Real-world analysis of clinical and economic impact of 21-gene recurrence score (RS) testing in early-stage breast cancer (ESBC) in Ireland.

PURPOSE: Results from TAILOR-X suggest that up to 70% of hormone receptor-positive (HR+) node-negative (N0) ESBC patients (pts) may avoid chemotherapy (CT) with RS ≤ 25. We assess clinical and economic impacts of RS testing on treatment using real-world data. METHODS: From October 2011 to February 2019, a retrospective, cross-sectional observational study was conducted of HR+ N0 ESBC pts who had RS testing in Ireland. Pts were classified low risk (RS ≤ 25) and high risk (RS > 25). Clinical risk was calculated. Data were collected via electronic patient records. Cost data were supplied by the National Healthcare Pricing Regulatory Authority. RESULTS: 963 pts. Mean age is 56 years. Mean tumour size is 1.7 cm. 114 (11.8%), 635 (66%), 211 (22%), 3 (0.2%) pts had G1, G2, G3 and unknown G, respectively. 796 pts (82.8%) low RS, 159 (16.5%) high RS and 8 pts (0.7%) unknown RS. 263 pts (26%) were aged ≤ 50 at diagnosis; 117 (45%) had RS 0-15, 63 (24.5%) 16-20, 39 (15.3%) 21-25 and 40 (15.2%) RS 26-100. 4 pts (1.5%) had unknown RS. Post-RS testing, 602 pts (62.5%) had a change in CT decision; 593 changed to hormone therapy (HT) alone. In total, 262 pts received CT. Of pts receiving CT; 138 (53%) had RS > 25, 124 (47%) had RS ≤ 25. Of pts aged ≤ 50, 153 (58%) had high clinical risk, of whom 28 had RS 16-20. Assay use achieved a 62.5% change in treatment with 73% of pts avoiding CT. This resulted in savings of €4 million in treatment costs. Deducting assay costs, savings of €1.9 million were achieved. CONCLUSION: Over the 8 years of the study, a 62.5% reduction in CT use was achieved with savings of over €1,900,000.

Value of a 21-gene expression assay on core biopsy to predict neoadjuvant chemotherapy response in breast cancer: systematic review and meta-analysis.

BACKGROUND: A recurrence score based on a 21-gene expression assay predicts the benefit of adjuvant chemotherapy in oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This systematic review aimed to determine whether the 21-gene expression assay performed on core biopsy at diagnosis predicted pathological complete response (pCR) to neoadjuvant chemotherapy. METHODS: The study was performed according to PRISMA guidelines. Relevant databases were searched to identify studies assessing the value of the 21-gene expression assay recurrence score in predicting response to neoadjuvant chemotherapy in patients with breast cancer. The Newcastle-Ottawa Scale was used to assess the quality of the studies. Results are reported as risk ratio (RR) with 95 per cent confidence interval using the Cochrane-Mantel-Haenszel method for meta-analysis. Sensitivity analyses were carried out where appropriate. RESULTS: Seven studies involving 1744 patients reported the correlation between pretreatment recurrence score and pCR. Of these, 777 patients (44.6 per cent) had a high recurrence score and 967 (55.4 per cent) a low-intermediate score. A pCR was achieved in 94 patients (5.4 per cent). The pCR rate was significantly higher in the group with a high recurrence score than in the group with a low-intermediate score (10.9 versus 1.1 per cent; RR 4.47, 95 per cent c.i. 2.76 to 7.21; P < 0.001). A significant risk difference was observed between the two groups (risk difference 0.10, 0.04 to 0.15; P = 0.001). CONCLUSION: A high recurrence score is associated with higher pCR rates and a low-intermediate recurrence score may indicate chemoresistance. Routine assessment of recurrence score by the 21-gene expression assay on core biopsy might be of value when considering neoadjuvant chemotherapy in patients with ER-positive, HER2-negative breast cancer.

Clinical and Survival Outcomes Using Percutaneous Cholecystostomy Tube Alone or Subsequent Interval Cholecystectomy to Treat Acute Cholecystitis.

BACKGROUND: Percutaneous cholecystostomy (PCT) is a safe method of gallbladder drainage in the setting of severe or complicated acute cholecystitis (AC), particularly in patients who are high-risk surgical candidates. Small case series suggest that PCT aids resolution of acute cholecystitis in up to 90% of patients. However, reluctance is observed in utilising PCT more frequently, due to concerns that we are committing comorbid patients to an interval surgical procedure for which they may not be suitable. AIM: The aim of this study was to assess the clinical and survival outcomes of PCT use, with particular emphasis on a subgroup of patients who did not proceed to cholecystectomy. METHODS: A retrospective analysis was performed of all patients with severe acute cholecystitis who required PCT insertion in a tertiary referral hospital from 2010 to 2015. Patient demographics and clinical data including systemic inflammatory response (SIRS) scores at presentation, readmissions and clinical and survival outcomes were analysed. Statistical analysis was performed using SPSS v.22 and GraphPad Prism v.7. RESULTS: In total, 157 patients (59% males) with AC underwent PCT insertion during the study period. Median age at presentation was 71 years (range 29-94). A median SIRS score of 3 was noted at presentation. Patients required a median of two cholecystostomy tube changes/replacements (range 1-10) during treatment. Transhepatic tube placement was the preferred approach (69%) with 31% of tubes being placed via transabdominal approach. Only 55% proceeded to interval cholecystectomy. Of the 70 patients treated with PCT alone, their median age was 75 years. In this subgroup, only 12.9% (n = 9) developed recurrent biliary sepsis necessitating readmission following initial resolution of symptoms and tube removal. All episodes of recurrent biliary sepsis presented within 6 months of index presentation, and definitive PCT removal in this group was performed at a median of 3 months. No difference in survival was observed between both groups. CONCLUSION: Almost 90% of patients with AC who are managed definitively with a PCT will recover uneventfully without recurrent sepsis following PCT removal. This is a viable option for older, comorbid patients who are unfit for surgical intervention and is not associated with significantly increased mortality.

The approach to an isolated close anterior margin in breast conserving surgery.

INTRODUCTION: Although close radial margins after breast-conserving surgery routinely undergo re-excision, appropriate management of patients with close anterior margins remains a topic of controversy. An increasing body of literature suggests that re-excision of close anterior margins yields low rates of residual malignancy and may only be necessary in selected patients. The aim of this study was to examine the management of close anterior margins after breast conserving surgery in a single institution and to analyse the rate of residual disease in re-excised anterior margins. METHODS: All patients having breast conserving surgery at St Vincent's University Hospital from January 2008 to December 2012 were reviewed retrospectively. Data collected included patient demographics, tumour characteristics, margin positivity, re-excision rates and definitive histology of the re-excision specimens. A close margin was defined as les than 2 mm. RESULTS: A total of 930 patients were included with an average age of 65 years (range 29-94 years). Of these, 121 (13%) had a close anterior margin. Further re-excison of the anterior margin was carried out in 37 patients (30.6%) and a further 16 (13.2%) proceeded to mastectomy. Residual disease was found in 18.5% (7/36) of those who underwent re-excision and 7/16 (43.75%) of those who underwent mastectomy. Overall, 11.57% (14/121) of patients with close anterior margins were subsequently found to have residual disease. CONCLUSION: The low yield of residual disease in re-excised anterior margins specimens supports the concept that routine re-excision of close anterior margins is not necessary. Further research is required to definitively assess its influence on the risk of local recurrence.

Meta-analysis of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with initial biopsy-proven node-positive breast cancer.

BACKGROUND: Neoadjuvant chemotherapy for breast cancer has the potential to achieve a pathological complete response in up to 40 per cent of patients, converting disease that was initially node-positive to node-negative. This has raised the question of whether sentinel lymph node biopsy could be an alternative to axillary lymph node dissection in these patients. The aim was to undertake a systematic review and meta-analysis of the accuracy and reliability of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with initial biopsy-proven node-positive breast cancer. METHODS: A literature search was conducted using PubMed, Ovid MEDLINE, Embase and Web of Science databases up to 30 April 2017. Inclusion criteria for studies were pathological confirmation of initial node-positive disease, and sentinel lymph node biopsy performed after neoadjuvant chemotherapy followed by axillary lymph node dissection. RESULTS: A total of 13 studies met the inclusion criteria and were included in the analysis (1921 patients in total). The pooled estimate of identification rate was 90 (95 per cent c.i. 87 to 93) per cent and the false-negative rate was 14 (11 to 17) per cent. In subgroup analysis, the false-negative rate with use of dual mapping was 11 (6 to 15) per cent, compared with 19 (11 to 27) per cent with single mapping. The false-negative rate was 20 (13 to 27) per cent when one node was removed, 12 (5 to 19) per cent with two nodes removed and 4 (0 to 9) per cent with removal of three or more nodes. CONCLUSION: Sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with biopsy-proven node-positive breast cancer is accurate and reliable, but requires careful patient selection and optimal surgical techniques.

Meta-analysis of the cumulative risk of endometrial malignancy and systematic review of endometrial surveillance in extended tamoxifen therapy.

BACKGROUND: Optimal management of the endometrium in patients with oestrogen receptor-positive breast cancer taking extended tamoxifen therapy (for 10 years) remains uncertain. A meta-analysis was performed to determine the cumulative risk ratio (RR) for endometrial malignancy following extended compared with standard tamoxifen treatment. A systematic review was undertaken to identify whether routine endometrial surveillance in patients receiving tamoxifen is associated with earlier detection and reduced incidence of endometrial malignancy. METHODS: Two independent searches were undertaken in the Cochrane Library, PubMed and MEDLINE. A meta-analysis was performed of RCTs reporting on endometrial malignancy risk in extended tamoxifen therapy. A systematic review included prospective studies investigating the benefit of endometrial surveillance during tamoxifen therapy. RESULTS: Four RCTs reported on endometrial risk in extended tamoxifen therapy. The cumulative risk of endometrial malignancy increased twofold from 1·5 to 3·2 per cent with extended therapy compared with the standard 5 years of tamoxifen (RR 2·29, 95 per cent c.i. 1·60 to 3·28; P < 0·001). Four studies analysed the value of endometrial screening in 5-year cohorts. Endometrial cancer rates of up to 2 per cent were reported, which is higher than rates in the large extended tamoxifen trials. CONCLUSION: Extended adjuvant tamoxifen is associated with an increase in endometrial cancer. No clear benefit has been shown for routine endometrial surveillance in asymptomatic patients on tamoxifen therapy.

Impact of receptor phenotype on nodal burden in patients with breast cancer who have undergone neoadjuvant chemotherapy.

BACKGROUND: Optimal evaluation and management of the axilla following neoadjuvant chemotherapy (NAC) in patients with node-positive breast cancer remains controversial. The aim of this study was to examine the impact of receptor phenotype in patients with nodal metastases who undergo NAC to see whether this approach can identify those who may be suitable for conservative axillary management. METHODS: Between 2009 and 2014, all patients with breast cancer and biopsy-proven nodal disease who received NAC were identified from prospectively developed databases. Details of patients who had axillary lymph node dissection (ALND) following NAC were recorded and rates of pathological complete response (pCR) were evaluated for receptor phenotype. RESULTS: Some 284 patients with primary breast cancer and nodal metastases underwent NAC and subsequent ALND, including two with bilateral disease. The most common receptor phenotype was luminal A (154 of 286 tumours, 53·8 per cent), with lesser proportions accounted for by the luminal B-Her2 type (64, 22·4 per cent), Her2-overexpressing (38, 13·3 per cent) and basal-like, triple-negative (30, 10·5 per cent) subtypes. Overall pCR rates in the breast and axilla were 19·9 per cent (54 of 271 tumours) and 37·4 per cent (105 of 281) respectively. Axillary pCR rates were highest in the Her2-overexpressing group (27 of 35, 77 per cent) and lowest in the luminal A group (35 of 153, 22·9 per cent) (P < 0·001). Nodal burden (median number of positive nodes excised) was lower in the Her2-overexpressing group compared with the luminal A group (0 versus 3; P < 0·001). CONCLUSION: Her2 positivity was associated with increased rates of axillary pCR and reduced nodal burden following NAC.

A Positive Node on Ultrasound-Guided Fine Needle Aspiration Predicts Higher Nodal Burden Than a Positive Sentinel Lymph Node Biopsy in Breast Carcinoma.

INTRODUCTION: Axillary status remains an important prognostic indicator in breast cancer. Certain patients with a positive sentinel node (SLNB) may not benefit from axillary clearance (AC). Uncertainty remains if this approach could be applied to patients diagnosed with axillary metastases on ultrasound-guided fine needle aspiration cytology (USFNAC). The aim of this study was to compare nodal burden in patients with positive USFNAC and a positive SLNB. METHODS: A retrospective study was performed involving all BC patients between 2007 and 2014 who had either pre-operative USFNAC or a SLNB. Patient/tumour characteristics and nodal burden were examined in all patients proceeding to AC. RESULTS: 974 patients were eligible for analysis. 439 patients (45 %) had positive USFNAC and 535 (55 %) had a positive SLNB. USFNAC-positive patients were more likely to undergo mastectomy (Chi-square test; p < 0.001), have extra-nodal extension (p < 0.001), be oestrogen receptor negative (p < 0.001) and be HER2 positive (p < 0.001). The median total number of lymph nodes (LNs) excised during AC was higher in the USFNAC group (Mann-Whitney test; 23 vs. 21; p < 0.001). The median total number of involved LNs was 3 (range 1-47) in FNAC-positive patients versus 1 (range 1-37) in SLNB-positive patients (p < 0.001). The median number of involved LNs in level 1 was 3 in FNAC-positive patients versus 1 in SLNB-positive patients (p < 0.001). Within the SLN-positive group, 49 % of the patients had only one involved LN, 28 % had two nodes involved and 23 % had ≥3. In comparison, within the FNAC-positive group only 13 % of the patients had one involved LN, 12 % had two nodes involved and 74 % had ≥3. CONCLUSION: Patients with positive USFNAC have more aggressive clinico-pathological characteristics and higher nodal burden compared to SLNB-positive patients. Currently, the authors advocate that patients not receiving neoadjuvant chemotherapy, with a positive USFNAC, should proceed directly to an axillary ALND.

Role of bone scan in addition to CT in patients with breast cancer selected for systemic staging.

BACKGROUND: The majority of women with breast cancer present with localized disease. The optimal strategy for identifying patients with metastatic disease at diagnosis remains unclear. The aim of this study was to evaluate the additional diagnostic yield from isotope bone scanning when added to CT staging of the thorax, abdomen and pelvis (CT-TAP) in patients with newly diagnosed breast cancer. METHODS: All patients diagnosed with breast cancer who underwent staging CT-TAP and bone scan between 2011 and 2013 were identified from a prospective database of a tertiary referral breast cancer centre that provides a symptomatic and population-based screening breast service. Criteria for staging included: biopsy-proven axillary nodal metastases; planned neoadjuvant chemotherapy or mastectomy; locally advanced or inflammatory breast cancer and symptoms suggestive of metastases. RESULTS: A total of 631 patients underwent staging by CT-TAP and bone scan. Of these, 69 patients (10·9 per cent) had distant metastasis at presentation, with disease confined to a single organ in 49 patients (71 per cent) and 20 (29 per cent) having metastatic deposits in multiple organs. Bone metastasis was the most common site; 39 of 49 patients had bone metastasis alone and 12 had a single isolated metastatic deposit. All but two of these were to the axial skeleton. No preoperative histological factors identified a cohort of patients at risk of metastatic disease. Omission of the bone scan in systemic staging would have resulted in a false-negative rate of 0·8 per cent. CONCLUSION: For patients diagnosed with breast cancer, CT-TAP is a satisfactory stand-alone investigation for systemic staging.

Running in the family: A rare diagnosis of familial papillary thyroid cancer.

INTRODUCTION: Whilst inherited medullary thyroid cancer has been extensively reported, familial non-medullary thyroid cancer is a rare and less well described clinical entity. Familial forms of the disease demonstrate more aggressive features than sporadic non-medullary thyroid cancer. PRESENTATION OF CASE: A 54 year old lady was referred with globus on a background of a longstanding goitre. Three first degree relatives had a history of non-medullary thyroid carcinoma. Investigations revealed a papillary thyroid carcinoma and the patient proceeded to total thyroidectomy and ipsilateral Level VI neck dissection, followed by adjuvant radioiodine ablation. DISCUSSION: Familial papillary thyroid carcinoma syndrome is defined as three or more first degree relatives diagnosed with the disease in the absence of other known associated syndromes. It is often associated with the presence of benign thyroid disorders, and is characterised by the early onset of multi-focal bilateral locally advanced tumours. CONCLUSION: Familial papillary thyroid cancer is a rare clinical entity but should be considered where ≥3 first degree relatives are diagnosed with non-medullary thyroid cancer. It is necessary to exclude other familial tumour syndromes to make the diagnosis. It demonstrates more aggressive features with higher rates of local recurrence than its sporadic counterpart, and therefore mandates more aggressive management than might otherwise be indicated. Screening of first degree relatives should be considered. SUMMARY: The case of a 54 year old female diagnosed with familial non-medullary thyroid carcinoma is reported.

A comparison of clinical-pathological characteristics between symptomatic and interval breast cancer.

BACKGROUND: An association between interval breast cancers (cancer detected after a normal mammogram and before the next scheduled mammogram) and tumour aggressiveness has been postulated which may reflect their relatively poor overall prognosis. The aim of this study was to evaluate known prognostic features of screen detected breast cancers compared to interval breast cancers. METHODS: Patients diagnosed with breast cancer between January 2010 and 2013 at a single unit of the National Breast Screening Program (NBSP) in Ireland and those between the ages of 50 and 65 diagnosed at a symptomatic breast clinic were included in the study. Patients who had not had a screening mammogram within the proceeding two years or had a previous history of breast cancer were excluded. Data were retrospectively collected on patient demographics, tumour type, grade, hormone receptor status and stage of disease at presentation. RESULTS: There were 915 patients included in the study, with 92% (n = 844) diagnosed through the NBSP. Ductal carcinoma in-situ accounted for 19% (n = 160) of screen-detected breast cancers but only 2.8% of interval cancers (p < 0.05). The most common type of invasive cancer was invasive ductal carcinoma. Tumour grade was significantly higher in interval breast cancers (p < 0.05). Interval cancers were identified at a significantly higher stage (Stage 1 versus 2; p < 0.001) than screen-detected cancers. Interval breast cancers were less likely to be ER positive (76% versus 81%; p < 0.05) and significantly more likely to over-express HER2 (20% vs 10%, p < 0.05) than screen-detected cancers. CONCLUSION: This study highlights the fact that interval cancers appear to have a number of adverse prognostic markers for overall breast cancer survival when compared to women with screen-detected breast cancers. Interval cancers were more likely to be invasive, of a higher grade and stage and with a greater predominance of HER2 and triple negative molecular subtypes. Therefore this heterogeneous group of tumours may be biologically more aggressive and account disproportionately to overall breast cancer mortality.

Axillary nodal burden in primary breast cancer patients with positive pre-operative ultrasound guided fine needle aspiration cytology: management in the era of ACOSOG Z011.

INTRODUCTION: Recent years have seen a dramatic shift to more conservative management of the axilla in patients with a positive sentinel lymph node biopsy (SLNB). Identification of nodal disease with positive pre-operative ultrasound guided axillary fine needle aspiration cytology (AUS/FNAC) may represent a higher axillary disease burden mandating an axillary clearance and thus an upfront SLNB may be avoided. The aims of this study were to quantify nodal burden in patients with positive pre-operative AUS/FNAC and identify patients who may have been able to avoid an axillary clearance (ALND) based on ACOSOG Z011 criteria. METHODS: A retrospective review of a prospectively maintained database identified patients with positive pre-operative AUS/FNAC between 2007 and 2012. Core biopsies were excluded. Demographic and tumour characteristics were analysed. Eligibility for ACOSOG Z011 criteria was assessed and patients who may have avoided ALND were identified. RESULTS: 432 patients were identified with positive AUS/FNAC. 85 patients were excluded leaving 347 for analysis. Median age was 56 years (22-87), median tumour size was 25 mm (1.5 mm-150 mm) and median tumour pathology was grade 3 (50%) and invasive ductal carcinoma (82%). Median number of nodes removed at ALND was 23 (1-55) with a median number of positive nodes being 4 (1-47). 134 (39%) patients had ≤2 positive nodes identified on ALND making them eligible for the ACOSOG Z011 study. When other ACOSOG Z011 exclusion factors were applied only 27 (7.8%) patients may have avoided ALND. CONCLUSIONS: Nodal positivity on AUS/FNAC is associated with higher axillary disease burden. Few patients would satisfy ACOSOG/Z011 criteria and avoid ALND making an upfront SLNB unnecessary.

Malignant melanoma: factors affecting the surgical interval from excision biopsy to definitive surgical management.

INTRODUCTION: Surgery remains the mainstay of treatment for malignant melanoma. Despite previous studies examining the surgical interval (SI) between the diagnostic excision biopsy (DEB) and definitive surgical management there remains few guidelines regarding an optimal time interval. The aim of this study was to determine the SI between DEB and definitive surgery and elucidate factors associated with delays in management of malignant melanoma. METHODS: A retrospective study of 107 consecutive patients who had a DEB and subsequent wide local excision between January 2011 and June 2012 was performed. Mode of referral and dates of diagnostic biopsy/definitive surgery were documented. Patient demographics and tumour characteristics were reviewed. RESULTS: The mean age was 59.6 years, and male:female ratio was 1:1.3. Median duration of the SI was 41 ± 27 days (range 6-137 days). The SI was increased when dermatologists performed the DEB as opposed to general surgeons (p = 0.035). The anatomic location of the lesion predicted the SI, with lesions of the head/neck undergoing definitive excision 48 ± 32.3 days after DEB vs. 37.5 ± 22.6 days for all other sites (p = 0.001). Neither demographic factors nor histopathological prognostic features affected the SI. Reasons for a prolonged SI included referrals to different services and time for pre-operative planning. CONCLUSIONS: Significant variations were noted in the SI predominantly accounted for by mode of referral and location of the malignant melanoma. Further investigation is required to elucidate factors affecting the SI and its subsequent effect on patient outcomes.

Incidental Phaeochromocytoma on Staging PET-CT in a Patient with a Sigmoid Tumour and Situs Inversalis Totalis.

An adrenal "incidentaloma" is defined as an unexpected finding on radiological imaging performed for unrelated indications. Improvements in radiological technology have seen a dramatic increase in this phenomenon. We report the unique case of a 60-year-old female presenting with a 6-month history of abdominal pain, altered bowel habit, and rectal bleeding. Her past medical history included situs inversus totalis and a patent ductus arteriosus. Colonoscopy revealed an ulcerated tumour in her sigmoid colon. Staging PET-CT confirmed a sigmoid tumour and also identified a large heterogenous enhancing FDG-avid right adrenal mass. Biochemical testing/MIBG imaging confirmed a right adrenal phaeochromocytoma. Hypertension was controlled and excision was performed via a transperitoneal laparoscopic adrenalectomy, in the left lateral decubitus position. Uniquely, liver retraction was not required due to its position in the left hypochondrium. Histology confirmed a benign 46 mm phaeochromocytoma. Subsequent uncomplicated sigmoid colectomy/right salpingo-oophorectomy for a locally advanced colonic tumour was performed with adjuvant chemotherapy. This case highlights the importance of accurately identifying functioning adrenal tumours before elective surgery as undiagnosed phaeochromocytomas carry significant intraoperative morbidity/mortality. Right adrenalectomy was made easier in this patient by the liver's unique position. Uncomplicated colorectal resection was made possible by combined preoperative functional/anatomical imaging.

Postmastectomy radiotherapy: indications and implications.

BACKGROUND: Although breast conservation surgery, when combined with radiotherapy, has been shown to provide excellent locoregional control for breast cancer, approximately one third of women with breast cancer require mastectomy. Many of these women are offered immediate reconstruction. Postmastectomy radiotherapy (PMRT) is indicated in some cases, but is associated with side-effects, including its impact on the reconstructed breast. OBJECTIVE: To review the pertinent issues surrounding PMRT, including patient selection for radiotherapy and the effect of radiotherapy on reconstructive decisions. METHODS: A literature review was performed using the Medline database. CONCLUSIONS: PMRT is indicated in patients who are deemed to have a high risk of loco-regional recurrence. Although PMRT is strongly recommended for patients with four or more positive lymphnodes, other indications for PMRT remain controversial. Immediate reconstruction post mastectomy has been shown to have favorable outcomes. However, PMRT may increase the need for revision surgery post immediate reconstruction. There are few randomized trials looking at these key issues, and the evidence is largely derived from observational retrospective studies. Patients should be carefully counseled before a decision is made to proceed with immediate reconstruction, where there is a high chance that PMRT may be indicated.

Ultrasound predictors of malignancy in indeterminate thyroid nodules.

BACKGROUND: Asymptomatic thyroid nodules are an increasingly common clinical problem. Lesions greater than a centimetre require cytological assessment. Indeterminate lesions often need surgical excision to establish a definitive diagnosis and plan further management. If a definitive diagnosis could be accurately predicted pre-operatively, the most appropriate surgical procedure could be performed at the initial operation. AIM: The aim of this study was to identify whether specific thyroid ultrasound features could predict malignancy in indeterminate thyroid nodules. METHODS: A retrospective review of all patients undergoing surgery for an indeterminate thyroid lesion between 2006 and 2012 was performed. Demographic features, surgical intervention and final histological findings were determined. Pre-operative ultrasound findings and final histology were correlated and the ultrasonic markers predictive of malignancy were determined. RESULTS: A total of 40 patients were identified as having undergone surgical intervention for indeterminate thyroid nodules. The majority of patients were diagnosed with a follicular adenoma (n = 22; 55 %). Papillary thyroid carcinoma was identified in three patients (7.5 %) and follicular carcinoma in a further 3 (7.5 %). Ultrasound features associated with malignancy included poorly defined nodule borders and increased vascularity. The presence of malignancy was not related to nodule size, echogenicity or the presence of calcifications. CONCLUSIONS: The majority of indeterminate thyroid lesions are benign on final histological assessment. High nodule vascularity associated with ill-defined borders is associated with malignancy. Further research is warranted to identify predictors of malignancy in indeterminate nodules in order to avoid unnecessary or repeated procedures.

ADAM-17: a novel therapeutic target for triple negative breast cancer.

BACKGROUND: Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR/HER family of receptors. PATIENTS AND METHODS: Expression of ADAM-17 was measured in 86 triple-negative and 96 non-triple-negative breast cancers. The ADAM-17 specific inhibitor, PF-5480090 (TMI-002, Pfizer) was tested in a panel of breast cancer cell lines for effects on functional outputs. RESULTS: In this study we show using both Western blotting and immunohistochemistry that ADAM-17 is expressed at significantly higher levels in TN than non-TN breast cancers. Using a panel of breast cancer cell lines in culture, PF-5480090 was found to decrease release of the EGFR ligand, TGF-alpha, decrease levels of phosphorylated EGFR and block cell proliferation in a cell-type-dependent manner. Potentially important was the finding of a significant and moderately strong correlation between ADAM-17 activity and extent of proliferation inhibition by PF-5480090 (r = 0.809; p = 0.003; n = 11). Pretreatment of cell lines with PF-5480090 enhanced response to several different cytotoxic and anti-EGFR/HER agents. CONCLUSION: It is concluded that inhibition of ADAM-17, especially in combination with chemotherapy or anti-EGFR/HER inhibitors, may be a new approach for treating breast cancer, including patients with TN disease.

mTOR in breast cancer: differential expression in triple-negative and non-triple-negative tumors.

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptors (ER), progesterone receptors (PR) and overexpression of HER2. Targeted therapy is currently unavailable for this subgroup of breast cancer patients. mTOR controls cancer cell growth, survival and invasion and is thus a potential target for the treatment of patients with TNBC. Using immunohistochemistry, mTOR and p-mTOR were measured in 89 TNBCs and 99 non-TNBCs. While mTOR expression was confined to tumor cell cytoplasm, p-mTOR staining was located in the nucleus, perinuclear area and in the cytoplasm. Potentially important, was our finding that nuclear p-mTOR was found more frequently in triple-negative than non triple-negative cancers (p < 0.001). These results suggest that mTOR may play a more important role in the progression of TNBC compared to non-TNBC. Based on these findings, we conclude that mTOR may be a new target for the treatment of triple-negative breast cancer.