Tumor PIK3CA Genotype and Prognosis in Early-Stage Breast Cancer: A Pooled Analysis of Individual Patient Data.

Purpose Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data. Patients and Methods Associations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive diseasefree survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes. Results Data from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P, .001). Prevalence of PIK3CAmutationswas 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84;P, .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P , .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); . 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS (P = .043), but not for the DDFS and OS end points. Conclusion In this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors. J Clin Oncol 36:981-990. © 2018 by American Society of Clinical Oncology

[1]  S. Loi,et al.  Abstract S1-10: Clinical implications of somatic mutations in post-menopausal early-stage estrogen receptor (ER)-positive HER2-negative breast cancer (BC): Results from the BIG 1-98 study , 2017 .

[2]  H. Gogas,et al.  Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study , 2015, PloS one.

[3]  D. Rea,et al.  Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Diether Lambrechts,et al.  Biology of breast cancer during pregnancy using genomic profiling. , 2014, Endocrine-related cancer.

[5]  A. Giobbie-Hurder,et al.  Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. , 2014, The New England journal of medicine.

[6]  S. Loi,et al.  PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data , 2014, Breast Cancer Research.

[7]  C. Sotiriou,et al.  Somatic Mutation Profiling and Associations With Prognosis and Trastuzumab Benefit in Early Breast Cancer , 2013, Journal of the National Cancer Institute.

[8]  R. Rad,et al.  Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. , 2013, Cancer cell.

[9]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[10]  K. Kalland,et al.  High-Throughput Mutation Profiling of Primary and Metastatic Endometrial Cancers Identifies KRAS, FGFR2 and PIK3CA to Be Frequently Mutated , 2012, PloS one.

[11]  S. Loi,et al.  Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway inhibition: a breakthrough in the management of luminal (ER+/HER2−) breast cancers? , 2012, Current opinion in oncology.

[12]  A. Laenkholm,et al.  PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[13]  A. Sivachenko,et al.  Sequence analysis of mutations and translocations across breast cancer subtypes , 2012, Nature.

[14]  M. Shackleton,et al.  Physiological Levels of Pik3ca H1047R Mutation in the Mouse Mammary Gland Results in Ductal Hyperplasia and Formation of ERα-Positive Tumors , 2012, PloS one.

[15]  A. Børresen-Dale,et al.  The landscape of cancer genes and mutational processes in breast cancer , 2012, Nature.

[16]  E. Lerma,et al.  Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas , 2012, British Journal of Cancer.

[17]  Rosette Lidereau,et al.  PIK3CA mutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgroups , 2012, Breast Cancer Research.

[18]  Y. Drouet,et al.  Mutational characterization of individual breast tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in different subtypes , 2012, Breast Cancer Research and Treatment.

[19]  J. Balko,et al.  Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  D. Carrasco,et al.  PIK3CA mutations in in situ and invasive breast carcinomas. , 2010, Cancer research.

[21]  Paul Ellis,et al.  PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor–positive breast cancer , 2010, Proceedings of the National Academy of Sciences.

[22]  Robert L Sutherland,et al.  PI3K pathway activation in breast cancer is associated with the basal‐like phenotype and cancer‐specific mortality , 2010, International journal of cancer.

[23]  T. Mukohara,et al.  Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  J. Cuzick,et al.  Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  Jeffrey Wyckoff,et al.  Differential enhancement of breast cancer cell motility and metastasis by helical and kinase domain mutations of class IA phosphoinositide 3-kinase. , 2009, Cancer research.

[26]  W. Gerald,et al.  PIK3CA Mutation Associates with Improved Outcome in Breast Cancer , 2009, Clinical Cancer Research.

[27]  V. Velculescu,et al.  Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. , 2009, The American journal of pathology.

[28]  G. Rewcastle,et al.  Functional differences between two classes of oncogenic mutation in the PIK3CA gene. , 2009, Biochemical and biophysical research communications.

[29]  Zhi Hu,et al.  An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. , 2008, Cancer research.

[30]  Li Zhao,et al.  Helical domain and kinase domain mutations in p110α of phosphatidylinositol 3-kinase induce gain of function by different mechanisms , 2008, Proceedings of the National Academy of Sciences.

[31]  R. Schiff,et al.  Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. , 2008, Cancer research.

[32]  G. Mills,et al.  A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. , 2007, Cancer cell.

[33]  A. Marchetti,et al.  Different Prognostic Roles of Mutations in the Helical and Kinase Domains of the PIK3CA Gene in Breast Carcinomas , 2007, Clinical Cancer Research.

[34]  L. Skoog,et al.  PIK3CA Mutations and PTEN Loss Correlate with Similar Prognostic Factors and Are Not Mutually Exclusive in Breast Cancer , 2007, Clinical Cancer Research.

[35]  Sally Hunsberger,et al.  Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  M. Monden,et al.  Clinicopathologic Analysis of Breast Cancers with PIK3CA Mutations in Japanese Women , 2007, Clinical Cancer Research.

[37]  Ji Luo,et al.  The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism , 2006, Nature Reviews Genetics.

[38]  B. Iacopetta,et al.  PIK3CA mutations in breast cancer are associated with poor outcome , 2006, Breast Cancer Research and Treatment.

[39]  J. Engelman,et al.  Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. , 2005, Cancer research.

[40]  S. Schwartz,et al.  The prevalence of PIK3CA mutations in gastric and colon cancer. , 2005, European journal of cancer.

[41]  Carlo Rago,et al.  Mutant PIK3CA promotes cell growth and invasion of human cancer cells. , 2005, Cancer cell.

[42]  Hanina Hibshoosh,et al.  PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. , 2005, Cancer research.

[43]  P. Vogt,et al.  Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  M. Loda,et al.  The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.