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Supplementary Figure S3: In vitro effects of PTEN loss on taselisib sensitivity in PIK3CA-mutant breast cancer cells.

The identification of early breast cancer patients who may benefit from adjuvant chemotherapy has evolved to include assessment of clinicopathologic features such as tumor size and nodal status, as well as several gene-expression profiles for ER-positive, HER2-negative cancers. However, these tools do not reliably identify patients at the greatest risk of recurrence. The mutation and copy-number landscape of triple-negative breast cancer (TNBC) subtypes defined by gene expression is also largely unknown, and elucidation of this landscape may shed light on novel therapeutic opportunities. The USO01062 phase III clinical trial of standard chemotherapy (with or without capecitabine) enrolled a cohort of putatively high-risk patients based on clinical features, yet only observed a 5-year disease-free survival event rate of 11.6%. In order to uncover genomic aberrations associated with recurrence, a targeted next-generation sequencing panel was used to compare tumor specimens from patients who had a recurrence event with a matched set who did not. The somatic mutation and copy-number alteration landscapes of high-risk early breast cancer patients were characterized and alterations associated with relapse were identified. Tumor mutational burden was evaluated but was not prognostic in this study, nor did it correlate with PDL1 or CD8 gene expression. However, TNBC subtypes had substantial genomic heterogeneity with a distinct pattern of genomic alterations and putative underlying driver mutations.Implications:The present study uncovers a compendium of genomic alterations with utility to more precisely identify high-risk patients for adjuvant trials of novel therapeutic agents.

Supplemental Methods describing NGS and gene expression studies.

Supplementary Table S1. Patient Demographics and Disease Characteristics. Supplementary Table S2. Treatment-Related Adverse Events of Grade 3 or Higher Observed in either Cycle 1 or Cycle greater than or equal to 2. Supplementary Table S3. Adverse Events in greater than or equal to 10% of Patients Regardless of Attribution. Supplementary Table S4. Adverse Events of Grade 3 or Higher Regardless of Attribution. Supplementary Figure S1. Trellis plot of individual and fitted tumor volumes to day 21 following treatment with taselisib (GDC-0032). Supplementary Figure S2. PI3K pathway suppression was evaluated in KPL-4 tumor xenografts following a single oral dose of 1, 5 and 25 mg/kg taselisib or MCT (0.5% methylcellulose/0.2% Tween-80) vehicle at the time points indicated. Supplementary Figure S3. Schematic showing the decision-making related to selection of recommended dose for future studies. Supplementary Figure S4. Mean plasma concentration vs. time following single dose on day 1 (A) and multiple dose on day 15 (B). Supplementary Figure S5. Duration of treatment of patients treated via PIK3CA mutation status and dose level. Supplementary Figure S6. Antitumor activity observed with taselisib treatment. Supplementary Figure S7. Example of patient with partial response upon taselisib treatment and changes in circulating tumor DNA (ctDNA).

FoundationOne sequencing data for n=399 breast cancer population. Each sheet contains a distinct type of alteration. The clinical covariates used in our analysis are included.

Enriched Pathway Analysis.

Supplemental figures 1,2,4-8 as supporting figures to the manuscript.

Supplementary Tables

Supplementary Methods

Supplementary Figures

Background: Mutations in PIK3CA, encoding the catalytic subunit p110α of PI3K, are present in ~40% of ER+/HER- BC. Taselisib (TAS) is a potent and selective β-sparing PI3K inhibitor that improves outcomes in combination with endocrine therapy in pts with PIK3CAmut advanced breast cancer (aBC). To better understand the molecular alterations associated with response to PI3K inhibition, we profiled the genomic landscape of ctDNA collected from PIK3CAmut, ER+, HER2- aBC pts immediately prior to treatment (tx) with TAS or placebo (PBO) plus fulvestrant (FUL). Methods: Pts were enrolled as part of a phase III randomized study of TAS or PBO plus FUL in ER+, HER2- PIK3CAmut aBC (SANDPIPER, NCT02340221). Pre-tx ctDNA samples from 508 pts underwent comprehensive genomic profiling using the FoundationOne Liquid NGS assay at Foundation Medicine, Inc.; the 339 pts with PIK3CAmut ctDNA were further analyzed herein. The top mutated genes were analyzed for prognostic value against investigator-assessed progression-free survival (PFS) for both tx regimens using Cox proportional hazards regression modeling. As analysis was exploratory, no adjustments were made for multiple testing. Results: The top altered genes were TP53 (44%), ESR1 (37%), CDH1 (17%), FGFR1 (12%), NF1 (11%), CHEK2 (10%), and PTEN (9%). In pts treated with PBO+FUL, alterations in PTEN (HR 2.8; 95% CI 1.4-5.7; p=0.0107) and TP53 (HR 2.0; 95% CI 1.3-3.1; p=0.0025) were associated with a worse prognosis compared to pts with no mutation detected (NMD) in these genes. In pts treated with TAS+FUL, alterations in FGFR1 (HR 2.4; 95% CI 1.5-3.7; p=0.0006), TP53 (HR 1.9; 95% CI 1.4-2.6; p=0.0001) and PTEN (HR 1.8; 95% CI 1.1-2.8; p=0.0265) were associated with a worse prognosis compared to pts with NMD in these genes. Alterations in ESR1, CDH1, or CHEK2 were not associated with prognosis (p≥0.05) in either tx arm. A trend towards worse prognosis was observed in pts with NF1 altered ctDNA treated with PBO+FUL (HR 2.1; 95% CI 1.1-4.1; p=0.0527), which was not observed in pts treated with TAS+FUL (HR 0.97; 95% CI 0.57-1.65; p=0.901). Within the NF1-altered subgroup, a significant PFS difference was observed between TAS- vs PBO-treated pts (HR 0.28; 95% CI 0.11-0.67; p=0.0058; median 5.65 vs 1.94 months, respectively). Conclusions: We report that the most frequently mutated genes identified are consistent with previous studies in pts with ER+, HER2- aBC. This analysis shows that alterations in TP53 and PTEN were associated with poor prognosis in both tx arms, and FGFR1 alterations were associated with a poor prognosis in TAS+FUL treated pts. Further, NF1 alterations were associated with a poor prognosis in PBO+FUL treated pts, an association that was not observed with TAS+FUL. These findings may inform future rational combination strategies for the clinical development of PI3K inhibitors. Citation Format: Jessica W. Chen, Susan Dent, William Jacot, Javier Cortés, Ian E. Krop, Thomas J. Stout, Frauke Schimmoller, Heidi M. Savage, Katherine E. Hutchinson, Timothy R. Wilson. The genomic landscape and prognostic implications of somatic alterations in patients (pts) with ER+, HER2-, PIK3CA mutated (mut) advanced breast cancer treated with taselisib and fulvestrant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5165.

Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (Patients were enrolled on the basis of localA total of 166 patients withTaselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target

Poinsettias (Euphorbia pulcherrima) are popular for their colorful bracts and long keeping quality under indoor conditions. However, along with the long display life comes the maintenance issue of labor-intensive repeated waterings. Three experiments were conducted to determine whether using cellulosic water (CW) applied to the surface of the soilless growing medium as postproduction treatment could extend the days to wilt and intervals between waterings under simulated home/office conditions. CW is a gel composed of water bound in a cellulose matrix; as the cellulose is broken down the water is released. In addition, polyacrylamide (PAM) granules, applied dry into holes in the growing medium or hydrated to the medium surface, were evaluated for the same purpose in the final experiment. In the first experiment, pots containing cultivar Advent Red were treated with 0, 150, or 300 g of CW gel. In the second experiment, pots with ‘Prestige Early Red’ plants received 0, 125, or 250 g of CW gel. Pots were weighed and monitored for wilt daily. The days-to-wilt response was positively linear with CW application rates. Days to wilt (time between waterings) increased by over 3 days for each 100 g of CW applied to the pots during both Expts. 1 and 2 (y = 20 + 0.031x, r2 = 0.54 and y = 18.6 + 0.032x, r2 = 0.624, respectively, where y = days to wilt and x = grams of CW). In the third experiment, CW results were similar to those of the previous experiments. In addition, PAM initially also increased days to wilt compared with the control, with hydrated PAM applied at the same rate as CW providing the same benefits. However, PAM did not rehydrate adequately upon rewatering after the first wilt to delay the second wilt. This may have been due to fertilizer salts and to limited contact with the growing medium. Transpiration rates measured on the days before the untreated plants started wilting were not different among the treatments; therefore, the increased days to wilt provided by CW and PAM were due only to their providing additional water. Both CW and PAM gels were effective when used postproduction to supply supplemental water and lengthen the time period before the potted poinsettias wilted when held in interiorscapes.