Medical Management of Breast Cancer: Update from the San Antonio Breast Cancer Symposium 2009

The evolving epidemiology statistics relative to breast cancer world wide are alarming. The cumulative incidence of breast cancer is 6.3% in developed countries compared with 1.0% in undeveloped countries. Western developed areas show increasing rates, with projections of 2 million cases diagnosed annually.

Advances in understanding of the causes of breast cancer, epidemiology, risk factors, and both maturing data and new findings on hormonal, cytotoxic, and biological approaches were presented at the 32nd annual San Antonio Breast Cancer Symposium.

Risk factors

Kwan and associates reviewed the relationship between alcohol use and breast cancer recurrence and survival in 1898 women with stage I, II, or IIIA breast cancer who participated in the Life After Cancer Epidemiology (LACE) study.¹ They found that those who consumed more than 6 g/day of alcohol had a 1.5-fold increase in death and a 1.3- fold increase in recurrence.

Obesity is also associated with a poor prognosis after breast cancer. A population- based cohort study of almost 19,000 patients showed that although on univariate analysis the risk of local or regional cancer recurrence was not related to body mass index (BMI), the risk of distant metastases increased with increasing BMI.² The investigators also found that the risk of dying from breast cancer remains elevated for obese women (BMI 25) throughout 30 years of observation.

On a more positive note, in a population- based case-control study, the use of bisphosphonates for more than 1 year was shown to lead to a 29% reduction in the risk of postmenopausal breast cancer.³ When tumors did develop in bisphosphonate users, they tended to have a more favorable prognostic factors profile.

A head-to-head comparison of denosumab with zoledronic acid in 2048 women revealed an 18% reduction in risk of developing a skeletal-related event in those receiving denosumab.⁴ A 6% absolute risk reduction and a 16% relative risk reduction were found in the denosumab group. The findings also showed a 22% reduction in skeletal morbidity rate in the denosumab arm. Compared with zoledronic acid, denosumab significantly delayed the time to first radiation to bone and first on-study skeletal-related event or hypercalcemia of malignancy. The US Food and Drug Administration has not approved denosumab.

Results of a subanalysis from the E1199 study revealed that, although black women are one third less likely than women of other races to develop breast cancer, they are 30% more likely to die if they are diagnosed with the disease.⁵ In this analysis, black race was associated with significantly poorer disease- free survival (DFS) and overall survival (OS). Potential explanations for the disparities noted include poorer adherence to endocrine therapy, obesity and associated hyperinsulinemia, or other factors.

Advances in drug therapy

The Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial randomized 9775 women with hormone receptor–positive early breast cancer to either 5 years of the aromatase inhibitor (AI) exemestane as initial therapy or 5 years of tamoxifen followed by exemestane.⁶ The 5-year update showed there was no advantage to switching and 5 years of an AI provided superior efficacy.

The Intergroup Exemestane Study (IES) evaluated exemestane taken for 2 to 3 years followed by randomization to either exemestane or tamoxifen for a total of 5 years of adjuvant endocrine therapy.⁷ The study showed a 2.4% increase in survival in those in the exemestane arm as well as fewer events overall, including second primaries. As determined in the MA17 trial of letrozole versus placebo, extending hormonal therapy in the adjuvant setting beyond 5 years has been found to have a DFS advantage, particularly for those with estrogen receptorpositive disease.⁸

The role of bevacizumab in the metastatic setting was examined in several studies. In the AVADO trial (a double- blind, placebo-controlled, phase 3 study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of locally recurrent or metastatic breast cancer), women who received bevacizumab 15 mg/kg combined with docetaxel had a 33% increase in progression-free survival (PFS) as well as better response rates compared with the group that received placebo. To date, however, no survival advantage with the bevacizu mab- docetaxel combination has been demonstrated.⁹

The RIBBON 2 trial was a phase 3 study of bevacizumab used in combination with chemotherapy in the secondline treatment of human epidermal growth factor receptor type 2 (HER2)- negative metastatic breast cancer.¹⁰ Patients eligible for this study had previously received one prior cytotoxic treatment. They were randomized to chemotherapy plus placebo or chemotherapy plus bevacizumab—the chemotherapy component being the investigator’s choice (a taxane [304], gemcitabine [160], capecitabine [144], or vinorelbine [76]). PFS, the primary end point of the study, was 7.2 months in the bevacizumab arm compared with 5.1 months in the placebo arm. This was statistically significant and represented a 22% decrease in the risk of relapse. The OS rate of 15 months for bevacizumab versus 16.4 months for placebo was not significantly different between the two groups.

The SOLTI-0701 phase 2b trial compared sorafenib/capecitabine with capecitabine alone in the second-line setting.¹¹ The overall response rate of 38.3% (sorafenib/capecitabine) compared with 30% (capecitabine alone) in women with locally advanced or metastatic breast cancer. PFS was 7.6 months compared with 4.1 months, respectively, in the first-line setting and 5.7 months compared with 4.1 months, respectively, in the second-line setting. These improvements, however, were offset by toxicity, which included grade 3 hand-foot syndrome in 45% of the participants.

A review of studies in HER2-positive breast cancer included EGF104900, a phase 3 randomized trial.¹² The population for this trial included women with HER2-positive metastatic breast cancer who had progressed on prior trastuzu - mab-containing regimens. The trial compared lapatinib 1500 mg alone with lapatinib 1000 mg combined with trastuzumab. At relapse, patients treated with lapatinib alone were allowed to cross over to the combination arm. In the intent-to-treat analysis, a 4.5- month improvement in OS was demonstrated in the combination arm with a statistically significant hazard ratio of 0.76. PFS was 12 weeks with the combination regimen compared with 8.1 weeks with lapatinib alone. Median survival was 14 months for lapatinib/ trastuzumab compared with 9.5 months for lapatinib alone. There was also a survival benefit, which reflected a 24% reduction in death.

Slamon and collegues presented the third planned analysis of BCIRG 006 trial, a multicenter, phase 3, randomized trial comparing doxorubicin/cyclophosphamide followed by docetaxel with doxorubicin/cyclophosphamide followed by docetaxel/trastuzumab (ACTH) and with docetaxel/carboplatin/ trastuzumab (TCH) in the adjuvant treatment of node-positive and high-risk, node-negative patients with operable HER2-positive breast cancer.¹³ With a median follow-up of 65 months, the DFS rates were 84% for the ACTH arm and 81% for the TCH arm compared with 75% for the control arm. OS rates were 92% for the ACTH arm, 91% for the TCH arm, and 87% for the control arm. TCH continued to show efficacy equivalent to ACTH, although the study was not designed to determine equivalence. There were 21 cases of congestive heart failure with the ACTH regimen compared with four with TCH. Also, 194 patients in the ACTH arm had sustained reductions in left ventricular ejection fraction compared with 97 in the TCH arm. These findings suggest that a nonanthracyline-containing regimen is an effective alternative for patients at high risk for anthracyclineassociated cardiac toxicities.

Perez and colleagues presented an update to N9831, the only randomized phase 3 trial comparing the safety and efficacy of the addition of trastuzumab to doxorubicin/cyclophosphamide (AC) either following paclitaxel (ACpaclitaxeltrastuzumab) or starting concurrently with paclitaxel (ACpaclitaxel/trastuzumab) in women with stage I to III invasive HER2-positive breast cancer.¹⁴ Giving paclitaxel and trastu zumab concurrently was found to be superior to the sequential approach. Five-year DFS was increased from 80% with ACpacli-taxeltrastuzumab to 84% with AC paclitaxel/trastuzumab. These results set the stage for trastuzumab therapy being given concurrently with paclitaxel chemotherapy.

Conclusion

There continues to be much to learn about breast cancer from an epidemiology standpoint, much more to unravel at the scientific level, and an incalculable need to make available effective therapies without exorbitant costs. Never theless, the exciting developments reported in San Antonio attest to the efforts of scientists, clinicians, patients, caregivers, and advocates who participate in clinical trials and work to advance our understanding of breast cancer.

References

1. Kwan ML, Kushi LH, Weltzien E, et al. Alcohol and breast cancer survival in a prospective cohort study. Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX.

2. Ewertz M, Jensen M-B, Gunnarsdottir K, Cold S; for the Danish Breast Cancer Co-operative Group. Effect of obesity on prognosis after early breast cancer. Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX.

3. Rennert G, Pinchev M, Rennert HS. Use of bisphosphonates and risk of postmenopausal breast cancer. Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX.

4. 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. Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX.

5. Sparano JA, Wang W, Stearns V, et al; for the Cancer and Leukemia Group B. Black race is associated with a worse outcome in patients with hormone receptor positive, HER2-normal breast cancer treated with adjuvant chemohormonal therapy. Presented at: San Antonio Breast Cancer Symposium. December 11, 2009. San Antonio, TX.

6. Rea D, Hasenburg A, Seynaeve C, et al. Five years of exemestane as initial therapy compared to 5 years of tamoxifen followed by exemestane: the TEAM trial, a prospective, randomized, phase III trial in postmenopausal women with hormonesensitive early breast cancer. Cancer Res. 2009;69(meeting abstract suppl):Abstract nr11.

7. Bliss JM, Kilburn LS, Coleman RE, et al. Disease related outcome with long term followup: an updated analysis of the Intergroup Exemestane Study (IES). Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX.

8. Goss PE, Mamounas E, Jakesz R, et al. Aromatase inhibitors vs not after 5 years tamoxifen in postmenopausal breast cancer: meta-analysis of the randomized trials. Presented at: San Antonio Breast Cancer Symposium. December 10, 2009. San Antonio, TX.

9. Miles DW, Chan A, Romieu G, et al. Final overall survival (OS) results from the randomised, double-blind, placebo-controlled, phase III AVADO study of bevacizumab (BV) plus docetaxel (D) compared with placebo (PL) plus D for the first-line treatment of locally recurrent (LR) or metastatic breast cancer (mBC). Presented at: San Antonio Breast Cancer Symposium. December 11, 2009. San Antonio, TX.

10. Brufsky A, Bondarenko IN, Smirnov V, et al. RIBBON- 2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of HER2- negative metastatic breast cancer. Presented at: San Antonio Breast Cancer Symposium. December 11, 2009. San Antonio, TX.

11. Baselga J, Roché H, Costa F, et al. [SOLTI- 0701]: a multinational double-blind, randomized phase 2b study evaluating the efficacy and safety of sorafenib compared to placebo when administered in combination with capecitabine in patients with locally advanced or metastatic breast cancer (BC). Presented at: San Antonio Breast Cancer Symposium. December 11, 2009. San Antonio, TX.

12. Blackwell KL, Burstein HJ, Sledge GW, et al. Updated survival analysis of a randomized study of lapatinib alone or in combination with trastuzu mab in women with HER2-positive metastatic breast cancer progressing on trastuzu - mab therapy. Presented at: San Antonio Breast Cancer Symposium. December 12, 2009. San Antonio, TX.

13. Slamon D, Eiermann W, Robert N, et al; for the BCIRG006 Investigators. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2/neu positive early breast cancer patients: BCIRG 006 Study. Presented at: San Antonio Breast Cancer Symposium. December 12, 2009. San Antonio, TX.

14. Perez EA, Suman VJ, Davidson NE, et al. Results of chemotherapy alone, with sequential or concurrent addition of 52 weeks of trastuzumab in the NCCTG N9831 HER2-positive adjuvant breast cancer trial. Presented at: San Antonio Breast Cancer Symposium. December 12, 2009. San Antonio, TX.