National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 26, 2012 • Volume 9 / Number 13

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Cancer Research Highlights

Breast Cancers Can Change Biologically as They Progress and Relapse

In many women with recurrent breast cancer, the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status of their tumors changes between treatment for the primary tumor and relapse, a large retrospective study has found. The findings, published June 18 in the Journal of Clinical Oncology, support previous studies that have also detected changes in these biomarkers during cancer progression.

These three biomarkers help doctors choose the best treatments for individual women. Therefore, tumors that recur in the breast or appear elsewhere in the body should be biopsied “as a routine procedure” because the results may influence treatment decisions, recommended the authors led by Dr. Linda Lindström of Cancer Center Karolinska in Sweden.

Dr. Lindström and her colleagues used information from pathology reports for 1,010 women treated at three hospitals in Stockholm, all of whom had biopsies taken from their primary and recurrent breast tumors. All three hospitals had stringent quality-control methods for verifying the accuracy of all three biomarkers.

Primary and recurrent tumors from 459 women were tested for ER expression. In almost 33 percent of those women, the ER status of the tumor changed (ER expression started or stopped) between treatment and relapse. More than 40 percent of the 430 women whose tumors were tested for PR expression had a change in PR status between treatment and relapse. And almost 15 percent of the 104 women whose primary and recurrent tumors were tested for HER2 expression had a change in HER2 status between treatment and relapse.

In women whose cancers relapsed multiple times, similar proportions of changes to biomarkers were observed.

Prior treatment appeared to influence some biomarker changes. For example, women previously treated with hormone therapy were more likely than women who did not receive hormone therapy to have changes in tumor ER expression. The authors also found that women with ER-positive primary tumors that lost ER expression at relapse had a higher risk of death than women with stable tumor ER expression.

Treatment for metastatic breast cancer is often based on primary tumor characteristics. For some patients, biopsy results will show that the tumor has changed. Therefore, “verifications will be important and may change management options,” concluded the authors.

World Health Organization Classifies Diesel Exhaust a Human Carcinogen

On June 12, the International Agency for Research on Cancer (IARC), part of the World Health Organization, classified diesel engine exhaust as carcinogenic to humans (a group 1 carcinogen). The decision was based on an IARC working group’s opinion that the body of evidence supports an association between diesel exhaust exposure and an increased risk of lung cancer. The working group also found a positive association—though with limited evidence—between diesel exhaust exposure and bladder cancer.

IARC published a summary of the working group’s evaluation in Lancet Oncology on June 18.

In 1988, IARC classified diesel exhaust as probably carcinogenic to humans (a group 2A carcinogen), and in 1998 an agency advisory group recommended a priority review of the association. The revised classification is based on results from several large human studies, including the recently published Diesel Exhaust in Miners Study (DEMS), led by NCI and the National Institute for Occupational Safety and Health.

“We are pleased that data from our study played an important role in the re-evaluation by providing some of the strongest evidence of an association between diesel exhaust and lung cancer risk,” said Dr. Debra Silverman, chief of the Occupational and Environmental Epidemiology Branch in NCI’s Division of Cancer Epidemiology and Genetics and a lead investigator on the DEMS study.

“There was a tremendous amount of scientific evidence…around the potential harmful effects of diesel exhaust: dozens of epidemiological studies, dozens if not hundreds of laboratory studies in laboratory animals, and then literally thousands of molecular biology and other types of studies looking at fundamental cellular processes and how they’re affected” by diesel exhaust or its constituents, said Dr. Christopher Portier, chair of the IARC working group, at a press conference.

“Our role has been to summarize the scientific evidence and to put that into the public domain” but not to address permissible levels of exposure or other regulatory issues, explained IARC Director Dr. Christopher Wild. “Having provided that evidence base, it’s really then up to national and international regulatory authorities to weigh that [in] the balance with other factors,” he added.

These issues may be particularly important in the developing world, where older, more polluting diesel technology is still widely used and where emissions regulations are lacking, he concluded.

Pre-Existing Mutations May Explain Development of Resistance to Targeted Cancer Drugs

Most patients with advanced colorectal cancer treated with the drug panitumumab (Vectibix) develop resistance to the treatment, and a new study suggests why. Even before patients begin the treatment, a small percentage of their tumor cells may harbor genetic mutations that make the tumors resistant to the drug, researchers reported in Nature on June 13.

Colorectal tumors without KRAS gene mutations usually develop resistance to panitumumab within several months. To study why, Dr. Luis Diaz of the Sidney Kimmel Comprehensive Cancer Center and his colleagues analyzed blood samples from 28 patients for common mutations in the KRAS gene that confer resistance to the drug. The blood samples were collected before treatment and at 4-week intervals during treatment.

Four of the 28 patients were known to harbor KRAS mutations in their tumors, and the researchers detected mutant forms of the KRAS gene in blood samples from 3 of these patients before they began treatment. No KRAS mutations were detected in blood samples obtained before treatment from the 24 patients whose tumor tissue was believed to contain nonmutated KRAS.

An analysis of blood samples taken during treatment indicated that 9 of those 24 patients developed KRAS mutations over the course of treatment. The timing of the appearance of the KRAS mutations was consistent with the time it typically takes for panitumumab resistance to emerge, 5 or 6 months.

The researchers used these findings to develop a mathematical model of tumor evolution in patients who initially responded to panitumumab. The model indicated that tumors probably contained cells with KRAS mutations before the patients started panitumumab treatment. Once treatment started, the number of resistant cells increased. The authors suggest that “resistance is therefore a fait accompli.”

The fact that a substantial proportion of patients in the study developed mutations in a single gene suggests that only a limited number of mutations and genes may confer resistance, the researchers noted. This finding is encouraging because it may be possible to avoid resistance by treating patients with drugs that target at least two pathways, they concluded.

Testing Combination Therapy Could Reveal Clues to Biology of Pancreatic Cancer

A small number of patients with advanced pancreatic cancer have responded to an experimental treatment regimen in which a targeted drug is given alone and then in combination with chemotherapy. Although they are preliminary, the results suggest that some patients with this deadly disease may benefit from the regimen, researchers reported at the Pancreatic Cancer: Progress and Challenges meeting, held June 18–21 in Lake Tahoe, NV.

The 18 trial participants initially received vismodegib (Erivedge) alone for several weeks and then vismodegib plus gemcitabine. After 3 months, half of the patients showed no disease progression or had a partial response. Vismodegib, a pill that is approved for some patients with skin cancer, inhibits the Hedgehog signaling pathway, a growth-promoting pathway that is inactive in most adult tissues but switched on in some pancreatic cancer cells.

The activated Hedgehog pathway may also help prevent chemotherapy drugs from reaching pancreatic tumors by contributing to the development of dense stromal cells around tumors, explained lead investigator Dr. Edward Kim of the University of Michigan Comprehensive Cancer Center at a press briefing. Vismodegib, he suggested, has the potential to alter these cells in a way that makes chemotherapy more effective.

But Dr. Kim noted that even if the combination therapy benefits the patient for a time, cancer stem cells within pancreatic tumors may lead to resistance. These cells are thought to have the ability to self-renew. Previous studies have indicated that the Hedgehog pathway may be more active in pancreatic cancer stem cells than in other pancreatic tumor cells.

A goal of the current trial is to learn whether targeting the Hedgehog pathway in pancreatic cancer stem cells might benefit patients. A comparison of biopsies taken before and after starting vismodegib could show the effects of the drug on the Hedgehog pathway and reveal which patients are most likely to benefit from the regimen.

A trial of another Hedgehog inhibitor in pancreatic cancer was recently stopped after negative results. So it will be important to learn more about this pathway and its role in pancreatic cancer, noted Dr. Daniel Von Hoff of the Translational Genomics Research Institute, who moderated the press briefing.

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