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The Capital Region of Denmark - a part of Copenhagen University Hospital
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Curriculum

Education

June 2015: Cand. Med. University of Copenhagen (KU).

Employments

February 2016 - July 2016: General practice, Marianne Halgreen, Gentofte. Rotation.

August 2015 - January 2016: Department of Abdominal Surgery, Hvidovre. Rotation.

September 2014 - July 2015: Department of Neurology, Glostrup. Junior doctor locum.

Clinical activities

August 2013 - December 2013: Department of Breast Surgery, Rigshospitalet. Research assistant.

July 2013: Department of Breast Surgery, Rigshospitalet. Optional clinical stay.

Jyly 2012 - August 2012: Department of Plastic Surgery, Mater Dei Hospital, Malta. Clinical exchange, IMCC.

Teaching

March 2015 - July 2015: Coding Pirates - Datalogisk Institut Københavns Universitet (DIKU). Teacher.

October 2013: Teaching at the Department of Breast Surgery, Rigshospitalet. Topic: Reduced Risk of Axillary Lymphatic Spread in Triple-negative Breast Cancer.

Academic activities

March 2016: Seminar in Plastic Surgery, årsmøde, Korsør. Yngre Plastikkiruger (YPK).

November 2015: Seminar in Plastic Surgery, Theoretical course in basic plastic surgery, Herlev. YPK.

Organizational activities

September 2014 - November 2014: Member of the Working Group for Research and Education. Future University og Køge.

Poster and abstract, international conference

March 2014: 9th European Breast Cancer Conference (EBCC9), Glasgow, Scotland. Poster presentation and abstract: Holm-Rasmussen EV, Jensen MB, Balslev E, Kroman N, Tvedskov TF: Reduced Risk of Axillary Lymphatic Spread in Triple-negative Breast Cancer.  Breast Cancer Res Treat. 2015, Jan;149(1):229-236

Poster and  abstract, national conference

Oktober 2013: Dansk Mammakirurgisk årsmøde, København. Oral presentation and abstract: Holm-Rasmussen EV, Jensen MB, Balslev E, Kroman N, Tvedskov TF: Reduced Risk of Axillary Lymphatic Spread in Triple-negative Breast Cancer.  Breast Cancer Res Treat. 2015, Jan;149(1):229-236

Scholarships

2010-2012: Assigned the scholarship of Peter and Emma Thomsen, 120.000kr consecutive for three years.

Main research areas

Breast cancer.

Brief presentation

Due to The Danish Breast Cancer screening programme still more women are diagnosed with early stages of breast cancer: ductal carcinoma in situ (DCIS), micro invasive cancer < 1mm and small tumors < 1 cm. Spread to the axillary lymph nodes is potential even when the breast cancer is detected early. In the case of lymphatic spread removal of the lymph nodes is required. The least invasive method used to treat and identify lymphatic spread is sentinel lymph node dissection (SLND). Despite the great advantages compared to axillary lymph node dissection, the SLND can cause side effects. The risk of lymphatic spread in patients with DCIS or micro invasive cancer is low and thus the majority of the patients don’t benefit from SLND.

The lymph nodes removed by SLND are often examined peroperatively. If the peroperative examination is omitted and a lymphatic spread is found postoperatively, the patient must undergo a second surgery. The peroperative examination can however last up to 45 minutes. The risk of spread to the sentinel node (SN) in patients with small tumors is under 10% and peroperative examination of lymph nodes in these patients could be questioned.

The purpose of this study is to identify risk factors of lymphatic spread in patients with early stages of breast cancer to distinguish between patients who will benefit from SLND and those who will not, to reduce the risk of women getting permanent injury after surgery. Furthermore we will try to identify patients where peroperative examination of lymph nodes is not needed due to a low risk of SN metastases to shorten the operation time.

This study will be performed as a nationwide retrospective register-based study using data from the DBCG database.

Current research

Background

Axillary nodal status is the most important prognostic factor in breast cancer. Axillary lymph node dissection (ALND) was previously the standard procedure for staging of the axilla. However, this procedure is associated with considerable morbidity (1,2) and is redundant for women without lymph node metastases. Sentinel lymph node dissection (SLND) can be used to accurately stage the axilla by removing on average only two lymph nodes and results in less morbidity than ALND (3). ALND is offered only in cases of metastases to the sentinel node. SLND has gradually replaced ALND as the standard procedure for staging of the axilla in patients with primary breast cancer. Today, more than 3000 SLNDs are performed in Denmark every year as a part of the surgical treatment of breast cancer. This procedure spares thousands of Danish breast cancer patients the risk of arm morbidity.

Despite the obvious advantages of SLND, the procedure is not without side effects. It has been shown that 25–50% of patients experience pain two to three years after SLND and 31–56% experience sensory disturbances (1,2). Today, all patients with primary invasive breast cancer are offered axillary surgery—either SLND or ALND. Axillary surgery is sometimes even offered to patients with only ductal carcinoma in situ (DCIS) because in 13–40% of these patients, an unsuspected small area with invasive carcinoma is found upon histopathological examination after the final surgery (4,5). In the vast majority of patients diagnosed with only DCIS or microinvasive disease <1 mm, the sentinel node is without metastasis and SLND is therefore redundant (6). International studies have shown that metastases are found in the sentinel node in only 1–3% of patients diagnosed with only DCIS or microinvasion of the breast (7-9).The risk of metastases to other lymph nodes in these cases is basically unknown, and thus the need for completion ALND. The number of patients diagnosed with DCIS or microinvasive disease <1 mm increased after the introduction of the National Mammographic screening program, thereby increasing the risk of overtreatment with unnecessary SLNDs (10).

Lymphatic spread in the case of DCIS could be due to a small occult cancer in the breast not found during histopathological examination. However, it could also be caused by iatrogenic displacement of tumor cells. Studies have shown a significant association between the risk of sentinel node metastases and a recent excisional or needle biopsy in patients with invasive carcinomas (11) and DCIS (12). The need for ALND in the case of iatrogenically displaced tumor cells in the sentinel nodes of patients with DCIS in unknown.

Due to the low risk of sentinel node metastases in patients with DCIS or microinvasive disease, earlier studies on this subject have only been able to include 14–67 patients with sentinel node metastases (12-14). This small number makes it difficult to identify risk factors for sentinel node metastases or to estimate the risk of non-sentinel node metastases. Identification of risk factors for sentinel and non-sentinel node metastases in these patients could enable a tailor-made treatment of the axilla and prevent overtreatment in the form of redundant SLNDs.

Even in patients with small invasive carcinomas of the breast, the risk of sentinel node metastases is small. Studies have shown that less than 10% of clinically node-negative breast cancer patients with tumors < 1 cm in size have lymph node metastases (15). These patients are all offered an SLND, often with perioperative frozen sections. In patients without metastases in the sentinel node, the prolonged operating time of 20–45 minutes, caused by waiting time for frozen sections, is without benefit for the patient. However, if frozen sections are omitted and metastases are found during conventional postoperative histological examinations, patients must undergo a second operation for completion ALND. It could be advantageous if a subgroup could be identified where the risk of sentinel node metastases is sufficiently small to justify the omission of perioperative frozen sections.

 

Objectives

In Denmark, clinical and histopathological data on women with breast cancer have been collected in a national database managed by the Danish Breast Cancer Cooperative Group (DBCG) since 1977, and clinical and histopathological data on women with DCIS have been collected since 1982. Today, the database contains information on more than 100,000 breast cancer patients (16). The database thus contains data material of a unique size to identify risk factors for sentinel node metastases in patients diagnosed with only DCIS or micro invasion or small cancers under 1 cm in the breast.

This study is planned as a nationwide retrospective register-based study using data from the DBCG database and the aim is to:

1. Identify risk factors for metastases in the sentinel node and the risk of further metastatic spread to non-sentinel nodes in breast cancer patients with DCIS or micro invasive disease in the breast and to identify subgroups of patients who benefit from SLND or even ALND and subgroups for whom axillary surgery can safely be omitted;

2. Investigate whether sentinel node metastases in patients with DCIS in the breast can be caused by iatrogenic displacement after recent surgical excisional biopsy of a breast tumor and to clarify whether an ALND is indicated in this group of patients; and

3. Identify risk factors for sentinel node macrometastases in breast cancer patients with small carcinomas < 1 cm and identify a group with a low risk of lymphatic spread where perioperative frozen sections can be omitted.

 

Method

Risk factors for sentinel node and non-sentinel node metastases in patients with DCIS in the breast:

Patients with metastases in the sentinel node but only DCIS in the breast are registered in the DBCG database as having invasive cancers. The tumor size is registered as “unknown”, “missing”, or “0”. Between 2001 and 2015, 503 breast cancer patients with tumor size “unknown”, “missing” or “0” have been registered in the DBCG database. No axillary metastases were recorded for 124 of these patients. Information on the remaining 379 patients will be validated using the original patient files to identify patients diagnosed with DCIS and sentinel node metastases. Even after validation of the data, we expect a substantially larger sample size compared to earlier studies that included 9–67 patients (12-14). Patients with DCIS and sentinel node metastases will be compared to patients with DCIS but without sentinel node metastases. Information on patients diagnosed with DCIS and offered an SLND between 2001 and 2015 will be retrieved from the DBCG database. The risk of sentinel node and non-sentinel node metastases will be estimated. Information on palpability, size of DCIS, focality, Van Nuys classification, hormone receptor status, HER2 status, nodal status, and recent excision biopsy will be retrieved from the DBCG database. Associations between potential risk factors and sentinel node metastases will be calculated in a multivariate design, including whether an increased risk is found in patients who have had a recent excisional biopsy.

 

Risk factors for sentinel node and non-sentinel node metastases in patients with micro invasive disease in the breast:

Patients with tumor size < 1 mm offered SLND between 2001 and 2014 will be identified in the DBCG database. Information on histological type, focality, malignancy grade, hormone receptor status, HER2 status, Ki67 index, lymphovascular invasion, and nodal status will be retrieved from the DBCG database. The risk of sentinel node and non-sentinel node metastases will be estimated, and associations between potential risk factors and sentinel node metastases will be calculated in a multivariate design.

 

Risk of sentinel node metastases in patients with small breast cancers:

Patients treated with SLND for primary breast cancers < 1 cm between 2001 and 2014 will be included in this part of the study. Nationwide information on tumor size, nodal status, histological type, malignancy grade, hormone receptor status, lymphovascular invasion, Ki67 index, and HER2 status will be retrieved from the DBCG database. A logistic regression analysis will be performed to identify the risk factors for sentinel node metastases, and a model will be developed to identify a group of patients with a low risk of sentinel node metastases where perioperative frozen sections can be omitted. A less than 10% risk of sentinel node metastases is considered acceptable.

 

References

(1) Gartner R, Jensen MB, Nielsen J et al. Prevalence of and factors associated with persistent pain following breast cancer surgery. JAMA 2009; 302(18):1985-92.

(2) Gartner R, Jensen MB, Kronborg L et al. Self-reported arm-lymphedema and functional impairment after breast cancer treatment--a nationwide study of prevalence and associated factors. Breast 2010; 19(6):506-15.

(3) Christiansen P, Friis E, Balslev E, Jensen D, Moller S. Sentinel node biopsy in breast cancer: five years experience from Denmark. Acta Oncol 2008; 47(4):561-8.

(4) Doyle B, Al-Mudhaffer M, Kennedy MM et al. Sentinel lymph node biopsy in patients with a needle core biopsy diagnosis of ductal carcinoma in situ: is it justified? J Clin Pathol 2009; 62(6):534-8.

(5) Polom K, Murawa D, Wasiewicz J, Nowakowski W, Murawa P. The role of sentinel node biopsy in ductal carcinoma in situ of the breast. Eur J Surg Oncol 2009; 35(1):43-7.

(6) Gojon H, Fawunmi D, Valachis A. Sentinel lymph node biopsy in patients with microinvasive breast cancer: A systematic review and meta-analysis. Eur J Surg Oncol 2014; 40(1):5-11.

(7) Intra M, Rotmensz N, Veronesi P et al. Sentinel node biopsy is not a standard procedure in ductal carcinoma in situ of the breast: the experience of the European institute of oncology on 854 patients in 10 years. Ann Surg 2008; 247(2):315-9.

(8) Veronesi P, Intra M, Vento AR et al. Sentinel lymph node biopsy for localised ductal carcinoma in situ? Breast 2005; 14(6):520-2.

(9) Xiao S. et al. Sentinel lymph node biopsy in patients with breast ductal carcinoma in situ: Chinese experiences. Oncol Lett. 2015; 10(3): 1932–1938.

(10) Christiansen P, Vejborg I, Kroman N et al. Position paper: Breast cancer screening, diagnosis, and treatment in Denmark. Acta Oncol 2014.

(11) Tvedskov TF, Jensen MB, Kroman N, Balslev E. Iatrogenic displacement of tumor cells to the sentinel node after surgical excision in primary breast cancer. Breast Cancer Res Treat 2011.

(12) AM, Haugen CE, Grimes LM et al. Is Sentinel Lymph Node Dissection Warranted for Patients with a Diagnosis of Ductal Carcinoma In Situ? Ann Surg Oncol 2015.

(13) Meretoja TJ, Heikkila PS, Salmenkivi K, Leidenius MH. Outcome of patients with ductal carcinoma in situ and sentinel node biopsy. Ann Surg Oncol 2012; 19(7):2345-51.

(14) Lyons JM, III, Stempel M, Van Zee KJ, Cody HS, III. Axillary node staging for microinvasive breast cancer: is it justified? Ann Surg Oncol 2012; 19(11):3416-21.

(15) Meretoja TJ, Heikkila PS, Mansfield AS et al. A predictive tool to estimate the risk of axillary metastases in breast cancer patients with negative axillary ultrasound. Ann Surg Oncol 2014; 21(7):2229-36.

(16) Moller S, Jensen MB, Ejlertsen B et al. The clinical database and the treatment guidelines of the Danish Breast Cancer Cooperative Group (DBCG); its 30-years experience and future promise. Acta Oncol 2008; 47(4):506-24.

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