|
对于部分HER2阳性早期乳腺癌患者，术前帕妥珠单抗＋曲妥珠单抗新辅助治疗无论是否化疗，病理完全缓解率和长期生存率都较高。不过，并非任何患者术前妥妥不化疗都有效，故有必要对术后病理完全缓解和长期生存结局进行早期预测以决定能否避免化疗。由于肿瘤组织代谢需要摄取大量葡萄糖，将氟-18同位素取代葡萄糖第二个羟基的氧原子注入人体，可被肿瘤组织摄取，并逐渐衰变发射出正电子，用计算机扫描成像，能够精准反映不同组织对葡萄糖的摄取分布情况，已被用于HER2阳性早期乳腺癌术前治疗2周时预测术后病理缓解情况。不过，治疗2周时预测术后病理缓解情况可能过早。为此，西班牙、意大利、法国、德国、比利时、英国、葡萄牙于2017年联合发起PHERGain研究，探讨了HER2阳性早期乳腺癌术前曲妥珠单抗＋帕妥珠单抗治疗±化疗6周时进行氟-18代脱氧葡萄糖正电子发射扫描成像（18F-FDG-PET）预测术后病理缓解情况以及根据病理缓解情况及时调整是否化疗的可行性、安全性和有效性。2021年，英国《柳叶刀》肿瘤学分册发表PHERGain研究中位5.7个月随访结果，证实术前治疗6周时18F-FDG-PET可预测术后病理缓解情况。那么，18F-FDG-PET能否预测长期生存结局？PHERGain (NCT03161353): Chemotherapy-free Trastuzumab and Pertuzumab in HER2-positive Breast Cancer: FDG-PET Response-adapted Strategy 2024年4月3日，国际四大医学期刊之首、创刊201周年的英国《柳叶刀》正刊在线发表PHERGain研究中位43.3个月随访结果，报告了HER2阳性早期乳腺癌术前曲妥珠单抗＋帕妥珠单抗±化疗6周时18F-FDG-PET预测3年无浸润癌生存以及根据病理缓解情况及时调整是否化疗的可行性、安全性和有效性。 该国际多中心随机非盲非对照二期临床研究于2017年6月26日～2019年4月24日从7个国家45家医院入组集中确诊为HER2阳性I～IIIA期肿瘤≥1.5厘米可手术乳腺浸润癌至少1个乳腺病变可被18F-FDG-PET检出、美国东部肿瘤学协作组体力状态评分为0或1、基线左心室射血分数≥55%、年龄≥18岁女性356例，按1∶4的比例并按激素受体状态随机分为两组进行术前治疗：- A组71例：曲妥珠单抗＋帕妥珠单抗＋多西他赛＋卡铂
随机分组之前以及2轮治疗（6周）时进行18F-FDG-PET并集中读片。 对于A组患者，无论18F-FDG-PET结果如何，全部完成每3周×6轮治疗。 对于B组患者，全部先接受曲妥珠单抗＋帕妥珠单抗×2轮治疗。随后，根据治疗前后18F-FDG-PET最大标准化摄取值：- 如果减少≥40%：继续曲妥珠单抗＋帕妥珠单抗×6轮治疗
- 如果减少<40%：改为曲妥珠单抗＋帕妥珠单抗＋多西他赛＋卡铂×6轮治疗
末次治疗给药后2～6周进行手术。根据术前治疗、病理缓解、激素受体状态、诊断时临床分期，选择术后治疗方案。- B组完成8轮治疗后18F-FDG-PET最大标准化摄取值减少≥40%患者的术后乳腺和腋窝病理完全缓解率，由当地病理医师判定
结果，A组63例（89%）和B组267例（94%）患者完成手术。根据激素受体状态、治疗周期，影像完全缓解率和病理完全缓解率变化如下。 截至2022年11月4日第二次分析时，中位随访43.3个月，范围0.0～63.0个月，B组3年无浸润癌生存率为94.8%（95%置信区间：91.4～97.1，与预设至少93%相比，P=0.001）达到主要终点。 未见新的安全问题，A组与B组患者相比，不良事件发生率显著较高： B组18F-FDG-PET最大标准化摄取值减少≥40%伴病理完全缓解的患者≥3级治疗相关不良事件发生率最低，仅1%，且无任何严重不良事件。 因此，该小样本随机非对照研究中位43.3个月随访结果表明，对于HER2阳性早期乳腺癌术前曲妥珠单抗＋帕妥珠单抗治疗患者，根据术前治疗6周时18F-FDG-PET和术后病理缓解情况及时调整是否化疗的策略，3年无浸润癌生存率高达94.8%，该策略确定大约三分之一的HER2阳性早期乳腺癌患者可以安全免化疗，故有必要进一步开展大样本随机对照研究长期随访进行验证。 对此，英国剑桥大学发表同期评论：HER2阳性早期乳腺癌化疗的安全降级。Lancet. 2024 Apr 3. IF: 168.9 3-year invasive disease-free survival with chemotherapy de-escalation using an (18)F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial. Pérez-García JM, Cortés J, Ruiz-Borrego M, Colleoni M, Stradella A, Bermejo B, Dalenc F, Escrivá-de-Romaní S, Calvo Martínez L, Ribelles N, Marmé F, Cortés A, Albacar C, Gebhart G, Prat A, Kerrou K, Schmid P, Braga S, Di Cosimo S, Gion M, Antonarelli G, Popa C, Szostak E, Alcalá-López D, Gener P, Rodríguez-Morató J, Mina L, Sampayo-Cordero M, Llombart-Cussac A; PHERGain Trial Investigators. International Breast Cancer Center (IBCC), Barcelona, Spain; Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain; Institut Català D'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Hospital Clinic of Barcelona, Barcelona, Spain; Translational Genomics and Targeted Therapies Group, IDIBAPS, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Universidad Europea de Madrid, Madrid, Spain; Oncology Biomedical Research National Network (CIBERONC-ISCIII), Madrid, Spain; University Hospital Ramón y Cajal, Madrid, Spain; University Hospital Virgen del Rocío, Sevilla, Spain; Hospital Clínico Universitario de Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain; Universidad de Valencia, Spain; Hospital Arnau de Vilanova, Universidad Católica de Valencia, Valencia, Spain; Hospital Universitario A Coruna, A Coruna, Spain; UGC Oncología Intercentros, Hospitales Universitarios Regional y Virgen de la Victoria de Málaga, Instituto de Investigaciones Biomédicas de Málaga (IBIMA), Málaga, Spain; Hospital Universitari Sant Joan de Reus, Reus, Spain; European Institute of Oncology IRCCS, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; European Institute of Oncology, IRCCS, Milan, Italy; University of Milan, Milan, Italy; Oncopole Claudius Regaud- IUCT, Toulouse, France; Tenon Hospital IUC-UPMC, Sorbonne University, Paris, France; INSERM U938 (Cancer Biology and Therapeutics), Paris, France; University Hospital Mannheim, Heidelberg University, Mannheim, Germany; Institut Jules Bordet, Hopital Universitaire de Bruxelles (HUB), Université Libre de Bruxelles (ULB), Brussels, Belgium; Barts Cancer Institute, Queen Mary University of London, UK; Barts Hospital NHS Trust, London, UK; Unidade de Mama, Instituto CUF de Oncologia, Lisbon, Portugal; NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal. BACKGROUND: PHERGain was designed to assess the feasibility, safety, and efficacy of a chemotherapy-free treatment based on a dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer (EBC). It used an 18fluorine-fluorodeoxyglucose-PET-based, pathological complete response (pCR)-adapted strategy. METHODS: PHERGain was a randomised, open-label, phase 2 trial that took place in 45 hospitals in seven European countries. It randomly allocated patients in a 1:4 ratio with centrally confirmed, HER2-positive, stage I-IIIA invasive, operable breast cancer with at least one PET-evaluable lesion to either group A, where patients received docetaxel (75 mg/m2, intravenous), carboplatin (area under the curve 6 mg/mL per min, intravenous), trastuzumab (600 mg fixed dose, subcutaneous), and pertuzumab (840 mg loading dose followed by 420 mg maintenance doses, intravenous; TCHP), or group B, where patients received trastuzumab and pertuzumab with or without endocrine therapy, every 3 weeks. Random allocation was stratified by hormone receptor status. Centrally reviewed PET was conducted at baseline and after two treatment cycles. Patients in group B were treated according to on-treatment PET results. Patients in group B who were PET-responders continued with trastuzumab and pertuzumab with or without endocrine therapy for six cycles, while PET-non-responders were switched to receive six cycles of TCHP. After surgery, patients in group B who were PET-responders who did not achieve a pCR received six cycles of TCHP, and all patients completed up to 18 cycles of trastuzumab and pertuzumab. The primary endpoints were pCR in patients who were group B PET-responders after two treatment cycles (the results for which have been reported previously) and 3-year invasive disease-free survival (iDFS) in patients in group B. The study is registered with ClinicalTrials.gov (NCT03161353) and is ongoing. FINDINGS: Between June 26, 2017, and April 24, 2019, a total of 356 patients were randomly allocated (71 patients in group A and 285 patients in group B), and 63 (89%) and 267 (94%) patients proceeded to surgery in groups A and B, respectively. At this second analysis (data cutoff: Nov 4, 2022), the median duration of follow-up was 43.3 months (range 0.0-63.0). In group B, the 3-year iDFS rate was 94.8% (95% CI 91.4-97.1; p=0.001), meeting the primary endpoint. No new safety signals were identified. Treatment-related adverse events and serious adverse events (SAEs) were numerically higher in patients allocated to group A than to group B (grade ≥3 62% vs 33%; SAEs 28% vs 14%). Group B PET-responders with pCR presented the lowest incidence of treatment-related grade 3 or higher adverse events (1%) without any SAEs. INTERPRETATION: Among HER2-positive EBC patients, a PET-based, pCR-adapted strategy was associated with an excellent 3-year iDFS. This strategy identified about a third of patients who had HER2-positive EBC who could safely omit chemotherapy. FUNDING: F Hoffmann-La Roche PMID: 38582092 DOI: 10.1016/S0140-6736(24)00054-0 Lancet. 2024 Apr 3. IF: 168.9 Safe de-escalation of chemotherapy in HER2-positive early breast cancer. Earl HM. University of Cambridge, Cambridge, UK. PMID: 38582093 DOI: 10.1016/S0140-6736(24)00535-X
|
