Differential presentation and survival of de novo and recurrent metastatic breast cancer over time: 1990–2010

Background

Differences in de novo (dnMBC) and recurrent metastatic breast cancer (rMBC) presentation and survival over time have not been adequately described.

Methods

A retrospective cohort study, 1990–2010, with follow up through 2015 of dnMBC patients (stage IV at diagnosis) and rMBC patients with subsequent distant metastatic recurrence (stage I–III initial diagnosis) [dnMBC = 247, rMBC = 911)]. Analysis included Chi squared tests of categorical variables, Kaplan–Meier survival estimates, and Cox proportional adjusted hazard ratios (HzR) and 95% confidence intervals (CI). Disease specific survival (DSS) was time from diagnosis or distant recurrence to BC death.

Results

Over time, 1990–1998, 1999–2004, and 2005–2010, dnMBC incidence was constant (3%) and rMBC incidence decreased [18% to 7% (p < 0.001)] with no change in dnMBC hormone receptor (HR) or her2-neu (HER2) status but a decrease in rMBC HER2-positive cases and increase in triple negative breast cancer (HR-negative/HER2-negative) (p = 0.049). Five-year dnMBC DSS was 44% vs. 21% for rMBC (p < 0.001). Five-year dnMBC DSS improved over time [28% to 55% (p = 0.008)] and rMBC worsened [23% to 13%, p = 0.065)]. Worse DSS was associated with HR-negative status (HzR = 1.63; 1.41, 1.89), rMBC (HzR = 1.88; 1.58, 2.23), older age (70 +) (HzR = 1.88; 1.58, 2.24), > 1 distant metastases (HzR 1.39; 1.20, 1.62), and visceral dominant disease (HzR 1.22; 1.05, 1.43). After 1998, HER2-positive disease was associated with better DSS (HzR = 0.72, 95% CI 0.56, 0.93).

Conclusions

Factors associated with the widening survival gap and non-equivalence between dnMBC and rMBC and decreased rMBC incidence warrant further study.

     

Loco-regional treatment in metastatic breast cancer patients: Is there a survival benefit?

A number of studies have recently demonstrated a survival benefit in stage IV breast cancer patients following surgical resection of the primary tumor. Here, we investigate the relationship between loco-regional treatment and survival in patients with metastatic breast cancer and evaluate the impact of different loco-regional treatments. We conducted a systematic review of the literature using PubMed to analyze studies with the following criteria: Type of loco-regional treatment (surgery alone or combined with radiation, radiotherapy), overall survival, progression-free survival, selection factors for local treatment, and complication rates. Thirteen studies evaluated the effect of loco-regional treatment on overall survival with overall median survival increasing from a range of 12.6–28.3 months among patients without surgery to a range of 25–42 months among patients with surgery. In addition, six studies reported a 3-year survival benefit of 28–95% and 17–79% in women with and without loco-regional therapy respectively. Two studies did not find any improvement in overall survival. One study found an improvement in 5-year breast cancer-specific survival of 27% with negative surgical margins versus 12% with no surgery. Three studies reported an advantage in progression-free survival in the treatment group compared with the non-treatment group. Loco-regional treatment for breast cancer patients with distant metastases at diagnosis is an important issue because of possible improvement of survival or disease-free survival. The possibility of surgery and/or radiotherapy following induction chemotherapy should be weighed and left to individual practice. Participation in randomized controlled trials should be encouraged.     

Can patients with metastatic breast cancer be cured after introduction of newer and more effective agents?

Unlike early stage breast cancer, metastatic breast cancer (MBC) is generally considered incurable except for a small number of patients with oligometastatic disease. The goal of treatment of MBC should be the prolongation of life and improvement of symptoms and quality of life. The prognoses of patients with MBC, however, have been improved with the introduction of newer, more effective agents. Therefore, the clinical question arises whether MBC patients can be cured with these new therapeutic agents. However, there are a couple of problems in tackling this question, including the duration of follow-up and the presence of strong adjuvant therapy. Firstly, most trials in MBC have a relatively short follow-up; long-term surveillance (>3?C5?years) is exceptional, so little is known about the definitive outcome and the exact proportion of long-term survivors. Secondly, most of the patients have received pre- or postoperative adjuvant therapy. The cancer cells at metastatic sites are considered to be relatively resistant to the agents used in metastatic settings. Promisingly, a number of novel therapeutic agents including antibody?Cdrug conjugates, irreversible small molecule HER2-tyrosine inhibitors, and HER2 dimerization inhibitors show promise in the treatment of HER2-overexpressing MBC, as well as PARP-1 [poly(ADP-ribose) polymerase-1] inhibitors for triple-negative breast cancer.     

Adjuvant chemotherapy in elderly patients with breast cancer: where are we?

PURPOSE OF REVIEW: Breast cancer in elderly patients is a major health concern that will only increase in the future. For early-stage breast cancer, adjuvant chemotherapy may be indicated in this patient group following adequate local treatment and before possible hormone therapy. This review summarizes the current knowledge and provides guidelines for the use of adjuvant chemotherapy in elderly patients with breast cancer. RECENT FINDINGS: Most data are extracted from large multicenter trials with upper age limits of 65 or 70 years. Only one multicenter randomized study investigated the potential benefit of an adjuvant anthracycline-based chemotherapy regimen added to endocrine treatment after the age of 65 years. Retrospective analyses from international group databases show the same potential absolute benefit derived from adjuvant chemotherapy in elderly compared with younger patients, however. This benefit must be weighed against life expectancy and tolerability of chemotherapy. SUMMARY: Limited confidence of medical oncologists with cytotoxic chemotherapy administration to the elderly and a lack of both prospective studies and shared guidelines for decision making in this subpopulation are the main factors responsible for the limited use of adjuvant chemotherapy in elderly patients with breast cancer. Fortunately this contrasts with an increasing awareness among clinicians, who should learn to integrate absolute benefit, life expectancy, and tolerance of chemotherapy in their clinical decisions. Discrimination on the basis of older age alone is no longer acceptable.     

‘Tablet burden’ in patients with metastatic breast cancer

The implications for patients with cancer, of the ‘tablet burden’ resulting from increasing use of oral anticancer drugs and medication for co-morbidities have not previously been well explored.AimWe sought to (i) quantify tablet burden in women with metastatic breast cancer (MBC), (ii) establish which groups of drug contribute most to this burden and (iii) gain insight into patients' attitudes towards oral anti-cancer treatment.MethodsOne hundred patients with MBC anonymously completed a questionnaire describing their medication histories and attitudes towards their tablets.ResultsThe patients (mean age 60, range 31–95) were all female and taking a median of six tablets (range 0–31) daily; 37 patients were taking >10 tablets. Oral anticancer treatment constituted the category of treatment taken by the highest proportion of patients, followed by symptomatic cancer treatments, proton pump inhibitors and cardiovascular medication. Numerically, however, symptomatic drugs accounted for 44% of all tablets and specific anti-cancer treatment for 15%; medication not directly related to the cancer accounted for the remaining 40% of tablets. A quarter of patients reported inconvenience in taking their tablets, the main reason being tablet size and one third reported forgetting their tablets at least once a week. Nearly two thirds of patients expressing a preference favoured oral anticancer treatment, the commonest reason being greater convenience.ConclusionTablet burden is considerable for many patients with MBC and can be problematic. A significant proportion of tablets represent treatment for co-morbidities, the significance of which may be questionable in women with MBC.     

Erythropoietin-stimulating agents and clinical outcomes in metastatic breast cancer patients with chemotherapy-induced anemia: a closed debate?

Erythropoietin-stimulating agents (ESAs) are used in breast cancer patients with chemotherapy-induced anemia to alleviate anemia and in turn, reduce fatigue. These drugs may also decrease overall survival and increase the incidence of serious adverse effects such as thrombovascular events (TVEs). This review evaluates the evidence to date on administering ESAs to breast cancer patients with chemotherapy-induced anemia. Our findings suggest a clear need for well-designed clinical trials that follow current Food and Drug Administration (FDA) ESA label changes to guide clinical practice in an effort to reduce harm to these patients.     

Crosstalk between breast cancer stem cells and metastatic niche: emerging molecular metastasis pathway?

Metastatic colonization represents the final step of metastasis, and is the major cause of cancer mortality. Metastasis as an “inefficient” process requires the right population of tumor cells in a suitable microenvironment to form secondary tumors. Cancer stem cells are the only capable population of tumor cells to progress to overt metastasis. On the other hand, the occurrence of appropriate microenvironmental conditions within the target tissue would be critical for metastasis formation. Metastatic niche seems to be the specialized microenvironment to support tumor initiating cells at the distant organ. Master regulators not only determine cancer stem cell state, but also may have regulatory roles in metastatic niche elements. Meanwhile, both cancer stem cell and metastatic niche may function like two sides of the metastatic coin. Hypoxia inducible factors have multiple roles in regulation of both sides of this coin. TGF-β superfamily, also, have been considered as master regulators of epithelial to mesenchymal transition and metastasis and may play crucial roles in regulation of metastatic niche as well. In this regard, we hypothesize the presence of a possible emerging molecular pathway in the biological process of breast cancer metastasis. In this process, non-Smad TGF-β-induced metastasis connects cancer stem cell and metastatic niche formation through a central path, “Metastasis Pathway”.     

Weekly docetaxel (Taxotere?) in patients with metastatic breast cancer

Background:Docetaxel (Taxotere®) has demonstrated highantitumour activity in first- and second-line treatment of metastaticbreast cancer. This study analysed the efficacy and toxicity ofdocetaxel given weekly. Patients and methods:Thirty-five patients with metastatic breast cancer receiveddocetaxel, 35 mg/m² weekly for six weeks, followed by twoweeks without treatment. Additional cycles (three weekstreatment, two weeks rest) were given until disease progression.All patients had received prior chemotherapy: 32 and 5 patients hadreceived prior anthracycline-containing and taxane-containing regimens,respectively. Docetaxel was administered for a total of 359 doses(median 9, range 6–22). Results:There was onecomplete response (3%), 11 partial responses (31%), 17patients with stable disease (49%) and six with diseaseprogression (17%). Overall response rate was 34%(95% confidential interval (95% CI):18%–51%). Median survival was 307 days; medianprogression-free survival was 2.6 months (range 1.5 to 5.5 months).Three patients showed grade 3 neutropenia, 14 showed grade 3 alopecia,and various grade 1–2 non-haematological toxicities were observed.Treatment was delayed in two patients due to haematotoxicity, andstopped in one patient due to painful nail toxicity. Conclusion:Weekly administration of docetaxel at a dose of35 mg/m² is effective and of low toxicity in patients withmetastatic breast cancer.     

Is there association between handedness and radiosensitivity in breast cancer women?

Radiosensitivity is a biological response to radiation. This response depends on many factors such as radiation factors as well as biological system factors. It is shown that identical doses of radiation for the treatment of Cancer patients produce different biological responses that are assumed to be depend on different specifications of the biological systems. However, by elimination of these factors, people may still show different biological responses such as acute and low responses to radiotherapy in similar doses of radiation. Some reports indicate that breast cancer, immune diseases including autoimmune diseases such as lupus, Myasthenia Gravies and even the rate of allergy are more frequent in left-handed compared to right-handed individuals. The main goal of the present study is determination of radiosensitivity in left-handed compared to right-handed in breast cancer women by cytogenetic assay. Peripheral venous blood samples (10?ml) of 30 breast cancer women (10 left- and 20 right-handed) were divided into two identical parts. One part is exposed to 2?Gy Co-60 gamma rays, and the second part is considered as non-exposed controls. Lymphocytes were cultured in standard media, and cytokinesis blocked to score micronuclei in bi-nucleated cells. The frequency of micronuclei in 1,000 cells in each sample is considered as the rate of radiosensitivity and was compared in left- and right-handed breast cancer women by appropriate statistical analysis. Results showed that radiosensitivity index in left-handers is higher than right-handers also mean frequency of MN in exposed group of left-handers compare to right-handers is elevated. It seems that left-handed breast cancer women are more radiosensitive than right-handed. More investigations on right- and left-handed healthy people are ongoing in our laboratory.     

Is chemotherapy in elderly patients with metastatic or recurrent gastric cancer as tolerable and effective as in younger patients?

Aim: To analyze the chemotherapy regimens and outcomes of advanced gastric cancer (AGC) patients older than 70 years of age. Methods: Between May 2001 and October 2009, 1135 patients with metastatic or recurrent gastric cancer received palliative chemotherapy. Of these patients 56 (4.9%) were ≥70 years old and were analyzed retrospectively. Results: The median age at the time of first‐line chemotherapy was 73 years (range, 70–85) and the median Charlson comorbidity index was 0 (0–5). In all 17 patients (30%) received surgery with curative or palliative intent; 43 (77%) were treated by doublet or triplet first‐line chemotherapy regimens and 13 patients (23%) received single agent chemotherapy. Median progression‐free survival for first‐line chemotherapy was 3.97 months (95% CI 2.05–5.89) with an overall response rate of 26%. After the first‐line chemotherapy, only 18 of 56 (32%) patients received second‐line chemotherapy. The median overall survival (OS) was 12.4 months (95% CI 2.81–21.99). In multivariate analysis, receiving surgery and disease control for first‐line chemotherapy were independent prognostic factors for increased OS for all 56 patients. Conclusion: Patients older ≥70 years with metastatic or recurrent gastric cancer might achieve clinical benefit from chemotherapy. Receiving surgery and response of over more stable disease for first‐line chemotherapy were independent prognostic factors for increased OS.     

High incidence of central nervous system involvement in patients with?metastatic or locally advanced breast cancer treated with epirubicin?and?docetaxel

Background:Clinically overt central nervous system (CNS)involvement occurs in 10%–15% of patients with advancedbreast cancer. Patients and methods:The International Breast Cancer Study Group(IBCSG) conducted a dose-finding phase I trial of epirubicin (E) and docetaxel(D) as first-line therapy in advanced breast cancer patients. The study wasexpanded into a phase II at the recommended doses of E 90 mg/m² andD 75 mg/m² every three weeks. From July 1996 to May 1998, a totalof 92 patients (median age 50 years) entered the two studies. Results:Twenty-eight out of ninety-two patients treated with thecombination of E and D (30%) developed CNS metastases (95%confidence limits, 26%-35%), which were cerebral in twenty-fivepatients, leptomeningeal in two, and both in one. Of these 28 patients, 19(68%) had an objective response. Median time for the development of CNSmetastases from the start of chemotherapy was 15 months (range 5–42),if excluding the 6 patients presenting CNS progression within 3 months fromstart of treatment. It is notable that 11 patients (39%) hadprogression in the CNS only. Median survival from appearance of brainmetastases in the whole group was only three months (range 1–22).C-erbB-2 overexpression was found in 14 out of 16 patients (87%) inwhom the assay was performed (3+ in 10, 2+ in 1 and 1+ in 3 cases). Conclusions:As anthracycline- and taxane-containing regimens areincreasingly used both in the metastatic and in the adjuvant setting, acareful monitoring of any neurological symptom is advisable. Our preliminaryobservation on the possible increase of incidence of CNS involvement inpatients with advanced breast cancer receiving this effective drug combinationrequires further evaluation.     

Neoadjuvant chemotherapy in young breast cancer patients: correlation between response and relapse?

The aim of this analysis was to assess how the clinical response to chemotherapy corresponded to long-term prognosis in patients of less than 35 years of age. A retrospective analysis was made of response and survival data of 609 premenopausal patients who had been treated by four cycles of neoadjuvant chemotherapy followed by surgery and/or radiotherapy. Patients were stratified into three age groups (group 1, ≤35 years; group 2, 35–40 years; group 3, ≥41 years). Objective and complete clinical response rates were significantly higher in the youngest patients (below 35 yrs: P=0.005 and P=0.001, respectively) in stark contrast to a particularly poor outcome of this subpopulation. Five-year local recurrence rates were 31% in the youngest patients, compared with 26% and 16% in groups 2 and 3, respectively (P=0.0007). Group 1 patients also had significantly higher 5-year metastatic relapse rates (41% versus 35% and 28%; P=0.007) and 5-year survival figures were 70%, 82% and 84% for groups 1, 2 and 3 respectively (P=0.002). Finally, stratification by age and by response revealed that, whilst the outcome of the youngest patients was highly dependent on their response to primary chemotherapy, complete responders showed disease-free survival rates at 5 years that were lower than these of older patients, whatever their response. Despite a seemingly better control of the primary tumour by chemotherapy, the patients in the youngest age group remained at a high risk for local and metastatic relapse. This apparent paradox may be in part attributable to rapid disease progression of micrometastatic tumour subpopulations that are refractory to chemotherapy.     

Dose-escalation phase I study in metastatic breast cancer patients with combination of paclitaxel and tegafur·uracil

The study present the results of the dose-setting study of concomitant weekly administration of paclitaxel and tegafur·uracil (UFT) for metastatic breast cancer. Eligible patients who entered the study underwent two or more courses of weekly paclitaxel + UFT therapy as the protocol therapy. The initial dose (level 1) was paclitaxel, 80 mg/m(2) and UFT, 400 mg/day. At level 2, paclitaxel remained the same, but UFT was increased to 600 mg/day. At level 3, only paclitaxel was increased to 90 mg/m(2). Twelve patients were enrolled in this study between September 2000 and September 2002. Three patients were assigned to level 1. Grade 3 liver dysfunction (increased aspartate aminotransferase and alanine aminotransferase) was noted in one patient and grade 4 neutropenia was noted in one patient, showing that dose-limiting toxicity was detected in 2/3 patients. In accordance with the protocol, UFT was fixed at 400 mg/day and paclitaxel was decreased to 60 mg/m(2) at level -1, and then increased to 70 mg/m(2) at level 0. The overall effective rate after completion of two courses was 33% (3/9) including one case of complete response and two cases of partial responses. The remaining patients presented with stable diseases and no patient had progressive disease. In this study, weekly paclitaxel with concomitant UFT was administered. The recommended doses of paclitaxel and UFT were determined to be 70 mg/m(2) and 400 mg/day, respectively. As the toxicity profile shows, the highest toxicity level of this regimen was neutropenia and liver dysfunction, and dose-limiting toxicity was neutropenia.     

Neoadjuvant endocrine therapy of breast cancer: which patients would benefit and what are the advantages?

Aromatase inhibitors (AIs) were more effective than tamoxifen as a neoadjuvant endocrine therapy (NAE) for postmenopausal women with estrogen receptor (ER)-positive breast cancer. Neoadjuvant AIs were shown to reduce tumor volume and to allow the performance of breast-conserving surgery (BCS) in cases that would normally require mastectomy. Predictive markers of neoadjuvant AIs may be ER-rich, progesterone receptor (PgR)-rich and human epidermal growth factor receptor 2 (HER2)-negative tumors. However, the ability of HER2 expression to predict a response to neoadjuvant AIs is controversial. Pathological tumor size, nodal status, Ki67 level, and ER score are predictive for the survival of postmenopausal women with breast cancer who have been treated with NAE. These factors could be useful in order to select patients who do not require chemotherapy. Indeed, neoadjuvant AIs are a potential treatment option for postmenopausal women with ER-rich breast cancer who prefer BCS despite having large tumors suitable for mastectomy.