Association of PIK3CA Mutation With Pathologic Complete Response and Outcome by Hormone Receptor Status and Intrinsic Subtype in Early-Stage ERBB2/HER2-Positive Breast Cancer.

Autor:	Zagami P; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.; Division of Medical Oncology, University of Milan, Milan, Italy., Fernandez-Martinez A; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.; Department of Genetics, University of North Carolina, Chapel Hill., Rashid NU; Department of Biostatistics, University of North Carolina, Chapel Hill., Hoadley KA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.; Department of Genetics, University of North Carolina, Chapel Hill., Spears PA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill., Curigliano G; Division of Medical Oncology, University of Milan, Milan, Italy.; Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy., Perou CM; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.; Department of Genetics, University of North Carolina, Chapel Hill., Carey LA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.; Division of Medical Oncology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill.
Jazyk:	angličtina
Zdroj:	JAMA network open [JAMA Netw Open] 2023 Dec 01; Vol. 6 (12), pp. e2348814. Date of Electronic Publication: 2023 Dec 01.
DOI:	10.1001/jamanetworkopen.2023.48814
Abstrakt:	Importance: PIK3CA mutations may be associated with outcomes of patients with ERBB2/HER2-positive early breast cancer (EBC). Objectives: To assess if PIK3CA mutations among patients with ERBB2/HER2-positive EBC are associated with treatment response and outcome, and if these associations vary by hormone receptor (HR) status or intrinsic molecular subtype (IMS). Design, Setting, and Participants: This cohort study derived data on 184 patients from the phase 3 neoadjuvant Cancer and Leukemia Group B (CALGB) 40601 trial that enrolled patients with ERBB2/HER2-positive EBC in North America between January 1, 2008, and December 31, 2012. Participants received neoadjuvant paclitaxel with trastuzumab, lapatinib, or both. Statistical analysis was performed from March 23, 2022, to March 9, 2023. Exposures: Gene expression profiling by RNA sequencing with Prediction Analysis of Microarray 50-determined IMS and PIK3CA mutations from whole-exome sequencing were obtained from pretreatment biopsies from 184 of 305 trial participants. Main Outcomes and Measures: The primary end point was pathologic complete response (pCR) and the secondary end point of event-free survival (EFS). The association of PIK3CA mutations with pCR and EFS by HR status and IMS was estimated using logistic and Cox proportional hazards regression models. Results: All 184 participants were women, with a median age of 49 years (range 24-75 years). A total of 121 participants (66%) had clinical stage II tumors; 32 (17%) had PIK3CA mutations, most frequently H1047R (38% [12 of 32]) and E545K (22% [7 of 32]). PIK3CA mutations were present in 20 of 102 cases of HR-positive EBC (20%) and 12 of 82 cases HR-negative EBC (15%) and varied by IMS (luminal B, 9 of 25 [36%]; luminal A, 2 of 21 [10%]; and ERBB2/HER2-enriched tumors, 19 of 102 [19%]). Pathologic complete response rates were lower in PIK3CA mutated than PIK3CA wild type in the overall population (34% [11 of 32] vs 49% [74 of 152]; P = .14) and were significantly different among those receiving trastuzumab (30% [7 of 23] vs 54% [63 of 117]; P = .045). At a median follow-up of 9 years, PIK3CA mutations were significantly associated with worse EFS in the overall cohort (hazard ratio, 2.58 [95% CI, 1.24-5.35]; P = .01), which persisted in a multivariable model including pCR, HR status, stage, and IMS (hazard ratio, 2.52 [95% CI, 1.16-5.47]; P = .02). The negative association of PIK3CA mutation was significant in HR-positive (hazard ratio, 3.60 [95% CI, 1.45-8.96]; P = .006) and luminal subtypes (hazard ratio, 4.84 [95% CI, 1.08-21.70]; P = .04), but not in nonluminal and HR-negative tumors. Conclusions and Relevance: In ERBB2/HER2-positive EBC, PIK3CA mutations were associated with lower pCR rates and independently associated with worse long-term EFS. These findings appear to be associated with PIK3CA mutations in HR-positive and luminal EBC.
Databáze:	MEDLINE
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