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Conference News ONCOLOGY CONGRESS
PARP Inhibitors Show Promise in Trials By Laird Harrison
SAN FRANCISCO—Poly(ADP-rib - maintained for a long period of time, ose) polymerase (PARP) inhibitors are getting close to 1 year in the average showing impressive potency against patient,” said Armstrong. ovarian cancer in early clinical trials, The drug appears to work by interferaccording to Deborah Armstrong, MD, ing with the process by which tumor an associate professor of oncology, gyne- cells repair themselves. cology, and obstetrics at Johns Hopkins DNA damage can happen for many University, Baltimore, Maryland. reasons, including platinum therapy. At least eight companies are testing Cells repair single-strand DNA damage PARP inhibitors and one through a process called agent, iniparib (BSI-201, base excision repair. They BiPar Sciences), is in phase 3 repair double-strand damclinical trials with applicaage through homologous tions to the US Food and recombination (otherwise Drug Administration (FDA) known as nonhomologous clearly on the horizon, she end-joining). said at the sixth annual Base excision repair deOncology Congress. “One pends on PARP, which of these drugs will see the binds to single-strand breaks light of day fairly soon and and recruits DNA repair Deborah Armstrong, MD will be going to the FDA enzymes. Without PARP, pretty quickly,” Armstrong single-strand breaks are not predicted. repaired; instead they become doublePARP inhibitors appear especially strand breaks. effective when combined with platinum This is germane to cells with BRCA drugs, but even on their own they can mutations, because the BRCA1 and improve ovarian cancers in some BRCA2 genes supply proteins critical patients, she said. And the drugs have for the repair of a double-strand break. shown some promise against breast can- Without these proteins, a doublecer as well. strand break results in a collapsed fork In ovarian cancer, PARP inhibitors and cell death. appear most effective in patients with People with BRCA gene mutations mutation in the BRCA1 or BRCA2 gene. have one normal and one mutated copy In one recent trial in patients with a of these genes. Cancers occur when the BRCA1 or BRCA2 mutation and recur- normal gene is damaged by an event rent ovarian cancer (Audeh MW, et al. such as exposure to ionizing radiation. Lancet. 2010;376:245-251), 11 of 33 However, only the tumor cells have two patients responded to 400-mg twice- damaged copies; the body’s other cells daily olaparib. “These responses were maintain a normal copy of the gene.
If PARP is inhibited, single-strand breaks become double-strand breaks in both the tumor cells and the healthy cells. The tumor cells cannot repair this damage so they die. But the healthy cells are able to repair their DNA using homologous recombination with proteins provided by their normal BRCA1 or BRCA2 genes. “So the tumor cells are much more sensitive to low-level PARP inhibition,” said Armstrong. “And this gives us a very nice clinical window to use.” Because some patients without BRCA defects also respond to PARP inhibition, researchers are wondering if there could be other types of defects related to the homologous recombination pathway that repairs double-strand breaks. Besides BRCA mutations, a somatic deletion of both BRCA genes or promoter methylation could also interrupt the pathway. Some investigators have proposed defects in other genes involved in homologous recombination, such as RAD51. Others have suggested somatic mutations affecting the pathway. “High-grade serous ovarian cancers may be defined by the defects in this pathway,” said Armstrong. “There have been estimates this could be in as many as 5% to 31% of ovarian cancers.” She cited a survey reported by Doug Levine, MD, a gynecologic oncologist at Memorial Sloan-Kettering Cancer Center, New York, which found that 49% of the ovarian cancers they studied had defects in the homologous recombination pathway.
“So I think that leads us to the concept that maybe this is a good target for at least a significant minority of hybrid ovarian cancers, and potentially even the majority of high-grade serous cancers,” Armstrong said. The latest research also supports therapies in which a PARP inhibitor is paired with platinum therapy. In a study presented last year by O’Shaughnessy and colleagues, the PARP inhibitor BSI-201 was combined with gemcitabine/carboplatin in patients with triple-negative metastatic breast cancer (J Clin Oncol. 2009;27:18[suppl]:Abstract 3). Of the 44 patients receiving only the chemotherapy, seven (16%) achieved an objective response. Of the 42 patients receiving the BSI-201 in addition to the chemotherapy, 20 (48%) responded, a statistically significant difference (P = .002). “This is the really astounding data,” said Armstrong. “You essentially saw a tripling of the response rate.” She added that in the O’Shaughnessy study there was essentially no additional toxicity when BSI-201 was added to the chemotherapy. However, she warned that there are still very little data on toxicity because PARP inhibitors have rarely been matched against placebo in clinical trials. “We have DNA repair processes for a reason,” she said. “Will we be seeing a higher rate of secondary malignancies if we are inhibiting DNA repair processes?” She’s looking forward to that answer from the next round of research, now under way. ●
Prevention (CDC) invited 15 experts to serve on the Advisory Committee on Breast Cancer in Young Women. This committee is tasked with helping the agency develop evidence-based approaches to its mission. The experts, ranging from researchers to clinicians to breast cancer survivors, will work on approaches to prevention research, public awareness campaigns, and education efforts.
Americans worry about. For example: • 80% of respondents did not know that lung cancer is the number one killer • 83% of female respondents and 75% of male respondents did not know that lung cancer takes more lives than breast and prostate cancer, respectively • Only 12% of respondents knew the symptoms of lung cancer, as well as that radon is the second leading cause of lung cancer • Only 6% of respondents had spoken to their doctor about their risk for lung cancer • 32% of respondents knew that half of lung cancer occurred in patients who had previously quit smoking • 98% of respondents recognized that lung cancer does not just affect people who smoke. ●
News Notes Position Statement for AYA Patients with Cancer The LIVESTRONG Young Adult Alliance has released a position statement on quality cancer care for adolescents and young adults (AYAs). The statement notes four critical elements of care: (1) timely detection; (2) efficient processes for diagnosis, initiation of treatment, and promotion of adherence; (3) access to healthcare professionals who possess knowledge specific to the biomedical and psychosocial needs of this population; and (4) research that will ultimately derive objective criteria for the development of AYA oncology care guidelines. The statement details specific critical elements, sample strategies, and outcome measures for improving survival, quality of life, and quality of care throughout the cancer care continuum.
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The LIVESTRONG Young Adult Alliance intends for this statement to be a first step toward raising awareness of the need for guidelines for AYA patients with cancer and recognizes the need to test and validate the extent to which its recommendations result in improved survival and quality of life. The position statement was the outcome of a meeting of clinicians, re searchers, and advocates convened in June 2009.
CDC Advisory Committee on Breast Cancer in Young Women As part of its efforts to develop initiatives to improve knowledge of breast health and breast cancer, particularly in women younger than 40 years of age and those at elevated risk, the US Centers for Disease Control and
Americans Need Lung Cancer Education Americans lack knowledge about lung cancer—its causes, its symptoms, its death rates—according to a survey released by the National Lung Cancer Partnership. The survey of 1000 adult men and women found that even though lung cancer is the number one cancer killer, it is not a disease that
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