Understanding the molecular makeup of triple-negative breast cancer reveals new therapeutic targets.
People say that I’m a miracle, and I don’t know how to feel about it,” says 49-year-old Brenda Beguin, who received a diagnosis of triple-negative breast cancer (TNBC) in 2005. “They told me that this [disease] was going to take my life,” she recalls, “and the only thing I could do to treat it was chemotherapy.”
At the time, Beguin was going through a divorce and didn’t feel she had the emotional or physical support to cope with the rigors of chemotherapy. So, against her doctors’ recommendation, she had only a lumpectomy followed by 36 rounds of radiation therapy, which kept her cancer at bay for more than four years.
Beguin’s cancer returned in 2010 as an aggressive tumor on her right lung. Remarried but struggling with domestic abuse, she again rejected chemotherapy. But four weeks later, the cancer had spread to a lymph node attached to her trachea, and her oncologist told her to get her affairs in order. “It’s the hardest thing when someone who’s supposed to give you the answers tells you that it’s over,” Beguin recalls.
This time, she decided to try chemotherapy. In June 2011, she joined a phase 1 trial of the PARP inhibitor veliparib combined with cisplatin and vinorelbine. PARP, which stands for poly ADP-ribose polymerase, is an enzyme that is key to repairing defective DNA—particularly DNA that has been damaged by chemotherapy—so PARP inhibitors make cancer cells more vulnerable to treatment. Beguin’s tumors vanished within six months of her starting the trial, and she was declared cancer-free. While such a dramatic response to a trial is not typical, it illustrates how our growing understanding of the genetics of individual tumors could open more treatment options.
TNBC, which is more common among younger women and African-Americans, refers to breast cancers that lack overexpression of the estrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2). Because these tumors are not fueled by hormones or the HER2 protein, they do not respond to targeted breast cancer drugs, such as tamoxifen or Herceptin (trastuzumab), which target ER and HER2, respectively. Thus chemotherapy—before surgery (neoadjuvant) or after (adjuvant), or for metastatic disease—remains the standard treatment for these patients.
The good news is that TNBC is generally sensitive to chemotherapy, and a good predictor of longer survival in TNBC is lack of any detectable disease after neoadjuvant (prior to surgery) chemotherapy—a so-called pathological complete response—which happens in 20 to 40 percent of cases. Patients whose tumors respond poorly or continue to grow during chemotherapy have a poorer outlook.
“These tumors are difficult to treat and can be very aggressive if we can’t find an effective therapy,” says Jennifer Litton, a breast cancer specialist at the MD Anderson Cancer Center in Houston.
Cancer recurs in roughly 30 percent of patients with early-stage TNBC, usually within the first few years after treatment. If ER-negative tumors crop up locally and can be surgically removed, additional chemotherapy is beneficial, nearly doubling the five-year, disease-free survival rate compared with surgery alone. For patients with metastatic TNBC, however, treatment options are limited, and average survival drops to one year. Thus, although TNBC accounts for 10 to 20 percent of the roughly 230,000 new breast cancer cases in the U.S. each year, it leads to 25 percent of all breast cancer-related deaths.
Teacher’s aide Melissa Paskvan of Toledo, Ohio, considers herself fortunate to have had the type of cancer that responds to chemotherapy. In 2009, at age 41, she discovered a 2-centimeter lump in her left breast that turned out to be TNBC. “I remained calm,” says Paskvan, “but I was really scared of the unknown.” She had a lumpectomy followed by chemotherapy with a doxorubicin-cyclophosphamide cocktail, paclitaxel and 33 rounds of radiation. Paskvan suffered the typical side effects of chemotherapy, including nausea, hair loss and decreased white cell counts, but she has remained disease-free.
At the moment, chemotherapy for TNBC is similar to that used against non-TNBC, and there are new agents joining the list. Combinations of anthracyclines and taxanes are typically used in early breast cancer (in addition to surgery and sometimes radiation). Taxanes are often the first drugs used if the cancer returns, but there are many others that have shown efficacy in TNBC. Xeloda (capecitabine) and platinum drugs, among many others, are often used for relapsed disease. Platinum-based chemotherapy drugs, such as cisplatin and carboplatin, are also proving highly effective for a subset of patients with TNBC whose tumors carry a mutation in the DNA repair gene BRCA1. More than 75 percent of these tumors are TNBC. “These tumors have a defect in their ability to repair damaged DNA,” explains Kent Osborne, director of the Smith Breast Center at Baylor College of Medicine in Houston. As such, he goes on to say, they respond better to DNA-damaging agents, such as platinum drugs, than to other TNBC tumors.
These tumors have a defect in their ability to repair damaged DNA, so they respond better to DNA damaging agents.
Newer chemotherapy drugs also offer options in advanced TNBC. Ixempra (ixabepilone) and Halaven (eribulin) jam up the cell’s division machinery. In a phase 3 trial, Halaven improved median overall survival of heavily pre-treated metastatic breast cancer compared with the treatment of physician’s choice, and was approved by the Food and Drug Administration in this setting in 2010. And Ixempra doubled progression-free survival of patients with TNBC when combined with Xeloda, compared with those taking Xeloda alone.
Oncologists are encouraged by strides in chemotherapy but hope that targeted drugs, which cripple specific growth and survival pathways that keep tumor cells alive, will offer more options for patients with advanced disease. But finding the right pathways in TNBC is proving to be a challenge, partly because these tumors may not rely on one dominant pathway, as do ER-positive or HER2-positive tumors.
Studies are now focused on identifying the key genetic and molecular features of individual TNBC tumors to expose vulnerabilities, with the expectation that therapies could be tailored accordingly. It’s clear that TNBC tumors are a very mixed bag, but clinically important sub-sets have begun to emerge.
“If you start to subdivide tumors we call TNBC, there are ultimately going to be several subgroups,” Osborne says. “How many, I don’t know.”
If you start to subdivide tumors we call TNBC, there are ultimately going to be several subgroups. How many, I don’t know.
A study by researchers at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., published in 2011, identified seven molecular subtypes of TNBC and suggested that tailoring treatment to the distinct subtype potentially could predict outcomes. Now, researchers at MD Anderson are trying to do just that. Their preliminary results, presented at this year’s annual meeting of the American Society of Clinical Oncology, support the earlier research but will need to be validated in larger studies.
Because TNBC tumors are so diverse, doctors will need an array of targeted drugs on hand. That’s why breast cancer expert Lisa Carey, medical director of the University of North Carolina Breast Center in Chapel Hill, N.C., stresses the need to expand the collection.
“The pipeline is full of drugs targeting various things,” Carey says. “We just don’t know whether they’re any good or not. And the more subsets [of TNBC] you have, the harder it is to do a clinical trial.”
Patients with BRCA1 mutations make up an important subset of TNBC. For the same reason these tumors are more responsive to platinum-based chemotherapy drugs, they might also be sensitive to PARP inhibitors. PARP proteins also promote DNA repair, providing the cancer cell a way to rescue itself in the absence of BRCA1 activity. “If you lose BRCA1, you have a three-legged table,” Carey explains, “so if you knock out PARP, now you have a two-legged table, and it’s going to fall over.”
Beguin’s tumor quickly responded to the veliparib regimen, and, at her first scan, there was no sign of cancer. “I thought I was going to die, and all of a sudden I have the first clear scan I’ve had in years,” she says. Beguin made it through five rounds of treatment but developed severe neuropathy and low white cell counts in response to the regimen, eventually finding it difficult to function. Ultimately, she opted to curtail chemotherapy, one of the most difficult decisions of her life, she says. But because she’d had a complete response, she continued taking veliparib on its own. A related drug, olaparib, is being tested in patients with confirmed mutations in BRCA1 and the related gene BRCA2.
TNBC tumors also frequently express high levels of receptors that promote tumor growth, including a HER2 relative called the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), which drive the growth of blood vessels to the tumor. EGFR inhibitors, including Iressa (gefitinib), Tarceva (erlotinib) and Erbitux (cetuximab), are currently being tested in TNBC, but so far the results have been mixed.
“EGFR inhibitors have been disappointing to some extent,” says Osborne, who attributes this to the biology of the disease. “In TNBC, there may be several pathways driving the tumor, so if you only block one, you won’t make much progress.”
The VEGF blocker Avastin (bevacizumab) allowed patients to live longer without their cancer progressing when added to first- or second-line chemotherapy for relapsed disease. It did not extend overall survival, however. While not yet clear whether it is beneficial in the neoadjuvant or adjuvant setting, one adjuvant trial in TNBC did not show an effect. Two VEGF inhibitors, Sutent (sunitinib) and Nexavar (sorafenib), showed some activity in phase 2 trials of participants with metastatic breast cancer, but follow-up studies have not been encouraging. TNBC is so complex, experts say, that more detailed information about its underlying biology will be essential to more effective drug therapy.
Before her success with veliparib, Beguin was enrolled in a phase 2 clinical trial for Avastin (combined with Abraxane [albumin-bound paclitaxel]) followed by maintenance therapy with Avastin and Tarceva. Her tumor initially responded to treatment, but she developed a severe skin rash in response to the Tarceva (a common side effect) and decided to go off the trial and “take her chances.”
Another tantalizing target in about 20 percent of TNBC tumors is the androgen (male hormone) receptor, which is also highly expressed in prostate cancer. Early evidence from a phase 2 trial suggests that the prostate cancer drug bicalutamide, which targets the androgen receptor, may stabilize TNBC in some patients, but its ultimate efficacy in the disease awaits the results of larger trials. A similar drug, Xtandi (enzalutamide), is currently in phase 2 trials.
Osborne is particularly excited about a group of proteins called phosphatases, which act as brakes for many different survival pathways in normal cells. The PTEN phosphatase, which inhibits the pro-growth PI3K/Akt pathway, is lost in a majority of TNBC tumors. PTEN loss is associated with reduced disease-free survival but might also render the tumor susceptible to PI3K/Akt inhibitors.
Thomas Westbrook, a colleague of Osborne, found that a related phosphatase, PTPN12, is also missing in roughly 60 percent of TNBC tumors. PTPN12 normally keeps several growth and survival pathways in check, including EGFR and HER2, so its loss turns on many cellular pathways. But combining existing drugs that block these pathways might halt tumor cell growth. Osborne’s group will soon launch a phase 1/2 clinical trial to determine whether these drug combinations work in patients with PTPN12-deficient tumors.
Pre-clinical studies are adding more variability to the mix by revealing additional pathways that are altered in TNBC, including the hedgehog, wnt/b-catenin and notch stem cell pathways. Efforts to inhibit these pathways are currently being tested in animals and in early-phase trials. What is becoming clear, however, is that drug combinations are likely to be key in TNBC. “We’re going to have to hit these tumors with multiple agents,” Litton says. “One targeted therapy [alone] won’t be the answer.”
We’re going to have to hit these tumors with multiple agents. One targeted therapy [alone] won’t be the answer.
Throughout her journey, Beguin found hope at Seattle Cancer Care, and strength in online support groups, where she and Paskvan became close friends.
“There were many times I felt like I was dying,” she says, “and I would turn to this group of women that I’d never met, and they would encourage me to keep fighting.” Beguin sometimes wonders if her journey would have been easier if she’d listened to her doctors and had chemotherapy early on, but she says she has no regrets and vows to use the extra time she’s been given to help others.
View Illustration: Turning Off DNA Repair