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Results from multiple clinical trials involving aromatase inhibitors have added to the knowledge base relating to endocrine therapy of postmenopausal women with hormone receptor–positive early breast cancer. In the extended adjuvant setting, data from the Austrian Breast and Colorectal Cancer Study Group 6a trial showed an advantage for anastrozole following 5 years of tamoxifen treatment, consistent with the more robust MA.17 trial that examined letrozole versus placebo following 5 years of tamoxifen treatment. The combined analysis of the Austrian Breast and Colorectal Cancer Study Group 8 trial and the German Arimidex Nolvadex 95 trial, plus the Italian Tamoxifen Anastrozole trial, have shown the advantage of switching to anastrozole over continuing the tamoxifen to complete the full 5 years of adjuvant therapy. These trials support the previously reported larger and double-blind Intergroup Exemestane Study. The Arimidex, Tamoxifen, Alone or in Combination trial now has data out to 68 months of median follow-up showing the maintenance of a significant advantage of anastrozole over tamoxifen for disease-free survival. In this initial treatment setting, the Breast International Group 1-98 trial recently showed a significant advantage for letrozole over tamoxifen. The current debate is centered on whether the optimal strategy is to give an aromatase inhibitor initially or after several years of tamoxifen treatment. Multiple important questions remain, including the predictive value of molecular markers such as progesterone receptor, the optimal duration of aromatase inhibitor therapy, the long-term adverse effects, and the relative efficacy and toxicity of the different aromatase inhibitors.

We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer.The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel.By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P0.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (P=0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831.Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer. (ClinicalTrials.gov numbers, NCT00004067 and NCT00005970.)

Purpose To evaluate the impact of letrozole compared with placebo after adjuvant tamoxifen on quality of life (QOL) in the MA.17 trial. Methods Patients completed the Short Form 36-item Health Survey (SF-36) and the Menopause Specific Quality of Life Questionnaire (MENQOL) at baseline, 6 months, and annually. Mean change scores from baseline were compared between groups for summary measures and domains. A response analysis compared the proportion of patients who demonstrated an important change in QOL. Results Of 5,187 randomly assigned women in the trial, 3,612 (69.9%) participated in the QOL substudy: 1,799 were allocated to placebo and 1,813 were allocated to letrozole. No differences were seen between groups in mean change scores from baseline for the SF-36 physical and mental component summary scores at 6, 12, 24, and 36 months. Small (< 0.2 standard deviations) but statistically significant differences in mean change scores from baseline were seen for the SF-36 domains of physical functioning (12 months), bodily pain (6 months) and vitality (6 and 12 months), and the MENQOL vasomotor (6, 12, and 24 months) and sexual domains (12 and 24 months). On the response analysis, a significant difference was seen between groups for the bodily pain domain (percentage of patients reporting a worsening of QOL, 47% placebo v 51% letrozole; P = .009) and the vasomotor domain (22% placebo v 29% letrozole; P = .001). Conclusion Letrozole did not have an adverse impact on overall QOL. Small effects were seen in some domains consistent with a minority of patients experiencing changes in QOL compatible with a reduction in estrogen synthesis.

Background: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. Methods: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. Results: After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P

In postmenopausal women with advanced breast cancer, numerous phase III trials have been performed comparing the third-generation non-steroidal aromatase inhibitors (NS-AIs) anastrozole and letrozole and the steroidal AI (S-AI) exemestane in the “first-line” setting against tamoxifen and in the “second-line” setting against megestrol acetate. In both settings, the AIs were at least as efficacious or superior in some endpoints with a preferable toxicity profile including a lower incidence of thrombotic events. Relatively small differences in potency between the three AIs have been identified and it has not been demonstrated that these differences have clinical implications. The recent establishment of the value of AIs in the adjuvant setting for postmenopausal women will impact on their utilization in advanced disease. In premenopausal women the third-generation AIs have not been studied as monotherapy and there is a paucity of data in combination with ovarian function suppression in the advanced disease setting. The main area of future investigations for the AIs in premenopausal women will be in the adjuvant therapy setting in combination with suppression of ovarian function.

This 2-stage, phase II cooperative group trial examined the efficacy and toxicity of 1000 mg/m2 gemcitabine plus 25 mg/m2 cisplatin weekly for 3 weeks and repeated every 28 days for patients with previously treated metastatic breast cancer.Eligible patients had to have measurable metastatic disease. Progression on prior treatment with at least 1 chemotherapy program for metastatic disease and 1 prior anthracycline and/or taxane-containing regimen in either the metastatic or adjuvant setting was required. Patients who had received more than 2 chemotherapy treatments were not eligible for this study.Fifty-eight eligible patients were entered on this 2-stage study. A 38% incidence of grade 4 thrombocytopenia observed in the first stage of accrual required lowering the chemotherapy doses to 800 mg/m2 gemcitabine plus 20 mg/m2 cisplatin weekly for the first 3 weeks of a 4-week cycle during the second stage of the study. The overall response rate was 29% (95% confidence interval [CI], 11-52%) among patients receiving the original study dose and 32% (95% CI, 18-50%) for patients receiving the lower dose. In the original- and lower-dose groups, median time to progression was 30.7 weeks (95% CI, 12.7-43.4 weeks) and 26.0 weeks (95% CI, 19.0-32.1 week), respectively. Median survival of the original- and low-dose groups was 67.9 weeks (95% CI, 42.3-90.6 weeks) and 54.1 weeks (95% CI, 41.6-73.6 weeks), respectively. Hematologic toxicities were more manageable in the lower-dose group, whereas the nonhematologic toxicity profile was similar in the 2 dose groups.The response rate of this combination of gemcitabine and cisplatin is similar to that reported by other investigators but may not differ substantially from reports with single-agent gemcitabine in this patient population. The original dose level we used had unacceptable toxicity, which required lowering the doses of both gemcitabine and cisplatin by 20% to achieve acceptable toxicity and preserve clinical activity.

The recent past has witnessed the appearance of substantial data relating to endocrine therapy of breast cancer. In the adjuvant therapy setting in early breast cancer, several large, well-conducted, randomized, double-blind clinical trials have provided evidence for the value of the third-generation aromatase inhibitors (AI) anastrozole, exemestane, and letrozole. The three major studies to date [i.e., Arimidex, tamoxifen alone, or in combination (ATAC), International Exemestane Study (IES), and letrozole after 5 years of tamoxifen (MA.17)] evaluated three different populations of women from the standpoints of duration of prior tamoxifen and thus time since the treatment of the primary breast cancer. A consistent pattern of improvement in disease-free survival was seen whether the control arm was tamoxifen (ATAC and IES) or placebo following tamoxifen (MA.17). From a toxicity standpoint, the major findings with the AIs were a decreased incidence of thromboembolic events and endometrial cancers but an increase in musculoskeletal complaints and potential for decreasing bone density. The last issue should be clarified with ongoing studies addressing the impact of the three AIs on bone density and fractures. In summary, based on ATAC, IES, and MA.17, respectively, the following conclusions can be drawn relating to postmenopausal women with hormone receptor positive early breast cancer: anastrozole is a reasonable choice for initial endocrine adjuvant therapy, exemestane should be considered for women who have received 2 to 3 years of tamoxifen, and letrozole should be considered for those who have completed about 5 years of tamoxifen. In the prevention setting, tamoxifen has been evaluated in multiple trials involving >28,000 women and, despite clear evidence of benefit, the level of acceptance of this agent by women seems to be low. Two recently developed prevention trials, IBIS 2 and MAP.3, involve the study of aromatase inhibitors against a placebo control rather than tamoxifen. Whereas the recent adjuvant trials have established the value of the third-generation aromatase inhibitors in early-stage breast cancer, the marked reductions in contralateral breast cancers seen in these trials suggest they will be of value in the prevention setting in women at increased risk of developing the disease.

Objective: A phase II multi-institutional clinical trial conducted to evaluate the efficacy and tolerability of docetaxel and carboplatin as first-line therapy for women with metastatic breast cancer. Methods: Patients had histologically confirmed metastatic breast cancer with at least one measurable lesion. Prior adjuvant chemotherapy was permitted, provided that at least 12 months had elapsed between any prior taxane and platinum therapy. Patients received docetaxel 75 mg/m2 with carboplatin AUC 6 mg/ml·min every 21 days until disease progression or prohibitive toxicity. Results: All 53 patients enrolled were evaluable for response and toxicity. Median number of cycles delivered was 6. Overall response rate was 60%, with 3 complete responses (6%) and 29 partial responses (54%). Median time to disease progression was 9.6 months. Median survival time was 20.4 months. Myelosuppression was the predominant toxicity, with grade 3 or 4 neutropenia occurring in 94% of patients and 15% of patients experiencing febrile neutropenia. The overall incidence (grades 1–3) of neurosensory toxicity was 57% and neuromotor toxicity was 25%, respectively, with grade 3 toxicity occurring in 4% of patients each. Conclusions: The combination of docetaxel and carboplatin is highly active in metastatic breast cancer. Prophylactic growth factor support is recommended in any further evaluation of this combination in the treatment of patients with breast cancer.

Purpose To evaluate changes in left ventricular ejection fraction (LVEF) after four cycles of adjuvant doxorubicin plus cyclophosphamide (AC) in women with human epidermal growth factor receptor 2–positive (node-positive or node-negative) breast cancer enrolled onto the North Central Cancer Treatment Group N9831 Intergroup Adjuvant Trial. Patients and Methods Patients were randomly assigned to receive standard doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) every 3 weeks for four cycles followed by (1) weekly paclitaxel for 12 weeks; (2) weekly paclitaxel for 12 weeks, then weekly trastuzumab for 52 weeks; or (3) weekly paclitaxel plus trastuzumab for 12 weeks, then weekly trastuzumab for 40 weeks. LVEF was monitored before and after AC. Results Of the 1,576 eligible patients who completed AC, 1,458 had pre- and post-AC LVEF measurements taken using the same methodology (multiple-gated acquisition in 1,153 patients and echocardiogram in 305 patients). Among these 1,458 patients, 745 (51.1%) had ≤ 15% decrease in LVEF and LVEF that remained at or above the radiologic lower limit of normal (LLN); 42 patients (2.9%) had ≤ 15% decrease in LVEF and LVEF that decreased to or below the LLN; and 37 patients (2.5%) had an LVEF decrease of more than 15%. There was grade 2 LVEF toxicity in 96 (6.6%) of the 1,458 patients. Conclusion Standard AC chemotherapy is associated with frequent decreases in LVEF, which are noted when measured 3 weeks after completion of the fourth cycle. Patients are being observed to determine the long-term significance of this and the potential impact on subsequent treatment options.

BACKGROUND In 1994, the Eastern Cooperative Oncology Group (ECOG) initiated for the Breast Intergroup a randomized clinical trial (E3193) in premenopausal patients with early-stage breast carcinoma (lymph node-negative and receptor-positive, with tumors measuring ≤ 3 cm) comparing tamoxifen as adjuvant systemic therapy with tamoxifen and ovarian ablation by one of three different methods. Ovarian ablation could be accomplished either via radiotherapy (RT) (20 Gray [Gy]/10 fractions to a modified pelvic volume), surgical oophorectomy, or goserelin/leuprolide injections as per patient/physician choice. In the current study, we report the efficacy of pelvic RT with this dose-fractionation scheme in the induction of ovarian ablation. METHODS Twenty-two of 174 patients (13%) who were randomized to treatment with tamoxifen and ovarian ablation received RT for ovarian ablation. RT quality assurance was performed. Of the 22 patients, 19 were treated per protocol, 1 patient had a minor violation (20 elapsed days for 10 RT fractions), and 2 patients had major violations (1 patient who was treated with RT as per protocol but who was treated at a non-Intergroup center, and 1 patient who was treated at a dose of 15 Gy/5 fractions). RESULTS No acute Grade 3 or 4 (according to the Common Toxicity Criteria of the National Cancer Institute) toxicities were reported during RT. Of the 22 patients receiving RT, evaluable follow-up data were available for 20 patients. Based on postmenopausal levels of estradiol or follicle-stimulating hormone at varying intervals after the completion of RT, 15 of 20 patients (75%) achieved successful ovarian ablation with RT. At a median follow-up of 54 months (range, 21–66 months), no Grade 3 or 4 complications from RT were observed. CONCLUSIONS Ovarian ablation by RT as performed in the current trial (given at a dose of 20 Gy in 10 fractions to a modified pelvic treatment volume) was found to be effective for ovarian ablation in the majority of patients, but may take some months to be complete. Consequently, patients should be evaluated to ascertain that ablation has been accomplished. Cancer 2004. © 2004 American Cancer Society.

Purpose A pressing need exists for agents active against anthracycline- or taxane-refractory metastatic breast cancer (MBC), or both. Previous clinical trials suggested that irinotecan might have such activity. We conducted this multicenter phase II study to assess efficacy and tolerability of two irinotecan schedules. Patients and Methods MBC patients who experienced disease progression after one to three chemotherapy regimens, including at least one anthracycline- or taxane-based regimen, were randomly assigned to irinotecan in 6-week cycles comprising 100 mg/m2 weekly for 4 weeks, then a 2-week rest (weekly) or 240 mg/m2 every 3 weeks. Results The weekly arm had 52 assessable patients; the every-3-weeks arm had 51 assessable patients. In the weekly arm, the objective response (complete regression [CR] + partial regression [PR]) rate was 23% (one CR, 11 PR; 95% CI, 13% to 37%). Median response duration was 4.9 months (range, 1.9 to 15.9 months), and median overall survival was 9.7 months (95% CI, 8.0 to 14.2 months). In the every-3-weeks arm, the objective response rate was 14% (nine PR; 95% CI, 6% to 26%), median response duration was 4.2 months (range, 3.1 to 13.9 months), and median overall survival was 8.6 months (95% CI, 7.0 to 12.3 months). Treatment generally was well tolerated, especially in the weekly arm. Grade 3 to 4 adverse events with ≥ 10% incidence included neutropenia (29%) and diarrhea (17%) in the weekly arm and neutropenia (36%), vomiting (20%), dyspnea (18%), nausea (16%), and diarrhea (12%) in the every-3-weeks arm. Conclusion Irinotecan is active with good tolerability in refractory MBC. Irinotecan (especially weekly) warrants additional study as monotherapy and in combination regimens in this setting.

TGF beta/Smad signaling pathway members are potent tumor suppressors for many types of cancers. We hypothesize that breast tumors differentially express these genes and that this expression pattern plays a role in the proliferation of breast cancer. We examined the mRNA levels of TIEG, Smad7, Smad2, and Bard1 using real-time RT/PCR in 14 normal breast, five non-invasive, 57 invasive (including 29 with outcome data), and five metastatic breast tumor tissues. TIEG and Smad7 mRNA levels were lower in non-invasive tumors compared to normal breast tissues. TIEG, Bard1, and Smad2 mRNA levels were lower in invasive cancers compared to normal breast tissues. In addition, TIEG, Smad2, and Bard1, provided discriminatory ability to potentially distinguish between normal and tumor samples, N- and N+ tumors, and N-/good (no recurrence for at least 5 years) and N-/bad (recurrence within 3 years) outcome patients. TIEG mRNA levels accurately discriminated between normal breast tissue and primary tumors with a sensitivity and specificity of 96 and 93%, respectively. TIEG, in combination with Smad2, distinguished between N+ and N- primary tumors with a sensitivity and specificity of 75 and 85%, respectively. TIEG in combination with Bard1 discriminated between N-/bad outcome from N-/good tumors with a sensitivity and specificity of 83 and 82%, respectively. Our results support the hypothesis that the differential gene expression of TIEG, Smad2, and Bard1, which are tumor suppressor genes, plays a significant role in the proliferation of breast cancer. Further investigation is necessary to validate the ability of these genes to discriminate between different populations of breast cancer patients.

The Third International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer, cochaired by Steven Come, MD, and Aman Buzdar, MD, was held in Cambridge, Massachusetts, June 21–22, 2003. The conference was organized with the objective of analyzing recent

The third-generation aromatase inhibitors anastrozole, exemestane and letrozole have become firmly established as the agents of choice in patients with tamoxifen-resistant tumors. Large, well-conducted, double-blind clinical trials directly comparing the non-steroidal aromatase inhibitors anastrozole and letrozole with tamoxifen in the advanced disease setting have matured. Based on these trials, there is sufficient evidence to choose one of these agents over tamoxifen because of a superior time to disease progression and acceptable toxicity which includes a lower incidence of thromboembolic complications. Information for the steroidal aromatase inhibitor exemestane will be forthcoming from a phase III trial which has completed accrual. Consistent with the findings in the advanced disease setting, a double-blind trial comparing letrozole with tamoxifen in the neoadjuvant setting revealed superiority for letrozole in terms of clinical response rate. This provides a strong impetus for further study of the aromatase inhibitors in the preoperative setting.

Purpose: Using a 2 × 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node–positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities. Patients and Methods: A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A × 4 (doses) → T × 4 → C × 4 with doses every 3 weeks, (II) sequential A × 4 → T × 4 → C × 4 every 2 weeks with filgrastim, (III) concurrent AC × 4 → T × 4 every 3 weeks, or (IV) concurrent AC × 4 → T × 4 every 2 weeks with filgrastim. Results: A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P = .010), and OS (RR = 0.69; P = .013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens. Conclusion: Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.

The well-established hormonal risk factors for breast cancer and laboratory models of estrogen-driven breast cancer cell growth have long provided a rationale for hormonal therapy. After the early use of therapeutic oophorectomy, antiestrogens, now known as selective estrogen response modulators (SERMs), became widely used. Large-scale trials have now shown that the SERM prototype, tamoxifen, is effective for palliation in advanced breast cancer, for improvements in recurrence and mortality risk in early stage disease, local recurrence in ductal carcinoma in situ (DCIS), and as prevention for early stage breast cancer. Questions still remain about the optimal selection of patients for early stage disease, DCIS, and prevention. New highly potent aromatase inhibitors (AIs) have now been tested in advanced stage disease, where they have become the treatment of choice for postmenopausal patients. Early results from a large randomized trial (Anastrozole, Tamoxifen, Alone or in Combination [ATAC]) suggest that the AI anastrozole is superior to tamoxifen in lowering the risk of recurrence. Fewer vaginal symptoms and hot flashes were seen with anastrozole, but more bone fractures in this group have raised the concern of long-term bone mineral density and other hormonal effects in a population of patients who are less likely to die of breast cancer than of other causes. AIs are also being tested for primary prevention, and a hint of this benefit was seen in the ATAC trial. Signs of hormonal deficiency are a common problem in women who have been treated for breast cancer, and this adversely affects their overall quality of life. The controversies concerning hormonal supplementation and the limited data in this regard are discussed.

5 Background: Triple-negative breast cancer (TNBC) is an immunogenic breast cancer subtype, with a greater percentage of tumors containing tumor-infiltrating lymphocytes (TILs) compared to non-TNBC. TILs are prognostic for recurrence and predictive for chemotherapy benefit in TNBC, but not in estrogen receptor (ER)-positive tumors. A subset of TNBC expresses the androgen receptor (AR), and resembles ER-positive breast cancer in terms of demographics (older age) and clinical course (later recurrences that tend to involve bone). However, little is known regarding the association between TILs and AR expression in TNBC. Methods: From a cohort of 9982 women with surgically-treated non-metastatic breast cancer, patients who met criteria for TNBC (ER/PR < 1% and HER2-negative) by centralized-pathology review were included as previously published [Leon-Ferre et al, Breast Cancer Res Treat 2017]. Stromal TILs in these tumors were quantified on full-face hematoxylin and eosin sections from the surgical specimen, following the 2014 TIL Working Group recommendations [Salgado et al, Ann Oncol 2014]. The expression of AR [EPR1535(2), Abcam] was scored as a continuous variable (1% increments), and categorized as absent (0%), low (1-25% ), low-moderate (26-50%) moderate (51-75%) and high (> 75%) and correlated with TIL density. Results: 605 patients met criteria for TNBC. The median age was 56 years. Most tumors were T1-2 (95%), N0-1 (86%), and high grade (88%). The median stromal TIL content was 20% (0-90%). Tumor tissue was available for AR staining in 509/605 patients. 165 (32%) tumors expressed AR as follows: low: 12%, low-moderate: 7%, moderate: 5%, and high: 8%. Apocrine tumors (n = 30) expressed AR most frequently (86%) and at higher levels (AR high: 50%). For all 509 tumors, the median stromal TIL content according to AR expression was AR absent: 20%, AR low: 20%, AR low-moderate: 15%, AR high: 10%. AR and stromal TILs (both as continuous variables) demonstrated a weak inverse correlation (correlation coefficient -0.1064, p = 0.017). Conclusions: AR expression in TNBC is associated with lower levels of stromal TILs. Additional data correlating the AR, stromal TILs and outcomes in this cohort will be presented at the meeting.

In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady-state concentrations (Endx Css). The ¹³C-dextromethorphan breath test (DM-BT), labeled with ¹³C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DM-BT and Endx Css.DM-BT and tamoxifen pharmacokinetics were obtained at baseline, 3, and 6 months following tamoxifen initiation. Potent CYP2D6 inhibitors were prohibited. The correlation between baseline DM-BT with CYP2D6 genotype and Endx Css was determined. The association between baseline DM-BT (where values ≤0.9 is an indicator of poor in vivo CYP2D6 metabolism) and Endx Css (using values≤11.2 known to be associated with poorer recurrence free survival) was explored.A total of 91 patients were enrolled and 77 were eligible. CYP2D6 genotype was positively correlated with baseline, 3, and 6 months DM-BT (r ranging from 0.457-0. 60; P0.001). Both CYP2D6 genotype (r=0.47, 0.56, P0.0001), and baseline DM-BT (r=0.60, 0.54, P0.001) were associated with 3 and 6 months Endx Css, respectively. Seven (78%) of nine patients with low (≤11.2 nmol/l) 3 month Endx Css also had low DM-BT (≤0.9) including 2/2 CYP2D6 PM/PM and 5/5 IM/PM. In contrast, one (2%) of 48 patients with a low DM-BT had Endx Css more than 11.2 nmol/l.In patients not taking potent CYP2D6 inhibitors, DM-BT was associated with CYP2D6 genotype and 3 and 6 months Endx Css but did not provide better discrimination of Endx Css compared with CYP2D6 genotype alone. Further studies are needed to identify additional factors which alter Endx Css.

The 14th St Gallen International Breast Cancer Conference (2015) reviewed substantial new evidence on locoregional and systemic therapies for early breast cancer. Further experience has supported the adequacy of tumor margins defined as 'no ink on invasive tumor or DCIS' and the safety of omitting axillary dissection in specific cohorts. Radiotherapy trials support irradiation of regional nodes in node-positive disease. Considering subdivisions within luminal disease, the Panel was more concerned with indications for the use of specific therapies, rather than surrogate identification of intrinsic subtypes as measured by multiparameter molecular tests. For the treatment of HER2-positive disease in patients with node-negative cancers up to 1 cm, the Panel endorsed a simplified regimen comprising paclitaxel and trastuzumab without anthracycline as adjuvant therapy. For premenopausal patients with endocrine responsive disease, the Panel endorsed the role of ovarian function suppression with either tamoxifen or exemestane for patients at higher risk. The Panel noted the value of an LHRH agonist given during chemotherapy for premenopausal women with ER-negative disease in protecting against premature ovarian failure and preserving fertility. The Panel noted increasing evidence for the prognostic value of commonly used multiparameter molecular markers, some of which also carried prognostic information for late relapse. The Panel noted that the results of such tests, where available, were frequently used to assist decisions about the inclusion of cytotoxic chemotherapy in the treatment of patients with luminal disease, but noted that threshold values had not been established for this purpose for any of these tests. Multiparameter molecular assays are expensive and therefore unavailable in much of the world. The majority of new breast cancer cases and breast cancer deaths now occur in less developed regions of the world. In these areas, less expensive pathology tests may provide valuable information. The Panel recommendations on treatment are not intended to apply to all patients, but rather to establish norms appropriate for the majority. Again, economic considerations may require that less expensive and only marginally less effective therapies may be necessary in less resourced areas. Panel recommendations do not imply unanimous agreement among Panel members. Indeed, very few of the 200 questions received 100% agreement from the Panel. In the text below, wording is intended to convey the strength of Panel support for each recommendation, while details of Panel voting on each question are available in supplementary Appendix S2, available at Annals of Oncology online., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

While the effects of bisphosphonates on bone-resorbing osteoclasts have been well documented, the effects of bisphosphonates on other cell types are not as well studied. Recently, we reported that bisphosphonates have direct effects on bone-forming human fetal osteoblast cells (hFOB) [1]. In this report, the role of the mevalonate pathway in the actions of bisphosphonates on hFOB, and MDA-MB-231 human breast cancer cells was examined. These studies included a novel bisphosphonate analog, the anhydride formed between arabinocytidine 5′ phosphate and etidronate (Ara-CBP). Ara-CBP was the most potent inhibitor of hFOB and MDA-MB-231 cell proliferation, and stimulator of hFOB cell mineralization compared to etidronate, the anhydride formed between AMP and etidronate (ABP), pamidronate, and zoledronate. Inhibition of hFOB cell proliferation by Ara-CBP and zoledronate was partially reversed by mevalonate pathway intermediates, and stimulation of hFOB cell mineralization was completely reversed by mevalonate pathway intermediates. These results suggest that zoledronate and Ara-CBP act, at least in part, via inhibition of the mevalonate pathway in hFOB cells. In contrast, none of the mevalonate pathway intermediates reversed the inhibition of MDA-MB-231 cell proliferation by the bisphosphonates, or the effects of pamidronate on hFOB cells. As a positive control, the effects of mevastatin on hFOB and MDA-MB-231 cells were completely reversed by mevalonate. In summary, these data suggest that zoledronate and Ara-CBP induce human osteoblast differentiation via inhibition of the mevalonate pathway. In contrast, the inhibition of MDA-MB-231 cell proliferation by the bisphosphonates appears to be through mechanisms other than inhibition of the mevalonate pathway.

Background: NOTCH oncogenic signaling induces epithelial-to-mesenchymal transition (EMT) and tumor stemness that play a critical role in driving tumor progression. Following interaction of NOTCH receptors (NOTCH 1, 2, 3, and 4) with their ligands (DELTA-LIKE 1, 3, 4 and JAGGED 1, 2), γ- secretase complex performs an intra-membrane cleavage releasing the NOTCH intracellular domain (NNICD). NNICD translocates to the nucleus and induces the expression of HEY1 and HES1 transcription factors that in turn orchestrate NOTCH-mediated EMT and stemness reprogramming. Materials and Methods: Parental MCF-7 and unique metastatic MCF-7RAF-1 xenografts with constitutively active MAPK signaling (D’Assoro et al., Oncogene 2014: 33:599-610) were used to define the extent to which increased expression of NOTCH signaling was linked to distant metastases. SKY analysis was performed to assess the grade of chromosomal instability (CIN) in tumor xenografts. Stemness activity was assessed by culturing breast cancer cells under non-adherent conditions to generate mammospheres. Expression of CD24 luminal marker was characterized by FACS analysis and immunofluorescence. Global transcriptome analysis was performed using Affymetrix® microarray. Highly invasive MDA-MB 231 breast cancer cells were used to perform a tail vein cancer cell-seeding assay. The LY411575 γ-secretase inhibitor (Pan-NOTCH inhibitor) was used to block NOTCH signaling in MDA-MB 231 cells. Results: Metastasis Initiating Cells (MICs) isolated from the lungs of nude mice carrying MCF-7RAF-1 xenografts exhibited a higher degree of genomic stability than primary tumor xenografts that was characterized by the absence of centrosome amplification and non-clonal chromosomal abnormalities. MICs also showed higher mammosphere forming capacity that was linked to lower expression of luminal marker CD24. Significantly, global transcriptome analysis showed that expression of NOTCH3 and HES1 stemness genes was increased in MICs. To corroborate the role of NOTCH signaling in inducing metastatic seeding, MDA-MB 231 breast cancer cells were pre-treated with 1 µM of LY411575 After 72 hours viable cells were injected into the tail vein of immune-compromised mice to develop lung metastases. While animals injected with untreated MDA-MB 231 cells developed lung metastases, those injected with the LY411575-treated MDA-MB 231 cells failed to develop lung metastatic lesions. Conclusions: These preliminary findings demonstrate the role of NOTCH stemness signaling in promoting metastatic seeding of breast cancer cells. Since NOTCH signaling is a “druggable target”, these results also provide the rationale to develop novel NOTCH-targeted therapies to inhibit tumor stemness and early onset of distant metastases. Citation Format: Alexey Leontovich, Jeffrey Salisbury, Candace L. Haddox, Lisa Mills, Tufia Haddad, James McCubrey, Matthew Goetz, James Ingle, Evanthia Galanis, Antonino B. D'Assoro. NOTCH signaling promotes metastatic seeding and growth of human breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4851. doi:10.1158/1538-7445.AM2017-4851

533 Background: Current guidelines define TNBC as complete absence of estrogen (ER) and progesterone receptor (PR), without HER2 amplification. However, the prognostic impact of clinical and histopathological factors, sTILs, and AdjCT in TNBC meeting these strict criteria is unknown. Methods: From a cohort of 9985 women who underwent upfront surgery for M0 breast cancer (BC) at Mayo Clinic Rochester from 1985-2012, 1159 pts with ER negative or low (≤10%) BC were identified for central ER/PR/HER2 staining and HER2 FISH (IHC2+ only) to select those with TNBC by modern definitions. Cox proportional hazards models were used to assess the impact of clinicopathological variables on invasive disease-free (IDFS) and overall survival (OS). Results: Tumors from 605 pts (median age 56.3 yrs) met criteria for TNBC (ER < 1%, PR < 1% and HER2 0, 1 or 2+ and FISH negative). 51% were T1, 65% N0, 88% grade 3, and 75% had Ki67 > 15%. Histologically, 39% were anaplastic, 26% invasive ductal, 16% medullary, 8% metaplastic, 6% apocrine and 5% others. Median sTILs was 20% (0-90%). 55% pts received AdjCT [21% anthracycline (A), 19% A + taxane, and 15% other]. Median follow-up for IDFS and OS were 7.4 and 10.6 yrs, respectively. Multivariate analyses demonstrated that higher N stage (p < 0.01), lower sTILs (p = 0.01) and no AdjCT (p < 0.01) were independently associated with worse IDFS and OS. Histology (medullary subtype) was associated with better IDFS in univariate (HR 0.56, 95% CI, 0.35-0.89) but not in multivariate analyses, once sTILs were accounted for. Among systemically untreated pts (n = 182), higher N (p < 0.01) and lower sTILs (p = 0.04) were associated with worse IDFS. For systemically untreated T1N0 pts (n = 111), the 5-yr IDFS was 70% (95% CI, 61-81) [T1a: 83% (95% CI, 63-100), T1b: 68% (95% CI, 52-88) and T1c: 67% (95% CI, 55-83)], compared to 78% (95% CI, 68-84) for T1N0 pts treated with AdjCT. Conclusions: In TNBC pts, N stage, sTILs and receipt of AdjCT were independently prognostic for IDFS and OS. sTILs remained prognostic for IDFS in systemically untreated TNBC. In N0 TNBC, the risk of recurrence or death was substantial in the absence of chemotherapy, even for those with T1 tumors.

1043 Background: In estrogen receptor (ER) positive MBC, mutations (e.g. ESR1), identified from tumor biopsies or cfDNA, confer resistance. The concordance between mutations observed in tumor and cfDNA and the implications for response to Z-endoxifen, a potent anti-estrogen, are unknown. Methods: We previously conducted a phase I trial of Z-endoxifen in endocrine refractory, ER positive MBC. Seven dose levels were considered ranging from 20 to 160 mg/day followed by expansion cohorts (EC) of 40, 80, and 100 mg/day. Pretreatment blood samples (all pts) and fresh tumor biopsies (EC) were collected prospectively. Tumor and cfDNA were evaluated by targeted NGS. Results: 41 pts (38 evaluable) were enrolled. Prior endocrine therapy included aromatase inhibitors (37/38, 97%), fulvestrant (22/38, 58%) and tamoxifen (26/38, 68%). Substantial endoxifen exposure without DLTs at doses above 80 mg/day led to a halt in dose escalation and opening of the EC. Overall clinical benefit (stable > 6 months [7 pts.] or partial response by RECIST criteria [3 pts.]) rate was 26.3% (95%CI: 13.4-43.1%). cfDNA was obtained from 36 pts and mutations were identified in 13 (36%) including ESR1 [ Y537N or D538G] (5), PIK3CA [ H1047R or E542K] (8), TP53 [ K132R, R248Q, R267Q, or H179Y] (4), AKT ( Q79K) (1), and KRAS ( G12D) (1). In 5 pts with cf ESR1 mutations, 4 had additional cfDNA mutations including PIK3CA (3), and TP53 (1). PFS was shorter in pts with cfDNA mutations relative to those without (median: 61 vs.132 days; log-rank p = 0.021). Discordance was observed between tumor and cfDNA mutations where 3/7 PIK3CA tumor mutations were detected by cfDNA, 1/2 TP53 tumor mutations were detected by cfDNA, and 0/1 AKT tumor mutations were detected by cfDNA. Conversely, 2 pts had cfDNA mutations (either ESR1, TP53 or AKT) undetected in tumor. Conclusions: The absence of cfDNA mutations in patients with endocrine resistant, MBC treated with Z-Endoxifen was associated with significantly longer PFS. Given the discordance between tumor and cfDNA sequence data, future studies must determine which approach maximizes prognosis and prediction of benefit for estrogen-targeted therapy. Clinical trial information: NCT01327781.

The third-generation aromatase inhibitors are an important class of drugs for use in adjuvant therapy for postmenopausal women with resected estrogen receptor positive breast cancer. Multiple large prospective randomized trials have established their value in this setting and provided guidance for their use in clinical management. This review will outline the trials that have provided evidence on the value of the aromatase inhibitors in the adjuvant setting as well as the ongoing trials that will expand our knowledge of how to use them most effectively.

BACKGROUND Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor-positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain. METHODS We randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal. RESULTS After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen-ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen-ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane-ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87). CONCLUSIONS Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression. (Funded by Pfizer and others; SOFT ClinicalTrials.gov number, NCT00066690.).

Purpose Treatment-emergent symptoms with adjuvant tamoxifen and aromatase inhibitors (AIs) have been associated with superior recurrence-free survival (RFS). We hypothesized that MA.27 anastrozole- or exemestane-treated patients with new or worsening vasomotor and/or joint symptoms would have improved RFS. Patients and Methods MA.27 randomly assigned 7,576 postmenopausal women with breast cancer to 5 years of anastrozole or exemestane. Patient-reported symptoms were collected using the Common Terminology Criteria for Adverse Events version 3.0 at protocol-specified baseline and 6- and 12-month clinical visits. Symptoms were considered present with either vasomotor and/or joint complaints. Associations between symptoms and baseline patient characteristics were examined with χ2 and Fisher's exact tests. Subsequent effects of new or worsening symptoms on RFS were examined with landmark analyses and stratified univariable and multivariable Cox models. We examined the effects of 3-month symptoms arising from unplanned clinic visits as a result of severe toxicity. Results Patients were assessable if eligible for the MA.27 trial, received some trial therapy, and had no disease recurrence at the end of a symptom assessment period; 96% of patients (n = 7,306 patients) were included at 6 months, and 96% (n = 7,246) were included at 12 months. Thirty-four percent of patients had baseline symptoms. For patients without baseline symptoms, 25% and 52% had new symptoms by 6 and 12 months, respectively. Neither treatment-emergent nor baseline symptoms significantly impacted RFS (P > .10) in patients with or without baseline symptoms. Conclusion In MA.27, anastrozole or exemestane treatment-emergent symptoms were not associated with improved RFS. Women should be supported through treatment and encouraged to remain on their AI regardless of their symptoms.

Controversy exists regarding the impact of CYP2D6 genotype on tamoxifen responsiveness. We examined loss of heterozygosity (LOH) at the CYP2D6 locus and determined its impact on genotyping error when tumor tissue is used as a DNA source.Genomic tumor data from the adjuvant and metastatic settings (The Cancer Genome Atlas [TCGA] and Foundation Medicine [FM]) were analyzed to characterize the impact of CYP2D6 copy number alterations (CNAs) and LOH on Hardy Weinberg equilibrium (HWE). Additionally, we analyzed CYP2D6 *4 genotype from formalin-fixed paraffin-embedded (FFPE) tumor blocks containing nonmalignant tissue and buccal (germline) samples from patients on the North Central Cancer Treatment Group (NCCTG) 89-30-52 tamoxifen trial. All statistical tests were two-sided.In TCGA samples (n =627), the CYP2D6 LOH rate was similar in estrogen receptor (ER)-positive (41.2%) and ER-negative (35.2%) but lower in HER2-positive tumors (15.1%) (P.001). In FM ER+ samples (n = 290), similar LOH rates were observed (40.8%). In 190 NCCTG samples, the agreement between CYP2D6 genotypes derived from FFPE tumors and FFPE tumors containing nonmalignant tissue was moderate (weighted Kappa = 0.74; 95% CI = 0.63 to 0.84). Comparing CYP2D6 genotypes derived from buccal cells to FFPE tumor DNA, CYP2D6*4 genotype was discordant in six of 31(19.4%). In contrast, there was no disagreement between CYP2D6 genotypes derived from buccal cells with FFPE tumors containing nonmalignant tissue.LOH at the CYP2D6 locus is common in breast cancer, resulting in potential misclassification of germline CYP2D6 genotypes. Tumor DNA should not be used to determine germline CYP2D6 genotype without sensitive techniques to detect low frequency alleles and quality control procedures appropriate for somatic DNA.

Recent genetic studies have identified common variation in susceptibility loci that stratify lifetime risks of breast cancer and may inform prevention and screening strategies. However, whether these loci have similar implications for women treated with tamoxifen or raloxifene (SERMs) is unknown. We conducted a matched case–control study of 592 cases who developed breast cancer and 1,171 unaffected women from 32,859 participants on SERM therapy enrolled on NSABP P-1 and P-2 breast cancer prevention trials. We formed a quantitative polygenic risk score (PRS) using genotypes of 75 breast cancer-associated single nucleotide polymorphisms and examined the PRS as a risk factor for breast cancer among women treated with SERMs. The PRS ranged from 3.98 to 7.74, with a one-unit change associated with a 42 % increase in breast cancer (OR = 1.42; P = 0.0002). The PRS had a stronger association with breast cancer among high-risk women with no first-degree family history (OR = 1.62) compared to those with a positive family history (OR = 1.32) (P intx = 0.04). There was also suggestion that PRS was a stronger risk factor for ER-positive (OR = 1.59, P = 0.0002) than ER-negative (OR = 1.05, P = 0.84) breast cancer (P intx = 0.10). Associations did not differ by tamoxifen or raloxifene treatment, age at trial entry, 5-year predicted Gail model risk or other clinical variables. The PRS is a strong risk factor for ER-positive breast cancer in moderate to high-risk individuals treated with either tamoxifen or raloxifene for cancer prevention. These data suggest that common genetic variation informs risk of breast cancer in women receiving SERMs.

Background The role and clinical value of ERβ1 expression is controversial and recent data demonstrates that many ERβ antibodies are insensitive and/or non-specific. Therefore, we sought to comprehensively characterize ERβ1 expression across all sub-types of breast cancer using a validated antibody and determine the roles of this receptor in mediating response to multiple forms of endocrine therapy both in the presence and absence of ERα expression. Methods Nuclear and cytoplasmic expression patterns of ERβ1 were analyzed in three patient cohorts, including a retrospective analysis of a prospective adjuvant tamoxifen study and a triple negative breast cancer cohort. To investigate the utility of therapeutically targeting ERβ1, we generated multiple ERβ1 expressing cell model systems and determined their proliferative responses following anti-estrogenic or ERβ-specific agonist exposure. Results Nuclear ERβ1 was shown to be expressed across all major sub-types of breast cancer, including 25% of triple negative breast cancers and 33% of ER-positive tumors, and was associated with significantly improved outcomes in ERα-positive tamoxifen-treated patients. In agreement with these observations, ERβ1 expression sensitized ERα-positive breast cancer cells to the anti-cancer effects of selective estrogen receptor modulators (SERMs). However, in the absence of ERα expression, ERβ-specific agonists potently inhibited cell proliferation rates while anti-estrogenic therapies were ineffective. Conclusions Using a validated antibody, we have confirmed that nuclear ERβ1 expression is commonly present in breast cancer and is prognostic in tamoxifen-treated patients. Using multiple breast cancer cell lines, ERβ appears to be a novel therapeutic target. However, the efficacy of SERMs and ERβ-specific agonists differ as a function of ERα expression. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-749) contains supplementary material, which is available to authorized users.

The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. We developed cMethDNA, a quantitative multiplexed methylation-specific PCR assay for a panel of ten genes, consisting of novel and known breast cancer hypermethylated markers identified by mining our previously reported study of DNA methylation patterns in breast tissue (103 cancer, 21 normal on the Illumina HumanMethylation27 Beadchip) and then validating the 10-gene panel in The Cancer Genome Atlas project breast cancer methylome database. For cMethDNA, a fixed physiologic level (50 copies) of artificially constructed, standard nonhuman reference DNA specific for each gene is introduced in a constant volume of serum (300 μL) before purification of the DNA, facilitating a sensitive, specific, robust, and quantitative assay of tumor DNA, with broad dynamic range. Cancer-specific methylated DNA was detected in training (28 normal, 24 cancer) and test (27 normal, 33 cancer) sets of recurrent stage IV patient sera with a sensitivity of 91% and a specificity of 96% in the test set. In a pilot study, cMethDNA assay faithfully reflected patient response to chemotherapy (N = 29). A core methylation signature present in the primary breast cancer was retained in serum and metastatic tissues collected at autopsy two to 11 years after diagnosis of the disease. Together, our data suggest that the cMethDNA assay can detect advanced breast cancer, and monitor tumor burden and treatment response in women with metastatic breast cancer. Cancer Res; 74(8); 2160–70. ©2014 AACR.

Purpose Exemestane, a steroidal aromatase inhibitor, reduced invasive breast cancer incidence by 65% among 4,560 postmenopausal women randomly assigned to exemestane (25 mg per day) compared with placebo in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MAP.3 (Mammary Prevention 3) trial, but effects on quality of life (QOL) were not fully described. Patients and Methods Menopause-specific and health-related QOL were assessed by using the four Menopause-Specific Quality of Life Questionnaire (MENQOL) domains and the eight Medical Outcomes Study Short Form Health Survey (SF-36) scales at baseline, 6 months, and yearly thereafter. MENQOL questionnaire completion was high (88% to 98%) in both groups at each follow-up visit. Change scores for each MENQOL and SF-36 scale, calculated at each assessment time relative to baseline, were compared by using the Wilcoxon rank-sum test. Clinically important worsened QOL was defined as a MENQOL change score increase of more than 0.5 (of 8) points and an SF-36 change score decrease of more than 5 (of 100) points from baseline. Results Exemestane had small negative effects on women's self-reported vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. However, these changes represented only a small excess number of women being given exemestane with clinically important worsening of QOL at one time or another; specifically, 8% more in the vasomotor domain and 4% more each in the sexual domain and for pain. No other between-group differences were observed. Overall, slightly more women in the exemestane arm (32%) than in the placebo arm (28%) discontinued assigned treatment. Conclusion Exemestane given for prevention has limited negative impact on menopause-specific and health-related QOL in healthy postmenopausal women at risk for breast cancer.

Summary Background Treatment of breast cancer with aromatase inhibitors is associated with damage to bones. NCIC CTG MA.27 was an open-label, phase 3, randomised controlled trial in which women with breast cancer were assigned to one of two adjuvant oral aromatase inhibitors—exemestane or anastrozole. We postulated that exemestane—a mildly androgenic steroid—might have a less detrimental effect on bone than non-steroidal anastrozole. In this companion study to MA.27, we compared changes in bone mineral density (BMD) in the lumbar spine and total hip between patients treated with exemestane and patients treated with anastrozole. Methods In MA.27, postmenopausal women with early stage hormone (oestrogen) receptor-positive invasive breast cancer were randomly assigned to exemestane 25 mg versus anastrozole 1 mg, daily. MA.27B recruited two groups of women from MA.27: those with BMD T-scores of −2·0 or more (up to 2 SDs below sex-matched, young adult mean) and those with at least one T-score (hip or spine) less than −2·0. Both groups received vitamin D and calcium; those with baseline T-scores of less than −2·0 also received bisphosphonates. The primary endpoints were percent change of BMD at 2 years in lumbar spine and total hip for both groups. We analysed patients according to which aromatase inhibitor and T-score groups they were allocated to but BMD assessments ceased if patients deviated from protocol. This study is registered with ClinicalTrials.gov, NCT00354302. Findings Between April 24, 2006, and May 30, 2008, 300 patients with baseline T-scores of −2·0 or more were accrued (147 allocated exemestane, 153 anastrozole); and 197 patients with baseline T-scores of less than −2·0 (101 exemestane, 96 anastrozole). For patients with T-scores greater than −2·0 at baseline, mean change of bone mineral density in the spine at 2 years did not differ significantly between patients taking exemestane and patients taking anastrozole (−0·92%, 95% CI −2·35 to 0·50 vs −2·39%, 95% CI −3·77 to −1·01; p=0·08). Respective mean loss in the hip was −1·93% (95% CI −2·93 to −0·93) versus −2·71% (95% CI −4·32 to −1·11; p=0·10). Likewise for those who started with T-scores of less than −2·0, mean change of spine bone mineral density at 2 years did not differ significantly between the exemestane and anastrozole treatment groups (2·11%, 95% CI −0·84 to 5·06 vs 3·72%, 95% CI 1·54 to 5·89; p=0·26), nor did hip bone mineral density (2·09%, 95% CI −1·45 to 5·63 vs 0·0%, 95% CI −3·67 to 3·66; p=0·28). Patients with baseline T-score of −2·0 or more taking exemestane had two fragility fractures and two other fractures, those taking anastrozole had three fragility fractures and five other fractures. For patients who had baseline T-scores of less than −2·0 taking exemestane, one had a fragility fracture and four had other fractures, whereas those taking anastrozole had five fragility fractures and one other fracture. Interpretation Our results demonstrate that adjuvant treatment with aromatase inhibitors can be considered for breast cancer patients who have T-scores less than −2·0. Funding Canadian Cancer Society Research Institute, Pfizer, Canadian Institutes of Health Research.

Background We conducted a randomized trial in which we compared high-dose chemotherapy plus hematopoietic stem-cell rescue with a prolonged course of monthly conventional-dose chemotherapy in women with metastatic breast cancer. Methods Women 18 to 60 years of age who had metastatic breast cancer received four to six cycles of standard combination chemotherapy. Patients who had a complete or partial response to induction chemotherapy were then randomly assigned to receive either a single course of high doses of carboplatin, thiotepa, and cyclophosphamide plus transplantation of autologous hematopoietic stem cells or up to 24 cycles of cyclophosphamide, methotrexate, and fluorouracil in conventional doses. The primary end point was survival. Results The median follow-up was 37 months. Of 553 patients who enrolled in the study, 58 had a complete response to induction chemotherapy and 252 had a partial response. Of these, 110 patients were assigned to receive high-dose chemotherapy plus hematopoietic stem ce...

PURPOSE: To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone metastases in breast cancer and their role relative to other therapies for this condition. METHODS: An expert multidisciplinary panel reviewed pertinent information from the published literature and meeting abstracts through May 1999. Additional data collected as part of randomized trials and submitted to the United States Food and Drug Administration were also reviewed, and investigators were contacted for more recent information. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the panel. Expert consensus was used if there were insufficient published data. The panel addressed which patients to treat and when in their course of disease, specific drug delivery issues, duration of therapy, management of bony metastases with other therapies, and the public policy implications. The guideline underwent external review by selected physicians, members of the American Society of Clinical Oncology (ASCO) Health Services Research Committee, and the ASCO Board of Directors. RESULTS: Bisphosphonates have not had an impact on the most reliable cancer end point: overall survival. The benefits have been reductions in skeletal complications, ie, pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia. Intravenous (IV) pamidronate 90 mg delivered over 1 to 2 hours every 3 to 4 weeks is recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. For women with only an abnormal bone scan but without bony destruction by imaging studies or localized pain, there is insufficient evidence to suggest starting bisphosphonates. Starting bisphosphonates in patients without evidence of bony metastasis, even in the presence of other extraskeletal metastases, is not recommended. Studies of bisphosphonates in the adjuvant setting have yielded inconsistent results. Starting bisphosphonates in patients at any stage of their nonosseous disease, outside of clinical trials, despite a high risk for future bone metastasis, is currently not recommended. Oral bisphosphonates are one of several options which can be used for preservation of bone density in premenopausal patients with treatment-induced menopause. The panel suggests that, once initiated, IV bisphosphonates be continued until evidence of substantial decline in a patient’s general performance status. The panel stresses that clinical judgment must guide what is a substantial decline. There is no evidence addressing the consequences of stopping bisphosphonates after one or more adverse skeletal events. Symptoms in the spine, pelvis, or femur require careful evaluation for spinal cord compression and pathologic fracture before bisphosphonate use and if symptoms recur, persist, or worsen during therapy. The panel recommends that current standards of care for cancer pain, analgesics and local radiation therapy, not be displaced by bisphosphonates. IV pamidronate is recommended in women with pain caused by osteolytic metastasis to relieve pain when used concurrently with systemic chemotherapy and/or hormonal therapy, since it was associated with a modest pain control benefit in controlled trials. CONCLUSION: Bisphosphonates provide a meaningful supportive but not life-prolonging benefit to many patients with bone metastases from cancer. Further research is warranted to identify clinical predictors of when to start and stop therapy, to integrate their use with other treatments for bone metastases, to identify their role in the adjuvant setting in preventing bone metastases, and to better determine their cost-benefit consequences.

BACKGROUND This Phase II multicenter study evaluated the efficacy and toxicity of paclitaxel (200 mg/m2 by 3-hour infusion) with carboplatin (area under the curve 6 mg/mL per minute) administered every 3 weeks as first-line therapy for women with metastatic breast carcinoma. METHODS Eligible patients had measurable metastatic disease and an Eastern Cooperative Oncology Group performance status of 0–2. Prior adjuvant chemotherapy, including anthracycline-based therapy, was allowed, as was prior hormonal therapy as part of either adjuvant treatment or treatment for metastasis. Prior therapy with taxanes or platinum was not allowed. RESULTS A total of 53 patients were enrolled in this study, with 50 patients evaluable for response and toxicity. The overall response rate was 62% (95% confidence interval [CI], 48–75%); 16% of patients had complete responses and 46% had partial responses. The median time to progression was 7.3 months (95% CI, 5.9–12.9), and the 12-month survival estimate was 72% (95% CI, 61–86%). Therapy was generally well tolerated. Grade 3–4 neutropenia was the predominant toxicity, observed in 82% of patients, but there were no episodes of febrile neutropenia or sepsis. Hematopoietic growth factors were not routinely necessary. Grade 3 peripheral neuropathy occurred in 16% of patients. CONCLUSIONS Paclitaxel (200 mg/m2) with carboplatin (area under the curve 6 mg/mL per minute) demonstrated substantial efficacy in patients with metastatic breast carcinoma, and the 12-month survival rate of 72% was encouraging. This therapy represents a viable option for patients with metastatic disease. Cancer 2000;88:124–31. © 2000 American Cancer Society.

BACKGROUND Tamoxifen (TAM) is generally considered the hormonal agent of choice for postmenopausal women with hormone receptor positive breast carcinoma. The somatostatin analogues, including octreotide, have demonstrated inhibition of breast carcinoma cell lines and multiple endocrinologic actions, including reduction of insulin-like growth factor I (IGF-I), a potent mitogen for breast carcinoma cells. In an attempt to improve the efficacy of TAM, this randomized trial was performed. METHODS One hundred thirty-five eligible postmenopausal women with metastatic breast carcinoma were randomized to TAM (10 mg twice daily) alone or combined with octreotide 150 μg (administered subcutaneously thrice daily). The two groups were well balanced, except the TAM group had higher proportions of patients with visceral disease (50% vs. 37%) and a disease free interval longer than 5 years (47% vs. 34%). A cohort of 18 patients was evaluated for the impact of treatment on serum IGF-I, free IGF-I, IGF binding protein 3 levels, and total IGF binding capacity. RESULTS The median time to progression was estimated to be 14.2 months with TAM and 10.3 months with TAM plus octreotide. The distribution of progression free survival times revealed no significant difference (P = 0.26), and the progression hazard ratio (TAM/TAM + octreotide) was 0.81 (95% confidence interval [CI], 0.56–1.17). The distribution of survival times revealed no significant difference (P = 0.92), and the death hazard ratio was 0.98 (95% CI, 0.62–1.55). When the 106 patients with measurable or evaluable disease were considered, the objective response rate was 49% with TAM alone and 43% with TAM plus octreotide (P = 0.70). Patients who received TAM plus octreotide had higher incidences of nausea, diarrhea, and steatorrhea. The percentage of decline in serum IGF-I, from pretreatment levels to those following 3–6 weeks of treatment, was significantly greater (P < 0.01) with TAM plus octreotide than with TAM alone. CONCLUSIONS There is no indication that the combination of TAM plus octreotide as administered in this study is substantially more efficacious than TAM alone in the treatment of postmenopausal women with metastatic breast carcinoma. The limited cohort included in IGF-I studies suggests that TAM plus octreotide produces a significantly greater reduction in serum IGF-I levels. Cancer 1999;85:1284–92. © 1999 American Cancer Society.

One hundred fifty-one postmenopausal women with progressive metastatic breast cancer and no prior hormonal therapy were treated with either diethylstilbestrol (DES) or tamoxifen (TAM). One hundred forty-three eligible patients were followed until death or for a minimum of 14.1 years on the DES arm or 16.7 years on the TAM arm. The overall objective response was 42% for DES and 33% for TAM (p = 0.31) and the median duration of response was 11.8 months for DES and 9.9 months for TAM (p = 0.38). Duration of response and progression-free survival were not found to be significantly different between DES and TAM (p = 0.32 and 0.65, respectively). The median survival was 3.0 years for DES vs. 2.4 years for TAM. The 5-year survival was 35% for the DES arm and 16% for the TAM arm. Survival was significantly better for women on DES than for women on TAM (adjusted p = 0.039). Review of records did not show any difference in pattern of treatment failure or subsequent treatments in the DES and TAM arms. Treatment with DES was more commonly associated with toxicity such as nausea, edema, vaginal bleeding, and cardiac problems, whereas hot flashes were commonly seen with TAM therapy. The initial treatment with DES is associated with increased survival. The basis of this survival advantage is not known. TAM still is the preferred agent in the treatment of metastatic breast cancer, but this trial underscores the fact that estrogens have activity and remain in the armamentarium for treatment of selected patients with metastatic breast cancer.

OBJECTIVE: A Phase I study was conducted to determine the safety, toxicity, and maximum tolerated dose of preirradiation chemotherapy using carmustine (BCNU) and cisplatin in the treatment of high-grade gliomas. METHODS: Patients with newly diagnosed high-grade gliomas received BCNU and cisplatin after surgery, both before and during definitive radiation therapy. Preirradiation chemotherapy consisted of an administration of 40 mg/m 2 BCNU on Days 1 through 3 and 30 mg/m 2 cisplatin on Days 1 through 3 and 29 through 31 and repeated at 8 weeks to coincide with the start of radiation therapy. Postradiation chemotherapy consisted of an administration of 200 mg/m 2 BCNU once every 8 weeks for four cycles. Radiation therapy consisted of 160-cGy fractions administered twice daily for 15 days, yielding a total dose of 4800 cGy. Dose escalation of BCNU was planned. If hematological toxicity was mild, the dose of cisplatin was to be held constant and BCNU dose escalated to 50 mg/m 2 on Days 1 through 3. RESULTS: Eighteen patients were studied. The hematological toxicity was dose-limiting. Grade 3 or 4 leukopenia occurred in each of 10 patients (56%), and Grade 3 or 4 thrombocytopenia occurred in each of 9 patients (50%). Other toxicities included anorexia (94%), nausea (83%), emesis (33%), alopecia (94%), mild ototoxicity (50%), and, in one patient, death as a result of BCNU pulmonary toxicity. The median survival time was 14 months. Objective responses occurred in 45% of the patients evaluable for response. The maximum tolerated dose of this combination was 50 mg/m 2 BCNU on Days 1 through 3 and 30 mg/m 2 cisplatin on Days 1 through 3 and 29 through 31 before radiation and repeated in 8 weeks to coincide with the start of radiation. CONCLUSION: This schedule of the preirradiation administration of BCNU and cisplatin with accelerated hyperfractionated radiation therapy for the treatment of high-grade gliomas provides a less toxic alternative to that of previous studies of preirradiation chemotherapy with these agents and merits further investigation.

Mammographic density is one of the strongest risk factors for breast cancer. Numerous lines of evidence suggest that mammographic density is influenced by estrogen exposures ([1][1]-[5][2]). CYP19 produces aromatase, the enzyme responsible for conversion of androgens to estrogens in all tissues

BACKGROUND In contrast to female breast carcinoma, information regarding the prevalence and prognostic information of new molecular markers is limited in male breast carcinoma. The objective of this study was to assess the degree of expression and prognostic value of estrogen receptors (ER), progesterone receptors (PR), androgen receptors (AR), bcl-2, p53, HER-2/neu, cyclin D1, and MIB-1 in a cohort of male breast carcinoma patients. METHODS A computerized search of the medical index, tumor registry, and tissue registry was used to identify 111 male patients with a diagnosis of primary adenocarcinoma of the breast seen between 1950-1992 at the Mayo Clinic. Of these, 77 patients had adequate tissue specimens available for the immunohistochemical analysis of the markers. Immunoperoxidase staining was performed by an automated avidin-biotin complex method. Progression free (PFS) and overall (OS) survival distributions were estimated using the Kaplan-Meier method. The log rank test was used to determine whether any patient characteristic, tumor feature, or molecular marker was associated significantly with PFS or OS. RESULTS The majority of tumor specimens were positive for ER (91%), PR (96%), AR (95%), and bcl-2 (94%). Fewer positive specimens were found for cyclin D1 (58%), MIB-1 (38%), HER-2/neu (29%), and p53 (21%). The 5-year PFS and 10-year OS for the entire patient cohort was estimated to be 66% (95% confidence interval [CI], 57-77%) and 38% (95% CI, 29-50%), respectively. PFS was decreased significantly for those patients with tumors staining positively for MIB-1 (P = 0.012) or negatively for cyclin D1 (P = 0.009). OS was not found to differ significantly with respect to these markers. CONCLUSIONS The nearly universal expression of hormone receptors in these tumors suggests a central role for endogenous hormones in male breast carcinoma. The high degree of AR expression would suggest that antiandrogen therapy should be explored further. The high frequency of bcl-2 positivity may implicate antiapoptotic mechanisms in the carcinogenesis of male breast carcinoma. The finding of decreased PFS in MIB-1 positive tumors supports the role of proliferative activity as a negative prognostic factor in male breast carcinoma. Positive cyclin D1 expression is associated with increased PFS in male breast carcinoma patients, which suggests that interactions among cell cycle regulatory proteins may be important in this disease. Cancer 1998;83:1947-1955. © 1998 American Cancer Society.

The folate metabolism pathway contributes to important metabolic processes, such as RNA and DNA synthesis, DNA repair, and DNA methylation ([1][1]). Previous observations have suggested a potential relationship between altered folate levels and tumorigenesis ([2][2]). Therefore, inherited genetic

Endoxifen has recently been identified as the predominant active metabolite of tamoxifen and is currently being developed as a novel hormonal therapy for the treatment of endocrine sensitive breast cancer. Based on past studies in breast cancer cells and model systems, endoxifen classically functions as an anti-estrogenic compound. Since estrogen and estrogen receptors play critical roles in mediating bone homeostasis, and endoxifen is currently being implemented as a novel breast cancer therapy, we sought to comprehensively characterize the in vivo effects of endoxifen on the mouse skeleton. Two month old ovariectomized C57BL/6 mice were treated with vehicle or 50 mg/kg/day endoxifen hydrochloride via oral gavage for 45 days. Animals were analyzed by dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, micro-computed tomography and histomorphometry. Serum from control and endoxifen treated mice was evaluated for bone resorption and bone formation markers. Gene expression changes were monitored in osteoblasts, osteoclasts and the cortical shells of long bones from endoxifen treated mice and in a human fetal osteoblast cell line. Endoxifen treatment led to significantly higher bone mineral density and bone mineral content throughout the skeleton relative to control animals. Endoxifen treatment also resulted in increased numbers of osteoblasts and osteoclasts per tissue area, which was corroborated by increased serum levels of bone formation and resorption markers. Finally, endoxifen induced the expression of osteoblast, osteoclast and osteocyte marker genes. These studies are the first to examine the in vivo and in vitro impacts of endoxifen on bone and our results demonstrate that endoxifen increases cancellous as well as cortical bone mass in ovariectomized mice, effects that may have implications for postmenopausal breast cancer patients.

Development of endocrine resistance during tumor progression represents a major challenge in the management of estrogen receptor alpha (ERα) positive breast tumors and is an area under intense investigation. Although the underlying mechanisms are still poorly understood, many studies point towards the 'cross-talk' between ERα and MAPK signaling pathways as a key oncogenic axis responsible for the development of estrogen-independent growth of breast cancer cells that are initially ERα+ and hormone sensitive. In this study we employed a metastatic breast cancer xenograft model harboring constitutive activation of Raf-1 oncogenic signaling to investigate the mechanistic linkage between aberrant MAPK activity and development of endocrine resistance through abrogation of the ERα signaling axis. We demonstrate for the first time the causal role of the Aurora-A mitotic kinase in the development of endocrine resistance through activation of SMAD5 nuclear signaling and down-regulation of ERα expression in initially ERα+ breast cancer cells. This contribution is highly significant for the treatment of endocrine refractory breast carcinomas, because it may lead to the development of novel molecular therapies targeting the Aurora-A/SMAD5 oncogenic axis. We postulate such therapy to result in the selective eradication of endocrine resistant ERαlow/- cancer cells from the bulk tumor with consequent benefits for breast cancer patients.

Inflammatory breast cancer (IBC) is an angioinvasive and most aggressive type of advanced breast cancer characterized by rapid proliferation, chemoresistance, early metastatic development and poor prognosis. IBC tumors display a triple-negative breast cancer (TNBC) phenotype characterized by centrosome amplification, high grade of chromosomal instability (CIN) and low levels of expression of estrogen receptor α (ERα), progesterone receptor (PR) and HER-2 tyrosine kinase receptor. Since the TNBC cells lack these receptors necessary to promote tumor growth, common treatments such as endocrine therapy and molecular targeting of HER-2 receptor are ineffective for this subtype of breast cancer. To date, not a single targeted therapy has been approved for non-inflammatory and inflammatory TNBC tumors and combination of conventional cytotoxic chemotherapeutic agents remains the standard therapy. IBC tumors generally display activation of epithelial to mesenchymal transition (EMT) that is functionally linked to a CD44+/CD24-/Low stem-like phenotype. Development of EMT and consequent activation of stemness programming is responsible for invasion, tumor self-renewal and drug resistance leading to breast cancer progression, distant metastases and poor prognosis. In this study, we employed the luminal ER+ MCF-7 and the IBC SUM149PT breast cancer cell lines to establish the extent to which high grade of CIN and chemoresistance were mechanistically linked to the enrichment of CD44+/CD24low/- CSCs. Here, we demonstrate that SUM149PT cells displayed higher CIN than MCF-7 cells characterized by higher percentage of structural and numerical chromosomal aberrations. Moreover, centrosome amplification, cyclin E overexpression and phosphorylation of retinoblastoma (Rb) were restricted to the stem-like CD44+/CD24-/Low subpopulation isolated from SUM149PT cells. Significantly, CD44+/CD24-/Low CSCs displayed resistance to conventional chemotherapy but higher sensitivity to SU9516, a specific cyclin-dependent kinase 2 (Cdk2) inhibitor, demonstrating that aberrant activation of cyclin E/Cdk2 oncogenic signaling is essential for the maintenance and expansion of CD44+/CD24-/Low CSC subpopulation in IBC. In conclusion, our findings propose a novel therapeutic approach to restore chemosensitivity and delay recurrence of IBC tumors based on the combination of conventional chemotherapy with small molecule inhibitors of the Cdk2 cell cycle kinase.

BACKGROUND It is common practice to utilize a series of different hormonal agents in the treatment of postmenopausal women who, despite disease progression, continue to be candidates for hormonal therapy on a clinical basis. Letrozole is a new highly selective and potent aromatase inhibitor. There are limited data on third-line hormonal therapy in general, and this study was undertaken to evaluate letrozole in this context. METHODS A randomized trial involving two independent Phase II trials of two letrozole dosage levels, 0.5 mg and 2.5 mg per day, was performed. Eligibility requirements included failure on two prior hormonal therapies and measurable or evaluable disease. RESULTS Ninety-one patients, 46 receiving 0.5 mg and 45 receiving 2.5 mg of letrozole per day, were assessable for response. At the lower dose, 9 patients (20%) achieved an objective response; 6 patients (13%) had this documented on 2 occasions separated by 3 months. At the higher dose, 10 patients (22%) achieved a response; 8 patients (18%) had this documented on 2 occasions separated by 3 months. The median times to progression were 97 days for the lower dose and 154 days for the higher dose. Toxicity was considered acceptable. CONCLUSIONS Letrozole has definite antitumor activity as third-line hormonal therapy for women with metastatic breast carcinoma at doses of 0.5 and 2.5 mg per day. It is an effective and generally well-tolerated hormonal agent. Cancer 1997; 80:218-24. © 1997 American Cancer Society.

We performed a meta-analysis of randomized trials comparing tamoxifen to ovarian ablation carried out either by surgery or irradiation as first-line hormonal therapy for pre-menopausal women with metastatic breast cancer. Patients in all trials included were required to have measurable disease and to be currently menstruating or within 1 year of cessation of menses, and to have estrogen receptor (ER) positive or unknown disease (ER negative women were admitted to one of the studies). Individual patient data were obtained from the four studies identified and the results updated to June 1992. A total of 220 eligible patients were enrolled in the four trials. There was no difference in overall response rate between tamoxifen and oophorectomy across the four trials (p = 0.94, Mantel-Haenszel test). The odds reduction for progression was 14% ± 12% and for mortality 6% ± 13% in favour of tamoxifen, results which were not statistically significant (p = 0.32 and 0.72, respectively). Although the design of all four studies included a cross-over to the other therapy, only 54/111 patients receiving ovarian ablation and 34/109 patients receiving tamoxifen as primary therapy actually crossed over to the other arm at the time of disease progression. Response to initial treatment with tamoxifen was predictive of subsequent response to ovarian ablation (p < 0.05), and response to initial therapy with ovarian ablation was predictive of subsequent response to tamoxifen (p < 0.05). Support curves based on log-likelihood ratios revealed that this meta-analysis provides moderate evidence rejecting a 14% advantage for ovarian ablation compared to tamoxifen in terms of odds of disease progression. A 25% advantage for ovarian ablation with respect to odds of death is also rejected with moderate evidence. We conclude that the efficacy of tamoxifen appears to be similar to that of ovarian ablation by surgery or irradiation as first-line therapy for premenopausal, ER positive metastatic breast cancer, and is unlikely to be substantially inferior.

Based on reports of substantial antitumor efficacy of the combination of mitoxantrone (DHAD), 5-fluorouracil (FU) and leucovorin (LV), a clinical trial was performed to attempt augmentation of the dose of DHAD with filgrastim support. The doses and schedules, all intravenous, were DHAD (total dose divided over days 1 and 2), level I, 16 mg/m2; II, 20 mg/m2; III, 24 mg/m2; IV, 32 mg/m2; and LV, 300 mg, followed by FU, 350 mg/m2, on days 1-3. Filgrastim was given at 5 micrograms/kg/day subcutaneously on days 4-13. The planned cycle length was 21 days. Three or 4 patients were to be entered at each dose level and the maximum tolerated dose (MTD) was defined as the dose immediately below that which resulted in 2 patients with dose-limiting toxicity (DLT) in cycle 1. Once an apparent MTD was identified, an additional 6 patients were to be entered. Twenty patients (pts) were entered: level I: 3 pts; II: 3 pts; III: 10 pts: IV: 4 pts. The major toxicity was found to be cumulative thrombocytopenia with platelet counts < or = 20,000/microL occurring after cycle 1 at all levels beyond level I and five pts (25%) were removed from treatment solely because of platelet toxicity. Additional serious toxicities included grade 4 stomatitis in one patient (level IV) and cardiac toxicity in 2 patients with prior doxorubicin exposure. Ten pts had measurable and 8 had evaluable disease, and in 17 pts assessed, 5 (29%) achieved an objective response. The response rates in this study are lower than reported in the literature for the combination of DHAD, 5FU, LV and this may be related to the fact that only 40% of the patients were removed from protocol treatment because of disease progression. On the basis of limited DHAD-dose augmentation, toxicities observed, and modest response rate, the filgrastim-supported DHAD, 5FU, LV regimen as utilized in this study cannot be recommended for further development for treatment of women with metastatic breast cancer.

To prospectively assess tolerance to accelerated hyperfractionation radiation therapy in patients undergoing breast-conservation therapy and to exclude, with 90% confidence, a 20% or greater risk of an acute toxic reaction of at least grade 3 (severe).Thirty-seven patients (aged 33-80 years) with evaluatable cases received 48 Gy in twice-daily 1.6-Gy fractions to the breast and regional lymph nodes (if three or more lymph nodes were involved) and a boost of 9.6 Gy in twice-daily 1.6-Gy fractions. Acute and late effects were scored by using the Radiation Therapy Oncology Group and European Organization for the Research and Treatment of Cancer radiation morbidity criteria.One patient developed a grade 3 acute skin toxic reaction and another grade 3 (continuous) acute edema. There have been no grade 4 (life-threatening) acute toxic reactions, local recurrences, or cancer- or treatment-related deaths.This breast-conservation accelerated hyperfractionation radiation therapy schedule is tolerable. Additional follow-up is necessary to determine long-term morbidity and cosmesis, and further study in a larger patient group is necessary to confirm efficacy.