OCC Program FAQs

Addressing Audience Questions on Herceptin

  • Q: How is Herceptin used differently in the adjuvant setting vs. the metastatic breast cancer setting?
  • A:
    • The goals of adjuvant and metastatic treatment are different. Adjuvant treatment aims to prevent disease recurrence, keeping patients disease-free as long as possible. Treatment of metastatic disease aims to improve the duration of response, prolong time to progression, and palliate symptoms, but it is not curative.
    • Patient population differs, though HER2 overexpression is required in both settings. Adjuvant treatment is used to treat early-stage, nonmetastatic disease.
    • Treatment regimens differ: In the adjuvant setting, Herceptin can be given for treatment of HER2- overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature*) breast cancer (1) as part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, (2) with docetaxel and carboplatin, or (3) as a single agent following multi-modality anthracycline-based therapy (Herceptin PI, May 2008). In the metastatic setting, Herceptin can be given (1) in combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer, or (2) as a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease (Herceptin PI, May 2008).
      • *High risk is defined as ER/PR-positive with one of the following: tumor size >2cm, age <35 years, or histologic and/or nuclear grade 2/3.
    • Duration of therapy differs: For metastatic disease, Herceptin is given weekly until disease progression. In the adjuvant setting, Herceptin is given for a total of 52 weeks (Herceptin PI, May 2008).
      • In combination with chemotherapy, Herceptin is administered once weekly during the chemotherapy phase (12 to 18 weeks), then once every 3 weeks during the monotherapy phase.
      • As a single agent, Herceptin is administered once every 3 weeks for 52 weeks.

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  • Q: What is the right adjuvant regimen for my patient?
  • A: With incorporation of the BCIRG data into the adjuvant label, there are several dosing options available. Deciding what regimen is right for your patient can take into account lifestyle and adherence, as well as the patient''s cardiac risk. Patients should discuss what option is best with their health care providers. All adjuvant regimens involve 52 weeks of Herceptin (Herceptin PI, May 2008).

    Herceptin adjuvant treatment is initiated after the completion of doxorubicin + cyclophosphamide, in combination with paclitaxel or docetaxel or as a regimen consisting of docetaxel and carboplatin in combination with Herceptin.
    • In the adjuvant setting, Herceptin may be administered according to one of the following dosing schedules for a total of 52 weeks of Herceptin therapy.
      • During and following paclitaxel, docetaxel, or docetaxel/carboplatin:
        • Initial dose of 4 mg/kg as an infusion over 90 minutes then at 2 mg/kg as an IV infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin).
        • One week following the last weekly dose of Herceptin, administer Herceptin at 6 mg/kg as an IV infusion over 30 to 90 minutes every 3 weeks.
      • As a single agent within 3 weeks following completion of multi-modality anthracycline-based chemotherapy:
        • Initial dose of Herceptin is 8 mg/kg as an IV infusion over 90 minutes
        • Subsequent doses at 6 mg/kg as an IV infusion over 30 to 90 minutes every 3 weeks.

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  • Q: What are some distinguishing features of the TCH regimen?
  • A:
    • In the TCH regimen, patients begin Herceptin at the initiation of the treatment course. In the AC→TH regimen, Herceptin is administered after completion of AC chemotherapy.
    • The total length of the TCH regimen is 12 months. The total length of the AC→TH regimen is 15 months.
    • The TCH regimen avoids the use of anthracyclines and the potential for anthracycline-related cardiotoxicity that may prevent Herceptin initiation and completion.

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  • Q: How often should cardiac function be evaluated in the adjuvant setting? In patients with metastatic breast cancer?
  • A: Left ventricular cardiac dysfunction was first identified as a serious side effect in clinical trials in the metastatic setting (the first indication for Herceptin). Based on this experience in the metastatic setting, cardiac function was prospectively and closely monitored in adjuvant studies. Stringent cardiac criteria were applied to study entry, in addition to frequent monitoring of left ventricular function for any signs of deterioration.

    The following cardiac guidelines apply to patients receiving Herceptin (Herceptin PI, May 2008):
    • Candidates for treatment with Herceptin should undergo a thorough baseline cardiac assessment, including history, physical examination, and an assessment of left ventricular ejection fraction (LVEF) by echocardiogram or MUGA scan, prior to the first dose of Herceptin. The following schedule was used to monitor cardiac function in clinical studies:
      • Baseline LVEF measurement immediately prior to initiation of Herceptin
      • LVEF measurements every 3 months during and upon completion of Herceptin
      • Repeat LVEF measurement at 4-week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction
      • LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy
      Discontinue Herceptin treatment in patients receiving adjuvant therapy for breast cancer and strongly consider discontinuation of Herceptin in patients with metastatic breast cancer who develop a clinically significant decrease in left ventricular function.
    • The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied.
    Recommended monitoring schedule in the adjuvant setting

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  • Q: What CARDIAC signs and symptoms should I watch for in patients on Herceptin?
  • A: Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death. Herceptin can also cause asymptomatic decline in LVEF. In the BCIRG study, there was a higher incidence of cardiac ischemia/infarction in the Herceptin-containing regimens (TCH [0.2%] and AC→TH [0.3%]) as compared to the non-Herceptin-containing regimen (AC→T [0.0%]) (Herceptin PI, May 2008).

    Manifestations associated with heart failure are dyspnea (shortness of breath not related to exercise or exertion), fatigue, and fluid retention. Other signs and symptoms that suggest heart failure include irregular heartbeat (tachycardia, S3 gallop), jugular vein distention, peripheral edema, sudden weight gain, swelling or pain in the abdomen, decreased exercise tolerance, trouble sleeping, frequent dry, hacking cough or wheezing, loss of appetite, confusion/decreased alertness, chest pain/palpitations, fainting/lightheadedness, and low amounts of urine (A.D.A.M. Medical Encyclopedia, 2006; American Heart Association, 2007; Francis et al, 2001; Hunt et al, 2005; Keefe, 2002).

    LVEF should be assessed prior to initiation of Herceptin and at regular intervals during treatment.
    • More frequent monitoring should be employed if Herceptin is withheld in patients who develop significant left ventricular cardiac dysfunction.
    • Discontinue Herceptin for clinically significant decreases in left ventricular function (congestive heart failure [CHF]).
    Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness, or loss of consciousness.

    In patients with asymptomatic declines in LVEF, the following management protocol is recommended*:
    • Withhold Herceptin dosing for at least 4 weeks for either of the following:
      • ≥16% absolute decrease in LVEF from pretreatment values
      • LVEF below institutional limits of normal and ≥10% absolute decrease in LVEF from pretreatment values
    • Resume Herceptin if, within 4 to 8 weeks, LVEF returns to normal limits and the absolute decrease from baseline is ≤15%.
    • Permanently discontinue Herceptin for a persistent (>8 weeks) LVEF decline or for suspension of Herceptin dosing on more than three occasions for cardiomyopathy.
    In Herceptin patients who experience a clinically symptomatic decrease in LVEF: discontinue Herceptin treatment in patients receiving adjuvant therapy, and strongly consider discontinuation in patients with metastatic breast cancer.

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  • Q: Can we identify patients with risk factors that would predict cardiotoxicity?
  • A: The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens.

    An analysis of potential risk factors for Herceptin/chemotherapy-induced CHF was conducted in adjuvant study NSABP B-31 (Tan-Chiu et al, 2005). Factors that statistically affected the risk of CHF were:
    • Declining LVEF after completion of AC chemotherapy
    • Increasing age
    *These treatment modification guidelines stated in the Herceptin Full Prescribing Information should not be used as a substitute for independent medical management. The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied.

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  • Q: Do most patients recover from Herceptin-induced LVEF dysfunction?
  • A:
    Adjuvant
    Among 32 patients in studies B-31 and N9831 receiving adjuvant Herceptin treatment with clinical cardiac events as determined by an external safety committee, one patient died of cardiomyopathy and all other patients were receiving cardiac medication at last follow-up.
    • Approximately half of the surviving patients had recovery to normal LVEF (defined as ≥50%) on continuing medical management.

    Metastatic (Seidman et al, 2002; Slamon et al, 2001)
    In the pivotal trial, 63 patients receiving AC (anthracycline and cyclophosphamide) or paclitaxel chemotherapy with or without Herceptin experienced symptomatic cardiac dysfunction (39 patients had received AC + Herceptin; 11 AC only; 12 paclitaxel + Herceptin; 1 paclitaxel alone). An independent cardiac review and evaluation committee reviewed the data from these patients.
    • Of the 63 patients with cardiac dysfunction, 44 received standard medical treatment.
    • The condition improved in 33 of these 44 patients, did not change in 5, worsened in 4, and 2 patients died.

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  • Q: Can Herceptin be continued in patients who experience cardiotoxicity?
  • A: The safety of continuation or resumption of Herceptin in patients who experience Herceptin-induced left ventricular cardiac dysfunction has not been studied.

    Patients should undergo monitoring for decreased left ventricular function before Herceptin treatment, and frequently during and after Herceptin treatment.

    In patients with asymptomatic declines in LVEF, Herceptin may be held and resumed up to 3 times using the guidelines below (Herceptin PI, May 2008).

    Withhold Herceptin dosing for at least 4 weeks for either of the following:
    • ≥16% absolute decrease in LVEF from pretreatment values
    • LVEF below institutional limits of normal and ≥10% absolute decrease in LVEF from pretreatment values.
    • Herceptin may be resumed if, within 4 to 8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤15%.
    • Permanently discontinue Herceptin for a persistent LVEF decline (>8 weeks) or for suspension of Herceptin dosing on more than three occasions for cardiomyopathy.
    Patients exhibiting an asymptomatic LVEF decline in adjuvant clinical trials were managed as follows:

    Dose Modification Guidelines for Asymptomatic Decreases in LVEF
    Dose Modification Guidelines for Asymptomatic Decreases in LVEF

    Symptomatic cardiac dysfunction guidelines: Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin in patients with metastatic breast cancer who develop a clinically significant decrease in left ventricular function.

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  • Q: Is cardiotoxicity a continuing risk after Herceptin treatment is finished?
  • A: Cardiac monitoring should continue after completion of Herceptin treatment.
    • LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy
    If Herceptin is withheld for significant cardiac dysfunction, LVEF measurement should be repeated at 4-week intervals.

    LVEF should be assessed by echocardiogram or MUGA scan.

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  • Q: In the adjuvant setting, is it important that Herceptin be continued for 52 weeks?
  • A: The Prescribing Information states that for adjuvant treatment of breast cancer, Herceptin is administered for 52 weeks.

    In the NSABP B-31 and NCCTG N9831 clinical trials, clinical benefit was reported following 52 weeks of Herceptin therapy (administered weekly) compared with the control group.
    • The AC→TH regimen resulted in a 52% reduction in relative risk of disease recurrence (hazard ratio, 0.48 [95% confidence interval, 0.39-0.59]; P<0.0001).
    In the HERA clinical trial, clinical benefit was reported following 52 weeks of Herceptin therapy (administered every 3 weeks) compared with the control group.
    • Treatment with Herceptin administered on a q3w schedule resulted in a 46% reduction in the relative risk of disease recurrence (hazard ratio, 0.54 [95% confidence interval, 0.44-0.67]; P<0.0001).
    In the BCIRG trial, clinical benefit was reported following 52 weeks of Herceptin therapy (administered weekly with chemotherapy, q3w following completion of chemotherapy) compared with the control group (AC→T).
    • The TCH regimen resulted in a 33% reduction in the relative risk of disease recurrence (hazard ratio, 0.67 [95% confidence interval, 0.54-0.84]; P=0.0006).
    • The AC→TH regimen resulted in a 40% reduction in the relative risk of disease recurrence (hazard ratio, 0.60 [95% confidence interval, 0.48-0.76]; P≤0.0001).
    In the 4 adjuvant trials, Herceptin was given for 52 weeks. Clinical trials supporting Herceptin-containing regimens, together involving over 10,000 patients, all demonstrated a significant clinical benefit when 52 weeks of Herceptin were added to standard adjuvant therapy. Efficacy data are shown in the tables below (primary endpoint=disease-free survival; secondary endpoint=death) (Herceptin PI, May 2008).

    Adjuvant Treatment: Weekly Herceptin Regimen (B-31/N9831 Joint Analysis)
    Adjuvant Treatment: Weekly Herceptin Regimen (B-31/N9831 Joint Analysis)
    NS=nonsignificant

    Adjuvant Treatment: q3w Herceptin Regimen (HERA)
    Adjuvant Treatment: q3w Herceptin Regimen (HERA)
    NS=nonsignificant

    Adjuvant Treatment: TCH Herceptin Regimen (BCIRG)
    Adjuvant Treatment: TCH Herceptin Regimen (BCIRG)
    NS=nonsignificant

    The National Comprehensive Cancer Network® (NCCN) guidelines recommend using Herceptin for 1 year in the adjuvant setting, with cardiac monitoring, on the weekly or every three weekly schedule (NCCN, v2.2008).

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  • Q: If a patient misses one or two doses of adjuvant Herceptin, should she "make up" those doses?
  • A: Clinical data are available only for patients receiving weekly or q3w dosing in the adjuvant setting and weekly dosing in the metastatic setting.

    The Herceptin PI and NCCN breast cancer treatment guidelines make no recommendation regarding making up missed doses for weekly administration of Herceptin.

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  • Q: Is it safe to give Herceptin along with radiation?
  • A: In the adjuvant clinical trials B-31 and N9831, radiation therapy, if administered, was initiated concomitantly with Herceptin, after completion of chemotherapy. In addition, patients treated with lumpectomy were to receive whole-breast radiotherapy with an optional boost to the tumor bed. Regional radiotherapy after lumpectomy or mastectomy was optional in NSABP B-31; however, in NCCTG N9831 it was required in patients with at least four positive nodes. Irradiation of internal mammary nodes was prohibited in both trials (Romond et al, 2005; Tan-Chiu et al, 2005). In the HERA trial, Herceptin was initiated after completion of radiation, if given (for patients undergoing a lumpectomy).

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  • Q: Can patients who are pregnant receive Herceptin?
  • A: Herceptin can cause fetal harm when administered to a pregnant woman.
    • Post-marketing reports suggest that Herceptin use during pregnancy increases the risk of oligohydramnios (insufficient amount of amniotic fluid) during the second and third trimester.
    • Advise women with reproductive potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin.
    • If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin, she should be apprised of the potential hazard to the fetus.
    • Pregnant women with breast cancer who are using Herceptin are encouraged to enroll in MotHER, the Herceptin Pregnancy Registry (1-800-690-6720).

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  • Q: Is progress really being made in the treatment of breast cancer?
  • A: Significant progress has been made in recent years due to improvements in education, prevention, detection, and treatment. However, breast cancer still ranks second among cancer deaths in women (after lung cancer). An estimated 182,460 new cases of invasive breast cancer and 40,480 breast cancer deaths are expected to occur among women in the United States in 2008 (ACS, 2008).
    • After steadily increasing for more than 20 years, female invasive breast cancer incidence rates decreased by 3.5% per year from 2001 to 2004. Incidence rates have also stabilized since the late 1990s for in situ breast cancer. Reduced incidence rates may be related to:
      • Decreased use of hormone replacement therapy (HRT) following publication of the 2002 Women's Health Initiative report linking HRT to increased risk of heart diseases and breast cancer.
      • A slight drop in use of mammography in women aged 40 and older.
    • Death rates from breast cancer have decreased in women since 1990, with a larger decrease seen in women younger than 50 years.
      • These decreases are thought to be due to a combination of earlier detection and improved treatment.

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  • Q: What's the difference between IHC and FISH?
  • A: IHC and FISH are two different FDA-approved methodologies for assessing HER2 protein overexpression and gene amplification levels, respectively, in biopsy samples. It can be (1) determined directly through immunohistochemistry (IHC), or (2) inferred indirectly through measurement of HER2 gene amplification levels via a method known as fluorescence in situ hybridization (FISH).

    These tests are quite different in what they detect/measure, how they are scored, and how the results are interpreted. NCCN and ASCO have guidelines for what defines HER2 positivity with respect to IHC and FISH results.
    • IHC is qualitative; it measures expression of the HER2 protein on the surface of cells. The HER2 protein has been found to be expressed in higher numbers (known as overexpression) in approximately 25% of primary breast cancers. In IHC, the HER2 protein is detected using an antibody against HER2, which in turn is detected with a second labeled antibody. The intensity of cell staining is scored on a 0 to 3 scale; measurement of HER2 staining is qualitative. The NCCN guidelines state that 1+ is negative, 2+ is borderline and needs to be retested by a validated complementary method (e.g., FISH), and 3+ is a positive HER2 status (NCCN, v2.2008).
    • FISH is quantitative; it specifically measures the number of HER2 gene copies in the nucleus. In normal breast epithelial cells, there are two copies of the HER2 gene, one on each copy of chromosome 17. In HER2-positive tumors, the HER2 is amplified: there are an increased number of copies of the HER2 gene per chromosome 17. This is referred to as gene amplification. Gene amplification can result in the subsequent increase in the amount of HER2 receptor protein on the surface of the cells, known as HER2 overexpression. FISH is scored as a ratio of the HER2 probe to an internal control (CEP17). A ratio of >2.2 is considered positive (FISH+); 1.8-2.2 is borderline, requiring retesting by FISH, testing by a validated IHC method, or counting more cells; and <1.8 is negative (NCCN, v2.2008). Note: Patients with a HER2/CEP17 ratio ≥2.0 were eligible to receive Herceptin for all adjuvant studies.
    NCCN and ASCO Testing Guidelines
    NCCN and ASCO Testing Guidelines

    *ASCO

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  • Q: Why is it clinically important to determine HER2 status?
  • A: HER2 is both a prognostic and predictive marker. HER2 is overexpressed in approximately 25% of all primary breast cancers and is associated with aggressive tumors and poor outcome. Knowing the HER status of the tumor can help predict what types of therapies will be most beneficial. Because of this, the NCCN recommends HER2 status determination on all newly diagnosed invasive breast cancers (NCCN, v2.2008).

    Detection of HER2 protein expression, either directly through IHC or indirectly through gene amplification, is necessary for selection of patients appropriate for Herceptin therapy.
    • NCCN Guidelines: Patients with tumors that are HER2-positive may derive benefit from treatment with Herceptin as a single agent or in combination with selected chemotherapeutic agents. NCCN recommends selecting patients for Herceptin therapy who have tumors that are either positive for HER2 by FISH or 3+ by IHC. Patients whose tumors are IHC 0 or 1 + or FISH negative have very low rates of Herceptin response; therefore, Herceptin therapy is not warranted (NCCN, v2.2008).
    The accuracy of HER2 assays used in clinical practice is a major concern; the NCCN and ASCO have issued recommendations on this subject (Carlson et al, 2006; Herceptin PI, May 2008; Wolff et al, 2007).
    • Due to limitations in assay precision, assessment of HER2 should be performed only by laboratories with demonstrated proficiency in the specific technology used.
    • It is also inadvisable to rely on a single method (IHC or FISH) to rule out potential Herceptin benefit due to limitations in assay precision and the direct linkage between FISH assay result (HER2 amplification) and HER2 protein overexpression.
      • A false positive could expose a patient to potentially harmful side effects and not produce clinical benefit.
      • A false negative could deny a HER2-positive patient exposure to treatments such as Herceptin with proven clinical benefit in the adjuvant and metastatic settings.

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  • Q: What about patients who can't afford Herceptin?
  • A: Access Solutions is a reimbursement resource that provides patients with helpful insurance information regarding Herceptin.

    Herceptin Access Solutions


    Patients may also be eligible for special assistance with coverage issues through the Genentech Access to Care Foundation (GATCF). For more information, call 1-800-530-3083.

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