Results from two of the small, early studies reviewed here suggest that adding the experimental targeted therapy olaparib to a taxane chemotherapy such as Taxol (chemical name: paclitaxel) or Abraxane (chemical name: albumin-bound paclitaxel) may be effective against triple-negative breast cancer. These results were presented at the 2010 American Society of Clinical Oncology (ASCO) annual meeting.
Triple-negative breast cancer is cancer that is estrogen-receptor-negative, progesterone-receptor-negative, and HER2-negative. Triple-negative breast cancers tend to be aggressive and difficult to treat.
DNA carries genetic information in both healthy and cancer cells. Chemotherapy medicines such as Taxol and Abraxane treat cancer by damaging its DNA or blocking DNA reproduction. But all cells can fix DNA damage caused by chemotherapy medicines. So sometimes cancer cells may not respond or stop responding to Taxol or Abraxane. When cancer stops responding to a treatment, it's called "treatment resistance."
Olaparib is a PARP inhibitor. The PARP (poly ADP-ribose polymerase) enzyme fixes DNA damage in cells, including DNA damage caused by chemotherapy medicines. Scientists developed PARP inhibitors based on the idea that a medicine that interferes with or inhibits the PARP enzyme might make it harder for cancer cells to fix damaged DNA, which would make the cancer more susceptible to chemotherapy and make it harder for cancer to become resistant to chemotherapy.
All the studies reviewed here were very small and very preliminary.
In the first study, nine women diagnosed with advanced-stage, triple-negative breast cancer were treated with a combination of olaparib and Taxol. Three of the women had some response to the treatment. Still, four of the nine women developed a low white blood cell count (neutropenia), which can be a serious side effect of both Taxol and olaparib. White blood cells are part of the immune system and help fight infection.
In the second study, 10 women diagnosed with advanced-stage, triple-negative breast cancer were treated with a combination of olaparib and Taxol along with a granulocyte colony stimulating factor, a medicine that helps keep white blood cell counts normal during treatment. The women were given a granulocyte colony stimulating factor because so many women developed neutropenia in the first study. Neupogen (chemical name: filgrastim) and Neulasta (chemical name: pegfilgrastim) are both granulocyte colony stimulating factor medicines.
Four of the 10 women in the second study had some response to the treatment. Two women developed neutropenia even though they received a granulocyte colony stimulating factor medicine.
Because women in both studies developed neutropenia, the researchers used a Taxol dose that was lower than they wanted to use.
In the third study, olaparib was used alone to treat women diagnosed with either ovarian cancer (64 women) or triple-negative breast cancer (24 women). Although 41% of the ovarian cancers had some response to olaparib alone, none of the breast cancers had any response to olaparib alone.
All three studies were phase I or II studies. Phase I and II studies help researchers figure out the best dose of a new treatment that can be used safely without serious side effects. They also help researchers figure out if a larger study involving more people makes sense. Based on these promising results, doctors are continuing to study the potential benefits of using olaparib and other PARP inhibitors to treat breast and other cancers.
If you're being treated for triple-negative breast cancer, you and your doctor may be considering a number of treatment options, especially if the cancer has stopped responding to standard treatments. If you're willing to participate in a clinical trial, you may have even more options available, possibly including an experimental PARP inhibitor such olaparib. Talk to your doctor about clinical trials that might be a good fit for you and your unique situation. Visit the Breastcancer.org Clinical Trials pages for more information.
CHICAGO (MedPage Today) -- Treatment with the investigational poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib may have some activity against triple-negative breast cancer when combined with paclitaxel, researchers suggested here.
But their enthusiasm for olaparib in this combination is muted by toxicity, particularly neutropenia, they said here at the annual meeting of the American Society of Clinical Oncology.
In the Phase 1 study, three of nine women responded to therapy, but four of the women experienced neutropenia. None of these women were given white blood cell growth factor support.
In a second study with 10 women, all of whom were given granulocyte-colony stimulating factor, four achieved a partial response while two women still developed neutropenia.
"The combination of olaparib plus paclitaxel had a generally manageable toxicity profile but was associated with a higher-than-expected incidence of neutropenia, which resulted in a lower paclitaxel (Taxol) dose intensity," said Rebecca Dent, MD, head of breast cancer clinical trials at Sunnybrook and Women's Health Sciences Centre.
"Despite the lower paclitaxel dose intensity, encouraging response rates were seen with this olaparib-plus-paclitaxel regimen," she told MedPage Today at her poster presentation.
In another presentation at the meeting, Karen A. Gelmon, MD, head of the Breast Cancer Tumor Group at the British Columbia Cancer Agency, Vancouver, reported that in a phase II translational study of olaparib, about 41.2% of 64 women with ovarian cancer achieved objective responses when the drug was used as a single agent. She did not observe any responses in 24 patients with triple-negative advanced breast cancer.
Triple negative breast cancer is defined as underexpression of estrogen receptors, progesterone receptors and HER2-receptors. The women in Dent's study had a mean age of 50 years and had good performance status. They were required to have had at least one prior cytotoxic treatment. Of the 19 women in the study, 14 underwent adjuvant treatment regimens, most of which were taxane-based.
"The level of neutropenia in this study is concerning," said Sumanta Pal, MD, assistant professor of medical oncology and therapeutics research at the City of Hope Comprehensive Cancer Center, Duarte, Calif. "It is a big limitation for this treatment."
He said that attempts to find other treatment regimens are warranted.
The olaparib studies were sponsored by AstraZeneca. Dent and her co-authors disclosed financial relationships with AstraZeneca, GlaxoSmithKline, Novartis, and Roche. Gelmon disclosed financial relationships with AstraZeneca. Pal disclosed financial relationships with Pfizer and GlaxoSmithKline.
Primary source: Journal of Clinical Oncology Source reference: Dent R et al, "Safety and efficacy of the oral PARP inhibitor olaparib (AZD2281) in combination with paclitaxel for the first- or second-line treatment of patients with metastatic triple-negative breast cancer: Results from the safety cohort of a phase I/II multicenter trial" J Clin Oncol 2010; 28: 118s.Additional source: Journal of Clinical OncologySource reference: Gelmon K et al, "Can we define tumors that will respond PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer" J Clin Oncol 2010; 28: 233s.
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