Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results.

PURPOSE: EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer. PATIENTS AND METHODS: This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects. RESULTS: Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002). CONCLUSIONS: Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.

Optimum duration of neoadjuvant letrozole to permit breast conserving surgery.

The aim of this multicenter, prospective, longitudinal phase IV study was to establish the optimal duration of neoadjuvant letrozole that would allow breast conservation surgery (BCS) in patients with early breast cancer who were initially unsuitable. Primary, invasive, estrogen-receptor- and/or progesterone-receptor-positive breast cancer patients, with large tumors (≥T2 i.e., >20 mm) not initially suitable for BCS, received 2.5 mg letrozole p.o. daily. Patients continued treatment until they became eligible for BCS, progressed, failed to meet criteria for BCS and withdrew for scheduled mastectomy, withdrew for other reasons, or completed 12 months of letrozole treatment without a BCS decision being made. A total of 146 patients were enrolled; seven patients who did not have a valid postbaseline tumor assessment were excluded from the final efficacy analysis. At study closure, 69 % of patients (96 of 139) were eligible for BCS. The median time to achieve a tumor response sufficient to allow BCS with neoadjuvant letrozole was 7.5 months (95 % CI 6.3-8.5 months). Letrozole was well tolerated, and most adverse events were mild-to-moderate (grade 1-2). The results from this trial suggest that extended letrozole therapy in the neoadjuvant setting (7.5 months), as opposed to conventional treatment of 4 months, is optimal to achieve maximum reduction in tumor volume sufficient for BCS.

Patterns and predictors of early recurrence in postmenopausal women with estrogen receptor-positive early breast cancer.

Previous studies suggest that disease recurrence peaks at around 2 years in patients with early stage breast cancer (EBC), but provide no data regarding recurrence type. This retrospective analysis aimed to identify early recurrence types and risk factors in estrogen receptor-positive (ER+) EBC patients treated with adjuvant tamoxifen following breast cancer surgery. Postmenopausal women diagnosed with ER+ EBC from 1995 to 2004 were evaluated. Annual hazard ratios (HR) for recurrence at different sites were calculated. Time-dependent Cox regression analysis was used to identify predictors of recurrence within 2.5 years of diagnosis, including factors that were more strongly predictive of early than later recurrence. Of 3,614 patients evaluated, 476 developed recurrence during the 5-year median follow-up. Cumulative recurrence rates at 2.5 years (95% confidence interval) were: overall 6.3% (5.5-7.1), locoregional 1.1% (0.7-1.5), contralateral 0.5% (0.3-0.7), and distant 4.8% (4.0-5.6). The annual HR of overall recurrence peaked at 2 years (4.3% per annum). The majority of this peak represented distant recurrence (3.4% per annum). In Cox regression analysis, tumor size and grade, lymph node involvement, lymphovascular invasion, and symptomatic presentation were significant independent predictors of early recurrence. Age at diagnosis was independently predictive of recurrence within 2.5 years of diagnosis but not later recurrence. This study identified an early recurrence peak at 2 years, most of which were distant recurrences. Implementing an aromatase inhibitor after an initial 2-3 years of tamoxifen fails to address this early peak of distant recurrence and the potential breast cancer-associated mortality.