Response to neo-adjuvant chemotherapy in BRCA1 and BRCA2 related stage III breast cancer

Pathological features and consequently, tumor response differ between BRCA1/2 carriers and sporadic breast cancer (BC) cases. It is expected that BRCA1/2 associated tumors will be more vulnerable to DNA damaging agents and irradiation due to their function in DNA repair. In addition, very high pathological complete response (pCR) rate of approximately 40–50% to neo-adjuvant chemotherapy were reported by two studies. We describe the clinical outcome, i.e.; complete response (cCR), major pathological response (more than 80% reduction in tumor mass), pathologiacl CR (pCR) and local control rates in 15 BRCA1 and 7 BRCA2 carriers, all diagnosed at stage III and treated with anthracyclin based chemotherapy, mastectomy, and irradiation. cCR were found in 6/15 carriers and in 1/7 BRCA2 carriers (P = 0.3). Rate of major pathological response were 4/15 (26.6%) in BRCA1 compared with none of BRCA2 carriers (P = 0.3). Of them, pCR was recorded in 2/15 of BRCA1 carriers. Clinical and pathological nodal involvements were lower in BRCA1 carriers. While all BRCA2 carriers remained node positive as compared to 50% of BRCA1 carriers (P = 0.047), overall survival was similar in both groups. However, approximately 1/3 of BRCA1 carriers did not respond to chemotherapy and 4/15 died within 5 years of diagnosis. We found a non-significant higher clinical and pathological response rate among BRCA1 carriers in response to neo-adjuvant chemotherapy compared with BRCA2 carriers. Our results suggest chemoresistance of approximately a 1/3 of BRCA1 associated tumors. Tumors of BRCA2 carriers are resistant to chemotherapy, while the estrogen receptor positive nature of tumors results in better post recurrence survival.     

Breast conservation in BRCA1 or BRCA2 mutation carriers with early stage breast cancer

The role of breast conservation therapy (limited surgery and irradiation of the breast with/without axilla) in the approximately 5% of breast cancer patients who harbour a germline mutation in BRCA1 or BRCA2, is a largely unexplored area and is seen by some as controversial. The relatively high cumulative risk of second primary cancers in such patients and concern about a possible decreased ability of mutation carriers to repair DNA damage caused by radiation has fuelled this controversy. Published studies of breast conservation therapy in carriers of a mutation in BRCA1 or BRCA2 are reviewed, with particular attention to their methodology. These studies have not demonstrated any increase in radiation sensitivity of normal tissues in mutation carriers, either in terms of increased early or late toxicity or tumourigenesis. Likewise, tumour sensitivity to radiotherapy, which might be expected based on the known functions of the BRCA1 and BRCA2 genes, has not been documented to date in mutation carriers. Further, methodologically rigorous studies of large numbers of breast cancer patients who carry a mutation in BRCA1 or BRCA2 are required to fully elucidate these issues.     

BRCA基因及其相关乳腺癌

BRCA基因是家族性乳腺癌的易感基因，已经明确的有BRCA1和BRCA2，是否存在“BRCA3”是目前研究的热点。BRCA相关乳腺癌有特殊的临床病理学特征。BRCA基因突变携带者接受预防性双侧乳腺或卵巢切除能降低乳腺癌发生风险。单纯保乳术不适用于BRCA相关乳腺癌，应该考虑行双侧乳腺切除或保乳术联合双侧卵巢切除。BRCA基因可能是某些人群的不良预后因素。     

Childhood cancer in families with and without BRCA1 or BRCA2 mutations ascertained at a high-risk breast cancer clinic

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are associated with breast cancer, ovarian cancer and other malignancies. Biallelic mutations of BRCA2 are a cause of Fanconi anemia and characteristic childhood cancers. We undertook this study to evaluate the contribution of familial BRCA mutations to childhood cancer in hereditary breast cancer families. PATIENTS AND METHODS: We compared the prevalence of childhood cancers in 379 families with BRCA1 or BRCA2 mutations and 426 families without mutations. All families were ascertained at a high-risk breast cancer clinic. Our study included first- through fourth-degree relatives of BRCA mutation carriers and cancer-affected individuals with negative testing for BRCA mutations. The primary endpoint was any case of childhood cancer (diagnosed < age 21). RESULTS: 20 cases of childhood cancer occurred in 379 families with BRCA1 or BRCA2 mutations and 35 cases of childhood cancer occurred in 426 families with negative mutation testing (p = 0.12). Nine childhood cancers occurred in 240 families with BRCA1 mutations, and 11 childhood cancers occurred in 141 families with BRCA2 mutations (p = 0.1). 13 of 18 families with childhood cancer and BRCA1 or BRCA2 mutations (72%) and 13 of 31 families with childhood cancer and negative mutation testing (42%) met the Birch criteria for Li-Fraumeni like syndrome (LFL). CONCLUSIONS: In this retrospective analysis, heterozygous BRCA1 and BRCA2 mutations were not a risk factor for childhood cancer in hereditary breast cancer families. These data support the current practice of delaying BRCA mutation testing until adulthood.     

Age at menarche and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers

Age at menarche is a strong and consistent predictor of breast cancer risk in the general population, but has not been well studied in women with a family history of breast cancer. We conducted this study to examine whether the presence of a deleterious BRCA1 or BRCA2 mutation influences age at menarche and to investigate whether or not there is an association between age at menarche and the risk of breast cancer in BRCA1 or BRCA2 mutation carriers. The presence of a deleterious BRCA1 or BRCA2 mutation did not appear to influence a woman’s age at menarche. A matched case–control study was conducted on 1311 pairs of women who have been identified to be carriers of a deleterious mutation in either the BRCA1 (n = 945 pairs) or the BRCA2 gene (n = 366 pairs). Information about age at menarche was derived from a questionnaire routinely administered to carriers of a mutation in either gene. Among women who carried a deleterious BRCA1 mutation, age at menarche was inversely associated with the risk of breast cancer (p trend = 0.0002). This association was not observed among BRCA2 mutation carriers (p trend = 0.49). Compared with BRCA1 carriers whose age at menarche was ≤11 years, women with a menarcheal age between 14 and 15 years old had a 54% reduction in risk (OR = 0.46; 95% CI 0.30–0.69). This study implicates early age at menarche as a determinant of breast cancer among women with a BRCA1 mutation. * Address correspondence to: Steven A. Narod, Centre for Research in Women’s Health, University of Toronto, 790 Bay Street, Room 750, 7th Floor, Women’s College Hospital, Toronto, Ontario, M5G 1N8, Canada. Ph.: +1-416-351-3765; Fax: +1-416-351-3767; E-mail: steven.narod@swchsc.on.ca     

Patients with gallstones develop gallbladder cancer at an earlier age.

Significant proportions of Indian patients with gallbladder cancer are young. Multiple risk factors for gallbladder cancer are recognized among Indian patients. The effect of these risk factors on the age of development of gallbladder cancer is not known. We conducted a study to determine the influence of risk factors on the age at diagnosis of patients with gallbladder cancer and to assess the interactions between these risk factors. Patients with gallbladder cancer from two tertiary care institutions during the period 1994-2001 were prospectively studied. An ultrasound examination was done to look for the presence of gallstones. The influence of gender, gallstones, socio-economic status, smoking, residence in rural areas and in the Gangetic belt on the age at presentation was analysed using univariate analysis, logistic and linear regression analyses. The mean age of the 121 patients studied was 55+/-11.7 (SD) years. There were 51 (42%) patients aged less than 50 years. The younger patients (age < or =50 years) were more likely to have gallstones (88 versus 66%; P=0.008) and to have come from a lower socio-economic background (88 versus 71%; P=0.02) in comparison with older patients. However, there was no effect of the other risk factors. The independent determinants for younger age of patients with gallbladder cancer on logistic regression analysis were gallstones [odds ratio (OR) 4, 95% confidence interval (CI) 1.5-11; P=0.006] and lower socio-economic status (OR 3.1, 95% CI 1.1-8.6; P=0.03). On linear regression analysis, age at presentation was lowered by 5.6 years if there were associated gallstones. The mean age of patients with these two risk factors was significantly lower than that of those with one risk factor or no risk factor (52+/-12 years versus 57+/-11 years versus 61+/-9 years; P=0.007). In conclusion, the presence of gallstones and lower socio-economic status were both independently associated with a younger age at diagnosis of gallbladder cancer and their effect was additive.     

Age at first birth and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers

An early age at first full-term birth is associated with a reduction in the subsequent development of breast cancer among women in the general population. A similar effect has not yet been reported among women who carry an inherited BRCA1 or BRCA2 mutation. We conducted a matched case–control study on 1816 pairs of women with a BRCA1 (n = 1405) or BRCA2 (n = 411) mutation in an attempt to elucidate the relationship between age at first full-term pregnancy and the risk of developing breast cancer. Information about the age at first childbirth and other pregnancy-related variables was derived from a questionnaire administered to women during the course of genetic counselling. There was no difference in the mean age at first full-term birth in the cases and controls (24.9 years vs. 24.8 years; P = 0.81, respectively). Compared to women whose first child was born at or before 18 years of age, a later age at first full-term birth did not influence the risk of developing breast cancer (OR = 1.00 per year; 95% CI 0.98–1.03; P-trend = 0.67). Stratification by mutation status did not affect the results. These findings suggest that an early first full-term birth does not confer protection against breast cancer in BRCA mutation carriers. Nonetheless, BRCA mutation carriers opting for a prophylactic oophorectomy as a breast and/or ovarian cancer risk-reducing strategy should complete childbearing prior to age 40 when this prevention modality is most effective. Other members of the Hereditary Breast Cancer Clinical Study Group—J. Garber, Dana Farber Cancer Center, D. Gilchrist, University of Alberta, M. Osborne, Strang Cancer Prevention Centre, New York, NY, USA, D. Fishman, Northwestern University, E. Warner, Toronto-Sunnybrook Regional Cancer Center, Toronto, ON, Canada, J. McLennan, University of San Francisco, W. McKinnon, University of Vermont, S. Merajver, University of Michigan Comprehensive Cancer Center, H. Olsson, Jubileum Institute, Department of Oncology, Lund University Hospital, Lund, Sweden, D. Provencher, University of Montreal, B. Pasche, Northwestern Medical Facility, Chicago, IL, USA, G. Evans, Regional Genetics Service, St. Mary’s Hospital, Manchester, UK, WS Meschino, North York General, North York, ON, Canada, E. Lemire, Division of Medical Genetics, Royal University Hospital and the University of Saskatchewan, Canada, A. Chudley, Children’s Hospital, Winnipeg, Manitoba, Canada, D. Rayson, Queen Elizabeth Health Sciences Centre, Halifax, Nova Scotia, Canada and C. Bellati, Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Italy.     

BRCA1 and BRCA2 germline mutations in Korean breast cancer patients at high risk of carrying mutations

We analyzed the mutation spectrum of BRCA1 and BRCA2 genes in 354 Korean breast cancer patients. Overall, 40 patients carried 25 distinct BRCA1/2 mutations including 12 novel mutations. Seven district mutations were found in multiple unrelated patients, with the BRCA2 c.7480C>T mutation detected in eight unrelated patients, accounting for 50% of the mutations detected in BRCA2. The large number (25/40, 62.5%) of recurrent mutations suggests the possibility of developing a simple screening test for these mutations. The frequency of mutations was related to the number and kinds of risk factors, varying from 10.4 to 25% in the five major risk factor groups. The frequency of BRCA mutations in patients with two or more risk factors was markedly higher than that in patients with one risk factor.     

Deprivation,stage at diagnosis and cancer survival

The association between an area-based measure of deprivation and survival from the 10 most common cancers was studied in 155,682 patients diagnosed between 1980 and 1989 in the area covered by the South Thames Regional Health Authority. Furthermore, the impact of stage of disease at diagnosis on this association was studied. The measure of deprivation was the Car-stairs Index of the census enumeration district of each patient's residence at diagnosis (5 categories) and the cancers studied were: lung, breast, colorectum, bladder, prostate, stomach, pancreas, ovary, uterus and cervix. In the univariate analyses the measure of outcome was the relative survival rate and in the multivariate analyses it was the hazard ratio. Both univariate and multivariate analyses showed that patients from affluent areas had better survival than patients from deprived areas for cancers of the lung, breast, colorectum, bladder, prostate, uterus and cervix. Stage of disease at diagnosis did not explain the survival differences by deprivation category. For cancers of the stomach, pancreas and ovary, no variation in survival by deprivation category was found. For most cancer sites, a clear gradient in survival by deprivation category was observed, which implies a large potential reduction of cancer mortality among the lower socioeconomic groups. Future studies need to incorporate other possible explanatory factors, besides stage, of the association between deprivation and survival.     

BRCA1 and BRCA2 as ovarian cancer susceptibility genes

Individuals carrying germline mutations in one allele of the BRCA1 or BRCA2 genes are at significantly increased risk of developing cancer. Although the increased risk of breast cancer is often highlighted, cancer at several other sites is also considerably more common in these individuals. Here, we discuss existing knowledge of the role of BRCA1 and BRCA2 mutation in pre-disposition to ovarian cancer. The risk of an individual with a mutation developing cancer of the ovary appears to be influenced by the position of the mutation within the BRCA gene, the presence of allelic variants of modifying genes and the hormonal exposure of the carrier. Once cancer has developed, the pathology and clinical behaviour of BRCA-associated tumours is distinct from sporadic cases. Comparison of the pathogenesis of breast and ovarian cancers caused by BRCA mutation provides insight into the function of BRCA proteins as tumour suppressors in different cellular environments.     

Breast cancer stage at diagnosis: Caucasians versus Hispanics

In the Department of Defense health care system,all women have the same ability to accesshealth care. Thus, there should be no racialdifferences in stage at diagnosis solely based onability to seek health care. A retrospective reviewof breast cancer cases from 1980–1992 was conductedto determine if there were any differences instage at diagnosis between Caucasian and Hispanic females.Data was available for 6134 Caucasian and 182Hispanic females. Although not statistically significant, Hispanic femaleshad fewer Stage I (41% versus 53%) andmore Stage IIA (37% versus 28%) breast cancersthan Caucasian females. Hispanic females had statistically fewertumors 1 cm (p < 0.001). Caucasianfemales were older (median age 58 years) atpresentation than Hispanic females (median age 51 years).Significantly (p = 0.002) more Hispanic females (44%)were < 50 years old compared to Caucasianfemales (28%). When access to care is notan issue, Hispanic females tended to present ata more advanced stage although this did notreach statistical significance. Hispanic females with breast cancerwere significantly younger than Caucasian females.     

Breast self examination and breast cancer stage at diagnosis

The relationship between breast self examination (BSE) and breast cancer stage at diagnosis was examined in 616 women aged 15-59 years. Differences in tumour characteristics between those not practising BSE and those practising but not taught were small and inconstant. However, women who had both practised and had been taught BSE had more favourable tumours than the non-practising group. The difference was most marked in terms of tumour size and the involvement of axillary nodes. The proportions of women in the non-BSE and taught-BSE groups with each characteristic were respectively: size less than or equal to 2 cm 33% and 45%, T1 clinical stage 27% and 42%, and N0 pathological stage 37% and 50%. This advantage to taught-BSE women persisted after adjustment for the identified confounding factors of age, social class and oral contraceptive use. The likely impact on breast cancer mortality is difficult to assess, although the potential benefit of the lead time gained must not be ignored when assessing the costs and benefits of BSE.     

晚期前列腺癌的外照射治疗

目的：研究晚期前列腺癌的外照射治疗的疗效。方法：１９９３年３月－１９９９年３月共收治晚期前列腺癌４５例,Ｃ期３２例,Ｄ期１３例,对所有病例均予外照射治疗,局部肿瘤量达５５－７０Ｇｙ／５．５－７周。结果：所有病例放疗后排尿困难、骨转移疼痛改善,血尿消失,放疗后血前列腺特异性抗原（ＰＳＡ）均明显下降,为０．０１－２．８ｎｇ／ｍｌ,平均０．３５ｎｇ／ｍｌ,放疗后９个月复查局部肿瘤消失２９例,明显缩小１６