Peter Kneeshaw

Current applications and future direction of MR mammography

Compared with triple assessment for symptomatic and occult breast disease, magnetic resonance mammography (MRM) offers higher sensitivity for the detection of multifocal cancer, which is important in selecting patients appropriately for breast-conserving surgery. It is an ideal tool for the screening of patients with a high risk of breast cancer or where there is axillary disease or nipple discharge and conventional imaging has not revealed the primary focus. Techniques are now available to biopsy lesions only apparent on MRM. MRM can differentiate scar tissue from tumour; therefore, it is useful in patients in which there is possible recurrent disease. Clinical and X-ray mammographic assessment of response to neoadjuvant chemotherapy may be unreliable because of replacement of the tumour with scar tissue. MRM can identify responders and nonresponders with more accuracy. It is the modality of choice for the assessment of breast implants for rupture with accuracy higher than X-ray mammography and ultrasound. Advances in both spatial and temporal resolutions, the imaging sequences employed, pharmacokinetic modelling of contrast uptake, the use of dedicated and now phased-array breast coils, and gadolinium-based contrast agents have all played their part in the advancement of this imaging technique. Despite the limitations of patient compliance, scan-time and cost, this review describes how MRM has become a valuable tool in breast disease, especially in cases of diagnostic uncertainty. However, MRM must make the transition from research institutions into routine clinical practice.

Pilot and feasibility study: comparative proteomic analysis by 2-DE MALDI TOF/TOF MS reveals 14-3-3 proteins as putative biomarkers of response to neoadjuvant chemotherapy in ER-positive breast cancer

Neoadjuvant chemotherapy is used to treat oestrogen receptor-positive breast cancer however chemo-resistance is a major obstacle in this molecular subtype. The ability to predict tumour response would allow chemotherapy administration to be directed towards patients who would most benefit, thus maximising treatment efficacy. We aimed to identify protein biomarkers associated with response to neoadjuvant chemotherapy, in a pilot study using comparative 2-DE MALDI TOF/TOF MS proteomic analysis of breast tumour samples. A total of 3 comparative proteomic experiments were performed, comparing protein expression between chemotherapy-sensitive and chemotherapy-resistant oestrogen receptor-positive invasive ductal carcinoma tissue samples. This identified a list of 132 unique proteins that were significantly differentially expressed (≥ 2 fold) in chemotherapy resistant samples, 57 of which were identified in at least two experiments. Ingenuity® Pathway Analysis was used to map the 57 DEPs onto canonical signalling pathways. We implicate several isoforms of 14-3-3 family proteins (theta/tau, gamma, epsilon, beta/alpha and zeta/delta), which have previously been associated with chemotherapy resistance in breast cancer. Extensive clinical validation is now required to fully assess the role of these proteins as putative markers of chemotherapy response in luminal breast cancer subtypes.

Proteomic identification of predictive biomarkers of resistance to neoadjuvant chemotherapy in luminal breast cancer: a possible role for 14-3-3 theta/tau and tBID?

INTRODUCTION Chemotherapy resistance is a major obstacle in effective neoadjuvant treatment for estrogen receptor-positive breast cancer. The ability to predict tumour response would allow chemotherapy administration to be directed towards only those patients who would benefit, thus maximising treatment efficiency. We aimed to identify putative protein biomarkers associated with chemotherapy resistance, using fresh tumour samples with antibody microarray analysis and then to perform pilot clinical validation experiments. MATERIALS AND METHODS Chemotherapy resistant and chemotherapy sensitive tumour samples were collected from breast cancer patients who had received anthracycline based neoadjuvant therapy consisting of epirubicin with cyclophosphamide followed by docetaxel. A total of 5 comparative proteomics experiments were performed using invasive ductal carcinomas which demonstrated estrogen receptor positivity (luminal subtype). Protein expression was compared between chemotherapy resistant and chemotherapy sensitive tumour samples using the Panorama XPRESS Profiler725 antibody microarray containing 725 antibodies from a wide variety of cell signalling and apoptosis pathways. A pilot series of archival samples was used for clinical validation of putative predictive biomarkers. RESULTS AbMA analysis revealed 38 differentially expressed proteins which demonstrated at least 1.8 fold difference in expression in chemotherapy resistant tumours and 7 of these proteins (Zyxin, 14-3-3 theta/tau, tBID, Pinin, Bcl-xL, RIP and MyD88) were found in at least 2 experiments. Clinical validation in a pilot series of archival samples revealed 14-3-3 theta/tau and tBID to be significantly associated with chemotherapy resistance. CONCLUSIONS For the first time, antibody microarrays have been used to identify proteins associated with chemotherapy resistance using fresh breast cancer tissue. We propose a potential role for 14-3-3 theta/tau and tBID as predictive biomarkers of neoadjuvant chemotherapy resistance in breast cancer. Further validation in a larger sample series is now required.

Xanthogranulomatous inflammation involving latissimus dorsi donor site and implant breast reconstruction: case report and literature review

Xanthogranulomatous inflammation is a rare clinico-pathological condition involving many organ systems. Breast involvement with this rare condition reported from a few cases of mastitis has been limited to only microscopic involvement on histology. We would like to report an unusual presentation of this inflammatory process presenting as a solid lump mimicking malignancy in latissimus dorsi donor site scar and implant-based breast reconstruction as a result of a ruptured silicone gel implant. To our knowledge there have been no previous reports on similar presentation published in the literature. This case highlights a rare complication of a leaked silicone gel implant triggering a xanthomatous response in the absence of the usual infective or obstructing etiologies. This condition is of benign nature with complete clearance on surgical excision and excellent clinical prognosis reported from other organ involvement.

Stopping tamoxifen peri-operatively for VTE risk reduction: A proposed management algorithm

Tamoxifen is a selective oestrogen receptor modulator used in pre-menopausal oestrogen receptor positive breast cancer patients as adjuvant endocrine treatment. Increased risk of venous thrombo-embolism with the use of Tamoxifen is well known from published literature. This risk further increases in patients undergoing surgical procedures of high risk involving prolonged period of immobilization, therefore withholding Tamoxifen treatment in the immediate peri-operative period should be considered as a risk reducing measure. In the absence of nationally agreed guidelines on the safe duration for stoppage of treatment in the pre and post operative period without worsening cancer prognosis, operating surgeons and individual trusts have adopted their own guidelines based on individual experience. From the available evidence in the literature on the VTE risk assessments based on age, operative procedure and pharmacokinetics of the Tamoxifen drug we would like to propose a working algorithm for selecting the right patient group and safe treatment stoppage durations. These proposed guidelines are formulated taking all the risk factors of VTE, operative risks, pharmacokinetics of the drug and chemotherapy risks into consideration. With this guidance, we aim to help surgeons across different specialities in the decision making process through a structured evidence based approach.

Clinical response to primary letrozole therapy in elderly patients with early breast cancer: possible role for p53 as a biomarker.

Primary tamoxifen therapy has been widely used to treat elderly women with ER-positive breast cancer in the past. Aromatase inhibitors may be more beneficial than tamoxifen when used as primary endocrine therapy in elderly patients. We aimed to retrospectively evaluate a series of elderly women with ER-positive breast cancer treated with primary letrozole therapy as sole therapy with a minimum of 5 years follow up. To identify possible predictive biomarkers a pilot immunohistochemical analysis was performed to assess the expression of PR, HER2, EGFR, BCL2 and p53. A total of 45 women, aged more than 70 years with a diagnosis of ER-positive breast cancer that was treated with primary letrozole therapy were identified. A case note review was undertaken to obtain clinical information. Formalin fixed paraffin embedded tumour tissue from diagnostic core biopsies was available for all patients. Immunohistochemical analysis was performed to establish the protein expression status of p53, PR, HER2, EGFR and BCL2. The mean age of the 45 patients was 87 years (range 70-101). Clinical benefit was seen in 60% of the patients. Median progression free survival was 53 months (95% CI - 34-72) and the median time to progression was 43 months (95% CI - 22-64). BCL2 was expressed in 45/45 (100%); PR in 38/45 (84%); EGFR in 13/45 (28%); HER2 in 9/45 (20%) and p53 in 5/45 (11%) of tissue samples. Positive expression of p53 was associated with poor progression free survival (p = 0.03) in this pilot study. This study demonstrates that letrozole as sole treatment appears to be a suitable treatment option for elderly patients with ER-positive breast cancer who are not fit for, or decline, surgery. The analysis of p53 in a larger study is warranted in order to assess its role as a biomarker in this patient group.

Role of magnetic resonance imaging in the diagnosis and single-stage surgical resection of invasive lobular carcinoma of the breast (Br J Surg 2002; 89: 1296-1301).

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Gastric obstruction secondary to metastatic breast cancer: a case report and literature review.

IntroductionGastrointestinal tract soft tissues metastasis is a well-known occurrence with invasive lobular breast cancer subtypes. Gastric involvement is more common, with reports of both diffuse and localized involvements. Usually, a gastric localized involvement presents as wall thickening with an appearance similar to that of a gastrointestinal stromal tumour; rarely does a localized metastatic deposit grow aggressively to present as a large tumour causing obstructive symptoms. Our case highlights one such unusual presentation in a patient presenting with non-specific gastrointestinal symptoms. To the best of our knowledge, there have been no previous reports on a similar presentation occurring from a localized metastasis.Case presentationA 65-year-old Caucasian woman awaiting an outpatient oral gastroduodenoscopy for symptoms of intermittent vomiting, epigastric pains and weight loss of six weeks’ duration presented acutely with symptoms of haematemesis and abdominal distension. An initial contrast-enhanced computed tomography scan showed a grossly dilated stomach with a locally advanced stenosing tumour mass at the pylorus. Our patient had a history of left mastectomy and axillary clearance followed by adjuvant endocrine therapy for an oestrogen receptor- and progesterone receptor-positive, grade 2, invasive lobular breast cancer. The oral gastroduodenoscopy confirmed the computed tomography findings; biopsies of the pyloric mass on immunohistochemistry stains were strongly positive for pancytokeratin and gross cystic disease fluid proteins, consistent with an invasive lobular breast cancer metastasis. She received a palliative gastrojejunal bypass and her adjuvant endocrine treatment was switched over to exemestane.ConclusionOur case highlights the aggressive behaviour of a localized gastric metastasis that is unusual and unexpected. Gastrointestinal symptomatology can be non-specific and, at times, non-diagnostic on conventional mucosal biopsies. A high index of clinical suspicion in patients with a previous history of invasive lobular breast cancer can aid in an early diagnosis and treatment. A combined treatment approach with chemoendocrine therapies achieves remission and improves patient survival.

Safety of vacuum-assisted biopsy/mammatome guided, non-operative management of B3 lesions without atypia: a 7-year follow-up study

B3 management balances safe treatment of potential malignancy against the morbidity of surgical excision of benign lesions. Vacuum-assisted biopsy (VAB) increases diagnostic accuracy, removing some lesions entirely without surgery. Few follow-up data are available to assess the safety and effectiveness of this approach.

Reply: Improved safety and effectiveness of imaging predicted for MR mammography

Sir, We read with interest the comments regarding a possible relationship between female carriers of ataxia telangiectasia (AT) with susceptibility to low-dose ionising radiation and the induction of breast cancers in women of screening age. Although MR mammography does not use ionising radiation, its use in screening of women at a high risk of breast cancer is currently being evaluated, both because of the inherent high sensitivity of the technique, especially in dense pre-menopausal breast tissue and the safety issues particularly in Li-Fraumeni syndrome. The UK Magnetic Resonance Imaging for Breast Screening study (MARIBS) is a multicentre ongoing trial comparing the efficacy of X-ray mammography and MRI as a method for screening genetically high-risk women aged 35–50 years. This trial will close in 2005. Results from Kuhl et al (2003) and Kriege et al (2003) presented recently at the American Society of Clinical Oncology, relating to similar trials again of genetically high-risk subjects have indicated promising results. The authors are unaware of any current trials comparing imaging modalities for screening the 50– 64-year age group, or indeed if such a trial is contemplated. The results of such a comparison including health economic issues would need to be very carefully evaluated before embarking on a long-term follow-up trial to elucidate the risks of screening using techniques dependent on ionising radiation.