New expert advice on cancer in pregnancy.

Cancer in pregnancy is rare, and most physicians lack knowledge in handling pregnant cancer patients. This review summarises the present knowledge on this condition. In the Netherlands, an Advisory Board on Cancer in Pregnancy was established in 2012. The board supports Dutch physicians' decisions in the management of pregnant patients with cancer. In 2021 the International Advisory Board on Cancer in Pregnancy was established, and in continuation, the Danish Advisory Board on Cancer in Pregnancy (DABCIP) has now been founded. DABCIP consists of 22 members from 13 different medical disciplines.

Real-World Survival and Treatment Regimens Across First- to Third-Line Treatment for Advanced Triple-Negative Breast Cancer.

Background: Metastatic triple-negative breast cancer (mTNBC) is an aggressive subtype of breast cancer with poor survival. Currently, the literature lacks comprehensive real-world evidence on locally recurrent and mTNBC patients. To validate the optimal treatment for patients with mTNBC, real-world evidence in combination with data from clinical trials must be evaluated as complementary. Objectives: The objective of the study is to examine outcomes and treatment patterns of patients with advanced triple-negative breast cancer (TNBC) utilizing real-world data of patients from all oncology sites across Denmark. Design: This is a retrospective, non-interventional, multi-site, population-based observational study conducted across all oncology departments in Denmark. Methods: We included all women diagnosed with metastatic or locally recurrent TNBC from January 1, 2017, to December 31, 2019, using the national Danish Breast Cancer Group database. The primary endpoints were overall survival (OS) and progression-free survival (PFS) in the first to third treatment line. Results: The study included 243 women diagnosed with metastatic or recurrent TNBC. The median OS (mOS) was 11.6 months after the first line of treatment, 6.5 months after the second line, and 6.5 months after the third line. De novo mTNBC was associated with shorter OS (mOS: 8.3 vs 14.2 months), and those with a relapse within 18 months of primary diagnosis had shorter OS than those with a relapse after 18 months (mOS: 10.0 vs 18.2). In the first line, taxane was the preferred choice of treatment for patients with de novo mTNBC, whereas capecitabine was preferred for patients with recurrent TNBC. Conclusions: This real-world, nationwide study demonstrated poor OS among patients with metastatic or recurrent TNBC, with a mOS of 11.6 months (95% CI, 9.9-17.3). Patients who presented with de novo mTNBC or who had a relapse of their breast cancer within 18 months of primary diagnosis had shorter OS. Registration: The study was registered and approved by the Danish Capital Regions research overview (P-2021-605).

Atezolizumab and nab-paclitaxel for advanced breast cancer in Danish real-world patients.

INTRODUCTION: The Danish Medicines Council recommends that patients with estrogen receptor and human epidermal growth factor receptor 2-negative, programmed death-ligand 1 (PD-L1)-positive advanced breast cancer receive atezolizumab in combination with nab-paclitaxel. The approval was largely based on results from Impassion130 that showed a beneficial progression-free survival (PFS) and overall survival (OS) in PD-L1-positive patients who received atezolizumab and nab-paclitaxel. METHODS: We conducted a retrospective, population-based study that included patients who received atezolizumab for advanced breast cancer from October 2019 to September 2022. The primary endpoints were PFS and OS. RESULTS: This study included 74 advanced breast cancer patients. Their median age was 54.5 years, and 21 (28.4%) of the patients had de novo advanced disease. Most patients received first-line treatment with atezolizumab (83.8%). The median PFS was 6.0 months (95% confidence interval (CI): 4.7-8.4 months) and the median OS was 14.3 months (95% CI: 9.9-22.2 months). A total of 48 patients received atezolizumab and nab-paclitaxel in accordance with guidelines from the Danish Medicines Council. CONCLUSIONS: This real-world study expectedly showed numerically lower survival outcomes than the phase III trial Impassion130, but met the standards of efficacy set by real-world studies in other countries. A need exists for increased attention to the criteria for receiving atezolizumab. FUNDING: none. TRIAL REGISTRATION: The study was approved by the Oncological Committee of the DBCG, the Research Overview of the Capital (P-2022-828) and the Centre for Health of the Capital Region (R-22060674).

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.

BACKGROUND: Between 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. AIM: To 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. METHODS: A 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. RESULTS: Overall 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]. CONCLUSION: The 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.

Symptom trajectories in breast cancer survivors: growth mixture analysis of patient-reported pain, fatigue, insomnia, breast and arm symptoms.

BACKGROUND: Variations in symptom development among breast cancer (BC) survivors are understudied. We examined: (Q1) Symptom trajectories of pain, fatigue, insomnia, breast, and arm symptoms in BC survivors, (Q2) possible patterns or cluster-like associations between trajectory classification of different symptoms, and (Q3) characteristics of survivors assigned to high-burden symptom trajectories. MATERIAL AND METHODS: Participants were 968 women (mean age = 59.6 years) treated for early-stage BC and followed across a three-year postoperative period. As part of routine follow-up procedures, patients reported symptom burden and functioning levels at each hospital visit using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the BC-specific module (QLQ-BR-23). Growth mixture modeling (GMM) analysis was used to differentiate potential subgroups of individuals with similar longitudinal symptom patterns, i.e., symptom trajectories (Q1). With this approach, groups experiencing persistent, highly distressing cancer- and treatment-related late effects (LEs) may be identified. Latent class analysis (LCA) was used for Q2 and logistic regression analysis for Q3. RESULTS: GMM identified two relatively parallel trajectories across the tested symptoms: The majority of the sample exhibited a low-burden symptom trajectory (74.4-89.2%) and a minority by a high-burden symptom trajectory (10.8-25.6%). LCA revealed that approximately one in five women (18.8%) were likely to be members of the high-burden symptom trajectory across all tested symptoms. In addition to a high probability of being burdened over time across multiple symptoms, these women were also characterized by poorer self-reported physical and social functioning. CONCLUSION: A substantial minority followed a high-burden symptom trajectory for several years following BC treatment. Associations were found in trajectory classification across symptoms, indicating that cancer-related LEs appear in clusters of multiple concurrent symptoms.

Patient-reported outcomes in postmenopausal breast cancer survivors - comparisons with normative data.

BACKGROUND: Survival rates for breast cancer (BC) are increasing, leading to growing interest in treatment-related late-effects. The aim of the present study was to explore late effects using Patient-Reported Outcome Measures in postmenopausal BC survivors in standard follow-up care. The results were compared to age- and gender-matched data from the general Danish population. MATERIAL AND METHODS: Postmenopausal BC survivors in routine follow-up care between April 2016 and February 2018 at the Department of Oncology, Aarhus University Hospital, Denmark were asked to complete the EORTC QLQ-C30 and BR23 questionnaires together with three items on neuropathy, myalgia, and arthralgia from the PRO-CTCAE. Patients were at different time intervals from primary treatment, enabling a cross-sectional study of reported late effects at different time points after primary treatment. The time intervals used in the analysis were year ≤1, 1-2, 2-3, 3-4, 4-5 and 5+. The QLQ-C30 results were compared with reference data from the general Danish female population. Between-group differences are presented as effect sizes (ESs) (Cohen's d). RESULTS: A total of 1089 BC survivors participated. Compared with the reference group, BC survivors reported better global health status 2-3 and 4-5 years after surgery (d = 0.26) and physical functioning 2-3 years after (0.21). Poorer outcomes in BC survivors compared with the reference group were found for cognitive functioning (0-4 and 5+ years), fatigue (0-2 years), insomnia (1-3 years), emotional functioning (3-4 years), and social functioning (≤1 year after surgery) with ESs ranging from 0.20 to 0.41. For the remaining outcomes, no ESs exceeded 0.20. CONCLUSION: Only small to medium ESs were found for better global health and physical functioning and poorer outcomes for cognitive functioning, fatigue, insomnia, emotional functioning, and social functioning in postmenopausal BC survivors, who otherwise reported similar overall health-related quality of life compared with the general Danish female population.

Understanding Differences in Cancer Survival between Populations: A New Approach and Application to Breast Cancer Survival Differentials between Danish Regions.

Large variations in cancer survival have been recorded between populations, e.g., between countries or between regions in a country. To understand the determinants of cancer survival differentials between populations, researchers have often applied regression analysis. We here propose the use of a non-parametric decomposition method to quantify the exact contribution of specific components to the absolute difference in cancer survival between two populations. Survival differences are here decomposed into the contributions of differences in stage at diagnosis, population age structure, and stage-and-age-specific survival. We demonstrate the method with the example of differences in one-year and five-year breast cancer survival between Denmark's five regions. Differences in stage at diagnosis explained 45% and 27%, respectively, of the one- and five-year survival differences between Zealand and Central Denmark for patients diagnosed between 2008 and 2010. We find that the introduced decomposition method provides a powerful complementary analysis and has several advantages compared with regression models: No structural or distributional assumptions are required; aggregated data can be used; and the use of absolute differences allows quantification of the survival that could be gained by improving, for example, stage at diagnosis relative to a reference population, thus feeding directly into health policy evaluation.

Inflammatory breast cancer: A review from our experience.

INTRODUCTION: Inflammatory Breast Cancer (IBC) is a distinct and rare type of breast cancer accounting for up to 6% of all breast cancer cases in Europe. The aim of this study was to investigate diagnostic methods, treatments, and outcome after IBC in patients treated at a single institution in Denmark. METHOD: All patients treated for IBC at Aarhus University Hospital between 2000 and 2014 were identified and included in the cohort. Survival was assessed using Kaplan-Meier curves and log-rank statistics. RESULTS: A total of 89 patients were identified with a median follow up of 3.6 years. The overall survival at 5 and 10 years were 41% and 18%, respectively. The disease free survival at 5 and 10 years were 47% and 27%, respectively. Thirty-four percent had distant metastasis at time of diagnosis. Patients with ER positive tumors had a significantly better overall survival than patients with ER negative tumors (p = 0.01). CONCLUSION: Despite a more aggressive systemic and loco-regional treatment today, IBC is still a very serious disease with a high mortality.

Adjuvant Cyclophosphamide and Docetaxel With or Without Epirubicin for Early TOP2A-Normal Breast Cancer: DBCG 07-READ, an Open-Label, Phase III, Randomized Trial.

Purpose Administration of anthracycline and taxane therapy in the adjuvant setting is considered a standard for breast cancer. We evaluated a non-anthracycline-based regimen in TOP2A-normal patients. Patients and Methods In this multicenter, open-label, phase III trial, 2,012 women with early TOP2A-normal breast cancer and at least one high-risk factor were randomly assigned to receive six cycles of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (DC) or three cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by three cycles of docetaxel (100 mg/m2; EC-D). The primary end point was disease-free survival (DFS) after a median of 5 years of follow-up. Secondary end points were patient-reported toxicity, overall survival (OS), and distant disease-free survival. Results At a median estimated potential follow-up of 69 months, 5-year DFS was 87.9% (95% CI, 85.6% to 89.8%) in the EC-D arm and 88.3% (95% CI, 86.1% to 90.1%) in the DC arm. There was no significant difference in the risk of DFS events (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00), distant disease-free survival (HR, 1.12; 95% CI, 0.86 to 1.47; P = .40), or mortality (HR, 1.15; 95% CI, 0.83 to 1.59; P = .41) in the intent-to-treat analysis. A significant interaction between menopausal status and treatment group was observed for DFS ( P = .04) but not for OS ( P = .07). Patients with grade 3 tumors derived most benefit from DC, and patients with grade 1 to 2 tumors derived most benefit from EC-D (DFS: interaction P = .02; and OS: interaction P = .03). Patients receiving EC-D reported significantly more stomatitis, myalgia or arthralgia, vomiting, nausea, fatigue, and peripheral neuropathy, whereas edema was more frequent after DC. Conclusion This study provides evidence to support no overall outcome benefit from adjuvant anthracyclines in patients with early TOP2A-normal breast cancer.

Short and long term radiation induced cardiovascular disease in patients with cancer.

Radiation-induced cardiovascular disease is well described as a late effect in cancer patients treated with radiation therapy. Advancements in surgery, radiotherapy, and chemotherapy have led to an increasing number of cancer survivors with resultant long-term side effects related to their cancer treatments. In this review, we describe the short- and long-term cardiovascular consequences of mediastinal radiotherapy and discuss the optimal cardiovascular assessments and diagnostic tools in asymptomatic and symptomatic patients.

Loco-regional morbidity after breast conservation and axillary lymph node dissection for early breast cancer with or without regional nodes radiotherapy, perspectives in modern breast cancer treatment: the Skagen Trial 1 is active.

BACKGROUND: Axillary lymph node dissection (ALND) and adjuvant radiotherapy (RT) in early breast cancer are associated with a risk of morbidity, including lymphedema and impaired shoulder mobility. The aim of this study was to evaluate loco-regional morbidity after breast conserving surgery (BCS), ALND, taxane-based chemotherapy and whole breast irradiation (WBI) with or without regional nodes RT. MATERIAL AND METHODS: Eligible patients had BCS and ALND from 2007 to 2012 followed by adjuvant taxane-based chemotherapy and if indicated, trastuzumab and endocrine treatment. The RT consisted of WBI and regional nodes RT in case of ≥ pN1 disease (group 1) and WBI only in case of pN0-1(mic) disease (group 2). The dose was 50 Gy in 25 fractions. The patients were invited to participate in a cross-sectional study evaluating morbidity. RESULTS: Of the 347 eligible patients, 277 patients (79%) accepted the invitation. Of these, 185 patients (67%) belonged to group 1 and 92 patients (33%) to group 2. The median time from RT to evaluation of morbidity was 3.3 years (group 1) and 4.3 years (group 2). In group 1, 34 patients (18%) and in group 2, 15 patients (16%) had ≥2 cm enlargement in circumference of ipsilateral upper or lower arm (p = .67). The frequence of impairment of ipsilateral shoulder abduction to ≤120° was 3% in both groups and of shoulder flexion to ≤120° was 1% and 2% (group 1 versus 2). No difference in patient reported outcome measure (PROM) data regarding heaviness or enlargement of ipsilateral upper and lower arm or mobility and sensory disturbances. CONCLUSION: The risk of lymphedema was low in patients after ALND and not related to use of regional nodes RT. Impairment of shoulder function was rare, and no differences in PROM were detected regarding use or not of regional nodes RT.

[Cardiovascular complications following thoracic radiotherapy in patients with cancer].

Cardiovascular complications following thoracic radiotherapy in patients with cancer are well described. Advancements in surgery, radiotherapy and systemic treatments have led to an increasing number of cancer survivors and thus an increasing number of patients with long-term side effects of their cancer treatments. This article describes the short- and long-term cardiovascular morbidity and mortality following thoracic radiotherapy and further, optimal cardiovascular assessments and diagnostic tools in asymptomatic and symptomatic patients.

Is regional nodes radiotherapy an alternative to surgery?

Sentinel node biopsy (SN) in breast cancer treatment was introduced in the mid-1990s in order to be able to stage patients before decision of definitive surgery. Since then, both the pathological examinations of the SN and the systemic adjuvant treatment have improved and cause new challenges in the correct decision making regarding whether or not to radically treat the axilla in case of a positive SN. In SN positive patients, current St. Gallen guidelines support no completion ALND (axillary lymph node dissection) in clinically node-negative patients with 1-2 macrometastatic sentinel nodes operated with breast conservation and receiving tangential field adjuvant radiotherapy (RT). ALND is being questioned due to increased morbidity compared with SN biopsy alone, and to limited long term benefit on disease free survival in selected patients. An alternative to ALND is treating the axilla with nodal RT although this treatment is mostly used as adjuvant treatment after ALND in high risk patients. Few studies have investigated the benefit of nodal RT compared to ALND, and no consensus has yet been reached. Clinical decision making regarding treating the axilla should be based on relevant data, and in this review studies aiming at deciding whether or not and how the axilla should be treated in SN positive patients will be discussed. Furthermore treatment choice will be discussed, since besides ALND, both breast irradiation and nodal irradiation might cure residual disease after SN. Also the issue of improved systemic adjuvant treatment will be discussed in relation to eventually no regional axillary treatment.

Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group.

PURPOSE: To examine the importance of estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER-2), and constructed subtypes in a large study randomly assigning patients to receive or not receive postmastectomy radiotherapy (PMRT). PATIENTS AND METHODS: The present analysis included 1,000 of the 3,083 high-risk breast cancer patients randomly assigned to PMRT in the Danish Breast Cancer Cooperative Group (DBCG) protocol 82 trials b and c. Tissue microarray sections were stained for ER, PgR, and HER-2. Median follow-up time for patients alive was 17 years. End points were locoregional recurrence as isolated first event, distant metastases, and overall survival. For statistical analyses four subgroups were constructed from hormonal receptors (Rec). Rec+ was defined as ER+ and/or PgR+. Rec-as both ER-and PgR-. The four subgroups were Rec+/HER-2-, Rec+/HER-2+, Rec-/HER-2-(triple negative), and Rec-/HER-2+. RESULTS: A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients (including the two Rec+ subtypes). No significant overall survival improvement after PMRT was found among patients with an a priori poor prognosis, the hormonal receptor-negative and HER-2+ patients, and in particular the Rec-/HER-2+ subtype. Furthermore, comparing hazard ratios and 95% CIs, significantly smaller improvements in locoregional recurrence control after PMRT were found for ER-and PgR-tumors compared with the ER+ and PgR+ tumors (P = .003 and .04, respectively), and for the triple-negative (P = .02), and the Rec-/HER-2+ subtypes (P = .003) compared with the Rec+/HER-2-subtype. CONCLUSION: Hormonal receptor status, HER-2, and the constructed subtypes may be predictive of locoregional recurrence and survival after postmastectomy radiotherapy.

[Loco-regional recurrence of breast cancer]. / Lokoregionalt recidiv af cancer mammae.

The treatment of loco-regional recurrence (LRR) after breast cancer is based on the achievement of loco-regional control by radical surgery and adjuvant postoperative radiotherapy. Antiestrogens used as treatment in patients with steroid receptor positive LRR can increase disease free survival. Adjuvant chemotherapy is not applied to patients with LRR who have had radical loco-regional salvage treatment. Further studies are needed to elucidate this issue.

Audit of the radiotherapy in the DBCG 82 b&c trials--a validation study of the 1,538 patients randomised to postmastectomy radiotherapy.

INTRODUCTION: In the DBCG 82 b&c trials 3083 patients with stages II and III breast cancer were randomised to receive postmastectomy radiotherapy (RT) versus no RT in addition to systemic therapy. The study showed a decrease in loco-regional recurrences and an improved survival in patients receiving RT. The aim of the present study was to describe the delivered RT for the 1538 patients who were randomised to RT, and to evaluate the compliance with the RT guidelines. PATIENTS AND METHODS: Basic information about the given RT was recorded in the DBCG data centre. For the current study, missing and additional information was collected from individual RT treatment charts. We defined some criteria for complying with the DBCG RT guidelines regarding target coverage and dose and fractionation and based on that we also defined some criteria for having clinically acceptable RT treatments. RESULTS: Of the 1538 patients, 87% received megavoltage RT, 8% had orthovoltage RT and 5% never began or completed RT. Of the 1341 megavoltage irradiated patients, the guideline compliance regarding target coverage of the axillary/periclaviculary region, internal mammary nodes and chest wall was 88, 79 and 85%, respectively. Only 0, 0.2 and 0.4% did not have clinically acceptable target coverage. The dose and fractionation was according to the guidelines in 96% and none had clinically unacceptable dose and fractionation schedules. CONCLUSION: The guideline compliance for megavoltage RT was high with 88, 79 and 85% complying with the guidelines regarding target coverage of the axillary/periclaviculary region, internal mammary nodes and chest wall, respectively, and with 96% complying with the guidelines regarding dose and fractionation schedules. Less than 1% had clinically unacceptable target coverage and none had unacceptable dose and fractionation schedules.