Gene expression profiles in clinically T1-2N0 ER+HER2- breast cancer patients treated with breast-conserving therapy: their added value in case sentinel lymph node biopsy is not performed.

PURPOSE: Omitting sentinel lymph node biopsy (SLNB) in breast cancer treatment results in patients with unknown positive nodal status and potential risk for systemic undertreatment. This study aimed to investigate whether gene expression profiles (GEPs) can lower this risk in cT1-2N0 ER+ HER2- breast cancer patients treated with BCT. METHODS: Patients were included if diagnosed between 2011 and 2017 with cT1-2N0 ER+ HER2- breast cancer, treated with BCT and SLNB, and in whom GEP was applied. Adjuvant chemotherapy recommendations based on clinical risk status (Dutch breast cancer guideline of 2020 versus PREDICT v2.1) with and without knowledge on SLNB outcome were compared to GEP outcome. We examined missing adjuvant chemotherapy indications, and the number of GEPs needed to identify one patient at risk for systemic undertreatment. RESULTS: Of 3585 patients, 2863 (79.9%) had pN0 and 722 (20.1%) pN + disease. Chemotherapy was recommended in 1354 (37.8% guideline-2020) and 1888 patients (52.7% PREDICT). Eliminating SLNB outcome (n = 722) resulted in omission of chemotherapy recommendation in 475 (35.1% guideline-2020) and 412 patients (21.8% PREDICT). GEP revealed genomic high risk in 126 (26.5% guideline-2020) and 82 patients (19.9% PREDICT) in case of omitted chemotherapy recommendation in the absence of SLNB. Extrapolated to the whole group, this concerns 3.5% and 2.3%, respectively, resulting in the need for 28-44 GEPs to identify one patient at risk for systemic undertreatment. CONCLUSION: If no SLNB is performed, clinical risk status according to the guideline of 2020 and PREDICT predicts a very low risk for systemic undertreatment. The number of GEPs needed to identify one patient at risk for undertreatment does not justify its standard use.

Quality assurance of radiation therapy after breast-conserving surgery among patients in the BOOG 2013-08 trial.

BACKGROUND AND PURPOSE: In the BOOG 2013-08 trial (NCT02271828), cT1-2N0 breast cancer patients were randomized between breast conserving surgery with or without sentinel lymph node biopsy (SLNB) followed by whole breast radiotherapy (WBRT). While awaiting primary endpoint results (axillary recurrence rate), this study aims to perform a quality assurance analysis on protocol adherence and (incidental) axillary radiation therapy (RT) dose. MATERIALS AND METHODS: Patients were enrolled between 2015 and 2022. Data on prescribed RT and (in 25% of included patients) planning target volumes (PTV) parameters were recorded for axillary levels I-IV and compared between treatment arms. Multivariable linear regression analysis was performed to determine prognostic variables for incidental axillary RT dose. RESULTS: 1,439/1,461 included patients (98.5%) were treated according to protocol and 87 patients (5.9%) received regional RT (SLNB 10.9%, no-SLNB 1.5 %). In 326 patients included in the subgroup analysis, the mean incidental PTV dose at axilla level I was 59.5% of the prescribed breast RT dose. In 5 patients (1.5%) the mean PTV dose at level I was ≥95% of the prescribed breast dose. No statistically or clinically significant differences regarding incidental axillary RT dose were found between treatment arms. Tumour bed boost (yes/no) was associated with a higher incidental mean dose in level I (R2 = 0.035, F(6, 263) = 1.532, p 0.168). CONCLUSION: The results indicate that RT-protocol adherence was high, and that incidental axillary RT dose was low in the BOOG 2013-08 trial. Potential differences between treatmentarms regarding the primary endpoint can thus not be attributed to different axillary radiation doses.

Analysis of TNF-α and interleukin-6 in seroma of patients undergoing mastectomy with or without flap fixation: is there a predictive value for seroma formation and its sequelae?

BACKGROUND: Seroma formation is a common complication after mastectomy. Flap fixation has the potential to prevent seroma formation, but identifying patients that are at risk of developing seroma, remains challenging. The aim of this study was to assess the association between pro-inflammatory cytokines in seroma fluid one day after surgery and seroma formation and it sequelae. METHODS: Patients undergoing mastectomy were randomized into one of three groups: no flap fixation, flap fixation using sutures or flap fixation using tissue glue. Seroma samples from 40 consecutive patients undergoing mastectomy were collected on the first postoperative day for analysis of interleukin-6 and tumor necrosis factor-α. Seroma formation and its sequelae were assessed in the outpatient clinic ten days, six weeks and three months after surgery. RESULTS: TNF-α concentrations were not detectable in the seroma samples of any of the 40 patients. BMI (p = 0.001) and weight of the resected surgical specimen (p = 0.003) were associated with higher IL-6 levels in seroma on the first postoperative day after mastectomy. A higher seroma concentration of IL-6 was associated with significantly fewer patients with clinical seroma formation three months after surgery (p = 0.027). CONCLUSION: IL-6 is associated with clinical seroma formation three months after surgery. There is however no evident association between IL-6 and complications related to seroma formation. Higher IL-6 levels are predictive of less long-term seroma formation. Application of flap fixation does not seem to influence the level of IL-6.

Does the subtype of breast cancer affect the diagnostic performance of axillary ultrasound for nodal staging in breast cancer patients?

INTRODUCTION: Imaging findings can be affected by histopathological characteristics, such as breast cancer subtypes. The aim was to determine whether the diagnostic performance, in particular negative predictive value (NPV), of axillary US differs per subtype of breast cancer. METHODS: All patients diagnosed between 2008 and 2016 in our hospital with primary invasive breast cancer and an axillary US prior to axillary surgery were included. Histopathology of axillary surgery specimens served as gold standard. The NPV, sensitivity, specificity, positive predictive value (PPV) and accuracy of the axillary US were determined for the overall population and for each subtype (ER+/PR+HER2-,HER2+, triple negative tumors). The Chi-square test was used to determine the difference in diagnostic performance parameters between the subtypes. RESULTS: A total of 1094 breast cancer patients were included. Of these, 35 were diagnosed with bilateral breast cancer, resulting in 1129 cancer cases. Most common subtype was ER+/PR+HER2- in 858 cases (76.0%), followed by 150 cases of HER2+ tumors (13.3%) and 121 cases of triple negative tumors (10.7%). Sensitivity, specificity and accuracy of axillary US did not significantly differ between the subtypes. There was a significant difference for NPV between triple negative tumors and HER2+ tumors (90.3% vs. 80.2%, p = 0.05) and between HER2+ and ER/PR+HER2- tumors (80.2% vs. 87.2%, p = 0.04). CONCLUSION: There was no significant difference in the diagnostic performance of axillary US between the subtypes, except for NPV. This was highest in triple negative subtype and lowest in HER2+ tumors. This can be explained by the difference in prevalence of axillary lymph node metastases in our cohort.

A multi-center, double blind randomized controlled trial evaluating flap fixation after mastectomy using sutures or tissue glue versus conventional closure: protocol for the Seroma reduction After Mastectomy (SAM) trial.

BACKGROUND: Seroma formation is a common complication after mastectomy and is associated with delayed wound healing, infection, skin flap necrosis, patient discomfort and repeated visits to the out patient clinic to deal with seroma and its sequelae. Closing the dead space after mastectomy seems to be key in reducing seroma and its complications. Various methods have been described to reduce the dead space after mastectomy: closed suction drainage, quilting of the skin flaps and application of adhesive tissue glues. The aim of this trial is to compare seroma formation and its sequelae in the various methods of flap fixation. METHODS: This is a multicenter, double-blind, randomized controlled trial in female breast cancer patients undergoing mastectomy, with or without axillary clearance. Exclusion criteria consist of breast conserving therapy, direct breast reconstruction and incapacity to comprehend implications and extent of study and unable to sign for informed consent. A total of 336 patients will be randomized. Patients will be randomly allocated to one of three treatment arms consisting of flap fixation using ARTISS tissue glue with a low suction drain, flap fixation using sutures and a low suction drain or conventional wound closure (without flap fixation) and low suction drainage. Follow up will be conducted up to twelve months post surgery. The primary outcome is the number of seroma aspirations and secondary outcomes consist of number of out patient clinic visits, surgical skin infection rate, shoulder function, cosmesis, health-related quality of life and costs and cost-effectiveness (cost/QALY). DISCUSSION: This is the first study of its kind to evaluate the effect of flap fixation and its sequelae (ie seroma aspirations, number of out patient clinic visits, infection, shoulder function, patient assessed cosmesis, quality of life and cost-effectiveness) in a double blind randomized controlled trial. TRIAL REGISTRATION: This trial was approved by the hospitals' joint medical ethical committee (14-T-21, 2 June 2014). The SAM Trial is registered in ClinicalTrials.gov since October 2017, Identifier: NCT03305757 .

Surgical removal of fibrous axillary seroma pocket and closing of dead space using a lattisimus dorsi flap.

Seroma formation after axillary dissection is a common problem in breast cancer surgery. We report the case of a 68-year-old female with breast cancer who underwent a wide local excision and axillary clearance due to stage III breast cancer. Patient received post-operative whole breast irradiation therapy and developed a painful, infected seroma one month after surgery. This was treated with antibiotic therapy after which the infection subsided. One year after surgery patient presented with a painful persisting seroma in the left axilla. We decided to surgically treat the seroma by removing the fibrous seroma capsula and closing of the dead space with a latissimus dorsi flap. Six weeks after surgery, patient was pain and seroma free and was happy with the surgical result. Latissimus dorsi flap harvesting is an ideal way to treat persisting fibrous encapsulated seroma pockets after axillary clearance in the treatment of breast cancer.

Diagnostic performance of gadofosveset-enhanced axillary MRI for nodal (re)staging in breast cancer patients: results of a validation study.

AIM: To evaluate diagnostic performance of gadofosveset (GDF)-enhanced magnetic resonance imaging (MRI) in addition to T2-weighted (T2W) MRI for nodal (re)staging in newly diagnosed breast cancer patients. MATERIALS AND METHODS: Ninety patients underwent axillary T2W- and GDF-MRI. Two radiologists independently scored each lymph node; first on T2W-MRI, subsequently adjusting their score on GDF-MRI. Diagnostic performance parameters were calculated on node-by-node and patient-by-patient validation with histopathology as the reference standard. Furthermore, learning curve analysis for reading GDF-MRI was performed. RESULTS: In patient-by-patient validation, overall reader performances for T2W- and GDF-MRI were similar with area under the receiver operating characteristic curves (AUC) of 0.75 and 0.77 (p=0.731) for reader 1 and 0.79 and 0.72 (p=0.156) for reader 2. For node-by-node validation, AUC values of T2W- and GDF-MRI were 0.76 and 0.82 (p=0.018) and 0.77 and 0.77 (p=0.998) for reader 1 and 2. The AUC for reader 1 was 0.71 for first one-third of nodes evaluated, improving to 0.80 and 0.95 for the next and last one-third, respectively. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) improved from 38%, 89%, 56%, and 79% to 60%, 93%, 64%, and 92%. The AUC of reader 2 improved from 0.69 to 0.79. CONCLUSION: The present study confirmed that GDF-MRI, in addition to T2W-MRI, has potential as a non-invasive method for nodal (re)staging in breast cancer.

Clinically node negative breast cancer patients undergoing breast conserving therapy, sentinel lymph node procedure versus follow-up: a Dutch randomized controlled multicentre trial (BOOG 2013-08).

BACKGROUND: Studies showed that axillary lymph node dissection can be safely omitted in presence of positive sentinel lymph node(s) in breast cancer patients treated with breast conserving therapy. Since the outcome of the sentinel lymph node biopsy has no clinical consequence, the value of the procedure itself is being questioned. The aim of the BOOG 2013-08 trial is to investigate whether the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients treated with breast conserving therapy. METHODS: The BOOG 2013-08 is a Dutch prospective non-inferiority randomized multicentre trial. Women with pathologically confirmed clinically node negative T1-2 invasive breast cancer undergoing breast conserving therapy will be randomized for sentinel lymph node biopsy versus no sentinel lymph node biopsy. Endpoints include regional recurrence after 5 (primary endpoint) and 10 years of follow-up, distant-disease free and overall survival, quality of life, morbidity and cost-effectiveness. Previous data indicate a 5-year regional recurrence free survival rate of 99% for the control arm and 96% for the study arm. In combination with a non-inferiority limit of 5% and probability of 0.8, this result in a sample size of 1.644 patients including a lost to follow-up rate of 10%. Primary and secondary endpoints will be reported after 5 and 10 years of follow-up. DISCUSSION: If the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients undergoing breast conserving therapy, this study will cost-effectively lead to a decreased axillary morbidity rate and thereby improved quality of life with non-inferior regional control, distant-disease free survival and overall survival. TRIAL REGISTRATION: The BOOG 2013-08 study is registered in ClinicalTrials.gov since October 20, 2014, Identifier: NCT02271828. https://clinicaltrials.gov/ct2/show/NCT02271828.

Sentinel lymph node biopsy can be omitted in DCIS patients treated with breast conserving therapy.

Breast cancer guidelines advise sentinel lymph node biopsy (SLNB) in patients with ductal carcinoma in situ (DCIS) on core biopsy at high risk of invasive cancer or in case of mastectomy. This study investigates the incidence of SLNB and SLN metastases and the relevance of indications in guidelines and literature to perform SLNB in order to validate whether SLNB is justified in patients with DCIS on core biopsy in current era. Clinically node negative patients diagnosed from 2004 to 2013 with only DCIS on core needle biopsy were selected from a national database. Incidence of SLN biopsy and metastases was calculated. With Fisher exact tests correlation between SLNB indications and actual presence of SLN metastases was studied. Further, underestimation rate for invasive cancer and correlation with SLN metastases was analysed. 910 patients were included. SLNB was performed in 471 patients (51.8 %): 94.5 % had pN0, 3.0 % pN1mi and 2.5 % pN1. Patients undergoing mastectomy had 7 % SLN metastases versus 3.5 % for breast conserving surgery (BCS) (p = 0.107). The only factors correlating to SLN metastases were smaller core needle size (p = 0.01) and invasive cancer (p < 0.001). Invasive cancer was detected in 16.7 % by histopathology with 15.6 % SLN metastases versus only 2 % in pure DCIS. SLNB showed metastases in 5.5 % of patients; 3.5 % in case of BCS (any histopathology) and 2 % when pure DCIS was found at definitive histopathology (BCS and mastectomy). Consequently, SLNB should no longer be performed in patients diagnosed with DCIS on core biopsy undergoing BCS. If definitive histopathology shows invasive cancer, SLNB can still be considered after initial surgery.

The value of completion axillary treatment in sentinel node positive breast cancer patients undergoing a mastectomy: a Dutch randomized controlled multicentre trial (BOOG 2013-07).

BACKGROUND: Trials failed to demonstrate additional value of completion axillary lymph node dissection in case of limited sentinel lymph node metastases in breast cancer patients undergoing breast conserving therapy. It has been suggested that the low regional recurrence rates in these trials might partially be ascribed to accidental irradiation of part of the axilla by whole breast radiation therapy, which precludes extrapolation of results to mastectomy patients. The aim of the randomized controlled BOOG 2013-07 trial is therefore to investigate whether completion axillary treatment can be safely omitted in sentinel lymph node positive breast cancer patients treated with mastectomy. DESIGN: This study is designed as a non-inferiority randomized controlled multicentre trial. Women aged 18 years or older diagnosed with unilateral invasive clinically T1-2 N0 breast cancer who are treated with mastectomy, and who have a maximum of three axillary sentinel lymph nodes containing micro- and/or macrometastases, will be randomized for completion axillary treatment versus no completion axillary treatment. Completion axillary treatment can consist of completion axillary lymph node dissection or axillary radiation therapy. Primary endpoint is regional recurrence rate at 5 years. Based on a 5-year regional recurrence free survival rate of 98 % among controls and 96 % for study subjects, the sample size amounts 439 per arm (including 10 % lost to follow-up), to be able to reject the null hypothesis that the rate for study and control subjects is inferior by at least 5 % with a probability of 0.8. Results will be reported after 5 and 10 years of follow-up. DISCUSSION: We hypothesize that completion axillary treatment can be safely omitted in sentinel node positive breast cancer patients undergoing mastectomy. If confirmed, this study will significantly decrease the number of breast cancer patients receiving extensive treatment of the axilla, thereby diminishing the risk of morbidity and improving quality of life, while maintaining excellent regional control and without affecting survival. TRIAL REGISTRATION: The BOOG 2013-07 study is registered in the register of ClinicalTrials.gov since April 10, 2014, Identifier: NCT02112682 .

The changing role of axillary treatment in breast cancer: Who will remain at risk for developing arm morbidity in the future?

Primary aim is to give an overview of changes in axillary staging and treatment of breast cancer patients. Secondly, we aim to identify patients with a high arm/shoulder morbidity risk, and describe a strategy to improve early detection and treatment. Recent and initiated studies on axillary staging and treatment were evaluated and clustered for clinically node negative and clinically node positive breast cancer patients, together with studies on pathology, detection and (surgical) prevention and treatment of lymphedema. For clinically node negative patients, the indication for axillary lymph node dissection in sentinel node positive patients is fading. On the contrary, clinically node positive patients are routinely subjected to an axillary lymph node dissection, in combination with other therapies associated with an increased lymphedema risk, such as mastectomy, adjuvant radiation- and (taxane-based) chemotherapy. Techniques for prevention, early detection and (surgical) treatment of lymphedema are being developed. Axillary staging and treatment in breast cancer patients with a clinically node negative status will become less invasive, thereby reducing the incidence of morbidity. Nevertheless, in patients with a clinically node positive status, aggressive treatment will still be required for oncologic control. For these patients, a surveillance program should be implemented in order to apply (curative) surgical treatment for lymphedema.

Inconsistent selection and definition of local and regional endpoints in breast cancer research.

BACKGROUND: Results in breast cancer research are reported using study endpoints. Most are composite endpoints (such as locoregional recurrence), consisting of several components (for example local recurrence) that are in turn composed of specific events (such as skin recurrence). Inconsistent endpoint selection and definition might lead to unjustified conclusions when comparing study outcomes. This study aimed to determine which locoregional endpoints are used in breast cancer studies, and how these endpoints and their components are defined. METHODS: PubMed was searched for breast cancer studies published in nine leading journals in 2011. Articles using endpoints with a local or regional component were included and definitions were compared. RESULTS: Twenty-three different endpoints with a local or regional component were extracted from 44 articles. Most frequently used were disease-free survival (25 articles), recurrence-free survival (7), local control (4), locoregional recurrence-free survival (3) and event-free survival (3). Different endpoints were used for similar outcomes. Of 23 endpoints, five were not defined and 18 were defined only partially. Of these, 16 contained a local and 13 a regional component. Included events were not specified in 33 of 57 (local) and 27 of 50 (regional) cases. Definitions of local components inconsistently included carcinoma in situ and skin and chest wall recurrences. Regional components inconsistently included specific nodal sites and skin and chest wall recurrences. CONCLUSION: Breast cancer studies use many different endpoints with a locoregional component. Definitions of endpoints and events are either not provided or vary between trials. To improve transparency, facilitate trial comparison and avoid unjustified conclusions, authors should report detailed definitions of all endpoints.

The impact of the pathological lymph node status on adjuvant systemic treatment recommendations in clinically node negative breast cancer patients.

Several independent randomized controlled trials are initiated to investigate whether sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients with negative axillary ultrasound findings, who are treated with breast conserving therapy. A consequence of omitting sentinel lymph node biopsy is absence of pathological lymph node status information. We aimed to investigate the impact of omitting sentinel lymph node biopsy on adjuvant systemic treatment recommendations. Data from all consecutive patients with invasive breast cancer and negative axillary ultrasound findings treated with breast conserving therapy and sentinel lymph node biopsy between 2008 and 2012 were collected from a prospective database. Two methods, Adjuvant! Online and the Dutch breast cancer guideline 2012, were used to determine the adjuvant systemic treatment recommendations of every patient. At first, each patient was considered to be lymph node negative, and secondly the patients' true pathological lymph node status was used. A total of 303 patients were consecutively included. Pathological lymph node status was pN0 in 72.3 %, pN0(i+) in 12.9 %, pN1mi+ in 5.6 %, pN1 in 7.3 %, and pN2 in 2.0 % of the patients. The decision to recommend adjuvant systemic treatment changed due to the pathological lymph node status in 1.0 % of the patients (3/303) when using Adjuvant! Online and in 3.6 % (11/303) when using the 2012 Dutch breast cancer guideline. The impact of the pathological lymph node status on adjuvant systemic treatment recommendations in clinically node negative breast cancer patients with negative axillary ultrasound findings treated with breast conserving therapy is limited. The safety of omitting the sentinel lymph node biopsy should be confirmed by the initiated randomized controlled trials.

Axillary ultrasound for preoperative nodal staging in breast cancer patients: is it of added value?

BACKGROUND: New insights show that an axillary lymph node dissection (ALND) may not always be indicated for metastases detected by ultrasound (pathologically proven). This study investigated whether axillary ultrasound accurately predicts pN0, pN1 and pN2-pN3 status. METHODS: Data were retrospectively collected from all consecutive patients with invasive breast cancer who underwent (primary) surgery between 2008 and 2012. False negative percentages and negative predictive values (NPVs) for sonographic nodal staging were calculated for all patients and again for cT1-2 patients treated by breast conserving therapy (BCT). RESULTS: A total of 577 axillary ultrasounds were included. After negative ultrasound findings (cN0), pathology showed pN2-pN3 disease in 4.4% of these cases, with an NPV of 95.5% (93.4-97.1%). When cN1 (1-3 suspicious nodes) was predicted, pathology showed pN2-pN3 disease in 41.2%, with an NPV of 58.5% (44.2-71.5%). In the subgroup of patients with cT1-2 breast cancer that were treated by BCT, pathology showed pN2-pN3 disease in 2.3% after negative ultrasound findings (cN0), with an NPV of 97.7% (94.9-99.0%). When cN1 was predicted (n = 12), pathology showed pN2-pN3 disease in 50.0%, with an NPV of 50.0% (22.3-77.9%). A direct ALND was performed in these 12 cN1 cases; pathology showed six patients with pN1 (three patients with one and three with two macrometastases) and six with pN2-pN3 disease (4, 5, 11, 13, 16 or 22 macrometastases, respectively). CONCLUSION: In conclusion, a negative axillary ultrasound generally excludes the presence of pN2-pN3 disease. An axillary ultrasound cannot accurately differentiate between pN1 and pN2-pN3. It could be argued that the standard performance of an axillary ultrasound in breast cancer patients is questionable; multidisciplinary discussion could guide decisions on the use of axillary ultrasound for the individual patient.