By Stephanie Pappas
Illustration by Matt Bandsuch
Louisa Gloger was already having a rough day. Her daughters, a 3-year-old and a 14-month-old, fussed all morning. She was frazzled. She needed a shower.
So she corralled her daughters into the bathroom and stood under the spray with her youngest in her arms.
That’s when she felt the lump in her breast. “Immediately, it was like alarm bells went off in my head,” the 31-year-old Mill Valley woman says. “It didn’t feel right.”
In some ways, Gloger had built her life around the possibility that this might happen. Her mother was diagnosed with breast cancer at 35, when Gloger herself was just a year old. Gloger’s aunt had the disease in her 30s as well. Both women developed cancer again 20 years later. Gloger’s aunt survived her second bout. Her mother didn’t.
Gloger knew she was at risk, so she did the things that are supposed to keep breast cancer at bay. She exercised, ate organic, avoided the birth control pill, had both babies before 30, breastfed. Yet she got cancer anyway. And when the final diagnosis came, it was still a surprise.
“I was just totally blindsided,” Gloger says.
She was all the more blindsided when her doctor at the California Pacific Medical Center in San Francisco told her she had triple-negative cancer. Gloger had never heard the term before, but her doctor explained it’s a particularly aggressive form that doesn’t respond well to traditional chemotherapy.
“That’s when he said, ‘You need to go down to Stanford and see Dr. Melinda Telli,’” Gloger says. “He told me, ‘It’s your best hope for a cure.’”
Hope is something that triple-negative breast cancer patients have been short on. In this form of cancer, which makes up 15 percent of all breast cancer, the tumor cells lack abundant receptors for estrogen, progesterone and a growth factor called HER2. Since current breast cancer treatments work by targeting these proteins, there’s little doctors can do for triple-negative patients.
“Even though they represent a small proportion of breast cancers overall, this is the group that’s responsible for a large proportion of cancer deaths,” says Melinda Telli, MD, an assistant professor of oncology at Stanford and the leader of a clinical trial testing a new therapy for triple-negative cancer. According to a 2007 study of all stages of breast cancer, women with triple-negative strains have a 77 percent chance of surviving five years, compared with a 93 percent chance for other cancer types. Triple-negative cancers hit early and disproportionately affect women of African and Hispanic descent. As a young woman with an African-American parent, Gloger fit the profile.
For years, researchers have failed to find a way to target triple-negative cancers. But now, research conducted at Stanford has revealed a new possibility: drugs called PARP inhibitors. Pharmaceutical companies had been testing PARP inhibitors as a chemotherapy adjunct for years, but in the last five years, research on the drug class has exploded. If PARP inhibitors help stem triple-negative cancer, they’ll represent one of the biggest steps forward in breast cancer treatment in years.
They’ll also be in the vanguard of personalized medicine, the attempt by doctors and researchers to match drug treatments to patients most likely to be helped. Breast cancer is fertile ground for personalized medicine, with drugs specifically made to target tumors’ receptors already on the market. Tamoxifen, for example, fights estrogen-positive cancers. Herceptin, a drug approved in 2005 for use on early-stage tumors positive in the HER2 protein, was celebrated as “revolutionary” in the New England Journal of Medicine. As technology has improved, ferreting out more individualized treatments has become a major goal of cancer researchers.
“The idea of personalized or targeted treatments is to tailor treatments to an individual’s cancer based on its genetic makeup,” says James Ford, MD, professor of oncology and of genetics. “The technical feasibility and the cost for sequencing DNA have really gotten into the range where this is now feasible in the individual.”
When Gloger first called Telli in mid-October 2009, she didn’t know what to expect. Her primary physician had told her Telli was running a clinical trial on PARP inhibitors. The idea discomforted Gloger. She didn’t want to be a guinea pig.
But Telli is the kind of doctor described by her patients, unbidden, as warm and compassionate, the kind of doctor who will stay on the phone with you for two hours on a Saturday to discuss an experimental treatment’s pros and cons.
That’s what Telli did when Gloger called. The PARP inhibitor would be combined with DNA-damaging chemotherapy drugs that also target triple-negative breast tumors, she explained. PARP inhibitors target one of the tumor’s strongest lines of defense, a DNA-repair enzyme called poly (ADP-ribose) polymerase, or PARP. If the drug, BSI-201 (now called Iniparib), worked as planned, it would be a one-two punch: The chemotherapy would do the dirty work of breaking up the tumor’s DNA, while the PARP inhibitors would block DNA repair. Though PARP inhibitors had been tested in women with advanced breast cancer with encouraging findings, Gloger would be one of the first potentially curable, early-stage patients to receive the drug. For women with localized breast cancers the stakes are high, Telli says. The risk of spread with this aggressive form of breast cancer is substantial, yet long-term side effects of therapy are also a possibility.
Gloger weighed her options and decided to participate. She and her husband began planning a trip to Europe for the next summer to give her something to look forward to. She e-mailed her friends and family telling them she’d be standing on a mountaintop in the Alps in just a few short months. But before that, she had to make it through 12 weeks of the investigational treatment.
To understand how researchers fingered PARP inhibitors as a potential triple-negative cancer treatment, you have to rewind to 1994. That’s when the first breast cancer gene, dubbed BRCA1, was found. A year later, researchers found BRCA2. An inherited mutation in these genes raises the lifetime risk of breast cancer by 65 percent and 45 percent, respectively.
The discoveries told doctors little about why these broken genes cause breast cancer. What it gave them was the chance to test women for the mutations that raised their risk. Myriad Genetics, a firm based in Utah, swiftly patented both genes, making it the only company legally allowed to run the test. For a few thousand dollars, a woman with a family history could have her blood drawn and learn within a few weeks whether she was at increased risk to develop cancer.
A woman who discovers she has a BRCA mutation faces hard choices, from extra screening all the way up to prophylactic mastectomy and oophorectomy (removal of the ovaries). If she has a BRCA1 mutation and develops breast cancer, odds are 80 percent it will be triple-negative, and thus tough to treat. The BRCA discoveries had improved doctors’ ability to predict cancer and take steps to prevent it, but not to cure it.
Then, in 2005, a pair of in vitro laboratory studies on PARP inhibitors published in Nature changed the game.
The first study, carried out by scientists at Cancer Research UK, found that PARP inhibitors weaken BRCA1- and BRCA2-related tumor cells drastically, causing them to stop dividing and die.
The second study’s results were even more promising: When researchers at the University of Sheffield in England treated BRCA2 tumor tissue with PARP inhibitors in the lab, the tumors died. Cells without the BRCA2 mutation survived, suggesting that PARP inhibitors could target tumors without destroying healthy tissue.
The Nature studies marked the first time PARP inhibitors had been tested in BRCA-mutant cancers. Their effectiveness made sense. The BRCA1 and BRCA2 genes make proteins involved in DNA repair. When a tumor is deficient in either BRCA protein (as is the case with the BRCA mutations), it relies more heavily on alternate DNA repair pathways — like PARP — to patch up genetic breaks and keep growing.
In other words, PARP is like a tumor’s plan B. Knock it out, and the cancer runs out of options. Finally, it seemed that the BRCA discoveries of a decade earlier had paid off.
With the publication of the two Nature papers, the oncology field burst into a flurry of research on PARP inhibitors. Around the country, clinical trials were launched in patients carrying BRCA mutations. Meanwhile, in his lab on the Stanford campus, Jim Ford noticed something about the mutations that suggested a route to treating triple-negative breast cancer.
Ford had been studying the BRCA1 mutation for years, trying to determine what goes wrong with a BRCA1-deficient cell’s DNA repair mechanisms. The overlap between BRCA1 and triple-negative cancers intrigued him, and he wondered if there might be some underlying similarity in their defects.
As it turned out, there was. Using cancer cell lines in the lab, Ford showed triple-negative cancers almost completely share the DNA-repair defects of BRCA-related cancers.
“It was kind of an ‘aha’ moment,” Ford says. If BRCA cancers and triple-negative cancers are both driven by the same DNA repair deficiencies, he reasoned, they should respond to the same treatment. He tested triple-negative tumor tissue in the lab with PARP inhibitors and found that, just like BRCA tumors, triple-negative tumors responded.
Ford shared his results with Telli. She was immediately intrigued, and agreed to lead a clinical study to test the idea in breast cancer patients. The two contacted BiPar Sciences (now owned by Sanofi-Aventis), a South San Francisco drug development firm that makes the PARP inhibitor BSI-201, and arranged a collaboration. By this time, BiPar had launched a clinical trial testing its drug in women with the advanced form of this disease. Ford and Telli obtained additional funding through the Breast Cancer Research Foundation to start a clinical trial in newly diagnosed patients. Last year, the trial began. The plan was to recruit 36 patients in the early stages of triple-negative breast cancer.
The study would provide an opportunity to target a group that stood to benefit the most from treatment. It would also allow Telli and Ford to look for links between individual cancers’ biological features and the cancers’ response to the treatment.
“The early-stage patients are the ones where there is real curative potential,” Telli says.
As one of these patients, Gloger began her treatments at the Stanford Cancer Center in early November 2009. She hated the needles and felt worn out after sessions, but she didn’t become the balding, emaciated cancer victim she’d imagined. Instead, she kept her hair, kept exercising, kept up with her kids.
Even better, she got to watch the tumor shrink away. By the second treatment, it was noticeably smaller, she says. By the third, she couldn’t feel it anymore. While a shrinking tumor doesn’t always mean cancer has been cured, the PARP inhibitor treatment was declared an initial success for Gloger.
“That was kind of amazing,” Gloger says. “And awesome.”
Originally planned as a 36-person trial, the study is now expanding to 80 patients through the Eastern Cooperative Oncology Group. About 40 patients are enrolled, with the other 40 expected by the end of the year.
The biggest remaining question mark — and one the current study won’t fully address — is whether PARP inhibitors are safe in the long term. Inhibiting DNA repair in a tumor is a good thing, but in normal cells it can cause cancer. Ironically enough, it’s possible that by treating cancer now, PARP inhibitors set patients up for a new cancer later.
Researchers hope this won’t be the case, since healthy cells have other DNA repair mechanisms besides PARP. But BSI-201 has been tested only since 2006, Telli warns, and mostly in patients with incurable cancer who died soon after. Cancer patients who live need to be followed for years to be sure that new drugs are safe.
“That’s where you really need to be cautious, when you move it into lower-risk patients,” Telli says.
Meanwhile, in June 2009, just after Telli launched her study, researchers presented the results of BiPar’s clinical trial on their PARP inhibitor in metastatic triple-negative cancer. One hundred twenty women with advanced triple-negative breast cancer tested two DNA-damaging chemotherapy drugs, gemcitabine and carboplatin, the same Telli and Ford used, and the same that Ford’s laboratory had shown worked particularly well together with PARP inhibitors. Half the women also got BSI-201.
In women who got the PARP inhibitor, tumors shrank three times as fast as in women who received chemotherapy without it. The median survival time was 5.7 months for women whose treatment did not include the PARP inhibitor. Those who received chemotherapy including the inhibitor had a median survival of 9.2 months, 3.5 months longer.
The oncology community was amazed. Three extra months of life represents one of the biggest treatment gains ever seen in patients with this aggressive form of metastatic breast cancer, says Brian Leyland-Jones, MD, PhD, a cancer researcher at Emory University and expert on cancer genetics.
“These differences in response and median survival are almost unheard of in such a small trial,” he says.
BiPar Sciences recently completed recruiting cancer patients to participate in a large, multi-institution phase-3 trial of the BSI-201/chemo combination in metastatic triple-negative cancer. Phase-3 trials are the final step to FDA approval of a drug. If the trial goes well, Telli says, FDA approval of BSI-201 could come very soon.
No matter how convincing the science, this personalized approach to breast cancer is not a guaranteed success. Any lab can test for triple-negative disease, but Myriad Genetics still holds a monopoly on the BRCA tests, and some critics say the company has set its prices too high.
Test costs can be a problem when trying to recruit patients for clinical trials, Telli says.
“Even now, there may be patients out there who are eligible for our study, but if they don’t know their mutation status then how can they participate?” she says. “There’s a lot of socioeconomic discrimination in terms of who can access these technologies.”
In March, a federal judge struck down Myriad’s patents on the BRCA genes, which would open up the testing market and possibly drive down prices. Myriad has appealed the decision, and it remains to be seen how the case will play out.
For her part, Gloger got her moment in the Alps. Her treatments finished, she and her family spent three weeks of the summer soaking in Switzerland and Italy. But she’s not putting her cancer experience entirely behind her. She and another woman, who lost her sister to triple-negative cancer, recently teamed up to start a nonprofit called Triple Step for the Cure. The organization is designed to help women deal with the everyday difficulties of cancer treatment. They’ve already raised $175,000 to pay for things like housekeeping, child care and meal services, and they’re supporting their first cancer patient by flying her family to California while she’s in treatment.
“The day that I was able to talk to her and tell her the way in which we’ll be able to help her, it felt like all of this had happened, not for a reason, but like I’m taking something really awful that happened to me and making it something good,” Gloger says. “We feel like we’re filling a gap.”
Meanwhile, Telli and Ford continue to work on filling the treatment gap for women with triple-negative cancer. Telli will be leading another trial of PARP inhibitors in triple-negative breast cancer, this time in combination with different chemotherapy drugs. Her ultimate goal is to conduct a randomized study that will compare different PARP-inhibitor strategies to standard chemotherapy in women with early-stage disease.
Ford is taking tumor samples from before and after patients’ treatment with the PARP inhibitor to look at the molecular changes in the tissue. He hopes to find clues that will help doctors target the treatment even further.
“Is there some signature or some added molecular data that predicts who did very well or who didn’t do very well with the treatment?” he asks. “Maybe there’s a subgroup for whom this is a particularly good treatment.”
The narrower the target, the more personalized cancer therapies can become, Ford says. After all, when it comes to matching treatments to an individual’s genome, it hardly matters what works on the scale of hundreds or thousands of people.“What you really want to know,” Ford says, “is in this patient in my examining room, what is going on in her tumor?”