Danish Breast Cancer Cooperative Group Research Articles

Residual Axillary Metastases in Node-Positive Breast Cancer Patients After Neoadjuvant Treatment: A Register-Based Study.

Lymph node (LN) metastasis after neoadjuvant chemotherapy (NACT) generally warrants axillary lymph node dissection, which opposes guidelines of upfront surgery in many cases. We investigated the risk of having additional metastases in the axilla when the LNs removed by targeted axillary dissection (TAD) harbored metastases after NACT. We aimed to identify subgroups suitable for de-escalated axillary treatment. This register-based study used data from the Danish Breast Cancer Cooperative Group database. Data were analyzed with logistic regression models. The primary outcome was the metastatic burden in non-TAD LNs in patients with positive TAD LNs after NACT. Among 383 patients, < 66.6% positive TAD LNs (adjusted odds ratio [OR] 0.34, 95% confidence interval [CI] 0.17-0.62), only isolated tumor cells (ITCs) [OR 0.11, 95% CI < 0.01-0.82], and breast pathological complete response (pCR) [OR 0.07, 95% CI < 0.01-0.56] were associated with a low risk of having more than three positive non-TAD LNs. In 315 patients with fewer than three positive non-TAD LNs, the proportion of positive TAD LNs (OR 0.45, 95% CI 0.27-0.76 for 33.3-66.6% vs. > 66.6%), size of the TAD LN metastasis (OR 0.14, 95% CI 0.04-0.54 for ITC vs. macrometastasis), tumor size at diagnosis (OR 0.30, 95% CI 0.15-0.64 for 20-49mm vs. ≥ 50mm) and breast pCR (OR 0.38, 95% CI 0.15-0.96) were associated with residual LN metastases in the axilla. Breast pCR or ITC only in TAD LNs can, with reasonable certainty, preclude more than three positive non-TAD LNs. Additionally, patients with only ITCs in the TAD LN had a low risk of having any non-TAD LN metastases after NACT. De-escalated axillary treatment may be considered in both subgroups.

Abstract PO2-14-07: Association between expression of androgen receptor in tumor tissue and risk of breast cancer recurrence among premenopausal Danish women

Abstract Background: Breast cancer prognosis is influenced by tumor biomarker expression. For example, tumors that express the estrogen receptor (ER+) have a lower hazard of recurrence in the first five years following treatment than tumors that do not express the estrogen receptor. Identifying additional biomarkers that are prognostic of breast cancer recurrence may aid in risk stratification and the development of targeted therapies. The androgen receptor (AR) is one such candidate biomarker. While some previous studies have found lower breast cancer mortality associated with AR expression, others have shown no association. However, these studies were conducted in populations exclusively or primarily comprised of postmenopausal women. Since menopause is associated with an increased concentration of androgens relative to estrogens, the role of AR may differ in premenopausal women. Methods: Using the Predictors of Breast Cancer Recurrence cohort (N=5,959)—a prospective cohort study of premenopausal women diagnosed with stage I–III primary breast cancer between 2002 and 2011 and registered in the Danish Breast Cancer Cooperative Group (DBCG) clinical database—we measured the association between tumor AR expression and breast cancer recurrence. The majority of the cohort (77%) had ER+ tumors and were intended to be treated with tamoxifen. Primary paraffin-embedded tumors were collected from treating hospitals, and 2–3 cores were included in a tissue microarray for immunohistochemistry. AR staining of each core was automatically scored using a trained software application and quantified as the percent of tumor nuclei with positive staining. Patients were considered to have AR positive (AR+) tumors if the maximum score across replicate cores was &amp;gt;1% positive. Otherwise patients were classified as having AR negative (AR−) tumors. Patients were followed from breast cancer diagnosis until the first of recurrence, death, emigration, another malignancy, or 10 years. The DBCG defines breast cancer recurrence as any breast cancer diagnosed after the initial course of treatment, including contralateral breast cancers. The association between AR expression and breast cancer recurrence was computed as an unadjusted risk ratio and corresponding 95% confidence interval. Results: Among the 4,658 cohort members with available tumor tissue, 72% had AR+ tumors; 720 recurrences occurred over the 10-year follow-up. Patients with AR+ tumors were less likely to experience a recurrence than patients with AR− tumors [14% vs. 18% respectively; unadjusted risk ratio=0.80, 95% CI: (0.70, 0.92)]. Conclusion: AR expression in primary tumor tissue was associated with a lower risk of breast cancer recurrence in a large population-based cohort of premenopausal women. Additional analyses adjusting for clinical factors, examining the association by breast cancer subtype, and accounting for time to recurrence are forthcoming. Citation Format: Rebecca Nash, Anders Kjærsgaard, Kristina Christensen, Thomas Ahern, Lindsay Collin, Stephen Hamilton-Dutoit, Lauren McCullough, Joellen Schildkraut, Henrik Sørensen, Kevin Ward, Kirsten Woolpert, Timothy Lash, Deirdre Cronin-Fenton. Association between expression of androgen receptor in tumor tissue and risk of breast cancer recurrence among premenopausal Danish women [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-14-07.

Prognostic Value of Pretreatment Plasma C-Reactive Protein in Patients with Early-Stage Breast Cancer.

Breast cancer incidence is now the highest among all cancers and accountable for 6.6% of all cancer-related deaths worldwide. Studies of the prognostic utility of plasma C-reactive protein (CRP) measurement in early-stage breast cancer have given discrepant results. We identified 6,942 patients in the Danish Breast Cancer Cooperative Group database with early-stage breast cancer diagnosed between 2002 and 2016 who had a measure of pretreatment plasma CRP. Outcomes were recurrence-free interval and survival for a period up to 10 years. We analyzed associations with plasma CRP using Fine-Gray proportional subdistribution hazards model with recurrence-free interval. Data on plasma CRP were analyzed per doubling of concentration and in relation to CRP levels of <3 mg/L, 3 to 10 mg/L, and >10 mg/L and stratified according to standard clinical parameters in sensitivity analyses. A doubling of the plasma CRP concentration was associated with increased risk of recurrence (multivariate adjusted HR, 1.05; 95% CI, 1.01-1.08) and shorter survival (HR, 1.13; 95% CI, 1.09-1.16) in multivariate analyses. Survival was shorter in patients with plasma CRP levels of 3 to 10 and >10 mg/L versus <3 mg/L, with multivariate adjusted HRs of 1.30; 95% CI, 1.17-1.45 and 1.65; 95% CI, 1.39-1.95, respectively. Elevated plasma CRP measured before treatment in patients with early-stage breast cancer is an independent biomarker of increased risk of recurrence and early death. CRP measures before treatment might be used to individualize follow-up of patients with early-stage breast cancer.

Trajectories of body mass index across the lifecourse and associations with post-menopausal breast cancer by estrogen receptor status

BackgroundAssociations between a high body mass index (BMI) at single timepoints during child- and adulthood and risks of post-menopausal breast cancer are well-established, but associations with BMI across the lifecourse remains largely unknown. Therefore, we examined whether lifecourse BMI trajectories were associated with risks of post-menopausal breast cancer overall and by estrogen receptor (ER) status. MethodsWe included 6698 Danish women born 1930–1946. Information on BMI at ages 6–15 years came from the Copenhagen School Health Records Register, and information on BMI at ages 20, 30, 40, 50 and/or 50–64 years came from the Diet, Cancer and Health cohort. Breast cancer cases (n = 577) were identified in the Danish Breast Cancer Cooperative Group database. Six BMI trajectories were identified using latent class trajectory modelling. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression models. ResultsCompared to women with a trajectory characterized by an average BMI gain across life, women with the two trajectories with steep increases in BMI during childhood and adolescence that thereafter largely stabilized, had lower risks of post-menopausal breast cancer and ER-positive tumors. The adjusted HRs for ER-positive tumors were 0.67 (95% CI: 0.47–0.95) and 0.68 (95% CI: 0.46–1.01), respectively. In contrast, women with a trajectory with a low gain in BMI during childhood and adolescence followed by a subsequent steep increase during adulthood, had higher risks of post-menopausal breast cancer and ER-positive tumors when compared to women with an average BMI gain. The adjusted HR for ER-positive tumors was 1.28 (95% CI: 0.98–1.67). ConclusionsOur findings suggest that the timing of excess gain in BMI across the lifecourse impacts subsequent post-menopausal breast cancer risks. Thus, the BMI development across life is likely useful in the identification of women at increased risks of post-menopausal breast cancer.

Diagnosis and treatment of breast cancer in Denmark during the COVID-19 pandemic: a nationwide population-based study

Background The COVID-19 pandemic was a global health crisis with population-wide behavioural restrictions imposed worldwide to reduce transmission of infection and to limit the potential burden on the healthcare systems. We examined whether there was any change in the diagnosis or treatment of breast cancer during the pandemic as compared to previous years. Material and Methods The study population comprised all women aged ≥18 years diagnosed with breast cancer in 2015-2021 with data obtained from the clinical quality registry of the Danish Breast Cancer Cooperative Group (DBCG). Data on socioeconomic factors were retrieved from Statistics Denmark. Prevalence ratios (PR) with 95% confidence intervals (CI) were estimated from a generalised linear model (GLM) with a log link for the Poisson family with robust standard errors (SE) of each outcome, using the COVID-19 pandemic period in Denmark as the exposure of interest. Results In total, 30,598 breast cancers were diagnosed during the study period. There was a small decrease (4.5%) in the total number of breast cancer cases in 2020 compared with previous years. During the pandemic, a lower proportion of the patients diagnosed with breast cancer had a short educational level (28.5 vs. 26.9%; PR = 0.91; 95% CI: 0.88–0.95), a low income (20.5 vs. 19.0%; PR = 0.90; 0.85-0.95) and fewer than expected in the age group 60-69 years (27.8 vs. 25.3; PR = 0.90; 0.86-0.94) were diagnosed, as compared with the pre-pandemic period. No difference in type of surgery or tumour size was observed. A higher proportion of patients received neo-adjuvant chemotherapy (49.0 vs 55.0%; PR = 1.15; 1.06–1.24), whereas a lower proportion received adjuvant chemotherapy (93.5 vs 85.6%; PR = 0.92; 0.90–0.93) during the pandemic, compared with the pre-pandemic period. Conclusions During the pandemic, a small decrease in the number of breast cancer diagnoses was observed particularly among socially disadvantaged groups. Overall, the quality of breast cancer treatment was maintained.

Birthweight, childhood body size, and timing of puberty and risks of breast cancer by menopausal status and tumor receptor subtypes

BackgroundAssociations of birthweight, childhood body size and pubertal timing with breast cancer risks by menopausal status and tumor receptor subtypes are inconclusive. Thus, we investigated these associations in a population-based cohort of Danish women.MethodsWe studied 162,419 women born between 1930 and 1996 from the Copenhagen School Health Records Register. The register includes information on birthweight, measured childhood weights and heights at the age of 7–13 years, and computed ages at the onset of the growth spurt (OGS) and at peak height velocity (PHV). The Danish Breast Cancer Cooperative Group database provided information on breast cancer (n = 7510), including estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2) and menopausal status. Hormone replacement therapy use came from the Danish National Prescription Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regression.ResultsWe found that birthweight was not associated with any breast cancer subtypes. While childhood BMI was not statistically significantly associated with ER+ tumors nor consistently with ER− tumors among pre-menopausal women, consistent inverse associations were found among postmenopausal women. At the age of 7 years, the HRs for postmenopausal ER+ and ER− tumors were 0.90 (95% CI 0.87–0.93) and 0.84 (95% CI 0.79–0.91) per BMI z-score, respectively. Similarly, childhood BMI was inversely associated with pre- and postmenopausal HER2− tumors, but not with HER2+ tumors. Childhood height was positively associated with both pre- and postmenopausal ER+ tumors, but not with ER− tumors. At the age of 7 years, the HRs for postmenopausal ER+ and ER− tumors were 1.09 (95% CI 1.06–1.12) and 1.02 (95% CI 0.96–1.09) per height z-score, respectively. In general, childhood height was positively associated with HER2+ and HER2− tumors among pre- and postmenopausal women. Ages at OGS and PHV were not associated with any breast cancer subtypes.ConclusionsWe showed that a high BMI and short stature in childhood are associated with reduced risks of certain breast cancer subtypes. Thus, childhood body composition may play a role in the development of breast cancer.

Increased morbidity evaluated on hospital contacts and prescriptions among 100,834 Danish breast cancer survivors.

Cardiovascular disease competes with breast cancer (BC) as the leading cause of death for females diagnosed with breast cancer. Not much is known concerning morbidity and medicine use in the short and long term after a BC diagnosis. The aim of this study was to determine acute and long-term morbidity in Danish women treated for BC. A nationwide registry-based cohort study of 100,834 BC patients identified in the clinical database of Danish Breast Cancer Cooperative Group (DBCG) and 1,100,320 (10 per patient) age-matched Danish women without BC, serving as controls. Morbidity was studied using complete data on hospital contacts and medicinal use. The risk of hospital contacts was significantly increased in BC survivors compared with controls evaluated both by means of Cox regression and negative binomial regression analysis both during and after cessation of breast cancer treatment. Young age at breast cancer diagnosis was associated with the most pronounced increase in risk of hospital contacts, both during and after cessation of BC treatment. Medicinal use was significantly increased among BC patients compared to controls, both during (HR 1.27 (1.26-1.28), p < 0.0001) and after BC treatment (HR 1.18 (1.17-1.19), p < 0.0001, and present for all subgroups of medicine. Overall, BC survivors have a pronounced increase in hospital contacts and medicinal use compared to women without BC. Premenopausal status at BC diagnosis was associated with an overall higher excess morbidity and a higher burden both during and after treatment.

Postmastectomy radiotherapy in high-risk breast cancer patients given adjuvant systemic therapy. A 30-year long-term report from the Danish breast cancer cooperative group DBCG 82bc trial

BackgroundBetween 1982 and 1990 the Danish Breast Cancer Cooperative Group (DBCG) conducted a randomized trial in high-risk pre- and postmenopausal (<70 years) breast cancer patients comparing mastectomy plus adjuvant systemic therapy alone versus the same treatment plus postoperative irradiation. AimTo present a comprehensive analysis of the complete DBCG 82bc study with a 30-year long-term follow-up of the cancer therapeutic effect and survival, together with an additional focus on the potential long-term life-threatening morbidity related to cardiac irradiation and/or the risk of secondary cancer induction. MethodsA total of 3083 patients with pathological stage II and stage III breast cancer were after mastectomy randomly assigned to receive adjuvant systemic therapy and postoperative irradiation to the chestwall and regional lymph nodes (1538 pts), or adjuvant systemic therapy alone (1545 pts). Pre- and menopausal patients (DBCG 82b) received 8–9 cycles of CMF with an interval of 4 weeks, whereas postmenopausal patients (DBCG 82c) received tamoxifen 30 mg daily for one year. The median follow-up time was 34 years. The primary endpoints were loco-regional recurrence (LRR) and overall mortality, and the secondary endpoints were distant metastasis, breast cancer mortality, and irradiation related late morbidity. ResultsOverall the 30-year cumulative incidence of loco-regional recurrence was 9% in irradiated patients versus 37% in non-irradiated patients who received adjuvant systemic therapy alone (HR: 0.21 [95% cfl 0.18–0.26]). Distant metastasis probability at 30 years was 49% in irradiated patients compared to 60% in non-irradiated (HR: 0.77 [0.70–0.84]). Consequently, these figures resulted in a reduced breast cancer mortality: 56% vs 67% (HR: 0.75 [0.69–0.82], and overall mortality (81% vs 86% at 30 years (p < 0.0001), HR: 0.83 [0.77–0.90] in favor of irradiation. Radiotherapy did not result in any significant excess death of other courses, such as ischemic heart disease, HR: 0.82 [0.58–1.18]; nor secondary lung cancer HR: 1.44 [0.92–2.24], or other non-cancer related death HR: 1.15 [0.92–1.45]. ConclusionThe study definitely demonstrate that optimal long-term treatment benefit of high-risk breast cancer can only be achieved if both loco-regional and systemic tumor control are aimed for. Therefore, radiotherapy has an important role in the multidisciplinary treatment of breast cancer. The PMRT treatment did not result in excess ischemic heart damage, nor in other non-breast cancer related death.

Outdoor light at night and breast cancer incidence in the Danish Nurse Cohort

BackgroundKnowledge of the role of melatonin, xenograft experiments, and epidemiological studies suggests that exposure to light at night (LAN) may disturb circadian rhythms, possibly increasing the risk of developing breast cancer. ObjectivesWe examined the association between residential outdoor LAN and the incidence of breast cancer: overall and subtypes classified by estrogen (ER) and progesterone (PR) receptor status. MethodsWe used data on 16,941 nurses from the Danish Nurse Cohort who were followed-up from the cohort baseline in 1993 or 1999 through 2012 in the Danish Cancer Registry for breast cancer incidence and the Danish Breast Cancer Cooperative Group for breast cancer ER and PR status. LAN exposure data were obtained from the U.S. Defense Meteorological Satellite Program (DMSP) available for 1996, 1999, 2000, 2003, 2004, 2006, and 2010 in nW/cm2/sr unit, and assigned to the study participants’ residence addresses during the follow-up. Time-varying Cox regression models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between LAN and breast cancer, adjusting for individual characteristics, road traffic noise, and air pollution. ResultsOf 16,941 nurses, 745 developed breast cancer in total during 320,289 person-years of follow-up. We found no association between exposure to LAN and overall breast cancer. In the fully adjusted models, HRs for the highest (65.8–446.4 nW/cm2/sr) and medium (22.0–65.7 nW/cm2/sr) LAN tertiles were 0.97 (95% CI: 0.77, 1.23) and 1.09 (95% CI: 0.90, 1.31), respectively, compared to the lowest tertile of LAN exposure (0–21.9 nW/cm2/sr). We found a suggestive association between LAN and ER-breast cancer. ConclusionThis large cohort study of Danish female nurses suggests weak evidence of the association between LAN and breast cancer incidence.

Radiation-induced risk of ischemic heart disease following breast cancer radiotherapy in Denmark, 1977–2005

Background and purposeThe increase in the risk of heart disease from incidental exposure of the heart during radiotherapy for breast cancer has been estimated previously from retrospective data in Danish and Swedish women. Here we present an analysis of the Danish material updated with new cases and controls, extended follow-up period, and with refined dose estimates using simulator films or CT data. Material and methodsFrom the database of the Danish Breast Cancer Cooperative Group, we identified 531 women diagnosed with early-stage breast cancer from 1977 to 2005, who developed subsequent ischemic heart disease (cases) and matched them to 1069 controls without heart disease after radiotherapy. Data were available for precise dose estimation for 196 cases and 413 controls receiving tangential photon techniques. ResultsThe median of the mean heart doses for the women receiving tangential radiotherapy was 2.41 Gy for left- and 0.68 Gy for right-sided radiotherapy. The mean heart dose was higher for cases than controls (0.84 Gy and 0.71 Gy, respectively; p < 0.001). In this group, the linear increase in the excess odds ratio of major coronary events per gray of mean heart dose (K) was 19 percent (95% Confidence Interval(CI) 1% to 63%, p = 0.02). For patients treated with electron techniques, there was no significant association between mean heart dose and the risk of major coronary events (K = −0.05, 95% CI −12% to 9%, p = 1.00). ConclusionThe increase in the excess odds of major coronary events per gray mean heart dose using individual dose estimates is higher than previously reported.

The long-term course of fatigue following breast cancer diagnosis

PurposeFatigue following breast cancer is a well-known problem, with both high and persistent prevalence. Previous studies suffer from lack of repeated measurements, late recruitment and short periods of follow-up. The course of fatigue from diagnosis and treatment to the long-time outcome status is unknown as well as differences in the level of fatigue between treatment regimens. The purpose of this study was to describe the long-time course of fatigue from the time of clinical suspicion of breast cancer, its dependence of patient characteristics and treatment regimens and the comparison with the course of fatigue among women with the same suspicion, but not diagnosed with breast cancer.MethodsThree hundred thirty-two women referred to acute or subacute mammography was followed with questionnaires from before the mammography and up to 1500 days. Fatigue was measured by the Multidimensional Fatigue Inventory (MFI-20). The women reported their initial level of fatigue before the mammography and thus without knowledge of whether they had cancer or not. Both women with and without cancer were followed. Women with cancer were identified in the clinical database established by Danish Breast Cancer Cooperative Group (DBCG) to collect information on treatment regimen.ResultsCompared to fatigue scores before diagnosis, women with breast cancer reported a large increase of fatigue, especially in the first 6 months, followed by a slow decrease over time. Despite the long follow-up period, the women with breast cancer did not return to their level of fatigue at time of the mammography. Women without breast cancer, experienced a rapid decrease of fatigue after disproval of diagnosis followed by a steadier period.ConclusionsFatigue is a persistent problem in women diagnosed with breast cancer, even several years following diagnosis and treatment. The women with breast cancer were most affected by fatigue in the first 6 months after diagnosis.

Adherence to treatment guidelines and survival in older women with early-stage breast cancer in Denmark 2008–2012

Objectives: The aims of this study were to compare patients 70 years or older with younger patients, to examine whether Danish patients with early-stage breast cancer aged 70 years or more received treatment according to guidelines, the reasons for deviating from the guidelines, and to analyze whether such deviations affected survival.Methods: From the Danish Breast Cancer Cooperative Group (DBCG) database we identified 23,247 women diagnosed with early-stage breast cancer in Denmark from 2008 to 2012. 17,391 were aged less than 70 years and 5856 were 70+ years. We reviewed medical charts of 441 patients aged 70+ years from Funen (a region of Denmark) to ascertain whether treatment was given according to the guidelines of DBCG and if not, the reason for deviating. Overall survival was analyzed by Cox proportional hazards models.Results: Up to age 80 years most women (94%) had surgery according to guidelines, decreasing to 41% in women aged 85+ years, the main reason for omitting surgery being patients’ requests. Patients with breast cancer over the age of 80 years did not have an excess mortality compared with the general population in Funen. Compared with women who had surgery according to guidelines, women who did not have surgery had a significantly higher risk of dying with a hazard ratio (HR) of 8.38 (95% Confidence Intervals (CI) 4.46–15.8) if they were less than 80 years and HR = 2.56 (95% CI 1.63–4.01) if they were 80 years or more (p = .003 for interaction).Conclusions: Adherence to treatment according to guidelines decreases with increasing age, mainly for patients aged 80+ years. Our results suggest that surgery is important for the survival of patients aged less than 80 years.

Definition of Internal Mammary Node Target Volume Based on the Position of the Internal Mammary Sentinel Lymph Nodes Presented on SPECT/CT Fusion Images.

Purpose: Mapping the distribution of internal mammary sentinel lymph nodes (IM-SLNs) presented on single photon emission computed tomography in conjunction with computed tomography (SPECT/CT) images to explore the value of IM-SLN to guide tailored clinical target volume (CTV) delineation of postoperative prophylactic IMNI.Materials and methods: Ninety-seven patients who underwent preoperative lymphoscintigraphy by SPECT/CT and had imaging of IM-SLN were selected in this study. The imaging IM-SLNs on SPECT/CT of eligible patients were projected onto corresponding anatomical positions of a representative axial CT image. The IMN CTVs were delineated on the representative axial CT images according to the Radiation Therapy Oncology Group (RTOG) and Danish Breast Cancer Cooperative Group (DBCG) guideline, and defined as CTVRTOG and CTVDBCG. The location of the IM-SLNs was compared with the RTOG and DBCG guidelines of IMN target volume delineations, respectively. The intercostal space distribution of IM-SLNs was recorded. The distances from the CTVRTOG and CTVDBCG to the IM-SLNs were measured, respectively.Results: The total number of imaging IM-SLNs was 136. IM-SLNs were mostly found in the first intercostal space (40.4%), with 30.2, 24.3, 4.4, and 0.7% of IM-SLNs in the second, third, fourth, and fifth intercostal space, respectively. The average distance from the edge of the CTVRTOG and the edge of CTVDBCG to the central points of the IM-SLNs was 4.10 mm (SD, 3.3 mm) and 1.60 mm (SD, 2.6 mm), respectively (t = 16.640, P = 0.000). The average distance from the edge of CTVRTOG and the edge of CTVDBCG to the lateral border IM-SLN was 6.40 mm (SD, 3.5 mm) and 3.34 mm (SD, 3.3 mm), respectively (t = 19.815, P = 0.000). Only 18.4% of IM-SLN central points were included in the CTVRTOG, and 60.3% of IM-SLN central points were included in the CTVDBCG. When covering 90 and 100% of the IM-SLN center points, the CTVRTOG needs to expand 8 and 15 mm, respectively, and the CTVDBCG needs to expand 5 and 13 mm, respectively.Conclusion: Neither the RTOG nor DBCG consensus guideline about the delineation of IMN CTV was sufficient to cover 90% of IM-SLNs. For 90% coverage of IM-SLN central points, CTVRTOG needed to be expanded by 8 mm, and CTVDBCG needed to be expanded by 5 mm.

Patient-reported outcome after oncoplastic breast surgery compared with conventional breast-conserving surgery in breast cancer

IntroductionOncoplastic breast surgery (OBS) has developed as an extension of breast-conserving surgery (BCS) in an effort to improve esthetic and functional outcome following surgery for breast cancer. The aim of the present study was to evaluate the possible benefits of OBS, as compared with BCS, with regard to health-related quality of life (HRQoL), using patient-reported outcome measures (PROMs).Patients and methodsPatients treated with OBS (n = 200) and BCS (n = 1304) in the period 1 January 2008 to 31 December 2013 were identified in a research database and in the Danish Breast Cancer Cooperative Group (DBCG) registry. Data on patient, tumor, and treatment characteristics were retrieved from the DBCG registry. Patients were sent a survey including the Breast-Q™ BCT postoperative module and a study-specific questionnaire (SSQ) in 2016. A good outcome in the Breast-Q module was defined as above the median. OBS was compared to BCS using a logistic regression analysis, and then adjusted for potential confounders, yielding odds ratios (OR) with 95% confidence intervals.ResultsThere was a statistically significant better outcome considering the HRQoL domain “Psychosocial Well-being “ for patients treated with OBS as compared with BCS (OR 2.15: 1.25–3.69). No statistically significant differences were found for the domains “Physical Well-being” (0.83: 0.50–1.39), “Satisfaction with Breast” (0.95: 0.57–1.59), or “Sexual Well-being” (1.42: 0.78–2.58).ConclusionThe present study indicates better outcomes of HRQoL for breast cancer patients treated with OBS as compared to patients treated with BCS. There was no increase in physical discomfort among OBS patients despite more extensive surgery.

Oncoplastic Breast Surgery Compared to Conventional Breast-Conserving Surgery With Regard to Oncologic Outcome

IntroductionOncoplastic breast surgery (OBS) has been implemented with increasing frequency in the treatment of breast cancer. The aim of this study was to compare the oncologic outcome after OBS to the outcome after conventional breast-conserving surgery (BCS) in patients with invasive breast cancer. Patients and MethodsIn all, 197 patients treated with OBS were compared to 1399 patients treated with conventional BCS from 2008 to 2013. We evaluated nonradical primary tumor excision, time to initiation of adjuvant therapy, disease-free survival (risk of recurrent disease), and survival (cause specific and overall). Identification of patients and follow-up were made using the Danish Breast Cancer Cooperative Group registry and the Danish Cause of Death registry. Multivariate logistic regression and the Cox proportional hazard analysis were used to obtain odds ratios and hazard ratios with 95% confidence intervals (CI). ResultsThere was a lower risk for nonradical primary tumor excision for patients undergoing OBS versus conventional BCS (adjusted odds ratio:95% CI, 0.50:0.29-0.84). No significant differences were found with regard to a delay in initiation of adjuvant chemotherapy (adjusted hazard ratio:95% CI, 1.14:0.89-1.45) or radiotherapy (0.91:0.71-1.16), disease-free survival (1.23:0.61-2.47), breast cancer as cause of death (1.46:0.52-4.09), breast cancer as underlying or multiple cause of death (0.90:0.34-2.37), or overall survival (0.90:0.51-1.60). ConclusionWe found no significant differences in oncologic outcome comparing OBS to conventional BCS. However, a lower risk of nonradical primary tumor excision was found for patients treated with OBS. These results indicate that OBS is a safe procedure.

Doxorubicin response prediction in neoadjuvant breast cancer therapy.

e12119 Background: Neoadjuvant treatment for breast cancer (BC) is an important remedy if the tumors are responding adequately. Still, there is no biomarker guidance resulting in many patients receiving chemotherapy with no efficient antitumor effect. We study a multigene mRNA-based technology for drug response prediction (DRP). DRP has been thoroughly validated in other settings, latest in prediction of epirubicin efficacy in advanced BC [1]. Here are the results of the DRP method in the prediction of response to neoadjuvant doxorubicin in early BC. Methods: The DRP correlates sensitivity of the applicable drug in cell lines with background mRNA. This is combined with gene expression patterns from &gt;2.000 tumors of different origin to ensure clinically usefulness. The higher DRP score, the higher likelihood of response. Blinded predictions of doxorubicin DRP scores were compared to response data which originated from a phase II trial [2], where the study population received neoadjuvant doxorubicin and cyclophosphamide (N=279). The patients had histologically confirmed primary invasive breast adenocarcinoma (T2-3, N0-3, M0, tumor size ≥ 2.0 cm, ER+/- and HER2+/-). Statistical analysis was done using logistic regression. Results: Table shows the distribution of response and DRP scores, showing higher DRPs are correlated to better clinical outcome. This is demonstrated by logistic regression ( p=0.002), odds ratio for response 2.2 (95% CI:1.3-3.4). Multivariate analysis showed that the DRP was independent of other covariates. Conclusions: The DRP can predict which patients will be high likelihood responders to neoadjuvant doxorubicin. Modern multigene technologies may help assist clinicians in choosing between upfront surgery or neoadjuvant chemotherapy. Complete response (CR), Partial response (PR), Stable disease (SD), Progression of Disease (PD). 1. Buhl ASK, et al. (2018): Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study. Breast cancer research and treatment. doi: 10.1007/s10549-018-4918-4. 2. Horak CE et al. (2013): Biomarker analysis of neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer. Clinical cancer research. doi: 10.1158/1078-0432.ccr-12-1359.[Table: see text]

Long-Term Risk of Heart Failure in Breast Cancer Patients After Adjuvant Chemotherapy With or Without Trastuzumab

ObjectivesThis study sought to evaluate the long-term risk of developing heart failure (HF) in patients receiving trastuzumab therapy. BackgroundTrastuzumab has improved the prognosis in patients with HER2-positive breast cancer, but it can induce left ventricular dysfunction with reduced ejection fraction or HF during treatment. The long-term risk of HF is less well described. MethodsIn a nationwide Danish retrospective cohort study, 9,901 patients scheduled for adjuvant treatment for early-stage breast cancer were identified in the Danish Breast Cancer Cooperative Group database. Of these, 8,812 patients (25% HER2-positive; 51.7 ± 8.5 years of age) received chemotherapy including anthracycline; and if they were HER2 positive, trastuzumab was added. The primary endpoint was a diagnosis of HF assessed before and after 18 months in a landmark analysis to distinguish short- and long-term risks. ResultsMedian follow-up was 5.4 years (interquartile range [IQR]: 4.1 to 6.8 years). In the trastuzumab group, 60 patients had HF by 9 years versus 51 in the group who were treated with chemotherapy alone, corresponding to incidence rates per 1,000 patient years of 5.3 (95% confidence interval [CI]: 4.1 to 6.8) versus 1.4 (95% CI: 1.1 to 1.8), respectively. The cumulative incidence of HF was higher in the trastuzumab group at both the short- and long-term (p < 0.01), yielding adjusted hazard ratios of 8.7 (95% CI: 4.6 to 16.5; p < 0.01) for early HF and 1.9 (95% CI: 1.2 to 3.3; p = 0.01) for late HF associated with trastuzumab treatment. ConclusionsTrastuzumab treatment is associated with a 2-fold increased risk of late HF compared with chemotherapy treatment alone.

Long-term exposure to road traffic noise and incidence of breast cancer: a cohort study

BackgroundExposure to road traffic noise was associated with increased risk of estrogen receptor (ER)-negative (ER-) breast cancer in a previous cohort study, but not with overall or ER-positive (ER+) breast cancer, or breast cancer prognosis. We examined the association between long-term exposure to road traffic noise and incidence of breast cancer, overall and by ER and progesterone receptor (PR) status.MethodsWe used the data from a nationwide Danish Nurse Cohort on 22,466 female nurses (age > 44 years) who at recruitment in 1993 or 1999 reported information on breast cancer risk factors. We obtained data on the incidence of breast cancer from the Danish Cancer Registry, and on breast cancer subtypes by ER and PR status from the Danish Breast Cancer Cooperative Group, up to 31 December 2012. Road traffic noise levels at the nurses’ residences were estimated by the Nord2000 method between 1970 and 2013 as annual means of a weighted 24 h average (Lden) at the most exposed facade. We used time-varying Cox regression to analyze the associations between the 24-year, 10-year, and 1-year mean of Lden and breast cancer, separately for total breast cancer and by ER and PR status.ResultsOf the 22,466 women, 1193 developed breast cancer in total during 353,775 person-years of follow up, of whom 611 had complete information on ER and PR status. For each 10 dB increase in 24-year mean noise levels at their residence, we found a statistically significant 10% (hazard ratio and 95% confidence interval 1.10; 1.00–1.20) increase in total breast cancer incidence and a 17% (1.17; 1.02–1.33) increase in analyses based on 611 breast cancer cases with complete ER and PR information. We found positive, statistically significant association between noise levels and ER+ (1.23; 1.06–1.43, N = 494) but not ER- (0.93; 0.70–1.25, N = 117) breast cancers, and a stronger association between noise levels and PR+ (1.21; 1.02–1.42, N = 393) than between noise levels and PR- (1.10; 0.89–1.37, N = 218) breast cancers. Association between noise and ER+ breast cancer was statistically significantly stronger in nurses working night shifts (3.36; 1.48–7.63) than in those not working at night (1.21; 1.02–1.43) (p value for interaction = 0.05).ConclusionLong-term exposure to road traffic noise may increase risk of ER+ breast cancer.

Low-dose aspirin use and risk of contralateral breast cancer: a Danish nationwide cohort study

Observational studies of aspirin use and breast cancer risk have provided inconsistent results. The occurrence of contralateral breast cancer (CBC) among breast cancer survivors may serve as a useful high-risk model to identify preventive drug effects. Using this model, we examined the association between post-diagnosis use of low-dose aspirin and risk of CBC. We identified all women recorded with a first primary breast cancer in the Danish Breast Cancer Cooperative Group Database between 1996 and 2012. Information on drug use, tumor and patient characteristics, treatment, and CBC was obtained from nationwide registries. In the main analysis, we defined time-varying post-diagnosis low-dose aspirin use as two or more prescriptions filled during follow-up and applied a one-year exposure lag. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis low-dose aspirin use and CBC risk. Among 52,723 breast cancer patients, 1,444 women developed CBC during a median follow-up of 4.8 years. The adjusted HR for CBC associated with post-diagnosis use of low-dose aspirin was 0.91 (95% CI: 0.75–1.09). We observed no substantial variation in HRs according to pattern of low-dose aspirin use or estrogen receptor status of the first or the contralateral breast cancer. In conclusion, this large nationwide cohort study of breast cancer survivors does not provide strong evidence suggesting an association between post-diagnosis use of low-dose aspirin and risk of CBC.

Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study

PurposeAnthracyclines remain a cornerstone in the treatment of primary and advanced breast cancer (BC). This study has evaluated the predictive value of a multigene mRNA-based drug response predictor (DRP) in the treatment of advanced BC with epirubicin. The DRP is a mathematical method combining in vitro sensitivity and gene expression with clinical genetic information from > 3000 clinical tumor samples.MethodsFrom a DBCG cohort, 140 consecutive patients were treated with epirubicin between May 1997 and November 2016. After patient informed consent, mRNA was isolated from archival formalin-fixed paraffin-embedded primary breast tumor tissue and analyzed using Affymetrix arrays. Using time to progression (TTP) as primary endpoint, the efficacy of epirubicin was analyzed according to DRP combined with clinicopathological data collected retrospectively from patients’ medical records. Statistical analysis was done using Cox proportional hazards model stratified by treatment line.ResultsMedian TTP was 9.3 months. The DRP was significantly associated to TTP (P = 0.03). The hazard ratio for DRP scores differing by 50 percentage points was 0.55 (95% CI –0.93, one-sided). A 75% DRP was associated with a median TTP of 13 months compared to 7 months following a 25% DRP. Multivariate analysis showed that DRP was independent of age and number of metastases.ConclusionThe current study prospectively validates the predictive capability of DRP regarding epirubicin previously shown retrospectively allowing the patients predicted to be poor responders to choose more effective alternatives. Randomized prospective studies are needed to demonstrate if such an approach will lead to increased overall survival.