Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases.

BACKGROUND: Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups. METHODS: We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44. RESULTS: Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy-only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy-only group and 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin. CONCLUSIONS: The omission of completion axillary-lymph-node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. (Funded by the Swedish Research Council and others; SENOMAC ClinicalTrials.gov number, NCT02240472.).

Preoperative detection of sentinel lymph nodes with hybrid SPECT/computed tomography imaging may improve the accuracy of sentinel lymph node biopsies in patients with early stages of cancer of the oesophagus or gastro-oesophageal junction.

OBJECTIVES: The aim of this study was to investigate the sentinel lymph node biopsy (SLNB) method in patients with cancer of the oesophagus or gastro-oesophageal junction (GOJ) guided by preoperative hybrid single-photon emission tomography/computed tomography (SPECT/CT) lymphoscintigraphy. METHODS: Thirty-nine patients with stage T1-T3, any N-stage, M0 cancer of the oesophagus or GOJ planned for curatively intended esophagectomy underwent preoperative SPECT/CT lymphoscintigraphy following endoscopically guided submucosal injection of radiocolloid and intraoperative radio-guided SLNB using a hand-held gamma scintillation device. RESULTS: The detection rate in preoperative SPECT/CT imaging was 88%. The median number of detected SLN stations in preoperative imaging was 1 (range 0-4). At least one suspected SLN was identified in all intraoperative SLNP procedures. In six cases, no lymph nodes were identified in the SLNB. In six cases, the SLNB was false negative. The sensitivity for successful SLNB procedures was 20%, the specificity was 100% and the accuracy was 75%. CONCLUSIONS: Preoperative SLN mapping using SPECT/CT yields a high number of detected SLN stations compared to previous studies using planar imaging. The accuracy of the SLNB method in patients with predominantly ≥T3-stage tumours and with a history of previous neoadjuvant treatment is poor, and the method is not recommended in these patient groups.

"Sentinel lymph node imaging with sequential SPECT/CT lymphoscintigraphy before and after neoadjuvant chemoradiotherapy in patients with cancer of the oesophagus or gastro-oesophageal junction - a pilot study".

BACKGROUND: In current best practise, curatively intended treatment for oesophageal cancer usually consists of neoadjuvant chemo-radiotherapy (nCRT) or perioperative chemotherapy, and oesophagectomy. Sentinel Lymph Node Biopsy (SLNB) has the potential to identify patients without lymph node metastases and thus improve the staging accuracy and influence treatment. The impact of neoadjuvant treatment on the lymphatic drainage of oesophageal cancers and subsequently the SLNB procedure in this tumour type has previously not been well studied. PURPOSE: To evaluate changes in lymphatic drainage patterns of the tumour in patients with cancer of the oesophagus or gastro-oesophageal junction (GOJ) using Sentinel Lymph Node (SLN) hybrid SPECT/CT lymphoscintigraphy before and after nCRT. METHODS: Patients with clinical stage T2-T3, any N-stage, M0 cancer of the oesophagus or GOJ underwent endoscopically guided peri-/intratumoral injection of radio-colloid followed by hybrid SPECT/CT lymphoscintigraphy prior to, and once again following, nCRT. SPECT/CT images were evaluated to number and location of SLNs and compared between the two examinations. RESULTS: Ten patients were included in this pilot trial. SPECT/CT lymphoscintigraphy was performed in twenty procedures. The same Sentinel Lymph Node station before and after nCRT was observed in one single patient. In two patients, no SLN was detected before nCRT. In three patients no SLN was detected following nCRT. In four patients, the SLN stations were not the same station at baseline compared to follow-up examination. CONCLUSIONS: The reproducibility SLN detection in patients with cancer of the oesophagus/GOJ following nCRT was very poor. nCRT appears to alter lymphatic drainage patterns and thus may affect detection of SLNs and potentially also the accuracy of an SLNB in these patients. On the basis of these initial results, we abort further patient recruitment in our institution. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR). Identifier ACTRN12618001433291 . Date registered: 27/08/2018. Retrospectively registered.

Swedish prospective multicenter trial evaluating sentinel lymph node biopsy after neoadjuvant systemic therapy in clinically node-positive breast cancer.

PURPOSE: Patients with clinically node-positive breast cancer planned for neoadjuvant systemic therapy (NAST) may draw advantages from the nodal downstaging effect and reduce the extent of axillary surgery with sentinel lymph node biopsy (SLNB) performed after NAST. Since there are concerns about lower sentinel lymph node (SLN) detection and higher false-negative rates (FNR) in this setting, our aim was to define the accuracy of SLNB after NAST. METHODS: This Swedish national multicenter trial prospectively recruited 195 breast cancer patients from ten hospitals with T1-T4d biopsy-proven node-positive disease planned for NAST between October 1, 2010 and December 31, 2015. Clinically node-negative axillary status after NAST was not mandatory. SLNB was always attempted and followed by a completion axillary lymph node dissection (ALND). RESULTS: The SLN identification rate was 77.9% (152/195) but improved to 80.7% (138/171) with dual mapping. The median number of SLNs was two (range 1-5). A positive SLNB was found in 52% (79/152), almost 66% (52/79) of whom had additional positive non-sentinel lymph nodes. The overall pathologic nodal response rate was 33.3% (66/195). The overall FNR was 14.1% (13/92) but decreased to 4% (2/50) when only patients with two or more sentinel nodes were analyzed. CONCLUSIONS: In biopsy-proven node-positive breast cancer, SLNB after NAST is feasible even though the identification rate is lower than in clinically node-negative patients. Since the overall FNR is unacceptably high, the omission of ALND should only be considered if two or more SLNs are identified.

Swedish prospective multicenter trial on the accuracy and clinical relevance of sentinel lymph node biopsy before neoadjuvant systemic therapy in breast cancer.

PURPOSE: The timing of sentinel lymph node biopsy (SLNB) in the context of neoadjuvant systemic therapy (NAST) in breast cancer is still controversial. SLNB before NAST has been evaluated in few single-institution studies in which axillary lymph node dissection (ALND), however, was commonly not performed in case of a negative SLNB. We investigated the potential clinical relevance of SLNB before NAST by performing ALND in all patients after NAST. METHODS: This national multicenter trial prospectively enrolled clinically node-negative breast cancer patients planned for NAST at 13 recruiting Swedish hospitals between October 2010 and December 2015. SLNB before NAST was followed by ALND after NAST in all individuals. Repeat SLNB after NAST was encouraged but not mandatory. RESULTS: SLNB before NAST was performed in 224 patients. The identification rate was 100% (224/224). The proportion of patients with a negative SLNB before NAST but positive axillary lymph nodes after NAST was 7.4% (nine of 121 patients, 95% CI 4.0-13.5). Among those with a positive SLNB before NAST, 23.2% (86/112) had further positive lymph nodes after NAST. CONCLUSIONS: In clinically node-negative patients, SLNB before NAST is highly reliable. With this sequence, ALND and regional radiotherapy can be safely omitted in patients with a negative SLNB provided good clinical response to NAST. Additionally, SLNB-positive patients upfront will receive correct nodal staging unaffected by NAST and be consequently offered adjuvant locoregional treatment according to current guidelines pending the results of ongoing randomized trials.

Comparison of handheld ultrasound and automated breast ultrasound in women recalled after mammography screening.

Background Automated breast volume scanner (ABVS) is an ultrasound (US) device with a wide scanner that sweeps over a large area of the breast and the acquired transverse images are sent to a workstation for reconstruction and review. Whether ABVS is as reliable as handheld US is, however, still not established. Purpose To compare the sensitivity and specificity of ABVS to handheld breast US for detection of breast cancer, in the situation of recall after mammography screening. Material and Methods A total of 113 women, five with bilateral suspicious findings, undergoing handheld breast US due to a suspicious mammographic finding in screening, underwent additional ABVS. The methods were assessed for each breast and each detected lesion separately and classified into two categories: breasts with mammographic suspicion of malignancy and breasts with a negative mammogram. Results Twenty-six cancers were found in 25 women. In the category of breasts with a suspicious mammographic finding (n = 118), the sensitivity of both handheld US and ABVS was 88% (22/25). The specificity of handheld US was 93.5% (87/93) and ABVS was 89.2% (83/93). In the category of breasts with a negative mammography (n = 103), the sensitivity of handheld US and ABVS was 100% (1/1). The specificity of handheld US was 100% (102/102) and ABVS was 94.1% (96/102). Conclusion ABVS can potentially replace handheld US in the investigation of women recalled from mammography screening due to a suspicious finding. Due to the small size of our study population, further investigation with larger study populations is necessary before the implementation of such practice.

Sequencing-based breast cancer diagnostics as an alternative to routine biomarkers.

Sequencing-based breast cancer diagnostics have the potential to replace routine biomarkers and provide molecular characterization that enable personalized precision medicine. Here we investigate the concordance between sequencing-based and routine diagnostic biomarkers and to what extent tumor sequencing contributes clinically actionable information. We applied DNA- and RNA-sequencing to characterize tumors from 307 breast cancer patients with replication in up to 739 patients. We developed models to predict status of routine biomarkers (ER, HER2,Ki-67, histological grade) from sequencing data. Non-routine biomarkers, including mutations in BRCA1, BRCA2 and ERBB2(HER2), and additional clinically actionable somatic alterations were also investigated. Concordance with routine diagnostic biomarkers was high for ER status (AUC = 0.95;AUC(replication) = 0.97) and HER2 status (AUC = 0.97;AUC(replication) = 0.92). The transcriptomic grade model enabled classification of histological grade 1 and histological grade 3 tumors with high accuracy (AUC = 0.98;AUC(replication) = 0.94). Clinically actionable mutations in BRCA1, BRCA2 and ERBB2(HER2) were detected in 5.5% of patients, while 53% had genomic alterations matching ongoing or concluded breast cancer studies. Sequencing-based molecular profiling can be applied as an alternative to histopathology to determine ER and HER2 status, in addition to providing improved tumor grading and clinically actionable mutations and molecular subtypes. Our results suggest that sequencing-based breast cancer diagnostics in a near future can replace routine biomarkers.

Impact of previous surgery on sentinel lymph node mapping: Hybrid SPECT/CT before and after a unilateral diagnostic breast excision.

BACKGROUND: Earlier studies have shown conflicting results regarding the accuracy of sentinel lymph node biopsy after previous breast surgery, especially after a surgical biopsy. PURPOSE: To compare lymph drainage patterns before and after a diagnostic unilateral surgical biopsy using the exact anatomical localisation of sentinel lymph nodes defined by SPECT/CT. MATERIAL AND METHODS: Thirty-seven women planned for unilateral surgical excision of an unsuspicious breast lesion were prospectively examined between September 2011 and January 2015. Hybrid SPECT/CT lymphoscintigraphy of the thorax and neck region with bilateral subareolar injections of 99mTc-Nanocoll was performed one week before and six weeks after surgery. The non-operated side served as a control. The primary outcome measure was the concordance between pre- and postoperative number and localisation of sentinel lymph nodes. RESULTS: Sentinel lymph node detection rate with SPECT/CT on operated sides was 91.9 per cent (34 of 37 procedures), to be compared with a detection rate of 93.7 per cent on all non-operated sides (104 of 111 procedures, P = 0.771). Partial or total concordance regarding the localisation and number of sentinel lymph nodes was 85.7 per cent (30 out of 35) on operated and 88.9 per cent (32 out of 36 patients) on non-operated breast sides (P = 0.735). CONCLUSION: Breast surgery slightly decreased the concordance between pre- and postoperative sentinel lymph nodes, but this finding was not statistically significant. Our results thus support that it is feasible to perform a sentinel lymph node biopsy after previous breast excisional surgery with an acceptable level of safety.

Evaluation of exome sequencing to estimate tumor burden in plasma.

Accurate estimation of systemic tumor load from the blood of cancer patients has enormous potential. One avenue is to measure the presence of cell-free circulating tumor DNA in plasma. Various approaches have been investigated, predominantly covering hotspot mutations or customized, patient-specific assays. Therefore, we investigated the utility of using exome sequencing to monitor circulating tumor DNA levels through the detection of single nucleotide variants in plasma. Two technologies, claiming to offer efficient library preparation from nanogram levels of DNA, were evaluated. This allowed us to estimate the proportion of starting molecules measurable by sequence capture (<5%). As cell-free DNA is highly fragmented, we designed and provide software for efficient identification of PCR duplicates in single-end libraries with a varying size distribution. On average, this improved sequence coverage by 38% in comparison to standard tools. By exploiting the redundant information in PCR-duplicates the background noise was reduced to ∼1/35,000. By applying our optimized analysis pipeline to a simulation analysis, we determined the current sensitivity limit to ∼1/2400, starting with 30 ng of cell-free DNA. Subsequently, circulating tumor DNA levels were assessed in seven breast- and one prostate cancer patient. One patient carried detectable levels of circulating tumor DNA, as verified by break-point specific PCR. These results demonstrate exome sequencing on cell-free DNA to be a powerful tool for disease monitoring of metastatic cancers. To enable a broad implementation in the diagnostic settings, the efficiency limitations of sequence capture and the inherent noise levels of the Illumina sequencing technology must be further improved.

Influence of lifestyle factors on mammographic density in postmenopausal women.

BACKGROUND: Mammographic density is a strong risk factor for breast cancer. Apart from hormone replacement therapy (HRT), little is known about lifestyle factors that influence breast density. METHODS: We examined the effect of smoking, alcohol and physical activity on mammographic density in a population-based sample of postmenopausal women without breast cancer. Lifestyle factors were assessed by a questionnaire and percentage and area measures of mammographic density were measured using computer-assisted software. General linear models were used to assess the association between lifestyle factors and mammographic density and effect modification by body mass index (BMI) and HRT was studied. RESULTS: Overall, alcohol intake was positively associated with percent mammographic density (P trend  = 0.07). This association was modified by HRT use (P interaction  = 0.06): increasing alcohol intake was associated with increasing percent density in current HRT users (P trend  = 0.01) but not in non-current users (P trend  = 0.82). A similar interaction between alcohol and HRT was found for the absolute dense area, with a positive association being present in current HRT users only (P interaction  = 0.04). No differences in mammographic density were observed across categories of smoking and physical activity, neither overall nor in stratified analyses by BMI and HRT use. CONCLUSIONS: Increasing alcohol intake is associated with an increase in mammography density, whereas smoking and physical activity do not seem to influence density. The observed interaction between alcohol and HRT may pose an opportunity for HRT users to lower their mammographic density and breast cancer risk.

Radiotherapy in implant-based immediate breast reconstruction: risk factors, surgical outcomes, and patient-reported outcome measures in a large Swedish multicenter cohort.

The purpose of this large cohort study was to analyze the effects of prior and postoperative radiotherapy (RT) on surgical outcomes and patient-reported outcome measures (PROMs) in implant-based immediate breast reconstruction (IBR). All breast cancer patients (n = 725, of whom 29 had bilateral IBR) operated with implant-based IBR at four Stockholm hospitals from 2007 to 2011 were included. The median follow-up was 43 months. Three groups were compared: no RT (n = 386), prior RT (n = 64), and postoperative RT (n = 304). Outcomes were IBR failure (implant loss with or without secondary autologous reconstruction), unplanned reoperations, and PROMs, as measured by the BreastQ(®) questionnaire. IBR failure occurred in 22/386 (6 %) of non-irradiated cases, 16/64 (25 %) after prior and 45/304 (15 %) after postoperative RT (p < 0.001). Failure risk was higher after prior than postoperative RT (HR 9.28 vs. 3.08). Further risk factors were high BMI, less surgeon reconstructive experience, and postoperative infection, while the use of permanent implants lowered the risk of IBR failure. The estimated 5 years IBR failure rate was 10.4 % for non-irradiated, 28.2 % for previously and 25.2 % for postoperatively irradiated patients (p < 0.001). At least one unplanned reoperation occurred in 169/384 of non-irradiated (44 %), 42/64 (66 %) of previously, and 180/303 (59 %) of postoperatively irradiated breasts (p < 0.001). Further contributing factors were the use of one-stage expander and permanent implants, less surgeon reconstructive experience, and smoking. RT significantly impaired scores on all scales of the BreastQ(®). However, a clear majority of women in all groups would choose IBR again. Implant-based IBR remains a feasible option for women undergoing mastectomy as patient satisfaction levels are high. After prior RT, however, autologous alternatives should be considered.

Hybrid SPECT/CT imaging of sentinel nodes in esophageal cancer: first results.

BACKGROUND: Sentinel node (SN) biopsy in esophageal cancer has the potential of becoming an important tool for ruling out the presence of lymph node metastases in patients opted for less extensive surgery without neoadjuvant treatment. PURPOSE: To investigate preoperative SN imaging in esophageal cancer using hybrid single photon emission computed tomography (SPECT)/CT. MATERIAL AND METHODS: Eight patients with esophageal cancer scheduled for thoracoabdominal esophagectomy after neoadjuvant treatment, underwent endoscopic submucosal injection of (99m)Tc-nanocoll the day before surgery, followed by imaging with SPECT/CT for preoperative detection. Intraoperative detection of SNs was performed with a gamma probe. RESULTS: SNs were identified by SPECT/CT in 7/8 cases (88%) and by gamma probe in all cases. The median number of identified lymph node stations with SN in the operating field was 1 (range 0-2) for SPECT/CT and 1 (range 1-3) for gamma probe. The median distance between the perceived location of the respective SN according to SPECT/CT and the location identified with the gamma probe was <5 mm (range <5-15 mm). In one patient who had a complete histologic response to neoadjuvant treatment in the primary tumor, there was one single metastasis that was not contained in one of the SNs. CONCLUSION: Preoperative identification of sentinel nodes with hybrid SPECT/CT after endoscopic injection of radiocolloid is a technique with obvious potential for SN mapping in esophageal cancer.

Differentiation between benign and malignant breast tumors using kinetic features of real-time harmonic contrast-enhanced ultrasound.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) has gained interest because of its ability to gather vascular information in diverse organs. There is still a subject of debate concerning its value in breast lesions, especially as a differential diagnostic tool. PURPOSE: To investigate whether kinetic parameters of CEUS can differentiate between malignant and benign breast lesions. MATERIAL AND METHODS: We evaluated 75 malignant and 21 benign lesions in the breast or axilla. Contrast harmonic imaging (CHI) US was performed after the injection of a bolus dose of 2.4 mL of Sono Vue® (Bracco, Milano, Italy). The following parameters were calculated for kinetic analysis: initial slope, time to peak enhancement, wash-out ratios W(21) and W(50) (relative decrease in signal intensity from the peak enhancement to 21 s and 50 s, respectively). RESULTS: A significant difference was found between the benign and malignant lesions in time-to-peak (P value <0.05) and wash-out ratios W(21) (P value <0.001) and W(50) (P value <0.001). The mean time-to-peak was 9.3 s for malignant and 14.6 s for benign lesions. The mean signal drop from peak to signal intensity measured at 50 s was 85% for malignant and 66% for benign lesions. There was no difference in absolute values of peak signal intensity and initial slope. The most significant difference between standardized benign and malignant wash-out curves was found at 21 s but statistical significance was reached in the range of 14-50 s. CONCLUSION: Real-time CEUS can evolve into a new non-invasive option for differentiate malignant from benign breast lesions.