Cecile T.M. Brekelmans

The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype.

Because of genetic heterogeneity, the identification of breast cancer-susceptibility genes has proven to be exceedingly difficult. Here, we define a new subset of families with breast cancer characterized by the presence of colorectal cancer cases. The 1100delC variant of the cell cycle checkpoint kinase CHEK2 gene was present in 18% of 55 families with hereditary breast and colorectal cancer (HBCC) as compared with 4% of 380 families with non-HBCC (P<.001), thus providing genetic evidence for the HBCC phenotype. The CHEK2 1100delC mutation was, however, not the major predisposing factor for the HBCC phenotype but appeared to act in synergy with another, as-yet-unknown susceptibility gene(s). The unequivocal definition of the HBCC phenotype opens new avenues to search for this putative HBCC-susceptibility gene.

Use of Genetic Testing and Prophylactic Mastectomy and Oophorectomy in Women With Breast or Ovarian Cancer From Families With a BRCA1 or BRCA2 Mutation

PURPOSE To analyze the use of genetic testing, prophylactic mastectomy, and oophorectomy among women with breast and/or ovarian cancer from families with a BRCA1 or BRCA2 mutation. PATIENTS AND METHODS We examined prospectively the use of BRCA1/BRCA2 testing in all women with a primary breast or ovarian cancer from a consecutive series of 112 high-risk families in which a BRCA1/BRCA2 mutation eventually was identified. The rate of prophylactic bilateral and contralateral mastectomy and prophylactic oophorectomy was analyzed in the women who carried a BRCA1/BRCA2 mutation and who had no metastatic disease at the time of the genetic test disclosure. We examined predictors for genetic test uptake and prophylactic surgery using univariate and multivariate analysis. RESULTS Overall, 192 of 220 women (87%) with primary tumors underwent genetic testing. Eleven of these 192 tested women (6%) appeared not to carry the family-specific BRCA1/BRCA2 mutation. Genetic testing occurred significantly more frequently at ages younger than 50 years (P =.04) and in persons with multiple primary tumors (P =.02). Among eligible women, 35 of 101 (35%) requested bilateral or contralateral mastectomy, and 47 of 95 (49%) requested oophorectomy. Women aged younger than 50 years and women who developed their first tumor after the initial identification of a BRCA1/BRCA2 mutation in the family were significantly (both P =.01) more likely to opt for prophylactic bilateral or contralateral mastectomy. CONCLUSION In a clinical setting, we show a high demand for BRCA1/BRCA2 testing and for prophylactic surgery by women with breast and/or ovarian cancer from high-risk families.

Prophylactic Mastectomy in BRCA1/2 Mutation Carriers and Women at Risk of Hereditary Breast Cancer: Long-Term Experiences at the Rotterdam Family Cancer Clinic

BackgroundBRCA1/2 mutation carriers and women from a hereditary breast(/ovarian) cancer family have a highly increased risk of developing breast cancer (BC). Prophylactic mastectomy (PM) results in the greatest BC risk reduction. Long-term data on the efficacy and sequels of PM are scarce.MethodsFrom 358 high-risk women (including 236 BRCA1/2 carriers) undergoing PM between 1994 and 2004, relevant data on the occurrence of BC in relation to PM, complications in relation to breast reconstruction (BR), mutation status, age at PM and preoperative imaging examination results were extracted from the medical records, and analyzed separately for women without (unaffected, n = 177) and with a BC history (affected, n = 181).ResultsNo primary BCs occurred after PM (median follow-up 4.5 years). In one previously unaffected woman, metastatic BC was detected almost 4 years after PM (primary BC not found). Median age at PM was younger in unaffected women (P < .001), affected women more frequently were 50% risk carriers (P < .001). Unexpected (pre)malignant changes at PM were found in 3% of the patients (in 5 affected, and 5 unaffected women, respectively). In 49.6% of the women opting for BR one or more complications were registered, totaling 215 complications, leading to 153 surgical interventions (71%). Complications were mainly related to cosmetic outcome (36%) and capsular formation (24%).ConclusionsThe risk of developing a primary BC after PM remains low after longer follow-up. Preoperative imaging and careful histological examination is warranted because of potential unexpected (pre)malignant findings. The high complication rate after breast reconstruction mainly concerns cosmetic issues.

Sensitivity to First-Line Chemotherapy for Metastatic Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

PURPOSE Preclinical as well as a few small retrospective, neoadjuvant studies suggest that breast cancer (cells) without functional BRCA1 or BRCA2 protein have an increased sensitivity to some chemotherapeutic agents causing double-strand DNA breaks. In this study we assessed the sensitivity to standard first-line chemotherapy of metastatic BRCA1/2-associated breast cancer, compared with sporadic breast cancer patients. PATIENTS AND METHODS From the Family Cancer Clinic database, we selected 93 BRCA1- and 28 BRCA2-associated breast cancer patients treated with chemotherapy for metastatic disease before January 1, 2007. Objective response (OR), progression-free survival (PFS), and overall survival (OS) after start of first-line chemotherapy were compared with those of sporadic patients, matched for year of birth, age at diagnosis of primary breast cancer, and year of detection of metastatic disease. RESULTS The chemotherapy regimens most frequently used were anthracycline-based (n = 147) and cyclophosphamide, methotrexate, and fluorouracil (CMF)/CMF like (n = 68). As compared to sporadic patients, BRCA2-associated patients had a significantly higher OR (89% v 50%; P = .001), a longer PFS (hazard ratio multivariate [HR(mult)] 0.64; P = .04) and a prolonged OS (HR(mult), 0.53; P = .005) after start of first-line chemotherapy for metastatic breast cancer. For BRCA1-associated patients, a nonsignificant trend for an increased OR (66% v 50%; P = .07), and a longer PFS (HR(mult), 0.79; P = .14) after first-line chemotherapy for metastatic breast cancer was observed, but not for OS. CONCLUSION BRCA2-associated breast cancer is more sensitive to standard first-line chemotherapy for metastatic breast cancer in comparison with sporadic breast cancer, especially to anthracyclines. For BRCA1-associated breast cancer no statistically significant higher sensitivity was observed.

Differences between first and subsequent rounds of the MRISC breast cancer screening program for women with a familial or genetic predisposition

Within the Dutch MRI Screening (MRISC) study, a Dutch multicenter screening study for hereditary breast cancer, the authors investigated whether previously reported increased diagnostic accuracy of magnetic resonance imaging (MRI) compared with mammography would be maintained during subsequent screening rounds.

Standard psychological consultations and follow up for women at increased risk of hereditary breast cancer considering prophylactic mastectomy

BackgroundWomen at increased (genetic) risk of breast cancer have to weigh the personal pros and cons of prophylactic mastectomy (PM) as an option to reduce their cancer risk. So far, no routine referral to a psychologist has been investigated for women considering PM. Aim of this study was to asses: 1) the acceptance of the offer of a standard psychological consultation as part of pre-surgical decision-making in high-risk women, 2) reasons for PM and reasons for postponing it, 3) the need for additional psychological interventions, and factors associated, and 4) the frequency of psychiatric/psychological treatment history.MethodsDuring a 30 months period, women at high risk considering PM were offered a psychological consultation. The content of these, and follow-up, consultations were analyzed.ResultsMost women (70 out of 73) accepted the psychological consultation, and 81% proceeded with PM. Main reasons for undergoing PM were to reduce anxiety about cancer, and to reduce the cancer risk. Uncertainty about surgery and the need for further information were the reasons given most frequently for postponing PM. Additional psychological support was given to 31% before and 14% after PM. The uptake of additional support was significantly higher in women with a BRCA1/2 mutation. A history of psychiatric/psychological treatment was present in 36%, mainly consisting of depression and grief after death of a mother.ConclusionThe uptake-rate of the standard psychological consultation indicates a high level of acceptability of this service for women deciding about PM. Since anxiety is one of the main reasons for considering PM, and depression and grief were present in a third, a standard consultation with a psychologist for high-risk women considering PM may be indicated. This may help them arrive at an informed decision, to detect and manage psychological distress, and to plan psychological support services.

Contralateral recurrence and prognostic factors in familial non-BRCA1/2-associated breast cancer

A higher incidence of contralateral breast cancer and ipsilateral recurrence has been reported in familial breast cancer than in sporadic cancer. This study investigated the influence of contralateral cancer and tumour stage on survival in patients with familial non‐BRCA1/BRCA2‐associated breast cancer.

A family history of breast cancer will not predict female early onset breast cancer in a population-based setting

BackgroundAn increased risk of breast cancer for relatives of breast cancer patients has been demonstrated in many studies, and having a relative diagnosed with breast cancer at an early age is an indication for breast cancer screening. This indication has been derived from estimates based on data from cancer-prone families or from BRCA1/2 mutation families, and might be biased because BRCA1/2 mutations explain only a small proportion of the familial clustering of breast cancer. The aim of the current study was to determine the predictive value of a family history of cancer with regard to early onset of female breast cancer in a population based setting.MethodsAn unselected sample of 1,987 women with and without breast cancer was studied with regard to the age of diagnosis of breast cancer.ResultsThe risk of early-onset breast cancer was increased when there were: (1) at least 2 cases of female breast cancer in first-degree relatives (yes/no; HR at age 30: 3.09; 95% CI: 128-7.44), (2) at least 2 cases of female breast cancer in first or second-degree relatives under the age of 50 (yes/no; HR at age 30: 3.36; 95% CI: 1.12–10.08), (3) at least 1 case of female breast cancer under the age of 40 in a first- or second-degree relative (yes/no; HR at age 30: 2.06; 95% CI: 0.83–5.12) and (4) any case of bilateral breast cancer (yes/no; HR at age 30: 3.47; 95%: 1.33–9.05). The positive predictive value of having 2 or more of these characteristics was 13% for breast cancer before the age of 70, 11% for breast cancer before the age of 50, and 1% for breast cancer before the age of 30.ConclusionApplying family history related criteria in an unselected population could result in the screening of many women who will not develop breast cancer at an early age.

Tailoring breast cancer therapy to genetic status.

The conservative management of breast cancer with wide local excision followed by radiation therapy has been proven to be of equivalent efficacy to mastectomy for patients with stage I/II disease, and has been accepted as the standard of care for most patients with early-stage breast cancer. On the contrary, the appropriateness of breast-conserving therapy in carriers of a deleterious BRCA1/BRCA2 mutation is still a matter of debate, in view of the possible increased risk of an ipsilateral recurrence (either a true recurrence or a new primary breast cancer). Furthermore, there are concerns about the presumed damage of radiation on DNA in carriers of the BRCA1/BRCA2 mutation. Recently, Mark Robson and co-workers further explored the former issue and put this in perspective. The risk of radiation-associated side-effects in mutation carriers is not well studied. The only report investigating this issue in BRCA1/BRCA2 mutation carriers compared with sporadic controls was reported by Pierce et al. They found no differences in the rates of acute or chronic complications after a 5-year median follow-up. Several authors, including our group, investigated the occurrence of ipsilateral and contralateral breast events after breast-conserving therapy in BRCA mutation carriers. While the risk of a contralateral breast cancer is uniformly high in all studies, whether family-based or population-based, results for ipsilateral recurrence are more disparate. One of the reasons for this inconsistency might be the difficulty in distinguishing a true recurrence from a second primary tumour in the same breast. Ways to disentangle these two entities are, for instance, to compare morphological and histochemical characteristics, to examine the location within the breast of the two events, and to consider the time elapsed since the primary tumour. Generally, recurrences that are (according to these criteria) more likely to represent a second primary tumour in the same breast appear more often in BRCA1/BRCA2 mutation carriers, whereas the risk of a relapse of the first tumour appears not to be higher than expected, probably by the protective effect of the radiation therapy. Robson and co-workers provide additional data on the rates of ipsilateral and contralateral breast cancer after breast-conserving therapy in 87 patients identified as BRCA1 or BRCA2 mutation carriers at one institution. Their conclusions, with a median follow-up of 76 months, agree with most of the previous reports, confirming the high risk of contralateral breast cancer, whereas the overall risk of an ipsilateral recurrence appeared similar to those of young women with sporadic breast cancer, with 5-year and 10-year probabilities of 11·2% and 13·6%, respectively. A drawback of Robson and co-workers’ study is that no comparisons were made with an internal control group but only with published data. Furthermore, it might have been interesting to present subgroup analyses excluding the small group of BRCA2 mutation carriers, as tumours associated with BRCA1 and BRCA2 clearly constitute different entities. The issue of ascertainment/longevity bias is recognised and discussed by Robson and co-workers. This problem is well-known in this type of study, in patients that have to be alive at the moment of DNA testing. The time between the date of initial diagnosis of breast cancer and the DNA result is described by Robson. For the risk of a contralateral breast cancer, Robson presents separate analyses for women with a breast cancer diagnosis less and more than 2 years before the DNA diagnosis, showing no significant difference between the subgroups in 5-year risk of a contralateral breast cancer. However, these subgroup analyses were not done for the other endpoint, local recurrence risk, although Robson does present data showing that the interval between breast cancer and DNA diagnosis was significantly longer in women with a local recurrence than in those without. The reason for this inconsistency is unclear. Robson and co-workers’ paper presents a detailed overview of other published studies on the subject. Tailoring breast cancer therapy to genetic status

Comment on Screening by MRI Mentioned in the Reviews by Narod and Møller

Currently many women from families with a high risk of breast cancer due to a familial or genetic predisposition, including carriers of a BRCA1/2 germline mutation, opt for intensive surveillance [1]. Several guidelines advise screening by mammography and clinical breast examination. However, the value of this screening scheme in women that often start screening under the age of 40 has never been proven. There are indications that the sensitivity of mammography is especially low in carriers of a BRCA1 or BRCA2 mutation [2,3]. This is the main reason why the value of MRI screening is being investigated in various family cancer clinics worldwide. To date only preliminary data from small studies are available about the effectiveness of this MRI screening [4-6]. In these preliminary studies, MRI appears to be a more sensitive screening method than mammography, but this does not mean that it detects breast cancer at an earlier stage. It might be expected that MRI can detect breast cancer at an earlier stage than mammography. However, no study has been published that compares the tumour stage of patients detected within an MRI screening programme with that of comparable symptomatic patients. As stated by Narod, the main goal of screening is a stage shift towards earlier breast cancer diagnosis that might lead to a reduction in breast cancer mortality, against acceptable side effects. While the high financial costs are mentioned by Narod, many other negative effects of MRI screening have been described. For instance, some studies described a specificity much lower as compared to mammography, causing unnecessary additional investigations. These negative effects should be taken into account when making a decision to use a new screening tool. To date no longer-term prospective studies with data about the potential of MRI to diagnose breast cancer at an earlier stage, the possible reduction of breast cancer mortality and the cost-effectiveness are available. These data can be expected from several ongoing studies in the near future [7,8]. In this respect we agree with Moller that only when these data are available definitive and evidence-based advice about screening in high risk women can be given. In the meantime we advise, as Narod and Moller, to consider MRI screening in high risk women in addition to the routine screening program, especially in women where mammography screening has the smallest effect, such as mutation carriers, until we have results from large prospective studies.