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© 2001 American Society for Clinical Oncology Tamoxifen and Chemotherapy for Axillary Node-Negative, Estrogen Receptor–Negative Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-23From the National Surgical Adjuvant Breast and Bowel Project; Pittsburgh PA. Address reprint requests to Bernard Fisher, MD, National Surgical Adjuvant Breast and Bowel Project, 4 Allegheny Center, Suite 602, Pittsburgh, PA 15212-5234; email: bernard.fisher{at}nsabp.org
PURPOSE: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor–negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study. PATIENTS AND METHODS: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status.
RESULTS: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P = .96, .8, and .8, respectively), for those aged CONCLUSION: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.
BEFORE THE LATE 1980s, it was considered inappropriate to use systemic therapy to treat women with invasive breast cancer and tumor-negative axillary nodes because there was inadequate information from randomized trials to justify its use.1 However, preliminary findings from a nonrandomized study reported by Bonadonna et al2 in 1987 and information from four randomized trials published simultaneously in February 19893-6 led to a change in the way such patients were subsequently managed. Particularly significant among the 1989 reports were findings from two National Surgical Adjuvant Breast and Bowel Project (NSABP) studies that showed a benefit from chemotherapy in both premenopausal and postmenopausal women with negative nodes and estrogen receptor (ER)–negative tumors3 and demonstrated an advantage from tamoxifen (TAM) in a similar population of women with ER-positive tumors.4 Although the findings in the NSABP reports led to a shift in the paradigm that governed the treatment of such patients, they gave increase to numerous questions. These issues related to whether there were cohorts of ER-negative or ER-positive patients who (1) had such a favorable prognosis that chemotherapy or TAM therapy was unnecessary, (2) failed to benefit from either chemotherapy or TAM therapy and would, thus, be excluded from receiving those agents, or (3) benefited so greatly from a particular therapy as to preclude the need to identify other regimens for their treatment. There was also concern about which of the various chemotherapeutic regimens that had demonstrated a benefit was most appropriate for use in clinical practice, whether chemotherapy should be given in addition to TAM to women with ER-positive tumors, and how patients with occult invasive cancer should be managed. Another concern related to the propriety of using TAM to treat patients with ER-negative tumors and negative nodes. North American investigators were reluctant to use TAM to treat such women because no data were available from clinical trials that had been specifically conducted to determine the worth of the drug in women whose tumors were ER negative. However, findings from two British trials that evaluated TAM in women with either negative or positive nodes and tumors with negative, positive, or unknown ER status resulted in a different opinion among British investigators. One of these studies was conducted by the Nolvadex Trial Organization7-10 and the other by the Scottish Cancer Trials Office.11 In both instances, investigators concluded that there was an overall advantage from TAM therapy that was independent of menopausal, nodal, or ER status. It was their view that the ER content of a primary tumor was, at best, a weak predictor of treatment effect and that their study findings provided justification for considering the use of TAM in node-negative patients with ER-negative tumors. However, findings from an earlier trial conducted by the NSABP had demonstrated a positive association between the ER content of a primary tumor and the probability of response to TAM that had been administered in combination with cytotoxic chemotherapy.12 Palshof,13 however, had failed to demonstrate a selective benefit according to tumor ER status. The NSABP considered these diverse opinions to be of sufficient clinical importance to justify the conduct of a trial aimed primarily at obtaining information about the value of TAM in the treatment of this patient population. There were also two other compelling reasons for conducting such a study. One related to experimental evidence that had demonstrated that TAM might exert its antitumor effect through a variety of biologic mechanisms unrelated to its binding to tumor ER.14-21 Another related to the fact that, when the study was being designed, one of the goals of the NSABP was to attempt to establish the worth of an adjuvant therapy regimen that could be used for all patients, regardless of their nodal, tumor receptor, or menopausal status. The beneficial effect from chemotherapy used in the treatment of node-negative patients with ER-negative tumors had already been firmly established,3 and findings from two earlier studies conducted by the NSABP had demonstrated that a chemotherapy and TAM regimen was better than chemotherapy alone in the treatment of node-positive patients with ER-positive tumors.12,22 Thus, when we designed the study to test the worth of TAM for the treatment of women with ER-negative tumors, it was deemed inappropriate to withhold chemotherapy and administer TAM alone, as had been done in both of the British trials.7,11 That decision prompted consideration about which chemotherapeutic regimen should be given with TAM. Because a combination of cyclophosphamide, methotrexate, and fluorouracil (CMF) was most frequently used to treat node-negative patients at that time, that regimen was deemed appropriate. There were, however, several reasons for considering the use of doxorubicin (Adriamycin, Pharmacia & Upjohn, Pepack, NJ) and C (AC) as well. Findings from an earlier NSABP study had demonstrated that the outcome in node-positive patients after treatment with AC therapy administered for 63 days was equivalent to that achieved with 6 months of conventional CMF.23 In addition, when considered relative to quality of life and toxicity, AC was preferable. However, because AC had never been evaluated in node-negative patients, it was considered necessary that such information be obtained to estimate its worth as a comprehensive treatment. These reasons prompted the NSABP to initiate the B-23 trial, a study designed to determine whether AC was comparable or superior to CMF when used to treat node-negative patients with ER-negative tumors and whether, when given with TAM, either of those chemotherapy regimens was more effective than when administered with placebo. This report presents the initial findings from the B-23 trial.
Women at participating NSABP institutions in the United States and Canada who had primary operable, histologically node-negative, ER-negative breast cancer and a life expectancy of at least 10 years were eligible for this study if they fulfilled other eligibility criteria. After they had undergone surgery and had given written, informed consent, they were stratified according to age (  49 or  50 years), tumor size as determined by clinical examination (< 2 or 2 cm), and type of surgery (total mastectomy and axillary node dissection, or lumpectomy and axillary node dissection followed by breast irradiation). Randomization was performed within these strata by use of a biased-coin approach to ensure that treatment assignment was balanced with respect to these characteristics. Between May 12, 1991, and December 31, 1998, patients were randomly assigned to one of four treatment groups after surgery: six courses of CMF plus placebo, six courses of CMF plus TAM, four courses of AC plus placebo, or four courses of AC plus TAM. Patient and treatment assignment information is listed in Table 1. A total of 2,008 patients were randomized to the study (1,005 to CMF and 1,003 to AC). One half of the patients randomly assigned to CMF received placebo and one half received TAM in addition to CMF; a similar distribution occurred among those randomly assigned to AC therapy. Of the 2,008 patients randomized to the study, 1.7% were ineligible and there was no follow-up information for an additional 1.3%. Ineligible patients and those without follow-up were fairly evenly distributed among the four groups. Of those randomly assigned to CMF or AC, 98% and 96% of the patients, respectively, were eligible with follow-up. The average time on study was 65 months (range, 10 to 102 months).
The distribution of patient and tumor characteristics used as stratification variables was similar among the groups ( Table 2). Approximately 55% of the patients were younger than 50 years. Approximately 12% had tumors 1.0 cm (T1a,b), and, in approximately 42%, tumors were between 1.1 and 2.0 cm (T1c). Approximately one third of tumors were from 2.1 to 4.0 cm (T2). Tumors were ER negative (0-9 fmol per mg of cytosol protein) in 98% of the patients, whereas in 13%, they were progesterone receptor (PgR)–positive (10 fmol per mg of cytosol protein). Slightly more than one half (55%) of the patients were treated with lumpectomy and postoperative breast irradiation. Tumor specimens from 2,008 patients were assayed for both ER and PgR levels by means of sucrose density gradient, dextran-coated charcoal titrations (894, 45%), enzyme immunoassay (372, 19%), or immunocytochemical assay (735, 37%). The method used was unstated in fewer than 1% of patients. There was concordance in the distribution of the methods used among the four groups. Although measurement of both tumor ER and PgR concentrations was required for entry onto the study, only the ER measurement was used to determine eligibility.
All patients received TAM or placebo (10 mg orally twice a day) for 5 years. TAM therapy was begun simultaneously with the administration of CMF or AC, ie, approximately 14 and 35 days after surgery, respectively. CMF was administered in accordance with the standard Milan regimen. C (100 mg/m2) was given orally as a single dose on days 1 to 14, inclusive, every 28 days for six cycles. M (40 mg/m2) and F (600 mg/m2) were given intravenously (IV) on days 1 and 8 every 28 days for six cycles. Patients assigned to AC received A (60 mg/m2 IV) and C (600 mg/m2 IV) every 21 days for four cycles. Detailed criteria and scheduling for dose modification or drug delay in the event of drug toxicity have been reported for CMF and AC.23 Patients who were treated with lumpectomy also received breast irradiation. When administered in conjunction with CMF, radiation therapy was begun within 1 week after day 8 of the first cycle of CMF when there was no evidence of hematologic toxicity. Subsequent doses of CMF were delayed until radiation therapy was completed and until evidence of hematologic toxicity was absent. Breast irradiation was begun after the completion of all AC therapy when blood counts permitted, and in all treatment groups, the administration of TAM or placebo was continued during radiation.
Statistical Methods The protocol for B-23 stated that a reduction of 40% in death rates for each of the two major hypotheses would be considered for power calculations. It was assumed that the two primary comparisons would involve CMF versus AC and placebo versus TAM. A Bonferroni adjustment for two comparisons would require approximately 147 deaths to have at least 80% power to detect the stated difference. As of December 31, 1999, the number of deaths observed exceeded the number projected for the final analysis. Life-table analysis24,25 and Cox proportional hazards models26 were performed on the end points; in both, adjustments were made for the stratification variables. Unadjusted life-table results were also tabulated and yielded similar results. The latter analyses are presented in this report. Treatment comparisons were made by using two-sided log-rank tests over all available observation times.27,28 Treatment by covariate interactions were also tested for all stratification variables.29 Analyses were performed on all patients by using all women with follow-up, regardless of whether they met the eligibility criteria defined in the protocol (the intention-to-treat analysis) and including only those women who met eligibility criteria (the analysis per protocol). The results of these analyses did not differ. Analyses obtained by using the intention-to-treat principle are presented here. Toxicity and compliance data were summarized for all patients for whom information was provided, regardless of their eligibility. The cutoff date for toxicity information was February 27, 2000.
Comparison of the Four Treatment Groups RFS, EFS, and survival. There was no significant difference in RFS among the four groups through 5 years of follow-up (P = .96; Fig 1). The RFS for the groups treated with CMF plus placebo and for those treated with CMF plus TAM was 88% and 87%, respectively; the RFS for each group that received AC plus either placebo or TAM was 87%. When the RFS was evaluated according to patient age, there were no significant differences among the four groups for women aged 49 years; the RFS was 87%, 88%, 86%, and 85% (P = .97). A similar circumstance prevailed for women aged 50 years; the RFS for the two groups treated with CMF was 88% and 85%; it was 89% and 88% for the groups treated with AC plus placebo and AC plus TAM, respectively (P = .7).
As with RFS, there was no significant difference in EFS among the four groups through 5 years of follow-up (P = .8, not shown). The 5-year EFS for each of the groups treated with CMF plus placebo and CMF plus TAM was 83%; for the two groups treated with AC plus placebo or AC plus TAM, it was 83% and 82%, respectively. Similarly, when EFS was evaluated according to patient age, there was no significant difference among the four groups (not shown). The 5-year EFS for women aged 49 years in the four groups was 84%, 85%, 82%, and 80% (P = .5). For those aged 50 years, it was 82%, 81%, 84%, and 84% in the four groups (P = .6).
A comparison of survival distributions demonstrated no significant difference in survival among the four groups (P = .8; Fig 2). There was an 89% survival for both of the CMF-treated groups and a 90% survival for both of the AC-treated groups. As with RFS and EFS, there was no significant difference in survival either within or across age groups. In the two groups treated with CMF, the overall survival among patients aged
Comparison of CMF- With AC-Treated Patients RFS, EFS, and survival. When the two groups of CMF-treated patients who received placebo or TAM were combined and compared with the two AC-treated groups that had similarly been combined, no significant difference in RFS was observed through 5 years of follow-up (P = .9; Fig 3). The RFS for both the CMF- and the AC-treated groups was identical, 87%. When the RFS was evaluated according to patient age, there was no significant difference between the two groups for women aged 49 years (88% for those treated with CMF and 85% for those who received AC; P = .7). A similar circumstance prevailed for women aged 50 years: the RFS was 86% for those treated with CMF and 89% for those who received AC (P = .4).
As with RFS, there was no significant difference in EFS between the CMF and AC groups overall; it was 83% in the former and 82% in the latter (P = .6, not shown). Similarly, when EFS was evaluated according to patient age, there was no significant difference between the two groups (not shown). For women aged 49 years, the EFS was 84% and 81% for the CMF- and AC-treated groups, respectively (P = .1). For women aged 50 years, it was 81% and 84%, respectively (P = .3).
There was no significant survival difference between the two groups overall; survival was 89% for women treated with CMF and 90% for those treated with AC (P = .4; Fig 4). There was, likewise, no significant survival difference between women treated with CMF and those treated with AC in either age group. Survival was 90% for women aged
Comparison Between Chemotherapy-Treated Patients Who Received Placebo and Chemotherapy-Treated Patients Who Received TAM RFS, EFS, and survival. When the CMF- and AC-treated groups were combined and women who received placebo were compared with those who received TAM, no significant difference in RFS was observed; the RFS was 87% in both groups (P = .6; Fig 5). There was, likewise, no difference when RFS was related to age. In women aged 49 years, it was 87% in both groups (P = .9); in those aged 50 years, it was 88% and 87% in the two groups, respectively (P = .4).
The EFS of the placebo and TAM-treated groups overall was 83% and 82%, respectively (P = .4). In women aged 49, the EFS of both groups was 82% (P = .8). In women aged 50 years, it was 83% for both groups (P = .4, not shown). The 5-year survival outcomes were practically identical for women who received either placebo or TAM. Both groups had a survival of 90% (P = .8), and those values were similar for both age groups (P = .98 for women aged 49 years, and P = .7 for women in the older age group; Fig 6).
Sites of First Events According to Treatment Regimen The rate of all breast cancer events, ie, local-regional, distant, and events in the contralateral breast, was similar across all four groups, ie, approximately 13% ( Table 3). The incidence of IBTRs, when these were considered local-regional treatment failures, was only 2%. When related to all patients who were treated with lumpectomy and breast irradiation (1,110 women), the rate of IBTR was 3% through 5 years. One percent of the 558 women treated with lumpectomy, postoperative radiation therapy, and either CMF or AC with placebo developed an IBTR; 5% of the 552 patients who received TAM in addition to chemotherapy demonstrated an IBTR. The incidence of second primary tumors and deaths with no evidence of disease was small but equivalent across all groups. The total number of events in women in the CMF- and AC-treated groups that received placebo was combined and compared with those in women in CMF- and AC-treated groups that received TAM. Although few events occurred at some sites, there was no suggestion of either a reduction or an increase in treatment failures from the addition of TAM. Among the 2,008 randomized patients, 241 (12%) had tumors of 1.0 cm. There were 12 deaths, 10 with evidence of metastatic disease, and 27 breast cancer-related events among the 241 women.
Drug Compliance and Toxicity As of February 28, 1999, information about drug-related toxicity was recorded for 1,983 patients, 997 who received CMF and 986 who received AC. A total of 5,606 courses ofprotocol therapy had been completed by patients who received CMF (average, 5.7 courses of a possible six per patient), and 3,864 courses had been completed by patients who received AC (average, 3.9 courses of a protocol-mandated four courses per patient). Approximately 1% of patients did not begin their therapy, ie, nine patients assigned to CMF and 10 to AC ( Table 4). More women who began CMF discontinued chemotherapy (10%) than did women who received AC (4%). Twenty-eight percent of all of the women who received TAM discontinued the drug. There was no difference in that regard between those who received TAM with CMF or with AC, ie, 28% in the former and 27% in the latter. Of those who received TAM, 64%, 51%, 38%, and 29% received the drug for 2, 3, 4, and 5 years, respectively. The overall percentage of women who discontinued placebo was similar, ie, 27%. In women who received placebo with CMF, it was 31%; it was 22% in women who received AC and placebo. Patient withdrawal was the most common reason for discontinuing therapy.
Information about the severity of toxicity, ie, the greatest toxicity per patient, is summarized in Table 5. Overall, approximately 10% more patients on CMF than on AC had grades 3 and 4 toxicity. The differences between patients who received placebo or TAM within a treatment group, ie, CMF or AC, were similar. Granulocyte depression was also less serious after AC than after CMF therapy. The frequency of life-threatening toxicity was fairly equally distributed across all treatment groups, ie, 5% to 7%, as was the frequency of other toxicities, which occurred less often. There were six endometrial cancers; one occurred in the CMF group that received placebo and five in the CMF group treated with TAM. None were observed in either of the groups treated with AC. All five of the endometrial cancers in the TAM group were International Federation of Gynecology and Obstetrics stage I, ie, localized tumors. The one endometrial cancer in the placebo group was International Federation of Gynecology and Obstetrics stage II. Only one patient in the study (in the AC group receiving placebo) was reported as having had a stroke. The occurrence of thromboembolism was observed in four of the patients who received CMF and placebo, seven of those given CMF and TAM, none who received AC and placebo, and four treated with AC and TAM. Five deaths have been reported within 3 months of patients being on chemotherapy: three in women who received CMF and two in those treated with AC. All women were older than 60 years. One of the three patients who received CMF died of septic shock after four courses. One of the other two patients died from myocardial infarction after three courses and the other from cardiac arrhythmia on completion of her fourth course of therapy. One patient died from pneumonia and respiratory failure after her fourth course of AC. The other died from myocardial infarction after three courses of AC. In addition, two other deaths occurred in patients who received CMF, more than 3 months after the completion of chemotherapy. One of these deaths was in a 57-year-old woman and was caused by acute myocardial infarction 20 months after chemotherapy. The other death, in a 38-year-old woman, was caused by a pulmonary embolus that occurred 9 months after completion of CMF therapy. Both patients were receiving placebo.
The findings in this report have defined the relative worth of the CMF and AC regimens for the treatment of patients with ER-negative tumors and negative axillary nodes. Although no significant difference in RFS, EFS, or survival was observed among women who received the different regimens, the findings provide further support for the use of AC as a comprehensive adjuvant therapy that benefits patients with breast cancer, regardless of their nodal status, age, or ER status. When the same regimens were compared in women with ER-negative tumors and positive nodes in the NSABP B-15 study, findings almost identical to the ones in this report were obtained.23 Furthermore, findings from the NSABP B-16 trial supported the efficacy of AC therapy in node-positive patients with ER-positive tumors.22 This is an indication that AC administered with TAM was more efficacious than was TAM alone. When CMF was given with TAM to node-negative patients who had ER-positive tumors, it was more effective than was TAM alone. In view of our current findings demonstrating the comparability of CMF and AC in a variety of settings, it is likely that AC would be similarly effective in that patient cohort. As has been previously described, other reasons justify the use of AC therapy.23 One relates to the fact that the duration of AC therapy is shorter than that of CMF, ie, 63 days versus 154 days or longer, respectively. Another advantage from AC administration is that patients who receive that regimen usually see a physician or other health care provider only four times to receive therapy, whereas patients who receive CMF must be seen 12 times for that purpose. In addition, it has been found that four courses of AC therapy given for 63 days is no more toxic than 6 months’ treatment with conventional CMF. Finally, the need for treatment of side effects is less often necessary after AC therapy, because almost all CMF-treated women have required medication to control nausea and other side effects throughout each 14-day course of therapy, ie, for approximately 84 days. In contrast, such medication is administered to patients on AC for only 12 days, ie, for approximately 3 days after each course. It is worth noting that, in the B-23 study, more women (10%) discontinued CMF than stopped AC therapy (4%). Thus, there is justification for the use of AC therapy in either premenopausal or postmenopausal breast cancer patients who have either negative or positive axillary nodes, as well as in breast cancer patients with ER-negative or ER-positive tumors in whom the use of adjuvant chemotherapy is considered appropriate. This report has also provided information about the efficacy of administering TAM with chemotherapy to women who have ER-negative tumors and negative axillary nodes. In 1991, when patients began to enroll onto the B-23 study, there was sufficient uncertainty about such an approach in ER-negative patients to justify the conduct of the trial. In 1998, the Early Breast Cancer Trialists’ Cooperative Group provided an overview of findings from 8,000 patients with ER-poor (low or zero) tumors who received TAM for any length of time, ie, 1, 2, or 5 years.30 Women with both positive and negative axillary nodes were included. In these trials, in which adjuvant TAM was compared with no adjuvant TAM, some investigators scheduled no chemotherapy for either group, but others randomly assigned women to TAM plus chemotherapy versus the same chemotherapy given alone. It was stated that "the benefits of treatment were less clear [than those from patients with ER-positive tumors]. Overall, irrespective of duration of tamoxifen, the proportional reduction was 10% (SD 4; P = .007; 95% CI, 2% to 17%)." When contralateral breast cancers were not included, the reduction in recurrence was 9% (SD 4; P = .02). There was no trend toward greater benefit with longer TAM treatment. The mortality reduction was only 6% (SD 4; not significant). In summarizing the findings of the Early Breast Cancer Trialists’ Cooperative Group meta-analysis, the authors stated that "It is difficult to know whether these recurrence and mortality results represent real benefit in some women whose tumours would, even by the best ER assay methods, still be wholly ER negative, or whether they reflect real benefit only among women whose tumours would have had detectable, albeit low, receptor levels by current methods." It was also considered that the existence of some real benefit could not be excluded for those women whose tumors were categorized as ER poor or PR poor and could not be assumed for those whose tumors were ER poor, PR positive. The authors concluded that, "for women with tumors that have been reliably shown to be ER-negative, adjuvant tamoxifen remains a matter for research." Based on the information in this report of B-23, it is difficult to justify the administration of TAM to patients with ER-negative breast tumors and negative axillary nodes. In that regard, it is necessary to comment on the fact that it took nearly 8 years to complete accrual of patients in the B-23 trial and that 28% of TAM-treated women discontinued the drug. The occurrence of these events, unusual in the history of the NSABP, was unrelated to apathy about the importance of the study or to toxicity experienced by women who took the drug. Both circumstances were the result of unwarranted and unfavorable publicity related to certain putative adverse effects from TAM and to external interference with the conduct of all NSABP studies. Because, however, the median duration of TAM administration to patients in the B-23 study was 36.4 months and 29% of the patients received 5 years of TAM, and because it has been shown that 2 or more years of therapy is effective,25 the failure to demonstrate a benefit cannot be attributed to the fact that there were patients who discontinued TAM therapy.
The current findings, which demonstrated neither a significant benefit nor a detriment from TAM when the drug was given in conjunction with either CMF or AC to women aged
Because our findings provide no evidence to suggest that TAM administration in conjunction with chemotherapy for the treatment of patients with ER-negative tumors has any worth, it seems that the question of whether the administration of TAM to such patients results in negative effect is moot. Because, however, it has been reported that the proportional reduction in contralateral breast cancer appears to be approximately the same size in women whose initial tumors were ER-positive (29%) as in those whose first breast cancers were ER-negative (30%),30 giving TAM to women despite their ER-negative tumor status so as to prevent second primary tumors might warrant consideration. If, however, a negative interaction results when the drug is used for treatment of the initial tumor, that idea certainly has no virtue. Because of the extremely low incidence of contralateral breast cancers in all groups of patients in the current study, ie, A compelling justification for implementing the B-23 trial to evaluate the effect of TAM on ER-negative tumors related to the presence of biologic information that suggested that mechanisms responsible for the control of tumor growth by TAM were unrelated to the role of ER.36-38 Laboratory investigations had demonstrated that TAM might be effective in inhibiting the proliferation of hormone-independent breast cancer cells by altering production of growth factors such as transforming growth factor beta19,20,39,40; by stimulating natural-killer cell activity and, consequently, the risk for tumor recurrence18; and by decreasing insulin-like growth factor I, which modifies the regulation of cancer cell kinetics.17 Information demonstrating that breast cancer growth and metastases are related to angiogenesis41 and that noncorticosteroidal antiestrogens like TAM inhibit angiogenesis21 provided compelling evidence to support the thesis that the antitumor effect of antiestrogens is not entirely related to the inhibition of ER-mediated action. Thus, there was adequate justification for formulating a hypothesis that TAM might be beneficial for the treatment of women with ER-negative tumors. Because the clinical findings from B-23 failed to demonstrate any semblance of a benefit from TAM, it might be considered that the thesis that biologic mechanisms other than ER might be responsible for TAM’s effect has been repudiated. Because the B-23 trial was not designed to estimate those biologic changes, either individually or collectively, it is not possible to conclude, or even to speculate, how they were affected by TAM in the population comprising this study. Nonetheless, the findings from B-23 seem to indicate, in keeping with generally accepted concepts, that tumor cell ER is a major, if not the only, mechanism by which TAM exerts its antitumor effect.
APPENDIX
This investigation was supported by Public Health Service grants U10-CA-12027, U10-CA-69651, U10-CA-37377, and U10-CA-69974 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. We thank Ronelle Evans and Pat Slobada for data management, Darlene Kiniry and Ken Duff, for programming support, Cheryl Butch, RN, and Barbara Harkins, RN, MN, for data review, Tanya Spewock for editorial assistance, and Mary Hof for preparation of the article.
1. Consensus conference: Adjuvant chemotherapy for breast cancer. JAMA 254: 3461-3463, 1985 2. Bonadonna G, Valagussa P, Zambetti M, et al: Milan adjuvant trials for stage I-II breast cancer, in Salmon SE (ed): Adjuvant Therapy for Cancer V. Orlando, FL, Grune & Stratton, 1987, pp 211-221 3. Fisher B, Redmond C, Dimitrov NV, et al: A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med 320: 473-478, 1989[Abstract] 4. Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320: 479-484, 1989[Abstract] 5. Mansour EG, Gray R, Shatila AH: Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer: An intergroup study. N Engl J Med 320: 485-490, 1989[Abstract] 6. The Ludwig Breast Cancer Study Group: Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med 320: 491-496, 1989[Abstract] 7. Nolvadex Adjuvant Trial Organisation: Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer. Lancet 1: 257-261, 1983[Medline] 8. Nolvadex Adjuvant Trial Organisation: Improved survival amongst patients treated with adjuvant tamoxifen after mastectomy for early breast cancer. Lancet 2: 450, 1983 9. Nolvadex Adjuvant Trial Organisation: Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer: Analysis at six years by ‘Nolvadex’ Adjuvant Trial Organisation. Lancet 1: 836-840, 1985[Medline] 10. Baum M, Brinkley DM, Dosset JA, et al: Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer: Analysis at eight years by Nolvadex Adjuvant Trial Organization. Br J Cancer 57: 608-611, 1988[Medline] 11. Bartlett K, Eremin O, Hutcheon A, et al: Adjuvant tamoxifen in the management of operable breast cancer: The Scottish trial—Report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC), Edinburgh. Lancet 2: 171-175, 1987[Medline] 12. Fisher B, Redmond C, Brown A, et al: Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med 305: 1-6, 1981[Abstract] 13. Palshof T: Adjuvant endocrine therapy in the management of primary breast cancer. Rev End-Rel Cancer 7: 65-75, 1981 (suppl) 14. Sutherland RL, Green MD, Hall RE, et al: Tamoxifen induces accumulation of MCF-7 human mammary carcinoma cells in the G0/G1 phase of the cell cycle. Eur J Cancer Clin Oncol 19: 615-621, 1983[Medline]
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17.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
