Rosai–Dorfman Disease with Activating <i>KRAS</i> Mutation — Response to Cobimetinib

Jacobsen, Eric; Shanmugam, Vignesh; Jagannathan, Jyothi P.

doi:10.1056/nejmc1713676

Cited by 90 publications

(71 citation statements)

References 4 publications

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“…However, our study is the first to investigate CCND1 expression in RDD as a distinct entity (i.e., not in association with another haematological malignancy at the same site). Our study not only underscores the potential for rational MAPK‐directed therapies for RDD (Jacobsen et al , ), but also identifies CCND1 expression as an important diagnostic property of RDD, which, in the appropriate morphological context, can support the diagnosis. However, it is critical to note that other reactive (Abdulla et al , ) and neoplastic histiocytic proliferations may also demonstrate CCND1 expression, albeit much more dimly as we have shown and, as such, CCDN1 expression, particularly when not brightly expressed, is not specific to RDD (Wu et al , ).…”

Section: Discussionsupporting

confidence: 63%

Cyclin D1 expression and novel mutational findings in Rosai‐Dorfman disease

et al. 2019

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Summary Rosai‐Dorfman disease (RDD) is an enigmatic histiocytic disorder classically diagnosed by a distinctive combination of pathological features: emperipolesis, or migration of intact haematological cells through the voluminous cytoplasm of lesional histiocytes, and expression of S100 by these histiocytes. The pathogenesis has long been elusive until the recent detection of recurrent and mutually exclusive mutations in several oncogenes in the mitogen‐activated protein kinase (MAPK) pathway. Based on these findings, we investigated a cohort of 21 RDD patients and found that the lesional histiocytes in 86% (18/21) of patients exhibited strong and diffuse nuclear Cyclin D1 expression, which not only may provide a diagnostic marker for this sometimes pathologically challenging disease, but also probably reflects constitutive MAPK pathway activation because we additionally identified phosphorylated‐ERK expression in 90% (19/21) of cases. Further, we performed massively parallel sequencing on a subset (6/18) of the CyclinD1 positive cases, identifying several mutations that have not been previously reported in RDD. Taken together, our findings bolster the concept of RDD as a disease of MAPK activation in a substantial percentage of cases and enhance the current understanding of the pathogenesis of RDD.

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Section: Discussionsupporting

confidence: 63%

Cyclin D1 expression and novel mutational findings in Rosai‐Dorfman disease

et al. 2019

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“…For instance, they established that KRAS mutations-which are present in over 20% of diverse cancers and are often considered not 'druggable'-had high sensitivity to targeted agents, including dasatinib (targeting SRC and BCR-ABL), BYL719 (a PI3K inhibitor) and trametinib (a MEK inhibitor). This observation is important, and consistent with a case report recently published showing that a patient with Rosai-Dorfman syndrome and a KRAS mutation had a remarkable response to cobimetinib (a MEK inhibitor like trametinib) 10 . On the other hand, previous results from our group suggest that the use of PI3K inhibitors in patients with RAS alterations is associated with resistance 4,11 .…”

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confidence: 90%

An avatar for precision cancer therapy

Kato

Kurzrock

2018

Nat Biotechnol

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Precision oncology aims to match patients to therapies on the basis of the genomic alterations in their tumors.This approach of combining molecular diagnostics with therapeutics has not only transformed the standard-ofcare management for certain malignancies 1-3 , but is also integral to treatment selection in pan-cancer, precision medicine clinical trials 4,5 . In clinical practice, however, such factors as intra-and inter-tumor molecular

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“…Although targeting RAS has been challenging, early phase clinical trial with AMG 510 (a novel small molecule inhibitor specifically for KRAS G12C) among KRAS G12C altered cancer patients demonstrated clinical responses and further enrollment is ongoing . Moreover, the MEK inhibitor cobimetinib induced a remarkable response in a patient with Rosai–Dorfman syndrome, whose disease harbored a KRAS mutation but no other characterized alterations . Therefore, factors such as genomic coalterations might also attenuate responsiveness to agents that directly or indirectly impact Ras signaling.…”

Section: Introductionmentioning

confidence: 99%

Prognostic implications of RAS alterations in diverse malignancies and impact of targeted therapies

Kato

Okamura

Sicklick

et al. 2020

Intl Journal of Cancer

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RAS alterations are often found in difficult-to-treat malignancies and are considered "undruggable." To better understand the clinical correlates and coaltered genes of RAS alterations, we used targeted next-generation sequencing (NGS) to analyze 1,937 patients with diverse cancers. Overall, 20.9% of cancers (405/1,937) harbored RAS alterations. Most RAS-altered cases had genomic coalterations (95.3%, median: 3, range: 0-51), often involving genes implicated in oncogenic signals: PI3K pathway (31.4% of 405 cases), cell cycle (31.1%), tyrosine kinase families (21.5%) and MAPK signaling (18.3%). Patients with RAS-altered versus wild-type RAS malignancies had significantly worse overall survival (OS; p = 0.02 [multivariate]), with KRAS alterations, in particular, showing shorter survival. Moreover, coalterations in both RAS and PI3K signaling or cell-cycle-associated genes correlated with worse OS (p = 0.004 and p < 0.0001, respectively [multivariate]). Among RASaltered patients, MEK inhibitors alone did not impact progression-free survival (PFS), while matched targeted therapy against non-MAPK pathway coalterations alone showed a trend toward longer PFS (vs. patients who received unmatched therapy) (HR: 0.79, 95% CI: 0.61-1.03, p = 0.07). Three of nine patients (33%) given tailored combination therapies targeting both MAPK and non-MAPK pathways achieved objective responses. In conclusion, RAS alterations correlated with poor survival across cancers. The majority of RAS alterations were accompanied by coalterations impacting other oncogenic pathways. MEK inhibitors alone were ineffective against RAS-altered cancers while matched targeted therapy against coalterations alone correlated with a trend toward improved PFS. A subset of the small number of patients given MEK inhibitors plus tailored non-MAPK-targeting agents showed responses, suggesting that customized combinations warrant further investigation. *S.M.L. and R.K. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

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Rosai–Dorfman Disease with Activating KRAS Mutation — Response to Cobimetinib

Cited by 90 publications

References 4 publications

Cyclin D1 expression and novel mutational findings in Rosai‐Dorfman disease

Cyclin D1 expression and novel mutational findings in Rosai‐Dorfman disease

An avatar for precision cancer therapy

Prognostic implications of RAS alterations in diverse malignancies and impact of targeted therapies

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