Since the identification of the first HSP90 inhibitor almost two decades ago, there has been substantial progress made in the development of potent and selective molecules that inhibit this chaperone and that have anticancer activity. In turn, these compounds have been invaluable for probing how HSP90 supports the profound changes in cellular physiology that characterize the malignant state. Unfortunately, when used as single agents HSP90 inhibitors have demonstrated disappointing activity against advanced cancers in most of the clinical trials reported to date. This problem may be due to the major pharmacological liabilities of the first-generation HSP90 inhibitors that have been most extensively studied. We suggest, however, that it may well be intrinsic to the target itself. Systemically tolerable exposure to HSP90 inhibitors may not be highly cytotoxic for the majority of common clinical cancers. Instead, HSP90 inhibitors might better be used to enhance the activity of other antineoplastic agents while simultaneously reducing the capacity of tumors to adapt and evolve drug resistance; the overall result being more durable disease control. This review will focus on these fundamental issues with the goal of suggesting ways to make the clinical development of HSP90 inhibitors become less empiric and ultimately more successful.

Background: While great strides have been made in the treatment of estrogen receptor-positive (ER+) metastatic breast cancer (MBC), therapeutic resistance invariably occurs. A better understanding of the underlying resistance mechanisms is critical to enable durable control of this disease. Methods: We performed whole exome sequencing (WES) and transcriptome sequencing (RNA-seq) on metastatic tumor biopsies from 88 patients with ER+ MBC who had developed resistance to one or more ER-directed therapies. For 27 of these patients, we sequenced the treatment-naïve primary tumors for comparison to the resistant specimens. Tumors were analyzed for point mutations, insertions/deletions, copy number alterations, translocations, and gene expression. Detailed clinicopathologic data was collected for each patient and linked to the genomic information. Results: WES of all metastatic samples demonstrated several recurrently altered genes whose incidence differed significantly from primary, treatment-naïve ER+ breast cancers sequenced in the TCGA study (TCGA). These include ESR1 mutations (n=17, 19.3%; 32.86 fold enrichment, q.value<7.5e-12), CCND1 amplification (n=52, 59.1%; 2.3 fold enrichment, q.value<0.0073), and MAP2K4 biallelic inactivation (n=14, 15.9%; 3.04 fold enrichment, q.value< 0.054). Comparing to matched primary samples from the same patient, many alterations were found to be acquired in several cases, including for ESR1, ERBB2, PIK3CA, PTEN, RB1, AKT1, and others. Initial analysis of RNA-seq data from metastatic samples (n=59) allowed classification of individual resistance mechanisms into broader resistance modes based on the observed transcriptional state. Conclusions: We present a genomic landscape of resistant ER+ MBC using WES and RNA-seq. Multiple genes were recurrently altered in these tumors at significantly higher rates than in ER+ primary breast cancer. When compared with matched primary tumors from the same patient, alterations in these and other genes were often found to be acquired after treatment, suggesting a role in resistance to ER-directed therapies and/or metastasis. Potential resistance mechanisms appear to fall into several categories; integrating RNA-seq data may enhance the ability to identify these categories even when genomic alterations are not identified. Multiple clinically relevant genomic and molecular alterations are identified in metastatic biopsies– with implications for choice of next therapy, clinical trial eligibility, and novel drug targets. Citation Format: Cohen O, Kim D, Oh C, Waks A, Oliver N, Helvie K, Marini L, Rotem A, Lloyd M, Stover D, Adalsteinsson V, Freeman S, Ha G, Cibulskis C, Anderka K, Tamayo P, Johannessen C, Krop I, Garraway L, Winer E, Lin N, Wagle N. Whole exome and transcriptome sequencing of resistant ER+ metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-01.

Background Abemaciclib is a selective CDK4 & 6 inhibitor approved to treat patients (pts) with HR+, HER2- advanced breast cancer (ABC) on a continuous dosing schedule as monotherapy or in combination with endocrine therapy.1,2,3 Clinical data demonstrate that abemaciclib can penetrate the blood brain barrier resulting in comparable abemaciclib concentrations in brain metastases tissues, cerebrospinal fluid, and plasma.4 We report safety and efficacy results of abemaciclib in pts with leptomeningeal metastases (LM) arising from HR+, HER2- ABC. Methods Study I3Y-MC-JPBO (NCT02308020) is a multicenter, open-label, Phase 2 trial evaluating the safety and efficacy of abemaciclib in 6 cohorts of pts with brain metastases secondary to HR+ ABC, non-small cell lung cancer, or melanoma. Here we discuss a subgroup of cohort F: pts with HR+, HER2- LM from ABC, documented by positive CSF cytology or by clinical signs and symptoms associated with abnormal MRI features. Pts with concomitant parenchymal brain metastases were allowed, but must have been stable for ≥4 weeks following wholebrain radiotherapy or stereotactic radiosurgery. Abemaciclib was orally administered 200mg twice daily on a 21-day cycle.The key exploratory objectives were to assess the effect of abemaciclib on pts with LM secondary to HR+, HER2- ABC based on safety and tolerability, and radiological assessment from the Response Assessment in Neuro-Oncology leptomeningeal metastases (RANO-LM) criteria. Results Between December 2015 and July 2016, 17 pts were enrolled in cohort F. This study reports on the 7 pts with HR+, HER2- ABC LM of which 4 pts were diagnosed with concurrent parenchymal brain metastases. Median duration of treatment was 3.9 months (range, 0.9-10.6), with 3 pts remaining on treatment for more than 6 months. Pts discontinued treatment due to progressive disease (PD, n=5) and adverse events (n=2). Median overall survival (OS) was 8.4 months (range, 3.3-14.2). Best investigator-assessed overall response was stable disease (SD) in 5 pts and progressive disease (PD) in 2 pts. Efficacy, as per CNS imaging, revealed SD in 4 pts (no imaging, n=1), 2 of which had stable or improved symptoms per neurological assessment response. Best overall intracranial response of parenchymal metastases was 1 complete response, 1 SD, and 2 PD. All 4 pts with extracranial disease had best overall response of SD. All pts experienced ≥1 TEAE, with the most common grade 3 TEAEs including nausea (28.6%), pain (28.6%), and vomiting (28.6%); 1 pt (14.3%) experienced grade 4 anemia and grade 4 upper gastrointestinal hemorrhage. Conclusion OS for pts with LM arising from HR+, HER2- ABC is typically 4 months or less despite available therapies5. Here we report the median OS within this subgroup as 8.4 months. Concurrent intracranial and extracranial disease control was observed. Safety and tolerability results are similar to those previously reported with abemaciclib. Further study of abemaciclib in a larger pt cohort is warranted. References 1. Dickler et al, Clin Cancer Research 2017 2. Sledge et al, J Clin Oncology 2017 3. Goetz et al, J Clin Oncology 2017 4. Sahebjam et al, 2016 ASCO Annual Meeting, Abstract 14 5. Morikawa et al, Clin Breast Cancer 2017 Citation Format: Tolaney SM, Sahebjam S, Le Rhun E, Lin NU, Markel Bear M, Yang Z, Chen Y, Anders CK. A phase 2 study of abemaciclib in patients with leptomeningeal metastases secondary to HR+, HER2- breast cancer [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 P1-19-01.