Search

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., (© 2021. The Author(s).)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aims: Deep inspiratory breath-hold (DIBH) techniques for left breast and chest wall radiotherapy can reduce cardiac dose. We investigated the use of 'upfront selection' criteria for DIBH based on tumour bed position and whether cardiac shielding was used., Materials and Methods: Four methods of selecting patients for DIBH were assessed retrospectively in a cohort of left breast and chest wall treatments. These were: (1) free breathing scan on all patients, selecting DIBH treatment for those with a predicted mean heart dose ≥3 Gy; (2) selective DIBH for those with maximum heart depth (MHD) on free breathing scan ≥1 cm; (3) use of an 'upfront selection process' using tumour bed position as initial selection and measurement of MHD on those not selected upfront; (4) DIBH on all. The methods were assessed on predicted mean heart dose, proportion needing two scans, sensitivity, specificity and the positive and negative predictive values. These were compared with method (1) as the gold standard., Results: In total 134 cases were analysed. The predicted mean heart dose in free breathing was ≥3 Gy in 28 (20.9%). Therefore, applying method (1), 28/134 (20.9%) would be selected for DIBH treatment. Applying method (2), 66/134 (49.2%) would be selected for DIBH treatment, all requiring two scans. Of these, 40/66 (60.6%) would receive < 3 Gy in free breathing so are over-selected; 2/68 (2.9%) would have received >3 Gy in free breathing so failed to be selected. Selection using method (3) was similar to method (2), but only five patients required two planning scans; 61/134 (45.5%) cases would be selected for DIBH upfront and 5/134 (3.7%) after initial free breathing scan; 42/66 (63.6%) of those selected for DIBH treatment would receive <3 Gy in free breathing and 4/68 not selected (6%) would receive >3 Gy in free breathing. For methods (2) and (3) most patients not selected for DIBH would have had a mean heart dose of ≤3 Gy (64/68, 90%). Using method (3), 86% (95% confidence interval 67-96%) of patients with a mean heart dose >3 Gy would be selected for DIBH treatment. The estimated mean and standard error for the area under the receiver operator characteristic curve for MHD as a predictor for mean heart dose was 0.85 (0.03)., Conclusion: This study supports the use of proposed an 'upfront selection process' as a means of selecting patients for treatment with DIBH and avoiding two radiotherapy planning scans. Calculation of MHD can be used as a surrogate for mean heart dose in the selection of cases for DIBH., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

The advent of sentinel lymph node biopsy has revolutionised surgical management of axillary nodal disease in patients with breast cancer. Patients undergoing neo-adjuvant chemotherapy for large breast primary tumours may experience complete pathological response on a previously positive sentinel node whilst not eliminating the tumour from the other lymph nodes. Results from 2 large prospective cohort studies investigating sentinel lymph node biopsy after neo-adjuvant chemotherapy demonstrate a combined false negative rate of 12.6-14.2% and identification rate of 80-89% with the minimal acceptable false negative rate and identification rate being set at 10% and 90%, respectively. A false negative rate of 14% would have been classified as unacceptable when compared to the figures obtained by the pioneers of sentinel lymph node biopsy which was 5% or less., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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.

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.

We analysed the molecular genetic profiles of breast cancer samples before and after neoadjuvant chemotherapy with combination doxorubicin and cyclophosphamide (AC). DNA was obtained from microdissected frozen breast core biopsies from 44 patients before chemotherapy. Additional samples were obtained before the second course of chemotherapy (D21) and after the completion of the treatment (surgical specimens) in 17 and 21 patients, respectively. Microarray-based comparative genome hybridisation was performed using a platform containing approximately 5800 bacterial artificial chromosome clones (genome-wide resolution: 0.9 Mb). Analysis of the 44 pretreatment biopsies revealed that losses of 4p, 4q, 5q, 12q13.11-12q13.12, 17p11.2 and 17q11.2; and gains of 1p, 2p, 7q, 9p, 11q, 19p and 19q were significantly associated with oestrogen receptor negativity. 16q21-q22.1 losses were associated with lobular and 8q24 gains with ductal types. Losses of 5q33.3-q4 and 18p11.31 and gains of 6p25.1-p25.2 and Xp11.4 were associated with HER2 amplification. No correlations between DNA copy number changes and clinical response to AC were found. Microarray-based comparative genome hybridisation analysis of matched pretreatment and D21 biopsies failed to identify statistically significant differences, whereas a comparison between matched pretreatment and surgical samples revealed a statistically significant acquired copy number gain on 11p15.2-11p15.5. The modest chemotherapy-driven genomic changes, despite profound loss of cell numbers, suggest that there is little therapeutic selection of resistant non-modal cell lineages.

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.

Background: We present extended follow-up from a prospective randomised trial evaluating the role of neoadjuvant chemoendocrine therapy in the treatment of operable breast cancer., Patients and Methods: 309 women were randomised to primary surgery followed by eight cycles of adjuvant mitoxantrone, methotrexate with tamoxifen (2MT) or 2MT with mitomycin-C (3MT) versus the same regimen for four cycles before followed by four cycles after surgery. For this analysis the median follow-up of patients was 112 months., Results: After 10 years follow-up there is still no statistically significant difference in disease-free survival (DFS) (71% versus 71%) or overall survival (OS) (63% versus 70%) when comparing adjuvant versus neoadjuvant treatment, respectively. Of 144 evaluable patients in the neoadjuvant arm, 74 achieved a good clinical response and 70 patients achieved a poor clinical response. Good responders had a superior DFS (80% versus 64%, P=0.01) and OS (77% versus 63%, P=0.03) compared to poor responders., Conclusions: At 10 years, neoadjuvant and adjuvant treatment continue to have equivalent OS and DFS. Good clinical response to neoadjuvant chemotherapy is associated with superior DFS and OS. This supports the use of clinical response of primary breast cancer to neoadjuvant therapy as a surrogate marker of survival benefit.

Purpose: Over the past three decades our centre has adopted a policy of conservative surgery followed by adjuvant radicaldose radiotherapy for medium-and high-grade soft tissue sarcomas. For all cases of local recurrence following this treatment we aimed to define the spatial relationship between sites of recurrence and the positions of the phase 1 and 2 radiotherapy volumes., Patients: We identified 25 cases of local recurrence recorded on our soft tissue sarcoma database between 1986 and 1999 inclusive. We excluded patients with macroscopic residual disease following surgery. Most patients were treated with a phase I volume corresponding to the entire muscle compartment (50 Gy in 25 fractions over 5 weeks) and a phase II volume corresponding to the tumour bed (10 Gy in five fractions). Six of the patients were treated according to a hyperfractionated regimen., Methods: For each case we reviewed the diagnostic imaging, planning radiographs and prescription sheets. We audited whether treatment had been given according to protocol and defined whether recurrence had arisen in the phase 1 volume, phase 2 volume or 'out of field'., Results: Four (16%) patients recurred within the phase I volume, 17 (68%) recurred within the phase II volume and four (16%) outside the irradiated volume including one marginal recurrence. In six patients there had been deviation from our radiotherapy protocol (usually unavoidable) including all three true out of field recurrences., Discussion: The majority of recurrences occur in the phase 2 volume. Prospective multi-centre data collection and, ideally, a prospective randomised trial are required to formulate an improved treatment policy with respect to radiotherapy margins and dose.

Man has evolved sophisticated defence mechanisms over millions of years to combat insertion of foreign DNA into his cells. However, gene therapy carries huge potential for the treatment of cancer. The challenge is therefore to translate our scientific knowledge into a clinical reality.

A 12-question survey designed to examine venepuncture techniques and instruction and uptake of hepatitis B vaccination was completed by 172 of the 275 medical students to whom it was distributed (a response rate of 62.5%). Seventy-five injuries were reported, at an average of 0.3 per student per year. Of the respondents, 63% resheathed needles after use, a practice frequently cited as a cause of needlestick injury. However, in this sample resheathing was not significantly associated with a higher or lower injury rate (chi 2 = 2.07, P > 0.1). Of the respondents from the most recent intake, only 20 out of 57 had completed a course of hepatitis B vaccinations prior to the commencement of venepuncture duties. There was almost universal ignorance concerning the correct course of action following 'sharps' injury. Recommendations are made concerning hepatitis B vaccination and teaching strategies for medical students.