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Usefulness of BRCA1 and BRCA2 testing questioned
THE LANCET
SCIENCE AND MEDICINE
T
he genes, BRCA1 and BRCA2 had heavy coverage in the New England Journal of Medicine last week with several studies addressing the question of how useful it is to know whether a woman is a carrier of a BRCA1 or BRCA2 mutation. Jeffery Struewing (US National Cancer Institute, Bethesda, MD, USA) and colleagues looked for BRCA1 and BRCA2 mutations in 5318 Jewish volunteers from the Washington DC area. 120 carriers were identified and the cancer rates in first-degree relatives of carriers and non-carriers were compared. Previous estimates have suggested that carriers of germline mutations from high-risk families have an 85% risk of developing breast cancer. But Struewing et al put the risk at only 56% by the age 70. This result, they say, “forces us to confront the ethical issues raised by testing for genetic predisposition for cancer”. Fergus Couch (University of Pennsylvania, Philadelphia, PA, USA) et al estimated the incidence of detectable BRCA1 mutations among women from families with few affected members. Only 16% of the women with breast cancer and a family history of breast cancer and/or ovarian cancer had BRCA1 mutations—the estimate based on genetic-linkage analysis of families is that 45% of all hereditary cases of breast cancer are associated with BRCA1 mutations. “These results suggest”, write the authors, “that even in a referral clinic specializing in screening women from high-risk families, the majority of tests for BRCA1 mutations will be negative and therefore uninformative”. Deborah Schrag (Dana-Farber Cancer Institute, Boston, MA, USA) and co-workers used decision analysis to calculate whether prophylactic mastectomy and oophorectomy lead to gains in life expectancy. While prophylactic mastectomy may increase the life expectancy of a 30-year-old woman carrying a BRCA mutation by up to 5 years, prophylactic oophorectomy would give only 1·7 years more life at most, they calculate. For 60-yearold women prophylactic surgery would be of minimal use. Jane Bradbur y
1524
Treatment of psoriasis moves on onsidering how common psoriasis is (prevalence estimates worldwide range between 0·5% and 4·0%), real advances in therapy are slow coming. But, as described at an IBC-organised conference (London, UK, May 12–13), some promising new treatments are now available or being tested, although there is no sign yet of a permanent cure. According to Knud Kragballe (University of Aarhus, Denmark), topical treatment with the vitamin-D3 analogue calcipotriol improves psoriasis in the “average” patient, without necessarily leading to complete clearance of lesions.Vitamin-D3 analogues have a dose-dependent effect on the proliferation of keratinocytes, although it is not clear whether this is a direct action or takes place via immune modulation. Marvin Garovoy (XOMA, USA) described hu1124—a humanised mouse monoclonal antibody to CD11a that does affect immune function. A phase I trial is underway of hu1124 in psoriasis, where it should work by blocking recruitment of lymphocytes into psoriatic skin.
C
BCX-34 is another experimental drug that acts at the immunological level. BCX-34 inhibits purine nucleoside phosphorylase, an enzyme necessary for T-cell proliferation in man. Although a randomised trial of 1% BCX-34 dermal cream in 90 adults with plaque psoriasis showed only a modest clinical effect, George Omura (BioCryst Pharmaceuticals, USA) reported that 351 patients have now been enrolled in a phase III study. Kragballe is conducting a phase II trial of an ointment formulation of BCX-34 that should give better delivery of active drug to the skin. A preliminary clinical study of oral BCX-34 is also underway at Emory University (AL, USA). An effective alternative to drugs is narrow-band ultraviolet-B phototherapy. James Ferguson (Ninewells Hospital, Dundee, UK) believes that this form of phototherapy is at least as effective as the psoralen plus ultraviolet-A regimen, and is also cheaper, more convenient for patients, and has a lower risk of carcinogenesis. John McConnell
Grapefruit juice: the leveller of drug metabolism glasses a day for 6 days (J Clin Invest hen scientists accidentally 1997; 99: 2545–53). discovered that taking grape“Acute and chronic grapefruit fruit juice with felodipine increased juice caused a dramatic drop in its bioavailability, no-one paid much intestinal CYP3A4 . . . down to fairly attention. But the clinical conseuniform levels between patients”, quences of this interaction have since says Lown. The higher become apparent with the baseline value of other medications, such intestinal CYP3A4 was, as terfenadine, cyclothe more CYP3A4 sporin, and saquinavir. values fell. So, adding Now, the mysteries of the active substance the “grapefruit-juice in grapefruit juice to effect” are being drugs metabolised by unravelled. CYP3A4 could mean Previous evidence that standard drug suggested that grapedoses would be equally fruit juice inhibits effective in everyone. CYP3A4, a cytochrome “We are currently P450, which breaks working to identify the down about one-third Keep on the level active compound, of all drugs. Kenneth although there may be more than Lown, University of Michigan (Ann one”, says Lown. Arbor, MI, USA) and co-workers in For now, “The key is consistency”, the USA and Canada now report cautions Lown. “If you never take or how grapefruit juice taken acutely or always drink grapefruit juice you are chronically affects CYP3A4. Changes unlikely to have problems with medin intestinal CYP3A4 and the ications. It is intermittent juice intake pharmocokinetics of oral felodipine that can cause problems.” were examined in 10 healthy male volunteers, at baseline, after one glass of grapefruit juice, and after three Kelly Morris
W
Food Features
Usefulness of BRCA1 and BRCA2 testing questioned
Vol 349 • May 24, 1997
SCIENCE AND MEDICINE
T
he genes, BRCA1 and BRCA2 had heavy coverage in the New England Journal of Medicine last week with several studies addressing the question of how useful it is to know whether a woman is a carrier of a BRCA1 or BRCA2 mutation. Jeffery Struewing (US National Cancer Institute, Bethesda, MD, USA) and colleagues looked for BRCA1 and BRCA2 mutations in 5318 Jewish volunteers from the Washington DC area. 120 carriers were identified and the cancer rates in first-degree relatives of carriers and non-carriers were compared. Previous estimates have suggested that carriers of germline mutations from high-risk families have an 85% risk of developing breast cancer. But Struewing et al put the risk at only 56% by the age 70. This result, they say, “forces us to confront the ethical issues raised by testing for genetic predisposition for cancer”. Fergus Couch (University of Pennsylvania, Philadelphia, PA, USA) et al estimated the incidence of detectable BRCA1 mutations among women from families with few affected members. Only 16% of the women with breast cancer and a family history of breast cancer and/or ovarian cancer had BRCA1 mutations—the estimate based on genetic-linkage analysis of families is that 45% of all hereditary cases of breast cancer are associated with BRCA1 mutations. “These results suggest”, write the authors, “that even in a referral clinic specializing in screening women from high-risk families, the majority of tests for BRCA1 mutations will be negative and therefore uninformative”. Deborah Schrag (Dana-Farber Cancer Institute, Boston, MA, USA) and co-workers used decision analysis to calculate whether prophylactic mastectomy and oophorectomy lead to gains in life expectancy. While prophylactic mastectomy may increase the life expectancy of a 30-year-old woman carrying a BRCA mutation by up to 5 years, prophylactic oophorectomy would give only 1·7 years more life at most, they calculate. For 60-yearold women prophylactic surgery would be of minimal use. Jane Bradbur y
1524
Treatment of psoriasis moves on onsidering how common psoriasis is (prevalence estimates worldwide range between 0·5% and 4·0%), real advances in therapy are slow coming. But, as described at an IBC-organised conference (London, UK, May 12–13), some promising new treatments are now available or being tested, although there is no sign yet of a permanent cure. According to Knud Kragballe (University of Aarhus, Denmark), topical treatment with the vitamin-D3 analogue calcipotriol improves psoriasis in the “average” patient, without necessarily leading to complete clearance of lesions.Vitamin-D3 analogues have a dose-dependent effect on the proliferation of keratinocytes, although it is not clear whether this is a direct action or takes place via immune modulation. Marvin Garovoy (XOMA, USA) described hu1124—a humanised mouse monoclonal antibody to CD11a that does affect immune function. A phase I trial is underway of hu1124 in psoriasis, where it should work by blocking recruitment of lymphocytes into psoriatic skin.
C
BCX-34 is another experimental drug that acts at the immunological level. BCX-34 inhibits purine nucleoside phosphorylase, an enzyme necessary for T-cell proliferation in man. Although a randomised trial of 1% BCX-34 dermal cream in 90 adults with plaque psoriasis showed only a modest clinical effect, George Omura (BioCryst Pharmaceuticals, USA) reported that 351 patients have now been enrolled in a phase III study. Kragballe is conducting a phase II trial of an ointment formulation of BCX-34 that should give better delivery of active drug to the skin. A preliminary clinical study of oral BCX-34 is also underway at Emory University (AL, USA). An effective alternative to drugs is narrow-band ultraviolet-B phototherapy. James Ferguson (Ninewells Hospital, Dundee, UK) believes that this form of phototherapy is at least as effective as the psoralen plus ultraviolet-A regimen, and is also cheaper, more convenient for patients, and has a lower risk of carcinogenesis. John McConnell
Grapefruit juice: the leveller of drug metabolism glasses a day for 6 days (J Clin Invest hen scientists accidentally 1997; 99: 2545–53). discovered that taking grape“Acute and chronic grapefruit fruit juice with felodipine increased juice caused a dramatic drop in its bioavailability, no-one paid much intestinal CYP3A4 . . . down to fairly attention. But the clinical conseuniform levels between patients”, quences of this interaction have since says Lown. The higher become apparent with the baseline value of other medications, such intestinal CYP3A4 was, as terfenadine, cyclothe more CYP3A4 sporin, and saquinavir. values fell. So, adding Now, the mysteries of the active substance the “grapefruit-juice in grapefruit juice to effect” are being drugs metabolised by unravelled. CYP3A4 could mean Previous evidence that standard drug suggested that grapedoses would be equally fruit juice inhibits effective in everyone. CYP3A4, a cytochrome “We are currently P450, which breaks working to identify the down about one-third Keep on the level active compound, of all drugs. Kenneth although there may be more than Lown, University of Michigan (Ann one”, says Lown. Arbor, MI, USA) and co-workers in For now, “The key is consistency”, the USA and Canada now report cautions Lown. “If you never take or how grapefruit juice taken acutely or always drink grapefruit juice you are chronically affects CYP3A4. Changes unlikely to have problems with medin intestinal CYP3A4 and the ications. It is intermittent juice intake pharmocokinetics of oral felodipine that can cause problems.” were examined in 10 healthy male volunteers, at baseline, after one glass of grapefruit juice, and after three Kelly Morris
W
Food Features
Usefulness of BRCA1 and BRCA2 testing questioned
Vol 349 • May 24, 1997