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CANCER GENETICS RESEARCH OFFERS NEW DIRECTIONS FOR PREVENTION AND TREATMENT
-- Latest Findings Reveal Prevalence of Breast Cancer Gene and Attitudes about Testing; Prognosis for Colon Cancer Gene Carriers; Prostate Cancer Gene Linked to Early Onset and More Aggressive Disease --
-- Press Briefing Sunday, May 18, 9:30 AM (MDT) --
Denver, CO -- May 18, 1997 -- Cancer genetics has proven one of the more controversial areas of clinical cancer research, with physicians, patients and policy makers uncertain about the benefits of genetic testing, the implications of identifying genetic mutations, and the impact they may have on disease progression. Definitive gene mutations isolated among breast, ovarian and colorectal cancer patients pose important challenges to patients and physicians, who need concrete data to make appropriate decisions regarding testing.
Four studies presented today at a press conference on cancer genetics at the Thirty-third Annual Meeting of the American Society of Clinical Oncology provide data to address many unanswered questions, and contribute significant knowledge to the field. Key questions include: How do perceptions of risk compare with reality of prevalence? What motivates women to seek genetic testing for the BRCA1/2 mutation? How do patients diagnosed with hereditary colorectal cancer compare with those who didnÃt inherit the gene mutation? And how close are we to identifying the prostate cancer gene?
ìAs we move cautiously into the application of genetics in clinical care, we need studies such as these to inform our opinions about the clinical utility of genetic tests,î said Olufunmilayo I. Olopade, MBBS, FACP of the University of Chicago
Pritzker School of Medicine, moderator of the press conference. ìASCO has launched a large cancer genetics education initiative which is aimed at practicing oncologists and other health care professionals who care for cancer patients and their families. It is anticipated that in the next few years, practicing oncologists will acquire the knowledge and skills needed to bring this cutting edge service into their clinical practices to the benefit of patients.î
The topic of cancer genetics will also be featured at the Karnofsky Memorial Lecture on Monday, May 19, delivered by Alfred G. Knudson, MD, PhD, of the Fox Chase Cancer Center. A geneticist and physician, Knudson is internationally recognized for his ìtwo-hitî theory of cancer causation, which explained the relationship between the hereditary and non-hereditary forms of a cancer, and predicted the existence of anti-oncogenes -- genes that can suppress cancer cell growth. This now-confirmed theory has significantly advanced understanding of errors in the genetic program that turn normal cells into cancer cells.
New Research on Breast Cancer Gene Could Clarify Decisions About Testing; History of Ovarian Cancer Found to be Major Risk Factor
E. Winer, et al, Duke University Medical Center, ìAttitudes and Risk Perceptions of Women with Breast Cancer Considering Testing for BRCA 1/2î (Poster Discussion Session, Monday May 19, 11 a.m. [MDT], Room A105-107, Abstract #1937)
T.S. Frank, et al, Myriad Genetic Laboratories, Inc., ìAnalysis of 611 Women with Breast or Ovarian Cancer for Mutations on BRCA1 by Gene Sequencingî (Oral Session, Monday May 19, 9:00 a.m., [MDT] Ballroom 1, Abstract #1914)
Little concrete information exists to guide decisions about the use of genetic testing to identify women who carry the genetic mutation linked to breast cancer. Two new studies provide physicians and patients with important data to inform their decisions, including a comprehensive evaluation of the incidence of the mutation among breast cancer patients, and attitudinal assessments of breast cancer patientsà motivation to get tested, and their perceptions of risks and benefits.
Women with cancer who are considering genetic testing as part of a university-based research program believe that they are likely to have a mutation, and have a strong sense that they want to undergo testing, but have little information about its downsides, according to a new study surveying womenÃs attitudes and knowledge about genetic testing. Eric Winer, MD of the Duke University Medical Center presented data on the first 86 study participants in a randomized trial that plans to include 200 women diagnosed with breast cancer who are considering genetic testing.
The data reveal some of the motivations for testing among women diagnosed with breast cancer: 72% of the women believed they were likely or very likely to have a BRCA1/2 mutation; 97% percent thought that testing would be advantageous to their families; two-thirds thought testing could help them take steps to prevent cancer; and 57% thought a negative result would be reassuring and would decrease anxiety. Nearly half of the women said their doctors had advised them to get tested.
The only major downside cited by the women was concern over insurance coverage, cited by 42% of women; few other disadvantages were noted. Ninety-two percent of the participants said they would probably or definitely be tested; however, the same number said they would prefer to learn more about their risk for carrying the mutation before making a final decision.
* * * An important new study provides the most comprehensive data to date on the prevalence of one of the altered breast cancer susceptibility genes among women with breast or ovarian cancer, and the extent to which age of diagnosis and family history raises a woman's chance of carrying a mutation.
Presenting data on the largest study to date of breast and ovarian cancer diagnosis and the presence of BRCA1 genetic mutations, Tom S. Frank, MD, Medical Director of Myriad Genetic Laboratories, Inc., reported that approximately 1 in 6 women diagnosed with breast cancer under age 40 carry a mutation, and that the presence of ovarian cancer in the family greatly increases the likelihood of having a BRCA1 mutation. The study authors anticipate that these data may help to define which women would benefit most from BRCA1 testing.
BRCA1 is one of two genes responsible for most inherited forms of breast cancer (the other is BRCA2). Although a mutation in BRCA1 is relatively uncommon among the general population, and accounts for only about 5% of breast cancer diagnoses, an estimated 1,000,000 women in the U.S. and Europe carry mutations. Women who carry a mutation in BRCA1 have a greatly increased risk of developing breast and ovarian cancer during their lifetimes. Among women who have already had breast cancer, those carrying a predisposing mutation are more likely to experience a second breast cancer and ovarian cancer.
The study analyzed data from sequencing the BRCA1 gene (over 5,500 chemical ìlettersî) in 830 women with breast cancer, ovarian cancer or both and compared the results to family history and age of onset. Overall, 161 women in the study (19%) were found to carry abnormalities in the BRCA1 gene, of which 117 mutations (14% of the total, or 73% of those with any alterations) were known to contribute to the development of cancer.
A woman with breast cancer by age 50 and no other relatives with breast or ovarian cancer was found to have a 1 in 14 chance of carrying a BRCA1 mutation. If that woman has a single relative with ovarian cancer, however, the risk jumps to 1 in 3. Even families in which there were not many breast cancers were found to be at increased risk of having a BRCA1 mutation if there was any history of ovarian cancer and if any of the breast cancers occurred at or before age 50. Ashkenazi ancestry was also found to increase the likelihood of finding a mutation in BRCA1.
A deleterious mutation in BRCA1 was found among the following group of study participants: approximately 17% of women with breast cancer before the age of 40 (56 of 332, half of whom had at least one relative with ovarian cancer); 29% (13 of 45) of families in which just one woman had breast cancer between ages 40 and 50 and at least one relative had ovarian cancer; 15% (6 of 40) of Ashkenazi families with at least one woman with breast cancer under age 40 but no relatives had ovarian cancer; and 64% (20 of 31) of Ashkenazi families with just one woman with breast cancer under age 40 and at least one relative with ovarian cancer. A similar study is underway to determine who is likely to carry mutations in BRCA2.
* * * ìThe risk of developing ovarian cancer for women with an altered BRCA1 gene ranges from 10% to 80% during a lifetime, which is markedly increased over the 1 in 70 risk for the average American woman,î said Dr. Olopade. ìDr. FrankÃs data tell us that having a family member with ovarian cancer appears to be a strong determinant of whether a woman is likely to carry a BRCA1 mutation. Having this information may be useful to women and their physicians in planning a personalized strategy to reduce the risk of dying from ovarian or breast cancer.î
Better Survival Among Patients with Hereditary Colorectal Cancer
H. Lynch, et al, Creighton University, ìColorectal Cancer, Pathology Staging and Survival in Hereditary Colorectal Cancerî (Oral Session, Monday May 19, 10:15 a.m., [MDT] Ballroom 1, Abstract #1912)
In a significant and surprising finding, patients diagnosed with hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, have a significantly better prognosis for survival than those with ìsporadicî colorectal cancer, according to new research presented by Henry Lynch, MD, of Creighton University. The study compared 274 colorectal cancer patients from 68 families with HNPCC with 820 sporadic colorectal cancer patients. This first detailed examination of survival among patients with mutated MSH2 and MLH1 genes -- linked to colorectal cancer in HNPCC families -- found a 62% 10-year survival, compared with 29% for those patients without the gene mutations. After correction for age and stage at diagnosis, the difference was still significant.
Furthermore, despite similar primary tumors, hereditary patients are less likely to have stage IV disease, and they have significantly fewer liver metastases than patients with sporadic disease -- only 48% of hereditary patients with stage IV disease had liver metastases compared with 71% of sporadic cases (p<0.02) -- which may explain their improved survival rates. (Note: p-values are an indicator of statistical significance; the lower the p-value, the more statistically significant the finding.)
According to the study authors, research into the biological and molecular basis of this phenomenon may provide clues for new avenues of treatment, such as gene therapy, of both hereditary and sporadic colorectal cancer.
Researchers Gain Ground on Prostate Cancer Gene Identification; Linkage to Gene Correlates with Earlier Onset and More Aggressive Disease
H. Gronberg, et al, Umea University, Umea, Sweden ìHPC1: A Major Susceptibility Locus for Prostate Cancer on Chromosome 1î (Oral Session, Monday May 19, 8:00 a.m., [MDT] Ballroom 1, Abstract #1910)
Epidemiological studies have suggested that approximately 5-10% of all prostate cancer is hereditary. Research has shown that the hereditary prostate cancer gene is likely to be on chromosome 1, and Dr. Henrik Gronberg at the Umea University in Sweden reports that a multinational research team is closing in on identifying the gene.
In addition, while the researchers had previously not found a correlation between the gene and disease prognosis, the current analysis has uncovered important differences between patients linked to the gene, dubbed HPC1 (Hereditary Prostate Cancer 1), and those who are not. Preliminary data show that carrying the genetic susceptibility results in earlier onset of the disease, and a more aggressive form of prostate cancer.
The study examined a large group of North American and Swedish families with at least three first-degree relatives with prostate cancer. Data from 75 North American and 12 Swedish families suggest that 30-40% of these families are ìlinkedî to the HPC1 location -- i.e., are likely to have the predisposing gene. The data also show that the likelihood of having the gene is greater among families in whom prostate cancer was diagnosed under age 65. Moreover, men with prostate cancer from families linked to HPC1 are diagnosed with disease at a significantly more advanced clinical stage than men from families not linked to the gene.
The HPC1 gene has not been identified (cloned) yet, however the region in which HPC1 is located has been narrowed to a short fragment on chromosome 1. Because the gene has not been identified, testing for it is not yet feasible.
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