PIK3CA Mutations in Metastatic Breast Cancer

How they affect tumor behavior and treatment

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PIK3CA gene mutations are genetic changes found in some breast cancers (as well as other cancers) that appear to promote the growth of the tumors. PIK3 (phosphoinositide 3-kinase), the protein produced by this gene, is part of a signaling pathway that has been studied extensively in the hope of halting the growth of metastatic breast cancer. PIK3CA gene mutations are common in breast cancer, occurring in roughly 30% to 40% of tumors, and most commonly found in estrogen receptor-positive breast cancer.

The mutation appears to be important in the development of cancer, progression, and resistance to some treatments including HER2 targeted therapies and chemotherapy in people with HER2 positive breast cancer. While the mutation was thought to be associated with a poorer prognosis in the past, it may indicate a better prognosis in hormone receptor-positive breast cancers, at least in the first ten years following diagnosis.

In 2019, the medication Piqray (alpelisib) was approved for postmenopausal women and men with hormone receptor-positive metastatic breast cancer that tests positive for a PIK3CA mutation. When used in this setting, the combination of Piqray and Faslodex (fulvestrant) almost doubled progression-free survival in people who had progressed on hormone therapy.

PIK3 Mutations

Understanding the genetic changes (genomic alterations) in cancer cells not only helps researchers better understand how cancers can grow and spread, but may provide targets for medications that can control the growth of tumors.

Cancer cells arise when a series of mutations or other genetic changes in a normal cell lead to a cell that grows unchecked. Not all mutations are important in cancer.

PIK3 mutations are considered "driver mutations," in that the proteins produced by the genetic change drive the growth of the cell.

Genetic alterations in cancer cells can also help a cell evade death (apoptosis), alter its metabolism, and enhance its ability to break free and travel to other parts of the body (metastasize).

For those who are familiar with some of the signaling pathways involved in cancer growth, PIK3CA is in the P13K/AKT/mTOR pathway, a pathway that is involved in a number of different processes in cell growth.

Conditions and Cancers Associated with PIK3CA Mutations

With genetic testing now available to look for a predisposition to cancer, talking about gene mutations that drive the growth of cancer can be very confusing. This is easier to understand by breaking these mutations down into two categories:

  • Germline (inherited) mutations: Germline mutations are genetic changes that are present from the time of conception (hereditary) and are found in every cell in the body. These mutations may raise the risk of cancer but are not usually targeted in the treatment of cancer. BRCA mutations are an example of germline mutations. Most germline mutations (such as those in BRCA genes) occur in tumor suppressor genes, genes that code for proteins that function to repair damaged DNA (for example, from environmental toxins) or eliminate cells that can't be repaired so that they can't develop into cancer cells.
  • Somatic (acquired) mutations: Mutations such as PIK3CA mutations are considered somatic mutations and are acquired in the process of a cell becoming a cancer cell. They are found only in the tissue or organ affected by cancer and not other cells of the body. They are not considered hereditary and cannot be passed from a mother or father to a child. When drugs (targeted therapies) are available that target these mutations, the mutations are referred to as "targetable" (treatable) mutations or genetic alterations.

    In addition to playing a role in many breast cancers, PIK3CA mutations have been noted in a dozen other cancers, particularly uterine cancer, bladder cancer, colon cancer, and head and neck cancers.

    When somatic PIK3CA mutations occur in early development (embryonic development) they can lead to a number of rare disorders characterized by overgrowth of tissues. The timing of the mutation influences the type of overgrowth disorder; disorders that can be mild or severe and range from an enlarged finger, to an enlarged leg, to massive enlargement of large blood vessels.

    Surprisingly, the incidence of cancer in people with these overgrowth disorders is not increased. PIK3CA mutations have also been noted in some benign skin conditions such as seborrheic keratoses.

    History

    The enzyme coded for by the PIK3CA gene, phosphoinositide 3-kinase (P13K) was first discovered as a signal transducer in cell growth in 1988, and first found in solid cancers in 2004. Since that time, hyperactivation of P13K/AKT signaling has been noted to be a common "driver" genetic alteration in a number of cancers.

    While a number of different medications have been studied that target P13K for the treatment of metastatic breast cancer, it was not until recently that a medication targeting a specific subunit of this enzyme (the alpha subunit) was found to be effective in some people with metastatic breast cancer but with reasonable toxicity.

    The medication Piqray (alpelisib) was approved in May of 2019 for postmenopausal women and men with metastatic breast cancer that has progressed on endocrine therapy.

    Role of PIK3CA Mutations in Breast Cancer

    In discussing PIK3CA mutations in breast cancer it's important to note that this mutation can coexist with other genetic alterations (such as HER2).

    A few of the ways in which PIK3CA mutations are thought to play a role in breast cancer include:

    • Development of breast cancer: PIK3CA mutations appear to play an important role in oncogenesis, or the process of cancer developing in the first place. This is supported by the fact that there appears to be a high frequency of PIK3CA mutations in stage 0 breast cancer or DCIS (ductal carcinoma in situ).
    • Evading cell death: PIK3CA mutations are thought to be associated with breast cancer cell's ability to evade programmed cell death (apoptosis).
    • Ability to spread: PIK3CA mutations (the proteins produced) may enhance the ability of cancer cells to break free and migrate to other regions (metastasis).
    • Treatment resistance: PIK3CA mutations may be associated with resistance to hormonal treatments for breast cancer (endocrine resistance), resistance to targeted therapies (specifically HER2 targeted therapies), and resistance to some chemotherapy drugs.

    Prevalence and Hotspots

    The prevalence of PIK3CA mutations in breast cancer overall has been estimated in a few studies. In a 2018 study, the mutation was detected in 34.1% to 41.1% of tissue biopsies and 27.5 to 43.3 percent of liquid biopsies. The chance that an individual breast tumor will carry a PIK3CA mutation, however, varies with the receptor status of the cancer.

    Roughly 80% of mutations occur in three "hotspots" on the gene: H1047R, E545K, and E542K.

    Characteristics in Early Stage Breast Cancer

    There are some characteristics associated with PIK3CA mutations in early-stage breast cancer, according to a 2018 review published in the Journal of Clinical Oncology.

    • Receptor status: PIK3CA mutations are seen more often in tumors that are estrogen receptor-positive (ER+) and less commonly in tumors that were HER2 positive (HER+). In this study, PIK3CA mutations were found in 37% of ER+/HER2- tumors, 22% of HER2+ tumors, and 18% of ER-/HER2- tumors.
    • Age at diagnosis: The age of people with tumors harboring a PIK3CA mutation is slightly older (61 years versus 58.4 years).
    • Tumor grade: Breast tumors harboring a PIK3CA mutation tend to be less aggressive (have a lower tumor grade) than those without the mutation.
    • Tumor size: Tumors that have PIK3CA mutations tend to be diagnosed at a smaller size than those without the mutation.
    • Prognosis: While people with breast cancer harboring PIK3CA mutations were found to have better disease-free survival rates in the early years of follow-up, especially during the first five years after diagnosis, this was not true for overall survival rate. In other words, PIK3CA mutations appear to be associated with a better prognosis early on after diagnosis (especially in the kinase domain H1047R) but don't seem, at least with the current data available, to have a significant effect on long-term prognosis with breast cancer. This may be related to the timing of recurrence and may change now that medication is available for treating people with metastatic breast cancer positive for a PIK3CA mutation.
    • Timing of recurrence (early versus late): PIK3CA mutations are more common in people with estrogen receptor-positive breast cancer, and it's now known that late breast cancer recurrence (sometimes even a few decades out) is more common in this situation. Recent evidence suggests that hormone-positive breast cancers are actually more likely to recur (come back) five to ten years after diagnosis than in the first five years. In people who have breast tumors harboring PIK3CA mutations, recurrence-free survival is better than in those without the mutation in the period from diagnosis until five years post-diagnosis, and slightly better in the period from five years to ten years after diagnosis, but prognosis after ten years is unaffected.

    Effect of PIK3CA Mutations on Breast Cancer Treatments

    PIK3CA mutations have been linked to both a better and a poorer response to breast cancer treatments depending on the receptor status and type of treatment used.

    HER2 Positive Breast Cancers

    A 2014 study found that HER2 positive breast cancers with a PIK3CA mutation (21.4% of the cancers in the study) were less likely to achieve a complete pathological response when treated with a combination of neoadjuvant chemotherapy (chemotherapy given before surgery) plus HER2 targeted therapies. The chemotherapy was a combination of a taxane such as Taxol (paclitaxel) and an anthracycline such as Adriamycin (doxorubicin).

    This was true even in people who were treated with two HER2 targeted therapy drugs, both Herceptin (trastuzumab) and Tykerb (lapatinib). That said, disease-free and overall survival were similar in both those with and without the mutation.

    Several subsequent studies have found similar results, especially in people who had both HER2 positive and estrogen receptor-positive tumors.

    Metastatic Estrogen Receptor-Positive Breast Cancer

    A 2019 study found that people with metastatic ER+ breast cancer who had tumors with a PIK3CA mutation in the H1047R domain were more sensitive (responded better) to the drug Afinitor (everolimus). Afinitor is a drug that is classified as an mTOR inhibitor.

    Treatment specifically targeting the mutation is now available.

    Testing

    Testing for a PIK3CA mutation can be done on either a sample of tissue (from a biopsy) or a blood sample (liquid biopsy). A liquid biopsy is less invasive, but if the test is negative a tissue biopsy is then recommended to look for the mutation.

    Along with the approval of Piqray for people with metastatic breast cancer (MBC) with PIK3CA mutations, a companion diagnostic test Therascreen was approved. In addition to determining who may respond to Piqray, testing may help predict prognosis with early-stage breast cancer and predict response to other treatments.

    Piqray (Alpelisib) for MBC with PIK3CA Mutations

    Until recently, drugs had been evaluated for the treatment of metastatic breast cancer that targeted P13K. Unfortunately, the toxicity of these therapies (that targeted all subunits of the enzyme) limited the benefit.

    The drug Piqray (alpelisib) was the first P13K inhibitor approved for breast cancer in 2019. Unlike previous drugs, Piqray targets only the α subunit (a P13Kα subunit-specific inhibitor), the only subunit that is usually activated.

    In a 2019 phase 3 clinical trial (SOLAR-1) published in the New England Journal of Medicine, the combination of Piqray and Faslodex (fulvestrant) almost doubled the progression-free survival rate of people with metastatic breast cancer positive for PIK3CA mutations from 5.7 months to 11.0 months.

    Piqray is now approved for postmenopausal women and men with estrogen receptor-positive metastatic breast cancer who have progressed on endocrine (hormone) therapy such as tamoxifen or an aromatase inhibitor. The most common side effects include high blood sugar (hyperglycemia), rash, and diarrhea.

    A Word From Verywell

    Determining the mutations present in a breast tumor that drive growth may help to predict the behavior of these cancers, the potential response to treatments, and whether people qualify for a drug that has been found to improve progression-free survival in metastatic breast cancer. While many advances have been made in the treatment of early-stage breast cancer, metastatic breast cancer remains challenging to treat, with a median survival rate of only three years. Seeing advances in the treatment for advanced-stage cancers such as this is encouraging and needed if survival rates are to be improved.

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