Should internal mammary chain (IMC) sentinel node biopsy be performed? Outcome in 90 consecutive non-biopsied patients with a positive IMC scintigraphy.

INTRODUCTION: Although the status of the regional lymph nodes is an important determinant of prognosis in breast cancer, harvesting sentinel nodes (SN) detected in the internal mammary chain (IMC) is still controversial. AIMS: To determine in how many patients a positive IMC-SN might change the systemic or locoregional adjuvant therapy, with a possible benefit in outcome. PATIENTS AND METHODS: During 6 1/2 years data of T1-2 breast cancer patients, having an SN procedure, were prospectively collected. Our policy was not to explore the IMC even if it was the only localization of an SN. RESULTS: In 86 of 571 patients lymphoscintigraphy showed an IMC-SN. In 64 of these, the axillary SN was negative and only 25 of these patients did not have an indication for adjuvant systemic treatment based on their tumor characteristics. In the literature, IMC metastases are found in 0-10% of axillary negative patients. Routine IMC-SN biopsies would have resulted in an indication for adjuvant systemic therapy in 2-3 of our patients. Four parasternal recurrences were found during a median follow-up of 51 months. CONCLUSIONS: Harvesting IMC-SNs is a procedure of which only a limited number of patients have therapeutical benefit. Even with a thorough selection of patients, the extra morbidity of the procedure should be weighed against the potential benefit for the patient.

Ipsilateral breast tumour recurrence in hereditary breast cancer following breast-conserving therapy.

The overall rate of an ipsilateral breast tumour recurrence (IBTR) after breast-conserving therapy (BCT) ranges from 1% to 2% per year. Risk factors include young age but data on the impact of BRCA1/2 mutations or a definite positive family history for breast cancer are scarce. We investigated IBTR after BCT in patients with hereditary breast cancer (HBC). Through our family cancer clinic we identified 87 HBC patients, including 26 BRCA1/2 carriers, who underwent BCT between 1980 and 1995 (cases). They were compared to 174 patients with sporadic breast cancer (controls) also treated with BCT, matched for age and year of diagnosis. Median follow up was 6.1 years for the cases and 6.0 years for controls. Patient and tumour characteristics were similar in both groups. An IBTR was observed in 19 (21.8%) hereditary and 21 (12.1%) sporadic patients. In the hereditary patients more recurrences occurred elsewhere in the breast (21% versus 9.5%), suggestive of new primaries. Overall, the actuarial IBTR rate was similar at 2 years, but higher in hereditary as compared to sporadic patients at 5 years (14% versus 7%) and at 10 years (30% versus 16%) (P=0.05). Post-relapse and overall survival was not different between hereditary and sporadic cases. Hereditary breast cancer was therefore associated with a higher frequency of early (2-5 years) and late (>5 years) local recurrences following BCT. These data suggest an indication for long-term follow up in HBC and should be taken into account when additional 'risk-reducing' surgery after primary BCT is eventually considered.

Clinical experience of prophylactic mastectomy followed by immediate breast reconstruction in women at hereditary risk of breast cancer (HB(O)C) or a proven BRCA1 and BRCA2 germ-line mutation.

AIM: Women with a proven BRCA1 or BRCA2 germ-line mutation or with a 50% risk of carrying the mutation, have an increased risk of breast cancer. Regular surveillance, chemoprevention or prophylactic mastectomy (PM) are options to detect breast cancer at an early stage or to reduce the risk. We describe the management of women who have opted for PM, the postoperative complications of PM, especially in combination with immediate breast reconstruction (IBR), and the oncological follow-up. METHODS: The medical records of all women who underwent a PM from December 1993 to December 1999 have been reviewed with respect to management, patient characteristics, complications and oncological follow-up. RESULTS: During the study period 112 women with a median age of 38.8 years opted for a PM: 76 were germline mutation carriers. After PM, 79 women without breast or ovarian cancer in their medical history, were free of disease after 2.5 years (median). Before PM, 29 women had been treated for breast cancer, 3.9 years (median) previously; 5 of these women had developed metastatic disease by the last consultation. Before PM, 2 patients had been treated for DCIS and 2 patients for ovarian cancer. Four DCIS were found; none of these women had evidence of disease 4.0 years (median) after PM. In 59 women laparoscopic prophylactic bilateral oophorectomy (PBO) was performed; 36 simultaneously with PM and 23 separately. A total of 103 women (92%) opted for IBR. After PM, the complication rate for IBR was 21%: 11% within 6 weeks and 10% at long-term follow-up (median 3.5) after PM, including the removal of 10 prostheses. CONCLUSIONS: Women with an increased risk of breast cancer due to a genetic predisposition should be adequately informed about the different treatment options in the setting of a multidisciplinary approach. PM can simultaneously be combined with PBO and IBR. IBR can facilitate the decision to undergo a PM. PM followed by IBR has an acceptable complication rate.

Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families.

In 517 Dutch families at a family cancer clinic, we screened for BRCA1/2 alterations using the Protein Truncation Test (PTT) covering approximately 60% of the coding sequences of both genes and direct testing for a number of previously identified Dutch recurrent mutations. In 119 (23%) of the 517 families, we detected a mutation in BRCA1 (n=98; 19%) or BRCA2 (n=21; 4%). BRCA1/2 mutations were found in 72 (52%) of 138 families with breast and ovarian cancer (HBOC), in 43 (13%) of the 339 families with breast cancer only (HBC), in 4 (36%) of 11 families with ovarian cancer only (HOC), and in nine of 29 families with one single young case (<40 years) of breast cancer. Between the different subgroups of families (subdivided by the number of patients, cancer phenotype and age of onset) the proportion of BRCA1/2 mutations detected, varied between 6 and 82%. Eight different mutations, each encountered in at least six distinct families, represented as much as 61% (73/119 families) of all mutations found. The original birthplaces of the ancestors of carriers of these eight recurrent mutations were traced. To estimate the relative contribution of two important regional recurrent mutations (BRCA1 founder mutation IVS12-1643del3835 and BRCA2 founder mutation 5579insA) to the overall occurrence of breast cancer, we performed a population-based study in two specific small regions. The two region-specific BRCA1 and BRCA2 founder mutations were detected in 2.8% (3/106) and 3.2% (3/93) of the unselected breast tumours, respectively. Of tumours diagnosed before the age of 50 years, 6.9% (3/43) and 6.6% (2/30) carried the region-specific founder mutation. Thus, large regional differences exist in the prevalence of certain specific BRCA1/BRCA2 founder mutations, even in very small areas concerning populations of approximately 200000 inhabitants.

Molecular profiles of BRCA1-mutated and matched sporadic breast tumours: relation with clinico-pathological features.

About 5-10% of breast cancers are hereditary; a genetically and clinically heterogeneous disease in which several susceptibility genes, including BRCA1, have been identified. While distinct tumour features can be used to estimate the likelihood that a breast tumour is caused by a BRCA1 germline mutation it is not yet possible to categorize a BRCA1 mutated tumour. The aim of the present study is to molecularly classify BRCA1 mutated breast cancers by resolving gene expression patterns of BRCA1 and matched sporadic surgical breast tumour specimens. The expression profiles of 6 frozen breast tumour tissues with a proven BRCA1 gene mutation were weighed against those from 12 patients without a known family history but who had similar clinico-pathological characteristics. In addition two fibroblast cultures, the breast cancer cell-line HCC1937 and its corresponding B-lymphoblastoid cell line (heterozygous for mutation BRCA1 5382insC) and an epithelial ovarian cancer cell line (A2780) were studied. Using a high density membrane based array for screening of RNA isolated from these samples and standard algorithms and software, we were able to distinguish subgroups of sporadic cases and a group consisting mainly of BRCA1-mutated breast tumours. Furthermore this pilot analysis revealed a gene cluster that differentially expressed genes related to cell substrate formation, adhesion, migration and cell organization in BRCA1-mutated tumours compared to sporadic breast tumours.

Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.

BACKGROUND: Women with a BRCA1 or BRCA2 mutation have a high risk of breast cancer and may choose to undergo prophylactic bilateral total mastectomy. We investigated the efficacy of this procedure in such women. METHODS: We conducted a prospective study of 139 women with a pathogenic BRCA1 or BRCA2 mutation who were enrolled in a breast-cancer surveillance program at the Rotterdam Family Cancer Clinic. At the time of enrollment, none of the women had a history of breast cancer. Seventy-six of these women eventually underwent prophylactic mastectomy, and the other 63 remained under regular surveillance. The effect of mastectomy on the incidence of breast cancer was analyzed by the Cox proportional-hazards method in which mastectomy was modeled as a time-dependent covariate. RESULTS: No cases of breast cancer were observed after prophylactic mastectomy after a mean (+/-SE) follow-up of 2.9+/-1.4 years, whereas eight breast cancers developed in women under regular surveillance after a mean follow-up of 3.0+/-1.5 years (P=0.003; hazard ratio, 0; 95 percent confidence interval, 0 to 0.36). The actuarial mean five-year incidence of breast cancer among all women in the surveillance group was 17+/-7 percent. On the basis of an exponential model, the yearly incidence of breast cancer in this group was 2.5 percent. The observed number of breast cancers in the surveillance group was consistent with the expected number (ratio of observed to expected cases, 1.2; 95 percent confidence interval, 0.4 to 3.7; P=0.80). CONCLUSIONS: In women with a BRCA1 or BRCA2 mutation, prophylactic bilateral total mastectomy reduces the incidence of breast cancer at three years of follow-up.

Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk.

PURPOSE: Women with a high breast cancer risk due to a familial predisposition may choose between preventive surgery and regular surveillance. The effectiveness of surveillance in high-risk women and especially BRCA1/2 mutation carriers is unknown. We present first results from a single large family cancer clinic. PATIENTS AND METHODS: Women with breast cancer risk over 15% were examined by physical examination every 6 months and mammography every year. Detection rates and screening parameters were calculated for the total group and separately for different age and genetic risk groups. RESULTS: At least one examination was performed in 1,198 women: 449 moderate and 621 high-risk women and 128 BRCA1/2 mutation carriers. Within a median follow-up of 3 years, 35 breast cancers were detected (four ductal carcinoma-in-situ; 31 invasive tumors); the average detection rate was 9.7 per 1,000. Detection rates (95% confidence interval) for moderate and high-risk women and BRCA1/2 carriers were 3.3 (1.1 to 8.6), 8.4 (5.4 to 13.2), and 33 (17 to 63) per 1,000 person-years, respectively. The ratio of observed cases versus breast cancers expected in an average-risk population of comparable age was 2.7, 7.0 and 23.7 respectively. Overall, node negativity was 65%; 34% of primary tumors were less than 10 mm; sensitivity was 74%. Results with respect to tumor stage and sensitivity were less favorable in BRCA1/2 carriers and in women under the age of 40. CONCLUSION: It is possible to identify young women at high risk for breast cancer. The number of cancers detected was significantly greater than expected in an age-matched average-risk population and related to the risk category. Overall, screening parameters were comparable to population screening data, with less favorable results in the youngest age group (< 40) and BRCA1/2 carriers.

Prognostic significance of germline BRCA2 mutations in hereditary breast cancer patients.

PURPOSE: Breast cancer in BRCA2 gene mutation carriers differs from BRCA1-associated breast cancer or so-called sporadic breast cancer in clinical features and behavior. These differences may be of importance for the prevention, screening, and ultimately treatment of breast cancer in women with such germline mutations. METHODS: We reviewed the few studies that have reported on survival in patients with BRCA2-associated breast cancer. In this article we discuss why family history is no substitute for hereditary breast cancer with regard to studying survival and possible reasons why studies using family history yield contradictory results, why BRCA2-associated breast cancer should be considered a unique entity, and what methodological problems may exist, especially with regard to family-based studies. RESULTS: Five studies have reported on survival in BRCA2-associated breast cancer. Two studies showed a statistically significant worse survival for BRCA2 patients, but the patients from one of these studies were later claimed to have a trend toward better prognosis when controls were matched for age and year of diagnosis. The other study found that the unfavorable prognosis of BRCA2 patients was, to a great extent, due to a worse stage of the disease at time of diagnosis. The remaining three studies showed no significant effect of germline BRCA2 mutations on survival. The numbers of BRCA2 patients investigated in these studies were 42, 20, 23, 28, and 54 patients. Five-year overall survival in these patients varied from 65% to 74%. CONCLUSION: No definite conclusion can be made with regard to the prognosis of BRCA2-associated breast cancer, but large differences in comparison with sporadic breast cancer are not likely to exist. Breast cancer caused by BRCA2 mutations is also a distinct entity with its own features when compared with BRCA1-associated breast cancer. In contrast with BRCA1-associated breast cancer, BRCA2 tumors tend to be more often steroid receptor-positive.

Contralateral breast cancer risk is influenced by the age at onset in BRCA1-associated breast cancer.

BRCA1/2 mutation carriers diagnosed with breast cancer have a strongly elevated life-time risk of developing a contralateral tumour. We studied the contralateral breast cancer risk in 164 patients from 83 families with a proven BRCA1 mutation in relation to the age at diagnosis of the first primary breast cancer. In the actuarial outcomes after 10 years' follow-up, 40% of the 124 BRCA1-patients diagnosed with breast cancer < 50 years had developed contralateral breast cancer, vs 12% of the 40 patients > 50 years at first diagnosis (Plogrank = 0.02). These data suggest that age at diagnosis of the first tumour should be taken into account when prophylactic mastectomy in BRCA1-patients is considered.

Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation.

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes highly predispose to breast and ovarian cancer. In families with BRCA1 or BRCA2 mutations, identification of mutation carriers is clinically relevant in view of the options for surveillance and prevention. METHODS: We assessed presymptomatic DNA testing and prophylactic surgery in 53 consecutive families presenting to the Rotterdam Family Cancer Clinic with a known BRCA1 or BRCA2 mutation. We identified predictors for DNA testing and prophylactic surgery with univariate and multivariate analysis. FINDINGS: 682 unaffected individuals with a 50% risk (275 women and 271 men) or with a 25% risk (136 women) for carrying a mutation were identified and offered a DNA test. Presymptomatic DNA testing was requested by 48% (198 of 411) of women and 22% (59 of 271) of men (odds ratio for difference between sexes 3.21 [95% CI 2.27-4.51]; p<0.001). In women, DNA testing was significantly more frequent at young age, in the presence of children, and at high pre-test genetic risk for a mutation. Of the unaffected women with an identified mutation who were eligible for prophylactic surgery, 51% (35 of 68) opted for bilateral mastectomy and 64% (29 of 45) for oophorectomy. Parenthood was a predictor for prophylactic mastectomy but not for prophylactic oophorectomy. Age was significantly associated with prophylactic oophorectomy, but not with prophylactic mastectomy, although there was a tendency towards mastectomy at younger ages. INTERPRETATION: In a clinical setting, we show a high demand for BRCA1 and BRCA2 testing by unaffected women at risk, and of prophylactic surgery by unaffected women with the mutation. Young women with children especially opt for DNA testing and prophylactic mastectomy.

Survival in hereditary breast cancer associated with germline mutations of BRCA2.

PURPOSE: Breast cancer in BRCA1 and BRCA2 gene-mutation carriers may differ from so-called sporadic breast cancer in clinical features and behavior. These potential differences may be of importance for the prevention, screening, and, ultimately, treatment of breast cancer in women with such germline mutations. Thus far, there have been very few studies on the survival of BRCA2-associated breast cancer patients. PATIENTS AND METHODS: We determined the disease-free and overall survival of 28 breast cancer patients from 14 consecutive families with eight different BRCA2 germline mutations. These patients' survival and tumor characteristics were compared with those of a control group of 112 sporadic breast cancer patients matched to them by age and year of diagnosis. RESULTS: The 5-year disease-free survival was 52% for each group (P =.91); the overall survival was 74% for BRCA2 carriers and 75% for sporadic cases (P =.50). At the time of diagnosis, tumors from the BRCA2 carriers were borderline significantly larger in comparison to the tumors in sporadic cases (P =.05), but axillary nodal status was not significantly different in the two groups (node-negativity, 63% v 52. 8%, respectively; P =.34). With respect to steroid receptor status, BRCA2-associated tumors were more likely to be steroid receptor-positive, especially regarding progesterone receptor status (100% v 76.7% positive, respectively; P =.06). Stage-adjusted recurrence and death rates were nonsignificantly better for BRCA2 cases (hazard ratios of 0.84 and 0.59 [P =.61 and P =.19], respectively). In contrast, after 5 years, the rate of metachronous contralateral breast cancer in BRCA2 patients was 12% (v 2% in controls; P =.02). CONCLUSION: Patients with hereditary breast cancer due to BRCA2 have a similar prognosis when compared with age-matched sporadic breast cancer patients. Contrary to our previous observation regarding BRCA1-associated breast cancer, BRCA2 tumors tended to be steroid receptor-positive, instead of steroid receptor-negative.

Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1.

BACKGROUND: Hereditary breast cancer has been associated with mutations in the BRCA1 and BRCA2 genes and has a natural history different from sporadic breast cancer. We investigated disease-free and overall survival for patients with a proven BRCA1 alteration. METHODS: We estimated disease-free and overall survival for 49 Dutch patients from 19 consecutive families with a proven specific BRCA1 mutation and one family with strong evidence for linkage to the BRCA1 gene. We compared clinical outcome and data on tumour size, histology, axillary nodal status, contralateral breast cancer, and oestrogen-receptor and progesterone-receptor status with those of 196 patients with sporadic breast cancer, matched for age and year of diagnosis. FINDINGS: Disease-free survival for BRCA1 and sporadic patients at 5 years was 49% (95% CI 33-64) and 51% (43-59), respectively (p=0.98). Overall survival at 5 years was 63% (47-76) and 69% (62-76), respectively (p=0.88). Recurrence and death rates did not differ significantly between groups. Hazard ratios for recurrence and death among BRCA1 patients were 1.00 (0.65-1.55) and 1.04 (0.63-1.71) relative to sporadic patients (p=0.88), and these did not differ significantly after adjustment for prognostic factors. Patients with BRCA1-associated breast cancer had twice as many progesterone-receptor-negative tumours (p<0.005) and development of contralateral breast cancer was four to five times as frequent as in the sporadic group (p<0.001). INTERPRETATION: We showed that disease-free and overall survival were similar for sporadic and hereditary breast cancer in the presence of different tumour characteristics, which has implications for screening prophylactic therapy, and different treatments of hereditary breast cancer.