Research Spotlight

Rugo, H. S., J. Cortes, A. Awada, J. O’Shaughnessy, C. Twelves, S. A. Im, A. Hannah, L. Lu, S. Sy, K. Caygill, D. A. Zajchowski, D. W. Davis, M. Tagliaferri, U. Hoch and E. A. Perez (2018). “Change in Topoisomerase 1-Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol.” Clin Cancer Res 24(14): 3348-3357.

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APurpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTC) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP).Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician’s choice (TPC). Blood from 656 of 852 patients (77%) was processed with ApoStream to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers [topoisomerase 1 (Top1), topoisomerase 2 (Top2), Ki67, RAD51, ABCG2, gammaH2AX, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)] in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan-Meier analyses.Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median, 47-63 CTCs/mL; range, 0-2,020 CTCs/mL). Top1, Top2, and TUNEL expression was detected in 52% to 90% of samples; no significant associations with OS were observed in pretreatment samples for either group. EP-treated patients with low C2D1Top1(+) CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P = 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P = 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P = 0.01).Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit. Clin Cancer Res; 24(14); 3348-57. (c)2018 AACR.

McLaughlin, C. M., J. Gonzalez-Hernandez, M. Bennett and H. G. Piper (2018). “Pediatric breast masses: an argument for observation.” J Surg Res 228: 247-252.

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BACKGROUND: Pediatric breast masses can be a diagnostic challenge. Nearly all are benign, but there is no consensus on which should be removed. We hypothesized that children with asymptomatic breast lesions can be safely managed nonoperatively. METHODS: We performed a single-institution retrospective review of children (less-than-or-equal-to 18 y) who underwent breast mass excision from 2008 to 2016. Male patients with gynecomastia and those who had needle biopsy without formal excision were excluded. Pearson correlation was used to compare ultrasound and pathologic size. Kruskal-Wallis test was used to compare size and final diagnosis. RESULTS: One hundred ninety-six patients were included (96% female). Mean age was 15 +/- 3 y. Most patients (71%) presented with a painless mass. Preoperative ultrasound was obtained in 70%. Pathology included fibroadenoma (81.5%), tubular adenoma (5%), benign phyllodes tumor (3%), benign fibroepithelial neoplasm (0.5%), and other benign lesions (10%). There were no malignant lesions. Ultrasound size had a Pearson correlation of 0.84 with pathologic size (P < 0.0001). There was no association between the size and final diagnosis. CONCLUSIONS: Over 9 y, all pediatric breast masses removed at a single center were benign, most commonly fibroadenoma. Ultrasound was an accurate predictor of size, but large lesions did not necessarily confer a high malignancy risk. Observation is appropriate for asymptomatic breast masses in children. Decision for surgery should be individualized and not based on size alone.

McKenna, G. J. (2018). “Medication trade-offs-Not all noncompliance is what it seems.” Transpl Int 31(8): 861-863.

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“The Prevalence, Risk Factors, and Outcomesof Medications Tradeoffs in Kidney and Liver Tran s-plant Recipients” (Serper et al., 2018) examines a subject that seems familiarat first glance, but is actually one that has not beenstudied or reported in great detail. The authors work isso timely, because these issues are presently in flux andevolving—even as this editorial is being written. U.S.lawmakers are currently debating the survival of theAffordable Care Act, the fate of patient insurance subsi-dies, and the overall accessibility of health insuranceand care in the U.S., and by the time this article is evenpublished, events may further amplify the significanceof the data these authors present regarding the impactof medication trade-offs. (Excerpt from text, p. 861; no abstract available.)

Konda, V. J. A. and R. F. Souza (2018). “Biomarkers of Barrett’s Esophagus: From the Laboratory to Clinical Practice.” Dig Dis Sci 63(8): 2070-2080.

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The currently recommended approach to managing cancer risk for patients with Barrett’s esophagus is endoscopic surveillance including a biopsy protocol to sample the esophageal tissue randomly to detect dysplasia. However, there are numerous limitations in this practice that rely on the histopathological grading of dysplasia alone to make clinical decisions. The availability of in silico models demonstrating the potential cost-effectiveness of biomarker-based stratification has increased interest in finding a clinically relevant “Barrett’s biomarker.” The success of endoscopic eradication therapy in preventing neoplastic progression of dysplastic Barrett’s esophagus has promoted the desire to stratify non-dysplastic Barrett’s esophagus to those with “high risk” that may benefit from endotherapy. Furthermore, on the other end of the spectrum, there is interest in searching for a “low risk” marker that may identify those that would not likely benefit from endoscopy screening or surveillance. This review highlights recent data from the genomics (r)evolution revealing new genetic biomarkers of susceptibility to the development of Barrett’s esophagus and novel pathways for its neoplastic progression, addresses the development of new modes of tissue sampling and imaging to detect early neoplasia in Barrett’s esophagus, and discusses current progress in moving biomarkers from the laboratory into clinical practice in the era of precision medicine.

Langer, C. J., E. S. Kim, E. C. Anderson, R. M. Jotte, M. Modiano, D. E. Haggstrom, M. P. Socoteanu, D. A. Smith, C. Dakhil, K. Konduri, T. Berry, T. J. Ong, A. Sanford, K. Amiri, J. W. Goldman and J. Weiss (2018). “nab-Paclitaxel-Based Therapy in Underserved Patient Populations: The ABOUND.70+ Study in Elderly Patients With Advanced NSCLC.” Front Oncol 8: 262.

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The phase 4 ABOUND.70+ trial assessed the safety and efficacy of nab-paclitaxel/carboplatin continuously or with a 1-week break between cycles in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients >/=70 years with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-paclitaxel days 1, 8, 15 plus carboplatin day 1 of a 21-day cycle (21d) or the same nab-paclitaxel/carboplatin regimen with a 1-week break between cycles (21d + break; 28d). The primary endpoint was the percentage of patients with grade >/= 2 peripheral neuropathy (PN) or grade >/= 3 myelosuppression. Other key endpoints included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). A total of 143 patients were randomized (71 to 21d, 72 to 21d + break). The percentage of patients with grade >/= 2 PN or grade >/= 3 myelosuppression was similar between the 21d and 21d + break arms (76.5 and 77.1%; P = 0.9258). Treatment exposure was lower in the 21d arm compared with the 21d + break arm. Median OS was 15.2 and 16.2 months [hazard ratio (HR) 0.72, 95% CI 0.44-1.19; P = 0.1966], median PFS was 3.6 and 7.0 months (HR 0.48, 95% CI 0.30-0.76; P < 0.0019), and ORR was 23.9 and 40.3% (risk ratio 1.68, 95% CI 1.02-2.78; P = 0.0376) in the 21d and 21d + break arms, respectively. In summary, the 1-week break between treatment cycles significantly improved PFS and ORR but did not significantly reduce the percentage of grade >/= 2 PN or grade >/= 3 myelosuppression. Overall, the findings support the results of prior subset analyses on the safety and efficacy of first-line nab-paclitaxel/carboplatin in elderly patients with advanced NSCLC.