Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases.

BACKGROUND: Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups. METHODS: We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44. RESULTS: Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy-only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy-only group and 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin. CONCLUSIONS: The omission of completion axillary-lymph-node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. (Funded by the Swedish Research Council and others; SENOMAC ClinicalTrials.gov number, NCT02240472.).

Antibodies toward Na+,HCO3--cotransporter NBCn1/SLC4A7 block net acid extrusion and cause pH-dependent growth inhibition and apoptosis in breast cancer.

BACKGROUND: Na+,HCO3--cotransporter NBCn1/Slc4a7 accelerates murine breast carcinogenesis. Lack of specific pharmacological tools previously restricted therapeutic targeting of NBCn1 and identification of NBCn1-dependent functions in human breast cancer. METHODS: We develop extracellularly-targeted anti-NBCn1 antibodies, screen for functional activity on cells, and evaluate (a) mechanisms of intracellular pH regulation in human primary breast carcinomas, (b) proliferation, cell death, and tumor growth consequences of NBCn1 in triple-negative breast cancer, and (c) association of NBCn1-mediated Na+,HCO3--cotransport with human breast cancer metastasis. RESULTS: We identify high-affinity (KD ≈ 0.14 nM) anti-NBCn1 antibodies that block human NBCn1-mediated Na+,HCO3--cotransport in cells, without cross-reactivity towards human NBCe1 or murine NBCn1. These anti-NBCn1 antibodies abolish Na+,HCO3--cotransport activity in freshly isolated primary organoids from human breast carcinomas and lower net acid extrusion effectively in primary breast cancer tissue from patients with macrometastases in axillary lymph nodes. Inhibitory anti-NBCn1 antibodies decelerate tumor growth in vivo by ~50% in a patient-derived xenograft model of triple-negative breast cancer and pH-dependently reduce colony formation, cause G2/M-phase cell cycle accumulation, and increase apoptosis of metastatic triple-negative breast cancer cells in vitro. CONCLUSIONS: Inhibitory anti-NBCn1 antibodies block net acid extrusion in human breast cancer tissue, particularly from patients with disseminated disease, and pH-dependently limit triple-negative breast cancer growth.

Impact of type 2 diabetes on complications after primary breast cancer surgery: Danish population-based cohort study.

BACKGROUND: Knowledge is sparse on the impact of type 2 diabetes (T2D) on surgical outcomes after breast cancer surgery. This study investigated the association between T2D and risk of complications after primary breast cancer surgery, and evaluated the biological interaction between T2D and co-morbidities. METHODS: Using the Danish Breast Cancer Group clinical database, a cohort of all Danish women diagnosed with early-stage breast cancer during 1996-2022 was created. All patients underwent mastectomy or breast-conserving surgery. Information on prevalent T2D was collected from Danish medical and prescription registries. Surgical complications were defined as hospital diagnoses for medical or surgical complications developing within 30 days after primary breast cancer surgery. The 30-day cumulative incidence proportion of complications was calculated, and Cox regression was used to estimate HRs. Interaction contrasts were computed to determine the additive interaction between T2D and co-morbidities on the incidence rate of complications. RESULTS: Among 98 589 women with breast cancer, 6332 (6.4%) had T2D at breast cancer surgery. Overall, 1038 (16.4%) and 9861 (10.7%) women with and without T2D developed surgical complications, yielding cumulative incidence proportions of 16 (95% c.i. 15 to 17) and 11 (10 to 11)% respectively, and a HR of 1.43 (95% c.i. 1.34 to 1.53). The incidence rate of surgical complications explained by the interaction of T2D with moderate and severe co-morbidity was 21 and 42%, respectively. CONCLUSION: Women with breast cancer and T2D had a higher risk of complications after primary breast cancer surgery than those without T2D. A synergistic effect of T2D and co-morbidity on surgical complications can explain this association.

Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer.

BACKGROUND: Carbonic anhydrases catalyze CO2/HCO3- buffer reactions with implications for effective H+ mobility, pH dynamics, and cellular acid-base sensing. Yet, the integrated consequences of carbonic anhydrases for cancer and stromal cell functions, their interactions, and patient prognosis are not yet clear. METHODS: We combine (a) bioinformatic analyses of human proteomic data and bulk and single-cell transcriptomic data coupled to clinicopathologic and prognostic information; (b) ex vivo experimental studies of gene expression in breast tissue based on quantitative reverse transcription and polymerase chain reactions, intracellular and extracellular pH recordings based on fluorescence confocal microscopy, and immunohistochemical protein identification in human and murine breast cancer biopsies; and (c) in vivo tumor size measurements, pH-sensitive microelectrode recordings, and microdialysis-based metabolite analyses in mice with experimentally induced breast carcinomas. RESULTS: Carbonic anhydrases-particularly the extracellular isoforms CA4, CA6, CA9, CA12, and CA14-undergo potent expression changes during human and murine breast carcinogenesis. In patients with basal-like/triple-negative breast cancer, elevated expression of the extracellular carbonic anhydrases negatively predicts survival, whereas, surprisingly, the extracellular carbonic anhydrases positively predict patient survival in HER2/ErbB2-enriched breast cancer. Carbonic anhydrase inhibition attenuates cellular net acid extrusion and extracellular H+ elimination from diffusion-restricted to peripheral and well-perfused regions of human and murine breast cancer tissue. Supplied in vivo, the carbonic anhydrase inhibitor acetazolamide acidifies the microenvironment of ErbB2-induced murine breast carcinomas, limits tumor immune infiltration (CD3+ T cells, CD19+ B cells, F4/80+ macrophages), lowers inflammatory cytokine (Il1a, Il1b, Il6) and transcription factor (Nfkb1) expression, and accelerates tumor growth. Supporting the immunomodulatory influences of carbonic anhydrases, patient survival benefits associated with high extracellular carbonic anhydrase expression in HER2-enriched breast carcinomas depend on the tumor inflammatory profile. Acetazolamide lowers lactate levels in breast tissue and blood without influencing breast tumor perfusion, suggesting that carbonic anhydrase inhibition lowers fermentative glycolysis. CONCLUSIONS: We conclude that carbonic anhydrases (a) elevate pH in breast carcinomas by accelerating net H+ elimination from cancer cells and across the interstitial space and (b) raise immune infiltration and inflammation in ErbB2/HER2-driven breast carcinomas, restricting tumor growth and improving patient survival.

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.

Educational differences in healthcare use among survivors after breast, prostate, lung, and colon cancer - a SEQUEL cohort study.

BACKGROUND: Many cancer survivors experience late effects after cancer. Comorbidity, health literacy, late effects, and help-seeking behavior may affect healthcare use and may differ among socioeconomic groups. We examined healthcare use among cancer survivors, compared with cancer-free individuals, and investigated educational differences in healthcare use among cancer survivors. METHODS: A Danish cohort of 127,472 breast, prostate, lung, and colon cancer survivors from the national cancer databases, and 637,258 age- and sex-matched cancer-free individuals was established. Date of entry was 12 months after diagnosis/index date (for cancer-free individuals). Follow-up ended at death, emigration, new primary cancer, December 31st, 2018, or up to 10 years. Information about education and healthcare use, defined as the number of consultations with general practitioner (GP), private practicing specialists (PPS), hospital, and acute healthcare contacts 1-9 years after diagnosis/index date, was extracted from national registers. We used Poisson regression models to compare healthcare use between cancer survivors and cancer-free individuals, and to investigate the association between education and healthcare use among cancer survivors. RESULTS: Cancer survivors had more GP, hospital, and acute healthcare contacts than cancer-free individuals, while the use of PPS were alike. One-to-four-year survivors with short compared to long education had more GP consultations (breast, rate ratios (RR) = 1.28, 95% CI = 1.25-1.30; prostate, RR = 1.14, 95% CI = 1.10-1.18; lung, RR = 1.18, 95% CI = 1.13-1.23; and colon cancer, RR = 1.17, 95% CI = 1.13-1.22) and acute contacts (breast, RR = 1.35, 95% CI = 1.26-1.45; prostate, RR = 1.26, 95% CI = 1.15-1.38; lung, RR = 1.24, 95% CI = 1.16-1.33; and colon cancer, RR = 1.35, 95% CI = 1.14-1.60), even after adjusting for comorbidity. One-to-four-year survivors with short compared to long education had less consultations with PPS, while no association was observed for hospital contacts. CONCLUSION: Cancer survivors used more healthcare than cancer-free individuals. Cancer survivors with short education had more GP and acute healthcare contacts than survivors with long education. To optimize healthcare use after cancer, we need to better understand survivors' healthcare-seeking behaviors and their specific needs, especially among survivors with short education.

Amplified Ca2+ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation.

Intracellular Ca2+ dynamics shape malignant behaviors of cancer cells. Whereas previous studies focused on cultured cancer cells, we here used breast organoids and colonic crypts freshly isolated from human and murine surgical biopsies. We performed fluorescence microscopy to evaluate intracellular Ca2+ concentrations in breast and colon cancer tissue with preferential focus on intracellular Ca2+ release in response to purinergic and cholinergic stimuli. Inhibition of the sarco-/endoplasmic reticulum Ca2+ ATPase with cyclopiazonic acid elicited larger Ca2+ responses in breast cancer tissue, but not in colon cancer tissue, relative to respective normal tissue. The resting intracellular Ca2+ concentration was elevated, and ATP, UTP and acetylcholine induced strongly augmented intracellular Ca2+ responses in breast cancer tissue compared with normal breast tissue. In contrast, resting intracellular Ca2+ levels and acetylcholine-induced increases in intracellular Ca2+ concentrations were unaffected and ATP- and UTP-induced Ca2+ responses were smaller in colon cancer tissue compared with normal colon tissue. In accordance with the amplified Ca2+ responses, ATP and UTP substantially increased proliferative activity-evaluated by bromodeoxyuridine incorporation-in breast cancer tissue, whereas the effect was minimal in normal breast tissue. ATP caused cell death-identified with ethidium homodimer-1 staining-in breast cancer tissue only at concentrations above the expected pathophysiological range. We conclude that intracellular Ca2+ responses are amplified in breast cancer tissue, but not in colon cancer tissue, and that nucleotide signaling stimulates breast cancer cell proliferation within the extracellular concentration range typical for solid cancer tissue.

Hypoxia-inducible factor-1α expression and breast cancer recurrence in a Danish population-based case control study.

BACKGROUND: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that facilitates the adaptation of cancer cells to hypoxic conditions and may be prognostic of breast cancer recurrence. We evaluated the association of HIF-1α expression with breast cancer recurrence, and its association with timing of breast cancer recurrence. METHODS: In this population-based case-control study, we included women diagnosed with stage I-III breast cancer between 1985 and 2001, aged 35-69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with estrogen receptor (ER)-positive disease who were treated with tamoxifen for at least 1 year (ER+ TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER-negative disease, not treated with tamoxifen, who survived at least 1 year (ER-/TAM-). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, cancer stage, and county of residence. Expression of HIF-1α was measured by immunohistochemistry on tissue microarrays. We fitted logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating HIF-1α expression with recurrence, and with timing of recurrence. RESULTS: HIF-1α expression was observed in 23% of cases and 20% of controls in the ER+/TAM+ stratum, and in 47% of cases and 48% of controls in the ER-/TAM- stratum. We observed a near-null association between HIF-1α expression in both ER/TAM groups (ER+/TAM+ OR = 1.21, 95%CI 0.88, 1.67 and ER-/TAM- OR = 0.97, 95%CI 0.68, 1.39). HIF-1α expression was not associated with time to recurrence among women in the ER+/TAM+ stratum, but was associated with early recurrence among women in the ER-/TAM- stratum. CONCLUSION: In this study, HIF-1α expression was not associated with breast cancer recurrence overall but may be associated with early recurrence among women diagnosed with ER- breast cancer.

Comparison of contrast-enhanced CT, dual-layer detector spectral CT, and whole-body MRI in suspected metastatic breast cancer: a prospective diagnostic accuracy study.

OBJECTIVES: To compare diagnostic accuracy of contrast-enhanced CT, dual-layer detector spectral CT (DL-CT), and whole-body MRI (WB-MRI) for diagnosing metastatic breast cancer. METHODS: One hundred eighty-two biopsy-verified breast cancer patients suspected of metastatic disease prospectively underwent contrast-enhanced DL-CT and WB-MRI. Two radiologists read the CT examinations with and without spectral data in consensus with 3-month washout between readings. Two other radiologists read the WB-MRI examinations in consensus. Lymph nodes, visceral lesions, and bone lesions were assessed. Readers were blinded to other test results. Reference standard was histopathology, previous or follow-up imaging, and clinical follow-up. RESULTS: Per-lesion AUC was 0.80, 0.84, and 0.82 (CT, DL-CT, and WB-MRI, respectively). DL-CT showed significantly higher AUC than CT (p = 0.001) and WB-MRI (p = 0.02). Sensitivity and specificity of CT, DL-CT, and WB-MRI were 0.66 and 0.94, 0.75 and 0.95, and 0.65 and 0.98, respectively. DL-CT significantly improved sensitivity compared to CT (p < 0.0001) and WB-MRI (p = 0.002). Per-patient AUC was 0.85, 0.90, and 0.92 (CT, DL-CT, and WB-MRI, respectively). DL-CT and WB-MRI had significantly higher AUC than CT (p = 0.04 and p = 0.03). DL-CT significantly increased sensitivity compared to CT (0.89 vs. 0.79, p = 0.04). WB-MRI had significantly higher specificity than CT (0.84 vs. 0.96, p = 0.001) and DL-CT (0.87 vs. 0.96, p = 0.02). CONCLUSIONS: DL-CT showed significantly higher per-lesion diagnostic performance and sensitivity than CT and WB-MRI. On a per-patient basis, DL-CT and WB-MRI had equal diagnostic performance superior to CT. KEY POINTS: • Spectral CT has higher diagnostic performance for diagnosing breast cancer metastases compared to conventional CT and whole-body MRI on a per-lesion basis. • Spectral CT and whole-body MRI are superior to conventional CT for diagnosing patients with metastatic breast cancer. • Whole-body MRI is superior to conventional CT and spectral CT for diagnosing bone metastases.

Oncoplastic breast surgery versus conventional breast conserving surgery - a prospective follow-up study of subjective loco-regional late morbidity.

Background and aim: Few studies have focused on the symptoms of loco-regional morbidity in shoulders, arms, and breasts related to oncoplastic breast surgery (OPS). This study aimed to determine if a difference exists in the prevalence or variety of subjective symptoms of shoulder, arm, and breast morbidity in patients undergoing OPS compared with patients receiving conventional breast conserving surgery (C-BCS). Cosmetic result and body image were included as secondary endpoints.Methods: This prospective follow-up study with 18 months of questionnaire-based follow-up included women with breast cancer or ductal carcinoma in situ. They were divided into two groups - C-BCS or OPS - depending on type of surgery performed. Furthermore, patient, disease, and treatment characteristics were recorded.Results: Among 334 completers, 229 (69%) received C-BCS and 105 (31%) received OPS. Participants were comparable regarding age, comorbidity, BMI, re-excision rate (15-16%), and axillary surgery. As for tumor characteristics, a more advanced disease stage was shown in the OPS than in the C-BCS group with larger tumor and lumpectomy size, more multifocality, and the corresponding following systemic adjuvant therapy.The questionnaire revealed that the two groups were comparable with no significant differences in frequency or variety of symptoms of shoulder and arm morbidity. Overall, participants were highly satisfied with the cosmetic results in both groups and no significant inter-group differences were observed.Conclusion: In patients with larger tumors, breast conserving surgery utilizing oncoplastic techniques yields results regarding subjective shoulder, arm, and breast morbidity as well as cosmetic outcome comparable with those of C-BCS performed on smaller tumors.Trial registration: ClinicalTrials.gov, registration number: NCT02159274 (2014).HIGHLIGHTSSubjective symptoms of shoulder, arm, and breast morbidity are comparable when oncoplastic breast surgery is compared to conventional breast conserving surgery.The variety of symptoms of shoulder and arm morbidity following oncoplastic surgery does not differ from symptoms following conventional breast conserving surgery.The cosmetic outcome following oncoplastic breast surgery is comparable to breast conserving surgery without oncoplastic techniques.

Long-term follow-up on shoulder and arm morbidity in patients treated for early breast cancer.

Background: A prospective study on shoulder and arm morbidity was conducted in Denmark in 2003-2005. This study demonstrated that sentinel lymph node biopsy was associated with better outcomes than axillary lymph node dissection 18 months after surgery. We here aimed to describe subjective symptoms and objective findings in these patients 10+ years after they underwent breast cancer surgery and to assess how symptoms and findings developed during this period.Material and methods: Participants in the prospective study completed a questionnaire and underwent an objective, bilateral examination of their shoulder and arm morbidity, which included measurement of arm volume, range of motion, and sensibility.Results: Seventy participants completed follow-up. Thirty-four (49%) had one or more functional impairments, and 64% had one or more subjective loco regional symptoms like pain, swelling of the arm, and decreased shoulder mobility. Objective evaluation showed 34 ml's of increased arm volumes and 3-25% had severe reduced shoulder mobility on the operated side. Compared to the findings at 18 months postoperatively, small but significant differences in occurrence of subjective findings were observed. A significant progression regarding most objective findings was revealed.Conclusion: More than 11 years after breast cancer surgery, the majority of participants complained of one or more subjective symptoms of shoulder and arm morbidity. Objective findings were mild or modest in most cases. During the prolonged follow-up period of 10 years, a worsening in symptoms and objective findings was observed.HIGHLIGHTSShoulder and arm morbidity in relation to breast cancer treatment seems to progress beyond 10 years.The most frequent symptoms were pain, swelling or heaviness of the arm, and decreased shoulder mobility.The objective evaluation showed higher arm volumes and reduced shoulder mobility on the operated side.Objective findings are mild and modest but may affect activities of daily living, and most participants with late symptoms stated that this was a daily problem.

Predictive pharmacogenetic biomarkers for breast cancer recurrence prevention by simvastatin.

Background: Statins treat hyperlipidemia and prevent cardiovascular morbidity and mortality. Evidence suggests that they also have anti-neoplastic activity. Several studies show a reduced rate of breast cancer recurrence among lipophilic statin users (e.g., simvastatin), motivating calls for clinical trials of statins in breast cancer patients. We measured the impact of genetic variation in statin-metabolizing enzymes and drug transporters on the recurrence rate in simvastatin-treated breast cancer patients.Methods: We conducted a nested case-control study among Danish women diagnosed with non-metastatic, invasive breast cancer between 2004-2010 who had filled ≥1 prescription for simvastatin after diagnosis. Cases were all breast cancer recurrences from the source population; one control was matched to each case on cancer stage, estrogen receptor and hormone therapy status, calendar period of diagnosis, and duration of simvastatin exposure. We genotyped variants in simvastatin-metabolizing enzymes (CYP3A4/rs35599367 and CYP3A5/rs776746) and drug transporters (ABCB1/rs2032582 and SLCO1B1/rs4149056), and estimated their association with recurrence with logistic regression models.Results: We observed protective (though imprecisely-measured) associations between variants in genes encoding drug transporters (ABCB1 and SLCO1B1) and simvastatin-metabolizing enzymes (CYP3A4 and CYP3A5) and breast cancer recurrence in simvastatin-treated women. For example, carrying two variant alleles in ABCB1 was associated with a 31% lower rate of recurrence (multivariable OR = 0.69, 95% CI: 0.31, 1.5).Conclusion: Our study provides weak evidence to support the use of genetic variation in ABCB1, SLCO1B1, CYP3A4, and CYP3A5 as biomarkers of breast tumor response to simvastatin. Validation of these findings within adjuvant clinical trials is encouraged.

Expression of survivin does not appear to influence breast cancer recurrence risk.

BACKGROUND: Survivin is an inhibitor of apoptosis, and its expression associates with poor outcomes in multiple cancers. It may be a therapeutic target due to its unique expression in cancer cells. METHODS: We estimated the association between nuclear and cytoplasmic survivin expression in primary tumors and breast cancer recurrence. In this case-control study, we included women age 35-69, diagnosed with stage I-III breast cancer between 1985 and 2001, and registered with the Danish Breast Cancer Group. We identified 541 patients with breast cancer recurrence with estrogen receptor-positive disease who were treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 with estrogen receptor-negative carcinomas, not treated with tamoxifen, and who survived at least 1 year (ER-/TAM-). Controls were matched to cases on ER/TAM status, date of surgery, menopausal status, stage and county. Survivin expression was estimated by immunohistochemistry on tissue microarrays. We fit logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) associating nuclear and cytoplasmic survivin expression with recurrence. RESULTS: Associations between nuclear and cytoplasmic survivin expression and breast cancer recurrence were near-null in both ER+/TAM + and ER-/TAM - strata. For the cytoplasmic to nuclear ratio (CNR) of survivin expression, we found a null association in the ER+/TAM + group comparing CNR ≥5 with CNR <5, but an association (OR =2.48, 95% CI: 1.15, 5.31) in the ER-/TAM - group. CONCLUSIONS: Survivin expression was not associated with breast cancer recurrence in this study. The CNR ratio may warrant further investigation especially among ER - tumors.

Surgical breast cancer patient pathway: Experiences of patients and relatives and their unmet needs.

BACKGROUND AND AIM: Breast cancer is the most common cancer disease in women worldwide. In Denmark, the law prescribes cancer patient pathways (CPPs) in general and thus also for breast cancer. Although results from patient satisfaction surveys show overall satisfaction with the pathway, a call for improvement has been voiced for some areas. The aim of this study was to explore patients' and relatives' experiences with the surgical breast CPP and to identify any unmet needs. METHOD: This study was based on focus groups with patients who had surgery for breast cancer, and their relatives. The settings were two Danish surgical breast cancer clinics. FINDINGS: Overall, patients and relatives found the structure of the surgical breast CPP satisfactory. The time in the surgical department was short, and most patients found it difficult to cope with the situation. Empathy and a supportive relationship between patients, relatives and health-care professionals were of great importance. Five key points were identified in which some of the participants had unmet needs. Suggestions for change were related to information, communication, choice of treatment, flexibility in the pathway and easy access to the clinic after surgery. CONCLUSION: Although patients and relatives found the CPP for breast cancer satisfactory and well planned, suggestions for change were made relating to unmet needs with respect to five key points in the pathway. Implementing findings from this study in clinical practice requires co-operation between health-care professionals and support from the leaders of the organization.

The clinical database and implementation of treatment guidelines by the Danish Breast Cancer Cooperative Group in 2007-2016.

BACKGROUND: Since 40 years, Danish Breast Cancer Cooperative Group (DBCG) has provided comprehensive guidelines for diagnosis and treatment of breast cancer. This population-based analysis aimed to describe the plurality of modifications introduced over the past 10 years in the national Danish guidelines for the management of early breast cancer. By use of the clinical DBCG database we analyze the effectiveness of the implementation of guideline revisions in Denmark. METHODS: From the DBCG guidelines we extracted modifications introduced in 2007-2016 and selected examples regarding surgery, radiotherapy (RT) and systemic treatment. We assessed introduction of modifications from release on the DBCG webpage to change in clinical practice using the DBCG clinical database. RESULTS: Over a 10-year period data from 48,772 patients newly diagnosed with malignant breast tumors were entered into DBCG's clinical database and 42,197 of these patients were diagnosed with an invasive carcinoma following breast conserving surgery (BCS) or mastectomy. More than twenty modifications were introduced in the guidelines. Implementations, based on prospectively collected data, varied widely; exemplified with around one quarter of the patients not treated according to a specific guideline within one year from the introduction, to an almost immediate full implantation. CONCLUSIONS: Modifications of the DBCG guidelines were generally well implemented, but the time to full implementation varied from less than one year up to around five years. Our data is registry based and does not allow a closer analysis of the causes for delay in implementation of guideline modifications.

Concurrent new drug prescriptions and prognosis of early breast cancer: studies using the Danish Breast Cancer Group clinical database.

BACKGROUND: Myriad reports suggest that frequently used prescription drugs alter the viability of breast cancer cells in pre-clinical studies. Routine use of these drugs, therefore, may impact breast cancer prognosis, and could have important implications for public health. METHODS: The Danish Breast Cancer Group (DBCG) clinical database provides high-quality prospectively collected data on breast cancer diagnosis, treatment, and routine follow-up for breast cancer recurrence. Individual-level linkage of DBCG data to other population-based and medical registries in Denmark, including the Danish National Prescription Registry, has facilitated large population-based pharmacoepidemiology studies. A unique advantage of using DBCG data for such studies is the ability to investigate the association of drugs with breast cancer recurrence rather than breast cancer mortality - which may be misclassified - or all-cause mortality. Here we summarize findings from pharmacoepidemiological studies, based on DBCG data, on the association between routinely used prescription drugs and risk of breast cancer recurrence. RESULTS: Our findings suggest that concurrent use of glucocorticoids, ACE inhibitors, aspirin, NSAIDs, selective COX-2 inhibitors, digoxin, and opioids has little impact on breast cancer recurrence. Similarly, patients who use SSRIs concurrently with tamoxifen treatment are not at increased risk of recurrence. In contrast, post-diagnostic use of simvastatin, a lipophilic statin, correlates with a decreased risk of breast cancer recurrence, providing a rationale for a prospective randomized clinical trial investigating simvastatin as an adjuvant therapy for breast cancer. CONCLUSION: As a whole, findings of pharmacoepidemiological studies based on DBCG data provide reassurance to physicians and healthcare personnel who provide supportive care during and after cancer (including prescriptions for comedications) and to breast cancer survivors for whom the risk of breast cancer recurrence is a major concern.

Forty years of landmark trials undertaken by the Danish Breast Cancer Cooperative Group (DBCG) nationwide or in international collaboration.

BACKGROUND: Over the past 40 years the Danish Breast Cancer Cooperative Group (DBCG) has made significant contributions to improve outcome and to make treatment of patients with early breast cancer more tolerable through nationwide and international trials evaluating loco-regional and systemic treatments. These trials have been instrumental to establish standards for the treatment of early breast cancer. METHODS: The DBCG 82 trials had a global impact by documenting that the significant gain in loco-regional recurrence from postmastectomy radiation added to systemic therapy was associated with a reduction in distant recurrence and mortality in high-risk pre- and postmenopausal patients. The DBCG trials comparing breast conserving surgery and radiotherapy with mastectomy and more recently the trial of internal mammary node irradiation also had a major impact of practice. The trials initiated by the DBCG 40 years ago on tamoxifen and cyclophosphamide based chemotherapy became instrumental for the development of adjuvant systemic therapy not only due to their positive results but by sharing these important data with other members of the Early Breast Cancer Trialist' Collaborative Group (EBCTCG). Trials from the DBCG have also been important for highlighting the relative importance of anthracyclines and taxanes in the adjuvant setting. Furthermore, DBCG has made a major contribution to the development of aromatase inhibitors and targeted adjuvant treatment for human epidermal growth factor receptor 2 positive breast cancers. RESULTS: The substantial impact of these treatment improvements is illustrated by a 46.7% 10-year overall survival of early breast cancer patients treated in 1978-1987 compared to 71.5% for patients treated 2008-2012. CONCLUSIONS: The trials conducted and implemented by the DBCG appear to have a major impact on the substantial survival improvements in breast cancer.

Breast conserving surgery versus mastectomy: overall and relative survival-a population based study by the Danish Breast Cancer Cooperative Group (DBCG).

BACKGROUND: Observational studies have pointed at a better survival after breast conserving surgery (BCS) compared with mastectomy. The aim of the present study was to evaluate whether this remains true when more extensive tumor characteristics and treatment data were included. METHODS: The cohort included patients registered after primary surgery for early invasive breast cancer in the database of the Danish Breast Cancer Cooperative Group, in the period 1995-2012. The cohort was divided into three groups: (i) patients who primarily had a mastectomy, (ii) patients treated by BCS, and (iii) patients who primarily had BCS and then mastectomy [intention to treat (ITT) by BCS]. The association between overall mortality and standard mortality ratio (SMR) and risk factors was analyzed in univariate and multivariate Poisson regression models. RESULTS: A total of 58,331 patients were included: 27,143 in the mastectomy group, 26,958 in the BCS group, and 4230 in the BCS-ITT group. After adjusting for patient and treatment characteristics, the relative risk (RR) was 1.20 (95% CI: 1.15-1.25) after mastectomy and 1.08 (95% CI: 1.01-1.15) after BCS first and then mastectomy, as compared to BCS. Statistically significant interactions were not observed for age, period of treatment, and nodal status, but patients with Charlson's Comorbidity Index (CCI) score 2+ had no increased mortality after mastectomy, as opposed to patients with CCI 0-1. Loco-regional radiation therapy (RT) in node positive patients did not reduce the increased risk associated with mastectomy [RR = 1.28 (95% CI 1.19-1.38)]. CONCLUSION: Patients assigned to BCS have a better survival than patients assigned to mastectomy. Residual confounding after adjustment for registered characteristics presumably explained the different outcomes, thus consistent with selection bias. Diversities in RT did not appear to explain the observed difference in survival after BCS and mastectomy.