Claire Holloway

Sentinel Node Biopsy After Neoadjuvant Chemotherapy in Biopsy-Proven Node-Positive Breast Cancer: The SN FNAC Study

PURPOSE An increasing proportion of patients (> 30%) with node-positive breast cancer will obtain an axillary pathologic complete response after neoadjuvant chemotherapy (NAC). If sentinel node (SN) biopsy (SNB) is accurate in this setting, completion node dissection (CND) morbidity could be avoided. PATIENTS AND METHODS In the prospective multicentric SN FNAC study, patients with biopsy-proven node-positive breast cancer (T0-3, N1-2) underwent both SNB and CND. Immunohistochemistry (IHC) use was mandatory, and SN metastases of any size, including isolated tumor cells (ypN0[i+], ≤ 0.2 mm), were considered positive. The optimal SNB identification rate (IR) ≥ 90% and false-negative rate (FNR) ≤ 10% were predetermined. RESULTS From March 2009 to December 2012, 153 patients were accrued to the study. The SNB IR was 87.6% (127 of 145; 95% CI, 82.2% to 93.0%), and the FNR was 8.4% (seven of 83; 95% CI, 2.4% to 14.4%). If SN ypN0(i+)s had been considered negative, the FNR would have increased to 13.3% (11 of 83; 95% CI, 6.0% to 20.6%). There was no correlation between size of SN metastases and rate of positive non-SNs. Using this method, 30.3% of patients could potentially avoid CND. CONCLUSION In biopsy-proven node-positive breast cancer after NAC, a low SNB FNR (8.4%) can be achieved with mandatory use of IHC. SN metastases of any size should be considered positive. The SNB IR was 87.6%, and in the presence of a technical failure, axillary node dissection should be performed. We recommend that SN evaluation with IHC be further evaluated before being included in future guidelines on the use of SNB after NAC in this setting.

Imaging of HER2/neu expression in BT-474 human breast cancer xenografts in athymic mice using [99mTc]-HYNIC- trastuzumab (Herceptin) Fab fragments

ObjectiveTo evaluate the ability of trastuzumab (Herceptin) Fab, labelled with 99mTc through introduced hydrazinenicotinamide (HYNIC) functionalities, to image HER2/neu-overexpressing human breast cancer xenografts in athymic mice. MethodsFab fragments were produced by immobilized papain digestion of trastuzumab immunoglobulin G (IgG), followed by purification by ultrafiltration. The immunoreactivity of trastuzumab Fab was evaluated by receptor-binding assays against HER2/neu-positive SK-BR-3 human breast cancer cells. Trastuzumab Fab fragments were labelled with 99mTc following modification with HYNIC N-hydroxysuccinimide ester. Biodistribution and tumour imaging studies were performed in athymic mice bearing subcutaneous HER2/neu-overexpressing BT-474 human breast cancer xenografts following intravenous injection of 1.1 or 25 MBq of [99mTc]-trastuzumab Fab (30 μg), respectively. The specificity of tumour uptake was assessed by comparison with that of [99mTc]-labelled irrelevant anti-CD33 HuM195 Fab. ResultsTrastuzumab Fab was pure and exhibited preserved immunoreactivity towards SK-BR-3 cells (Kd=1.6×10−8 M). Modification with HYNIC diminished its receptor-binding affinity fourfold. [99mTc]-trastuzumab Fab localized avidly and specifically in BT-474 xenografts, achieving a tumour uptake of 10.7% of the injected dose (ID) per gram and a tumour to blood (T/B) ratio of 3 : 1 at 24 h. The tumour uptake and T/B ratio for [99mTc]-trastuzumab Fab were significantly higher than those for control [99mTc]-HuM195 Fab (2.6% ID · g−1 and 0.9 : 1, respectively; P<0.05). Tumours were imaged as early as 2 h post-injection of [99mTc]-trastuzumab Fab, but were more clearly visualized at 6 and 24 h post-injection. Conclusions[99mTc]-HYNIC-trastuzumab Fab localized specifically in HER2/neu-overexpressing human breast cancer xenografts in athymic mice, allowing imaging of the tumours within the useful lifetime of the radionuclide.

Prospective Study of 2-[18F]Fluorodeoxyglucose Positron Emission Tomography in the Assessment of Regional Nodal Spread of Disease in Patients With Breast Cancer: An Ontario Clinical Oncology Group Study

PURPOSE 2-[(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is potentially useful in assessing lymph nodes and detecting distant metastases in women with primary breast cancer. PATIENTS AND METHODS Women diagnosed with operable breast cancer within 3 months underwent FDG-PET at one of five Ontario study centers followed by axillary lymph node assessment (ALNA) consisting of sentinel lymph node biopsy (SLNB) alone if sentinel lymph nodes (SLNs) were negative, SLNB with axillary lymph node dissection (ALND) if SLNB or PET was positive, or ALND alone if SLNs were not identified. RESULTS Between January 2005 and March 2007, 325 analyzable women entered this study. Sentinel nodes were found for 312 (96%) of 325 women and were positive for tumor in 90 (29%) of 312. ALND was positive in seven additional women. Using ALNA as the gold standard, sensitivity for PET was 23.7% (95% CI, 15.9% to 33.6%), specificity was 99.6% (95% CI, 97.2% to 99.9%), positive predictive value was 95.8% (95% CI, 76.9% to 99.8%), negative predictive value was 75.4% (95% CI, 70.1% to 80.1%), and prevalence was 29.8% (95% CI, 25.0% to 35.2%). Using logistic regression, tumor size was predictive for prevalence of tumor in the axilla and for PET sensitivity. PET scan was suspicious for distant metastases in 13 patients; three (0.9%) were confirmed as metastatic disease and 10 (3.0%) were false positive. CONCLUSION FDG-PET is not sufficiently sensitive to detect positive axillary lymph nodes, nor is it sufficiently specific to appropriately identify distant metastases. However, the very high positive predictive value (96%) suggests that PET when positive is indicative of disease in axillary nodes, which may influence surgical care.

A prospective study of mastectomy patients with and without delayed breast reconstruction: Long-term psychosocial functioning in the breast cancer survivorship period

For women who have mastectomy, breast reconstruction is an option which may improve psychosocial functioning. The purpose of this study was to evaluate changes in psychosocial functioning over a long follow‐up period after mastectomy, specifically examining the differences between those with mastectomy alone and those who underwent postmastectomy delayed breast reconstruction (DBR).

Measuring the Quality of Sentinel Lymph Node Biopsy in Breast Cancer Using Newly Developed Quality Indicators: A Feasibility Study

BackgroundMeasurement of the quality of sentinel lymph node biopsy (SLNB) has not been reported beyond the false-negative rate and sentinel lymph node identification rate. This study’s purpose is to determine the feasibility of measuring 11 quality indicators (QIs) that were recently developed using a modified Delphi process.MethodsAll patients who underwent SLNB for breast cancer at a tertiary health-care center from January 1st 2005 to December 31st 2007 were identified using a SLNB registry. Patient charts were reviewed retrospectively and the QIs were abstracted.ResultsNine of the 11 QIs were measurable: 7 required chart-level abstraction, 2 were confirmed at an institutional level, and 2 were immeasurable due to registry limitations. Of the 497 identified patients, 13 patients had failed SLNB, resulting in 484 SLNBs. The axillary positivity rate was 19%. The method of SLN identification was reported in 97% of cases, and in 388 (80%) more than one SLN was removed. All SLNs were serially sectioned according to protocol, though only 102 (21%) of pathology reports explicitly stated the cancer stage. Nearly all SLNBs were performed alongside the primary breast surgery. Among SLN-positive patients: 78 (87%) underwent axillary lymph node dissection, 10 patients refused, and chart data were missing in 2 others. No “ineligible” patients had SLNB.ConclusionMeasurement of newly developed QIs for SLNB is feasible for abstraction from inpatient charts at a single institution. These QIs can provide baseline measures for ongoing quality assessment of SLNB using hospital chart review.

Development of an MRI/x-ray/ultrasound compatible marker for pre-operative breast tumour localization

This paper describes an in vitro investigation into the composition, structure and development of an magnetic resonance imaging (MRI), ultrasound (US) and x-ray imaging compatible marker for breast tumour localization. The marker is composed of 0.4-0.6 mm glass and iron-containing aluminium microspheres suspended in a gelatin matrix. The final form of the marker is a cylindrical shape 7 mm long with 2.05 mm diameter to facilitate delivery through a 12 gauge biopsy needle. To get optimal reflectivity for the US contrast, the glass microsphere concentration was found to be 40% by weight. US contrast is independent of marker orientation and the cylindrical shape made its US signal appearance distinctive thus ensuring confident identification. To control the MRI contrast, iron content was varied to generate a clear and local susceptibility signal void to reflect the marker position. Optimal iron content was found to be 52 microg iron which produced a clear signal void in spoiled gradient recalled MR images. The appearance of the susceptibility artefact is determined by the markers shape, orientation and echo time. The final marker produces a dark artefact in MRI while appears as a clear hyperintense structure with acoustic shadowing in US images. The x-ray image showed the marker as a radio-opaque structure. This in vitro study demonstrates that the marker forms an alternative to traditional wire localization currently used for breast surgical procedures and creates new opportunities for US guided surgical procedures.

Phase I trial of intraoperative detection of tumor margins in patients with HER2-positive carcinoma of the breast following administration of 111In-DTPA-trastuzumab Fab fragments

INTRODUCTION Our aim was to conduct a Phase I clinical trial to determine the feasibility of intraoperative detection of tumor margins in HER2 positive breast carcinoma using a hand-held γ-probe following administration of (111)In-DTPA-trastuzumab Fab fragments. Accurate delineation of tumor margins is important for preventing local recurrence. METHODS Six patients with HER2-positive in situ or invasive ductal carcinoma were administered 74MBq (0.5mg) of (111)In-DTPA-trastuzumab Fab fragments and counts in the tumor, surgical cavity wall and en face margins were measured intraoperatively at 72h post-injection using the Navigator or C-Trak γ-probes. Margins were evaluated histologically. Quantitative whole body planar imaging was performed to estimate radiation absorbed doses using OLINDA/EXM software. SPECT imaging of the thorax was performed to evaluate tumor uptake. The pharmacokinetics of elimination from the blood and plasma were determined over 72h. RESULTS There were no acute adverse reactions from (111)In-DTPA-trastuzumab Fab fragments and no changes in hematological or biochemical indices were found over a 3month period. (111)In-DTPA-trastuzumab Fab fragments exhibited a biphasic elimination from the blood and plasma with t1/2α=11.9h and 7.5h, respectively, and t1/2β=26.6 and 20.7h, respectively. The radiopharmaceutical accumulated in the liver, spleen and kidneys. SPECT imaging did not reveal tumor in any patient. The mean effective dose was 0.146mSv/MBq (10.8mSv for 74MBq). Counts in excised tumors were low but were higher than in margins. Margins in two patients harboured tumor but this was not correlated with counts obtained using the γ-probes. Surgical cavity counts were high and likely due to detection of γ-photons outside the surgical field. CONCLUSION We conclude that it was not feasible, at least at the administered amount of radioactivity used in this study, to reliably detect the margins of disease in patients with in situ or invasive ductal carcinoma intraoperatively using a hand-held γ-probe and (111)In-DTPA-trastuzumab Fab fragments due to low uptake in the tumor and involved margins.

A human bone NOD/SCID mouse model to distinguish metastatic potential in primary breast cancers

In this study, we created a clinically relevant model using NOD/SCID mice engrafted with human bone fragments in both right and left flanks, and show that the human bone implants are viable and functional for more than six months. To investigate the growth and metastatic behavior of breast cancer, human primary breast tumor specimens were transplanted into human bone grafts under only the right flanks of the human-bone NOD/SCID mice. Some of the engrafted tumors proliferated extensively with massive neo-vascularization and also metastasized to the initially tumor-free left flank bone grafts. We show for the first time that this mouse model can be used to distinguish between primary breast tumors that do or do not proliferate and metastasize to contralateral human bone implants that were initially tumor-free.

Intraoperative Consultation for Axillary Sentinel Lymph Node Biopsy: An 8-Year Audit

To summarize the authors’ 8-year institutional experience with intraoperative consultation via frozen section (FS) on sentinel lymph node biopsy (SLNB) in breast cancer patients we recorded the, complete operative procedure including additional surgery on the ipsilateral axilla and intraoperative consultation and permanent histopathologic processing for all cases with inoperative consultation on SLNB in breast cancer patients between the groups, χ2 and Fisher’s exact tests were used. Intraoperative consultation was positive in 116/706 cases (16.4%) and final pathology in 158/706 cases (22.4%); the false-negative rate was 26.6%, the false-positive rate was 0%, and the overall accuracy was 94%. False-negative rate was significantly associated with the size of metastasis (micro vs macrometastasis; P < .002) but not significantly associated with the histologic type (P = 0.76) or pathologist expertise (P = 0.08). The rate of spared second procedures was 92% when calculated exclusively for patients who ultimately underwent ALND. Intraoperative consultation via FS for SLNB is a safe practice that can reliably save clinically node-negative patients a second surgery.

Evaluating wait times from screening to breast cancer diagnosis among women undergoing organised assessment vs usual care

Background:Timely coordinated diagnostic assessment following an abnormal screening mammogram reduces patient anxiety and may optimise breast cancer prognosis. Since 1998, the Ontario Breast Screening Program (OBSP) has offered organised assessment through Breast Assessment Centres (BACs). For OBSP women seen at a BAC, an abnormal mammogram is followed by coordinated referrals through the use of navigators for further imaging, biopsy, and surgical consultation as indicated. For OBSP women seen through usual care (UC), further diagnostic imaging is arranged directly from the screening centre and/or through their physician; results must be communicated to the physician who is then responsible for arranging any necessary biopsy and/or surgical consultation. This study aims to evaluate factors associated with diagnostic wait times for women undergoing assessment through BAC and UC.Methods:Of the 2 147 257 women aged 50–69 years screened in the OBSP between 1 January 2002 and 31 December 2009, 155 866 (7.3%) had an abnormal mammogram. A retrospective design identified two concurrent cohorts of women diagnosed with screen-detected breast cancer at a BAC (n=4217; 47%) and UC (n=4827; 53%). Multivariable logistic regression analyses examined associations between wait times and assessment and prognostic characteristics by pathway. A two-sided 5% significance level was used.Results:Screened women with breast cancer were two times more likely to be diagnosed within 7 weeks when assessed through a BAC vs UC (OR=1.91, 95% CI=1.73–2.10). In addition, compared with UC, women assessed through a BAC were significantly more likely to have their first assessment procedure within 3 weeks of their abnormal mammogram (OR=1.25, 95% CI=1.12–1.39), ⩽3 assessment procedures (OR=1.54, 95% CI=1.41–1.69), ⩽2 assessment visits (OR=1.86, 95% CI=1.70–2.05), and ⩾2 procedures per visit (OR=1.41, 95% CI=1.28–1.55). Women diagnosed through a BAC were also more likely than those in UC to have imaging (OR=1.99, 95% CI=1.44–2.75) or a biopsy (OR=3.69, 95% CI=2.64–5.15) vs consultation only at their first assessment visit, and two times more likely to have a core or FNA biopsy than a surgical biopsy (OR=2.08, 95% CI=1.81–2.40). Having ⩽2 assessment visits was more likely to reduce time to diagnosis for women assessed through a BAC compared with UC (BAC OR=10.58, 95% CI=8.96–12.50; UC OR=4.47, 95% CI=3.94–5.07), as was having ⩽3 assessment procedures (BAC OR=4.97, 95% CI=4.26–5.79; UC OR=2.95, 95% CI=2.61–3.33). Income quintile affected wait times only in women diagnosed in UC, with those in the two highest quintiles more likely to receive a diagnosis in 7 weeks.Conclusions:Women with screen-detected breast cancer in OBSP were more likely to have shorter wait times if they were diagnosed through organised assessment. This might be as a result of women diagnosed through a BAC having more procedures per visit, procedures scheduled in shorter intervals, and imaging or biopsy on their first visit. Given the significant improvement in timeliness to diagnosis, women with abnormal mammograms should be managed through organised assessment.