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  • Review Article
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Mutation Detection of Phosphatidylinositol-4,5-bisphosphate 3-Kinase Catalytic Subunit Alpha for Treatment Guidance in Breast Cancer

  • Willy Sandhika1,2,* ,
  • Lina Patricia Gutjahr3 and
  • Lusiani Tjandra4
 Author information  Cite
Cancer Screening and Prevention   2024;3(2):91-96

doi: 10.14218/CSP.2024.00013

Abstract

Molecular analysis of breast cancer tissue has revealed that breast cancer is not a uniform disease. Each breast cancer patient has several molecular signatures that differ from those of others. Therefore, breast cancer therapy should be personalized, depending on its molecular signatures. Breast cancer with hormonal receptors can be treated with a selective estrogen receptor modulator or selective estrogen receptor degrader therapy, while breast cancer with overexpression of human epidermal growth factor receptor 2 (HER2)-neu gene responds excellently to anti-HER2-neu therapy. For patients with advanced breast cancer that already has distant metastasis and a poor prognosis, a new agent has been discovered. The phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) inhibitor has been proven effective in treating advanced breast cancer with a PIK3CA gene mutation. This therapy can be administered to HER2-negative breast cancer patients and in combination with selective estrogen receptor degrader therapy for post-menopausal patients with positive hormonal receptors. Although this treatment is effective, it cannot be given to every advanced breast cancer patient. Before administering the treatment, a PIK3CA mutation test is compulsory. PIK3CA mutation detection in breast cancer can predict the cancer’s response to the PIK3CA inhibitor, providing information on which patients will benefit from the treatment.

Keywords

Breast cancer, Personalized medicine, PIK3CA mutation, PIK3CA inhibitor, Targeted therapy, Molecular classification

Introduction

In women in the United States and worldwide, breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death.1,2 Approximately 287,850 women would be diagnosed with invasive breast cancer in the United States in 2022. In the same year, 40,920 deaths were recorded due to breast cancer. During that time, 92,700 women were projected to die from breast cancer in Europe.3 Although breast cancer in men is rare,4,5 accounting for less than 1% of breast cancer diagnoses, the same treatment is recommended for both sexes. Depending on mutations in breast cancer patients, the treatment can be adjusted if a mutation is detected.3,4 Recently, one type of mutation affecting the therapy management of advanced breast cancer patients is a mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene. Due to mutated PIK3CA genes, hyperactivation of the p110α subunit of phosphoinositide 3-kinase (PI3K) is induced.6 Thus, targeted treatment can be guided by PI3KCA mutation testing. Hence, the importance and utility of PIK3CA mutation testing in advanced breast cancer patients increases to guide treatment decisions.7 PIK3CA inhibitor therapy, such as Alpelisib, is primarily effective for somatic PIK3CA mutations in the context of breast cancer treatment, especially in human epidermal growth factor receptor 2 (HER2)-negative type and post-menopausal patients with positive hormonal receptors. Therefore, it is vitally relevant to perform PIK3CA mutation tests to detect genetic alterations in the PIK3CA gene, which plays an important role in the PI3K signaling pathway.8–10

Review contents

Personalized therapy for breast cancer

Breast cancer therapy has evolved from conventional therapy to personalized therapy (Fig. 1). Targeted therapy for breast cancer involves drugs or treatments that specifically target certain molecules or pathways involved in the growth and survival of cancer cells. The choice of targeted therapy depends on the specific characteristics of the breast cancer, such as the presence of certain receptors on the cancer cells.11,12 There are several common targeted therapies used in the treatment of breast carcinoma. (1) Tamoxifen and Aromatase Inhibitors: These are used for hormone receptor-positive breast cancers. Tamoxifen blocks the estrogen receptor, while aromatase inhibitors reduce the production of estrogen. (2) Trastuzumab: This monoclonal antibody targets the HER2 protein, which is overexpressed in some breast cancers. Trastuzumab can be used alone or in combination with chemotherapy. (3) Pertuzumab: Another HER2-targeted monoclonal antibody, often used in combination with trastuzumab. (4) Poly(ADP-ribose) polymerase (PARP) (c) Inhibitors: Drugs such as olaparib, talazoparib, and niraparib are used for breast cancers with BRCA1 or BRCA2 gene mutations. They inhibit the PARP enzyme, leading to DNA damage and cell death. (5) PI3K Inhibitors: Alpelisib is a drug that targets the PI3K pathway and is used in combination with fulvestrant for hormone receptor-positive and HER2-negative breast cancer with PIK3CA mutations.13,14

Conventional therapy and personalized therapy in Breast cancer treatment.
Fig. 1  Conventional therapy and personalized therapy in Breast cancer treatment.

HER2, human epidermal growth factor receptor 2; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.

Hormone receptor status and endocrine-based therapy for breast cancer

Estrogen receptor (ER) and progesterone receptor (PR) assays help classify breast cancers into subtypes based on hormonal receptor status. This classification is crucial for tailoring treatment strategies.15,16 Hormone receptor-positive breast cancers are often more responsive to hormonal therapies, while receptor-negative cancers may be treated with other approaches, such as chemotherapy. ER-positive (ER+)/PR-positive (PR+) breast cancers tend to have a relatively better prognosis compared to ER-negative (ER-)/PR-negative (PR-) cancers. ER- and PR- breast cancers may have a less favorable prognosis compared to hormone receptor-positive tumors. These receptors allow cancer cells to respond to hormones like estrogen and progesterone, promoting their growth.17 ER+/PR+ breast cancer, constituting approximately 70% of breast cancers, is the most common subtype.18 Since ER+/PR+ tumors overexpress multiple ER/PR, hormone therapies are often used for their treatment.17,19 Endocrine-based therapies are standard for hormonal receptor (HR)-positive breast cancer. These therapies target hormone receptors (ER and PR) and hormone signaling pathways driving HR-positive (HR+) breast cancer cell growth. Endocrine therapies include aromatase inhibitors (e.g., letrozole, anastrozole), selective estrogen receptor modulators (SERMs, e.g., tamoxifen), and selective estrogen receptor degraders (SERDs, e.g., fulvestrant).17,19,20

Tamoxifen, a common SERM in breast cancer treatment, has a dual effect on estrogen receptors. It acts as an agonist (mimicking the action of estrogen) in certain tissues (e.g., bone), where estrogen is beneficial, and as an antagonist in breast tissue, blocking estrogen receptors to inhibit estrogen’s growth-promoting effects on cancer cells. Tamoxifen is used in both premenopausal and postmenopausal women with ER+/PR+ breast cancer as adjuvant therapy to reduce recurrence risk post-surgery and in advanced stages of breast cancer.21 Fulvestrant, a common SERD in breast cancer treatment, works by binding to estrogen receptors and promoting their degradation, reducing their numbers within the cell. Unlike SERMs, SERDs do not have agonistic effects and act purely as antagonists, effectively blocking the estrogen signaling pathway. Fulvestrant is typically used in postmenopausal women with advanced ER+/PR+ breast cancer that has progressed after other hormonal therapies. The key difference between SERMs and SERDs lies in their mechanisms of action. SERMs have dual effects, acting as both agonists and antagonists, while SERDs specifically promote estrogen receptor degradation without exhibiting agonistic effects.22

Despite the initial effectiveness of endocrine-based therapies, resistance can develop over time in advanced cases of ER+/PR+ breast cancer, as well as in some early stages of this malignancy.18 Tumor cells may adapt and find ways to bypass or resist the inhibitory effects of these therapies. In a recent study, HR+ and HER2- metastatic breast cancers were found to respond poorly to certain chemotherapy treatments and showed lower survival rates. In HR+ breast cancer, PIK3CA mutations can contribute to resistance to endocrine-based therapies and may drive cancer progression.19,20 To improve progression-free survival rates, new treatments are needed. Since PIK3CA mutations are associated with HR+, HER2- breast cancer, a PIK3CA inhibitor was designed. It is expected to reduce hyperactivation of PIK in postmenopausal women and men with advanced breast cancer whose tumors possess this combination of mutations. In addition to endocrine-based therapy, which hinders estrogen’s impact on cancer cells, this oral inhibitor drug is administered.7,10,18,23–27

HER2/ c-erbB2 status in breast cancer

HER2 status is a critical factor in the diagnosis and treatment of breast cancer. HER2 is a protein that can promote the growth of cancer cells when it is overexpressed or amplified. Determining HER2 status is crucial because it helps classify breast cancer into different subtypes and guides treatment decisions. HER2 status assays in breast cancer patients have been used for (1) Classification of breast cancer subtypes: If the breast cancer cells overexpress or have amplified levels of the HER2 protein, the tumor is classified as HER2-positive (HER2+). Approximately 15–20% of breast cancers are HER2+. HER2-negative (HER2-): Tumors without overexpression or amplification of HER2 are classified as HER2-. (2) Prognostic Information: HER2+ breast cancers tend to be more aggressive and have a higher risk of recurrence compared to HER2- tumors. (3) Treatment Implications: HER2+ breast cancers are typically more responsive to targeted therapies directed against the HER2 protein, such as Trastuzumab.28

Some breast cancers overexpress the HER2 protein and are classified as HER2+. HER2 is a receptor tyrosine kinase that can lead to aggressive growth and behavior of cancer cells when overexpressed.17 HER2+ breast cancer is typically treated with targeted therapies such as HER2 inhibitors, e.g., trastuzumab, pertuzumab, or ado-trastuzumab emtansine, which specifically target HER2. In some cases, breast cancers may have both HER2 overexpression and PIK3CA mutations. HER2- breast cancer lacks overexpression or amplification of the HER2 gene and HER2 protein.19

PIK3CA mutation and PIK3CA inhibitor therapy for breast cancer

The PI3K signaling pathway is a crucial cellular pathway that regulates various processes such as cell growth, survival, proliferation, and metabolism. It plays a pivotal role in transmitting signals from cell surface receptors to intracellular effectors, influencing cellular responses to extracellular stimuli. The key functions of the PI3K pathway include (1) Cell growth and survival: The PI3K pathway promotes cell growth and survival by activating signaling cascades that stimulate protein synthesis and inhibit programmed cell death (apoptosis). Activation of Akt plays a central role in promoting cell survival by regulating the expression of anti-apoptotic proteins and inhibiting pro-apoptotic factors. (2) Cell proliferation: The pathway is involved in regulating the cell cycle and promoting cell proliferation. Activation of PI3K signaling can stimulate cell division by influencing the expression of genes involved in cell cycle progression.29,30

Negative regulation of the PI3K signaling pathway: To maintain cellular homeostasis, the PI3K pathway is tightly regulated by negative feedback mechanisms. For example, the tumor suppressor phosphatase and tensin homolog dephosphorylates PIP3, counteracting the action of PI3K.31

Germline mutations in the PIK3CA gene are hereditary mutations present in a patient’s inherited DNA and are typically found in all cells of the body, including normal and cancerous cells. While germline PIK3CA mutations can cause various conditions, such as PIK3CA-related overgrowth syndromes, somatic PIK3CA mutations occur specifically within cancer cells.32–34 These somatic mutations are genetic changes that develop during a person’s lifetime and are acquired mutations not present in the patient’s inherited DNA.35 Somatic mutations in the PIK3CA gene are found in many types of cancer, including brain, breast, lung, ovary, stomach, and colorectal cancers. These mutations alter single amino acids in the p110α protein, leading to activation of the PI3K signaling pathway in cancer cells.35–39

Functions regulated by this pathway in cancer cells include angiogenesis, cell proliferation, cell migration, glucose metabolism, survival, and translational regulation of protein synthesis.40 In tumor tissues, activating somatic missense mutations of the PIK3CA gene have been identified to increase the kinase activity of the PI3Kα protein, contributing to cellular transformation in different human cancers.41 However, researchers suspect that PIK3CA gene mutations alone do not cause cancer but rather influence cancer risk, often in combination with mutations in other genes. The oral drug alpelisib has been approved by the U.S. Food and Drug Administration in combination with endocrine therapy fulvestrant to treat breast cancer with mutations in the PIK3CA.36

Detection of molecular signature in cancer cells

The molecular signature of cancer cells can be detected by immunohistochemistry techniques for protein expression, such as ER/PR and HER2 neu protein. On the other hand, molecular techniques such as polymerase chain reaction (PCR) are needed for the detection of HER2 neu gene amplification and PIK3CA gene mutation (Fig. 2).

Detection techniques of molecular signature in cancer cells.
Fig. 2  Detection techniques of molecular signature in cancer cells.

HER2, human epidermal growth factor receptor 2; PCR, polymerase chain reaction; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.

Different methods for screening PIK3CA mutations have been described in the past. With the approval of the novel drug alpelisib, detection of mutations in the PIK3CA gene has become increasingly important. Immunohistochemistry assays can detect mutated proteins expressed from the PIK3CA gene, although they are not intended to predict response to alpelisib therapy. While not directly detecting PIK3CA mutations, immunohistochemistry for protein phosphatase and tensin homolog, a key negative regulator of the PI3K pathway, may provide indirect information about pathway dysregulation. Hu et al.42 detected PIK3CA mutations using immunohistochemistry assays in triple-negative breast cancer. Fluorescent in situ hybridization (FISH) assays can also be used to detect PIK3CA mutations, but their results are not intended to predict therapy response with alpelisib.43 FISH, although less commonly used for PIK3CA specifically, can detect gene amplifications or structural alterations by using fluorescent probes that bind to specific DNA sequences, visualized under a microscope. In cervical carcinoma, both FISH and PCR can assess PIK3CA gene amplification and mutation.44 PCR selectively amplifies the region of interest in the PIK3CA gene, followed by sequencing to identify mutations. Techniques such as allele-specific PCR or quantitative PCR can detect specific mutations. Cossu-Rocca et al.45 utilized a real-time PCR procedure with the cobas® DNA Sample Preparation Kit (Roche Mannheim, Germany) to detect mutations in the PIK3CA gene in isolated genomic DNA from triple-negative breast cancer patients. For analyzing tumor tissue specimens and/or plasma specimens with isolated circulating tumor DNA to select patients with PIK3CA gene mutations, the U.S. Food and Drug Administration approved the therascreen® PIK3CA RGQ PCR Kit in May 2019.8

The importance of PIK3CA mutation detection in breast cancer and detection method

Personalized therapy for breast cancer depends on its molecular signature. In hormone receptor-positive breast cancer (HR+), patients can be treated with tamoxifen or aromatase inhibitors. However, when the cancer progresses to an advanced stage, there is new hope with PIK3CA inhibitor treatment. Pathology examination plays a pivotal role in detecting specific mutations crucial for personalized treatment.46 The presence of PIK3CA mutations in HR+ breast cancer can significantly impact treatment decisions. Targeted therapies that inhibit the PI3K pathway, such as the PIK3CA inhibitor alpelisib, have been developed to address resistance associated with these mutations. Clinical trials such as the SOLAR-1 trial have shown significantly improved progression-free survival in postmenopausal women and men diagnosed with HR+, HER2-, PIK3CA-mutated advanced breast cancer when treated with a combination of alpelisib and fulvestrant, an endocrine therapy.23,25 However, PIK3CA inhibitor therapy is not recommended for early breast cancer.47 The use of alpelisib in combination with fulvestrant exemplifies personalized medicine in breast cancer treatment, allowing oncologists to tailor therapy based on the specific genetic and molecular characteristics of the tumor. Molecular profiling of breast cancer tumors by pathologists, including the identification of PIK3CA mutations, HER2 amplification, and other molecular alterations, is essential for selecting appropriate targeted therapies.10,24

Conclusions

Personalized therapy has been developed for breast cancer treatment. Therefore, it is important to have molecular classification for every breast cancer patient. The discovery of PIK3CA inhibitors has opened a new way to treat advanced breast cancer that is HER2-negative. It can be used in combination with SERD therapy for hormone receptor-positive breast cancer. Detection of PIK3CA mutations is necessary to determine which patients benefit from PIK3CA inhibitor therapy.

Declarations

Acknowledgement

The authors would like to thank Yedida Gracia Sandika, a student at the Medical Faculty Universitas Airlangga for preparing and proofreading this manuscript.

Funding

None.

Conflict of interest

The authors declare that there is no conflict of interest related to this publication.

Authors’ contributions

Writing of the main concept of this article (WS), writing of the details of article (LPG); technical support and manuscript revision (LT). All authors have made a significant contribution to this study and have approved the final manuscript.

References

  1. DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding Sauer A, et al. Breast cancer statistics, 2019. CA Cancer J Clin 2019;69(6):438-451 View Article PubMed/NCBI
  2. Decker JT, Ma JA, Shea LD, Jeruss JS. Implications of TGFβ Signaling and CDK Inhibition for the Treatment of Breast Cancer. Cancers (Basel) 2021;13(21):5343 View Article PubMed/NCBI
  3. QIAGEN. Therascreen PIK3CA RGQ PCR kit. Available from: https://www.qiagen.com/us/products/diagnostics-and-clinical-research/oncology/therascreen-solid-tumor/therascreen-pik3ca-rgq-pcr-kit-us. Accessed February 18, 2024
  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68(1):7-30 View Article PubMed/NCBI
  5. Bratulic S, Gatto F, Nielsen J. The translational status of cancer liquid biopsies. Regen Eng Transl Med 2021;7:312-352 View Article
  6. Grill S, Klein E. Incorporating Genomic and Genetic Testing into the Treatment of Metastatic Luminal Breast Cancer. Breast Care (Basel) 2021;16(2):101-107 View Article PubMed/NCBI
  7. Toppmeyer DL, Press MF. Testing considerations for phosphatidylinositol-3-kinase catalytic subunit alpha as an emerging biomarker in advanced breast cancer. Cancer Med 2020;9(18):6463-6472 View Article PubMed/NCBI
  8. Narayan P, Prowell TM, Gao JJ, Fernandes LL, Li E, Jiang X, et al. FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer. Clin Cancer Res 2021;27(7):1842-1849 View Article PubMed/NCBI
  9. Raphael A, Salmon-Divon M, Epstein J, Zahavi T, Sonnenblick A, Shachar SS. Alpelisib Efficacy in Hormone Receptor-Positive HER2-Negative PIK3CA-Mutant Advanced Breast Cancer Post-Everolimus Treatment. Genes (Basel) 2022;13(10):1763 View Article PubMed/NCBI
  10. Juric D, Rodon J, Tabernero J, Janku F, Burris HA, Schellens JHM, et al. Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. J Clin Oncol 2018;36(13):1291-1299 View Article PubMed/NCBI
  11. Ding S, Chen X, Shen K. Single-cell RNA sequencing in breast cancer: Understanding tumor heterogeneity and paving roads to individualized therapy. Cancer Commun (Lond) 2020;40(8):329-344 View Article PubMed/NCBI
  12. Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 2017;389(10075):1195-1205 View Article PubMed/NCBI
  13. Franzese E, Centonze S, Diana A, Carlino F, Guerrera LP, Di Napoli M, et al. PARP inhibitors in ovarian cancer. Cancer Treat Rev 2019;73:1-9 View Article PubMed/NCBI
  14. Castel P, Toska E, Engelman JA, Scaltriti M. The present and future of PI3K inhibitors for cancer therapy. Nat Cancer 2021;2(6):587-597 View Article PubMed/NCBI
  15. Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther 2018;186:1-24 View Article PubMed/NCBI
  16. Wu N, Fu F, Chen L, Lin Y, Yang P, Wang C. Single hormone receptor-positive breast cancer patients experienced poor survival outcomes: a systematic review and meta-analysis. Clin Transl Oncol 2020;22(4):474-485 View Article PubMed/NCBI
  17. Andrahennadi S, Sami A, Manna M, Pauls M, Ahmed S. Current Landscape of Targeted Therapy in Hormone Receptor-Positive and HER2-Negative Breast Cancer. Curr Oncol 2021;28(3):1803-1822 View Article PubMed/NCBI
  18. Stravodimou A, Voutsadakis IA. The Future of ER+/HER2- Metastatic Breast Cancer Therapy: Beyond PI3K Inhibitors. Anticancer Res 2020;40(9):4829-4841 View Article PubMed/NCBI
  19. Zouein J, Noujaim C, Kourie HR. Targeting PIK3CA in HER2-positive breast cancer: what are the opportunities and the challenges?. Biomark Med 2021;15(9):609-613 View Article PubMed/NCBI
  20. Goldberg J, Pastorello RG, Vallius T, Davis J, Cui YX, Agudo J, et al. The Immunology of Hormone Receptor Positive Breast Cancer. Front Immunol 2021;12:674192 View Article PubMed/NCBI
  21. Hernando C, Ortega-Morillo B, Tapia M, Moragón S, Martínez MT, Eroles P, et al. Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective. Int J Mol Sci 2021;22(15):7812 View Article PubMed/NCBI
  22. Soleja M, Raj GV, Unni N. An evaluation of fulvestrant for the treatment of metastatic breast cancer. Expert Opin Pharmacother 2019;20(15):1819-1829 View Article PubMed/NCBI
  23. Rugo HS, André F, Yamashita T, Cerda H, Toledano I, Stemmer SM, et al. Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Ann Oncol 2020;31(8):1001-1010 View Article PubMed/NCBI
  24. Rugo HS, Lerebours F, Ciruelos E, Drullinsky P, Ruiz-Borrego M, Neven P, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol 2021;22(4):489-498 View Article PubMed/NCBI
  25. André F, Ciruelos EM, Juric D, Loibl S, Campone M, Mayer IA, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol 2021;32(2):208-217 View Article PubMed/NCBI
  26. Juric D, Janku F, Rodón J, Burris HA, Mayer IA, Schuler M, et al. Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncol 2019;5(2):e184475 View Article PubMed/NCBI
  27. André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2019;380(20):1929-1940 View Article PubMed/NCBI
  28. Pernas S, Tolaney SM. Management of Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. JCO Oncol Pract 2021;17(6):320-330 View Article PubMed/NCBI
  29. Koundouros N, Poulogiannis G. Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer. Front Oncol 2018;8:160 View Article PubMed/NCBI
  30. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K Pathway in Human Disease. Cell 2017;170(4):605-635 View Article PubMed/NCBI
  31. Liu Y, Liu C, Tan T, Li S, Tang S, Chen X. Sinomenine sensitizes human gastric cancer cells to cisplatin through negative regulation of PI3K/AKT/Wnt signaling pathway. Anticancer Drugs 2019;30(10):983-990 View Article PubMed/NCBI
  32. Rivière JB, Mirzaa GM, O’Roak BJ, Beddaoui M, Alcantara D, Conway RL, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 2012;44(8):934-940 View Article PubMed/NCBI
  33. Vahidnezhad H, Youssefian L, Uitto J. Klippel-Trenaunay syndrome belongs to the PIK3CA-related overgrowth spectrum (PROS). Exp Dermatol 2016;25(1):17-19 View Article PubMed/NCBI
  34. Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, et al. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A 2015;167A(2):287-295 View Article PubMed/NCBI
  35. Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ, Salpekar A, et al. Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 2008;453(7195):662-666 View Article PubMed/NCBI
  36. Denorme P, Morren MA, Hollants S, Spaepen M, Suaer K, Zutterman N, et al. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum: A brief report. Pediatr Dermatol 2018;35(3):e186-e188 View Article PubMed/NCBI
  37. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell 2017;171(3):540-556.e25 View Article PubMed/NCBI
  38. Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, et al. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet 2012;44(8):928-933 View Article PubMed/NCBI
  39. Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet 2012;90(6):1108-1115 View Article PubMed/NCBI
  40. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001;17:615-675 View Article PubMed/NCBI
  41. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304(5670):554 View Article PubMed/NCBI
  42. Hu H, Zhu J, Zhong Y, Geng R, Ji Y, Guan Q, et al. PIK3CA mutation confers resistance to chemotherapy in triple-negative breast cancer by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway. Ann Transl Med 2021;9(5):410 View Article PubMed/NCBI
  43. Chia SKL, Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, et al. PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial. Breast Cancer Res 2019;21(1):39 View Article PubMed/NCBI
  44. Razia S, Nakayama K, Nakamura K, Ishibashi T, Ishikawa M, Minamoto T, et al. Clinicopathological and biological analysis of PIK3CA mutation and amplification in cervical carcinomas. Exp Ther Med 2019;18(3):2278-2284 View Article PubMed/NCBI
  45. Cossu-Rocca P, Orrù S, Muroni MR, Sanges F, Sotgiu G, Ena S, et al. Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer. PLoS One 2015;10(11):e0141763 View Article PubMed/NCBI
  46. Han HS, Magliocco AM. Molecular Testing and the Pathologist’s Role in Clinical Trials of Breast Cancer. Clin Breast Cancer 2016;16(3):166-179 View Article PubMed/NCBI
  47. Fuso P, Muratore M, D’Angelo T, Paris I, Carbognin L, Tiberi G, et al. PI3K Inhibitors in Advanced Breast Cancer: The Past, The Present, New Challenges and Future Perspectives. Cancers (Basel) 2022;14(9):2161 View Article PubMed/NCBI
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  • Cancer Screening and Prevention
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  • eISSN 2835-3315

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Mutation Detection of Phosphatidylinositol-4,5-bisphosphate 3-Kinase Catalytic Subunit Alpha for Treatment Guidance in Breast Cancer

Willy Sandhika, Lina Patricia Gutjahr, Lusiani Tjandra
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