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Breast Cancer

Massachusetts General Hospital, Boston, Massachusetts, USA

Correspondence: Irene Kuter, M.D., D. Phil., Massachusetts General Hospital, Cox 640, Hematology-Oncology Unit, 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 Management of Early Stage... Hormonal Issues in Adjuvant... Chemoprevention of Breast Cancer... Trastuzumab and HER-2 Update Tamoxifen Resistance References

 
Several interesting aspects of breast cancer were covered at this year's American Society of Clinical Oncology meeting. Sentinel lymph node (SN) mapping is now in widespread use, in concert with the general trend toward trying to decrease the morbidity of breast cancer surgery. With every advance, however, comes new challenges, and there was a timely presentation from Giuliano's group addressing the controversial issue of how to interpret the presence of cells in the SN seen only with keratin stains but not by routine hematoxylin and eosin stains. Two abstracts addressed the issue of whether for certain women with invasive breast cancer radiation therapy could be omitted after lumpectomy. Another interesting topic related to hormonal issues in the adjuvant treatment of premenopausal women. An analysis from the ZIPP-TRIAL reported on bone marrow density studies in young women given two years of ovarian suppression in the adjuvant setting: it seems that the loss of bone density may be reversible and, more interestingly, may be prevented with concurrent tamoxifen. Two other presentations looked at the prognostic significance of drug-induced amenorrhea in young women treated with adjuvant chemotherapy and at the efficacy of ovarian suppression during chemotherapy in preserving fertility.

In an unpublicized presentation, Mary-Claire King presented very interesting results from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial suggesting that tamoxifen may be an effective chemopreventive drug for women with BRCA2, but not BRCA1, mutations. Two important presentations re-analyzed the outcome of the pivotal trials using Herceptin to treat metastatic breast cancer and nicely show that FISH analysis of HER-2 overexpression is a more accurate indicator of response to Herceptin than immunohistochemical staining. Finally, there were two interesting presentations related to tamoxifen resistance which may be relevant clinically, pertaining to subsequent raloxifene use and the interaction of the estrogen receptor and EGF receptor pathways, respectively.

Key Words. Sentinel node micrometastases • Radiation after lumpectomy • Amenorrhea • Tamoxifen and BRCA mutations • HER-2/FISH • Tamoxifen resistance

	MANAGEMENT OF EARLY STAGE BREAST CANCER

Top Abstract Management of Early Stage... Hormonal Issues in Adjuvant... Chemoprevention of Breast Cancer... Trastuzumab and HER-2 Update Tamoxifen Resistance References

 
Clinical Significance of Axillary Micrometastases in Breast Cancer: How Small is Too Small? NM Hansen, BJ Grube, W Te, ML Brennan, R Turner, AE Giuliano (ABSTRACT 91).

This prospective study was designed to determine the significance in terms of survival of micrometastases in sentinel lymph nodes (SNs) detected only by immunohistochemistry (IHC). Between January 1992 and April 1999, 696 patients underwent SN mapping and were classified into four groups: A) SN negative by both hematoxylin and eosin (H&E) staining (n = 425); B) SN H&E^–/IHC⁺ (n = 56); C) SN H&E⁺, micrometastases 2 mm (n = 76), and D) SN H&E⁺, macrometastases >2 mm (n = 139). With a median follow-up of 38 months, the size of SN metastases was a significant predictor of disease-free survival (DFS) but not overall survival (OS). However, as seen in Table 1, there was no significant difference in DFS or OS between SN^– patients and those with SNs that were IHC⁺ but H&E^–. The authors conclude that IHC should not be performed routinely on the SN nor should treatment decisions be made until results of large multicenter studies such as the American College of Surgeons Oncology Group (ACSOG) Z0010 are reported.

Preliminary Results of a Randomized Study of Tamoxifen ± Breast Radiation in T1/2 N0 Disease in Women Over 50 Years of Age. A Fyles, D McCready, L Manchul, M Trudeau, I Olivotto, P Merante, M Pintilie, L Weir (ABSTRACT 92).

Comparison of Lumpectomy Plus Tamoxifen With and Without Radiotherapy (RT) in Women 70 Years of Age or Older Who Have Clinical Stage I, Estrogen Receptor Positive (ER⁺) Breast Carcinoma. KS Hughes, L Schnaper, D Berry, C Cirrincione, B McCormick, B Shank, JD Lu, T Smith, B Smith, C Shapiro, W Wood, C Henderson, L Norton (ABSTRACT 93).

In these two studies, the question being addressed is whether there is a subset of women who could forgo radiation therapy (RT) after excision of an invasive cancer. In both studies, tamoxifen was given to all the women, but only half received breast radiation after lumpectomy. In the Fyles study, 638 women over 50 years old with T1 or T2, N0 breast cancers participated. Ipsilateral breast tumor relapse (IBTR) was seen in 22 of 384 (5.7%) patients in the tamoxifen arm compared with 2 of 385 (0.5%) in the tamoxifen plus radiation arm (Table 2). There was no difference in the relapse rate at regional or distant sites or in the contralateral breast, and survival was not influenced by RT. The authors concluded that tamoxifen and radiation therapy significantly lowered the rate of breast relapse compared with tamoxifen alone in women older than 50 with node-negative breast cancer.

	HORMONAL ISSUES IN ADJUVANT THERAPY

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Bone Mineral Density in Premenopausal Patients in a Randomized Trial of Adjuvant Endocrine Therapy (ZIPP-TRIAL). Á Sverrisdóttir, T Fornander, L Rutqvist (ABSTRACT 96).

In this interesting presentation, Sverrisdóttir presented data from the Swedish cohort participating in the European (Sweden/United Kingdom/Italy) ZIPP-TRIAL. Seventy-three premenopausal women with node-negative breast cancer participating in this trial were assigned to adjuvant therapy for 2 years with Zoladex, tamoxifen, Zoladex plus tamoxifen, or no adjuvant endocrine therapy. No adjuvant chemotherapy was given. Total body bone mineral content (TBBM) was measured using dual photon x-ray absorptiometry at initiation of treatment, at 12 months, 24 months, and 36 months (one year after treatment ended). As shown in Table 4, there is a significant reduction in bone mineral density after 2 years of therapy with Zoladex (p < 0.0001). In the updated analysis presented at the conference, the TBBM actually improved after cessation of Zoladex. Tamoxifen alone did not significantly affect TBBM and compensated for the loss caused by Zoladex.

Incidence and Prognostic Impact of Amenorrhea During Adjuvant Therapy in High Risk Premenopausal Breast Cancer Patients: Analysis of a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Phase III Study. W Parulekar, ME Trudeau, L Shepherd, J Ottaway, A Day, E Franssen, V Bramwell, M Levine, K Pritchard (ABSTRACT 97).

The authors of this study looked at the incidence and prognostic impact of amenorrhea occurring in the National Cancer Institute of Canada Clinical Trials Group study of CEF versus CMF. This study, which demonstrated the superiority of CEF over CMF, involved 716 women of whom 541 fulfilled all the criteria for eligibility, namely normal menstruation at randomization and receipt of six cycles of chemotherapy. Drug-induced amenorrhea (DIA) was defined as cessation of menses for 3 months during treatment. No patients in the study were given adjuvant tamoxifen. With a median follow-up of 7.7 years, the incidence of DIA was significantly higher in the CEF group, 73.9% versus 61.9% (p = 0.005). However, DIA did not affect relapse-free survival (53% versus 49%) for patients with and without amenorrhea, respectively (p = 0.3).

Commentary
Since alkylators have long been thought to be the major etiological agent in drug-induced amenorrhea associated with adjuvant treatment, it is curious that CEF caused a higher rate of amenorrhea than CMF since the cumulative dose of cyclophosphamide was lower after the CEF regimen (median cumulative dose of cyclophosphamide 5,395 mg/m² in the CEF group compared with 7,839 mg/m² with CMF). The main point of the presentation, however, is that after stratification for other variables, there was no difference in DFS between those patients who did or those who did not have amenorrhea. The debate over the possible benefit of DIA in women who were premenopausal when breast cancer treatment was initiated has been ongoing for many years. Unfortunately, this study probably does not help settle the issue since it is unlikely that a benefit would be derived unless the amenorrhea is significantly more than 3 months, assuming the mechanism of benefit is analogous to that of tamoxifen (when prolonged antagonism of estrogen is necessary for efficacy). Amenorrhea lasting at least 2 years, or permanent amenorrhea, is more likely to be clinically significant, and the benefit of such can only be assessed in prospective randomized trials, many of which are currently ongoing. Even if amenorrhea offers some advantage, it has been questioned whether this would afford an increased benefit over tamoxifen alone, and ongoing studies will also help address this issue. None of the women in the above study were given tamoxifen.

Preventing Chemotherapy-Associated Amenorrhea (CRA) with Leuprolide in Young Women with Early-Stage Breast Cancer. KR Fox, JE Ball, R Mick, HC Moore (ABSTRACT 98).

Although, as noted above, the benefits of amenorrhea in the young breast cancer patient are still debated, it is not uncommon for a young woman diagnosed with breast cancer to ask for treatment that will optimize her chance of future fertility. In this small study, 13 premenopausal women were treated with leuprolide during their adjuvant chemotherapy with the goal of protecting the ovaries from the cytotoxic effect of chemotherapy. Patients ranged in age from 26 to 39 years old (median 35). Six patients were treated with four cycles of AC, five patients with AC followed by four cycles of paclitaxel, one received CAF x 6 months, and one received doxorubicin/paclitaxel followed by CMF. All were given concurrent leuprolide, and all became amenorrheic by the second cycle of chemotherapy; however, all recovered their menses within 1 year of completing chemotherapy.

Commentary
Using ovarian suppression during chemotherapy in an attempt to prevent toxicity to developing follicles is not a new idea, but it has not convincingly been shown to offer an advantage for maintenance of fertility. It is not currently widely used for this reason. In addition, its use during chemotherapy places another burden on the patient, namely coping with acute menopausal symptoms while also dealing with the direct side effects of the chemotherapy. Although, as the author states, it is encouraging that all the patients in this study recovered their periods, it cannot be stated that a role for leuprolide has been demonstrated. Chemotherapy-induced amenorrhea is very age- and regimen-dependent. It has been shown that AC is less likely than CMF to induce amenorrhea, and 11 of 13 patients were treated with this regimen (half also were given Taxol, which, anecdotally, does not seem to be as toxic to the ovary as cyclophosphamide), and the question is whether less ovarian suppression is being seen in this group of young women than would be seen without the use of the leuprolide. Nancy Davidson, in a commentary, quoted the results of a single institution study reported at the San Antonio Breast Conference last year [3] in which only 8% of patients younger than 40 years old treated with AC developed amenorrhea; however, 33% of those treated by AC followed by Taxol did so. At this point, more research needs to be done on the use of GnRH agonists in the adjuvant setting. If there is an advantage with respect to future fertility, it will have to be demonstrated in a large prospective randomized trial. There are insufficient data on efficacy to justify use of these drugs for the purpose of maintaining fertility at this time.

	CHEMOPREVENTION OF BREAST CANCER IN BRCA1 AND BRCA2 GENE MUTATION CARRIERS

Top Abstract Management of Early Stage... Hormonal Issues in Adjuvant... Chemoprevention of Breast Cancer... Trastuzumab and HER-2 Update Tamoxifen Resistance References

 
Tamoxifen and Breast Cancer Incidence Among Women with BRCA1 or BRCA2 Mutations: A Genomics Resequencing Project Embedded in the Breast Cancer Prevention Trial.

In a special session not previously advertised and for which no abstract is available, Mary-Claire King presented, the initial results of protocol P-1G. This is a genomics project embedded in the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 Breast Cancer Prevention Trial (BCPT), carried out at the King laboratory at University of Washington with the collaboration of NSABP investigators. The project used blood samples (anonymized) from patients who developed breast cancer while enrolled on the NSABP P-1 BCPT. In this trial, over 13,000 high-risk women had been randomly assigned to tamoxifen or placebo, and there was a 49% decrease in incidence of breast cancer in the tamoxifen group compared with placebo. When the genetic study began, 315 participants in the BCPT had developed invasive breast cancer. Samples from 288 of these women were available for DNA sequencing, and, of these, 19 (6.6%) had a mutation in either the BRCA1 or BRCA2 gene. Women carrying mutations were more likely to have earlier disease onset (16% of women diagnosed before age 50 had mutations compared with 4% of women diagnosed at age 50 or older) and to have close relatives with breast cancer. Eight women with inherited mutations in BRCA1 developed breast cancer during the BCPT. Five had been randomized to tamoxifen and three to placebo. Thus, the risk ratio for tamoxifen versus placebo among women with BRCA1 mutations was 1.67 (95% CI, 0.41, 8.00) suggesting no reduction in breast cancer incidence. Eleven women with inherited mutations in BRCA2 developed breast cancer. Three had been randomized to tamoxifen and eight to placebo. The risk ratio for tamoxifen versus placebo was 0.38 (95% CI, 0.06, 1.5). This is equivalent to a reduction in incidence due to tamoxifen of 62%. Although this reduction in incidence was not statistically significant, it is similar to the statistically significant 52% decrease in incidence for the 269 women with detectable mutations in BRCA1 or BRCA2. Dr. King pointed out that approximately 80% of breast cancers occurring in women with BRCA1 mutations are ER^– and this might be why tamoxifen did not reduce the breast cancer risk in BRCA1 mutation carriers. In contrast, 80% of tumors developing in BRCA2 mutation carriers are ER⁺, and this is probably why tamoxifen was effective in decreasing breast cancer incidence in BRCA2 mutation carriers.

Commentary
These preliminary, long-awaited results are extremely interesting. Given that the work was conducted in the King laboratory and that, during the study, mutations in DNA samples from known mutation carriers not participating in the trial were all identified correctly, it is likely that the results to date are accurate. Although the number of cancers is small, the large size of the study (>13,000 participants) makes it quite unlikely that mutation carriers would be significantly imbalanced between the placebo and tamoxifen groups. Thus the imbalance in occurrence of cancers between the placebo and tamoxifen groups in the BRCA2 mutation carriers, but the lack of imbalance in the BRCA1 carriers, is likely to be meaningful (though not statistically significant). It was shown in the BCPT that the incidence of ER⁺ tumors was lowered in the participants as a whole by 49%. ER^– tumor incidence was, however, not affected by tamoxifen [4]. For the ER⁺ subset, there was a 68% reduction in incidence from tamoxifen treatment. This is similar to the 62% reduction seen from tamoxifen in the BRCA2 mutation carriers, which, as the authors point out, are usually ER⁺ tumors. It is interesting that not only was there no decrease in risk of cancers in the BRCA1 mutation carriers, there was a trend to increased incidence with the use of tamoxifen. Though clearly not statistically significant, it is curious to note that a trend toward increased incidence of ER^– tumors was seen in the entire group participating in the BCPT trial [4]. A similar trend toward increased incidence of ER^– cancers was also seen in the Multiple Outcomes of Raloxifene Evaluation trial in the women treated with raloxifene compared with placebo [5]. These statistically insignificant trends in both trials most likely are a curious coincidence, but, as we prescribe selective estrogen receptor modulators (SERMs) for prevention, it must be borne in mind that we have not totally ruled out a possible increase in incidence of ER^– tumors in the treatment group compared with placebo. Are these data persuasive enough for us to prescribe tamoxifen routinely to BRCA2 carriers? Probably most of us would feel comfortable with these data because they are plausible and in line with other data. Should we not prescribe tamoxifen to BRCA1 carriers? This would probably be premature since data from two sources are at odds with these early results from the G-1 study. First of all, oophorectomy is known to protect BRCA1 carriers significantly from developing tumors [6]. Secondly, a large case control study from the Hereditary Breast Cancer Clinical Study Group [7] showed that tamoxifen use decreased the incidence of contralateral breast cancers in BRCA1 carriers by 62% and in BRCA2 carriers by 32%. The protective effect was independent of that of oophorectomy. One explanation of the apparent discrepancy in the results of these studies is that only 13% of the BRCA1 carriers in the Narod study had received tamoxifen. It is likely that tamoxifen had only been prescribed for the BRCA1 carriers who had ER⁺ tumors. If patients with ER⁺ tumors are at increased risk of having a second ER⁺ tumor, the protective benefit would be explained. Finally, the authors took pains to point out that their result pertained only to prevention. If a patient with a BRCA1 mutation develops ER⁺ breast cancer, there is no reason not to assume that tamoxifen will be as helpful in decreasing recurrence risk as it is in other patients with ER⁺ cancers.

	TRASTUZUMAB AND HER-2 UPDATE

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Improved Survival Benefit from Herceptin (Trastuzumab) in Patients Selected by Fluorescence in Situ Hybridization (FISH). RD Mass, M Press, S Anderson, M Murphy, D Slamon (ABSTRACT 85).

Superior Outcomes with Herceptin (Trastuzumab) (H) in Fluorescence in Situ Hybridization (FISH)-Selected Patients. CL Vogel, M Cobleigh, D Tripathy, R Mass, M Murphy, SJ Stewart (ABSTRACT 86).

In the pivotal phase III trial of chemotherapy (AC or Taxol) ± trastuzumab as first-line treatment of HER-2-overexpressing breast cancer, there was an advantage to the addition of Herceptin in terms of response rates (50% versus 38%) and survival (odds ratio [OR], 0.80) despite a trial design resulting in 65% of control patients receiving Herceptin at disease progression [8]. To be eligible for this trial, patients' tumors had to overexpress HER-2 (2⁺ or 3⁺ by IHC). The IHC was run in a central lab. In the current study, archived blocks from patients in the study were subjected to FISH analysis. A HER-2:CEP 17 signal ratio was detected using the PathVysion dual probe FISH assay system. HER-2 gene amplification was detected in 76% of the patients on the study. Ninety-two percent of 3⁺ overexpressors and 32% of 2⁺ overexpressors were FISH⁺. The addition of Herceptin to chemotherapy improved the response rates in the FISH⁺ subgroup (54% versus 30.8%, p < 0.0001) (Table 5), while there was no improvement in the FISH^– subgroup (38% versus 37.5%, p = NS). FISH results also predicted survival benefit: in the FISH⁺ group, addition of Herceptin to chemotherapy provided a significant survival benefit (OR 0.71, p = 0.009) not seen in the FISH^– group (OR 1.11, p = NS).

	TAMOXIFEN RESISTANCE

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Effect of Raloxifene After Tamoxifen on Breast Endometrial Cancer Growth. RM O'Regan, C Gajdos, R Dardes, A de los Reyes, DJ Bentrem, VC Jordan (ABSTRACT 95).

In this interesting study, O'Regan et al. looked at animal cancer models with respect to the effect of raloxifene given after tamoxifen. In each model, human tumor cells were grown in athymic mice in the presence of estrogen, tamoxifen, raloxifene, or a SERM together with estrogen. The mice were implanted on one side with breast cancer cells and on the other side with endometrial cancer cells. When the breast cancer cells were from a line resistant to tamoxifen (generated by long-term exposure to the drug), tamoxifen actually stimulated the growth of the tumor in the athymic mice, and raloxifene stimulated these cells to the same degree. When the source of the endometrial cancer cells was a tamoxifen-resistant line, again there was stimulation of growth by tamoxifen and a similar degree of stimulation by raloxifene, suggesting tamoxifen resistance in both a breast cancer and an endometrial cancer model confers raloxifene resistance, too.

Commentary
Although not a clinical study, this intriguing report from Dr. Jordan's group merits contemplation. In brief, raloxifene is considered to be a safer drug for long-term use than tamoxifen, since it appears not to stimulate the endometrium. After 5 years of adjuvant tamoxifen for breast cancer, many physicians are putting their patients on raloxifene for preservation of bone mineral density. Tamoxifen is not currently recommended for more than 5 years in the adjuvant setting because in two small studies randomizing women to 5 years versus 10 years of tamoxifen, there were actually more recurrences in the group assigned to 10 years, and there was also an increase in endometrial cancer risk in the patients given 10 years of the drug. The question arises as to whether substituting raloxifene after 5 years of tamoxifen is safer than continuing tamoxifen for 10 years. This study suggests that it may, in fact, not be a good idea since raloxifene was unable to inhibit tamoxifen-resistant breast cancer cells and, in fact, appears to stimulate their growth in a fashion similar to tamoxifen. Furthermore, raloxifene, tamoxifen, and estrogen had similar stimulating effects on the growth of the endometrial cancer cells. Until clinical trials provide more data, the possible benefit of raloxifene after 5 years of tamoxifen needs to be balanced against the possible risks of stimulating dormant residual cancer cells and even possibly the risk of acting with the prior tamoxifen to stimulate endometrial cancer growth. At present, the American Society of Clinical Oncology guidelines [10] caution that there are no good data to support the sequential use of SERMs, such as tamoxifen followed by raloxifene.

The EGFR-Selective Tyrosine Kinase Inhibitor ZD1839 (Iressa) is an Effective Inhibitor of Tamoxifen-Resistant Breast Cancer Growth. JM Gee, IR Hutcheson, JM Knowlden, D Barrow, ME Harper, AE Wakeling, RI Nicholson (ABSTRACT 282).

In another study using a breast cancer cell line model MCF7, breast cancer cells exposed to tamoxifen acquired resistance to the drug. These cells were found to overexpress EGFR and HER-2, which were present as heterodimers. Tumor necrosis factor-, an epidermal growth factor receptor (EGFR) ligand, increased the phosphorylation of the EGFR and the growth of the tamoxifen-resistant cells to a much greater degree than wild-type cells. ZD1839 (Iressa), a selective EGFR small molecule inhibitor, was able to wipe out the phosphorylation of the EGFR and of phosphorylated intermediates in the MAP kinase pathway, resulting in marked inhibition of growth of the tamoxifen-resistant cells. In contrast, the drug had no effect on wild-type (tamoxifen-sensitive) cells. When wild-type cells were grown in the presence of tamoxifen, growth inhibition by tamoxifen gradually declined, resulting in resistance by 3 months. The acquisition of resistance was abolished if Iressa was also added to the cells with the tamoxifen. The author concludes that the EGFR/MAP kinase pathway is important in the generation of tamoxifen resistance in this model system, and its inhibition by Iressa could prevent the development of this resistance in vitro.

Commentary
Although tamoxifen is a potent drug for treating ER⁺ breast cancer, drug resistance usually develops after 1 to 2 years of treatment. The EGFR is also commonly overexpressed in breast cancer, and it has been suggested that growth stimulation via the EGFR pathway might be an important mechanism by which tamoxifen resistance can occur. HER-2 overexpression has also been linked to tamoxifen resistance. In this study, data are presented to support the hypothesis that tamoxifen resistance occurs because an alternative pathway of growth stimulation, via the MAP kinase pathway (stimulated by an activated EGFR) stimulates growth of the cells. Iressa was able to reverse the molecular activation of the MAP kinase pathway seen in the tamoxifen-resistant cells, and this was accompanied by effective growth inhibition of tamoxifen-resistant (but not tamoxifen-sensitive) cells. Although a cautionary note should be added that data from cells lines can differ significantly from real life cancers, this exciting observation suggests that the drug be tested in clinical trials to see if it can prevent or reverse resistance to tamoxifen in patients. It should be noted that studies are already under way to see if Herceptin can restore tamoxifen sensitivity to ER⁺ breast cancers overexpressing HER-2 since HER-2 overexpression also leads to a relative resistance to antiestrogen treatment. Studies of the interaction of the tyrosine kinase-mediated pathways and the ER pathways might lead to some exciting new developments in endocrine treatment of breast cancer in the next few years.

© Sean P. Murphy

	ACKNOWLEDGMENTS

Top Abstract Management of Early Stage... Hormonal Issues in Adjuvant... Chemoprevention of Breast Cancer... Trastuzumab and HER-2 Update Tamoxifen Resistance References

 
I.K. is a member of the speakers' bureau for AstraZeneca and Genentech.

	References

Top Abstract Management of Early Stage... Hormonal Issues in Adjuvant... Chemoprevention of Breast Cancer... Trastuzumab and HER-2 Update Tamoxifen Resistance References

 

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3. Stone ER, Slack RS, Novielli A et al. Rate of chemotherapy related amenorrhea associated with adjuvant Adriamycin and Cytoxan (AC) and Adriamycin and Cytoxan followed by Taxol (AC+T) in early stage breast cancer. 23rd Annual San Antonio Breast Cancer Symposium. Breast Cancer Res Treat 2000;64:61a.
4. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–1388.[Abstract/Free Full Text]
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7. Narod SA, Brunet JS, Ghadirian P et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Lancet 2000;356:1876–1881.[CrossRef][Medline]
8. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792.[Abstract/Free Full Text]
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