Breast cancer is a complex disease, and its characteristics vary significantly among individuals. Understanding the unique genetic makeup of a tumor has become increasingly important for guiding personalized treatment approaches. Advancements in scientific research are providing a deeper understanding of the genetic changes that drive cancer growth, paving the way for more tailored and effective therapies. This evolving knowledge is transforming how breast cancer is diagnosed and treated, moving towards precision medicine.
The PIK3CA Gene and Its Normal Function
The PIK3CA gene provides instructions for creating a protein called p110 alpha (p110α), which serves as a component of an enzyme known as phosphatidylinositol 3-kinase (PI3K). The p110α protein is the catalytic subunit of PI3K, performing its primary action while another subunit regulates its activity. Like other kinase enzymes, PI3K adds a phosphate group to other proteins, a process called phosphorylation. This action triggers a series of reactions that transmit chemical signals within cells.
PI3K signaling is involved in many cellular activities, including cell growth, division, movement, and survival. It also plays a role in the production of new proteins and the transport of materials within cells. This gene is thus fundamental for maintaining healthy cellular function and regulating various biological processes. Understanding its normal role helps clarify the profound impact when its function is disrupted.
PIK3CA Mutations and Breast Cancer Development
A PIK3CA mutation involves a change in the gene’s DNA sequence, leading to an abnormally active p110α protein. This altered protein causes the PI3K enzyme to become overactive, triggering unregulated chemical signaling within cells. Such unchecked signaling promotes continuous cell growth and division, contributing to the development and progression of various cancers, including breast cancer. Genes like PIK3CA, which can transform normal cells into tumor cells, are referred to as oncogenes.
PIK3CA mutations are among the most frequently observed genetic alterations in human cancers. In breast cancer, these mutations are found in approximately 30-40% of tumors. They are particularly prevalent in hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancers, occurring in about 40% of these cases. Additionally, PIK3CA mutations are detected in around 30-37% of HER2-positive breast cancers and about 8-15% of triple-negative breast cancers. The most common mutations often occur in specific regions of the gene, notably at H1047 in exon 20, and E542 and E545 in exon 9.
Detecting PIK3CA Mutations
Identifying PIK3CA mutations is an important step in personalizing breast cancer treatment. One common method involves analyzing tumor tissue obtained through a biopsy. This allows for direct examination of the genetic material within cancer cells.
Another approach is liquid biopsies, which analyze circulating tumor DNA (ctDNA) found in a blood sample. This less invasive method detects genetic changes released by tumor cells into the bloodstream. Both tissue and liquid biopsies are part of molecular profiling in cancer, identifying specific genetic alterations that guide treatment decisions.
Targeted Therapies for PIK3CA-Mutated Breast Cancer
Targeted therapies specifically interfere with the activity of mutated proteins, unlike traditional chemotherapy that broadly attacks rapidly dividing cells. For breast cancers with a PIK3CA mutation, PI3K inhibitors block the overactive PI3K pathway. Alpelisib (Piqray) specifically targets the p110α subunit of PI3K.
Alpelisib works by selectively inhibiting the PI3K enzyme, disrupting uncontrolled growth and survival signals in cancer cells caused by the PIK3CA mutation. This drug is approved in combination with fulvestrant, an endocrine therapy, for postmenopausal women and men with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer that has progressed after prior endocrine therapy. Clinical trials have shown that this combination can significantly improve progression-free survival for patients with PIK3CA-mutated tumors.
Beyond alpelisib, other PI3K inhibitors like inavolisib and taselisib are being investigated. Inavolisib, in combination with palbociclib and fulvestrant, has shown promising results as a first-line treatment for HR+, HER2-, PIK3CA-mutated metastatic breast cancer. Ongoing research explores next-generation PI3Kα inhibitors, aiming for improved selectivity and reduced side effects, such as hyperglycemia. These advancements highlight a continuous effort to develop more precise and effective treatments that specifically address the genetic drivers of breast cancer.