[Show abstract][Hide abstract] ABSTRACT: Considerable heterogeneity exists amongst oestrogen receptor positive (ER+ve) breast cancer in both its molecular profile and response to therapy. Attempts to better define variation amongst breast tumours have led to the definition of four main "intrinsic" subtypes of breast cancer with two of these classes, Luminal A and B, composed almost entirely of ER+ve cancers. In this study we set out to investigate the significance of intrinsic subtypes within a group of ER+ve breast cancers treated with neoadjuvant anastrozole. RNA from tumour biopsies taken from 104 postmenopausal women before and after 2 weeks treatment with anastrozole was analyzed on Illumina 48K microarrays. Gene-expression based subtypes and risk of relapse (ROR) scores for tumours pre- and post-treatment were determined using the PAM50 method. Amongst pre-treatment samples, all intrinsic subtypes were found to be present, although luminal groups were represented most highly. Luminal A and B tumours obtained similar benefit from treatment, as measured by the proportional fall in the proliferation marker Ki67 upon treatment (mean suppression=75.5% vs 75.7%). Tumours classified as basal and Her2-like showed poor reductions in Ki67 upon treatment. Residual Ki67 staining after two weeks remained higher in the Luminal B group. ROR score was significantly associated with anti-proliferative response to AI and with clinical response. These results suggest that in the short-term, Luminal A and B tumours may gain similar benefit from an AI but that the higher residual Ki67 level seen in Luminal B is indicative of poorer long term outcome.
[Show abstract][Hide abstract] ABSTRACT: The degree of arterial hypoxemia during air travel in individuals with obstructive sleep apnea (OSA) is not known. The Aerospace Medical Association considers a ground level arterial oxygen tension (PaO₂) above 9.3 kPa as safe before air travel.
Fifteen subjects with untreated OSA (mean apnea-hypopnea index [AHI] 43/h) and 14 with treated OSA (mean AHI on CPAP 1.9/h) completed an assessment including hypoxic challenge test (HCT). The groups had similar mean age, mean BMI and pre-treatment OSA severity.
Four subjects, all in the untreated group and with resting PaO₂ >9.3 kPa and oxygen saturation (SpO₂) >95%, had a positive HCT (PaO₂ <6.6 kPa and/or SpO₂ <85%). The PaO₂ at the end of the HCT was significantly correlated with the minimum overnight SpO₂ (r=.754, p=.002) but not with the daytime PaO₂ and SpO₂. Using a cut off value of 65%, the minimum overnight SpO₂ had positive and negative predictive values of 57% and 100% respectively.
OSA can be an additional risk factor for developing significant arterial hypoxemia during HCT. Baseline PaO₂ and SpO₂ did not predict arterial hypoxemia during the HCT. Minimum overnight SpO₂ <65% may be used as a cut off to advise further assessment. Effective treatment of OSA seems to be the best option before air travel.
[Show abstract][Hide abstract] ABSTRACT: The majority of breast cancer patients who have estrogen receptor positive (ER(+)) tumors whose proliferation is reduced after estrogen deprivation by aromatase inhibitors (AI). This study investigates any link between proliferation and hypoxia, a major determinant of tumor biology, and defines the effect of estrogen deprivation on hypoxia-associated genes. Methods: Genome-wide expression profiles were obtained from tumor biopsies from 81 ER(+) postmenopausal patients, before and after 2 weeks' anastrozole treatment. A hypoxia metagene was developed by identifying genes clustered with classical hypoxia-regulated genes, excluding those associated with proliferation. Proliferation was measured by Ki67 and a proliferation metagene derived from two published breast cancer data sets.
Hypoxia and proliferation metagenes were associated at baseline (Pearson correlation coefficient, r = 0.67, P < 10(-4)) and after 2 weeks (r = 0.71, P < 10(-4)). Hypoxia metagene at baseline was associated with 2-week Ki67 (r = 0.43, P = 0.0002) and more weakly with poor 2-week Ki67 change consistent with a weak association with AI resistance. Hypoxia metagene was significantly downregulated with AI. This downregulation was significantly associated with change in the proliferation metagene and with Ki67 but, importantly, not with the substantial change in expression of classical estrogen-dependent genes.
Hypoxia metagene is closely associated with proliferation before and after AI treatment. The downregulation of hypoxia metagene after AI therapy is most likely the result of changes in proliferation. There may be a weak effect of hypoxia metagene on de novo resistance to AIs. These findings are important to consider in coapplication of antiproliferative agents with antiangiogenic or antihypoxia agents.
Full-text · Article · Feb 2011 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: To evaluate the clinicopathological associations and predictive value of the transcription factor NF-κB in a large series of breast cancer patients treated with neoadjuvant chemotherapy.
A retrospective search of a prospectively maintained database was performed to identify patients. Immunohistochemistry was used to assess the p65 subunit of NF-κB, using nuclear staining as a surrogate of activation.
Nuclear NF-κB expression was found in 26.3% (35/133) of cases. Nuclear NF-κB staining was associated with high histological grade (p=0.05), oestrogen receptor (ER) negativity (p=0.01) and higher Ki67 index (p=0.002). Patients with nuclear NF-κB staining had a higher pathological complete response (pCR) rate than those without (26.5% vs 6.0% respectively, p=0.004); there was no significant association with clinical response or outcome. In an exploratory hypothesis-generating analysis, in the ER+/HER2- subgroup (n=43) a significantly lower clinical response rate was observed in those with nuclear NF-κB staining compared with those who had no nuclear NF-κB staining (14.3% vs 61.0%, p=0.038). There were no pCRs in ER+/ HER2- tumours.
Nuclear NF-κB expression is associated with ER negativity, higher Ki67 index and tumour grade. It was also found to be significantly associated with increased pCR but not clinical response to neoadjuvant chemotherapy.
No preview · Article · Feb 2011 · Journal of clinical pathology
[Show abstract][Hide abstract] ABSTRACT: For many years, one of the main aims of neoadjuvant therapy has been to identify short term endpoints that will predict for long-term outcome in adjuvant treatment. Th e advantages are obvious: in contrast to adjuvant trials, neoadjuvant trials require hundreds rather than thousands of patients, are very much less expensive to run and produce outcome data many years earlier. A key primary endpoint for neoadjuvant trials has been objective clinical response and this still remains the case . Nevertheless, major studies have frequently shown that clinical response, including complete clinical remission, does not predict for long-term outcome. For example, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial no diff erence in outcome was seen between patients who achieved clinical response versus those who did not . Likewise, in the NSABP B-27 trial in which 2,411 patients were randomised to neoadjuvant adriamycin/cyclophospha mide (AC) versus the same treatment followed by sequential docetaxel, the complete response rate was 64% for the sequential, docetaxel-containing arm compared with 40% for the AC arm alone (P < 0.001), but no signifi cant diff erence was seen in long-term survival [3,4]. Likewise, for neoadjuvant endocrine therapy, the IMPACT (Immediate Preopera tive Anastrozole, Tamoxifen, or Combined With Tamoxifen) trial compared neo adjuvant anastrazole versus tamoxifen versus the combination and was the neoadjuvant equivalent of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) adjuvant trial. No signifi cant diff erence was seen in response rate between the three arms of IMPACT  and this failed, therefore, to correlate with the long-term disease-free survival advantage of anastrazole in ATAC. Likewise, in the IMPACT trial a large diff erence was seen in response rates for patients with human epidermal growth factor receptor 2 (HER2)-positive tumours in favour of anastrazole (7 of 12 responders; 58%) compared with tamoxifen (2 of 9 responders; 22%) and yet no selective disease-free survival advantage for anastrazole over tamoxifen in patients with HER2-positive tumours was subsequently seen in ATAC . A possible explana tion for this is that it is entirely possible that tumour growth rate may be slowed by neoadjuvant therapy (as measured, for example, by a reduction in proliferation factor Ki67) without a formal clinical response being achieved but with a consequent gain in relapse free survival. In the IMPACT trial, for example, only 37% of tumours achieved an objective clinical response rate to anastrazole whereas 75% had a signifi cant reduction in Ki67 .
Preview · Article · Dec 2010 · Breast cancer research: BCR
[Show abstract][Hide abstract] ABSTRACT: To assess the prevalence of defective homologous recombination (HR)-based DNA repair in sporadic primary breast cancers, examine the clincopathologic features that correlate with defective HR and the relationship with neoadjuvant chemotherapy response.
We examined a cohort of 68 patients with sporadic primary breast cancer who received neoadjuvant anthracylcine-based chemotherapy, with core biopsies taken 24 hours after the first cycle of chemotherapy. We assessed RAD51 focus formation, a marker of HR competence, by immunofluorescence in postchemotherapy biopsies along with geminin as a marker of proliferative cells. We assessed the RAD51 score as the proportion of proliferative cells with RAD51 foci.
A low RAD51 score was present in 26% of cases (15/57, 95% CI: 15%-40%). Low RAD51 score correlated with high histologic grade (P = 0.031) and high baseline Ki67 (P = 0.005). Low RAD51 score was more frequent in triple-negative breast cancers than in ER- and/or HER2-positive breast cancer (67% vs. 19% respectively; P = 0.0036). Low RAD51 score was strongly predictive of pathologic complete response (pathCR) to chemotherapy, with 33% low RAD51 score cancers achieving pathCR compared with 3% of other cancers (P = 0.011).
Our results suggest that defective HR, as indicated by low RAD51 score, may be one of the factors that underlie sensitivity to anthracycline-based chemotherapy. Defective HR is frequent in triple-negative breast cancer, but it is also present in a subset of other subtypes, identifying breast cancers that may benefit from therapies that target defective HR such as PARP inhibitors.
Full-text · Article · Dec 2010 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Trastuzumab has revolutionised the treatment of HER2-positive early-stage breast cancer and is now standard of care in combination with chemotherapy for patients with tumours larger than 1 cm. However, 5 years after publication of the landmark trials establishing the efficacy of the drug, the management of small (≤1 cm), HER2-positive tumours remains difficult. Most small breast cancers have a good prognosis and adjuvant chemotherapy is not routinely recommended. However, retrospective data suggest that some small HER2-positive cancers might have a worse clinical outcome than others. This notion raises the key clinical question of whether patients with small HER2-positive cancers should be offered adjuvant trastuzumab and chemotherapy. The pivotal adjuvant trastuzumab trials did not include patients with tumours smaller than 1 cm, but a subset analysis of one trial showed that patients with tumours 1-2 cm in size derived at least as much clinical benefit from 1 year of adjuvant trastuzumab as did the overall cohort. Clinicians face the dilemma of whether the potential reduction in risk of recurrence in this patient group warrants the toxic effects and risks of adjuvant chemotherapy and trastuzumab. In this review, we discuss the evidence for prognosis of small HER2-positive cancers, and for possible benefit from adjuvant trastuzumab. We suggest potential treatment strategies and clinical trial designs to address this important issue. On the basis of present evidence, we recommend that the benefits and risks of adjuvant trastuzumab should be discussed with patients with small, HER2-positive breast cancer.
No preview · Article · Dec 2010 · The Lancet Oncology
[Show abstract][Hide abstract] ABSTRACT: A PUBMED SEARCH OF THE MEDICAL LITERATURE SHOWS THAT THE FIRST mention of "triple-negative" breast cancer was in October 2006; since then, the term has appeared in more than 600 publications.1 This increase reflects the growing recognition of the importance of triple-negative breast cancer (see the Glossary for this and other key terms) by oncologists, pathologists, and geneticists, as well as by the approximately 12 to 17% of women with breast cancer who have triple-negative breast cancer. As a group, patients with triple-negative tumors have a relatively poor outcome and cannot be treated with endocrine therapy or therapies targeted to human epidermal growth factor receptor type 2 (HER2). A close cousin of triple-negative breast cancer is basal-like breast cancer (synonymous terms include "basal-type," "basal-epithelial phenotype," "basal breast cancer," and "basaloid breast cancer"). This molecular subtype of breast cancer is characterized by a gene-expression profile that is similar to that of the basal-myoepithelial layer of the normal breast. 2 Immunohistochemical markers have been used as a surrogate for this profile. The multiplicity of names reflects an underlying uncertainty as to the true nature of this entity.
Preview · Article · Nov 2010 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Hypoxic challenge testing (HCT) is not readily available in all hospitals. It has recently been shown that resting oximetry does not reliably predict the results of HCT in patients with extrapulmonary restrictive lung disease. We assessed other clinical tests to see if they might be used as an alternative screen for HCT.
People with primary thoracic scoliosis were recruited. Resting SpO(2), arterial blood gases (ABG's), lung function and shuttle walking test (SWT) were measured. All subjects underwent HCT breathing an inhaled oxygen fraction of 15% for 20 min, or until SpO(2) fell below 85%, when ABG's were taken.
Fourteen people (5 male) with thoracic scoliosis, Cobb angle 93 (31) degrees , aged 65 (8.5) years, FEV(1) 0.86 (0.4) L, FVC 1.2 (0.4)L were studied. The resting SpO(2) was 96 (2) %, PaO(2) 9.2 (1) kPa and PaCO(2) 6.1 (0.4) kPa. HCT was positive in 11 subjects (PaO(2) <6.6 kPa). Eight of 11 HCT positive subjects had a resting SpO(2) > 95%. Positive correlation was found between SpO(2) at SWT termination and PaO(2) following HCT (r = 0.56, p = 0.02). Those with saturations of 92% or under at SWT termination had positive HCT.
Despite normal resting SpO(2) subjects with thoracic scoliosis may have positive HCT. Current recommendations for air travel do not accurately identify these people. Desaturation following a SWT may provide a useful screening tool, however a low threshold for performing HCT on people with thoracic scoliosis prior to air travel is warranted.
Preview · Article · Oct 2010 · Respiratory medicine
[Show abstract][Hide abstract] ABSTRACT: Very few studies have investigated whether the time elapsed between surgical resection and tissue fixation or the difference between core-cut and excision biopsies impact on immunohistochemically measured biomarkers including phosphorylated proteins in primary breast cancer. The aim of this study was to characterize the differences in immunoreactivity of common biomarkers that may occur (a) due to tissue handling at surgery and (b) between core-cuts and resected tumours.
Core-cuts taken from surgical breast cancer specimens immediately after resection (sample A) and after routine X-ray of the excised tumour (sample B) were formalin-fixed and paraffin-embedded and compared to the routinely fixed resection specimen (sample C). The variation in immunohistochemical expression of Ki67, oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor 2 (HER2), p-Akt and p-Erk were investigated.
Twenty-one tissue sets with adequate tumour were available. Median time between collection of core-cuts A and B was 30 minutes (range 20 to 80). None of the markers showed significant differences between samples A and B. Similarly, Ki67, ER, PgR and HER2 did not differ significantly between core-cuts and main resection specimen although there was a trend for lower resection values for ER (P=0.06). However, p-Akt and p-Erk1/2 were markedly lower in resections than core-cuts (median 27 vs 101 and 69 vs 193, respectively; both P<0.0001 [two-sided]). This difference was significantly greater in mastectomy than lumpectomy specimens for p-Erk1/2 (P=0.01).
The delay in fixation in core-cuts taken after post-operative X-ray of resection specimens has no significant impact on expression of Ki67, ER, PgR, HER2, p-Akt or p-Erk1/2. However extreme loss of phospho-staining can occur during routine fixation of resection specimens. These differences are likely attributable to suboptimal fixation and may have major repercussions for clinical research involving these markers.
Full-text · Article · Sep 2010 · Breast cancer research: BCR
[Show abstract][Hide abstract] ABSTRACT: Patients with ventilatory failure at discharge from hospital following an exacerbation of COPD (ECOPD) have increased work of breathing and reduced inspiratory muscle strength compared with those with a normal arterial carbon dioxide tension (PaCO(2)). They also have a significantly worse prognosis. Long-term non-invasive positive pressure ventilation (NIPPV) may offer a treatment strategy but benefits have not been established.
We examined the outcomes of 35 patients, with a PaCO(2) >7.5 kPa and normal pH, following hospital admission with an ECOPD. Patients were initiated on long-term NIPPV. Our aims were to establish if NIPPV was tolerated and to describe the effects on ventilatory parameters.
Daytime arterial blood gases and nocturnal ventilatory parameters improved significantly on NIPPV. Diurnal PaO(2), self-ventilating, rose from (mean (SD)) 7.3 (1.8) to 8.1 (0.9) kPa (P = 0.005) and PaCO(2) fell from 8.8 (1.3) to 7.3 (0.8) kPa (P <or= 0.001). Mean overnight oxygen saturations increased from 82% (7%) to 89% (2%) (P <or= 0.001) and mean overnight transcutaneous carbon dioxide fell from 7.6 (1.3) to 5.6 (1.7) kPa (P <or= 0.001). Similar changes were seen in a group of stable COPD patients, who initiated NIPPV without a preceding exacerbation, suggesting improvements were not solely due to recovery from exacerbation. Acceptance (89%) and compliance (8.4 (3.5) h/day) with domiciliary treatment were good. Median survival was 28.6 months (95% CI: 10.9-46.8).
NIPPV was well tolerated in this group and appears to improve ventilation. Our preliminary data support further investigation of NIPPV in patients who remain hypercapnic after hospital admission with ECOPD.
[Show abstract][Hide abstract] ABSTRACT: Treatments for inflammatory breast cancer (IBC) have changed over the last 15 to 20 years. The authors of this report undertook a retrospective review of patients who were treated at the Royal Marsden Hospital (RMH) to determine whether recurrence-free survival (RFS) and overall survival (OS) have improved as treatment regimens have altered.
Detailed clinical-pathologic data were collected on patients who were treated for primary IBC at RMH between 1990 and 2007. A Cox regression model was used to investigate the factors that influenced OS.
The median OS was 3 years and 4 months, and the median RFS was 1 year and 10 months. RFS was better in patients who had received taxane-containing regimens; however, there was no OS benefit. A pathologic complete response (pCR) was observed in 13 of 89 patients (15%), and those who achieved a pCR had significantly better RFS but no improvement in OS. The type of chemotherapy did not affect the pCR rate. One hundred thirty of 155 patients received radiotherapy, and those who did not receive radiotherapy had significantly worse outcomes. A multivariate Cox regression analysis indicated that the date of diagnosis, estrogen receptor (ER) status, and the presence of metastatic disease at diagnosis were significant prognostic factors. Patients who were diagnosed during or after 2000 had a relative risk of mortality of 0.5 compared with patients who were diagnosed before 2000. ER-positive patients had a median OS of 4.5 years and a median of RFS of 2.6 years versus 2.9 years and 1.4 years, respectively, for ER-negative patients. Patients who had metastatic disease at presentation had an OS of 1.7 years versus 3.9 years for those without metastatic disease at presentation.
Achieving a pCR improved RFS but had no impact on OS. Patients who had metastatic disease at the outset fared much worse, and positive ER status conferred a better outlook.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE 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. Results 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). CONCLUSION 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.
Full-text · Article · Mar 2010 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: The concentration of estradiol (E(2)) in breast tumors is significantly higher than that in plasma, particularly in postmenopausal women. The contribution of local E(2) synthesis versus uptake of E(2) from the circulation is controversial. Our aim was to identify possible determinants of intratumoral E(2) levels in breast cancer patients.
The expression of genes involved in estrogen synthesis, metabolism, and signaling was measured in 34 matched samples of breast tumor and normal breast tissue, and their correlation with estrogen concentrations assessed.
ESR1 (9.1-fold; P < 0.001) and HSD17B7 (3.5-fold; P < 0.001) were upregulated in ER(+) tumors compared with normal tissues, whereas STS (0.34-fold; P < 0.001) and HSD17B5 (0.23-fold; P < 0.001) were downregulated. Intratumoral E(2) levels showed a strong positive correlation with ESR1 expression in all patients (Spearman r = 0.55, P < 0.001) and among the subgroups of postmenopausal (r = 0.76, P < 0.001; n = 23) and postmenopausal ER(+) patients (r = 0.59, P = 0.013; n = 17). HSD17B7 expression showed a significant positive correlation (r = 0.59, P < 0.001) whereas HSD17B2 (r = -0.46, P = 0.0057) and HSD17B12 (r = -0.45, P = 0.0076) showed significant negative correlations with intratumoral E(2) in all patients. Intratumoral E(2) revealed no correlation to CYP19, STS, and HSD17B1 expression. Multivariate models comprising ESR1 and plasma E(2) predicted between 50% and 70% of intratumoral E(2) variability.
Uptake due to binding to the ER, rather than intratumoral estrogen synthesis by aromatase or sulfatase, is the single most important correlate and a probable determinant of intratumoral E(2). An increased expression of HSD17B7 may explain the increased ratio of E(2) to estrone (E(1)) in breast tumors compared with normal tissue.
Full-text · Article · Mar 2010 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Volume-assured non-invasive ventilation (NIV) theoretically guarantees minute ventilation with circuit leak compensation unlike other modes of NIV. Bench testing demonstrated that minute ventilation was maintained with varying lung compliance and resistance with minimal effect from circuit leak, confirming for the first time the core features of volume-assured NIV.
Volume-assured non-invasive positive pressure ventilation (va-NIPPV) is a novel mode designed to adapt pressure support (PS) to achieve a target minute ventilation (TgV). This may optimize ventilation; however, no data confirm that va-NIPPV compensates appropriately for the changes in pulmonary mechanics and circuit leak seen in clinical practice. Bench testing assessed these principles.
A ventilator featuring a va-NIPPV mode was studied. A test lung with varying compliance and resistance, and pneumotachograph were used. Eight lung model settings were chosen: (i) low resistance and high compliance; (ii) low resistance and low compliance; (iii) high resistance and high compliance; and (iv) high resistance and low compliance, all with and without additional circuit leak. An expiration valve, respiratory rate of 15, inspiratory time of 1 s and PS between 3 and 21 cm H2O were used. Va-NIPPV was tested with varying TgV after establishing the range of minute ventilation possible in a pressure preset mode.
At a TgV of 10 L/min, va-NIPPV delivered minute ventilation of (median (interquartile range) ): 11 (10.9-11, 10.2 (10.2-10.3), 12.4 (12.4-12.4) and 11.2 (10.9-11.2) L/min in test lung settings 1, 2, 3 and 4, respectively. Additional leak between 8-33 L/min had little effect. Similar results were seen at other TgV, within the ventilator's PS capabilities.
These data confirm that va-NIPPV is able to approximate a preset TgV with varying lung compliance and resistance, and that additional circuit leak has little effect on the delivered minute ventilation.
[Show abstract][Hide abstract] ABSTRACT: Substantial progress is being made in endocrine therapy for breast cancer. Here we review the results from recent trials,
highlight key areas of current translational research, and discuss the potential for brief preoperative studies to identify
molecular markers predicting outcome in the individual patient. A key challenge for translational research is to optimize
endocrine therapy based on patient and tumor characteristics. A further challenge is to identify tumors with acquired or innate
resistance and to develop the use of signal transduction inhibitors in combination with endocrine therapy as a means to overcome
resistance. Key to the success of such approaches will be clinical trial designs that incorporate appropriate tumor selection
and validation of biomarkers predicting benefit.
No preview · Article · Dec 2009 · Current Breast Cancer Reports