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 and Laura

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)

Ob-La-Di, Ob-La-Da

 

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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 50th 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

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

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

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

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

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.

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.

HER2+ breast cancer, Perjeta Patient Information, Genentech

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 12th , 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 12th 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.

ODAC meeting at White Oak Campus

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 30th, the FDA went on to approve pertuzumab in this setting, indeed making it the first FDA-approved pre-surgical breast cancer drug.

Perjeta (pertuzumab)

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.