Originally Published in VICC Momentum September 23, 2020 | Dana Brantley-Sieders, PhD
Note: This is an essay I wrote last summer. Though my journey continues thanks to residual disease and a mastectomy after I submitted the essay, the spirit and information in the essay hold true. I have hope. And I’m still working hard to fight cancer inside the laboratory and out in the wider world.
I had been studying breast cancer for more than 20 years when I was diagnosed with invasive ductal carcinoma. My professional life was filled with hours of watching tumor cells grow and spread on plastic dishes, marveling as they branched and blebbed in three-dimensional matrices, monitoring the size of lumps from spontaneous or transplanted breast tumor tissue in experimental mouse models, and if I was lucky, watching their growth slow or even seeing them shrink when a new experimental therapeutic worked in pre-clinical testing.
Over the years, family and friends had come to me for information, reassurance and comfort in the face of their diagnoses. I’d lost a close cousin to the ravages of aggressive breast cancer. She was only 37 years old.
When my mother was diagnosed with breast cancer, I emptied her surgical drains after her double mastectomy, caring for her with a toddler clinging to my leg and a baby balanced on my hip. I brought meals to a close friend who was diagnosed with stage 3 breast cancer, visiting with her as she endured chemotherapy, surgery, reconstruction, and finding her new normal while our pre-teen daughters hovered in the background, their infectious laughter a balm to the devastation wrought by the big “C.”
After all of this, I thought I knew breast cancer. Then it kicked me in my left breast and flung me, bleeding, on the curb of uncertainty. Turns out, I had a lot to learn.
When Brent Rexer, MD, my medical oncologist, walked in to my first appointment at the Vanderbilt Breast Center, he greeted me with kindness and a wry smile. “It’s good to see you again, though I wish it was under better circumstances.” I’d known Brent for years. He and his wife were classmates of mine in graduate school, and we’d crossed paths at research seminars in the Vanderbilt-Ingram Cancer Center. I’d crossed paths with many of the clinicians and providers who would become a part of my care team. I was lucky. I knew I was in great hands.
When I got cancer, I came home.
What did I learn from the laboratory bench to my own bedside? For starters, I learned that nothing, not even a career spent tackling this disease, can prepare you for your own diagnosis. I was as shocked, devastated, and numb as any woman who hears those three terrible words — you have cancer.
I learned that radiologists save lives. The radiologist who spotted the suspicious spot on a routine mammogram and later during an ultrasound examination has over 30 years of experience in the field. Because I’m a geek, I always ask to see what’s going on in any exam. I’m “that patient,” the one who’ll ask if I can look at the computer screen after a boob squeeze, à la mammography, and in the middle of having the goo-covered wand gliding over my exposed boob during an ultrasound. When I had the chance to look at my tumor and a previously detected benign lesion side by side, I realized that this radiologist’s years of training and sharp eyes (that could tell the difference between two grainy spots on an ultrasound that looked the same to me) caught one tumor before it could become immediately life threatening. We later learned that I had two tumors of the same subtype in the same breast, which is pretty rare. But we would not have caught the smaller one, which was actually growing faster, had my radiologist not spotted the larger mass.
I learned that I had the option of saving most of my breast tissue. Thanks to years of study following outcomes of patients who chose lumpectomy and those who chose mastectomy as surgical options, we know that choosing breast conserving surgery does not increase a woman’s risk for distant recurrence. There is an increased risk for local recurrence, but that can be mitigated with radiation therapy. I was fortunate enough to be a good candidate for partial mastectomy followed by oncoplastic reconstruction, which is essentially a breast reduction and lift. I’m not going to lie – it’s like being 18 again. I’m perky! Better still, it preserved sensation in my breast skin and nipples, and the recovery time was much shorter than with a mastectomy. Note: there are no wrong choices, only informed choices. The decision to keep or remove one or both breasts after a cancer diagnosis is a deeply personal one. Each individual patient must consider the options, the benefits and risks, and decide what is right for her. This was the best decision for me, and I’m glad I was a good candidate for this surgical option.
I learned that surgeons are brilliant, and by working together, they can give you back much of what you lost. My surgical team, including Ingrid Mezoely, MD, and Galen Perdikis, MD, worked together on a plan that allowed Dr. Mezoely to remove my tumors and Dr. Perdikis to perform oncoplastic reconstruction just after. A year and a half later, I am pleased with the result, like the way I look and feel, and while I’ll never be the same as B.C. (before cancer), my new normal is better than I ever imagined.
I learned that radiation therapists are some of the nicest, funniest people on the planet. My go-to coping mechanism is humor. When I came in for a dry run prior to my first radiation therapy, the technician placed several markers on my left breast in order to properly align the beam for more precise targeting of the area where the tumors were removed while minimizing potential damage to my heart and lungs. The shiny markers formed a cute little circular pattern, so I joked that we could make it into a pastie. All I need would be some glitter and a tassel. We both cracked up, and I was able to relax, hold my breath for the designated time, and get prepared for my treatment course. During those visits, I talked with the therapists and Bapsi Chakravarthy, MD, about topics big and small — kids, work, life, research, politics, favorite books and television shows, and all manner of topics that made the discomfort during the last weeks of treatment much more bearable.
I learned the depths of compassion and generosity of my colleagues, both in the laboratory setting and in the clinic. Disclosing a cancer diagnosis to your employer and co-workers can be frightening. Will you be at risk for losing your job (a reality for too many Americans)? Will your colleagues see you and treat you differently? Will moving forward be awkward, with colleagues feeling uncomfortable and at a loss for words? I was lucky and found support and comfort, with offers to help keep the research in my laboratory going while I was out on medical leave, with encouragement, and with the honor of serving as a reminder of what all of us in cancer research work for — helping patients diagnosed with cancer survive and thrive.
I learned that, having been on both the research side and patient side of the breast cancer experience, I have a unique perspective and the opportunity to help people outside of the laboratory. Scientists are very good at communicating with one another within the research community, but I believe we need to expand our efforts to communicate with the public. After all, most of us are funded by the National Institutes of Health, which is in turn supported by tax dollars. I feel an obligation to be able to explain my work and why it’s important to anyone who asks, be it my 11-year-old son or a person sitting next to me at the airport. I have a new mission: to be an advocate for science and bring science to the public, particularly when it comes to breast cancer. Sadly, we live in an age of fake news and pseudoscience, made worse by the pervasive anti-intellectual and anti-science political culture gripping the United States and much of the world. The internet and social media are plagued by scammers selling “alternative medicine” and woo woo “cures” for cancer. Knowledge is power, and lack thereof can be deadly. I can lend my voice to fighting myths and scams for the public good through speaking, blogging and writing.
I learned that there will be good days and bad days, and that it’s OK to seek help. My prognosis is great, but my type of breast cancer can recur years or decades after surgery and treatments are complete. That thought often keeps me up and night and serves as a source of worry. Shortly after my diagnosis, I worked to the point of exhaustion in the lab, at home, and on my side gig, staying up late in the name of productivity and maximizing creativity, but I wasn’t fooling anyone. I was terrified. After a year and a half of ups and downs, I acknowledged that I was not fine, and that I needed help in the form of therapy. I’m glad I did. Tackling my fears and anxieties head on has helped me be my best self, accept my new normal as a cancer survivor and focus on living the life I have with joy and purpose. And when I go back into the well of despair, as many survivors do, I now have the tools to climb back out and get back on track, which is very empowering.
Finally, I learned that I’m still learning. I have the best job as a researcher in that I get to be a lifelong learner. So many strides have been made since I entered the field, when Herceptin was first developed for HER2-positive breast cancer. Now, we have so many new tools in diagnostics and prognostics (3D mammography and OncoType DX testing), treatments (aromatase inhibitors, CDK inhibitors, and immune therapy), and amazing new treatments on the horizon. We still have so much work to do, but we are making a difference, and I am privileged to be a part of that process.
So I’m 5 months out from my mastectomy, waiting for reconstruction of my left breast, and I feel fugly. Not just ugly, but the kind of grotesque that can only come from looking in the mirror and STILL being shocked to see one nipple hanging significantly higher than the other. When I’m clothed it’s slightly better. I can shove my fake boob into my bra and sort of look balanced.
I say “sort of” because the damned insert moves around and is slightly bigger than my intact right boob, so I have to stuff the other freakin’ side with inserts from sports bras, which also move around, and I swear I can tell that I’m lopsided when I look at recent photos.
My family assures me that no one else notices, and maybe they’re right, but I notice, and it makes me self-conscious. It sucks. I also feel old. I’m coming up on my 48th birthday, which technically means I’m still middle-aged. But between the breast cancer diagnosis three years ago, two surgeries, radiation, and three years in medically-induced menopause plus estrogen suppression, I swear I’ve aged ten years.
Am I grateful to be alive? You bet! Do I feel lucky that my prognosis is great? Of course! Is every day a gift? Abso-fucking-lutely! But there are days when cancer and all that comes with it crashes down on me and I get sad, tired, and pissed off about what the big C has done to me.
I’m not alone. If you’re out there feeling the same way, you aren’t alone. We are strong. We are survivors. But we are also human and we will have bad days. And that’s okay. We can’t avoid them, and we have to endure them, but we don’t have to get sucked into the pit of despair. Here are some coping strategies I’ve found helpful. Maybe they’ll help you.
Put on some cute clothes
Fall is here, and that means it’s time to pull out those fuzzy sweaters, leggings, boots, and cute scarves. I’m self conscious about my neck and my cleavage, so scarves have REALLY helped. I’m not going out as much thanks to Covid, but I’ve made it a point, at least once a week, to put on real clothes (instead of the athleisure wear I’ve been rocking since work-from-home became a thing). I choose colors that make me feel bright and shiny, and select from outfits that I’ve been complimented on before. It helps! Those are the days when I can focus more on what I like about my body and face rather than what I don’t like. Have fun, wear what makes YOU feel beautiful, and don’t worry about the folks who say women of a certain age/weight/body type shouldn’t wear certain clothing. The only thing a woman should NEVER wear is the weight of other people’s expectations.
Have Fun with Makeup
I’ve always been pretty basic when it comes to makeup. Foundation, blush, concealer on the blemishes, and boom – done! Fortunately, I have a teen who is super creative, into cosplay, and LOVES makeup. Thanks to her, I’ve upped my makeup game and it has helped me feel pretty. A lovely sales associate at Sephora taught me how to contour, another fantastic salesperson at Ulta recommended primer and an eyeshadow pallet that I LOVE – dramatic eyes really work in the era of masks – and my teen routinely helps me out with the eye makeup game. The old barn does look better with some fresh paint!
Simple Self Care
Anything from drugstore face masks to bathbombs to nice-smelling lotion can be cheap ways to pamper yourself when you’re feeling like a wart on the ass end of a troll. Have a soak, wash your hair (especially if it’s been daaaaaaaaays), brush your teeth, put on some perfume, and treat yourself like the absolute fucking QUEEN you are. You are worth it.
Take a Freakin’ Selfie and Send it To Your Friends
I stole this one from “Everything is Awful and I’m Not Okay,” which I totally recommend you print out and post to your bedroom door. Take a selfie, send it to your friends and/or put it on social media – Facebook, Instagram, Snapchat, hell, make a TikTok video. Speaking of TikTok, get on there and find yourself some support from Your Fairy Godmother @starr_mcqeen_, Your Non Binary Uncle @thaddeusshafer, and the aggressively supportive @angryreactions. They don’t think you are pretty, precious, loved, and worthy, and awesome, they KNOW it and they’ll tell you. Your friends and social contacts will tell you you’re pretty, and you’ll believe them and feel better.
Send ME a selfie and I’ll tell you how pretty you are!
Got any other tips? Let me know. I can use all the help I can get, and I’ll share the love!
Want to help? Donate to my fundraiser and I’ll feature your survival story (or a loved one’s story) on my blog. You can make the donation in honor of someone you love who’s battled breast cancer. My fundraiser is dedicated to my mom, a 10 year survivor, and my cousin, who I lost at the age of 37 to HER2+ breast cancer.
Want something more tangible? Well, my side hustle is writing fiction, including paranormal romance and urban fantasy, which you can read all about at D.B. Sieders. I’m donating all of my royalties from October and November to Making Strides. So you can buy some books, enjoy them, and know that your money is supporting a great cause.
It occurred to me that while I’ve told you that I’m a cancer researcher, you might not know what that actually means. There are many kinds of researchers who conduct many diverse types of cancer research, as detailed here. All are important and complimentary, and they often overlap. I am an academic (work at a University) laboratory researcher in the broad field of Cell Biology, with a focus on Cancer Biology and Cancer Treatment research, specifically working as a “wet lab” researcher. This means I conduct and supervise hands-on experimental research with cells in a dish, mouse models, and tissue/cell extracts (where we grind up or pulverize tissues and cells, separate them into their components like DNA, RNA, or protein, and analyze them using molecular biology or biochemistry). Other researchers use computational models and datasets to conduct their “dry lab” research.
Both types of research are important, and one informs and shapes the other. For example, I’ll use information found in large databases generated by dry labs that containing data from actual human cancers (e.g. cBioPortal for Cancer Genomics, Kaplan-Meier plotter, and The Human Cancer Metastasis Database) to find clues about how the gene product molecules I study might be driving cancer cell growth, survival, and invasion. The data I generate then feeds back into these databases, linking known functions in laboratory models along with data about where these gene product molecules are expressed and at what level in human cancers. In fact, all of the cancer research fields listed in the link feed into and fuel each other. Science these days is multi-disciplinary, meaning scientists from diverse fields bring their expertises to the table in order to do better, more advanced, more impactful science. Case in point – I’m working with Dr. Craig Duvall, Biomedical Engineer right now, applying his cutting-edge nanoparticle and carrier technologies to targeting the expression of cancer-driving genes in the cell culture and mouse models in my laboratory.
So, what is it exactly that I do…do?
These days, I split my time between the bench (doing actual experiments, which is why I became a scientist in the first place) and the office (doing endless paperwork as quickly and as efficiently as possible so I can get back to the bench). I also supervise a phenomenal medical student and co-mentor insanely smart graduate students, support and collaborate with a team of amazing junior and senior faculty, write grant proposals (more on that below), write up scientific findings into manuscripts for peer review and publication, prepare and deliver scientific talks, maintain compliance (biosafety, environmental safety, radiation safety, responsible care and use of laboratory animals, etc.), make sure the laboratory staff have what they need to perform their research, make sure equipment gets serviced and is operational, attend faculty meetings, scientific seminars, professional development meetings, student thesis committee meetings.
Lots of meetings…
As far as what I research, I use cell culture and mouse models of breast cancer, including metastatic breast cancer, to test new experimental therapeutics.
The goal is to discover more specific, effective, less toxic (looking at you, chemo) treatments for breast cancer. I’ll blog more about specific projects later, but what this normally involves is seeing if the new drug makes cancer cells in a petri dish stop growing and/or die, stops cancer cells in a dish from moving and invading, and if a new drug stops tumors in mice from growing or kills them, and, better yet, if the new drugs can actually shrink the tumors. For more information, see the copy of my NIH Biosketch, the mini-resume that we add to every grant application to prove our published expertise, pasted below.
How did I become a cancer researchers? Lots of school and training! I earned a B.A. in Biology from Maryville College in 1995. After graduating, I completed graduate studies at Vanderbilt University, earning a Ph.D. in Cell Biology in 2000. After graduate studies, I completed postdoctoral training in the laboratory of Jin Chen at Vanderbilt University Medical Center from 2000-2003, supported by an American Heart Association Postdoctoral Fellowship Award (I was studying tumor blood vessels, so it was legit!) and a Department of Defense Breast Cancer Research Program Postdoctoral Fellowship award, before being promoted to Research Instructor. I was promoted to Research Assistant Professor in 2006, and during that time I earned a K01 career transition award from the National Institutes of Health/National Cancer Institute. (NIH/NCI – the major funding agency for biomedical cancer research in the united states). This led to my first NIH/NCI independent investigator R01 award in 2011. I was promoted to Assistant Professor of Medicine, Tenure Track, in 2015, and am still at Vanderbilt University Medical Center. I am currently supported by 2 NIH/NCI R01 grants as well as funds from my institution that allow me to generate preliminary data necessary to apply for more grants.
Have you spotted a theme? The theme is “grants” or “awards.” One of the most important jobs I have for my research laboratory is to successfully apply for grants – meaning I write up a proposal about the cool science I want to do, explaining how and why it will benefit patients with breast cancer and move the field forward, and I submit it to the funding agency and compete with a bunch of other super smart, top notch scientists for limited research dollars. These days, money is tough to come by. When I first entered the field as an independent scientist, the top 15% of NCI applications were funded (compared with a funding rate of 25% earlier). These days, it’s at 10%. My colleagues and I literally just missed out on getting a really innovative research proposal funded by 1%! I’m worried how Covid-19 will affect funding over the next 5-10 years, too, as are most of my colleagues. Why is that important? Well, if we want the U.S. to remain on the cutting edge of research and innovation, and if we want to keep discovering new and better ways to detect and treat cancer, we need to invest in science, especially academic science. If you are a cancer survivor, know a survivor, or just want to make the world a better place with less cancer, write your representatives Congress to let them know you want support and full funding of the National Institutes of Health and the National Cancer Institute.
OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)
NAME: Dana M. Brantley-Sieders
eRA COMMONS USER NAME (credential, e.g., agency login): BRANTLDM
POSITION TITLE: Assistant Professor, Medicine/Rheumatology, Vanderbilt University School of Medicine
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION
DEGREE (if applicable)
Completion Date MM/YYYY
FIELD OF STUDY
Maryville College, Maryville, Tennessee
Vanderbilt University School of Medicine
Vanderbilt University Medical Center
A. Personal Statement
I have the expertise, leadership, training, and motivation to successfully carry out the proposed investigation of how EphA2 receptor tyrosine kinase contributes to breast cancer bone metastasis, particularly in terms of tumor-osteoclast interactions that mediate osteolysis in clinically relevant in vivo models that mimic human breast-to-bone metastasis. I have a broad background in cancer research, with specific training and expertise in mouse models of breast cancer and host-tumor interactions (genetically engineered mouse models and orthotopic allograft/xenograft models, including PDX), as well as three-dimensional cell culture and co-culture models, and data mining human tissue microarray and patient datasets to validate clinical relevance of findings in my laboratory model systems. I also have experience testing novel experimental therapeutics in clinically relevant models of breast cancer, including metastatic disease. My research includes analysis of breast cancer cell growth (multiple molecular subtypes), survival, invasion, and host-tumor interactions. Dr. Sterling, Dr. Pellecchia, and I have established a fruitful collaboration that will continue as a part of this exciting investigation
Werfel, T.A., Wang, S., Jackson, M.A., Kavanaugh, T.E., Joly, M.M., Lee, L.H., Hicks, D.J., Sanchez, V., Ericsson, P.G., Kilchrist, K.V., Dimobi, S.C., Sarett, S.M., Brantley-Sieders,D.M., Cook, R.S., and Duvall, CL. (2018) Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival. Cancer Res 78:1845-1858. PMID: 29358172. PMCID: PMC5882532.
Sarett, S.M., Werfel, T.A., Lee, L., Jackson, M.A., Kilchrist, K.V., Brantley-Sieders, D., and Duvall, C.L. (2017) Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing. PNAS 114: E6490-E6497. doi: 10.1073/pnas.1621240114. Epub 2017 Jul 24. PMID: 28739942. PMCID: PMC5558996.
Song, W., Hwang, Y., Youngblood, V.M., Cook, R.S., Balko, J.M., Chen, J., and Brantley-Sieders, D.M. (2017) Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers. Oncogene 36: 5620-30. PMID: 28581527. PMCID: PMC5629103.
Shiuan, E., Inala, A., Wang, S., Song, W., Youngblood, V., Chen, J., and Brantley-Sieders, D.M. (2020). Host deficiency in ephrin-A1 inhibits breast cancer metastasis. [version 2; peer review: 3 approved]. F1000Research 2020, 9:217 (https://doi.org/10.12688/f1000research.22689.2). PMID: 32399207. PMCID: PMC7194498.
B. Positions and Honors
Positions and Employment
Postdoctoral Fellowship, Vanderbilt University School of Medicine
Research Instructor, Vanderbilt University School of Medicine
2006-2015 Research Assistant Professor of Medicine, Vanderbilt University School of Medicine
2015-present Assistant Professor of Medicine, Vanderbilt University School of Medicine
Other Experience and Professional Memberships
1998 Molecular Biology and Pathology of Neoplasia, Edward A. Smuckler Memorial Workshop,Keystone, Colorado
1998-present Member, American Association for Cancer Research
2002 Harvard Medical School Department of Continuing Medical Education and Massachusetts General Hospital Department of Radiation Oncology Seventeenth Annual Offering of Critical Issues in Tumor Microcirculation, Angiogenesis, and Metastasis; Biological Significance and Clinical Relevance Workshop, Cambridge, Massachusetts
2005 National Cancer Institute (NCI)-sponsored Organotypic Models Training Program; received training in orthotopic tumor cell transplantation in mice within several organs, including mammary gland fat pad, bone, lung, spleen, pancreas, bladder, and cecum in the laboratory of Dr. Isaiah J. Fidler, MD Anderson Cancer Center, Houston, Texas
2007-present Ad hoc reviewer for Nature, Cancer Research, PLoS One, Oncogene, Clinical Cancer Research, Neoplasia, European Journal of Cell Biology
2009-2016 Peer reviewer Department of Defense Breast Cancer Research Program
2012 Peer reviewer NCI TME study section
1997-1998 Department of Defense Breast Cancer Pre-doctoral Fellowship
1998-1999 Dissertation Enhancement Award, Vanderbilt University Graduate School
1998-1999 Coordinator for Developmental Biology Student Organization, Vanderbilt University
2000-2001 Public Health Service Vascular Biology Postdoctoral Fellowship
2001-2003 American Heart Association Postdoctoral Fellowship
2001-2002 American Heart Association Basic Cardiovascular Science Council
2003 NIH NRSA Postdoctoral Fellowship 1 F32 CA101419-01 (award offered, declined due to overlap with 2003 DOD award)
2003-2006 Department of Defense Breast Cancer Research Program Postdoctoral Fellowship DAMD17-03-1-0379
2006-2011 NCI Mentored Career Development Award K01CA117915
C. Contributions to Science
My early publications from graduate studies directly addressed how signaling pathways that regulate normal mammary epithelial morphogenesis (e.g. NF-kappaB transcription factors) can contribute to hyperplasia, a hallmark of neoplastic transformation. These publications provided the first evidence that NF-kappaB transcription factors are expressed and active in normal mammary epithelium during post-pubertal development, and that IkappaBalpha deletion in mammary epithelium, which promotes constitutive activation of NF-kappaB transcriptional activity, promotes pervasive intraductal hyperplasia in vivo. These studies laid the foundation for investigating the role of these transcription factors in breast cancer, and also provided training for me in animal models and mammary fat pad clearing and transplantation techniques that have formed a cornerstone of my independent research program and contributed to numerous collaborations, including those with Dr. Chen. I served as primary author for each of these studies and independently designed experiments, interpreted data, and prepared the manuscripts for publication. Funding from my Department of Defense Breast Cancer Pre-doctoral Fellowship award supported this work. I also contributed directly to collaborations that led to publication of work related to the role of NF-kappaB transcription factors to development and disease as a part of my graduate studies.
Brantley, D.M., Yull, F.E., Muraoka, R.S., Hicks, D.J., Cook, C.M., and Kerr, L.D. (2000) Dynamic expression and activity of NF-kappaB during post-natal mammary gland morphogenesis. Mech Dev 97:149-55. PMID: 11025216.
Brantley, D.M., Chen, C.-L., Muraoka, R.S., Bushdid, P. B., Bradberry, J. L., Kittrell, F., Medina, D., Matrisian, L. M., Kerr, L.D., and Yull, F. E. (2001) Nuclear factor-kappaB (NF-kappaB) regulates proliferation and branching in mouse mammary epithelium. Mol Biol Cell 12: 1445-55. PMID: 11359934. PMCID: PMC34596.
Bushdid PB, Brantley DM, Yull FE, Blaeuer GL, Hoffman LH, Niswander L, Kerr LD. (1998) Inhibition of NF-kappaB activity results in disruption of the apical ectodermal ridge and aberrant limb morphogenesis. Nature 392: 615-8. PMID: 9560159.
I continued to pursue the connection between signaling pathways that regulate development and contribute to tumorigenesis and progression during my post-doctoral training, providing the first evidence that EphA2 receptor tyrosine kinase regulates angiogenesis and tumor neovascularization. These publications showed that EphA2 regulates endothelial cell assembly and motility through a PI3K/Rac1-GTPase-dependent mechanism and regulates tumor angiogenesis in cooperation with the VEGF signaling pathway in vivo, providing novel insight on the molecular regulation of tumor angiogenesis and host-tumor interactions. I served as primary author for each of these studies and independently designed experiments, interpreted data, and prepared manuscripts for publication. Funding from my American Heart Association and Department of Defense Breast Cancer Postdoctoral Fellowship awards supported this work.
Brantley, D. M., Cheng, N., Thompson, E. J., Lin, Q., Brekken, R. A., Thorpe, P. E., Muraoka, R. S., Pozzi, A., Jackson, D., Lin, C., and Chen, J. (2002). Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21: 7011-26. PMID: 12370823.
Brantley-Sieders, D. M., Caughron, J., Hicks, D., Pozzi, A., Ruiz, J. C., and Chen, J. (2004). EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation. J Cell Sci 117: 2037-49. PMID: 15054110.
Brantley-Sieders, D.M., Fang, W.B., Hicks, D.J., Zhuang, G., Shyr, Y., and Chen, J. (2005) Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression. FASEB J 19: 1884-6. PMID: 16166198.
Brantley-Sieders, D.M., Fang, W.B., Hwang, Y., Hicks, D., and Chen, J. (2006) Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism by EphA2 receptor and Vascular Endothelial Growth Factor (VEGF) in mice. Cancer Res 66: 10315-24. PMID: 17079451.
As PI or co-investigator on several university- and NIH-funded grants, I laid the groundwork for an independent research program by showing that (1) EphA2 receptor tyrosine kinase is necessary for normal mammary epithelial morphogenesis, (2) EphA2 receptor tyrosine kinase promotes mammary tumorigenesis and metastasis in vivo in HER2-dependent models of breast cancer through physical and functional interaction with HER2 and activation of Ras/Erk and RhoA signaling, and, (3) demonstrating clinical relevance of these observations by interrogating patient mRNA datasets and human tissue microarrays to show that high levels of EphA2 correlate negatively with overall and recurrence-free survival in human breast cancer across multiple subtypes.
Brantley-Sieders, D.M., Zhuang, G., Hicks, D., Fang, W.B., Hwang, Y., Cates, J.M.M., Coffman, K., Jackson, D., Bruckheimer, E., Muraoka-Cook, R.S., and Chen, J. (2008) EphA2 receptor tyrosine kinase amplifies ErbB2 signaling, promoting tumorigenesis and metastatic progression of mammary adenocarcinoma. J Clin Invest 118: 64-78. PMID: 18079969. PMCID PMC2129239.
Brantley-Sieders, D.M., Jiang, A., Sarma, K., Badu-Nkansah, A., Walter, D.L., Shyr, Y., and Chen, J. (2011) Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome. PLoS One 6: e24426. PMID: 21935409. PMCID: PMC3174170.
Zhuang G, Brantley-Sieders DM, Vaught D, Yu J, Xie L, Wells S, Jackson D, Muraoka-Cook R, Arteaga C, Chen J. (2010) Elevation of receptor tyrosine kinase EphA1 mediates resistance to trastuzumab therapy. Cancer Res 70: 299-308. PMID: 20028874. PMCID: PMC3859619.
My independent research career continues to focus on molecular mechanisms that regulate breast tumorigenesis, host-tumor interactions, and metastatic progression in clinically relevant cell culture and in vivo models. Work initiated in my mentor’s laboratory and supported by an NCI K01 Career Development Award pioneered a role for angiocrine factors regulated by EphA2 in tumor cell growth and invasion in culture and in vivo, providing the first evidence that inhibition of the tumor suppressive angiocrine factor, Slit2, by EphA2 receptor tyrosine kinase promotes tumor cell proliferation and invasion. These studies became the basis of my first independent NIH/NCI R01 grant (CA148934) and publications dissecting the molecular mechanisms through which EphA2 receptor and ephrin-A1 ligand cooperate with VEGF and Slit2 to modulate normal vascular remodeling and tumor angiogenesis in vivo. I served as primary author for the first study and senior author/PI for subsequent studies. I have also recently initiated a collaborative investigation of the role of Rictor/mTORC2 in mammary epithelial morphogenesis and breast cancer with Dr. Rebecca Cook.
Youngblood, V.Y., Wang, S., Song, W., Walter, D., Hwang, Y., Chen, J., and Brantley-Sieders, D.M. (2015)Elevated Slit2 activity impairs VEGF-induced angiogenesis and tumor neovascularization in EphA2-deficient endothelium. Mol Cancer Res. 13:524-37. PMID: 25504371. PMCID: PMC4416411.
Morrison-Joly, M., Hicks, D.J., Jones, B., Sanchez, V., Estrada, M.V., Young, C., Williams, M., Rexer, B.N., Sarbassov, D.D., Muller, W.J., Brantley-Sieders, D., and Cook, R.S. (2016) Rictor/mTORC2 drives progression and therapeutic resistance of HER2-amplified breast cancers. Cancer Res 76:4752-64. PMID: 27197158.
In addition to the contributions described above, with a team of collaborators, my experience in manipulation of the mouse mammary gland, including xenograft/allograft models, has directly promoted numerous studies elucidating the molecular mechanisms that regulate breast cancer growth/survival, metastatic progression, and host-tumor interactions. Moreover, these studies have benefitted the community at large (e.g. 2012 PLoS One community profiling study provided data for resource allocation requests by Susan G. Komen for the Cure Middle Tennessee Affiliate) and have forged collaborations that will be key in developing new research directions. I served as a collaborator on these studies, contributing to experimental design, interpretation of data, and manuscript preparation/application for funding (some projects).
Takahashi, K., Sumarriva, K., Kim, R., Jiang, R., Brantley-Sieders, D.M., Chen, J., Mernaugh, R.L., and Takahashi, T. (2016) Determination of the CD148-interacting region in thrombospondin-1. PLoS One 11: 5):e0154916. doi: 10.1371/journal.pone.0154916. eCollection 2016. PMID: 27149518. PMCID: PMC4858292.
Young, C.D., Zimmerman, L.J., Hoshino, D., Formisano, L., Hanker, A.B., Gatza, M.L., Morrison, M.M., Moore, P.D., Whitwell, C.A., Dave, B., Stricker, T., Bhola, N.E., Silva, G.O., Patel, P., Brantley-Sieders, D.M., Levin, M., Horiates, M., Palma, N.A., Wang, K., Stephens, P.J., Perou, C.M., Weaver, A.M., O’Shaughnessy, J.A., Chang, J.C., Park, B., Liebler, D.C., Cook, R.S., and Arteaga, C.L. (2015) Activating PIK3CA mutations induce an EGFR/ERK paracrine signaling axis in basal-like breast cancer. Mol Cell Proteomics 14: 1959-76. PMID: 25953087. PMCID: PMC4587316.
Stanford, J.C., Young, C., Hicks, D., Owens, P., Williams, A., Vaught, D.B., Morrison, M.M., Lim, J., Williams, M., Brantley-Sieders, D.M., Balko, J.M., Tonetti, D., Earp, H.S. 3rd, and Cook, R.S. (2014) Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J Clin Invest 124: 4737-52. PMID: 25250573. PMCID: PMCID: PMC4347249.
Brantley-Sieders DM, Fan KH, Deming-Halverson SL, Shyr Y, Cook RS. (2012) Local breast cancer spatial patterning: a tool for community health resource allocation to address local disparities in breast cancer mortality. PLoS One 7:e45238. PMID: 23028869. PMCID: PMC3460936.
Complete List of Published Work in MyBibliography:
*Gap in publications 2018-2019 due to personal breast cancer diagnosis and medical leave.
NextGen RNAi delivery to breast tumors for selective mTORC2 blockade.
The goal of this study is to optimize advanced nanocarrier technologies for application to targeting the conventionally undruggable cancer driver mTORC2 in breast cancer, including the impact of systemic rictor-targeting RNAi delivery, alone or in combination with chemo and molecularly targeted therapies, on tumor growth/survival, progression, metastasis, and the tumor microenvironment.
Role: Multi-PI with Craig Duvall and Rebecca Cook – no overlap
The Role of EphA2 Receptor Signaling in Host-Tumor Interactions
The goal of this study is to determine if native, membrane tethered ephrin-A1 ligand activates endothelial expressed EphA2 RTK, linking specific domains of the receptor to initiation of endothelial cell migration and neovascularization.
The Role of EphA2 Receptor Signaling in Host-Tumor Interactions
NIH/NCI (Brantley-Sieders) 04/01/2011-03/31/2017
EphA2 receptor in endothelial cell-mediated tumor progression
The goal of this study is to determine how angiocrine factors secreted by tumor endothelilum enhance tumor cell growth and motility, as well as angiogenesis.
NIH/NCI (Chen and Brantley-Sieders) 07/14/2014-05/31/2019
Ephrin-A1 in lipogenesis and breast cancer metastatic progression
The goal of this study is to determine how ligand-independent signaling of EphA receptors in the absence of eprhin-A1 promotes HER2-dependent breast tumor progression, metastasis, and lipid metabolism.
When you’re diagnosed with breast cancer, no matter what stage or subtype, odds are you’ll be looking at surgery as part of your treatment plan. Got a tumor in your boob? Gotta have it cut out. Thankfully, patients have options when it comes to surgery, and, this is important…
THERE ARE NO RIGHT OR WRONG CHOICES – ONLY INFORMED CHOICES.
Whew, now that I got that off my chest (see what I did there?), let’s talk about two of those surgical options: lumpectomy and mastectomy (single mastectomy in my case, though many women opt for a double mastectomy and that’s okay). A lumpectomy involves removal of the tumor and surrounding tissue while preserving the rest of the natural breast tissue. A mastectomy is complete removal of breast tissue, leaving only skin and the underlying chest muscle behind. I’ve had both, so I speak from personal experience as well as through the lens of science. Here’s the scoop:
In 2018, I opted for a large lumpectomy followed by oncoplastic reconstruction. I’ll blog more about reconstruction options later, but oncoplasty refers to a breast reduction and lift. My tumors were small, I was early stage, and was a great candidate for this less invasive, breast conserving surgery. Even though I was later diagnosed with residual disease, I regret nothing. I simply got unlucky, and mastectomy was always an option if I had recurrence just as it was an option when I was diagnosed with residual disease.
In 2020, when we detected a pesky little 6 mm tumor that didn’t show up the first time, I opted for a mastectomy for the left breast. I chose this so I could maintain sensation on my right side. This was a personal choice – again, no right or wrong choices, only informed choices. I have the same risk of developing cancer in the right breast as I always had (no additional risk by having it in my left breast), and for me, being able to feel touch on the right side was important. Plus, as this 2017 article notes, “Contralateral prophylactic mastectomy (taking off both breasts including the one without cancer) is becoming increasingly common in the United States, and patients considering this option must be counseled about its lack of a survival benefit, its higher complication rate, and the fact that it is risk-reducing but not risk-eliminating.”
When combined with radiation, patients who opted for lumpectomy had outcomes that were comparable (even slightly better on average) than patients who opted for mastectomy. Bottom line – for early stage disease, outcomes are comparable for breast conserving surgery versus breast removal.
*Disclaimer – ALWAYS ask your doctor about outcomes and survival odds for your specific breast cancer type, stage, and grade.
For the lumpectomy, my surgeon removed my tumors and surrounding tissue. Before that, my tumors were marked with Savi Scout devices, radar locators inserted into my left breast with GIANT FUCKING NEEDLES THE SIZE OF SCREWDRIVERS WHILE MY LEFT BOOB WAS IN MAMMOGRAM COMPRESSION. Yes, this is horrifying, but it’s waaaaay better than wire localization, having ACTUAL WIRES STICKING OUT OF YOUR BOOBS to help the surgeon find the target area. After my breast cancer surgeon cut out the tumor, my plastic surgeon took over to perform a reduction (cutting out tissue on both sides) and lift (cutting around my nipples and jacking them up along with the attached breast tissue and stitching the whole thing up in what I like to call an “anchors away” pattern.
For my mastectomy, which was a skin and nipple-sparing procedure, my surgeon cut out all of my breast tissue except for a small portion underneath the skin that contains blood vessels necessary to sustain the remaining skin. The point is to de-epithelialize (fancy term for getting rid of the glandular epithelium that is the source of breast cancer) the tissue to make sure no cancer/pre-cancerous cells are left in the chest area. In many cases, including mine, a tissue expander was implanted between the remaining skin and my chest muscle. After recovery and removal of surgical drains (see below), you go to your plastic surgeon’s office to have a nurse locate the built in port with a magnetic port finder and then stick a GIANT FUCKING NEEDLE into the port to fill it up with saline solution, stretching your skin in preparation for reconstruction. After the final fill, you have to wait THREE MONTHS with a HELLA UNCOMFORTABLE foreign body in your chest before reconstruction. That’s where I’m at right now – waiting for my surgery date.
Pros and cons? If you opt for mastectomy, you can most likely skip post surgical radiation therapy. Radiation therapy sucks! It’s painful, causes fatigue, and it takes several months to fully recover. If you opt for a lumpectomy, your surgical recovery time is much faster! I was up and about within 2-3 weeks after lumpectomy/oncoplastic reconstruction. For my mastectomy on the left side, I was down for the count for 6 weeks and not really back to myself until after 8 weeks and completing physical therapy (didn’t need PT with lumpectomy – another advantage). For lumpectomy, I was able to maintain sensation in both breasts/nipples. I could even still feel the one that got nuked (i.e. radiation therapy). For my mastectomy, sensation on the left side is all gone and most likely will never return. Lumpectomy followed by oncoplastic reconstruction gave me a great shape and aesthetic result. My tits were GORGEOUS (as a part of the reconstruction process, I had a reduction and lift on the right breast in order to achieve symmetry)! I went from saggy D cups to very perky, pretty C cups. It was like being 18 again! But, even though the odds were low, I was one of the unlucky patients who had residual disease following lumpectomy and radiation.
Another consideration – mastectomy required surgical drains. With the removal of tissue and damage resulting from cutting into the body, fluid accumulates in the wounded area and, if undrained, can result in a seroma. To mitigate this complication, the surgeon leaves plastic tubes in the area attached to external suction devices that look like grenades and that need to be emptied several times a day. What comes out ranges from pale liquid to blood red liquid to what I can only describe as “chunky salsa” as pieces of tissue drain out and can sometimes clog the drain and/or the bulb. Yes, it’s that gross. These drains can stay in for up to two weeks, making it impossible to shower, bathe comfortably, exercise, and otherwise operate like a normal, functional human being.
Okay, you CAN function normally, but you’ll fucking pay for it when your drains start filling up faster with bloody, chunky salsa because you overdid it, dumbass. Yeah, I was a total dumbass because “the rules don’t apply to me.”
The rules totally apply to me. Chunky. Salsa.
And, as noted. spending a minimum of three months with one or two expanders in your body following a mastectomy is a level of sucktastic that I can only describe as follows: I’m kinda like a femebot but without the cool guns. I mean, if you’re going to be a cyborg, you should at least get some cool powers, right? That’s a BIG con when it comes to mastectomy. My oncoplastic reconstruction for lumpectomy happened immediately after my tumor removal surgery, which was super efficient and came with a relatively easy recovery.
Bottom line (louder, for the folks in the back): THERE ARE NO RIGHT OR WRONG CHOICES – ONLY INFORMED CHOICES. Knowledge is power. Get as much information from your healthcare team as possible. Ask questions. Do your research (using reputable sources that cite peer-reviewed data). Ask more questions. You are your own best advocate!
It’s been a while! I’ve taken time to recover from my mastectomy (will blog about that later) and, like many folks in self-isolation, I’ve been doing things like gardening, cooking/baking, home improvement, and family activities to fill the time. I waver between being grateful, bored, peaceful, restless, and generally anxious about the immediate and long-term future.
And, like many other people battling cancer in the midst of the pandemic, I’ve been dealing with uncertainty about my ongoing treatments on top of the “normal” concerns. I’ll get to my specific case in a bit, but first we’ll go over highlights from a recently published article.
How has cancer care changed in the era of Covid? A recent article from the New England Journal of Medicine provides insight into some of the challenges for breast cancer care. The article is part case study and part discussion of alternative approaches to cancer care designed to mitigate risks of cancer patient exposure to SARS-CoV-2 in healthcare settings. These include delays in surgical tumor removal in some cases where rapid growth/progression of the tumor isn’t a significant risk. One interesting approach is the use of neoadjuvant (a fancy term for treatment before surgery) endocrine therapy (a fancy term for use of estrogen hormone blocking agents like tamoxifen and aromatase inhibitors). As discussed in the article, the advantages of this approach for hormone receptor positive breast cancer include: 1) shrinking the tumor before surgery and improving chances of getting clear margins (no extra tumor left behind after surgery); 2) making breast conserving surgery a safer and more aesthetically pleasing option; 3) giving more time for genomic testing (e.g. OncoType DX – will blog about this later, too) results to come back; 4) determining sensitivity of the patient’s tumor to estrogen suppression, which can also help with the decision whether or not to add chemotherapy.
The downside, of course, is that delayed surgery and neoadjuvant endocrine therapy require more monitoring (examination, imaging, biopsy, etc.), which takes place in healthcare settings and increases the risk of exposure to the virus. With chemotherapy, which targets rapidly dividing cancer cells (along with hair follicles, cells lining the gut, and immune cells), the risks for exposure to coronavirus is especially problematic as patients are rendered immunocompromised (unable to fight off infections with the body’s natural defenses) or immune fragile (less able to fight off infections). Approaches to mitigate these risks are discussed in the article for hormone receptor positive breast cancer as well as HER2+ and triple negative subtypes. It also discusses ways healthcare providers can and should effectively communicate with patients about treatment decisions and risk management.
Communication – this is an ongoing issue with my care. There are many factors, not the least of which is Covid-19, but we’ve had some…confusion about the schedule for reconstruction following my mastectomy (Note: the surgical team managing my case are PHENOMENAL at what they do, but in both cases, communication with me has not been on par with their skills). When we first scheduled the mastectomy, we also discussed which option might be best for reconstruction and settled on a TUG flap autologous reconstruction. This will involve using a flap of skin, fat, muscle (transverse upper gracilis), and blood vessels from the upper thigh is used to reconstruct the breast. It is a rather involved surgery, which includes microsurgery to reattaches the blood vessels of the TUG flap to the blood vessels in the chest. The nature of the grafting procedure means close monitoring to make certain the graft has sufficient blood flow to survive and thrive, and therefore requires a one night stay in the ICU.
An ICU stay in the era of Covid-19 is a risky and scary prospect!
Because of the risks, my plastic surgeon called and suggested we postpone reconstruction (could have theoretically been done immediately after mastectomy) to minimize the risks of exposure to the coronavirus. That made perfect sense and I agreed. During this conversation, he mentioned reconstruction 6-8 weeks following mastectomy (scheduled for May 11 – meaning reconstruction around June 22 – July 6).
This did not happen. I *think* what happened was a change in timeline due to the need for an expander implant after surgery – this serves as a temporary, fillable implant that can stretch the skin in preparation for reconstruction. I had a skin/nipple sparing mastectomy (glad the nip made it – it was dicey for a week or so), and the expander sat underneath the skin. With an expander, weekly injections into the port with saline gradually increases tension on the skin and stretches it. When I first started expansion, there was talk from the doctor about reconstruction in August.
This did not happen. I *think* it’s because the doctor forgot to let me know that there’s a three month waiting period between the last expansion and reconstruction. Right now, as far as we know, I’m looking at reconstruction around the end of September/beginning of October.
I hope this happens. Again, healthcare providers and patients must be flexible during the pandemic. I trust that my team will make the safest decision about reconstruction.
First off, apologies for the long absence. Between working from home, homeschooling, gardening (I’ve got a CRAPTON of veggie plants and flowers that I love, pet, kiss, and call my green babies), bread baking (while the yeast lasted), quilting (I’m seriously turning into my grandmother), I’ve been a little busy in quarantine.
Busy is good. Busy has kept me from wallowing and perseverating over my upcoming mastectomy. Two years after oncoplastic surgery to remove the tumor in my left breast and reconstruction involving a breast reduction and lift, we found residual disease. My left breast has to go.
Thanks to Covid-19, my reconstruction will be delayed. That’s not super unusual, as women who opt for implants normally get expanders to stretch their skin prior to permanent placement of the implant. But it’s still stressful. I’ll be lopsided for a while, but I opted to keep the right breast to preserve sensation on at least one side. You knew you lose ALL sensation following mastectomy, right? The new boobs look fantastic and do you no good from an intimacy standpoint.
More on that in a later post.
This post is about perspective, looking ahead to tomorrow, the next few weeks, the next few months, and how to move forward. I received the following message from a Facebook friend, and it is perfect. I’d like to share it with all of you:
“Happy Mother’s Day, Dana. The most Hallmarkesque of the Hallmark Holidays. I trust that Patrick and the brood are making a fuss over you today, and every day.
Patrick has spilled the beans about tomorrow. I imagine that you must be both determined and more than a little whacked out and scared. If you weren’t, I’d be more worried about you.
Surgery is a big deal, and you wonder what life will be like on the other side. At least I did as I prepared for mine last year, when I was blindsided by news that my prostate had to go. I’ll spare you the gory details, but I am delighted that you will be spared the indignity of having a rubber tube jammed up your wee wee for 2 weeks.
I can report that almost a year later, life is still good. Turns out that my masculinity had virtually nothing to do with the operational status of Mr Happy. Your femininity has nothing to do with your hooters, to use the most inoffensive yet funny term I can think of. Bazooms ran a close second.
The most attractive part of a woman to me is her brain. I pray that with the surgery behind you, your brain can be free from worry, and that you can fill it with more good, tranquil and beautiful thoughts.
Your family loves you, especially that bizarre Dutch guy. We are all pulling for you, and send healing thoughts, love and joy.”
Thank you, Survivor Brother. That’s exactly what I needed.
On this, my second “Cancerversary,” I want to urge my fellow citizens to take this pandemic seriously, shelter-in-place, flatten the curve, and listen to scientists and health experts rather than politicians and rabble-rousers who value the economy over health and safety.
I originally submitted this as an Op-Ed to several news outlets, but in light of my upcoming surgery, the first of two thanks to Covid-19 dangers that have delayed my reconstruction following mastectomy, I decided to do a blog post. This is important. We’re all in this together, and those who choose to ignore expert advice are putting people like me in danger.
This isn’t the time to be selfish. Self-isolation isn’t just about you.
Like many Americans, I’ve been working remotely to comply with social-distancing and shelter-at-home measures. As a biomedical research scientist, I understand the particularly insidious way SARS-Cov-2, the coronavirus behind the deadly pandemic, can be transmitted exponentially through populations. Death tolls are rising. We’ve been told we need to flatten the curve, which means we need to slow the spread of the virus so we do not exceed the capacity of the healthcare system to treat severely affected patients. There are a limited number of ventilators available, a message that was driven home by Dr. Emily Porter, board-certified emergency physician and sister of U.S. Representative Katie Porter. Dr. Porter used her sister’s approach to educate the public on how exponential spread of the virus could overwhelm the U.S. Healthcare system, forcing doctors to ration resources and decide who gets a vent and who doesn’t. It’s a horrifying, ugly scenario with 1 patient in 50 getting a vent, and 49 patients left to die.
Her words at sent chills down my spine. “Imagine if you had to say, ‘Oh, I’m sorry. You’ve had cancer before, so therefore you don’t have a perfectly clean bill of health, so you’re not worth saving.’” I am a person living with cancer. My surgery has already been postponed due to the pandemic. Luckily, my tumor is slow-growing, giving me the luxury of time. Many thousands of other Americans and cancer patients around the world do not have that luxury. Cancer treatments cannot be suspended during the pandemic. As I passed through the Vanderbilt-Ingram Cancer Center on my last day of work, I saw a room full of men, women, and children, some in masks, waiting for their chemotherapy treatments. On the floor below, others waited for radiation therapy, and in the hospital a block away, cancer patients were recovering from surgery. These people are not only at risk for exposure while at their appointments, they are also immune-compromised or immune-fragile due to their cancer treatments and are less capable of fighting off the virus. To put that in perspective, a portion of the roughly 650,000 cancer patients who receive chemotherapy annually, not counting those receiving radiation therapy or the host of other patients with co-morbidities, are already more vulnerable to covid-19 death. Without ventilators, an unfathomable number of these patients will likely die. If we ration ventilators based on co-morbidities like cancer, I wouldn’t get a vent if I became infected.
I don’t want to die. None of these cancer patients, or patients with co-morbidities like autoimmune diseases, obesity, diabetes, or others want to die. Can you imagine beating cancer only to succumb to a virus, knowing that your fellow humans didn’t care enough to follow measures to flatten the curve and that’s why you can’t get lifesaving ventilation? Imagine your mother, your grandmother, your child, a newborn baby, your best friend, your colleagues, and imagine life without them—knowing they are gone because the people in their communities didn’t care enough to follow the rules.
Until recently, Tennessee has had a subpar response to the pandemic. Nashville has fared better thanks to measures implemented by the mayor, but there are too many state and local communities that aren’t taking this seriously. I implore them and I implore each of you reading this: follow the rules. Social-distance, shelter-at-home, don’t go out unless absolutely necessary, and take precautions when you do. Wash your hands. Hunker down. We can and will get through this, but only if we all do our part. Please do your part so people like me don’t have to die.
Metastasis – the spread of cancer from its initial tissue of origin to another part (or parts) of the patient’s body – is deadly. Metastatic disease is, by and large, what kills people with cancer. It is an ongoing challenge for healthcare providers and researchers, and, as you may have guessed, it’s complicated.
But what exactly is metastasis? How does the process work? And why is it so hard to treat? I’ll cover what we know in this blog post, current and emerging therapies, and ongoing research designed to treat metastatic disease and allow cancer patients to survive and thrive by keeping their metastatic tumors at bay.
Here are the basics: tumor cells that have the ability to break away from the primary mass and invade the surrounding tissue can travel through the body via circulation (by entering the bloodstream directly or or by entering lymph nodes and from there, lymph vessels that shunt fluid back into circulation), invade a secondary organ, and begin to grow and form a new mass at the second location.
This isn’t easy for cancer cells to do. One of my grad school professors once referred to metastatic cancer cells as the decatheletes of cancer cells. Losing cell-cell contact with the tumor mass, invading the surrounding tissue, which is often a hostile environment without resources available to the primary tumor mass, is risky. Entering circulation is even more risky. The cells of origin for cancer cells are not normally equipped to withstand shear forces produced by flowing blood. They also have to avoid detection and destruction by immune cells, not only in circulation, but within the tissue of origin and within lymph nodes. Immune cells are programmed to seek out and destroy unhealthy cells, which may harbor bacterial or viral pathogens that threaten the body as a whole. Metastatic cells also have to crawl along blood vessel walls or hitch a ride on platelets, surviving in circulation without the resources available within the primary tumor mass.
If the metastatic cells manage to survive breaking away from the primary mass, evade vigilant immune cells, and travel through the harsh environment of the circulatory system, they face the arguably greater challenge of exiting circulation and setting up shop in an entirely different organ system that may or may not be similar to their original home. Think of them as colonists. They need to secure a space to live, gather resources from an unfamiliar landscape by competing with native cells that are better equipped because they belong, and they need to adapt and change the behavioral programs controlled by their genetic instructions in order to grow and establish a new tumor.
For breast cancer cells, common sites of metastasis include liver, lung, bone, and brain. Why those sites? One theory, the “seed and soil” hypothesis, argues that tumor cells are like plant seeds, which travel in all directions but can only live and grow if they land in compatible soil, meaning something about these particular organ environments allows tumor cells to take root. It’s an old theory, first posed by English surgeon Stephen Paget after studying autopsy records of 735 patients who died of breast cancer and spotting patterns.
During the process of invasion and metastatic spread, cancer cells experience a lot of pressures, and combined with a relatively unstable genome (covered in previous post), these pressures select for survival of cells that adapt in a process comparable to evolution by natural selection: cells that survive long enough to divide are more likely to pass favorable traits to their daughter cells. One effect of this process is that tumors formed by metastatic cells are often very different from the primary tumor, making them resistant to the therapies used to treat the primary tumor as well as other treatments. Often, they cannot be removed easily by surgery, are resistant to or quickly become resistant to chemotherapy, radiation, and targeted therapies, and grow at a rate that depletes the patient’s body of life-giving resources and causing the organs in which they are lodged to fail. In a nutshell, metastatic disease is incredibly difficult to treat.
So what can we do about it? The good news is that it is possible to manage metastatic disease in some cases, allowing patients to live longer with better quality of life. More therapies are extending the lives of patients living with metastatic breast cancer, including CDK inhibitors like Palbociclib [Ibrance; other similar drugs include Abemaciclib (Verzenio), palbociclib (Ibrance) and ribociclib (Kisqali)] that target cyclin dependent kinases that drive rapid proliferation of cancer cells, slowing their growth. Others include HER2 antibody-chemotherapy drug conjugates (delivers chemotherapy more specifically to HER2+ metastatic breast cancer cells), second-line HER2 targeted therapies, PI3-kinase inhibitors (which target a signaling pathway that is aberrantly activated in ~60% of cancers), PARP inhibitors (block DNA damage repair pathways to make cancer cells respond better to DNA damage inducing chemotherapy), and immune checkpoint inhibitors (activates T-cells in tumors and allows them to kill metastatic tumor cells) among others. See previous post for information about some of these molecular targets. For more on tumor immunology, click here.
These therapies extend the lives of metastatic breast cancer patients, but they are still a temporary fix. As mentioned above, metastatic tumor cells are tough, incredibly adaptable, and able to develop resistance to therapy. Another approach involves finding a way to induce or maintain tumor dormancy, a state in which tumor cells survive but remain quiescent rather than growing rapidly. Many metastatic lesions can persist in a state of dormancy for decades, and we do not yet understand what keeps them dormant, and perhaps more importantly, what activates their growth. But as researchers unravel the molecular mechanism that regulate dormancy and reactivation, new therapies can be developed to maintain dormancy – thus allowing cancer patients to survive and thrive during a normal lifespan in spite of their tumor burden.
Take home message: metastasis is a complex process that enables invading tumor cells to break away from the primary tumor, travel through the patient’s body, and set up shop in different organs. They are difficult to treat and are the main cause of cancer deaths, but current and emerging therapies to manage metastatic cancer are allowing patients to live longer, better quality lives.
Update on previous post: Hubby replied to Dave’s email. He’s awesome, is (once again) Captain of Team D Beats C, and I hope he writes about his experiences as a caregiver and spouse of someone living with cancer someday. I also called AACR and spoke to Josh, a very nice and caring human being who agreed that the response I first received was not appropriate or kind. He asked that I forward my correspondence to him so that he could look into it.
He also expressed heartfelt wishes for me as I deal with another round of breast cancer.
Later, I received a call from Sheraine, Customer Service Team Lead from Compusystems. She offered an apology and heartfelt wishes for a speedy recovery. She assured me that there are scripted responses that are available and appropriate for cases of illness and they would make sure those responses are used in the future.
A little kindness goes a long way. I’m pleased with the outcome.