Response-adaptive breast cancer care in the grey zones: integrating ER and HER2 targeted PET, FDG PET/CT under immunotherapy, and ctDNA kinetics

Abstract

Breast cancer management increasingly hinges on decisions made in “grey zones” where tissue sampling is scarce, and tumour biology evolves under therapeutic pressure. This narrative review synthesises evidence on how whole-body imaging biomarkers and circulating tumour DNA (ctDNA) can support response-adaptive pathways at the interface of surgical and systemic care. Four clinically actionable domains are discussed. (a) 16α-[¹⁸F]fluoro-17β-estradiol ([¹⁸F]FES) positron emission tomography/computed tomography (PET/CT) enables non-invasive, whole-body mapping of functional oestrogen receptor (ER) expression to address receptor discordance, heterogeneous metastases, and selection of endocrine-based strategies. (b) Human epidermal growth factor receptor 2 (HER2)-targeted PET (notably⁸⁹Zr-trastuzumab, with emerging alternatives) provides whole-body receptor assessment to uncover actionable HER2-positive disease despite HER2-negative primaries, informing anti-HER2 treatment selection when repeat biopsy is infeasible. (c) In triple-negative breast cancer treated with immune checkpoint inhibitors,¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT offers quantitative response and whole-body burden assessment but requires immunotherapy-aware interpretation (e.g., confirmation strategies for apparent early progression) to mitigate pseudoprogression and dissociated responses, while simultaneously visualising immune-related adverse events. (d) Pairing early metabolic change on FDG PET/CT with ctDNA kinetics is presented as a biologically complementary approach for response monitoring and risk stratification, with potential to inform trial-embedded response-adaptive hypotheses, with ctDNA offering a rapid systemic trajectory and PET providing lesion-level localisation in heterogeneous or oligoprogressive disease. Overall, these tools add value only when linked to prespecified clinical questions and consensus actions; prospective studies are needed to validate standardised, outcome-improving response-adaptive algorithms that integrate imaging and liquid biopsy. Key implementation challenges include tracer availability, harmonised acquisition/reconstruction, threshold definition, and avoiding overtesting. Near-term impact may be greatest in problem-solving and in trial-embedded decision rules that operationalise biomarker-guided care.

Keywords

breast cancer / PET/CT / FDG / FES / HER2 imaging / trastuzumab / ctDNA / response-adaptive therapy

References

[1] Specht JM, van Geel JJL, Song S, Liu C, Hippe DS, DiGregorio NA, et al. The Role of Estrogen Receptor-Targeted PET with 16α-¹⁸F-Fluoro-17β-Estradiol in Predicting Response to Endocrine Therapies in Metastatic Breast Cancer: A Metaanalysis. J Nucl Med. 2026; 67: 36-42.

[2] Piccardo A, Fiz F, Treglia G, Bottoni G, Trimboli P. Head-to-Head Comparison between¹⁸F-FES PET/CT and¹⁸F-FDG PET/CT in Oestrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-Analysis. J Clin Med. 2022; 11: 1919.

[3] You S, Xie Y, Ji M, Liu C, Zhao Y, Gong C, et al. ER status conversion and subsequent treatment: an assessment of negative ER expression detected by¹⁸F-FES PET in metastatic breast cancer patients with ER-positive primary tumors. Ther Adv Med Oncol. 2023; 15: 17588359231216093.

[4] Zhou W, Franc BL, DeMartini WB, Rosen EL. Estrogen Receptor-targeted PET Imaging for Breast Cancer. Radiology. 2024; 312: e240315.

[5] Ulaner GA, Silverstein M, Nangia C, Tetef M, Vandermolen L, Coleman C, et al. ER-Targeted PET for Initial Staging and Suspected Recurrence in ER-Positive Breast Cancer. JAMA Netw Open. 2024; 7: e2423435.

[6] Manohar PM, Peterson LM, Jenkins IC, Wu QV, Kurland BF, Novakova-Jiresova A, et al. [¹⁸F]-Fluoroestradiol PET (FES-PET) and [¹⁸F] Flurodeoxyglucose PET (FDG-PET) Imaging May Aid in Managing Therapy in Patients with Metastatic Lobular Breast Cancer. Mol Imaging Biol. 2025; 27: 410-20.

[7] Sanò MV, Russo A, Marino L, Pafumi S, Pietro MD, Ricciardi GRR. Could¹⁸F-FES PET Be a New Driver in Therapeutic Choice for Metastatic HR+/HER2- Patients? Diagnostics (Basel). 2025; 15: 2139.

[8] Cuzzocrea M, Micco RD, Colombo GE, Rizzo SMR, Paone G, Casati V, et al. The Role of [¹⁸F]FES PET/CT in Breast Cancer Management: An Umbrella Review. Cancers (Basel). 2025; 17: 1644.

[9] Xu Y, Yao R, Hao Z, Chen F, Liu B, Sun Q, et al. [¹⁸F]F-FES PET for diagnosis, staging, and endocrine therapy prediction in ER-positive breast cancer: a systematic review and meta-analysis. EJNMMI Res. 2025; 15: 17.

[10] Munter-Young R, Fuentes-Alburo A, DiGregorio N, Neeser K, Gultyaev D. Clinical and economic outcomes of adding [¹⁸F]FES PET/CT in estrogen receptor status identification in metastatic and recurrent breast cancer in the US. PLoS One. 2024; 19: e0302486.

[11] Matushita CS, Coelho FARFB, Stasiak CES, Rodrigues DF, Pianta DB, Kurkowski FD, et al. ¹⁸F-fluoroestradiol positron emission tomography in patients with breast cancer: a systematic review and meta-analysis. Rev Assoc Med Bras (1992). 2023; 69: e2023S116.

[12] Liu C, Hu S, Xu X, Zhang Y, Wang B, Song S, et al. Evaluation of tumour heterogeneity by¹⁸F-fluoroestradiol PET as a predictive measure in breast cancer patients receiving palbociclib combined with endocrine treatment. Breast Cancer Res. 2022; 24: 57.

[13] Peterson LM, Kurland BF, Yan F, Jiresova AN, Gadi VK, Specht JM, et al. ¹⁸F-Fluoroestradiol PET Imaging in a Phase II Trial of Vorinostat to Restore Endocrine Sensitivity in ER+/HER2- Metastatic Breast Cancer. J Nucl Med. 2021; 62: 184-90.

[14] Ulaner GA, Jhaveri K, Chandarlapaty S, Hatzoglou V, Riedl CC, Lewis JS, et al. Head-to-Head Evaluation of¹⁸F-FES and¹⁸F-FDG PET/CT in Metastatic Invasive Lobular Breast Cancer. J Nucl Med. 2021; 62: 326-31.

[15] Liu C, Gong C, Liu S, Zhang Y, Zhang Y, Xu X, et al. ¹⁸F-FES PET/CT Influences the Staging and Management of Patients with Newly Diagnosed Estrogen Receptor-Positive Breast Cancer: A Retrospective Comparative Study with¹⁸F-FDG PET/CT. Oncologist. 2019; 24: e1277-85.

[16] Salem K, Kumar M, Powers GL, Jeffery JJ, Yan Y, Mahajan AM, et al. ¹⁸F-16α-17β-Fluoroestradiol Binding Specificity in Estrogen Receptor-Positive Breast Cancer. Radiology. 2018; 286: 856-64.

[17] Wang Y, Ayres KL, Goldman DA, Dickler MN, Bardia A, Mayer IA, et al. ¹⁸F-Fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression during a Phase I Trial of the Novel Estrogen Receptor-Targeted Therapeutic GDC-0810: Using an Imaging Biomarker to Guide Drug Dosage in Subsequent Trials. Clin Cancer Res. 2017; 23: 3053-60.

[18] van Kruchten M, Glaudemans AWJM, de Vries EFJ, Schröder CP, de Vries EGE, Hospers GAP. Positron emission tomography of tumour [(¹⁸)F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy. Eur J Nucl Med Mol Imaging. 2015; 42: 1674-81.

[19] Ulaner GA, Hyman DM, Ross DS, Corben A, Chandarlapaty S, Goldfarb S, et al. Detection of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer Using⁸⁹Zr-Trastuzumab PET/CT. J Nucl Med. 2016; 57: 1523-8.

[20] Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001; 344: 783-92.

[21] Ulaner GA, Hyman DM, Lyashchenko SK, Lewis JS, Carrasquillo JA. ⁸⁹Zr-Trastuzumab PET/CT for Detection of Human Epidermal Growth Factor Receptor 2-Positive Metastases in Patients With Human Epidermal Growth Factor Receptor 2-Negative Primary Breast Cancer. Clin Nucl Med. 2017; 42: 912-7.

[22] Bensch F, Brouwers AH, Lub-de Hooge MN, de Jong JR, van der Vegt B, Sleijfer S, et al. ⁸⁹Zr-trastuzumab PET supports clinical decision making in breast cancer patients, when HER2 status cannot be determined by standard work up. Eur J Nucl Med Mol Imaging. 2018; 45: 2300-6.

[23] Lindström LS, Karlsson E, Wilking UM, Johansson U, Hartman J, Lidbrink EK, et al. Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J Clin Oncol. 2012; 30: 2601-8.

[24] Dehdashti F, Wu N, Bose R, Naughton MJ, Ma CX, Marquez-Nostra BV, et al. Evaluation of [⁸⁹Zr]trastuzumab-PET/CT in differentiating HER2-positive from HER2-negative breast cancer. Breast Cancer Res Treat. 2018; 169: 523-30.

[25] Linders DGJ, Deken MM, van Dam MA, Wasser MNJM, Voormolen EMC, Kroep JR, et al. ⁸⁹Zr-Trastuzumab PET/CT Imaging of HER2-Positive Breast Cancer for Predicting Pathological Complete Response after Neoadjuvant Systemic Therapy: A Feasibility Study. Cancers (Basel). 2023; 15: 4980.

[26] Mortimer JE, Bading JR, Frankel PH, Carroll MI, Yuan Y, Park JM, et al. Use of⁶⁴Cu-DOTA-Trastuzumab PET to Predict Response and Outcome of Patients Receiving Trastuzumab Emtansine for Metastatic Breast Cancer: A Pilot Study. J Nucl Med. 2022; 63: 1145-8.

[27] Kurihara H, Hamada A, Yoshida M, Shimma S, Hashimoto J, Yonemori K, et al. (⁶⁴)Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients. EJNMMI Res. 2015; 5: 8.

[28] Ulaner GA, Lyashchenko SK, Riedl C, Ruan S, Zanzonico PB, Lake D, et al. First-in-Human Human Epidermal Growth Factor Receptor 2-Targeted Imaging Using⁸⁹Zr-Pertuzumab PET/CT: Dosimetry and Clinical Application in Patients with Breast Cancer. J Nucl Med. 2018; 59: 900-6.

[29] Massicano AVF, Lee S, Crenshaw BK, Aweda TA, Sayed RE, Super I, et al. Imaging of HER2 with [⁸⁹Zr]pertuzumab in Response to T-DM1 Therapy. Cancer Biother Radiopharm. 2019; 34: 209-17.

[30] Sörensen J, Velikyan I, Sandberg D, Wennborg A, Feldwisch J, Tolmachev V, et al. Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [⁶⁸Ga]ABY-025 Affibody PET/CT. Theranostics. 2016; 6: 262-71.

[31] Mansur A, McConathy JE, Stringer-Reasor E, Rocque G, Khoury K, Eltoum N, et al. Quantitative [⁸⁹Zr]Zr-Trastuzumab PET and Diffusion-Weighted MRI for Characterization of Metastatic HER2-Positive Breast Cancer with PET/MRI. J Nucl Med. 2025; 66: 1018-26.

[32] Vaz SC, Graff SL, Ferreira AR, Debiasi M, de Geus-Oei LF. PET/CT in Patients with Breast Cancer Treated with Immunotherapy. Cancers (Basel). 2023; 15: 2620.

[33] Filippi L, Urso L, Ferrari C, Guglielmo P, Evangelista L. The impact of PET imaging on triple negative breast cancer: an updated evidence-based perspective. Eur J Nucl Med Mol Imaging. 2024; 52: 263-79.

[34] Marinelli B, Espinet-Col C, Ulaner GA, McArthur HL, Gonen M, Jochelson M, et al. Prognostic value of FDG PET/CT-based metabolic tumor volumes in metastatic triple negative breast cancer patients. Am J Nucl Med Mol Imaging. 2016; 6: 120-7.

[35] Yue Y, Cui X, Bose S, Audeh W, Zhang X, Fraass B. Stratifying triple-negative breast cancer prognosis using¹⁸F-FDG-PET/CT imaging. Breast Cancer Res Treat. 2015; 153: 607-16.

[36] Bouron C, Mathie C, Seegers V, Morel O, Jézéquel P, Lasla H, et al. Prognostic Value of Metabolic, Volumetric and Textural Parameters of Baseline [¹⁸F]FDG PET/CT in Early Triple-Negative Breast Cancer. Cancers (Basel). 2022; 14: 637.

[37] Xie Y, Liu C, Zhao Y, Gong C, Li Y, Hu S, et al. Heterogeneity derived from¹⁸F-FDG PET/CT predicts immunotherapy outcome for metastatic triple-negative breast cancer patients. Cancer Med. 2022; 11: 1948-55.

[38] Vogsen M, Bülow JL, Ljungstrøm L, Oltmann HR, Alamdari TA, Naghavi-Behzad M, et al. FDG-PET/CT for Response Monitoring in Metastatic Breast Cancer: The Feasibility and Benefits of Applying PERCIST. Diagnostics (Basel). 2021; 11: 723.

[39] Depardon E, Kanoun S, Humbert O, Bertaut A, Riedinger J, Tal I, et al. FDG PET/CT for prognostic stratification of patients with metastatic breast cancer treated with first line systemic therapy: Comparison of EORTC criteria and PERCIST. PLoS One. 2018; 13: e0199529.

[40] Kiyoto S, Sugawara Y, Hosokawa K, Nishimura R, Yamashita N, Ohsumi S, et al. Predictive Ability of¹⁸F-fluorodeoxyglucose Positron Emission Tomography/computed Tomography for Pathological Complete Response and Prognosis after Neoadjuvant Chemotherapy in Triple-negative Breast Cancer Patients. Asia Ocean J Nucl Med Biol. 2016; 4: 3-11.

[41] Wu Y, Li Y, Chen B, Zhang Y, Xing W, Guo B, et al. ¹⁸F-FDG PET/CT for early prediction of pathological complete response in breast cancer neoadjuvant therapy: a retrospective analysis. Oncologist. 2024; 29: e1646-55.

[42] Roy S, Whitehead TD, Li S, Ademuyiwa FO, Wahl RL, Dehdashti F, et al. Co-clinical FDG-PET radiomic signature in predicting response to neoadjuvant chemotherapy in triple-negative breast cancer. Eur J Nucl Med Mol Imaging. 2022; 49: 550-62.

[43] Gelardi F, Cavinato L, Sanctis RD, Ninatti G, Tiberio P, Rodari M, et al. The Predictive Role of Radiomics in Breast Cancer Patients Imaged by [¹⁸F]FDG PET: Preliminary Results from a Prospective Cohort. Diagnostics (Basel). 2024; 14: 2312.

[44] Groheux D, Ferrer L, Vargas J, Martineau A, Borgel A, Teixeira L, et al. FDG-PET/CT and Multimodal Machine Learning Model Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer. Cancers (Basel). 2025; 17: 1249.

[45] Magbanua MJM, Gumusay O, Kurzrock R, van ‘t Veer LJ, Rugo HS. Immunotherapy in Breast Cancer and the Potential Role of Liquid Biopsy. Front Oncol. 2022; 12: 802579.

[46] Xu J, Gao H, Guan X, Meng J, Ding S, Long Q, et al. Circulating tumor DNA: from discovery to clinical application in breast cancer. Front Immunol. 2024; 15: 1355887.

[47] Easaw S, Hsu J, Steuerwald N, Heeke AL. Liquid clues: tracking early-stage breast cancer with ctDNA - a mini review. Front Oncol. 2025; 15: 1634859.

[48] Amato O, Giannopoulou N, Ignatiadis M. Circulating tumor DNA validity and potential uses in metastatic breast cancer. NPJ Breast Cancer. 2024; 10: 21.

[49] Turner NC, Kingston B, Kilburn LS, Kernaghan S, Wardley AM, Macpherson IR, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol. 2020; 21: 1296-308.

[50] Mouhanna P, Ståhlberg A, Andersson D, Albu-Kareem A, Elinder E, Eriksson O, et al. Integration of personalised ultrasensitive ctDNA monitoring of patients with metastatic breast cancer to reduce imaging requirements. Int J Cancer. 2025; 156: 1509-17.

[51] Panet F, Papakonstantinou A, Borrell M, Vivancos J, Vivancos A, Oliveira M. Use of ctDNA in early breast cancer: analytical validity and clinical potential. NPJ Breast Cancer. 2024; 10: 50.

[52] Parsons HA, Blewett T, Chu X, Sridhar S, Santos K, Xiong K, et al. Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030. Ann Oncol. 2023; 34: 899-906.

[53] Li S, Li Y, Wei W, Gong C, Wang T, Li G, et al. Dynamic ctDNA tracking stratifies relapse risk for triple negative breast cancer patients receiving neoadjuvant chemotherapy. Nat Commun. 2025; 16: 2786.

[54] Hsu H, Lee K, Karmakar R, Mukundan A, Attar RS, Liu P, et al. From Innovation to Application: Can Emerging Imaging Techniques Transform Breast Cancer Diagnosis? Diagnostics (Basel). 2025; 15: 2718.

[55] Leung J, Karmakar R, Mukundan A, Thongsit P, Chen M, Chang W, et al. Systematic Meta-Analysis of Computer-Aided Detection of Breast Cancer Using Hyperspectral Imaging. Bioengineering (Basel). 2024; 11: 1060.