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Purpose: It is not known whether the risk of breast cancer among BRCA1 and BRCA2 mutation carriers after age 60 is high enough to justify intensive screening or prophylactic surgery. Thus, we conducted a prospective analysis of breast cancer risk in BRCA1 and BRCA2 mutation carriers from age 60 until age 80. Methods: Subjects had no history of cancer and both breasts intact at age 60 (n = 699). Women were followed until a breast cancer diagnosis, prophylactic bilateral mastectomy or death. We calculated the annual cancer rate and cumulative incidence of breast cancer (invasive and in situ) from age 60 to age 80. We assessed the associations between hormone replacement therapy, family history of breast cancer and bilateral oophorectomy and breast cancer risk. Results: Over a mean follow-up of 7.9years, 61 invasive and 20 in situ breast cancers were diagnosed in the cohort. The mean annual rate of invasive breast cancer was 1.8% for BRCA1 mutation carriers and 1.7% for BRCA2 mutation carriers. The cumulative risk of invasive breast cancer from age 60 to 80 was 20.1% for women with a BRCA1 mutation and was 17.3% for women with a BRCA2 mutation. Hormone replacement therapy, family history and oophorectomy were not associated with breast cancer risk. Conclusions: Findings from this large prospective study indicate that the risk of developing breast cancer remains high after age 60 in both BRCA1 and BRCA2 mutation carriers. These findings warrant further evaluation of the role of breast cancer screening in older mutation carriers.

It is not clear if early oral contraceptive use increases the risk of breast cancer among young women with a breast cancer susceptibility gene 1 (BRCA1) mutation. Given the benefit of oral contraceptives for the prevention of ovarian cancer, estimating age-specific risk ratios for oral contraceptive use and breast cancer is important. We conducted a case-control study of 2,492 matched pairs of women with a deleterious BRCA1 mutation. Breast cancer cases and unaffected controls were matched on year of birth and country of residence. Detailed information about oral contraceptive use was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the odds ratios (OR) and 95 % confidence intervals (CI) for the association between oral contraceptive and breast cancer, by age at first use and by age at diagnosis. Among BRCA1 mutation carriers, oral contraceptive use was significantly associated with an increased risk of breast cancer for women who started the pill prior to age 20 (OR 1.45; 95 % CI 1.20-1.75; P = 0.0001) and possibly between ages 20 and 25 as well (OR 1.19; 95 % CI 0.99-1.42; P = 0.06). The effect was limited to breast cancers diagnosed before age 40 (OR 1.40; 95 % CI 1.14-1.70; P = 0.001); the risk of early-onset breast cancer increased by 11 % with each additional year of pill use when initiated prior to age 20 (OR 1.11; 95 % CI 1.03-1.20; P = 0.008). There was no observed increase for women diagnosed at or after the age of 40 (OR 0.97; 95 % CI 0.79-1.20; P = 0.81). Oral contraceptive use before age 25 increases the risk of early-onset breast cancer among women with a BRCA1 mutation and the risk increases with duration of use. Caution should be taken when advising women with a BRCA1 mutation to take an oral contraceptive prior to age 25.

Background: Hormone therapy (HT) is commonly given to women to alleviate the climacteric symptoms associated with menopause. There is concern that this treatment may increase the risk of breast cancer. The potential association of HT and breast cancer risk is of particular interest to women who carry a mutation in BRCA1 because they face a high lifetime risk of breast cancer and because many of these women take HT after undergoing prophylactic surgical oophorectomy at a young age. Methods: We conducted a matched case-control study of 472 postmenopausal women with a BRCA1 mutation to examine whether or not the use of HT is associated with subsequent risk of breast cancer. Breast cancer case patients and control subjects were matched with respect to age, age at menopause, and type of menopause (surgical or natural). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with conditional logistic regression. Statistical tests were two-sided. Results: In this group of BRCA1 mutation carriers, the adjusted OR for breast cancer associated with ever use of HT compared with never use was 0.58 (95% CI = 0.35 to 0.96; P =. 03). In analyses by type of HT, an inverse association with breast cancer risk was observed with use of estrogen only (OR = 0.51, 95% CI = 0.27 to 0.98; P =. 04); the association with use of estrogen plus progesterone was not statistically significant (OR = 0.66, 95% CI = 0.34 to 1.27; P =. 21). Conclusion: Among postmenopausal women with a BRCA1 mutation, HT use was not associated with increased risk of breast cancer; indeed, in this population, it was associated with a decreased risk.

Among women with a mutation in BRCA1 or BRCA2, the risk of breast cancer is high, but it may be modified by exogenous and endogenous factors. There is concern that exposure to carcinogens in cigarette smoke may increase the risk of cancer in mutation carriers. We conducted a matched case-control study of 2,538 cases of breast cancer among women with a BRCA1 (n = 1,920) or a BRCA2 (n = 618) mutation. One non-affected mutation carrier control was selected for each case, matched on mutation, country of birth, and year of birth. Odds ratios were calculated using conditional logistic regression, adjusted for oral contraceptive use and parity. Ever-smoking was not associated with an increased breast cancer risk among BRCA1 carriers (OR = 1.09; 95% CI 0.95-1.24) or among BRCA2 carriers (OR = 0.81; 95% CI 0.63-1.05). The result did not differ when cases were restricted to women who completed the questionnaire within two years of diagnosis. A modest, but significant increase in risk was seen among BRCA1 carriers with a past history of smoking (OR = 1.27; 95% CI 1.06-1.50), but not among current smokers (OR = 0.95; 0.81-1.12). There appears to be no increase in the risk of breast cancer associated with current smoking in BRCA1 or BRCA2 carriers. There is a possibility of an increased risk of breast cancer among BRCA1 carriers associated with past smoking. There may be different effects of carcinogens in BRCA mutation carriers, depending upon the timing of exposure.

To outline modern principles of surgery, radiation therapy, and systemic treatment of breast cancer, and to review preliminary data on breast cancer prevention.A MEDLINE search was conducted from 1966 to the beginning of 1999; most of the studies reviewed are randomized clinical trials.Breast conservation surgery should be offered to all women with early breast cancer because studies demonstrate survival rates equivalent to those with mastectomy. If mastectomy is chosen, breast reconstruction should be offered. Most women with breast cancer are treated systemically with either chemotherapy or tamoxifen, or both, and mortality is substantially reduced. Data indicating that tamoxifen prevents breast cancer are promising; more studies with both tamoxifen and raloxifene are under way. All women should be strongly encouraged to enter clinical trials.Because many issues face women recently diagnosed with breast cancer, they often seek out family physicians as advisors to help negotiate a complex treatment path. The possibility of preventing breast cancer will undoubtedly raise questions among family members of women with breast cancer that should appropriately be answered and referred, if necessary, by family physicians.

To examine the costs of routine outpatient follow-up after curative treatment of endometrial cancer, and to determine whether this leads to early detection of recurrence or survival. The impact of specific disease characteristics on survival is examined.Retrospective chart review, and calculation of costs.Ottawa Regional Cancer Centre-Civic Division (ORCC-C).All 432 patients referred to the ORCC-C with endometrial cancer between 1982 and 1991 who received treatment with curative intent and who continued with routine follow-up.Cancer recurred in 50 patients (11.57%). There was no statistically significant difference in overall survival between patients with symptomatic and asymptomatic recurrences, or between those with recurrences detected during routine follow-up visits or in the interval between routine visits. Of 4830 Papanicolaou (Pap) smears performed routinely, cancer was detected in 6 cases. The mean cost of the routine follow-up procedures for each patient with a recurrence was $19,200.Intensive follow-up of women with endometrial cancer does not result in improved survival. A prospective randomized study is warranted to evaluate other potential benefits of follow-up, such as improved quality of life or decreased morbidity. There is no economic or clinical justification for the routine use of the Pap smear in the follow-up of patients with endometrial cancer. The potential benefits of routine follow-up in endometrial cancer and other types of cancer with favourable prognoses warrant critical evaluation.

Crystals of sickle-cell deoxyhemoglobin were grown from solutions containing polyethylene glycol and citrate-phosphate buffer at a pH between 5 and 6. The crystals have the symmetry of the monoclinic space group P21, with a=63·28 A, b=184·19 A, c=52·84 A, and β=92·67°. The structure was determined by rotational and translational search procedures. Structure amplitudes and phases were calculated from the atomic co-ordinates of deoxy Hb§ A molecules appropriately positioned in the unit cell of the deoxy Hb S crystal. An Fo−Fo difference Fourier for the Hb S cristal was compouted at 5 A resolution. Portions of the Hb S molecules near the Val6β residues do not appear to be significantly different from the same portions of deoxy Hb A molecules crystallized in polyethylene glycol solutions at pH 7. In the Hb S crystal the molecular x axes enclose angle of less than 10° with the crystallographic a axis. The molecules are arranged in pairs of interlocking strands aligned with the a axis. The two strands in each pair are related approximately a 2-fold screw axis running between them longitudinally. Intermolecular contacts within each pair of strands involve Val6β and other residues that are believed to affect sickling interactions. Double strands, similar to those found in the Hb S crystal, can be incorporated into a fiber model that is consistent with available information on the structure of deoxy Hb S fibers in vivo.

A table has been compiled of the spatial disposition of the amino acid residues in the human deoxy hemoglobin tetramer. The table also indicates regions of possible contact between residues in each subunit and possible contacts between subunits.

The structure of a new crystal form of deoxyhemoglobin A grown from polyethylene glycol solutions has been determined at 3·5 A resolution. The molecular orientations and positions were found by means of rotation and translation functions using the squared molecular transform of horse deoxyhemoglobin. Phases were calculated using atomic co-ordinates previously determined for deoxyhemoglobin A grown in another crystalline form. A difference Fourier synthesis showed minor structural differences near intermolecular contacts, the heme groups, and the β 1 carboxyl terminus. Some of these differences may be caused by the different crystalline environment; others may be due to errors in the analytical method. These apparent structural differences will be useful for interpreting results of a similar analysis of deoxyhemoglobin S crystals grown from the same solvent.

The crystal structure of haemoglobin V from the sea lamprey Petromyzon marinushas been analysed by X-ray diffraction. This report describes the structure of the cyanide complex of methaemo-globin crystals, type D2.

The separation and purification of the six lamprey hemoglobins from Petromyzon marinus is reported. These six hemoglobins, which are single-chain, single heme, molecules (mol. wt. = 18,400), differ in their electrophoretic mobilities and isoelectric points. They show slight differences in their absorption spectra at different pH values, minor differences in solubility in strong salt solutions, and minor differences in stability at acid and alkaline pH. All these differences indicate that the primary structures of the six hemoglobins are different. Four of the six hemoglobins (1, 3, 4, 5) have been crystallized.

OBJECTIVES: To assist family physicians in stratifying women with a family history of breast cancer as being at low, moderate, or high risk of hereditary breast cancer (HBC). To present guidelines for managing each of these risk groups. QUALITY OF EVIDENCE: A MEDLINE search was conducted from January 1976 to December 1997 using key words related to breast cancer risk factors, risk assessment, prevention, and screening. Risk stratification criteria were derived empirically and assessed using retrospective chart review. MAIN FINDINGS: Although up to 20% of women in the general population have a family history of breast cancer, less than 5% are at high risk for HBC. Certain features in a family history suggest increased risk. Women with none of these features are at low risk for HBC and should have annual clinical breast examinations and mammography at least every 2 years starting at age 50. Women with one or more features of increased risk who do not meet criteria for referral to a familial cancer clinic are at moderate risk for HBC and should begin annual mammography and clinical breast examination at age 40. Women who meet referral criteria are at high risk for HBC and should be counseled regarding referral to a familial cancer clinic for more detailed risk assessment and consideration for genetic testing. All women should be taught proper breast self-examination technique and encouraged but not pressured to practise it monthly for life. CONCLUSION: A simple algorithm can assist physicians in stratifying women into low, moderate, and high HBC risk groups. Management strategies for each group are given in this article and the two following (Heisey et al page 114 and Carroll et al page 126).

Introduction BRCA1 and BRCA2 mutation carriers are at increased risk for developing both breast and ovarian cancer. It has been suggested that carriers of BRCA1/2 mutations may also be at increased risk of having recurrent (three or more) miscarriages. Several reproductive factors have been shown to influence the risk of breast cancer in mutation carriers, but the effects of spontaneous and therapeutic abortions on the risk of hereditary breast cancer risk have not been well studied to date. Methods In a matched case-control study, the frequencies of spontaneous abortions were compared among 1,878 BRCA1 mutation carriers, 950 BRCA2 mutation carriers and 657 related non-carrier controls. The rates of spontaneous and therapeutic abortions were compared for carriers with and without breast cancer. Results There was no difference in the rate of spontaneous abortions between carriers of BRCA1 or BRCA2 mutations and non-carriers. The number of spontaneous abortions was not associated with breast cancer risk among BRCA1 or BRCA2 mutation carriers. However, BRCA2 carriers who had two or more therapeutic abortions faced a 64% decrease in the risk of breast cancer (odds ratio = 0.36; 95% confidence interval 0.16–0.83; p = 0.02). Conclusion Carrying a BRCA1 or BRCA2 mutation is not a risk factor for spontaneous abortions and spontaneous abortions do not appear to influence the risk of breast cancer in carriers of BRCA1 or BRCA2 mutations. However, having two or more therapeutic abortions may be associated with a lowered risk of breast cancer among BRCA2 carriers.

Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.