Impact of the menstrual cycle on commercial prognostic gene signatures in oestrogen receptor-positive primary breast cancer.

PURPOSE: Changes occur in the expression of oestrogen-regulated and proliferation-associated genes in oestrogen receptor (ER)-positive breast tumours during the menstrual cycle. We investigated if Oncotype® DX recurrence score (RS), Prosigna® (ROR) and EndoPredict® (EP/EPclin) prognostic tests, which include some of these genes, vary according to the time in the menstrual cycle when they are measured. METHODS: Pairs of test scores were derived from 30 ER-positive/human epidermal growth factor receptor-2-negative tumours sampled at two different points of the menstrual cycle. Menstrual cycle windows were prospectively defined as either W1 (days 1-6 and 27-35; low oestrogen and low progesterone) or W2 (days 7-26; high oestrogen and high or low progesterone). RESULTS: The invasion module score of RS was lower (- 10.9%; p = 0.098), whereas the ER (+ 16.6%; p = 0.046) and proliferation (+ 7.3%; p = 0.13) module scores were higher in W2. PGR expression was significantly increased in W2 (+ 81.4%; p = 0.0029). Despite this, mean scores were not significantly different between W1 and W2 for any of the tests and the two measurements showed high correlation (r = 0.72-0.93). However, variability between the two measurements led to tumours being assigned to different risk categories in the following proportion of cases: RS 22.7%, ROR 27.3%, EP 13.6% and EPclin 13.6%. CONCLUSION: There are significant changes during the menstrual cycle in the expression of some of the genes and gene module scores comprising the RS, ROR and EP/EPclin scores. These did not affect any of the prognostic scores in a systematic fashion, but there was substantial variability in paired measurements.

Cardiac safety evaluation in cancer clinical trials.

Identification and quantification of the cardiac adverse effects of new cancer therapeutics is important when comparing treatment arms in clinical trials. Heart failure and left ventricular dysfunction are some of the most common adverse cardiac effects of a range of cancer treatments, including anthracyclines, trastuzumab and other targeted agents. Using the example of trastuzumab-induced cardiac dysfunction, we evaluated phase III clinical trials performed over the past decade to establish the methods used to identify heart failure and impairment of left ventricular function. Both these adverse events are difficult to accurately quantify. A clinical diagnosis of heart failure is subjective, and measurement of left ventricular ejection fraction has high interobserver variability depending on the method used to measure it. We found there was heterogeneity in methods used to diagnose both these adverse events. In addition, the use of quality assurance techniques to reduce measurement variability was low. We discuss and propose methods to standardise and reduce variability of cardiac event assessment in cancer clinical trials. This will allow true comparison of cardiac events between arms and trials with the aim of ensuring cardiac safety data are accurate.

Patient attitudes towards undergoing additional breast biopsy for research.

BACKGROUND: Acquisition of additional breast tissue has become integral to breast oncology research. This questionnaire study examines patient willingness to undergo research-dedicated breast biopsies either at time of diagnostic biopsy (T1) or after carcinoma diagnosis has been confirmed and eligibility for a specific study established (T2), and influencing factors thereof. METHODS: Prior to consultation, patients attending breast clinics were recruited to complete a questionnaire examining willingness to undergo an extra fine needle aspirate (FNA) and/or core needle biopsy (CNB) for research either at T1 or T2. Descriptions of FNA and CNB procedures were supplied to those with no prior experience. Patient perspectives towards donating surplus tissue remaining from a diagnostic procedure and/or surgery for future research were also explored. FINDINGS: A total of 100 patients were recruited, 42% with prior history of breast carcinoma (BC), 22% with family history of BC (FHBC) and 65%/42% with previous experience of CNB/FNA respectively. Overall, 57% were willing to undergo additional biopsy at one or both time points. Willingness to undergo additional biopsy was greater for T1 than T2, but equivalent for CNB and FNA (willingness CNB T1, 50% vs T2, 26%, willingness FNA T1 50% vs T2 29%). A statistically significant increase in willingness to undergo CNB and/or FNA at T1 and/or T2 was seen in association with prior diagnosis of BC, FHBC, previous visit to breast clinic and prior experience of breast biopsy. 83% of patients expressed a willingness to allow surplus tissue to be stored in a biobank for future research. INTERPRETATION: Where possible patients should be approached to undergo baseline research biopsies at time of diagnostic process rather than subsequently. Patients do not find FNA more acceptable than core biopsy. Prior exposure to the biopsy procedure increases willingness to undergo research-dedicated biopsies.

Is the presence of small volume disease in the sentinel node an indication for axillary clearance?

The finding of micrometastases (M(i)) and isolated tumour cells (ITC) within the axillary lymph nodes of patients with breast cancer has raised the question whether either/both have some prognostic significance. Several studies have shown that compared to node-negative patients, prognosis is significantly poorer in patients with M(i) and ITC. The fact that patients with M(i)/ITC in their sentinel lymph nodes have a systemic relapse risk that is higher than that of node-negative patients may be considered as an indication for systemic treatment. Most studies in the literature suggest that in patients with M(i) or ITC in their sentinel nodes who receive systemic therapy and whole breast radiotherapy, the risk of axillary relapse without axillary lymphadenectomy is under 2%. Given the fact that axillary lymphadenectomy is associated with a 5-25% risk of lymphoedema, we propose that a policy of close follow up should be adopted in these patients rather than axillary lymphadenectomy.

Two-stage resection for bilobar colorectal liver metastases: R0 resection is the key.

BACKGROUND: Two-stage liver resection (2-SLR) is used clinically in conjunction with portal vein embolization for bilobar disease to increase the number of patients suitable for liver resection. The long-term outcomes after 2-SLR for multiple bilobar colorectal liver metastases (CLM) was examined. METHODS: Patients who sought care between November 2003 and April 2006 with multiple CLM considered suitable for 2-SLR were prospectively followed. Clinicopathological data were collected. Surgical outcomes were defined as complete clearance of tumor (R0/R1/R2), postoperative morbidity (within 3 months), 30 day mortality, disease-free survival (DFS), and overall survival (OS). RESULTS: A total of 131 patients with CLM underwent liver resection during the study period, 38 of whom were planned for a 2-SLR for multiple bilobar disease. Only 33 (87%) completed the 2-SLR with a curative intent. Five patients did not undergo stage II resection because of disease progression. The postoperative morbidity was 11 and 33% after stage I and stage II liver resections, respectively. Five patients (13%) encountered postoperative complications specific to liver surgery. The median interval from stage II resection to disease recurrence in the R0 group was 18 months versus 3 months in the R1/R2 group (P < 0.001). R0 resection with curative intent versus R1/R2 noncurative resection has a significantly longer period of DFS (P < 0.001) and OS (P = 0.04). CONCLUSIONS: The 2-SLR combined with portal vein embolization is an effective and safe method for resecting previously unresectable multiple bilobar CLM. However, a positive resection margin leads to poor DFS and OS.

Should Internal Mammary Lymph Node Biopsy be A Routine Step in Recurrent Breast Cancer? Report of Three Cases With Negative Axilla and Positive Internal Mammary Node.

Lymph node status is the most important clinicopathological prognostic factor for breast cancer patients and in most breast units it reflects only the axillary lymph nodes. A second often overlooked basin consists of the internal mammary lymph nodes (IMLNs) whose evaluation is not done as a routine step during the staging process. We highlight the need to consider incorporation of IMLNs into a patient's staging by presenting three cases of recurrent breast cancer with negative axilla and positive IMLN, a finding which altered their final management. We suggest that biopsy of IMLN should be a routine step in recurrent breast cancer when axillary lymphatics are disrupted by previous surgery although further research is required to define the optimal management of node positive cases.

A 2009 update on the treatment of patients with hormone receptor-positive breast cancer.

In up to 75% of breast cancers, estrogen receptor (ER) signaling is a key promoter of tumor proliferation, and inhibition of this pathway has clear therapeutic efficacy. The principal clinical means of inhibiting ER signaling comprise selective ER modulators, such as tamoxifen, that act as partial receptor agonists; measures to reduce the circulating level of estrogen, including ovarian ablation, gonadotropin-releasing hormone analogues, and aromatase inhibition; and antagonism and downregulation of ER by the antiestrogen fulvestrant. Each of these therapies is effective in a proportion of ER-positive breast cancers, but de novo and acquired resistance remain significant problems. Emerging knowledge of the biology of ER signaling will provide insights into the mechanisms of resistance and help guide development of therapeutic strategies to maximize response. This review summarizes the contemporary treatment of early-stage and advanced ER-positive breast cancer in premenopausal and postmenopausal women, with an emphasis on recently published or presented data. Mechanisms of resistance to endocrine interventions and trials exploring strategies to overcome them will also be discussed.

The effect of the stromal component of breast tumours on prediction of clinical outcome using gene expression microarray analysis.

INTRODUCTION: The aim of this study was to examine the effect of the cellular composition of biopsies on the error rates of multigene predictors of response of breast tumours to neoadjuvant adriamycin and cyclophosphamide (AC) chemotherapy. MATERIALS AND METHODS: Core biopsies were taken from primary breast tumours of 43 patients prior to AC, and subsequent clinical response was recorded. Post-chemotherapy (day 21) samples were available for 16 of these samples. Frozen sections of each core were used to estimate the proportion of invasive cancer and other tissue components at three levels. Transcriptional profiling was performed using a cDNA array containing 4,600 elements. RESULTS: Twenty-three (53%) patients demonstrated a 'good' and 20 (47%) a 'poor' clinical response. The percentage invasive tumour in core biopsies collected from these patients varied markedly. Despite this, agglomerative clustering of sample expression profiles showed that almost all biopsies from the same tumour aggregated as nearest neighbours. SAM (significance analysis of microarrays) regression analysis identified 144 genes which distinguished high- and low-percentage invasive tumour biopsies at a false discovery rate of not more than 5%. The misclassification error of prediction of clinical response using microarray data from pre-treatment biopsies (on leave-one-out cross-validation) was 28%. When prediction was performed on subsets of samples which were more homogeneous in their proportions of malignant and stromal cells, the misclassification error was considerably lower (8%-13%, p < 0.05 on permutation). CONCLUSION: The non-tumour content of breast cancer samples has a significant effect on gene expression profiles. Consideration of this factor improves accuracy of response prediction by expression array profiling. Future gene expression array prediction studies should be planned taking this into account.