PIK3CA Gene Mutation Linked to Poor Response to Anti-HER2 Treatment
Researchers say early-stage, HER2-positive breast cancer is more resistant to treatment when the tumor has a PIK3CA gene mutation, even when two targeted therapies are given with chemotherapy before surgery.
Background and Goals
The PIK3CA gene, on chromosome 3, is found in every human body. It affects many aspects of cell life, including growth and survival. A mutation of the PIK3CA gene is seen in about 20 percent of breast cancers and in 20 to 25 percent of HER2-positive breast cancers. Breast cancer is HER2-positive if breast cells multiply too fast because of too many copies of the human epidermal growth factor receptor 2 protein. A PIK3CA mutation is thought to sometimes prevent standard anti-HER2 medicines that are given before surgery from working.
Researchers wanted to learn more about how much this mutation blocks the treatments. They planned to do that by measuring pCR, pathologic complete response. In this study, pCR meant cancer was no longer found in the breasts or lymph nodes. Achieving pCR after pre-surgery treatment is associated with a good outcome in HER2-positive breast cancer.
The researchers also wanted to see if:
- hormone receptor status, whether cancer grows in the presence of estrogen or progesterone, would affect how much the mutation blocks treatments
- getting trastuzumab (Herceptin),which treats HER2-positive breast cancer by binding to HER2, with or without lapatinib (Tykerb), another anti-HER2 medicine, would affect how much the mutation blocks the treatments
- a PIK3CA mutation’s presence could predict a person’s overall survival, OS, the time from the start of treatment to death from any cause
Researchers used data from 504 people with early-stage, HER2-positive disease who took part in one of three clinical trials that studied pre-surgery, anti-HER2 treatment. Of those people,
- 47.6 percent received chemotherapy, trastuzumab and lapatinib
- 34 percent received chemotherapy and trastuzumab
- 18 percent received chemotherapy and lapatinib
Of the group, 21.4 percent had a PIK3CA mutation. The mutation was seen about equally in hormone-positive and hormone-negative tumors.
The overall pCR rate was 30 percent, but that rate changed when the gene mutation was taken into account. pCR was achieved by
- 19.4 percent of people with a PIK3CA mutation
- 32.8 percent without the mutation
When cancer was hormone receptor-positive, pCR was achieved by
- 11.3 percent of people with a PIK3CA mutation
- 27.5 percent without the mutation
When cancer was hormone receptor-negative, pCR was achieved by
- 30.4 percent of people with a PIK3CA mutation
- 40.1 percent without the mutation
Overall, cancers without a PIK3CA mutation responded better to treatment, no matter the hormone receptor status.
Broken down by treatment, the researchers found these differences:
pCR with lapatinib and chemotherapy
- 16 percent with a mutation
- 18.2 percent without a mutation
pCR with trastuzumab and chemotherapy
- 24.3 percent with a mutation
- 33 percent without a mutation
pCR with all three medicines
- 17.4 percent with a mutation
- 37.1 percent without a mutation
The combination of all three medicines had the best results overall, but was still impacted by the presence of the gene mutation.
At a median follow up of about 3.5 years, the team found that OS was the same regardless of whether there was a PIK3CA gene mutation.
What This Means for You
We’ve come a long way in treating HER2-positive breast cancer. But this subtype can still be hard to manage, especially if a PIK3CA mutation is involved. This is the largest study to date that looked at these mutations and how they relate to the body’s response to neoadjuvant therapy. Most other smaller studies have shown similar results, but not all are identical. More research needs to be done to find out exactly how this gene mutation impacts treatment.
Tests for these mutations are not often available outside of clinical trials. At this early stage in research, knowing your PIK3CA mutation status would not affect your treatment plan. But if treatment for HER2-positive disease hasn’t been very effective for you, knowing researchers are looking at reasons for that and how they can improve your care may be comforting to you.
Researchers are looking into new treatments, including PIK3 inhibitors, which could treat breast cancers that have a PIK3CA mutation by blocking overactive PIK3 pathways. New treatments like PIK3 inhibitors can only be approved if people like you take part in clinical trials.
Consider looking at ClinicalTrials.gov to see what studies are recruiting participants and ask your doctor if you could be eligible.
Loibl, Sibylle; von Minckwitz, Gunter; Schneeweiss, Andreas. PIK3CA Mutations Are Associated With Lower Rates of Pathologic Complete Response to Anti–Human Epidermal Growth Factor Receptor 2 (HER2) Therapy in Primary HER2-Overexpressing Breast Cancer. Journal of Clinical Oncology. Published online before print September 8, 2014;doi: 10.1200/JCO/2014.57.6132.