Pertuzumab for Breast Cancer - A Comprehensive Overview

What Is Pertuzumab?

Pertuzumab is a cancer medicine that belongs to the group of drugs called antineoplastic agents. Pertuzumab is a humanized monoclonal antibody derived from a mouse. Pertuzumab is used to treat metastatic HER2-positive (human epidermal growth factor receptor 2) breast cancer. Pertuzumab is combined with Trastuzumab and Docetaxel and administered as an intravenous infusion to treat HER2-positive breast cancer.

Pertuzumab was developed by Genentech and was approved in 2012. The National Institute for Health and Care Excellence (NICE) in England evaluated Pertuzumab in 2015 and found that this drug could be more cost-effective. In May 2016, NICE rejected Pertuzumab for neoadjuvant breast cancer treatment, as it was unknown if the drug combination provides survival benefits. This decision was reversed within 6 months, and NICE approved Pertuzumab as a breast cancer drug, with Roche pledging to provide it at an undisclosed discount to patients in the NHS (National Health Service).

What Is Pertuzumab Used For?

• Pertuzumab is combined with Trastuzumab and Docetaxel to treat HER2-positive metastatic breast cancer in patients who have not previously received anti-HER2 therapy or chemotherapy.

• It is combined with Trastuzumab and chemotherapy for neoadjuvant therapy (shrinks the cancer cells and prepares for other treatments like radiation therapy) in HER2-positive, locally advanced, inflammatory, or early-stage breast cancer.

• Pertuzumab is combined with Trastuzumab and chemotherapy for adjuvant therapy in HER2-positive early breast cancer at high risk for recurrence.

Dosage Strength and Forms:

Pertuzumab is an injectable drug available in 840 mg and 420 mg. Pertuzumab is usually given once every three weeks. It is usually used in combination and administered as an intravenous infusion. Initially, 840 mg is administered intravenously over 60 minutes, followed by 420 mg over 30 to 60 minutes every three weeks to treat HER2-positive metastatic breast cancer.

Pertuzumab Administration:

HER2-Positive Metastatic Breast Cancer:

Pertuzumab, Trastuzumab, and Docetaxel are administered as an intravenous infusion. Initially, 840 milligrams (mg) of Pertuzumab is combined with Trastuzumab and Docetaxel and administered intravenously every 3 weeks in cycles. After that, 420 mg of Pertuzumab is administered intravenously in combination with Trastuzumab and Docetaxel.

Neoadjuvant Therapy for HER2-Positive Early Breast Cancer:

Initially, 840 mg of Pertuzumab is administered intravenously, followed by 420 mg of Pertuzumab in combination with Trastuzumab every three weeks for three to six cycles. Pertuzumab and Trastuzumab are continued post-surgery to complete one year of therapy. Up to 18 cycles are required for treatment.

Adjuvant Therapy for HER2-Positive Early Breast Cancer:

Initially, 840 mg of Pertuzumab combined with Trastuzumab is administered intravenously on the first day of the first taxane-containing cycle, followed by 420 mg of Pertuzumab combined with Trastuzumab every 3 weeks for 1 year, up to 18 cycles or until the disease recurs.

For Patients

Why Are Chemotherapy Drugs Used for HER2-Positive Breast Cancer?

HER2-positive breast cancer is a type of breast cancer in which cancer cells make too much of a protein called HER2. This protein sends strong growth signals that make the cancer grow and spread faster than other breast cancers. It occurs because of changes in the ERBB2 gene (erythroblastic oncogene B). This gene amplification leads to HER2 overexpression in 15-30% of breast cancers. Overexpression of HER2 leads to uncontrolled cell growth.

Chemotherapy refers to cancer-fighting medicines that slow down or stop the growth of rapidly dividing cancer cells. These drugs work by damaging or blocking the processes that cancer cells need to survive and multiply. Different chemotherapy drugs work in different ways, and they are often used together, like Pertuzumab are used in combination with other medicines.

Chemotherapy can be given in many forms, including IV (intravenous) infusions, tablets, injections, creams, or special wafers placed near the tumor during surgery. It may be used as the main treatment to destroy leftover cancer cells after surgery, to shrink tumors before radiation or surgery, or to relieve symptoms in advanced stages of cancer.

Why Is Pertuzumab Prescribed?

Pertuzumab is used to treat HER2-positive breast cancer because it effectively blocks the signals that make these cancer cells grow quickly. On their own, Pertuzumab or Trastuzumab does not control the cancer as well. When both drugs are given together, they work better at stopping cancer cell growth. This combination has been shown to improve treatment results in people with early-stage breast cancer. Pertuzumab is also commonly used before surgery (neoadjuvant therapy) to shrink tumors and after surgery (adjuvant therapy) to reduce the chance of the cancer coming back.

How Does Pertuzumab Work?

HER2 is a receptor found on the surface of some breast cancer cells. When activated, it sends signals within the cell that promote rapid growth and division. In HER2-positive breast cancer, changes in the ERBB2 gene cause too much HER2 to be produced, which happens in about 15 to 30 percent of breast cancers. HER2 often pairs with another receptor, such as HER3, to activate strong growth signals.

Pertuzumab works by binding to HER3 and preventing HER2 and HER3 from pairing. This blocks the growth signals that tell cancer cells to multiply. Trastuzumab, given along with Pertuzumab, binds directly to HER2 and further inhibits its activity. Together, these drugs more effectively stop cancer cell growth.

How Should I Use Pertuzumab?

Pertuzumab is given directly into a vein (IV infusion) by a doctor or healthcare professional. Pertuzumab is an injectable medicine and is not available as a tablet or syrup. The treatment is usually given once every 3 weeks and is often used with other cancer medicines. For HER2-positive metastatic breast cancer, the first dose is typically 840 mg infused over about 60 minutes. After that, a maintenance dose of 420 mg is given every three weeks, usually over 30 to 60 minutes.

Staying on Pertuzumab

Tips to Stay on Track:

Many of you may feel better once treatment with Pertuzumab begins. If any side effects occur during therapy, tell your doctor right away. Pertuzumab is given on a strict treatment schedule, so try not to miss appointments. If a visit ever needs to be delayed, always inform your doctor so they can adjust your treatment plan safely.

What Pertuzumab Precautions Should I Follow?

Things to Inform the Doctor Before Pertuzumab Is Prescribed:

• Pertuzumab should not be used if you are allergic to it or any similar drugs.

• It should not be given to pregnant women. Pregnancy or pregnancy planning should be discussed with the doctor.

• If you have any history of heart problems, such as heart failure, previous heart attacks, irregular heartbeat, or uncontrolled high blood pressure.

• The history of prior chemotherapy and radiotherapy, if present, should be communicated to the doctor.

Do's and Don'ts While Under Pertuzumab:

• You must visit the doctor regularly to monitor progress and any potential side effects. Appointments should not be skipped.

• Pertuzumab will harm the unborn baby. Therefore, effective birth control methods should be followed during and for seven months after completing the treatment. If pregnancy occurs during the treatment, you should inform the doctor.

• Pertuzumab is known to cause cardiac failure. Therefore, it should be informed if symptoms of heart failure, like chest pain, breathing difficulty, and swelling of hands and feet, occur.

• It causes infusion-related reactions like chills, dizziness, vomiting, breathing difficulty, headache, and chest pain. If such complaints are present, they should be informed.

• You may have allergic reactions like rashes, hives, breathing difficulties, and swelling of the face, hands, and feet. If such reactions are present, they should be reported to the doctor.

Advice for Caregivers:

The caregivers should inform the doctor if the patient develops allergic reactions, such as rashes or hives, breathing difficulties, chest pain, or other abnormalities.

Things to Do After Taking Pertuzumab:

It is essential to inform the doctor of any noticeable symptoms after taking Pertuzumab. Any signs of an allergic reaction or symptoms such as chest pain should be reported immediately to the doctor.

Diet Modifications

Diet changes are not usually needed unless advised by the doctor. You should try to eat a healthy, balanced diet during treatment. It is best to avoid alcohol and tobacco, as these interfere with recovery and overall health.

What Are the Side Effects of Pertuzumab?

If you are taking Pertuzumab, you should be aware of both common and rare side effects so you can recognize them early and report them to your doctor. Some side effects may not be listed below, but any unusual symptoms should be reported to the doctor.

The common side effects include the following:

• Burning, tingling, or painful sensations.

• Black stools.

• Chills.

• Cough.

• Fast or irregular heartbeat.

• Fever.

• Itching or rashes.

• Lower back pain.

• Painful urination.

• Sore throat.

• Chest tightness.

• Redness of the skin.

• Ulcers or sores in the mouth.

• Breathing and swallowing difficulty.

• Unusual bleeding.

• Unusual tiredness.

• Loss of taste.

• Nasal congestion.

• Nausea.

• Vomiting.

For Doctors

Clinical Pharmacology

Pertuzumab Mechanism of Action:

ERBB2 gene amplification leads to HER2 overexpression in 15-30% of breast cancers. HER2 or HER3 dimers activate the signaling pathway. Upon activation, HER2, an extracellular receptor, initiates signal transduction through various pathways and stimulates cell proliferation and growth. It causes uncontrolled cell growth when overexpressed. Pertuzumab binds to HER3, prevents the formation of HER2 or HER3 dimers, and blocks signaling, thereby inhibiting cell growth. Trastuzumab also binds to HER2 and prevents its function.

Pharmacodynamics:

Pertuzumab mediates antibody-dependent cell-mediated cytotoxicity. It inhibits the signaling pathways that cause abnormal cell growth. Pertuzumab alone can inhibit tumor cell proliferation. In combination with Trastuzumab, it induces anti-tumor activity against HER2 overexpression.

Pharmacokinetics:

Absorption

Intravenously administered 840 mg of Pertuzumab was followed by a maintenance dose of 420 mg every three weeks, which reached steady-state concentration after the first maintenance dose.

Distribution

The average volume of distribution of Pertuzumab following intravenous administration is 3.53 to 2 liquid gallons.

Metabolism

No information on the metabolism of Pertuzumab is available. However, monoclonal antibodies are subject to catabolism, metabolized into smaller peptides and proteins before elimination.

Elimination

The median half-life is 18 days, and the clearance rate of Pertuzumab is 0.24 L/day.

What Are the Warnings for Pertuzumab?

1. Left Ventricular Dysfunction: Pertuzumab decreases left ventricular function. It causes left ventricular systolic dysfunction. The patient's cardiac function should be evaluated before and during treatment with Pertuzumab. The drug should be discontinued if left ventricular function decreases.

2. Pregnancy: Pertuzumab is embryotoxic and fetotoxic. It causes harm to the fetus and should not be used in pregnant women. A pregnancy test should be performed before taking this drug. Effective birth control methods should be used during therapy and for seven months after discontinuation of this drug to prevent pregnancy.

3. Lactation: The distribution of Pertuzumab in breast milk is unknown. The risks and benefits should be weighed before starting Pertuzumab in breastfeeding mothers.

4. Infusion-Related Reactions: Patients should be monitored for infusion-related reactions like pyrexia (also called fever), fatigue, vomiting, chills, myalgia (muscle pain), dysgeusia (altered sense of taste), and headache during infusion. The infusion rate should be reduced or the drug permanently discontinued if such reactions are present.

5. Hypersensitivity Reactions: The drug should be discontinued if hypersensitivity reactions like swelling of the face and extremities, rashes, hives, and breathing difficulty occur.

6. HER2 Evaluation: Pertuzumab should be used in patients with HER2 gene amplification or HER2 gene overexpression. If HER2 is not present, the results may be unreliable.

Considerations for Administration

• Pertuzumab should be given to patients with HER2 overexpression.

• Patients should be closely observed for 60 minutes after infusion, as it may cause infusion-related reactions.

• Patients should be observed for hypersensitivity reactions after administration.

• Pertuzumab and Trastuzumab may be administered in any order.

Who Should Not Use Pertuzumab?

Contraindications for Pertuzumab are as follows:

• Pertuzumab decreases left ventricular function. It causes left ventricular systolic dysfunction. Therefore, the patient's cardiac function should be evaluated before and during treatment with Pertuzumab. The drug should be discontinued if left ventricular function decreases.

• Pertuzumab harms the fetus and should not be used in pregnant women. A pregnancy test should be performed before starting this drug. Effective birth control methods should be used during therapy and for seven months after discontinuation of this drug to prevent pregnancy.

• The distribution of Pertuzumab in breast milk is not known. Therefore, the risks and benefits should be weighed before starting Pertuzumab in breastfeeding mothers.

• Pertuzumab may cause hypersensitivity reactions. Therefore, it is contraindicated in patients who are allergic to Pertuzumab. The drug should be discontinued if hypersensitivity reactions like swelling of the face and extremities, rashes, hives, and breathing difficulty occur.

• Pertuzumab should be used in patients with HER2 gene amplification or HER2 gene overexpression. If HER2 is not present, the results may be unreliable.

Clinical Trials

A multicenter, double-blind, placebo-controlled trial called CLEOPATRA was performed on 808 patients with HER2-positive metastatic breast cancer. Patients were randomly assigned to receive either placebo plus Trastuzumab and Docetaxel or Pertuzumab, Trastuzumab, and Docetaxel. Pertuzumab was initially administered intravenously at a dose of 840 mg, followed by 420 mg every three weeks. Docetaxel, 75 mg per square meter, was administered intravenously every 3 weeks for at least 6 cycles. This study revealed a drastic improvement in the Pertuzumab-treated group compared to the placebo group. Patients showed improved symptoms at the end of the analysis.

Drug Interactions

Interactions With Other Drugs:

Pertuzumab should not be used with the following medications. If both medicines are prescribed, the doctor may adjust the dose or the frequency for one or both. It includes the following drugs:

• Daunorubicin.

• Daunorubicin Citrate Liposome.

• Daunorubicin Liposome.

• Doxorubicin.

• Epirubicin.

• Idarubicin.

• Pirarubicin.

• Pixantrone.

• Tofacitinib.

• Valrubicin.

Specific Populations:

Left Ventricular Dysfunction

Pertuzumab decreases left ventricular function. It causes left ventricular systolic dysfunction. The patient's cardiac function should be evaluated before and during treatment with Pertuzumab. The drug should be discontinued if left ventricular function decreases.

Pregnancy

Pertuzumab is embryotoxic and fetotoxic. It causes harm to the fetus and should not be used in pregnant women. A pregnancy test should be performed before starting this drug. Effective birth control methods should be used during therapy and for seven months after discontinuation of this drug to prevent pregnancy.

Lactation: The distribution of Pertuzumab in breast milk is unknown. The risks and benefits should be weighed before starting Pertuzumab in breastfeeding mothers.

Infusion-Related Reactions: Patients should be monitored for infusion-related reactions, including pyrexia, headache, fatigue, chills, vomiting, myalgia, and dysgeusia, during infusion. The infusion rate should be reduced or the drug permanently discontinued if such reactions are present.

Hypersensitivity Reactions: The drug should be stopped if hypersensitivity reactions such as swelling of the face and extremities, rashes, hives, or breathing difficulty occur.

Hepatic Impairment: No specific dosage modifications are required for patients with hepatic impairment.

Renal Impairment: Dosage adjustment is not required for patients with mild or moderate renal impairment. No information is available on dose adjustments for patients with severe renal impairment.

Pediatric Use: The safety and efficacy of Pertuzumab in pediatric patients are not established.

Geriatric Use: No differences in safety or efficacy compared with young adult patients.