Emerging Therapies for HER2-Positive and Triple-Negative Breast Cancers

Recognition of breast cancer subtypes and research into their underlying biologies is driving the development of new therapies.

Joyce A. O'Shaughnessy, MD

Co-Director, Breast Cancer Research

Baylor Charles A. Sammons

Cancer Center

Texas Oncology/US Oncology

Dallas, TX

Recognition of breast cancer subtypes and research into their underlying biologies is driving the development of new therapies, with several novel agents approaching clinical use. At the 2012 Miami Breast Cancer Conference, Joyce O’Shaughnessy, MD, co-director of breast cancer research at the Baylor Charles A. Sammons Cancer Center in Dallas, Texas, summarized the latest research into new strategies for treating triple-negative and HER2-positive breast cancers.

Triple-negative breast cancer (TNBC) is an aggressive subtype that is often resistant to current therapies and represents a significant area of unmet medical need. There has been an explosion of interest in this subtype in recent years, although most research is still in its nascent phase.

Much of the TNBC research is focused on methods of identifying patient subsets with greater sensitivity to certain therapies. For example, array-CGH may aid in identifying patients with defective DNA repair pathways, while status of the tumor suppressor PTEN may be useful for selecting patients for EGFR-targeted therapies. Next-generation sequencing of individual tumors may be able to identify specific mutations that direct the personalized selection of therapeutic agents.

Several novel agents are also being investigated for TNBC. Early-phase clinical trials are currently evaluating drug combinations that inhibit the PI3K and MAPK pathways, which are frequently mutated in TNBC. Other agents that are being explored are JAK2 inhibitors, based on preclinical studies suggesting the involvement of this signaling pathway in stem cell—like breast cancer cells, and inhibitors of ALK, which is activated in some inflammatory breast cancers.

Therapies for HER2-positive breast cancer are in more advanced stages of clinical investigation. The combination of trastuzumab (Herceptin) plus lapatinib (Tykerb) significantly increased pathological complete response rates compared to either agent alone in the preoperative Neo-ALTTO trial, and results in the adjuvant setting from the ALTTO trial are eagerly awaited.

Another agent being investigated is pertuzumab, a monoclonal antibody that blocks HER2 dimerization, including heterodimerization with HER3. In the randomized CLEOPATRA trial, the addition of pertuzumab to a first-line regimen of docetaxel plus trastuzumab significantly improved median progression-free survival (PFS) by 6.1 months (18.5 vs 12.4 months; P < .0001) in patients with metastatic HER2-positive disease. Interim analysis of overall survival also suggests a significant benefit. No increase in cardiac events has been observed, and the only adverse events that were increased with the triplet were febrile neutropenia and grade 1 diarrhea. A phase III trial (APHINITY) now underway in the adjuvant setting is comparing pertuzumab plus trastuzumab and chemotherapy against standard care.

Another new agent in the later stages of clinical development is trastuzumab emtansine (T-DM1), a HER2-targeted antibody conjugate that combines trastuzumab with a cytotoxic maytansine derivative. A randomized phase II trial compared T-DM1 to the combination of trastuzumab plus docetaxel as first-line therapy. T-DM1 significantly improved median PFS by 5 months (14.2 months vs 9.2 months; P = .0353). A phase III trial (EMILIA) is comparing T-DM1 to the combination of lapatinib plus capecitabine in progressive HER2-positive disease, and results from this study are expected in the near future.

Finally, some patients may benefit from combined blockade of the HER2 signaling pathway as well as the PI3K pathway. A phase III trial, BOLERO-1, is currently comparing first-line treatment with paclitaxel plus trastuzumab with or without the mTOR inhibitor everolimus (Afinitor), and results of this trial are eagerly anticipated.

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