Does CDKN2A Loss Predict Palbociclib Benefit?

Gao, Jennifer; Adams, RF; Swain, Sandra M.

doi:10.3747/co.22.2700

Cited by 17 publications

(16 citation statements)

References 13 publications

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“…CDKN2A (p16) is a negative regulator of CDK 4 and 6. Previously a patient with metastatic estrogen receptor- positive, HER2-negative breast cancer with CDKN2A loss responded to palbociclib, as briefly described above, which is consistent with the results of the present study, where palbociclib inhibited the Ewing's sarcoma PDOX, which lost CDKN2A , by targeting CDK4/6 [33]. …”

Section: Discussionsupporting

confidence: 92%

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

et al. 2016

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Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.

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Section: Discussionsupporting

confidence: 92%

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

et al. 2016

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“…Preclinical data suggest that tumors with loss of p16INK4a function may be sensitive to CDK4/6 inhibitors, such as palbociclib . In contrast to the patient response reported herein and a similar response reported for a patient with breast cancer , large‐scale clinical studies of breast cancer failed to show significant correlation between p16INK4a loss or inactivation and therapeutic benefit of palbociclib .…”

Section: Discussioncontrasting

confidence: 86%

Clinical Benefit in Response to Palbociclib Treatment in Refractory Uterine Leiomyosarcomas with a Common CDKN2A Alteration

Elvin¹,

Ort

Shuluk

et al. 2017

The Oncologist

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Background. Uterine leiomyosarcoma (uLMS) responds poorly to conventional chemotherapeutic agents, and personalized therapies have yet to be systematically explored. Comprehensive genomic profiling (CGP) can identify therapeutic targets and provide insight into the biology of this highly aggressive tumor. We report a case of uLMS treated with the CGP-matched therapy palbociclib, a CDK4/6 inhibitor, with sustained clinical benefit in this rare and deadly malignancy. Materials and Methods. This study analyzed 279 clinically advanced/recurrent uLMS samples. Median patient age was 54 years (range, 23-83 years). DNA was extracted from 40 mm of formalin-fixed, paraffin-embedded sections, and CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 405 cancer-related genes plus introns from up to 31 genes frequently rearranged in cancer. Sequencing data were analyzed for base pair

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“…CDKN2A/B protein products restrict cell-cycle progression by inhibiting CDK4/6 kinase activity, and aberrations in these genes lead to cancer progression by dysregulation of the cell cycle [ 34 ]. The association between CDKN2A/B deletion and the sensitivity to palbociclib, an FDA-approved CDK4/6 inhibitor, has been demonstrated in many cancers [ 35 – 38 ]. Therefore, it is worth investigating the clinical utility of the above-mentioned targeted therapies for GCs with corresponding gene alterations to establish precision medicine in GC.…”

Section: Discussionmentioning

confidence: 99%

Actionable gene-based classification toward precision medicine in gastric cancer

et al. 2017

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BackgroundIntertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed.MethodsA total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status.ResultsComprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomically stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM cluster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster.ConclusionsThis actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0484-3) contains supplementary material, which is available to authorized users.

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Does CDKN2A Loss Predict Palbociclib Benefit?

Cited by 17 publications

References 13 publications

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

Clinical Benefit in Response to Palbociclib Treatment in Refractory Uterine Leiomyosarcomas with a Common CDKN2A Alteration

Actionable gene-based classification toward precision medicine in gastric cancer

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