 乳腺癌易感基因BRCA1和BRCA2是重要的抑癌基因，主要负责修复DNA，一旦发生致病突变，容易引起三阴性乳腺癌等恶性肿瘤，如果突变发生于种系（旧称胚系或生殖系）细胞还可进一步遗传。奥拉帕利是全球首个多腺苷二磷酸核糖聚合酶PARP抑制剂，对种系BRCA突变型三阴性乳腺癌有效。那么，奥拉帕利对于种系BRCA野生型三阴性乳腺癌是否有效？ 2024年4月8日，全球自然科学三大旗舰期刊之首、创刊155年的英国《自然》正刊以加速预览形式与美国癌症研究协会第115届年会同步发表英国剑桥大学牵头、阿斯利康赞助的PARTNER研究报告原稿，首次探讨了奥拉帕利联合铂类新辅助治疗种系BRCA野生型三阴性乳腺癌术前患者的有效性和安全性。奇怪的是，2016年5月该研究方案设计公布时只字未提种系BRCA野生型，只提到种系BRCA阳性。
英国《自然》正刊作为自然科学期刊，主要发表基础研究，较少发表临床研究，以“乳腺癌”和“试验”对标题进行检索，创刊155年来仅此一篇。而且，英国《自然》正刊极少以加速预览形式发表未经编辑校对、可能存在错误的“毛坯”，以前大多发生于重大创新突破研究。
2024年5月9日，经过一个月的等待，英国《自然》正刊终于完成该研究报告原稿的编辑校对、正式发布清样，标题加了“化疗”两个字，那么内容有没有重大创新突破？
该全国多中心II～III期非盲随机对照临床试验于2016年9月至2021年12月从29个英国中心入组种系BRCA野生型三阴性乳腺癌早期术前患者559例，按1∶1随机分为两组，其中287例（研究组）给予卡铂联合紫杉醇化疗＋奥拉帕利（间歇方案：每3周第3至14天每天2次口服150毫克）新辅助治疗4个周期，其余320例（对照组）给予卡铂联合紫杉醇化疗4个周期，两组随后给予蒽环类化疗3个周期，再进行手术。另有93例给予卡铂联合紫杉醇化疗＋奥拉帕利（连续方案：每3周每天2次口服150毫克）由于安全性、便利性、合规性和有效性被叫停。此外，种系BRCA突变型三阴性乳腺癌早期术前患者组成另外一个队列进行研究。
该研究主要终点为病理完全缓解，次要终点包括无事件生存和总生存。 结果，截至2023年11月30日，中位随访38个月，研究组与对照组相比：
无论是否联合奥拉帕利，病理完全缓解与未病理完全缓解患者相比：
因此，英国《自然》正刊以加速预览形式首次发表的乳腺癌临床试验报告原稿经过经过一个月编辑校对清样，结果表明对于种系BRCA野生型三阴性乳腺癌早期术前患者，将奥拉帕利加入卡铂＋紫杉醇＋蒽环类新辅助化疗，病理完全缓解率、无事件生存率或总生存率并未显著提高，不良事件发生率倒是不低。 不过，该研究种系BRCA突变型三阴性乳腺癌早期术前患者组成另外一个队列结果据说完全不同，奥拉帕利组的无事件生存和总生存显著获益，36个月总生存率达100%，不知将来会不会被英国《自然》正刊十万火急地发表。
Nature. 2024 Apr 8. IF: 64.8 The PARTNER trial of neoadjuvant olaparib in triple-negative breast cancer. The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer. Abraham JE, Pinilla K, Dayimu A, Grybowicz L, Demiris N, Harvey C, Drewett LM, Lucey R, Fulton A, Roberts AN, Worley JR, Chhabra A, Qian W, Vallier AL, Hardy RM, Chan S, Hickish T, Tripathi D, Venkitaraman R, Persic M, Aslam S, Glassman D, Raj S, Borley A, Braybrooke JP, Sutherland S, Staples E, Scott LC, Davies M, Palmer CA, Moody M, Churn MJ, Newby JC, Mukesh MB, Chakrabarti A, Roylance RR, Schouten PC, Levitt NC, McAdam K, Armstrong AC, Copson ER, McMurtry E, Tischkowitz M, Provenzano E, Earl HM. University of Cambridge, Cambridge, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK; The City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK; Royal Bournemouth General Hospital, Bournemouth, UK; Royal Wolverhampton NHS Trust, Wolverhampton, UK; Russells Hall Hospital, Dudley, West Midlands, UK; Ipswich Hospital, East Suffolk and North Essex NHS Foundation Trust, Ipswich, UK; University Hospital of Derby and Burton, Derby, UK; Bedford Hospital, Bedfordshire Hospitals NHS Foundation Trust, Bedford, UK; Pinderfields Hospital, Mid Yorkshire Teaching NHS Trust, Wakefield, UK; University Hospitals Southampton and Hampshire Hospitals Foundation Trusts, Southampton, UK; University of Southampton, Southampton, UK; Basingstoke & North Hampshire Hospital, Basingstoke, UK; Royal Hampshire Hospital, Winchester, UK; Velindre Cancer Centre, Cardiff, Wales, UK; Swansea Bay University Health Board, Swansea, Wales, UK; University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK; Mount Vernon Cancer Centre, Northwood, UK; Queens Hospital, Barking, Havering and Redbridge University Hospitals NHS Trust, Romford, UK; Beatson West Of Scotland Cancer Centre, Glasgow, Scotland, UK; Hinchingbrooke Hospital, North West Anglia NHS Foundation Trust, Huntingdon, UK; West Suffolk Hospital NHS Foundation Trust, Bury Saint Edmunds, UK; Worcestershire Acute Hospitals NHS Trust, Worcester, UK; Alexandra Redditch Hospital, Redditch, UK; Hospital, Kidderminster, Worcestershire, UK; Royal Free London NHS Foundation Trust, London, UK; University College London Hospitals NHS Foundation Trust, London, UK; Colchester General Hospital, East Suffolk & North Essex NHS Trust, Colchester, UK; University Hospitals Dorset NHS Foundation Trust, Poole, UK; Oxford University Hospital NHS Foundation Trust, Oxford, UK; Peterborough City Hospital, North West Anglia NHS Foundation Trust, Peterborough, UK; The Christie NHS Foundation Trust, Manchester, UK; EMC2 Clinical Consultancy Ltd, Sale, Manchester, UK; Athens University of Economics and Business, Athens, Greece. We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply. PARTNER is a prospective, phase II-III, randomised controlled clinical trial, which recruited patients with Triple Negative Breast Cancer (TNBC), who were gBRCA wild type (gBRCAwt). Patients (n=559) were randomised on a 1:1 basis to neoadjuvant carboplatin with paclitaxel +/- olaparib 150mg twice daily, days 3 to 14, for 4 cycles (gap schedule olaparib, research arm) followed by 3 cycles of anthracycline chemotherapy before surgery. The primary endpoint was pathological complete response (pCR), and secondary endpoints included event-free survival (EFS), and overall survival (OS). pCR was achieved in 51% in the research arm and 52% in the control arm (p=0.753). Estimated EFS at 36 months in research and control arms were 80% and 79% (log-rank p>0.9); OS were 90% and 87.2% (log-rank p=0.8) respectively. In patients with pCR, estimated EFS at 36 months was 90%, and with non-pCR was 70% (log-rank p < 0.001) and OS was 96% and 83% (log-rank p < 0.001) respectively. Neo-adjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin/paclitaxel and anthracycline chemotherapy in patients with TNBC (gBRCAwt). This is in marked contrast to the major benefit of olaparib (gap schedule) in those with gBRCA pathogenic variants (gBRCAm) which is reported separately (gBRCAm article). ClinicalTrials.gov ID: NCT03150576 PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer, who were germline BRCA1 and BRCA2 wild type. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR), and secondary end points included event-free survival (EFS) and overall survival (OS). pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 PMID: 38588696 DOI: 10.1038/s41586-024-07384-2 |
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