Toxicity Troubles | The Aftermath of Cancer Treatment

 

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I had the pleasure of presenting to the Georgetown Breast Cancer Program on behalf of the Georgetown Breast Cancer Advocates a couple of weeks ago at their annual retreat. In my brief talk, I hoped to encourage them to engage patient advocates as part of their research team. I was sure to point out that as advocates, we try to represent more positions than just our own.

Anytime I have a forum to speak “on behalf of the patient voice,” I try to be sure to incorporate more voices than just mine. I don’t like the idea of a few elite patients doing all the talking when researchers, clinicians, and pharma decide to engage patients. And so, when I’m planning a talk, I try to ask for input.

Next week I will be part of a session at the Society of Toxicology shedding some light on the many toxicities that patients face as they undergo cancer treatment, and those that continue for years, or follow them for their entire life. But I need some help! Do you have any burning questions or things that you think need to be considered more than they are? What would you like researchers to address going forward? Please feel free to comment here, on Facebook, or email me– I really do want to be sure I address YOUR concerns!

The Thing with Clinical Trials

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Yes, that’s me working on my computer in a quiet corner while my kids are at the pool. Talk about multitasking.

Having the kids home from school over the summer while I simultaneously started two new jobs made things a little hectic. Couple that with family travel and dealing with the loss of a friend to breast cancer and writing my first eulogy, I was pretty much in survival mode. Things got done, but mostly only the urgent things got done, and then only just before they absolutely had to. So this week I’ve been trying to catch up on things that got put on the back burner, and I’ve been trying to think about some things in a bigger context.

So for a day or so this week, I started wondering about the wisdom of accepting two jobs at the same time. I’ve wanted the position with the MBCproject at the Broad for over a year, it definitely falls into the dream job category, and I accepted the position at Cure Forward before I knew that the MBCproject was going to work out. It wasn’t something that I’d been looking for, but I loved the idea of a company valuing the patient voice enough to build a team of advocates. That’s a big thing, and I wanted to be a part of it. Still, I don’t want to feel like I’m selling out, offering to speak for anyone who will hire me. I wanted to be sure that both projects were a good fit for me.

But then today I was answering some interview questions for an upcoming feature on the Cure Forward blog. Because they match patients with clinical trials, the interviewer wanted to know what I thought about trials. Well, friends, they are super important. That’s how the FDA knows if a drug is safe and effective to treat disease. The problem with clinical trials in cancer is that only about 5% of cancer patients participate in a clinical trial. Now, to be clear, not all patients need to be treated on a clinical trial. Sometimes there just aren’t trials for that cancer. But there are a lot of people who could be on a trial but just don’t know about them. That’s so sad. It keeps a potentially good drug from a patient, and lower recruitment means it will take longer to figure out if a drug is good. I think we all agree that getting a good drug to patients faster is the best outcome. There are also a lot of people who would like to be on a trial that would treat their tumor, but a long list of exclusionary criteria keeps them out. All those exclusionary criteria keep the trial neat and tidy– it’s easier to analyze results that aren’t muddied with heavily pretreated patients or patients who have other health issues, too. But not including patients in the trial who will be ultimately treated if the drug is approved seems like a misstep. This is obviously a big thing to fix, and I’m so heartened that every time I hear Rick Pazdur speak (he’s the acting director for the Oncology Center of Excellence at the FDA), he talks about finding ways to fix this problem. Still, there are so many patients who will never be on a trial, either because they don’t qualify or they live too far from a center, or they just can’t find the trial that’s right for them, and their experiences are important, too. Finding a way to capture and analyze the real world experience of all treated patients would be a game changer.

More data is what drives science forward. So today it occurred to me that all my interests really are aligned. Cure Forward is trying to break down that first data barrier by helping patients find clinical trials that will work for them, and they make it easy on the patient to participate. The MBCproject is trying to move science forward on the back end– capturing all the clinical and genomic data after the fact, including every single metastatic breast cancer patient, not just those 5% that could participate in a trial. They make it easy for the patient to participate, too. Both these groups are moving the science of cancer research forward in an important way, and they are including patients in the process. So I’m on board. If someone is working hard to move the science of cancer research forward and they want to include a patient voice in the process, I don’t see a downside. It’s going to take a lot of different people working in lots of different ways to make an impact, and I hope that lending my experiences might help patients participate in moving science forward for us all.

Precision Medicine and Coinstar Machines

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First of all, thanks for all the love on my last post. Being part of the MBCproject team has been an awesome experience even in the first few months, and I promise I’ll update on some of the details soon! But I also wanted to share another cool project that I’ve been a part of over the summer.

I started working with Cure Forward, which is basically a matching service to help cancer patients find clinical trials based on the DNA profiles of their tumors. Though I hadn’t heard about the company before I was approached to be part of their Precision Medicine Advocates team, I knew the patient advocate who would be leading the team, so I looked into it a bit more. It was one of the private companies specifically listed in Vice President Biden’s Cancer Moonshot to help make finding a clinical trial easier, and I love the fact that they are willing to work with patient advocates to make sure that everything they do remains focused on delivering the best care to patients in the easiest way possible.

I’ve written a few things for them, and my first post went live last week. As I tried to explore what precision medicine means to me– and why it’s exciting but not the silver bullet for all of the cancers ever (right now, at least!)– I was left with the image of a Coinstar Machine in my head. That’s sort of how we do cancer care now– dump all the patients in a sorting machine and they end up in categories that determine their treatment. Head on over to my post at Cure Forward if you want to see why I think Precision Medicine is an improvement on good-old coin counting!

When I Grow Up

When I was in the third grade, I had to write an autobiography, closing with what I wanted to be when I grew up. I’m not sure how I decided that I wanted to be a scientist, or if I ever wanted to be anything else before then, but it never occurred to me to rethink the decision once I put it in writing in the third grade. Before I reached my teenage years, I had decided that I wanted to go to college in Boston– preferably MIT, but Harvard would also work– and I would play my violin with the Boston Pops. (Don’t you love the big dreams and confidence of an 11 year old?!) By my sophomore or junior year of high school, I had my sights set on a biochemistry degree, and while I was still hoping to head to the east coast, I had (quite wisely) abandoned the idea of playing my violin professionally while I was also in college. Even though I didn’t make it out east for college, I did end up in DC for graduate school at Georgetown University, so I figured I’d pretty much gotten the dream. It wasn’t until about halfway through graduate school that I realized that I didn’t really know what I wanted to be when I grew up, I really needed to know more than “scientist.” I knew that I loved science and wanted to use that to make a difference in the lives of breast cancer patients, but I didn’t see myself making a career in academic science. I enjoyed thinking about how science could inform the way patients are treated, and I was convinced of the importance of ensuring that patients and the public really understand the interaction between science and medicine. Unsure of how to turn those things into a career, but quite sure of how much I wanted to stay at home with my tiny new baby, I decided to revisit the “What I Want to be When I Grow Up” saga in a few years, and left the lab with my PhD after Emma Clare was born.

As I sent baby #2 off to kindergarten, I apprehensively decided it was time to think about what I wanted to be when I grew up. Or maybe I should give myself a few months, and then it would be time. Instead, during those few months I was taking to get the kids settled in school– procrastinating, I know– I was diagnosed with breast cancer. After chemo and surgery and with no evidence of disease, I once again struck out to find my grown up job, though this time with a bit more hope and purpose. I’d wanted to work with breast cancer advocates before but was unsure how to transition from being a scientist among scientists to being a scientist among advocates. Now as a survivor, I had gained automatic entry into the advocate’s world. I talked to several people who declared me a unique trifecta of researcher-patient-advocate, and offered to help me get the job I wanted. All I had to do was tell them what I wanted. Which meant I needed to know what I wanted.

So I’ve spent the last three years saying, “Yes.” I went to every meeting I could, met all the people, did all the twitter chats. I blogged on my own site and wrote for anyone else who would have me. I did live and recorded interviews, gave talks big and small. Though I’ve been paid for a few small projects, it’s pretty much been like a three year internship. But I figured if I talked to enough people and did enough different things, I’d surely figure out exactly what it was that I actually wanted. It took two long years of saying “yes” to figure out what I wanted to do, and another year of saying “yes” to actually make it happen, but I finally figured out what I want to be when I grow up, and I’m starting my first real grown up job today! Just in the nick of time, too. Forty is knocking on my door, and it seems like it’s high time that I consider myself a proper grown up.

After two years of saying, “yes,” I ended up sitting next to an interesting young woman at a dinner at AACR in Philadelphia. Corrie was a scientist about my age, had two young kids, and she was a cancer survivor, too. I think we talked a little about her job at the Broad Institute where she was able to combine some patient advocacy and outreach with her scientific position, but mostly we talked about kids and cancer and the plight of young scientists pursuing a career in academic research. I came home from AACR with a stack of cards, contacts who I thought might eventually help me land a job, and a new cancer friend, Corrie.

I wasn’t surprised when I saw her name on the announcement for a twitter chat coming up a few months later to talk about the new, still unreleased Metastatic Breast Cancer Project at the Broad Institute. The surprise came from my response to the project. As the minutes of the twitter chat ticked by and I learned more about the project, I found myself becoming increasingly excited at its promise, truly believing that this team was uniquely positioned to make huge advances in breast cancer research and the way breast cancer patients will be treated in the future. (I won’t rehash it here, but read what I wrote about the MBC Project after it launched in October.) I signed off the chat that night realizing that I might have figured out what I wanted to do when I grew up, or at the very least, I’d found the place I wanted to do it. I felt a little uncomfortable, but figured it would cost me nothing, so I got in touch with Corrie. After reminding her what a charming dinner companion I’d been in Philadelphia, I gushed unabashedly about the project and told her that if she had a place on her team for a scientist/advocate in Washington, DC, I hoped she’d consider me. They were still a few months from the official launch and couldn’t really grow the staff at that point, but we talked for nearly an hour about the project and how I might ultimately contribute to the team. After another year of saying “yes” to most anyone and staying in contact with Corrie, the MBC Project has grown by leaps and bounds, and I’ll be joining the team! Technically, I think my job title is “patient advocate,” I’ll be doing outreach and education with patients and the MBC Project advocacy partners. We have a lot of ideas about exactly what I’ll be doing, but hopefully I’ll start by interacting with patients– those who are already part of the project and those who want to know more before they say “Count me in.” Corrie and Nick, the oncologist who had the remarkable vision of a research project that directly engages patients, have built a great patient community.  I hope to be a resource for those men and women, not only answering their questions, but equipping those with ideas to grow the MBC Project among their communities. I hope to interact with the advocacy groups who have partnered with the MBC Project and to form new partnerships that will broaden the diversity of MBC Project participants.  And lots more things! It’s a part-time position, and I can work from home. I will do a little bit of travel, and I’ll probably go up to Boston every month or two.

Wait. Did I forget to mention that the Broad Institute is in Boston? So maybe I should also mention that its official name is the Eli and Edythe L. Broad Institute of MIT and Harvard. Yup. I didn’t get to go to school at MIT, but now they’re paying me. Pretty stinking cool. Maybe that 11 year old wasn’t so naive after all. (But sorry Mom, I’m not going to be busting out the violin anytime soon, I don’t think the Boston Pops have a place for a DC based violin player who hasn’t played the violin in a very long time.)

ASCO Clinical Guidelines | Patient Perspective on Breast Cancer Treatment

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As a scientist, publications are everything. Whoever coined the phrase “publish or perish” was not joking. Publishing a first author paper was a requirement of my graduate program, and once you get on the career path in academia, publishing papers is the way to get a grant which is the way to get tenure, which is the way to keep your job. Publications are everything.

(A little background on the publication process: In science, the order of authorship is very important, but this convention is different in other disciplines. The first author is the one who did all the work, or at least most of it, and did the bulk of the writing. That’s who really gets the credit for the publication. The other names are listed in decreasing level of contribution until the last author. The last name is the senior author– usually the one in whose lab the work was done. Scientific publications are peer reviewed, meaning experts in the field are asked to review the paper, give feedback, and decide if the study is worth of publication.)

I got the required publication in graduate school, and I quickly accepted that my days as a published author were over when I decided to leave the lab after my defense. Of course, after my cancer diagnosis, I began writing, though few things were actually “published,” at lease anywhere besides my own blog! And it turns out that self-publishing is a lot less stringent than the peer review process…

But a few weeks ago, I got to add a new line to the “peer reviewed publications” section of my CV! The FDA approves drugs for specific indications, but leaves it to oncologists to decide exactly how they are used in practice. The American Society of Clinical Oncologists (ASCO) publishes clinical guidelines for practice that inform oncologists the best practices and protocols for the treatment of cancer. I was the patient representative on one of these panels where we were reviewing the guidelines that a Canadian group had just released on the best ways to treat early breast cancer patients after their surgery. (Adjuvant therapy is the treatment that follows surgery.) You don’t have to read it– it gets a little heavy, it was meant to be read by oncologists, after all– but I was honored to be included to represent the patient voice as the oncologists in the group discussed the evidence for the best ways to treat breast cancer patients. It was a pretty straightforward discussion since the Canadian group had just reviewed all the pertinent literature. We discussed recent findings and minor clinical differences between the US and Canada, and my comments and opinions were well regarded, even solicited.

Being a part of such a prestigious group is a distinct honor. As a patient advocate, representing the patient voice in such an important forum is a responsibility I don’t take lightly. But as a scientist, having another peer reviewed publication is super cool. I mean, I’m one step closer to tenure! ::fighting the urge to insert winky-face emoji here!::

If you want to check out the publication, start with the abstract. The full text is a little heavier, but available here.

Research Advocacy at the University of Illinois

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I definitely enjoyed being back on campus at the University of Illinois, seeing all the familiar sites and eating Papa Del’s pizza, reliving my glory days! But of course, that wasn’t the reason for the trip. Zeynep and Erik Nelson are undertaking the task of starting a research advocacy group as part of the Cancer Community @ Illinois, and I was thrilled not only with their enthusiasm, but with the support they are getting from director of the Cancer Community, Rohit Bhargava.  It was a pleasure to spend time with them, learning about their hopes for the new Cancer Community that will be a part of the new medical school on the UIUC campus.

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They had a full trip planned for me, starting with an informal graduate student and post doc seminar where I talked a little about myself and what I do as a research advocate. Mostly, though, they asked questions. Most of them weren’t familiar with the concept of research advocacy,  and so they had lots of questions about how they could incorporate the perspective a research advocate into their projects.

 

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Probably the best exercise for me was the talk that I gave after lunch to a group of faculty. When Zeynep said that she’d like me to give a 40-45 minute talk, I initially panicked, not sure what I would have to say to fill that much time! Yet I took a deep breath, did my wonderwoman pose, and started planning a talk. I figured once I had it planned, I could bulk it up to fill the time. And yet, when I was done, I found that it was actually a few minutes too long! So I made it a little more concise and smooth and finished it in 42 minutes– perfect.  Part of what made me a little apprehensive, though, was not so much the length– I can always find something to talk about! I’ve given a lot of thought to what a research advocate should do and why an investigator should include them as part of the team, but planning this talk forced me to really organize my thoughts into a concise delivery. Before I had even realized it, I had a polished presentation explaining what a research advocate does, what we don’t do (just as important!), where to find a research advocate, and how to work together as part of a mutually beneficial team. I also got to spend time with some of the key stakeholders in what will become the new Cancer Research Advocacy Group, and sat in on a graduate level class. Zeynep asked her students to explain their research in a way that would be understandable to an advocate– training that few scientists ever receive! They did great, and I enjoyed the discussions that resulted after their presentations.

It was such a fun trip on so many levels. But most of all, it was such a privilege to be involved in the earliest stages of the formation of a group that I think will be such an asset to the research community in a place that is so near and dear to my heart. I can’t wait to see what kinds of ideas will result from the collaboration of biologists, research advocates, and the brilliant engineering minds for which the University of Illinois is known.

A Run Down Memory Lane

 

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I just got back from the coolest trip. I met Zeynep Madak-Erdogan on twitter a year or so ago (thank you #bcsm!), and when I saw that she was a breast cancer researcher at the University of Illinois, we quickly bonded as I told her about my time there. In the months since, she has asked me to work with her on a few different projects, and she even invited me to come to campus as the Cancer Community @ Illinois starts a new cancer research advocacy group!

I’m going to get some of the “official photos” soon and I’ll share a little of the more science-y stuff I did there, but until then, the fun stuff! Zeynep and the rest of the cancer working group set up a great itinerary for me, but she was sure to ask if I wanted her to arrange any specific meetings. My only request was dinner at Papa Del’s, which apparently made me one of the cooler campus visitors and showed my UIUCroots to anyone who hadn’t already heard I was an alum. We drove around campus, and seeing the buildup of research park on the south farms where there used to be nothing but sheep was probably the biggest change. Fortunately (or unfortunately?) there are still some farms on the other side of First Street, so I immediately recognized the familiar smell of spring on the South Farms.

My other request was a slightly later start on the second day so that I could get in a run to visit some of my old haunts. Of course, as a student, I wasn’t a runner, so roller blading or taking the Red bus would have been more accurately nostalgic way to get around campus, but I enjoyed taking my new habit to my old stomping grounds.

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Of course I had to snap a quick picture with the Alma Mater and on the Quad, which like the Union and much of campus, were as I remembered them. (My apologies if this one is upside down. WordPress and I can not agree on how to make it right side up on all devices. Agh!) At one point, we were noticing all the new hipster food trucks near the Beckman Institute and I commented that the only food truck in my day was the weird smelling silver truck outside Noyes Lab. When we walked past that spot moments later, Derald’s Catering Truck was still there, as if it had never moved, save to get a snazzy new paint job on one side!)

imageThis is the entrance to one of the new buildings on campus– the Carl Woese Institute of Genomic Biology. Besides the cutting edge science that goes on inside the building, the art of science is prominently featured throughout the building with temporary themed exhibits. These three sculptures outside the building show tRNA at three different stages.

imageGreen Street looked different, too, with many high rise buildings towering up over the familiar streetfront stores and restaurants. But IGB is probably one of the shortest new buildings on campus, built only a few stories high because of its proximity to the Morrow Plots– the oldest continuously planted experimental cornfield in the United States. And as all my fellow Illini friends know, you can’t throw shade on the corn! (OK, it’s a long video, but gives you the whole story of the Morrow Plots and why the Undergrad Library is underground. The song starts at around 8:30.)

I had a great visit and especially enjoyed my run down memory lane. Stay tuned for some pictures of me dressed like a grown up and being all professional and everything to find out why I was actually there!

 

Department of Defense Breast Cancer Research Program | My Consumer Story

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Well, isn’t that cool. It seems like I’ve had a lot of surreal experiences lately– and I’m still new enough at all this to think it’s pretty cool. That’s my face on the home page for the Army CDMRP— Congressionally Directed Medical Research Programs. It feels like kind of a big deal to me! (Of course, I’ve been a bit of a slacker, or rather I’ve been totally overrun by my kids’ activities, so I’m now the fifth slide to load on the page. Be patient if you want to check it out!)

I’ve talked about the DOD Breast Cancer Research Program before, it’s a congressionally funded research program that is administrated by the army, the army is NOT using their budget to fund breast cancer research. This program is very forward thinking both in the design of the awards, which are created to fund high risk/high reward projects and early career investigators, and in the inclusion of “consumers” (patient advocates!) on the peer review panel.

I was asked to share my story as both an awardee and now a consumer reviewer for the BCRP. I won’t rewrite it here, but suffice it to say, I was honored to be asked. As a first time consumer reviewer, I had worried that the scientists on the panel might not value my input, but have always been impressed by the way the scientists give value to our comments and help us understand the tricky, science-y parts of the applications. I can’t say enough good things about this program, please head over and read my consumer story!

Summer Writing | AACR “How To” Series

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I saw a friend over the weekend who told me she was so happy I’m posting on the blog again. (Hi, Julie!) I have to admit to being a bit of a blog slacker this summer. Somehow, I’d think an eight year old and an eleven year old would be easier than toddlers– they can do so much on their own now, it seems like there should be less for me to do, no? I know all of you parents just a few years ahead of me already know this, but the activities ramped up like crazy this summer and I felt like I was going from one thing to another all summer long! Things like thinking and writing (and showering– the pool counts, right?) kind of took a backseat.

I know that I didn’t post here over the summer, but that’s not to say that I wasn’t doing anything. The bookends to my summer were grant review sessions, one of which required quite a bit more prep than the Department of Defense Breast Cancer Research Program study sections I’ve done before. I spent some time chatting with an early career researcher who has some super exciting ideas, and I’m getting a little closer to figuring out what I want to be when I grow up and how to get there.

One of the writing projects I worked on was for part of a how-to series that the American Association for Cancer Research has on their Advocacy page. I was invited to write a “How To Share Your Story” post for them, and it was such an honor to have my writing featured by such a prestigious organization. For me, seeing my story featured on their advocacy page felt a bit like how I imagine a Broadway star feels seeing their name in lights! I explained a bit about why I started this blog and how it’s changed in the almost three years (gracious, time flies!) since I was first diagnosed with breast cancer. As it’s a how-to series, I also gave a few pointers to anyone interested in sharing their own story. The quick summary: if you don’t want to go the GoDaddy route and pay for a site, there are a lot of free options with varying privacy settings and they’re all pretty easy. Think about your audience when you write, and be yourself. If you want the more detailed version, head over and read the whole thing on the AACR site.

And stay tuned, as my other summer projects go live, I’ll be sure to fill you in! Happy fall, all!

AACR Annual Meeting Report #2: The Poster Session

IMG_2462.2015-04-20_133455While a very few people are asked to give talks at AACR each year, the vast majority of the science presented at the conference is done by the person who actually does all the work– the graduate student or post doc– at a poster session. It’s kind of like a grown-up science fair, but without all the baking soda and vinegar volcanoes. Literally thousands of people put up a poster on a board for four hours, talk to other scientists about their work, and then take it down so several more thousand people can start all over again in the afternoon. What makes a poster session so great is that you have the opportunity to actually talk to the investigator, to interact, ask questions, make connections. These are great opportunities for beginning collaborations between scientists. During two of these sessions, the advocates had a row to put up our own posters. I would love to see us be able to mix in more with the scientific posters to perhaps get a little better traffic, but it was still a tremendous opportunity to present a poster at such a big meeting.

The poster I presented was a true collaborative effort, put together from ideas from the other ladies in the group at Georgetown. In truth, I was hoping to have an audience of scientists, to sell them on the virtues of including advocates in the research process. Thus, our poster described the credentials and the diversity of our group. The youngest in our group are in their mid-thirties, and we also have members in their seventies, and our members represent many different professions.  I’m the most recent diagnosis, but we also have one (never diagnosed) high risk woman and a couple of ladies who are over twenty years out from their diagnosis. The women in our group have worked very hard to learn an incredible amount about breast cancer; many have attended the National Breast Cancer Coalition’s Project LEAD as well as other smaller educational activities. I wanted to emphasize that not only were were diverse and passionate, but that we are a group of educated advocates. But I knew that there was one thing that would be even more important to scientists than education: funding. In fact, quite a few in our group have served as full voting members as consumer reviewers for the Department of Defense Breast Cancer Research Program, and others have also reviewed for Komen, NCI, and state programs in Texas and New York. No one was too interested in reading our publication history, but they were all very impressed to see that members of our group have served on ASCO guideline review panels as well.  Not only are we capable of understanding some of the science and representing a broader patient population, we have done it in some pretty high profile places!

Let me tell you friends, if you have to present a poster for four hours, this is the kind you want to have. Everyone who stopped by listened intently and was thoroughly impressed by the group that Ayesha, our fearless leader and scientific adviser, has built. Many advocates wanted to know how to start such a program in their community, and, as I’d hoped, the scientists were impressed (surprised, though impressed!) by the credentials our members possess.

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Since the conference was nearby in Philadelphia, I was lucky enough to have some of the ladies from the Georgetown group join me for the poster session. There were definitely times when we had more than one discussion going, so it was good to have extra people on hand to chat.But frankly, having five of us there was even a more impressive display of our commitment to learning about cancer and becoming more effective research advocates. And selfishly, I loved having the opportunity to get to know the ladies better– two hours a month in a meeting with a full agenda is not the quickest way to build a relationship!

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And since we’re talking relationships, it’s worth mentioning that we were lucky enough to have a few VIP scientists stop by our poster.  Robert Clarke, PhD, DSc, is the Co-Director of the Breast Cancer Program at Lombardi, and Ayesha Shajahan-Haq, PhD is the Georgetown faculty member who first dreamed of a group like ours at Georgetown and then worked tirelessly to make it happen. She established the group four years ago, and we owe her a tremendous debt of gratitude. And perhaps even more exciting than presenting my poster in the advocate row at AACR is the fact that it now hangs proudly in the hall of The Research Building (such a fancy name for a place where people do research, no?) just outside of Robert Clarke’s lab. Perhaps hanging there, our poster will finally get a good audience of scientists, after all.

I was privileged to participate in AACR as a part of the Scientist <-> Survivor Program. Read about my SSP experience here.