Abstract
Targeting of HER2-positive tumors with trastuzumab has shown to improve survival in early stage and advanced breast cancer. The addition of pertuzumab, another anti-HER2 antibody, to trastuzumab-containing regimens has demonstrated a modest increase in disease-free survival in the adjuvant setting. Unexpectedly, when pertuzumab was explored in combination with the antibody-drug conjugate TDM1 in the metastatic setting, no additional benefit was observed compared with dual targeting of HER2 with pertuzumab and trastuzumab, together with chemotherapy. Similar results were observed when exploring pathologic complete response in the neoadjuvant setting. In this article, we discuss basic science and translational data that may explain the limited efficacy observed with the combination of TDM1 and pertuzumab, including tumor heterogeneity, clonal selection, bystander effect or downregulation of the receptor by competitive binding. In addition, we review ongoing studies that could help to understand these findings.
References
Jan 27, 2004·Molecular Biology of the Cell·Anette M HommelgaardBo van Deurs
Sep 10, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Roberto GennariAlberto Costa
Mar 1, 2005·Oncogene·Giorgio ValabregaSilvia Giordano
Apr 19, 2006·Cancer Research·Hans K EricksonWalter A Blättler
Dec 14, 2011·The New England Journal of Medicine·José BaselgaUNKNOWN CLEOPATRA Study Group
Oct 2, 2012·The New England Journal of Medicine·Sunil VermaUNKNOWN EMILIA Study Group
May 6, 2014·The Lancet Oncology·Ian E KropUNKNOWN TH3RESA study collaborators
Dec 4, 2014·Nature·Antonina V KurtovaKeith Syson Chan
Dec 18, 2014·MAbs·Sripad RamE Sally Ward
Mar 22, 2016·Scientific Reports·Niamh E BuckleyManuel Salto-Tellez
Apr 8, 2016·Annals of Oncology : Official Journal of the European Society for Medical Oncology·M MartinJ A Garcia-Saenz
May 12, 2016·Experimental and Therapeutic Medicine·Yuan-Yuan ChenBin Xiong
Jun 15, 2016·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Hannah DzimitrowiczRashmi Murthy
Jan 6, 2017·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Edith A PerezPaul Ellis
Jun 6, 2017·The New England Journal of Medicine·Gunter von MinckwitzUNKNOWN APHINITY Steering Committee and Investigators
Jul 9, 2017·Cancer Research·Carla Ríos-LuciAtanasio Pandiella
Oct 25, 2017·British Journal of Cancer·Alexander H Staudacher, Michael P Brown
Nov 28, 2017·The Lancet Oncology·Sara A HurvitzDennis Slamon
Apr 15, 2018·Cancer Research·Sara García-AlonsoAtanasio Pandiella
Apr 24, 2018·Cell·Charissa KimNicholas E Navin
May 12, 2018·Cancer Treatment Reviews·Noam PondéMartine Piccart
May 31, 2018·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Antonio C WolffMitchell Dowsett
Citations
Apr 25, 2020·EMBO Molecular Medicine·Lucía Gandullo-SánchezAtanasio Pandiella
May 16, 2020·Journal of Cellular and Molecular Medicine·Rao Fu, Jing-Shan Tong
Mar 23, 2019·Cancers·Denis M CollinsGerhard Niederfellner
Oct 19, 2019·Breast Cancer Research : BCR·D J P van UdenC F J M Blanken-Peeters
Dec 17, 2019·British Journal of Cancer·Francis W HunterStephen M F Jamieson
Nov 13, 2020·European Journal of Nuclear Medicine and Molecular Imaging·Betül AltunayFelix M Mottaghy
Feb 24, 2020·The American Journal of Cardiology·Oscar Calvillo-ArgüellesPaaladinesh Thavendiranathan
Aug 9, 2021·Seminars in Oncology·Pei LuJennifer Y Sheng