Abstract PS5-06: Prospective testing for PIK3CA/AKT1/PTEN alterations in tumor tissue from 1440 patients with advanced hormone receptor-positive HER2-negative breast cancer (HR+/HER2- BC) or triple-negative breast cancer (TNBC) screened for the IPATunity130 randomized phase 3 trial
Authors: Savage Heidi , Lin Wendy , Oliveira Mafalda , Barrios Carlos , O’Shaughnessy Joyce , Turner Nicholas , Dent Rebecca , Isakoff Steven J , Saji Shigehira , Lian Qinshu , Bradley Denise , Reilly Sarah-Jayne , Hinton Heather , Wongchenko Matthew J , Mani Aruna , Kim Sung-Bae 
Published: February 2021

Abstract
Background The PI3K/AKT signaling pathway plays a significant role in both HR+ BC and TNBC. IPATunity130 is a double-blind, placebo-controlled, randomized phase 3 trial of ipatasertib in combination with paclitaxel in patients with PI3K/AKT1/PTEN-altered HR+ or TNBC. A next-generation sequencing (NGS)-based assay from Foundation Medicine Inc. (FMI) was used to select patients prospectively for enrollment in this trial.Patients and methods An investigational clinical trial assay (CTA) of a composite 3-gene biomarker signature [Kim, Lancet Oncol 2017] based on the FoundationOne® CDx assay was used to identify patients with PI3K/AKT pathway-activated tumors as eligible for enrollment in IPATunity130 (NCT03337724). Qualifying alterations for the 3-gene signature (referred to as ‘biomarker-positive’) comprised activating mutations in PIK3CA and/or AKT1, and/or loss of function (LOF) alterations in PTEN represented by homozygous or heterozygous deletions, dominant-negative mutations, or inactivating mutations under loss of heterozygosity. Study sites were required to submit formalin-fixed paraffin-embedded archival or fresh biopsy tissue derived from primary or metastatic tumors for patient screening. IPATunity130 includes three independent cohorts: Cohort A (biomarker-positive TNBC); Cohort B (biomarker-positive HR+/HER2– BC); and Cohort C (biomarker-negative TNBC). Results In total, 1736 patients were screened, from whom 1690 samples were tested by FMI. Of these, 1475 (87%) produced a valid NGS result. The remaining 215 (13%) failed quality control for reasons including insufficient tissue, DNA yield, lab error, and computational failure. Alteration status for PIK3CA and/or AKT1 and/or PTEN was positive in 703 (49%) of 1440 CTA-evaluable samples. In the HR+/HER2– cohort, the breakdown of CTA-positive samples was 301/356 (85%) PIK3CA/AKT1 mutations and 86/356 (24%) PTEN LOF alterations. In TNBC, 183/347 (53%) had PIK3CA/AKT1 mutations and 193/347 (56%) had PTEN LOF alterations. CTA results according to baseline characteristics are shown overall and by subtype below.
The most common mutations detected outside the 3-gene biomarker signature in the screened population were in the TP53, BRCA1, RB1, BRCA2, and NF1 genes in the TNBC cohort and the TP53, GATA3, CDH1, MAP3K1, and ESR1 genes in the HR+/HER2– cohort. In the HR+/HER2– cohort, 30 (14%) of 213 metastatic tumors had ESR1 mutations compared with 10/414 (2%) primary tumors. Tumor BRCA1 mutations were more common in patients aged ≤50 years whereas MAP3K1 mutations were more common in those aged &gt;50 years.Conclusions IPATunity130 is the first reported pivotal trial to utilize the 3-gene biomarker CTA in HR+/HER2– BC and TNBC to screen for patients with PI3K/AKT pathway-activated tumors. The 3-gene biomarker CTA detected alterations in 49% of screened patients, with a higher prevalence of PIK3CA/AKT1/PTEN alterations in HR+/HER2– BC than TNBC. Additional analyses are planned to assess correlations between clinical outcomes and tumor characteristics.
SubgroupPIK3CA/AKT1/PTEN alteration, n/N (%)OverallHR+/HER2–TNBCAll patient samples703/1440 (49)356/647 (55)347/793 (44)Age, years≤50219/475 (46)99/195 (51)120/280 (43)&gt;50484/965 (50)257/452 (57)227/513 (44)Sample sourcePrimary456/941 (48)232/414 (56)224/527 (43)Metastatic222/448 (50)112/213 (53)110/235 (47)Geographic regionNorth America60/102 (59)33/49 (67)27/53 (51)Asia-Pacific172/330 (52)81/145 (56)91/185 (49)Europe301/633 (48)171/310 (55)130/323 (40)Rest of world170/375 (45)71/143 (50)99/232 (43)
Citation Format: Heidi Savage, Wendy Lin, Mafalda Oliveira, Carlos Barrios, Joyce O’Shaughnessy, Nicholas Turner, Rebecca Dent, Steven J Isakoff, Shigehira Saji, Qinshu Lian, Denise Bradley, Sarah-Jayne Reilly, Heather Hinton, Matthew J Wongchenko, Aruna Mani, Sung-Bae Kim. Prospective testing for PIK3CA/AKT1/PTEN alterations in tumor tissue from 1440 patients with advanced hormone receptor-positive HER2-negative breast cancer (HR+/HER2- BC) or triple-negative breast cancer (TNBC) screened for the IPATunity130 randomized phase 3 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-06.