2 Landmark Trials Suggest Changes in Practice; Brachytherapy Controversy Attracts Attention

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

As in previous years, the 2011 CTRC-AACR San Antonio Breast Cancer Symposium was associated with a number of important presentations and an element of controversy. This commentary will highlight 2 highly clinically relevant abstracts that discussed the results of phase III randomized trials likely to substantially impact standard management of breast cancer, and a retrospective review of a large national database that has been strongly criticized based on its overall conclusions.

BOLERO-2 Results Support Benefit for Everolimus Plus Exemestane Regimen

In the BOLERO-2 randomized phase III trial, investigators compared single-agent exemestane with the hormonal agent combined with the mTOR inhibitor everolimus.¹ A total of 724 hormone receptor-positive postmenopausal women with metastatic breast cancer were treated in this landmark placebo-controlled study. Patients randomized to the combination regimen experienced more than a doubling in the median time to subsequent disease progression (7.4 mo vs 3.2 mo; hazard ratio [HR], 0.44; P <1 x 10-16) compared with the exemestane control group.

Further, the percentage of individuals classified as having achieved “clinical benefit” from the treatment regimen (defined as complete response, partial response, or stable disease lasting for longer than 6 mo) also doubled (50.5% vs 25.5%) in the everolimus plus exemestane arm compared with the control regimen. It remains premature to make any statement regarding the impact of this innovative management strategy on overall survival, but these data are awaited with considerable interest.

Finally, and of considerable importance for a strategy designed to optimize the quantity as well as the quality of life, this unique combination regimen was reasonably well tolerated, although clearly more toxic than hormonal therapy alone (grade 3-4 adverse events: fatigue [4% vs 1%]; stomatitis [8% vs 1%]; anemia [7% vs 1%]; dyspnea [4% vs 1%]; hyperglycemia [5% vs <1%]).

Snapshot of Key Trial Results^a

BOLERO-2

Placebo exemestane

(n = 239)

Everolimus exemestane

(n = 485)

Progression-free survival^b (median)

3.2 mo

7.4 mo

Clinical benefit rate^c

25.5%

50.5%

CLEOPATRA

Placebo trastuzumab docetaxel

Pertuzumab trastuzumab docetaxel

Progression-free survival (median)

12.4 mo

(n = 406)

18.5 mo

(n = 402)

Objective response rate

Complete response rate

Partial response rate

(n = 336)

69.3%

14%

65.2%

(n = 343)

80.2%

5.5%

74.8%

^aBased on data presented at 2011 CTRC-AACR San Antonio Breast Cancer Symposium.

^bLocally assessed

^cIncludes complete response, partial response, stable disease >6 months.

CLEOPATRA Data Endorse Adding Pertuzumab for Dual Blockade

The second major presentation concerned the results of the CLEOPATRA trial, a randomized placebocontrolled phase III study involving 808 HER2-positive patients with breast cancer who either received the combination of docetaxel plus trastuzumab or these 2 agents plus pertuzumab. ^2,3 There was a rather striking improvement in the median time to disease progression (18.5 mo vs 12.4 mo; HR, 0.62; P <.0001) associated with treatment with the 3-drug “dual HER2 blockade” regimen compared with management with docetaxel and trastuzumab.

Again, while data on overall survival remain immature (at the time of the presentation of this report at the symposium), a numerically greater number of deaths were noted in the patient population who were managed with the 2-drug regimen.

Finally, the 3-drug program of docetaxel, trastuzumab, and pertuzumab was also associated with a higher objective response rate (80.2% vs 69.3%). This novel regimen was reported to be reasonably well tolerated, importantly with no evidence for an increased risk of cardiac events associated with 2 antineoplastic agents designed to interfere with the functioning of the HER2 receptor.

Analysis Finds Higher Risks of Mastectomy With Brachytherapy

In what was likely the most controversial presentation at the symposium, investigators reported a retrospective analysis of the impact of local brachytherapy versus standard postoperative radiation as adjunctive treatment following primary conservative surgical management of breast cancer.⁴ The researchers utilized the administrative Medicare claims database (patients aged >66 y) and specifically examined women diagnosed with invasive breast cancer from the years 2000 to 2007. The populations examined were women who received conservative surgery followed by “standard” postoperative whole-breast radiation versus partial-breast brachytherapy (in the absence of whole-breast radiation) during this time interval.

Of interest, the investigators noted that the use of brachytherapy for breast cancer in this Medicare population increased from less than 1% of the population in 2000 to 13% in 2007 (P < .001). As a group, the patients managed with the brachytherapy approach were somewhat older than individuals undergoing whole-breast radiation.

However, the major finding in this report was that women who received local brachytherapy experienced a doubling (4% vs 2.2%) in their subsequent risk of undergoing a mastectomy compared with the population of individuals managed with whole-breast radiation after surgery. The investigators also noted an increased incidence of infectious and noninfectious complications (rib fracture, fat necrosis, breast pain) associated with the brachytherapy management strategy compared with whole-breast radiation.

The controversy regarding this presentation developed quickly following the meeting with these preliminary results being widely disseminated in the popular press. Several groups involved in the development of accelerated partial-breast radiation strategies provided a strong public rebuttal to this report,⁵ noting that: (1) cancer recurrence rates were not reported in this analysis; (2) the rate of subsequent mastectomy did not equate with the risk of recurrence, since a mastectomy could have been undertaken for a number of other reasons, including infection or personal choice; (3) the stated risk of complications in this analysis was considerably higher than that reported in published studies specifically addressing this issue for accelerated partial-breast radiation; and (4) newer improved strategies for local radiation in the management of breast cancer have been developed since the years covered in the Medicare database.

Of course, it is important to note that presentations at the San Antonio Breast Cancer Symposium, as is the case at all such meetings, must be considered preliminary reports until the data have been subjected to appropriate detailed analysis and published in the peer-reviewed medical literature. That being said, it is clear that this meeting remains one of the most important international forums for the presentation and discussion of critically important study results related to the management of breast cancer.

Maurie Markman, MD, editor-in-chief of OncologyLive, is senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, Pennsylvania. maurie.markman@ctca-hope.com

References

1. Hortobagyi GN, Piccart M, Rugo H, et al. Everolimus for postmenopausal women with advanced breast cancer: updated results of the BOLERO-2 phase III trial. Abstract S3-7.
2. Baselga J, Kim SB, Im SA, et al. A phase III, randomized, double-blind, placebo-controlled registration trial to evaluate the efficacy and safety of pertuzumab trastuzumab docetaxel vs placebo trastuzumab docetaxel in patients with previously untreated HER2-positive metastatic breast cancer (CLEOPATRA). Abstract S5-5.
3. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. Published online ahead of print December 7, 2011. doi: 10.1056/NEJMoa1113216.
4. Smith GL, Xu Y, Buchholz TA, et al. Partial breast brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole breast irradiation in older patients. Abstract S2-1.
5. MDs dispute study on breast cancer brachytherapy [news release]. San Francisco, CA: Dowling & Dennis Public Relations; December 19, 2011. http://www.businesswire.com/news/home/20111219005325/en/MDs-Dispute-Study-Breast-Cancer-Brachytherapy. Accessed January 5, 2012.