Research Spotlight

Schadendorf, D., J. D. Wolchok, F. S. Hodi, V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J. J. Grob, C. L. Cowey, C. D. Lao, J. Chesney, C. Robert, K. Grossmann, D. McDermott, D. Walker, R. Bhore, J. Larkin and M. A. Postow (2017). “Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: A pooled analysis of randomized phase ii and iii trials.” J Clin Oncol: 2017 Aug [Epub ahead of print].

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Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs ( P = .97). Median overall survival had not been reached in either group ( P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy.

Pierobon, M., C. Ramos, S. Wong, K. A. Hodge, J. Aldrich, S. Byron, S. P. Anthony, N. J. Robert, D. W. Northfelt, M. Jahanzeb, L. Vocila, J. Wulfkuhle, G. Gambara, R. I. Gallagher, B. Dunetz, N. Hoke, T. Dong, D. W. Craig, M. Cristofanilli, B. Leyland-Jones, L. A. Liotta, J. A. O’Shaughnessy, J. D. Carpten and E. F. Petricoin (2017). “Enrichment of pi3k-akt-mtor pathway activation in hepatic metastases from breast cancer.” Clin Cancer Res 23(16): 4919-4928.

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Purpose: Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis.Experimental Design: Next-generation sequencing-based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 unmatched primary breast tumors. The proportion of cases with PI3K-AKT-mTOR genomic alterations or signaling network activation were compared between hepatic and nonhepatic lesions.Results:PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than nonhepatic lesions (P < 0.01, P = 0.056, and P = 0.053, respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (P = 0.32 and P = 0.19 for activated AKT and p70S6K, respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis [AKT (S473), mTOR (S2448), and 4EBP1 (S65); P < 0.01, P = 0.02, and P = 0.01, respectively]. Similar results were also seen between liver metastases and primary breast tumors [AKT (S473) P < 0.01, mTOR (S2448) P < 0.01, 4EBP1 (S65) P = 0.01]. This signature was lost when primary tumors were compared with all metastatic sites combined.Conclusions: Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K-AKT-mTOR signaling network.

Mack, M. and P. Grayburn (2017). “Guideline-directed medical therapy for secondary mitral regurgitation: More questions than answers!” JACC Heart Fail 5(9): 660-662.

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Secondary (also known as functional) mitral regurgitation (MR) is common in heart failure patients. Secondary MR is not caused by a primary abnormality of the mitral leaflets but rather to dilation/dysfunction of the left ventricle (LV). As a result, there is apical-lateral displacement of the papillary muscles resulting in tethering of the mitral leaflets and subsequent failure of anatomically normal leaflets to coapt (1) . Secondary MR results in further LV volume overload and a resulting vicious cycle of more severe MR leading to further LV dilation and congestive heart failure. This mechanism of MR is termed type IIIb in the Carpentier classification of mitral valve leaflet motion and can be due to both ischemic and nonischemic dilated cardiomyopathies (2) . The mainstay of therapy is guideline-directed medical therapy (GDMT) for heart failure including diuretics, beta blockers, aldosterone antagonists, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocking agents. It is an area of intense interest in the fields of surgery and medical device therapy because of the overall poor prognosis with medical therapy alone. Although it is widely recognized that secondary MR is associated with a worse prognosis in heart failure patients, it remains uncertain whether surgical correction of the MR and breaking the “vicious cycle” changes the dismal course of the disease.

Dickler, M. N., S. M. Tolaney, H. S. Rugo, J. Cortes, V. Dieras, D. Patt, H. Wildiers, C. A. Hudis, J. O’Shaughnessy, E. Zamora, D. A. Yardley, M. Frenzel, A. Koustenis and J. Baselga (2017). “Monarch 1, a phase ii study of abemaciclib, a cdk4 and cdk6 inhibitor, as a single agent, in patients with refractory hr+/her2- metastatic breast cancer.” Clin Cancer Res 23(17): 5218-5224.

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Purpose: The phase II MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor-positive (HR+), HER2- metastatic breast cancer (MBC).Experimental Design: MONARCH 1 was a phase II single-arm open-label study. Women with HR+/HER2- MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS), and overall survival (OS).Results: Patients (n = 132) had a median of 3 (range, 1-8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had >/=3 metastatic sites. At the 12-month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI, 13.3-27.5; 15% not excluded); clinical benefit rate (CR+PR+SD>/=6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%).Conclusions: In this poor-prognosis, heavily pretreated population with refractory HR+/HER2- metastatic breast cancer, continuous dosing of single-agent abemaciciclib was well tolerated and exhibited promising clinical activity.

Gupta, N., V. Konda and U. Siddiqui (2017). “Gastric cardia lesion with abnormal volumetric laser endomicroscopy imaging.” Gastrointest Endosc: 2017 Aug [Epub ahead of print].

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A 71-year-old male with a history of epigastric pain and dyspepsia had previously been found to have Barrett’s esophagus (BE) with low-grade dysplasia. He presented to our institution for repeat EGD to thoroughly assess the Barrett’s segment. EGD showed short-segment BE with a 2-cm area of nodular, polypoid-appearing mucosa on the gastric cardia side of the gastroesophageal junction (A). The area was examined by high-definition white-light endoscopy (WLE) and narrow-band imaging (NBI) with near focus (A). Volumetric laser endomicroscopy (VLE) was also used (NVisionVLE, NinePoint Medical) and showed suspicious features including irregular surface (blue arrow) and atypical glands (red circle) in the area corresponding to the nodular mucosa (B).