National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
January 27, 2009 • Volume 6 / Number 2

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Cancer Research Highlights

Removal of Ovaries and Fallopian Tubes Cuts Cancer Risk for BRCA1/2 Carriers

Surgery that removes the ovaries and fallopian tubes, called salpingo-oophorectomy, is one of the most effective ways to decrease a woman's risk of breast and gynecologic cancer if she carries a BRCA1 or BRCA2 gene mutation. However, the true degree of risk reduction has not been precisely defined. A new meta-analysis of 10 independent studies has revealed with greater confidence than ever before that the risk reduction of this surgery can be 80 percent for ovarian or fallopian tube cancer and 50 percent for breast cancer. The full results of the analysis appeared online January 13 in the Journal of the National Cancer Institute.

A team of researchers led by Dr. Timothy R. Rebbeck of the University of Pennsylvania looked at overall breast cancer risk, breast cancer risk according to BRCA mutation, and ovarian or fallopian cancer risk. Women who had BRCA1 mutations and women who had BRCA2 mutations benefited equally in terms of breast cancer risk after the surgery, according to their analysis. The authors pointed out, however, that this conflicts with results from their previous prospective cohort study which indicated that the surgery may have more benefit for BRCA2 mutation carriers.

“[Studies] that used retrospective cohort or case-control approaches did not observe this difference, and therefore, there was no difference in the pooled estimates,” they wrote, noting that the issue deserves further investigation. Data were not available for the meta-analysis to make this BRCA-type distinction for gynecologic cancer risk after the surgery.

In a related editorial, Drs. Mark H. Greene and Phuong L. Mai of NCI's Division of Cancer Epidemiology and Genetics commended the study authors, noting that their attempt to “disentangle potential differences between BRCA1 and BRCA2 mutation carriers who, despite having superficial similarities with regard to phenotype, have important biological differences” strengthens the findings of their report. “The risk estimates presented in the study represent the most accurate current measures of potential benefits from risk-reducing salpingo-oophorectomy,” said Dr. Greene, “and genetics providers should use them in their daily practice.”

Double Transplantation of One's Own Stem Cells Is Not Warranted for Multiple Myeloma

The addition of a second (tandem) hematopoietic stem cell transplant (HSCT) procedure using one's own (autologous) blood cells does not appear to improve either event-free or overall survival in multiple myeloma, according to a meta-analysis of trials comparing single versus tandem transplants head-to-head published online January 13 in the Journal of the National Cancer Institute. Researchers led by Dr. Ambuj Kumar at the H. Lee Moffitt Cancer Center and Research Institute concluded that “the routine use of tandem transplant in its current form is not justified.”

This conclusion reflects another finding in their review: While the response rate improved 21 percent in patients receiving tandem treatments, the risk of treatment-related mortality (TRM) increased by 71 percent in this group. The data were drawn from six randomized controlled trials published or presented at meetings since 2003, in which a total of 1,803 patients were enrolled.

Multiple myeloma is a rarely curable malignancy of blood plasma cells that is nonetheless highly treatable, especially when certain patients are conditioned with different chemotherapy combinations before undergoing autologous HSCT. Tandem transplantation became feasible in the early 1990s, and these six trials were subsequently mounted to determine its value and safety in clinical practice.

While the earliest trial published in 2003 showed tandem transplantation improved overall and event-free survival, the authors of the meta-analysis noted that those results “also indicated that tandem transplant may not benefit all patients equally,” and that the subsequent trials did not stratify patients according to biologic and genomic factors that are thought to influence risk. Therefore, they wrote, “it is not known if a benefit in terms of [overall survival] may exist” in a subgroup of patients receiving the tandem treatment, “or if a survival benefit might emerge as strategies to reduce TRM are improved.”

Race May Not Be a Survival Factor in Triple-negative Breast Cancer

Compared with white women, young African American women have a higher incidence of triple receptor-negative (TN) breast cancer, tumors that don't respond to treatment with hormone therapy or trastuzumab (Herceptin). This higher incidence has been proposed as the principal biological factor that, along with social and economic factors, may contribute to why African American women have higher breast cancer mortality rates compared with white women.

Now, a new study from investigators at the University of Texas M.D. Anderson Cancer Center published in the January 10 Journal of Clinical Oncology suggests that African American and white women with TN breast cancer treated at the same institution under the same treatment conditions have similar survival outcomes.

The investigators reviewed data collected from 471 women with TN breast cancer who were treated with preoperative chemotherapy at M.D. Anderson between 1996 and 2005. All of the women underwent surgery after chemotherapy and received radiation therapy if their tumors had not responded to the preoperative chemotherapy. The proportion of women who received mastectomy versus breast-conserving surgery and who had lymph nodes removed did not differ significantly between racial groups.

Sixty-eight percent of African American women experienced a 3-year recurrence-free interval after treatment, compared with 62 percent of white women or women of other racial groups. Three-year overall survival was 71 percent for both groups. Women in both groups who had a pathologic complete response to preoperative chemotherapy (absence of invasive disease in the breast or axillary lymph nodes) had improved survival.

“We hypothesize that when similar treatment and follow up are delivered within a specialized cancer institution to women with TN disease, survival among black and white/other patients is similar. These observations need to be confirmed in a larger prospective study,” concluded the authors.

Method Could Reveal Fused Genes in Common Cancers

Researchers have developed a way to search for genes that are inappropriately fused in cancer cells and that may drive the disease. These gene rearrangements are common in cancers of the blood, and recent studies have suggested that they may be important in other tumor types as well, particularly prostate and lung. But until now there has been no efficient way to hunt for them.

A team led by Dr. Arul Chinnaiyan of the University of Michigan Medical School and an NCI Early Detection Research Network (EDRN) investigator developed a solution called “integrative transcriptome sequencing.” The method involves using two types of “next-generation” sequencing techniques to analyze messenger RNA from cancer cells. This generates relatively long RNA sequences that become scaffolds for assembling many shorter sequences (produced by another technology). The integration is critical because each method on its own yields many false-positive results, the researchers reported online in Nature January 11.

As a demonstration of the technique, the team “re-discovered” known fusions, including BCR-ABL1 in chronic myelogenous leukemia, as well as previously unknown examples. Once a fused gene has been found, the researchers stress, the next steps include asking whether the fusion occurs in other patients and contributes to cancer progression.

“The whole field is looking for these fusions, and our study shows that you can find them using next-generation sequencing and by focusing on the RNA of cancer cells,” said Dr. Chinnaiyan. Fused genes represent an underappreciated class of mutations that may be missed by sequencing the genomes of tumor samples, he added.

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