Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases.

AIM OF THE STUDY: Results on tumour characteristics and survival of hereditary breast cancer (BC), especially on BRCA2-associated BC, are inconclusive. The prognostic impact of the classical tumour and treatment factors in hereditary BC is insufficiently known. METHODS: We selected 103 BRCA2-, 223 BRCA1- and 311 non-BRCA1/2 BC patients (diagnosis 1980-2004) from the Rotterdam Family Cancer Clinic. To correct for longevity bias, analyses were also performed while excluding index patients undergoing DNA testing 2 years after BC diagnosis. As a comparison group, 759 sporadic BC patients of comparable age at and year of diagnosis were selected. We compared tumour characteristics, the occurrence of ipsilateral recurrence (LRR) and contralateral BC (CBC) as well as distant disease-free (DDFS), BC-specific (BCSS) and overall survival (OS) between these groups. By multivariate modelling, the prognostic impact of tumour and treatment factors was investigated separately in hereditary BC. RESULTS: We confirmed the presence of the particular BRCA1-phenotype. In contrast, tumour characteristics of BRCA2-associated BC were similar to those of non-BRCA1/2 and sporadic BC, with the exception of a high risk of CBC (3.1% per year) and oestrogen-receptor (ER)-positivity (83%). No significant differences between BRCA2-associated BC and other BC subgroups were found with respect to LRR, DDFS, BCSS and OS. Independent prognostic factors for BC-specific survival in hereditary BC (combining the three subgroups) were tumour stage, adjuvant chemotherapy, histologic grade, ER status and a prophylactic (salpingo-)oophorectomy. CONCLUSIONS: Apart from the frequent occurrence of contralateral BC and a positive ER-status, BRCA2-associated BC did not markedly differ from other hereditary or sporadic BC. Our observation that tumour size and nodal status are prognostic factors also in hereditary BC implies that the strategy to use these factors as a proxy for ultimate mortality appears to be valid also in this specific group of patients.

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.

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.

Earlier detection of breast cancer by surveillance of women at familial risk.

A positive family history increases the risk for breast cancer which oft en occurs at a much younger age than in the general population. We stud ied whether surveillance of these women resulted in the detection of bre ast cancer in an earlier stage than in symptomatic patients with a famil y history. Between January 1994 and April 1998, 294 women with 15-25% r isk (moderate), mean age:43.3 (22-75) years, were screened with a yearly physical examination and mammography from 5 years before the youngest ag e of onset in the family and 384 women with >25% risk (high) for breast cancer, mean age: 42.9 (20-74) years were screened with a physical examination every 6 months and yearly mammography. From September 1995 breast magnetic resonance imaging (MRI) was also carried out for 109 high risk women where mammography showed over 50% density. 26 breast cancers detected under surveillance were significantly more often found in an early T1N0 stage than the 24 breast cancers in patients with a family history referred in that period because of symptoms: 81 versus 46% (P=0.018). Patients under surveillance were also less frequently node-positive than the symptomatic group: 19 versus 42% (P=0.12). 20 patients with a family history referred by our national screening programme in that period had 21 breast cancers detected, 81% in stage T1N0 and 5% node-positive, which was comparable to the results in our national screening programme T1N0 66%, N+ 24% resulting in a 30% reduction in mortality. The incidence in women under surveillance was 10.1 per 1000 in the 'high' risk group and 13.3 per 1000 in the 'moderate' risk group. Expected incidence in an average risk population aged 40-50 years is 1.5, expected if the group consisted of only gene carriers 15 per 1000. 23% of the breast cancers in the surveillance group were detected at physical examination, but occult at mammography. 38% were detected at mammography and clinically occult. Breast MRI (in the subgroup) detected 3 occult breast cancers. The results of this study show that women with a family history benefit from surveillance as breast cancer was detected significantly more often in a favourable T1N0 stage and a mortality reduction comparable to that obtained in our national screening programme may be expected also in women <50 years of age. Both physical examination and mammography contribute to this result, but the former in this study only contributed in women before menopause. Starting surveillance some years before the youngest age of onset in the family may result in higher detection rates. Screening with MRI can detect breast cancers, still occult at physical examination and mammography.

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.

[Good results in periodic screening in women with increased risk of breast cancer; retrospective study]. / Gunstige resultaten van periodieke controle bij vrouwen met verhoogd risico van borstkanker; retrospectief onderzoek.

OBJECTIVE: To determine the efficiency of surveillance among women with a high risk of breast cancer by semiannual breast examination and annual mammography. SETTING: 'Dr. Daniel den Hoed' Cancer Centre, Rotterdam, the Netherlands. DESIGN: Retrospective study. METHOD: In 1994 breast cancer was diagnosed in 92 patients: in 19 patients during surveillance (SU), in 48 referred because of symptoms (SY) and in 25 during the national screening programme (SC). The contributions of physical examination, mammography, ultrasound and fine needle aspiration cytology to the diagnosis were evaluated and the tumour stages in the 3 groups were compared. RESULTS: The mean age was 53 years in the SU group, 51 years in the SY group and 64 years in the SC group. Breast cancer was detected by mammography only in 6%, 40% and 42% in the SY, SC and SU groups, respectively. 42% of patients had a family history of breast cancer in the SU group. Mammography failed to reveal malignancy in 25% of patients in the SU and SY groups combined. In women in the SU group 53% of breast cancers were: carcinoma in situ (Tis) or minimal invasive carcinoma (< 0.5 cm diameter; T1a). In patients with a family history of breast cancer 75% (6/8) were diagnosed in stages Tis or T1a, by surveillance. In the SY group 4% were Tis or T1a and 40% N1 + 2, in the SC group 8% and 20% respectively. 15.7% of the SU group had axillary lymph node metastases (N1) but only one of the 8 patients with a family history of breast cancer. CONCLUSIONS: Surveillance by palpation and mammography in women with a high risk of breast cancer is useful, because it detects this disease frequently at an early stage, when the prognosis is still good.

Passive coping and psychological distress in women adhering to regular breast cancer surveillance.

Since 2000 the MRISC study evaluates the psychological consequences of regular breast cancer surveillance for women at increased risk for hereditary breast cancer. Coping style may influence these psychological consequences. In a cohort of 357 women at increased risk for hereditary breast cancer, the impact of coping styles on the course, divided into level and trend of psychological distress (general and breast cancer specific) was examined, around two consecutive surveillance appointments. With structural equation modelling we found passive coping to be associated with higher levels of both general and breast cancer specific distress. Seeking social support, expression of emotions and thinking comforting thoughts were associated with lower levels of psychological distress. Coping style was not associated with the trend of psychological distress around the two surveillance appointments. It is recommendable to take coping styles into account when counselling these high-risk women.

Tumor characteristics and detection method in the MRISC screening program for the early detection of hereditary breast cancer.

In the MRISC study, women with an inherited risk for breast cancer were screened by a 6-month clinical breast examination (CBE) and yearly MRI and mammography. We found that the MRISC screening scheme could facilitate early breast cancer diagnosis and that MRI was a more sensitive screening method than mammography, but less specific. In the current study we investigated the contribution of MRI in the early detection of breast cancer in relation to tumor characteristics. From November 1999 to October 2003, 1909 women were included and 50 breast cancers were detected, of which 45 were evaluable and included in the current study. We compared the characteristics of tumors detected by MRI-only with those of all other (non-palpable) screen-detected tumors. Further, we compared the sensitivity of mammography and MRI within subgroups according to different tumor characteristics. Twenty-two (49%) of the 45 breast cancers were detected by MRI and not visible at mammography, of which 20 (44%) were also not palpable (MRI-only detected tumors). MRI-only detected tumors were more often node-negative than other screen-detected cancers (94 vs. 59%; P=0.02) and tended to be more often

Survival and prognostic factors in BRCA1-associated breast cancer.

BACKGROUND: Studies comparing survival in BRCA1-associated and sporadic breast cancer (BC) report inconsistent results and frequently concern small sample sizes. Further, the prognostic impact of the classical tumour and treatment factors is unclear in BRCA1-associated BC. PATIENTS AND METHODS: We selected 223 BC patients diagnosed between 1980 and 2001 within families with a deleterious germline BRCA1-mutation ascertained at the Rotterdam Family Cancer Clinic. To correct for ascertainment bias, the group of index patients undergoing DNA testing more than 2 years after BC diagnosis (n = 53) was separated from the other BRCA1-patients (n = 170). All BRCA1-associated patients were matched in a 1:2 ratio for age and year of diagnosis to sporadic BC patients. We compared the occurrence of ipsi- and contralateral BC (CBC) as well as distant disease-free (DDFS), BC-specific (BCSS) and overall survival (OS). By multivariate modelling, the prognostic impact of tumour and treatment factors was investigated separately in BRCA1-associated and sporadic breast cancers. RESULTS: For the total group of 669 cases, the median follow-up was 5.1 years, the median age at diagnosis 39 years. We confirmed the existence of the typical BRCA1-associated tumour type and the high CBC incidence. No significant differences between BRCA1-associated and sporadic tumours were found with respect to ipsilateral BC recurrence (HR(mult) 0.7; P = 0.24), DDFS (HR(mult) 1.2; P = 0.37) or BC-specific survival (HR(mult) 1.3; P = 0.23). A trend towards a worse survival was found for BRCA1-associated ductal BC (HR(mult) 1.5, P = 0.07). Prognostic factors for BRCA1-associated BC were age at diagnosis, tumour size and morphology, and nodal status. Further, survival was non-significantly improved by systemic treatment and a bilateral salpingo-oophorectomy. No effect on survival of a contralateral prophylactic mastectomy was seen. CONCLUSIONS: BRCA1-associated BC is characterised by specific tumour characteristics, a high incidence of CBC and a trend towards a worse survival for the ductal tumour type. Our observation that tumour size and nodal status are also prognostic factors for BRCA1-associated BC implies that the strategy to use these factors as a proxy for ultimate mortality, for instance in BC screening programmes or the consideration of (contralateral) preventive mastectomy, appears to be valid in this specific group of patients.

Mastitis and toxic shock syndrome (tampon disease).

The present report draws attention to the toxic shock syndrome in combination with non-menstruation-associated disease. A patient with mastitis and TSS is described. The relevant literature is reviewed and discussed in relation to this patient. Physicians should be alert for TSS when a patient presents with non-understood shock and fever in the absence of positive blood cultures, even when there is no relation to menstruation or no history of previous use of tampons.

Weekly low-dose mitoxantrone plus doxorubicin as second-line chemotherapy for advanced breast cancer.

Weekly low dose mitoxantrone (3 mg/m2) plus doxorubicin (8 mg/m2) was administered as second-line chemotherapy to 33 patients with advanced breast cancer. Four out of 28 evaluable patients (14%) obtained a partial response with a median duration of 34 weeks (range 18-67+ weeks), while 8 patients (29%) showed stable disease with a median duration of 28 weeks (range 11+-60 weeks). Gastrointestinal toxicity and alopecia were mild. Grade II and III leukopenia occurred in 63% of the courses without serious infectious disease. Four patients experienced an asymptomatic drop of 16-20% in the left ventricular ejection fraction (LVEF) after relatively low cumulative doses of each drug, and one patient with a history of pericarditis carcinomatosa and mediastinal irradiation developed a heart failure. In conclusion, this second-line combination treatment had moderate activity in breast cancer and caused only few subjective side effects, especially with respect to gastrointestinal symptoms.

Impact of screening for breast cancer in high-risk women on health-related quality of life.

The effectiveness of intensive surveillance in women at high risk for breast cancer due to a familial or genetic predisposition is uncertain and is currently being evaluated in a Dutch magnetic resonance imaging (MRI) screening (MRISC) study, in which annual imaging consists of mammography and MRI. Unfavourable side effects on health-related quality of life may arise from this screening process. We examined the short-term effects of screening for breast cancer in high-risk women on generic health-related quality of life and distress. A total of 519 participants in the MRISC study were asked to complete generic health-status questionnaires (SF-36, EQ-5D) as well as additional questionnaires for distress and items relating to breast cancer screening, at three different time points around screening. The study population showed significantly better generic health-related quality of life scores compared to age-/sex-adjusted reference scores from the general population. Neither generic health-related quality of life scores nor distress scores among the study sample (n=334) showed significant changes over time. The impact of the screening process on generic health status did not differ between risk categories. Relatively more women reported mammography as quite to very painful (30.1%) compared to MRI. Anxiety was experienced by 37% of the women undergoing MRI. We conclude that screening for breast cancer in high-risk women does not have an unfavourable impact on short-term generic health-related quality of life and general distress. In this study, high-risk women who opted for regular breast cancer screening had a better health status than women from the general population.

Psychological distress and breast self-examination frequency in women at increased risk for hereditary or familial breast cancer.

BACKGROUND: The Magnetic Resonance Imaging Screening study evaluates the efficacy and psychological impact of a surveillance program for women at increased risk for hereditary or familial breast cancer in the Netherlands. Surveillance consists of biannual physical examination, annual mammography, annual MRI and monthly breast self-examination (BSE). OBJECTIVE: To examine the association between psychological distress and reported BSE frequency. METHODS: Two months prior to surveillance demographics, BSE frequency, general distress (Hospital Anxiety and Depression Scale and the somatic scale of the Symptom Checklist-90) and breast cancer-specific distress (Impact of Event Scale) were assessed in 316 women (mean age 40.5 years, range 21-63 years). RESULTS: The majority (57%) reported performing monthly BSE. Ten percent reported never performing BSE, 20% less frequently than once a month and 13% at least once a week. Women below the age of 40 who examined their breasts more frequently than recommended (i.e. at least once a week) were shown to be significantly more distressed than the other women in the sample (p = 0.03). These women represented 15% of all the women below the age of 40 years in our study sample. CONCLUSION: Higher breast cancer-specific distress scores were observed among younger women who examined their breasts at least once a week. It is important for physicians to be aware of this hypervigilant behaviour, especially since it is correlated with breast cancer-specific distress.

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.

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.