HER2-overexpressing breast cancer: FDG uptake after two cycles of chemotherapy predicts the outcome of neoadjuvant treatment

FULL PAPER British Journal of Cancer (2013) 109, 1157–1164 | doi: 10.1038/bjc.2013.469 Keywords: 18F-FDG-PET/CT; breast cancer; HER2; neoadjuvant chemotherapy; metabolic response; pathologic complete response HER2-overexpressing breast cancer: FDG uptake after two cycles of chemotherapy predicts the outcome of neoadjuvant treatment D Groheux*,1,2, S Giacchetti3, M Hatt4, M Marty3,5, L Vercellino1,2, A de Roquancourt6, C Cuvier3, F Coussy3, M Espié3 and E Hindié7 1 Nuclear Medicine, Saint-Louis Hospital, 1 avenue Claude Vellefaux, Paris 75475, France; 2B2T, Doctoral School, IUH, University of Paris VII, Paris, France; 3Breast Diseases Unit, Saint-Louis Hospital, Paris, France; 4INSERM, UMR 1101 LaTIM, Brest, France; 5Centre for Therapeutic Innovation, Saint-Louis Hospital, Paris, France; 6Pathology, Saint-Louis Hospital, Paris, France and 7Nuclear Medicine, Bordeaux University Hospital, University of Bordeaux, Bordeaux, France Background: Pathologic complete response (pCR) to neoadjuvant treatment (NAT) is associated with improved survival of patients with HER2 þ breast cancer. We investigated the ability of interim positron emission tomography (PET) regarding early prediction of pathology outcomes. Methods: During 61 months, consecutive patients with locally advanced or large HER2 þ breast cancer patients without distant metastases were included. All patients received NAT with four cycles of epirubicin þ cyclophosphamide, followed by four cycles of docetaxel þ trastuzumab. 18F-fluorodeoxyglucose (18F-FDG)-PET/computed tomography (CT) was performed at baseline (PET1) and after two cycles of chemotherapy (PET2). Maximum standardised uptake values were measured in the primary tumour as well as in the axillary lymph nodes. The correlation between pathologic response and SUV parameters (SUVmax at PET1, PET2 and DSUVmax) was examined with the t-test. The predictive performance regarding the identification of non-responders was evaluated using receiver operating characteristics (ROC) analysis. Results: Thirty women were prospectively included and 60 PET/CT examination performed. At baseline, 22 patients had PET þ axilla and in nine of them 18F-FDG uptake was higher than in the primary tumour. At surgery, 14 patients (47%) showed residual tumour (non-pCR), whereas 16 (53%) reached pCR. Best prediction was obtained when considering the absolute residual SUVmax value at PET2 (AUC ¼ 0.91) vs 0.67 for SUVmax at PET1 and 0.86 for DSUVmax. The risk of non-pCR was 92.3% in patients with any site of residual uptake 43 at PET2, no matter whether in breast or axilla, vs 11.8% in patients with uptake p3 (P ¼ 0.0001). The sensitivity, specificity, PPV, NPV and overall accuracy of this cutoff were, respectively: 85.7%, 93.8%, 92.3%, 88.2% and 90%. Conclusion: The level of residual 18F-FDG uptake after two cycles of chemotherapy predicts residual disease at completion of NAT with chemotherapy þ trastuzumab with high accuracy. Because many innovative therapeutic strategies are now available (e.g., addition of a second HER2-directed therapy or an antiangiogenic), early prediction of poor response is critical. *Correspondence: Dr D Groheux; E-mail: Received 18 May 2013; revised 17 July 2013; accepted 21 July 2013; published online 13 August 2013 & 2013 Cancer Research UK. All rights reserved 0007 – 0920/13 www.bjcancer.com | DOI:10.1038/bjc.2013.469 1157 BRITISH JOURNAL OF CANCER Neoadjuvant chemotherapy was initially developed for primary inoperable breast cancer, and is now also widely used in operable but large breast cancer not eligible to breast-conserving therapy (NCCN Guidelines, 2013). Positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (18F-FDG-PET/CT) is a useful staging modality in these patients (Fuster et al, 2008; Groheux et al, 2012a, 2013a). Moreover, some studies have demonstrated a correlation between early changes in 18F-FDG primary tumour uptake after one or two courses of chemotherapy and the extent of pathology response at completion of treatment, at the tumour level (Schwarz-Dose et al, 2009; Wang et al, 2012), as well as in axillary lymph nodes (Straver et al, 2010; Rousseau et al, 2011). However, the ability to implement 18F-FDG-PET/CT as a surrogate marker for treatment efficacy remains unclear because of substantial heterogeneities across studies and also because breast cancer cannot be examined as a single entity (Groheux et al, 2011a, 2012b, 2013b; Humbert et al, 2012). Breast cancer comprises different phenotypes with different response rates to chemotherapy, different treatment options and different prognoses (NCCN Guidelines, 2013). We therefore suggested that the clinical aims of early 18F-FDG monitoring and the criteria used to predict efficacy should be determined in specific subgroups (Groheux et al, 2011a, 2012b, 2013b). Overexpression of the HER2 receptor occurs in roughly 20% of breast tumours. The prognosis of this aggressive entity has been improved with the advent of trastuzumab therapy, an antibody targeting the HER2 receptor (Gianni et al, 2010). In the neoadjuvant setting, pathologic complete response (pCR) at surgery is higher with the addition of trastuzumab and is correlated with improved outcomes, suggesting that it may serve as a surrogate marker of clinical benefit (Gianni et al, 2010; Untch et al, 2011; Von Minckwitz et al, 2012). Identifying poor responders before completion of neoadjuvant treatment (NAT) might be useful for improving outcome by allowing an early switch to a different chemotherapy regimen, and/or the use of more than one targeted therapy (Baselga et al, 2012; Gianni et al, 2012; Guarneri et al, 2012; Pierga et al, 2012). The objective of this prospective study was to assess the value of interim 18F-FDG-PET/CT for early identification of HER2 þ breast cancer patients who will not achieve pCR with a conventional chemotherapy/trastuzumab NAT. MATERIALS AND METHODS Patients. During 61 months, patients with clinical stage II or III HER2 þ breast cancer seen at the breast disease unit of Saint Louis hospital, and scheduled for NAT were included. All patients underwent an 18F-FDG-PET/CT scan at baseline (PET1) and another scan after two cycles of chemotherapy (PET2). Patients with distant metastases identified at initial staging were not included, because these patients receive treatments tailored to metastatic state and patient characteristics. After completion of NAT, all patients underwent surgery and response to treatment was assessed by pathology examination of surgical specimens. The study followed the guidelines of the institutional ethical committee with informed patient consent. Neoadjuvant treatment. All patients received four cycles of epirubicin (75 mg m  2) plus cyclophosphamide (750 mg m  2) administered every 3 weeks, followed by four courses of docetaxel (100 mg m  2 every 3 weeks) plus trastuzumab (8 mg kg  1 loading dose, followed by 6 mg kg  1 every 3 weeks). 18 F-FD (...truncated)