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.

Feasibility of use of a barbed suture (v-loc 180) for quilting the donor site in latissimus dorsi myocutaneous flap breast reconstruction.

BACKGROUND: Latissimus dorsi (LD) myocutaneous flap is a popular method of breast reconstruction which can be associated with high incidence of seroma formation. Quilting sutures at the harvest site are used to reduce this. Barbed sutures are self anchoring sutures which avoid multiple knotting and can be useful in quilting. METHODS: A retrospective analysis of prospectively maintained database of patients who underwent LD flap breast reconstruction between January 2009 and January 2011 was carried out. Seroma formation at the harvest site, wound related complications, inpatient stay and duration of surgery were analysed and a comparison was made between two groups where quilting was done with barbed (V-Loc) suture and conventional polydioxanone (PDS) II sutures. RESULTS: Fifty-seven patients were included of which 33 had quilting by V-Loc sutures and in 24 patients PDS II suture was used. Median age in the PDS group was 55 years (interquartile range [IQR)], 45 to 61 years) which was comparable to the V-Loc group (53 years [IQR, 48 to 59 years]; P-value 0.948). Sixteen patients (28%) had significant seroma formation and 5 (9%) patients developed superficial wound dehiscence. Incidences of seroma or wound complications were comparable (P-value 0.378 and 1.00, respectively). Secondary outcomes such as total duration of surgery, total inpatient stay, total amount of drain at the donor site were also similar in two groups. CONCLUSIONS: Use of barbed sutures for quilting the donor site in LD flap reconstruction is a feasible option and the associated seroma formation and wound complications are comparable with conventional sutures.

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

INTRODUCTION: Gastrointestinal 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 PRESENTATION: A 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. CONCLUSION: Our 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.

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.

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.