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Genetic screening for breast cancer in Ashkenazi women
COMMENTARY
Genetic screening for breast Ashkenazi women
cancer
in
See pages 1643, 1645 The identification of the BRCA1 gene locus has launched investigators and clinicians on an exciting and productive search to learn more about the gene’s characteristics. Two papers in this week’s Lancet add to our knowledge-base on the heritability of breast cancer in one population, Jewish women living in the USA. However, we must carefully consider the persistent deficits in our understanding that need to be addressed before we can explain the findings to these women. Late last year, Struewing and colleagues’ reported that 8 of 858 Ashkenazi people attending for genetic counselling for conditions unrelated to breast cancer had a specific frameshift mutation (185delAG) of the BRCA1 locus, a prevalence much higher than estimates of 0-2% for clinically significant BRCA1 mutations in the general American population.’ This finding prompted Egan and colleagues to investigate whether women of Jewish origin or religion have a higher risk of breast cancer than the rest of the population. Their case-control data do not show an overall increased risk, but some of the information suggests that, among Jewish women, family history of breast cancer may be a more powerful predictor of risk than it is in non-Jewish women. Although the authors suggest that this relation may be even stronger for women with early-onset disease, the very small numbers (only five Jewish women aged 50 or younger had a positive family history) make the confidence intervals too wide to state the strength of the relation with any degree of confidence. Earlier this year, FitzGerald and colleagues reported that, of 39 Jewish women who developed breast cancer before the age of 41, 21% carried the 185delAG mutation.2 Offit’s group measured the prevalence of this defect in special subpopulations of Ashkenazi women. The 185delAG mutation was identified in 19% of the 80 women with breast cancer diagnosed before age 42, and in 32% of the 57 women with breast cancer diagnosed before age 51 and a positive family history. What do these results mean for Ashkenazi women, particularly for those with a family history of breast cancer? Is genetic screening of this group of adults feasible or advisable? Although the test may be, as Offit and colleagues suggest, useful in the context of genetic counselling in these high-risk groups, there are many caveats, some of them suggested by the authors themselves, which need careful consideration before
anything approaching population-based screening is suggested for this group of women. The authors of the papers on Ashkenazi people have noted that the population prevalence of the 185del AG mutation may not reflect expected values in the total Ashkenazi population, since one group was selected from individuals attending for genetic counselling, and the second from women with early-onset breast cancer, some of whom were identified from genetic counselling clinics. A more insidious effect of potential selection bias is the impact on estimates of BRCA1 gene-mutation penetrance. Current estimates of penetrance are based on families that came to researchers’ attention because of the high frequency of the breast/ovarian cancer phenotype in the families;’-3 thus, it is reasonable to assume that these
1638
families would have high penetrance. It is not yet known, however, what the risk for breast cancer is among women with BRCA gene defects but not an exceptionally strong family history of the cancer. Offit wisely counsels that we follow heterozygotes to determine their eventual risk. The very act of identifying them as heterozygotes, though, might affect their apparent risk, by magnifying it through earlier detection under surveillance, or diminishing it
through preventive measures. If such a defect is identified, what primary or secondary prevention measures can be offered? Mammographic screening is the only one of the three commonly recommended early-detection strategies (the other two being clinical breast examination and breast selfexamination) found effective in randomised controlled trials. Even so there is agreement on its benefit only for women aged over 50. Thus, the value of mammography is unknown in the context of a BRCA1 gene defect, which has much of its impact on women younger than those for whom screening is known to be effective. Further, whilst the risk:benefit ratio of mammography-balancing the theoretical risk of radiation-induced cancer against mortality reduction through early detection-is favourable in the general population over 50, there is room for reflection about the risks and benefits for young women whose genetic makeup already puts them at strikingly higher risk of breast cancer than the general population. Primary prevention strategies are also in their infancy. Although some would suggest that there is no harm in placing such women on a low-fat diet,4 for example, it may not be helpful, either. Even when results of trials investigating the impact of lowered dietary fat or tamoxifen become available, their generalisability to this especially vulnerable group may not be certain. There are also few data on the degree of risk reduction that can be expected with surgical prophylaxis, through mastectomy and possibly oophorectomy of women ;5 current studies suggest that the risk will not be lowered to zero. Finally, there are the potential psychological, social, and ethical issues related to screening. Particular difficulties with BRCA11 screening arise from the potentially uninformative nature of this test.’ Many women with a negative test will still develop breast cancer, and some with a positive test will not. Further, this particular defect will be responsible for the increased incidence in only a portion of high-risk families. BRCA1screening test should thus not be recommended as a population screening test for Ashkenazi women or any other group at this time. It still needs to be done in a research context, with ample access to genetic counselling and close surveillance of interventions and outcomes. 1,3,4,6
Heather Bryant Division of Epidemiology, Prevention, and Screening, Alberta Cancer Board, 3330 Hospital Drive NW, Calgary, Alberta, Canada TN2 4N1 1
3
Struewing JP, Abeliovich D, Peretz T, et al. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 1995; 11: 198-200. FitzGerald MG, MacDonald DJ, Krainer M, et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. N Engl J Med 1996; 334: 143-49. Collins FS. BRCA1—lots of mutations, lots of dilemmas. N Engl J
4
Lerman C, Croyle R.
2
Med 1996; 334: 186-88. cancer
susceptibility.
Psychological issues in genetic testing for breast Arch Intern Med 1994; 154: 609-16.
5 Hoskins KF, Stopfer JE, Calzone KA,
et
al. Assessment and
counselling for women with a family history of breast cancer. A guide for clinicians. JAMA 1995; 273: 577-85. 6 National Advisory Council for Human Genome Research. Statement on use of DNA testing for presymptomatic identification of cancer risk. JAMA 1994; 271: 785.
Orthoses for rheumatoid feet: does it matter what’s underfoot? Since he began making shoes, man has used foot orthoses support the foot and relieve pain. As our understanding of the biomechanics of the foot and ankle has increased, so has our usage of foot orthoses to support joints, with the intention of preventing deformity and providing pain relief. These devices are commonly used in the management of patients with rheumatoid arthritis (RA), who commonly complain of foot pain and deformity due combined effects of inflammation, bony to the destruction, and connective tissue damage. Although the to
metatarsophalangeal joints
are most commonly affected, synovial joints of the foot and ankle can be involved.’ Surprisingly, the clinical effectiveness of foot orthoses in this patient population had not been assessed in a doubleblind randomised manner until the recent completion of a clinical trial of functional posted (use of corrective wedge) foot orthoses vs placebo orthoses. The results were published in two separate papers, one reporting the effects on the progression of hallux valgus2 and the other the effects on foot pain and disability. 102 men with the diagnosis of classical or definite RA were enrolled at five American, university-affiliated Veterans Affairs hospitals and followed up for 3 years. The patients-all in American
all
Rheumatism Association functional class I or II-had active disease and stage I or II radiological changes in one or both feet. The actual amount of hindfoot valgus was measured in degrees but not described. Patients with severe foot dermatitis were not included in the study. The functional orthoses were fabricated from Rohadur, a rigid thermoplastic. They were posted on the basis of a clinical assessment made by a podiatrist, with the aim of maintaining the subtalar joint in a neutral position at midstance. Metatarsal relief, in the form of a pad or bar proximal to the metatarsal joints, was apparently not
incorporated into the orthoses. The authors concluded that patients wearing functional posted orthoses were 73% less likely (adjusted odds ratio 0-27, 95% CI 0-08-0-92) to demonstrate progression of hallux valgus deformity than were those in the control group." However, functional posted foot orthoses provided no significant benefit over placebos in limiting disability or pain.3 This latter finding is not only contrary to the findings of previous uncontrolled trials but also to prevailing beliefs about good clinical practice.-6 The design of this study was exemplary in many respects-randomisation and blinding procedures, extended follow-up, intention-to-treat analyses, and the use of a range of outcome measures, most of which have previously been validated. For example, weight-bearing radiographs of the feet were used to assess progression of hallux valgus deformities in the treatment and control groups.-’A more subjective measure, the foot function index (FFI),was designed and implemented during the study to assess foot pain, disability, and activity limitation. Unfortunately, this scale may not discriminate disability
Figure: Top
view
Foot orthoses
(left)
and bottom view
(nght)
related to the foot from that related to the lower extremities. Additionally, although the FFI included questions on foot pain, none focused specifically on the weight-bearing forefoot pain so common in RA. The functional foot orthoses were designed primarily to limit pronation by holding the subtalar joint in a neutral position, thereby limiting stresses on the forefoot that promote hallux valgus deformities.8-" We do not know how much correction was provided to achieve this positioning. If the orthoses maintained a neutral subtalar position rather than corrected it, a significant alteration in pain would not be anticipated. Further, since metatarsalgia is the commonest source of foot pain in RA, more effective pain relief might have been provided by orthoses made from a material with more shock-absorbing property than Rohadur, and including metatarsal relief.6,8 In summary, the conclusions are not surprising. These foot orthoses were not designed primarily to limit pain and secondary disability related to rheumatoid foot pathology. Repeating this study with semi-rigid foot orthoses with forefoot and hindfoot posting, as well as metatarsal relief, and with use of more sensitive outcome measures may well yield different results, demonstrating that it really does matter what goes under the rheumatoid foot. Meridith B Marks, Robert J R McKendry Physical Medicine and Rehabilitation Unit; and Rheumatic Disease Unit, University of Ottawa Faculty of Medicine, Ottawa, Canada 1 2
3
4 5
6
Cracchiolo A. In: Gould JS, ed. The foot book. Baltimore: Williams & Wilkins, 1988: 239-67. Budiman-Mak E, Conrad KJ, Roach KE, et al. Can foot orthoses prevent hallux valgus deformity in rheumatoid arthritis? A randomized clinical trial. J Clin Rheumatol 1995; 1: 313-21. Conrad KJ, Budiman-Mak E, Roach KE, Hedeker D. Impacts of foot orthoses on pain and disability in rheumatoid arthritics. J Clin Epidemiol 1996; 49: 1-7. Merritt JL. Advances in orthotics for the patient with rheumatoid arthritis. J Rheumatol 1987; 14 (suppl 15): 62-67. Craxford AD, Stevens J, Park C. Management of the deformed rheumatoid forefoot—a comparison of conservative and surgical methods. Clin Orthop Rel Res 1982; 166: 121-26. Tmley P. Appliances for the rheumatoid foot. Baillierè’s Clin Rheumatol
1987; 1: 383-102. Budiman-Mak E, Conrad KJ, Roach KE. The foot function index: a measure of foot pain and disability. J Clin Epidemiol 1991; 44: 561-70. 8 Philps JW, ed. The functional foot orthosis. New York: Churchill Livingstone, 1990. 9 Smidt L. The subtalar joint and rheumatoid arthritis. Baillierè’s Clin Rheumatol 1987; 1: 275-87. 10 Lang LMG. The anatomy of the foot. Baillierè’s Clin Rheumatol 1987; 1: 215-40. 7
1639
Genetic screening for breast Ashkenazi women
cancer
in
See pages 1643, 1645 The identification of the BRCA1 gene locus has launched investigators and clinicians on an exciting and productive search to learn more about the gene’s characteristics. Two papers in this week’s Lancet add to our knowledge-base on the heritability of breast cancer in one population, Jewish women living in the USA. However, we must carefully consider the persistent deficits in our understanding that need to be addressed before we can explain the findings to these women. Late last year, Struewing and colleagues’ reported that 8 of 858 Ashkenazi people attending for genetic counselling for conditions unrelated to breast cancer had a specific frameshift mutation (185delAG) of the BRCA1 locus, a prevalence much higher than estimates of 0-2% for clinically significant BRCA1 mutations in the general American population.’ This finding prompted Egan and colleagues to investigate whether women of Jewish origin or religion have a higher risk of breast cancer than the rest of the population. Their case-control data do not show an overall increased risk, but some of the information suggests that, among Jewish women, family history of breast cancer may be a more powerful predictor of risk than it is in non-Jewish women. Although the authors suggest that this relation may be even stronger for women with early-onset disease, the very small numbers (only five Jewish women aged 50 or younger had a positive family history) make the confidence intervals too wide to state the strength of the relation with any degree of confidence. Earlier this year, FitzGerald and colleagues reported that, of 39 Jewish women who developed breast cancer before the age of 41, 21% carried the 185delAG mutation.2 Offit’s group measured the prevalence of this defect in special subpopulations of Ashkenazi women. The 185delAG mutation was identified in 19% of the 80 women with breast cancer diagnosed before age 42, and in 32% of the 57 women with breast cancer diagnosed before age 51 and a positive family history. What do these results mean for Ashkenazi women, particularly for those with a family history of breast cancer? Is genetic screening of this group of adults feasible or advisable? Although the test may be, as Offit and colleagues suggest, useful in the context of genetic counselling in these high-risk groups, there are many caveats, some of them suggested by the authors themselves, which need careful consideration before
anything approaching population-based screening is suggested for this group of women. The authors of the papers on Ashkenazi people have noted that the population prevalence of the 185del AG mutation may not reflect expected values in the total Ashkenazi population, since one group was selected from individuals attending for genetic counselling, and the second from women with early-onset breast cancer, some of whom were identified from genetic counselling clinics. A more insidious effect of potential selection bias is the impact on estimates of BRCA1 gene-mutation penetrance. Current estimates of penetrance are based on families that came to researchers’ attention because of the high frequency of the breast/ovarian cancer phenotype in the families;’-3 thus, it is reasonable to assume that these
1638
families would have high penetrance. It is not yet known, however, what the risk for breast cancer is among women with BRCA gene defects but not an exceptionally strong family history of the cancer. Offit wisely counsels that we follow heterozygotes to determine their eventual risk. The very act of identifying them as heterozygotes, though, might affect their apparent risk, by magnifying it through earlier detection under surveillance, or diminishing it
through preventive measures. If such a defect is identified, what primary or secondary prevention measures can be offered? Mammographic screening is the only one of the three commonly recommended early-detection strategies (the other two being clinical breast examination and breast selfexamination) found effective in randomised controlled trials. Even so there is agreement on its benefit only for women aged over 50. Thus, the value of mammography is unknown in the context of a BRCA1 gene defect, which has much of its impact on women younger than those for whom screening is known to be effective. Further, whilst the risk:benefit ratio of mammography-balancing the theoretical risk of radiation-induced cancer against mortality reduction through early detection-is favourable in the general population over 50, there is room for reflection about the risks and benefits for young women whose genetic makeup already puts them at strikingly higher risk of breast cancer than the general population. Primary prevention strategies are also in their infancy. Although some would suggest that there is no harm in placing such women on a low-fat diet,4 for example, it may not be helpful, either. Even when results of trials investigating the impact of lowered dietary fat or tamoxifen become available, their generalisability to this especially vulnerable group may not be certain. There are also few data on the degree of risk reduction that can be expected with surgical prophylaxis, through mastectomy and possibly oophorectomy of women ;5 current studies suggest that the risk will not be lowered to zero. Finally, there are the potential psychological, social, and ethical issues related to screening. Particular difficulties with BRCA11 screening arise from the potentially uninformative nature of this test.’ Many women with a negative test will still develop breast cancer, and some with a positive test will not. Further, this particular defect will be responsible for the increased incidence in only a portion of high-risk families. BRCA1screening test should thus not be recommended as a population screening test for Ashkenazi women or any other group at this time. It still needs to be done in a research context, with ample access to genetic counselling and close surveillance of interventions and outcomes. 1,3,4,6
Heather Bryant Division of Epidemiology, Prevention, and Screening, Alberta Cancer Board, 3330 Hospital Drive NW, Calgary, Alberta, Canada TN2 4N1 1
3
Struewing JP, Abeliovich D, Peretz T, et al. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 1995; 11: 198-200. FitzGerald MG, MacDonald DJ, Krainer M, et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. N Engl J Med 1996; 334: 143-49. Collins FS. BRCA1—lots of mutations, lots of dilemmas. N Engl J
4
Lerman C, Croyle R.
2
Med 1996; 334: 186-88. cancer
susceptibility.
Psychological issues in genetic testing for breast Arch Intern Med 1994; 154: 609-16.
5 Hoskins KF, Stopfer JE, Calzone KA,
et
al. Assessment and
counselling for women with a family history of breast cancer. A guide for clinicians. JAMA 1995; 273: 577-85. 6 National Advisory Council for Human Genome Research. Statement on use of DNA testing for presymptomatic identification of cancer risk. JAMA 1994; 271: 785.
Orthoses for rheumatoid feet: does it matter what’s underfoot? Since he began making shoes, man has used foot orthoses support the foot and relieve pain. As our understanding of the biomechanics of the foot and ankle has increased, so has our usage of foot orthoses to support joints, with the intention of preventing deformity and providing pain relief. These devices are commonly used in the management of patients with rheumatoid arthritis (RA), who commonly complain of foot pain and deformity due combined effects of inflammation, bony to the destruction, and connective tissue damage. Although the to
metatarsophalangeal joints
are most commonly affected, synovial joints of the foot and ankle can be involved.’ Surprisingly, the clinical effectiveness of foot orthoses in this patient population had not been assessed in a doubleblind randomised manner until the recent completion of a clinical trial of functional posted (use of corrective wedge) foot orthoses vs placebo orthoses. The results were published in two separate papers, one reporting the effects on the progression of hallux valgus2 and the other the effects on foot pain and disability. 102 men with the diagnosis of classical or definite RA were enrolled at five American, university-affiliated Veterans Affairs hospitals and followed up for 3 years. The patients-all in American
all
Rheumatism Association functional class I or II-had active disease and stage I or II radiological changes in one or both feet. The actual amount of hindfoot valgus was measured in degrees but not described. Patients with severe foot dermatitis were not included in the study. The functional orthoses were fabricated from Rohadur, a rigid thermoplastic. They were posted on the basis of a clinical assessment made by a podiatrist, with the aim of maintaining the subtalar joint in a neutral position at midstance. Metatarsal relief, in the form of a pad or bar proximal to the metatarsal joints, was apparently not
incorporated into the orthoses. The authors concluded that patients wearing functional posted orthoses were 73% less likely (adjusted odds ratio 0-27, 95% CI 0-08-0-92) to demonstrate progression of hallux valgus deformity than were those in the control group." However, functional posted foot orthoses provided no significant benefit over placebos in limiting disability or pain.3 This latter finding is not only contrary to the findings of previous uncontrolled trials but also to prevailing beliefs about good clinical practice.-6 The design of this study was exemplary in many respects-randomisation and blinding procedures, extended follow-up, intention-to-treat analyses, and the use of a range of outcome measures, most of which have previously been validated. For example, weight-bearing radiographs of the feet were used to assess progression of hallux valgus deformities in the treatment and control groups.-’A more subjective measure, the foot function index (FFI),was designed and implemented during the study to assess foot pain, disability, and activity limitation. Unfortunately, this scale may not discriminate disability
Figure: Top
view
Foot orthoses
(left)
and bottom view
(nght)
related to the foot from that related to the lower extremities. Additionally, although the FFI included questions on foot pain, none focused specifically on the weight-bearing forefoot pain so common in RA. The functional foot orthoses were designed primarily to limit pronation by holding the subtalar joint in a neutral position, thereby limiting stresses on the forefoot that promote hallux valgus deformities.8-" We do not know how much correction was provided to achieve this positioning. If the orthoses maintained a neutral subtalar position rather than corrected it, a significant alteration in pain would not be anticipated. Further, since metatarsalgia is the commonest source of foot pain in RA, more effective pain relief might have been provided by orthoses made from a material with more shock-absorbing property than Rohadur, and including metatarsal relief.6,8 In summary, the conclusions are not surprising. These foot orthoses were not designed primarily to limit pain and secondary disability related to rheumatoid foot pathology. Repeating this study with semi-rigid foot orthoses with forefoot and hindfoot posting, as well as metatarsal relief, and with use of more sensitive outcome measures may well yield different results, demonstrating that it really does matter what goes under the rheumatoid foot. Meridith B Marks, Robert J R McKendry Physical Medicine and Rehabilitation Unit; and Rheumatic Disease Unit, University of Ottawa Faculty of Medicine, Ottawa, Canada 1 2
3
4 5
6
Cracchiolo A. In: Gould JS, ed. The foot book. Baltimore: Williams & Wilkins, 1988: 239-67. Budiman-Mak E, Conrad KJ, Roach KE, et al. Can foot orthoses prevent hallux valgus deformity in rheumatoid arthritis? A randomized clinical trial. J Clin Rheumatol 1995; 1: 313-21. Conrad KJ, Budiman-Mak E, Roach KE, Hedeker D. Impacts of foot orthoses on pain and disability in rheumatoid arthritics. J Clin Epidemiol 1996; 49: 1-7. Merritt JL. Advances in orthotics for the patient with rheumatoid arthritis. J Rheumatol 1987; 14 (suppl 15): 62-67. Craxford AD, Stevens J, Park C. Management of the deformed rheumatoid forefoot—a comparison of conservative and surgical methods. Clin Orthop Rel Res 1982; 166: 121-26. Tmley P. Appliances for the rheumatoid foot. Baillierè’s Clin Rheumatol
1987; 1: 383-102. Budiman-Mak E, Conrad KJ, Roach KE. The foot function index: a measure of foot pain and disability. J Clin Epidemiol 1991; 44: 561-70. 8 Philps JW, ed. The functional foot orthosis. New York: Churchill Livingstone, 1990. 9 Smidt L. The subtalar joint and rheumatoid arthritis. Baillierè’s Clin Rheumatol 1987; 1: 275-87. 10 Lang LMG. The anatomy of the foot. Baillierè’s Clin Rheumatol 1987; 1: 215-40. 7
1639