Adjuvant chemotherapy in patients with ER-negative/HER2-negative, T1abN0 breast cancer: a nationwide study.

PURPOSE: The purpose of this study was to examine the effect of chemotherapy on invasive disease-free survival (iDFS) and overall survival (OS) in a nationwide cohort of patients with estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative, T1abN0 breast cancer. METHODS: Patients with ER-negative/HER2-negative, T1abN0 breast cancer registered in the Danish Breast Cancer Group database between 2007 and 2016 were identified. The effect of adjuvant chemotherapy on iDFS and OS was analyzed with Cox proportional hazards analysis. RESULTS: In total, 296 patients were included in the statistical analyses. Of these, 235 (79.4%) received chemotherapy and 61 patients (20.6%) did not. Patients treated with chemotherapy were significantly younger, had a significantly higher proportion of grade 3 tumors, T1b tumors, and tumors of ductal subtype. With 7.7 years of median follow-up, treatment with chemotherapy was associated with a significant improvement in OS in the adjusted analysis, Hazard Ratio 0.35 (95% Confidence Interval (0.15-0.81), p = 0.02), chemotherapy vs. no chemotherapy. In the unadjusted analyses, patients with both T1a and T1b tumors had significantly improved OS with chemotherapy. At 5 years, OS was 100% vs. 94.4% and 93.8% vs. 81.3% for patients with T1a and T1b tumors, respectively, chemotherapy vs. no chemotherapy. With 4.9 years of median follow-up, iDFS was not significantly improved with chemotherapy. CONCLUSION: Patients with ER-negative/HER2-negative, T1abN0 breast cancer had significantly improved OS when treated with chemotherapy. This improvement was significant in patients with both T1a and T1b tumors, respectively. The effect was, however, limited in patients with T1a tumors.

Benefit of adjuvant chemotherapy and trastuzumab in patients with HER2-positive, node-negative breast tumors ≤ 10 mm: a nationwide study.

PURPOSE: The purpose of this study was to evaluate the effect of chemotherapy and trastuzumab on invasive disease-free survival (iDFS) and overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2) positive, T1abN0 breast cancer. METHODS: In the Danish Breast Cancer Group database, patients with HER2-positive, T1abN0 tumors diagnosed between 2007 and 2016 were identified. Cox proportional hazards analysis was performed to analyze the association between adjuvant chemotherapy and trastuzumab and iDFS and OS. RESULTS: Of 605 patients included in the analyses, 465 patients received chemotherapy and trastuzumab and 140 patients did not. Chemotherapy and trastuzumab did not improve iDFS or OS significantly in adjusted analyses. 5-year iDFS was 92.3% vs. 89.9%, Hazard ratio (HR) 1.01 (p = 0.98), and 5-year OS was 97.4% vs. 94.3%, HR 0.60 (p = 0.15), chemotherapy and trastuzumab vs. no chemotherapy/trastuzumab. In unadjusted analyses, significant treatment benefit on OS was found in patients with T1b tumors. The largest absolute treatment benefits were found in patients with T1b tumors and estrogen receptor (ER) negative tumors, respectively, whereas treatment effects in patients with T1a tumors and ER-positive tumors, respectively, were limited. CONCLUSION: Adjuvant chemotherapy and trastuzumab did not improve OS or iDFS significantly in patients with HER2-positive, T1abN0 breast cancers in adjusted analyses. In unadjusted analyses, significant OS benefit was found in patients with T1b tumors. The largest absolute benefit was observed in patients with T1b tumors and ER-negative tumors, respectively, whereas the effect was limited in patients with T1a tumors and ER-positive tumors, respectively.

Synchronous bilateral breast cancer: a nationwide study on histopathology and etiology.

PURPOSE: The aim of the present study was to describe histopathologic characteristics of synchronous bilateral breast cancer (SBBC), and by comparing SBBC to unilateral breast cancer (UBC), identify possible etiological mechanisms of SBBC. METHODS: Patients with primary SBBC (diagnosed within 4 months) and UBC diagnosed in Denmark between 1999 and 2015 were included. Detailed data on histopathology were retrieved from the Danish Breast Cancer Group database and the Danish Pathology Register. Associations between bilateral disease and the different histopathologic characteristics were evaluated by odds ratios and estimated by multinomial regression models. RESULTS: 1214 patients with SBBC and 59,221 with UBC were included. Patients with SBBC more often had invasive lobular carcinomas (OR 1.29; 95% CI 1.13-1.47), a clinically distinct subtype of breast cancer, than UBC patients. Further, they were older than UBC patients, more often had multifocal cancer (OR 1.13; 95% CI 1.01-1.26), and a less aggressive subtype than UBC patients. Invasive lobular carcinoma was associated with having multiple tumors in breast tissue-both in the form of bilateral disease and multifocal disease, and this association was independent of laterality. No similar pattern was observed for other tumor characteristics. CONCLUSION: We identified two etiological mechanisms that could explain some of the occurrence of SBBC. The high proportion of less aggressive carcinomas and higher age of SBBC compared to UBC patients suggests that many are diagnosed at a subclinical stage as slow-growing tumors have a higher probability of simultaneous diagnosis. The high proportion of invasive lobular carcinoma observed in bilateral and multifocal disease, being independent of laterality, suggests that these patients have an increased propensity to malignant tumor formation in breast tissue.

25-Hydroxyvitamin D at time of breast cancer diagnosis and breast cancer survival.

PURPOSE: Previous studies have shown that low levels of 25-hydroxyvitamin D (25(OH)D) are associated with a poorer breast cancer survival. The relationship between vitamin D status and breast cancer outcomes is however still debated. The aim of the present study was to investigate the association between 25(OH)D blood levels measured at time of diagnosis and event-free survival (EFS) and overall survival (OS) in a large cohort of patients with early-stage primary invasive breast cancer. METHODS: From April 2008 to April 2013, 25(OH)D status was measured at time of diagnosis in all women operated for early stage primary invasive breast cancer at Rigshospitalet, Copenhagen, Denmark. Associations between 25(OH)D and EFS and OS were investigated using a Cox Proportional hazards model, adjusting for age, disease characteristics, time period, and BMI. Differences in survival were evaluated by hazard ratios (HR). RESULTS: In the present study, 2510 women with primary invasive breast cancer were included. Women with the lowest 25(OH)D levels (≤ 52 nmol/L) had an inferior EFS with a HR of 1.63 (95% CI 1.21-2.19) compared to women in the third quartile (76-99 nmol/L). Women with the highest 25(OH)D levels (≥ 99 nmol/L) also had an inferior EFS with a HR of 1.37 (95% CI 1.02-1.83). Plotting 25(OH)D status against EFS, the association was inversely J-shaped. For OS, a similar association with 25(OH)D status was observed. CONCLUSION: We confirmed previous findings suggesting that a low 25(OH)D status is associated with an inferior breast cancer survival, but unlike previous findings, we found an indication of poorer breast cancer survival also among women with high 25(OH)D levels.

Breast cancer mortality in synchronous bilateral breast cancer patients.

BACKGROUND: Evidence suggests that patients with synchronous bilateral breast cancer (SBBC), diagnosed within 4 months, have an inferior prognosis compared to unilateral breast cancer (UBC) patients. Using data from nationwide Danish clinical databases, this cohort study investigated whether the inferior prognosis could be explained by SBBC patients having a more aggressive disease, or whether the prognosis could be explained by the fact that they have two simultaneous cancers. METHODS: Patients were diagnosed from 1999-2015. The main outcome was excess mortality, subtracting background population mortality from observed mortality. Differences between SBBC and UBC patients were evaluated by rate ratios (RR) and estimated by Poisson regression. RESULTS: In total, 1214 SBBC and 59 177 UBC patients were included. SBBC patients had a significantly higher excess mortality than UBC patients after adjustment for age and period (RR = 1.73; 95% CI:1.44-2.08; p < 0.01) and after adjusting for characteristics of the worst tumour as traditionally done (RR = 1.31; 95% CI:1.08-1.57; p = 0.01). However, adjusting for characteristics of both tumours, using a more advanced competing risks model, no difference was observed (RR = 1.01; 95% CI:0.83-1.22; p = 0.93). CONCLUSIONS: Our study does not support that the inferior prognosis in SBBC patients is due to having more aggressive tumours per se, but rather the combined effect of having two simultaneous cancers.

Preoperative Distress Predicts Persistent Pain After Breast Cancer Treatment: A Prospective Cohort Study.

PURPOSE: Persistent pain after breast cancer treatment (PPBCT) affects 25% to 60% of breast cancer survivors and is recognized as a clinical problem, with 10% to 15% reporting moderate to severe pain several years after treatment. Psychological comorbidity is known to influence pain perception, and evidence links signs of depression and anxiety with development of PPBCT. The purpose of this study was to assess preoperative distress as a predictive factor for development of PPBCT. METHODS: Between October 2008 and October 2009, 426 women diagnosed with primary breast cancer, undergoing surgery at the Department of Breast Surgery, Rigshospitalet, Denmark, were invited to participate in the study. Patients filled out a questionnaire preoperatively, and 4 and 8 months after surgery. Preoperative distress was measured with the Distress Thermometer (DT; 11-point scale, 0-10). We examined the association between severe preoperative distress (using DT ≥7) and moderate to severe PPBCT 8 months after diagnosis using a logistic regression model. RESULTS: A total of 357 patients participated in this study and 291 (82%) returned all follow-up questionnaires. Preoperative distress was significantly associated with moderate to severe PPBCT at 8 months, with an adjusted odds ratio (OR) of 2.05 (95% CI, 1.18-3.59; P=.01), and at 4 months, with an OR of 2.23 (95% CI, 1.23-4.05; P=.01). CONCLUSIONS: Preoperative distress was associated with PPCBT, suggesting distress as an independent risk factor for PPBCT. Preoperative identification of patients at risk for PPBCT allows for further research in psychological and pharmacological treatment of this condition.

Neuropathic pain after surgery - A clinical validation study and assessment of accuracy measures of the 5-item NeuPPS scale.

OBJECTIVE: The aim of this study was to validate the Neuropathic Pain for Post-Surgical Patients (NeuPPS) scale against clinically verified neuropathic pain (NP) by quantitative sensory testing (QST) as well as evaluation of other psychometric properties. The NeuPPS is a validated 5-item scale designed to evaluate NP in surgical populations. METHODS: Data from 537 women aged >18 years scheduled for primary breast cancer surgery enrolled in a previous study for assessing risk factors for persistent pain after breast cancer treatment were used. Exclusion criteria were any other breast surgery or relevant comorbidity. A total of 448 eligible questionnaires were available at 6 months and 455 at 12 months. At 12 months, 290 patients completed a clinical examination and QST. NeuPPS and PainDETECT were analyzed against patients with and without clinically verified NP. NP was assessed using a standardized QST protocol including a clinical assessment. Furthermore, the NeuPPS and PainDETECT scores were psychometrically tested with an item response theory method, the Rasch analysis, to assess construct validity. Primary outcomes were the diagnostic accuracy measures for the NeuPPS, and secondary measures were psychometric analyses of the NeuPPS after 6 and 12 months. PainDETECT was also compared to clinically verified NP as well as NeuPPS comparing the stability of the estimates. RESULTS: Comparing the NeuPPS scores with verified NP using a receiver operating characteristic curve, the NeuPPS had an area under the curve of 0.80. Using a cutoff of 1, the NeuPPS had a sensitivity of 88% and a specificity of 59%, and using a cutoff of 3, the values were 35 and 96%, respectively. Analysis of the PainDETECT indicated that the used cutoffs may be inappropriate in a surgical population. CONCLUSION: The present study supports the validity of the NeuPPS as a screening tool for NP in a surgical population.

High Self-Reported Satisfaction After Top Surgery in Gender-Affirming Surgery: A Single-Center Study.

Purpose: Top surgery, or masculinization of the chest, is often the first and sometimes only procedure in gender-affirming surgery for transgender- and gender-diverse persons assigned female at birth. In recent years, there has been improved access to care for transgender individuals and increased demand for top surgery. Our aim was to investigate the degree of satisfaction with the postoperative outcome after top surgery in transgender men. Methods: Ninety transgender men who underwent top surgery between September 1, 2013 and August 31, 2018 were included. Patients were surveyed from 5 to 62 months after surgery. Participants' files were evaluated for complications, and 84 (response rate 93.3%) participants answered a questionnaire evaluating patient satisfaction postoperatively. Results: Patients were either satisfied or partially satisfied with the overall experience of undergoing surgery and the postoperative result in 90.5% of responses. Patients were very satisfied with their clothed appearance in 89.3% of responses, whereas only 44.1% were very satisfied with their nonclothed appearance and 46.4% partially satisfied. Patients were also very satisfied with postoperative scars in 47.6% of responses and nipple reconstruction in 48.8%. Only two patients expressed their regret. Conclusion: Satisfaction outcomes after top surgery are generally positive, especially in respect of clothed appearance, self-confidence, and self-acceptance.

Low Risk of Persistent Pain, Sensory Disturbances, and Complications Following Mastectomy After Gender-Affirming Surgery.

Purpose: In recent years, there has been a significant increase in referrals for gender-affirming surgery to departments of plastic surgery in Denmark. There is currently no literature on postsurgical pain in trans men after mastectomy. We aimed at investigating the prevalence and severity of postsurgical persistent pain, sensory disturbances, and complications in trans men after mastectomy. Methods: The 90 trans men who underwent bilateral mastectomy between September 1, 2013 and August 31, 2018 were included. Patients' files were evaluated for complications, and 84 (response rate 93.3%) patients answered a questionnaire (validated for women undergoing oncologic mastectomy) regarding persistent pain and sensory disturbances. Results: Twenty-three patients (27.4%) reported either unilateral or bilateral persistent pain after mastectomy. Of these, 14 (60.9%) patients categorized the pain as mild. However, 77 (95.2%) of the patients did not use analgesics and nonopioid pain medication was sufficient for the remainder. Sensory disturbances were found in 44 (47.5%) of the patients, and 4 (4.8%) patients reported clear signs of neuropathic pain. Seven (7.8%) patients developed hematomas, and areola necrosis was seen in four (4.4%) patients. Due to infection, seven (7.8%) patients received antibiotics. Conclusion: Mastectomy as a part of gender-affirming surgery is a safe procedure with a few, nonsevere, complications. Although a quarter of the patients experienced persistent pain, the majority of that pain is mild, intermittent and can be treated with nonopioid pain medication.

Development and Validation of a Screening Tool for Surgery-Specific Neuropathic Pain: Neuropathic Pain Scale for Postsurgical Patients.

BACKGROUND: Despite the existence of several screening tools for neuropathic pain, none of these are specific to surgery. We have developed a simple questionnaire tool, the Neuropathic Pain scale for Postsurgical patients (NeuPPS), to measure neuropathic pain in postsurgical patients. OBJECTIVES: The aim was to validate this tool in a breast cancer population using an item response theory model, resulting in an easy-to-use scale. STUDY DESIGN: Development was based on literature reviews and interviews with patients and experts and consisted of 6 items. It was tested among 2,217 long-term breast cancer survivors, and cross-validated in another data set of breast cancer survivors with 18 months follow-up. SETTING: We tested the questionnaire tool among breast cancer survivors in 2 cohorts, one nationwide and one of consecutively treated patients at Rigshospitalet, Copenhagen, Denmark. METHODS: Items were assessed for criterion-related construct validity using the Rasch model, and for convergent validity by comparison to another neuropathic pain screening tool, the self-report version of the Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) pain scale. RESULTS: The selected 5-item model showed good fit, unidimensionality, monotonicity, and homogeneity. This result was reproducible in the cross-validation population. In a combined dataset with data from both studies, the model displayed a slightly lower fit, suggesting that items to some degree may vary over time. The Spearman rank correlation between the NeuPPS and S-LANSS was P = 0.57. LIMITATIONS: We observed differential item functioning between the primary study population and the cross-validation population, meaning that some items behave differently at different follow-up times or study populations. CONCLUSIONS: With the NeuPPS, we have validated a simple and easy-to-fill-out questionnaire tool for the measurement of neuropathic pain among postsurgical patients. The items are additive, giving a total score that measures neuropathic pain symptoms. KEY WORDS: Scale validation, Rasch analysis, item response model, persistent postoperative pain, intercostobrachial nerve, neuropathy, neuropathic pain, quantitative sensory testing, breast cancer.

Development in self-reported arm-lymphedema in Danish women treated for early-stage breast cancer in 2005 and 2006--a nationwide follow-up study.

The main purpose of this nationwide follow-up study was to examine the development of self-reported lymphedema in the population of women with early-stage breast cancer in Denmark. In 2008 and 2012 two identical questionnaires were sent to the women aged 18-70 years treated for unilateral primary breast cancer in 2005 and 2006. 2293 women (87%) reported on lymphedema in 2008 and 2012. Overall 37% reported lymphedema in 2008 while 31% reported lymphedema in 2012 and severity of symptoms decreased. 50% of women treated with SLNB and reporting lymphedema in 2008 did not report symptoms by 2012 in contrast to 30% treated with ALND. However, 19% of women treated with ALND and not reporting lymphedema in 2008 had developed lymphedema by 2012. In conclusion lymphedema remains a frequent problem, years after treatment for breast cancer, though, number of women reporting lymphedema and overall severity of symptoms decreased.

Persistent pain and sensory disturbances after treatment for breast cancer: six year nationwide follow-up study.

OBJECTIVE: To examine the development of persistent pain after treatment for breast cancer and to examine risk factors associated with continuing pain. DESIGN: Repeated cross sectional study in a previously examined nationwide cohort. All eligible women who underwent surgery for primary breast cancer in Denmark in 2005 and 2006 and were examined in 2008 were surveyed again with the same questionnaire. SETTING: Surgical centres in Denmark. MAIN OUTCOME MEASURES: Prevalence, location, and severity of persistent pain after treatment for breast cancer in well defined treatment groups and changes in pain reporting and sensory disturbances from 2008 to 2012. PARTICIPANTS: In 2012, 2828 women were eligible in our database, and 108 were excluded. Exclusion criteria were death; new, recurrent, or other cancer; reconstructive breast surgery; and emigration. RESULTS: 2411 (89%) women returned the questionnaire. Prevalence of persistent pain after treatment for breast cancer ranged from 22% to 53% depending on treatment. In 2012, 903 (37%) women reported such pain, a fall from 45% in 2008. Of these, 378 (16%) reported pain of ≥ 4 on a numerical rating scale (scale 0-10), a fall from 19%. Among women reporting pain in 2008, 36% no longer reported it in 2012. In contrast, 15% of the women who did not report pain in 2008 reported it in 2012. Risk factors for having pain were axillary lymph node dissection rather than sentinel lymph node biopsy (odds ratio 2.04, 95% confidence interval 1.60 to 2.61; P<0.001) and age ≤ 49 (1.78, 1.25 to 2.54; P<0.001). No particular method of treatment or age was associated with an increase in pain from 2008 to 2012. CONCLUSIONS: Persistent pain after treatment for breast cancer remains an important problem five to seven years later. The problem is not static as it can either progress or regress with time. TRIAL REGISTRATION: Clinicaltrials.gov NCT No 01543711.

Breast reconstruction with an expander prosthesis following mastectomy does not cause additional persistent pain: a nationwide cross-sectional study.

INTRODUCTION: Few studies have examined the prevalence of persistent pain after breast reconstruction with an implant after tissue expansion in comparison to mastectomy without breast reconstruction. Our primary objective was to evaluate the prevalence of persistent pain after breast reconstruction with a subpectoral implant after tissue expansion in a population-based study. Secondary objectives were to evaluate sensory disturbances, lymphoedema and functional impairment. METHOD: This was a nationwide cross-sectional questionnaire study of breast cancer patients aged 18-69 years who were treated with or without reconstruction after mastectomy for primary breast cancer in Denmark between 1 January 2005 and 31 December 2006. The response rate was 84% for mastectomy without reconstruction and 83% for patients treated with breast reconstruction. RESULTS: A total of 129 patients treated with mastectomy and breast reconstruction with a subpectoral implant were compared with 1131 patients treated with mastectomy without reconstruction. Prevalence of persistent pain for patients treated with mastectomy followed by reconstruction with an implant was 40% compared to 48% of patients treated only with mastectomy. We found no increased risk of persistent pain in patients having a reconstruction with an implant compared with mastectomy without reconstruction (odds ratio (OR) 0.82, 95% confidence interval (CI) 0.55-1.22, P=0.33) when adjusting for age, axillary procedure, radiotherapy and chemotherapy. We observed no difference in the prevalence of pain between patients treated with immediate or delayed breast reconstruction (P=0.116). CONCLUSION: Breast reconstruction with a subpectoral implant after tissue expansion does not confer increased prevalence of persistent pain.