Life Number Two

Life Number Two
When I stepped outside that morning, everything was gray. I plugged in my doctor's number and waited to hear her voice on the other end of the line.

You'd be hard pressed to find anyone not able to remember, in chilling detail, where they were and how they felt when they first heard the words: you have cancer.

For Samantha Mergen, the gray rainy day when she stepped outside her office to take the call from her doctor will always represent a turning point. As she went on to describe in the blog she posted about that defining day back in October 2013, she felt "shocked, shaken." This wasn't supposed to happen to her, a healthy 27-year-old woman with no family history, and only a week away from her first wedding anniversary. Rudely and unexpectedly, breast cancer entered her life.

For Mona Melms, the same verdict was delivered by her doctor 25 years ago, but in person. "I remember waking up in the OR from my biopsy—it was only a few days before that I first found the lump in my breast—and he told me how sorry he was…"

Like Samantha, Mona was unusually young for such a harsh diagnosis. Only 33 years old, and the mother of two young daughters, she felt it was a death sentence. Her doctor was grim. Her family began to mourn.

Mona and Samantha. Twenty-five years span the gap between these two women and their experiences with breast cancer. One had a poor prognosis and limited options for treatment involving toxic levels of drugs which nearly killed her. The other, a methodical plan of attack that provided her hope and a sense of confidence about her chances of survival. Two women—who happen to be friends—represent an inspiring story that illustrates the difference between what was then and what is now.

Unraveling the Biology of Breast Cancer

Twenty five years ago cancer clinicians and research scientists had a limited understanding about breast tumor cells. Survivability rates were discouraging, and medical oncologists often had little choice but to treat breast cancer patients with a "one size fits all" approach.

At the time of Mona's diagnosis, a solid body of research had already established that reproductive hormones such as estrogen play a role in breast cancer growth. The estrogen receptor (ER), a protein that resides on some tumor cells, mediates the signal sent by the hormone estrogen, communicating the dangerous message to grow uncontrollably. This critical understanding led to a successful effort to develop drugs targeting the ER as a means of halting tumor growth.

Yet Mona's biopsy revealed that her cancer was ER-negative, and few treatments were available to her. Her oncologists urged her to consider a clinical trial involving a combination of three experimental chemotherapy drugs. To her relief she was deemed eligible to enroll. The bad news? The trial entailed a regimen described as quadruple toxicity.

Still, it was a no-brainer for Mona. "My doctor told me that he hoped the trial might buy me another year's time, eighteen months if I was really lucky."

The discovery of other hormone receptors linked to breast tumor development proved to be a valuable leap forward. The identification of the progesterone receptor (PR), which responds to the hormone progesterone, elevated the role of both ER and PR as important clinical biomarkers. Recent statistics from the American Cancer Society report that about 80 percent of all breast cancers are ER-positive; nearly 65 percent of these are also PR-positive. Their presence or absence allows physicians to differentiate between specific types of tumors.

With the realization that hormone receptors are so prevalent in breast cancer, clinicians needed to know if they could serve as predictive markers in determining the best treatment options. Randomized, controlled clinical trials involving hundreds of thousands of patients around the world have helped to answer such questions. The results of these studies have revealed vital knowledge about whether a certain drug—tamoxifen for example—or a combination of drugs is effective in shrinking hormone-responsive tumors.

The detection of even more breast cancer markers, most notably HER2 (for human epidermal growth factor receptor), has characterized the advances in breast cancer research in recent years. Nearly 25 percent of breast cancers test positive for HER2, inspiring scientists to develop drugs such as Herceptin® designed to target cells harboring the molecule. Herceptin also represents a new class of breast cancer therapy, or immune-targeted therapy, as not only does it bind to HER2 effectively blocking those cells from receiving signals to grow and multiply, it also alerts the immune system to destroy those cells to which the drug has attached.

Breast Cancer Subtypes

Today, women diagnosed with breast cancer often begin their journey with a biopsy report stating the presence or absence of these three main breast cancer biomarkers, ER, PR and HER2. In cancer lingo, a patient is "triple positive" if positive for all three, or "triple negative" if negative for all three markers. The alphabet of letters that label an individual's breast cancer at the time of diagnosis becomes critical to what lies ahead. A patient's treatment regimen is often formulated on this information, with the cancer cell type, grade and stage factored in as well.

Tailoring Treatments for More Effective Results

Only a few years ago Samantha underwent a biopsy after finding a lump in her breast. Her biopsy revealed that her tumor was positive for ER and PR, but negative for HER2. Dr. Amye Tevaarwerk, the University of Wisconsin Carbone Cancer Center oncologist who treated Samantha, explains that this information provided a clear direction as to what needed to be done.

"Knowing that Samantha had ER positive, HER2 negative breast cancer, we tailored her treatments for exactly that," says Tevaarwerk. "Without those kinds of details about Mona's cancer, there was no opportunity for Mona to receive treatments tailored to her disease."

Samantha’s surgery, scheduled just a few weeks after her biopsy confirmed she had cancer, revealed new and unexpected information that influenced her treatment plan.

"I underwent a unilateral mastectomy of my left breast with sentinel node dissection, and at that time the surgeon discovered the cancer had spread to my lymph nodes. It was the last thing we expected to hear," recalls Samantha. "Because the cancer had spread, the decision was made to proceed with chemotherapy followed by radiation."

Again, her team of physicians knew precisely what needed to be done and immediately outlined the plan of attack. They also had the foresight to recommend Samantha undergo egg retrieval for in vitro fertilization knowing that she and her husband had dreams of eventually having a family. Options were abundant, and every step of the way Samantha was reassured that her disease was beatable.

There's no doubt that over time, as researchers get a better grasp of how breast tumor cells grow, move and react to therapies, more effective treatment options become available. "Patients are doing better," says Tevaarwerk. "We're making progress by targeting therapies more specifically for a patient's particular cancer."

Another significant difference between then and now is the measure of finesse that characterizes a patient's treatment. "Now we try harder to 'peel back' treatments. Patients who don't need as much—we give less, and for those who need more, we do our best to offer clinical trials to step up efforts," Tevaarwerk explains. "These are among the reasons why it is so important for patients to consider participating in clinical trials—so that we can get better at what we do even faster!"

We've tended to over-treat cancer in the past, and we want to change this. Most efforts now are focused on who needs what. Amye Tevaarwerk, MD
Amye Tevaarwerk

The movement to dial back chemotherapy when possible, without sacrificing its benefits, probably resonates best with those who have been personally touched by the experience. Chemotherapy cures because it kills by seeking out cancerous cells and destroying them, and it is no secret that chemo remains a difficult and debilitating way to fight cancer.

Chemotherapy is especially critical for keeping metastatic cells at bay. Metastatic cells are cancer cells that escape the margins of the original tumor and migrate throughout the body seeding new and destructive tumors. The majority of breast cancer deaths today are attributed to metastasis.

Metastasis

As many cancer patients can tell you, chemotherapy often feels worse than the disease it's intended to fight. But pharmaceutical research has paid off in the past several decades so that the effects of administering such powerful chemicals into a patient's bloodstream are now less detrimental and more bearable.

"I remember my weekly trips to Madison General Hospital every Monday for sixteen consecutive weeks," recalls Mona. "With each treatment I'd get a 'happy pill' which was essentially an anti-psychotic drug that sedated and helped me to get through the infusion. It was all that the doctors really had in their toolbox at that time."

At the end of each treatment Mona was wheeled out in a wheelchair and sent home where she would be "out of it for the next couple of days." She also recounts several trips to the emergency room during her chemotherapy period when she'd become so ill from the toxic side effects she needed emergency medical care.

Samantha's Treatment

Samantha's ordeal also lasted four months, but her regimen required an infusion every other week, giving her a longer time to recover between treatments and half the number of total treatments. She also benefitted from the arsenal of auxiliary medications now available to ease the very worst of chemo's notorious side effects. No more "happy pills" to knock her out during an infusion, she instead spent those hours surrounded by family and friends who did their best to keep her spirits up and her body comfortable.

That being said, her experience was far from enjoyable. "I managed to go to work on Fridays, the day after my Thursday infusions, but I needed to spend my weekends in bed," she laughs.

Treating Cancer on a Personal Level

A solid body of scientific and clinical research advances characterizes the span of time between Mona and Samantha's breast cancer diagnoses; the differences in their respective experiences are proof that the field of oncology has come far. But what about the next 25 years? What kind of hope in the form of research breakthroughs are on the horizon?

Dr. Mark Burkard of the University of Wisconsin Carbone Cancer Center is a researcher and clinician at the forefront of what's yet to come. "Looking forward, there is optimism for the future," says Burkard. "A continuation of current trends will lead us to recognize even more types of breast cancer, and there really are so many diverse types of breast cancer that each need to be treated in unique ways."

The challenge however is in how to treat so many different kinds of breast cancer at a personalized level. "Clinical trials designed to address the new information we're uncovering, while helpful, are not always so specific in the answers they provide."

What excites Burkard is the potential of achieving this goal through the power of molecular genomics. Pushing beyond what lies on the surface of a breast tumor cell and going deeper into a cell—into the nucleus and the tight tangle of DNA it houses—to identify specific genes that may be contributing to a cancer. As more gene mutations linked to cancer are identified and cataloged, the role those genes play in causing cancer can be elucidated. And then, clinicians hope to use that information to develop more powerful treatments and design treatment plans to specifically target the molecular processes that have gone awry in cancer cells. This approach is what lies at the heart of personalized medicine.

In Burkard's research lab, the focus is on how to best customize chemotherapy to address individual breast tumors. His ultimate goal is to be able to offer every breast cancer patient a more customized treatment to increase the likelihood of eradicating their cancer. Given that chemotherapy drugs, as he states, really work on only one-third to one-half of patients, he sees tremendous room for improvement. And in his mind, the big question is: Why does a tumor often NOT respond?

"For so many years the standard treatment has been to mix a combination of chemo drugs in the hopes that some version of the mix will be effective," says Burkard. "I want to discover and identify unique characteristics of each person's cancer to tailor chemo to them. If two of the three drugs they are given are not going to work, then let's give only the one drug that will work." This strategy is not unlike the first wave of customized treatments described by his colleague Dr. Tevaarwerk where chemotherapeutic agents are chosen to some extent for patients based on the receptors present on the surface of their tumor cells.

Now research scientists are trying to explore what is happening inside tumor cells at the level of specific protein and genes. How do they even begin to find answers?

The key, explains Burkard, is to gather information not only about a patient's genetic makeup, but also about how and if a particular drug works in that individual's tumor cells. His experimental methods involve obtaining patient biopsies after an initial round of chemotherapy to test for the drug's activity. He then asks and answers the questions—is the drug actually getting into the tumor, and if so, how is the tumor responding? A more challenging question may then follow: what is the escape mechanism of that drug in the tumor and what are the genes that dictate this behavior?

There's no doubt that Burkard's goals are ambitious; yet, he is not one to be deterred. Like all the scientists who have collectively succeeded in pushing breast cancer treatment forward, the work is daunting and the stakes are high—life or death for many patients. But with each small step forward the science has progressed and patients have benefitted. That kind of payoff makes it all worthwhile.

"If you look today, cancer death rates have finally turned around, and there is a lot of hope for the future," he says. "We may not be precisely where we want to be at this time, but we are making progress!"

As oncologists, we're optimists. Mark Burkard, MD, PhD
Mark Burkard

Looking to the Next 25 Years

Identifying the specific genes in a cancer cell that may impact the effectiveness of a particular cancer-killing drug is paramount to pushing cancer treatment to the next level. In parallel, so are the tools that allow oncologists to offer state-of-the-art care to their patients.

The advent of molecular diagnostics in recent years illustrates how far research has come. A concept that did not exist when Mona was first diagnosed, it is now becoming a more routine aspect of cancer treatment. Early in Samantha's treatment she was offered the option to have her DNA tested for three known cancer-related genes, BRCA1, BRCA2, and p53. She was thrilled to learn that she is negative for all three mutations and doesn't have to worry about passing them on if she eventually has children.

As more breast cancer-related genes are identified, the cumulative information these genes can reveal becomes more powerful. And oncologists have more resources to offer their patients to help them make decisions about their treatments and prepare for what may lie ahead with respect to heritable cancer-causing genes and even cancer recurrence.

Companies are now developing and commercializing multigene panels, which are essentially scorecards containing numerous genes found to be linked to breast cancer. This technology enables the simultaneous testing of dozens of cancer genes at once, providing a patient with more precise and personalized information. With this knowledge, the belief is that the chance of recurrence can be more accurately predicted. Gene panel results may also influence treatment options. While not yet standard protocol by any means, such tools are gaining recognition and credibility, and further research should only enhance their level of accuracy.

Dr. William Rehrauer, a research scientist and Director of the Molecular Diagnostics Laboratory at the University of Wisconsin School of Medicine and Public Health, agrees that molecular genomics represents the future of cancer treatment. "We're continuing to work on more genomic based testing for oncology—from single targeted tests for known genetic mutations with directed therapies already established, to more broad based panels of oncogenes that comprise a subset of targets in combination," he explains. "We know that cancer is complicated and involves many different mutations, so the big question is: what exactly is activated in an individual's tumor?"

Another diagnostic technology with tremendous potential may revolutionize the way cancer patients undergo biopsies. Unlike the surgical procedure both Mona and Sam endured when they first discovered the presence of a lump in their breast, a simple blood draw may offer the same information. The discovery that tumor cells can shed their DNA directly into the general bloodstream and circulate with "normal" non-tumor DNA led scientists to develop a technique for isolating the tumor DNA and distinguishing it from normal DNA. The hope is that eventually cancer can be routinely and accurately diagnosed with a simple blood sample.

Circulating DNA

Celebrating Life Number Two

Today Mona and Samantha are both healthy, vibrant, and grateful. Both feel fortunate to be alive. Samantha is especially appreciative of the treatments that were available to her at this time, knowing what Mona had to endure 25 years ago. "I feel like I was part of a progressive and knowledgeable team that presented me with everything possible and was considerate of my choices and decisions," she says.

Samantha also had the advantage of battling cancer at a time and in an environment that is supportive and receptive to such an experience. Thanks to the Internet and the popularity of social media, she connected with people around the world who could personally relate to her struggles. "It made such a difference to know that I was not alone," she says. "All I had to do was get online, and I could interact with others going through the same thing."

For Mona, the, pre-Internet landscape made it more challenging. She felt isolated and even alienated to some extent, for as she points out, back then cancer was still referred to as the "C-word." Yet with the support of her family, as well as friends and a compassionate healthcare team, she made it through her punishing cancer treatments.

What both women now face, every single day, is the phase that follows successful treatment of cancer: survivorship. And for Samantha who is new to this, the transition has proven to be a surprise both physically and emotionally. She's discovered that it's a process that includes not only grieving, but also redefining her identity. One person she turns to for guidance is Mona who, with nearly a quarter century of survivorship under her belt, is a source of inspiration.

At the same time, they both acknowledge that part of the challenge of survivorship is the constant fear that their cancer will return.

"What happens is that your doctor tells you that you can now wait a year between checks, and suddenly that is really scary!" explains Samantha. "You think, no, I want to keep seeing my oncologist more regularly and feeling reassured that the cancer has not come back."

The researchers and clinicians who have played a role in getting both Mona and Samantha to this point of survivorship might be pleased to know that such a concern even exists. Each may think that their individual contribution to the pursuit of understanding what causes breast cancer and how to best treat it was minor, yet collectively they have made a remarkable difference. In the gap of time separating Mona and Samantha's diagnoses, overall breast cancer mortality has decreased by 36 percent.

Mona and Samantha—their stories are inextricably linked and span 25 years of critical advances in breast cancer research. Thankfully they are stories that share the same happy ending.

Samantha and Mona