National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
September 20, 2011 • Volume 8 / Number 18

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Cancer Research Highlights

For Young Women, Breast Conserving Surgery May Be Acceptable Alternative to Mastectomy

Women under age 40 who had breast-conserving surgery (BCS) did not have higher rates of local recurrence or poorer overall survival compared with women who underwent mastectomy, according to results from two retrospective studies. Young age at diagnosis is thought to be a risk factor for disease recurrence, and many young women with breast cancer choose mastectomy for treatment.

The research was presented at the 2011 American Society of Clinical Oncology Breast Cancer Symposium in San Francisco. “These studies support [the idea] that breast conserving surgery with lumpectomy and radiation is an excellent option for young women, and may be the preferred approach,” commented Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in NCI’s Division of Cancer Treatment and Diagnosis, who was not involved in the research.

In the first study, researchers led by Dr. Julliette Buckley of Massachusetts General Hospital reviewed the medical records of 628 young women with stage I to stage III breast cancer treated at their hospital between 1996 and 2008. The median follow-up time after treatment was 6 years. During the study period, 7.1 percent of women who had breast conserving therapy and 7.5 percent of women who underwent mastectomy had a local recurrence—a difference that was not statistically significant.

The local recurrence rates seen in this study are lower than in previous studies, stated the researchers. These new results suggest “that lumpectomy is indeed a safe option for young women,” said Dr. Buckley during a press briefing. “We believe that awareness of the genetic risk of breast cancer, advances in the screening for breast cancer, and improvements in systemic and radiation therapy have contributed to the longer overall survival for young women with breast cancer that we have demonstrated,” she explained.

In the second study, investigators led by Dr. Usama Mahmood of the University of Texas M. D. Anderson Cancer Center examined data from NCI’s Surveillance, Epidemiology, and End Results database for 14,760 women between the ages of 20 and 39 who were diagnosed with stage I or stage II breast cancer between 1990 and 2007. All patients who received BCS underwent radiation therapy. The 10-year overall survival rate was virtually identical between the two groups: 83.5 percent for women who had BCS and 83.6 percent for women who had mastectomy.

“We found similar survival with either breast conservation therapy or mastectomy in the treatment of young women with early-stage breast cancer,” said Dr. Mahmood. “This serves as a reminder that women should be counseled appropriately regarding their treatment options and should not choose mastectomy based on an assumption of improved survival.”

Dr. Andrew Seidman, of Memorial Sloan-Kettering Cancer Center, who moderated the press conference, added: “It’s very important that we periodically revisit conventional wisdom, and…this is an important revisitation of the conventional wisdom that young women who have breast cancer really need to have mastectomy.”

Fluorescent Probe Helps Surgeons Find Ovarian Cancer Cells

In a proof-of-concept study, a fluorescent probe designed to bind to epithelial ovarian cancer cells was used safely to visualize small deposits of cancer in the abdominal cavity during surgery, thus helping the surgeon remove the cells. The target of the probe, called folate receptor-alpha, is found in 90 to 95 percent of ovarian cancers but not in normal tissue. The study, the first in of its kind in humans, was led by Dr. Gooitzen M. van Dam of the University of Groningen in the Netherlands and published online September 18 in Nature Medicine.

Ovarian cancer often spreads widely throughout the abdominal cavity, and small deposits of cancer can be difficult to see with the naked eye or detect during surgery. To improve the visualization of tumor cells and allow surgeons to remove more tumor tissue, the researchers tested the imaging agent, which consists of folate linked to a compound (fluorescein isothiocyanate) that glows green under fluorescent light.

The researchers injected 10 women with the probe before surgery. During surgery, the surgeon performed a standard inspection of the abdominal cavity for tumor tissue; the researchers then captured and examined fluorescent images with a three-camera system that did not interfere with the surgical procedure. After the surgeon removed all suspected tumor tissue identified by eye and by the fluorescent probe, the researchers captured a second set of fluorescent images to look for remaining tumor cells. The surgeon then took biopsy specimens of remaining fluorescent tissue to make sure the probe did not give false-positive results (that is, did not mark normal tissue as tumor tissue).

Nine of the patients had tumors that expressed folate receptor-alpha, and the researchers detected fluorescence in tumor tissue in all of these patients during surgery. No fluorescence was seen in adjacent normal tissue. “Real-time image-guided excision of fluorescent tumor deposits [less than 1 mm in diameter] was feasible, and all fluorescent tissue was confirmed to be malignant,” wrote the authors. One woman’s tumor did not express folate receptor-alpha, and the camera system could not detect the tumor cells in her abdomen.

“The use of targeted fluorescent agents could provide a paradigm shift in surgical imaging,” stated the authors, potentially improving the outcomes for patients after surgery by allowing for more thorough removal of tumor tissue. Large studies are needed to confirm these results and determine whether use of the probe can improve diagnosis and surgical treatment, Dr. van Dam and his colleagues concluded.

Nurse Practitioners, Physician Assistants Could Alleviate Projected Oncology Workforce Shortage

The regular use of nurse practitioners and physician assistants in the care of patients with cancer may be a viable solution to the projected shortage of oncologists in the United States, a new study has found. Patients in practices that used this approach were "highly satisfied" with their care, and the oncologists, nurse practitioners, and physician assistants in these practices were also "highly satisfied" with the collaborative care arrangements, according to the study published September 15 in the Journal of Oncology Practice.

The study “shows that coordinated and integrated cancer care provided by both oncologists and nonphysician providers is a very successful model,” said Dr. Dean Bajorin, who co-chairs the American Society of Clinical Oncology’s (ASCO) Workforce Advisory Group.

The study was conducted under the auspices of ASCO's Study of Collaborative Practice Arrangements initiative. ASCO launched this effort in March 2009 in response to the organization’s earlier report that forecast a major shortage of oncologists by 2020.

The first part of the study was a national survey of 226 oncology practices to identify those that commonly use nonphysician practitioners (NPPs). The researchers then analyzed a subset of 31 practices of different sizes and from varied geographic locations, of which only 27 provided complete data. As was the case with the overall survey group, most of the practices in the study group were physician-owned private practices. (Practices at academic centers were excluded from the study group.)

In both groups, NPPs most commonly performed duties such as assisting patients during treatment visits, managing pain and symptoms, educating and counseling patients, and providing follow-up care for patients in remission. Nearly all of the patients knew they were seeing an NPP, the study showed.

The most common approach to collaborative care was what study leader Elaine Towle of Oncology Metrics and her colleagues called the incident-to-practice model (ITPM). In this model, NPPs see patients independent of the oncologists in their practice (although they discuss patients’ care plans prior to the visit with an oncologist), but the oncologists are in the office and available for consultation.

In 60 percent of the practices in the study group, the NPPs work with all of the physicians in the practice. This arrangement appeared to be more efficient—increasing the number of patients seen by nearly 20 percent—than those in which the NPPs worked only with specific physicians in the practice.

The ITPM also offers some practical advantages, the authors explained. “In the private practice setting, the ITPM allows practices to bill Medicare for NPP services as though they were rendered by the physician and to receive reimbursement at the full physician fee schedule.” If these visits were billed under the NPP’s provider number, they noted, reimbursement would be 85 percent of the physician fee schedule.

Study Suggests How the BRCA1 Protein May Help Suppress Tumors

Mutations in the BRCA1 gene are known to increase a woman’s lifetime risk of developing breast and ovarian cancers, but researchers are still investigating how the protein encoded by this gene helps suppress the formation of tumors. A study by Dr. Inder Verma and his colleagues at the Salk Institute for Biological Studies in the September 8 Nature offers some clues.

Using mice and human breast cancer cells, the researchers identified a series of abnormalities in cells lacking the BRCA1 protein. Taken together, the findings suggest that BRCA1 helps to preserve the integrity of a cell’s genome by “silencing” stretches of repetitive DNA that might harm the cell if “awakened,” or transcribed.

When BRCA1 is missing, the researchers found, certain chromosome regions are no longer maintained in a condensed state. Normally, these regions (known as constitutive heterochromatin) are bound tightly; as a result, certain stretches of repetitive DNA are silent. In the absence of BRCA1, however, cells may produce relatively large amounts of RNA from the repetitive regions.

This activity, in turn, may make the genome less stable and set the stage for cancer. “When cells make a lot of this noncoding RNA, it can lead to DNA damage,” said co-author Dr. Quan Zhu. “This kind of damage is thought to cause cancer.”

The maintenance of distinct chromosomal regions in a condensed state may underlie the tumor-suppressive effect of the protein, wrote Dr. Ashok Venkitaraman of the Hutchison/Medical Research Council Research Centre, Cambridge, UK, in an accompanying editorial. The finding, he added, “might herald a breakthrough” for the field.

Over the past decade and a half, many studies have proposed potential functions for the normal BRCA1 protein, such as repairing damaged DNA or helping with transcription. Dr. Verma and his colleagues believe their findings could provide a framework for understanding the role this protein plays in a number of cellular functions.

By and large, the researchers note, their observations in mice and in human cells are consistent with previous studies of BRCA1. “We observed all of the cellular problems that people have reported over the years related to the loss of BRCA1,” said co-author Dr. Gerald Pao.

The activation of repetitive DNA observed in this study was seen in mouse and human tumors. “Whether, and how, this event promotes cancer development in carriers of germline BRCA1 mutations is not yet evident,” Dr. Venkitaraman wrote. Nonetheless, the study “reveals an intriguing new pathway for tumor suppression,” he added. 

Bacterium Associated with Stomach Cancer Directly Damages DNA

A new study helps explain how infection with the stomach bacterium Helicobacter pylori, the strongest known risk factor for gastric (stomach) cancer, may lead to cancer. Researchers have found that H. pylori infection triggers breaks in both strands of the DNA double helix in the nucleus of gastric epithelial cells. These DNA double-strand breaks activate the cells’ machinery for repairing DNA damage, but prolonged H. pylori infection overloads this machinery, which could lead to mutations involved in gastric cancer development.

Drs. Anne Müller and Massimo Lopes of the University of Zurich and their colleagues reported the findings online September 6 in Proceedings of the National Academy of Sciences.

“Human biopsies from infected individuals reveal higher mutation rates of gastric mucosal cells, and results from animal models suggested the same,” Dr. Müller wrote in an e-mail. “But very little is known regarding the mechanism” that causes these mutations.

Using techniques that analyze DNA integrity, the researchers showed that exposing laboratory-grown cells to H. pylori caused DNA double-strand breaks in human gastric cancer cells and in normal mouse gastric epithelial cells. The frequency of double-strand breaks—the most harmful lesions a cell can encounter, according to the authors—depended on the intensity and duration of exposure.

The researchers also showed that DNA damage depends on direct contact of live H. pylori bacteria with their host cells and is not caused by factors such as toxins that these bacteria secrete.

“Our study is one of the few suggesting direct DNA damage as the cause for mutations,” Dr. Müller noted. Other studies have suggested that chronic H. pylori infection and resulting inflammation lead indirectly to DNA damage by triggering the production of chemicals known as reactive oxygen species, which cause oxidation of DNA, but this study ruled out a role for oxidation.

Although most DNA breaks were repaired efficiently by the cell when H. pylori was eliminated by antibiotics, continuous exposure of human gastric cancer cells for 48 hours or longer appeared to flood the DNA-repair machinery. “DNA damage followed by potentially imprecise repair…may contribute to the genetic instability and frequent chromosomal aberrations that are a hallmark of gastric cancer,” the study authors wrote.

Dr. Richard Peek of Vanderbilt University Medical Center, whose research focuses on the role of H. pylori in gastric cancer, commented, “These findings suggest that therapies directed at reducing inflammation, without concomitant elimination of H. pylori, may not be effective in preventing DNA damage that develops in response to this pathogen.”

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