In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N = 34), lapatinib (L; N = 36), or both (TL; N = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30–65%) and TL (52%, 95% CI 38–65%), and a lower pCR rate with L (25%, 95% CI 13–43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N = 110), after one cycle of HER2-targeted therapy alone (N = 89), and at time of surgery (N = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.

Background monarchE, a phase 3, open-label, randomized study evaluating endocrine therapy with or without abemaciclib in patients with node positive, HR+, HER2-, high risk early breast cancer, resulted in a statistically significant improvement in invasive disease-free survival (IDFS) at a pre-planned interim analysis. Ki-67, a marker of cellular proliferation in breast cancer, was used in addition to other clinical and/or pathological features to identify patients whose cancer may be at higher risk of recurrence. A key secondary endpoint was to evaluate IDFS in patients with high (≥20%) Ki-67 tumors. Methods Patients with ≥4 positive nodes, or 1-3 nodes and either grade 3 disease, tumor size ≥5 cm, or central Ki-67 ≥20% were eligible for monarchE. Ki-67 was centrally assessed for all eligible patients with suitable untreated breast tissue using a standardized kit produced by Agilent/Dako (MIB-1). A sequential gatekeeping strategy was utilized to test the statistical significance in IDFS for patients with high Ki-67 tumors. Data on this subgroup are presented. Results Primary outcome results in the ITT population are presented separately and resulted in a significant 28.7% reduction in the risk of developing invasive disease with abemaciclib plus ET versus ET alone (HR = 0.713; 95% CI = 0.583, 0.871). Of the 5637 patients enrolled in monarchE, 4425 (78.5%) had Ki-67 samples eligible for testing. Of those tested, 2498 patients (56.5%) had Ki-67 ≥20% (Ki-67H). Results from the Ki-67H population are presented separately and showed that abemaciclib plus ET demonstrated superior IDFS versus ET alone with a 30.9% reduction in the risk of invasive disease (p=.0111; HR = 0.691; 95% CI = 0.519, 0.920). There was an absolute improvement of 4.5% in IDFS rate at 2 years (91.6% in the abemaciclib arm and 87.1% in the control arm). An additional planned analysis was performed evaluating efficacy in 2003 patients with high Ki-67 tumors enrolled in cohort 1 (patients with ≥4 positive nodes or 1-3 nodes and either tumor size ≥5 cm and/or grade 3 disease). The IDFS treatment benefit in this group was statistically significant with a HR of 0.643 (95% CI = 0.475, 0.872) corresponding to a 35.7% reduction in the risk of developing invasive disease. Two-year IDFS rates in this group were 91.3% in the abemaciclib group and 86.1% in the control arm, representing a 5.2% absolute improvement at 2 years. A clinically meaningful improvement was also observed in distant relapse-free survival (DRFS) in both populations. Baseline characteristics were balanced across arms in both Ki-67H populations. An exploratory analysis was conducted evaluating patients in cohort 1 with low Ki-67 (<20%) and will be presented. Conclusion This represents the first time a prespecified threshold of ≥20% for Ki-67 has been used to prospectively evaluate the utility of Ki-67 in a phase III registration trial with a standardized assay. There was a statistically significant improvement in IDFS for patients with high Ki-67 tumors across the ITT population (HR = 0.691) and in cohort 1 (HR = 0.643). These results suggest that Ki-67 ≥20% is an additional clinicopathological feature that can be used in conjunction with high risk features of nodal involvement, tumor size, and grade, to select patients with a higher risk of recurrence who may benefit from treatment with abemaciclib in the adjuvant setting. ClinicalTrials.gov: NCT03155997 Ki-67H Ki-67H Cohort 1EndpointAbemaciclib + ETN=1262ET aloneN=1236Abemaciclib + ETN=1017ET aloneN=986IDFS# events, n (%)82 (6.5)115 (9.3)71 (7.0)106 (10.8)log rank Pvalue, HR (95% CI)p=.0111 0.691 (0.519, 0.920)p=.00420.643 (0.475, 0.872)Rate (%) at 2-years (95% CI)91.6(89.4, 93.4)87.1(84.3, 89.5)91.3(88.9, 93.2)86.1(83.1, 88.7)DRFS# events, n (%)65 (5.2)102 (8.3)56 (5.5)96 (9.7)log rank Pvalue,HR (95% CI)p=.0018 0.609 (0.445, 0.833)p=.00040.554 (0.397, 0.773)Rate (%) at 2 years (95% CI)93.6(91.6, 95.1)88.5(85.7, 90.7)93.3(91.2, 95.0)87.384.4, 89.8) Citation Format: Nadia Harbeck, Stephen Johnston, Peter Fasching, Miguel Martin, Masakazu Toi, Priya Rastogi, Chuangui Song, David Molthrop, Jacqueline Vuky, Toshinari Yamashita, Georgina Garnica Jaliffe, Mahmut Gumus, Desiree Headley, Ran Wei, Susana Barriga, Maria Munoz, Michael Method, Valerie Andre, Hans Kreipe, Joyce O'Shaughnessy. High Ki-67 as a biomarker for identifying patients with high risk early breast cancer treated in monarchE [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-01.

In this neoadjuvant trial (TRIO-US B07), participants with early-stage HER2-positive breast cancer (N=128) were randomized to receive trastuzumab (T), lapatinib (L), or both (TL) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. We observed similar pathologic complete response (pCR) rates between T and TL, and a lower pCR rate with L. Higher-level amplification of HER2 and hormone receptor-negative status were associated with a higher pCR rate. Higher pre-treatment immune infiltrate trended toward higher pCR rate in T-treated groups, and greater HR expression correlated with lower immune infiltrate. Large shifts in tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.

No abstract

A new class of antineoplastic agents, the diarylsulfonylureas entered clinical trials with the testing of Sulofenur (LY186641). Phase I trials and preclinical studies showed the dose limiting toxicity to be methemoglobinemia. We studied the incidence of methemoglobinemia, sulfhemoglobinemia and cytochrome b5 reductase deficiency in nine consecutive patients enrolled in a phase II trials using Sulofenur. The specific Malloy method as well as clinically standard co-oximeter measurements were used to determine methemoglobin levels and marked discrepancies were noted. One patient with symptomatic methemoglobinemia had enzyme levels and family history consistent with a heterozygous state for a cytochrome b5 reductase deficiency. We conclude that the clinical incidence of methemoglobinemia will be overestimated by co-oximeter measurements but that Sulofenur does produce clinically significant methemoglobinemia in cytochrome b5 reductase deficient patients.