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Table 1 Lessons learned over the past decade of target-directed research in breast cancer

From: Patterns in target-directed breast cancer research

Lesson Examples
Trial populations  
 Conduct trials in either positively-selecteda or target-matchedb populations Identification of 6 intrinsic biological BC subtypes (luminal A; luminal B; HER2-enriched; basal-like; normal breast-like; and claudin-low) (Perou et al. 2000; Sorlie et al. 2001; Carey et al. 2006; Prat et al. 2010)
Recurrence scores (e.g. OncotypeDX, PAM50, MammaPrint or IHC4) to help select patients that can forego adjuvant CT (Paik et al. 2006; Albain et al. 2010; Paik et al. 2004; Parker et al. 2009; Chia et al. 2012; Barton et al. 2012; Dowsett et al. 2008; Cuzick et al. 2011; van ‘t Veer et al. 2002; Cardoso et al. 2008; Rutgers et al. 2011; van de Vijver et al. 2002)
Positive trial outcomes
HER2-inhibitors in HER2-positive populations (Slamon et al. 2001; Guan et al. 2013; Goldhirsch et al. 2013; Marty et al. 2005; Perez et al. 2011; Vogel et al. 2002)
ET in HR-positive populations (Fisher et al. 1989; Early Breast Cancer Trialists’ Collaborative Group 2005)
Negative trial outcomes
Bevacizumab combinations in HER2-negative populations (Miller et al. 2005, 2007; Miles et al. 2010; Robert et al. 2011; Brufsky et al. 2011)
Cetuximab combinations in non-KRAS wild-type (Carey et al. 2012; Baselga et al. 2010; O’Shaughnessy et al. 2007)
Inaparib in triple-negative populations (O’Shaughnessy et al. 2011a)
Interventions  
 Consider combining T-D with CT Trastuzumab plus CT (Goldhirsch et al. 2013; Marty et al. 2005; Perez et al. 2011; Slamon et al. 2001; Inoue et al. 2010; Swain et al. 2013) in HER2-positive populations
T-DM1 (Verma et al. 2012) in HER2-positive populations
 Consider multi-T-D strategies based on a biological rationale Everolimus plus ET in HR-positive (Baselga et al. 2012b)
Dual HER2-inhibition in HER2-positive (Baselga et al. 2012c; Swain et al. 2013; Gianni et al. 2012)
 Consider continued T-D therapy Early setting
Positive trial outcomes
Additional 5 years of tamoxifen (Davies et al. 2013; Gray et al. 2013) or letrozole (Goss et al. 2005) in HR-positive populations
Negative trial outcomes
An additional year of trastuzumab in HER2-positive populations (Goldhirsch et al. 2013)
Advanced setting
Sequential ET in HR-positive populations (Baselga et al. 2012b)
Continued HER2-inhibition in HER2-positive across multiple lines of therapy (Cameron et al. 2008; Verma et al. 2012; von Minckwitz et al. 2009)
Trial design  
 Consider the neo-adjuvant setting as a platform for accelerated testingc Pertuzumab (Gianni et al. 2012, 2015), trastuzumab plus FEC and paclitaxel (Buzdar et al. 2013) in HER2-positive NAT populations
Trastuzumab plus lapatinib (Baselga et al. 2012a; Robidoux et al. 2012) in HER2-positive patient NAT populations
 Utilize phase III trials to arrive at conclusive findings Negative trial outcomes
Iniparib in TN populations (O’Shaughnessy et al. 2011a, b)
Positive trial outcomes
The majority of currently established T-D agents (Baselga et al. 2012b, c; Buzdar et al. 1996, 1998; Cameron et al. 2008; Fisher et al. 1989; Slamon et al. 2001; The Nolvadex Adjuvant Trial Organisation 1985; Verma et al. 2012)
 Are powered to assess improved survivald Negative trial outcomes
Bevacizumab combinations in first-line (Miles et al. 2010; Miller et al. 2007; Robert et al. 2011)
Positive trial outcomes
EGF104535 (Guan et al. 2013), CLEOPATRA (Swain et al. 2012; Verma et al. 2012), EMILIA (Baselga et al. 2012c; Swain et al. 2013)
  1. CT chemotherapy, ET endocrine therapy, FEC fluorouracil, epirubicin and cyclophosphamide, HER2 human epidermal growth factor receptor 2, HR hormone receptor, NAT neoadjuvant therapy, OS overall survival, pCR pathological complete response, T-D target-directed therapy, T-DM1 trastuzumab emtansine, TN triple negative
  2. aPatient selection is based on over-expression, mutation or other modification of one or more biomarkers or on a multi-biomarker profile/signature with prognostic or predictive value
  3. bBiomarker used to positively-select patients is targeted by the investigational T-D agent
  4. cDepends on use of pCR as surrogate for survival (pCR translates to disease-free survival and overall survival according to results of the NOAH trial) (Gianni et al. 2013)
  5. dOverall survival (or surrogate) as primary end-point