Welcome to the first edition of OncoFacts for 2010. As in past years, we will be reporting relevant and breaking issues on a monthly basis. In this issue, I will be highlighting abstracts that were released in December at the 2009 San Antonio Breast Cancer Symposium.

Hormone therapy for Early and Advanced Breast Cancer

Several presentations from the 2009 San Antonio Breast Cancer Symposium (SABCS) revolved around updates of data from the previously presented phase III aromatase inhibitor (AI) trials in postmenopausal women with HR-positive early breast cancer.

The TEAM trial was initiated in 2001 originally as a head-to-head trial comparing tamoxifen for 5 years versus exemestane for 5 years. During the conduct of the trial, other phase III AI trials found that switching patients from tamoxifen to an AI was superior to continuing on tamoxifen for 5 years. As a result, the protocol was modified so that patients originally randomized to 5 years of tamoxifen would be switched over to exemestane after 2.5 to 3 years. This required that additional patients be added to the trial. The primary endpoints were revised to included disease-free survival (DFS) at 2.75 years (which essentially would be looking at the tamoxifen versus exemestane comparison) and 5 years (which would account for the switching patients versus exemestane for 5 years alone. The presentation by Rea et al involved 9779 patients, all of whom were either ER-positive and/or PR-positive. The results are as follows:

Disease-free survival was 85% in the tamoxifen followed by exemestane group, and 86% in the exemestane group. Overall survival (OS) was 91% and 90.5%, respectively. The time-to-recurrence (TTR) was 10.9 months versus 10.2 months. Clearly none of these comparisons were statistically different. Stratification for nodal status did not change the outcome. Safety data were consistent with the known toxicities for tamoxifen and exemestane with more gynecologic abnormalities in patients receiving tamoxifen, and more musculoskeletal issues in those receiving exemestane.

The authors concluded that either tamoxifen followed by exemestane or exemestane alone could be considered for a postmenopausal woman with HR-positive early breast cancer in the adjuvant setting. It should be noted that this finding is different from that reported in the BIG 1-98 trial where 5 years of letrozole was found to be superior to tamoxifen followed by letrozole, most notably in the patients who were lymph node-positive.

Reference
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 hormone-sensitive early breast cancer. Cancer Res. 2009;69(24 Suppl 3). Abstract 11 and oral presentation at: San Antonio Breast Cancer Symposium; December 9 – 13, 2009. San Antonio, TX.

The Intergroup Exemestane Study (IES) was also updated with a 91-month median follow-up. The IES randomized 4724 postmenopausal women to receive 2 to 3 years of tamoxifen followed either by 2 to 3 years of additional tamoxifen or 2 to 3 years of exemestane. The primary statistical endpoint was DFS with exploratory analyses of breast cancer-free survival, site of distant recurrence, and incidence of non-breast second primary cancers. At 8 years of follow-up, OS was improved with an absolute difference of 2.4% and a hazard ratio (HR) of 0.86 with a P-value =.04. Disease-free survival was improved with an absolute difference of 4.4% and a HR of 0.82 and a P-value = .0009. Breast cancer-free survival was improved with an absolute difference of 4.1% with a HR of 0.81 and a P-value =.001. All prognostic sub-groups favored the use of 5 years of exemestane, including age, lymph node status, prior use of chemotherapy, duration of tamoxifen use, and ER-unknown status.

With regards to the hypothesis-generating results of site of distant recurrence, there was a suggestion of a smaller number of recurrences to bone in the exemestane arm (147 of 303) who developed metastases for exemestane, and 192 of 346 for tamoxifen followed by exemestane. There were also fewer non-breast second primaries in the exemestane arm (106 vs 159). The risk of second primaries was statistically related to age, as would be expected.

The authors concluded that switching from tamoxifen to exemestane demonstrated an improvement in DFS, breast cancer-free survival, and OS out to 9 years.

Reference
Bliss JM, Kilburn LS, Coleman RE, et al. Disease related outcome with long term follow-up: An updated analysis of the Intergroup Exemestane Study (IES). Cancer Res. 2009;69(24 Suppl 3). Abstract 12 and oral presentation at: San Antonio Breast Cancer Symposium; December 9 – 13, 2009. San Antonio, TX.

Ductal Carcinoma In Situ (DCIS)

Multiple randomized trials have shown the benefit of radiation to patients with locally excised DCIS. The UK/ANZ DCIS trial was presented by Cuzick et al giving long-term results with a median follow-up of 12.7 years. In this trial, 1694 women with DCIS were randomized in a 2 x 2 fashion to control, radiation therapy, tamoxifen, or radiation plus tamoxifen. Of these patients, 1576 women underwent tamoxifen randomization and 1030 underwent radiation therapy randomization. When evaluating the data by breast cancer events, 16% of the women overall developed such an event. Twenty-two percent were in the control arm, 18% in the tamoxifen alone arm, 8% in the radiation therapy arm, and 6% in the tamoxifen + radiation therapy arm.

For those patients receiving radiation therapy versus no radiation, the ipsilateral recurrence at years 5, 10, and 15 are as follows:

• 4% vs 13% at year 5, 7% vs 19% at year 10, and 7% vs 22% at year 15. For all new breast events, radiation benefit was confined to ipsilateral recurrence, with no benefit in contralateral disease.

For those patients receiving tamoxifen versus no tamoxifen, any recurrence at years 5, 10, and 15 are as follows:

• 13% vs 17% at year 5, 18% vs 24% at year 10, and 20% vs 26% at year 15. With regards to all new breast events, the effect of tamoxifen was larger on the reduction of contralateral new primary lesions than ipsilateral recurrences. There was also noted to be a larger effect in low-grade and intermediate-grade tumors compared with high-grade tumors.

Reference
Cuzick J, Sestak I, Pinder SE, et al. Beneficial effect of tamoxifen for women with DCIS: Long-term results from the UK/ANZ DCIS trial in women with locally excised DCIS. Cancer Res. 2009;69(24 Suppl 3). Abstract 34 and oral presentation at: San Antonio Breast Cancer Symposium; December 9 – 13, 2009. San Antonio, TX.

Fulvestrant in Advanced Breast Cancer

Two trials reported on the use of fulvestrant in the advanced breast cancer setting.

The FACT trial is a phase III trial comparing the use of first-line fulvestrant + anastrozole, versus anastrozole alone. In this trial, 514 eligible women with HR-positive advanced breast cancer were randomly assigned to fulvestrant 500 mg day 0, 250 mg, days 14 and 28, and then 250 mg per month plus anastrozole 1 mg per day versus anastrozole alone. The primary statistical endpoint was time-to-progression (TTP).

Results:
There were no differences in median TTR (10.8 months vs 10.2 months), median OS (37.8 months vs 38.2 months), overall response rate (ORR [16% vs 15%]) or clinical benefit rate (55% vs 55%) between those who received the combination versus the anastrozole alone. Of all toxicities observed, only hot flushes were more common in the combination arm. The authors concluded that there was no benefit to combining an aromatase inhibitor with a selective estrogen receptor downregulator in the setting of metastatic breast cancer.

Although fulvestrant is US Food and Drug Administration (FDA) approved at a dose of 250 mg intramuscularly (IM) monthly, many physicians will load the patient by giving 500 mg on day 0, 250 mg on day 14 and day 28, and then begin monthly doses. The loading regimen is done to bring the drug concentrations up to a steady state much more rapidly. However, what has not been evaluated is the best dose for patients because of the inconvenience of IM dosing and the large fluid volume given with each IM shot.

The CONFIRM trial is a phase III randomized trial comparing fulvestrant 250 mg IM days 1, 14, 28 and then every 28 days to the same schedule, but with a dose of 500 mg IM each time. In this trial, 736 postmenopausal women with ER-positive advanced disease were randomly assigned to 1 of these 2 arms. The primary statistical endpoint was time-to-tumor-progression (TTP). Secondary endpoints were OS, ORR, clinical benefit rate (CBR), duration of response, safety, and quality of life (QOL). Of these patients, 57.5% had received a prior antiestrogen, and 42.5% had received prior AI’s. Although the median TTP was statistically improved, there was only an absolute 1-month improvement. Additionally, ORR, CBR, median duration of benefit, and OS were not statistically improved. A Trans-CONFIRM trial is underway to see if there are any histologic, biologic, or genetic subgroups that might benefit from the use of high-dose fulvestrant.

References
Bergh J, Jönsson PE, 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. Cancer Res. 2009;69(24 Suppl 3). Abstract 23 and oral presentation at: San Antonio Breast Cancer Symposium; December 9 – 13, 2009. San Antonio, TX.

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 advance breast cancer. Cancer Res. 2009;69(24 Suppl 3). Abstract 25 and oral presentation at: San Antonio Breast Cancer Symposium; December 9 – 13, 2009. San Antonio, TX.

OncoFacts™ Editor:

Christy Russell, MD

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