Elaine Schattner, MD

It was the mid-1990s and cancer researcher John Dick, PhD, now a senior scientist at the Toronto General Research Institute, found that a particular subset of acute myeloid leukemia cells—those most resembling blood-forming stem cells&mdash;formed new malignancies when placed in mice. He realized that not all cancer cells were alike.

There is a “pecking order,” he thought, with cancer stem cells at the base. Cancer stem cells, he observed, are essential in both creating and sustaining tumors. That’s how they form new cancers in mice, he concluded. These early findings led scientists to consider that malignant stem cells within a tumor might resist treatment and lead to recurrences. 

Now, as cancer stem cell theory gains traction, it is revolutionizing how some doctors think about cancer and how they search for new oncology drug targets.

For Max Wicha, MD, a medical oncologist who heads the University of Michigan’s Comprehensive Cancer Center, studying cancer stem cells is personal. While attending medical school at Stanford University, his mother was diagnosed with breast cancer and underwent extensive treatments. “She never had a recurrence,” he says. “She lived to be 97 years old. That’s the thing about this disease. It’s so variable.”

Back in the 1970s, we didn’t really know what cancer was,” he says. “Clinical trials were based in trial and error, and it was brutal.” He felt drawn to the field because he “wanted a challenge and an area in which new therapies are desperately needed.” 

“My feeling was if you’re going to make an impact, you have to understand what was going on with the cancerous cells.”

Wicha, a full professor with a busy lab and an active clinic, was among the first researchers to describe breast cancer stem cells.

These primitive, long-lasting elements—however few&mdash;tend to resist chemotherapy and other treatments. “Ultimately, survival may be determined by the relatively small number of stem cells that persist after treatment,” Wicha says. “To permanently eradicate the disease, you have to eliminate the stem cells.”

These cells tend to resist toxins, cellular and environmental stresses. They also divide more slowly than regular cancer cells, making them less sensitive to chemotherapy. 

Some suggest that cancer stem cells are a bit like seeds and key to a tumor’s durability. Like spores of a flowering plant or a weed, these hardy cells can survive a harsh environment once other parts of an organism are diminished or gone. They can persist after the bulk of a tumor is destroyed by chemotherapy and even remain dormant for long periods of time. Then these adaptive, immature cells can spread from one location to another where they bloom.

“Using tumor shrinkage as an endpoint doesn’t make sense if survival and recurrences depend on the stem cells,” Wicha explains. “We’re taking the wrong measurements.”

When she moved to Houston in 1997, Jenny Chang, MD, wasn’t planning to study breast cancer stem cells. Born in Singapore and trained in England, she preferred seeing patients in the clinic. 

“I still see 25 patients in a day, twice each week,” she says. 

Before coming to the U.S., she studied predictive biomarkers—molecules that offer clues about a patient’s prognosis. In Texas, she collaborated with Jeffrey M. Rosen, PhD, a molecular and cellular biologist at the Baylor College of Medicine in Houston, who was researching normal mammary gland stem cells and their counterparts in cancer. 

In Houston, Chang cared for breast cancer patients from an underserved area where it was common for women to seek medical help after their tumors were quite large; 10-centimeter tumors were not uncommon. Many opted for neoadjuvant chemotherapy, which is given before surgery to shrink the cancers. This preoperative therapy gave researchers the chance to examine the women’s breast cancer cells by biopsy samples before and after chemotherapy.

Chang and Rosen used cell surface molecules that characterized stem cells in the breast biopsies. After treatment, they found the proportion of the molecules with features that may define breast cancer stem cells were enriched. Collaborators agreed that these potentially dormant, chemotherapy-resistant cells should be targeted. 

“When you treat cancers with chemo, it’s not just that the percentage of stem cells go up. The absolute number of stem cells goes up, so they are resistant,” Wicha says of his colleagues’ findings.

Stem cells, like other cells, can be triggered and prodded by messages received through countless and varied signaling pathways. These molecular tracks, like a complex subway system, have interconnecting, parallel and sometimes divergent routes. Within each cell these tightly controlled chemical pathways extend from the cell’s membrane, through the cytoplasm to the nucleus, and back. Scientists are working to unlock the specific signaling routes essential to normal and cancer stem cells’ growth.

To find ways to turn off cancer stem cells, Chang and her colleagues applied mathematical and bioinformatics models to screen for compounds that might be effective against cancer stem cells in the database of FDA-approved agents. They identified chloroquine (an old malaria drug) and its derivatives, as potential cancer stem cell killers.

“Chloroquine is an interesting drug,” Chang says. “It exerts its actions through very primitive pathways.” 

Working closely with collaborators, she’s in the midst of planning a randomized, multicenter trial of chloroquine in women with advanced triple-negative breast cancer. The plan is to give study participants a taxane, with or without chloroquine. She expects the trial will begin before the end of the year.

Wicha, in Michigan, is thinking forward. Investigations in his lab probe signaling pathways with peculiar-sounding names like notch, hedgehog and wnt (pronounced “wint”) that mediate many cell functions, including stem cell behavior. 

“What we’re finding in some tumors is a predominance of one pathway over another,” he notes. “Just as we’re talking about personalized medicine, we have to look at stem cells in each patient’s tumor.” 

For this reason, doctors will need an array of drugs targeting distinct pathways. Ultimately, the drugs might be used in combination with traditional chemotherapies in the adjuvant and advanced disease settings. The idea is that most of the dividing cancer cells will succumb to chemotherapy, but the rare resistant stem cell, which would otherwise remain and repopulate the tumor, could be eradicated with stem cell-targeting agents.

We've gone from not understanding it at all, to knowing genetics and pathways and much more.

Benjamin Neel, MD, PhD, a senior scientist at the Ontario Cancer Institute, is among many experts with reservations about the cancer stem cell model. Neel moderated a discussion on the topic at the 2011 annual meeting of the American Association of Cancer Researchers. 

“We all agree there’s a subset of resistant cells in most cancers,” he says. The crux of the debate is whether these cells have distinct stem cell properties. It could be, instead, that some mature cancer cells develop survival advantages from random genetic mutations. What’s more, some cancer cells might oscillate between mature and stem-like phases. “These scientific issues need to be resolved,” he adds. 

Rosen says stem cells aren’t everything. “The concept that you’re just going to treat the cancer stem cells is naive.” Caveats include cell plasticity, the tumor’s microenvironment and epigenetic factors. “You have to look at the whole tumor complexity,” he says. 

Moreover, stem cell therapies may have significant side effects. “Selective toxicity is one of the most basic issues in cancer treatment,” he says. Because the major cancer stem cell signaling pathways are also active in normal stem cells, like other cancer treatments, these inhibitors are likely to affect stem cells in the gut, bone marrow and elsewhere.

Still, Rosen is optimistic: “Although we argue about details and concepts, from a clinical point of view, that doesn’t matter—this research is leading to new insights.” 

“It’s a new paradigm,” he adds. “These ideas have brought a fresh approach to oncology. Even my colleagues who’ve been treating patients for a long time are very excited.”

Wicha has been studying breast cancer and seeing patients with the disease since he arrived in Ann Arbor in 1980. The transplanted New Yorker could easily settle into a comfortable life that includes cheering his beloved University of Michigan football team and biking in northern Michigan, where he has a cottage. But he’s still passionate about his research

“Thirty years ago, oncology was one of the least scientific fields in medicine,” he says, upon reflection. “We’ve gone from not understanding it at all, to knowing genetics and pathways and much more. 

“But there’s still much more that we don’t know about cancer,” he adds. This means there is much work ahead.

For decades, researchers have examined how primitive embryonic cells mature and eventually form human beings and other creatures. Nonmalignant stem cells are “pluripotent,” meaning they can differentiate, or develop, into specialized, distinct cell types. At the same time, they’re capable of self-renewal—always generating new stem cells. Mature cells, by contrast, have already “decided” what they’ll be&mdash;whether that’s a smooth muscle cell lining the small intestine, a super-specialized neuron delivering signals to the brain from smell receptors in the nose or a glandular cell producing milk in a breast duct.

The possibility of cancer stem cells has percolated for almost 50 years. The concept draws on knowledge of nonmalignant stem cells, with scientists borrowing the “lingo” used to describe healthy stem cells in embryos and placental tissues. As researchers in the conventional stem cell field began to better understand the cellular behavior and set of proteins that mark stem cells, they noted parallel characteristics in a small percentage of cancer cells. 

Still, a persistent controversy centers on how to define these cells. Most researchers agree that cancer stem cells have the capacity to form new tumors, and can mature into “regular” cancer cells—those that form the tumor’s bulk and, in general, are easier to kill.

Wicha and collaborators completed a phase 1 trial of MK0752 in women with advanced breast cancer and other solid tumors. This drug blocks an enzyme required for activation of the notch pathway. Results from this preliminary, phase 1 trial may be available later this year.

One agent emerging from early trials is a hedgehog pathway inhibitor called vismodegib (GDC-0449). Interest in this drug surged after the 

 published a pair of reports, along with a positive 

, in 2009 on its efficacy in advanced local and metastatic 

Investigations by Michael Kahn, PhD, a molecular pharmacologist at the University of Southern California Norris Comprehensive Cancer Center in Los Angeles, are focusing on the wnt pathway signaling. This complex pathway—one of the first-described embryonic growth regulators&mdash;affects how cells mature in organisms ranging from fruit flies to humans. Over the past decade, researchers have linked defects in wnt signaling to several types of malignancies, including colorectal and breast cancers. 

The problem with killing cancer stem cells is that it’s hard to do without destroying normal stem cells. But, “It turns out wnt has divergent effects,” Kahn says. His group identified a compound that exploits this distinction. “It forces cancer stem cells to differentiate, so they become more vulnerable to chemotherapy while nonmalignant stem cells in the bone marrow keep self-renewing.”

Kahn, a chemist by training, utilized in vitro and mouse models to dissect stem cell pathways. “It’s one thing to cure mice,” he says. “It’s another when you see patients responding to an agent you’ve spent a decade developing.” The selective wnt modulator PRI-724 developed by Prism Biolab in collaboration with Kahn’s team is now in a phase 1 trial for patients with advanced pancreatic and colorectal cancers.

Articles

Scientists research whether cancer stem cells are the key to eradicating the disease.

Unlocking the Mystery of Cancer Stem Cells

	Ever since he was a child, Adam Holloway wanted to be a pilot. He was well on his way in spring 2010. Holloway received his private pilot’s license the previous July and was only a semester away from earning a degree in aeronautical technology at Kansas State University Salina—the final step before earning a commercial pilot’s license.

	Then in March 2010, while on spring break at his family’s home in McAllen, Texas, he received a diagnosis of stage 4 Hodgkin lymphoma, a cancer of the lymphatic system. He was treated with surgery at M.D. Anderson Cancer Center in Houston. Then he received chemotherapy, supplemented with an experimental treatment, SGN-35, on a clinical trial.

	The chemotherapy worked, and Holloway’s cancer went into remission. But sometime in the midst of his 12 treatment cycles of chemotherapy, Holloway lost his mental focus and began having trouble with short-term memory.

	"I seemed to forget stuff that had happened," Holloway says. "Usually I'm pretty good at remembering names of people. I found myself saying, 'Sorry, I forgot your name.'"

	Holloway’s mother, a nurse who has worked with oncology patients, was the first person to suggest that he might have chemobrain, an ill-defined disorder experienced by some cancer patients who have struggled with cognitive function. “I was having trouble thinking of something, and my mom was joking with me that it’s chemobrain,” he recalls. “That’s how I learned about it.”

	While patients have been telling their oncologists about unexpected difficulties with word recall, memory and concentration for years, most doctors were hesitant to acknowledge the condition. It took decades for research on chemobrain to gain traction, says Tim Ahles, PhD, a behavioral psychologist who leads the neurocognitive research lab at Memorial Sloan-Kettering Cancer Center. Ahles says investigators have had a tough time applying science to cancer patients with such a range of cognitive complaints and diverse diagnoses. In addition, patients often suffer from accompanying problems, such as anemia, pain, depression and other illnesses that can affect brain function. 

	Christina Meyers, MD, PhD, director of the neuropsychology section at M.D. Anderson, says cognitive dysfunction related to cancer treatment has become a burgeoning area of investigation, one where patient advocacy has helped move the research forward. “When I started at M.D. Anderson, I was just a lone person giving memory tests to people who had cancer,” she reflects. That was 26 years ago. 

	Meyers says that cognitive function issues are seen in survivors “across the board.”  She has seen it in patients with leukemia, lung and testicular cancers. She estimates about 60 percent of patients she has assessed show a cognitive decline. “Often the patients look really good, but it’s a huge effort. The mental cost to function at that level is very taxing,” she adds.

	Meyers says the most common problems she encounters are lapses in short-term memory, difficulty finding intended words and impaired executive function—the brain function that is necessary for multitasking and focusing. Other frequent complaints include difficulty reading and trouble with math. Some patients experience a more global sense of mental fatigue. Meyers says research has also shown that chemobrain can include impaired balance and motor skills in some patients where fine motor dexterity and speed of accomplishing manual tasks are affected. “This kind of impairment can be a stumbling block for someone who wants to go back to college or work,” she says. 

	Ahles says he isn’t surprised that physicians don’t recognize the disorder because they are not trained in cognitive dysfunction. Among patients with just one cancer type, treatments range in forms, doses and regimens. “It’s hard to know which agents are the bad actors because everything’s given in combination,” Ahles points out. 

	Add to that the fact that the condition lacks a precise definition and has a variety of symptoms that are subjective and vague. There isn’t a formal medical term for the syndrome, nor is there a listing in the current 

Diagnostic and Statistical Manual of Mental Disorders

. Results of studies are often subtle, as well, Ahles says. “Cancer patients who come to academic medical centers for cognitive testing appear to have normal capabilities. Yet they often score a lot worse than you’d expect based on their age and occupation.”

	Yet the concept has been around since the 1970s, Ahles says. In 1980, Thomas Oxman, MD, and Peter Silberfarb, MD, published a 

 describing cognitive decline in cancer patients receiving chemotherapy in the 

: “Mild cognitive impairment may go undetected, yet it may influence a patient’s ability to perform routine daily functions and to comply with treatment protocols,” they wrote. 

	Most early clinical studies on the issue focused on cognitive changes in breast cancer and lymphoma patients because they are the largest groups of relatively young, surviving patients who’ve received chemotherapy. In patients who are elderly, there’s more of a risk of mental decline due to vascular changes, dementia and other illnesses, Ahles says.  

	A current focus is to understand who is at risk for chemobrain so that patients can better gauge their risk for cognitive impairment. Ahles says age is an obvious factor, but genetics might also play a role. Ahles and other scientists are examining specific genes that may contain inherited variants associated with more susceptibility to cognitive deterioration as a result of cancer treatment. These include a variant of apolipoprotein E (APOE), which is implicated in Alzheimer’s disease, and the gene for catechol-O-methyltransferase (COMT), an enzyme that may alter brain activity and signaling. 

	Other potential culprits include faulty DNA repair mechanisms and factors already associated with elevated risk for neurological diseases, such as Alzheimer’s and Parkinson’s, but none of these have been proven, Ahles emphasizes. He anticipates that emerging data from animal research studies will help elucidate the effects of specific chemotherapy agents, but making decisions about trading off the benefits of chemotherapy against the cognitive side effects is difficult because of the lack of quantitative information about who is at risk, how likely one is to have side effects and how severe or prolonged they might be.  

	Since the large randomized trials that compare treatment regimens to gather and analyze cognitive data are still in the future, Ahles says patients should address this aspect of chemotherapy side effects as part of the informed decision-making process.

	“It’s kind of like when a fluorescent bulb goes on and off, and sometimes flickers in between,” says 59-year-old Mary Kemp, who has metastatic breast cancer and has experienced two versions of chemobrain.

	At the time of her original diagnosis in 1993, Kemp received adjuvant chemotherapy for a stage 2 tumor. She was working in the library at University of Wisconsin River Falls. At that time, her chemobrain was limited to word-finding difficulty. “There was a disconnect between my mind and my tongue,” she recalls. “I’d want to say the word ‘tree,’ and my mind would picture a tree, but I couldn’t say it.”

	The symptoms reversed entirely once chemotherapy ended. “I was only 42 then. It got better.” Her oncologist didn’t believe that chemotherapy affected the brain, she says. “But they didn’t believe in chemo-caused fatigue then, either.”

	Kemp resumed her full-time work at the library while taking tamoxifen for seven years. She divorced and remarried, and her life seemed back on course. In 2008, the cancer came back in her bones. Now, at 59 and a grandmother of three, she’s been on various hormonal treatments and chemotherapy. She complains of mental cloudiness that affects her activities most days. 

	Kemp, who was an avid reader, says her attention span is now limited when enjoying books. “I can’t remember who the characters are,” she explains. “I go back to reread the first pages.” She says she still “power knits,” but her typing skills have been affected. 

	Kemp says she realizes that her chemobrain symptoms might come from other causes besides her cancer treatment. “It could be emotional changes or other medications or the cancer itself,” she says. Still, she’s convinced that chemobrain is very real and disabling. “It irritates me when the people without cancer minimize it and say, ‘Yeah, I have chemobrain,’ if they forget something. Those remarks downplay the syndrome’s reality.”

	Recent studies also call into question whether hormonal therapy can affect cognitive function, says Steven Castellon, PhD, a neuropsychology specialist at UCLA Medical Center’s Stewart and Lynd Resnick Neuropsychology Hospital in Los Angeles. His group has reported that long-term breast cancer survivors who received tamoxifen, an anti-estrogen, in addition to adjuvant chemotherapy tend to experience cognitive decline several years after treatment, as compared with breast cancer survivors who received chemotherapy alone or who took no adjuvant treatment. He says the condition affects men too, including patients with prostate cancer who undergo hormonal therapies. “Chemobrain does not discriminate by gender,” he says. “Fewer men are out there who are willing to admit it.”

	Castellon wants to be sure patients understand that these changes are not like those seen in Alzheimer’s. “Still, most researchers agree there’s a subset of patients who suffer a variety of cognitive problems during and shortly after chemotherapy. A smaller group will have lingering complaints after completing treatment,” he says. “It’s possible there’s a vascular insult that happens with certain chemotherapies,” he added. “Taken together, there’s a definite risk for cognitive defects.

	“If we can develop a strong science around it, we can get to the point where people can make more informed treatment decisions,” he says, adding that there is enough information now for oncologists to bring it up with their patients as a possible long-term effect.  

	Holloway finished physical and occupational therapy in McAllen, where he worked on balance, hand manipulation and mental exercises. He is now back at KSU Salina finishing his class work and considering his future as he moves beyond treatment for Hodgkin lymphoma. 

	“I would love to get back and fly,” he says. Still, he doesn’t regret his decision to receive needed cancer treatment. 

New research helps clarify what chemobrain is and why it happens.Â 

Lifting the Fog on Chemobrain

Lately, it’s hard to keep pace with breast cancer advances. Innovative drugs—targeted agents, monoclonal antibodies, kinase inhibitors, cancer vaccines, hormone modulators and novel versions of old chemotherapies&mdash;are emerging so rapidly that patients, and even some doctors, may not be fully aware of new treatment options. For patients facing critical decisions, it’s worth knowing what’s out there and what’s headed to market.

For the women in the U.S. with metastatic breast cancer, some promising treatments include Halaven (eribulin), a newly approved synthetic substance that incapacitates dividing cells, and poly (ADP-ribose) polymerase (PARP) inhibitors, a group of drugs that block repair of single-strand DNA breaks.

While these drugs are being tested in a variety of tumor types, in the case of PARP inhibitors, some of the immediate benefit—and buzz&mdash;applies to their apparent activity in some women with metastatic, triple-negative breast cancer (TNBC).

Stephanie Robin of Boca Raton, Florida, is an energetic mother and fundraiser who has been living with breast cancer since she was diagnosed in 2004 at age 36.

After undergoing bilateral mastectomy with reconstruction and months of chemotherapy, her cancer came back in multiple lung spots in 2007. She received additional treatment cycles to no avail. A genetic counselor, who had determined that Robin harbors a BRCA mutation, encouraged her to enroll in a clinical trial with a PARP inhibitor.

The study explores how PARP inhibitors work in women with advanced breast cancer who have an underlying BRCA deficiency, says Mark Robson, MD, an oncologist and director of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center in New York City. He’s taken care of Robin since November 2007, when she began taking the investigational PARP inhibitor, olaparib.

People who inherit mutations in the BRCA gene are prone to malignancies because that protein, when present, repairs double-strand DNA breaks. In normal cells, PARP handles single-stranded DNA nicks. The theory is this: together, these non-overlapping repair systems protect cells with damaged genetic material from dividing. If either mechanism is out-of-whack, chromosomal damage can be propagated and progressive, leading to malignancy.  If both enzymes are knocked out, the DNA-damaged cells can’t replicate, and they die—exactly what you’d want to happen to cancerous cells. But normal cells would not be affected since they have normal BRCA function.

“There are two general ways we might use the PARP inhibitors,” Robson suggests. First, they can enhance the effects of other agents. “A lot of drugs cause double-strand DNA breaks,” he explains. PARP inhibitors increase the burden of those breaks by neutralizing the ability of chemotherapy-exposed cells to repair genetic damage. This chemo-sensitizing effect may apply to many tumors; it might also be effective regardless of BRCA status.

The second mechanism applies to patients, such as Robin, who carry BRCA mutations, he says. “For this reason, PARP inhibitors are unlikely to work as single agents except in BRCA-deficient cases,” he says.

Robin is continuing treatment and says she feels fine. She flies to New York City periodically for CT scans and other evaluations for the experimental protocol. Still, she’s aware that many patients on the study, which is restricted to women with BRCA mutations, haven’t fared so well.

Kathy Miller, MD, a breast cancer specialist at Indiana University School of Medicine, has considered this question from an oncologist’s  perspective.  “What the experience has already made clear is that, while many of these drugs will be profoundly successful, they’ll probably be beneficial to just a small subset of patients,” she says.

In TNBC, typically tough to treat, the tumor cells lack estrogen receptors, progesterone receptors and HER2 overexpression, rendering them insensitive to hormonal treatments and drugs targeting HER2, such as Herceptin (trastuzumab).

TNBC cases account for approximately 15 percent of breast cancers and up to 20 percent for black women and younger, premenopausal women. As things stand, patients with metastatic TNBC have few treatment options apart from chemotherapy.

It’s for this reason that some trials of PARP inhibitors and the chemotherapy drug Halaven, reported at this past June’s meeting of the American Society of Clinical Oncology (ASCO), drew so much attention.

During the meeting, researchers reported on the intravenous PARP inhibitor iniparib and the results of a randomized trial of 116 patients with metastatic TNBC.  In the study, women received a commonly used chemotherapy combination regimen, gemcitabine and carboplatin, either alone or in combination with iniparib.

The clear results have since been updated to show that, for women with metastatic TNBC, the addition of iniparib bumped the response rate from 21 to 62 percent and lengthened overall survival from 7.7 months to 12.2 months on average.

The original iniparib trial looked very promising, Miller says. It generated lots of interest in PARP inhibitors, especially for women with triple-negative disease. But she cautions that it was a small study, and other trials so far have not yielded such positive results.

Everybody's been so fixated on the triple-negative breast cancer, but the benefits may be broader.

Some researchers have suggested that PARP inhibitors, because they impede a DNA repair pro- cess, might enhance the risks of secondary cancers from treatment. “We haven’t seen that,” Miller says. “But that theoretical risk might matter more as we use these drugs in the adjuvant setting as opposed to in patients with advanced disease.”

Patients with HER2-positive, metastatic breast cancer have some reason for hope that there may be another treatment with low toxicity because of a drug being studied called T-DM1.

While the data on T-DM1 are preliminary, results of a phase 2 trial released in October at the European Society for Medical Oncology generated enthusiasm among researchers there. At a six-month follow-up, the T-DM1 arm of the study had an overall response rate of 48 percent comparedto 41 percent in the trastuzumab (Herceptin) and docetaxel (Taxotere) arm of the trial. In addition, three of 67 women treated with T-DM1 had complete responses, compared to one of 70 given trastuzumab and docetaxel.

For those women with advanced, refractory breast cancer, the other up-and-coming agent that gained attention with a major ASCO presentation is Halaven. This intravenous drug, derived from the natural marine sponge product halichondrin B, works by crippling microtubules, which are essential to the intracellular scaffolding required for chromosome separation during division.

What’s interesting, says Christopher Twelves, MD, professor at the Leeds Institute of Molecular Medicine and St. James’s Institute of Oncology in the U.K., is that other cancer drugs, such as Taxol (paclitaxel), also bind to tubulin but in a different way. “In the laboratory, cancer cells that are not sensitive to Taxol can still be sensitive to eribulin [Halaven],” he says.

These drugs require us to think differently of breast cancer—as a group of related but very different diseases that happen to occur in the breast.

Twelves presented the clinical findings from a phase 3 open-label study of 762 patients with heavily pretreated, metastatic breast cancer.

In that EMBRACE trial, median overall survival was 13.1 months for patients who received eribulin and 10.6 months for those who didn’t. The drug extends life, on average, by 2.5 months.

Some critics are puzzled by the hype, but Twelves is enthusiastic about the findings thus far.

“Eribulin [Halaven] is more effective compared to other ‘real life’ choices for chemotherapy in terms of likelihood of shrinking the cancer, delaying its progression and also prolonging survival,” he says, adding that it’s the first drug to significantly prolong survival in women with such heavily pretreated disease.

In addition, he says, side effects, such as tiredness and a fall in blood counts, are generally no more troublesome than with other agents.

Miller, in Indiana, is cautiously optimistic about the PARP inhibitors and the growing understanding of breast cancer biology.

“These drugs require us to think differently of breast cancer—as a group of related but very different diseases that happen to occur in the breast.”

According to Miller, distinct breast tumors may need to be treated, diagnosed and even prevented differently.  In this context, it’s understandable that some patients, physicians and researchers are encouraged by large studies that demonstrate small benefits. Survival statistics don’t tell the whole story. For a small but significant fraction of patients, such as Robin, who is particularly sensitive to PARP inhibitors, and perhaps other outliers who respond to drugs for reasons unknown, the difference could be a matter of years.

Understanding breast cancer biology provides some new targets.

Elaine Schattner, MD

Unlocking the Mystery of Cancer Stem Cells

Lifting the Fog on Chemobrain

New Drugs, New Direction

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