Citations

Abstract Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - investigational agent(I) +paclitaxel(T) qwk, doxorubicin & cyclophosphamide(AC) q2-3 wk x 4 vs. T/AC (control arm). The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify/graduate regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Regimens may also leave the trial for futility (< 10% probability of success) or following accrual of maximum sample size (10%< probability of success <85%). We report the results for experimental arm Ganitumab, a type I insulin-like growth factor receptor (IGF1R) inhibitor. IGF1R inhibitors are known to induce insulin resistance and all patients assigned to Ganitumab received metformin. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ and HER2+ tumors were ineligible for randomization. Hemoglobin A1C≥ 8.0% were ineligible. MRI scans (baseline, 3 cycles after start of therapy, at completion of weekly T and prior to surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. Ganitumab was given at 12mg/kg q2 weeks and metformin at 850mg PO BID, while receiving ganitumab. Analysis was intention to treat with patients who switched to non-protocol therapy counted as non-pCRs. Ganitumab/metformin was open only to HER2- patients, and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Results: Ganitumab/metformin did not meet the criteria for graduation in the 3 signatures tested. When the maximum sample size was reached, accrual to this arm stopped. Ganitumab/metformin was assigned to 106 patients; there were 128 controls. We report probabilities of superiority for Ganitumab/metformin over control and Bayesian predictive probabilities of success in a neoadjuvant phase 3 trial equally randomized between Ganitumab/metformin and control, for each of the 3 biomarker signatures, using the final pathological response data from all patients. Safety data will be presented. SignatureEstimated pCR Rate (95% probability interval)Probability Ganitumab/ Metformin Is Superior to ControlPredictive Probability of Success in Phase 3 Ganitumab/ Metformin N = 106Control N = 128 All HER2-22% (13%-31%)16% (10%-23%)89%33%HR+/HER2-14% (4%-24%)12% (4%-19%)66%21%HR-/HER2-32% (17%-46%)21% (11%-32%)91%51% Conclusion: The I-SPY 2 adaptive randomization study estimates the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. The value of I-SPY 2 is to give insight about the performance of an investigational agent's likelihood of achieving pCR. For Ganitumab/metformin, no subtype came close to the efficacy threshold of 85% likelihood of success in phase 3, and this regimen does not appear to impact upfront reduction of tumor burden. Our data do not support its continued development for the neoadjuvant treatment of breast cancer. Citation Format: Yee D, Paoloni M, van't Veer L, Sanil A, Yau C, Forero A, Chien AJ, Wallace AM, Moulder S, Albain KS, Kaplan HG, Elias AD, Haley BB, Boughey JC, Kemmer KA, Korde LA, Isaacs C, Minton S, Nanda R, DeMichele A, Lang JE, Buxton MB, Hylton NM, Symmans WF, Lyandres J, Hogarth M, Perlmutter J, Esserman LJ, Berry DA. The evaluation of ganitumab/metformin plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial [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 P6-11-04.

Abstract Background:Pathologic complete response(pCR) after neoadjuvant therapy is an established prognostic biomarker for high-risk breast cancer(BC). Improving pCR rates may identify new therapies that improve survival. I-SPY 2 uses response-adaptive randomization within biomarker subtypes to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer; the goal is to identify regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR), HER2 status and MammaPrint (MP). We report the results for Ganetespib, a selective inhibitor of Hsp90 that induces the degradation/deactivation of key drivers of tumor initiation, progression, angiogenesis, and metastasis.Ganetespib + taxanes previously have resulted in a superior therapeutic response compared to monotherapy in multiple solid tumor models including BC. Methods:Women with tumors ≥2.5cm were eligible for screening and participation. MP low/HR+ tumors were ineligible for randomization. QTcF >470msec and HbA1C >8.0% were ineligible. MRI scans (baseline, +3 cycles, following weekly paclitaxel, T, and pre-surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. Ganetespib was given with weekly T at 150 mg/m2 IV weekly (3 weeks on, 1 off). Patients were premedicated (dexamethasone 10mg and diphenhydramine HCl 25-50 mg, or therapeutic equivalents). Analysis was intention to treat with patients who switched to non-protocol therapy counted as non-pCRs. The Ganetespib regimen was open only to HER2- patients, and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2- and HR-/HER2-. Results:Ganetespib did not meet the criteria for graduation in the 3 signatures tested. When the maximum sample size was reached, accrual stopped. Ganetespib was assigned to 93 patients; there were 140 controls. We report probabilities of superiority for Ganetespib over control and Bayesian predictive probabilities of success in a neoadjuvant phase 3 trial equally randomized between Ganetespib and control, for the 3 biomarker signatures, using the final pCR data from all patients. Safety data will be presented. SignatureEstimated pCR Rate (95% probability interval)Probability Ganetespib Is Superior to ControlPredictive Probability of Ganetespib Success in a Phase 3 Trial Ganetespib N = 93Control N = 140 All HER2-26% (16%-37%)18% (8%-28%)91%47%HR+/HER2-15% (4%-27%)14% (4%-24%)60%19%HR-/HER2-38% (23%-53%)22% (9%-35%)96%72% Conclusion:The I-SPY 2 adaptive randomization model efficiently evaluates investigational agents in the setting of neoadjuvant BC. The value of I-SPY 2 is that it provides insight as to the regimen's likelihood of success in a phase 3 neoadjuvant study. Although no signature reached the efficacy threshold of 85% likelihood of success in phase 3, we observed the most impact in HR-/HER2- patients, with a 16% improvement in pCR rate. While our data do not support the continued development of Ganetespib alone for neoadjuvant BC, combinations with Ganetespib, which could potentiate its effect, may be worth pursuing in I-SPY 2 or similar trials. Citation Format: Forero A, Yee D, Buxton MB, Symmans WF, Chien AJ, Boughey JC, Elias AD, DeMichele A, Moulder S, Minton S, Kaplan HG, Albain KS, Wallace AM, Haley BB, Isaacs C, Korde LA, Nanda R, Lang JE, Kemmer KA, Hylton NM, Paoloni M, van't Veer L, Lyandres J, Perlmutter J, Hogarth M, Yau C, Sanil A, Berry DA, Esserman LJ. Efficacy of Hsp90 inhibitor ganetespib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial [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 P6-11-02.

Abstract Background: While genomic alterations are central players in tumor progression, proteins are the targets for precision therapy. The degree by which “actionable” genomic alterations translate into activated/altered proteins and pathway is still under investigation. Using a multi-OMIC approach from the SideOut 2 metastatic breast cancer (MBC) trial, this study explored the concordance between selected “actionable” genomic alterations and protein expression/activation. Methods: Snap frozen biopsies from 29 MBC patients enrolled in a prospective phase II trial were used for this analysis. Exome WES and RNASeq data was processed using an in-house developed pipeline and identified amplification of CCND1 (6/29), FGFR1 (4/29), and FGF 3, 4, 5, and 19 (4/29) as some of most frequent “actionable” genomic alterations in our MBC cohort. Signaling analysis of the 29 cases was performed using Reverse Phase Protein Microarray coupled with Laser Capture Microdissection. Protein expression/phosphorylation was measured in a continuous scale and classified based on quartile distribution. Concordance between CCND1 amplification and Cyclin D1 expression, along with the activation of FOXM1 T600 and Rb S780, was explored. Amplification of the FGFR1 locus or its ligands was correlated with the level of activation/phosphorylation of FGFR1 Y653/654. Results: While Cyclin D1 protein expression was greater than the population mean for 4/6 (67%) patients with CCND1 amplification, only 2/6 (33%) patients with CCND1 amplification had Cyclin D1 level within the top quartile of the population (n=29). FOXM1 T600 activation was independent from CCND1 amplification, with high levels of FOXM1 T600 predominantly in the CCND1 wild-type population. Only 1/6 (17%) patients with CCND1 amplification had FOXM1 T600 level similar to the top quartile of the population while a second patient was above the population median. Activation of Rb S780 was above the population median, but below the top quartile, in 2/6 (33%) CCND1 amplified patients. Similarly, none of the patients with activation of FGFR Y653/654 equal to the top quartile harbored an FGFR1 amplification. Only 1/4 (25%) patients carrying an FGFR1 amplification had an activation of FGFR Y653/654 above the population median. Similarly, 1/4 (25%) patients with FGF ligand amplification showed FGFR Y653/654 level within the top quartile while three patients had FGFR Y653/654 activation below the population median. No significant results were found between proteomic (below/above the median) and genomic characteristics by Fisher test (p>0.05). Conclusion: Molecular genotyping of “actionable” cancer targets alone may be insufficient in predicting whether the actual drug target protein is expressed and/or activated in any given patient's tumor. Although these results need further validation, the combination of genomic and proteomic data may represent a more informative approach for identifying real molecular drivers of individual lesions as well as “actionable” protein/phosphoprotein targets in the absence of genomic events. Multi-OMIC approaches may lead to more effective stratification in precision medicine trials. Citation Format: Pierobon M, Wong S, Reeded A, Anthony S, Robert N, Northfelt DW, Jahanzeb M, Vocila L, Wulfkuhle J, Dunetz B, Aldrich J, Byron S, Craig D, Liotta L, Carpten J, Petricoin EF. A multi-OMIC analysis to explore the impact of “actionable” genomic alterations on protein pathway activation: Clinical implication for precision medicine in 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 P1-07-09.

497 Background: As activating RAS mutations have been shown to predict lack of benefit from anti-EGFR therapies in advanced CRC, NCCN guidelines recommend testing for KRAS exon 2 and non-exon 2 mutations; however, these alterations are thought to explain only a subset of de novo resistance to targeted therapy. In a large set of CRC assayed with comprehensive genomic profiling (CGP) in the course of clinical care, we assessed the frequency of less common KRAS short insertions that may predict failure of anti-EGFR therapy. Methods: 4,422 CRC cases were assayed with CGP performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of > 650X for at least 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. All classes of genomic alterations (GA) were identified, including base pair substitutions, insertions/deletions, copy number alterations, and rearrangements. Pertinent available prior molecular testing results and clinical history was reviewed for selected cases. Results: Out of 4,422 CRC cases analyzed, KRAS short variants were identified in 50.9% of cases. A majority of cases contained a KRAS alteration at either codon G12 (35.5%) or G13 (9.1%), while alterations at codons Q61 or A146 were identified in 2.2% and 3.1% of cases, respectively. KRAS insertions were identified in 8 ( < 0.5%) cases. All KRAS insertions identified fell within codons 9-13, and 6/8 cases harbored V9_G10 insertions. Out of 6 patients with prior KRAS testing results available, 5 (83%) were negative by previous testing. Conclusions: CGP identifies KRAS insertions within or adjacent to hotspot regions in CRC cases which have previously tested negative for KRAS mutations. Given the importance of KRAS alterations in predicting lack of response to anti-EGFR therapies in CRC, accurate detection of these alterations in the course of clinical care is essential for effective treatment. CGP offers the possibility of identifying KRAS insertions that may impact efficacy of anti-EGFR targeted therapy and should be considered when previous focused testing for KRAS mutations is negative.

570 Background: Vascular endothelial growth factor- (VEGF-) and mammalian target of rapamycin- (mTOR-) directed therapies represent a standard of care in metastatic renal cell carcinoma (mRCC). However, these agents are not employed based on an assessment of predictive biomarkers such as genomic alterations (GA). We sought to determine if an association exists between GA detected by comprehensive genomic profiling (CGP) and the response to VEGFR and mTOR pathway targeted therapies in a cohort of mRCC treated in a clinical practice setting. Methods: The results of CGP performed in the course of clinical care on 31 consecutive mRCC obtained from patients who had received VEGFR- and/or mTOR-inhibitors were reviewed. Duration of treatment (DOT), extent and duration of clinical response was obtained from review of medical records. All classes of genomic alterations - base substitutions, short insertions, deletions, gene fusions, rearrangements and copy number - were assessed via CGP. Descriptive statistics were used to determine the frequency of GAs in groups segregated by the DOT with VEGF-directed agents. Results: The most common GAs detected in this series were in VHL (70%), PBRM1 (48%), SETD2 (32%), TSC1 (29%), MLL (19%), TERT (16%), ARID1B (16%) and KDM5C (16%). Across 61 administrations of VEGF-directed therapy in 27 patients, exceptional responses (DOT > 21 months) were more frequent amongst patients with GAs in KDM5C, PBRM1, and VHL. Conversely, these patients also featured a lower frequency of GA associated with response to mTOR-directed therapy, such as TSC1. Conclusions: Multiple GAs are more prevalent in exceptional responders to VEGF-directed therapy. Prospective validation of these findings may lead to use of CGP to optimize therapeutic selection.

SummarySimtuzumab, a monoclonal antibody inhibitor of extracellular matrix enzyme lysyl oxidase‐like‐2, showed preclinical promise and was well tolerated in clinical studies. A phase 2, open‐label study of simtuzumab was conducted in patients with primary myelofibrosis (MF), post‐polycythaemia vera MF and post‐essential thrombocythaemia MF. Fifty‐four patients were randomized to receive simtuzumab alone (200 or 700 mg [n = 12 each group]) or simtuzumab (200 or 700 mg) with ruxolitinib (n = 15 each group) for 24 weeks. Simtuzumab alone or in combination with ruxolitinib showed no clinical benefit at 24 weeks. The mean serum simtuzumab trough concentrations appeared to increase dose‐proportionally between the 200‐mg and 700‐mg treatment groups. Therapy‐related serious adverse events were pyrexia, pain in extremity (both in 1 patient) and infusion reaction (in another patient). Bone marrow fibrosis (BMF) score was reduced at 24 weeks in 2 patients (16·7%) in the simtuzumab 700‐mg group, 1 (6·7%) in the simtuzumab 200‐mg + ruxolitinib group, and 2 (13·3%) in the simtuzumab 700‐mg + ruxolitinib group; similar numbers of patients had increased BMF. Simtuzumab alone or with ruxolitinib was well tolerated but did not produce clinical benefit nor consistently reduce BMF in patients with MF by 24 weeks.

Despite the widespread inclusion of diversity-related curricula in U.S. medical training, racial disparities in the quality of care and physician bias in medical treatment persist. The present study examined the effects of both formal and informal experiences on non-African American medical students’ ( N = 2,922) attitudes toward African Americans in a longitudinal study of 49 randomly selected U.S. medical schools. We assessed the effects of experiences related to medical training, accounting for prior experiences and attitudes. Contact with African Americans predicted positive attitudes toward African Americans relative to white people, even beyond the effects of prior attitudes. Furthermore, students who reported having witnessed instructors make negative racial comments or jokes were significantly more willing to express racial bias themselves, even after accounting for the effects of contact. Examining the effects of informal experiences on racial attitudes may help develop a more effective medical training environment and reduce racial disparities in healthcare.

Malignant catatonia (MC) is a life-threatening manifestation which can occur in the setting of an underlying neuropsychiatric syndrome or general medical illness and shares clinical and pathophysiological features and medical comorbidities with the Neuroleptic Malignant Syndrome (NMS). The subsequent diagnosis and definitive therapy of MC are typically delayed, which increases morbidity and mortality. We present two cases of MC and review recent literature of MC and NMS, illustrating factors which delay diagnosis and management. When clinical features suggest MC or NMS, we propose early critical care consultation and stabilization with collaborative psychiatric management.