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ASCO Update–Long!

Forums Ocular Melanoma Community ASCO Update–Long!

  • Post
    mrf
    Keymaster

     

    NOTES FROM ASCO 2014

    I thought some on this board would like a report from the recent meeting of ASCO. This is a long post, but I have tried not to make it too technical.

    Tim–MRF

    Once melanoma spreads beyond the initial spot, or lesion, it has been notoriously difficult to treat. If it gets to other organs, the numbers have been appalling, with half of all patients dying of the cancer within about 10 months. Now that is changing.

    The 50th meeting of the American Society for Clinical Oncology (ASCO) was held in Chicago May 30 through June 5. Some of the most exciting presentations of the weekend focused on melanoma. Here are a few highlights.

    ipi + nivo:  In March, 2011 Yervoy (ipilimumab or “ipi”) became the first new drug to be approved for use in metastatic melanoma in 13 years. Ipi is a checkpoint inhibitor. In other words, it disables a natural braking mechanism—checkpoint—on the immune system that prevents the body from destroying cancer cells. An important component of our immune system is a group of cells called T-cells. If the T-cell count is low, as happens in HIV, the body is unable to fight off infection. If T-cells are too active they cause autoimmune diseases. The body regulates T-cells through a series of checkpoints, and melanoma cells seem particularly good at using these checkpoints to hide from T-cells.

    The cancer research community is very excited about a new class of checkpoint inhibitors called anti-PD1, or simply PD-1 drugs. Several companies are working on these but BMS has combined their drug “ipi” with their PD-1 drug nivolumab, or “nivo”. The results are rather astonishing.

    First the bad news. This was a somewhat small study, so numbers can change, and the combination is fairly toxic. In clinical trials doctors watch for adverse events, and they rank those events on a scale from 1 (mild) to 5 (death). In this combination study about 2/3 of patients had a grade 3 or grade 4 adverse events. That is a big number, though researchers report that many of these episodes were managed quickly and easily.

    The good news, though, is the incredible response rate. Remember that the median survival time of metastatic melanoma is around 10 months. In this study, 82% of patients were still alive after a year, and after 2 years an impressive 75% of patients were still alive. The study looked at several doses, and some doses showed 1 and 2 year survival of 93% and 88%. No previous study in melanoma has come close to these results.

    Anti-PD1:  Nivo was also studied by itself, in a group of about 100 patients who had gone through other melanoma treatment but had not had ipi. Just over a third of patients showed a response to nivo. Looking at the entire group, many of whom had gone through three or more prior therapies without success, 63% were still alive at 1 year, 48% at two years, and 41% at three years. Remember, these are patients who have already tried other drugs but those drugs didn’t work or stopped working. Presumably a group of patients who received nivo as a first treatment would do better.

    Data from a study of Merck’s anti-PD1 drug, pembrolizumab (pembro or MK-3475) were also presented and generated a great deal of enthusiasm. The 18 month survival on a very large study was impressive, with about 2/3 of patients still alive. Side effects did not seem to be a major concern with this program; certainly no worse than other melanoma drugs. Response rates remain very high and much better than anything currently on the market.

    Here are the numbers. The study looked at patients who had previously received ipi, and patients who had not received ipi. Presumably, those who had received ipi would be less responsive to another checkpoint inhibitor and that is how the data came out. About 40% of patients who had not received ipi responded to pembro; for patients who had previously been treated with ipi the number dropped to 28%. A sizeable group of patients had durable response, with 88% of that group still responding at the time the data was presented. About 12% of the more than 400 patients in this study had grade 3 or 4 adverse events.

    T-VEC: A few companies are working on drugs that are injected into lesions on the skin or into cancerous lymph nodes. Amgen’s T-VEC seems to be the farthest along. This is a modified virus that has been designed only to infect tumor cells. When it infects the cell, the virus takes over the cell’s DNA and forces it to make more virus and also to make a compound that stimulates the immune system, GM-CSF. The altered DNA makes so many viruses they cause the cell to burst apart. This releases a lot of debris that can activate the immune response, along with GM-CSF that will ramp up that response.

    T-VEC was compared to GM-CSF alone and definitely did better—though not as well as the checkpoint inhibitors. Median overall survival was 23.3 months, vs. 18.9 months on GM-CSF. The drug did not cause very many severe side effects.

    Three or four years ago this information would have generated a lot of excitement. Now, however, the field has progressed so the numbers don’t look as strong as what is being seen in some of the studies mentioned earlier. A number of researchers are interested, however, in combining T-VEC with one of the checkpoint inhibitors or some other treatment.

    BRAF and MEK: While therapies involving the immune system have received a lot of attention in the past couple of years, clinicians are still seeing positive results in treatments that go into tumor cells and shut down one or more of the mutations that is causing them to grow. Genentech’s Zelboraf (vemurafenib) was the first such drug to be approved; it blocks a compound called BRAF that is part of a series of steps transmitting signals from the cell surface to the nucleus of the cell. Two years later, GSK had their own BRAF drug, Tafinlar (trametinib), approved. They also had saw Mekinist (dabrafenib) approved; it blocks MEK, the next step after BRAF. More significantly, they showed that the BRAF and MEK inhibitors worked better when given together and now Genentech is actively studying their own MEK inhibitor to pair with Zelboraf.

    Further data muddied the waters, unfortunately. These more comprehensive studies show little added benefit of giving trametinib and dabrafenib together over giving trametinib alone. The difference in time before relapse was only two weeks. The surprising part of the data is that patients on the combination did about the same as in earlier studies. The difference was that patients who only received trametinib did much better than has been seen in any previous study of a BRAF inhibitor. Some suggest that this is because doctors understand better how to give the drug than they did in the past. Others point to some odd statistical anomalies in the study. Several patients were dropped from the study very early on. Had they been included and recorded as having relapsed early, the numbers make much better sense.

    Many doctors will prescribe the combination regardless of the data because patients experience fewer side effects on the combination than on either of the drugs alone.

    Another study of the GSK combination looked at overall survival of patients receiving both drugs vs. those receiving only the BRAF inhibitor. The key data is to find how long it takes before half of the patients on each study arm to succumb to melanoma. Median overall survival for the monotherapy arm was about 20 months. When the data was reported the study was at almost 24 months and patients on the combination had not yet reached the median mark.

    NRAS: Only those patients whose tumor has a BRAF mutation can take the BRAF inhibitors. This is about 40-50% of melanoma patients. Another 20% have a mutation upstream from BRAF, at a point called NRAS. These mutations have proven difficult to target. Researchers conducted a study in which they used a MEK inhibitor (two steps down from NRAS) and also blocked a different pathway that is impacted by NRAS. This second drug is called a CDK4 inhibitor.

    This was a small study, involving only 14 patients, but the results were encouraging. The drugs led to tumor shrinkage in several patients. Six patients had an actual response and six others had stable disease, or no additional tumor growth. Clearly more work needs to be done in this area.

    Adjuvant: The primary—and often only—treatment for early stage melanoma is surgery to remove the melanoma and, if necessary, one or more lymph nodes.  Once the surgery is done and all of the known cancer is removed, patients are said to be in the adjuvant setting. Despite the fact that some patients are known to be at elevated risk of recurrence, the standard of care is not to offer more treatment but, rather, to follow the patient with close observation. With some new drugs on the market for advanced melanoma, researchers have begun to study the effectiveness of these drugs on lowering the rate of recurrence in high-risk patients. Data was presented on the adjuvant study of ipi, and the results are mixed.

    The good news is that ipi does work to lower the risk of melanoma recurrence. Nearly 1000 Stage III patients were split into two groups, one of which received ipi and the other of which received a placebo. (Adjuvant studies are one of the rare instances in which placebos are used in oncology.) After three years, 45.6% of patients on ipi were cancer free, vs. 34.8% in the placebo arm. This is a clear benefit for being on ipi.

    The story is more complicated than this, unfortunately. The study was started when the best dose of ipi had not yet been determined. The dose in this study was more than three times as strong as what is given routinely to metastatic patients. This resulted in a high number of adverse events. More than half of the patients on the ipi arm of the study dropped out before the three year period because of side effects. Five of the patients on the arm died, possibly due to drug-related issues.

    Another study is currently underway comparing ipi to Interferon, but using the lower dose of ipi. This may provide more clarity, but results from that study are not expected for a couple of years.

    Miscellaneous: ASCO was awash in melanoma data, including many presentations that consisted simply of a large poster with data, graphs, and charts. Some key findings include:

    ·         Biologic tests show that patients with brain metastasis demonstrate significant levels of compounds related to immune response. This suggests that drugs such as ipi and the PD1 drugs would be effective in treating these tumors.

    ·         Ipi is just as effective in acral melanoma as in other cutaneous melanomas.

    ·         The level of Vitamin D in patients at the time of their diagnosis has no impact on their ultimate outcomes.

    ·         Uveal melanoma patients with liver metastases responded better to treatment using microbeads infused with a chemotherapy agent than did patients receiving other therapies, with about a six month survival advantage.

    ·         Pregnancy may impact melanoma. Melanoma cells grown in the lab grow faster in the presence of sera from pregnant women or in the presence of specific pregnancy-related hormones.

    ·         Tumor cells isolated from a simple blood sample can be tested for BRAF mutation. The presence or absence of such cells can be an indicator of whether or not the patient is responding to a BRAF inhibitor.

    ·         Stage IV patients with uveal melanoma have similar survival rates as Stage IV cutaneous melanoma patients. Stage IV mucosal melanoma patients, however, tend to do worse.

    This is only a fraction of what came out of the conference. The melanoma field is more robust and promising than it has ever been in the past, with no sign that the current rate of progress is slowing.

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  • Replies
      ed williams
      Participant

      I have been watching the videos from ASCO on youtube over the last week and I must say that you have written out the new data that was presented in a way that is very easy to follow (Thank you). To see survival data on the new PD-1 drugs and combinations with CTLA-4 is bring hope to many and my family especially. Last fall 2013, I found my self with a check off list that included ( Will, banking, and  life insurance.) I am very happy to say that my new check off list includes, mountain bike trip, cottage and Disney trip. I have been very lucky to get on to one of the studies you talked about. I hope that the results keeps coming in like the 2014 ASCO!!!!!!!

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      ed williams
      Participant

      I have been watching the videos from ASCO on youtube over the last week and I must say that you have written out the new data that was presented in a way that is very easy to follow (Thank you). To see survival data on the new PD-1 drugs and combinations with CTLA-4 is bring hope to many and my family especially. Last fall 2013, I found my self with a check off list that included ( Will, banking, and  life insurance.) I am very happy to say that my new check off list includes, mountain bike trip, cottage and Disney trip. I have been very lucky to get on to one of the studies you talked about. I hope that the results keeps coming in like the 2014 ASCO!!!!!!!

      Loading spinner
      ed williams
      Participant

      I have been watching the videos from ASCO on youtube over the last week and I must say that you have written out the new data that was presented in a way that is very easy to follow (Thank you). To see survival data on the new PD-1 drugs and combinations with CTLA-4 is bring hope to many and my family especially. Last fall 2013, I found my self with a check off list that included ( Will, banking, and  life insurance.) I am very happy to say that my new check off list includes, mountain bike trip, cottage and Disney trip. I have been very lucky to get on to one of the studies you talked about. I hope that the results keeps coming in like the 2014 ASCO!!!!!!!

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      BrianP
      Participant

      Thanks Tim for the outstanding summary.  I have to admit that at first I was a little disappointed there wasn't much new coming out of ASCO this year but after more time to reflect it really was some good news stories.  I think I was hoping for the "next new thing" and instead we got a lot of confirmation that the things we have are pretty good and even better with some combinations.  I've heard some slight rumblings of new inhibitors on the horizon such as IDO which I thought we may hear something about but maybe it's just a little too soon for these to presented at ASCO.  I'm curious on your thoughts regarding Merck and BMS's PD-1 drugs and BMS's combo of Ipi and Nivo.  It seems like Merck as both a time advantage and perhaps even an effectiveness advantage in getting their PD1 to market but the results of BMS's Ipi and Nivo combo are too impressive not to be available to everyone as soon as possible.  It seems to me that with all the combo trials BMS is running with those drugs they are putting a full court press on getting that combo approved as quickly as possible.  Did you get any sense at ASCO when that combo may be approved?  I know that is always anyones best guess but I just curious if it's being talked about.

      Brian

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      BrianP
      Participant

      Thanks Tim for the outstanding summary.  I have to admit that at first I was a little disappointed there wasn't much new coming out of ASCO this year but after more time to reflect it really was some good news stories.  I think I was hoping for the "next new thing" and instead we got a lot of confirmation that the things we have are pretty good and even better with some combinations.  I've heard some slight rumblings of new inhibitors on the horizon such as IDO which I thought we may hear something about but maybe it's just a little too soon for these to presented at ASCO.  I'm curious on your thoughts regarding Merck and BMS's PD-1 drugs and BMS's combo of Ipi and Nivo.  It seems like Merck as both a time advantage and perhaps even an effectiveness advantage in getting their PD1 to market but the results of BMS's Ipi and Nivo combo are too impressive not to be available to everyone as soon as possible.  It seems to me that with all the combo trials BMS is running with those drugs they are putting a full court press on getting that combo approved as quickly as possible.  Did you get any sense at ASCO when that combo may be approved?  I know that is always anyones best guess but I just curious if it's being talked about.

      Brian

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        Tim–MRF
        Guest

        Brian:

        I think you have it right. Merck is almost certain to be approved first, and their numbers look good. There is definitely something there about the ipi/nivo combo, though. The challenge is the toxicity. Also will be interesting to see the pricing situation. Merck faces that same problem.

        Once a company determines the price of an infusion drug, that price cannot easily change. I am  not stating this very clearly, but here is what I mean. The approved dose of "ipi" is 3mg/kg. The stated wholesale cost when the drug was approved was $30,000 per infusion, but in fact the cost could vary from patient to patient because of their body weight.  The more kg, the more mg needed to get to that 3mg/kg level.

        Some studies of "ipi' have been done at 10 mg/kg. By statute, the company would have to price that infusion at the same rate as the 3 mg/kg dose. This means each infusion would be about $100,000! ($30,000 for 3 mg/kg therefore $100,000 for 10 mg/kg.) 

        The studies of Merck's PD1 have been done at several different doses. They will have to price it at some point, but what if subsequent studies show that a higher dose works better? Will it then be priced out of reach?  Right now the focus must be on getting these things approved, but at some point these pricing discussions must come into play. 

        A lot of interesting things are in very early development, but I didn't talk much about those. Genentech has a very early study looking at an antibody-drug conjugate (ADC). This is a monoclonal antibody that binds only to tumor cells. The antibody has a chemotherapy drug attached to it and the drug is released at the tumor site when the binding occurs. 

        Another company has early stage anti-PD1 and anti PDL1.  PDL1 is the PD1 ligand (hence the "L") which is the place where PD1 binds. This company is starting a trial combining the two drugs.

        Still another company is looking at a different immunotherapy approach, a drug that blocks phosphatidylserine (PS). This is a compound found on the inside of cell membranes that flips to the outside when the cell gets old and starts to die. It prevents T-cells from attacking the aging cell so the body can get rid of it without invoking an inflammatory response. Tumors express a lot of PS, which may be one of the ways they hide from the immune system. 

        So, a lot of good things are happening. The spectrum of the pipeline, from early stage to late stage development, appears robust and promising.

        Tim–MRF

         

         

         

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        Tim–MRF
        Guest

        Brian:

        I think you have it right. Merck is almost certain to be approved first, and their numbers look good. There is definitely something there about the ipi/nivo combo, though. The challenge is the toxicity. Also will be interesting to see the pricing situation. Merck faces that same problem.

        Once a company determines the price of an infusion drug, that price cannot easily change. I am  not stating this very clearly, but here is what I mean. The approved dose of "ipi" is 3mg/kg. The stated wholesale cost when the drug was approved was $30,000 per infusion, but in fact the cost could vary from patient to patient because of their body weight.  The more kg, the more mg needed to get to that 3mg/kg level.

        Some studies of "ipi' have been done at 10 mg/kg. By statute, the company would have to price that infusion at the same rate as the 3 mg/kg dose. This means each infusion would be about $100,000! ($30,000 for 3 mg/kg therefore $100,000 for 10 mg/kg.) 

        The studies of Merck's PD1 have been done at several different doses. They will have to price it at some point, but what if subsequent studies show that a higher dose works better? Will it then be priced out of reach?  Right now the focus must be on getting these things approved, but at some point these pricing discussions must come into play. 

        A lot of interesting things are in very early development, but I didn't talk much about those. Genentech has a very early study looking at an antibody-drug conjugate (ADC). This is a monoclonal antibody that binds only to tumor cells. The antibody has a chemotherapy drug attached to it and the drug is released at the tumor site when the binding occurs. 

        Another company has early stage anti-PD1 and anti PDL1.  PDL1 is the PD1 ligand (hence the "L") which is the place where PD1 binds. This company is starting a trial combining the two drugs.

        Still another company is looking at a different immunotherapy approach, a drug that blocks phosphatidylserine (PS). This is a compound found on the inside of cell membranes that flips to the outside when the cell gets old and starts to die. It prevents T-cells from attacking the aging cell so the body can get rid of it without invoking an inflammatory response. Tumors express a lot of PS, which may be one of the ways they hide from the immune system. 

        So, a lot of good things are happening. The spectrum of the pipeline, from early stage to late stage development, appears robust and promising.

        Tim–MRF

         

         

         

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        Johnfdc7
        Participant

        Nice summary Tim  – thanks.

        BRAF inhibitor section is a little confusing as you have mixed up the names Dabrafenib and Trametinib a little:

        GSK BRAFi – Dabrafenib. Marketed as Tafinlar

        GSK MEKi – Trametinib. Marketed as Mekinist

        John

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        Johnfdc7
        Participant

        Nice summary Tim  – thanks.

        BRAF inhibitor section is a little confusing as you have mixed up the names Dabrafenib and Trametinib a little:

        GSK BRAFi – Dabrafenib. Marketed as Tafinlar

        GSK MEKi – Trametinib. Marketed as Mekinist

        John

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        Johnfdc7
        Participant

        Nice summary Tim  – thanks.

        BRAF inhibitor section is a little confusing as you have mixed up the names Dabrafenib and Trametinib a little:

        GSK BRAFi – Dabrafenib. Marketed as Tafinlar

        GSK MEKi – Trametinib. Marketed as Mekinist

        John

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        BrianP
        Participant

        Thanks Tim. 

        I heard recently on the MIF forum that Genetech won't be continuing the ADC research, at least in regards to melanoma.  I was surprised to hear this because it has seemed very promising.  Not sure if that rumor is true or not. 

        Brian

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        BrianP
        Participant

        Thanks Tim. 

        I heard recently on the MIF forum that Genetech won't be continuing the ADC research, at least in regards to melanoma.  I was surprised to hear this because it has seemed very promising.  Not sure if that rumor is true or not. 

        Brian

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        BrianP
        Participant

        Thanks Tim. 

        I heard recently on the MIF forum that Genetech won't be continuing the ADC research, at least in regards to melanoma.  I was surprised to hear this because it has seemed very promising.  Not sure if that rumor is true or not. 

        Brian

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        Tim–MRF
        Guest

        Brian:

        I think you have it right. Merck is almost certain to be approved first, and their numbers look good. There is definitely something there about the ipi/nivo combo, though. The challenge is the toxicity. Also will be interesting to see the pricing situation. Merck faces that same problem.

        Once a company determines the price of an infusion drug, that price cannot easily change. I am  not stating this very clearly, but here is what I mean. The approved dose of "ipi" is 3mg/kg. The stated wholesale cost when the drug was approved was $30,000 per infusion, but in fact the cost could vary from patient to patient because of their body weight.  The more kg, the more mg needed to get to that 3mg/kg level.

        Some studies of "ipi' have been done at 10 mg/kg. By statute, the company would have to price that infusion at the same rate as the 3 mg/kg dose. This means each infusion would be about $100,000! ($30,000 for 3 mg/kg therefore $100,000 for 10 mg/kg.) 

        The studies of Merck's PD1 have been done at several different doses. They will have to price it at some point, but what if subsequent studies show that a higher dose works better? Will it then be priced out of reach?  Right now the focus must be on getting these things approved, but at some point these pricing discussions must come into play. 

        A lot of interesting things are in very early development, but I didn't talk much about those. Genentech has a very early study looking at an antibody-drug conjugate (ADC). This is a monoclonal antibody that binds only to tumor cells. The antibody has a chemotherapy drug attached to it and the drug is released at the tumor site when the binding occurs. 

        Another company has early stage anti-PD1 and anti PDL1.  PDL1 is the PD1 ligand (hence the "L") which is the place where PD1 binds. This company is starting a trial combining the two drugs.

        Still another company is looking at a different immunotherapy approach, a drug that blocks phosphatidylserine (PS). This is a compound found on the inside of cell membranes that flips to the outside when the cell gets old and starts to die. It prevents T-cells from attacking the aging cell so the body can get rid of it without invoking an inflammatory response. Tumors express a lot of PS, which may be one of the ways they hide from the immune system. 

        So, a lot of good things are happening. The spectrum of the pipeline, from early stage to late stage development, appears robust and promising.

        Tim–MRF

         

         

         

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      BrianP
      Participant

      Thanks Tim for the outstanding summary.  I have to admit that at first I was a little disappointed there wasn't much new coming out of ASCO this year but after more time to reflect it really was some good news stories.  I think I was hoping for the "next new thing" and instead we got a lot of confirmation that the things we have are pretty good and even better with some combinations.  I've heard some slight rumblings of new inhibitors on the horizon such as IDO which I thought we may hear something about but maybe it's just a little too soon for these to presented at ASCO.  I'm curious on your thoughts regarding Merck and BMS's PD-1 drugs and BMS's combo of Ipi and Nivo.  It seems like Merck as both a time advantage and perhaps even an effectiveness advantage in getting their PD1 to market but the results of BMS's Ipi and Nivo combo are too impressive not to be available to everyone as soon as possible.  It seems to me that with all the combo trials BMS is running with those drugs they are putting a full court press on getting that combo approved as quickly as possible.  Did you get any sense at ASCO when that combo may be approved?  I know that is always anyones best guess but I just curious if it's being talked about.

      Brian

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      Bhnath10
      Participant

      Thank you very much for the thorough analysis of the research presented. My concern, as always, is the fact that no meta analysis seems to take place outside of ASCO. In a twist of irony, I was diagnosed with BRCA2 breast cancer 2 years after my husband's recurrent melanoma was diagnosed. One of the many cancers listed of which I now have an increased risk for getting in my lifetime is melanoma, so the poster showing the connection between pregnancy and melanoma didn't seem shocking to me. I hope that more information is shared across disciplines and specialties, as this will continue to offer a broad and thorough approach to attacking cancer, particularly on the genetic level. 

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      Bhnath10
      Participant

      Thank you very much for the thorough analysis of the research presented. My concern, as always, is the fact that no meta analysis seems to take place outside of ASCO. In a twist of irony, I was diagnosed with BRCA2 breast cancer 2 years after my husband's recurrent melanoma was diagnosed. One of the many cancers listed of which I now have an increased risk for getting in my lifetime is melanoma, so the poster showing the connection between pregnancy and melanoma didn't seem shocking to me. I hope that more information is shared across disciplines and specialties, as this will continue to offer a broad and thorough approach to attacking cancer, particularly on the genetic level. 

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      Bhnath10
      Participant

      Thank you very much for the thorough analysis of the research presented. My concern, as always, is the fact that no meta analysis seems to take place outside of ASCO. In a twist of irony, I was diagnosed with BRCA2 breast cancer 2 years after my husband's recurrent melanoma was diagnosed. One of the many cancers listed of which I now have an increased risk for getting in my lifetime is melanoma, so the poster showing the connection between pregnancy and melanoma didn't seem shocking to me. I hope that more information is shared across disciplines and specialties, as this will continue to offer a broad and thorough approach to attacking cancer, particularly on the genetic level. 

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