A Husband’s Thoughts on Cancer

Those of you who have read my blog know that my first cousin, Laura, was diagnosed with HER2+ breast cancer in 2012—and that just a year and a half later, she felt a lump in her neck, which led to the devastating news that she had metastatic recurrence to her lungs, liver, and multiple lymph nodes.  She immediately began treatment again, this time for metastatic breast cancer (MBC).

Fortunately, she responded incredibly well to her combined targeted HER2 treatment with Herceptin and a newly approved HER2 targeted agent, Perjeta, and was found to have no evidence of disease (“NED”) since October 2014.  But as she explained in her blog, in the spring of 2015: “I started feeling a tiny bit off when doing flip turns at the pool.  That’s all.  And my eyes felt bleary from what I assumed was my two day per week job in front of a computer where, with my reading glasses on, I had to be very close to the screen.  In my former life, I would have chalked it up to [being] tired or hungry.  In my occupation as cancer patient, I knew to request a brain MRI.”  And it was then that she learned her cancer had metastasized to her brain, with 18 lesions that were too poorly differentiated for localized gamma knife.   She therefore underwent whole brain radiation and, later, following the development of more brain lesions, gamma knife procedures.   In March of this year, Laura wrote the following about her most recent scans:  “’My body has no visible cancer right now.  Yea!  My brain has five tiny lesions that aren’t a big enough deal right now to treat.  Yea…..? This is a ‘great report’ from both of my brilliant docs.  Grace is my interior screaming, ‘What Kind of Fuckery is This?*’ while trying to be content with walking around with five cancerous lesions, however small and asymptomatic.”  (*As Laura explained, “It’s what Amy Winehouse sang so gorgeously in ‘Me and Mr. Jones.’  ‘WHAT KIND OF FUCKERY IS THIS?’  I love curses I’ve never heard before, especially when they fit a situation so well.”)

Also in March, Laura’s husband, Jon, wrote a deeply moving post on his Facebook page that brought me to tears.  In the days that followed, my thoughts kept returning to his words, and it struck me that far too many people have never heard such thoughts from the loved ones of women or men living with MBC.  I therefore contacted Jon to ask whether he would be willing for me to share his post on my blog, explaining that I had two reasons for my request.  First, there was no doubt that his words would deeply resonate with so many.  And second—and so importantly—his post could go far in educating others who have far too many misconceptions about MBC.  Jon graciously gave me his permission, and so, without further ado, I’m honored to share the following with you today.

Jon Graves and Laura Snyder

“My Thoughts on Cancer” 

“Every now and then, I try to write something about what it’s like with my wife having metastatic breast cancer (MBC).  Laura has been living with metastatic cancer for just over 33 months, which happens to be the median life expectancy for someone with MBC.  This statistic could be a little skewed, since there are a couple of new [targeted] drugs (Herceptin and Perjeta) that have become available over the past two to four years that should increase life expectancy for those with HER2 positive breast cancer.  She is [also] on chemotherapy and will continue on chemo of one type or another for the rest of her life.

“Right now, Laura has five brain mets (tumors) she is just walking around with.  They are very small, so her radiation oncologist just wants to wait before doing a procedure.  But this is me telling facts and not feelings.

“Ever looming is death.  Metastatic cancer is the cancer that kills.  So death is the first thing that is always lurking.  Every three months, she has scans, and we see if there is cancer in the body or in the brain.  Her cancer likes to invade her brain.

“But beside the big thing (death) is the human trait of planning ahead.  Thinking of the future.  Our future is lived in three month scan cycles.  But at the same time, I think about what is happening in ten years when I’m in my early 60s.

“My birthday is next week.  I will turn 53.  My Dad died when he was 52.  I have been afraid of 52 for a long time.  Laura made it past 52, and it looks like I will,  too.  But it brings up lots of emotions–especially the long-lasting void left for my wife and kids, who never met my real Dad.

“What is it like living with metastatic cancer (from a caregiver/observer view)?  Day to day can be good, generally is good.  Dog walks and amazing dinners.  Laura is cooking more than ever before in our marriage, and the food is amazing.  But there is a knot in my stomach, a catch in my throat, when someone talks of retirement or the future.  I wonder if I should be paying attention when people talk about swiping left or right on Tinder or Teaser (?) or whatever the dating app of choice is.  Will I be looking for someone to retire with in 15 years, or will Laura be there by my side?  Like everything in life, I just don’t know, but my mind wanders to the uncertain future late at night or early in the morning.

“I also feel guilty about wondering about my future when Laura is doing well while having cancer in her brain.  There are interesting and potentially life-saving drugs out there in trials that could make all the difference in the near future.

“Am I a bad person for making jokes that she can’t remember something?  She does not have nearly the cognitive abilities that she had five years ago.  Brain radiation will do that, as well as years of chemotherapy.  Her eyesight changes every few months, and she needs new glasses lenses, but I taunt her for not being able to see …  I know, I suck and should be better, but I can’t help making jokes about what is hard.

“We are thinking and dreaming of building out on our Knappa land above Big Creek.  It is great to think about moving out there when I retire, but what does that really mean–am I with Lu or alone?

“If you have read this far, please do not worry about me.  I am the same ebullient, happy-go-lucky fellow you know.  At times, I think too much, just like my lovely wife.”

Thank you, Laura and Jon, for allowing me to share this post.  I recalled that in an interview for the blog “Voices of Metastatic Breast Cancer,” when Laura was asked to share her favorite poem or song, she responded by saying that The Beatles ‘Ob-la-di, Ob-la-da’ really resonated with her in this phase of her life, as did Lucille Clifton’s poem, ‘Blessing the Boats.’”  I’m therefore sharing the below as a way of expressing my gratitude to you both.

blessing the boats

BY LUCILLE CLIFTON

                                    (at St. Mary’s)

may the tide

that is entering even now

the lip of our understanding

carry you out

beyond the face of fear

may you kiss

the wind then turn from it

certain that it will

love your back     may you

open your eyes to water

water waving forever

and may you in your innocence

sail through this to that

Lucille Clifton, “blessing the boats” from Blessing the Boats: New and Selected Poems 1988-2000. Copyright © 2000 by Lucille Clifton. Reprinted by permission of BOA Editions, Ltd., http://www.boaeditions.org.

Source: Blessing the Boats: New and Selected Poems 1988-2000 (BOA Editions Ltd., 2000)

 

This is the Hard Part: the Other Side of Advocacy

I’m not sorry to say good-bye to 2015.  It was a cruel year during which we lost several beloved patient advocates, who were wrenched away from their families, their friends, and so many loved ones by the monstrous, hydra-headed beast, cancer.   It was the year during which I learned that my first cousin had been diagnosed with brain metastases due to her stage IV HER2+ breast cancer. It was the year when I began to fear going onto Facebook, since I’ve now learned heartbreaking news about dear friends there far too many times. And it was the year when I began to dread receiving any emails whose subject lines simply contained the name of a fellow advocate with cancer—because it almost always meant the same thing, more tragic news, the loss of yet another dear friend and remarkable advocate.

In years not so long ago, when I was asked to explain what it meant to be a cancer research advocate, I welcomed the question. After all, I was being asked about my passion, what in many ways had become my raison d’etre. I could pinpoint with precision the very week when I stepped out of my role as a cancer patient and into that of a research advocate. After much difficult, fascinating, intellectually inspiring work, I was now sitting at the table as a partner with researchers, clinicians, and fellow advocates to drive the critical research questions that truly mattered to cancer patients themselves. I was an engaged, vocal participant at national cancer conferences, sometimes watching history being made as new treatment breakthroughs were being presented—and sharing deep disappointment with the oncologists, scientists, and advocates in the audience when novel agents that were followed with excitement ultimately failed to live up to their promise. And I was meeting highly passionate, intelligent, driven people from all parts of the country and, often, other nations, who were fellow cancer survivors and committed advocates, forming immediate deep friendships. It’s very difficult to describe how meaningful such friendships are. They involve an instant recognition of a kindred soul–one who knows first-hand just what you’ve been through from all aspects, including physically, emotionally, mentally, socially, spiritually, when cancer so rudely knocks at your door. These are folks who truly “get it,” to whom you immediately and without hesitation find yourself opening your heart and confiding the most private thoughts and concerns in a way you never could, nor wished to do so with your loved ones, in your reflex to protect them from your darkest thoughts and fears. Such friendships are life-changing, they are life-long, and they are one of the indescribable gifts that can give even the most difficult lives meaning. And yet. When your lifelong friend’s life ends far too soon—and due to the very reason that brought your life paths together when they otherwise never would have crossed—what then?

It’s now been more than 8 years since I’ve stepped into the role of an advocate. And with each year comes an increasing wave of devastating news. The terrible truth is that this should not have been unexpected for we who are cancer survivors and research advocates. For those of us affected by breast cancer, for example, we know that HER2+ and triple negative/basal-like breast cancer subtypes are associated with early relapse risk. And we know that ER+ tumors are associated with persistent late relapse risk beyond 5 years, with up to one-third of patients recurring potentially decades after active treatment. Yet every single time I learn that one of my advocate sisters or brothers has developed metastatic disease, I’m blindsided. And worse, when I receive the terrible news that a friend with stage IV cancer has passed, I still somehow allow myself to be blindsided yet again. After all, for my friends with metastatic breast cancer, I knew that they did not have curable disease. Each time, we prayed that their treatments would lead to “no evidence of disease” (NED) and that this would last indefinitely–or until additional, much more effective treatments became available. And for some friends with stage IV disease, they have remained with NED for several years. Others have sought new clinical trials after their cancer became resistant to their current treatment and were able to maintain stable disease for quite some time, sometimes for years—and if they became resistant to that agent, some were able to enroll on another clinical trial. And yet. There have been more of those times when, after seeing my friends year after year at the same conferences or grant review sessions, they suddenly were not there. Or they were, yet it was impossible to deny how frail they appeared, how very sick they were, that their cancer had become more adept at resisting treatment. And perhaps the most soul-shattering times were those when, after speaking with a friend who seemed to be doing extraordinarily well with her new treatment, we learned very shortly thereafter that she was no longer with us. Each and every time, I’ve been blindsided by their deaths; I’ve been lost, angry, completely unaccepting of their loss from this world.

When undergoing my active cancer treatment for Hodgkin’s and, later, for breast cancer, I often worried about my oncologists and the oncology nurses who spent so much time with us, who supported us at the scariest times of our lives, who provided comfort and strength not just to we as patients but to our families as well. Both of my oncologists and their oncology nurses essentially became honorary family members, as they did for so many others whom they treated day in and day out, year after year. How were they able to form such powerful, caring relationships, yet learn how to cope with their patients’ deaths, the deaths of far far too many patients? Fortunately, in more recent years, there has been increasing discussion and recognition about the impact of such repeated losses and the need for improved resources and support for oncology professionals. As noted in Cancer Therapy Advisor, “Everyone who enters the field of oncology knows that many of their patients will die, but foreknowledge is not protection against the cumulative effects of loss.” I would argue that the same is true for cancer research patient advocates, particularly for those of us who have been actively engaged for several years and are experiencing what has been described as “cumulative grief”–the compounding emotional, physical, and spiritual responses to repeated exposures to profound loss. Just weeks ago, upon learning of another friend’s death, I shared with a fellow breast cancer survivor that I was still reeling from the terrible news (and the awful news before that, and the devastating news before that)—and her response was direct, simple, and wise: “Deb, this is the hard part.”

That it is—and during this past year, the sheer weight of it was sometimes more than I thought I could bear. Yet it’s during those times that I try to remind myself: in addition to being advocates for cancer research, we’re here to advocate for one another, and the support we provide to our fellow advocates during these devastating times is crucial. Oncologists and oncology nurses have appropriately stressed the need for greater institutional and professional support to help them cope with their grief due to their patients’ deaths. It could be extraordinarily helpful if we, too, as dedicated cancer patient advocates, similarly received such supportive and educational resources through cancer organizations and professional societies on topics such as cumulative grief, end-of-life care, pain management, and palliative care. After all, as we know so well, knowledge is power and often provides the tools and the strength to transform even the most difficult, painful problems and emotions, including grief, into truly positive outcomes.

In addition, every time we experience these terrible losses, it serves as a stark, powerful reminder of why we became advocates in the first place. As cancer patients and advocates, we are the ones who bring a critical sense of urgency to identifying the cancer research questions that truly matter, that will have the most impact, that will ultimately lead to more cures. By working to support one another and to transform our grief into remembrance and renewed commitment to our advocacy efforts, perhaps that is the most appropriate, necessary, and powerful way to honor all of those we have lost.

“Grief starts to become indulgent, and it doesn’t serve anyone, and it’s painful. But if you transform it into remembrance, then you’re magnifying the person you lost and also giving something of that person to other people, so they can experience something of that person.”

~Patti Smith

A Postscript

It pains me to say that just 5 days after the new year, our cancer patient advocacy community has experienced yet another devastating loss.

Ellen Stovall was the Senior Health Policy Advisor at the National Coalition for Cancer Survivorship (NCCS) and a founding member of the Institute of Medicine (IOM)’s National Cancer Policy Board.  As I posted on Ellen’s wall on Facebook, she was a shining light to so many of us, and it is impossible to articulate the profound difference she has made for cancer survivors in this country. She spoke profoundly and powerfully on the need for further knowledge about the very serious late effects that can result from cancer treatment. Though I never had the honor of meeting Ellen face to face, I was and will always be inspired by her remarkable accomplishments in cancer survivorship advocacy.  As I’ve written about here in my blog, like Ellen, I was originally diagnosed with Hodgkin’s lymphoma, and I also went on to develop potentially life-threatening late effects of my treatment, including breast cancer and cardiac disease. It is absolutely devastating that Ellen passed away 2 days ago due to sudden cardiac complications secondary to her cancer treatments. Her passion and commitment touched so many lives, and her legacy will continue–a legacy of ensuring that cancer survivors are able to become true partners in their medical care and that shared decision-making with their medical team will help to prevent or mitigate such life-threatening late effects for many cancer patients. My first major focus as an advocate was the need for improved cancer treatments that minimized the development of serious acute and late effects while continuing to ensure optimal efficacy and positive patient outcomes. Going forward, my efforts in this critical area will be in tribute to Ellen, one of the true pioneers of the art and science of cancer survivorship.

Back in 2002, Ellen shared the following thoughts when speaking during a National Cancer Institute (NCI)/American Cancer Society Survivorship Symposium in Washington, DC, called “Cancer Survivorship: Resilience Across the Lifespan.” Fourteen years later, her words resonate just as deeply:

“So, my closing thoughts to you are, as you leave this room today to go back to the very, very important work of writing grants, reviewing grants, and helping people in your communities day to day deal with their personal journeys of survivorship, please know that the cancer advocacy community, represented by scores of organizations that were founded by and for cancer survivors, stands ready and eager to tell you our stories of survivorship with the belief that while grateful for the blessings of survivorship, for the increasing length of days, months, and years added because of new and improved therapies for cancer, that this diagnosis is filled with many punishing and adverse consequences as well as joy for living each day.

“The physician Victor Sidel once said that statistics are people with their tears wiped away. That is the way NCCS views cancer survivors, and on behalf of all of us at NCCS, thank you for your attention and for all you do for cancer survivorship.”

Thank you, Ellen, for all you have done for so many.  Rest in peace.

A Heart-Wrenching Meeting

Last month I was given a wonderful opportunity, receiving a Patient Advocate Scholarship from the Conquer Cancer Foundation to attend this year’s 50^th American Society of Clinical Oncology (ASCO) Annual Meeting.  As an independent advocate, I’m usually in the position of needing to cover my own expenses.  The result is that there are far too many important meetings I’d like to attend every year that I simply cannot, so I often have difficult choices to make.  It was for that reason that I hadn’t been able to attend ASCO’s Annual Meeting for a few years—so I was delighted to be on my way to Chicago to attend the sessions in person again, rather than following the news remotely.

ASCO 2014 Annual Meeting

The ASCO Annual Meeting is always a valuable conference and, for the oncologists who attend, it can be practice-changing.  When I first attended the ASCO Annual Meeting as a new advocate, it left a tremendous impression on me.  The sheer numbers of people streaming through the immense McCormick Conference Center, the different languages I heard all around me, the dozens of sessions occurring simultaneously, the camera crews interviewing oncologists about breaking news, and being right there in the audience, often with thousands of others, hearing long-awaited findings from critical clinical trials—all around, it was an invaluable experience for me as a survivor as well as a committed cancer research advocate.  But by far my most lasting impression resulted from my discussions with several fellow advocates who were also attending ASCO—some for the first time like myself and others who had been present every year for decades.  I had attended several breast-cancer-specific conferences by that time and had made many lasting friendships with breast cancer advocates.  But the ASCO meeting was the first time that I’d met a large number of advocates whose efforts focused on so many different types of cancer—pancreatic, lung, ovarian, and esophageal cancers, lymphomas, leukemias, and others.  And I found that of course, there were important differences in focus depending on the form of cancer: for example, the very real concerns about stigma impacting lung cancer patients, due to an unspoken feeling by some that they have somehow “caused themselves to have cancer by smoking”; the fact that there are smaller numbers of advocates and resources for pancreatic cancer, lung cancer, and other cancer types due to the unfortunate reality of poor survival rates and numbers of patients; and this names just a few.  BUT I was immediately struck by how much we all shared, having similar concerns, challenges, passions, and frustrations—and by how much we all could learn from and teach one another.  Thanks to that first ASCO meeting, I made friendships with many advocates that will last a lifetime, and we have all reached out to one another over the years since for advice, to share resources, to offer advocacy opportunities, to connect newly diagnosed patients with important support, and to collaborate on critical advocacy efforts.

And all that I just described held true for me during this year’s meeting: how gratifying it was to be surrounded by so many who are dedicating their lives to treating, preventing, and curing cancer; to see dear advocate friends again and to meet talented new advocates who are performing such crucial work; and to participate in and witness new collaborations and partnerships being formed between advocates, researchers, clinicians, and all stakeholders in the cancer landscape.

But …

Something happened during this year’s ASCO meeting that was quite literally heart-wrenching.  And it painfully brought into focus my changing perspective as a now older, perhaps more “hardened” advocate.

The moment occurred when I was sitting in the audience with hundreds of other people during a session entitled, “50 Years of Advances in Breast Cancer Treatment: What Have We Learned? Where Are We Going?”  And the fact is that in the last decade alone, we have made critical advances and learned so much about the biology of breast cancer, which in turn ultimately led to crucial new treatment approaches–perhaps most notably, trastuzumab (Herceptin®) for the targeted treatment of HER2+ breast cancers.  But as I listened to the speakers,  I found myself reflecting on how much we still do not know.  Are we just now only learning the right questions to ask?  What about the terrible reality of resistance that often develops to new agents, including targeted therapies–and of tumor dormancy for ER+ breast cancers that, in about one-third of patients, ultimately leads to a diagnosis of metastatic breast cancer often decades after a patient’s original diagnosis?  And what about what many call the incrementalism that impacts cancer research, where the investment of many years and millions of dollars, as well as the involvement of tens of thousands of cancer patients in clinical trials, may lead to a drug approval based on just weeks’ improvement in overall survival or on surrogate endpoints?  Most importantly, what about the fact that we do not yet have a cure for metastatic breast cancer?

Celebrating my 4th birthday with my first cousin (the cutie with the blond hair) and friends

To break my chain of thought, I glanced down at my cell phone, planning to quickly check my messages and then turn my full attention back to the speakers.  And that is the moment when I saw the message that broke my heart and turned everything around me grey.  My first cousin, my best friend when we were little, the one I worshipped, had just been diagnosed with metastatic HER2+ breast cancer.  As I sat in that conference room, and the speakers continued to talk about the crucial advancements made for breast cancer patients in the last 50 years, and the audience members all around me were taking notes, snapping pictures of the slides, talking about the presentation, or simply listening, I was angrily wiping tears from my face, thinking over and over to myself, “It’s not enough!  It’s nowhere near enough!  My cousin, my friends with mets, everyone with BC mets, they need a cure, and they need it NOW!”

These thoughts stayed with me during the remainder of the meeting, including when I was listening to what was perhaps the most reported session in the media—a session that made everything even greyer.  It was during this session that Dr. Martine Piccart-Gebhard reported the long-awaited results of a large, multicenter phase III study called the ALTTO trial, which randomized over 8,000 women with HER2+ breast cancer following surgery to either concurrent trastuzumab and lapatinib (Tykerb®), trastuzumab followed by lapatinib, or trastuzumab alone for one year.  The patients in the trial received anti-HER2 therapy either after completing all chemotherapy, concurrently with a non-anthracycline, platinum-based regimen, or concurrently with anthracycline followed by a taxane.  (A fourth arm of the trial, where lapatinib alone was compared to trastuzumab, was closed due to futility in 2011.)

Dr. Martine Piccart-Gebhart presenting the first ALTTO Trial Results

When Dr. Piccart-Gebhard presented these first results of the ALTTO trial during this meeting, she announced that the results disproved the hypothesis that dual anti-HER2 therapy with trastuzumab and lapatinib in the adjuvant (postsurgical) setting enhances clinical outcomes in patients with early-stage HER2+ breast cancer.  She reported that at four years, disease-free survival, the primary outcome of the trial, was 86% with trastuzumab alone, compared with 87% with trastuzumab followed by lapatinib (*P=.610, hazard ratio, 0.96) and with 88% with concurrent trastuzumab and lapatinib (P = .048; hazard ratio, 0.84).

Median overall survival rates were 94% with trastuzumab alone and 95% with both combination treatment arms.   Dr. Piccart-Gebhart also reported that lapatinib was associated with significant increases in diarrhea, skin rash, and liver events, stressing that this may explain why just 60% to 78% of patients in the lapatinib-receiving arms of the trial received at least 85% of the protocol’s specified dose.

In other words, the primary endpoint of disease-free survival was not statistically significant—i.e., no better with the combination of these two specific HER2-targeted agents when compared to trastuzumab alone—and furthermore, lapatinib was associated with more side effects. These results were a serious disappointment, and the expert commentary grimly emphasized the significance of the information gained from this trial.

*What is a P value and hazard ratio?

In most studies, a P value of less than .05 is selected to determine statistical significance, meaning that if the data show that the “null hypothesis” has less than a 5% chance of being correct, then it is wrong.  The null hypothesis is the hypothesis that an observed difference is due to chance alone and implies no effect or relationship between phenomena.  A hazard ratio is the measure of how frequently a specific event occurs in one group compared to how often it occurs in another group over time.  In cancer clinical trials, hazard ratios are frequently used to measure survival at a particular point of time in patients who have received a specific treatment compared to a control group who received another treatment or placebo.  A hazard ratio that equals 1 indicates that there is no difference in survival between the treatment and control groups, with a ratio of more or less than 1 meaning that survival was better in one of the groups.  Together, the P value is used to reject the null hypothesis that the hazard ratio equals 1—that is, that the treatment being studied is not beneficial.

Invited discussant Dr. George Sledge, Jr., former president of ASCO and chief of oncology and professor of medicine at Stanford University Medical Center, reminded the audience of the thrilling moment during the 2005 ASCO Annual Meeting, when the first results were announced for adjuvant treatment of early-stage HER2+ breast cancer with trastuzumab, the first anti-HER2 targeted therapy.  He described this as a “defining moment in our field,” where the associated 50% reduction in the annual risk of recurrence still “remains one of the great success stories.”  But “there was still real work to be done,” and he emphasized that such efforts involved evaluating biology-based approaches, explaining that the combination of trastuzumab with kinase inhibition “at the time appeared to be the best bet.”  (Kinases are enzymes that activate proteins by “signal transduction cascades,” when a molecule outside a cell activates a specific receptor either inside the cell or on its surface.  Activation of the receptor then triggers a cascade of events inside the cell, which may alter gene expression, the cell’s metabolism, or its ability to divide, for example.)  Lapatinib is an anti-HER2 agent that inhibits the intracellular tyrosine kinase domains of both the HER2 and HER1 receptors.   Because lapatinib inhibits two cell surface receptors and is a smaller molecule than trastuzumab, the hope was that it may prove to be more effective when combined with trastuzumab through the two agents’ different mechanisms of action, achieving dual HER2 blockade.

Dr. George Sledge Jr., former President of ASCO, Discussant for Plenary Session on the ALTTO Trial Results

This led to the development of the ALTTO trial, comparing use of trastuzumab alone against the combination of trastuzumab and lapatinib and, ultimately, the findings that there was no significant difference when lapatinib was added to treatment.  Dr. Sledge emphasized that the ALTTO trial required a strict P value of .025 or less to demonstrate statistical significance, and he stressed that no one should be misled by the disease-free survival P value of .048, thinking that this was a positive trial.  Rather, he firmly stated that “This is a negative trial.”  He then posed the important question of whether this trial might later turn statistically positive with further follow-up based on additional results.  His response: “Perhaps, but not very positive, given the results we’ve seen today.”

The negative results of the ALTTO trial were surprising due to the positive results of the earlier NeoALTTO trial, a study in which lapatinib and trastuzumab were compared with trastuzumab alone in the presurgical (neoadjuvant) setting.  Treatment with lapatinib, trastuzumab, and paclitaxel (Taxol®) was found to nearly double the pathologic complete response rate (pCR).  (Pathologic complete response, or no invasive or in situ residuals in the breast or lymph nodes, is proposed as a surrogate endpoint of tumor response that should be strongly correlated with more traditional endpoints such as overall survival and disease-free survival.)

These results are not only extremely disappointing based on lack of improvement with this specific combination therapy; rather, they also raise troubling questions on the approach to the development of new drugs for early breast cancer.   As Dr. Sledge noted, these negative findings “tell us at a simple level that we won’t be using lapatinib in the adjuvant setting,” since as discussed above, he predicts that further follow-up of the ALTTO trial results will not lead to a statistically significant positive result.   But he also stressed that these findings have produced several larger, critical questions: “You might be wondering why a negative adjuvant trial occupies a Plenary Session spot, a place usually reserved for practice-changing data.  I suggest that the answer requires us to rethink our approach to the development of new drugs for early breast cancer.  ALTTO represented a reasonable test of the hypothesis that improvements in pathologic complete response rates were associated with improved disease-free survival.  These hopes have now been dashed.”

Said another way, in recent years, many breast cancer researchers, clinicians, and advocates have become increasingly comfortable with the idea of conducting innovative, smaller neoadjuvant clinical trials, using pCR as a surrogate endpoint to predict outcomes  in the adjuvant setting.  Yet the negative results from the ALTTO trial, following the positive results from its sister neoadjuvant trial, NeoALTTO, serve to undermine confidence in the accuracy of predicting and translating treatment effectiveness and outcome from one clinical setting to another.  As Dr. Sledge noted, the ALTTO trial “invites a larger question” of whether agents that are found to be effective in the metastatic or neoadjuvant settings can be considered predictive of similar efficacy as adjuvant treatments.   “Why have these approaches failed in the adjuvant setting, despite a plethora of preclinical evidence and numerous positive trials in the metastatic setting that show an overall survival advantage?  These setbacks should prompt us to ask, are we facing a systemic crisis in the adjuvant failure of targeted therapies or just having a string of bad luck?”

ErbB family of receptors

Dr. Sledge went on to emphasize that results from another large adjuvant trial, called the APHINITY trial–which is also studying the efficacy of dual HER2 inhibition versus use of a single anti-HER2 agent–will be of great interest in light of ALTTO’s negative results.  APHINITY is a large Phase III randomized, double-blind, placebo-controlled trial that is comparing the efficacy and safety of chemotherapy, trastuzumab, and placebo against chemotherapy with trastuzumab and pertuzumab (Perjeta®) as adjuvant therapy in patients with HER2+ primary breast cancer.  Like trastuzumab, pertuzumab is a monoclonal antibody that targets the HER2 receptor, but it binds to a different part of the HER2 molecule and thus does not compete with trastuzumab.  Pertuzumab prevents the pairing (called “dimerization”) of HER2 with other HER (ErbB) receptors (HER1 [EGFR], HER3, and HER4), particularly the pairing of HER2/HER3, blocking the signaling pathways within the cell that lead to tumor growth.

 

And in fact, as I wrote in a previous blog posting, “All eyes will indeed be on the large adjuvant APHINITY trial …,” because last year, for the first time for any cancer, FDA approval was given to an oncologic agent—i.e., pertuzumab– in the neoadjuvant setting, based on pCR as a primary endpoint.  This was in no small part because of the ongoing, fully accrued APHINITY trial, whose results, if successful, could support conversion to regular FDA approval or, if negative, will even further emphasize the need to completely re-evaluate our current approach to drug development and clinical trials for agents to treat early breast cancer.

On this last point, when the Oncologic Drugs Advisory Committee (ODAC) voted on whether to support Accelerated Approval for pertuzumab in combination with trastuzumab and chemotherapy for neoadjuvant treatment of HER2+ breast cancer, many ODAC panel members (including myself as the patient representative on the panel) stressed a critical point: that if the results of the APHINITY trial were in fact negative, the sponsor, Genentech, should voluntarily remove pertuzumab for the neoadjuvant treatment of early-stage breast cancer.  As our committee chair, Dr. Mikkael Sekeres, emphasized to the FDA, “All eyes will be on the confirmatory APHINITY trial and on you to verify this initial signal of efficacy and to confirm the bandwidth of safety that we have seen so far.”

In light of the ALTTO findings, APHINITY’s long-awaited results will now carry even more impact, whether they are positive or negative.  In concluding his discussion, Dr. Sledge emphasized that trial failures such as ALTTO “must be elucidated in order to move forward and create new successes.”

At this writing my cousin has received two treatments thus far with chemotherapy, trastuzumab, and pertuzumab.  And in her husband’s words, per her oncologist’s first assessment of her response, “the couple centimeter lump of cancer on her neck” (which had resulted in her stage IV diagnosis) “has gone away.”  I pray daily that this means she is a strong responder to dual blockage with trastuzumab and pertuzumab.  I pray that some day she’ll hear the words that her stage IV breast cancer is now “NED,” meaning No Evidence of Disease. And I pray that in the words of Dr. Sledge, “ … Move forward, we shall, in HER2+ positive breast cancer” and that the many novel approaches actively being researched today will move us closer to the day when we have finally found a cure or cures for stage IV breast cancer–for my cousin, for my far too many friends with this disease, and for all those with stage IV disease.  Please pray with me.

Preserving Hope: Our Caregivers’ Journeys in the World of Cancer

Many folks might not understand this.  But I’ve lost track of how many times I’ve thanked God that I  and not one of my loved ones was the cancer patient.  After being diagnosed with lymphoma shortly after college, cancer shaped my life.  As I’ve said many times, being a cancer survivor has impacted every adult decision of my life: staying in a job that I disliked far too long due to fear of being without health insurance, my decision to become a medical writer, when to get married, and on and on.   But I’ve had to be matter-of-fact about this.  Cancer, its late effects, what seems like my bimonthly thyroid biopsies, the number of daily pills I’ll always have to take, my long list of specialists—it’s simply my reality.  But that’s okay.  Long ago, I subconsciously made this one of my roles: I took on the role of cancer patient, the one with the chronic health issues in my family, with the understanding—or perhaps more accurately stated, the magical thinking—that I gladly accept this role to protect any of my loved ones from EVER experiencing cancer, cardiac issues (another of my late effects), or any serious chronic health issue.  My message to myself was “I’ve got this.  I’ve got my family covered.”

My mother helped me to understand this at a more conscious level just last year, one which was  very difficult for my family.  I have two female first cousins, one on my mother’s side and one on my father’s side—and in one year, they both were diagnosed with stage 3 HER2+, ER+ breast cancer at the age of 49.  I was never angry about my own cancer diagnosis: the first time, my thought always was, “Well, why NOT me?,” and the second time I’d long understood that I had a greatly increased risk for breast cancer due to my radiation treatment as a young woman.  But when I learned that my first first-cousin had just been diagnosed, I was distraught and absolutely furious.  I literally screamed when I heard the news.  And when I learned a few months later that my second first-cousin had been diagnosed as well, my anger and distress were even blacker and deeper.  I couldn’t understand my reaction, and I pushed it down deep, because it was critical to me to be strong for my cousins and able to have my “advocate hat” firmly in place to provide all the possible information, resources, and support I could for them both.  But in talking with my mother one day, I shared with her how deeply furious I was that they were both going through this and how confused I was about feeling this way.   She said that she had the answer, asking “You don’t remember what you said to me, do you?”  Of course, I’m notorious among my family for not remembering anything (thank you, “chemobrain” parts 1 and 2), so we chuckled over that.  She then explained that shortly after my breast cancer diagnosis, she’d asked me why I wasn’t angry about being diagnosed now for a second time.  And she reminded me of my answer: “You said that as awful as it was, you knew you’d get through it, and you weren’t at all angry because, after all, that must mean that you had the family covered.”

And that’s true: I continue to pray every day that that’s IT—that cancer has learned now who’s boss and will not DARE touch another of my loved ones.  This may explain why I was so struck by something a fellow cancer survivor and advocate said during a panel discussion last year, where we were both participating as Patient Advocate Fellows during the Drug Information Association (DIA) annual meeting.  When my new friend and colleague, Deborah Cornwall, began her portion of our panel’s presentation, she explained that she was a breast cancer survivor, but that her own “brush with cancer was trivial” compared to the caregiver and patient stories she’d had the honor of hearing while working on her recent book, “Things I Wish I’d Known: Cancer Caregivers Speak Out.”  She explained that although there were so many books for the cancer patient, as there should be, there were very few for the cancer caregivers–for the spouses, the parents, the children, the siblings.  As Deborah discussed her book, its purpose, and the meaning that it had for her and the many caregivers she interviewed, I was deeply moved, thinking about just how important this book was—that in addition to the patients themselves, it’s just as critical that the loved ones who are caring for them receive the support they need and how cancer also turns their worlds upside down.

A few weeks following the conference, Deborah graciously agreed to an interview, during which I asked her about the genesis of her book, any critical overarching themes that arose while speaking with the caregivers, and the experience itself of speaking with so many people about what was often the most heartbreaking time of their lives.  Following is some of the conversation that Deborah and I had, including several quotes from Deborah and the caregivers themselves.

Cancer Caregivers Speak Out

“Why do people love firemen? People love firemen because when everyone else is running out of a burning building, they’re running in.  It’s easier to run away.  Caregivers are running into the burning building…”

~Chuck’s Mother

In the introduction of Deborah’s book, she shares the following, describing the beginning of the caregiver journey:

“Most caregivers describe their reactions to a loved one’s cancer diagnosis in violent terms: a fast-moving or violent physical assault, a punch in the stomach, a car hitting a deep pothole at high speed, a hijacking, an earthquake, a lightning strike, or a vicious animal bite.  A few mentioned a sensation of being frozen and unable to move, or feeling as though a rug had been pulled out from under them.

“If you have been suddenly thrust into the caregiver’s role, you may have experienced similar sensations when a loved one or close friend received the cancer diagnosis.  There’s so much information coming from all directions that you may feel overwhelmed, angry, or bewildered. ‘Normal’ has just disappeared from your life.  You may be fantasizing that you’ll wake up tomorrow and find out that this was all a bad dream.  You may even feel resentful: After all, you didn’t sign up to set your own life aside to become a caregiver.

“Your emotions are real, and confronting them is the first step in coming to grips with your caregiver role.  You’re probably wondering how this unexpected journey will go, and how it will end.  You may be looking for support, guidance, or help—perhaps for the first time in your life—at the same time that you’re uncertain where to look, or even what to ask for.

“That’s another reason why I’ve written this book.”

“In reading about the key issues you’re likely to face and what others did when encountering similar situations, you’ll have the opportunity to learn from their approaches and use them in creating your own solutions to your unique caregiving challenges.  While this book won’t serve as a complete ‘how-to’ guide or steer you to every resource you might need—caregiving often requires invention under pressure—it will provide guidance and build your confidence in inventing your own way.

“I was honored that the people I interviewed chose to share their stories and life lessons.  Their candor and intimacy were unexpected gifts that enriched my life immeasurably and made this book a reality.  In turn, I share their reflections with you in the belief that they will help you on your journey.  Their hard-earned insights, their indomitable hope, and their desire to help others to stay focused in the face of adversity represent their way of giving something back to those who helped them.”

~Deborah Cornwall, Marshfield, Massachusetts, 2012

~~~~~~~~~~~~~

Our interview began with Deborah’s sharing how “Things I Wish I’d Known” came to be:

“Writing a book of some sort actually came from my aunt, who is 95 years old now.  So she was about 91 when the idea came up.  I was talking with her about various experiences that I had had at Hope Lodge, [which provides] free lodging for cancer patients and their caregivers who come in from more than 30 miles away for regular care for cancer treatment…I had been involved on the American Cancer Society Board of Directors in New England when we decided to build the [Hope Lodge in] Boston.  I kind of adopted it personally.  My husband and I would go there periodically to serve holiday meals, because our daughter lives elsewhere and can’t always be with us.  While there, I would always meet people whose stories were just amazing and far more dramatic than my own.  Afterward, I would share them with my elderly aunt on the telephone.  Then one day, she said, “You have got to write a book” … I kind of pooh-poohed it, because your relatives always believe you can do anything.  But a few weeks later, after the idea had had time to germinate,  I realized she was right.”

In thinking about the shape that the book would take, Deborah realized that there were few books that specifically focused on the stories of the cancer caregivers, how they coped, what resources were most helpful to them, and, upon reflection, what they wished they had known beforehand but learned only in the midst of their experiences as a caregiver.  So that is the book that she wanted to create.  Deborah noted, “That’s when I charged off on my own and said, ‘Okay, I need to find people who are willing to talk to me.’  She explained that with HIPAA (the Health Insurance Portability and Accountability Act) privacy regulations, “that’s a bit tricky.  So I needed to spread information out in the right places and let people know how to contact me if they were interested in talking about their experiences.”

Deborah stressed that the sourcing of interviewees was itself a fascinating process.  “I think the most interesting piece of it was that in addition to posting invitations at several of the Hope Lodges, I would also send out waves of emails to groups of my own contacts,  asking them to spread the word.  I got a phone call one day from a woman who had received my email, which I’d sent to someone out of state, who forwarded it to somebody else in another state, who in turn forwarded it to the woman who called me.  It turned out that on the third forwarding, it went to [this woman] who lives five minutes from my house!  Isn’t that bizarre?  So there are all sorts of fascinating procurement stories in terms of finding these people.”  Deborah went on to share another example of such serendipitous connections: “I received a phone call from a woman who had just lost her husband.  [She’d been] in a park walking with her daughter and newborn son, and a friend of mine happened to be passing through that city when they met and created the connection.  This woman has sustained our relationship and become a good friend. There were all sorts of really random types of connections, but essentially, when I got to 86—and there was nothing magic in the number–I thought to myself that I’m hearing the same things frequently enough that I believe I have enough to work on.  So that was the genesis.” In the second edition of the book, Deborah added another nine conversations focused on healing, bringing the total to 95.

Deborah emphasized how moved she was that so many caregivers were willing to speak with her for her book.  “I was stunned at how eager people were to talk and how much they wanted to share with me, usually as a complete stranger.  Two-thirds to three-quarters of the caregivers were complete strangers with not even a personal referral connection, not even a mutual friend . It was really stunning to me how eager they were to pour out their most intimate life stories.  And what it said to me once I got going was just how important they thought the book could be.”  She also noted that during their caregiving experiences, “some of these caregivers were deserted by people they thought they were close to.  So I think that in some ways, that made them want to talk about it more, because family members or friends didn’t know what to say and didn’t know how to have a conversation about what the caregivers were going through.  In a way, to talk to a stranger who really wanted to know what happened was nourishing to them.  After one particularly moving conversation, one interviewee said he felt better because it felt as though he’d just been to therapy.  It had presented the opportunity to voice things that he’d kept inside since his wife had died. I think that the interviews did allow people to get in touch with how they had really navigated the experience when maybe they really hadn’t had the opportunity to reflect on it before.”

In fact, folks were so open to speaking with Deborah about their caregiving experiences that her first interview for the book occurred even before she thought she was prepared.  “My first interview was with a woman I’d known for years who was on the staff of the American Cancer Society.  Just before a scheduled meeting started, I [mentioned] to her that I was writing a book on caregivers. Her immediate response was, ‘Oh, I’m a caregiver.  Talk with me!  I have time right after the meeting is over.’   My first thought was, ‘So soon? I haven’t even finished the interview guide yet!,’ but I did it.  Her story was a rich one. She had been the primary caregiver for her father, who was dying of cancer, and at the same time for her mother, who was having a nervous breakdown. My friend was a single mother of two young children, she had two siblings who were uninvolved, and she was trying to work at the same time.  At one point, I asked her, ‘Where were your siblings?  Did they ever ask how you were doing during this whole process?’  It took her several minutes to respond. Then she looked at me with these wide deer-in-the-headlight eyes, and all of a sudden, tears started rolling down her face.  That’s when I realized that I was on to something really important.”

Deborah shared that when she completed and submitted the initial draft to her professional editor, his feedback was positive, yet she was taken aback when he stressed that, ‘It’s only twice as long as it can afford to be to get read.’  She stressed that pruning down the stories she shared was an extremely emotional process for her, because “I feel like I still carry their stories with me all the time.  They shared so much of themselves that I really felt that I owed them to tell their stories.”

Overarching Themes Expressed by Caregivers

When I asked Deborah whether any themes emerged when speaking with family caregivers, she noted that there were several:

“Yes, the first was control, a theme that really permeated every conversation:  the feeling of loss of control.  As you grow up, you develop a profession, you buy a house, you get married, and somehow you start believing that you actually have some control over your life.  Then, all of a sudden, when you’re told that you or a loved one has cancer, that sense of control is gone.  That theme was particularly significant for some of the male caregivers.  I had a couple of them who described themselves as control freaks who had to learn to let go of the fiction that they had any control.

“The second theme was the need to somehow preserve hope and, even for those who were told that they were in very dire straits, to see their situation in a more positive light.  When one was told that x percentage of people only survive a certain period of time, she and her husband said, ‘Fine:  we’ll be in the other percent.’  Even if it was a mind game, these caregivers found some way to create some hope in the situation, but also to make sure that today was a joyful day, that there was something today that I could do to help the person not just get through the day, but really enjoy the day.  And for many of them, that was hard.  But you know, there were several stories of people dying at home, where even the death experience was turned into something that would feel positive and in their control, as opposed to being in a hospital, where you couldn’t control who was coming in and giving you shots and doing all sorts of things.

“The third theme was isolation–the feeling that so many of the caregivers had of being cut off from the people they used to see often. I called those people ‘pull-aways,’ the friends who didn’t know what to say or do, and so didn’t talk about it or didn’t make contact as they might have back before the cancer diagnosis.  And there were some situations where the patient was too sick to go out, and so the caregiver’s solution for overcoming isolation was to invite friends in, but to be very clear about when it was time for them to go.  The caregiving experience changed caregivers’ social patterns, but they really felt its absence unless they invented new ways to interact with friends.

“[Another important] piece was normalcy.  People wanted so badly to get back to normal, and yet there was never going to be a normal again. Maybe a new normal would evolve, but life would never go back to the pre-cancer world.”

Deborah also noted that when reflecting on their experiences as caregivers, “All noted that their caregiving had enriched their lives.  It really did.  And I was really surprised when I asked them, ‘How are you different?’ I just didn’t know what I was going to hear.  It was encouraging and also really striking how many of them engaged in an activity that will in some way give meaning to their caregiving experience, particularly if their loved one died.  Even though this matched my own experience, I didn’t realize just how widespread that giving-back phenomenon would be.  Sometimes it’s focused on a specific type of cancer, such as leukemia or lymphoma.  Sometimes people actually created a new foundation, like two caregiving families living next door to one another who together created a brain tumor organization to benefit a local hospital, for example.  It’s fascinating to hear the creativity people use in determining how to get involved and how they want their loved one either to be honored or remembered.”

I asked Deborah if hearing such emotionally trying, heartfelt stories was ever difficult for her both as an interviewer and as a cancer survivor herself.  She agreed that it was:  “A couple of times, I did break up on the phone, and I apologized.  But I found it didn’t matter to the interviewee.  In fact, it revealed that I cared.  I always felt self-conscious about it, but it turned out to be okay.  To have them talking about the last minutes of somebody’s life and to be able to do so in such a loving and really clear descriptive way, it was hard to imagine putting myself in their shoes and being able to have gone through what they experienced with as much grace.  They really all gave a tremendous gift to me and to anyone who reads the book, because of the raw emotions that they shared.  Equally riveting were their descriptions of their lives afterwards and how they have healed.  I’ve actually written an article about healing and added some of these insights into the second edition of the book, because I think it’s really helpful to those who are still going through the process.”

Starting the Healing Before the Caregiving is Over 

“One of the important things I learned was that people who do it well start the healing process before the caregiving is over,” Deborah stressed.  “And in fact, in some cases, the patient actually helps start that process.  One young man whose mother died described one of her last days, [when she gave] him instructions about how she wanted to be buried.  She asked him to make sure that she was wearing nothing but her full-length mink coat and red high heels!  And that’s what he did.  He can still laugh now when he talks about it, because it was such a funny funny request and reflected so much about her personality.  The other thing she had done that was so fascinating: as an experienced oncology nurse, she surrounded him with many of her nurse friends, so that if he ever had any questions as she was going through treatment, he had this network that could be a safety net for him.  There were several examples of patients who had done something like that.  It turned out to be really important to each caregiver’s healing later.”

The Keys

I couldn’t let Deborah go without asking her about the cover design for her book.  As shown below, the cover displays three large, antique keys that immediately grab the eye.  She explained that “I’d looked at several alternatives, [but] this was the one that struck me.  I think that the keys have meaning in the sense that … it’s almost like there are trap doors throughout the caregiving process.  And knowing what door to open and which key to use, it was almost an analogy of finding answers–‘What’s behind this door? What’s behind that door?’ There are hidden things that you need to find out behind each door.  The key design was really the message of the book and the best way to show it.  Somehow it spoke to me.”

Messages from the Caregivers

What better way to conclude than sharing the words of some of the caregivers from “Things I Wish I’d Known: Cancer Caregivers Speak Out”?

“Professional caregivers don’t experience the emotional ups and downs that a family caregiver does.  The family caregiver truly bears the brunt to support the patient in the right ways, not too much or too little.  It’s critical for the patient’s progress.”

~Ellen M, registered nurse and cancer survivor, sharing her perspective on the role of her husband as  caregiver

“Caregivers have a difficult emotional time.  They don’t face the daily adrenaline surge that the patient does, but they have to pick up the pieces when things aren’t going well.  It’s hard for them to know when to reach in and when not to.  They walk a tightrope between letting the patient be in control and being able to take care of them without letting their loved one feel incapacitated.  Caregivers haven’t experienced the physical pain, but they also can’t make it go away.  The caregiver has to be strong, but not overpowering; sympathetic and optimistic, but not saccharine; realistic but not discouraging; upbeat but not inappropriately happy.”

~ Bobbi, long-time breast cancer survivor, articulating the challenge of caregiving

“There’s no better way to learn about dealing with cancer as a caregiver than hearing other people’s stories.”

~ Debbie B’s husband

~~~~~~~~~~~~~~~~~~~

The Book

Interested readers can locate Deborah’s book in paperback or electronic forms at the following websites:

“Things I Wish I’d Known: Cancer Caregivers Speak Out”

Amazon.com

Barnes & Noble

A Historic Moment: First Pre-Surgical Drug Approved for High-Risk Breast Cancer

As far too many of us know, a diagnosis of breast cancer is shattering, frightening, overwhelming … a maelstrom of one emotion after another.   And while trying to come to terms with this life-altering diagnosis, many of us have found that we’re confronting a new language where pathologic terms and molecular subclasses, the biology and behavior of our breast cancer, are driving our treatment options, our choices, our prognoses.

Shortly before I learned that I had breast cancer in 2007, patients diagnosed with what is known as HER2+ breast cancer were told that their cancers were very aggressive and that their prognoses were poor.  Normally, the protein known as “HER2,” a receptor on breast cells, helps to control breast cell growth, division, and repair.  But in those with HER2+ breast cancer, more than the two copies of the HER2 gene may be present, leading to overproduction of the receptors on the cell’s surface, HER2+ overexpression, and uncontrolled breast cell division and growth.  The day that I finally gained the courage to read my pathology report after my surgery, I was aware of this–that HER2+ breast cancers were considered more aggressive, tended to grow and spread more rapidly, and were less responsive to certain therapies when compared to other breast cancer subtypes.   And though I already knew that my tumor was found to be estrogen-receptor positive (ER+), I didn’t yet know my HER2/neu status.  Either that conversation with my surgeons had taken place during the drug-induced haze immediately following my surgery, or it hadn’t happened yet.

As I turned the pages of my pathology report, I registered that the estrogen receptors were 62%–and that a higher percentage would have been considered “better,” but that this was still considered “good” prognostically.  When I saw 0% for progesterone receptors, I recognized that that actually wasn’t so “good”:  after all, it was labeled right there on the report as of “unfavorable prognostic significance.”  But it was the next line that I was most nervous about:  and there it was, my HER2/neu status … and it was “Negative.”

When I saw this, I did feel something akin to relief—though as I learned not long after, there is nothing clear-cut about breast cancer.  On that January afternoon in 2007, should my tumor’s HER2 status have been positive, I actually would have been in a much better position than women diagnosed just a few short years before my own diagnosis.  The fact was that recent advances had offered a critical new treatment option for patients with HER2+ breast cancer.  Just 2 months before, in November of 2006, trastuzumab (Herceptin®), a targeted biologic therapy, had been approved in the postsurgical (adjuvant) setting for early-stage HER2+ breast cancer (BC).   I was correct in my understanding that HER2+ disease is a particularly aggressive form of BC—and that because of the aggressiveness of breast cancers that overexpress the HER2 protein, patients with HER2+ disease have an increased risk of recurrence and decreased survival compared to those with HER2-negative disease.   But the development and approval of trastuzumab was truly a dramatic breakthrough for the treatment of HER2+ BC, both in reducing recurrence risk for those with early disease and increasing overall survival for patients with metastatic disease.  In fact, when the combined results of the adjuvant BC trials were presented during the American Society of Clinical Oncology (ASCO)’s 2005 Annual Meeting, the audience greeted the news with thunderous applause and a prolonged standing ovation.

Those who jumped to their feet when hearing the news about trastuzumab recognized this targeted therapy for the critical breakthrough that it was, one that has since changed the natural history of early HER2+ BC.  And yet …

Though trastuzumab and other targeted therapies since approved for breast cancer–and other cancers– have led to remarkable improvements in response to treatment and survival for some, resistance to targeted treatment, both intrinsic and acquired, has limited efficacy for others and is now a clear, sobering reality.   The upsetting truth: studies have also reported that depending on tumor characteristics and stage, 17 to 40% of patients treated with trastuzumab regiments for early-stage HER2+ BC go on to develop recurrences within 5 years.   Said another way, despite the fact that trastuzumab heralded a new era in the treatment of HER2+ BC, there remains a critical unmet medical need for preventing recurrence after treatment for early-stage HER2+ disease—and for preventing the approximately 6,000 to 8,000 deaths due to HER2+ metastatic disease every year in this country.  Accordingly, there also remains a need to expedite the development, study, and approval of safe, highly effective therapies for patients with high-risk early breast cancer.  And it is for this reason that the FDA released a draft guideline in May 2012 outlining an Accelerated Approval pathway for presurgical (neoadjuvant) treatments in breast cancer.

But why then the title above, “A Historic Moment”?  Last month, on Thursday, September 12^th , the FDA convened its Oncologic Drugs Advisory Committee (ODAC), asking ODAC for the first time to consider Accelerated Approval for an oncologic agent in the neoadjuvant setting, based on a primary endpoint known as “pathologic complete response” (pCR).”  Pathologic complete response is proposed as a “surrogate endpoint” of tumor response that should be strongly correlated with more traditional endpoints, such as disease-free survival or overall survival.  In other words, if approved, this would be the first neoadjuvant regimen formally approved by the FDA for any type of cancer.

During this September 12^th ODAC Panel, I had the privilege of serving as the Patient Representative as a temporary full voting member.  The question before the committee specifically concerned Accelerated Approval of the anti-HER2 therapy pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and docetaxel (Taxotere) for patients with HER2+ breast cancer in the neoadjuvant setting.   Like trastuzumab, pertuzumab is a monoclonal antibody that targets the HER2 receptor, yet it binds to a different part of the HER2 molecule and therefore does not compete with trastuzumab.   Pertuzumab prevents the pairing (called “dimerization”) of HER2 with other HER receptors (HER1, HER3, and HER4), serving to block the signaling pathways within the cell that lead to tumor growth.  When pertuzumab is combined with trastuzumab, it therefore provides a “dual” or more complete blockage of the HER pathway.

Approving an oncologic agent as a neoadjuvant therapy in early-stage disease would be historic since traditionally, new breast cancer drugs have first been approved in the setting of metastatic disease. Typically, approval for the treatment of early-stage BC then follows several years later based on the results of very large randomized postsurgical (adjuvant) trials with thousands of patients and prolonged follow-up.   If successful, neoadjuvant trials may therefore enable more rapid assessment of drug efficacy and expedite the approval of treatments for early breast cancer.

During this ODAC panel, the comprehensive discussion focused on several critical topics, including:

* the remaining unmet medical need for high-risk early HER2+ breast cancer and the far too many patients who have their cancer return as metastatic disease

* considerations regarding the use of pathologic complete response (pCR) as a primary endpoint in the neoadjuvant setting

* potential long-term toxicities associated with the neoadjuvant use of pertuzumab

* the need for very clear labeling to provide clear guidelines on proper patient selection (due to some data suggesting increased risk of cardiotoxicity) and the safest, most effective use of pertuzumab

*  the unique circumstances concerning pertuzumab, including its earlier approval as a first-line treatment for metastatic HER2+ BC based on statistically significant improvement in overall survival and its well-studied mechanism of action with the HER2 pathway and safety signals

* the need to consider the totality of the evidence concerning this agent

* the ongoing, now fully accrued APHINITY Phase III adjuvant trial that, if successful, could support conversion of accelerated approval to regular approval

On this last topic, many ODAC panel members stressed a critical point to the sponsor:  that if the results of the APHINITY adjuvant trial are in fact negative, Genentech should voluntarily remove the drug for the neoadjuvant treatment of early-stage breast cancer

During the public hearing portion of the session, many members of the public, including advocates, breast cancer survivors, and nonprofit advocacy organization leadership eloquently stressed the need for earlier, evidence-based treatment options and for treatments that may potentially prevent early high-risk HER2+ BC from later recurring, while also expressing the need for caution, urging Genentech to establish registries to follow those who receive pertuzumab specifically in the neoadjuvant setting for potential late toxicities.

Our panel ultimately voted 13-0 with one abstention in support of pertuzumab in combination with trastuzumab and doxetaxel for patients with HER2+ BC in the neoadjuvant setting.   And just a few weeks later, on September 30^th, the FDA went on to approve pertuzumab in this setting, indeed making it the first FDA-approved pre-surgical breast cancer drug.

As stated by Dr. Mikkael Sekeres, ODAC Committee Chair, “This is a historic moment as we have voted to support the first approval of a drug for the neoadjuvant treatment of breast cancer: pertuzumab.  In doing so, we are supporting the rapid movement of a highly active drug for metastatic breast cancer to the first-line setting, with the hope that women with earlier stages of breast cancer will live longer and better.  We do this with some words of advice to Genentech.  All eyes will be on the confirmatory APHINITY trial and on you to verify this initial signal of efficacy and to confirm the bandwidth of safety that we have seen so far.  If these are not confirmed we urge you to avoid a repeat performance of Avastin and voluntarily remove this drug from the market.”

Upon announcing the approval of pertuzumab, Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in an FDA statement, “We are seeing a significant shift in the treatment paradigm for early stage breast cancer.  By making effective therapies available to high-risk patients in the earliest disease setting, we may delay or prevent cancer recurrences.’’

All eyes will indeed be on the large adjuvant APHINITY trial, with the hope that this was ultimately a critical first step in truly expediting the approval and availability of safe, highly effective treatments for patients with high-risk early BC and in significantly decreasing the risk of developing metastatic disease.

For patients with HER2+ breast cancer, whether newly diagnosed or long-term survivors, the HER2 Support Group provides information, resources, and support at http://her2support.org/.

The FDA’s Meeting Materials for the September 12, 2013 Meeting of the Oncologic Drugs Advisory Committee (ODAC) are available on the FDA’s website at http://tinyurl.com/bdsgot2

In addition, if you are interested in learning more about the FDA’s Patient Representative Program, visit http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/patientinvolvement/ucm123858.htm.

Please note: The views expressed on these pages are mine alone and do not represent those of any other party.