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Background:  Breast cancer is a significant cause of mortality and morbidity worldwide, although death rates in the United States and some other countries are beginning to fall.
Methods:  Several sources of information in 1998, including publications and presentations at the 1998 meeting of the American Society of Clinical Oncology, are pertinent to contemporary breast cancer care.
Results:  It is now possible to prescribe hormonal therapy that will reduce the incidence of breast cancer.  Methods are available to reduce the morbidity from axillary node dissection, and improvements in adjuvant therapy and management of metastatic breast cancer are now at hand.
Conclusions:  The information presented provides a broad-based platform for new standards of care for breast cancer that will serve as a sound base for further progress in this important disease.

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Introduction

    Breast cancer continues to be a worldwide public health problem, and the many patients who develop the disease carry a heavy physical and emotional burden. This year, 180,300 individuals in the United States are expected to develop breast cancer, and 43,900 will die of its effects.¹ Some good news about the disease is already at hand. As a result of screening programs, many institutions report that approximately one third of new breast cancers are the highly curable in situ lesions,² and mortality rates from breast cancer are now trending down.³

    During the last few months, new information about several aspects of breast cancer has become available, including the long-awaited publication of the meta-analysis concerning tamoxifen adjuvant therapy.⁴ At the recent annual meeting of the American Society of Clinical Oncology (ASCO), several presentations highlighted significant advances pertinent to contemporary breast cancer care. This article summarizes some of those advances that relate to selected areas of clinical concern. Clearly, many treatment approaches are still not ideal and controversies remain, but the progress being made in understanding and managing breast cancer is tangible and real.

Prevention

    In the past, although it was recognized that oophorectomy appreciably reduced breast cancer risk,⁵ the only known approach to prevent breast cancer was prophylactic mastectomy, a procedure most commonly performed by plastic surgeons when the patient’s risk of developing a future contralateral breast cancer was deemed to be high. Now, several studies indicate that breast cancer incidence can be lowered by a variety of hormonal approaches.

Tamoxifen

    It has been evident for several years that the incidence of new breast cancers in the contralateral breast of patients with breast cancer who received tamoxifen was diminished. The latest meta-analysis of adjuvant tamoxifen treatment,⁴ in fact, reports that women who took tamoxifen for approximately five years had a 47% reduction in the risk for a contralateral breast cancer. These data stimulated trials of tamoxifen in women without breast cancer but who were considered to be at high risk for developing the disease.

    The recently unblinded US Breast Cancer Prevention Trial led by the National Surgical Adjuvant Breast and Bowel Project (NSABP) included more than 13,000 women who were at least 60 years of age, had a history of lobular carcinoma in situ, or were between 35 and 59 years of age and also had a five-year risk of developing breast cancer that, as judged by the Gail model,⁶ was at least equivalent to that of the average 60-year-old woman. The distribution of selected demographic characteristics is summarized in Table 1.

Table 1. -- Distribution of 12,542 Breast Cancer Prevention Trial Participants by Selected Demographic Characteristics
Age of Participants		First Degree Relatives With Breast Cancer		Relative Risk (RR) of Breast Cancer
Years	%	# Relatives	%	RR	%
35-39	2.7	0	23.1	1.0	0.1
40-44	12.1	1	57.6	1.01-2.0	7.6
45-49	24.7	2	16.4	2.01-3.0	15.9
50-54	18.4	3	2.5	3.01-5.0	37.5
55-59	12.2	>=4	0.5	5.01-10.0	28.9
60-64	14.1			>10.0	10.0
65-69	9.9
>=70	5.9

    The average relative risk of the trial participants according to age is summarized in Table 2, and the distribution according to the level of five-year risk of breast cancer is summarized in Table 3. This double-blind study allocated the participants to receive five years of treatment with 20 mg of tamoxifen daily or a placebo.

Table 2. -- Average Relative Risk of 12,542 Breast Cancer Prevention Trial Participants According to Age
Age (Yrs)	Average Relative Risk
35-39	9.6
40-44	7.6
45-49	6.4
50-54	5.3
55-59	5.1
60-64	3.9
65-69	3.7
>=70	3.9
All Ages	5.5

Table 3. -- Distribution of 12,542 Breast Cancer Prevention Trial Participants According to Level of Five-Year Risk of Breast Cancer
5-Year Risk of Breast Cancer (%)	%
<=2	24.7
2.1-3.0	31.6
3.1-4.0	18.4
4.1-5.0	8.5
>=5.1	16.8

    At the 1998 ASCO plenary session, it was reported that the mean follow-up time of study subjects in the prevention trial was 3.6 years and more than 57% had completed four years of treatment. One hundred fifty-four patients developed invasive breast cancers in the placebo group vs 85 in the tamoxifen-treated group. This 45% reduction in incidence was highly significant (P=0.00001). Benefit was evident in all age groups but was greatest in those over 60 years. More estrogen-receptor (ER)-positive carcinomas occurred in the placebo group, but the size of detected tumors was equivalent, with two thirds being less than 2 cm in diameter. The incidence of noninvasive tumors was also reduced in the tamoxifen-treated group. Thirty-three endometrial cancers, all stage 1, developed in the tamoxifen group vs 14 in the placebo group. There was no difference in the incidence of gastrointestinal, liver, or ovarian cancers in the two groups. Seventeen vascular events were noted with tamoxifen, and six were encountered with placebo.

Raloxifene

    The selective ER modulator raloxifene has estrogenic effects on bone and lipids, but it has estrogen antagonist effects on the breast and uterus.⁷ Again, at the 1998 ASCO plenary session,⁸ Dr Cummings described the "MORE" trial, a randomized, double-blind trial of raloxifene vs placebo in postmenopausal women with osteoporosis under 80 years of age. This trial was designed to test the hypothesis that raloxifene will reduce the risk of bone fractures. A total of 7,704 women were randomly assigned to active treatment or placebo, in a ratio of 2:1, to receive raloxifene in a dose of either 60 or 120 mg per day or a matching placebo. After a median of 28.9 months of follow-up, 32 cases of breast cancer had been confirmed, 11 in those patients assigned to raloxifene and 21 in those assigned to placebo. Thus, the annual rate of developing breast cancer for raloxifene was 1.4/1000 (with no difference noted between 60 mg and 120 mg dosage levels) compared with 4/1000 for the placebo. This gives a relative risk for raloxifene of 0.30 (P=.001). Endometrial cancer occurred in four cases in the raloxifene group and in four cases in the smaller placebo group. These numbers are too small to confirm a protective effect of raloxifene on the uterus.

Inhibition of Ovulation

    A third approach to breast cancer prevention was also postulated in an educational session at the 1998 ASCO meeting (Malcolm Pike, PhD, personal communication, 1998). Using the rationale that breast cancer risk is related to ovulatory frequency and estrogen production, the proposal was made to lower breast cancer incidence for premenopausal women by reducing ovulation with a luteinizing hormone-releasing hormone (LHRH) agonist/antagonist and by providing only small amounts of replacement estrogen, androgens, and progestins.

Discussion

    The demonstration of reduction in incidence of breast cancer induced by two "designer" estrogens is a real finding, and raloxifene may have an additional capacity of not increasing endometrial cancer risk. The premature closing of the US Breast Cancer Prevention Trial is understandable, but this action has reduced the chance that important endpoints other than cancer incidence, such as breast cancer mortality, also could have been made. Ongoing foreign trials that are similar in design to the US trial may provide such data. We should note that cancers developing in subjects who have taken tamoxifen or raloxifene will be more often ER-poor and will likely not derive survival benefit from adjuvant hormonal interventions. The raloxifene study, although positive in terms of reduction in breast cancer risk, should be viewed with some caution since patients with osteoporosis have a lower than average risk for breast cancer, and the primary focus of the trial was on reduction of fractures rather than reduction of breast cancer incidence. A follow-up trial enrolling 22,000 women without cancer will open later this year and should answer questions of comparative effectiveness of these two agents by directly comparing the cancer prevention effects and toxicities of tamoxifen and raloxifene. Other questions, such as the effectiveness of tamoxifen or raloxifene preventive measures in women carrying an abnormal breast cancer susceptibility gene (eg, BRCA1), are being addressed now.

Staging Localized Cancer

    A favorite multiple choice question for medical students asks which of several alternatives is the key prognostic factor for a patient with clinically localized breast cancer. The correct answer, of course, is "axillary node involvement." To quote S. Eva Singletary, MD,⁹ an eminent M.D. Anderson surgeon: "With the abandonment of routine axillary node dissection, the next hurdle for surgical therapy . . .!" Clearly, clinical practice regarding axillary node dissection is changing.

    Several issues need to be addressed when a formal axillary dissection is not performed as part of a initial staging and treatment, although the characteristics of the primary tumor (eg, size) are increasingly being used for adjuvant treatment decisions. It should be remembered, however, that there is an unacceptably high rate of local recurrence in the axilla in clinically node-negative patients with tumors >1 cm who receive no axillary treatment, and there is a finite incidence of axillary node metastasis in patients with small invasive tumors and even with ductal carcinoma in situ (DCIS).⁹

    Sentinel node mapping is a promising new technique that reliably predicts nodal status without the morbidity of axillary dissection.^10,11 My clinical experience underscores the large reduction in operative morbidity that occurs from a mapping/sentinel node procedure in comparison to that from a formal axillary dissection. The sentinel node technique is now being used more widely and may be particularly useful in patients for whom the indications for systemic adjuvant therapy are borderline, such as small invasive tumors. It is also applicable to many patients with DCIS.

    When a sentinel node or nodes are demonstrated to be involved by tumor using hematoxylin and eosin (H & E) staining techniques, a completion node dissection is indicated. The development of more sensitive techniques to evaluate resected lymph nodes for micrometastasis, however, has created new problems in staging management recommendations. Experience at the Moffitt Cancer Center using cytokeratin immunohistochemical (CKIHC) staining in addition to routine H & E stains in a group of 210 breast cancer patients¹² indicates that CKIHC staining of sentinel nodes shifted the stage of 9.4% of them from stage I to stage II. The effect was particularly strong in patients with tumor diameters <2.0 cm. Sixteen of 30 such node-positive T0 and T1 patients (53.3%) were upstaged by CKIHC staining.

    The upstaging effect from more sensitive and sophisticated diagnosis will increase apparent survival rates for both stages I and II breast cancer by the "Will Rogers" effect. The clinical meaning of these results, however, is unclear. This complicates decision making. Thus, we now have to ask if a patient with DCIS only, ie, with no invasive component in the primary cancer who has a "cytokeratin-only" nodal micrometastasis, should receive adjuvant therapy.

    Historical data from Pickren¹³ and Wilkerson et al,¹⁴ who studied serial sections of uninvolved nodes using H & E staining, suggest that the finding of microscopic-only nodal disease did not affect survival outcomes. Prospective trials will be needed to sort these issues out properly.

Patterns of Care

    Two presentations at the 1998 ASCO meeting addressed national patterns of care for patients with early breast cancer.^15,16 Joint studies of the American College of Surgeons and the American College of Radiology included 17,931 patients with stage I and stage II breast cancer treated at 827 institutions in 1994. One study evaluated management of the axilla.¹⁵ Ninety-three percent of the group underwent axillary lymph node dissection (ALND), but this procedure was performed less often in older patients, in those with T1a tumors, and in those with favorable histologies (tubular, papillary, and mucinous carcinomas). Patients not undergoing ALND were more likely to receive axillary radiation than those who did (27% vs 12%, respectively, P=0.0001), although only 30% of patients with >=10 nodal metastases received axillary radiation. This proportion seems inappropriately low.

    The second study evaluated treatment of the breast itself. There remain significant regional variations in the methods used to provide control of the primary tumor in the breast.¹⁶ Overall, only 44% of studied patients underwent breast conservation therapy. This option was followed mostly for patients with favorable prognostic indicators for survival, despite guidelines and data from randomized trials indicating that age, prognosis, and tumor type should not be used as selection criteria for conservation therapy. This misunderstanding is a major factor responsible for continued low national rates for breast-conserving therapy, and continued education on these points is indicated.

Postmastectomy Radiation

    Long a contentious issue, recommendations for postmastectomy radiation in patients with fewer than four axillary nodes involved and clear surgical tumor resection margins are in a state of flux. The issue seemed to have been put to rest by the meta-analysis published by the Early Breast Cancer Trialists’ Group in 1995.¹⁷ This meta-analysis concluded that "some of the local therapies for breast cancer had substantially different effects on the rates of local recurrence, such as the reduced recurrence with the addition of radiotherapy to surgery -- but there were no definite differences in survival at 10 years."

    The simultaneous publication of two well-conducted prospective trials^18,19 with long follow-up periods in premenopausal patients with breast cancer who were at high risk of recurrence and who received chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) ± radiation therapy last year, however, indicated that not only was local recurrence reduced but that survival rates were also improved by radiation. This evidence has stimulated considerable debate. The M.D. Anderson group reported at the 1998 ASCO meeting on 1,107 of their early breast cancer patients who received FAC (fluorouracil, doxorubicin, and cyclophosphamide) adjuvant therapy.²⁰ Retrospective analysis of outcomes between those who received radiation and those who did not (ie, not an entirely randomized study) showed that pretreatment characteristics of patients treated with or without radiation were similar. The risk of local failure was higher in the FAC alone group (11%) vs that for FAC plus radiation (5.6%), but there was no difference between the two groups in disease-free or overall survival. At that institution, postmastectomy radiation is not given to patients with fewer than 4 nodes. It is prescribed, of course, for those at high risk of local recurrence, including stage III and inflammatory cancer, positive resection margins, extensive extranodal axillary disease, or >=10 involved axillary nodes. This presentation will not put to rest the controversy regarding postmastectomy radiation in patients who have 1 to 3 nodes involved. Many clinicians would support a study that addresses this question directly. Meanwhile, discussions among medical and radiation oncologists will continue.

Adjuvant Systemic Therapy

    At long last, the final version of the first part of the updated report of the Early Breast Cancer Trialists’ Collaborative Group has been published,⁴ although preliminary observations concerning the 1995 Oxford Overview have previously been summarized.²¹

Tamoxifen

    The 1998 Lancet publication⁴ concerns tamoxifen and presents an analysis of 37,000 women with breast cancer in 55 trials that randomized between treatment with tamoxifen or not. Nearly 8,000 of the women had ER-negative tumors, and the effects of tamoxifen in these women are small. When the remaining women (18,000 with ER-positive tumors and nearly 12,000 with untested tumors, of which approximately 8,000 would have been ER-positive) were evaluated, the proportional cancer recurrence reductions produced during approximately 10 years of follow-up were 21%, 29%, and 47% for trials of one, two, and five years of adjuvant tamoxifen, respectively. The corresponding mortality reductions were 12%, 17%, and 26%. The proportional mortality reductions were similar for women with node-positive and node-negative disease, but the absolute mortality reductions were greater in node-positive women. In the trials of approximately five years of tamoxifen, the absolute improvements in 10-year survival were 10.9% for node-positive patients (61.4% vs 50.5%) and 5.6% for node-negative patients (78.9% vs 73.3%). These benefits were largely independent of age, menopausal status, and chemotherapy. The data now clearly show that tamoxifen is beneficial in premenopausal women.

    The proportional reductions in contralateral breast cancer were 13% (SD 13), 26% (SD 9), and 47% (SD 9) in the trials of one, two, or approximately five years of tamoxifen, respectively. The incidence of endometrial cancer increased with longer duration of tamoxifen, but the absolute decrease in contralateral breast cancer was approximately twice as large as the absolute increase in endometrial cancer incidence. No effect was reported in the incidence of colorectal, liver, or other cancers, or of other major categories of cause of death.

    Thus, in summary, beneficial effects of tamoxifen are clearly evident in patients with ER-positive carcinomas that may be node negative or node positive. Benefit is seen in premenopausal and postmenopausal patients, and the effects are independent of chemotherapy. Greater effects are seen with five years’ duration rather than with shorter durations of tamoxifen adjuvant therapy. Studies of adjuvant therapy using toremifene, as well as comparative studies of tamoxifen and anastrozole and the combination of the two drugs, are underway. I assume that the capability of raloxifene to control or delay systemic breast cancer growth and spread will also be evaluated.

Cytotoxic Therapy

    Perhaps the most commonly used cytotoxic adjuvant drug programs for breast cancer used in practice are CMF, CAF, and CA. The original or "classic" CMF program comprises 28-day cycles, with methotrexate and fluorouracil given on days 1 and 8 and cyclophosphamide given orally on days 1 through 14 of each cycle. At least in my geographic area, oncologists often prescribe an admittedly better-tolerated all-intravenous (IV) schedule given every three weeks. A "standard" course of adjuvant therapy consists of 6 cycles of the "classic" CMF, but I often see recommendations for only 6 cycles of the q 3 week IV CMF approach.

    The IV CMF program is less dose intensive than the "classic" 28-day program, and studies in patients with advanced breast cancer show better outcomes when the "classic" CMF schedule is used.²² Goldhirsch and colleagues from the International Breast Group²³ have recently reviewed this information and point out that reduction of doses has given inferior results in the adjuvant setting. The trials that demonstrated a significant benefit from the addition of CMF to tamoxifen, even in ER-positive tumors, used "classic" CMF. The authors suggest that "adherence to the classical dose and schedule is recommended when CMF is used in adjuvant therapy." I concur with this recommendation and suggest that practitioners who now routinely use the IV CMF treatment program review the data in the Goldhirsch article and consider changing their approach to reuse the "classic" CMF schedule.

    The preliminary results of the Intergroup trial of CMF vs CAF with and without tamoxifen in high-risk, node-negative breast cancer patients were featured in the 1998 ASCO plenary session.²⁴ This study of 4,406 patients classified the patients into three risk categories: high (tumor >=2 cm or ER- and PR-negative), low (tumor too small for biochemical hormone receptor studies), and uncertain (tumors <2 cm and ER-negative or PR-positive). Those in the uncertain group were assigned to the low-risk group if the S-phase fraction was low and to the high-risk group if it was high. The low-risk group was followed without adjuvant therapy. Table 4 summarizes the preliminary results.

Table 4. -- Differences in Five-Year Observed Survival (OS) and Disease-Free Survival (DFS) in 2,691 High-Risk and 1,208 Low-Risk Patients with Node-Negative Breast Cancer by Treatment
	Low risk by:		High risk:			All Patients:
	Small tumor	Low SPF	CAF+			Low Risk	High Risk
			CAF	TAM	CMF
OS	96%	97%	92%	93%	90%	96%	92%
DFS	89%	88%	85%	87%	82%	89%	85%
SPF = S-phase fraction

    CAF was marginally superior to CMF in increasing both disease-free and overall survival (one-sided P=0.03) but was somewhat more toxic. Tamoxifen provided additional benefit only in ER-positive patients. The subset of low-risk patients, chosen on the basis of tumor size, receptor status, and S-phase fraction do well without adjuvant therapy, thus validating the utility of these prognostic markers in node-negative patients.

    Preliminary results from another large intergroup trial for breast cancer, this time in node-positive patients, were also presented at the 1998 ASCO meeting.²⁵ The study had two components. The first was to evaluate whether dose-escalation of doxorubicin from 60 mg/m² to 75 mg/m² or 90 mg/m² in combination with 600 mg/m² of cyclophosphamide for 4 cycles would improve results. It did not. The second component of the trial evaluated the effects of the addition of 4 cycles of paclitaxel given at 175 mg/m² over 3 hours. Table 5 summarizes the results.

Table 5. -- Disease-Free Survival (DFS) and Observed Survival (OS) in 3,170 Breast Cancer Patients With Involved Lymph Nodes Treated by Cyclophosphamide Plus Doxorubicin Alone (CA) or by CA Followed by Paclitaxel (CA-›T)
	CA	CA-›T	P =
DFS	86% ± 1.2%	90% ± 1.0%	0.0077
OS	95% ± 0.7%	97% ± 0.6%	0.0390

    Evidence to date indicates that the sequential addition of paclitaxel to CA adjuvant therapy for node-positive breast cancer is well tolerated and significantly improves both disease-free and observed survival. Underscoring the value of this advance is the fact that the "standard" arm of the Intergroup adjuvant protocol #C9741 for patients with node-positive disease is 4 cycles of CA followed by 4 cycles of paclitaxel given at three-week intervals. The "test" treatment is the same drug regimen but given at two-week intervals, thus testing the "dose-dense" approach.

HER-2/neu

    An integrated symposium on HER-2/neu in breast cancer was held at the 1998 annual ASCO meeting. Interest lies in the value of measurements of overexpression of this gene in breast cancer tissue for prognostic and predictive information, and also on the value of an anti-HER-2/neu antibody as a treatment for breast cancer either alone or as an adjunct to cytotoxic therapy.

    HER-2/neu, also known as c-erb-B2, is found to be overexpressed in approximately one third of breast cancer specimens from women with localized breast cancer, and such expression is considered to predict overall for a poor outcome.²⁶ Presentations at this symposium reinforced these data. Information from a previous Cancer and Leukemia Group B trial²⁷ had suggested that patients with HER-2/neu overexpression were more likely to respond well to high-dose chemotherapy, although this finding has not been universally confirmed. A report from the Intergroup Trial 0100²⁸ provides tantalizing but as yet inconclusive evidence that HER-2/neu expression may be a predictor of chemoresponsiveness. Overexpression was measured using two different antibodies, MAb1 and CB11, on paraffin sections from 595 of 1,470 ER-positive, node-positive, postmenopausal patients who received either tamoxifen (T) or CAF plus T (CAFT). The four-year disease-free survival outcomes defined by treatment and gene expression are shown in Table 6.

Table 6. -- Correlation of Outcomes of ER-Positive, Node-Positive Postmenopausal Patients With Breast Cancer by Treatment and HER-2/neu Expression
Treatment	Antibody	Expression	N =	% DFS (4 yr)	P = (log rank)
CAFT	MAb1	Low	378	84%
T		Low	119	81%	0.39
CAFT	MAb1	High	82	74%
T		High	14	41%	0.01
CAFT	CB11	Low	387	84%
T		Low	115	82%	0.62
CAFT	CB11	High	76	75%
T		High	17	56%	0.07
CAFT=cyclophosphamide, doxorubicin, fluorouracil, paclitaxel
T=tamoxifen
DFS=disease-free survival

    CAFT appeared superior to tamoxifen, particularly in patients who overexpressed HER-2/neu, but the authors stressed that this study has low statistical power to answer predictive questions given the short follow-up, the 10:3 randomization of CAFT vs T, and the 16% rate of overexpression of HER-2/neu.

    Another report in this symposium²⁹ had longer follow-up and evaluated the correlation of HER-2/neu overexpression with tamoxifen effect. The Naples "GUN" trial included 433 patients randomized to receive tamoxifen (30 mg daily for two years) or not. Premenopausal node-positive patients also received CMF. HER-2/neu expression was evaluated in 245 cases. The median length of follow-up is 14 years and, overall, tamoxifen provided benefit in all subgroups. Table 7 summarizes the interaction between tamoxifen and HER-2/neu overexpression. Although the numbers in this study are small, the study suggests that HER-2/neu overexpression is a strong predictor of adjuvant tamoxifen failure.

Table 7. -- Interaction Between Tamoxifen (TAM) Adjuvant Treatment or Not With HER-2/neu Overexpression in Patients With Breast Cancer
	Relapses (Obs/Exp)		Deaths (Obs/Exp)
	HER-2/neu– (n = 182)	HER 2/neu+ (n = 63)	HER-2/neu– (n = 182)	HER 2/neu+ (n = 63)
TAM	0.80	1.22	0.81	1.57
no TAM	1.21	0.86	1.19	0.64

Treatment Opportunities

    Two clinical trials of the recombinant humanized monoclonal antibody Herceptin, which targets the extracellular domain of the HER-2/neu growth factor receptor, were reported. Both trials, of course, included only patients whose tumors overexpressed HER-2/neu. The first study³⁰ evaluated Herceptin in 222 women with metastatic breast cancer who had previously received chemotherapy. Sixty-nine percent (69%) had received adjuvant chemotherapy, 32% had one cycle of chemotherapy for metastatic disease, 68% had received two cycles, and 9% had received high-dose chemotherapy. Their mean age was 50 years. The treatment (4 mg/kg IV loading dose and 2 mg/kg IV weekly thereafter) was generally tolerated well, although cardiac toxicity was manifested by a fall in ejection fraction in nine patients, and one patient died of a ventricular arrhythmia. There was a 15% objective response rate with a median duration of 8.4 months.

    The second study³¹ compared first-line chemotherapy either alone (600 mg/m² of cyclophosphamide plus 60 mg/m² of doxorubicin [CA] or 175 mg/m² of paclitaxel every three hours every three weeks [T] if the patient had previously received anthracyclines), with or without Herceptin given in the same doses as the previous studies. Outcomes (that have not yet been confirmed by an independent response evaluation committee) are summarized in Table 8.

Table 8. -- Comparison of Investigator-Determined Outcomes in Patients With HER-2/neu Overexpressing Metastatic Breast Cancer Treated With First-Line Chemotherapy With or Without Herceptin
	Enrolled	TTP (mos)	Response Rate (%)	Adverse Events (%)
CRX	234	5.5	36.2	66
CRX + H	235	8.6	62.0	69
CA	145	6.5	42.1	71
CA + H	146	9.0	64.9	68
T	89	4.2	25.0	59
T + H	89	7.1	57.3	70
TTP = time to tumor progression
CRX = chemotherapy
H = Herceptin
CA = cyclophosphamide plus doxorubicin
T = paclitaxel

    The longer time-to-treatment progression (8.6 vs 5.5 months) and higher response rates (62% vs 36.2%) associated with the addition of Herceptin are statistically significant, but the magnitude of these differences may be modified after independent review. Again, a syndrome of myocardial dysfunction similar to that observed with anthracyclines was reported more commonly with CA plus Herceptin (18% grade 3/4) than with CA alone (3%), paclitaxel alone (0%), or with paclitaxel plus Herceptin (2%).

    These two reports suggest that this biologic approach can produce real benefits alone and can enhance conventional chemotherapeutic management of a specific subgroup of patients with breast cancer.

Conclusions

    Recent research reports indicate that significant progress is being made in the management of patients with breast cancer, where death rates are already trending downward. Two hormones can prevent some breast cancers from developing. Methods are now available to minimize morbidity from axillary node dissection and increase its sensitivity. There is continued progress and refinement of adjuvant treatment for localized breast cancer. Finally, a biologic approach has been shown to enhance chemotherapy effects in a subgroup of women with metastatic breast cancer.

Tables 1-3 were reproduced from Cancer Control (1997;1:78-86).

References

1. Landis SH, Murray T, Bolden S, et al. Cancer statistics, 1998. Ca: Cancer J Clin. 1998;48:6-29.

2. Choi WS, Parker BA, Pierce JP, et al. Regional differences in the incidence and treatment of carcinoma in situ of the breast. Cancer Epidemiol Biomarkers Prev. 1996;5:317-320.

3. Chu KC, Tarone RE, Kessler LG, et al. Recent trends in US breast cancer incidence, survival, and mortality rates. J Natl Cancer Inst. 1996;88:1571-1579.

4. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet. 1998;351:1451-1467.

5. Parazzini F, Braga C, LaVecchia C, et al. Hysterectomy, oophorectomy in premenopause, and risk of breast cancer. Obstet Gynecol. 1997;90:453-456.

6. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81:1879-1886.

7. Yang NN, Venugopalan M, Hardikar S, et al. Identification of an estrogen response element activated by metabolites of 17beta estradiol and raloxifene. Science. 1996;273:1222-1225.

8. Cummings SR, Norton L, Eckert S, et al. Raloxifene reduces the risk of breast cancer and may decrease the risk of endometrial cancer in post-menopausal women. Proc Annu Meet Am Soc Clin Oncol. 1998;17:2a. Abstract.

9. Singletary SE. Management of the axilla in early-stage breast cancer. In: Perry MC, ed. ASCO Educational Book 1998. Alexandria, Va: Am Soc Clin Oncol; 1998:139.

10. Giuliano AE, Kirgan DM, Guenther JM, et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg. 1994;220:391-398.

11. Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA. 1996;276:1818-1822.

12. Schreiber RH, Pendas S, Ku NN, et al. Microstaging of breast cancer patients using cytokeratin staining of the sentinel lymph node. Ann Surg Oncol. 1998. In press.

13. Pickren JW. Significance of occult metastases: a study of breast cancer. Cancer. 1961;14:1266.

14. Wilkinson EJ, Hause LL, Hoffman RG, et al. Occult axillary lymph node metastases in invasive breast carcinoma: characteristics of the primary tumor and significance of the metastases. Pathol Annu. 1982;17:67.

15. Brenin DR, Morrow M, Moughhan J, et al. Current management of axillary lymph nodes in breast cancer: a national patterns of care study. Proc Annu Meet Am Soc Clin Oncol. 1998;17:98a. Abstract.

16. Morrow M, Winchester DP, Chmiel JS, et al. Factors responsible for the underutilization of breast conserving surgery. Proc Annu Meet Am Soc Clin Oncol. 1998;17:98a. Abstract.

17. Early Breast Cancer Trialists’ Collaborative Group. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. N Engl J Med. 1995;333:1444-1455.

18. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med. 1997;337:949-955.

19. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997;337:956-962.

20. Theriault R, Buzdar AU, Hortobagyi GN, et al. Irradiation (XRT) following mastectomy in patients treated with FAC adjuvant therapy -- M D Anderson Cancer Center experience. Proc Annu Meet Am Soc Clin Oncol. 1998:17;99a. Abstract.

21. Horton J. 1995 Oxford breast cancer overview -- preliminary outcomes. Cancer Control: JMCC. 1996;3:78-79.

22. Engelsman E, Klijn JC, Rubens RD, et al. "Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer. An EORTC Breast Cancer Co-operative Group phase III trial (10808). Eur J Cancer. 1991;27:966-970.

23. Goldhirsch A, Coates AS, Colleoni M, et al. Adjuvant chemoendocrine therapy in postmenopausal breast cancer: cyclophosphamide, methotrexate and fluorouracil dose and schedule may make a difference. International Breast Cancer Study Group. J Clin Oncol. 1998;16:1358-1362.

24. Hutchins L, Green S, Ravdin P, et al. CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: first results of Intergroup Trial INT 0102. Proc Annu Meet Am Soc Clin Oncol. 1998;17:1a. Abstract.

25. Henderson IC, Berry D, Demetri G, et al. Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (PTS) with node-positive breast cancer (BC). Proc Annu Meet Am Soc Clin Oncol. 1998;17: 101a. Abstract.

26. Press MF, Bernstein L, Thomas PA, et al. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinoma. J Clin Oncol. 1997; 15:2894-2904.

27. Muss HB, Thor AD, Berry DA, et al. c-erb-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med. 1994;5:1260-1266.

28. Ravdin PM, Green S, Albain KS, et al. Initial report of the SWOG biological correlative study of c-erb B-2 expression as a predictor of outcome in a trial comparing adjuvant CAF T with tamoxifen (T) alone. Proc Annu Meet Am Soc Clin Oncol. 1998;17:97a. Abstract.

29. Bianco AR, De Laurentiis M, Carlomagno C, et al. 20-year update of the Naples GUN Trial of adjuvant breast cancer therapy: evidence of an interaction between c-erb B-2 expression and tamoxifen efficacy. Proc Annu Meet Am Soc Clin Oncol. 1998;17:97a. Abstract.

30. Cobleigh MA, Vogel CL, Tripathy D, et al. Efficacy and safety of Herceptin (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer. Proc Annu Meet Am Soc Clin Oncol. 1998;17:97a. Abstract.

31. Slamon D, Leyland-Jones B, Shak S, et al. Addition of Herceptin (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2+/MBC) markedly increases anticancer activity: a randomized multinational controlled phase III trial. Proc Annu Meet Am Soc Clin Oncol. 1998;17:98a. Abstract.