Affiliations of authors: B. Fisher, National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA; J. Dignam, S. Anderson, Department of Biostatistics, University of Pittsburgh; E. Tan-Chiu, NSABP and Allegheny General Hospital, Pittsburgh; E. R. Fisher, NSABP and Allegheny General Hospital; J. L. Wittliff, University of Louisville Hormone Receptor Laboratory, KY; N. Wolmark, NSABP and Allegheny General Hospital.
Correspondence to: Bernard Fisher, M.D., Scientific Director, National Surgical Adjuvant Breast and Bowel Project, 4 Allegheny Center, Suite 602, Pittsburgh, PA 152125234 (e-mail: bernard.fisher{at}nsabp.org).
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ABSTRACT |
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INTRODUCTION |
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Although evidence of a benefit from systemic adjuvant therapy in patients with axillary lymph node-positive breast cancer had been obtained by the mid-1970s (24), studies to determine the value of such therapy in patients with negative lymph nodes were not implemented until the 1980s. In fact, a National Institutes of Health consensus conference (5) convened in 1985 to make recommendations for the treatment of patients with primary breast cancer had judged the data to be inadequate to justify the use of systemic therapy in women with negative axillary lymph nodes. During the 10 years that followed, findings from four National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trials involving more than 10 000 patients with primary operable breast tumors of any size and negative axillary lymph nodes and results from studies conducted by other investigators (6,7) provided information about the worth of systemic therapy for such patients. Two of the NSABP trials (8,9) demonstrated the efficacy of chemotherapy for women with estrogen receptor (ER)-negative tumors, and one other study of patients with ER-positive tumors (10) demonstrated a benefit from tamoxifen. A second study of patients with ER-positive tumors (11) demonstrated that the outcome of patients treated with tamoxifen and chemotherapy was better than that of patients treated with tamoxifen alone. Although analyses conducted in each of the four NSABP trials indicated that all cohorts of patients benefited from systemic therapy, it was emphasized in the report of each study that the number of women with tumors of 1 cm or less was too few to permit determining whether or not they should receive such therapy.
For more than a decade, in addition to findings from NSABP randomized trials, numerous reports of information have been collected from the clinical records of women with small tumors and negative lymph nodes who had been treated outside the clinical trial setting at a particular institution. The outcome (i.e., natural history) of those patients has influenced thinking about whether adjuvant therapy should be included in their treatment (1223). Despite the equivocal way in which much of the data were obtained, many of the investigators concluded that patients with tumors of 1 cm or less were at sufficiently low risk for recurrence to warrant their being spared adjuvant therapy.
Continuing uncertainty on the part of physicians about the management of breast cancer patients with small tumors prompted us to determine whether combining data from similar cohorts of women among the 1259 patients with tumors of 1 cm or less who were enrolled in the NSABP randomized trials might produce information that could aid in determining the prognosis of such women and whether these patients could benefit from systemic adjuvant therapy. This article reports findings with regard to the prognosis of women who had either ER-negative or ER-positive tumors and who were treated with surgery (i.e., total mastectomy or lumpectomy with postoperative breast irradiation). It also presents information about the worth of chemotherapy in women with ER-negative tumors and the worth of tamoxifen with or without chemotherapy in those with ER-positive tumors.
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PATIENTS AND METHODS |
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Women with primary operable breast tumors of 1 cm or less (T1a is 5 mm or less, and T1b is larger than 5 mm but not larger than 10 mm in the greatest dimension) and no axillary lymph node metastases (N0) were selected from a group of 10 302 patients who, after having given written informed consent, were enrolled in NSABP trials B-13, B-14, B-19, B-20, or B-06five randomized clinical trials that were conducted at participating institutions in the United States and Canada. The tumor sizes recorded in the database were obtained from pathology reports that had been submitted to the NSABP Biostatistical Center (University of Pittsburgh, PA) at the time of patient entry.
NSABP Trials B-13 and B-19.
Both studies were limited to patients who had ER-negative tumors. In B-13, 760 patients were randomly assigned to receive either surgery alone (n = 384) or methotrexate followed by 5-fluorouracil (MF) and leucovorin (n = 376) (8). Immediately after randomization, an additional 356 patients who met the same protocol requirements as the randomly assigned patients and who were from the same institutions and were enrolled by the same investigators were registered to receive M
F therapy. The results demonstrated a significant improvement in disease-free survival (DFS) for women treated with M
F, as compared with women who received no systemic therapy. Those findings, as well as the results from studies conducted by other investigators (6,7), which had demonstrated a benefit from cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in patients with negative axillary lymph nodes and ER-negative tumors, led the NSABP to implement the B-19 trial, a study aimed at comparing the worth of M
F with that of conventional CMF. In B-19, 1095 patients were randomly assigned to treatment with surgery followed by M
F (n = 547) or to treatment with surgery followed by CMF (n = 548) (9). A report of the findings from B-19 and an update of the B-13 study (9) demonstrated that both M
F and CMF were effective when used to treat patients who had negative axillary lymph nodes and ER-negative tumors. CMF was more effective, particularly in premenopausal women.
NSABP Trials B-14 and B-20.
These studies were conducted concurrently with B-13 and B-19 to evaluate the worth of tamoxifen, either alone or in combination with chemotherapy, in the treatment of patients who had ER-positive tumors. A total of 1453 patients in the B-14 study were randomly assigned to receive placebo, and 1439 were randomly assigned to receive tamoxifen. Immediately upon completion of the accrual of 2892 patients to the randomized study, an additional 1235 women who met the same protocol requirements as the randomly assigned patients and who were from the same institutions and were enrolled by the same investigators were registered to receive tamoxifen. When a benefit from tamoxifen was demonstrated in B-14 (10,24), the B-20 study was initiated to test the hypothesis that the addition of MF or of CMF to tamoxifen would provide a greater benefit than would tamoxifen alone in patients with negative axillary lymph nodes and ER-positive tumors (11). Patients in B-20 (n = 2363) were randomly assigned to one of three treatment groups after surgery: tamoxifen alone (n = 788), tamoxifen plus M
F (n = 786), or tamoxifen plus CMF (n = 789) (11). Findings demonstrated that, when compared with tamoxifen alone, tamoxifen plus M
F and tamoxifen plus CMF significantly reduced the risk of breast cancer recurrence.
NSABP Trial B-06. The NSABP conducted the B-06 trial to compare the worth of lumpectomy with or without radiation therapy for breast preservation. Reports from that study (25,26) demonstrated the worth of lumpectomy followed by breast irradiation for the treatment of most patients with primary operable breast cancer. Because lumpectomy-treated patients in the other four trials received radiation therapy, which reduced their rate of a subsequent ipsilateral breast tumor recurrence (IBTR), patients in B-06 who received lumpectomy alone were excluded. Axillary lymph node-negative patients with tumors of 1 cm or less in B-06 who were treated either with a total mastectomy or with lumpectomy and radiation therapy and who had tumors with known ER status participated in the current study. A total of 84 patients had such tumors and had not received systemic therapy.
Among the 3196 patients with ER-negative tumors in the B-13, B-19, and B-06 trials, we identified 1055 women with axillary lymph node-negative tumors of 2 cm or less; 235 of these women had tumors that were of 1 cm or less (Table 1). A total of 61 women were treated with surgery alone; 174 women received chemotherapy. An additional 1024 women with tumors of 1 cm or less were identified among the 3990 patients in the B-14, B-20, and B-06 studies who had ER-positive, axillary lymph node-negative tumors of 2 cm or less; 264 of them were treated with surgery alone, 540 received tamoxifen, and 220 received tamoxifen and chemotherapy. For more detailed information about the design, entry requirements, eligibility criteria, treatment and compliance, conduct, outcome, and other aspects of each of the five studies, the reader is referred to the published reports (811,24).
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Before the late 1970s, there was little oversight of the ER and progesterone receptor (PgR) analyses that were being carried out. In 1976, a quality-assurance program to ensure the uniformity of ER and PgR analyses performed on tumors from patients enrolled in NSABP tamoxifen trials was established in collaboration with Dr. James L. Wittliff, Director of the University of Louisville Hormone Receptor Laboratory in Kentucky (2729). Tumor specimens were assayed for ER and PgR status by means of the sucrose-density gradient procedure, by dextran-coated charcoal treatment of ligand titrations with Scatchard analysis, or by the use of dextran-coated charcoal with a single saturating dose of labeled estradiol (2729). Tumor extracts containing less than 10 fmol of ER per milligram of cytosol protein were considered to be ER negative, and those containing 10 fmol or more of ER were judged to be ER positive. When the quality-assurance program was initiated, 1 cm3 of biopsy tissue, equivalent to 0.81.0 g, was requested for analyses. Because tumors were usually larger than those in the current studies, that amount of tissue was readily available for steroid receptor evaluation of cytosol preparations by radioactive steroid-binding assays and the sucrose density-gradient centrifugation procedure. It was soon demonstrated, however, that both the sucrose density-gradient method and the ligand-binding assay could also be performed on biopsy samples that were less than 200 mg. The cytosol extract from 23 mm3 of biopsy tissue, i.e., about 100 mg, could be analyzed by a miniaturized ligand-binding assay (30). When patients were being enrolled in the five NSABP trials, numerous laboratories estimating tumor receptor status were analyzing 100200 mg or 24 mm3 of tissue.
The U.S. Food and Drug Administration approved the use of the enzyme immunoassay kit from Abbott Laboratories (Chicago, IL) for analysis of ER and PgR in October 1988 and September 1990, respectively. The NSABP then allowed these methods to be used in their trials for determining receptor status in patients who had 24 mm3 of biopsy tissue that weighed 100200 mg. Later, it was reported (30) that the enzyme immunoassay procedures were highly reproducible in breast carcinoma biopsies of less than 100 mg of tissue taken from patients during the late 1980s and early 1990s.
Statistical Methods
In this study, data from several selected NSABP randomized clinical trials were combined. In that respect, our study differs from a typical meta-analysis and from most reports of retrospective information.
Recurrence-free survival (RFS) was defined as follow-up time after surgery free of breast cancer recurrence at local (including IBTR), regional, and distant anatomic sites. Second primary cancers and deaths before either recurrence or second primary cancer were treated as censored observations for RFS. Contralateral breast cancer was considered to be a second primary cancer and was not included as an event in the determination of RFS. Event-free survival (EFS), previously referred to as DFS, was defined as time free of breast cancer recurrence, occurrence of contralateral breast cancer or other primary cancer, or death before these events. Survival was defined as time from surgery until death from any cause. Distributions of time to these events were estimated by the KaplanMeier method (31). Because the studies had differing lengths of follow-up, but all studies had average follow-up times of at least 8 years, follow-up times in all studies were truncated at 8 years. The RFS data through 8 years of follow-up of cohorts of patients who contributed data from the individual trials were compared (Table 1) to ascertain whether or not there might be overt differences between them that precluded combining the data. In addition, patient and tumor characteristics were compared across trials to determine whether distributions of patient characteristics were similar.
The cumulative probabilities of occurrence for events included in EFS (i.e., breast cancer recurrence, occurrence of either contralateral breast cancer or of another second primary cancer, or death before these events) were estimated by the use of the cumulative incidence function, which correctly accounts for competing risks (32). Similarly, the estimated cumulative probability of death (the complement of the KaplanMeier survival time distribution) was partitioned into probabilities of death attributable to either breast cancer or other causes by means of the cumulative incidence function method.
The Cox proportional hazards model was used to assess the prognostic effect of patient and tumor characteristics on RFS, EFS, or survival (33). Tests of treatment differences were performed by the use of likelihood ratio tests in models including other potentially prognostic covariates (age, tumor size, and tumor type). A covariate was considered to be statistically significantly related to an outcome if the corresponding coefficient was associated with a P value of .05 or less from a two-sided statistical test. All statistical tests were two-sided.
Because all patients were enrolled in the B-13, B-14, B-19, or B-20 trial on the basis of the ER status of their tumors, all aspects of this investigation were carried out separately for women according to whether their tumors were ER negative or ER positive. Patients from the B-06 study were used in the analyses according to their tumor receptor status.
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RESULTS |
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When data on patients with tumors of 1 cm or less were examined according to age, it was observed that more women with ER-negative tumors were younger at diagnosis than were women with ER-positive tumors (Table 2). Nevertheless, the distribution of women by age among individual treatment groups within each receptor category was similar. When data were examined according to pathologic size of tumors, a similarity was observed when the distribution of tumor sizes among treatment groups within each ER category was examined. About 15% of the ER-negative and about 7% of the ER-positive tumors were classified as T1a. The rest, about 85% and 93%, respectively, were reported as being T1b. Almost 60% of both ER-negative and ER-positive T1b tumors were recorded as being 10 mm in size. When the distribution of tumors among the various treatment groups in women with tumors of less than or equal to 1 cm was examined according to histologic type as categorized by institutional pathologists, about 87% of ER-negative tumors and about 86% of ER-positive tumors of known type were identified as being either infiltrating ductal carcinoma or lobular invasive carcinoma. There were no marked differences in the surgical treatment of patients with ER-negative tumors in any of the treatment groups. Overall, 51% of the women with tumors of less than or equal to 1 cm had a mastectomy and 49% had a lumpectomy followed by breast irradiation. Among patients with ER-positive tumors who received systemic therapy, 49% were treated with lumpectomy and breast irradiation.
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When the data from the groups of women in B-06, B-13, and B-19 who received no systemic therapy were combined, the 8-year RFS was 81%. When the data from women who received chemotherapy in the three studies were combined, the 8-year RFS was 90% (P = .06; Fig. 1, A). The cumulative probabilities of events comprising EFS were computed for each treatment group (Fig. 2
). In women treated with surgery alone, the cumulative incidence of all events was 30%. There was an 18% probability of recurrence at local-regional or distant sites through 8 years; 10% of these events were distant recurrences, 3% were IBTR, and 5% were recurrences at other local-regional sites. The cumulative incidence of second cancer in the contralateral breast was 5%; the cumulative incidence of other second primary cancers was 7%. There were no deaths before recurrence or second cancer as a first event (deaths with no evidence of disease). In patients who received postoperative chemotherapy, the cumulative incidence of all events was 18% through 8 years; 9% of the total cumulative incidence was from local-regional recurrences (1% IBTR and 3% at other local-regional sites) or distant recurrences (5%), 4% was from cancers in the contralateral breast, 3% was from second cancers other than breast cancer, and 2% was from deaths with no evidence of disease (Fig. 2, B
). The frequency of IBTR after lumpectomy and breast irradiation decreased from 8% to 3% as a result of chemotherapy (data not shown).
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When the data from women in B-06 and B-14 who received no systemic therapy were combined, the 8-year RFS was 86%; when the data from tamoxifen-treated groups were combined, the RFS was 93% (P = .01). The RFS was 95% for women treated with tamoxifen and chemotherapy (tamoxifen compared with tamoxifen and chemotherapy; P = .07; Fig. 1, B). In women treated with surgery alone, 26% experienced an event through 8 years of follow-up (Fig. 3, A
). The cumulative probability of local-regional or distant breast cancer recurrence was 13% (7% distant metastases, 3% IBTR, and 3% at other local-regional sites). The cumulative incidence of contralateral breast cancers was 5%, of other second primary cancers was 4%, and of death without evidence of breast cancer (no evidence of disease) was 5%. Women treated with tamoxifen had an 18% cumulative incidence of any event. Seven percent of the cumulative incidence was local-regional (3% IBTR and <1% at other local-regional sites) or distant recurrence (3%), 3% was cancer of the opposite breast, 6% was second cancer other than breast cancer, and 2% was death with no evidence of disease (Fig. 3, B
). Women treated with tamoxifen and chemotherapy had a cumulative probability of an event of 11%, 5% of which was local-regional (IBTR <1%) or distant recurrence (2%), 2% was contralateral breast cancer, 3% was second cancer other than breast cancer, and 1% was death with no evidence of disease (Fig. 3, C
). The frequency of IBTR was 6% after surgery and radiation therapy, 6% when tamoxifen was administered, and 2% when both tamoxifen and chemotherapy were given (data not shown).
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Survival through 8 years of follow-up was 93% in women with ER-negative tumors of 1 cm or less who were treated with surgery alone and 91% for patients treated with surgery and systemic chemotherapy (P = .65; Fig. 4, A). Whereas 90% of surgery-treated patients with ER-positive tumors and 92% of tamoxifen-treated patients survived through 8 years (P = .41), survival in women treated with chemotherapy and tamoxifen (97%) was significantly better than survival in women treated with tamoxifen alone (P = .01; Fig. 4, B
). The overall survival of all patients, regardless of ER status or treatment, was 92% through 8 years. Of the 8% of patients who died, one half of the deaths could be attributed to breast cancer and the other half were attributed to other causes (data not shown).
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Several covariates were found to affect the risk of recurrence in both ER-negative and ER-positive patients who had tumors of 1 cm or less (Fig. 5). The risk of a recurrence was greater in women who had tumors of 1 cm in size than in women who had tumors of less than 1 cm for women with either ER-negative tumors (relative risk [RR] = 2.3; 95% confidence interval [CI] = 1.0 to 5.4) or ER-positive tumors (RR = 2.2; 95% CI = 1.3 to 3.6). Similarly, the age of patients at randomization and the type of tumor present were likely to affect the risk of tumor recurrence. The risk in women aged 49 years or younger was greater than that in women aged 50 years or older in those with either ER-negative tumors (RR = 2.0; 95% CI = 0.9 to 4.5) or ER-positive tumors (RR = 1.7; 95% CI = 1.1 to 2.6). Women who had either ER-negative or ER-positive infiltrating ductal carcinoma or lobular carcinoma had a greater risk of a breast cancer event than did women who had other histologic tumor types, i.e., tubular or mucinous (ER-negative, RR = 1.4 [95% CI = 0.4 to 4.6]; and ER-positive, RR = 1.6 [95% CI = 1.2 to 3.3]).
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DISCUSSION |
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As other investigators (13) noted, although the majority of tumor recurrences occur in the first decade of follow-up, the proportion of recurrences that occur during the second decade of follow-up increases in women with small tumors. Consequently, a follow-up time of longer than 8 years is likely to be necessary to allow for a more meaningful assessment of the outcome of our patients. In that regard, it was observed that, by 8 years of follow-up, there was an overall mortality of 8% for all patients with tumors of 1 cm or less, regardless of their tumor ER status or the treatment regimen that they received. One half of the deaths were related to breast cancer. To reiterate, the findings from patients with short follow-up times must be viewed with caution (34).
Before the current findings were obtained, most of the extant information about the relationship between the size of small tumors and prognosis reported by other investigators was derived from women who did not participate in clinical trials (Table 3). The findings noted in a series of publications, beginning in 1981 (1214), have been influential in promulgating the thesis that there is a low risk of breast cancer recurrence in women with tumors of 1 cm or less in diameter and negative axillary lymph nodes. The only information relating tumor size to prognosis that has been derived from patients in randomized clinical trials appeared in a report from the Natural History Data Base (35), which contained data on women enrolled in five randomized studies conducted in three countries. An 83% RFS after 10 years of follow-up was noted in the Natural History Data Base. Formulating conclusions from the reports noted in Table 3
about the prognosis and treatment of women with tumors of 1 cm or less on the basis of tumor size alone is difficult because of a number of factors. These factors include potential bias related to patient selection, the fact that most of the datasets had too few patients, disparate follow-up times, uncontrolled collection of follow-up information over many years, heterogeneity of patient populations within and across studies, and the making of numerous comparisons among small patient subsets. Moreover, it may be speculated as to how many of the small cancers noted in the various studies were of the so-called "microinvasive" type (i.e., invasive cancers of minimal size and ambiguous identity that may be associated with in situ ductal carcinoma). There were also differences in the definition of end points among studies; e.g., the events used for determining RFS in one study may have differed from the events used to obtain that outcome in another. In that regard, it should be noted that 81% of the 1395 patients in the 10 reports were treated with some type of mastectomy. Consequently, the possibility that these women would have developed an IBTR was extremely limited. (In the present study, that possibility was greater because only about 50% of the 1259 patients were treated with a mastectomy.) Despite all of these concerns, an international consensus panel convened in 1998 (36) considered pathologic tumor size to be the most important prognostic factor for estimating the risk of relapse.
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The way in which tumors were measured in our trials may be subjected to the same criticism that has been directed at tumor size estimation in other studies. There are, however, differences. In our trials, we used the measurements reported at patient entry. Consequently, there was a lack of bias that might be associated with reassessment of tumor size. Because, however, almost 60% of the tumors in our study were recorded as being of 1 cm, it may be conjectured that some that were a millimeter or 2 mm larger were rounded down and that some that were several millimeters less than 1 cm may have been rounded up. It is unlikely that the large number of pathologists who participated in our studies would have reported sizes that were reduced by one-half to 1 cm or more to allow for patient enrollment. Because patient entry was dependent on ER status and not on tumor size in the trials from which the current data were derived, there would have been no reason for pathologists to intentionally underestimate the size of tumors. Moreover, because these individuals were neither involved in nor aware of the clinical trials in which the patients were subsequently enrolled, the presence of physician bias associated with tumor size and ER would have been highly unlikely.
It has been conjectured that many of the tumors may have been too small to have their ER status accurately determined or that the tissue used for analysis was adequate only because it was taken from tumors that were larger than reported. Those contentions are unsubstantiated in that, as previously noted in this article, the ER analyses of the tumors of patients in this study were carried out in many laboratories in which the ER status from as little biopsy tissue as 23 mm3 weighing approximately 100 mg was able to be determined. Thus, there is a significant rationale to accept the evidence presented indicating that the ER status of small tumors (i.e., 1 cm) is a prognostic marker as well as a predictor of response to therapy.
The manner in which the information was obtained in our study also merits consideration. As has been noted, there were too few patients in each of the four NSABP trials evaluating systemic therapy to permit obtaining an estimate of prognosis and effect of such therapy. Because, however, there were 1259 patients with tumors of 1 cm or less, the data from patients in similarly treated groups in the trials were combined to increase statistical power. Before these data were combined, however, patient characteristics and outcomes were evaluated. This information was found to be sufficiently comparable to justify merging the data from similarly treated groups. The similarities in outcome were likely to have occurred because the patients had been stratified and randomly assigned in clinical trials that had stringent entry and follow-up requirements that had been defined a priori. In addition, the registered patients who were included in our patient population were subjected to the same rigid requirements as the patients who were randomly assigned.
Many of the same investigators (1215,1921,23,41,42) who have provided information relating tumor size to prognosis have reported findings with regard to a multiplicity of prognostic factors. It has been contended that, by combining tumor size with histologic differentiation and patient age, one can successfully identify high-risk and low-risk groups and that combining prognostic factors, such as DNA, ploidy, S-phase fraction, or cathepsin D, would aid in the decision-making process regarding the use of chemotherapy (15). Tumor histologic and nuclear grade, as well as tumor type, are purported to be of the greatest value; i.e., women with well-differentiated tumors and tumors that are tubular, medullary, or colloid are likely to have the best prognosis and have been judged by many investigators not to need systemic therapy. Unfortunately, the proportion of tumors of 1 cm or less in such a pathologic type is relatively small. Findings from this study that may aid in clinical decision making are those indicating that several covariates influenced the risk of recurrence in both ER-negative and ER-positive patients. The risk in women aged 49 years or younger was greater than that in women aged 50 years or older, and tumor type affected the risk; a greater risk was associated with infiltrating ductal and lobular invasive tumors than with other tumor types. Women with tumors of 1 cm had a greater risk than did women with tumors of less than 1 cm. Whether or not there is a minimal tumor size below 10 mm that would or would not justify the administration of systemic therapy remains to be established.
Few, if any, studies in patients with tumors of 1 cm or less have evaluated the worth of systemic therapy in such patients. Consequently, our current findings are unique in that they provide evidence to demonstrate that a benefit results from the treatment of women with such tumors. For patients with ER-negative tumors treated with chemotherapy, the increased RFS at 8 years and the reduced frequency of breast cancer recurrence are consistent with the findings for the entire group of women in B-13 and B-19, the population from which the cohort of patients with ER-negative tumors was derived (9,11). The observation that women who received the classical CMF treatment had a seemingly better outcome than did those treated with MF is also similar to findings in the entire population. In patients with ER-positive tumors, the findings were also in keeping with our observations in the overall populations in the B-14 and B-20 trials (11,24), i.e., an improvement in RFS and EFS after the administration of tamoxifen and an even better outcome after treatment with tamoxifen and chemotherapy. These benefits were due to an overall reduction in breast cancer events that occurred subsequent to the treatment of patients after removal of a primary tumor. Thus, it is pertinent to determine the extent to which events occurring at individual sites are apt to be prevented because events at some sites are apt to be more ominous with regard to patient outcome than are those at other sites. Even after the findings from all four trials were combined, there were still too few events at individual sites in our study to warrant obtaining definitive information from formal statistical analyses. In that regard, it is of interest that distant metastases occurred more frequently than did IBTRs and that much of the effect of systemic therapy observed in this study related to a reduction in incidence of metastatic disease.
It is unlikely that more precise information with regard to the appropriate management of individual patients with tumors of less than 1 cm will be determined by size alone. If therapeutic decision making (and, thus, the future well-being of patients) is affected by such a seemingly trivial action as misjudging the size of a tumor by a few millimeters, then using tumor size for subdividing small tumors into exact groups having different clinical significance may be unrealistic. Pathologic or biologic characterizations are likely to be more useful. While such efforts are in progress, any decision to deny women the opportunity of receiving a therapy from which they might benefit must be extremely circumspect in view of the fact that thousands of women with invasive breast cancer die each year despite receiving "effective" treatment or because they have received either inadequate or no treatment. Use of the histopathologic and ER status of a tumor of 1 cm or less in size or other aspects of a patient's clinical status is apt to be more helpful for making a decision about systemic therapy than is use of precise tumor size.
Appropriately designed prospective clinical trials are necessary to validate the observations in this article. Such studies will require large numbers of patients with prolonged follow-up. Until information from such trials becomes available, the findings from this study should be considered when decisions are made regarding the management of patients with tumors of 1 cm or less. Until these studies are completed, we conclude that use of chemotherapy and/or tamoxifen should be considered for the treatment of women with ER-negative or ER-positive tumors of 1 cm or less and no axillary lymph node metastases.
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NOTES |
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Supported by Public Health Service grants U10CA12027, U10CA69651, U10CA37377, and U10CA69974 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
We thank Tanya Spewock for editorial assistance and Mary Hof for preparation of the manuscript.
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Manuscript received June 26, 2000; revised November 6, 2000; accepted November 14, 2000.
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