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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. IMPACT: CRP measures before treatment might be used to individualize follow-up of patients with early-stage breast cancer.

Current treatment landscape of HR+/HER2- advanced breast cancer in the Nordics: a modified Delphi study.

BACKGROUND: This Delphi study aimed to assess current perspectives on hormone receptor-positive/human epidermal growth factor receptor 2-negative(HR+/HER2-) advanced breast cancer (aBC) treatment strategies across the Nordics, and to establish where consensus exists across the Nordics on HR+/HER2- aBC treatment. MATERIAL AND METHODS: A modified, three-round Delphi method was followed. A steering committee was appointed for study coordination, panellist selection, and questionnaire development. The questionnaires covered relevant topics on HR+/HER2- aBC treatment: treatment patterns in different lines of therapy (first [1L], second [2L], and third [3L]), oligometastatic disease, de novo aBC, brain metastases, age as influential factor, visceral crisis, radiotherapy, diagnostics, and clinical guidelines. Both open and closed-ended questions were included. Consensus was defined as at least 70% agreement. RESULTS: In total, 28 experienced BC oncologists participated in the study from all five Nordic countries. Overall, topics reaching consensus included: preferred treatment approach in 1L and 2L therapy, treatment of oligometastatic disease, visceral crisis, brain metastases, and age-related treatment considerations. No consensus was reached for 3L therapy and local treatment for primary tumour in de novo aBC. Endocrine therapy (ET) combined with a cyclin-dependent kinase (CDK)4/6 inhibitor was the treatment of choice for 1L and 2L therapy. Treatment patterns in clinical practice did not always follow recommendations in current Nordic guidelines, as seen in the case of recently approved treatments. DISCUSSION: ET in combination with a CDK4/6 inhibitor is the preferred frontline treatment for HR+/HER2- aBC in the Nordics. The observed discrepancy between current guidelines and clinical practice could be due to differences in the reimbursement of novel treatments in the Nordics. Collaborative research efforts are warranted for topics that lack consensus.

Physical deterioration and adaptive recovery in physically inactive breast cancer patients during adjuvant chemotherapy: a randomised controlled trial.

Cardiorespiratory fitness is an independent risk factor for cardiovascular disease and shortened life expectancy in breast cancer survivors. This randomised controlled trial (n = 153) was designed for patients with a physically inactive lifestyle prediagnosis and concurrently referred to adjuvant chemotherapy. We compared two 12-week exercise interventions aimed at physiological and patient-reported outcomes (cardiorespiratory fitness, muscle strength, metabolic markers, physical activity, pain, fatigue), including a 39-week follow-up. A supervised hospital-based moderate to high intensity group exercise intervention was compared to an instructed home-based individual pedometer intervention. The two 12-week interventions included oncologists' recommendations and systematic health counselling. Outcomes were measured at baseline and week 6, 12 and 39. Primary outcome cardiorespiratory fitness declined significantly during chemotherapy and was restored in both interventions at follow-up. The interventions effectively engaged breast cancer patients in sustaining physical activities during and following adjuvant treatment. A composite metabolic score improved significantly. Positive cardiorespiratory fitness responders had improved clinical effects on fatigue, pain and dyspnoea versus negative responders. We conclude that a loss of cardiorespiratory fitness among physically inactive breast cancer patients may be restored by early initiated interventions and by adapting to physical activity recommendations, leading to a decreased cardiovascular risk profile in breast cancer survivors.

Heavy-load resistance exercise during chemotherapy in physically inactive breast cancer survivors at risk for lymphedema: a randomized trial.

Background: Due to long-standing concerns that heavy-load lifting could increase the risk of developing lymphedema, breast cancer survivors have been advised to refrain from resistance exercise with heavy loads. This study prospectively evaluated the effect of heavy-load resistance exercise on lymphedema development in women receiving chemotherapy for breast cancer.Material and Methods: Physically inactive women receiving adjuvant chemotherapy for breast cancer (n = 153) were randomized to a HIGH (supervised, multimodal exercise including heavy-load resistance exercise: 85-90% 1 repetition maximum [RM], three sets of 5-8 repetitions) versus LOW (pedometer and one-on-one consultations) 12-week intervention. Outcomes (baseline, 12 and 39 weeks) included lymphedema status (extracellular fluid [bioimpedance spectroscopy] and inter-arm volume % difference [dual-energy X-ray absorptiometry], lymphedema symptoms [numeric rating scale 0-10]), upper-extremity strength (1 RM), and quality of life domains (EORTC- BR23). Linear mixed models were used to evaluate equivalence between groups for lymphedema outcomes (equivalence margins for L-Dex, % difference and symptoms scale: ±5, ±3% and ±1, respectively). Superiority analysis was conducted for muscle strength and quality of life domains.Results: Postintervention equivalence between groups was found for extracellular fluid (0.4; 90% CI -2.5 to 3.2) and symptoms of heaviness (-0.2; -0.6 to 0.2), tightness (-0.1; -0.8 to 0.6) and swelling (0.2; -0.4 to 0.8). Nonequivalence was found for inter-arm volume % difference (-3.5%; -17.3 to 10.3) and pain (-0.7; -1.3 to 0), favoring HIGH. Strength gains were superior in the HIGH versus LOW group (3 kg; 1 to 5, p < .05). Further, clinically relevant reductions in breast (-11; -15 to -7) and arm (-6; -10 to -1) symptoms were found in the HIGH group.Conclusion: Findings suggest that physically inactive breast cancer survivors can benefit from supervised heavy-load resistance exercise during chemotherapy without increasing lymphedema risk. Trial registration: ISRCTN13816000.

Are previous episodes of bacterial vaginosis a predictor for vaginal symptoms in breast cancer patients treated with aromatase inhibitors?

Objective To estimate the prevalence of vaginal symptoms in postmenopausal women with breast cancer exposed to aromatase inhibitors, and to investigate if the risk of vaginal symptoms is associated with previous episodes of bacterial vaginosis. Methods Patients from Rigshospitalet and Herlev University Hospital, Denmark, were identified through the register of Danish Breast Cancer Cooperation Group and 78 patients participated in the study. Semiquantitave questionnaires and telephone interview were used to assess the prevalence of vaginal symptoms and previous episode(s) of bacterial vaginosis. Multivariable logistic regression models were used to assess the association between vaginal symptoms and previous episodes of bacterial vaginosis. Results Moderate to severe symptoms due to vaginal itching/irritation were experienced by 6.4% (95% CI: 2.8-14.1%), vaginal dryness by 28.4% (95% CI: 19.4-39.5%), and dyspareunia by 23.1% (95% CI: 11.0-42.1%). Patients with earlier episodes of bacterial vaginosis had an increased risk of vaginal dryness when exposed to a treatment with an aromatase inhibitor, adjusted OR 5.5 (95% CI 1.3-21.6). Conclusion A considerable number of patients exposed to aromatase inhibitor have vaginal symptoms and the risk is highest among patients with earlier episodes of bacterial vaginosis.

Performance of seven criteria to assess CA125 increments among ovarian cancer patients monitored during first-line chemotherapy and the post-therapy follow-up period.

AIM: To investigate seven CA125 criteria to monitor progressive ovarian cancer among patients with stage IC-IV disease. MATERIALS & METHODS: Four criteria were used to asses CA125 increments starting from concentrations ≥35 U/ml and three criteria to asses increments starting from concentrations <35 U/ml. RESULTS: A total of 231 patients were allocated to CA125 monitoring. The performances of the CA125 criteria were similar with sensitivities of 30-55%, negative predictive values of 28-46%, positive predictive values of 90-100% and median lead times of 26-87 days. CONCLUSION: The criteria showed low sensitivity and inability to exclude progressive ovarian cancer. The study suggests that CA125 information cannot stand alone but should be considered used in conjunction with other investigative procedures.

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.

Clinical Use of Cancer Biomarkers in Epithelial Ovarian Cancer: Updated Guidelines From the European Group on Tumor Markers.

OBJECTIVE: To present an update of the European Group on Tumor Markers guidelines for serum markers in epithelial ovarian cancer. METHODS: Systematic literature survey from 2008 to 2013. The articles were evaluated by level of evidence and strength of recommendation. RESULTS: Because of its low sensitivity (50-62% for early stage epithelial ovarian cancer) and limited specificity (94-98.5%), cancer antigen (CA) 125 (CA125) is not recommended as a screening test in asymptomatic women. The Risk of Malignancy Index, which includes CA125, transvaginal ultrasound, and menopausal status, is recommended for the differential diagnosis of a pelvic mass. Because human epididymis protein 4 has been reported to have superior specificity to CA125, especially in premenopausal women, it may be considered either alone or as part of the risk of ovarian malignancy algorithm, in the differential diagnosis of pelvic masses, especially in such women. CA125 should be used to monitor response to first-line chemotherapy using the previously published criteria of the Gynecological Cancer Intergroup, that is, at least a 50% reduction of a pretreatment sample of 70 kU/L or greater. The value of CA125 in posttherapy surveillance is less clear. Although a prospective randomized trial concluded that early administration of chemotherapy based on increasing CA125 levels had no effect on survival, European Group on Tumor Markers state that monitoring with CA125 in this situation should occur, especially if the patient is a candidate for secondary cytoreductive surgery. CONCLUSIONS: At present, CA125 remains the most important biomarker for epithelial ovarian cancer, excluding tumors of mucinous origin.

Monitoring performance of progression assessment criteria for cancer antigen 125 among patients with ovarian cancer compared by computer simulation.

BACKGROUND: Cancer antigen 125 (CA125) is used to monitor tumor burden among patients with advanced serous epithelial ovarian cancer. The purpose is to compare the monitoring performance of seven previously proposed criteria. MATERIALS & METHODS: The CA125 assessment criteria were applied to simulated datasets. We investigated the ability to provide information on CA125 increments as well as their robustness against false positive signals. RESULTS: For baseline concentrations above cut-off, the best performing criterion was based on a confirmed increment ≥2.5-times the nadir concentration. For baseline concentrations below cut-off, the best performing criterion was based on a confirmed increment from ≤ cut-off to >two-times cut-off. DISCUSSION: Computer simulation models may be useful for a preclinical validation of criteria to be investigated in clinical trials.

Clinical outcome of percutaneous RF-ablation of non-operable patients with liver metastasis from breast cancer.

PURPOSE: Despite improved anti-neoplastic treatment the prognosis for patients with liver metastases from metastatic breast cancer remains poor. MATERIALS AND METHODS: Thirty-two consecutive patients with metastatic breast cancer treated with radiofrequency ablation (RFA) at the Department of Oncology, Herlev Hospital, University of Copenhagen, from 1996 to 2010. RESULTS: Time to intrahepatic progression was median 11 months (range 1.6-184 months). Median survival after first RFA was 33.5 months. Survival at 1, 2 and 3 years was 87, 68 and 48 %, respectively. The local recurrence rate was 22 %. CONCLUSIONS: In this small, highly selected cohort we found RFA safe and efficacious with a low local recurrence rate and a median survival above that expected with systemic treatment. Our data are in line with previous studies and underscore the need for a large prospective study using optimal chemotherapy regimens and RFA/surgery to clarify whether intense treatment protocols can prolong survival for certain patient groups.

A systematic review of dual targeting in HER2-positive breast cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15-20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer. MATERIALS AND METHODS: A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included. RESULTS: This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described. CONCLUSION: Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.

Design of tumor biomarker-monitoring trials: a proposal by the European Group on Tumor Markers.

A major application of tumor biomarkers is in serial monitoring of cancer patients, but there are no published guidelines on how to evaluate biomarkers for this purpose. The European Group on Tumor Markers has convened a multidisciplinary panel of scientists to develop guidance on the design of such monitoring trials. The panel proposes a 4-phase model for biomarker-monitoring trials analogous to that in use for the investigation of new drugs. In phase I, biomarker kinetics and correlation with tumor burden are assessed. Phase II evaluates the ability of the biomarker to identify, exclude, and/or predict a change in disease status. In phase III, the effectiveness of tumor biomarker-guided intervention is assessed by measuring patient outcome in randomized trials. Phase IV consists of an audit of the long-term effects after biomarker monitoring has been included into standard patient care. Systematic well-designed evaluations of biomarkers for monitoring may provide a stronger evidence base that might enable their earlier use in evaluating responses to cancer therapy.

Effect of adding gefitinib to neoadjuvant chemotherapy in estrogen receptor negative early breast cancer in a randomized phase II trial.

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has shown both anti-proliferative and anti-tumoral activity in breast cancer. This study was designed to determine the effect of adding gefitinib to neoadjuvant epirubicin and cyclophosphamide (EC) on tumor response rates. Women with unilateral, primary operable, estrogen receptor negative invasive breast cancer ≥ 2 cm were eligible for inclusion. Randomized patients were to receive four cycles of neoadjuvant EC plus 12 weeks of either gefitinib (250 mg daily) or placebo. Primary endpoint was pathologic complete response (pCR), and secondary endpoints were complete response (CR) and overall objective response (OR). 181 patients were randomized. A pCR was observed in 17% (12/71) of patients treated with gefitinib and in 12% (9/73) of patients treated with placebo (4.57% difference, 95% CI -7.19 to 6.33; P = 0.44). CR was observed in 10% of patients in both the gefitinib (7/71) and the placebo group (7/73) (0.27% difference, 95% CI -9.6 to 10.2; P = 0.96). There was no significant difference in OR (5.96%; 95% CI -9.9 to 21.9; P = 0.45) between the two groups. Post hoc subgroup analysis showed a significant difference in pCR between triple negative breast cancer (TNBC) and non-TNBC tumors (P = 0.03). More patients in the gefitinib arm had hematological toxicity (P = 0.15) and discontinued treatment (9/94 vs. 2/86) because of adverse events (AE). Tumor response rates were similar in the two groups. A significantly higher pCR rate was observed post hoc in TNBC versus non-TNBC independent of treatment. More patients in the gefitinib group discontinued treatment because of AE.

[Treatment of elderly patients with breast cancer]. / Behandling af brystkraeft hos aeldre.

The latest investigations have been searched in order to present new guidelines for the treatment of elderly patients with primary breast cancer. It is concluded that breast-conserving surgery should be offered as well as the sentinel node technique. Axillary lymph node dissection is not necessary in the case of micrometastases. Adjuvant radiotherapy can be omitted in low risk cases. Endocrine treatment can be used in adjuvant and neo-adjuvant settings, but surgery should be offered as well. In high risk cases with receptor-negative tumour chemotherapy should be considered as an option. Generalized follow-up is recommended.

[Neoadjuvant antihormonal treatment of women with breast cancer]. / Neoadjuverende antihormonal behandling af kvinder med brystkraeft.

The main goal of neoadjuvant treatment for large operable or locally-advanced breast cancer is downstaging tumors. It may allow breast-conserving surgery on tumors that are unsuitable at initial presentation or convert some inoperable breast cancers into tumors that are operable. Neoadjuvant antihormonal therapy for receptor positive tumors is an effective and safe alternative to chemotherapy in elderly postmenopausal women. This paper presents an updated overview of the results from early phase II studies of neoadjuvant endocrine therapy, randomized trials of tamoxifen as primary treatment versus primary operation, and randomized phase III trials which compare tamoxifen and aromatase inhibitors.

[Antiestrogen treatment in postmenopausal patients with metastatic breast cancer]. / Antiøstrogenbehandling af postmenopausale patienter med metastaserende cancer mammae.

This review discusses the evidence for endocrine treatment in postmenopausal patients with metastatic breast cancer. First line treatment with non-steroid aromatase inhibitors (AI) yields response rates of 30% and improves progression free survival, but not overall survival, compared to tamoxifen. With second line treatment using steroid AI, estrogen antagonists or selective estrogen receptor modulators prolonged disease stabilisation is achieved in 40% of patients. With third line treatment using steroid AI and estrogen antagonists disease stabilisation is achieved in up to 30% of patients.

[Adjuvant antihormonal therapy for postmenopausal women with primary operable breast cancer]. / Adjuverende antihormonal behandling af kvinder med primaer operabel brystkraeft.

Adjuvant hormonal therapy results in substantial improvements in disease-free and overall survival for women with operable breast cancer. Many randomised trials of adjuvant tamoxifen have been published, and an updated overview of their results is presented in this paper. The third-generation aromatase inhibitors have recently been compared with tamoxifen. These studies are also reviewed in this paper. The Danish Breast Cancer Cooperative Group recommends adjuvant hormonal therapy consisting of tamoxifen for 2.5 years followed by the aromatase inhibitor for 2.5 years, or 5 years of the aromatase inhibitor for women with contraindications to tamoxifen.