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SAFETY

Boxed WARNINGS and Additional Important Safety Information

  • Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed CHF died of cardiomyopathy
  • Evaluate cardiac function prior to and during treatment. For adjuvant breast cancer therapy, also evaluate cardiac function after completion of Herceptin. Discontinue Herceptin for cardiomyopathy
  • Herceptin can result in serious and fatal infusion reactions and pulmonary toxicity. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome
  • Exposure to Herceptin during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death
  • Exacerbation of chemotherapy-induced neutropenia has also occurred
  • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy
  • The most common adverse reactions associated with Herceptin in breast cancer were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia
  • The most common adverse reactions associated with Herceptin in metastatic gastric cancer were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia

Safety First! Before you start exploring, take the time to read the Important Safety Information. Roll over to read more.

HER2 Scoring Exercises

Improve your knowledge of HER2 in gastric/GEJ testing and scoring by completing the interactive HER2 scoring exercises. There are several exercises within the different topic areas which cover IHC and FISH testing methodologies using either surgical resection or biopsy samples. A panel of pathologists demonstrates how they apply the gastric/GEJ cancer specific HER2 IHC scoring criteria and how they would score specific samples using FISH and IHC, including those with heterogeneity. You can also score the specimens yourself with members of our panel providing their slide interpretations and scores.

Disclaimer: The interpretation and scoring of the tissue samples are for illustration purposes only and do not replace a physician's medical training, judgment, and experience in this matter.


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IHC Surgical Resection

Prior to the ToGA* trial, an international consensus panel established new criteria for gastric/GEJ cancer scoring due to incomplete reactive membranes and tumor heterogeneity observed in gastric/GEJ cancer samples.1 The ToGA* trial screening criteria were based on these recommendations.

According to the consensus recommendations: strong complete or basolateral membrane staining is considered 3+.2

In resection specimens, ≥10% of invasive tumor cells must be stained for HER2+ or equivocal results.3

*Trastuzumab for gastric cancer trial.

References
  1. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797-805.
  2. Bang Y-J, Van Cutsem E, Feyereislova A, et al; for the ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-697.
  3. Rüschoff J, Dietel M, Baretton G, et al. HER2 diagnostics in gastric cancer — guideline validation and development of standardized immunohistochemical testing. Virchows Arch. 2010;457:299-307.

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IHC Biopsy Sample

Due to tumor heterogeneity in gastric/GEJ tumor samples, HER2 IHC scoring criteria for biopsy samples and surgical resections differ.1

For biopsy samples, tumor cell clusters should be seen with strong complete, basolateral, or lateral membrane reactivity irrespective of percentage of invasive tumor cells stained, to be scored IHC 3+.2 Also, according to Rüschoff et al, in biopsy samples, cell clusters must consist of ≥5 cohesive stained tumor cells in order to be evaluated.1

References
  1. Rüschoff J, Dietel M, Baretton G, et al. HER2 diagnostics in gastric cancer — guideline validation and development of standardized immunohistochemical testing. Virchows Arch. 2010;457:299-307.
  2. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797-805.

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FISH

In the ToGA trial, tumor specimens with a HER2/CEP17 ratio ≥2.0 were considered HER2+.1 All FISH-negative scores were also tested with IHC.

Users should refer to the FDA-approved package insert and interpretation manual of specific HER2 testing kits for information on the intended use, validation and performance, and suggested testing algorithm for each assay.2



References
  1. Bang Y-J, Van Cutsem E, Feyereislova A, et al; for the ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-697.
  2. Herceptin Prescribing Information. Genentech, Inc. October 29, 2010.

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HER2 Heterogeneity

Compared with breast tissue, there is greater HER2 heterogeneity in gastric/GEJ tissue.1 To account for this heterogeneity, as well as incomplete reactive membranes, an international consensus panel established critical modifications to the breast cancer testing and scoring methodology.

Users should refer to the FDA-approved package insert and interpretation manual of specific HER2 testing kits for information on the intended use, validation and performance, and suggested testing algorithm for each assay.2

References
  1. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797-805.
  2. Herceptin Prescribing Information. Genentech, Inc. October 29, 2010.

Indications

Adjuvant Breast Cancer

Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature*) breast cancer:

  • As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
  • With docetaxel and carboplatin
  • As a single agent following multi-modality anthracycline-based therapy

* High-risk is defined as ER/PR positive with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.

Metastatic Breast Cancer

Herceptin is indicated:

  • In combination with paclitaxel for the first line treatment of HER2-overexpressing metastatic breast cancer
  • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease

Metastatic Gastric Cancer

Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease.


Boxed WARNINGS and Additional Important Safety Information

Cardiomyopathy

  • Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed CHF died of cardiomyopathy
  • Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death
  • Herceptin can also cause asymptomatic decline in LVEF
  • Discontinue Herceptin treatment in patients receiving adjuvant breast cancer therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in left ventricular function

Cardiac Monitoring

  • Evaluate cardiac function prior to and during treatment. For adjuvant breast cancer therapy, also evaluate cardiac function after completion of Herceptin
  • Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan
  • Monitor frequently for decreased left ventricular function during and after Herceptin treatment
  • Monitor more frequently if Herceptin is withheld for significant left ventricular cardiac dysfunction

Infusion Reactions

  • Herceptin administration can result in serious and fatal infusion reactions
  • Symptoms usually occur during or within 24 hours of Herceptin administration
  • Interrupt Herceptin infusion for dyspnea or clinically significant hypotension
  • Monitor patients until symptoms completely resolve
  • Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Strongly consider permanent discontinuation in all patients with severe infusion reactions
  • Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion include nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia

Embryo-Fetal Toxicity

  • Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death
  • Advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy and provide counseling to women of childbearing potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin
  • Advise nursing mothers treated with Herceptin to discontinue nursing or discontinue Herceptin, taking into account the importance of the drug to the mother
  • Encourage women who are exposed to Herceptin during pregnancy to enroll in MotHER—the Herceptin Pregnancy Registry by calling 1-800-690-6720

Pulmonary Toxicity

  • Herceptin administration can result in serious and fatal pulmonary toxicity, which includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions
  • Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity
  • Discontinue Herceptin in patients experiencing pulmonary toxicity

Exacerbation of Chemotherapy-Induced Neutropenia

  • In randomized, controlled clinical trials, the per-patient incidences of NCI CTC Grade 3-4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not

HER2 Testing

  • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Due to differences in tumor histopathology, use FDA-approved tests for the specific tumor type (breast or gastric/gastroesophageal adenocarcinoma) to assess HER2 overexpression and HER2 gene amplification. Tests should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

Most Common Adverse Reactions

  • The most common adverse reactions associated with Herceptin in breast cancer were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia
  • The most common adverse reactions associated with Herceptin in metastatic gastric cancer were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia

Please see Herceptin full Prescribing Information for Boxed WARNINGS and additional important safety information.

Herceptin

Herceptin