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Breast cancer genetics
THE LANCET 2
3
Farquhar CW, Spathis GS, Barron JL, Levin GE. Failure of thiazide diuretics to increase plasma calcium in mild primary hyperparathyroidism. Postgrad Med J 1990; 66: 714–16. Orwoll ES, Bauer DC, Vogt TM, Fox KM. Axial bone mass in older women. Ann Intern Med 1996; 124: 187–96.
of these drugs in these patients. Ali Al Zahrani, *Michael A Levine Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
1
Authors’ reply SIR—We are grateful to G S Spathis for both his complimentary and provocative comments. Spathis takes exception to our recommendation that diuretics, particularly thiazides, should be avoided in patients with primary hyperparathyroidism, and cites our lack of references supporting this position. On the contrary, he suggests that his own experiences, both published1 and anecdotal, provide evidence that thiazides are not contraindicated in these patients. His study was a retrospective analysis of 13 patients with mild and asymptomatic primary hyperparathyroidism who took thiazide diuretics intermittently over several years (range 1·5–10·7). Although this small study failed to demonstrate significant worsening of hypercalcaemia during periods when patients were actually taking the thiazides, other reports have documented the precipitation of severe hypercalcaemia in occasional patients with primary hyperparathyroidism who were taking these drugs.2 Although Spathis cites several important benefits that may derive from the use of thiazide diuretics, including prevention of kidney stones and improvement in bone mineral density, it remains unproved whether these salutatory effects occur in patients with primary hyperparathyroidism. Based on the sparse information concerning the safety, or benefit, of thiazides in patients with primary hyperparathyroidism, we felt it was reasonable to recommend against the routine use of these drugs. We did not assert, and the available data do not support, the proposition that thiazides are absolutely contraindicated in patients with primary hyperparathyroidism, however. Rather, we share Spathis’s hope that others will be emboldened to challenge current convention about the use of thiazides in patients with primary hyperparathyroidism, but would urge them to do so in the setting of a large, prospective, and well-designed clinical study that will provide meaningful information. With the excellent outcome of surgery in primary hyperparathyroidism, and the wide selection of alternative drugs available for the treatment of hypertension, it seems imprudent to use thiazide diuretics in patients with primary hyperparathyroidism until we know more about the long-term risks and benefits
Vol 350 • August 2, 1997
2
Farquahar CW, Spathis GS, Barron JL, Levin GE. Failure of thiazide diuretics to increase plasma calcium in mild primary hyperparathyroidism. Postgrad Med J 1990; 66: 714–16. Strong P, Jewell S, Rinker J, Hoch D, Crapo L. Thiazide therapy and severe hypercalcemia in a patient with hyperparathyroidism. West J Med 1991; 154: 338–40.
SIR—In their informative seminar Ali Al Zahrani and Michael A Levine1 include treatment with lithium and familial hypocalciuric hypercalcaemia in the differential diagnosis of primary hyperparathy-roidism. They state that familial hypocalciuric hypercalcaemia is characterised, among other features, by hypocalciuria. In this respect, it is of interest to add one point. Urine calcium excretion per 24 h among hypercalcaemic patients shows overlap between familial hypocalciuric hypercalcaemia and typical primary hyperparathyroidism. Part of the overlap is caused by variation in creatinine clearance, and with adjustment for this index the overlap of absolute values between the two conditions is diminished. A ratio of calcium clearance to creatinine clearance of 0·02 or more is most characteristic of patients with primary hyperparathyroidism, and a value of 0·01 or less is suggestive of familial benign hypercalcaemia. Values between 0·01 and 0·02 are common in both disorders. Francisco J Fernández-Fernández Department of Internal Medicine, Hospital Arquitecto Marcide, 15405 Ferrol, Spain
1
Zahrani AA, Levine MA. Primary hyperparathyroidism. Lancet 1997; 349: 1233–38.
Breast cancer genetics SIR—The Breast Cancer Linkage Consortium’s (BCLC) report (May 24, p 1505)1 describes the field of breast cancer genetics in a way that is misleading to physicians caring for breast cancer patients and families. In their introduction, the investigators introduce BRCA1 and BRCA2 and then go on to describe the “other genes that are known to increase the risk of breast cancer”. They fail to mention the ataxia-telangiectasia (A-T) gene despite the compelling, widely known, and highly cited, evidence that this gene is responsible for a high proportion, perhaps 6·6%, of all breast
cancer cases.2 This proportion of female breast cancer is higher than the proportion due to mutations at the BRCA1/BRCA2 loci, according to the most recent data.3,4 There are no reliable data that refute the predisposition of A-T heterozygotes to breast cancer. One of the three members of the BCLC writing committee, Douglas Easton, reviewed the relation between A-T heterozygosity and breast cancer for a published symposium volume,5 so he is certainly aware of it. Physicians can be misled by incorrect or obsolete information in the rapidly advancing field of breast cancer genetics. In turn, patients may be harmed or unduly alarmed if a distorted account of breast cancer genetics leads to inappropriate referral for genetic testing or prophylactic surgery. Michael Swift Institute for the Genetic Analysis of Common Diseases, New York Medical College, Hawthorne, NY 10532, USA
1
2
3
4
5
Breast Cancer Linkage Consortium Pathology of familial lung cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 1997; 349: 1505–10. Athma P, et al. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogene 1996; 92: 130–34. FitzGerald MG, MacDonald DJ, Krainer N, 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. Anton-Culver H, Kurosaki T, Taylor TH, et al. Validation of family history of breast cancer and identification of the BRCA1 and other syndromes using a population-based registry. Genet Epidemiol 1996; 13: 193–205. Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol 1994; 66: S177–82.
SIR—The Breast Cancer Linkage Consortium1 has highlighted the morphological attributes of breast cancers associated with BRCA1 and BRCA2 mutations.Their results and the accompanying commentary from I Craig Henderson and Anthony J Patek2 have clearly suggested that the such tumours are biologically and histologically more aggressive than sporadic breast cancers. Do the aggressive features such as the higher histological grade (which includes tubular differentiation, proliferation rate, and nuclear pleomorphism) actually mean that the heritable breast cancers respond poorly to therapy or imply decreased survival. There have been only a few studies addressing the issue of prognosis in heritable breast cancers. Contrary to our expectations, these studies have suggested a better survival among the
365
3
Farquhar CW, Spathis GS, Barron JL, Levin GE. Failure of thiazide diuretics to increase plasma calcium in mild primary hyperparathyroidism. Postgrad Med J 1990; 66: 714–16. Orwoll ES, Bauer DC, Vogt TM, Fox KM. Axial bone mass in older women. Ann Intern Med 1996; 124: 187–96.
of these drugs in these patients. Ali Al Zahrani, *Michael A Levine Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
1
Authors’ reply SIR—We are grateful to G S Spathis for both his complimentary and provocative comments. Spathis takes exception to our recommendation that diuretics, particularly thiazides, should be avoided in patients with primary hyperparathyroidism, and cites our lack of references supporting this position. On the contrary, he suggests that his own experiences, both published1 and anecdotal, provide evidence that thiazides are not contraindicated in these patients. His study was a retrospective analysis of 13 patients with mild and asymptomatic primary hyperparathyroidism who took thiazide diuretics intermittently over several years (range 1·5–10·7). Although this small study failed to demonstrate significant worsening of hypercalcaemia during periods when patients were actually taking the thiazides, other reports have documented the precipitation of severe hypercalcaemia in occasional patients with primary hyperparathyroidism who were taking these drugs.2 Although Spathis cites several important benefits that may derive from the use of thiazide diuretics, including prevention of kidney stones and improvement in bone mineral density, it remains unproved whether these salutatory effects occur in patients with primary hyperparathyroidism. Based on the sparse information concerning the safety, or benefit, of thiazides in patients with primary hyperparathyroidism, we felt it was reasonable to recommend against the routine use of these drugs. We did not assert, and the available data do not support, the proposition that thiazides are absolutely contraindicated in patients with primary hyperparathyroidism, however. Rather, we share Spathis’s hope that others will be emboldened to challenge current convention about the use of thiazides in patients with primary hyperparathyroidism, but would urge them to do so in the setting of a large, prospective, and well-designed clinical study that will provide meaningful information. With the excellent outcome of surgery in primary hyperparathyroidism, and the wide selection of alternative drugs available for the treatment of hypertension, it seems imprudent to use thiazide diuretics in patients with primary hyperparathyroidism until we know more about the long-term risks and benefits
Vol 350 • August 2, 1997
2
Farquahar CW, Spathis GS, Barron JL, Levin GE. Failure of thiazide diuretics to increase plasma calcium in mild primary hyperparathyroidism. Postgrad Med J 1990; 66: 714–16. Strong P, Jewell S, Rinker J, Hoch D, Crapo L. Thiazide therapy and severe hypercalcemia in a patient with hyperparathyroidism. West J Med 1991; 154: 338–40.
SIR—In their informative seminar Ali Al Zahrani and Michael A Levine1 include treatment with lithium and familial hypocalciuric hypercalcaemia in the differential diagnosis of primary hyperparathy-roidism. They state that familial hypocalciuric hypercalcaemia is characterised, among other features, by hypocalciuria. In this respect, it is of interest to add one point. Urine calcium excretion per 24 h among hypercalcaemic patients shows overlap between familial hypocalciuric hypercalcaemia and typical primary hyperparathyroidism. Part of the overlap is caused by variation in creatinine clearance, and with adjustment for this index the overlap of absolute values between the two conditions is diminished. A ratio of calcium clearance to creatinine clearance of 0·02 or more is most characteristic of patients with primary hyperparathyroidism, and a value of 0·01 or less is suggestive of familial benign hypercalcaemia. Values between 0·01 and 0·02 are common in both disorders. Francisco J Fernández-Fernández Department of Internal Medicine, Hospital Arquitecto Marcide, 15405 Ferrol, Spain
1
Zahrani AA, Levine MA. Primary hyperparathyroidism. Lancet 1997; 349: 1233–38.
Breast cancer genetics SIR—The Breast Cancer Linkage Consortium’s (BCLC) report (May 24, p 1505)1 describes the field of breast cancer genetics in a way that is misleading to physicians caring for breast cancer patients and families. In their introduction, the investigators introduce BRCA1 and BRCA2 and then go on to describe the “other genes that are known to increase the risk of breast cancer”. They fail to mention the ataxia-telangiectasia (A-T) gene despite the compelling, widely known, and highly cited, evidence that this gene is responsible for a high proportion, perhaps 6·6%, of all breast
cancer cases.2 This proportion of female breast cancer is higher than the proportion due to mutations at the BRCA1/BRCA2 loci, according to the most recent data.3,4 There are no reliable data that refute the predisposition of A-T heterozygotes to breast cancer. One of the three members of the BCLC writing committee, Douglas Easton, reviewed the relation between A-T heterozygosity and breast cancer for a published symposium volume,5 so he is certainly aware of it. Physicians can be misled by incorrect or obsolete information in the rapidly advancing field of breast cancer genetics. In turn, patients may be harmed or unduly alarmed if a distorted account of breast cancer genetics leads to inappropriate referral for genetic testing or prophylactic surgery. Michael Swift Institute for the Genetic Analysis of Common Diseases, New York Medical College, Hawthorne, NY 10532, USA
1
2
3
4
5
Breast Cancer Linkage Consortium Pathology of familial lung cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 1997; 349: 1505–10. Athma P, et al. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogene 1996; 92: 130–34. FitzGerald MG, MacDonald DJ, Krainer N, 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. Anton-Culver H, Kurosaki T, Taylor TH, et al. Validation of family history of breast cancer and identification of the BRCA1 and other syndromes using a population-based registry. Genet Epidemiol 1996; 13: 193–205. Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol 1994; 66: S177–82.
SIR—The Breast Cancer Linkage Consortium1 has highlighted the morphological attributes of breast cancers associated with BRCA1 and BRCA2 mutations.Their results and the accompanying commentary from I Craig Henderson and Anthony J Patek2 have clearly suggested that the such tumours are biologically and histologically more aggressive than sporadic breast cancers. Do the aggressive features such as the higher histological grade (which includes tubular differentiation, proliferation rate, and nuclear pleomorphism) actually mean that the heritable breast cancers respond poorly to therapy or imply decreased survival. There have been only a few studies addressing the issue of prognosis in heritable breast cancers. Contrary to our expectations, these studies have suggested a better survival among the
365