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Breast Cancer Update

Massachusetts General Hospital, Boston, Massachusetts, USA

Correspondence: Irene Kuter, M.D., D. Phil., Massachusetts General Hospital, Cox 640, Hematology-Oncology Department, 100 Blossom Street, Boston, Massachusetts 02114, USA. Telephone: 617-726-8743; Fax: 617-724-3166; e-mail: kuter.irene{at}mgh.harvard.edu

	ABSTRACT

Top Abstract Adjuvant Hormonal Therapy Adjuvant Chemotherapy HER-2 as a Predictive... References

 
The large number of excellent presentations on breast cancer at this year's ASCO meeting reflects the enormous interest in clinical trials of this common disease. In the reports of adjuvant hormonal therapy, the most interesting included Abstract 273 by Boccardo et al., who reported that postmenopausal women with estrogen receptor positive (ER⁺⁾ cancers who had already completed three years of tamoxifen experienced better overall survival if treated with two years of subsequent aminoglutethimide (a first-generation aromatase inhibitor) rather than another two years of tamoxifen. This whets our appetite for studies currently under way to define the role of third-generation aromatase inhibitors in the adjuvant setting. A report by Fisher from the National Surgical Adjuvant Breast and Bowel Project B-23 study (Abstract 277) provided confirmation of what is rapidly becoming accepted, that the addition of tamoxifen to chemotherapy does not benefit breast cancer patients with negative lymph nodes who have ER^– cancers. In premenopausal women, another report of the benefit of hormonal therapy, this time by the French Adjuvant Study Group using complete hormonal blockade with a luteinizing hormone-releasing hormone agonist and tamoxifen (Abstract 279) showed that hormonal therapy can be at least as good as, if not better, than six cycles of 5-fluorouracil 500 mg/m², epirubicin 50 mg/m², cyclophosphamide 500 mg/m² in terms of disease-free survival and overall survival.

Among the papers on adjuvant chemotherapy, a controversial paper from the German Adjuvant Breast Cancer Group reported that three cycles of CMF (a dose-intense regimen with all three drugs being given on days 1 and 8) were as good as six cycles (Abstract 283). Another report, from the International Breast Cancer Study Group, raised the controversial question of whether there really is much added benefit from the addition of chemotherapy to tamoxifen in postmenopausal women with negative lymph nodes if their tumors have ERs (Abstract 281). A second study (the first was the CALGB study reported at ASCO in 1998) showing a benefit to the addition of Taxol to an anthracycline-based adjuvant regimen, was reported from the M.D. Anderson Cancer Center (Abstract 285), giving further impetus to the inclusion of Taxol in standard adjuvant treatment.

Finally, there were a number of interesting presentations on HER-2. Reported here are three of these, all addressing the effect of HER-2 overexpression on the response to hormonal therapy. Taken together, they uphold the emerging concern that women with ER⁺ cancers may not benefit significantly from endocrine treatment if the tumors also overexpress HER-2. Observations such as these will afford us the ability to predict more accurately which women will benefit from specific treatments.

Key Words. Hormonal therapy • HER-2 • ER⁺ • Breast cancer therapy • Tamoxifen

	ADJUVANT HORMONAL THERAPY

Top Abstract Adjuvant Hormonal Therapy Adjuvant Chemotherapy HER-2 as a Predictive... References

 
Tamoxifen (TAM) versus Aminoglutethimide (AG) in Breast Cancer Patients (Pts) Previously Treated with Adjuvant TAM, Preliminary Results of a Multicentric Comparative Study. F Boccardo, A Rubagotti, D Amoroso, M Mesiti, L Gallo, A Farris, G Cruciani, E Villa, G Schieppati, G Mustacchi (ABSTRACT 273).

In this study, postmenopausal women who had already completed three years of adjuvant tamoxifen (TAM) were randomized to continue on TAM for two more years or take low-dose (250 mg daily) aminoglutethimide for two years. Three hundred and eighty-one patients (90% of whose tumors were known to be estrogen receptor-positive [ER⁺]) were randomized. Patients in the two groups were comparable (approximately 30% had negative lymph nodes, approximately 40% had one to three involved lymph nodes, approximately 30% had 4 involved lymph nodes). At a median follow-up of 53 months, 51 women in each arm had suffered an event, either disease recurrence (34 in the TAM arm versus 39 in the aminoglutethimide arm), a second primary cancer (7 versus 10), or had died without experiencing a relapse (10 versus 2) (Table 1). In the TAM group there were 28 deaths, 16 due to progressive disease. In the aminoglutethimide arm there were 12 deaths, eight of which were due to progressive disease. Although event-free survival was similar between the two groups, overall survival was significantly better in the aminoglutethimide group (p = 0.005) (Table 2). The patients who relapsed in the aminoglutethimide arm did better than those who relapsed in the TAM arm (median time to relapse 53 months in the TAM arm compared with 63 months in the aminoglutethimide arm). The aminoglutethimide was less well tolerated than the TAM and led to a greater number of withdrawals, with fatigue, rash/pruritis, headaches, and dizziness being the major reasons.

A new study by the same investigators, already under way, maintains the same design, but substitutes anastrozole for aminoglutethimide. Since anastrozole is more selective, there will be fewer side effects and therefore better compliance. Since it is a more potent inhibitor, the study should answer more definitively the question of the role of aromatase inhibitors after TAM. It is one of a number of proposed and/or ongoing trials of aromatase inhibitors in the adjuvant setting which is currently being conducted.

Chemotherapy With or Without Tamoxifen for Patients with ER Negative Breast Cancer and Negative Nodes: Results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B23. B Fisher, S Anderson, N Wolmark, E Tan-Chiu. NSABP (ABSTRACT 277).

In this trial, 2,008 women with breast cancer with negative axillary lymph nodes and whose tumors were ER^– (ER 0-9 fm/mg protein) were randomized to be given four cycles of cyclophosphamide and Adriamycin (AC), once every 21 days, or six cycles of classic CMF (cyclophosphamide 500 mg/m², methotrexate 40 mg/m², and 5-fluorouracil [5-FU] 600 mg/m²) given every 28 days for six months. In each group, women were further randomized to take either placebo or TAM 20 mg a day for five years. There was no significant difference in disease-free survival or overall survival between the women who received AC or CMF, or between those who received placebo or TAM with either chemotherapy regimen (Table 3). Furthermore, this was true both for women under 50 and over 50.

Complete Hormonal Blockade Versus Chemotherapy in Premenopausal Early-Stage Breast Cancer Patients (Pts) with Positive Hormone-Receptor (HR⁺) and 1-3 Node-Positive (N⁺) Tumor: Results of the FASG 06 Trial. HH Roche, P Kerbrat, J Bonneterre, P Fargeot, P Fumoleau, A Monnier, I Chapelle-Marcillac, M Bardonnet (ABSTRACT 279).

This trial of the French Adjuvant Study Group included premenopausal women with ER⁺ or progesterone-positive (PR⁺) early-stage breast cancer with one to three involved axillary lymph nodes. The trial was designed to test the hypothesis that complete hormonal blockade (CHB) might be an effective alternative to chemotherapy in these young women. After primary surgery the women were randomized to either TAM 30 mg a day plus a luteinizing hormone-releasing hormone (LHRH) agonist (Triptoreline 3.75 mg i.m.) monthly x 3 years or FEC (5-FU 500 mg/m², epirubicin 50 mg/m², cyclophosphamide 500 mg/m²) q 3 weeks x 6 cycles, followed by radiation therapy. Three hundred and thirty-three women were randomized. In the FEC arm tolerability was good and 98% of the planned treatment was delivered. Eight out of 160 (5%) of the women on hormonal therapy withdrew because of toxicity. Of the women treated with FEC, 41.5% became permanently amenorrheic. The majority of the women on TAM/LHRH agonist regained their periods after the treatment. At 54 months median follow-up, as shown in Table 4, there was a trend to lower relapse and death rates in the CHB arm, with an increase in disease-free survival (80.9% in FEC arm, 91.7% in CHB arm) and time to progression (31.7 months in the FEC arm, 49.5 months in the CHB arm), favoring the CHB group. Only the difference in time to progression approached statistical significance (p = 0.015).

Commentary
For as long as it has been known that adjuvant chemotherapy causes amenorrhea in premenopausal women, it has been actively debated how much of the benefit from the chemotherapy can be ascribed to this indirect endocrine effect. When, in the worldwide meta-analysis by the EBCTSG, oophorectomy was found in older studies to give a benefit similar in magnitude to that seen with adjuvant chemotherapy, the role of oophorectomy or ovarian suppression became a hot topic [5]. In a small Scottish study young premenopausal women with involved axillary lymph nodes were assigned to either CMF or oophorectomy [6]. The two treatments overall were equivalent but oophorectomy was superior in the subgroup with ER⁺ tumors and CMF more effective in the ER^– subset. At last year's ASCO meeting, the results of a Swedish trial (DBCG 89B) comparing CMF to ovarian ablation in premenopausal women with hormonal receptor-positive (HR⁺) tumors was reported, showing the two treatments seemed comparable in efficacy [7]. At the same meeting the results of Trial V of the Austrian Breast Cancer Study Group were reported, showing that TAM x 5 years plus an LHRH agonist for three years was at least as good as (if not superior to) CMF [8].

In this study there was a slight imbalance in randomization. Twenty percent of the women in the TAM/LHRH group had grade I tumors, compared to only 11% of those assigned to FEC. Otherwise, however, the two groups were well balanced. The results are encouraging and in line with the above-mentioned studies, that hormonal therapy seems to be at least as good as adjuvant chemotherapy in these young women with ER⁺ tumors. It is additionally interesting that the women who achieved amenorrhea with FEC fared better than those who did not (although presumably, since amenorrhea is age-related, one could argue that this reflects the known worse prognosis in younger women). The cumulative evidence is in favor of the feasibility and efficacy of hormonal therapy as adjuvant treatment in young women with HR⁺ breast cancer. As addressed in an Eastern Cooperative Oncology Group study, also reported at the 1999 ASCO meeting, the next challenge is to discover how much additional benefit can be obtained from combining CHB and chemotherapy in these young women [9].

	ADJUVANT CHEMOTHERAPY

Top Abstract Adjuvant Hormonal Therapy Adjuvant Chemotherapy HER-2 as a Predictive... References

 
3 Versus 6 Cycles of CMF in Breast Cancer Patients with 1 to 9 Positive Nodes: Results of the German Adjuvant Breast Cancer Group (GABG) III Trial. H Maass (ABSTRACT 283).

This trial by the German Adjuvant Breast Cancer Group (GABG) included women with involved axillary lymph nodes. Premenopausal women with either ER⁺ or ER^– tumors, and postmenopausal women with ER^– tumors were included. The women were randomly assigned to either three or six cycles of CMF given on days 1 and 8 every 28 days. Seven hundred and eighty-nine patients were randomized, but there was a high rate of ineligibility and only 667 patients were actually eligible. There was a slight (not statistically significant) imbalance between the groups, with 29% of the shorter treatment group having four to nine involved axillary lymph nodes, compared with 37% of the longer treatment group. In a multivariate analysis, the only significant prognostic variables were age, extent of lymph node involvement, and PR expression. At a median follow-up of 70 months, there was no statistically significant difference in either recurrence (33.3% versus 30.4%) or death (14.8% versus 12.8%) in the overall groups assigned to three or six months of CMF. There was a trend to an increased benefit for six cycles in the women under 40, and a greater trend to an increased benefit from six cycles in the women with four to nine involved axillary lymph nodes, but these did not reach statistical significance.

Commentary
Since the NSABP study showing that four cycles of CA are equivalent to six cycles of CMF, CA x 4 has been increasingly used as the standard adjuvant regimen because of its brevity, and the quality-of-life study run in parallel with it that showed that the women actually preferred it [4]. If CMF x 3 were to be shown to be equivalent to CMF x 6, then one might see this trend away from CMF being reversed. The other major reason for using CA instead of CMF for women with involved axillary lymph nodes is the report from a Cancer and Leukemia Group B (CALGB) trial showing a significant benefit from adding Taxol to CA x 4 [10]. This rapidly resulted in CA followed by Taxol being adopted as the standard regimen for all women with involved axillary lymph nodes. Comparable data have not been generated for CMF followed by Taxol, no doubt partly because classical CMF followed by Taxol would generate a nine-month regimen which would be distinctly unpopular.

Should this report from the GABG result in our adopting three months of CMF as standard instead of six? I think this would be premature for several reasons. First of all, the high ineligibility rate (blamed by the presenter on "poor cooperation in the clinics") raises questions about the quality of the study. Second, there is a high variability in CMF regimens. In the regimen used here all three drugs were given on days 1 and 8 of a 28-day cycle. In other CMF regimens the drugs are given once every three weeks and in the original CMF the cyclophosphamide was given orally, not i.v. Thus this regimen is slightly more dose-intense than some CMF regimens. It will be important to see further follow-up among the sub-groups. There is already a trend for increased efficacy of six cycles in women under 40 and in women with four to nine involved axillary lymph nodes. In view of the preceding paper, it would be interesting to look at the rate of amenorrhea in young women exposed to six versus three cycles of CMF and whether this influenced recurrence risk. It would be wonderful if three cycles of CMF were adequate, even just in women >40 with one to three involved lymph nodes, but in view of the above reservations, and in the face of a report last year (ASCO 1999, Abstract 252) reporting that FEC x 6 was superior to FEC x 3, it would be premature to shorten the duration of standard CMF at this time [11]. We should await confirmatory studies.

Is the Addition of Adjuvant Chemotherapy Always Necessary in Node Negative (N^–) Postmenopausal Breast Cancer Patients (Pts) Who Receive Tamoxifen (TAM)?: First Results of IBCSG Trial IX. M Castiglione-Gertsch, KN Price, ML Nasi, J Lindtner, D Erzen, D Crivellari, A Veronesi, M Fey, O Pagani, J Collins, J Forbes, C Rudenstam (ABSTRACT 281).

In this trial, number IX run by the International Breast Cancer Study Group, postmenopausal women with node-negative breast cancer were randomly assigned to adjuvant chemotherapy with three cycles of CMF followed by TAM for five years or TAM alone for five years. One thousand, seven hundred and fifteen patients were accrued. Of these, 1,668 were found to be eligible. The groups seem to be evenly balanced. Seventy-three percent of the patients had ER⁺ tumors. Both treatments were given with minimal toxicity (two deaths in each group).

For the entire group of women in the study, there was a significant increase in disease-free survival using the combination compared with TAM alone, but there was no difference in overall survival. When the results were analyzed by ER status, the benefits were found to be confined to the ER^– subgroup, in which there was a statistically significant benefit for both disease-free survival and overall survival, favoring the addition of chemotherapy to TAM. In the ER⁺ subgroup there was no benefit for the addition of chemotherapy for either disease-free survival or overall survival. The authors conclude that for postmenopausal women with ER⁺ breast cancer, TAM alone may be reasonable.

Commentary
While individual trials of combination chemotherapy with TAM versus TAM alone have given conflicting results, the meta-analysis by the EBCTSG concluded that there was a 19% decrease in the risk of recurrence and an 11% decrease in the risk of death for postmenopausal women given chemotherapy in addition to TAM [1]. Why, then, would one trial failing to show a benefit influence our thinking on this issue? As pointed out by Dr. Kathy Albain, who discussed this abstract, the different results from different trials may reflect variations in the duration of adjuvant TAM, variations in efficacy of different CMF regimens chosen, as well as variability in dose reductions and duration of the regimens used. Given that we are becoming aware that TAM alone does not benefit women with ER^– tumors (see discussion on Abstract 277 above), it is hardly surprising that the addition of CMF is beneficial. The results in the ER⁺ subgroup contradict those from the NSABP study B-20 where CMF added to TAM gave significant benefit in similar postmenopausal women with ER⁺ breast cancers [12]. In the NSABP trial the CMF was given for six cycles and it is hard to escape the conclusion that, notwithstanding the above study (Abstract 283) claiming that three cycles of CMF are as good as six, the negative results presented here may simply have been obtained because three cycles of CMF are not adequate. That having been said, it should be stated that even if, as seems likely, the NSABP trial data will stand, the conclusion from this presentation still is valid. In other words, TAM alone may well be reasonable for postmenopausal women with ER⁺, node-negative disease. Even a small reproducible benefit from chemotherapy may be foregone if its benefit (which is small in absolute terms, only amounting to an absolute improvement in survival of 2%-3%) is not perceived as substantive enough by the patient for her to wish to endure the side effects of the chemotherapy.

Role of Paclitaxel in Adjuvant Therapy of Operable Breast Cancer: Preliminary Results of Prospective Randomized Clinical Trial. E Thomas, A Buzdar, R Theriault, S Singletary, D Booser, V Valero, N Ibrahim, T Smith, D Frye, N Manuel, S Kau, M McNeese (ABSTRACT 285).

This M.D. Anderson study of women with early-stage invasive breast cancer included women who were given either neoadjuvant (174 patients) or standard adjuvant (350 patients) chemotherapy. Women were treated either with eight cycles of FAC (5-FU 500 mg/m² days 1 and 4, Adriamycin 50 mg/m² by continuous infusion over 72 h, and cyclophosphamide 500 mg/m² day 1) or four cycles of Taxol (250 mg/m² over 24 h) followed by four cycles of FAC. Both chemotherapy regimens were given once every 21 days. For women who were treated with neoadjuvant chemotherapy, local therapy was delivered after the Taxol and before the FAC. At 43.5 months of follow-up, disease-free survival is 81.5% in the FAC group, and 85.2% in the Taxol/FAC group (p = 0.2). Response rates were approximately 80% in each arm in the neoadjuvant subset.

Commentary
The report at the 1998 ASCO meeting from the CALGB trial showing a 22% reduction in recurrence risk and a 26% reduction in mortality with CA followed by Taxol, compared with CA alone in patients with involved lymph nodes, has already altered the standard of care towards CA followed by Taxol for women with involved lymph nodes [10]. The results of the equivalent study run by the NSABP have not yet been released. This study gives another look at the benefit of Taxol in an adjuvant (or neoadjuvant) setting. FAC, the standard M.D. Anderson regimen, is more intensive than AC. Although the data are a little premature, and due to the small number of recurrences to date there is no statistically significant difference between the arms, it is interesting to note that the reduction in recurrence risk in the study (20%) is very similar to that seen in the CALGB study (22%). Clearly, more events will be needed before a definitive conclusion can be drawn and any impact on survival can be assessed, but this study is well on its way to validating the CALGB results. There was one criticism of the CALGB study (which will apply equally to the NSABP study) and that is that the total duration of treatment was only three months in the CA group and six months in the CA followed by Taxol group, leaving open the question of whether what was perceived as a benefit from Taxol was in fact a benefit from the longer duration of treatment. If the benefit to the Taxol arm holds up in this M.D. Anderson study, that criticism will be invalidated since in this trial the duration of treatment was identical in both arms.

	HER-2 AS A PREDICTIVE MARKER

Top Abstract Adjuvant Hormonal Therapy Adjuvant Chemotherapy HER-2 as a Predictive... References

 
Prolonged Follow-up of the Swedish Randomized Trial of Two Versus Five Years of Adjuvant Tamoxifen for Postmenopausal Early Stage Breast Cancer and Relationships to Hormone Receptor and ERBB2 Levels. B Nordenskjold, J Carstensen, L Rutqvist, O Stal, P Malmstrom, M Ferno, A Borg, J Bergh, N Gengtsson, T Hatschek, A Wallgren (ABSTRACT 276).

HER2 Overexpression Predicts Adjuvant Tamoxifen (TAM) Failure for Early Breast Cancer (EBC): Complete Data at 20 Yr of the Naples GUN Randomized Trial. AR Bianco, M De Laurentiis, C Carlomagno, C Gallo, L Panico, S De Placido (ABSTRACT 289).

A Metanalysis of the Interaction Between Her2 and the Response to Endocrine Therapy (ET) in Metastatic Breast Cancer (MBC). M De Laurentiis, G Arpino, E Massarelli, C Carlomagno, F Ciardiello, G Tortora, AR Bianco, S De Placido (ABSTRACT 300).

Three presentations dealt with the predictive value of HER-2 expression on response to endocrine manipulation. In the Swedish trial, 4,587 patients less than 75 years old (lymph node-positive or lymph node-negative) were treated with adjuvant TAM. Two thousand, one hundred and thirty-three patients discontinued tamoxifen at two years, and 2,050 continued TAM for another three. Only 2.5% of patients received adjuvant chemotherapy. As shown in Table 5, there were fewer recurrences and deaths in the five-year arm compared with the two-year arm.

In the second of these studies related to the predictive value of HER-2 staining, Bianco displayed a poster giving an update of the Naples GUN Trial, a report which had caused a significant stir at ASCO in 1998. In this trial, 433 patients were assigned randomly to either TAM (n = 206) or no TAM (n = 227). Premenopausal women with positive axillary lymph nodes also received nine cycles of CMF. Among eight biological markers retrospectively assayed was staining for the HER-2 antigen. At a median follow-up of 15 years, HER-2 expression alone of these markers was predictive of TAM efficacy. The results were expressed as hazard ratio of death (HR) of TAM over no TAM with 95% confidence intervals. The authors report a detrimental effect of TAM in the HER-2⁺ group (HR = 2.23) in contrast to a positive benefit from TAM in the HER-2^– group (HR = 0.54) (Table 6). There was no predictive effect of HER-2 expression in women who also received adjuvant CMF.

In the third of these pertinent presentations, De Laurentiis displayed a meta-analysis of trials involving patients treated with endocrine therapy for metastatic breast cancer (MBC) in which a correlation had been made between response rate and HER-2 status. For each study, the odds of disease progression were taken as an indicator of tumor resistance to the treatment, and the odds ratio (OR) for HER-2⁺ over HER-2^– patients was calculated as an estimate of the predictive effect of HER-2. The overall OR was 2.46, indicating that MBCs overexpressing HER-2 are resistant to endocrine therapy (Table 7).

Commentary
Since the report of CALGB trial 8541 in which overexpression of HER-2 predicted improved benefit for patients given increased dose-intensity of CAF in the adjuvant setting, the role of HER-2 as a predictive marker has been widely debated [20]. Most data have supported an improved benefit from Adriamycin in HER-2 overexpressors, but the data on CMF have been more conflicting. It has been widely speculated that overexpression of HER-2 confers resistance to endocrine therapy. This is supported by preclinical data. Slamon's group transfected the HER-2 gene into an ER⁺ breast cancer cell line, resulting in overexpression of HER-2 [21]. When heregulin (a ligand that activates the HER-2 receptor) was added, genes normally turned on by estradiol were activated but the cells did not respond to inhibition by TAM, suggesting cross-talk between the HER-2 pathway and the ER pathway with resulting loss of hormonal regulation. The Swedish trial shows that women whose tumors are ER⁺ but also overexpress HER-2 do not benefit from an additional three years of TAM. Further subset analysis needs to be done to see if these women benefit from TAM at all. The GUN trial which was first presented at the 1998 ASCO meeting purports to show not only that women whose tumors overexpress HER-2 do not benefit from adjuvant TAM (HR of TAM over no-TAM = 0.59 for HER-2^– patients, 1.09 for HER-2⁺ patients) which seems plausible, but also that the HER-2 overexpressors actually do worse on TAM if they do not receive adjuvant chemotherapy, too [22]. Certainly one could hypothesize that HER-2⁺ cells which express ER could be stimulated instead of inhibited by TAM; however, before we jump to the conclusion that TAM should be withheld from these women, it should be noted that the confidence intervals on the HR for the HER-2 overexpressors overlap one and thus these data, although provocative, cannot be taken as statistically significant at this time. Finally, the meta-analysis of patients with metastatic disease treated with endocrine therapy certainly suggests that HER-2-overexpressing breast cancers progress more readily on hormone therapy than HER-2^– tumors. It should, however, be noted that this same result would be seen if the tumors were equally sensitive to hormonal therapy but had a higher growth fraction, allowing a resistant subpopulation to emerge more quickly. Overall, however, the data from these trials taken together will make us more wary of overestimating any benefit to adjuvant TAM or hormonal therapy for metastatic disease in the patient with an HER-2-overexpressing tumor.

	REFERENCES

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