Adjuvant Therapy in Breast Cancer: An Update from SABCS 2004

Adjuvant Therapy in Breast Cancer: An Update from SABCS 2004San Antonio, TXDecember 8-11, 2004

Introduction

The 27th Annual San Antonio Breast Cancer Symposium, held December 8-11, 2004, continued its tradition of preeminence among international breast cancer meetings. With over 7,000 attendees, hundreds of posters and scores of oral presentations, advances across the entire spectrum of breast cancer were presented. In the area of adjuvant systemic therapy for breast cancer, themes of this year’s meeting included a maturation of trials exploring the role of aromatase inhibitors for hormone receptor-positive patients and a number of studies expanding our knowledge on the role of taxane therapy in the adjuvant setting of breast cancer.

Hormonal Therapy

The ATAC trial conducted in the late 1990s directly compared tamoxifen (T), the gold standard of hormonal therapy, to Arimidex® (anastrozole) (A), a small molecule aromatase inhibitor.

[1]This was the first study to establish the potential benefit of an aromatase inhibitor in the adjuvant setting. ATAC was updated at San Antonio this year; with a median follow-up of 68 months and only 8% of patients still remaining on trial therapy, this is a mature result.

[2]The absolute difference in disease-free survival continues to improve for patients on Arimidex® compared to tamoxifen, now reaching 3.3% absolute benefit at six years of follow up. The hazard ratio for the intent-to-treat population was 0.87, p=0.01 and for the 84% of patients who were hormone receptor-positive (HR+), the hazard ratio for Arimidex® vs. tamoxifen was 0.83, p=0.005. Time to recurrence was also improved. The benefit of Arimidex® was seen throughout the treatment, including years 1-3 when the peak rates of recurrence occur with tamoxifen. Arimidex® reduced the incidence of contralateral breast cancer by 53% in HR+ patients compared to tamoxifen and time to distant recurrence was improved by 14% in the whole population. At this time, there is a trend towards fewer breast cancer deaths in the Arimidex® arm, but no difference in overall survival for patients receiving Arimidex® or tamoxifen.< /SPAN>

Placed in perspective, the 50% reduction in recurrence rate caused by tamoxifen is reduced 26% further by the alternative of Arimidex®. Subgroup analysis showed similar benefits regardless of nodal status, tumor type, or prior chemotherapy. A retrospective, hypothesis-generating subgroup analysis suggests the benefit of Arimidex® is greater in the estrogen receptor-positive (ER+) progesterone receptor-negative (PgR-) cohort of patients, with a hazard ratio of 0.79. Patients treated with Arimidex® had fewer drug-related adverse events, and adverse events leading to withdrawal.

In terms of prespecified adverse events, patients receiving tamoxifen experienced more hot flashes, vaginal symptoms, vascular events and endometrial cancer. Patients receiving Arimidex® had more joint symptoms and fractures. The fracture rate did not seem to increase over time. Interestingly, patients on Arimidex® had a 1.3% hysterectomy rate vs. 5.1% in tamoxifen patients.

Overall, Arimidex® is superior to tamoxifen in reducing all recurrences, distant recurrence and contralateral breast cancer, with efficacy benefits emerging early after initiation of therapy within 1-3 years. Additionally, Arimidex® was better tolerated overall.

Another approach to aromatase inhibitor use is switching to an aromatase inhibitor after two years of tamoxifen. The Australian Breast Cancer Study Group 1-98 and the German ARNO 95 trial were similarly designed to test this hypothesis. A combined analysis presented at San Antonio showed a three-year EFS improvement of 3.1% in patients switching to Arimidex® rather than remaining on tamoxifen.

[3]The hazard ratio was 0.60, p=0.0009. Benefit was seen for local regional endpoints, contralateral breast cancer and distant recurrences. Arimidex® reduced distant recurrence-free survival by 39%. Subgroup analysis revealed no difference in outcome by age and nodal status, but Arimidex® was superior in grade I and II tumors. There was a trend towards better EFS in the ER+, PgR- group. Overall survival at three years demonstrated a trend towards improvement for Arimidex®, with a hazard ratio of 0.76, p=0.16. Both treatments were well tolerated with some increase in fractures in patients receiving Arimidex®.

The IES trial had a similar study design comprising a switch to an aromatase inhibitor, in this case Aromasin® Aromasin® (E), an irreversible steroidal aromatase inhibitor, after 2-3 years of tamoxifen. Preliminary results of IES were reported in the NEJM last year.

[4]This trial was also updated in December 2004.

[5]At initial report, after 2.5 years of follow-up, there was already benefit seen for Aromasin® compared to tamoxifen. In the current report, at a median follow up of 40 months, there were still fewer patients experiencing an event in the Aromasin® arm, compared to the tamoxifen arm. Disease-free survival was significantly better for Aromasin® (HR=0.73, p=0.001), as was breast cancer-free survival (HR 0.70, p=0.00005), and time to contralateral breast cancer (HR 0.5, p=0.04). In subgroup analysis, benefit was seen for Aromasin® vs. tamoxifen regardless of prior chemotherapy usage or number of nodes positive. The ER+, PgR- group appeared to derive more benefit from Aromasin®. OS trended towards improvement for Aromasin®-treated patients (HR 0.83, p= 0.08). Fewerthromboembolic events,less uterine cancer, and less lung cancer were seenin patients receiving Aromasin®, but musculoskeletal events were more common.< /SPAN>

Quality of life was explored in detail in the IES study.

[6]Baseline prevalence for endocrine symptoms following 2-3 years of tamoxifen remained problematic with both forms of endocrine therapy for a fraction of patients, but vaginal discharge was statistically lower in the Aromasin® arm. The authors concluded that the clinical benefits of Aromasin® over tamoxifen are achieved without any detrimental impact on quality of life.

It has been demonstrated that postmenopausal breast estrogen levels are 50 times higher than serum levels. The enzyme aromatase is responsible for most of this elevation. A pilot trial reported at SABCS demonstrated the ability of aromatase inhibitors to reduce Ki-67 level, a marker of proliferation in patients with atypia on random fine needle aspirations. This approach may be a prevention strategy in the future for women at high risk.

[7]

As Dr. Paul Goss discussed in his plenary lecture, there is much to still learn about aromatase inhibitors.

[8]For instance, we know there is non-cross resistance between different molecular classes of aromatase inhibitors in the metastatic breast cancer setting. Is the same true in the adjuvant setting? What is the effect of estradiol suppression from aromatase inhibitors in other tissues? The anti-estrogen effect appears beneficial in the endometrium in terms of decreasing proliferation. The IES study suggests Aromasin® may have an endometrial cancer protective effect.

The effects of aromatase inhibitors on bone are still controversial. In MA.17, a study of Femara® (letrozole) vs. placebo for five years in patients completing five years of tamoxifen, there was some increase in osteoporosis and a slight increase in fractures.

[9]However, the results of MA.17 and ATAC cannot directly be compared because tamoxifen before Femara® improves bone density. Moreover, the reduction in estradiol can cause a reciprocal increase in androgenic effect, which could potentially increase the tensile strength of bone without increasing bone mineral density. Understanding the correct endpoint to assess for bone health is important. Bone mineral density has been generally accepted as a surrogate marker, but may not completely reflect the physiologic effect.

Optimal sequencing of aromatase inhibitors, duration of therapy, and need for tamoxifen before or after an aromatase inhibitor, are among the questions the next generation of clinical trials will answer. Ultimately, patient selection will likely be driven by genetic signatures and individual tumors, based on the evaluation of important factors predict sensitivity or resistance to specific hormonal maneuvers. 

In premenopausal women who are candidates for endocrine therapy, tamoxifen remains the treatment of choice. Another approach to endocrine therapy in these patients is to render them medically postmenopausal by the temporary use of LHRH agonists. Combined endocrine treatment with Zoladex® (goserelin) and tamoxifen has been shown to be equivalent to CMF for premenopausal HR+ patients in prior trials.

[10]A concern has risen, however, as to accelerated bone loss with this approach. The ABCSG is studying Zoladex® and tamoxifen vs. Zoladex® and Arimidex® with or without zolendronic acid given every 6 months for three years. Results of a bone mineral density substudy were reported as this year’s meeting.

[11]After 36 months, lumbar spine BMD decreased 11.6% in the Zoladex®/tamoxifen arm vs. 17.4% in the Zoladex®/Arimidex® arm. However, for patients receiving either regimen plus zolendronic acid the lumbar spine BMD was not significantly reduced compared to baseline. There was no indication of renal safety issues for zolendronic acid given in this fashion. Other measures of bone health will require evaluation in the future including the clinical endpoint of fracture rate. Still, these results are encouraging. The recommendation was made to consider intervention with zolendronic acid in a premenopausal patient receiving combined endocrine therapy who demonstrates progressive loss of BMD.

Adjuvant Chemotherapy

Several large randomized clinical trials have established the role of taxanes in the adjuvant treatment of breast cancer.

[12],[13]The five-year results for the French study group trial PACS 01 were reported at the San Antonio meeting.

[14]This trial, open to women with node-positive operable breast cancer, compared six cycles of FEC 100 (the control arm) to three cycles of FEC 100 followed by three cycles of docetaxel. All chemotherapy was given every 21 days. Tamoxifen was given for five years after chemotherapy for HR+ patients. The primary endpoint of the trial was disease-free survival. With five years of follow up, the sequential FEC 100 to docetaxel arm enjoyed an absolute benefit in disease-free survival of 5.1%, with a hazard ratio of 0.83, p=0.041. Planned subset analyses explored interactions between number of lymph nodes or age in treatment. Significant benefit was seen in a group of women with 1-3 positive lymph nodes, but not in the group with more than 3 positive nodes. Surprisingly, patients over the age of 50 appeared to benefit more from sequential FEC/docetaxel than younger women. Other endpoints were in favor of the docetaxel-containing arm, with fewer first events, distant relapses and deaths, compared to FEC 100 alone. The FEC/docetaxel regimen was well tolerated. There were fewer cycle delays, cardiac events and less use of G-CSF. More neutropenia and growth factor usage was seen in the FEC 100 arm compared to the FEC/docetaxel arm. Sequential-arm patients experienced more nail disorders and edema. This trial, again, confirms the benefit of taxane after anthracycline therapy in node-positive patients.

The other eagerly awaited data was the first primary endpoint results of NSABP B-27, a large-scale neoadjuvant chemotherapy study.

[15]In this trial, almost 2,500 women with operable breast cancer were randomized to receive preoperative doxorubicin and cyclophosphamide x 4 cycles, 4 cycles of doxorubicin and cyclophosphamide followed by docetaxel x 4 cycles preoperatively, or doxorubicin and cyclophosphamide four cycles preoperatively followed by surgery and then four cycles of docetaxel in the adjuvant setting. All patients received tamoxifen for five years beginning with chemotherapy. Endpoints included OS, DFS and RFS. The latter two endpoints were defined as including local, regional and distant recurrences, residual disease after surgery, clinically inoperable cancers and death. DFS also included secondary cancers at other sites.

With a median of 68.8 months of follow up, there was no significant difference in disease-free survival. However, relapse free survival was improved (HR = 0.81, p= 0.003) compared to group 1. When both docetaxel arms were compared to the AC only arm, the trend persisted (HR = 0.86, p= 0.06). Surprisingly, docetaxel reduced the number of local recurrences, but not the number of distant recurrences.< /SPAN>

As in other studies, patients in B-27 who achieved a pathologic CR (pCR) in the breast had improved outcomes compared to those with a partial response. The hazard ratio for disease-free survival was 0.45 for patients having no invasive cancer in the breast after preoperative chemotherapy compared to those with a non-pCR. The overall survival was improved to 67% (p <0.0001) for patients achieving a pathologic CR. For patients without CR, the number of positive lymph nodes predicted outcome. Patients with clinical partial response after AC had benefit from the addition of preoperative docetaxel, with a hazard ratio of 0.68 compared to AC alone for DFS (p=0.003).< /SPAN>

Another phase III trial compared AC Q 3 wks x 4 cycles followed by paclitaxel Q 3 wks for 4 cycles (AC-T) to doxorubicin and paclitaxel q 3 wks x 4 cycles followed by weekly paclitaxel x 12 weeks (AT-WT).

[16]A total of 1,830 stage I-III breast cancer patients were enrolled. The median age was 52; 28% were node-negative, and 29% had more than 4 positive lymph nodes. The 3-year DFS rate for the intent-to-treat population was superior for AT-WT (88.4%) vs AC-T, (84.6%) (HR=0.74, p=0.005). Overall survival was significantly better as well, with AT-WT yielding 3 yr OS of 94.6% vs 91.7% for AC-T (p=0.005). There were more breast cancer-related deaths and other deaths in the AC-T arm. There was somewhat more grade 2 and 3 neuropathy in the weekly paclitaxel arm, but no difference in cardiac events. This trial establishes a non-cyclophosphamide regimen as a standard of care in early stage breast cancer. The trial design does not permit attribution of the better results to use of paclitaxel instead of cyclophosphamide vs. weekly paclitaxel vs. q 3 wk paclitaxel,or both.< /SPAN>

It is useful to know that we are making real progress in adjuvant breast cancer treatment over the long haul. Two presentations addressed this issue. From the clinical trial perspective, the 20-year experience of sequential large CALGB adjuvant trials was reviewed for benefit.

[17]In all three trials (8541, 9344 and 9741), there was significant advantage for the experimental arm compared to the control arm, which has held up with long follow-up. A consistent finding was the marked increased benefit of chemotherapy for HR- patients compared to HR+ patients, although HR+ patients also benefit significantly from chemotherapy in each of these studies. The biology of hormone receptor positive tumors is different from HR- tumors, in that ER- tumors tend to relapse early, within the first 2-3 years and then have a low rate of relapse over the next decade, while ER+ patients have a fairly constant relapse rate even extending out over a decade from diagnosis, which is only slightly higher during the first few years after diagnosis.

From the population perspective, the British Columbia Cancer Agency evaluated the benefit of adjuvant therapy in virtually all women in their province treated over a 10-year period.

[18]Breast cancer specific survival for stage I-II patients showed a 30% relative improvement in survival for patients receiving chemotherapy with or without tamoxifen. This population-based sample confirms that progress made in saving lives under clinical trial conditions translates into tangible benefit for real-life care of women with breast cancer.

References:

[1]Howell A, Cuzick J, Baum J, Buzdar A, Dowsett M, Forbes JF, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005 Jan 1:365(9453): 60-2.

[2]Howell A. The ATAC (Arimidex, tamoxifen, Alone or in Combination) trial in postmenopausal women with early breast cancer – updated efficacy results based on a median follow-up of 5 years. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 1.

[3]Jakesz R, Kaufmann M, Gnant M, Jonat W, Mittlboeck M, Greil R, et al. Benefits of switching postmenopausal women with hormone-sensitive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: combined results from 3,123 women enrolled in the ABCSG Trial 8 and the ARNO 95 Trial. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 2.

[4]Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. NEJM. 2004 Mar 11; 350(11): 1081-92.

[5]Coombes RC, Hall E, Snowdon CF, Bliss JM. The Intergroup Exemestane Study: a randomized trial in postmenopausal patients with early breast cancer who remain disease-free after two to three years of tamoxifen-updated survival analysis. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 3.

[6]Fallowfield LJ, Price MH, Hall E, Coombes RC, Bliss JM. Intergroup exemestane study: results of the quality of life sub-protocol. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 4.

[7]Fabian CJ, Kimler BF, Simonsen M, Metheny T, Zalles CM, Hall M. Reduction in breast epithelial cell proliferation after six months of letrozole in high-risk women on hormone replacement therapy with random periareolar fine needle aspiration evidence of atypia. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 5.

[8]Goss P. The rise and current status of aromatase inhibitors in breast cancer treatment. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Plenary Lecture 1.

[9]Goss PE, Ingle JN, Martino S, Robert JN, Muss HB, Piccart MJ. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. NEJM. 2003 Nov 6; 349 (19): 1793-802.

[10]Jakesz R, Hausmaninger H, Kubista E, Gnant M, Menzel C, Bauernhofer T. et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol. 2002 Dec 15; 20(24): 4621-7.

[11]Gnant M, Jakesz R, Mlineritsch B, Luschin-Ebengreuth G, Schmid M, Menzel C. Zolendronic acid effectively counteracts cancer treatment induced bone loss (CTIBL) in premenopausal breast cancer patients receiving adjuvant endocrine treatment with goserelin plus anastrozole versus goserelin plus tamoxifen – bone density subprotocol results of a randomized multicenter trial (ABCSG-12). Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 5.

[12]Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar W, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15; 21(8): 1431-9.

[13] Henderson IC, Berry, DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, et al. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15; 21(6): 976-83.

[14]Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Kerbrat P, et al. Five years analysis of the PACS 01 trial: 6 cycles of FEC100 vs 3 cycles of FEC100 followed by 3 cycles of docetaxel (D) for the adjuvant treatment of node positive breast cancer. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 27.

[15]Bear HD, Anderson S, Smith RE, Robidoux A, Kahlenberg MS, Margolese RG, et al. A randomized trial comparing preoperative (preop) doxorubicin/cyclophosphamide (AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by postoperative (postop) T in patients (pts) with operable carcinoma of the breast: results of NSABP B-27. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 26.

[16]Loesch D, Greco FA, O’Shaughnessy J, Asmar L, Senzer NN, Burris HA, et al. A randomized, multicenter phase III trial comparing regimens of doxorubicin + cyclophosphamide followed by paclitaxel or doxorubicin + paclitaxel followed by weekly paclitaxel as adjuvant therapy for patients with high risk breast cancer. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 28.

[17]Berry DA, Cirrincione C, Henderson IC, Citron ML, Dubman DR, Goldstein LJ, et al. Effects of improvements in chemotherapy on disease-free and overall survival of estrogen-receptor negative, node-positive breast cancer: 20-year experience of the CALGB & U.S. Breast Intergroup.

[18]Olivotto IA, Ravdin PM, Bajdik C, Speers C, Coldman A, Gelmon K, et al. Have randomized trial benefits been translated into population-based survival gains for women with breast cancer? Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 30.

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