Breast Cancer Milestones Are Unfolding on Several Fronts

Erika P. Hamilton, MD
Published: Monday, Jun 20, 2016
Sarah Cannon Research InstituteErika P. Hamilton, MD
Erika P. Hamilton, MD
Director, Breast and Gynecologic Cancer Research Program
Principal Investigator, Sarah Cannon Research InstituteErika P. Hamilton, MD
During the past 2 years, there have been a number of advancements in the treatment of metastatic breast cancer (MBC) that include the development of novel agents and new strategies in several disease settings, resulting in improved outcomes for patients. The following is an overview of recent milestones in MBC research and highlights of research going forward:

Hormone Receptor–Positive Disease

The clinical development of targeted therapies for breast cancer has been driven by both molecular classification and the identification of alterations in cellular signaling pathways within this disease.

Most recently, on February 19, 2016, the FDA extended the approval of palbociclib, a CDK 4/6 inhibitor, to women in combination with fulvestrant based on results from the PALOMA3 trial. In this study, women with aromatase inhibitor (AI)–resistant, hormone receptor (HR)–positive MBC were randomized 2:1 to receive fulvestrant plus palbociclib or placebo. There was an observed doubling in progression-free survival (PFS) with palbociclib compared with the control regimen (9.5 months vs 4.6 months; HR 0.461, P <.001).1,2

The earliest targeted therapies for breast cancer, tamoxifen and AIs, inhibited estrogen production and the estrogen receptor (ER), which led to improved outcomes for women with HR-positive MBC. Resistance mechanisms such as activation of the PI3K/Akt/mTOR pathway have now been recognized.

BOLERO-2 demonstrated that the combination of an mTOR inhibitor and an AI improves PFS in postmenopausal women with hormone-resistant advanced breast cancer, resulting in the first mTOR inhibitor approved for this population, everolimus. Inhibitors of this pathway have met with mixed success. The FERGI trial evaluated pictilisib, a pan-PI3K inhibitor, in combination with fulvestrant in HR-positive MBC resistant to AIs. No improvement was seen in either PI3K-mutant or wild-type (WT) tumors;3 however, in subset analysis, there was benefit for patients whose tumors were both ER-positive and progesterone-positive.

More recently, results from the BELLE-2 trial revealed a modest improvement in PFS when buparlisib, a pan-PI3K inhibitor, was added to fulvestrant compared with fulvestrant alone (6.9 months vs 5.0 months, respectively; P <.001).4

In contrast to FERGI, subset analysis of BELLE-2 data demonstrated improvement in PFS only for patients with PIK3CA mutations detected in circulating tumor DNA, and not for those with wild-type PIK3CA (7.0 months vs 3.2 months, respectively; P <.001). Phase III trials with alpha-specific PI3K inhibitors are underway (NCT02437318, NCT02340221).

ER itself has been implicated in the development of endocrine resistance, and selective ER down regulators (SERDs) such as fulvestrant have been successful here. Resistance to endocrine therapy is also mediated by mutations in ESR1, the gene encoding ER. Recent data using cell-free DNA isolated from blood samples from patients enrolled on BOLERO-2 revealed a 29% ESR1 mutation rate in essentially first- and second-line metastatic patients.5

The presence of ESR1 mutations led to a shorter median overall survival (OS) of 32.1 months in wildtype disease versus 20.7 months in ESR1 mutants; HR 1.40, P = .000037). Also noted was the increased frequency of ESR1 mutations in patients who had already been treated with AIs in the metastatic setting.

The novel SERDs GDC-0810 and AZD9496, which are orally bioavailable and have demonstrated activity in ESR1-mutant cell lines, are now being evaluated in clinical trials (NCT02569801; NCT02248090).

HER2-Amplified Breast Cancer

Single-agent trastuzumab emtansine (T-DM1), the first antibody–drug conjugate approved for the treatment of breast cancer, was found to prolong OS in patients with HER2-positive MBC. The median OS was 22.7 months with T-DM1 versus 15.8 months for patients assigned to physician’s choice (HR 0.68; P = .0007).6

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Cancer Summaries and Commentaries™: Update from Chicago: Advances in the Treatment of Breast CancerJul 31, 20181.0
Community Practice Connections™: Medical Crossfire®: Translating Lessons Learned with PARP Inhibition to the Treatment of Breast Cancer—Expert Exchanges on Novel Strategies to Personalize CareAug 29, 20181.5
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