Prescribing Information  |  Important Safety Information  |  For Patients and Caregivers  |  Text Size A A A

Understanding HER2 and breast cancer

HER2 (human epidermal growth factor receptor 2) is part of the HER tyrosine kinase signaling network that plays an important role in regulating cell growth, survival, and differentiation.1

HER2 is produced by the HER2/neu gene. All normal epithelial cells contain two copies of the HER2 gene and produce appropriate amounts of HER2 receptors to enable normal cell growth and division. Some cells, however, contain many more copies of the HER2 gene and in turn produce too many HER2 receptors. This "overexpression" of HER2 receptors results in a classification of HER2+, and occurs in 20% to 25% of breast cancers. The overexpression of HER2 in breast cancer is a key indicator for aggressive tumor development and is predictive of a poor prognosis.1

The focus on HER2

Cell signaling is the critical activity that ensures that all cells act in a coordinated fashion to optimize function. Constant communication is essential, as cells must be able to transfer information, interpret and integrate information, and then respond, typically by modulating gene expression.3

Abnormal cell signaling is a fundamental defect in carcinogenesis. Most proteins encoded by cancer genes are components of growth factor signaling pathways that regulate cell proliferation and survival. These proteins include growth factors and their receptors, molecular elements of intracellular signaling pathways, and transcription factors. A large group of oncogenes encodes growth factor receptors, of which the most common is the protein tyrosine kinase.4

Type 1 receptor kinases are members of the ErbB family, also known as the epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor (HER) family. The four members of this family are ErbB1 (EGFR or HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). The receptor inhibition properties of TYKERB impact the dysfunctional cell signaling of cancer cells, which in turn slows or stops cancer cell growth and proliferation.5



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Indication

TYKERB® is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.

Dose Modification Guidelines

For dose modification guidelines, please see complete Prescribing Information.


BOXED WARNING and Additional Important Safety Information

Hepatotoxicity
TYKERB has been associated with hepatotoxicity. Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be retreated with TYKERB.

Decreased Left Ventricular Ejection Fraction
TYKERB has been reported to decrease LVEF. Caution should be taken if TYKERB is to be administered to patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. Confirm normal LVEF before starting TYKERB, and continue evaluations during treatment.

Patients with Severe Hepatic Impairment
If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered.

Diarrhea
Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB and was the most common adverse reaction resulting in discontinuation of TYKERB therapy. Proactive management of diarrhea with anti-diarrheal agents is important, and severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of therapy with TYKERB.

Interstitial Lung Disease/Pneumonitis
TYKERB has been associated with interstitial lung disease and pneumonitis. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis and if symptoms are ≥ Grade 3 (NCI CTCAE), TYKERB should be discontinued.

QT Prolongation
TYKERB prolongs the QT interval in some patients. TYKERB should be administered with caution to patients who have or may develop prolongation of QTc. Hypokalemia or hypomagnesemia should be corrected prior to TYKERB administration. Baseline and on-treatment electrocardiograms with QT measurement should be considered.

Pregnancy
Pregnancy D
TYKERB can cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions
The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (65%, 40%), nausea (44%, 43%), vomiting (26%, 21%), palmar-plantar erythrodysesthesia (53%, 51%), rash (28%, 14%), and fatigue (46%, 47%).

The most common grade 3 and 4 adverse reaction (NCI CTC v3) with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (14%, 10%) and palmar-plantar erythrodysesthesia (12%, 14%).


Please see full US Prescribing Information, including BOXED WARNING for TYKERB.

Xeloda is a registered trademark of Roche Laboratories Inc.
Herceptin is a registered trademark of Genentech.

References:

  1. AACR cancer concepts: HER2. American Association for Cancer Research Web site. Available at
    http://www.aacr.org/home/public--media/for-the-media-fact-sheets/cancer-concepts. Accessed April 27, 2007.
  2. TYKERB [Sales Aid]. Research Triangle Park, NC: GlaxoSmithKline; 2007.
  3. Cell signaling. NIH. Available at
    http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=signaling,cell&rid=cooper.chapter.2198. Accessed July 23, 2007.
  4. The development and causes of cancer. NIH Web site. Available at
    http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=signaling,cell,cancer&rid=cooper.section.2603#2615. Accessed December 6, 2006.
  5. Vlahovic G, Crawford J. Activation of tyrosine kinases in cancer. The Oncologist. 2003;8:531-538.