HER2 is a transmembrane tyrosine kinase receptor and a member of the ErbB protein family, more commonly known as the epidermal growth factor receptor (EGFR) family. Activation of this class of cellular receptors is known to result in increased activity of a variety of molecular pathways associated with tumor growth and progression. Gene cloning has shown that the HER2 gene and the oncogene neu are identical. HER2 is overexpressed in 18-20% of invasive breast cancers, which has both prognostic and predictive implications.
Before the routine use of trastuzumab (Herceptin, a monoclonal antibody) in adjuvant therapy, HER2 overexpression was associated with a more aggressive tumor phenotype and worse prognosis (higher rate of recurrence and mortality), independent of other clinical features (eg, age, stage, tumor grade), especially in patients who did not receive adjuvant chemotherapy.
Additionally, HER2 status has been shown to be predictive for response to certain chemotherapeutic agents (ie, doxorubicin [Adriamycin]; and HER2-targeted therapies trastuzumab and lapatinib [Tykerb, a small-molecule oral tyrosine kinase inhibitor directed specifically to the HER2 receptor]).
Retrospectively analyzed results from clinical trials have shown that HER2-positive patients benefit from anthracycline-based regimens secondary to the co-amplification of topoisomerase II with HER2. Preliminary data also suggest that HER2 may predict response to and benefit from paclitaxel in the adjuvant setting.
Testing for HER2
Although several methods for HER2 testing have been developed, approximately 20% of current HER2 testing may be inaccurate. Therefore, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have recommended guidelines in HER2 testing to ensure accuracy.
Breast cancer specimens should initially undergo HER2 testing by a validated immunohistochemistry (IHC) assay (ie, HercepTest, Dako, Glostrup, Denmark) for HER2 protein expression. The scoring method for HER2 expression is based on the cell membrane staining pattern and is as follows:
- 3+: Positive HER2 expression - Uniform intense membrane staining of more than 30% of invasive tumor cells
- 2+: Equivocal for HER2 protein expression - Complete membrane staining that is either nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells
- 0 or 1+: Negative for HER2 protein expression
Breast cancer specimens with equivocal IHC should undergo validation using a HER2 gene amplification method, such as fluorescence in situ hybridization (FISH). More centers are relying on FISH alone for determining HER2 status.
In general, FISH testing is thought to be more reliable than IHC, but it is more expensive. Equivocal IHC results can be seen in 15% of invasive breast cancers, whereas equivocal HER2 FISH results are seen in less than 3% of invasive breast cancer specimens and those that had previously been considered HER2 positive. Discordant results (IHC 3+/FISH negative or IHC less than 3+/FISH positive) have been observed in approximately 4% of specimens. Currently, no data support excluding this group from treatment with trastuzumab.
Newer methodologies for establishing HER2 status, including reverse transcriptase–polymerase chain reaction (RT-PCR) and chromogenic in situ hybridization (CISH), have not yet been validated. The interpretation for HER2 FISH testing (HER2/CEP17 ratio and gene copy number) is given below:
- Positive HER2 amplification: FISH ratio is greater than 2.2 or HER2 gene copy is greater than 6.0
- Equivocal HER2 amplification: FISH ratio of 1.8-2.2 or HER2 gene copy of 4.0-6.0
- Negative HER2 amplification: FISH ratio is less than 1.8 or HER2 gene copy of less than 4.0
Treatment of HER2-Positive Metastatic Breast Cancer
In the metastatic setting, a pivotal phase III trial compared first-line chemotherapy (doxorubicin/epirubicin and cyclophosphamide or paclitaxel) plus trastuzumab versus chemotherapy alone in HER2-positive patients. Trastuzumab plus chemotherapy was associated with a significant improvement in time to disease progression (7.4 mo vs 4.6 mo), objective response rate (50% vs 32%), and 1-year survival (25.1 mo vs 20.3 mo) compared with chemotherapy alone.
Additionally, there is evidence suggesting that up-front use of trastuzumab with chemotherapy, in women with advanced HER2-positive breast cancer, prolongs life as compared with sequential administration, with trastuzumab reserved for the time of disease progression on an initial chemotherapy regimen. Based on these results, the FDA approved trastuzumab for first-line therapy in HER2-positive metastatic breast cancer. However, the question of optimal duration of trastuzumab therapy remains unresolved.
Clinical evidence to support continued trastuzumab treatment after initial progression has emerged. Retrospective studies have described a response to trastuzumab in multiple lines of therapy, and patients treated with more than 2 trastuzumab-containing regimens appear to have advantageous overall survival and TTP outcomes.
Results from a prospective, randomized study of 112 patients with HER2-positive metastatic breast cancer initially progressing on a trastuzumab-based therapy (GBG-26/BIG 3-05 study) showed that trastuzumab/capecitabine resulted in a longer progression-free survival (8.2 mo vs 5.6 mo) and overall survival (25.5 mo vs 20.4 mo) as compared with the capecitabine-only arm.[4] Objective response rates were also significantly improved in the combination arm (48.1%) versus capecitabine alone (27%). Larger trials are currently ongoing to assess the activity of trastuzumab in multiple lines of treatment.
Another agent used in the treatment of HER2-positive metastatic breast cancer is lapatinib, a tyrosine kinase inhibitor (TKI). Lapatinib was approved in 2007 for the treatment of metastatic breast cancer in HER2-positive patients after progression on trastuzumab. This small molecule is known to block multiple epidermal growth factor receptors (EGFRs), EGFR (HER-1) and HER2, and is generally well tolerated, with the main toxicities being diarrhea, skin rash, fatigue, and nausea.
An analysis of cardiac toxicity found that 1.6% of patients exposed to lapatinib experienced a decline in left ventricular ejection fraction (LVEF), with 0.2% being symptomatic, lower than the comparable incidence observed with trastuzumab. Preclinical data have indicated synergistic activity between lapatinib and trastuzumab, leading to a randomized study of this combination.
A phase III trial involving 296 heavily pretreated, trastuzumab-refractory metastatic breast cancer patients randomized to treatment with lapatinib alone or lapatinib with trastuzumab reported combination therapy significantly improved progression-free survival (8.4 wks vs 12 wks) compared with lapatinib alone.
There was a nonsignificant trend toward improved median overall survival. Diarrhea and rash were the most common side effects. An asymptomatic decline in LVEF was seen in 5% of patients in the combination arm, compared with 2% in the lapatinib-alone arm.
Contributor Information
Author
Maurie Markman, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, and American Society of Hematology.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine
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