NSABP B-17

Results

• Initial results were reported in 1993 after a median duration of 43 months follow-up and remain essentially unchanged through eight years of follow-up.

• All patients benefited from radiation regardless of clinical or mammographic tumor characteristics

NSABP B-24

Results

• Women in the tamoxifen group had fewer breast cancer events at five years than did those on placebo (8.2% vs 13.4%, p=0.0009) —a relative reduction of 37%.
  
  
• Tamoxifen reduced invasive breast cancer by 43% (p=0.004).
  
  
• Ipsilateral invasive breast cancer was reduced in the tamoxifen group by 44% (p=0.03). This lowered the absolute rate from 4.2% to 2.1%. This benefit was observed in premenopausal and postmenopausal women, those with positive and negative tumor margins, and in patients with and without comedonecrosis.
  
  
• Contralateral breast cancer risk for invasive and noninvasive new cancers was reduced by 52% (p=0.01).

Proposed New NSABP DCIS Trial

Rationale for the Trial

1. Giving a longer duration of tamoxifen does not add additional benefit as demonstrated by NSABP B-14.

2. Other SERMs do not present an obvious therapeutic advantage to tamoxifen in adjuvant treatment.

Justification for Comparing Arimidex versus Tamoxifen

1. Mechanism of action: In postmenopausal women, the major source of circulating estrogens is peripheral conversion of androgens via aromatase enzyme in fat, muscle and liver. Inhibition of aromatase thus reduces circulating and possibly intratumoral estrogen levels.

2. Tamoxifen has partial agonist effects. In the endometrium, this results in increased incidence of endometrial cancer. Nonsteroidal aromatase inhibitors (anastrozole and letrozole) have no intrinsic hormonal activity. Endometrium effects are unknown. In bone, tamoxifen has an agonist effect, which is beneficial in postmenopausal women. Bone effects of aromatase inhibitors are unknown.

3. Third generation aromatase inhibitors (nonsteroidal: anastrozole, letrozole. steroidal: exemestane) are potent, highly specific agents with an improved side effects/tolerability profile compared to the older agents such as aminoglutethimide.

4. A large international trial (ATAC) is comparing Arimidex to tamoxifen to a combination of Arimidex and tamoxifen as adjuvant therapy of invasive breast cancer. Initial results should be reported this year.

5. Direct comparisons of third generation aromatase inhibitors to tamoxifen in advanced breast cancer suggest at least equivalent antitumor effect and a better toxicity profile, particularly related to thromboembolic complications (see below).

Randomized trials comparing Arimidex to tamoxifen as first-line therapy for metastatic disease (Trial 30—North American Trial and Trial 27 —European Trial)

Key Results of Trials 27, 30 (median follow-up of 18-months)

Efficacy

• Trial 30 demonstrated an advantage to Arimidex in time to progression and clinical benefit rate. Trial 27 demonstrated equivalence. However, the fraction of patients with known estrogen receptor-positive tumors was greater in Trial 30 (89%) compared to Trial 27 (45%). A trend to improved efficacy was noted in receptor- positive patients in Trial 27.
  
  
• Conclusion: Antitumor efficacy of Arimidex is at least equivalent to tamoxifen in this setting.

Side Effects and Toxicity Profiles (combined data from Trials 27 and 30)

• The side effects were similar for both agents, with the exception of less vaginal bleeding and fewer thromboembolic events in patients receiving Arimidex. No differences were observed for weight gain, lethargy, vaginal dryness, hot flash, GI disturbance, tumor flare or depression.

Crossover Data

• The design of Trials 27 (European) and 30 (North American) did not include a planned crossover analysis to address whether the order of sequencing endocrine agents differentially affects patient outcomes.
  
  
• Questionnaires were sent to investigators, who provided data on patients who had crossed over to a second endocrine treatment (either Arimidex or tamoxifen) after failure on the first-line agent.
  
  
• Patients who crossed over from Arimidex to tamoxifen or vice versa received equivalent clinical benefit, regardless of whether or not they had intervening chemotherapy, endocrine treatment or a chemohormonal combination.

Response on Crossover to Second Endocrine Therapy

• These findings demonstrate that a significant fraction of patients will benefit from tamoxifen after progressing on Arimidex and vice versa.

References

Fisher B, Dignam J, Wolmark N et al. Lumpectomy and Radiation Therapy for the Treatment of Intraductal Breast Cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-17. Journal of Clinical Oncology 1998;16(2):441-452.

Fisher ER, Dignam J, Tan-Chiu E et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 1999;86(3):429-38. Fisher B, Dignam J, Wolmark N et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999;353(9169):1993-2000.

Nabholtz JM, Buzdar M, Pollak W et al. Anastrazole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Results of a North American multicenter randomized trial. Journal of Clinical Oncology 2000;18(22):3758-3767.

Bonneterre J, Thurlimann B, Robertson JFR et al. Anastrazole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: Results of the tamoxifen or Arimidex randomized group efficacy and tolerability study. Journal of Clinical Oncology 2000;18(22):3748-3757.

Robertson J, Buzdar A, Nabholtz J et al. Anastrozole (Arimidex®) versus tamoxifen as first-line therapy for advanced breast cancer (ABC) in post-menopausal (PM) women — prospective combined analysis from two international trials. European Journal of Cancer 2000;36(S5):Abstract 219.

* Jewish General Hospital, McGill University, Montreal Canada

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