Family Cancer Clinic Research Articles

The role of BRCA mutation testing in determining breast cancer therapy

Landmark discoveries in the field of breast cancer research include the identification of germline BRCA mutations as a cause of hereditary disease, and the use of gene-expression profiling to identify distinct subtypes of breast cancer. These findings, coupled with the availability of rapid germline testing, make it possible to identify a BRCA mutation carrier contemporaneous with a diagnosis of breast cancer. For the first time, testing for a germline mutation that predisposes to cancer has the potential to influence the immediate surgical, radiotherapeutic, and drug treatment choices of an individual with a new diagnosis of breast cancer. In this Review, we examine the implications of moving germline BRCA mutation testing from highly specialized family cancer clinics to mainstream settings.

Family history: the neglected risk factor in disease prevention

TO THE EDITOR: I agree with Emery and colleagues that family history can add much to downstream clinical interventions that provide tangible benefits to the presenting patient and his or her kin. The pedigree chart has some advantages over simple narrative recording of the same details, including the ability to instantly visualise relationships between individuals and the ease with which the chart can be updated and annotated. There is a familial aggregation (commonly an affected first-degree relative) in up to 25% of presenting cancer patients, while around 5% will harbour a highly penetrant genetic predisposition to cancer. In the cancer clinic, an acceptably detailed family cancer pedigree can typically be obtained in even less time than the 30 minutes suggested by Emery et al. Steps in drawing pedigrees have been outlined elsewhere and typically involve collecting information such as simple demographics, naming and symbolising different cancer types, and recording age of onset and age of death (if relevant) for the different individuals, starting with the presenting patient. The time required to construct a three-generation pedigree would typically be around 10 minutes, making it an attractive addition to routine history taking. If a cancer pattern emerges, the pedigree should be extended as far as possible. Of course, diagnosis verification (through death registries, etc) would be required before surveillance, prophylaxis and therapy decisions are addressed in the familial cancer setting. A convenient refresher for doctors who do not routinely draw pedigrees might be to first construct their own family tree, with reference to the symbols and relationship illustrators commonly used. It is likely that pedigrees in most clinics will be drawn by hand, at least initially, although there are software programs for pedigree creation available (eg, Family Tree Builder; ). Over the years, I have informally asked my specialist oncology trainees to routinely construct family pedigrees. I do not recall, among these highly clinically skilled doctors, one that was able to correctly draw a family pedigree until we had worked on it together. Given the benefits of family pedigree analysis across many disease categories, a little practice in pedigree drawing may be a useful exercise for many of us. Even without the requisite confirmation of disease status of the individuals represented, a simple pedigree chart, combined with quick reference to information on the potential clinical significance of any patterns it shows (eg, by consulting National Health and Medical Research Council guidelines), can help prioritise referrals to busy familial cancer clinics.

Association of Lynch syndrome and risk of invasive cervical cancer.

1501 Background: Lynch syndrome, a hereditary cancer syndrome characterized by germline mutations in mismatch repair (MMR) genes, is associated with an elevated lifetime risk of cancer development, predominantly endometrial, colorectal and ovarian. To date, no increased risk of cervical cancer for mutation carriers has been reported. Methods: Families with an identified pathologic mutation in one of the MMR genes MLH1, MSH2, MSH6 or PMS2 were obtained from Colon Cancer Family Registry (Australasia, USA and Canada). Families were ascertained via a population- based colorectal cancer case or via family cancer clinics. Attempts were made to obtain pathology reports for cases of cervical cancer. Modified segregation analyses incorporating rigorous corrections for ascertainment were used to estimate relative and cumulative risks of cervical cancer for mutation carriers. Binomial tests and t-tests and were used to compare observed histology and ages of diagnosis to population norms. Results: A total of 66 cases of cervical cancer were reported among 369 families (133 MLH1, 174 MSH2, 35 MSH6 and 27 PMS2) containing 7,119 females and 7,812 males, 2,033 of whom were genotyped (1,073 carriers and 960 non-carriers). The incidence of cervical cancer was estimated to be higher for carriers than non-carriers by a factor of 5.4 (95% CI 2.2-13.5; p > 0.002). The corresponding estimated cumulative risk to age 80 years for women from the USA sites was 4.4% (95% CI 1.8-11.0 %) for MMR mutation carriers compared with 0.8% for non-carriers. Mean age of cervical cancer diagnoses in carriers was 42.9 years (range 18-70), younger than the corresponding mean age of 47 years in the general population (p > 0.01, 95% CI 39.8-46.0) (seer.cancer.gov/csr/1973_1999/cervix.pdf). Pathology reports were available for 12 cases with 8 (67%) reported as either adenocarcinoma or mixed histology with a predominance of adenocarcinoma, significantly more (p > 0.003) than the expected proportion of 25% based on SEER data. Conclusions: These novel findings suggest that cervical cancer is associated with Lynch syndrome and that the histology of cervical cancers in MMR mutation carriers may vary from expected population standards. No significant financial relationships to disclose.

Activity of taxane chemotherapy for metastatic breast cancer (MBC) in BRCA1 and BRCA2 mutation carriers compared to sporadic BC patients.

1020 Background: BRCA1-associated BC is characterized by high differentiation grade and basal-like phenotype, while BRCA2-associated and sporadic BC have similar patterns. Preclinical and small retrospective studies suggest that BC (cells) without functioning BRCA1/2 protein have increased sensitivity to chemotherapy causing dsDNA breaks, and decreased sensitivity to spindle poisons. Clinical data on the activity of taxanes in BRCA1/2-associated BC are scarcely available. Therefore, we assessed the activity of taxane-based chemotherapy in BRCA1- and BRCA2-associated compared to sporadic MBC pts. Methods: From the Family Cancer Clinic database, we selected 32 BRCA1- and 13 BRCA2-associated BC pts treated with taxane chemotherapy for MBC. Sporadic pts (n=90, 1:2 ratio) were matched for year of birth, diagnosis and metastatic disease, and line of chemotherapy. Response rates (RR) were tested by chi-square test, progression-free survival (PFS) was analysed by Kaplan-Meier method. Results: BRCA1 pts significantly more often had ER-negative and contralateral BC, while no significant differences between BRCA2 and sporadic pts were observed. Taxane therapy consisted of docetaxel (n=106), paclitaxel (n=16), or taxane/trastuzumab regimen (n=7). Taxanes were given in first-line therapy n=22, second n=86, or third line setting n=27. Compared to sporadic pts, the RR in BRCA1 pts was worse (overall OR 25% vs. 38%, PD 59% vs. 20%, for second-/third-line: OR 24% vs. 36%, PD 60% vs. 18% (both p<0.001). BRCA2 pts had a better RR than sporadic pts (OR 75% vs. 36%, p=0.02). Median PFS in BRCA1 pts was shorter than in sporadic pts, overall: 2.0 vs. 4.5 mo (p=0.07), for second-/third-line therapy: 2.0 vs. 4.7 mo (p=0.03). Median PFS in BRCA2 and sporadic pts was similar (4.6 vs. 4.7 mo). Both RR and PFS were significantly different between BRCA1 and BRCA2 pts. Similar results were obtained after exclusion of pts receiving a taxane/trastuzumab regimen. Conclusions: Compared to sporadic pts, BRCA1-associated M1BC pts are less sensitive to palliative taxane therapy regarding OR and PFS, which is not observed in BRCA2 pts. In view of potential therapeutic implications, identification of genetic status at BC diagnosis may be(come) important. No significant financial relationships to disclose.

Short-term surgical outcome and safety of risk reducing salpingo-oophorectomy in BRCA1/2 mutation carriers

Objective Women with a BRCA1/2 mutation or members of a hereditary breast ovarian cancer family (HBOC) have an increased risk of developing ovarian cancer. The only effective strategy to reduce this risk is a risk reducing salpingo-oophorectomy (RRSO). The aim of this study was to evaluate the short-term surgical outcome and safety of a RRSO. Patient and methods Included were all consecutive women with a BRCA1/2 mutation or members of a HBOC family who visited our Family Cancer Clinic between September 1995 and March 2006, and choose for RRSO. Results 159 women were included, of which 97 (61.0%) BRCA1 and 32 (20.1%) BRCA2 mutation carriers, and 30 women of a HBOC family (18.9%). The median age at RRSO was 42.9 years (30.3–61.1) in the BRCA1 group, 48.4 years (33.5–66.9) in the BRCA 2 group and 46.4 (32.8–68.7) years in the HBOC group ( p = 0.02). The median body mass index (BMI) was 24.9 kg/m 2, 30.1% were overweighed (BMI 25–30) and 18.7% were obese (BMI > 30). The RRSO was performed by primary laparoscopy ( n = 154) or laparotomy ( n = 5). Intraoperatively, one (0.6%) major complication occurred and laparoscopy was converted to laparotomy. In one patient (0.6%) a minor complication occurred. Post-operatively five minor complications (3.1%) were observed. Median hospital stay was 1 day (0–13 days). Conclusion Laparoscopic RRSO in BRCA1/2 mutation carriers seems to be a safe procedure with a low intraoperative and post-operative complication rate (1.3% and 3.1% respectively), a low conversion rate (0.6%) and a short median hospital stay (1.0 day ).

Hereditary causes of kidney tumours

In most cases of renal cell carcinoma there is no family history of renal cancer and no hereditary cause of the disease. Hereditary renal cancer accounts for about 2-4% of cases. Recognition of this subgroup by clinicians is important because of the possibility of severe medical consequences for patients and their relatives. We review the latest data about different genetic conditions characterized by an increased risk of developing renal cancer and we formulate tools to recognize high-risk families. In general, a positive family history, young age at diagnosis of renal cancer, multiple and/or bilateral renal tumours and combined occurrence of different histological types of renal tumours should raise suspicion of a hereditary renal tumour syndrome. In addition, the presence of specific extrarenal symptoms in patients could assist in differentiating between tumour syndromes. A detailed medical and family history, along with physical examination are key factors to diagnose hereditary renal cancer syndromes. When a genetic predisposition for renal cancer is suspected, referral to a Family Cancer Clinic is warranted to initiate genetic examination and counselling on preventive options.

Psychosocial impact of Von Hippel–Lindau disease: levels and sources of distress

Von Hippel-Lindau disease (VHL) is a hereditary tumor susceptibility syndrome, characterized by an increased risk of developing multiple benign and malignant tumors at various sites and ages with limited preventive options. This study evaluates the prevalence of distress among VHL family members and factors associated significantly with such distress. Forty-eight families with a VHL mutation were identified via the nine family cancer clinics in the Netherlands. In total, 171 family members (carriers, 50% at-risk, non-carriers) were approached, of whom 123 (72%) completed a self-report questionnaire. Approximately 40% of the VHL family members reported clinically relevant levels of distress, approaching 50% among the carriers and, possibly even more striking, 36% among the non-carriers. Having lost a first degree relative due to VHL during adolescence (OR 11.2; 95% CI 1.4-86.9) was related significantly to heightened levels of distress. Approximately, only one-third of those who reported heightened levels of distress had received professional psychosocial support. A substantial percentage of family members experience clinically relevant levels of distress. We would recommend the introduction of a procedure for screening for distress in this vulnerable population. Special attention should be paid to those individuals who have lost a close relative due to VHL during adolescence.

PWE-067 Recessively inherited non-polyposis colorectal cancer: genotype and phenotype

Introduction Patients diagnosed before 50 years of age have a likely strong genetic or environmental aetiological factor. There is good evidence from population studies1 that recessive inheritance is common in young colorectal cancer patients. Methods A cohort of 133 colorectal cancer patients without multiple polyps or a family history of dominant inheritance were diagnosed under the age of 50 years. They were identified and recruited from the Bobby Moore database in the Family Cancer Clinic, St Mark9s Hospital, Harrow. MYH was screened for germline mutations. As these patients fulfilled Bethesda criteria they were tested for hereditary non-polyposis colorectal cancer (HNPCC) by microsatellite instability analysis and immunohistochemistry of mismatch repair proteins. Immunohistochemistry was also performed on β-catenin and P53. Loss of heterozygosity of the APC locus at 5q21–22 was tested using a set of microsatellite markers. Sequencing was used to identify somatic mutations in KRAS and BRAF. Results Forty-four patients (33%) had cancers proximal to the splenic flexure, 79 (59%) distal and had 11 (8%) synchronous colorectal cancers. Thirty-seven patients (28%) had an affected sibling and 33 (25%) patients had a second-degree relative with cancer at any site. The median age of diagnosis of colorectal cancer was 39 years (range 14–49 years of age). Twenty-six patients (20%) were found to harbour sequence variation in the MYH gene but none of these variants were likely to be pathogenic, and there was no difference in the frequency of these compared to a control group of 50 patients. Eighty percent of tumours were found to be microsatellite stable. 20/30 cancers had nuclear localisation of β-catenin and 21/30 had nuclear localisation of P53 antibodies on immunohistochemistry. Loss of heterozygosity of the APC locus at 5q21–22 was present in 14/30 cases. Thus Wnt pathway activation is likely by over half of this group of cancers. Four cancers had BRAF V600E mutations and five had KRAS codon 12 or 13 mutations. Conclusion In a cohort of 133 young colorectal cancer patients without multiple polyps, most tumours demonstrated Wnt pathway activation and other somatic changes consistent with the classical adenoma-to-carcinoma sequence. Germline mutations in the colorectal neoplasia predisposition gene MYH appear to be rare events in such patients. The majority of recessive inheritance in young patients is probably caused by mutations in unknown predisposition genes.

Treatment‐focused DNA testing for newly diagnosed breast cancer patients: some implications for clinical practice

There is accumulating evidence that women with breast cancer due to a familial BRCA1 or BRCA2 mutation benefit from specific surgical and chemotherapeutic treatment strategies. However, the rapid identification of such patients during the acute phase of treatment raises a number of issues. This study investigated Australian opinion leaders' views on the issues arising from such 'treatment-focused' genetic testing. Semi-structured interviews with 34 opinion leaders working in cancer genetics were undertaken. Interviewees acknowledged the introduction of treatment-focused DNA testing has the potential to positively transform the management of breast cancer patients, but were concerned that certain ethical and logistical issues have yet to be addressed. These include decision-making and consent, the familial nature of genetic information, and the management of genetics services within familial cancer clinics in the public hospital system in Australia. Service providers will need to have policies and strategies for managing the increased demand. It will also be necessary to include genetic counseling services within familial cancer clinics in the care pathway for newly diagnosed patients prior to any DNA testing to determine adjuvant treatment; such services may be more cost-effective than expecting surgeons and medical oncologists to fulfill this role.

553 Clinical characteristics and risk profile of individuals referred to Iranian familial breast cancer clinic: the necessity of genetic counseling

553 Clinical characteristics and risk profile of individuals referred to Iranian familial breast cancer clinic: the necessity of genetic counseling

Risks of Lynch syndrome cancers for MSH6 mutation carriers.

Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain. We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment. For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7). We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.

22. Hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report

Background Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial syndrome characterised by cutaneous and uterine leiomyoma and renal cell carcinoma. The kidney tumours are typically described as having features of type 2 papillary carcinoma; however, other types of renal cell cancers have also been reported. The tumours tend to be aggressive, with frequent and early nodal and distant metastases despite the often small size of the primary tumour. Case report We present an unusual case of HLRCC in a 53-year-old male who was referred to a Family Cancer Service with a strong personal and family history of renal cancer. He was diagnosed at age 31 with a ‘Grawitz tumour’. The histology of his renal cell carcinoma was reviewed following recognition of HLRCC in the family. The patient’s tumour had solid and cystic areas with tubulopapillary architecture. The tumour cells had a moderate amount of eosinophilic cytoplasm, with Fuhrman nuclear grade 3. Many of the nuclei showed prominent eosinophilic nucleoli, with a clear halo surrounding the nucleolus. No invasion of the renal capsule or vessels was seen. Initially no underlying genetic cause for renal cancer in the family was found. The family history then evolved with a female relative developing both cutaneous and uterine leiomyoma and her dermatologist suspected HLRCC as the cause. A New Zealand Family Cancer Clinic arranged genetic testing of an affected relative and a causative germline mutation was identified in the fumarate hydratase (FH) gene [p.Gly354Arg (G354R)]. Genetic testing for our patient was then arranged and this confirmed he had inherited the family mutation in the FH gene. He remains disease free. His offspring are being tested. Conclusion This case report reviews the molecular genetics of HLRCC and the pathological features of renal cell carcinoma, with discussion on possible characteristic histological features that may help to alert the pathologist to the possibility of a familial cancer syndrome.

Contralateral Breast Cancer in BRCA1/2 Mutation Carriers: Risk Assessment by Age at Diagnosis of the First Primary Breast Cancer.

Abstract Purpose Age at diagnosis of the first breast cancer is a known predictive factor of the risk of contralateral breast cancer (CBC) in BRCA1/2 mutation carriers. However, accurate risk estimates for different age subgroups are scarce.Methods We studied the risk of CBC in 560 women with a primary breast cancer (PBC) from families with a proven BRCA1 or BRCA2 mutation in relation to the age at diagnosis of the first PBC, taking into account history of oophorectomy. Time at risk was the period between diagnosis of the first PBC and date of contralateral breast cancer, contralateral mastectomy, metastatic disease, death or last follow-up. Oophorectomy was treated as a time-dependent covariate. Patients with bilateral breast cancer diagnosed before the first visit at the family cancer clinic were excluded.Results We observed 96 CBCs in 423 BRCA1 mutation carriers and 21 cases in 137 BRCA2 mutation carriers. Actuarial risk of CBC at 5, 10 and 15 years was 14%, 34% and 39%, respectively, for BRCA1-, and 13%, 22% and 27%, respectively, for BRCA2 mutation carriers. For BRCA1 carriers 10-year actuarial risk of CBC was 54% for women with a PBC ≤ 30 years, 39% for the group with PBC between 31-40 years, 26% for the 41-50 group and 17% for those with PBC &amp;gt; 50 years. In BRCA2 carriers 10-year risk of CBC was 28% for women with a PBC ≤ 40 years, 19% for the 41-50 group and 10% for those with PBC &amp;gt; 50 years. For BRCA1 carriers who had an oophorectomy, 10-year risk of CBC was 33% and 26%, respectively, for those with PBC younger and older than 40 years, against 44% and 24% in women who had no such treatment. In BRCA2 carriers with a history of oophorectomy 10-year risk of CBC was 21% and 14%, respectively, for those with PBC younger and older than 40 years, while the risk was 29% and 17%, respectively, in women without oophorectomy. Effect of adjuvant therapy is being analyzed and will be presented at the meeting.Conclusions The availability of risk estimates of CBC by more detailed age groups at PBC is a helpful tool in the counselling process concerning screening and/or preventive surgery for breast cancer patients with a BRCA1 or BRCA2 mutation. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 903.

Sensitivity to Taxane Chemotherapy for Metastatic Breast Cancer in BRCA1 and BRCA2 Mutation Carriers Compared to Sporadic Breast Cancer Patients.

Abstract Purpose: Data of in vitro and small retrospective studies suggest that breast cancer (BC) (cells) without functional BRCA1 or BRCA2 protein have an increased sensitivity to chemotherapeutic agents causing double strand DNA breaks, while sensitivity to spindle poisons, such as paclitaxel and docetaxel, has been found to be decreased. Clinical data on the latter, however, are very scarce. In this study, we assessed the sensitivity to taxane chemotherapy for metastatic BRCA1/2-associated compared with sporadic breast cancer.Methods: From the family cancer clinic database, we retrieved 36 BRCA1 and 13 BRCA2-associated BC patients treated with taxane chemotherapy for metastatic disease before October 1, 2008, and with available data on follow-up and response assessment. Objective response (OR), and progression-free survival (PFS) after start of taxane chemotherapy were compared with those of 62 sporadic patients with comparable age at diagnosis and year of detection of metastatic BC. A t-test or chi-square test was used to test for differences in characteristics and response types, and Kaplan-Meier survival analysis to calculate PFS.Results: Taxane chemotherapy consisted of docetaxel (n= 76) or paclitaxel (n=21), while 10 (9%) patients received a taxane/trastuzumab regimen. It was given as first-line palliative therapy in 9 BRCA1, 1 BRCA2 and 22 sporadic patients; but mainly as second/third line treatment (BRCA1 n=27, BRCA2 n=12, sporadic patients n=40, respectively). As compared to sporadic patients, BRCA1-associated patients had a significantly lower OR rate (ORR) overall (22% vs 46%, p&amp;lt;0.001) and to 2nd/3rd line taxane treatment (19% vs 46%, p&amp;lt;0.001). Median PFS was shorter in BRCA1 patients (2.0 vs 4.1 mo, p=0.08), with a trend for significance for 2nd/3rd line therapy (1.6 vs 3.9 mo, p=0.05). Also, compared to BRCA2 patients, the ORR in BRCA1 patients was significantly lower, overall as well as to 2nd/3d line therapy (both p=0.003). In BRCA2 mutation carriers compared to sporadic patients, the ORR was higher (75% vs 48%, p=0.28) and PFS longer (6.4 vs 4.1 mo, p=0.33). After exclusion of the patients receiving a taxane/trastuzumab schedule, similar data were observed.Conclusion: Objective response rate to taxane chemotherapy for metastatic disease is lower in BRCA1-associated BC in comparison with sporadic as well as BRCA2-associated BC, resulting in a shorter PFS. If confirmed, these data may have substantial clinical relevance. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2098.

A comparison of male attendees and nonattendees at a familial cancer clinic

PurposeThis retrospective descriptive Australian study aimed to determine predictors of nonattendance at a familial cancer clinic by men from high-risk breast/ovarian cancer families. MethodsTwo hundred twenty-six men from families with a known BRCA1 or BRCA2 mutation were recruited through an epidemiological database of high-risk breast cancer families and completed a self-administered questionnaire. ResultsMultivariate analyses using binary logistic regression showed that nonattendance at a familial cancer clinic by men from high-risk breast/ovarian cancer families was associated with younger age (51 vs. 55 years) (odds ratio = 1.03, P = 0.04) and lower cancer burden (one relative diagnosed versus two relatives diagnosed) (odds ratio = 2.6, P = 0.04). ConclusionCompared with men who attended a familial cancer clinic, nonattendees were younger and had fewer relatives diagnosed with breast/ovarian cancer. Unlike previous findings, cancer-specific worry, in particular avoidance was not associated with nonattendance. The number, age, and sex of biological children were not associated with attendance or nonattendance. Hence, some of the assumptions about what makes information on BRCA1 or BRCA2 status salient to men and may therefore influence their attendance at a cancer genetic clinic are not borne out in this study.

Is uptake of genetic testing for colorectal cancer influenced by knowledge of insurance implications?

To assess whether knowledge of insurance implications influenced uptake of genetic testing by participants in a research study of the causes of colorectal cancer. Analysis of uptake of genetic testing by participants in the population-based Victorian Colorectal Cancer Family Study during two periods: from 1999 to 2003, when participants were not informed of any potential effect of genetic testing conducted during the study on their eligibility for new insurance policies; and from 2003 to 2006, when the protocol was changed to provide participants with information on the potential effect of genetic testing on insurance eligibility. Uptake of genetic testing for germline mutations in DNA mismatch repair (MMR) genes at a family cancer clinic. The proportion of participants who declined genetic testing among those informed of insurance implications was more than double the proportion among those without this knowledge (29/59 [49%] v 9/47 [19%]; P = 0.002). This difference could not be explained statistically by adjusting for measured putative predictors. Identification of people with a mutation in an MMR gene has clinical importance, and such screening may be a cost-effective way to reduce the burden of colorectal cancer in the community. If people are choosing not to obtain genetic information because of how it will affect their eligibility for insurance, reforms to existing insurance practices are indicated.

Attitude towards pre-implantation genetic diagnosis for hereditary cancer

The use of pre-implantation genetic diagnosis (PGD) for hereditary cancer is subject to on-going debate, particularly among professionals. This study evaluates the attitude towards PGD and attitude-associated characteristics of those concerned: family members with a hereditary cancer predisposition. Forty-eight Von Hippel-Lindau and 18 Li–Fraumeni Syndrome families were identified via the 9 family cancer clinics in the Netherlands. In total, 216 high risk family members and partners were approached, of whom 179 (83%) completed a self-report questionnaire. Of the high risk family members, 35% expressed a positive attitude towards PGD. Those with a current desire to have children were significantly more likely to have a positive attitude: 48% would consider the use of PGD. No other sociodemographic, medical or psychosocial variables were associated significantly with a positive attitude. The most frequently reported advantage of PGD is the avoidance of a possible pregnancy termination. Uncertainty about late effects was the most frequently reported disadvantage. These results indicate that approximately half of those contemplating a future pregnancy would consider the use of PGD. The actual uptake, however, is expected to be lower. There is no indication that psychosocial factors affect interest in PGD.

BRCA testing of breast cancer patients: medical specialists' referral patterns, knowledge and attitudes to genetic testing

This study explores knowledge about hereditary breast cancer, attitudes about BRCA testing and referral pattern to a family cancer clinic among medical specialists. A total of 92 questionnaires were completed by surgeons (38), medical oncologists (29), radiation oncologists (13) and radiologists (12). The response rate was 51%. A substantial (11-56%) proportion of medical specialists do not refer patients who meet current criteria for BRCA testing. Although questions on inheritance were less well answered, overall knowledge was good. They had a positive attitude, but were concerned about the distress DNA testing might cause to family members. The majority (75%) stated that the best time for referral is after adjuvant therapy or during follow-up, but another important determinant was the patient's wish or need (12%). Further studies are needed to gain insight into the actual referral process, while ongoing training of medical specialists about genetic aspects of breast cancer is also necessary.

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

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. 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. 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. 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.

Men at Increased Risk of Developing Breast Cancer: Language Preferences for Naming a Cancer-Related Mutation

Patients attending familial cancer clinics may find the term "mutation" offensive and potentially stigmatizing, yet there is little consensus in the literature as to the most appropriate alternative terms to describe a cancer-related mutation to individuals considering genetic testing for cancer risk. This study aimed to describe a cancer-related mutation in a rare group of familial cancer clinic patients: men at increased risk of carrying a breast cancer-related mutation. Twenty-seven men completed a self-report questionnaire that assessed their preferences for language to describe a cancer-related mutation. Overall, men were most likely to spontaneously suggest the term "faulty gene" to describe a cancer-related mutation when asked an open-ended question about their language preferences. When asked to rate the term "faulty gene" in comparison to the terms "altered gene," "mutation," "nonworking gene," "malfunctioning gene," and "gene change," the term "faulty gene" received the highest mean preference rating in this sample of men at increased risk of developing breast cancer. This area of investigation remains controversial and would benefit from more formal and larger-scale investigations of the language preferences of individuals at increased risk of developing cancer.