodal staging technique yielding varying numbers of excised nodes. The nodal ratio of positive to excised nodes is an alternative that could address this variability. Our 2006 review found that the nodal ratio consistently outperformed the number of positive nodes, providing strong arguments for the use of nodal ratios in breast cancer staging and management. New evidence has continued to accrue confirming the prognostic significance of nodal ratios in various worldwide population settings. This review provides an updated summary of available data, and discusses the potential application of the nodal ratio to breast cancer staging and prognostication, its role in the context of modern surgical techniques such as sentinel node biopsy, and its potential correlations with new biologic markers such as circulating tumor cells and breast cancer stem cells.
TL;DR: Three pathways—vasculolymphatic, cell proliferation and metastatic—that could represent important targets in the treatment of IBC are discussed.
Abstract: Despite progress in combined-modality treatment with chemotherapy, surgery, and radiation therapy, the long-term outcome for patients with inflammatory breast cancer (IBC) remains poor. Therapies that target vasculolymphatic processes--angiogenesis, lymphangiogenesis, and vasculogenesis--have shown potential in the treatment for IBC, as represented by bevacizumab. Although the therapeutic effect of targeting lymphangiogenesis and vasculogenesis requires further investigation, targeting of angiogenesis has potential, not only through true antiangiogenic effects, but also through antitumor effects in concert with other pathways. Therapies that target cell proliferation pathways are the most promising targeted therapies for IBC. In particular, therapies that target human epidermal growth factor receptor 2 (for example, trastuzumab and lapatinib) have performed well in the clinical setting, leading to improved outcomes for patients with IBC. Metastatic pathways could have a unique, key role in the aggressiveness of the IBC phenotype. Further extensive work on the unique molecular characteristics of IBC is essential to ensure improved outcomes for patients with this disease. In this Review we discuss three pathways--vasculolymphatic, cell proliferation and metastatic--that could represent important targets in the treatment of IBC.
TL;DR: The aim is to develop and demonstrate the feasibility of multisequence and multiplanar MRI for whole‐body cancer detection and to test the application of this technology in clinical practice.
Abstract: Purpose
To develop and demonstrate the feasibility of multisequence and multiplanar MRI for whole-body cancer detection.
Materials and Methods
Two fast Dixon-based sequences and a diffusion-weighted sequence were used on a commercially available 1.5 T scanner for whole-body cancer detection. The study enrolled 19 breast cancer patients with known metastases and in multistations acquired whole-body axial diffusion-weighted, coronal T2-weighted, axial/sagittal pre- and postcontrast T1-weighted, as well as triphasic abdomen images. Three radiologists subjectively scored Dixon images of each series for overall image quality and fat suppression uniformity on a 4-point scale (1 = poor, 2 = fair, 3 = good, and 4 = excellent).
Results
Eighteen of the 19 patients completed the whole-body MRI successfully. The mean acquisition time and overall patient table time were 46 ± 3 and 69 ± 5 minutes, respectively. The average radiologists' scores for overall image quality and fat suppression uniformity were both 3.4 ± 0.5. The image quality was consistent between patients and all completed whole-body examinations were diagnostically adequate.
Conclusion
Whole-body MRI offering essentially all the most optimal tumor-imaging sequences in a typical 1-hour time slot can potentially become an appealing “one-stop-shop” for whole-body cancer imaging. J. Magn. Reson. Imaging 2009;29:1154–1162. © 2009 Wiley-Liss, Inc.
TL;DR: It is suggested that BRCA1/2-associated breast cancers progress through the same intermediate steps as sporadic breast cancers, and that DCIS should be considered as a part of the BRC a 1/2 tumor spectrum.
Abstract: Mutations in BRCA1 and BRCA2 increase a woman's lifetime risk of developing breast cancer by 43% to 84%. It was originally postulated that BRCA1/2-associated breast cancers develop more rapidly than sporadic cancers and may lack preinvasive lesions. More recent studies have found preinvasive lesions in prophylactic mastectomy specimens from mutation carriers; however, there is little information on the presence of preinvasive lesions in tissue adjacent to breast cancers. Our aim is to investigate the role of preinvasive lesions in BRCA-associated breast carcinogenesis. We retrospectively compared BRCA1/2-associated breast cancers and sporadic breast cancers for the prevalence of preinvasive lesions [ductal carcinoma in situ (DCIS), lobular carcinoma in situ, and atypical lobular hyperplasia] in tissue adjacent to invasive breast cancers. Pathology was reviewed for 73 BRCA1/2-associated tumors from patients with breast cancer. We selected 146 patients with mutation-negative breast cancer as age-matched controls. Among the BRCA1/2-associated breast cancers, 59% had at least one associated preinvasive lesion compared with 75% of controls. Preinvasive lesions were more prevalent in BRCA2 mutation carriers than in BRCA1 mutation carriers (70% versus 52%, respectively). The most common preinvasive lesion in both groups was DCIS; 56% of BRCA1/2-associated breast cancers and 71% of the sporadic breast cancers had adjacent intraductal disease, respectively. Preinvasive lesions, most notably DCIS, are common in BRCA1/2-associated breast cancers. These findings suggest that BRCA1/2-associated breast cancers progress through the same intermediate steps as sporadic breast cancers, and that DCIS should be considered as a part of the BRCA1/2 tumor spectrum.
TL;DR: Women at a high risk for breast cancer are offered choices for screening or prophylactic surgeries and opinions regarding screening and surgical strategies in high‐risk women are evaluated.
Abstract: BACKGROUND:
Women at a high risk for breast cancer are offered choices for screening or prophylactic surgeries. The aim of this study was to evaluate opinions regarding screening and surgical strategies in high-risk women.
METHODS:
Women at the authors' institution who received BRCA1 of 2 testing before July 2005 were sent a follow-up patient survey. The authors compared responses of women who tested positive for a deleterious mutation with those who tested negative. For those who expressed an opinion (agree vs disagree), a 2-sided Fisher exact test was used to compare responses.
RESULTS:
A total of 540 surveys were sent, and 312 were returned (58%). Of these, 217 had breast cancer, and 86 women tested positive for a mutation. No BRCA+ women felt mammograms were difficult to get because of discomfort, whereas 5.4% of the BRCA− group did (P = .039). Seventy percent of BRCA+ women agreed that prophylactic mastectomy (PM) is the most effective means for reducing risk, compared with 40% of BRCA− women (P < .001). PM was felt to be the only way to reduce worry in 64.7% of BRCA+ and in 34.4% of BRCA− women (P < .001). PM was felt to be too drastic for 36.1% of BRCA+ and 40.5% of BRCA− women (P = .562). Difficulty in deciding between screening and PM occurred in 23.9% of BRCA+ and 12.5% of BRCA− women (P = .046). After excluding women with bilateral breast cancers, 81.0% of women who agreed that PM was best to reduce risk underwent a PM versus 19.1% of those who disagreed (P < .001). Of women who felt PM was the only way to reduce worry, 84.2% underwent PM. Only 15.8% of women who did not believe that it was the only way to decrease worry underwent PM (P < .001).
CONCLUSIONS:
BRCA mutation carriers were more likely to believe PM to be the best way to reduce both risk and worry of breast cancer. High-risk women who agreed that PM was more likely to reduce risk and worry of breast cancer were more likely to proceed with this intervention. Cancer 2009. © 2009 American Cancer Society.
TL;DR: The genomic era has been characterized by an exponential increase in the number of targets in the management of breast cancer andGene expression profiles are being studied in order to improve predictions of response and toxicity.
Abstract: The genomic era has been characterized by an exponential increase in the number of targets in the management of breast cancer. Prognostic profiling has helped to determine which tumors are more likely to be associated with poor disease-free survival. Gene expression profiles are being studied in order to improve predictions of response and toxicity. Epigenetics is being evaluated for its ability to influence estrogen receptor expression. However, these fields require further validation. This review discusses the advances in the management of breast cancer through genomic evaluation.
TL;DR: Breast cancer patients with HER2+ T1a,bN0M0 tumors have a significant risk of relapse and should be considered candidates for adjuvant systemic therapy including anti-HER2 agents.
Abstract: #701 Background: Controversy surrounds the prognosis of breast cancer patients with T1a,bN0M0 tumors following locoregional therapy and the need for adjuvant systemic therapy, especially for HER2+ disease. The purposes of the study were to determine the recurrence-free survival (RFS), and distant recurrence-free survival (DRFS) in small HER2+ tumors compared with hormone receptor ( HR)+ and triple receptor- (TN) tumors. Methods: Stage T1a,bN0M0 breast cancers diagnosed between 1973-2003 were reviewed by dedicated breast pathologists. HER2+ tumors were defined as 3+ by IHC or gene amplification. Patients were categorized into 3 groups:TN (ER-, PR-and HER2-), HER2+ (regardless of HR status) and HR+ (HER2-). RFS and DRFS were estimated by the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards models were fit to determine the association of each group with the risk of recurrence after adjustment for other characteristics. Results: Of the 1796 patients, 427 were excluded from the analysis due to being male (2), lack of receptor information (249), and adjuvant chemotherapy (176) leaving 1369 pts for analysis. Median age was 57 years,(range, 26-88). There were 381(28%) T1a and 988(72%) T1b tumors; HR+ 68%, TN 23%, HER2+ 9%. Patients who had HER2+ breast cancer tended to be younger,(p=0.001); have more T1a tumors, (p=0.001); and have higher nuclear grade,(p Conclusions: Breast cancer patients with HER2+ T1a,bN0M0 tumors have a significant risk of relapse and should be considered candidates for adjuvant systemic therapy including anti-HER2 agents. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 701.
TL;DR: Patients with triple-receptor negative breast tumors may be an ideal cohort to target brain metastases preventive strategies and report higher early cumulative incidence compared to historical controls associated with poor survival.
Abstract: #6077 Background The purpose of this study was to determine the incidence of brain metastases in a cohort of women with early stage triple-receptor negative breast cancer and to evaluate the survival outcomes of these patients. Method Six hundred and seventy nine patients with early stage triple-receptor negative breast cancer diagnosed between 1980 and 2006 were identified. Cumulative incidence of brain metastases at 2- and 5-years following a diagnosis of early-stage triple receptor-negative breast cancer considering death as a competing risk was computed. Time to brain metastases was computed from the date of breast cancer diagnosis to the date of development of brain metastases. Cox proportional hazards models, adjusted for various patient and tumor characteristics, were then fitted to explore factors that could predict for the subsequent development of brain metastases in this cohort. Survival following a diagnosis of brain metastases was measured from the date of brain metastases diagnosis to the date of death from any cause. All survival outcomes were computed using the Kaplan – Meier product limit method and compared across groups using log rank statistic. Results Median age was 50 years (range 22 to 97 years) and median follow-up was 26.9 months (range 1.1 to 321.3 months. Overall 42 (6.2%) patients developed brain metastases of whom 16 (38.1%) had 3 brain lesions or less, 19 (45.2%) had more than 3 brain lesions and number of brain lesions was unknown in 7 (16.7%) patients. Overall cumulative incidence at 2- and 5-years was 5.6% (95% CI 3.8%-7.9%) and 9.6% (95% CI 6.8% - 13%) respectively. Twenty –four (3.5%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 2- and 5-years observed to be 2.0% (95% CI 2.6% -6.0%) and 4.9% (95% CI 3.2%-7.0%) respectively. In the multivariable model factors such as age at primary tumor diagnosis, initial clinical stage, histological tumor grade, number of lymph nodes examined and tumor lymph-vascular invasion were not significantly associated with time to brain metastases. For the whole group of patients who developed brain metastases median survival was 2.9 months (95% CI 2.0 – 7.6 months). Among those who developed brain metastases as the first site of recurrence median survival was 5.8 months (95% CI 1.7 – 11.0 months). Conclusion Data from published studies have reported a 5-year cumulative incidence of brain metastases of approximately 5 % in an unselected breast cancer population. In our large single institutional study patients with triple-receptor-negative breast tumors we report higher early cumulative incidence compared to historical controls associated with poor survival. Patients with triple-receptor negative breast tumors may be an ideal cohort to target brain metastases preventive strategies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6077.