Mutations and HER2-Negative Breast Cancer Treatment

Medically Reviewed by Mahammad Juber, MD on April 25, 2022

Advanced breast cancer, or stage IV, means that your cancer has spread beyond your breast to distant sites in your body. At this stage, the main treatments kill cancer cells all over your body. Your doctor may give you chemotherapy, targeted therapy, immunotherapy, or more than one of these treatments combined.

If your cancer continues to grow or your treatment stops working, it's time to try something else. Which course of care you get next depends on the genes and proteins that are active in your cancer. Your doctor will test a sample of tissue that has cancer cells from a biopsy to learn what these are.

HER2 is a protein that helps cancer cells grow. An HER2-negative breast cancer cell doesn't have much of this protein on its surface. Your doctor can decide which medications will work best on your condition if they know your HER2 status. They'll also need to know what changes, or mutations, you have to genes like BRCA 1, BRCA 2, and PIK3CA. 

HER2-Negative Breast Cancer With a BRCA Gene Mutation

The BRCA1 and BRCA2 genes make proteins that help fix damaged DNA. When you have a mutation in one or both of these genes, your body can't repair DNA as well as usual. This makes it more likely that you’ll get cancer.

Chemotherapy is the first treatment you'll try for HER2-negative, BRCA-positive breast cancer. After that, you may take a PARP inhibitor drug such as olaparib (Lynparza) or talazoparib (Talzenna). These medicines block a substance called PARP that helps cancer cells fix their own damaged DNA. When cancer cells can't repair their DNA, they die.

You take PARP inhibitors as a pill once or twice a day. The most common side effects from these drugs are:

  • Tiredness
  • Nausea
  • Headache
  • Vomiting
  • Diarrhea
  • Appetite loss

HER2-Negative Breast Cancer With a PIK3CA Mutation

The PIK3CA gene carries instructions to cells to make a protein that helps them divide and survive.

About 30% to 40% of breast cancers have a mutation in the PIK3CA gene that lets breast cancer cells multiply out of control and form tumors.

Alpelisib (Piqray) is the only drug that treats HER2-negative breast cancer with the PIK3CA gene mutation. Piqray is a targeted therapy called a PI3K inhibitor. It blocks a pathway that gives cancer cells the energy they need to grow.

You take Piqray as a pill by mouth. You'll take the hormone therapy drug fulvestrant (Faslodex) with it.

Piqray can cause side effects like these:

  • High blood sugar
  • Diarrhea
  • Rash
  • Nausea and vomiting
  • Tiredness
  • Appetite loss

Not everyone who takes Piqray will have these side effects. Tell your doctor about any problems you do have, especially severe rashes where your skin peels or forms blisters.

Triple-Negative Breast Cancer

Triple-negative breast cancer doesn't respond to the hormones estrogen or progesterone, or to therapies that target the HER2 protein. Hormone therapy isn't an effective treatment for this type of cancer. About 10% to 20% of breast cancers are triple-negative.

Treatment usually starts with chemo. If that stops working, your doctor will suggest a different treatment based on a protein your cancer makes. About 20% of triple-negative breast cancers make the protein PD-L1. This protein helps cancer cells hide from the immune system.

The immunotherapy drug atezolizumab (Tecentriq) treats triple-negative breast cancer that makes PD-L1. Tecentriq is a type of drug called a checkpoint inhibitor. It basically takes the brakes off your immune system so that it can kill the cancer cells. Along with Tecentriq, you'll get the chemotherapy drug paclitaxel (Abraxane).

You take these drugs through an infusion into a vein (IV) at a hospital or cancer center. The infusion takes 30 to 60 minutes.

The most common side effects from these drugs are:

  • Tiredness
  • Hair loss
  • Nausea
  • Fever
  • Cough
  • Constipation
  • Appetite loss

Sacituzumab govitecan-hziy (Trodelvy) is immune targeted therapy to treat triple negative breast cancer that has metastasized who have received at least two previous treatments for the metastatic disease. It works by directly targeting the cancer cell to keep it from growing. Delivered via IV, it, too can cause fatigue, hair loss. constipation, loss of appetite. It can also trigger a lowered white blood cell count.

Other Treatments

Your doctor has other treatments that don't stop the disease, but they may help you feel better. You could get radiation to relieve pain, or surgery to open up a blockage from the tumor. Or you might get bisphosphonate drugs to make your bones stronger and ease pain if the cancer has spread there.

Next Steps

Treatments for advanced breast cancer can slow the disease down, but they can't cure it. If you've tried a few and your cancer keeps growing or it comes back, your doctor might suggest that you enroll in a clinical trial.

A clinical trial gives you a chance to try a new treatment before it's available to the public. That new therapy may be more effective than ones that are currently available. Ask your doctor if a clinical trial is right for you.

Show Sources


American Cancer Society: "FDA Approves First PI3K Inhibitor for Breast Cancer," "Treatment of Stage IV (Metastatic) Breast Cancer."

BreastCancer.Org: "Piqray," "Triple-Negative Breast Cancer."

Cancer.Net: "Breast Cancer: Diagnosis."

Dana-Farber Cancer Institute: "What is PD-L1?"

FDA: "Prescribing Information: Lynparza," "Prescribing Information: Talzenna," "Prescribing Information: Tecentriq."

Genetics Home Reference: "PIK3CA Gene."

National Cancer Institute: "Atezolizumab Approved for Some Patients with Triple-Negative Breast Cancer," "BRCA Mutations: Cancer Risk and Genetic Testing," "HER2 Negative," "PARP Inhibitor."

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