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1.  Therapy related acute myeloid leukemia in breast cancer survivors, a population-based study 
The aim of this study was to determine the association between age and stage at diagnosis of breast cancer with the subsequent development of acute myeloid leukemia (AML). The National Cancer Institute’s Surveillance, Epidemiology, and End Results program were analyzed for incidence of second malignancies by age and stage at diagnosis of breast cancer. 420,076 female patients were identified. There was an age dependent risk of a subsequent diagnosis of AML in women younger than 50 years old (RR 4.14; P <0.001) and women 50–64 years old (RR 2.19; P <0.001), but not those 65 and older (RR 1.19; P = 0.123) when compared with the expected incidence of AML. A similar age dependent pattern was observed for second breast and ovarian cancers. There was also a stage dependent increase in risk of subsequent AML in younger women with stage III disease when compared with stage I disease (RR 2.92; P = 0.004), and to a lesser extent in middle age women (RR 2.24; P = 0.029), but not in older women (RR 0.79; P = 0.80).Younger age and stage III disease at the time of breast cancer diagnosis are associated with increased risk of a subsequent diagnosis of AML. This association maybe explained by either greater chemotherapy exposure or an interaction between therapy and genetic predisposition.
PMCID: PMC3400139  PMID: 19322652
Therapy-related acute myeloid leukemia; Breast cancer; Chemotherapy; SEER; Epidemiology; Radiation therapy
2.  Exemestane Versus Anastrozole in Postmenopausal Women With Early Breast Cancer: NCIC CTG MA.27—A Randomized Controlled Phase III Trial 
Journal of Clinical Oncology  2013;31(11):1398-1404.
In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non–cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss.
Patients and Methods
We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease–free survival, incidence of contralateral new primary breast cancer, and safety.
In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease–free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms.
This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor–positive breast cancer.
PMCID: PMC3612593  PMID: 23358971
3.  Activating HER2 mutations in HER2 gene amplification negative breast cancer 
Cancer discovery  2012;3(2):224-237.
Data from eight breast cancer genome sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized thirteen HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGFR exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings demonstrate that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.
PMCID: PMC3570596  PMID: 23220880
Genomics; Breast Cancer; Receptor Tyrosine Kinase; Oncogene
4.  The Genomic Landscape of Breast Cancer as a Therapeutic Roadmap 
Cancer discovery  2013;3(1):27-34.
The application of high throughput techniques to profile DNA, RNA and protein in breast cancer samples from hundreds of patients has profoundly increased our knowledge of the disease. The etiological events that drive breast cancer are finally coming into focus and should be used to set priorities for clinical trials. In this Research Focus we summarize some of the headline conclusions from six recent breast cancer ‘omics profiling’ papers in Nature, with an emphasis on the implications for systemic therapy.
PMCID: PMC3553590  PMID: 23319768
5.  Novel Sampling Strategies to Enable Microarray Gene Expression Signatures in Breast Cancer: A Study to Determine Feasibility and Reproducibility in the Context of Clinical Care 
Feasibility and reproducibility of microarray biomarkers in clinical settings are doubted because of reliance on fresh frozen tissue. We sought to develop and test a paradigm of frozen tissue collection from early breast tumors to enable use of microarray in oncology practice.
Experimental Design
Frozen core needle biopsies (CNBx) were collected from 150 clinical stage I patients during image-guided diagnostic biopsy and/or surgery. Histology and tumor content from frozen cores were compared to diagnostic specimens. Twenty eight patients had microarray analysis to examine accuracy and reproducibility of predictive gene signatures developed for estrogen receptor (ER) and HER2.
One hundred twenty seven (85%) of 150 patients had at least one frozen core containing cancer suitable for microarray analysis. Larger tumor size, ex vivo biopsy, and use of a new specimen device increased the likelihood of obtaining representative specimens. Sufficient quality RNA was obtained from 90% of tumor cores. Microarray signatures predictive ER and HER2 expression were developed in a training sets of up to 356 surgical samples and were applied to microarray data obtained from core samples collected in clinical settings. In these samples, a sensitivity / specificity of 94% / 100% and 82% / 72% for predicting ER and HER2, respectively was achieved. Predictions were reproducible in 83–100% of paired diagnostic and surgical samples.
Frozen CNBx can be readily obtained from most breast cancers without interfering with pathologic evaluation. Collection of tumor tissue at diagnostic biopsy and/or at surgery from lumpectomy specimens using image guidance resulted in sufficient samples for array analysis from over 90% of patients. Sampling of breast cancer for microarray data is reproducible and feasible in clinical settings and can yield signatures predictive of multiple breast cancer phenotypes.
PMCID: PMC3786337  PMID: 19224362
6.  Effect of continuous statistically standardized measures of estrogen and progesterone receptors on disease-free survival in NCIC CTG MA.12 Trial and BC Cohort 
We hypothesized improved inter-laboratory comparability of estrogen receptor (ER) and progesterone receptor (PgR) across different assay methodologies with adjunctive statistical standardization, akin to bone mineral density (BMD) z-scores. We examined statistical standardization in MA.12, a placebo-controlled pre-menopausal trial of adjuvant tamoxifen with locally assessed hormone receptor +/- tumours, and in a cohort of post-menopausal British Columbia (BC) tamoxifen-treated patients.
ER and PgR were centrally assessed for both patient groups with real time quantitative reverse transcription polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Effects on disease-free survival (DFS) were investigated separately for 345 MA.12 and 673 BC patients who had both qPCR and IHC assessments. Comparisons utilized continuous laboratory units and statistically standardized z-scores. Univariate categorization of ER/PgR was by number of standard deviations (SD) above or below the mean (z-score ≥1.0 SD below mean; z-score <1.0 SD below mean; z-score ≤1.0 SD above mean; z-score >1.0 SD above mean). Exploratory multivariate examinations utilized step-wise Cox regression.
Median follow-up for MA.12 was 9.7 years; for BC patients, 11.8 years. For MA.12, 101 of 345 (29%) patients were IHC ER-PgR-. ER was not univariately associated with DFS (qPCR, P = 0.19; IHC, P = 0.08), while PgR was (qPCR, P = 0.09; IHC, P = 0.04). For BC patients, neither receptor was univariately associated with DFS: for ER, PCR, P = 0.36, IHC, P = 0.24; while for PgR, qPCR, P = 0.17, IHC, P = 0.31. Multivariately, MA.12 patients randomized to tamoxifen had significantly better DFS (P = 0.002 to 0.005) than placebo. Meanwhile, jointly ER and PgR were not associated with DFS whether assessed by qPCR or by IHC in all patients, or in the subgroup of patients with IHC positive stain, for pooled or separate treatment arms. Different results by type of continuous unit supported the concept of ER level being relevant for medical decision-making. For postmenopausal BC tamoxifen patients, higher qPCR PgR was weakly associated with better DFS (P = 0.06).
MA.12 pre-menopausal patients in a placebo-controlled tamoxifen trial had similar multivariate prognostic effects with statistically standardized hormone receptors when tumours were assayed by qPCR or IHC, for hormone receptor +/- and + tumours. The BC post-menopausal tamoxifen cohort did not exhibit a significant prognostic association of ER or PgR with DFS. Adjunctive statistical standardization is currently under investigation in other NCIC CTG endocrine trials.
PMCID: PMC3978444  PMID: 23972025
7.  ER and PI3K independently modulate endocrine resistance in ER positive breast cancer 
Cancer discovery  2011;1(4):287-288.
Endocrine Therapy Resistant Estrogen Receptor Positive (ER+) Breast Cancer is the most common cause of breast cancer death. Miller et al. demonstrate that ligand-independent ER activity promotes the growth of breast cancer cells through CDK4/E2F. As an independent event the PI3K pathway is also up regulated in endocrine therapy resistant cells. Promising preclinical evidence by several groups for the combination of an inhibitor of ligand-independent ER, fulvestrant, with PI3K inhibition, has led to the activation of trials evaluating this concept.
PMCID: PMC3215586  PMID: 22096658
8.  Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline Substitution in the NCIC.CTG MA.5 Randomized Trial 
Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy.
Experimental Design
Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basal-like subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan-Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes.
Intrinsic subtypes were associated with RFS (P = 0005) and OS (P < 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non-HER2-E tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined Her2+ tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors [n = 94; HR, 1.1; 95% confidence interval (CI), 0.6−.1 for RFS and HR, 1.3; 95% CI, 0.7−2.5 for OS].
HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal- like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required.
PMCID: PMC3743660  PMID: 22351696
9.  A 50-Gene Intrinsic Subtype Classifier for Prognosis and Prediction of Benefit from Adjuvant Tamoxifen 
Gene expression profiling classifies breast cancer into intrinsic subtypes based on the biology of the underlying disease pathways. We have used material from a prospective randomized trial of tamoxifen versus placebo in premenopausal women with primary breast cancer (NCIC CTG MA.12) to evaluate the prognostic and predictive significance of intrinsic subtypes identified by both the PAM50 gene set and by immunohistochemistry.
Experimental Design
Total RNA from 398 of 672 (59%) patients was available for intrinsic subtyping with a quantitative reverse transcriptase PCR (qRT-PCR) 50-gene predictor (PAM50) for luminal A, luminal B, HER-2–enriched, and basal-like subtypes. A tissue microarray was also constructed from 492 of 672 (73%) of the study population to assess a panel of six immunohistochemical IHC antibodies to define the same intrinsic subtypes.
Classification into intrinsic subtypes by the PAM50 assay was prognostic for both disease-free survival (DFS; P = 0.0003) and overall survival (OS; P = 0.0002), whereas classification by the IHC panel was not. Luminal subtype by PAM50 was predictive of tamoxifen benefit [DFS: HR, 0.52; 95% confidence interval (CI), 0.32–0.86 vs. HR, 0.80; 95% CI, 0.50–1.29 for nonluminal subtypes], although the interaction test was not significant (P = 0.24), whereas neither subtyping by central immunohistochemistry nor by local estrogen receptor (ER) or progesterone receptor (PR) status were predictive. Risk of relapse (ROR) modeling with the PAM50 assay produced a continuous risk score in both node-negative and node-positive disease.
In the MA.12 study, intrinsic subtype classification by qRT-PCR with the PAM50 assay was superior to IHC profiling for both prognosis and prediction of benefit from adjuvant tamoxifen.
PMCID: PMC3743663  PMID: 22711706
10.  Neoadjuvant Therapy in Operable Breast Cancer: Application to Triple Negative Breast Cancer 
Journal of Oncology  2013;2013:219869.
Systemic treatment for triple negative breast cancer (TNBC: negative for the expression of estrogen receptor and progesterone receptor and HER2 amplification) has been limited to chemotherapy options. Neoadjuvant chemotherapy induces tumor shrinkage and improves the surgical outcomes of patients with locally advanced disease and also identifies those at high risk of disease relapse despite today's standard of care. By using pathologic complete response as a surrogate endpoint, novel treatment strategies can be efficiently assessed. Tissue analysis in the neoadjuvant setting is also an important research tool for the identification of chemotherapy resistance mechanisms and new therapeutic targets. In this paper, we review data on completed and ongoing neoadjuvant clinical trials in patients with TNBC and discuss treatment controversies that face clinicians and researchers when neoadjuvant chemotherapy is employed.
PMCID: PMC3747378  PMID: 23983689
11.  Practical implications of gene-expression-based assays for breast oncologists 
Gene-expression profiling has had a considerable impact on our understanding of breast cancer biology, and more recently on clinical care. Two statistical approaches underlie these advancements. Supervised analyses have led to the development of gene-expression signatures designed to predict survival and/or treatment response, which has resulted in the development of new clinical assays. Unsupervised analyses have identified numerous biological signatures including signatures of cell type of origin, signaling pathways, and of cellular proliferation. Included within these biological signatures are the molecular subtypes known as the ‘intrinsic’ subtypes of breast cancer. This classification has expanded our appreciation of the heterogeneity of breast cancer and has provided a way to sub-classify the disease in a manner that might have clinical utility. In this Review, we discuss the clinical utility of gene-expression-based assays and their technical potential as clinical tools vis-a-vis the performance of breast cancer biomarkers that are the current standard of care.
PMCID: PMC3703639  PMID: 22143140
12.  PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer 
To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical–pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance (p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-013-2416-2) contains supplementary material, which is available to authorized users.
PMCID: PMC3608881  PMID: 23423445
Breast cancer; Paclitaxel; PAM50 subtypes; PAM50 proliferation score; Prediction of paclitaxel efficacy
13.  Chronic Kidney Disease After Hematopoietic Cell Transplantation: a Systematic Review 
Advances in hematopoietic cell transplantation (HCT) have broadened its indications for use and resulted in more long-term HCT survivors. Some survivors develop chronic kidney disease (CKD), however, the incidence and risk factors are unclear. We performed a systematic review of studies identified from databases (MEDLINE, EMBASE, Science Citation Index), conference abstracts, and reference lists from selected manuscripts. From 927 manuscripts, 28 patient cohorts were identified in which 9,317 adults and children underwent HCT and 7,317 (79%) survived to at least 100 days, permitting inclusion of 5,337 (73% of survivors) in quantitative analyses. Although definitions and measurements varied widely, approximately 16.6% of HCT patients developed CKD and estimated glomerular filtration rate (eGFR in ml/min/1.73m2) decreased by 24.5 after 24 months. This decrease was greater amongst patients undergoing allogeneic HCT (ΔeGFR = −40.0 versus −18.6 for autologous transplants). Several commonly reported risk factors for CKD were investigated, including acute renal failure, total body irradiation, graft versus host disease, and long-term cyclosporine use. In conclusion, CKD following HCT is likely to be common, however, prospective studies with uniform definitions of CKD and risk factors are needed to confirm these findings and better define the underlying mechanisms to promote therapies that prevent this complication.
PMCID: PMC3564956  PMID: 18925905
chronic kidney disease (CKD); hematopoietic stem cell transplantation; bone marrow transplantation; renal failure; meta-analysis; systematic review; risk factor; complications
14.  Whole Genome Analysis Informs Breast Cancer Response to Aromatase Inhibition 
Nature  2012;486(7403):353-360.
To correlate the variable clinical features of estrogen receptor positive (ER+) breast cancer with somatic alterations, we studied pre-treatment tumour biopsies accrued from patients in a study of neoadjuvant aromatase inhibitor (AI) therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to hematopoietic disorders. Mutant MAP3K1 was associated with Luminal A status, low grade histology and low proliferation rates whereas mutant TP53 associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon AI treatment. Pathway analysis demonstrated mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in ER+ breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumor biology but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.
PMCID: PMC3383766  PMID: 22722193
15.  A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer 
Mutations in TP53 lead to a defective G1 checkpoint and the dependence on checkpoint kinase 1 (Chk1) for G2 or S phase arrest in response to DNA damage. In preclinical studies, Chk1 inhibition resulted in enhanced cytotoxicity of several chemotherapeutic agents. The high frequency of TP53 mutations in triple negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor, and HER2) make Chk1 an attractive therapeutic target. UCN-01, a non-selective Chk1 inhibitor, combined with irinotecan demonstrated activity in advanced TNBC in our Phase I study. The goal of this trial was to further evaluate this treatment in women with TNBC. Patients with metastatic TNBC previously treated with anthracyclines and taxanes received irinotecan (100–125 mg/m2 IV days 1, 8, 15, 22) and UCN-01 (70 mg/m2 IV day 2, 35 mg/m2 day 23 and subsequent doses) every 42-day cycle. Peripheral blood mononuclear cells (PBMC) and tumor specimens were collected. Twenty five patients were enrolled. The overall response (complete response (CR) + partial response (PR)) rate was 4 %. The clinical benefit rate (CR + PR + stable disease ≥6 months) was 12 %. Since UCN-01 inhibits PDK1, phosphorylated ribosomal protein S6 (pS6) in PBMC was assessed. Although reduced 24 h post UCN-01, pS6 levels rose to baseline by day 8, indicating loss of UCN-01 bioavailability. Immunostains of γH2AX and pChk1S296 on serial tumor biopsies from four patients demonstrated an induction of DNA damage and Chk1 activation following irinotecan. However, Chk1 inhibition by UCN-01 was not observed in all tumors. Most tumors were basal-like (69 %), and carried mutations in TP53 (53 %). Median overall survival in patients with TP53 mutant tumors was poor compared to wild type (5.5 vs. 20.3 months, p = 0.004). This regimen had limited activity in TNBC. Inconsistent Chk1 inhibition was likely due to the pharmacokinetics of UCN-01. TP53 mutations were associated with a poor prognosis in metastatic TNBC.
PMCID: PMC3539064  PMID: 23242585
Irinotecan; UCN-01; Chk1; Metastatic triple negative breast cancer; TP53; p53
16.  Lower-dose (6 mg Daily) versus High-dose (30 mg Daily) Oral Estradiol Therapy of Hormone-receptor-positive, Aromatase-inhibitor-resistant Advanced Breast Cancer: A Randomized Phase 2 Study 
Estrogen deprivation therapy with aromatase inhibitors (AI) has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy.
To determine if estradiol 6-mg daily is a viable endocrine therapy for postmenopausal women with advanced AI-resistant hormone-receptor-positive breast cancer.
Design, Setting and Patients
A randomized Phase 2 trial of 6-mg versus 30-mg oral estradiol daily opened in April 2004 and was closed to enrollment in February 2008 (NCT00324259). Eligible patients had metastatic breast cancer treated with an AI with at least 24 weeks progression-free survival, or relapse after two or more years of adjuvant AI. Patients at high risk of estradiol-related adverse events were excluded.
Main Outcome Measures
The primary endpoint was clinical benefit rate – CBR (response plus stable disease at 24 weeks). Secondary outcomes included toxicity, progression-free survival (PFS), time to treatment failure (TTF), quality of life (QOL) and the predictive properties of the FDG-PET metabolic flare reaction.
66 patients were enrolled. The grade 3+ adverse event rate on the 30-mg arm (11/32; 95% CI: 23%–47%) was higher than that in 6-mg arm (4/34; 95% CI: 5%–22%) (P=.03). CBRs were 28% (9/32; 95% CI: 18% – 41%) on the 30-mg arm and 29% (10/34; 95% CI: 19% – 42%) on the 6-mg arm. An estradiol44 stimulated increase in FDG uptake of ≥12% (prospectively defined) was predictive of response (positive predictive value of 80%; 95% CI: 61%–92%). Seven patients with estradiol-sensitive disease were retreated with AI upon estradiol progression, with two PR and one SD, suggesting resensitization to estrogen deprivation.
In women with advanced breast cancer and acquired resistance to AI, an estradiol dose of 6-mg daily provided a similar CBR as 30-mg daily, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials
PMCID: PMC3460383  PMID: 19690310
18.  Randomized Phase II Neoadjuvant Comparison Between Letrozole, Anastrozole, and Exemestane for Postmenopausal Women With Estrogen Receptor–Rich Stage 2 to 3 Breast Cancer: Clinical and Biomarker Outcomes and Predictive Value of the Baseline PAM50-Based Intrinsic Subtype—ACOSOG Z1031 
Journal of Clinical Oncology  2011;29(17):2342-2349.
Preoperative aromatase inhibitor (AI) treatment promotes breast-conserving surgery (BCS) for estrogen receptor (ER) –positive breast cancer. To study this treatment option, responses to three AIs were compared in a randomized phase II neoadjuvant trial designed to select agents for phase III investigations.
Patients and Methods
Three hundred seventy-seven postmenopausal women with clinical stage II to III ER-positive (Allred score 6-8) breast cancer were randomly assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary end point was clinical response. Secondary end points included BCS, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis.
On the basis of clinical response rates, letrozole and anastrozole were selected for further investigation; however, no other differences in surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only patients at presentation was 51%. PAM50 analysis identified AI-unresponsive nonluminal subtypes (human epidermal growth factor receptor 2 enriched or basal-like) in 3.3% of patients. Clinical response and surgical outcomes were similar in luminal A (LumA) versus luminal B tumors; however, a PEPI of 0 (best prognostic group) was highest in the LumA subset (27.1% v 10.7%; P = .004).
Neoadjuvant AI treatment markedly improved surgical outcomes. Ki67 and PEPI data demonstrated that the three agents tested are biologically equivalent and therefore likely to have similar adjuvant activities. LumA tumors were more likely to have favorable biomarker characteristics after treatment; however, occasional paradoxical increases in Ki67 (12% of tumors with > 5% increase after therapy) suggest treatment-resistant cells, present in some LumA tumors, can be detected by post-treatment profiling.
PMCID: PMC3107749  PMID: 21555689
19.  Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models 
The Journal of Clinical Investigation  2012;122(4):1541-1552.
Patients with triple-negative breast cancer (TNBC) — defined by lack of estrogen receptor and progesterone receptor expression as well as lack of human epidermal growth factor receptor 2 (HER2) amplification — have a poor prognosis. There is a need for targeted therapies to treat this condition. TNBCs frequently harbor mutations in TP53, resulting in loss of the G1 checkpoint and reliance on checkpoint kinase 1 (Chk1) to arrest cells in response to DNA damage. Previous studies have shown that inhibition of Chk1 in a p53-deficient background in response to DNA damage. We therefore tested whether inhibition of Chk1 could potentiate the cytotoxicity of the DNA damaging agent irinotecan in TNBC using xenotransplant tumor models. Tumor specimens from patients with TNBC were engrafted into humanized mammary fat pads of immunodeficient mice to create 3 independent human-in-mouse TNBC lines: 1 WT (WU-BC3) and 2 mutant for TP53 (WU-BC4 and WU-BC5). These lines were tested for their response to irinotecan and a Chk1 inhibitor (either UCN-01 or AZD7762), either as single agents or in combination. The combination therapy induced checkpoint bypass and apoptosis in WU-BC4 and WU-BC5, but not WU-BC3, tumors. Moreover, combination therapy inhibited tumor growth and prolonged survival of mice bearing the WU-BC4 line, but not the WU-BC3 line. In addition, knockdown of p53 sensitized WU-BC3 tumors to the combination therapy. These results demonstrate that p53 is a major determinant of how TNBCs respond to therapies that combine DNA damage with Chk1 inhibition.
PMCID: PMC3314455  PMID: 22446188
20.  Cancer Genome Sequencing and Its Implications for Personalized Cancer Vaccines 
Cancers  2011;3(4):4191-4211.
New DNA sequencing platforms have revolutionized human genome sequencing. The dramatic advances in genome sequencing technologies predict that the $1,000 genome will become a reality within the next few years. Applied to cancer, the availability of cancer genome sequences permits real-time decision-making with the potential to affect diagnosis, prognosis, and treatment, and has opened the door towards personalized medicine. A promising strategy is the identification of mutated tumor antigens, and the design of personalized cancer vaccines. Supporting this notion are preliminary analyses of the epitope landscape in breast cancer suggesting that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines.
PMCID: PMC3763418  PMID: 24213133
cancer genome sequencing; unique tumor antigen; DNA vaccine
21.  Molecular Basis of Triple Negative Breast Cancer and Implications for Therapy 
Triple negative breast cancer is an aggressive form of breast cancer with limited treatment options and is without proven targeted therapy. Understanding the molecular basis of triple negative breast cancer is crucial for effective new drug development. Recent genomewide gene expression and DNA sequencing studies indicate that this cancer type is composed of a molecularly heterogeneous group of diseases that carry multiple somatic mutations and genomic structural changes. These findings have implications for therapeutic target identification and the design of future clinical trials for this aggressive group of breast cancer.
PMCID: PMC3262606  PMID: 22295242
22.  A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor positive breast cancer 
To compare clinical, immunohistochemical and gene expression models of prognosis applicable to formalin-fixed, paraffin-embedded blocks in a large series of estrogen receptor positive breast cancers, from patients uniformly treated with adjuvant tamoxifen.
qRT-PCR assays for 50 genes identifying intrinsic breast cancer subtypes were completed on 786 specimens linked to clinical (median followup 11.7 years) and immunohistochemical (ER, PR, HER2, Ki67) data. Performance of predefined intrinsic subtype and Risk-Of-Relapse scores was assessed using multivariable Cox models and Kaplan-Meier analysis. Harrell’s C index was used to compare fixed models trained in independent data sets, including proliferation signatures.
Despite clinical ER positivity, 10% of cases were assigned to non-Luminal subtypes. qRT-PCR signatures for proliferation genes gave more prognostic information than clinical assays for hormone receptors or Ki67. In Cox models incorporating standard prognostic variables, hazard ratios for breast cancer disease specific survival over the first 5 years of followup, relative to the most common Luminal A subtype, are 1.99 (95% CI: 1.09–3.64) for Luminal B, 3.65 (1.64–8.16) for HER2-enriched and 17.71 (1.71–183.33) for the basal like subtype. For node-negative disease, PAM50 qRT-PCR based risk assignment weighted for tumor size and proliferation identifies a group with >95% 10 yr survival without chemotherapy. In node positive disease, PAM50-based prognostic models were also superior.
The PAM50 gene expression test for intrinsic biological subtype can be applied to large series of formalin-fixed paraffin-embedded breast cancers, and gives more prognostic information than clinical factors and immunohistochemistry using standard cutpoints.
PMCID: PMC2970720  PMID: 20837693
23.  Genome-Wide Associations and Functional Genomic Studies of Musculoskeletal Adverse Events in Women Receiving Aromatase Inhibitors 
Journal of Clinical Oncology  2010;28(31):4674-4682.
We performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse events (MS-AEs) in women treated with aromatase inhibitors (AIs) for early breast cancer.
Patients and Methods
A nested case-control design was used to select patients enrolled onto the MA.27 phase III trial comparing anastrozole with exemestane. Cases were matched to two controls and were defined as patients with grade 3 or 4 MS-AEs (according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0) or those who discontinued treatment for any grade of MS-AE within the first 2 years. Genotyping was performed with the Illumina Human610-Quad BeadChip.
The GWAS included 293 cases and 585 controls. A total of 551,358 SNPs were analyzed, followed by imputation and fine mapping of a region of interest on chromosome 14. Four SNPs on chromosome 14 had the lowest P values (2.23E-06 to 6.67E-07). T-cell leukemia 1A (TCL1A) was the gene closest (926-7000 bp) to the four SNPs. Functional genomic studies revealed that one of these SNPs (rs11849538) created an estrogen response element and that TCL1A expression was estrogen dependent, was associated with the variant SNP genotypes in estradiol-treated lymphoblastoid cells transfected with estrogen receptor alpha and was directly related to interleukin 17 receptor A (IL17RA) expression.
This GWAS identified SNPs associated with MS-AEs in women treated with AIs and with a gene (TCL1A) which, in turn, was related to a cytokine (IL17). These findings provide a focus for further research to identify patients at risk for MS-AEs and to explore the mechanisms for these adverse events.
PMCID: PMC3020700  PMID: 20876420
24.  Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women 
Journal of Clinical Oncology  2010;28(7):1161-1167.
To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)–positive breast cancers in postmenopausal women.
Materials and Methods
Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers.
The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = −0.179; P = .05; and r = −0.389; P = .0005, respectively).
Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.
PMCID: PMC2834467  PMID: 20124184
25.  Microarray data analysis in neoadjuvant biomarker studies in estrogen receptor-positive breast cancer 
Microarray data have been widely utilized to discover biomarkers predictive of response to endocrine therapy in estrogen receptor-positive breast cancer. Typically, these data have focused on analyses conducted on the diagnostic specimen. However, dynamic temporal changes in gene expression associated with treatment may deliver significant improvements to the current generation of predictive models. We present and discuss some statistical issues relevant to the paper by Taylor and colleagues, who conducted studies to model the prognostic potential of gene expression changes that occur after endocrine treatment.
PMCID: PMC2949646  PMID: 20804563

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