PIK3CA-Activated Mutation

PIK3CA-activated mutations are among the most common genetic changes found in cancer, affecting how cells grow, divide, and survive. These mutations lead to increased activity of a key protein that helps control cell growth, which can contribute to tumor development and affect how well certain treatments work.

Table of contents

• What is PIK3CA?
• How PIK3CA Mutations Occur
• Frequency of PIK3CA Mutations
• Cancers Affected by PIK3CA Mutations
• Testing for PIK3CA Mutations
• Treatment Approaches

What is PIK3CA?

The PIK3CA gene provides instructions for making a protein called p110 alpha (p110α), which is one piece of a larger enzyme called phosphatidylinositol 3-kinase, or PI3K for short^[1]. This protein plays an important role in many cell activities, including telling cells when to grow and divide, how to move, and when to survive or die^[1].

The p110α protein is called the catalytic subunit because it performs the main action of PI3K, while another piece produced by a different gene regulates how active the enzyme is^[1]. Like other similar enzymes, PI3K adds clusters of oxygen and phosphorus atoms to other proteins through a process called phosphorylation, which triggers a series of chemical signals within cells^[1].

The PIK3CA gene is located on chromosome 3q26.3, spans 34 kilobases in length, and comprises 20 sections called exons that encode a protein of 1,068 amino acids^[7]. Different exons encode different parts of the protein, with exon 9 encoding the helical domain and exon 20 encoding the kinase domain^[7].

How PIK3CA Mutations Occur

PIK3CA mutations are changes in the genetic code that alter the p110α protein structure. Most PIK3CA mutations associated with cancer are somatic mutations, meaning they occur randomly in body cells during a person’s lifetime and are not inherited from parents^[1][4]. These mutations cause the p110α protein to become overactive, leading to increased PI3K signaling that promotes uncontrolled cell growth and division^[1].

The mutations typically change single protein building blocks, called amino acids, in the p110α protein^[1]. Five specific PIK3CA mutations account for 73% of all PIK3CA mutations found in cancer: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%)^[5].

The mutations cluster in two main regions of the gene. About 80% of PIK3CA mutations are found in exon 9 and exon 20^[4]. Mutations in exon 9, such as E542K and E545K, result in overactivation of the PIK3CA pathway by altering the protein’s structure and disrupting the normal inhibitory interaction between p110α and its regulatory partner p85α^[7].

In rare cases, PIK3CA mutations can occur during early development before birth, affecting only some cells in the body. This mixture of cells with and without the mutation is called mosaicism^[1]. These early developmental mutations can cause certain overgrowth conditions but do not typically increase cancer risk^[1].

Frequency of PIK3CA Mutations

PIK3CA mutations are remarkably common across human cancers. Activating mutations in PIK3CA have been found in approximately 30 to 40 percent of patients with cancer^[5][10]. According to the Catalogue of Somatic Mutations in Cancer, PIK3CA mutations are present in about 25% of all cancers examined^[6].

The frequency of these mutations varies significantly by cancer type. In breast cancer, PIK3CA mutations are particularly common, with patients having PIK3CA-mutated tumors representing 35.7% of cases across large studies^[5]. In breast cancer specifically, mutations are present in about 30 to 40 percent of cases, with higher rates in certain subtypes^[11].

In colorectal cancer, PIK3CA mutations are found in 20 to 25% of colon cancers and 10% of rectal cancers^[4]. The majority of these mutations occur in exon 9 and exon 20, with exon 9 mutations being more common than exon 20 mutations^[4]. Only 3% of colorectal cancers have the PIK3CA exon 20 mutation^[4].

PIK3CA mutations are also more common in certain locations and cancer subtypes. For colorectal cancer, mutations are more frequently found in right-sided (proximal) colon cancers than in left-sided (distal) colon cancers and rectal cancers^[4]. In breast cancer, mutation rates are lower in triple-negative breast cancer (16%) compared to hormone receptor-positive/HER2-negative (42%) and HER2-positive (31%) breast cancer^[5].

Cancers Affected by PIK3CA Mutations

PIK3CA mutations have been identified in a broad spectrum of tumor types, making them one of the most frequently mutated genes in human cancer^[2]. The mutations promote growth factor-independent growth and increase cell invasion and metastasis, which is the spread of cancer to other parts of the body^[2].

Breast Cancer

In breast cancer, PIK3CA mutations are especially prevalent and have important clinical implications. The mutations are found in approximately 30 to 40 percent of breast cancers and are particularly enriched in hormone receptor-positive and human epidermal growth factor receptor 2-positive subtypes^[15]. The PI3K/AKT/mTOR pathway, which includes PIK3CA, has been associated with resistance to hormone therapy in patients with hormone receptor-positive/HER2-negative breast cancer^[5].

Bladder Cancer

Somatic mutations in the PIK3CA gene have been found in some cases of bladder cancer, a disease in which certain cells in the bladder become abnormal and multiply uncontrollably to form a tumor^[1]. A PIK3CA gene mutation has been found in about half of non-muscle invasive bladder cancer tumors^[1]. These mutations change single amino acids in the p110α protein, and the altered protein allows PI3K to become overactive, likely contributing to uncontrolled cell growth and the formation of bladder cancer^[1].

Colorectal Cancer

In colorectal cancer, PIK3CA serves as both a prognostic biomarker, which gives information about the likely course of the disease, and a predictive biomarker, which predicts which treatments will be effective^[4]. Tumors with certain PIK3CA mutations, particularly in exon 20, are less responsive to EGFR inhibitor treatment^[4]. However, colorectal cancer with PIK3CA mutation may have a good response to aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) as therapy given before or after the main treatment^[4].

Other Cancers

PIK3CA mutations have been found in over a dozen different cancers beyond breast, bladder, and colorectal cancer^[11]. These include uterine cancer, ovarian cancer, non-small cell lung cancer, head and neck cancers, and colon cancer^[4][11].

Non-Cancer Conditions

Mutations in the PIK3CA gene have been found in up to a quarter of people with a certain type of skin growth called epidermal nevus^[1]. Specifically, PIK3CA gene mutations are associated with some skin growths composed of skin cells called keratinocytes^[1]. The mutations cause cells to grow and divide more than normal, leading to formation of these skin growths^[1].

At least five mutations in the PIK3CA gene have been found to cause Klippel-Trenaunay syndrome, a condition characterized by a red birthmark called a port-wine stain, abnormal overgrowth of soft tissues and bones, and vein malformations^[1]. Despite the involvement of PIK3CA gene mutations in many cancers and the overgrowth of cells caused by changes in this gene, individuals with these overgrowth conditions do not appear to have an elevated risk of developing cancer^[1].

Testing for PIK3CA Mutations

Testing for PIK3CA mutations is performed on a sample of cancer cells, typically obtained through a biopsy or from a blood sample^[4][11]. PIK3CA testing is usually done by next-generation sequencing (NGS) in a multi-gene panel, which can provide more comprehensive information about PIK3CA and other gene alterations^[4].

For breast cancer, the doctor who treats the cancer may test for the PIK3CA gene mutation if a patient has an estrogen receptor-positive, HER2-negative breast cancer^[11]. The U.S. Food and Drug Administration (FDA) authorized a test for detecting mutations in the PIK3CA gene in 2019, called therascreen^[11].

A blood sample can be used for testing, performed in the same way as any other blood test^[11]. Breast tumors release small amounts of DNA into the bloodstream, which can be tested for the PIK3CA gene^[11]. This is called circulating tumor DNA (ctDNA) testing. If a blood test result is negative, a tissue biopsy should be performed to confirm the result^[11].

During a tissue biopsy, a doctor removes a sample of tissue from the tumor during a minor surgical procedure, and the tissue sample is sent to a laboratory where technicians test it for the PIK3CA gene mutation^[11]. PIK3CA mutation status does not always match between the primary tumor and metastasis, so both tumors may be tested^[4].

Test results are reported as either “PIK3CA wild-type (WT)” if there is no mutation, or “PIK3CA mutant” if a mutation is present^[4]. The report may name a specific mutation, such as “mutant exon 9” or “mutant exon 20”^[4].

Treatment Approaches

The discovery of PIK3CA mutations has led to the development of targeted therapies designed to specifically block the overactive PI3K pathway. In May 2019, the FDA approved alpelisib, an alpha-specific PI3K inhibitor, for the treatment of patients with advanced PIK3CA-mutated hormone receptor-positive/HER2-negative breast cancer^[5][10].

Alpelisib (Piqray) is an orally available, small-molecule drug that inhibits p110α approximately 50 times as strongly as other similar proteins^[5]. The drug was approved based on results from the SOLAR-1 phase III randomized trial, which evaluated the effectiveness of alpelisib plus fulvestrant in 572 patients with hormone receptor-positive/HER2-negative advanced breast cancer who had received prior hormone therapy^[5]. A clinically meaningful treatment benefit was only observed in patients with PIK3CA-mutated disease^[5].

If a patient has the PIK3CA mutation, their cancer may not respond as well to hormone therapy for metastatic breast cancer^[11]. However, the presence of the mutation suggests the patient may be a candidate for alpelisib, which is used as a targeted therapy known as a PI3K inhibitor^[11].

Next-generation therapies are being developed to overcome the limitations of existing treatments, which can have significant side effects including high blood sugar (hyperglycemia)^[8]. Several promising inhibitors, including RLY-2608, STX-478, and LOXO-783, have shown potential in early studies^[8]. These newer therapies aim to selectively inhibit mutant PI3Kα without affecting normal PI3K activity, reducing side effects and improving patient outcomes^[8].

For colorectal cancer with PIK3CA mutation, there are ongoing clinical trials for treatments targeting PIK3CA mutant colorectal cancers^[4]. Additionally, research suggests that colorectal cancer with PIK3CA mutation may respond well to aspirin or other NSAIDs as therapy given before or after the main treatment^[4].

Combination therapies are also being explored. Studies are investigating how PIK3CA mutations alter tumor metabolism, enhance immune evasion, and reshape the tumor environment^[8]. These insights are leading to combination approaches that integrate PI3K inhibitors with immunotherapy and drugs that target metabolism to improve response rates and treatment durability^[8].