Four Key Areas Are Focus of ASCO/SABCS Highlights

Debu Tripathy, MD

Co-Leader, Women’s Cancer Program

Professor of Medicine, Priscilla and Art Ulene Chair In Women’s Cancer

USC/Norris Comprehensive Cancer Center

University of Southern California

Los Angeles, CA

Studies that may lead to the approval of two new treatments and data that reveal new options for prevention and radiotherapy are among the breast cancer research highlights that will be reviewed today at the opening session of the 29th Annual Miami Breast Cancer Conference.

Notable research that includes findings with practice-changing potential will be discussed by Debu Tripathy, MD, co-leader of the Women’s Cancer Program at the Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.

Tripathy culled the highlights from abstracts presented in 2011 at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois, and at the CCTR-AARC San Antonio Breast Cancer Symposium (SABCS) in Texas.

Exemestane Prevents Cancer in High-Risk Women

Tripathy, in an interview before his presentation, identified key studies in four areas:The aromatase inhibitor exemestane significantly reduced the risk of invasive breast cancer among postmenopausal women at high risk for the disease with a reasonable adverse event profile, demonstrating a new preventive option.

The MAP.3 trial enrolled 4560 postmenopausal women between 2004 and 2010 with one or more risk factors for breast cancer (aged >60 yr, Gail score >1.66%, prior atypical ductal hyperplasia, and atypical lobular hyperplasia). Participants who were randomized to receive exemestane experienced a 65% lower risk of developing cancer (annual incidence of 0.19 vs 0.55%) compared with those who received a placebo.

Study Supports Early-Stage Regional Nodal Irradiation

Tripathy said the current alternatives of tamoxifen and raloxifene lower risk by 50%, but their use is limited by adverse events that include rare but dangerous effects such as thrombosis and uterine cancers observed with tamoxifen. Exemestane side effects include hot flashes, fatigue, and insomnia, according to the study. Tripathy noted that exemestane also lowers bone mineral density but that such effects can be counteracted with other therapies.Controversy continues over whether patients with a lower number of positive nodes after breast-conserving surgery should be treated with regional nodal radiation, a strategy that is infrequently employed in the United States but is a more common practice in Canada and Europe.

The MA.21 trial demonstrated that women with 1 to 3 positive nodes or other risk factors after surgery experienced a significant improvement in 5-year disease-free survival with extended radiation compared with those who did not receive the treatments (89.7 vs 84%, respectively). Both groups received standard breast irradiation of 50 Gy +/1 boost while the extended radiation group received 45Gy in 25 fractions to the internal mammary, supraclavicular, and high axillary lymph nodes.

Dual Blockades Promising in Advanced Breast Cancer

Extended radiation “improved not only local recurrences but also distant recurrences,” said Tripathy. “There’s no difference in survival yet, but the fact that it had an impact on distant recurrence has raised a lot of eyebrows. It remains to be seen how this affects the selection criteria for extended nodal irradiation, which may also have longer term side effects that are not yet apparent.”Much excitement was generated at SABCS as a result of two phase III trials that employed dual inhibitors of cell-signaling pathways with notable results.

The BOLERO-2 trial involved postmenopausal women with estrogen receptor-positive metastatic disease. A marked improvement in time to progression was evident when the mTOR inhibitor everolimus (Afinitor) was added to second-line exemestane hormonal therapy (11.0 mo vs 4.1 mo; hazard ratio = 0.36).

In the CLEOPATRA trial, the novel agent pertuzumab significantly improved progression-free survival (PFS) in women with metastatic HER2-positive disease when added to docetaxel plus trastuzumab (Herceptin). The pertuzumab group experienced a PFS of 18.5 months versus 12.4 months for those in the control arm.

Pertuzumab is a first-in-class inhibitor of HER2 dimerization, and trastuzumab blocks HER2. Genentech, a member of the Roche group, has filed an application with the FDA for the use of pertuzumab in patients with previously untreated HER2-positive metastatic disease.

Early Promise of PARP Inhibitor Evaporates

Tripathy anticipates that both drug regimens will be approved for these indications. “I think that’s big¾it makes a significant difference in outcome,” he commented.Iniparib (BSI-201) proved to be a weak inhibitor of poly ADP ribose polymerase (PARP) in patients with metastatic triple-negative breast cancer, according to the research team that conducted a phase III trial that failed to confirm more positive data from an earlier-stage study.

The trial compared the impact of adding iniparib to a combination regimen of gemcitabine and carboplatin (G/C) versus G/C alone. Although iniparib demonstrated a safety profile consistent with earlier results, it did not meet the primary endpoints of significantly improving overall survival and PFS.

Tripathy said more potent PARP inhibitors remain in development for triple-negative or BRCA mutation-associated breast cancers.

“The remaining questions for PARP inhibitors are whether they only work for BRCA-related cancers, and whether they may work for triple-negative cancers more broadly,” Tripathy said. “The enthusiasm has diminished but I wouldn’t say they are totally dead¾the most recent trial is showing possible benefit in patients receiving second- or third-line therapy.”

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Research

• Goss PE, Ingle JN, Ales-Martinez J, et al. Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—a randomized placebo-controlled clinical trial. J Clin Oncol. 2011;29(suppl; abstr LBA504).
• Whelan TJ, Olivotto I, Ackerman I, et al. NCIC-CTG MA.20: an intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol. 2011. (suppl; abstr LBA1003).
• 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. Presented at San Antonio Breast Cancer Symposium, December 6-10, 2011; San Antonio, TX. Abstr S3-7.
• 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). Presented at San Antonio Breast Cancer Symposium, December 6-10, 2011; San Antonio, TX. Abstr S5-5.
• O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol. 2011. (suppl; abstr 1007).