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Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes.

ABSTRACT: Metastatic breast cancers are still incurable. Characterizing the evolutionary landscape of these cancers, including the role of metastatic axillary lymph nodes (ALNs) in seeding distant organ metastasis, can provide a rational basis for effective treatments. Here, we have described the genomic analyses of the primary tumors and metastatic lesions from 99 samples obtained from 20 patients with breast cancer. Our evolutionary analyses revealed diverse spreading and seeding patterns that govern tumor progression. Although linear evolution to successive metastatic sites was common, parallel evolution from the primary tumor to multiple distant sites was also evident. Metastatic spreading was frequently coupled with polyclonal seeding, in which multiple metastatic subclones originated from the primary tumor and/or other distant metastases. Synchronous ALN metastasis, a well-established prognosticator of breast cancer, was not involved in seeding the distant metastasis, suggesting a hematogenous route for cancer dissemination. Clonal evolution coincided frequently with emerging driver alterations and evolving mutational processes, notably an increase in apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like-associated (APOBEC-associated) mutagenesis. Our data provide genomic evidence for a role of ALN metastasis in seeding distant organ metastasis and elucidate the evolving mutational landscape during cancer progression.

SUBMITTER: Ullah I

PROVIDER: S-EPMC5873882 | biostudies-other | 2018 Apr

REPOSITORIES: biostudies-other

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Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes.

Ullah Ikram I Karthik Govindasamy-Muralidharan GM Alkodsi Amjad A Kjällquist Una U Stålhammar Gustav G Lövrot John J Martinez Nelson-Fuentes NF Lagergren Jens J Hautaniemi Sampsa S Hartman Johan J Bergh Jonas J

The Journal of clinical investigation 20180226 4

Metastatic breast cancers are still incurable. Characterizing the evolutionary landscape of these cancers, including the role of metastatic axillary lymph nodes (ALNs) in seeding distant organ metastasis, can provide a rational basis for effective treatments. Here, we have described the genomic analyses of the primary tumors and metastatic lesions from 99 samples obtained from 20 patients with breast cancer. Our evolutionary analyses revealed diverse spreading and seeding patterns that govern tu ...[more]

PMID: 29480816

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Project description:ObjectiveAutomated breast ultrasound (ABUS) is a relevant imaging technique for early breast cancer diagnosis and is increasingly being used as a supplementary tool for mammography. This study compared the performance of ABUS and handheld ultrasound (HHUS) in detecting and characterizing the axillary lymph nodes (LNs) in patients with breast cancer.Materials and methodsWe retrospectively reviewed the medical records of women with recently diagnosed early breast cancer (≤ T2) who underwent both ABUS and HHUS examinations for axilla (September 2017-May 2018). ABUS and HHUS findings were compared using pathological outcomes as reference standards. Diagnostic performance in predicting any axillary LN metastasis and heavy nodal-burden metastases (i.e., ≥ 3 LNs) was evaluated. The ABUS-HHUS agreement for visibility and US findings was calculated.ResultsThe study included 377 women (53.1 ± 11.1 years). Among 385 breast cancers in 377 patients, 101 had axillary LN metastases and 30 had heavy nodal burden metastases. ABUS identified benign-looking or suspicious axillary LNs (average, 1.4 ± 0.8) in 246 axillae (63.9%, 246/385). According to the per-breast analysis, the sensitivity, specificity, positive and negative predictive values, and accuracy of ABUS in predicting axillary LN metastases were 43.6% (44/101), 95.1% (270/284), 75.9% (44/58), 82.6% (270/327), and 81.6% (314/385), respectively. The corresponding results for HHUS were 41.6% (42/101), 95.1% (270/284), 75.0% (42/56), 82.1% (270/329), and 81.0% (312/385), respectively, which were not significantly different from those of ABUS (P ≥ 0.53). The performance results for heavy nodal-burden metastases were 70.0% (21/30), 89.6% (318/355), 36.2% (21/58), 97.3% (318/327), and 88.1% (339/385), respectively, for ABUS and 66.7% (20/30), 89.9% (319/355), 35.7% (20/56), 97.0% (319/329), and 88.1% (339/385), respectively, for HHUS, also not showing significant difference (P ≥ 0.57). The ABUS-HHUS agreement was 95.9% (236/246; Cohen's kappa = 0.883).ConclusionAlthough ABUS showed limited sensitivity in diagnosing axillary LN metastasis in early breast cancer, it was still useful as the performance was comparable to that of HHUS.

Project description:BACKGROUND: Lymph node status is one of the decisive prognostic factors in breast cancer. Chemotherapy targeting regional lymphatic tissues has emerged as a promising therapy for the treatment of malignancies with a high tendency to disseminate lymphatically. The present study determined the drug concentrations in axillary lymph nodes after lymphatic chemotherapy (LC) in patients with breast cancer and compared the results with those receiving intravenous chemotherapy (VC) to investigate whether LC could improve the accumulation of anticancer drug in regional lymph nodes. METHODS: Sixty patients with breast carcinoma confirmed by preoperative puncture-biopsy were divided into two groups at random. The LC group (n = 30) received a subcutaneous injection of 4 ml of carboplatin-activated carbon suspension, containing 20 mg of carboplatin, adjacent to the primary tumour. The VC group (n = 30) received an intravenous administration of an equal dose of aqueous carboplatin. At 1, 12, 24, 36 and 48 hours after administration, modified radical mammectomies were performed on 12 patients at each time point, with 6 from each group. Axillary lymph nodes were removed for pathological examination. The platinum concentrations in nodes were determined by Zeeman atomic absorption spectrometry. RESULTS: A total of 275 axillary lymph nodes were resected, with 154 in the LC group and 121 in the VC group. Of the 275 lymph nodes, 136 (49.5%) from 23 patients (38.3%) had histopathologically detected metastases. At 1, 12, 24, 36 and 48 hours after injection, the carboplatin concentrations in the LC group were 11.82 +/- 3.50, 23.58 +/- 7.34, 18.22 +/- 4.93, 16.70 +/- 5.15 and 14.62 +/- 4.29 microg/g (means +/- SD), respectively, whereas those in the VC group were 0.06 +/- 0.02, 0.11 +/- 0.05, 0.10 +/- 0.02, 0.05 +/- 0.02 and 0 microg/g, respectively. Significant differences were found in each corresponding comparison (P < 0.001). Lymph node metastasis was uncorrelated with drug concentration (P > 0.05). CONCLUSION: LC can effectively and continuously improve the drug concentrations in axillary lymph nodes in patients with breast cancer, in comparison with VC.

Project description:PurposeObesity associated fat infiltration of organ systems is accompanied by organ dysfunction and poor cancer outcomes. Obese women demonstrate variable degrees of fat infiltration of axillary lymph nodes (LNs), and they are at increased risk for node-positive breast cancer. However, the relationship between enlarged axillary nodes and axillary metastases has not been investigated. The purpose of this study is to evaluate the association between axillary metastases and fat-enlarged axillary nodes visualized on mammograms and breast MRI in obese women with a diagnosis of invasive breast cancer.MethodsThis retrospective case-control study included 431 patients with histologically confirmed invasive breast cancer. The primary analysis of this study included 306 patients with pre-treatment and pre-operative breast MRI and body mass index (BMI) > 30 (201 node-positive cases and 105 randomly selected node-negative controls) diagnosed with invasive breast cancer between April 1, 2011, and March 1, 2020. The largest visible LN was measured in the axilla contralateral to the known breast cancer on breast MRI. Multivariate logistic regression models were used to assess the association between node-positive status and LN size adjusting for age, BMI, tumor size, tumor grade, tumor subtype, and lymphovascular invasion.ResultsA strong likelihood of node-positive breast cancer was observed among obese women with fat-expanded lymph nodes (adjusted OR for the 4th vs. 1st quartile for contralateral LN size on MRI: 9.70; 95% CI 4.26, 23.50; p < 0.001). The receiver operating characteristic curve for size of fat-enlarged nodes in the contralateral axilla identified on breast MRI had an area under the curve of 0.72 for predicting axillary metastasis, and this increased to 0.77 when combined with patient and tumor characteristics.ConclusionFat expansion of axillary lymph nodes was associated with a high likelihood of axillary metastases in obese women with invasive breast cancer independent of BMI and tumor characteristics.

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Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes.

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Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes.

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