Citations

This paper reviews a case of metastatic 1p/19q codeleted oligodendrioglioma causing diffuse osteosclerosis and pain. Primary central nervous system (CNS) tumors rarely metastasize outside the CNS, and metastatic oligodendroglioma is rarer still. The patient in this study had relief of pain after being treated with temozolomide. We discuss this rare presentation and potential treatment options, and review the literature in regards to metastatic oligodendrogliomas.

Abstract Estrogen receptor positive (ER+) breast cancer accounts for the majority of breast cancers diagnosed worldwide but fortunately, outcomes are markedly improved by pharmacological interventions that interrupt ER function. Unfortunately, suppression of relapse risk from early stage disease with endocrine therapy (anti-estrogens or aromatase inhibitors) is only ∼50%, and for advanced disease, pan endocrine therapy resistance is almost inevitable. While many mechanisms for intrinsic and acquired endocrine resistance have been explored, links between defects in DNA repair, the fundamental drivers of cancer pathogenesis, and endocrine therapy resistance have been understudied. Here we link mismatch repair (MMR) deficiency to poor clinical outcomes in ER+ breast cancer using whole exome DNA sequencing data and mRNA expression analysis. We subsequently demonstrate that MMR deficiency bypasses ER dependent cell cycle regulation through disruption of Chk2/p21-mediated feedback inhibition of CDK4 in breast cancer cell lines and tumor samples, as well as through correlations with human clinical data. We also show that pharmacological targeting of CDK4 significantly inhibits growth of MMR-deficient ER+ breast cancer cells in vitro and in vivo. This mechanism provides a new explanation for why endocrine therapy resistant ER+ breast cancers can respond to CDK inhibition and suggests that primary tumors exhibiting MMR deficiency are good candidates for adjuvant CDK4 inhibitor treatment. Citation Format: Haricharan S, Schmelz J, Schmidt C, Singh P, Holloway K, Anurag M, Suman V, Olson JA, Hunt K, Bainbridge MN, Ellis MJ. Mismatch repair deficiency induces endocrine therapy resistance in 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 PD2-06.

Abstract Background. We previously reported an alternative ESR1 somatic gain-of-function chromosomal translocation event in a patient presenting with aggressive, endocrine therapy resistant estrogen receptor (ER) positive disease, producing an in-frame fusion gene consisting of N-terminal ESR1 and the C-terminus of the Hippo pathway coactivator YAP1 (ESR1-YAP1). We recently identified another ESR1 fusion through RNA sequencing (RNA-seq) in advanced stage ER+ disease from a chest wall recurrence in a male patient that was refractory to multiple lines of treatment. Two examples of fusions discovered in primary breast cancer samples include ESR1 fused in-frame to C-terminal sequences from NOP2 (ESR1-NOP2), identified in a resistant cohort from a RNA-seq screen focused on 81 primary breast cancers from aromatase inhibitor clinical trials, and a second ESR1 fusion, fused in-frame to the entire coding sequence of POLH (ESR1-POLH), that was identified from RNA-seq analysis of 728 Cancer Genome Atlas breast samples. This current study extends our previous characterization of ESR1-YAP1 by comparing functional and pharmacological properties of these three additional ESR1 gene fusion events of both early stage and advanced breast cancers. Methods. In vitro and in vivo experiments were conducted to test ESR1 fusions to induce therapeutic resistance, and metastasis. The transcriptional and binding properties of each fusion was also examined. Pharmacological inhibition with Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, was utilized to assess drug sensitivity in ESR1 fusion containing breast cancer cells and in a patient derived xenograft (PDX) model expressing ESR1-YAP1 (WHIM18). Results. The YAP1 and PCDH11x fusions conferred estrogen-independent and fulvestrant-resistant growth. Immunohistochemistry revealed significantly higher numbers of ER+ cells in lungs of mice xenografted with T47D cells expressing the YAP1 and PCDH11x fusions compared to YFP control, NOP2 and POLH fusions. Results from ChIP-seq and microarray studies suggest that these two fusions promote proliferation and metastasis through genomic action by binding estrogen response elements (ERE) and subsequent gene activation. We thereby define these fusions as “canonical” fusions compared to “non-canonical” NOP2 and POLH fusions, which demonstrated dramatically decreased genomic binding ability. The non-canonical fusions induced genes associated with basal-like breast cancer and promoted HER2, EGFR, and MAPK gene expression signatures in contrast to genes associated with cell cycle/proliferation induced by canonical fusions. The proliferative ability of canonical fusion-containing ER+ cells was inhibited by Palbociclib in a dose-dependent manner. In vivo WHIM18 tumors in mice fed with Palbociclib-containing chow demonstrated significantly reduced tumor volume, growth rate, and weight compared to tumors in mice on control chow. Conclusions. In-frame ERE activating canonical fusions occur in end-stage drug resistant advanced breast cancer and can be added to ESR1 point mutations as a class of recurrent somatic mutation that may cause acquired resistance. Growth induced by these fusions can be antagonized by Palbociclib and is potentially clinically helpful. Citation Format: Lei JT, Shao J, Zhang J, Iglesia M, Cao J, Chan DW, He X, Kosaka Y, Schmidt C, Matsunuma R, Haricharan S, Crowder R, Hoog J, Phommaly C, Goncalves R, Ramalho S, Lai W-C, Hampton O, Rogers A, Tobias E, Parikh P, Davies S, Ma C, Suman V, Hunt K, Watson M, Hoadley KA, Thompson A, Chen X, Perou CM, Creighton CJ, Maher C, Ellis MJ. Recurrent functionally diverse in-frame ESR1 gene fusions drive endocrine resistance in 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 PD2-03.

Abstract Background: Locoregional recurrence (LRR) is a concern after neoadjuvant chemotherapy. Absolute risk of LRR and risk factors associated with LRR among women with node positive breast cancer treated with neoadjuvant chemotherapy on ACOSOG Z1071 were examined. Methods: ACOSOG Z1071 (Alliance for Clinical Trials in Oncology) enrolled cT1-3, N1-2 breast cancer patients treated with neoadjuvant chemotherapy from 2009-2011. All patients underwent axillary dissection. Data was analyzed for locoregional recurrence-free survival (LR-RFS) and multivariable analysis performed to identify factors impacting locoregional recurrence. Results: Of 756 women enrolled, 701 patients were eligible. Median follow-up was 4.0 years (range 0.03–6.2). 39 pts (5.6%) experienced LRR (32 LRR alone and 7 LRR concurrent with metastatic disease) and 96 patients (13.7%) died. LR-RFS was lowest in patients with triple negative tumors (TNBC) (87.6% at 3 years), followed by HER2-positive tumors (94.1%) compared with Hormone Receptor (HR) positive/HER2-negative tumors (96.9%). Residual in-breast disease was present in 57% of patients undergoing BCT and 73% of patients undergoing mastectomy (p<0.0001). LRR was higher in BCT compared to mastectomy (p=0.018), however when evaluated by subtype there was no significant difference in LRR by BCT vs mastectomy. There was no difference in LRR by clinical T stage at presentation or pathologic N stage, however LRR increased with higher pathologic T stage (p=0.006). Overall LRR was lower in patients who achieved a pathologic complete response (pCR) across all tumor subtypes (0% in HR positive/HER2-negative, 2.1% in TNBC, 4% in HER2-positive at 3 years) than in non-pCR patients (HR=0.37, p=0.04). By tumor subtype, pCR was associated with a lower LRR in patients with TNBC (HR=0.17, p=0.019), but was not significantly different by pCR in HER2-positive (HR=0.50, p=0.31) or HR-positive/HER2-negative tumors (HR=inestimable). In the multivariable model, factors associated with increased LRR risk were tumor subtype (TNBC and HER2-positive tumors, p<0.0001), lack of pCR in the breast (p=0.013), breast conservation surgery (p=0.018) and omission of adjuvant radiation therapy (p=0.010). Predictors of locoregional recurrence UnivariableMultivariableVariableHR (95% CI)p-valueHR (95% CI)p-valueClinical T stageT0-T2REF0.34REF0.087T3-T41.38 (0.72-2.65) 1.87 (0.91-3.84) Tumor BiologyHR+/Her2-REF0.002REF<0.0001Her2+1.49 (0.65-3.45) 2.11 (0.89-5.00) Triple negative3.59 (1.68-7.68) 5.53 (2.53-12.13) Path CR breastNoREF0.019REF0.013Yes0.35 (0.15-0.84) 0.27 (0.09-0.76) Path CR breastNoREF0.064REF0.81Yes0.51 (0.25-1.04) 0.67 (0.29-1.59) SurgeryBCTREF0.067REF0.018Mastectomy0.55 (0.29-1.04) 0.43 (0.22-0.87) RadiationYesREF0.033REF0.010No2.18 (1.06-4.48) 2.60 (1.26-5.39) Conclusion: In patients with node-positive breast cancer treated with neoadjuvant chemotherapy, early LRR is higher in TNBC and HER2-positive tumors. In TNBC patients pCR is associated with lower LRR than residual disease. In this contemporary cohort of node-positive, HER2-positive tumors treated with anti-HER2 therapy, patients achieving a pCR had low LRR rate. Adjuvant radiation appears to be important for locoregional control regardless of pCR. Citation Format: Boughey JC, Ballman KV, McCall LM, Mittendorf EA, Hunt KK. Predictors of locoregional recurrence after neoadjuvant chemotherapy and surgery for node positive breast cancer: Results from ACOSOG Z1071 (Alliance) [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 P6-09-01.

Abstract Purpose/Objectives: The optimal clinical target volume (CTV) for internal mammary node irradiation (IMNI) is uncertain in an era of increasingly conformal volume-based treatment planning for breast cancer. We mapped the location of gross internal mammary lymph node (IMN) metastases in order to identify areas at highest risk for harboring occult disease. Methods and Materials: Patients with axial imaging of IMN disease, including fluorodeoxyglucose F-18 (FDG18) positron emission tomography (PET-CT) and magnetic resonance imaging (MRI), were identified from a breast cancer registry. The IMN location was transferred by a radiation oncologist and breast radiologist onto the corresponding anatomic position on representative axial CT images of a patient in the treatment position. Distribution of lymph nodes, and their location was compared with consensus group guidelines of IMN target delineation. Results: Sixty-seven patients with 130 IMN metastases were mapped. The location was in the first three intercostal spaces in 102 of 130 (78%) nodal metastases. Eighteen of 130 (14%) IMN were located caudal to the third intercostal space, while 10 of 130 (8%) IMN were located cranial to the first intercostal space, including 3 patients with isolated IMN metastases at that location in the absence of distant disease. Of the 102 nodal metastases within the first three intercostal spaces, 54 (53%) were located within the RTOG consensus volume. Relative to the internal mammary (IM) vessels, 19 (19%) nodal metastases were located medially with a mean distance of 2.2 mm (SD 2.9 mm), while 29 (28%) were located laterally with a mean distance of 3.6 mm (SD 2.5 mm). Ninety and ninety-five percent of lymph nodes within the first three intercostal spaces would have been encompassed within a 4 mm and 6 mm medial and lateral expansion on the IM vessels, respectively. Conclusions: For women with indications for elective IMNI, a 4 mm medial and lateral expansion on the IM vessels within the first 3 intercostal spaces may be appropriate. In women with known IMN involvement, cranial extension to the confluence of the IM vein with the brachiocephalic vein +/- caudal extension to the 4th or 5th interspace with a 6 mm medial and lateral expansion may be considered, provided that normal tissue constraints are met. Citation Format: Jethwa KR, Kahila MM, Hunt KN, Brown LC, Corbin KS, Park SS, Yan ES, Boughey JC, Mutter RW. Delineation of internal mammary nodal target volumes in breast cancer radiotherapy [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 P1-10-09.

463 Background: The genomic assessment of cancer has been revolutionized by next-generation sequencing and is increasingly being applied in the clinic to guide therapeutic decision-making. Time to reporting of results, specimen quantity, and analyte quality have constrained initial clinical applications to gene panels and whole exome based strategies. Methods: Patients underwent surgical resection, excisional or core biopsies, or bone marrow biopsy. Samples were analyzed by whole genome or exome sequencing and RNA sequencing, bioinformatics analysis, and therapeutic target prioritization by a multi-disciplinary Clinical Genomics Board. All prioritized targets were CLIA validated using Sanger sequencing, RT-qPCR, FISH, or IHC as appropriate. Treatment was delivered using off-label FDA approved drugs, clinical trials, or single patient INDs. Results: We have enrolled 40 patients with advanced, treatment-refractory cancers of whom sequencing data is available on 33. The initial 6 patients were evaluated in a non-CLIA pilot phase and 27 in the CLIA enabled phase. Upon availability of the initial report, identified targets of putative therapeutic relevance were then prioritized by the CGB in 22/27 patients (81%) for subsequent CLIA validation. Eleven patients have been treated with genomically selected therapy with partial response in 3/10 assessed patients. A testicular cancer patient had aberrations in two testes specific genes, a copy number gain in TSSK6 and a novel gene fusion between thyroid hormone receptor associated protein 3 (THRAP3) and Tektin 2 (TEKT2). Additionally, a case of papillary renal cell carcinoma had an amplification of YAP1 and a previously unreported P287T mutation in CCND1, suggesting potential benefit with a CDK4/6 inhibitor. Treatment is ongoing and results will be reported. Conclusions: Integrated whole genome analysis in a CLIA setting is feasible. Integration of SNV, copy number and transcriptional data may allow for selection of putative driver genes to enhance targeted therapy decisions. Barriers for future broader implementation include the need for reduced time from biopsy to report and availability of therapies.

205 Background: Central review is an important trial management and validation tool. Multisite trials require data systems to accommodate diverse image acquisition and review. Breast cancer is challenging as its imaging objects are not always easily shared across departments. Quality Assurance Review Center (QARC) has a diverse portfolio of facile data acquisition and powerful informatics support that meets these needs. We report on the role of QARC in three of the current breast cancer trials from the American College of Surgeons Oncology Group. Methods: QARC data management system includes secure network infrastructure and a validated relational operating database (MAX). QARC has data acquisition/imaging re-distribution expertise for real time response reviews, response measuring tools and corresponding data archive for secondary reviews. MAX includes query ability; records link to digital information. QARC underwent systematic information systems validation process for 21 CFR Part 11. DICOM/non-DICOM files are stored in the QARC PACS. On-site/remote reviewers use MAX to retrieve, view, annotate and save images. Data extracted is securely sent to partner statistical centers. Results: In Z1031, a neoadjuvant endocrine therapy trial, all of the mammographic exams are archived at QARC. For Z1071, a sentinel lymph node trial, pre- and post-treatment ultrasound (US) images of 321 patients were remotely reviewed. For Z1072, the cryoablation US, pre and post-cryoablation MRI for 40 of 47 cases were remotely archived, retrieved and transferred to investigator workstation for post-processing and review. The other 7 patients did not have evaluable imaging studies. In all three trials, the costs of shipping hardcopies of exams and travel to QARC for central review functions were eliminated. Conclusions: QARC data management systems provide diverse informatics supports for multi-institutional trials, ranging from archives of images, provide remote access and download of data, and central review. The vibrant informatics supports meet the growing needs of clinical trials. Future directions include radiation field review for breast cancer trials and the incorporation of pathology microarray analysis as DICOM objects.