2009 San Antonio Breast Cancer Symposium: Potentially Practice-Changing Studies, Pt 1

[Hopeful]

2010 Jan 25, Lee Schwartzberg, MD, Editor-in-Chief

The 32nd San Antonio Breast Cancer Symposium, held December 9−13, 2009, brought together more than 8000 clinicians, scientists, medical oncologists, surgeons, and radiation oncologists, as well as professionals from a host of other disciplines, to hear several hundred oral and poster presentations on every aspect of breast cancer. Of the many important studies presented, some of the potentially practice-changing trials are summarized in this commentary, which will be presented in 2 parts. Part I reviews highlights of adjuvant hormonal therapy, hormonal therapy for metastatic disease, and bone-related issues.

Part II will review biologic therapy, particularly antiangiogenic therapy and anti-HER2 therapy in breast cancer.

Adjuvant hormonal therapy

Adjuvant aromatase inhibitors have become the mainstay of endocrine therapy in postmenopausal patients because of their enhanced efficacy and reduced toxicity compared with 5 years of tamoxifen. Whether there is benefit to a sequential approach utilizing both tamoxifen and aromatase inhibitors has been investigated in several trials, including 2 trials reported at San Antonio this year.

The Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial compared 5 years of exemestane against a switching strategy consisting of 2 to 3 years of tamoxifen followed by exemestane for 2 to 3 years in nearly 10,000 hormone-receptor−positive (HR+) women.¹ The 5-year disease-free survival (DFS) was nearly identical between the arms, 85.4% in the sequential arm compared with 85.7% for exemestane alone. Likewise, the 5-year overall survival (OS) and rate of recurrence were virtually identical between arms. The toxicity profile was consistent with the known effects of each drug.

Results of the Intergroup Exemestane Study (IES), comparing 5 years of tamoxifen against switching to exemestane after 2 to 3 years of tamoxifen, have been previously reported.² Long-term follow-up presented at San Antonio (median, 91 months) showed a 2.4% improvement in OS at 8 years for the group that switched to exemestane (hazard ratio [HR] = 0.86; P = .04), as well as a 4.4% favorable difference in DFS (HR = 0.82; P = .0009).³ Additionally, breast cancer−free survival was better overall for patients switching to exemestane. The incidence of the most frequently occurring breast cancer−specific event, distant recurrence, was reduced by exemestane, as was development of second primary breast cancers. Interestingly, there were fewer bone recurrences in patients switching to exemestane. Uterine cancers were half as likely in patients switching as in those remaining on tamoxifen, and so were lung cancer and kidney cancer.

Taken together, along with previous data reported from the Breast International Group (BIG) 1-98 trial, these 2 studies confirm that 5 years of an aromatase inhibitor, or 2 to 3 years of an aromatase inhibitor followed by tamoxifen, or 2 to 3 years of tamoxifen followed by an aromatase inhibitor are all acceptable strategies for postmenopausal women with estrogen-receptor—positive (ER+) early-stage breast cancer, and all are superior to 5 years of tamoxifen.

An increasingly common clinical situation is that of the premenopausal patient with breast cancer who becomes permanently menopausal during tamoxifen treatment. This may occur because of age-related factors alone, the effects of chemotherapy, the effects of tamoxifen, or any combination thereof. The question that has arisen is whether use of an aromatase inhibitor provides any additional benefit in this clinical scenario. The MA.17 study, conducted by the National Cancer Institute of Canada Clinical Trials Group, randomized postmenopausal women to 5 years of either letrozole or placebo after 5 years of tamoxifen. The results indicated significant benefit associated with extended adjuvant therapy with letrozole.⁴

A subgroup of patients in this trial were premenopausal at the time of breast cancer diagnosis (median age, 45 years) but were enrolled in the trial when they became menopausal after 5 years of tamoxifen. As reported at San Antonio 2009, the initially premenopausal women, as compared with the women who were postmenopausal at diagnosis, received greater benefit from letrozole in terms of DFS; this was shown in both node-negative and node-positive patients.⁵ Additionally, distant disease−free survival (DDFS) and OS were also better in the initially premenopausal women. The benefit accrued even in women who started letrozole up to 5 years after completing tamoxifen. The absolute benefit in DFS for premenopausal women was 8.2%, compared with 3% for postmenopausal women who were treated with 5 years of letrozole; the rate of DDFS with letrozole was 5.9% in premenopausal women, compared with 2.2% in postmenopausal women. These data support the concept that even patients who have completed tamoxifen years ago and are now clearly postmenopausal might benefit from extended adjuvant therapy with an aromatase inhibitor.

Endocrine therapy for metastatic disease

For hormone-receptor−positive breast cancer, the initial choice of therapy is typically endocrine in nature. Aromatase inhibitors and selective receptor modulators such as tamoxifen remain the mainstay of treatment choices. Recently, a third class of agent, the selective estrogen receptor down-regulator, typified by the drug fulvestrant, has shown benefits similar to those with aromatase inhibitors in prospective, randomized, controlled clinical trials. Many questions have remained, however, about the optimal dose and schedule of fulvestrant and whether or not a strategy of combined endocrine therapy might be superior to single-agent sequential therapy. San Antonio 2009 addressed several of these issues.

The dose of fulvestrant approved by the Food and Drug Administration, 250 mg by intramuscular (IM) injection once a month, does not achieve steady state plasma levels for several months. Concern has been expressed that the monthly, approved dose is not optimal for controlling breast cancer, even at steady state concentrations. Results recently published for a trial utilizing fulvestrant at a dose of 500 mg, compared with anastrozole, showed improved efficacy for the higher dose of fulvestrant over that shown in previous studies using the lower dose.⁶

The CONFIRM trial (COmparisoN of Faslodex In Recurrent or Metastatic breast cancer), presented this year by Di Leo et al, randomized ER+ women to IM administration of either standard-dose fulvestrant, 250 mg, or high-dose fulvestrant, 500 mg.⁷ High-dose fulvestrant increased median time to progression, from 5.5 months with the standard dose to 6.5 months with the high dose, with no change in response rate, but it also led to a 20% improvement in clinical benefit rate. Perhaps most intriguingly, there was a trend toward improved OS with the high dose, 25.1 vs 22.8 months (HR = 0.8; 95% confidence interval = 0.69-1.63). Essentially no difference in adverse events (all grades) was noted. Maturation of this trial will help answer the question of whether the higher dosing offers clinical and cost-effective advantages.

Another concept receiving attention is the combined use of endocrine blockade utilizing an aromatase inhibitor, which reduces breast cancer exposure to estrogen, along with fulvestrant, which degrades the estrogen receptor. This concept is supported by animal model experiments demonstrating a benefit from combined endocrine therapy.

First results from the Fulvestrant and Anastrozole in Combination Trial (FACT) were reported at San Antonio 2009. In this trial, patients were randomized to anastrozole alone vs anastrozole plus fulvestrant. Fulvestrant was administered at the higher loading dose of 500 mg IM on day 1, at 250 mg on days 15 and 28, and at 250 mg every 28 days.⁸ Unfortunately, no significant benefit was observed for the combination arm. Time to progression was 10.8 months with the combination therapy vs 10.2 months with anastrozole alone. Furthermore, no difference in OS, clinical benefit rate, or other efficacy parameters was noted. Adverse events were similar in both arms, except for an increase in hot flashes for the women receiving fulvestrant. Given these negative results, combined endocrine therapy remains an unproven concept in breast cancer.

Despite the strong benefit for adjuvant hormonal therapy shown in the clinical trial setting, it is important to understand how well this translates into the real-world situation. A study by the British Columbia Cancer Agency, which tracks virtually all newly diagnosed cancer patients in that province, shed some light on adherence to adjuvant hormonal therapy.⁹ The study matched diagnosis and prescription information available for 2400 postmenopausal women diagnosed with HR+ breast cancer from 2005 to 2008. Nonadherence was defined as less than 80% of eligible prescription-days filled. Overall, the nonadherence rate was 42% for tamoxifen, 37.5% for aromatase inhibitors, and 35% for tamoxifen followed by an aromatase inhibitor. In a multivariate analysis, use of chemotherapy in higher-grade tumors predicted for better adherence, and endocrine therapy prescribed by radiation oncologists predicted poorer adherence, as compared with prescription by a medical oncologist.

These sobering results suggest that many women may not be achieving maximal benefit from these drugs because of lack of adherence. Such preliminary data require confirmation from other studies and particularly in other settings where health care is delivered differently. Nonetheless, these results might underestimate nonadherence in the United States, where an additional barrier to adherence is the high cost of aromatase inhibitors for the majority of women without full prescription coverage.

Bone health and breast cancer

The skeleton is the most common site of metastasis from breast cancer. In recent years, the molecular interplay between breast cancer cells and the osseous stroma has been extensively studied and is now well understood. A complex feedback loop including elaborated bone cytokines can drive tumor growth, which, in turn, releases factors leading to osteoclast activation. The bisphosphonates are a group of drugs that interfere with osteoclast action and have been clinically utilized for many years in metastatic breast cancer to reduce skeletal-related events (SREs) such as pathologic fractures, need for radiation therapy, or surgery. The most potent bisphosphonate, the nitrogen-containing zoledronic acid, is proven to reduce SREs in breast cancer and osseous metastasis from other cancers. It is delivered as a monthly IV infusion.

More recently, a new class of agents has been developed showing promising activity against metastatic bone cancer. Denosumab is a first-in-class monoclonal antibody that inhibits RANK-ligand, a key factor in mediating osteoclast activity.

Stupeck et al presented results of a double-blind, randomized, controlled trial comparing denosumab with zoledronic acid for the prevention of SREs in patients with bone metastases who had not been previously exposed to IV bisphosphonates.¹⁰ Of 2000 patients enrolled, one-third had prior SREs; the median duration of the presence of bone metastases was 2 months. Compared with zoledronic acid, denosumab reduced the risk of the first SRE by 18%, the median time to first radiation by 26%, and the median time to first bone pain by 13%; all of these differences were statistically significant. The overall skeletal morbidity rate for patients receiving denosumab was reduced by 22% compared with the rate for those treated with zoledronic acid. There was no difference in the rate of disease progression.

Adverse events were similar in both groups, except for the incidence of renal toxicity, which was 8.5% in the zoledronic acid group vs 4.9% in the denosumab group. Acute-phase reactions occurred in 27.3% of patients receiving zoledronic acid but in 10.4% receiving denosumab. Osteonecrosis of the jaw was seen in both groups, at a 2% occurrence rate with denosumab and 1.4% with zoledronic acid. These encouraging results support the use of denosumab as a new standard of supportive therapy in the metastatic setting.

Bisphosphonates remain of intense interest in early-stage breast cancer because of accumulating evidence that their adjuvant usage could reduce the development of skeletal metastases and perhaps even improve DFS. A recent publication by the Austrian Breast Cancer Study Group in The New England Journal of Medicine, reporting on a clinical trial investigating hormonal therapy with or without bisphosphonates in premenopausal women, supported this concept.¹¹ Oral bisphosphonates are widely used by postmenopausal women who are at risk for, or who are already experiencing, osteoporosis. Some data in the past have also suggested that oral bisphosphonates may reduce the risk of breast cancer.

At San Antonio 2009, Rowan Chlebowski and colleagues presented provocative results from the Women’s Health Initiative, a huge lifestyle intervention trial involving postmenopausal women.¹² As part of this study, baseline oral bisphosphonate use was recorded; it was present in a small fraction of patients. These women differed from the main population in a number of other baseline factors, such as body mass index (lower), Gail model risk level (higher), and various other factors, which were all accounted for in a multivariate statistical analysis performed by the authors.

The incidence of invasive breast cancer was reduced in the women who used bisphosphonates by one-third, although the incidence of in-situ breast cancer was increased. Most of the reduction was in the group with invasive ER+ tumors. No difference in stage or grade was noted. Along with the evidence that intravenous bisphosphonates may improve DFS in both premenopausal and postmenopausal women, the results suggested that bisphosphonates may have an effect on the developmental pathway of invasive breast cancer. More direct, prospective data will, of course, be required to establish or refute this hypothesis. Nonetheless, the evidence is accumulating on the benefit of bisphosphonates in altering breast cancer occurrence and recurrence.

References

1. Rea D, Hasenburg A, Seynaeve C, et al. Five years of examestane as initial therapy compared to 5 years of tamoxifen followed by examestane: the TEAM trial, a prospective, randomized, phase III trial in postmenopausal women with hormone-sensitive early breast cancer (abstract 11). Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas.
2. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081-1092.
3. Bliss J, Kilburn L, Coleman R, et al. Disease related outcome with long term follow-up: an updated analysis of the Intergroup Exemestane Study (IES) (abstract 12). Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas.
4. Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Nat Cancer Inst. 2005;97(17):1262-1271.
5. Goss P, Ingle J, Martino S, et al. Outcomes of women who were premenopausal at diagnosis of early stage breast cancer in the NCIC CTG MA17 trial (abstract 13). Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas.
6. Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol. 2009;(27):4530-4535.
7. Di Leo A, Jerusalem G, Petruzelka L, et al. CONFIRM: a phase III, randomized, parallel-group trial comparing fulvestrant 250 mg vs. fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer (abstract 25). Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas.
8. Bergh J, Jonsson P, Lidbrink E, et al. First results from FACT: an open-label, randomized phase III study investigating loading dose of fulvestrant combined with anastrozole versus anastrozole at first relapse in hormone receptor positive breast cancer (abstract 23). Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas.
9. Chan A, Speers C, O’Reilly S, Pickering R. Adherence of adjuvant hormonal therapies in post-menopausal hormone receptor positive (HR+) early stage breast cancer: a population based study from British Columbia (abstract 36). Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas.
10. Stopeck A, de Boer R, Fujiwara Y, et al. A comparison of denosumab versus zoledronic acid for the prevention of skeletal-related events in breast cancer patients with bone metastases (abstract 22). Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas.
11. Gnant M, Mineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360 (7) 679-691.
12. Chlebowski R, Chen Z, Cauley J, et al. Oral bisphosphonate and breast cancer: prospective results from the Women’s Health Initiative (WHI) (abstract 21). Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, Texas.

Hopeful