Estrogens administered in high doses were commonly used for therapy of advanced breast cancer before the introduction of contemporary endocrine therapy. While the mechanism of the antitumor effect is unknown, in vitro investigations have shown estrogens in high concentrations to be toxic to cell growth. Further, it has been shown that exposure of MCF-7 cells to estrogens in low concentrations may enhance the sensitivity and also lower the toxicity threshold to estrogens. This study was designed to evaluate treatment with diethylstilbestrol (DES) in postmenopausal women with advanced breast cancer becoming resistant to estrogen deprivation. Thirty-two patients with advanced breast cancer previously exposed to multiple endocrine treatment regimens (median 4, range 2-10) were enrolled. Their tumor should have revealed evidence of endocrine sensitivity (previous partial response or at least stable disease for > or = 6 months to therapy). Each patient received DES 5 mg t.i.d. Four patients terminated therapy after < or = 2 weeks on therapy due to side effects; another two patients terminated therapy before progression for similar reasons (one patient after SD for 15 weeks and one with a PR after 39 weeks). Four patients obtained CR and six patients PR. In addition, two patients had SD for > or = 6 months duration. Five patients had an objective response and one patient a SD lasting for > or = 1 year. Our results reveal estrogens administered in high doses may have antitumor effects in breast cancer patients heavily pretreated with endocrine therapy. Such treatment represents a valuable alternative to chemotherapy in selected patients.

No abstract

Objective: This systematic review aimed to determine the effectiveness of psychoeducation, cognitive behavioural therapy (CBT) and social support interventions used in the rehabilitation of breast cancer (BC) patients.Methods: We conducted a systematic literature search to identify randomised controlled trials of female BC patients who underwent different psychosocial interventions during or after primary cancer treatment. The methodological quality of all studies was independently assessed by two reviewers. Studies with low quality, less than 20 participants in each group, patients with metastatic cancer, data not presented separately for BC and studies that included other cancer types were excluded.Results: Among 9617 identified studies, only 18 RCTs published between 1999 and 2008, including 3272 patients were finally included in this systematic evaluation. Outcome measures were categorised into quality of life (QoL), fatigue, mood, health behaviour and social function. Six trials examined psychoeducation had inconsistent results, both during and after the primary treatment. Seven trials examined the effect of CBT, four of which given after primary treatment (range 6-12 weeks) demonstrated improvements in QoL; the other three CBT studies given during primary treatment (range 9-20 weeks) had inconsistencies. Five studies addressed social support and showed no conclusive impacts of this intervention.Conclusions: Limited documentation exists on the efficacy of psychosocial rehabilitation interventions among BC patients. However, we found that patients might have QoL benefits from CBT given after primary BC treatment. More documentation is needed regarding the effects of CBT during primary treatment and the effects of psychoeducation and social support.

BackgroundChemoresistance is the main obstacle to cure in most malignant diseases. Anthracyclines are among the main drugs used for breast cancer therapy and in many other malignant conditions. Single parameter analysis or global gene expression profiles have failed to identify mechanisms causing in vivo resistance to anthracyclines. While we previously found TP53 mutations in the L2/L3 domains to be associated with drug resistance, some tumors harboring wild-type TP53 were also therapy resistant. The aim of this study was; 1) To explore alterations in the TP53 gene with respect to resistance to a regular dose epirubicin regimen (90 mg/m2 every 3 week) in patients with primary, locally advanced breast cancer; 2) Identify critical mechanisms activating p53 in response to DNA damage in breast cancer; 3) Evaluate in vitro function of Chk2 and p14 proteins corresponding to identified mutations in the CHEK2 and p14(ARF) genes; and 4) Explore potential CHEK2 or p14(ARF) germline mutations with respect to family cancer incidence.Methods and FindingsSnap-frozen biopsies from 109 patients collected prior to epirubicin (as preoperative therapy were investigated for TP53, CHEK2 and p14(ARF) mutations by sequencing the coding region and p14(ARF) promoter methylations. TP53 mutastions were associated with chemoresistance, defined as progressive disease on therapy (p = 0.0358; p = 0.0136 for mutations affecting p53 loop domains L2/L3). Germline CHEK2 mutations (n = 3) were associated with therapy resistance (p = 0.0226). Combined, mutations affecting either CHEK2 or TP53 strongly predicted therapy resistance (p = 0.0101; TP53 mutations restricted to the L2/L3 domains: p = 0.0032). Two patients progressing on therapy harbored the CHEK2 mutation, Arg95Ter, completely abrogating Chk2 protein dimerization and kinase activity. One patient (Epi132) revealed family cancer occurrence resembling families harboring CHEK2 mutations in general, the other patient (epi203) was non-conclusive. No mutation or promoter hypermethylation in p14(ARF) were detected.ConclusionThis study is the first reporting an association between CHEK2 mutations and therapy resistance in human cancers and to document mutations in two genes acting direct up/down-stream to each other to cause therapy failure, emphasizing the need to investigate functional cascades in future studies.