Search

PURPOSE Patients with triple-negative breast cancer (TNBC) and residual invasive disease (RD) after completion of neoadjuvant chemotherapy (NAC) have a high-risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the TNBC basal subtype. The EA1131 trial hypothesized that invasive disease-free survival (iDFS) would not be inferior but improved in patients with basal subtype TNBC treated with adjuvant platinum compared with capecitabine. PATIENTS AND METHODS Patients with clinical stage II or III TNBC with ≥ 1 cm RD in the breast post-NAC were randomly assigned to receive platinum (carboplatin or cisplatin) once every 3 weeks for four cycles or capecitabine 14 out of 21 days every 3 weeks for six cycles. TNBC subtype (basal v nonbasal) was determined by PAM50 in the residual disease. A noninferiority design with superiority alternative was chosen, assuming a 4-year iDFS of 67% with capecitabine. RESULTS Four hundred ten of planned 775 participants were randomly assigned to platinum or capecitabine between 2015 and 2021. After median follow-up of 20 months and 120 iDFS events (61% of full information) in the 308 (78%) patients with basal subtype TNBC, the 3-year iDFS for platinum was 42% (95% CI, 30 to 53) versus 49% (95% CI, 39 to 59) for capecitabine. Grade 3 and 4 toxicities were more common with platinum agents. The Data and Safety Monitoring Committee recommended stopping the trial as it was unlikely that further follow-up would show noninferiority or superiority of platinum. CONCLUSION Platinum agents do not improve outcomes in patients with basal subtype TNBC RD post-NAC and are associated with more severe toxicity when compared with capecitabine. Participants had a lower than expected 3-year iDFS regardless of study treatment, highlighting the need for better therapies in this high-risk population.

TPS1127 Background: Heat shock protein 90 (HSP90) is a molecular chaperone which is necessary for proper folding and stabilization of proteins. Client proteins of HSP90 include many oncogenic proteins known to be over-activated in triple negative breast cancer such as AKT, EGFR, members of RAS/MAPK signaling pathway and androgen receptor. High expression of HSP90 in breast cancer has been associated with poor outcome. In addition, over-expression of HSP90 client proteins such as AKT and c-RAF has been implicated in paclitaxel resistance. Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of HSP90 by binding to the amino terminal of the protein and has dissociation constant (Kd) of 0.71 nM. Methods: Patients with inoperable or metastatic, triple negative or < 10% hormone receptor positive breast cancer are treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel is given at a standard dose of 80 mg/m2 while the dose of onalespib is gradually increased using standard 3+3 design (see table). In order to assess the effect of each drug on pharmacokinetics of the other drug, onalespib is given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1 during which paclitaxel is administered alone. The primary objective of the study is to determine recommended phase II dose and assess the toxicity profile of the combination. The secondary objectives include pharmacokinetic of each agent. Overall response rate, response duration and progression-free survival will also be assessed. The study is currently enrolling patients to dose level 2. Clinical trial information: NCT02474173. [Table: see text]

e12126 Background: Even with neo-adjuvant chemotherapy (NAC) many breast cancer (BC) patients (pts) relapse, especially triple negative pts. The incorporation of checkpoint inhibitors into NAC for BC is being tested in clinical trials. How NAC affects checkpoint receptor expression is not known. Such information could aid in the rational selection of checkpoints to target during NAC. We sought to characterize changes in the frequency of circulating CD4 and CD8 T cells expressing PD1, CTLA4, LAG3, TIM3, and OX40 over the course of NAC. Methods: In this prospective trial, expression of PD-1, CTLA-4, Lag3, Tim3 and Ox40 on circulating CD4 and CD8 T cells were measured by FACS analysis in pts with operable breast cancer (BC) prior and at the end of NAC. The primary objective was to explore the association between NAC and expression levels of the immune checkpoints. Results: 1, 20 and 3 pts had clinical stage I, II, IIIA, respectively. Median age was 48. 11, 6 and 7 pts were triple negative (TN), HER2+ and hormone receptor (HR)+, respectively. Complete pathologic response rate was 45.8%. Globally CD4 T cells expressing CTLA4, Lag3, Ox40 and PD1 decreased following NAC (all p < 0.01). Conversely, CD8 T cells expressing CTLA4, Lag3 and Ox40 significantly increased (all p < 0.01). More CD8 T cells from HER2+ pts expressed Lag3 prior to therapy compared to HR+ pts (p < 0.05) with a similar trend compared to TN pts. Prior to therapy more CD8 T cells from HER2+ and TN pts expressed Tim3 compared to HR+ pts (p < 0.05 for each). Post therapy more CD4 T cells from HER2+ pts expressed PD1 compared to HR+ and TN pts (p = 0.027 and 0.018 respectively). Clinical response did not predict change in checkpoint expression. An interaction analysis revealed that HER2+ disease predicted a drop in CTLA4 CD4 T cells and a drop in Lag3 CD4 and CD8 T cells over NAC (p < 0.05). Conclusions: This analysis identified changes in checkpoint receptor expression by CD4 and CD8 T cells in BC pts after NAC. Differences in checkpoint receptor expression were found between BC subgroups. This data provides a starting point for understanding checkpoint receptor expression changes with NAC, and could help guide the selection and timing of incorporating checkpoint inhibitors in BC.

10102 Background: Many BC patients treated with aromatase inhibitors (AIs) develop AIA; 20% have symptoms severe enough to effect treatment compliance. Results of candidate gene studies to identify AIA risk are limited in scope. In this case-controlled study, we evaluated the potential of a NAA to predict AIA using germline single nucleotide polymorphism (SNP) data obtained prior to treatment initiation. Methods: Systematic chart review of 700 AI-treated patients with stage I-III BC between 2003-2012 identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained from peripheral blood cells and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. The identity of the cluster of SNPs that most closely defined AIA risk was discovered using an NAA that sequentially combined statistical filtering and a machine learning algorithm. NCBI PhenGenI and Ensemble databases were used to define gene attribution of the 200 most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Results: Cases and controls were similar in demographic characteristics. A cluster of 70 SNPs, correlated to 57 genes (accounting for linkage disequilibrium), was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally and ontologically consistent. Conclusions: Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias. An ongoing prospective companion study will be used to validate and to expand upon results.