Citations

Abstract Background We investigated the clinical outcomes and behavior of HER2+ EBC according to centrally tested HR status in pts treated with modern chemotherapy (CT) and trastuzumab (T)-based regimens. Patients and methods ALTTO is an international phase 3 trial in HER2+ EBC pts randomized to 4 adjuvant anti-HER2 treatment arms: T alone, lapatinib (L) alone, their sequence (T->L) or their combination (T+L). Pts in the L alone arm were excluded from the present analysis. HER2 and HR status were centrally tested for all patients. HER2 status was defined based on the 2007 ASCO/CAP guidelines. HR-positive (HR+) was defined as ≥1% tumor cells with expression of estrogen (ER) and/or progesterone receptors.We investigated the prognosis of pts with HR+ or negative (HR-) HER2+ EBC, the risk of developing early (years 0-5) and late (years 6-8) recurrences, the factors impacting this risk, and the patterns of relapse according to HR status. Univariate and multivariate Cox proportional hazard models were used to compare hazard rates within the HR subgroups; a conditional landmark analysis was conducted to investigate late recurrences. For the hazard ratios for HR status, an interaction between log(time) and HR status was included as proportional hazard assumption was not satisfied. Results This analysis included 6,271 HER2+ pts of whom 3,601 (57%) had HR+ and 2,670(43%) HR- EBC. Median follow-up was 6.93 years (range 6.81-6.96). 5-year disease-free survival (DFS) was 86% (85-87) in HR+ and 83% (82-85) in HR- pts; 8-year DFS was 80% (78-81) in HR+ and 79% (77-81) in HR- pts. The mean annual hazards of recurrence in years 0-5 were 3% in HR+ and 4% in HR- pts, while in years 6-8 they were 3% in HR+ and 2% in HR- pts. The hazard ratios for HR status (ref=HR-) were 0.60 (0.51-0.72) overall, 0.74 (0.65-0.85) for years 0-5 and 1.61 (1.17-2.24) for years 6-8. In HR+ pts, risk factors for recurrence overall were age ≥65 (p=0.01), tumor size pT3-4 (p<0.001), nodal status pN1-3 (p<0.001), tumor grade 2 or 3 (p<0.001), anthracycline-only CT (p<0.001), no use of aromatase inhibitors (p<0.001), and ER<10% (p=0.01). Main risk factors for recurrence in both years 0-5 and years 6-8 were pN2-3 (p=0.04 for both) and high (≥5) HER2 FISH ratio (p=0.02 for both). In HR- pts, risk factors for recurrence overall were BMI (obesity or underweight; p=0.01), pT3-4 (p<0.001), pN1-3 (p<0.001) and anthracycline-only CT (p<0.001). No significant risk factors for recurrence in years 0-5 were identified. Main risk factor for recurrence in years 6-8 was BMI (obesity; p=0.002). HR+ pts had lower incidence of visceral disease (58.8% vs. 69.6%; p=0.005) and lung metastasis (18.5% vs. 27.8%; p=0.006); bone was the most common site of first recurrence (30%). Conclusions This large analysis of centrally tested HR+ and HR- HER2+ EBC provides strong evidence on the existence of two different diseases within the HER2+ population based on HR expression. These up-to-date estimates of pts outcomes after modern CT and T-based regimens may be used as “historical control” for the design of future de-escalation or escalation trials separately in HR+ and HR- HER2+ EBC pts. Citation Format: Lambertini M, Campbell C, Gelber RD, Viale G, McCullough A, Tonghua L, Hilbers F, Korde LA, Werner O, Chumsri S, Jackisch C, Wolff AC, Vaz-Luis I, Ferreira AR, Prat A, Moreno Aspitia A, Piccart M, Loi S, de Azambuja E. Dissecting the effect of hormone receptor (HR) status expression in patients (pts) with HER2-positive (HER2+) early breast cancer (EBC): Exploratory analysis from the ALTTO (BIG 2-06) trial [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 P2-08-14.

Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.