Response to HER2 Targeted Therapies Seen Just 11 Days After Treatment Starts

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Treatment given to weaken and destroy breast cancer before surgery is called neoadjuvant treatment. Neoadjuvant treatment isn’t routinely used to treat early-stage breast cancer, but may be used if the cancer is large or aggressive. Neoadjuvant treatment is more commonly used before surgery for breast cancer that has spread outside the breast to other tissue in the breast area, such as the lymph nodes (locally advanced disease).

The targeted therapies Herceptin (chemical name: trastuzumab) and Tykerb (chemical name: lapatinib) (Tykerb is known as Tyverb in Europe) may be used in a neoadjuvant regimen if the cancer is HER2-positive. HER2-positive breast cancers have too many copies of the HER2/neu gene, which make too much of the HER2 protein. HER2-positive breast cancers tend to be aggressive, so doctors may recommend neoadjuvant treatment for them. Herceptin and Tykerb fight HER2-positive breast cancers by blocking the cancer cells’ ability to receive growth signals. Herceptin is given intravenously. Tykerb is a pill taken by mouth.

One way for doctors to judge the effectiveness of neoadjuvant treatment is to look at the tissue removed during surgery to see if any active cancer cells are present. If no active cancer cells are present, doctors call it a “pathologic complete response.”

A study suggests that some HER2-positive breast cancers may respond very quickly to the combination of Herceptin and Tykerb before surgery -- shrinking dramatically or disappearing entirely after just 11 days of treatment.

The study was presented on March 10, 2016 at the 2016 European Breast Cancer Conference. Read the abstract of “Effects of perioperative lapatinib and trastuzumab, alone and in combination, in early HER2+ breast cancer -- the UK EPHOS-B trial (CRUK/08/002).”

The UK EPHOS-B trial was conducted at several locations throughout the United Kingdom. The study had two parts. In part one, 130 women newly diagnosed with HER2-positive breast cancer that could be removed with surgery were randomly assigned to receive one of three treatments for 11 days after diagnosis and before surgery:

  • no treatment (the control group) -- 22 women
  • Herceptin only (6 mg per kg of body weight on days one and eight) -- 51 women
  • Tykerb only (1,500 mg per day) -- 57 women

As the study was recruiting women, results from other studies began suggesting that a combination of Herceptin and Tykerb were better than either medicine alone. So the researchers modified the UK EPHOS-B trial. In part two, 127 women newly diagnosed with HER2-positive breast cancer that could be removed with surgery were randomly assigned to receive one of three treatments for 11 days after diagnosis and before surgery:

  • no treatment (the control group) -- 29 women
  • Herceptin only -- 32 women
  • Herceptin and Tykerb in combination -- 66 women

After the 11 days of treatment was completed, the women had surgery to remove the cancer.

The researchers compared cancer tissue samples removed during the first biopsy that confirmed a diagnosis of cancer to samples of the cancer removed after the 11 days of targeted therapy treatment.

The researchers looked to see if there had been a drop in levels of the Ki-67 protein after targeted therapy treatment. The Ki-67 protein helps control how fast cancer cells grow. If levels of the Ki-67 protein dropped, it suggests that the cancer cells were growing more slowly.

The researchers also looked to see if there had been a 30% or more rise in apoptosis, also called programmed cell death. Apoptosis is one of two ways that a cell can die. Basically, the cell self-destructs. Apoptosis is a normal process in the body and gets rid of damaged, extra, or unwanted cells. Necrosis is the other way a cell can die. Necrosis happens when a cell is damaged by an external force, such as an infection, poison, or being cut off from its blood supply.

The researchers also reviewed the pathology reports on the tissue removed after targeted therapy treatment to see if the cancer had:

  • disappeared -- classified as pathologic complete response
  • shrunk so it was smaller than 5 mm in diameter -- classified as minimal residual disease
  • reacted in some other way -- classified as other

Results from part one:

  • Control group: No women had minimal residual disease or a pathologic complete response.
  • Tykerb-only group: No women had had minimal residual disease or a pathologic complete response.
  • Herceptin-only group: One woman had a pathologic complete response and one woman had minimal residual disease.

Results from part two:

  • Control group: No women had minimal residual disease or a pathologic complete response.
  • Herceptin-only group: No women had a pathologic complete response and one woman had minimal residual disease.
  • Herceptin-Tykerb combination group: 7 women had a pathologic complete response and 11 women had minimal residual disease; the cancer tissue samples also showed a drop in Ki-67 protein levels.

"This has ground-breaking potential because it allows us to identify a group of patients who, within 11 days, have had their tumors disappear with anti-HER2 therapy alone and who potentially may not require subsequent chemotherapy," said Dr. Nigel Bundred, professor of surgical oncology at the University of Manchester, who presented the study. "This offers the opportunity to tailor treatment for each individual woman."

"These results show that we can get an early indication of pathological response within 11 days, in the absence of chemotherapy, in these patients on combination treatment," said Dr. Judith Bliss, of the Institute of Cancer Research, London, who was the co-leader of the trial. "Most previous trials have only looked at the pathological response after several months of treatment. Clearly these results need further confirmation, but I suspect the excitement from seeing the speed of disappearance of the tumors will mean that several trials will attempt to confirm these results."

"Other trials have looked at anti-HER2 therapy, with and without chemotherapy, including an assessment of the combination of trastuzumab and lapatinib, and have reported impressive response rates, but these trials have only reported results after several months of therapy," added Dr. Bundred. "Potentially, giving treatment while waiting for surgery can identify a group of patients whose disease is particularly sensitive to anti-HER2 therapy, which would allow individualization of therapy in women with HER2-positive cancers."

This analysis didn’t include any information on side effects. Both Herceptin and Tykerb can cause side effects, some of them serious. Common side effects include diarrhea, liver problems, and rash. Heart problems can be a side effect of both Herceptin and Tykerb. In other studies, women who were treated with a combination of Herceptin and Tykerb before surgery had about the same side effects as women who got only Tykerb, but more severe side effects than women who got only Herceptin.

If you’ve recently been diagnosed with HER2-positive breast cancer and haven’t had surgery yet, you might want to talk to your doctor about this study and ask if treatment with Herceptin and Tykerb before surgery makes sense for your unique situation.

More research is being done that will help doctors understand how to best use these targeted therapies in combination before and after surgery, so stay tuned to Breastcancer.org for the updates.



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