Research Highlights For reprint orders, please contact: [email protected]
Pharmacogenomics
Highlights from the latest articles in pharmacogenomics research
Evaluation of: Egberts F, Bergner I, Krüger S et al. Metastatic melanoma of unknown primary resembles the genotype of cutaneous melanomas Ann. Oncol. 25(1), 246–250 (2014).
In 1–8% of metastatic melanoma the primary tumor cannot be found. Although 90% of melanomas are of cutaneous origin, other origins exist. It has been proposed that the mutational status (i.e., BRAF, NRAS, KIT ) can distinguish between different types of melanoma. Sixty-six melanomas of unknown primary origin from 44 melanoma patients were genotyped in order to identify the origin of the primary tumor and to evaluate the prognostic significance of mutational status. The authors found BRAF mutations in 52.3% of patients, NRAS mutations in 28.6% of patients and no patients with mutations in the KIT gene. These results point towards genetic patterns most similar to cutaneous melanoma, the majority of which harbor BRAF or NRAS mutations, as opposed to mucosal melanoma which mainly harbors KIT mutations. However this study found that mutational status had no prognostic impact on clinical outcome and overall survival, adding to the already existing discrepancies in respect of the prognostic impact of these mutations. – Written by Gal Markel and Gilli Galore-Haskel Evaluation of: Menzies AM, Haydu LE, Carlino MS et al. Inter- and intra-patient heterogeneity of response and progression to targeted therapy in metastatic melanoma. PLoS ONE 9(1), e85004 (2014).
BRAF targeted therapy generally and combined BRAF–MEK inhibition specifically
10.2217/PGS.14.55 © 2014 Future Medicine Ltd
has been a major breakthrough for the treatment of melanoma. Unfortuantely, resistance to therapy develops in most patients between a few weeks and a few years. Menzies et al. embarked on an ambitious project to categorize the clinical heterogeneity of response and progression to the combination of dabrafenib and trametinib (CombiDT). Quantification of every radiographic lesion was performed on 24 patients prior to commencement of CombiDT. The best RECIST1.1-defined outcome was as follows: 17% complete response (CR), 75% partial response (PR), 8% stable disease and 0% progression of disease (PD). In comparison, the response rate by metastatic lesion showed a dramatically higher CR rate, 52.6% (PR: 31.9%, stable disease: 13.3% and PD: 2.2%), though there remained a strong correlation between response of individual metastasis response and RECIST response (p < 0.001). Lastly, at time of PD, the investigators demonstrate marked heterogeneity in individual lesions for patients such that a patient may have new or existing lesions responsible for PD designation while other lesions remained in PR or CR. This study does an excellent job of documenting and summarizing the complexities of clinical heterogeneity.
Gal Markel*,1, Gilli Galore-Haskel1 & Ryan Sullivan‡,2 1 Tel Aviv University, Ramat Aviv, 6997801, Israel 2 Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA *Author for correspondence: Tel.: +972 3 5304591 [email protected] ‡ Author for correspondence: [email protected]
– Written by Ryan Sullivan Evaluation of: Shi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 4(1), 80–93 (2014).
Most mechanisms of resistance to BRAF inhibitor therapy in patients with BRAFmutant melanoma have been presented in the context of small numbers of patient samples.
Pharmacogenomics (2014) 15(8), 1063–1064
part of
ISSN 1462-2416
1063
Research Highlights Shi et al. present the most comprehensive study to date; an analysis of 100 tumors from 44 patients treated with BRAF inhibitors. The first relevant findings are that every tumor (71 out of 71) analyzed in the setting of BRAF inhibitor resistance harbored the original BRAF mutation documented for each individual patient (e.g., V600E or V600K) and that none of the 56 resistance tumors had acquired a second BRAF mutation (determined by deep sequencing). Next, they describe the specific mechanisms of resistance in these tumors and group these as either being associated with MAPK pathway reactivation or activation of a parallel growth pathway (PI3K–AKT). In 70% of cases, MAPK reactivation mechanisms were identified (these include RAS mutation, BRAF V600E amplification, BRAF splice variant formation, MEK1/2 mutation and CDKN2A loss). In 22%, PI3K–AKT pathway activation occurred either through activating mutations of PIK3CA, PIK3CG or AKT1/3 or through inactivation of PI3K–AKT regulating genes such as PTEN, PIK3R2 or PHLPP2. Dual pathway activation was seen 18% of the time. These findings represent definitive confirmation from dozens of smaller analyses about the preservation of the inciting BRAF mutation, lack of secondary BRAF mutations, and the mechanisms of MAPK reactivation and parallel pathway activation at time of resistance to BRAF inhibition. The novelty of this work is the description of marked, molecular tumor heterogeneity in individual patients at the time of BRAF inhibitor resistance; a finding that has implications for identifying next-line therapy for this patient population. – Written by Ryan Sullivan Evaluation of: Van Allen EM, Wagle N, Sucker A et al. The genetic landscape of clinical resistance
1064
Pharmacogenomics (2014) 15(8)
to RAF inhibition in metastatic melanoma. Cancer Discov. 4(1), 94–109 (2014).
A great deal of attention has been paid by investigators to determine the acquired mechanisms of resistance to BRAF inhibitors. However, relatively little attention has been paid to the genetic determinants of intrinsic resistance to BRAF inhibitors. In this report, Van Allen and colleagues set out to categorize the potential mechanisms of resistance of intrinsic and acquired resistance treatment, by whole-exome sequencing, in 45 patients who received BRAF inhibitor monotherapy. Patients were defined as having early resistance if time to disease progression was less than or equal to 12 weeks and as having acquired resistance if disease progression occurred greater than 12 weeks. The key finding is that there are genetic aberrations predicted to be associated with RAF inhibitor resistance in pretreatment samples in ten of 14 patients with early resistance and only seven of 31 patients with acquired resistance. Additionally, the previously described mechanisms of BRAF inhibitor resistance – NRAS mutations and BRAF amplification – were only seen in the acquired resistance subgroup of patients, suggesting that prolonged BRAF inhibitor therapy is responsible for the emergence of these resistance mechanisms. – Written by Ryan Sullivan Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production ofthis manuscript.
future science group
Pharmacogenomics
Highlights from the latest articles in pharmacogenomics research
Evaluation of: Egberts F, Bergner I, Krüger S et al. Metastatic melanoma of unknown primary resembles the genotype of cutaneous melanomas Ann. Oncol. 25(1), 246–250 (2014).
In 1–8% of metastatic melanoma the primary tumor cannot be found. Although 90% of melanomas are of cutaneous origin, other origins exist. It has been proposed that the mutational status (i.e., BRAF, NRAS, KIT ) can distinguish between different types of melanoma. Sixty-six melanomas of unknown primary origin from 44 melanoma patients were genotyped in order to identify the origin of the primary tumor and to evaluate the prognostic significance of mutational status. The authors found BRAF mutations in 52.3% of patients, NRAS mutations in 28.6% of patients and no patients with mutations in the KIT gene. These results point towards genetic patterns most similar to cutaneous melanoma, the majority of which harbor BRAF or NRAS mutations, as opposed to mucosal melanoma which mainly harbors KIT mutations. However this study found that mutational status had no prognostic impact on clinical outcome and overall survival, adding to the already existing discrepancies in respect of the prognostic impact of these mutations. – Written by Gal Markel and Gilli Galore-Haskel Evaluation of: Menzies AM, Haydu LE, Carlino MS et al. Inter- and intra-patient heterogeneity of response and progression to targeted therapy in metastatic melanoma. PLoS ONE 9(1), e85004 (2014).
BRAF targeted therapy generally and combined BRAF–MEK inhibition specifically
10.2217/PGS.14.55 © 2014 Future Medicine Ltd
has been a major breakthrough for the treatment of melanoma. Unfortuantely, resistance to therapy develops in most patients between a few weeks and a few years. Menzies et al. embarked on an ambitious project to categorize the clinical heterogeneity of response and progression to the combination of dabrafenib and trametinib (CombiDT). Quantification of every radiographic lesion was performed on 24 patients prior to commencement of CombiDT. The best RECIST1.1-defined outcome was as follows: 17% complete response (CR), 75% partial response (PR), 8% stable disease and 0% progression of disease (PD). In comparison, the response rate by metastatic lesion showed a dramatically higher CR rate, 52.6% (PR: 31.9%, stable disease: 13.3% and PD: 2.2%), though there remained a strong correlation between response of individual metastasis response and RECIST response (p < 0.001). Lastly, at time of PD, the investigators demonstrate marked heterogeneity in individual lesions for patients such that a patient may have new or existing lesions responsible for PD designation while other lesions remained in PR or CR. This study does an excellent job of documenting and summarizing the complexities of clinical heterogeneity.
Gal Markel*,1, Gilli Galore-Haskel1 & Ryan Sullivan‡,2 1 Tel Aviv University, Ramat Aviv, 6997801, Israel 2 Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA *Author for correspondence: Tel.: +972 3 5304591 [email protected] ‡ Author for correspondence: [email protected]
– Written by Ryan Sullivan Evaluation of: Shi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 4(1), 80–93 (2014).
Most mechanisms of resistance to BRAF inhibitor therapy in patients with BRAFmutant melanoma have been presented in the context of small numbers of patient samples.
Pharmacogenomics (2014) 15(8), 1063–1064
part of
ISSN 1462-2416
1063
Research Highlights Shi et al. present the most comprehensive study to date; an analysis of 100 tumors from 44 patients treated with BRAF inhibitors. The first relevant findings are that every tumor (71 out of 71) analyzed in the setting of BRAF inhibitor resistance harbored the original BRAF mutation documented for each individual patient (e.g., V600E or V600K) and that none of the 56 resistance tumors had acquired a second BRAF mutation (determined by deep sequencing). Next, they describe the specific mechanisms of resistance in these tumors and group these as either being associated with MAPK pathway reactivation or activation of a parallel growth pathway (PI3K–AKT). In 70% of cases, MAPK reactivation mechanisms were identified (these include RAS mutation, BRAF V600E amplification, BRAF splice variant formation, MEK1/2 mutation and CDKN2A loss). In 22%, PI3K–AKT pathway activation occurred either through activating mutations of PIK3CA, PIK3CG or AKT1/3 or through inactivation of PI3K–AKT regulating genes such as PTEN, PIK3R2 or PHLPP2. Dual pathway activation was seen 18% of the time. These findings represent definitive confirmation from dozens of smaller analyses about the preservation of the inciting BRAF mutation, lack of secondary BRAF mutations, and the mechanisms of MAPK reactivation and parallel pathway activation at time of resistance to BRAF inhibition. The novelty of this work is the description of marked, molecular tumor heterogeneity in individual patients at the time of BRAF inhibitor resistance; a finding that has implications for identifying next-line therapy for this patient population. – Written by Ryan Sullivan Evaluation of: Van Allen EM, Wagle N, Sucker A et al. The genetic landscape of clinical resistance
1064
Pharmacogenomics (2014) 15(8)
to RAF inhibition in metastatic melanoma. Cancer Discov. 4(1), 94–109 (2014).
A great deal of attention has been paid by investigators to determine the acquired mechanisms of resistance to BRAF inhibitors. However, relatively little attention has been paid to the genetic determinants of intrinsic resistance to BRAF inhibitors. In this report, Van Allen and colleagues set out to categorize the potential mechanisms of resistance of intrinsic and acquired resistance treatment, by whole-exome sequencing, in 45 patients who received BRAF inhibitor monotherapy. Patients were defined as having early resistance if time to disease progression was less than or equal to 12 weeks and as having acquired resistance if disease progression occurred greater than 12 weeks. The key finding is that there are genetic aberrations predicted to be associated with RAF inhibitor resistance in pretreatment samples in ten of 14 patients with early resistance and only seven of 31 patients with acquired resistance. Additionally, the previously described mechanisms of BRAF inhibitor resistance – NRAS mutations and BRAF amplification – were only seen in the acquired resistance subgroup of patients, suggesting that prolonged BRAF inhibitor therapy is responsible for the emergence of these resistance mechanisms. – Written by Ryan Sullivan Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production ofthis manuscript.
future science group
