Cancer Research Highlights

Diagnostic Radiation Exposure May Raise Breast Cancer Risk in Some BRCA1/2 Mutation Carriers

Radiation from conventional x-rays, mammograms, and other diagnostic tests before age 30 may increase the risk of breast cancer in women who carry BRCA1 or BRCA2 gene mutations. In a large, retrospective cohort study, this increased risk was seen at radiation doses considerably lower than those associated with increased risk of breast cancer in other cohorts exposed to radiation.

The findings, from an analysis of women in France, the Netherlands, and the United Kingdom who participated in the GENE-RAD-RISK study, were reported September 6 in the British Medical Journal.

Exposure to ionizing radiation is an established risk factor for breast cancer, particularly when the exposure occurs at an early age. Because the BRCA1 and BRCA2 proteins are important in repairing DNA damage, including damage caused by radiation, researchers have hypothesized that carriers of a mutation in one of these genes might be more sensitive than the general population to ionizing radiation. But previous studies designed to answer this question have yielded inconsistent results.

The new study, led by Dr. Flora van Leeuwen of the Netherlands Cancer Institute in Amsterdam, focused on 1,122 women aged 18 or older who were known to carry a BRCA1 or BRCA2 mutation. The women reported their histories of all diagnostic procedures involving radiation to the chest or shoulders. Researchers used this information to estimate the cumulative dose of radiation to the breast for each woman. They then used national registries or medical records to confirm breast cancer diagnoses among the participants.

When compared with no exposure, any exposure to diagnostic radiation before age 30 was associated with almost double the risk of breast cancer in BRCA1/2 mutation carriers. Women who received the highest doses of radiation before age 30 had an almost fourfold higher risk. By contrast, there was no evidence of an increased breast cancer risk associated with exposure at ages 30 to 39.

Because women with BRCA1 or BRCA2 mutations have a greatly increased risk of developing breast cancer, some guidelines recommend annual mammograms beginning at age 25 to 35 for these women.

These findings “support the recommendation to use non-ionising radiation imaging techniques (such as MRI) as the main tool for surveillance in young BRCA1 and BRCA2 mutation carriers,” the authors concluded.

Dr. Barry Kramer, director of NCI’s Division of Cancer Prevention, noted that the study “helps refine our knowledge” about the connection between radiation exposure and breast cancer risk in people who may be particularly sensitive to the effects of ionizing radiation. However, he cautioned, “the evidence in this study is not definitive.”

The authors acknowledge that their reliance on self report of prior radiation exposure could introduce statistical bias. “People who have cancer may be more likely than those without cancer to recall any radiation that they had,” Dr. Kramer explained.

Until more definitive evidence is available, he continued, “Women who carry BRCA1 or BRCA2 mutations ought to know what we do and don’t know.” Physicians should review the screening and prevention options with each woman and help her consider the potential benefits and downsides of each, he concluded.

Further reading: “Clinical Management of BRCA Mutation Carriers”

New Drug Improves Survival in Patients with Advanced Lung Cancer

Drug Targeting Tumor Suppressor Shows Promise in First Human Study

An experimental drug that reactivates mutant forms of the tumor suppressor protein p53 is safe for humans, according to results from a phase I trial. The drug, APR-246, also stimulated signaling pathways that control p53 in tumor cells isolated from peripheral blood.

The study, published in the Journal of Clinical Oncology, was led by Dr. Sören Lehmann of Karolinska University Hospital in Stockholm.

The findings represent “a major step forward in targeting the most frequently altered pathway in cancer,” wrote Drs. Brian D. Lehmann and Jennifer A. Pietenpol of Vanderbilt University School of Medicine in an accompanying article.

The p53 protein suppresses tumor growth by increasing the expression of genes that slow the cell cycle, that prevent cells from dividing, or that cause programmed cell death (apoptosis). At least half of all tumors develop inactivating mutations in TP53, the gene that produces p53, allowing the tumor to evade this regulation. APR-246 counteracts TP53 mutations by restoring the gene-regulatory activity of mutant p53 protein and by inducing the death of cancer cells.

The 22 participants enrolled in the trial had various forms of leukemia, hormone-refractory metastatic prostate cancer, non-Hodgkin lymphoma, or multiple myeloma. These patients were included because prostate cancers have a high rate of TP53 mutations and because, in preclinical studies, leukemia cells were particularly sensitive to drugs that target p53.

The patients received intravenous infusions of APR-246 for 4 consecutive days. After a follow-up period of 17 days, the most common side effects were fatigue, dizziness, headache, and confusion.

While the trial was not designed to assess the drug’s antitumor effects, several patients showed clinical responses. To investigate the biologic activity of APR-246, Dr. Lehmann and his colleagues analyzed circulating tumor cells obtained before and after the 4-day treatment from the six patients who had these cells. Four of these patients had fewer proliferating cells after receiving APR-246. The investigators also observed signs of apoptosis and increased expression of several p53 target genes.

Microarray analysis of RNA isolated from the circulating tumor cells showed changes in genes responsible for regulating cell growth and death. The level of expression of genes that promote apoptosis appeared to correlate with the dose of APR-246.

Trials are being designed to investigate the effects of higher exposures to APR-246 through longer infusion times and of combining APR-246 with other chemotherapy drugs, most of which depend on a functional version of p53 to be effective.

Study Reveals How Breast Cancer Spreads to Lymph Nodes

A recent study offers new insights into how breast cancer may spread to nearby lymph nodes and also suggests that a drug commonly used to treat heart failure, digoxin, may be able to interrupt the process. The findings were reported September 10 in the Proceedings of the National Academies of Sciences (PNAS).

The lymphatic system is an important route through which cancer cells reach the circulatory system and travel to distant organs, where they develop into metastatic tumors. Metastasis—which is responsible for most cancer deaths—is not well understood, and few treatments actively target it. In breast cancer, nearly all women with metastatic disease have lymph node involvement.

Using mice, Dr. Gregg Semenza of Johns Hopkins University and his colleagues showed that hypoxia-inducible factor-1 alpha (HIF-1α) plays a direct role in the spread of breast cancer cells to the lymph nodes. HIF-1 α is a subunit of the HIF-1 protein, which promotes blood vessel formation under low-oxygen conditions, such as those in tumors. HIF-1α, the researchers found, activates the PDGF-B gene, which codes for platelet-derived growth factor (PDGF-B).

When mice with tumors formed from injected human breast cancer cells were treated with digoxin (which inhibits HIF-1α) or with imatinib (Gleevec; which inhibits PDGF-B), cancer cell spread was dramatically reduced.

In addition, mice with tumors formed from breast cancer cells that were genetically modified to block production of HIF-1α had 75 percent fewer lymph node metastases than mice with tumors formed from unmodified breast cancer cells.

In biopsy samples from human breast cancers, the authors also found that 

• PDGF-B was highly active in cells that were starved of oxygen, 
• HIF-1α directly activated transcription of PDGF-B,
• the HIF-1α and PDGF-B proteins were found near each other in almost all of the biopsy samples they studied, and 
• levels of expression of these proteins in biopsy samples correlated with tumor grade.

Other studies have linked HIF-1α and PDGF-B to metastatic spread. “But this is the first time that anybody has connected all the dots in a single cancer,” Dr. Semenza explained.

Later this year, the Hopkins researchers plan to launch an early-phase clinical trial to test digoxin in women with operable breast cancer, Dr. Semenza said. Digoxin, an off-patent drug, will be given for about 2 weeks before surgery, and the researchers will analyze pre- and post-surgical tumor samples to determine whether the drug is inhibiting HIF-1 and its downstream target genes.

If the trial suggests that the drug is having the intended molecular effects, an early-phase trial combining digoxin with other standard treatments would likely be launched.