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Tumor PIK3CA genotype and prognosis in early-stage breast cancer : A pooled analysis of individual patient data

Zardavas, Dimitrios; Te Marvelde, Luc; Milne, Roger L.; Fumagalli, Debora; Fountzilas, George; Kotoula, Vassiliki; Razis, Evangelia; Papaxoinis, George; Joensuu, Heikki and Moynahan, Mary Ellen, et al. (2018) In Journal of Clinical Oncology 36(10). p.981-990
Abstract

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 disease-free 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... (More)

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 disease-free 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 PIK3CA mutations was 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.

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@article{1b5cd624-1b72-4b9b-aa8f-0e105942a187,
  abstract     = {<p>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 disease-free 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 PIK3CA mutations was 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.</p>},
  author       = {Zardavas, Dimitrios and Te Marvelde, Luc and Milne, Roger L. and Fumagalli, Debora and Fountzilas, George and Kotoula, Vassiliki and Razis, Evangelia and Papaxoinis, George and Joensuu, Heikki and Moynahan, Mary Ellen and Hennessy, Bryan T. and Bieche, Ivan and Saal, Lao H. and Stal, Olle and Iacopetta, Barry and Jensen, Jeanette Dupont and O'Toole, Sandra and Lopez-Knowles, Elena and Barbaraeschi, Mattia and Noguchi, Shinzaburo and Azim, Hatem A. and Lerma, Enrique and Bachelot, Thomas and Wang, Qing and Perez-Tenorio, Gizeh and Can De Velde, Cornelis J.H. and Rea, Daniel W. and Sabine, Vicky and Bartlett, John M.S. and Sotiriou, Christos and Michiels, Stefan and Loi, Sherene},
  issn         = {0732-183X},
  language     = {eng},
  month        = {01},
  number       = {10},
  pages        = {981--990},
  publisher    = {American Society of Clinical Oncology},
  series       = {Journal of Clinical Oncology},
  title        = {Tumor PIK3CA genotype and prognosis in early-stage breast cancer : A pooled analysis of individual patient data},
  url          = {http://dx.doi.org/10.1200/JCO.2017.74.8301},
  volume       = {36},
  year         = {2018},
}