March 8, 2009

Advances in the Treatment of Early-stage Breast Cancer: A Report from the 2008 San Antonio Breast Cancer Symposium


Advances in the Treatment of Early-stage Breast Cancer: A Report from the 2008 San Antonio Breast Cancer Symposium

The San Antonio Breast Cancer Symposium (SABCS) marked its 31st anniversary this year and was the first SABCS presented in collaboration by the CTRC (Cancer Therapy and Research Center at the University of Texas Health Science Center), AACR (American Association for Cancer Research), and the Baylor College of Medicine. As usual, the annual SBCS delivered results encompassing the entire spectrum of breast cancer, including prevention, screening, prognostic factors, adjuvant chemotherapy, hormonal therapy, and treatment of metastatic disease. In addition, researchers devoted a significant amount of time to thoughtful retrospective and subgroup analyses with the purpose of gaining insight from the past in order to provide guidance for future strategies in the prevention and treatment of all stages of breast cancer.

Aromatase Inhibitors

Although aromatase inhibitors (AIs) have generally been accepted as the preferred hormone therapy for most postmenopausal, hormone receptor-positive breast cancer patients (unless contraindicated), evaluation of data continues in regards to long-term outcomes, direct comparisons between different aromatase inhibitors, and subgroup analyses in this patient population.

Several large trials comparing AIs to tamoxifen have established the efficacy and safety of AIs for the treatment of hormone receptor-positive breast cancers among postmenopausal women. Follow-up of these trials continues to evaluate long-term outcomes and side effects of both classes of agents to individualize therapy for this group of patients. To further understand overall effects of AIs in breast cancer, researchers affiliated with the Aromatase Inhibitors Overview Group conducted a meta-analysis including results from the following six randomized trials that compared AIs to tamoxifen as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer:

  • Arimidex, Tamoxifen, Alone or in Combination (ATAC)
  • Breast International Group (BIG) 1-98/International Breast Cancer Study Group (IBCSG) 18-98
  • Austrian Breast and Colorectal Cancer Study Group (ABCSG)
  • German Austrian Breast Cancer Group (GABG)/Arimidex-Nolvadex (ARNO)
  • Intergroup Exemestane Study (IES)/BIG 2-97
  • Italian Tamoxifen Anastrozole (ITA)

The trials in this analysis had been initiated by the year 2000 and included both monotherapy trials, in which AIs were compared to tamoxifen as monotherapy for five years, and switch trials, in which five years of tamoxifen was compared to two to three years of tamoxifen followed by two years of an AI. The aromatase inhibitors in the trials included either Femara® (letrozole), Arimidex® (anastrozole), or Aromasin® (exemestane). Monotherapy trials and switch trials were evaluated as separate cohorts. Endpoints of the meta-analysis included relative recurrence and survival rates.

Among the monotherapy trials, the following results were reported:

  • Recurrence rates at five and eight years were 9.6% and 15.3% on the AI arm compared with 12.6% and 19.2% on the tamoxifen arm (P<0.00001).
  • Survival differences did not reach statistical significance between the two treatment arms

Among the switch trials, the following results were reported:

  • Recurrence rates at three and six years were 5.0% and 12.6% on the AI arm compared with 8.1% and 16.1% on the tamoxifen arm (P<0.00001).
  • Breast cancer mortality at six years was 6.3% on the AI arm compared with 8.0% on the tamoxifen arm (P=0.02).
  • Six-year risk of death from any cause was 10.8% on the AI arm compared with 13.0% on the tamoxifen arm (P=0.004).

The researchers stated that results from this meta-analysis provide clear evidence that AIs significantly reduce recurrences in early, hormone receptor-positive breast cancer compared with tamoxifen. As well, it appears that switching to AIs after two to three years of therapy with tamoxifen compared with five years of monotherapy with tamoxifen improved both breast cancer-specific and overall survival among these patients. However, the mean survival follow-up in this meta-analysis is only 3.9 years; longer follow-up may provide different results for this important endpoint.

Other data comparing AIs to tamoxifen were also presented at this year’s meeting, such as long-term follow-up data of the BIG 1-98 Phase III trial, which compared Femara to tamoxifen in postmenopausal, hormone receptor-positive breast cancer.1 In the BIG 1-98 trial, patients were randomized to either Femara or tamoxifen monotherapy for five years or sequential therapy with these agents (tamoxifen for two years followed by Femara for three years or Femara for two years followed by tamoxifen for three years). Results emerged in 2005 indicating a reduction in recurrences on the Femara arm, so patients initially randomized to the tamoxifen-only arm were unblinded and allowed to cross over to Femara for the remainder of the study. These updated results included a 76-month median follow-up among patients on the monotherapy arms as well as a 71-month follow-up and two pairwise comparisons among three blinded study arms (tamoxifen followed by Femara versus Femara; Femara followed by tamoxifen versus Femara).

  • Patients treated with Femara for five years following surgery had a 13% reduced risk of death compared with those treated with tamoxifen (p=0.08).
  • When patients who had crossed over to Femara were excluded from the analysis, the reduction in the mortality risk was 19%.
  • Five-year survival rates were 87.9% for women treated with Femara only; 86.2% for those treated with two years of tamoxifen followed by three years of Femara; and 87.6% for those receiving two years of Femara followed by three years of tamoxifen.
  • Benefit was most pronounced in patients with node-positive disease.
  • Outcomes were similar between groups of patients who were treated with Femara monotherapy compared with those treated with initial Femara and switched to tamoxifen; however, those initially treated with tamoxifen and switched to Femara had a worse overall survival (HR=1.13) and disease-free survival (HR=1.05) compared with Femara monotherapy.
  • Recurrences at five years were 7.3% for the groups of patients initially treated with Femara and those initially treated with Femara who switched to tamoxifen and 9.1% for those who were initially treated with tamoxifen and switched to Femara.
  • There were no unexpected side effects in any of the arms of the study.

The second trial comparing an aromatase inhibitor to tamoxifen in postmenopausal women with hormone receptor-positive, early breast cancer was the TEAM (tamoxifen, exemestane adjuvant multinational) study, which was a randomized, multinational Phase III trial comparing Aromasin® (exemestane) to tamoxifen for five years in this patient population.2 Patients were initially randomized to Aromasin or tamoxifen monotherapy for five years. However, as in the BIG 1-98 trial, planned interim analysis revealed improved outcomes for Aromasin, resulting in all patients on tamoxifen crossing over to Aromasin after 2.5 to three years of tamoxifen therapy. The results presented were of a 2.75-year follow-up of the amended trial, with five-year results expected in 2009.

  • Disease-free survival was improved by 17% among those initially treated with Aromasin on-study (p=0.02).
  • Patients initially treated with Aromasin also had a significant improvement in relapse-free survival and time to distant metastasis (p <0.05).
  • No unexpected side effects occurred in any of the treatment arms.

The researchers stated that up-front therapy with Aromasin provides improved outcomes compared with initial therapy with tamoxifen for the treatment of hormone receptor-positive, postmenopausal women with early breast cancer. These results remain consistent with those of other aromatase inhibitors in comparison with tamoxifen for treatment of this disease.


An area of concern surrounding AIs is bone health, as side effects associated with AI therapy include loss of bone mineral density, osteoporosis, and increased fracture risk. Bisphosphonates have been evaluated for the prevention or reduction of bone loss for patients treated with aromatase inhibitors; however, most bisphosphonates require intravenous administration and may cause renal complications as well as osteonecrosis of the jaw.

Denosumab is a fully human monoclonal antibody that specifically targets the receptor activator of nuclear factor kappa B ligand (RANKL), a key mediator of the resorptive phase of bone remodeling. Denosumab is being studied across a range of conditions, including osteoporosis, treatment-induced bone loss, rheumatoid arthritis, bone metastases, and multiple myeloma. A biologics license application (BLA) has recently been submitted to the U.S. Food and Drug Administration for Denosumab to be used in the treatment and prevention of postmenopausal osteoporosis in women and treatment and prevention of bone loss among patients undergoing hormone ablation for breast or prostate cancer.

To assess the effects of Denosumab on bone mineral density (BMD), researchers from the United States and Canada conducted a Phase III randomized, double-blind, placebo-controlled clinical trial among women with non-metastatic breast cancer who were being treated with an AI.3 This trial included 252 women, all of whom received 1,000 mg of calcium and at least 400 IU of vitamin D. All had low bone mass but did not have clinical osteoporosis. The trial lasted 24 months and indicated increases in bone mass and decreases in bone turnover markers in the Denosumab group. Results from the trial were presented at the 2007 annual SABCS.

To explore potential variables that may affect the effectiveness of Denosumab, the researchers conducted a post-hoc subgroup analysis of the Phase III trial.4 The primary objective of the analysis was to evaluate covariates influencing treatment effects of Denosumab at lumbar spine, total hip, femoral neck, and 1/3 radius on BMD at two years. Two hundred and forty nine patients from the original trial were included in the analysis, all of whom received at least one dose of study drug. Variables analyzed included prior therapies and risk factors for bone loss.

  • At two years significant improvements in BMD were achieved among those treated with Denosumab compared with those who received placebo in all skeletal sites and clinical subgroups analyzed, with the exception of BMD of the radius among women treated with steroidal aromatase inhibitors.
  • Rates of adverse events were similar between the Denosumab and placebo arms (91% and 90%, respectively), with the most common being arthralgia, extremity pain, and back pain.

The researchers concluded that Denosumab provides significant improvements in BMD across skeletal sites at two years among women undergoing adjuvant therapy with AIs for breast cancer, with the one exception being BMD at the radius among those treated with steroidal aromatase inhibitors. Prior therapies and risk factors for bone loss did not affect outcomes for those treated with Denosumab.


Zometa® (zoledronic acid) also continues to be evaluated in the prevention of bone loss of patients being treated with AIs. In addition, it is being evaluated as part of the primary therapeutic regimen among these patients, as there have been some recent hypothesis-generating results indicating a potential direct anti-tumor effect of Zometa. At this year’s ASCO, results were presented indicating the addition of Zometa to adjuvant endocrine therapy improved survival versus endocrine therapy alone in premenopausal women.5 The mechanism through which the proposed anti-tumor effect of Zometa occurs is still under debate.

Dr. Eidtmann and colleagues presented interim data from the ZO-FAST trial at this year’s meeting demonstrating the potential role of Zometa among patients on AIs. The ZO-FAST (Zometa-Femara Adjuvant Synergy Trial) is a multicenter, randomized, Phase III trial evaluating the timing of initiation of Zometa among 1,065 postmenopausal women with Stages I-IIIA breast cancer.6 All patients in the trial received Femara (2.5 mg daily) and were randomized to Zometa upon initiation of treatment or initiation of Zometa when the patient’s T score was ³ – 2 or upon evidence of a clinical or asymptomatic fracture at 36 months. Zometa was given IV (4 mg) every six months. Interim data include a follow-up of 36 months.

  • BMD in the lumbar spine and hip were both increased among patients treated with immediate Zometa, while BMD decreased in these areas among those treated with delayed Zometa (p<0.0001).
  • Fracture rates were 5% in each treatment arm.
  • Disease-free survival was improved in the group of patients treated with immediate Zometa compared with the group of patients treated with delayed Zometa: HR=0.588 (95% CI: 0.361-0.959; P=0.0314).
  • One patient in the immediate treatment group developed osteonecrosis of the jaw; otherwise, side effects were similar between the two groups of patients.

The researchers concluded that immediate treatment with Zometa in conjunction with Femara improves BMD and disease-free survival compared with use of Zometa upon symptoms of reduced BMD or fracture. Results such as these continue to demonstrate efficacy of Zometa both in bone-sparing effects and disease progression in breast cancer.

To further explore the potential anti-tumor effects of Zometa, researchers from the University of Sheffield in England conducted a retrospective, exploratory analysis evaluating the addition of Zometa to chemotherapy in breast cancer.7 The study included 205 pre- and postmenopausal women with Stages II or III breast cancer. Patients were randomized to standard neoadjuvant chemotherapy with or without neoadjuvant Zometa, All patients received standard adjuvant chemotherapy following surgery, and those initially randomized to neoadjuvant Zometa also received adjuvant Zometa (4 mg every three months for six doses, followed by five additional doses given six months apart).

  • Pathologic complete responses were achieved in 11% of patients treated with Zometa compared with only 6% of those treated with chemotherapy only (p=0.033).
  • According to a multivariate analysis, median minimum residual tumor size was 28.7 mm in the Zometa arm compared with 42.4 mm in the chemotherapy-only arm (p=0.002).
  • Mastectomy rates were 65.3% in the Zometa arm compared with 77.9% in the chemotherapy-only arm.

The researchers stated that these results provide further evidence that Zometa appears to have a direct anti-tumor capacity; however, these results are not practice-changing as this was not a prospectively-defined trial and further study is necessary to determine survival and quality-of-life effects of Zometa in this setting. Nonetheless, the implications that drugs aimed at bone health may provide anti-tumor activity will continue to be explored.


Although many novel treatment strategies have emerged for breast cancer, chemotherapy remains an important cornerstone of therapy for many patients with early-stage disease. Phase III data have demonstrated an improvement in survival with the addition of Xeloda® (capecitabine) to Taxotere® (docetaxel) in metastatic breast cancer.8 As well, Xeloda potentially provides synergistic activity with both Taxotere and cyclophosphamide, as the latter two chemotherapy agents enhance the activity of thymidine phosphorylase. Interim results of the FinXX trial evaluating Xeloda with combination chemotherapy in early breast cancer were presented at this year’s meeting.9 The FinXX trial is a randomized, multicenter Phase III trial comparing Xeloda plus T-CEF ([TX-CEX] Taxotere® (docetaxel), Xeloda, cyclophosphamide, Ellence® (epirubicin) to T-CEF (Taxotere, cyclophosphamide, Ellence, 5-fluorouracil) in high-risk early breast cancer. The trial has enrolled 1,500 patients from 20 medical centers in Finland and Sweden from 2004 to 2007 with a final study analysis anticipated in 2010. The primary objective is recurrence-free survival. The planned interim analysis was at 120 events or a median of three years. Patients were stratified by the number of involved nodes (1-3 versus >4), HER2 status, and study site. Patients were randomized to TX-CEX (Taxotere 60 mg/m2 on day 1, Xeloda 900 mg/m2 twice daily on days 1-15 for cycles 1-6, cyclophosphamide 600 mg/m2 on day 1, Ellence (75 mg/m2 on day 1) or T-CEF (Taxotere 80 mg/m2 on day 1 for cycles 1-3, cyclophosphamide 600 mg/m2 on day 1, Ellence 75 mg/m2 on day 1, 5-fluorouracil 600 mg/m2 on day 1 for cycles 4-6), and those who were hormone receptor-positive were treated with hormone therapy.

Approximately 43% of patients were premenopausal, and three-quarters of patients had hormone-sensitive cancers.

Median follow-up has been 36 months to date:

  • Recurrence-free survival is 92.5% for the TX-CEX arm and 88.9% for the T-CEF arm (HR=0.66, p=0.02).
  • Distant disease-free survival is 93% for the TX-CEX arm and 89.2% for the T-CEF arm (HR=0.64, p=.014).
  • Overall survival is 95.6% for the TX-CEX arm and 94.9% for the T-CEF arm (HR=0.66, p=.089).
  • More patients discontinued therapy in the Xeloda arm.
  • Grades III/IV hand-foot syndrome, stomatitis, and diarrhea were significantly greater in the TX-CEX arm; however, neutropenic complications were significantly greater in the T-CEF arm.

Final analysis in 2010 will ultimately reveal the differences in survival and recurrences with the addition of Xeloda in this group of patients.

Neoadjuvant Herceptin®

Targeted therapies such as Herceptin® (trastuzumab) have undoubtedly changed the treatment paradigm of breast cancer. Optimal use of Herceptin in different settings among HER2-positive breast cancer patients remains an area of active study with demonstration of clinical benefit along the continuum of stages continually emerging. Results from the international Phase III NOAH trial evaluating neoadjuvant Herceptin in locally advanced breast cancer were presented at this year’s meeting.

Locally advanced breast cancer poses a challenge for physicians, as patients with this stage of disease remain at a high risk for recurrence. Neoadjuvant therapy plays an integral role in the treatment of locally advanced breast cancer; but the role of Herceptin in the neoadjuvant setting in locally advanced breast cancer has not yet been established.

The NOAH trial is a multicenter, randomized, open-label trial that is the largest trial to date evaluating Herceptin in addition to anthracycline and taxane-based chemotherapy as neoadjuvant therapy in locally advanced breast cancer.10 It included 228 patients with HER2 positive, locally advanced breast cancer (T3N1 or any T plus N2 or N3 or ipsilateral supraclavicular node involvement). Patients were randomized to neoadjuvant therapy consisting of three cycles of Adriamycin® (doxorubicin) (60 mg/m ) and Taxol® (paclitaxel) (150 mg/m q3w), four cycles of Taxol (175 mg/m q3w), and three cycles of CMF (cyclophosphamide 600 mg/m, methotrexate 40 mg/m, 5-fluorouracil 600 mg/m q4w) on days 1 and 8, with or without concomitant Herceptin (8 mg/kg loading dose then 6 mg/kg q3w for one year) . Patients continued taking Herceptin for up to 52 weeks. The primary endpoint was event-free survival (EFS), defined as the time between randomization and recurrence after surgery, progression while on therapy, or death from any cause.

  • At three years event-free survival was 70% for patients treated with Herceptin compared with 53% among patients treated with chemotherapy only (HR =0.55, p=0.006).
  • Overall response rates were 89% for the Herceptin arm compared with 77% for the chemotherapy only arm (p=0.02).
  • Survival trended toward an improvement in the Herceptin arm; however, this did not reach statistical significance (HR=0.65, p=0.18).
  • Notably, 95% of patients had common toxicity criteria values of 0-1 for cardiac toxicity.
  • Few grade III/IV adverse events in the Herceptin arm were noted.

The researchers concluded, “This analysis of the NOAH study establishes neoadjuvant [Herceptin] with [chemotherapy] as a standard treatment option in women with HER2-positive LABC [locally advanced breast cancer].”

The 2008 SABCS delivered results on important advancements towards the ultimate goal of improving cure rates and long-term survival coupled with optimal quality of life for patients with all stages of breast cancer.

1 Mouridsen HT, et al. BIG 1-98: a randomized double-blind phase III study evaluating letrozole and tamoxifen given in sequence as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Proceedings from the 2008 San Antonio Breast Cancer Symposium. Abstract 13.

2 Jones SE, et al. Results of the first planned analysis of the TEAM (tamoxifen exemestane adjuvant multinational) prospective randomized phase III trial in hormone sensitive postmenopausal early breast cancer. Proceedings from the 2008 San Antonio Breast Cancer Symposium. Abstract 15.

3 Ellis GK, Bone HG, Chlebowski R, et al. A 24-month subgroup analysis of the effect of denosumab on bone mineral density in women with breast cancer undergoing aromatase inhibitor therapy. Presented at the 2008 Annual San Antonio Breast Cancer Symposium. Abstract 2106.

4 Ellis G, Bone HG, Chlebowski R, et al. A phase 3 study of the effect of denosumab therapy on bone mineral density in women receiving aromatase inhibitors for nonmetastatic breast cancer. Presented at the 2008 Annual San Antonio Breast Cancer Symposium. Abstract 47.

5 Gnant, M. et al. Efficacy of zoledronic acid in premenopausal women with breast cancer receiving adjuvant endocrine therapy – the ABCSG-12 trial. Presented at: the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Ill., 31 May – 2 June, 2008; Abstract LBA4

6 Eidtmann H, Bundred NJ, DeBoer R, et al. The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36 months follow-up of ZO-FAST. Program and abstracts of the 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 44.

7 Winter M et al. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response-exploratory evidence for direct antitumor activity in breast cancer. Proceedings from the 2008 San Antonio Breast Cancer Symposium. Abstract 5101.

8 O’Shaughnessy J, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002;20:2812-2823.

9 Joensuu H, et al. Significant improvement in recurrence-free survival (RFS) when capecitabine (X) is integrated into docetaxel (T) → 5-FU + epirubicin + cyclophosphamide (CEF) adjuvant therapy for high-risk early breast cancer (BC): interim analysis of the FinXX-trial. Proceedings from the 2008 San Antonio Breast Cancer Symposium. Abstract 78.

10 Gianni L, et al. Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial. San Antonio Breast Cancer Symposium 2008. Abstract 31.

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