333P - Evaluation of a composite PET/CT and HER2 tissue-based biomarker to predict response to neoadjuvant HER2-directed therapy in early breast cancer (TBCRC026)

Background

Early metabolic change on FDG PET/CT was predictive of response to neoadjuvant trastuzumab/pertuzumab (HP) in TBCRC026, with high negative predictive value (NPV) suggesting a lack of decline in SULmax at cycle 1 day 15 (C1D15) best predicts those who will not achieve pathological complete response (pCR) with HP alone. We hypothesized that a composite biomarker incorporating both PET and HER2 tissue-based biomarkers could improve biomarker performance in this setting.

Methods

Patients with stage II-III ER-negative/HER2-positive breast cancer received neoadjuvant HP. PET/CT was performed at baseline and C1D15. Promising imaging biomarkers included ≥40% SULmax decline between baseline and C1D15, and C1D15 SULmax ≤3 (n=83 evaluable). Baseline tissue-based biomarkers included HER2-enriched intrinsic subtype (72%, 46/64 available; Nanostring [NS] BC360), log2 tumor HER2 protein abundance (median 13.5, range 7.1-15.9; NS GeoMxTM DSP), HER2 3+ (83%, 64/77; immunohistochemistry central review). Logistic regressions were used to construct prediction models for pCR with the composite HER2/PET biomarker. Overall discriminatory power of the predictive model was evaluated using the C statistic. Sensitivity and specificity were evaluated at the optimal cut-off point determined by maximizing Youden's index in the receiver operating characteristic (ROC) analysis.

Results

Factors most predictive for response (pCR 22%, PMID 33999652) in single predictor models included D15 SULmax (OR 0.43; p=0.007, c=0.77), % reduction in SULmax (OR 1.03, p=0.006, c=0.72) and tumor HER2 protein abundance (OR 1.75; p=0.01, c=0.76). The composite of D15 SULmax and % reduction in SULmax combined with their interaction term, had improved probability (c=0.89 from c=0.78), with high sensitivity (100%) and NPV (100%). The addition of tumor HER2 protein did not further improve prediction power (c=0.90).

Conclusions

The composite HER2/PET biomarker had high prediction power for pCR, however was not superior to the prediction power of PET/CT alone. These data suggest clinical trials informed by early FDG PET/CT biomarkers warrant further evaluation to personalize breast cancer care.

Clinical trial identification

NCT01937117.

Editorial acknowledgement

Legal entity responsible for the study

Translational Breast Cancer Research Consortium.

Funding

TBCRC and its foundation partners (The Breast Cancer Research Foundation and Susan G. Komen for the Cure) ASCO CCF CDA 2013 Genentech (ML28190) SKCCC Core Grant (P30-CA006973) AVON Center of Excellence (01-2017-007) NCI Quantitative Imaging Network (QIN) contract (5U01CA140204) Breast Cancer Research Foundation (grant 21-161) Breakthrough Cancer Research.

Disclosure

M.A. Hennessy: Financial Interests, Personal, Sponsor/Funding: Roche, MSD, AstraZeneca. A. Cimino-Mathews: Financial Interests, Personal, Research Grant: BMS; Financial Interests, Personal, Other, Consultant Honoraria: BMS. J. Carter: Financial Interests, Personal, Other, Honorarium: AstraZeneca, Merck, Dako-Agilent, Roche. J. Leal: Financial Interests, Personal, Other, Consultant: PlenaryAI. V. Abramson: Financial Interests, Institutional, Other, Grants: Pfizer, Genentech, Gilead, AstraZeneca, Zentalis; Financial Interests, Personal, Other, Consulting: FirstThought, Daiichi Sankyo, SeaGen, AstraZeneca; Financial Interests, Personal, Other: Eisai. L.A. Carey: Financial Interests, Institutional, Funding, research funding: Syndax, Immunomedics, Novartis, Nanostring Technologies, AbbVie, Seattle Genetics, Veracyte; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: Sanofi, Novartis, G1 Therapeutics, Genentech/Roche, GSK, AstraZeneca/ Daiichi Sankyo, Apitude Health, Exact Sciences. M. Rimawi: Financial Interests, Personal, Other, Consulting: SeaGen, Genentech, AstraZeneca, Novartis, Macrogenics. J. Specht: Financial Interests, Personal, Other, Consultant: Volastra; Financial Interests, Personal, Advisory Board, and Consultant: GE Healthcare; Financial Interests, Personal, Advisory Board: Sensei Biotherapeutics, GSK, Daiichi Sankyo; Financial Interests, Personal, Royalties, ROR1 royalties: UW CoMotion; Financial Interests, Institutional, Research Grant: Celcuity, Pfizer, Xencor, Merck, Seagen, Seattle Genetics, Minerva, Myriad Pharmaceuticals, Novartis, Genentech, Cascadian Therapeutics, Abbvie, Nektar. A.M. Storniolo: Financial Interests, Personal, Other, Member of DSMB for phase III trials, no involvement with HER2 positive breast cancer trials or compounds used in this study: AstraZeneca. C. Vaklavas: Financial Interests, Personal, Other, Wife: Flatiron Health; Financial Interests, Personal, Other, Consultation: Guidepoint, Novartis, SeaGen; Financial Interests, Personal, Other, Consultant: Daiichi Sankyo; Financial Interests, Personal, Other, Consultant Honoraria: Gilead Sciences; Non-Financial Interests, Personal, Other, Non-compensated consultation: Genentech; Financial Interests, Personal, Other, Participation in non CME activity: Pfizer, Daiichi Sankyo/AstraZeneca. A.C. Wolff: Financial Interests, Personal, Other, DSMB for Impassion030 Alexandra trial (Roche trial led by BIG, received honorarium from BIG): Roche. R. Wahl: Financial Interests, Personal, Advisory Board: Clarity Pharmaceuticals, Voximetry , Seno Medical; Financial Interests, Personal, Stocks/Shares: Clarity Pharmaceuticals; Financial Interests, Personal, Stocks/Shares, Stock options: Voximetry; Financial Interests, Personal, Other, Honoraria: BMS, Actinium Pharmaceuticals, Jubilant Draximage, Abderra, Radiopharm Therapeutics, ITM; Financial Interests, Personal, Officer, Honoraria: Siemens; Financial Interests, Personal, Other, Research support: Actinium Pharmaceuticals, BMS, Bayer, ITM, Siemens, White Rabbit AI. V. Stearns: Financial Interests, Institutional, Research Grant: AbbVie, Biocept, Novartis, Pfizer, Puma Biotechnology, QUE Oncology; Other, Personal, Advisory Board: Novartis; Other, Personal, Advisory Board, DSMB: AstraZeneca; Other, Personal, Other: Foundation Medicine Study Assays. A. Thompson: Non-Financial Interests, Personal and Institutional, Other, Involved in beta testing both GeoMx and CosMx technology for NanoString Technologies, Inc. The nature of this work involves instrument training and analytical support from NanoString, focused upon developing and deploying analytical solutions for data analysis. No financial remuneration was involved.: NanoString Technologies. R.M. Connolly: Financial Interests, Institutional, Other, Unrestricted Education Grant: Pfizer; Financial Interests, Institutional, Research Funding: MSD Ireland, Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Other, Travel/Educational support: Novartis; Non-Financial Interests, Personal, Advisory Board: Roche; Non-Financial Interests, Personal, Advisory Board, Chair: SeaGen; Financial Interests, Personal, Advisory Board: AstraZeneca/Daiichi, AstraZeneca, Gilead; Financial Interests, Personal, Steering Committee Member: AstraZeneca/Daiichi Sankyo; Non-Financial Interests, Personal, Steering Committee Member: Develop Med UCD, ACRI, Decrescendo. All other authors have declared no conflicts of interest.