Austrian Breast And Colorectal Cancer Study Group Research Articles

Reducing the Risk of Cancer Treatment-Associated Bone Loss in Patients With Breast Cancer

Women with breast cancer, especially those receiving aromatase inhibitors, are at higher risk for bone loss and fracture. Postmenopausal women may already have multiple risk factors for fracture, and breast cancer therapies compound these risks. Current guidelines for bone health management in women with breast cancer are based on bone mineral density (BMD) measurements; however, many risk factors for fracture are independent of bone mineral density. Thus, consideration of other risk factors for fracture, including cancer therapies, aromatase inhibitor therapy, and age, may be necessary to accurately identify patients at high risk for bone loss. Bisphosphonates, inhibitors of osteoclast-mediated osteolysis, may be efficacious for the prevention of aromatase inhibitor-associated bone loss. Several clinical trials evaluating zoledronic acid in this setting have produced favorable results. In the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial, patients receiving anastrozole or tamoxifen plus goserelin experienced significant bone loss, and zoledronic acid treatment prevented bone loss in both groups. Results from the parallel studies Z-FAST, ZO-FAST, and E-ZO-FAST indicate that upfront zoledronic acid treatment increases BMD in patients receiving letrozole. These preliminary results are encouraging and suggest that zoledronic acid is an effective preventative therapy for bone loss in breast cancer patients receiving aromatase inhibitors.

Reducing the Risk for Breast Cancer Recurrence After Completion of Tamoxifen Treatment in Postmenopausal Women

Background: In postmenopausal women with hormone-sensitive early stage breast cancer, the risk for relapse persists after 5 years of treatment with adjuvant tamoxifen. Because tamoxifen is not indicated for adjuvant therapy beyond 5 years, the need for another therapy in the extended adjuvant setting to reduce late recurrence risk is clear. The National Cancer Institute of Canada Clinical Trials Group MA.17 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial found that extended adjuvant therapy with an aromatase inhibitor (AI) (eg, letrozole, exemestane, or anastrozole) rendered additional benefit in postmenopausal women with hormone receptor-positive breast cancer. The MA.17 trial was unblinded at the first interim analysis (median follow-up, 2.4 years) due to a significant reduction in relative risk for recurrence ( P < 0.001). Following the publication of the final analysis, several other MA.17 trial analyses and a postblinding analysis were also conducted. Recent data on the NSABP B-33 trial, which investigated exemestane in the extended adjuvant setting, and Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 6a, which evaluated anastrozole in the extended adjuvant setting, have also been reported. Objective: The goal of this article was to provide a current review of the MA.17 and NSABP B-33 resuits, together with additional data, to determine the benefit and tolerability of extended adjuvant AI therapy and the potential benefits of late extended adjuvant therapy with AIs after a prolonged (≤5 years) period after the completion of tamoxifen treatment. Methods: A literature search was performed. PubMed and MEDLINE were searched for descriptions of clinical trials published from 1990 to 2007 using the terms breast cancer, extended adjuvant, aromatase inhibitor, anastrozole, exemestane, and letrozole. Abstracts from several oncology meetings held between 2001 and 2007 also were searched to extract relevant data (disease-free survival [DFS], overall survival [OS]). Results: In MA.17 at 30 months, postmenopausal patients with early stage breast cancer who received extended adjuvant letrozole (n = 2593) experienced a significant (42%) improvement in DFS regardless of nodal status ( P < 0.001), and there was a significant (39%) improvement in as in node-positive patients ( P = 0.04), compared with placebo. At median follow-up (54 months), a postunblinding analysis found that patients who were switched to letrozole after a prolonged period (up to 5 years) after discontinuation of tamoxifen experienced a 69% improvement in DFS ( P < 0.001), a 72% improvement in distant DFS ( P = 0.002), and a 47% improvement in as ( P = 0.05) compared with patients who elected to continue with no treatment at trial unblinding. Results from 2 other extended adjuvant trials, the NSABP B-33, investigating exemestane in the extended setting (relapse-free survival, P = 0.03; no significant improvement in DFS or as), and the smaller ABCSG 6a, also support a benefit of extended adjuvant AI therapy. Conclusions: Current evidence supports the use of letrozole and perhaps exemestane in the extended adjuvant setting, while data on anastrozole are emerging. Based on the results from this review, initiation of letrozole treatment following a prolonged interval after completion of 5 years of tamoxifen treatment might be beneficial.

Cyclin D1 expression in breast cancer patients and tamoxifen therapy

523 Background: Adjuvant tamoxifen therapy improves survival of hormone receptor-positive breast cancer patients, but there is a subset of patients who fails to respond or develops resistance to tamoxifen. Cyclin D1 plays a central role in cell cycle regulation, directly affects the estrogen receptor and may predict outcome of tamoxifen therapy. Methods: We determined expression of cyclin D1 in formalin-fixed, paraffin-embedded surgical breast cancer specimens by means of immunohistochemistry. The patients had been enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 5 (test set) or ABCSG Trial 6 (validation set). Comparison of cyclin D1 expression with clinical parameters and survival of the patients was performed with cyclin D1 as a continuous variable and as a dichotomized variable. The median value of the percentage of cyclin D1-positive tumor cells was a priori chosen as cut-off point to classify cyclin D1- positive and cyclin D1-negative tumors. The cutpoint was established in the test set and validated in the validation set. Overall survival and relapse-free survival were analyzed with Cox models adjusted for clinical and pathological factors. Results: Cyclin D1 was positive (&gt;10% cyclin D1-positive tumor cells) in 140 of 253 (55%) tumors of the test set and in 569 of 948 (60%) tumors of the validation set. A benefit from adjuvant endocrine therapy was associated with absence of cyclin D1 in both cohorts. Overall survival was significantly shorter in patients with cyclin D1-positive tumors as compared to patients with cyclin D1-negative tumors (adjusted hazard ratio for death [test set], 2.47, 95% confidence interval [1.08–5.63] P=0.03; adjusted hazard ratio for death [validation set], 1.91, [1.45–2.51] P&lt;0.001). Relapse-free survival was also shorter in patients with cyclin D1-positive tumors than in patients with cyclin D1-negative tumors (adjusted hazard ratio for recurrence or death [test set], 2.73, [1.50–4.96] P=0.001; adjusted hazard ratio for recurrence or death [validation set], 1.60, [1.19–2.16] P=0.002). Conclusions: Women with early-stage, hormone receptor-positive breast cancer and cyclin D1-negative tumors benefit more from adjuvant tamoxifen therapy than women with cyclin D1-positive tumors. No significant financial relationships to disclose.

Lumpectomy Plus Tamoxifen or Anastrozole With or Without Whole Breast Irradiation in Women With Favorable Early Breast Cancer

In women with favorable early breast cancer treated by lumpectomy plus tamoxifen or anastrazole, it remains unclear whether whole breast radiotherapy is beneficial. Between January 1996 and June 2004, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) randomly assigned 869 women to receive breast radiotherapy +/- boost (n = 414) or not (n = 417) after breast-conserving surgery (ABCSG Study 8A). Favorable early breast cancer was specified as tumor size <3 cm, Grading 1 or 2, negative lymph nodes, positive estrogen and/or progesterone receptor status, and manageable by breast-conserving surgery. Breast radiotherapy was performed after lumpectomy with 2 tangential opposed breast fields with mean 50 Gy, plus boost in 71% of patients with mean 10 Gy, in a median of 6 weeks. The primary endpoint was local relapse-free survival; further endpoints were contralateral breast cancer, distant metastases, and disease-free and overall survival. The median follow-up was 53.8 months. The mean age was 66 years. Overall, there were 21 local relapses, with 2 relapses in the radiotherapy group (5-y rate 0.4%) vs. 19 in the no-radiotherapy group (5.1%), respectively (p = 0.0001, hazard ratio 10.2). Overall relapses occurred in 30 patients, with 7 events in the radiotherapy group (5-y rate 2.1%) vs. 23 events in the no-radiotherapy group (6.1%) (p = 0.002, hazard ratio 3.5). No significant differences were found for distant metastases and overall survival. Breast radiotherapy +/- boost in women with favorable early breast cancer after lumpectomy combined with tamoxifen/anastrazole leads to a significant reduction in local and overall relapse.

Austrian Breast and Colorectal Cancer Study Group (ABCSG)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Austrian Breast and Colorectal Cancer Study Group ABCSG. Clinical trials include:Adjuvant therapy with CMF versus goserelin plus tamoxifen in pre-menopausal, hormone-responsive, lymph node-positive or -negative patients. Study 5Adjuvant endocrine therapy in postmenopausal patients with hormone-responsive breast cancer: tamoxifen versus tamoxifen plus aminoglutethimide. Study 6Pre and postoperative chemotherapy versus conventional adjuvant chemotherapy alone in patients presenting with hormone receptor-negative breast cancer. Study 7Adjuvant endocrine therapy in postmenopausal patients with hormone-responsive breast cancer, G1 and G2 (ARNO). Study 8Adjuvant chemotherapy in postmenopausal patients with hormone-responsive breast cancer, G3. Study 9Adjuvant endocrine therapy and bisphosphonate therapy: tamoxifen in comparison to anastrozole, alone or in combination with zoledronate, in premenopausal patients presenting with hormone-responsive, Stage I and II breast cancer. Study 12Effect of 3 versus 6 cycles of epidoxorubicin/docetaxel G-CSF upon the rate of complete pathological remissions in the neoadjuvant treatment of patients with primary breast cancer and no distant metastases. Study 14SALSA (Secondary Adjuvant Long-term Study with Arimidex): a prospective, randomized, open, multicentre Phase III study to assess the efficacy of secondary adjuvant endocrine anastrozole therapy for 2 further years versus 5 further years in patients with hormone receptor-positive breast cancer after a 5-year primary adjuvant endocrine therapy. Study 16Neoadjuvant hormonal therapy with exemestane in postmenopausal patients with primary hormone receptor-positive breast cancer and no distant metastases. Study 17A randomized, double-blind, placebo-controlled, multi-centre phase 3 study to determine the treatment effect of denosumab in subjects with non-metastatic breast cancer receiving aromatase inhibitor therapy. Study 18A randomised Phase II study comparing anastrozole and fulvestrant to anastrozole for adjuvant treatment of postmenopausal patients with early breast cancer and disseminated tumour cells in bone marrow. Study 21A randomized Phase III study comparing epirubicin, docetaxel and capecitabine G-CSF to epirubicin and docetaxel G-CSF as neoadjuvant treatment for early HER-2 negative breast cancer and comparing epirubicin, docetaxel and capecitabine G-CSF trastuzumab to epirubicin and docetaxel G-CSF trastuzumab as neoadjuvant treatment for early HER-2 positive breast cancer. Study 24

Adjuvant Therapy With Aromatase Inhibitors for Postmenopausal Women With Early Breast Cancer: Evidence and Ongoing Controversy

Results of five major randomized trials have increased our understanding of the role of aromatase inhibitors in the adjuvant setting. Two of these trials, the Anastrozole or Tamoxifen Alone or in Combination (ATAC) trial and the International Breast Cancer Study Group's BIG 1-98 trial compared an aromatase inhibitor versus tamoxifen as initial hormonal therapy. Three other trial were designed as cross-over studies; the Intergroup Exemestane Study (IES) and the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8/German ARNO 95 trial compared a crossover from tamoxifen to an aromatase inhibitor versus continued tamoxifen in women who had completed 2 to 3 years of tamoxifen. The MA-17 trial compared the use of letrozole with placebo for 5 years, following 5 years of tamoxifen. Based on the results of these studies, the use of an aromatase inhibitor for the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer has largely replaced the previous standard of 5 years of tamoxifen. Still unanswered, however, are questions regarding optimal sequencing, selection of aromatase inhibitor, and duration of treatment. This review will provide an overview of the major studies with an emphasis on these important questions.

The use of aromatase inhibitors in adjuvant therapy for early breast cancer

Clinical evidence supporting the use of aromatase inhibitors (AIs) in adjuvant therapy for hormone-sensitive early breast cancer (EBC) has grown rapidly over the past few years and is reviewed in this article. The results of two studies-the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial and the Breast International Group (BIG) 1-98 trial-support the use of AIs as primary adjuvant therapy for EBC, with significantly prolonged disease-free survival, time to recurrence, and time to distant recurrence for both anastrozole and letrozole over tamoxifen. Furthermore, anastrozole has an established beneficial risk:benefit ratio compared with tamoxifen with mature data over the full 5-year recommended treatment period. For women who have already received 2-3 years of tamoxifen, switching studies with anastrozole [the Italian Tamoxifen Anastrozole (ITA) trial and the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8/Arimidex-Nolvadex (ARNO 95) trial] and exemestane [the Intergroup Exemestane Study (IES)] have also shown that 5 years of primary adjuvant tamoxifen therapy is not optimal and that switching to an AI should be considered. Finally, for those women who have completed 5 years of tamoxifen, based on the results of the MA 17 trial, extended adjuvant treatment with letrozole should be considered. Although no sequencing data are available yet, current evidence suggests that an AI should be the adjuvant treatment of choice over tamoxifen, and anastrozole is the only AI with mature adjuvant data to date.

High p27Kip1 expression predicts superior relapse-free and overall survival for premenopausal women with early-stage breast cancer receiving adjuvant treatment with tamoxifen plus goserelin.

To determine the predictive value of p27Kip1 in premenopausal women with early-stage hormone receptor-positive breast cancer. We retrospectively examined tumor specimens from 512 patients with breast cancer who were enrolled onto Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 5. In this trial, premenopausal, hormone receptor-positive breast cancer patients with stage I and II disease were randomly assigned to receive either 5 years of tamoxifen plus 3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil. p27Kip1 expression was assessed by immunohistochemistry, and its association with clinical outcome was determined. Statistical analyses were performed to test for interaction between p27Kip1 status and treatment. High p27Kip1 expression (nuclear p27Kip1 staining in >/= 50% of tumor cells) independently predicted superior relapse-free survival (RFS) and overall survival (OS) in both the total study population (RFS: relative risk [RR], 0.53; 95% CI, 0.34 to 0.82; P =.004; OS: RR, 0.29; 95% CI, 0.15 to 0.58; P <.001) and patients treated with combination endocrine therapy (RFS: RR, 0.32; 95% CI, 0.16 to 0.63; P =.001; OS: RR, 0.16; 95% CI, 0.05 to 0.53; P =.003). The interaction between p27Kip1 expression and treatment was statistically significant for RFS (P =.04) but not for OS (P =.27). High p27Kip1 expression was an independent predictor of responsiveness to hormonal therapy and thus may be useful for the selection of premenopausal women with early-stage hormone receptor-positive breast cancer for adjuvant combination endocrine therapy.

Assessment of medication unblinding in the multicenter diltiazem post-infarction trial: Mary W. Brown, Arthur J. Moss and Eric Carleen University of Rochester, Rochester. New York(P33)

Background: In postmenopausal women with hormone-sensitive early stage breast cancer, the risk for relapse persists after 5 years of treatment with adjuvant tamoxifen. Because tamoxifen is not indicated for adjuvant therapy beyond 5 years, the need for another therapy in the extended adjuvant setting to reduce late recurrence risk is clear. The National Cancer Institute of Canada Clinical Trials Group MA.17 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial found that extended adjuvant therapy with an aromatase inhibitor (AI) (eg, letrozole, exemestane, or anastrozole) rendered additional benefit in postmenopausal women with hormone receptor-positive breast cancer. The MA.17 trial was unblinded at the first interim analysis (median follow-up, 2.4 years) due to a significant reduction in relative risk for recurrence (P < 0.001). Following the publication of the final analysis, several other MA.17 trial analyses and a postblinding analysis were also conducted. Recent data on the NSABP B-33 trial, which investigated exemestane in the extended adjuvant setting, and Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 6a, which evaluated anastrozole in the extended adjuvant setting, have also been reported.Objective: The goal of this article was to provide a current review of the MA.17 and NSABP B-33 resuits, together with additional data, to determine the benefit and tolerability of extended adjuvant AI therapy and the potential benefits of late extended adjuvant therapy with AIs after a prolonged (≤5 years) period after the completion of tamoxifen treatment.Methods: A literature search was performed. PubMed and MEDLINE were searched for descriptions of clinical trials published from 1990 to 2007 using the terms breast cancer, extended adjuvant, aromatase inhibitor, anastrozole, exemestane, and letrozole. Abstracts from several oncology meetings held between 2001 and 2007 also were searched to extract relevant data (disease-free survival [DFS], overall survival [OS]).Results: In MA.17 at 30 months, postmenopausal patients with early stage breast cancer who received extended adjuvant letrozole (n = 2593) experienced a significant (42%) improvement in DFS regardless of nodal status (P < 0.001), and there was a significant (39%) improvement in as in node-positive patients (P = 0.04), compared with placebo. At median follow-up (54 months), a postunblinding analysis found that patients who were switched to letrozole after a prolonged period (up to 5 years) after discontinuation of tamoxifen experienced a 69% improvement in DFS (P < 0.001), a 72% improvement in distant DFS (P = 0.002), and a 47% improvement in as (P = 0.05) compared with patients who elected to continue with no treatment at trial unblinding. Results from 2 other extended adjuvant trials, the NSABP B-33, investigating exemestane in the extended setting (relapse-free survival, P = 0.03; no significant improvement in DFS or as), and the smaller ABCSG 6a, also support a benefit of extended adjuvant AI therapy.Conclusions: Current evidence supports the use of letrozole and perhaps exemestane in the extended adjuvant setting, while data on anastrozole are emerging. Based on the results from this review, initiation of letrozole treatment following a prolonged interval after completion of 5 years of tamoxifen treatment might be beneficial.