Early on-treatment transcriptional profiling as a tool for improving pathological response prediction in HER2-positive inflammatory breast cancer.

Background

Inflammatory breast cancer (IBC) is a rare and understudied disease, with 40% of cases presenting with human epidermal growth factor receptor 2 (HER2)-positive subtype. The goals of this study were to (i) assess the pathologic complete response (pCR) rate of short-term neoadjuvant dual-HER2-blockade and paclitaxel, (ii) contrast baseline and on-treatment transcriptional profiles of IBC tumor biopsies associated with pCR, and (iii) identify biological pathways that may explain the effect of neoadjuvant therapy on tumor response.

Patients and Methods

A single-arm phase II trial of neoadjuvant trastuzumab (H), pertuzumab (P), and paclitaxel for 16 weeks was completed among patients with newly diagnosed HER2-positive IBC. Fresh-frozen tumor biopsies were obtained pretreatment (D1) and 8 days later (D8), following a single dose of HP, prior to adding paclitaxel. We performed RNA-sequencing on D1 and D8 tumor biopsies, identified genes associated with pCR using differential gene expression analysis, identified pathways associated with pCR using gene set enrichment and gene expression deconvolution methods, and compared the pCR predictive value of principal components derived from gene expression profiles by calculating and area under the curve for D1 and D8 subsets.

Results

Twenty-three participants were enrolled, of whom 21 completed surgery following neoadjuvant therapy. Paired longitudinal fresh-frozen tumor samples (D1 and D8) were obtained from all patients. Among the 21 patients who underwent surgery, the pCR and the 4-year disease-free survival were 48% (90% CI 0.29-0.67) and 90% (95% CI 66-97%), respectively. The transcriptional profile of D8 biopsies was found to be more predictive of pCR (AUC = 0.91, 95% CI: 0.7993-1) than the D1 biopsies (AUC = 0.79, 95% CI: 0.5905-0.9822).

Conclusions

In patients with HER2-positive IBC treated with neoadjuvant HP and paclitaxel for 16 weeks, gene expression patterns of tumor biopsies measured 1 week after treatment initiation not only offered different biological information but importantly served as a better predictor of pCR than baseline transcriptional analysis.

Trial Registration

ClinicalTrials.gov identifier: NCT01796197 (https://clinicaltrials.gov/ct2/show/NCT01796197); registered on February 21, 2013.

Informations de copyright

© The Author(s), 2022.

Déclaration de conflit d'intérêts

Competing Interests: SP has served as an advisor/consultant for AstraZeneca, Daiichi Sankyo Eisai, Novartis, Polyphor, Roche, Pierre-Fabre, and SeattleGenetics. SG has received laboratory research funding from Eli Lilly and performs clinical research sponsored by Novartis and Eli Lilly. SG has served as a paid advisor to Eli Lilly, G1 therapeutics, and Novartis. JLG is a consultant for Glaxo-Smith Kline (GSK), Array BioPharma, Codagenix, Verseau Therapeutics, Kymera, Carisma, Kowa, Duke Street Bio and MPM Capital, and receives sponsored research support from GSK, Eli Lilly and Array BioPharma. NUL reports institutional research funding from Genentech, Merck, Pfizer, Seattle Genetics, AstraZeneca, Zion Pharmaceuticals, and Olema Pharmaceuticals; consultant/advisory board work for Pfizer, Puma, Seattle Genetics, Daiichi Sankyo, AstraZeneca, Prelude Therapeutics, Denali Therapeutics, Olema Pharmaceuticals, Aleta BioPharma, Affinia Therapeutics, Voyager Therapeutics, and Artera, Inc.; royalties from UpToDate; and stock or other ownership interests in Artera Inc. (a startup with no current value, but options only valued at <5% and <$50,000 will be provided at a later date). MR reports research funding (and/or provision of drug supply for clinical trials) from Novartis, Pfizer, Ipsen, TerSera, Merck, Ferring, Pierre Fabre, Roche, AstraZeneca, Bayer, Bristol-Myers Squibb; consulting or advisory role for Ipsen, Bristol-Myers Squibb, Tolmar Pharmaceuticals. BO has received clinical trial support from Genentech, Incyte, and Eisai. AM reports a consulting or advisory role for Lilly and Seagen, in-kind research support from Tempus, and institutional research funding from Eisai, Seagen, MTEM, Lilly, Seagen, Takeda Millennium, and Pfizer. EAM reports compensated service on scientific advisory boards for AstraZeneca, Exact Sciences, Merck, and Roche/Genentech; uncompensated service on steering committees for Bristol Myers Squibb, Lilly, and Roche/Genentech; honoraria from Physicians’ Education Resource; and institutional research support from Roche/Genentech (via SU2C grant) and Gilead. EAM reports the following nonfinancial interests, nonremunerated activities: Board of Directors for the American Society of Clinical Oncology and Scientific Advisor for Susan G. Komen for the Cure Foundation.