SLIDE 6.1 Results from large clinical trials should have an impact on clinical practice. Relatively few studies, though, have assessed the influence of clinical trial results on the practice of oncology.

 

SLIDE 6.2 In this paper, Buzdar and Macahilig attempt to determine the impact of the presentation and publication of the results from the ATAC trial on medical oncologists’ prescribing patterns for adjuvant hormonal therapy in the United States.

 

SLIDE 6.3 ATAC compared anastrozole, tamoxifen, or the combination as adjuvant therapy in postmenopausal women (n=9,366) with operable breast cancer. The primary endpoints for the trial were disease-free survival and safety/tolerability.

 

SLIDE 6.4 After a median follow-up of 68 months, there were significant improvements in disease-free survival and time to recurrence with anastrozole compared to tamoxifen. With hormonereceptor positive disease, the absolute difference in recurrence rates increased with each year of follow-up.

 

SLIDE 6.5 For each study period, 150 US oncologists were recruited. Participants were board certified, spent at least 50 percent of their time in office or private practice, treated at least 10 breast cancer patients in the past 30 days and wrote at least 100 prescriptions for hormone therapy in the past six months.

 

SLIDE 6.6 The medical oncologists were stratified by the number of prescriptions they wrote for hormonal therapy for breast cancer in the previous six months. Group 1 wrote 100 to 571 prescriptions. Group 2 wrote 572 to 870 prescriptions, and Group 3 wrote more than 870 prescriptions.

 

SLIDE 6.7 The data were collected via structured, computerassisted telephone interviews that lasted 45 to 60 minutes. Eight different study periods were used: July 2001, March 2002, July 2002, November 2002, February 2003, June 2003, August 2003 and November 2003.

 

SLIDE 6.8 Predefined questions were utilized in the telephone interviews. The medical oncologists were asked about their initial hormonal therapy choices for the last five postmenopausal patients with ER-positive, early breast cancer.

 

SLIDE 6.9 The majority of participants were males who were consistently distributed across the four US geographic regions. Each medical oncologist had treated a mean of 112 to 284 patients with breast cancer in the last six months. They all indicated that about 60 percent of their patients with early breast cancer were postmenopausal.

 

SLIDE 6.10 The reported use of adjuvant hormonal therapy for postmenopausal women with ER-positive early breast cancer increased from 81 percent in July 2001 to 98 percent in November 2003. During the same time, the use of adjuvant chemotherapy remained relatively stable, ranging from 36 to 50 percent.

 

SLIDE 6.11 After the initial ATAC trial results were presented in December 2001, the reported use of anastrozole increased from two percent (July 2001) to 14 percent (March 2002) of adjuvant hormonal therapies. By November 2003, anastrozole accounted for 53 percent of the hormonal therapy choices.

 

SLIDE 6.12 The reports of the positive ATAC trial results appear to have significantly influenced adjuvant hormonal therapy selection as reported by medical oncologists in the United States. Future trials should evaluate the influence of clinical trial results on prescribing patterns.

 

SLIDE 7.1 In a Phase II trial of bevacizumab in patients previously treated for metastatic breast cancer (MBC), the rates for objective response and stable disease at 22 weeks were 9.3 and 17 percent, respectively. Those benefits were the basis for a Phase III randomized trial comparing capecitabine with or without bevacizumab.

 

SLIDE 7.2 The eligibility criteria included MBC, prior anthracycline and taxane, one or two prior chemotherapy regimens for MBC or relapse <12 months after adjuvant anthracycline and taxane, progression after trastuzumab for HER2-positive disease, ECOG PS = 0 or 1 and adequate renal, hepatic and hematologic function.

 

SLIDE 7.3 All patients received capecitabine 2,500 mg/m2/day orally in two divided doses for 14 days followed by a seven-day rest. Patients randomly assigned to the combination arm received bevacizumab 15 mg/kg intravenously on day one of each threeweek cycle. Therapy continued for a maximum of 35 cycles.

 

SLIDE 7.4 The primary endpoints of the trial were progressionfree survival (PFS) and safety. Secondary endpoints included: PFS, objective response rate, duration of response, quality of life and survival.

 

SLIDE 7.5 A total of 462 patients were enrolled on the trial. Two hundred thirty patients were randomly assigned to capecitabine alone and 232 to capecitabine plus bevacizumab. The patients’ baseline demographic and tumor characteristics were balanced between the groups.

 

SLIDE 7.6 The addition of bevacizumab to capecitabine resulted in significantly improved objective response rate. However, PFS, response duration, overall survival or time to deterioration of quality of life were not altered. The IRF and investigators disagreed on disease progression in 105 patients.

 

SLIDE 7.7 Bevacizumab did not alter the frequency or severity of the Grade III toxicities associated with capecitabine.

 

SLIDE 7.8 The mean delivered dose intensity for capecitabine was similar for the patients in both randomization arms. Dosage reductions for capecitabine were required for 65 percent of those receiving capecitabine alone versus 79 percent of those receiving the combination.

 

SLIDE 7.9 Grade III hypertension and proteinuria occurred more frequently in patients receiving bevacizumab. Grade III bleeding was rare and not different between groups, but patients receiving capecitabine alone had fewer episodes of Grade I or II epistaxis.

 

SLIDE 7.10 In women with previously treated MBC, the addition of bevacizumab to capecitabine increases the response rate but not PFS or response duration. Patients with less advanced disease may obtain additional benefits from bevacizumab.

 

SLIDE 7.11 Currently, two Phase II trials are incorporating capecitabine and bevacizumab into first-line chemotherapeutic regimens for metastatic disease.

 

SLIDE 8.1 In breast cancer, a positive estrogen receptor (ER) status has correlated with disease-free survival and improved response with hormone therapy. Immunohistochemical (IHC) analysis of ER status may be more discriminatory for predicting overall and disease-free survival in routine assessments of hormone receptor status.

 

SLIDE 8.2 Initial observations from the daily IHC analysis of steroid receptors in the laboratory led Nadji et al to re-evaluate semiquantitation of the steroid receptor reaction. They conducted a study of the immunohistochemical staining for ER and PR in 5,993 consecutive breast cancer cases during a six-year period.

 

SLIDE 8.3 Mouse IgG monoclonal antibody (1D5) that reacts with the A/B region of the N terminal domain of ERα was used to detect ER. Monoclonal anti-PR antibody 636 was used to detect PR. Positive and negative controls were also used.

 

SLIDE 8.4 The stained slides were evaluated for the presence of positive reaction, cellular localization, staining pattern (focal or diffuse) and intensity of reaction in individual tumor cells (strong or weak). Any positive reaction for ER and PR, irrespective of percentage of reactive cells, was considered positive.

 

SLIDE 8.5 Of the tissue specimens, 75 percent were ER-positive, 55 percent were PR-positive, 55 percent were ER-positive/PR-positive, 20 percent were ER-positive/PR-negative and 25 percent were ERnegative/ PR-negative. All of the PR-positive specimens were also ER-positive; no specimens were ER-negative and PR-positive.

 

SLIDE 8.6 Among unspecified infiltrating ductal carcinoma specimens, 74 percent were ER-positive and 53 percent were PR-positive. All pure tubular, colloid, papillary and infiltrating lobular carcinomas and none of the apocrine, medullary or metaplastic carcinomas were ER-positive. PR positivity was less predictable.

 

SLIDE 8.7 Among 4,892 cases of infiltrating ductal carcinoma (no special type), all nuclear Grade I tumors were ER-positive. In contrast, 75 percent of the nuclear Grade II tumors and only two percent of the nuclear Grade III tumors were ER-positive.

 

SLIDE 8.8 In most cases, positive staining for ER was diffuse. The majority of the focal pattern observed in eight percent of ER-positive cases was due to inadequate fixation or focal tumor necrosis. Inadequate fixation did not account for the focal pattern of PR staining, which was observed in 21 percent of PR-positive cases.

 

SLIDE 8.9 ER positivity and negativity are predictable in certain histologic types and nuclear grades of breast cancer. With the ID5 monoclonal antibody and antigen retrieval, IHC staining for breast cancer is an all-or-none occurrence, which is clinically relevant in predicting survival. Quantitation of results is unnecessary.