Research Spotlight

Cowey, C. L., F. X. Liu, J. Black-Shinn, K. Stevinson, M. Boyd, J. R. Frytak and S. W. Ebbinghaus (2017). “Pembrolizumab Utilization and Outcomes for Advanced Melanoma in US Community Oncology Practices.” J Immunother.

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The programmed death-1 inhibitor pembrolizumab has demonstrated efficacy and safety in clinical trials for treating advanced (unresectable/metastatic) melanoma. We investigated the real-world utilization of pembrolizumab and associated patient outcomes for advanced melanoma in US community oncology practices. This retrospective, observational study used deidentified data from electronic health records for adult patients with advanced melanoma who received pembrolizumab at The US Oncology Network sites from September 2014 through December 2015, with follow-up through September 2016. Patients enrolled in clinical trials were excluded. Overall survival (OS) and physician-stated progression-free survival (PFS) were analyzed from pembrolizumab initiation using Kaplan-Meier, and associations between pembrolizumab therapy and OS/PFS, using multivariable Cox regression. Of 168 patients studied, 110 (65%) were male; the median age was 66 years (range, 26-over 90). Pembrolizumab was prescribed as first-line, second-line, and third-line/later for 39 (23%), 87 (52%), and 42 (25%) patients, respectively. In total, 41 patients (24%) had brain metastases. At pembrolizumab initiation, 21/129 (16%) had Eastern Cooperative Oncology Group performance status (ECOG PS) >1; 51/116 (44%) had elevated lactate dehydrogenase. Median follow-up was 10.5 months (range, 0-25.1); median OS was 19.4 months (95% confidence interval, 14.0-not reached); median PFS was 4.2 months (95% confidence interval, 2.9-5.3). Brain metastases, ECOG PS>1, elevated lactate dehydrogenase, and third-line/later (vs. first-line) pembrolizumab were significant predictors (P<0.01) of decreased survival. Treatment-related toxicity was a discontinuation reason for 25% (29/117) of patients, and for 10 of these 29 patients (6% of the full-study cohort) treatment-related toxicity was the only reported reason. The real-world effectiveness and safety of pembrolizumab for advanced melanoma are consistent with clinical trial findings.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Condorelli, R., L. Spring, J. O’Shaughnessy, L. Lacroix, C. Bailleux, V. Scott, J. Dubois, R. J. Nagy, R. B. Lanman, A. J. Iafrate, F. Andre and A. Bardia (2017). “Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer.” Ann Oncol.

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Background: While deregulation of the cyclin D1-CDK4/6-retinoblastoma pathway is common in hormone receptor positive (HR+) breast cancer, Rb is usually intact in HR+ breast cancer, and targeted CDK 4/6 inhibitors that act upstream of Rb, are routinely being utilized in clinical practice. However, factors that can lead to clinical resistance to CDK 4/6 inhibitors are not known. Patients and methods: We identified patients who had pre and post genotyping in tissue and peripheral blood samples after receiving CDK 4/6 inhibitors. Genotyping was performed in tumor tissue or blood collected before start of CDK 4/6 inhibitor and after disease progression on CDK 4/6 inhibitor, covering more than 90% of the coding region in RB1. Results: We identified detectable acquired RB1 mutations in ctDNA after exposure to CDK4/6 inhibitor (palbociclib, palbociclib, ribociclib) for 5,8, and 13 months respectively, in three patients. The RB1 mutations included substitution in donor splicing site of exon 8 of the RB1 gene in patient #1; substitution in donor splicing site of exon 22 of RB1 gene, exon 19 deletion, exon 3 insertion in patient #2; and RB1 exon 16 H483Y mutation in patient #3. None of these RB1 mutations were present in the pre-CDK 4/6 specimen highlighting these molecular alterations, which lead to functional loss of Rb1, likely emerged under selective pressure from the CDK4/6 inhibitor potentially confering therapeutic resistance. Conclusion(s): This is the first clinical report to describe the emergence of somatic RB1 mutations after exposure to palbociclib or ribociclib, in patients with metastatic breast cancer. Further research is needed to validate these findings, identify how these mutations temporally emerge under selective pressure of CDK 4/6 treatment, and develop rational therapeutic strategies.

Cho, J., E. M. Stock, I. C. Liao, J. E. Zeber, B. K. Ahmedani, R. Basu, C. C. Quinn and L. A. Copeland (2018). “Multiple chronic condition profiles and survival among oldest-old male patients with hip fracture.” Arch Gerontol Geriatr 74: 184-190.

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To improve understanding of survival among very elderly male patients with surgically repaired hip fractures, this study applied classification techniques to multiple chronic conditions (MCC) then modeled survival by latent class. Veterans Health Administration (VHA)’s electronic medical records on male inpatients age 85-100 years (n=896) with hip fracture diagnosis and repair were used. MCC defined by Charlson and Elixhauser disorders, medications, demographic covariates, and 5 years follow-up survival were included. Latent Class Analysis (LCA) identified three classes based on patterns of MCC, medications, and demographic covariates: Low-comorbidity (16%), High-longevity (55%), and High-comorbidity (29%). Overall, survival censored at 5 years post-op averaged 717days. The Low-comorbidity group was more likely to be Hispanic, less disabled per VHA determination of eligibility for care, with less risk of postoperative emergency department (ED) visit, and taking no prescription medications. The High-longevity group had longer survival. The High-comorbidity group had more MCC, more prescription medications and shorter survival than the other two groups. Accelerated failure time (AFT) modeled associations between MCC and 5-year survival by class. In AFT models, fewer days until first postoperative ED visit was significantly associated with survival across the three classes. About one in male hip fractured veteran patients over the age of 85 had high levels of MCC and ED use and experienced shorter survival. Hip fracture patients with MCC may merit enhanced post-discharge management. Close investigation targeted to MCC and hip fractures is needed to optimize clinical practices for oldest-old patients in community healthcare systems as well as VHA.

Blum, J. L., N. Robert, J. Andersen, A. Favret, P. Ward, C. Osborne and J. Pippen (2017). “Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy in Early-Stage Invasive Breast Cancer.” J Clin Oncol: Jco2017753756.

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TO THE EDITOR: Although we agree with the decision of the ASCO Guideline Panel members to update the use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer1 on the basis of the published results of the MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) trial,2 we take exception with two issues. One is the language used in most of the detailed recommendations in the update, which state that physicians “should” or “should not” use specific tests in specific situations. We believe that the use of directive language, such as should and should not, goes beyond the concept of recommended guidelines and becomes a directive to clinicians. We note that recommendation 1.2.1 includes language that states that physicians “may” use the 70-gene signature assay and does not use the more directive should or should not language.

Block, T. M., H. Alter, N. Brown, A. Brownstein, C. Brosgart, K. M. Chang, P. J. Chen, C. Cohen, H. El-Serag, J. Feld, R. Gish, J. Glenn, T. F. Greten, J. T. Guo, Y. Hoshida, K. V. Kowdley, W. Li, A. S. Lok, B. McMahon, A. Mehta, R. Perrillo, C. M. Rice, J. Rinaudo, R. F. Schinazi and K. Shetty (2017). “Research priorities for the discovery of a cure for chronic hepatitis B: Report of a workshop.” Antiviral Res 150: 93-100.

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In early 2017, the Hepatitis B Foundation invited 30 experts in the fields of hepatitis B and liver cancer research to identify projects they deemed important to the goal of finding a cure for chronic hepatitis B and D and the diseases with which these viral infections are associated. They were also asked to identify general categories of research and to prioritize sub-project topics within those areas. The experts generally agreed on broadly defined areas of research, but there was usually little difference between the highest and lowest scoring projects; for the most part, all programs described in this document were considered valuable and necessary. An executive summary of this discussion was recently published (Alter et al., Hepatology 2017). The present manuscript reports the areas of research identified by the workshop participants, provides a brief rationale for their selection, and attempts to express differences among the priorities assigned to each area of research, when such distinctions were expressed.