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In Breast Cancer, Targeted Agents Boost Hormonal Therapies

Anita T. Shaffer @Shaffer1
Published: Monday, Nov 12, 2012
Dr. Agustin A. Garcia

Agustin A. Garcia, MD

Although hormonal therapy has been long established in the treatment of breast cancer, novel combinations with targeted agents show promise for improved outcomes and are likely to become part of a new paradigm for managing patients.

The success of everolimus (Afinitor) in combination with exemestane has helped pave the way for such strategies, and agents aimed at various mechanisms of resistance to endocrine therapy are being explored, according to Agustin A. Garcia, MD, MMM, associate professor of Medicine at the Keck School of Medicine of the University of Southern California, Los Angeles.

In July, the FDA approved everolimus for use with exemestane to treat postmenopausal women with hormone receptor (HR)-positive, HER2-negative breast cancer whose disease has progressed after prior treatment with aromatase inhibitors (AIs). Everolimus targets mammalian target of rapamycin (mTOR) while exemestane is an AI.

In a presentation and interview at the Targeted Therapies congress, Garcia noted that the BOLERO-2 trial that led to the new everolimus indication has opened the door to new ways of thinking about boosting the effectiveness of endocrine therapy.

“We have to look very carefully into changing our approach to how we treat those women. Typically, we treated them with single-agent sequential therapies, usually until they developed clear resistance to endocrine therapy,” said Garcia. “What the BOLERO-2 trial shows us is that combination therapy may be indicated or appropriate for at least a group of those patients.”

Garcia noted that endocrine therapy has been employed as breast cancer treatment for more than a century, since Scottish surgeon Sir George Thomas Beatson first propounded the theory that oophorectomy was effective in 1896. Since then, many drugs with varying mechanisms of action have been developed to interrupt hormonal activity in breast cancer patients.

Hormonal therapy has become a “cornerstone” of treatment for HR-positive disease, showing efficacy in metastatic breast cancer as well as in ductal carcinoma in situ and in primary breast cancer prevention. However, a significant number of patients develop de novo and acquired resistance, Garcia said.

“We’re becoming better at understanding hormonal therapy as a targeted treatment. We still have to better understand the mechanism of resistance,” said Garcia. “Why is it that there’s a subset of patients who never respond to hormonal therapy? Why is it that virtually every patient who’s responding to hormonal therapy in the metastatic setting will eventually acquire resistance? That’s where we’re still in a very early process.”

Garcia said researchers have identified mechanisms of resistance in the tumor microenvironment, namely the estrogen receptor (ER) and its coregulators, and in cell-signaling molecules and growth factor receptor pathways associated with the tumor itself.

Research is under way to target these pathways both with novel agents and existing drugs in combination with hormonal therapies (Table).

Table. Combination Studies of Targeted Agents and Hormonal Therapies in Breast Cancer

Target Agent Sponsors Stage
Insulin-like growth factor type 1 (IGF-1) Ganitumab (AMG 479) Foundation for the National Institutes of Health Phase II (NCT01042379)
MEDI-573 MedImmune Phase I (NCT01446159)
Fibroblast growth factor receptor (FGFR) AZD4547 AstraZeneca Phase I/II (NCT01202591)
Epidermal growth factor family and HER2 Gefitinib (Iressa) AstraZeneca Phase II (NCT00077025)
Trastuzumab (Herceptin) Genentech/Roche Phase III (NCT00022672)
MM-121 Merrimack Pharmaceuticals Phase II (NCT01151046)
Cyclin dependent kinase (CDK) 4/6 PD-0332991 Pfizer Phase I/II (NCT00721409)
mTOR/PI3K Everolimus (Afinitor) Novartis Phase II (NCT01698918)
XL147
XL765
Sanofi Phase I/II (NCT01082068)
Histone deacetylase(HDAC) Entinostat (SNDX-275) Syndax Pharmaceuticals Phase II (NCT00676663)
Vascular endothelial growth factor/ angiogenesis Bevacizumab (Avastin) Cancer and Leukemia Group B/ National Cancer Institute Phase III (NCT00601900)

mTOR indicates mammalian target of rapamycin; PI3K, phosphatidylinositol 3 kinase.

In the realm of emerging research, Garcia said he is awaiting the results of the phase III Cancer and Leukemia Group B (CALGB) 40503 trial, in which 442 patients were randomized to receive tamoxifen or letrozole with or without bevacizumab (Avastin). The completion date for data collection is June 2013.


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