Table 2.

Examples of hypothesis-generating trials and their related hypothesis-confirming trials

Key question	Hypothesis-generating trial	Key results	Confirmatory adjuvant study
Anthracyclines followed by taxanes versus anthracyclines alone	ABERDEEN31, in which 162 patients received neoadjuvant CVAP (four cycles), followed by randomization (1:1) to a further four cycles of CVAP versus docetaxel in the 97 patients with a PR or better on initial CVAP	Improved ORR (94% vs 64%; P = 0.001), pCR rate (34% vs 16%; P = 0.04) and 3-year OS (P = 0.05) in patients receiving sequential docetaxel	Taxanes plus anthracyclines significantly reduce the 8-year risks of disease recurrence (30.2% vs 34.8%; RR 0.84, 95% CI 0.78–0.91; P = 0.00001), disease-specific mortality (21.1% vs 23.9%; RR 0.86, 95% CI 0.79–0.93; P = 0.0005) and overall mortality (23.5% vs 26.7%; RR 0.86, 95% CI 0.79–0.93; P = 0.0002) relative to anthracyclines only in a patient-level meta-analysis of data from 11,167 patients
Weekly versus 3-weekly paclitaxel	Green et al. (2005)32, in which 258 patients were randomized (1:1) to receive four cycles of weekly versus 3-weekly paclitaxel followed by four cycles of 3-weekly FAC	Improved pCR rate in patients receiving weekly paclitaxel (28.2% vs 15.7%; P = 0.02)	Weekly paclitaxel led to significant improvements in DFS (HR 0.84, 95% CI 0.73–0.96; P = 0.011) and OS (HR 0.87, 95% CI 0.75–1.02; P = 0.09) in a cohort of 4,954 patients receiving either weekly or 3-weekly paclitaxel or docetaxel following four cycles of doxorubicin plus cyclophosphamide116
Aromatase inhibitors versus tamoxifen	Ellis et al. (2001)33, in which 324 patients were randomized (1:1) to 4 months of neoadjuvant letrozole versus tamoxifen	Significantly improved ORR (60% vs 41%; P = 0.004) and BCS rates (48% vs 36%; P = 0.036) with aromatase inhibitors	Aromatase inhibitors significantly reduce the 10-year risk of disease recurrence (19.1% vs 22.7%, 95% CI 1.7–5.4; P < 0.00001), cancer-specific mortality (12.1% vs 14.2%, 95% CI 0.5–3.7; P = 0.009) and all-cause mortality (21.3% vs 24.0%, 95% CI 0.1–4.7; P = 0.01) in a patient-level meta-analysis of data from 31,920 patients16
	Dowsett et al.34,42, in which 330 patients were randomized (1:1:1) to 3 months of neoadjuvant tamoxifen, anastrozole, or tamoxifen plus anastrozole	No significant difference in ORRs between groups (ORRs 37%, 36% and 39%, respectively); significantly more patients in the anastrozole group became eligible for BCS relative to the tamoxifen group (46% vs 22%, respectively; P = 0.03)

BCS, breast-conserving surgery; CVAP, cyclophosphamide plus vincristine, doxorubicin and prednisone; DFS, disease-free survival; FAC, fluorouracil plus doxorubicin and cyclophosphamide; ORR, overall response rate; OS, overall survival; pCR, pathological complete response; PR, partial response.