Heterogeneity of BRAF Mutations – Clinical Implications
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Heterogeneity of BRAF Mutations – Clinical Implications

› Forums › General Melanoma Community › Heterogeneity of BRAF Mutations – Clinical Implications

  • Post
    • November 15, 2013 at 8:05 pm
    lou2
    Participant

      Mutation Landscape in Melanoma Patients: Clinical Implications of Heterogeneity of BRAF Mutations

      Br. J. Cancer 2013 Nov 05;[EPub Ahead of Print], L Heinzerling, M Baiter, S Kühnapfel, G Schuler, P Keikavoussi, A Agaimy, F Kiesewetter, A Hartmann, R Schneider-Stock

      Research · November 14, 2013
       
       

      TAKE-HOME MESSAGE

      • BRAF analysis from the primary tumor and multiple metastases showed a high degree of heterogeneity among patients with melanoma, with almost 20% having discordant BRAF-mutation results among different metastases.
      • This heterogeneity may have far-reaching clinical implications for treatment planning using molecularly targeted therapy. A single biopsy may be insufficient to determine BRAF-mutation status.

      – Richard Bambury, MD

      ABSTRACT

      Background: The detection of V600E BRAF mutations has fundamental clinical consequences as the treatment option with BRAF inhibitors such as vemurafenib or dabrafenib yields response rates of ∼48%. Heterogeneity with respect to BRAF mutation in different metastases has been described in single cases. As this has important implications for the determination of BRAF status and treatment of patients, it is essential to acquire more data.

      Methods: A total of 300 tumour samples from 187 melanoma patients were analysed for BRAF mutations by pyrosequencing. Equivocal results were confirmed by capillary sequencing. Clinical data with respect to melanoma type, tumour site and survival were summarised for 53 patients with multiple analysed tumour samples (2-13 per patient).

      Results: BRAF mutations were found in 84 patients (44.9%) and 144 tumour samples (48%) with BRAF mutations in 45.5% of primary tumours and 51.3% of metastases, respectively. In 10 out of 53 patients (18.9%) where multiple samples were analysed results were discordant with respect to mutation findings with wild-type and mutated tumours in the same patient. Mutations did not appear more frequently over the course of disease nor was its occurrence associated with a specific localisation of metastases.

      Conclusion: As heterogeneity with respect to BRAF mutation status is detected in melanoma patients, subsequent testing of initially wild-type patients can yield different results and thus make BRAF inhibitor therapy accessible. The role of heterogeneity in testing and for clinical response to therapy with a BRAF inhibitor needs to be further investigated.

      British Journal of Cancer

      Mutation Landscape in Melanoma Patients: Clinical Implications of Heterogeneity of BRAF Mutations

      Br. J. Cancer 2013 Nov 05;[EPub Ahead of Print], L Heinzerling, M Baiter, S Kühnapfel, G Schuler, P Keikavoussi, A Agaimy, F Kiesewetter, A Hartmann, R Schneider-Stock

      This abstract is available on the publisher's site.

      Access this abstract now

       

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    • Replies
        • November 16, 2013 at 12:00 am
        POW
        Participant

          I have heard some doctors say that they thought that melanoma tumors could be a mixture of BRAF mutated and non-mutated cells. This is the first time I have seen an actual study that proves it.

          Just based on the abstract, I see two clinically significant consequences: 1) if the first BRAF test comes out negative it might be a good idea to repeat the test with a biopsy sample from a different tumor (the insurance companies are going to scream about that one!), and 2) it does not bode well for ever getting long-term remission from the BRAF inhibitor drugs. Damn!

          • November 16, 2013 at 12:00 am
          POW
          Participant

            I have heard some doctors say that they thought that melanoma tumors could be a mixture of BRAF mutated and non-mutated cells. This is the first time I have seen an actual study that proves it.

            Just based on the abstract, I see two clinically significant consequences: 1) if the first BRAF test comes out negative it might be a good idea to repeat the test with a biopsy sample from a different tumor (the insurance companies are going to scream about that one!), and 2) it does not bode well for ever getting long-term remission from the BRAF inhibitor drugs. Damn!

            • November 16, 2013 at 12:00 am
            POW
            Participant

              I have heard some doctors say that they thought that melanoma tumors could be a mixture of BRAF mutated and non-mutated cells. This is the first time I have seen an actual study that proves it.

              Just based on the abstract, I see two clinically significant consequences: 1) if the first BRAF test comes out negative it might be a good idea to repeat the test with a biopsy sample from a different tumor (the insurance companies are going to scream about that one!), and 2) it does not bode well for ever getting long-term remission from the BRAF inhibitor drugs. Damn!

                • November 16, 2013 at 12:44 am
                lou2
                Participant

                  I got the impression that this was suggesting to get another biopsy for the purpose of extending the BRAF therapy to more patients.  If that is the case, why would it mean that mixed types would fare less well?  Why extend the treatment to more people with less positive outcomes?

                  You may be right, but it would seem that their statement about it being essential to add more data means we should not jump to conclusions just yet on this.

                  • November 16, 2013 at 12:44 am
                  lou2
                  Participant

                    I got the impression that this was suggesting to get another biopsy for the purpose of extending the BRAF therapy to more patients.  If that is the case, why would it mean that mixed types would fare less well?  Why extend the treatment to more people with less positive outcomes?

                    You may be right, but it would seem that their statement about it being essential to add more data means we should not jump to conclusions just yet on this.

                    • November 16, 2013 at 12:44 am
                    lou2
                    Participant

                      I got the impression that this was suggesting to get another biopsy for the purpose of extending the BRAF therapy to more patients.  If that is the case, why would it mean that mixed types would fare less well?  Why extend the treatment to more people with less positive outcomes?

                      You may be right, but it would seem that their statement about it being essential to add more data means we should not jump to conclusions just yet on this.

                      • November 16, 2013 at 1:22 am
                      POW
                      Participant

                        Yes, the authors are suggesting that a second biopsy on a BRAF negative patient may turn out to be BRAF positive so that patient may actually benefit from taking a BRAF inhibitor. However, since BRAF inhibitors don't work on wild-type (BRAF negative) cells, if tumors are a mixture of positive and negative then the inhibitor will kill some of the tumor cells but not all of them. Eventually, the wild-type cells will take over and the tumors will start to grow again. This is one of many possible explanations of why melanoma becomes resistant to Zelboraf and Taflinar. And, indeed, much more research will need to be done to figure out what is really going on here.

                        • November 16, 2013 at 1:22 am
                        POW
                        Participant

                          Yes, the authors are suggesting that a second biopsy on a BRAF negative patient may turn out to be BRAF positive so that patient may actually benefit from taking a BRAF inhibitor. However, since BRAF inhibitors don't work on wild-type (BRAF negative) cells, if tumors are a mixture of positive and negative then the inhibitor will kill some of the tumor cells but not all of them. Eventually, the wild-type cells will take over and the tumors will start to grow again. This is one of many possible explanations of why melanoma becomes resistant to Zelboraf and Taflinar. And, indeed, much more research will need to be done to figure out what is really going on here.

                          • November 16, 2013 at 1:22 am
                          POW
                          Participant

                            Yes, the authors are suggesting that a second biopsy on a BRAF negative patient may turn out to be BRAF positive so that patient may actually benefit from taking a BRAF inhibitor. However, since BRAF inhibitors don't work on wild-type (BRAF negative) cells, if tumors are a mixture of positive and negative then the inhibitor will kill some of the tumor cells but not all of them. Eventually, the wild-type cells will take over and the tumors will start to grow again. This is one of many possible explanations of why melanoma becomes resistant to Zelboraf and Taflinar. And, indeed, much more research will need to be done to figure out what is really going on here.

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