BackgroundRIBBON-1, a Phase III, multicenter, randomized, placebo-controlled trial in patients with previously untreated MBC was designed to evaluate the efficacy and safety of adding bevacizumab (B) to chemotherapy regimens including capecitabine (Cape; n=615); a taxane (T; n=307), or an anthracycline (Anth; n=315) compared with chemotherapy alone. Pre-specified analyses of progression-free survival PFS) in the Cape and pooled T/Anth cohorts, the primary endpoints of the study were increased upon addition of B. In the Cape cohort, median PFS increased from 5.7 to 8.6 mo (HR=0.69, p-value=0.0002) and in the T/Anth cohort, it increased from 8.0 to 9.2 mo (HR=0.64; p-value<0.0001).MethodsRECIST was used to determine objective response rate (ORR). Patients without a post-baseline tumor assessment were considered non-responders. The primary analysis for the ORR and the duration of response was performed using only patients with measurable disease at baseline. ORR was formally compared between the two treatment arms using the Mantel-Haenszel Chi-squared test, using the randomization stratification factors. Fisher's exact test was also performed. Clinical benefit rate (CBR) was defined as the proportion of patients with a complete or partial response or with stable disease at Week 24. Exploratory analyses of CBR and time to response are provided here. Summary statistics of time to response at Week 9 will be presented as will the final analysis of the secondary endpoint of overall survival.ResultsAnalyses of ORR and CBR are provided in the following table. CapeTaxaneAnth PL (n=206)B (n=409)PL (n=104)B (n=203)PL (n=103)B (n=212)Patients with measurable disease, n (%)161 (78.2)325 (61.1)85 (81.7)161 (79.3)92 (89.3)184 (86.8)ORR, %23.635.435.350.340.252.2CR, n (%)1 (0.6)7 (2.2)3 (3.5)4 (2.5)2 (2.2)3 (1.6)PR, n (%)37 (23.0)108 (33.2)27 (31.8)77 (47.8)35 (38.0)93 (50.5)Difference between arms, %11.815.012.0p-value, unstratified0.00940.030.073Duration of ORMedian, mo7.29.28.68.46.08.1HR (95% CI)0.61 (0.39–0.96)0.75 (0.45–1.27)0.53 (0.34–0.83)Log-rank p-value0.03260.2840.0047Clinical benefit rate*, %47.164.365.471.969.980.7p-value, unstratified<0.00010.240.04CR+PR at Week 9, %20.229.438.354.544.451.1B=bevacizumab, cape=capecitabine, CI=confidence interval, HR=hazard ratio, OR=objective response, PL=placebo, T/Anth=taxane/anthracycline.*For randomized patients.ConclusionsIn patients with HER2-negative MBC, the addition of bevacizumab to capecitabine, taxane or anthracycline chemotherapy induces more responses and those responses occur more rapidly. For capecitabine and anthracycline the addition of bevacizumab leads to objective responses that last longer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6084.

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Background: Recent trials showed potential benefit of extended adjuvant endocrine therapy and relatively high risk of relapse after 5 years (yr) in hormone receptor-positive (HR+) HER2- breast cancer. While risk of late relapse in HR+ HER2- is fairly well defined, the risk of late relapse in HER2+ remains largely unknown. Method: 4547 HER2+ patients treated with adjuvant chemotherapy alone or combined with trastuzumab (TH) were included (3132 from North Central Cancer Treatment Group [NCCTG, now Alliance] N9831; 1415 from National Surgical Adjuvant Breast and Bowel Project [NSABP, now NRG] B-31). Intrinsic subtypes were assessed by Prosigna test. Kaplan-Meier method and Cox proportional hazards model were used for analysis. Results: Median follow-up was 10.4 yr in N9831 and 7.0 yr in NSABP-B31. 54.5% of pts had HR+ disease. Pts were classified as HER2 enriched (77.4%), Luminal B (10.1%), Luminal A (7.7%), and Basal (4.8%). In multivariate Cox regression analysis in both treatment groups, HR+ was significantly associated with improved recurrence-free survival (RFS) during the first 5 yr (HR 0.65, 95% CI 0.56-0.77, p<0.001) but there was no significant difference during yr 5-10 (HR 1.32, 95% CI 0.93-1.88, p=0.12). In HR+HER2+ pts treated with TH, cumulative hazard for relapse or death was lower in the first 5 yr (10.96%, 95%CI 8.78-13.08) compared to HR-HER2+ (17.48%, 95%CI 14.59-20.27), with adjusted HR 0.60 (95%CI: 0.45-0.79, p<0.001). Unlike HR+HER2- disease, cumulative hazard of relapse or death in yr 5-10 in HR+HER2+ pts treated with TH was lower at 8.6% (95%CI 6.16-10.97). This is slightly higher than pts with HR-HER2+ at 5.75% (95%CI 3.18-8.24, adjusted HR=1.7, 95%CI 1.01-2.85, p=0.046). Compared to 22% and 31% risk of relapse after 5 yr in N0 and N1 HR+HER2- in recent publication, 3.23% (95%CI 0-9.25) of pts with HR+HER2+ with N0 developed recurrence in yr 5-10 and 6.39% (95%CI 3.09-9.59) in those with N1 disease. Albeit rare, pts with Luminal A tumors had 89.8% relapse-free survival at 10 yr compared to Luminal B 82.3%, HER2 enriched 76.8%, and Basal 74.19%. Conclusions: Even without extended adjuvant endocrine therapy in both trials, risk of late relapse in HR+ HER2+ appeared to be low, particularly in pts with N0 or N1 disease. The benefit of extended adjuvant endocrine therapy in this group of TH pts, particularly those with no lymph node involvement, may not outweigh side effects of continuing endocrine therapy beyond 5 yr. Support: U10CA180821, U10CA18082, U24CA196171; U10CA180868, UG1CA189867, U10CA180822, U24CA196067; ClinicalTrials.gov Id: NCT00005970, NCT00004067 Cumulative probability (%) of relapse or death.Nodal statusYear 0-5Year 5-10* HR+HR-HR+HR- Cumulative hazard (95%CI)Cumulative hazard (95%CI)Cumulative hazard (95%CI)Cumulative hazard (95%CI)07.71 ( 0.00, 15.74)16.05 ( 7.98, 23.42)3.23 ( 0.00, 9.25)8.86 ( 1.05, 16.04)16.70 ( 3.66, 9.64)10.63 ( 5.99, 15.04)6.39 ( 3.09, 9.59)5.57 ( 1.46, 9.51)213.68 ( 7.42, 19.52)20.99 (12.98, 28.26)5.10 ( 0.64, 9.35)1.22 ( 0.00, 3.57)310.25 ( 2.76, 17.17)39.76 (24.11, 52.18)13.19 ( 3.54, 21.88)8.52 ( 0.00, 19.16)*Based on pts who survived 5 yr without relapse Citation Format: Chumsri S, Li Z, Serie DJ, Mashadi-Hossein A, Colon-Otero G, Song N, Pogue-Geile K, Gavin P, Paik S, Moreno-Aspitia A, Perez EA, Thompson EA. Incidence of late relapse in HER2-positive (HER2+) breast cancer patients receiving adjuvant trastuzumab: Combined analysis of NCCTG (Alliance) N9831 and NSABP (NRG) B31 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-02.