Chemoendocrine Therapy For Breast Cancer Research Articles

Increased fracture rate in women with breast cancer: a review of the hidden risk

BackgroundWomen with breast cancer, particularly individuals diagnosed at a relatively early age, have an increased incidence of fractures. Fractures can have serious clinical consequences including the need for major surgery, increased morbidity and mortality, increased cost of disease management, and reduced quality of life for patients. The primary cause of the increased fracture risk appears to be an accelerated decrease in bone mineral density (BMD) resulting from the loss of estrogenic signaling that occurs with most treatments for breast cancer, including aromatase inhibitors. However, factors other than BMD levels alone may influence treatment decisions to reduce fracture risk in this setting. Our purpose is to review current evidence for BMD loss and fracture risk during treatment for breast cancer and discuss pharmacologic means to reduce this risk.ResultsFracture risk during treatment for breast cancer may be influenced by the rate of BMD loss and the consequent rapid alterations in bone microarchitecture, in addition to the established fracture risk factors in postmenopausal osteoporosis. The rapid decrease in BMD during adjuvant chemoendocrine therapy for breast cancer may necessitate more aggressive pharmacotherapy than is indicated for healthy postmenopausal women who develop osteoporosis. Over the last few years, clinical trials have established the effectiveness of bisphosphonates and other antiresorptive agents to preserve BMD during adjuvant therapy for early breast cancer. In addition, some bisphosphonates (eg, zoledronic acid) may also delay disease recurrence in women with hormone-responsive tumors, thereby providing an adjuvant benefit in addition to preserving BMD and potentially preventing fractures.ConclusionsIt is likely that a combined fracture risk assessment (eg, as in the WHO FRAX algorithm) will more accurately identify both women with postmenopausal osteoporosis and women with breast cancer who require bone-protective therapy.

Predictive implications of nucleoside metabolizing enzymes in premenopausal women with node-positive primary breast cancer who were randomly assigned to receive tamoxifen alone or tamoxifen plus tegafur-uracil as adjuvant therapy

Recent studies have demonstrated that tegafur-uracil (UFT) is useful for the adjuvant treatment of various types of cancers. To determine whether nucleoside metabolizing enzymes could be used to predict the response to UFT treatment in women with primary breast cancer, we retrospectively analyzed archived tumor tissue samples obtained from the 3rd Adjuvant Chemo-Endocrine Therapy for Breast Cancer (ACETBC) study, in which adjuvant treatment with tamoxifen (TAM) plus UFT for 2 years was compared with TAM alone for 2 years. Samples of tumor tissue were obtained from 192 premenopausal women with node-positive invasive breast cancer. The tissue samples were examined immunohistochemically to study the expression of thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), as well as the expression of Her2 and p53. In patients with TS-positive tumors, the risk of relapse was significantly lower in the tamoxifen plus UFT group than in the tamoxifen alone group. After 2 years, however, there was a trend towards a decrease in the relative predictive value (RPV) of TS with time. No relationship to outcome was detected for TP or DPD. Expression of Her2 or p53 was a significant prognostic indicator in the tamoxifen alone group. TS, but not TP or DPD, may be a useful predictor of response to UFT therapy. After 2 years, the RPV of TS decreased with time, suggesting that 2 years of treatment with oral fluorouracil derivatives may be inadequate. Further studies are required to investigate this possibility.

396 Randomized controlled study comparing surgery alone, surgery plus tamoxifen, and surgery plus tegafur-uracil in patients with node-negative breast cancer: 5-year results from the Kanto cooperative study group of adjuvant chemo-endocrine therapy for breast cancer (ACETBC) of Japan

Although systemic therapy is one of the cornerstones of therapy for premenopausal women with early stage breast cancer, there remain many unknowns regarding its optimal use. By accident of clinical trial design, much clinical investigation in premenopausal women has focused on chemotherapy. More recently the value of endocrine therapy (tamoxifen and ovarian suppression/ablation via surgery, LHRH agonists, or chemotherapy-induced menopause) has become apparent, and some form of endocrine therapy is viewed as standard for virtually all premenopausal women with early stage invasive breast cancer that expresses estrogen and/or progesterone receptor. Critical open questions include type and duration of endocrine therapy and the development of prognostic/predictive markers to help identify patients who are likely to benefit from chemotherapy in addition to endocrine therapy. For some years, five years of tamoxifen has been viewed as the standard endocrine therapy for premenopausal hormone-responsive breast cancer, although the ATLAS trial suggests that an additional five years of tamoxifen can be considered. The MA17 trial also suggests that an additional five years of an aromatase inhibitor can be considered for women who become postmenopausal during tamoxifen therapy. Information about the value of ovarian suppression continues to emerge, most recently with the demonstration of excellent outcome with goserelin plus tamoxifen in the ABCSG12 trial. The SOFT and TEXT trials, whose accrual is now complete, should help to define optimal endocrine therapy. In addition, use of the 21-gene recurrence score assay may help to delineate the additional value of chemotherapy for patients with node-negative breast cancer, and its utility in the setting of women with 1–3 positive lymph nodes is under study in the RxPONDER trial. Nonetheless, the need for other predictive biomarkers to select appropriate therapy remains real. Finally, attention to long term benefits and side effects of therapy will continue to be vital for these young women.

Adjuvant chemo-endocrine therapy for breast cancer: Combined or sequential?

Adjuvant chemo-endocrine therapy for breast cancer: Combined or sequential?

Axillary lymph node scarring and the association with tumour response following neoadjuvant chemoendocrine therapy for breast cancer

We observed that the axillary lymph nodes of some of our breast cancer patients who received neoadjuvant chemoendocrine therapy (NCT) showed evidence of scarring. The purpose of this study is to determine whether such scarring exists and, if so, whether it is confined to neoadjuvant patients and may be related to response to therapy of the primary tumour. We examined the axillary lymph nodes of a consecutive series of 255 breast cancer patients, all of whom had undergone radical axillary dissection. Fifty-three had received NCT; the remainder formed the control group. A scar was defined as an area of cellular fibrous tissue>0.25 mm in diameter and for each patient scar count, median size and score were recorded. Nodes with scars were stained immunohistochemically (IHC) with 2 epithelial markers for the presence of occult micrometastases. The nodes of 20.7% of patients who had received NCT contained scars compared with 13.4% of controls. The median scar size was significantly greater in neoadjuvant patients (P<0.001) and within this group scar count and score were significantly higher (P=0.026 and 0.020) in those with no or minimal evidence of residual primary tumour. Scars which were IHC-positive for micrometastases were almost exclusively confined to neoadjuvant patients. Our results suggest that axillary lymph node scarring does exist, but is not a common phenomenon. It is more significant in neoadjuvant patients and within this group is most marked in those with the greatest primary tumour response to therapy. We believe that scarring is likely to represent downstaging of axillary disease. A prospective study involving a larger group of patients receiving NCT is indicated, to confirm these preliminary findings and establish whether scarring has prognostic or predictive potential.

Meta-Analysis of the Second Collaborative Study of Adjuvant Chemoendocrine Therapy for Breast Cancer (ACETBC) in Patients with Stage II, Estrogen-Receptor-Positive Breast Cancer.

The second 5-year study of postoperative adjuvant therapy in patients with breast cancer between 1985 and 1988 was performed by the Study Group for Adjuvant Chemoendocrine Therapy for Breast Canecr (ACETBC). This report describes the results of a meta-analysis of the outcome. A total of 3012 patients with stage II, estrogen-receptor-positive primary breast cancer who underwent radical surgery (total mastectomy with at least axillary dissection) were eligible for the analyses. On the day of surgery, all patients received 13 mg/m(2) of mitomycin C (MMC) intravenously. Patients were then given one of two adjuvant chemoendocrine therapies for 2 years:regimen A, consisting of tamoxifen citrate (TAM) 30 mg/day, or regimen B, consisting of TAM 30 mg/day plus tegafur (Futraful, FT)600 mg/day. The results from all eligible patients were included in a meta-analysis according to the method of Peto et al. The odds reduction rate was 12 +/-13% (log-rank test, P= 0.35)for the 5-year survival rate and 16 +/- 10% (log-rank test, P=0.093)for the 5-year non-recurrence rate. In terms of the 5-year non-recurrence rate. regimen B(with FT)yielded slightly, but not significantly, better results than regimen A. In addition, stratified analyses were carried out with respect to the 5-year non-recurrence rate. Regimen B(with FT)yielded significantly better results than regimen A in patients with four or more positive axillary nodes (log-rank test, P= 0.039) and yielded slightly, but not significantly, better results than regimen A in premenopausal patients (log-rank test, P= 0.079).

Postoperative adjuvant randomised trial comparing chemoendocrine therapy, chemotherapy and immunotherapy for patients with stage II breast cancer: 5-year results from the nishinihon cooperative study group of adjuvant chemoendocrine therapy for breast cancer (ACETBC) of Japan

Between 1985 and 1988, the effect of using ftorafur (FT) or PSK (an immunotherapy agent) in combination with the conventional postoperative adjuvant therapy using mitomycin (MMC) plus tamoxifen (TAM) was assessed in stage II, oestrogen receptor-positive (ER+) breast cancer patients. Furthermore, in ER- breast cancer stage II patients, the effects of postoperative adjuvant therapy using MMC plus FT were compared with the effects of postoperative adjuvant therapy using MMC plus PSK. Patients had primary stage II breast cancer and had undergone total mastectomy plus axillary dissection or more radical surgery. On the day of surgery, MMC (13 mg/m 2) was administered intravenously. Then, ER+ patients received one of three regimens of drug therapy, starting 2 weeks after surgery: regimen A (daily oral treatment with 20 mg of TAM), regimen B (daily oral treatment with 20 mg of TAM and 600 mg of FT) or regimen C (daily oral treatment with 20 mg of TAM and 3 g of PSK). ER- patients received either regimen D (daily oral treatment with 600 mg of FT) or regimen E (daily oral treatment with 3 g of PSK), starting 2 weeks after surgery. Of the 540 ER+ patients registered, 525 were evaluated. The 5-year overall survival rate for ER+ patients was higher for patients who received regimen B (94.2%) than for those who received regimen A (86.9%) or regimen C (89.9%) ( P= 0.063). The 5-year relapse-free survival rate was higher for regimen B (88.9%) than for regimen A (78.6%) and regimen C (77.2%) ( P= 0.010). Stratified analysis revealed better results with the FT-combined therapy in patients positive for lymph node metastasis and premenopausal patients. These results indicate the effectiveness of using FT in combination with TAM. Of the 376 ER- patients registered, 364 were evaluated. The 5-year overall and relapse-free survival rate for ER- patients did not differ significantly between patients who received regimen D and those who received regimen E.

The Role of Chemoendocrine Agents in Postoperative Adjuvant Therapy for Breast Cancer: Meta-analysis of the First Collaborative Studies of Postoperative Adjuvant Chemoendocrine Therapy for Breast Cancer (ACETBC).

The first collaborative studies of postoperative adjuvant chemoendocrine therapy for breast cancer (ACETBA) were carried out in 6 regions of Japan from 1982 to 1985, and the results were subjected to meta-analysis. Subjects consisted of stage II and IIIa cases who underwent radical mastectomy with Brt + Ax or more extensive resection for primary breast cancer. Regimen A consisted of tegafur (Futraful:FT) alone at 600 mg/day, and regimen B of FT at 600 mg/day with tamoxifen (TAM) at 20 mg/day. The duration of the treatment was one year in the Tohoku and Kinki regions, and 2 years in the other 4 regions. Meta-alalysis by Peto's method showed an odds reduction of 20+/- 7% (logrank test: P = 0.0069) for the 5-year overall survival rate in 4740 eligible patients, and 25 +/- 6%(logrank test: P <0.0001)for the 5-year disease-free survival rate. The odds reductions were both statistically significant, indicating that the adjuvantchemoendocrine therapy was effective. Subset analysis of data on 5-year disease-free survival showed that FT plus TAM therapy was better in ER-positive and post-menopausal patients, whether axillary lymph nodes were positive or negative.

Positive effect of tamoxifen as part of adjuvant chemo-endocrine therapy for breast cancer

A prospective randomised multicentre clinical study was undertaken for 2 years and 3 months from November 1982, with the aim of examining the significance of using a combination of ftorafur (FT) and tamoxifen (TAM) for post-operative adjuvant therapy of breast cancer. Patients had either stage II or stage IIIa disease, were age 75 or below and had undergone radical mastectomy. Patients were divided into two groups and received one of the following treatment protocols: treatment A, intravenous administration of doxorubicin (DOX), 20 mg on the day of surgery and 10 mg the next day, followed by oral FT 50 mg day-1 for 2 years from the 14th day; treatment B, the same pattern of DOX administration for the first 2 days, followed by a combined therapy of FT and TAM 20 mg day-1 for 2 years. The number of patients was 546 (treatment A 274 and treatment B 272), of whom 34 (6%) were ineligible. The remaining 512 patients (treatment A 254 and treatment B 258) were followed up for 5 years for analysis. Significantly higher 5 year disease-free rate and 5 year survival rates were observed with treatment B compared with treatment A. When seen in terms of background factors, node-positive patients appeared to derive more benefit from tamoxifen than node-negative patients, but the oestrogen receptor-negative and premenopausal subgroups appeared to derive about the same benefit as those who were oestrogen receptor positive and post-menopausal. Indeed, survival in the premenopausal group was significantly better with tamoxifen (P = 0.04). No increase in side-effects was seen by combining TAM with FT. The study results demonstrate that concomitant administration of FT and TAM is better than FT alone for post-operative adjuvant therapy for breast cancer.

Patient Registration and Treatment Allocation in Multicenter Clinical Trials Using a FAX-OCR System

This article describes the design and results of implementation of an automated patient registration and treatment allocation system (RETAS) used in multicenter clinical trials. RETAS was developed using a FAX-OCR system by which handwritten Japanese and English characters, as well as numericals and forms with check boxes, are sent from participating institutions by Fax, processed using an optical character reader, and then transmitted to a host computer at a statistical center. Based on the facsimile data, RETAS can automatically review eligibility, collect patient identification data and provide a randomized treatment allocation. RETAS permits uninterrupted, unattended operation at a statistical center, 24 hours a day, 7 days a week. Therefore, it drastically decreases the workload of personnel at the statistical center needed to support central telephone registration coverage. Consequently, staff members are free to focus on patient registration, treatment allocation, and follow-up of patients. The treatment allocation procedure in this system is based on Pocock and Simon's minimization method combined with Zelen's method for institution balancing. By this system it was possible to balance treatment numbers for each level of various prognostic factors over an entire trial and, at the same time, balance the allocation of treatments within an institution. The system currently supports the protocol of a clinical trial for Adjuvant Chemo-Endocrine Therapy for Breast Cancer in West Japan.

Experimental studies on enhanced effects of chemoendocrine therapy for breast cancer

Synthetic androgens exhibit estrogenic/antiestrogenic and progestational activities in addition to their androgenic effects. To investigate the pharmacological action of the synthetic androgen, 7α-methyl-19-nortestosterone (MENT), we examined its action in female rodents. The criteria employed for estrogenic/antiestrogenic effects were, uterine weight increase, vaginal cornification, induction of progesterone receptors (PR) synthesis and stimulation of peroxidase activity in the uteri of ovariectomized rats and mice. MENT increased uterine weight in a dose dependent manner, but did not cause vaginal cornification or stimulate PR synthesis in the uterus. The uterotropic activity of MENT was 200-fold lower than that of estradiol. Estrogen receptor (ER) bound [3H]-E2 was displaced by E2 and MENT with ED50 values of 70 pg and 250 ng, respectively, a 3,500 fold difference in their binding affinity. The low binding of MENT to ER, in contrast to its relatively high uterotropic action, suggested that receptors other than ER may be involved in its action on the uterus. The progestational activity of MENT in immature rabbits using the McPhail index assay was comparable to that of progesterone. Binding affinities of MENT and progesterone to PR were also comparable. However, the action of MENT on the uterus does not seem to be a progestational effect since mifepristone, an antiprogestin, had no effect on MENT-induced uterine growth. Specific androgen receptors (AR) in uterine cytosol were demonstrated. The involvement of AR in MENT action was confirmed by using an antiandrogen (flutamide) and an antiestrogen (ICI-182) in ovariectomized mice. Although MENT did not block the uterotropic effect of E2, it inhibited the E2-induced cornification of vaginal epithelium, induction of uterine PR synthesis and increase in uterine peroxidase activity in ovariectomized rats. The antiestrogenic effect of MENT was also blocked by flutamide. These results suggest that the uterotropic and antiestrogenic effects of androgens are mediated via AR. It is concluded that the increase in uterine weight caused by MENT is attributable to its anabolic effects.