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Clinical Cancer Research Vol. 9, 495S-501s, January 2003
© 2003 American Association for Cancer Research

Supplement

National Surgical Adjuvant Breast and Bowel Project Update

Prevention Trials and Endocrine Therapy of Ductal Carcinoma in Situ1

Victor G. Vogel2, Joseph P. Costantino, D. Lawrence Wickerham and Walter M. Cronin

University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213-3180 [V. G. K.] and the NSABP Foundation, Inc., Pittsburgh, Pennsylvania 15212-5234 [J. P. C., D. L. W., W. M. C.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 STAR Trial Design
 Effect of Tamoxifen in...
 IBIS I
 New Drugs for the...
 Premenopausal Women
 Other Agents
 ASCO Technology Assessment
 Summary of Recommendations of...
 Open Discussion
 REFERENCES
 
Following up on the results of recent completed trials, several major breast cancer prevention trials are either underway or impending. In the Study of Tamoxifen and Raloxifene trial, eligible women are at least 35 years of age and postmenopausal, with either lobular carcinoma in situ or a 5-year risk of invasive breast cancer of at least 1.67%. The study will compare the ability of 5 years of tamoxifen or raloxifene to reduce the incidence of breast cancer. Subjects are randomly assigned to receive either 20 mg of tamoxifen or 60 mg of raloxifene daily. After 3 years of recruitment, 13,647 women have been randomized (20.7% of those eligible). The median age of randomized women is 58 years (mean age, 58 years), and their median 5-year risk of breast cancer is 3.3% (mean 5-year risk of breast cancer, 4.0%). Hysterectomy was reported by 52.5% of the randomized women; lobular carcinoma in situ was reported by 8.4% of subjects before randomization. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 trial, 1,804 women with ductal carcinoma in situ were randomly assigned tamoxifen after lumpectomy and radiation therapy. Women in the tamoxifen group had fewer breast cancer events at 5 years than did those on placebo (8.2% versus 13.4%, P = 0.0009). The proposed NSABP B-35 trial will have the same design as NSABP B-24 but will compare tamoxifen with anastrozole in postmenopausal women. Outcomes will include both ipsilateral and contralateral new breast cancer and recurrences, as well as the occurrence of regional and distant disease. Enrollment will begin in early 2003.


   Introduction
Top
 ABSTRACT
 Introduction
STAR Trial Design
 Effect of Tamoxifen in...
 IBIS I
 New Drugs for the...
 Premenopausal Women
 Other Agents
 ASCO Technology Assessment
 Summary of Recommendations of...
 Open Discussion
 REFERENCES
 
The BCPT3 P-1 was conducted by the NSABP with support from the National Cancer Institute and AstraZeneca Pharmaceuticals to determine whether tamoxifen could affect the incidence of primary breast cancer in women at increased risk. Tamoxifen reduced the risk of invasive breast cancer by 49%, with a cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively (1) . The decreased risk occurred among women aged 49 years or younger (44% risk reduction), 50–59 years (51%), and 60 years or older (55%). A greater degree of risk reduction was seen among women with a history of LCIS, in whom tamoxifen reduced risk by 56%; among women with atypical hyperplasia, risk was reduced by 86%. Tamoxifen also reduced the risk of DCIS by 50%. The benefit in BCPT was seen only among women with ER-positive tumors (69% reduction in risk), and none was seen among women with ER-negative tumors. A reduction in fractures of the hip, radius, and spine was also observed, but tamoxifen increased the risk of endometrial cancer, especially among postmenopausal women, for whom the relative risk was 4.01 (95% CI, 1.70–10.90). The rates of stroke, pulmonary embolism, and deep-vein thrombosis were also elevated in the tamoxifen group (2) .

The MORE trial was a multicenter, randomized, double-blind trial in which a total of 7705 postmenopausal women with osteoporosis took raloxifene or placebo and were followed from 1994 to 1998 at 180 clinical centers in 25 countries, mainly in the United States and Europe (3) . Clinical data in the MORE trial were maturing at the time the BCPT investigators reported their results. In a subset analysis of the MORE trial cohort, new cases of breast cancer confirmed by histopathology were tabulated in patients taking 120 mg of raloxifene daily, 60 mg of raloxifene, or placebo medication. Among the 5129 women assigned to raloxifene, 13 cases of breast cancer were confirmed on histopathological review compared with 27 cases of invasive breast cancer among 2576 women assigned to placebo (4) . The relative risk of invasive breast cancer associated with the use of raloxifene was thus 0.24 (95% CI, 0.13–0.44; P = 0.01).

Encouraged by these dramatic reductions in the risk of developing invasive breast cancer associated with both tamoxifen and raloxifene, NSABP investigators sought to find both safer and more effective strategies for breast cancer risk reduction. The primary objective of the STAR4 trial is to evaluate the effect of raloxifene compared with tamoxifen in reducing the incidence of invasive breast cancer. The trial is sufficiently powered to demonstrate equivalence of the two agents. Additional objectives include evaluation of the incidence of endometrial cancer, cardiovascular events, and the occurrence of bone fractures. Secondary objectives of the trial include the evaluation of the effect of raloxifene and tamoxifen on the incidence of LCIS, DCIS, and quality of life outcomes. The schema for the STAR trial design is shown in Fig. 1Citation .



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  		Fig. 1. STAR trial design schema.

 

   STAR Trial Design
Top
 ABSTRACT
 Introduction
 STAR Trial Design
Effect of Tamoxifen in...
 IBIS I
 New Drugs for the...
 Premenopausal Women
 Other Agents
 ASCO Technology Assessment
 Summary of Recommendations of...
 Open Discussion
 REFERENCES
 
Using the network of 194 clinical institutions that had participated in the BCPT and additional institutions that were new to NSABP, the STAR trial was launched in July 1999 in both the United States and Canada. Eligible women include postmenopausal subjects with no prior history of invasive breast cancer or DCIS who are at least 35 years or older. A summary of the eligibility requirements is shown in Table 1Citation . To enter the trial, the subjects must have a 5-year risk of developing invasive breast cancer equal to or greater than the risk of an average Caucasian female aged 60 years as determined by the Gail model (5) . The Gail model was used in BCPT and was shown to be a valid predictor of the short-term risk of developing breast cancer (6) .


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  		Table 1 Eligibility requirements for the STAR trial

 
The STAR trial opened to subject accrual on July 1, 1999. Because it is statistically powered to demonstrate the possible equivalence of raloxifene and tamoxifen in reducing the incidence of breast cancer, the required sample size is large: a total of 19,000 women will be enrolled. Through June 30, 2002, risk assessment forms have been evaluated in 118,797 individuals, of whom 65,867 (55.4%) have been judged to be risk-eligible to participate in the trial (Table 2)Citation . Among the risk-eligible women, 14,367 have submitted entry and eligibility forms for final review of their status regarding all eligibility criteria, and 97.3% of these women were eligible to participate in the trial. Of these women judged to be eligible, 13,647 have been randomized for participation. More than 58% of the randomized participants have 5-year Gail model risk scores of 3% or greater. The proportion of eligible subjects randomized increases with increasing levels of risk, as indicated in Table 2Citation . The median age of randomized women is 58 years, with a range of 35–79 years (Table 3)Citation . More than 40% of participants are 60 years or older. The proportion of participants who are risk-eligible increases with age through 74 years and then declines. Recruitment will continue for approximately 2 additional years to achieve the desired 19,000 participants.


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  		Table 2 STAR trial enrollment through June 30, 2002

 

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  		Table 3 STAR trial enrollment by age through June 30, 2002

 
In BCPT, 826 women reported a history of LCIS at the time of randomization. At the time the results were reported, the BCPT study was the largest prospective study of LCIS ever conducted. Among the women randomized in the STAR trial through June 30, 2002, 1152 women (8.4% of the randomized participants) report a history of LCIS. There are also 2715 women with a history of atypical ductal or lobular hyperplasia in the randomized cohort. Additionally in the STAR trial cohort, 52.5% of randomized subjects report a history of prior hysterectomy. In BCPT, 37.7% of women reported a prior hysterectomy among the study cohort, whose average age at study entry was 52 years.

The BCPT showed that substantial net benefit accrues to women with a diagnosis of either LCIS or atypical hyperplasia who take tamoxifen. This benefit is reflected in the 19.9% of the randomized participants in STAR who report a diagnosis of atypia on a previous breast biopsy. This is substantially higher than the 1–2% proportion of women in the postmenopausal population who have ever undergone a biopsy that reported cellular atypia. Because the presence of atypical hyperplasia of either the lobular or ductal type increases the risk of invasive breast cancer by approximately 3–6-fold and because that risk increases to approximately 7–12-fold in a women with at least one first-degree relative with breast cancer (7 , 8) , risk profiles from women with atypia and a family history of breast cancer demonstrate substantial potential net benefit from STAR trial participation. Significant net benefit was also seen in BCPT for women with LCIS. This benefit derives from the greater number of breast cancers prevented among women who are at significantly increased risk of breast cancer when compared with those women who are at only modestly increased risk. This fact appears to contribute significantly to a woman’s decision to participate in the STAR trial. Published evaluations of participant’s reasons for joining BCPT included a physician’s recommendation to enroll and reassurance about the cost of trial participation (9 , 10) , but no similar evaluation is yet available among STAR trial participants or their health care providers.

A substantial effort is being made to evaluate quality of life outcomes in the STAR trial. Overall, no large differences in symptoms were seen or reported among participants in BCPT when comparing tamoxifen with placebo (11 , 12) . Hot flashes and gynecological symptoms were slightly more common among perimenopausal women, but only 24% of women assigned to the tamoxifen group in the P-1 study discontinued trial participation due to side effects, whereas 20% of participants in the placebo arm discontinued study medication due to toxicity. The Medical Outcomes Study 36-Item Short Form Health Status Survey (MOS SF-36), a sexual functional scale, and a symptom check list are being used to evaluate quality of life outcomes in the STAR trial, as they were in the BCPT. The Center for Epidemiological Studies Depression Scale will be used to evaluate the occurrence of depression in trial participants. If tamoxifen and raloxifene are shown to have equal efficacy in reducing the incidence of invasive breast cancer, and if other important outcomes such as osteoporotic fractures and occlusive cardiovascular events are affected equally by each agent, information about quality of life outcomes will be important to determine which agent would have superior utility among older women seeking to reduce their incidence of breast cancer.


   Effect of Tamoxifen in Carriers of Predisposing Genetic Mutations
Top
 ABSTRACT
 Introduction
 STAR Trial Design
 Effect of Tamoxifen in...
IBIS I
 New Drugs for the...
 Premenopausal Women
 Other Agents
 ASCO Technology Assessment
 Summary of Recommendations of...
 Open Discussion
 REFERENCES
 
In a study of women who carried mutations of either the BRCA1 or the BRCA2 gene and who received adjuvant therapy for breast cancer, the multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 (95% CI, 0.28–0.89; Ref. 13 ). Tamoxifen protected against contralateral breast cancer both for carriers of BRCA1 mutations (odds ratio, 0.38; 95% CI, 0.19–0.74) and for those with BRCA2 mutations (odds ratio, 0.63; 95% CI, 0.20–1.50). The greater apparent benefit of tamoxifen in carriers of BRCA1 mutations as compared with carriers of BRCA2 mutations is paradoxical given the greater prevalence of ER-positive breast cancer reported among carriers of BRCA2 mutations (14) . This observation needs to be validated in future studies.

To evaluate the effect of tamoxifen on the incidence of breast cancer among women with inherited BRCA1 or BRCA2 mutations, genomic analysis of BRCA1 and BRCA2 was performed for 288 women who developed breast cancer after entry into BCPT (15) . Of the 288 breast cancer cases, 19 (6.6%) inherited disease-predisposing BRCA1 or BRCA2 mutations. Of eight patients with BRCA1 mutations, five received tamoxifen, and three received placebo (risk ratio, 1.67; 95% CI, 0.32–10.70). Of 11 patients with BRCA2 mutations, 3 received tamoxifen, and 8 received placebo (risk ratio, 0.38; 95% CI, 0.06–1.56).

Thus, tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers by 62%, similar to the reduction in incidence of ER-positive breast cancer among all women in BCPT. In contrast, tamoxifen use did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. These results must be interpreted with caution, however, given the small number of women with mutations of either BRCA1 or BRCA2 who were identified in BCPT. Additional studies of the effect of tamoxifen or other selective estrogen receptor modulators on cancers in women with predisposing genetic mutations are ongoing.

Larger, prospective studies of women with predisposing mutations will be required to provide conclusive evidence of either protection or lack of effect by tamoxifen in women with these mutations. However, it is unlikely that any significant proportion of the postmenopausal women in the STAR trial who did not have breast cancer at the time of study enrollment are carriers of predisposing genetic mutations, given the propensity for mutation carriers to develop invasive breast cancer at earlier ages. Lymphocytes are being stored for genetic evaluations in the future.


   IBIS I
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 ABSTRACT
 Introduction
 STAR Trial Design
 Effect of Tamoxifen in...
 IBIS I
New Drugs for the...
 Premenopausal Women
 Other Agents
 ASCO Technology Assessment
 Summary of Recommendations of...
 Open Discussion
 REFERENCES
 
The IBIS I trial closely replicated the findings of BCPT (16) . In IBIS I, more than 7000 women aged 35–70 years (median age, 50.7 years) at a high risk of breast cancer were randomly assigned to tamoxifen or placebo. The primary end point was the incidence of breast cancer including DCIS. Among the women randomized, 3574 received placebos, and 3578 received tamoxifen. The median follow-up was 50 months when the data were reported in March 2002, and the estimated compliance at 5 years was 77% in the placebo group and 67% among women taking tamoxifen. The women in the study had a 4-fold increased risk of developing breast cancer compared with the general population, in most cases because of family history. About 60% of participants had two or more first-degree relatives with breast cancer. One-third of the women reported having prior hysterectomies, and about 50% of women used hormone replacement therapy at some point during the trial.

The overall reduction in the risk of developing breast cancer when comparing women taking tamoxifen with those taking placebo was 33% and was statistically significant (P = 0.01). The reduction in invasive cancers (85 versus 63 among women taking placebo and tamoxifen, respectively) was 26%. Among women who took hormones during the trial, the reduction in the incidence of breast cancer was 27% as compared with 26% among women who had never taken hormones for menopausal symptoms. As in BCPT, all of the reduction in the incidence of invasive breast cancer was seen among women with ER-positive tumors. No effect was seen for ER-negative tumors. The reduction in breast cancer incidence associated with tamoxifen was independent of age, and there was no difference when comparing tamoxifen and placebo cases in nodal status, size, or grade of the breast cancers diagnosed. The data for both IBIS I and BCPT are summarized in Table 4Citation .


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  		Table 4 Summary of breast cancer risk reduction in two randomized trials of tamoxifen for women at increased risk for breast cancer

 

   New Drugs for the Reduction of Breast Cancer Risk
Top
 ABSTRACT
 Introduction
 STAR Trial Design
 Effect of Tamoxifen in...
 IBIS I
 New Drugs for the...
Premenopausal Women
 Other Agents
 ASCO Technology Assessment
 Summary of Recommendations of...
 Open Discussion
 REFERENCES
 
In advanced breast cancer, anastrozole is well tolerated and has a significant survival advantage over megestrol acetate as a second-line treatment (17) . It is also superior to tamoxifen with respect to time to progression when used as a first-line treatment for advanced breast cancer (18) . Based on these encouraging results in advanced disease, the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared tamoxifen with anastrozole alone and in combination with tamoxifen as adjuvant treatment for postmenopausal women with early operable breast cancer. More than 9300 patients with early breast cancer were recruited, of whom 3125 were randomly assigned anastrozole, 3116 were randomly assigned tamoxifen, and 3125 were randomly assigned the combination. Eighty-four percent (7839) of the patients were known to be hormone receptor positive, and median follow-up was 33.3 months when the data were reported in December 2001 (19) . Disease-free survival at 3 years was superior for women treated with anastrozole compared with women treated with tamoxifen.

An important (although very preliminary) finding with implications for breast cancer risk reduction was that the incidence of contralateral breast cancer was significantly lower with anastrozole than with tamoxifen (odds ratio, 0.42; 95% CI, 0.22–0.79; P = 0.007). Anastrozole was also significantly better than tamoxifen with respect to endometrial cancer (P = 0.02), vaginal bleeding and discharge (P < 0.0001 for both), cerebrovascular events (P = 0.0006), venous thromboembolic events (P = 0.0006), and hot flashes (P < 0.0001). Tamoxifen was significantly better than anastrozole, however, with respect to musculoskeletal disorders and fractures (P < 0.0001 for both).

Based on these early results from the ATAC trial, anastrozole has the potential to prevent up to 80% of hormone receptor-positive breast cancers in postmenopausal women. As a consequence, anastrozole will be incorporated in the design of the second IBIS II prevention trial (20) .

The NSABP conducted a double-blind, randomized, controlled trial to find out whether lumpectomy, radiation therapy, and tamoxifen was of more benefit than lumpectomy and radiation therapy alone for DCIS (21) . In the NSABP B-24 trial, 1804 women with DCIS were randomly assigned either lumpectomy, radiation therapy (50 Gy), and placebo (n = 902), or lumpectomy, radiation therapy, and tamoxifen (20 mg daily for 5 years, n = 902). Median follow-up was 74 months (range, 57–93 months). Women in the tamoxifen group had fewer breast cancer events at 5 years than did those on placebo (8.2% versus 13.4%; P = 0.0009). The cumulative incidence of all invasive breast cancer events in the tamoxifen group was 4.1% at 5 years: 2.1% in the ipsilateral breast; 1.8% in the contralateral breast; and 0.2% at regional or distant sites. The risk of ipsilateral breast cancer was lower in the tamoxifen group even when sample margins contained tumor and when DCIS was associated with comedo necrosis. The combination of lumpectomy, radiation therapy, and tamoxifen was effective, therefore, in the prevention of invasive cancer.

Anastrozole will also be tested in the upcoming NSABP Trial B-35. The schema for this trial is shown in Fig. 2Citation . Eligible subjects will be postmenopausal women with DCIS who are treated with lumpectomy and radiation therapy. They will be randomly assigned to treatment with either tamoxifen (20 mg daily) for 5 years or anastrazole (1 mg daily) for 5 years. The design and measured outcomes of the trial will be similar to those in NSABP Trial B-24: the occurrence of invasive breast cancer in either the ipsilateral or the contralateral breast, the occurrence of DCIS in the contralateral breast, and the recurrence of DCIS in the ipsilateral breast, as well as local, regional, and distant event rates. Recruitment for NSABP B-35 will begin in early 2003; a total of 3000 women will be enrolled. The trial is designed to demonstrate a 33% improvement by anastrozole compared with tamoxifen in all breast cancer-related events. If the safety of anastrozole, along with greater effectiveness than tamoxifen, was demonstrated in both IBIS II and NSABP B-35, then a large prospective trial to evaluate anastrozole for the primary prevention of breast cancer in postmenopausal women would be indicated. Before these results are obtained, using anastrozole (or any other aromatase inhibitor) for reducing the risk of breast cancer is not appropriate.



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  		Fig. 2. NSABP Protocol B-35 schema.

 

   Premenopausal Women
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 ABSTRACT
 Introduction
 STAR Trial Design
 Effect of Tamoxifen in...
 IBIS I
 New Drugs for the...
 Premenopausal Women
Other Agents
 ASCO Technology Assessment
 Summary of Recommendations of...
 Open Discussion
 REFERENCES
 
Tamoxifen reduces the incidence of primary breast cancer in premenopausal women, and it is reasonable to expect that raloxifene would have a similar effect in premenopausal women. Because raloxifene was developed as an agent to treat and prevent osteoporosis, there are no clinical data available about the long-term safety or efficacy of raloxifene in premenopausal women. A clinical trial to evaluate the safety of raloxifene in premenopausal women has enrolled 31 subjects at the National Cancer Institute clinical center and will report results soon. There are no plans, however, to open the STAR trial to enrollment of premenopausal women before recruitment is completed.


   Other Agents
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 ABSTRACT
 Introduction
 STAR Trial Design
 Effect of Tamoxifen in...
 IBIS I
 New Drugs for the...
 Premenopausal Women
 Other Agents
ASCO Technology Assessment
 Summary of Recommendations of...
 Open Discussion
 REFERENCES
 
There are multiple compounds that do not act directly through the ER but may be more active in tissues that contain ER protein (22) . These compounds include retinoids, rexinoids, and deltanoids. Compounds that theoretically have activity regardless of hormone receptor status include polyamine synthesis inhibitors, tyrosine kinase inhibitors, anti-epidermal growth factor receptor antibodies, cyclooxygenase 2 inhibitors, combined demethylating agents and histone deacetylase inhibitors, metalloprotease inhibitors (especially MMP-2 and MMP-9), angiogenesis inhibitors (especially anti-vascular endothelial growth factor), and miscellaneous compounds such as monoterpenes and sulindac sulfone whose major mechanism of action may be to induce apoptosis.

Clinical trials to evaluate these new compounds are being planned or are just beginning. Many of the new trials will evaluate intermediate biomarkers that could both reduce the number of subjects and shorten the duration of drug exposure if they are subsequently validated. If these more efficient trial designs produce valid end points, they will simplify the movement of compounds from the laboratory to the clinic, and they will reduce the cost of evaluating new putative chemoprevention agents.


   ASCO Technology Assessment
Top
 ABSTRACT
 Introduction
 STAR Trial Design
 Effect of Tamoxifen in...
 IBIS I
 New Drugs for the...
 Premenopausal Women
 Other Agents
 ASCO Technology Assessment
Summary of Recommendations of...
 Open Discussion
 REFERENCES
 
To update their technology evaluation of chemoprevention strategies for breast cancer risk reduction, the ASCO conducted an evidence-based assessment of chemoprevention interventions available to reduce the risk of developing invasive breast cancer (23) . Outcomes of interest included breast cancer incidence, breast cancer-specific survival, overall survival, and the net health benefit of the interventions. A comprehensive, formal literature review was conducted for the relevant topics, and testimony was collected from invited experts and interested parties following the ASCO-prescribed technology assessment procedure. More weight was given to published randomized trials than to other forms of evidence.

The ASCO Cancer Technology Assessment Working Group concluded that for women with a defined 5-year projected breast cancer risk of >1.66%, tamoxifen (20 mg daily) for 5 years may be offered to reduce their risk. Risk/benefit models suggest that the greatest clinical benefit with the least side effects is derived from use of tamoxifen in younger (premenopausal) women who are less likely to have thromboembolic sequelae and uterine cancer, in women without a uterus, and in women at higher risk for breast cancer. Available data do not yet suggest that tamoxifen provides an overall health benefit or increases survival, although survival was not an intended outcome of the completed studies. Use of tamoxifen combined with hormone replacement therapy, use of raloxifene, any aromatase inhibitor or inactivator, or fenretinide to lower the risk of developing breast cancer was not recommended outside the setting of a clinical trial.


   Summary of Recommendations of the United States Preventive Services Task Force
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 ABSTRACT
 Introduction
 STAR Trial Design
 Effect of Tamoxifen in...
 IBIS I
 New Drugs for the...
 Premenopausal Women
 Other Agents
 ASCO Technology Assessment
 Summary of Recommendations of...
Open Discussion
 REFERENCES
 
Like ASCO, the USPSTF evaluated the strategies that are available for the primary prevention of breast cancer (24 , 25) . Their recommendations were slightly more conservative and addressed issues relevant to entire populations of women rather than only women with specific risk factors. The USPSTF recommended against the routine use of tamoxifen or raloxifene for the primary prevention of breast cancer in women at low or average risk for breast cancer. The USPSTF found "fair evidence that tamoxifen and raloxifene may prevent some breast cancers in women at low or average risk for breast cancer, based on extrapolation from studies of women at higher risk." They concluded that the potential harms of chemoprevention may outweigh the potential benefits in women who are not at high risk for breast cancer. The task force concluded that the balance of benefits and harms may be favorable for some high-risk women but will depend on breast cancer risk, risk for potential harms, and individual patient preferences (26) .


   Open Discussion
Top
 ABSTRACT
 Introduction
 STAR Trial Design
 Effect of Tamoxifen in...
 IBIS I
 New Drugs for the...
 Premenopausal Women
 Other Agents
 ASCO Technology Assessment
 Summary of Recommendations of...
 Open Discussion
REFERENCES
 
Dr. Kent Osborne: Are there any supporting data for the atypical ductal hyperplasia findings beyond the subset analysis? Obviously you’re going to try and confirm it in the next trial. There’s certainly a biological rationale why these women might have a higher risk reduction. If it turns out to be true, it will be one of the most important observations to confirm the paradigm of breast cancer evolution that it goes through an ER-positive stage.

Dr. Victor G. Vogel: The so-called continuum hypothesis. Yes, we certainly are going to try to confirm it. No, I don’t know of any other clinical trial data on the effect of a selective estrogen receptor modulator on atypia. Now, it is a subset, but it was a planned subset in the P-1 trial with 600 patients per arm.

Dr. Osborne: The last analysis I saw was 23 events versus 3 events. Has that been updated?

Dr. Vogel: There have not been many events. The follow-up on P-1 is now complete; that is, every woman has reached the end of her 5 years of assigned therapy. The data set should be finalized by the early autumn, and by midwinter we should have the final updated analysis on those numbers from P-1. But as you know, there has been a high degree of crossover: 1800 women from the placebo arm of P-1 are in P-2. So there is a lot of contamination in those data.

Dr. Mitch Dowsett: Regarding the ASCO technical assessment that tamoxifen is for those women with a risk of above 1.67: as you commented, the women you actually get into the trial may be very different from the population defined by that cutoff. Have you addressed the issue of how generalizable the data may be, when the study population may be very different from the target population?

Dr. Vogel: I don’t think there’s any way you can fix that, and I would be the first to admit that these women are not representative of the general population of postmenopausal women. They’re certainly representative of that portion of the population who are at increased risk because of the various risk factors. They only represent about the top 15–20% of the whole population at risk.

Dr. Dowsett: When you then try to apply your findings to a population, do you use the study entry criteria or do you use a definition of the population you ended up with? I think you’ve done more of the former.

Dr. Vogel: I think it would be better to be more general, but then you have to extrapolate the data to a population from which data were not collected. So it is a challenge.


   FOOTNOTES
 
1 Presented at the Second International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer, June 28–29, 2002, Cambridge, MA. This work was supported by grants from the National Cancer Institute and Eli Lilly & Co. Back

2 To whom correspondence should be addressed, at Director Magee/UPCI Breast Program, University of Pittsburgh School of Medicine, 300 Halket Street, Room 3524, Pittsburgh, PA 15213-3180. Phone: (412) 641-6500; Fax: (412) 641-6461; E-mail: vvogel{at}mail.magee.edu Back

3 The abbreviations used are: BCPT, Breast Cancer Prevention Trial; DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ; STAR, Study of Tamoxifen and Raloxifene; NSABP, National Surgical Adjuvant Breast and Bowel Project; ER, estrogen receptor; CI, confidence interval; MORE, Multiple Outcomes of Raloxifene Evaluation; IBIS, International Breast Cancer Intervention Study; ASCO, American Society of Clinical Oncology; USPSTF, United States Preventive Services Task Force. Back

4 More information about the STAR trial for both clinicians and potential participants is available through the National Cancer Institute at 1-800-4-CANCER or via the NSABP web site at www.nsabp.pitt.edu. If clinicians are interested in becoming STAR investigators, they may submit an inquiry to NSABP via webmaster{at}nsabp.pitt.edu. Back


   REFERENCES
Top
 ABSTRACT
 Introduction
 STAR Trial Design
 Effect of Tamoxifen in...
 IBIS I
 New Drugs for the...
 Premenopausal Women
 Other Agents
 ASCO Technology Assessment
 Summary of Recommendations of...
 Open Discussion
 REFERENCES
 

  1. Fisher B., Costantino J. P., Wickerham D. L., Redmond C. K., Kavanah M., Cronin W. M., Vogel V., Robidoux A., Dimitrov N., Atkins J., Daly M., Wieand S., Tan-Chiu E., Ford L., Wolmark N., other National Surgical Adjuvant Breast and Bowel Project Investigators. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl. Cancer Inst. (Bethesda), 90: 1371-1388, 1998.[Abstract/Free Full Text]
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