National Cancer Institute®
Last Modified: May 1, 2002
UI - 11768602
AU - Mayfield S; Vaughn JP; Kute TE
TI - DNA strand breaks and cell cycle perturbation in herceptin treated breast cancer cell lines.
SO - Breast Cancer Res Treat 2001 Nov;70(2):123-9
AD - Wake Forest University Cancer Center, Winston-Salem, NC 27157-1072, USA.
BACKGROUND: Herceptin is a humanized antibody that binds to the product of the HER-2 oncogene. Clinical studies have indicated that treatment with Herceptin may slow disease progression in tumors expressing high levels of the HER-2 antigen. However, the mechanism of this action is not known. METHODS: Four different cell lines were used that had different levels of HER-2 expression. Treated and nontreated cells were analyzed for DNA strand breaks and cell cycle perturbation using standard flow cytometry methods. RESULTS: In this study we found that cell lines expressing high levels of HER-2, when treated with Herceptin, exhibited marked increases in DNA strand breaks as measured by the TUNEL assay, and that these cells also exhibited slowed growth. BT-474 and SKBR-3 cell lines, both of which express high levels of the HER-2 antigen, had significant increases in labeled nucleotide expression at 3 and 6 day time points following exposure to Herceptin at a concentration of 10 microg/ml. Similar treatment of MCF-7 and MDA-231 cell lines, both of which express low levels of HER-2, had little effect on the level of labeled nucleotide expression at either the 3 or 6 day time points. Following 4 days of Herceptin treatment, BT-474 and SKBR-3 cell lines had significant decreases in the percentage of cells in the S phase of growth. This effect was not seen in either the MCF-7 or MDA-231 cell lines. CONCLUSION: Herceptin has a biological effect only on cells that contain high levels of HER-2. This effect is a decrease in cell proliferation that is coincident with, and may be caused by an increase frequency of DNA strand breaks.
UI - 11818196
AU - Jakesz R; Hausmaninger H; Samonigg H
TI - Chemotherapy versus hormonal adjuvant treatment in premenopausal patients with breast cancer.
SO - Eur J Cancer 2002 Feb;38(3):327-32
AD - The Department of Surgery, University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria. email@example.com
Comparisons between the effects exerted by adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF)-based polychemotherapy and endocrine treatment in premenopausal breast cancer patients are validly drawn in the presence of steroid hormone receptor responsiveness. First, ovarian ablation still remains to show activity compared with chemotherapy in large patient groups. Second, tamoxifen is at least as active in this cohort and, by comparison, produces a significant effect in mortality reduction. Third, induction of reversible amenorrhoea by LHRH analogue administration has shown comparable effects in terms of recurrence-free survival. Finally, recent European investigations have indicated significant recurrence reductions with LHRH analogue-tamoxifen combination strategies. In conclusion, various endocrine treatment modalities have been substantiated as equiefficient to polychemotherapy. Tamoxifen added to a LHRH analogue further diminishes the recurrence rates and now appears to be a valid treatment alternative. We argue that selection of adjuvant systemic therapy for premenopausal breast cancer patients be increasingly guided by knowledge of the steroid hormone receptor levels.
UI - 11818200
AU - Del Mastro L; Costantini M; Morasso G; Bonci F; Bergaglio M; Banducci S;
TI - Viterbori P; Conte P; Rosso R; Venturini M Impact of two different dose-intensity chemotherapy regimens on psychological distress in early breast cancer patients.
SO - Eur J Cancer 2002 Feb;38(3):359-66
AD - Department of Medical Oncology, National Cancer Research Institute, Genova, Italy. firstname.lastname@example.org
In order to improve outcome, new, often more toxic chemotherapy regimens are continuously investigated in early breast cancer patients. Because the expected survival improvement is small, the possible increase in the negative effects of the new treatments should be carefully evaluated. Negative effects are represented not only by acute and chronic toxicity, but also by the adverse psychological impact of chemotherapy. The aim of this study was to evaluate the effect on patient-reported psychological distress of an increase in the dose-intensity of adjuvant chemotherapy compared with a standard regimen. Psychological distress was evaluated at baseline, during chemotherapy and after 6 and 12 months in breast cancer patients enrolled in a phase III multicentre study comparing the standard adjuvant chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil every 21 days (CEF21) with the same chemotherapy given every 14 days (CEF14). 392 patients were randomised in participating centres, and 363 were evaluable for this study. Overall, 1095 out of 1446 expected questionnaires (75.7%) were collected and evaluable. At baseline, the mean scores of psychological distress were similar in the two arms. During chemotherapy, a significantly higher psychological distress was observed in the CEF14 compared with the CEF21 arm (32.3 +/- 1.3 versus 27.6 +/- 1.3; P=0.009), as well as a higher cumulative incidence of anaemia, mucositis, diarrhoea, alopecia, bone pain and fatigue was observed in the CEF14 arm. In multivariate analyses, mucositis (P=0.01), asthenia (P=0.059), and CEF14 treatment (P=0.054) were independently associated with a higher psychological distress. After 6 months, psychological distress was again similar in the two arms and significantly lower when compared with baseline within each arm. A dose-intensive adjuvant regimen induces a higher, although transient, psychological distress in early breast cancer patients. Final results of the randomised trial will indicate whether such higher adverse effects of the dose-intensive regimen are counterbalanced by a higher efficacy of the experimental treatment in terms of survival.
UI - 11818202
AU - Burcombe RJ; Makris A; Pittam M; Lowe J; Emmott J; Wong WL
TI - Evaluation of good clinical response to neoadjuvant chemotherapy in primary breast cancer using [18F]-fluorodeoxyglucose positron emission tomography.
SO - Eur J Cancer 2002 Feb;38(3):375-9
AD - Marie Curie Research Wing, Mount Vernon Hospital, Rickmansworth Road, Middlesex HA6 2RN, Northwood, UK.
To determine whether [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) can predict complete pathological response (pCR) in patients achieving a good clinical response to neoadjuvant chemotherapy for primary breast cancer, 10 patients underwent FDG PET scanning prior to definitive breast surgery. Scan reports were compared with histopathological findings. No abnormal uptake at the primary tumour site was visualised in any patient. 9 of the 10 patients had residual invasive carcinoma at operation, ranging from 2 to 20 mm in maximum dimension. One patient achieved a complete pathological response. Of the 5 patients who underwent axillary surgery, no axillary FDG uptake was seen preoperatively although 3 of the 5 were histologically node-positive. FDG PET did not reliably identify residual disease in this series of good clinical responders to neoadjuvant chemotherapy, and its discriminatory power as a tool to predict complete pathological response therefore appears to be inadequate for clinical use in this setting.
UI - 11879565
AU - Gross JM; Yee D
TI - How does the estrogen receptor work?
SO - Breast Cancer Res 2002;4(2):62-4
AD - University of Minnesota Cancer Center, Department of Pharmacology, Minneapolis 55455, USA.
In breast cancer, interruption of estrogen receptor (ER)-alpha function is an effective therapeutic strategy. Despite the clinical benefit of interruption of ER-alpha function, the precise biological action of ER-alpha in breast tumors is not completely understood. Results of a recent study show that ER-alpha promotes growth of breast cancer cells by targeting expression of signaling components of the insulin-like growth factor system. Intriguingly, the authors of this study raise the possibility that unliganded ER-alpha itself may affect gene expression and breast cancer biology, and they suggest a potential mechanism for ER-alpha to stimulate proliferation in breast cancer.
UI - 11727972
AU - Hehl EM
TI - Opinion on the use of the antitumor drug trastuzumab (Herceptin) in patients with metastatic breast cancer in the county Mecklenburg-Vorpommern.
SO - Int J Clin Pharmacol Ther 2001 Nov;39(11):503-6
AD - Department Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Rostock, Germany. email@example.com
The recombinant humanized anti-HER-2 monoclonal antibody trastuzumab (Herceptin) is directed against the human epidermal growth factor receptor on the surface of breast cancer cells. Herceptin was approved involving women with metastatic breast cancer who had tumors overexpressing HER-2/neu. A prerequisite for its use is the diagnosis of the HER-2/neu receptor status in individual patients because trastuzumab is only effective in patients with a high (score +3) overexpression of the HER-2/neu receptor. The only approved diagnostic method is the immunohistochemical DAKO-Hercep test. Clinical experience with this novel biological agent has been obtained in 2 Phase III trials involving 469 and 222 patients, where trastuzumab was used as first- or second-line therapy. The addition of trastuzumab to chemotherapy regimens was associated with longer time to progression, a higher rate and duration of response and longer survival. When used as a single agent in metastatic breast cancer that had progressed after chemotherapy, there was an overall response rate of 15%. The median duration of response was 9.1 months and median survival was 13 months. Unwanted effects included potentially severe cardiotoxicity and in 40% of patients infusion-associated fever and/or shivering that usually occurred only during the first infusion. In patients with moderate HER-2/neu expression, unwanted drug effects outweigh a relatively weak therapeutic effect. In cases of high overexpression, the cancer may go into regression and survival may be prolonged with a relatively small impairment in the life quality. The costs of trastuzumab-therapy are high amounting to an additional 48,000 DM per patient per year. Recommendations for diagnosis and therapy in Mecklenburg-Vorpommern have been formulated in discussions between oncologists, practitioners, scientists and regulatory authorities.
UI - 11943196
AU - Mc Gee MM; Hyland E; Campiani G; Ramunno A; Nacci V; Zisterer DM
TI - Caspase-3 is not essential for DNA fragmentation in MCF-7 cells during apoptosis induced by the pyrrolo-1,5-benzoxazepine, PBOX-6.
SO - FEBS Lett 2002 Mar 27;515(1-3):66-70
AD - Biochemistry Department, Trinity College, 2, Dublin, Ireland.
Effector caspases-3, -6 and -7 are responsible for producing the morphological features associated with apoptosis, such as DNA fragmentation. The present study demonstrates that a member of a novel series of pyrrolo-1,5-benzoxazepines, PBOX-6, induces apoptosis in MCF-7 cells, which lack caspase-3. Apoptosis was accompanied by DNA fragmentation and the activation of caspase-7, but not caspases-3 and -6. Inhibition of caspase-7 activity reduced the extent of apoptosis induced, indicating that activation of caspase-7 is involved in the mechanism by which PBOX-6 induces apoptosis in MCF-7 cells. This study suggests that caspase-3 is not necessarily essential for DNA fragmentation and the morphological changes associated with apoptosis.
UI - 11850213
AU - Miller WR; Dixon JM; Cameron DA; Anderson TJ
TI - Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy.
SO - J Steroid Biochem Mol Biol 2001 Dec;79(1-5):103-7
AD - Department of Clinical Oncology, and Breast Unit, Western General Hospital, University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK. firstname.lastname@example.org
Postmenopausal women with large primary oestrogen receptor-rich (>20 fmol/mg protein or 80 histoscore) breast cancers have been treated neoadjuvantly with either letrozole (2.5 or 10 mg daily n=12 in each case) or anastrozole (1 or 10mg daily n=12 and 11, respectively). Tumour was available for analysis before treatment (wedge biopsy) and 3 months later at definitive surgery (wide local excision or mastectomy). Clinical response to treatment was assessed by sequential measurements of tumour volume based on caliper assessment, ultrasound and mammography. Results showed that in these selected groups of patients a reduction in tumour volume with treatment was observed in 43 of 47 cases (91%). Pathological responses, i.e. clear decrease in tumour cellularity or increased fibrosis was evident in 32 cases (68%). Furthermore, there was a decrease with therapy in immunohistochemical staining for Ki67 in all tumours. Staining for progesterone receptor (PgR) was reduced in all 21 PgR-positive cancers treated with letrozole and in 16 of 17 positive cancers treated with anastrozole. These effects are at least as great as those seen in a non-randomised group of patients treated with tamoxifen over the same time period (additionally tamoxifen treatment was often associated with an increase in PgR staining). The results suggest that potent specific aromatase inhibitors will be valuable in treating hormone-dependent cancers.
UI - 11850214
AU - Buzdar AU
TI - A summary of second-line randomized studies of aromatase inhibitors.
SO - J Steroid Biochem Mol Biol 2001 Dec;79(1-5):109-14
AD - Department of Breast Medical Oncology, M.D. Anderson Cancer Center, M.D. University of Texas, Box 424, 1515 Holcombe Blvd, Houston, TX 77030, USA. email@example.com
The new generation of selective aromatase inhibitors (anastrozole, letrozole and exemestane) offer a significant efficacy and safety advantage over both older agents in this class (aminoglutethimide) and the progestins (megestrol acetate (MA)), as second-line treatment for postmenopausal women with advanced hormone-dependent breast cancer who have failed on tamoxifen therapy. Exemestane, a steroidal aromatase inhibitor, has been shown to have activity after failure with the non-steroidal aromatase inhibitors, anastrozole and letrozole, and could be used as third-line treatment. Although the newer aromatase inhibitors belong to the same class and appear, from indirect comparisons, to have similar efficacy compared with the older therapies, they have different pharmacokinetic and pharmacodynamic profiles, suggesting the potential for clinical differences. Compared with exemestane and letrozole, anastrozole shows greater selectivity for aromatase, as it lacks any evidence of an effect on adrenal steroidogenesis and has no androgenic effects. Therefore, it is clear that these agents should not be considered to be similar in all respects. In summary, the introduction of the aromatase inhibitors represents a significant step forward in the treatment of advanced breast cancer in postmenopausal women. Studies in the adjuvant setting will ultimately determine whether the differences in pharmacokinetics and phamacodynamics will be of clinical relevance.
UI - 11850216
AU - Lonning PE
TI - Stepwise estrogen suppression manipulating the estrostat.
SO - J Steroid Biochem Mol Biol 2001 Dec;79(1-5):127-32
AD - Section of Oncology, Department of Medicine, Haukeland University Hospital, 5021, Bergen, Norway. firstname.lastname@example.org
Estrogen suppression is an effective endocrine treatment option in pre- as well as postmenopausal breast cancer patients. The fact that it produces clinical benefits not only in these two groups of patients that differ significantly with respect to plasma estrogen levels but also among patients with very low plasma estrogen levels due to previous hypophysectomy, adrenalectomy or treatment with first/second generation aromatase inhibitors, suggests estrogen deprivation to work independent of pretreatment plasma estrogen levels. Interestingly, in vitro studies have revealed MCF-7 cells to respond to estrogen deprivation by sensitization, causing maximum estradiol stimulation at a concentration 10(-5) to 10(-4) the concentration needed in wild-type cells. While results from recent phase III studies comparing novel aromatase inhibitors and inactivators to conventional therapy have suggested that a more effective hormone ablation may be translated into an improved clinical efficacy, the biochemical rationale for lack of complete cross-resistance between aromatase inhibitors and inactivators or aromatase inhibitors and megestrol acetate remains to be explained. Interestingly, patients becoming resistant to estrogen deprivation may still respond to estrogens administered in pharmacological doses. Future studies are warranted to explore alterations in gene expression and signaling mechanisms in response to different therapies in tumor tissue in vivo.
UI - 11850217
AU - Ragaz J
TI - Adjuvant trials of aromatase inhibitors: determining the future landscape of adjuvant endocrine therapy.
SO - J Steroid Biochem Mol Biol 2001 Dec;79(1-5):133-41
AD - British Columbia Cancer Agency, 600, West 10th Avenue, British Columbia, V5Z 4E6, Vancouver, Canada. email@example.com
This review will discuss the role of aromatase inhibitors (AIs) in the adjuvant setting, and will summarize major strategies behind individual adjuvant trials using aromatase inhibitors. Studies with the third generation AIs including anastrozole, letrozole and exemestane, have shown better outcome and improved therapeutic ratio over second line hormonal approaches (i.e. progestins or aminoglutethimide) and, more recently, over tamoxifen also. These promising results have led recently to testing of AIs in the adjuvant setting for postmenopausal patients. Most trials now in progress are evaluating the role of new AIs versus tamoxifen (T) given x 5 years, which in most institutions is currently the standard hormonal adjuvant therapy for breast cancer. Three adjuvant approaches are being tested. First is the use of AI+T x 5 years in combination versus each agent alone, as reflected in the recently completed ATAC trial. Second is a sequential approach T first x 2-3 years followed by AIs x 2-3 years, or the other way round; and third, T x 5 years followed by AIs for additional 5 years (i.e. total duration of adjuvant hormones of 10 years). Many patients in the above trials will survive their first cancer. Hence, the non-oncological outcomes known to be affected by hormones are of rising importance. Therefore, the assessment of lipids as surrogates for cardiovascular morbidity, and of bone mineral status, as a marker for osteoporosis/bone fractures, is an important component of these trials. Also discussed in this review are proposals for future studies of AIs with focus on hormone resistance, such as early alteration of multiple hormonal agents or their intermittent use, the impact of the new generation of SERMs or 'pure' antiestrogens on activity of AIs, and the rising importance of AIs interacting with biologicals, cytokines or hormone modulators.
UI - 11850227
AU - Robertson JF
TI - Faslodex (ICI 182, 780), a novel estrogen receptor downregulator--future possibilities in breast cancer.
SO - J Steroid Biochem Mol Biol 2001 Dec;79(1-5):209-12
AD - Nottingham City Hospital, Hucknall Road, NG5 1PB, Nottingham, UK. firstname.lastname@example.org
Tamoxifen is an effective treatment for breast cancer; however, as well as exerting antagonistic effects on the estrogen receptor (ER), tamoxifen acts as a partial agonists in estrogen-sensitive tissues, resulting in stimulation of the endometrium and tumor growth in some patients who become resistant to treatment.ICI 182, 780 (Faslodex), a steroidal estrogen antagonist, is the first in a new class of agent-an estrogen receptor downregulator. Pre-clinical breast cancer models show that ICI 182, 780 leads to a prolonged duration of response, and that it exerts its effects via a different mode of action to tamoxifen. This was confirmed in a small clinical study involving 19 post-menopausal advanced breast cancer patients, where ICI 182, 780 was highly effective after tamoxifen failure. Definitive evidence of the differing modes of action of ICI 182, 780 and tamoxifen, were provided in a study involving post-menopausal women with primary breast cancer, where analyses of tumor samples following short-term exposure to both drugs, showed that ICI 182, 780 reduced tumor ER levels in a dose-dependent manner, and to a significantly greater extent than tamoxifen. Additionally, unlike tamoxifen, ICI 182, 780 did not promote ER-mediated progesterone receptor expression, indicating that it lacks estrogen agonist activity.Ongoing studies in post-menopausal women with advanced breast cancer are comparing ICI 182, 780 to anastrozole and tamoxifen, respectively. Future studies being considered are whether ICI 182, 780 may also be effective in breast cancer in pre-menopausal women, in early breast cancer and in ductal carcinoma in situ in the breast, in combination with other hormonals, cytotoxics and biological modifiers.
UI - 11850229
AU - Howell A; Howell SJ; Clarke R; Anderson E
TI - Where do selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) now fit into breast cancer treatment algorithms?
SO - J Steroid Biochem Mol Biol 2001 Dec;79(1-5):227-37
AD - CRC Department of Medical Oncology, Christie Hospital NHS Trust, M20 4BX, Manchester, UK. email@example.com
The agents used for endocrine therapy in patients with breast cancer have changed markedly over the past decade. Tamoxifen remains the anti-oestrogen of choice, but could be replaced by the oestrogen receptor down-regulator ICI 182780 or by the fixed ring triphenylethylene arzoxifene (previously SERM III) soon. Whilst aminoglutethimide and 4-OH androstenedione were the aromatase inhibitors of choice, they have been replaced by non-steroidal (anastrozole and letrozole) and steroidal (exemestane) inhibitors of high potency and low side effect profile. Previously, often used treatments such as progestogens (megestrol acetate and medroxyprogesterone acetate) and androgens are now rarely used or confined to fourth or fifth line treatments. The LHRH agonist, goserelin, remains the treatment of choice for pre-menopausal patients with advanced breast cancer although recent randomised trials indicate a response, time to progression and survival advantage for the combination of goserelin and tamoxifen compared with goserelin alone.The newer treatments have led to questions concerning the optimum sequence of agents to use in advanced breast cancer and as neo-adjuvant and adjuvant therapy in relation to surgery. Two trials of anastrozole compared with tamoxifen and one trial of letrozole compared with tamoxifen indicate that the new triazole aromatase inhibitors have a significant advantage over the anti-oestrogen with respect to time to progression and survival. Similarly, triazole aromatase inhibitors give faster and more complete responses compared with tamoxifen when used in post-menopausal women before surgery.Major research questions remain with respect to the aromatase inhibitors used as adjuvant therapy. Anastrozole is being tested alone or in combination with tamoxifen compared with tamoxifen in the 'so-called' ATAC trial. Over 9000 patients have been randomised to this important study: the results will be available late-2001. A similar study comparing letrozole and tamoxifen started recently under the auspices of the Breast International Group. Importantly, this trial is also comparing the sequence of tamoxifen followed by letrozole (or vice versa). A similar trial of exemestane given after 2-3 years of tamoxifen compared with 5 years of tamoxifen is recruiting well as is a study comparing letrozole (or placebo) for 5 years after 5 years of adjuvant tamoxifen. These studies may show that aromatase inhibitors are superior to tamoxifen or that a sequence is preferable.ICI 182780 causes complete oestrogen receptor down-regulation leading to a the lack of agonist activity of the drug. Two trials of ICI 182780 compared with anastrozole for advanced disease will report later this year and a comparison with tamoxifen next year. Arzoxifene (SERM III) is being tested against tamoxifen. These studies are likely to result in new anti-oestrogens being introduced into the clinic.Most of our endocrine treatments deprived the tumour cell of oestradiol. In vitro experiments with MCF-7 cells indicate that tumour cells can adapt and then grow in response to low oestrogen concentrations in the tissue--culture medium. Importantly, the cells were shown to apoptose in response to high oestrogen concentrations. A recent clinical trial has demonstrated a high response rate to stilboestrol given after a median of four previous oestrogen depriving endocrine therapies. These data and the newer treatments available indicate a need to re-think our general approach to endocrine therapy and endocrine prevention.
UI - 11850211
AU - Boeddinghaus IM; Dowsett M
TI - Comparative clinical pharmacology and pharmacokinetic interactions of aromatase inhibitors.
SO - J Steroid Biochem Mol Biol 2001 Dec;79(1-5):85-91
AD - The Academic Department of Biochemistry, Royal Marsden Hospital, Fulham Road, SW3 6JJ, London, UK.
The clinical development of aromatase inhibitors (AIs) has been closely guided by clinical pharmacological investigations. During the early phases of development studies were focused on dose-related pharmacological effectiveness and specificity. More recently attention has been given to the metabolic changes which AIs elicit, with particular regard to their potential use in early breast cancer and the prophylactic setting. Pharmacological effectiveness has been studied with plasma oestrogen assays but primary oestrogens (E1 and E2) are not helpful in comparing the third generation inhibitors: anastrozole, letrozole, exemestane. All three of these compounds suppress whole body aromatisation by >96%. Most recently, we have established that significantly greater inhibition is achieved by letrozole than anastrozole at their clinically used dosages. This more complete inhibition is paralleled by significantly greater suppression of E1S.A broad panel of endocrine investigations has indicated that these compounds have essentially complete specificity at their clinical dosages. A minor androgenic effect of exemestane is revealed by a significant suppression of sex hormone binding globulin (SHBG). Lipid and bone biomarker data are being collected in many current studies. A pharmacokinetic interaction has been established between letrozole and tamoxifen, whereby reduced circulating levels of letrozole are found with combined application. Neither anastrozole nor letrozole have any effect on plasma concentrations of tamoxifen when given in combination with it.
UI - 11850212
AU - Miller WR; Dixon JM
TI - Local endocrine effects of aromatase inhibitors within the breast.
SO - J Steroid Biochem Mol Biol 2001 Dec;79(1-5):93-102
AD - Breast Unit, Department of Clinical Oncology, Western General Hospital, University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK. firstname.lastname@example.org
To determine the effects of aromatase inhibitors on oestrogen uptake, in situ aromatase activity and endogenous oestrogens in the breast, postmenopausal women with large primary ER-rich breast cancers have been treated neoadjuvantly for 3 months with either letrozole (2.5 or 10mg daily) or anastrozole (1 or 10mg daily) or exemestane (25mg daily). Patients were given an infusion of 3H-androstenedione and 14C-oestrone for 18h before and at the end of the study period. Blood, tumour and non-malignant breast were taken immediately after each infusion; oestrogens were extracted and purified. Tumour volume was measured before and during treatment at monthly intervals so that endocrinological changes could be related to clinical response. Treatment with each of the aromatase inhibitors was associated with a profound reduction in peripheral aromatase (as monitored by the level of plasma 3H-oestrone). There was no consistent effect on uptake of radioactively labelled oestrogen into breast tumours but a tendency for levels to increase after treatment in non-malignant breast. Conversely, therapy was associated with a marked inhibition of in situ oestrogen synthesis in both tumour and non-malignant breast (in occasional tissues, inhibitors appeared to be less effective but the effect was not related to clinical or pathological responses). Similar decreases were apparent in endogenous levels of oestrone and oestradiol. The absence of in situ aromatase activity tended to be associated with lack of clinical response to aromatase inhibition but the relationship was not absolute, limiting the utility of measurements of tumour aromatase as a predictive indices. Ex vivo studies of tissue aromatase indicated that such measurements consistently underestimate the inhibitory potential of reversible non-steroidal agents (and occasionally paradoxical in vitro increases in aromatase activity were seen with treatment). However, in situ assays demonstrate that new aromatase inhibitors such as anastrozole, exemestane and letrozole have profound effects on the local endocrinology within the postmenopausal breast, these being compatible with the clinico-pathological changes which occur with treatment.
UI - 11940467
AU - Campone M; Fumoleau P
TI - [Weekly administration of paclitaxel in the treatment of metastatic breast cancer: from rational to practice]
SO - Bull Cancer 2002 Mar;89(3):275-82
AD - Service d'oncologie, Centre Rene-Gauducheau, boulevard Jacques-Monod, 44805 Saint-Herblain Cedex.
Clinical studies showed that paclitaxel is active as single agent and in combination chemotherapy for the management of metastatic breast cancer. A variety of doses and administration schedules have been evaluated in phase II and III trials. Weekly administration of paclitaxel which is generally well tolerated increases the therapeutic index (efficacy/safety) resulting from anti-angiogenic and pro-apoptotic effects.
UI - 11943114
AU - Allweis TM; Boisvert ME; Otero SE; Perry DJ; Dubin NH; Priebat DA
TI - Immediate reconstruction after mastectomy for breast cancer does not prolong the time to starting adjuvant chemotherapy.
SO - Am J Surg 2002 Mar;183(3):218-21
AD - Center for Breast Health and the Department of Surgery, Washington Cancer Institute, Washington, DC, USA.
BACKGROUND: Immediate breast reconstruction is often performed after mastectomy for breast cancer. There has been concern that this will result in a delay in initiating chemotherapy and, as a consequence, may adversely impact survival. In this study we sought to determine whether immediate breast reconstruction affects the interval between surgery and adjuvant chemotherapy. METHODS: A single institution retrospective analysis was made using the institutional tumor registry and chart reviews. RESULTS: Forty-nine patients were identified who had undergone mastectomy with immediate reconstruction followed by adjuvant chemotherapy. They were compared with 308 patients undergoing mastectomy without reconstruction. Patients who underwent reconstruction were overall younger (46 versus 55, P <0.001), and had more advanced disease. The time to chemotherapy was significantly longer in the group receiving no reconstruction: 53 versus 41 days (P = 0.039). The type of reconstruction did not affect the time to chemotherapy. CONCLUSIONS: Immediate reconstruction after mastectomy does not increase the time to chemotherapy compared with mastectomy alone.
UI - 11977396
AU - Ost E; Illiger HJ
TI - [Comparison of epirubicin and cyclophosphamide in 2-dose levels and classical CMF protocol in node-positive breast cancer. An adjuvant Phase III trial]
SO - Strahlenther Onkol 2002 Jan;178(1):54-5
UI - 12004835
AU - Anonymous
TI - A better medication for treating breast cancer?
SO - Johns Hopkins Med Lett Health After 50 2002 May;14(3):3
UI - 11880131
AU - Juneja M; Jose R; Kekre AN; Viswanathan F; Seshadri L
TI - Tamoxifen-induced endometrial changes in postmenopausal women with breast carcinoma.
SO - Int J Gynaecol Obstet 2002 Mar;76(3):279-84
AD - Department of Obstetrics & Gynecology & Radiotherapy, Christian Medical College & Hospital, Vellore, India.
OBJECTIVES: To assess the effects of tamoxifen (TAM) on the endometrium in postmenopausal women. METHODS: A case control study of postmenopausal women with breast carcinoma, who were undergoing treatment in the Department of Radiotherapy and Surgery at the Christian Medical College Hospital, Vellore, India was done. Thirty-five women who were on tamoxifen (20 mg/day) for a period of at least 6 months formed the study group. Thirty-three women who were not receiving tamoxifen, formed the control group. Subjects in both groups had a pelvic examination and transvaginal sonogram followed by endometrial biopsy. RESULTS: There was a statistically significant difference in the mean endometrial thickness between the study group and control group (7.8+/-6.4 mm vs. 4.0+/-2.0 mm, respectively) More women in the tamoxifen group had an endometrial thickness of >5 mm but the number of women with polyps or hyperplasia of the endometrium did not differ significantly between the two groups. There were no women with endometrial carcinoma in either group. CONCLUSION: All patients on tamoxifen need to be evaluated by clinical examination annually. A transvaginal sonogram and endometrial biopsy/hysteroscopy may be performed on patients with abnormal vaginal bleeding, bloody discharge, staining or spotting.
UI - 11977645
AU - Liu X; Song S; Guan Z; Wu S; Duan Y; Yu J; Yang L
TI - [Capecitabine (xeloda) in the treatment of relapsed and metastatic breast cancer]
SO - Zhonghua Zhong Liu Za Zhi 2002 Jan;24(1):71-3
AD - 307 Hospital, Academy of Military Medical Sciences, Beijing 100039, China.
OBJECTIVE: To evaluate the response rate and adverse reactions of xeloda, an analogue of 5-fluorouracil, in the treatment of relapsed and metastatic breast cancer. METHODS: Twenty-two breast cancer patients who had recurrent and metastatic measurable foci were treated from Dec. 1999 to Feb. 2000. Xeloda was given, as a single drug, at a dose of or 2,510 mg/m2/d, bid, for two weeks followed by one week rest as one cycle, at least for one cycle in each patient. RESULTS: Among these 22 patients, there was no complete response. Rates of partial response 8(36.4%), stable disease 10(45.5%), progressive disease 4(18.2%), and clinical benefit response (CR + PR + SD) 18(81.8%). The response rate in patients who had failed in previous chemotherapy of taxanes and/or anthracycline was 30.0%-33.3%. The common adverse reactions were hand-foot syndrome, skin pigmentation, nausea, vomiting, anorexia and fatigue. Mild-moderate anemia and leukopenia were observed in 36.4% of patients. Stomatitis, dizziness, diarrhea and chest distress were present in some. One patient developed degree IV myelosuppression. Total bilirubin and alanine transaminase (ALAT) mild elevation occurred in a few patients. CONCLUSION: Xeloda is an effective drug in the treatment of patients with relapsed and metastatic breast cancer, especially for those who have failed in chemotherapy with taxanes and/or anthracycline. Xeloda is well tolerated but has mild adverse reactions.
UI - 10644098
AU - Ascher SM; Imaoka I; Lage JM
TI - Tamoxifen-induced uterine abnormalities: the role of imaging.
SO - Radiology 2000 Jan;214(1):29-38
AD - Department of Radiology, Georgetown University Medical Center, Washington, DC 20007-2197, USA. email@example.com
Tamoxifen citrate is an orally administered, nonsteroidal antiestrogen agent that is widely used for the treatment of breast cancer and that has recently been found to prevent breast cancer in some high-risk populations. Tamoxifen may, however, cause adverse effects at the uterine level. In this article, the authors review (a) the histopathologic uterine changes associated with tamoxifen therapy, (b) the spectrum of uterine imaging findings in women treated with tamoxifen, and (c) the recommendations of the American College of Obstetrics and Gynecology for women treated with tamoxifen. An algorithm for imaging evaluation of the uterus in women treated with tamoxifen is presented.
UI - 11977539
AU - Nomura Y; Tominaga T; Enomoto K; Aoyama H; Nakamura Y; Abe R; Sano M;
TI - Nomizu T; Tohge T; Takashima S; Ohashi Y [CGS 20267 (Letrozole), a new aromatase inhibitor: early phase II study for postmenopausal women with advanced breast cancer]
SO - Gan To Kagaku Ryoho 2002 Apr;29(4):551-62
AD - Dept. of Breast Surgery, National Kyushu Cancer Center.
A multicenter, open labeled, randomized early Phase II study for CGS 20267 was conducted at the doses 0.5 mg once daily and 1.0 mg once daily in postmenopausal women with advanced breast cancer. Sixty-four patients were randomly assigned to the doses of either 0.5 mg once daily (n = 33) or 1.0 mg once daily (n = 31). Thirty-one patients were eligible for 0.5 mg group, and 29 for 1.0 mg group. A total of 57 patients (30 in the 0.5 mg group and 27 in the 1.0 mg group) were eligible for the evaluation of efficacy. There were 3 CR, 5 PR, 5 stable disease (SD: NC lasting over 24 weeks), 7 NC and 10 PD in the 0.5 mg group. The objective response rate (ORR) was 26.7%. There were 4 CR, 7 PR, 8 SD, 3 NC and 5 PD in the 1.0 mg group. The ORR was 40.7%. A total of 57 patients (29 in the 0.5 mg group and 28 in the 1.0 mg group) were eligible for safety evaluation. Adverse clinical events related to CGS 20267 in the 0.5 mg group were headache, nausea, cold sweat, sleepiness and muscle ache in the lower extremities (2 patients, incidence rate 6.9%) whereas those in the 1.0 mg group were generalized itching and generalized hot feeling (2 patients, incidence rate 7.1%). All of the adverse events were grade 1 except the generalized itching which was grade 2. CGS 20267-related abnormalities in the laboratory tests for the 0.5 mg group were a decrease in WBC, and increases in GOT, GPT, LDH and gamma-GTP (5 patients, 14.3%) whereas those in the 1.0 mg group were increases in GPT, gamma-GTP, alkaline phosphatase, and total bilirubin (1 patient, 3.6%). The increases in GOT and GPT were grade 2, but others were grade 1. The data show both CGS 20267 0.5 mg once daily and 1.0 mg once daily to be effective and tolerable in the treatment of postmenopausal women with advanced breast cancer.
UI - 11977544
AU - Kuroi K; Tominaga T
TI - [Sustained complete response in lung metastasis of breast cancer by goserelin--report of two cases]
SO - Gan To Kagaku Ryoho 2002 Apr;29(4):589-94
AD - Breast Cancer Center, Toyosu Hospital, Showa University School of Medicine.
We report two patients with lung metastasis of breast cancer who had durable complete responses (CR) with goserelin. The first patient was a 48-year-old woman diagnosed with left breast cancer (T1N0M0, Stage I) at the age of 40, for which she underwent mastectomy. The tumor was estrogen receptor (ER) and progesterone receptor (PgR) positive. She received tamoxifen for 2 years as adjuvant therapy. After 8 years and 7 months, a lung metastasis was found by chest X-p, and treatment with goserelin was started. After 11 months of this treatment a CR was achieved, and the response lasted 3 years and 5 months. The second patient was a 38-year-old woman with a diagnosis of lung metastasis. She underwent right mastectomy at the age of 29 for breast cancer (T2N1M0, Stage IIB), and the tumor was ER and PgR positive. She received tamoxifen and doxifluridine for 2 years as adjuvant therapy. Eight years and 6 months after the mastectomy, a lung metastasis was found by chest X-p, and goserelin treatment was started. After 8 months of this treatment, chest X-p and CT revealed a complete regression of the lung metastasis, and response lasted 1 years and 7 months. Serum estradiol levels were suppressed below 10 pg/ml during the treatment in both patients. These results indicate the usefulness of LH-RH agonist in the treatment of recurrent breast cancer.
UI - 11836612
AU - Martin JH; Symonds A
TI - Synergistic antitumour effect of a combination of toremifene and interferon-alpha on ZR-75-1 human breast cancer cells: dependence on interferon-alpha subtype.
SO - Oncol Rep 2002 Mar-Apr;9(2):379-82
AD - Division of Biomedical Sciences, School of Applied Sciences, University of Wolverhampton, Wolverhampton, WV1 1SB, UK. firstname.lastname@example.org
We investigated the effect of toremifene, interferon-alpha2a, interferon-alpha2b and interferon-alpha2c, singly and in combination for their effect on the growth of ZR-75-1 human breast cancer cells. Median effect analysis was used to determine synergistic or additive effects. Anti-proliferative studies showed that the growth of ZR-75-1 cells was inhibited to a greater extent by combination treatment with toremifene plus interferon-alpha2a, resulting in a synergistic interaction (CI <1) for all concentrations tested. A combination of toremifene plus interferon-alpha2b resulted in a synergistic interaction (CI <1) for the two highest concentrations of toremifene (10(-6) and 10(-7) M) and an additive effect (CI approximately equal to 1) for the lower concentrations (10(-8) to 10(-10) M). When toremifene was combined with interferon-alpha2c no additive or synergistic interaction was determined.
UI - 11972458
AU - Alonso-Bartolome P; Ortega Garcia E; Garijo Ayensa F; de Juan Ferre A;
TI - Vega Bolivar A Utility of the tumor bed marker in patients with breast cancer receiving induction chemotherapy.
SO - Acta Radiol 2002 Jan;43(1):29-33
AD - Division of Radiology, University Hospital Marques de Vadecilla, Faculty of Medicine, Cantabria University, Avenida Valdecilla s/n, ES-39008 Santander, Spain.
PURPOSE: Induction or neoadjuvant chemotherapy is used in patients with locally advanced breast cancer to offer a higher rate of conservative surgery. The possibility of reduction in size, even in some cases complete clinical and mammographic regression, can make the localization of the tumor bed difficult at the time of surgery. The purpose of this study was to describe our experience about the utility of US-guided implantation of a metallic marker in patients with breast cancer before induction chemotherapy. MATERIAL AND METHODS: Forty-three patients with 44 masses were diagnosed with percutaneous biopsy of breast carcinoma. Before beginning of the induction chemotherapy all of them were referred for metallic marker placement. A metallic harpoon was placed under US guidance. RESULTS: One patient died during the chemotherapy. Six underwent mastectomy, and 9 still had a palpable tumor at the time of surgery. In the remaining 27 patients (with 28 lesions) pre-operative wire localization of the tumor bed was carried out: in 11 cases the harpoon was necessary for the localizati