Laetitia Huiart

Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome

CONTEXT Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome. OBJECTIVE To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes. DESIGN, SETTING, AND PARTICIPANTS Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed. MAIN OUTCOME MEASURE Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias. RESULTS Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations. CONCLUSIONS MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.

Age at Menarche and Menopause and Breast Cancer Risk in the International BRCA1/2 Carrier Cohort Study

Background: Early menarche and late menopause are important risk factors for breast cancer, but their effects on breast cancer risk in BRCA1 and BRCA2 carriers are unknown. Methods: We assessed breast cancer risk in a large series of 1,187 BRCA1 and 414 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study. Rate ratios were estimated using a weighted Cox-regression approach. Results: Breast cancer risk was not significantly related to age at menopause {hazard ratio [HR] for menopause below age 35 years, 0.60 [95% confidence interval (95% CI), 0.25-1.44]; 35 to 40 years, 1.15 [0.65-2.04]; 45 to 54 years, 1.02 [0.65-1.60]; ≥55 years, 1.12 [0.12-5.02], as compared with premenopausal women}. However, there was some suggestion of a reduction in risk after menopause in BRCA2 carriers. There was some evidence of a protective effect of oophorectomy (HR, 0.56; 95% CI, 0.29-1.09) and a significant trend of decreasing risk with increasing time since oophorectomy, but no apparent effect of natural menopause. There was no association between age at menarche and breast cancer risk, nor any apparent association with the estimated total duration of breast mitotic activity. Conclusions: These results are consistent with other observations suggesting a protective effect of oophorectomy, similar in relative effect to that in the general population. The absence of an effect of age at natural menopause is, however, not consistent with findings in the general population and may reflect the different natural history of the disease in carriers. (Cancer Epidemiol Biomarkers Prev 2007;16(4):740–6)

Phenotypic Heterogeneity in Multiple Myeloma Families

PURPOSE To describe a series of families with familial multiple myeloma (MM). Observations were used to generate hypotheses about the role of genetic factors, the mode of inheritance of these factors, and the association of other cancers with familial MM. PATIENTS AND METHODS This observational study consisted of 39 families with multiple cases of MM or related disorders from four collaborating research centers. Each center followed its usual family study method. Probands were interviewed, and, when possible, cancers were verified by medical records and pathology review. A working pedigree was compiled on each family. RESULTS Seventeen families had affected members in two or more generations, and eight families had two or more affected members in a single generation. Four families had two or more members with plasma cell dyscrasias, with or without a single case of MM. In the remaining 10 families, a single MM case occurred with a family history of other cancers. Other cancers observed in family members included hematologic malignancies and solid tumors. In families with MM in multiple generations, there was a decrease in the age at MM diagnosis in successive generations. CONCLUSION The study of familial MM may provide insights into the pathogenesis and, ultimately, the control and prevention of MM and related disorders. Population-based epidemiologic studies are crucial, but because of the rarity of familial MM, a concerted case-finding approach may also be fruitful. Therefore, we propose an international consortium to study familial MM, and we invite all interested colleagues to participate.

Value of the Sentinel Lymph Node Procedure in Patients With Large Size Breast Cancer

BackgroundWidely used in routine for small breast cancers, the sentinel lymph node (SN) biopsy is still discussed in tumors ≥ 3 cm.MethodsFrom 2000 to 2005, 152 patients with invasive breast tumor pT ≥ 3 cm had a SN biopsy systematically followed by complete level I/II axillary dissection. Surgery was always the first stage of the treatment. Detection was done after injection of radioisotope followed by a lymphoscintigraphy and injection of Patent Blue. The SN procedure systematically included palpation of the axilla with removal of any enlarged (>1 cm) and/or abnormally firm node even if neither blue nor radioactive. The sentinel lymph node status was compared with the final axillary status.ResultsTumor size ranged from 30 to 200 mm (median 42 mm). Lymphoscintigraphy was positive in 98% of the cases. At least one labeled sentinel node was retrieved in 97.4% of the patients. The median number of SN cleared out was 2 (range 1–9). The false negative risk was 4% (4/99). The false negative risk was not related to the tumor size and not related to the number of SN removed.ConclusionsThis study shows that the SN procedure is feasible in patients with breast tumors ≥ 3 cm with an acceptable false negative risk <5%, similar to false negatives reported for smaller tumors.

Concurrent use of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer recurrence.

Concurrent use of tamoxifen and cytochrome P450 2D6 (CYP2D6) inhibitors, such as selective serotonin reuptake inhibitors, has been shown to decrease plasma concentrations of tamoxifen metabolites. However, it is still unclear whether such concurrent use affects tamoxifen’s effectiveness. Thus, the objective of this study is to determine whether concurrent use of tamoxifen with CYP2D6 inhibitors increases the risk of recurrence in patients newly diagnosed with breast cancer. We conducted a nested case–control analysis within a population-based cohort from the UK General Practice Research Database. The cohort included women with a first-ever diagnosis of breast cancer who were prescribed tamoxifen between January 1, 1998 and June 30, 2008. Cases consisted of all patients with a breast cancer recurrence occurring during follow-up. Up to ten controls were matched to each case on year of birth, date of cohort entry, and duration of follow-up. Conditional logistic regression was used to estimate rate ratios (RR) of breast cancer recurrence in patients who concurrently used tamoxifen with CYP2D6 inhibitors, compared to patients who only used tamoxifen. The cohort included 9,209 incident users of tamoxifen, of whom 807 were diagnosed with a breast cancer recurrence. Concurrent use was not associated with an increased incidence of breast cancer recurrence (adjusted RR 1.07, 95% 0.88, 1.30). Type and strength of CYP2D6 inhibitors, as well as duration of concurrent use did not affect breast cancer recurrence. These results remained consistent after performing sensitivity analyses. The results of this large population-based study indicate that concurrent use of tamoxifen with CYP2D6 inhibitors does not increase the risk of recurrence.

Trends in the prescription of novel oral anticoagulants in UK primary care

AIMS Novel oral anticoagulants (NOACs) are alternatives to vitamin-K antagonists (VKAs) for the prevention of thromboembolism. It is unclear how NOACs have been adopted in the UK since first introduced in 2008. The present study was conducted to describe the trends in the prescription of NOACs in the UK, including dabigatran, rivaroxaban and apixaban. METHODS Using the UKs Clinical Practice Research Datalink, the rates of new use of NOACs and VKAs from 2009 to 2015 were calculated using Poisson regression. Patient characteristics associated with NOAC initiation were identified using multivariate logistic regression. RESULTS The overall rate of oral anticoagulant initiation increased by 58% over the study period [rate ratio (RR) 1.58; 95% confidence interval (CI) 1.23, 2.03], even as the rate of new VKA use decreased by 31% (RR 0.69; 95% CI 0.52, 0.93). By contrast, the rate of initiation of NOAC increased, particularly from 2012 onwards, with a 17-fold increase from 2012 to 2015 (RR 17.68; 95% CI 12.16, 25.71). In 2015, NOACs accounted for 56.5% of oral anticoagulant prescriptions, with rivaroxaban prescribed most frequently, followed by apixaban and then dabigatran. Compared to VKAs, new NOAC users were less likely to have congestive heart failure, coronary artery disease and peripheral vascular disease, and more likely to have a history of ischaemic stroke. CONCLUSIONS In the UK, the rate of initiation of NOACs has increased substantially since 2009, and these agents have now surpassed VKAs as the anticoagulant of choice. Moreover, the characteristics of patients initiated on NOACs have changed over time, and this should be accounted for in future studies comparing NOACs and VKAs.

BARD1 homozygous deletion, a possible alternative to BRCA1 mutation in basal breast cancer.

Hereditary breast cancers (BCs) are incompletely explained by BRCA genes abnormalities, as ∼70% of them are not associated with known genetic alterations. Array‐based comparative genomic hybridization (aCGH) of tumors provides an opportunity for identifying new BC susceptibility genes. By analyzing our database of high‐resolution aCGH profiles of 330 BCs, we identified a case with homozygous deletion of the entire BARD1 gene. The BARD1‐deleted case displayed a familial history of BC and other clinico‐pathological features of BRCAness, and a 17% probability of BRCA1/2 mutation. Analysis of constitutional DNA showed a BARD1 germline heterozygous deletion without BRCA1/2 mutation. Gene expression analysis using DNA microarrays classified the tumor as basal‐like, with very low BARD1 and ID4 expression, but high expression of BRCA1, RAD51, PARP1, CHEK1, and FANCA. The tumor displayed a BRCA1‐mutated expression profile. This is the first report of a non‐BRCA1/2‐mutated BC with somatic homozygous and germ‐line heterozygous deletion of the entire BARD1 gene. This observation suggests that BARD1 might be a BC susceptibility gene that follows the Knudson rule. Identification of BARD1 deletion could have clinical applications including screening for hereditary forms.

Effectiveness of motivational interviewing interventions on medication adherence in adults with chronic diseases: a systematic review and meta-analysis.

Background Medication adherence is frequently suboptimal in adults with chronic diseases, resulting in negative consequences. Motivational interviewing (MI) is a collaborative conversational style for strengthening a persons motivation and commitment to change. We aimed to assess whether MI interventions are effective to enhance medication adherence in adults with chronic diseases and to explore the effect of individual MI intervention characteristics. Methods We searched electronic databases and reference lists of relevant articles to find randomized controlled trials (RCTs) that assessed MI intervention effectiveness on medication adherence in adults with chronic diseases. A random-effects model was used to estimate a pooled MI intervention effect size and its heterogeneity (I 2 ). We also explored the effects of individual MI characteristics on MI intervention effect size using a meta-regression with linear mixed model. Results : Nineteen RCTs were identified, and 16 were included in the meta-analysis. The pooled MI intervention effect size was 0.12 [95% confidence interval (CI) = (0.05, 0.20), I 2 = 1%]. Interventions that were based on MI only [β = 0.183, 95% CI = (0.004, 0.362)] or those in which interventionists were coached during intervention implementation [β = 0.465, 95% CI = (0.028, 0.902)] were the most effective. MI interventions that were delivered solely face to face were more effective than those that were delivered solely by phone [β = 0.270, 95% CI = (0.041, 0.498)]. Conclusions This synthesis of RCTs suggests that MI interventions might be effective at enhancing of medication adherence in adults treated for chronic diseases. Further research is however warranted, as the observed intervention effect size was small.

Prediction of BRCA1 Germ-Line Mutation Status in Patients with Breast Cancer Using Histoprognosis Grade, MS110, Lys27H3, Vimentin, and KI67

Family structure, lack of reliable information, cost, and delay are usual concerns when deciding to perform BRCA analyses. Testing breast cancer tissues with four antibodies (MS110, lys27H3, vimentin, and KI67) in addition to grade evaluation enabled us to rapidly select patients for genetic testing identification. We constituted an initial breast cancer tissue microarray, considered as a learning set, comprising 27 BRCA1 and 81 sporadic tumors. A second independent validation set of 28 BRCA1 tumors was matched to 28 sporadic tumors using the same original conditions. We investigated morphological parameters and 21 markers by immunohistochemistry. A logistic regression model was used to select the minimal number of markers providing the best model to predict BRCA1 status. The model was applied to the validation set to estimate specificity and sensibility. In the initial set, univariate analyses identified 11 markers significantly associated with BRCA1 status. Then, the best multivariate model comprised only grade 3, MS110, Lys27H3, vimentin, and KI67. When applied to the validation set, BRCA1 tumors were correctly classified with a sensitivity of 83% and a specificity of 81%. The performance of this model was superior when compared to other profiles. This study offers a new rapid and cost-effective method for the prescreening of patients at high risk of being BRCA1 mutation carriers, to guide genetic testing, and finally to provide appropriate preventive measures, advice, and treatments including targeted therapy to patients and their families.

Quality of Life at 2 years Follow-up After Sentinel Lymph Node Biopsy, Immediate or Delayed Axillary Dissection for Breast Cancer

To the Editor: Axillary lymph node status is one of the major issues of breast cancer’s care. Numerous studies evaluate morbidity after axillary surgery, comparing axillary dissection (AD) with sentinel lymph node biopsy (SLB); however few assess its repercussion on quality of life (1). We followed a cohort of patients who underwent axillary surgery, to compare medium term quality of life and morbidity after SLB with AD, and after immediate AD with delayed AD. All patients were over 18 years old, and were operated for a primary breast cancer. SLB was performed for invasive cancers, or high grade in situ cancers, clinically smaller than 3 cm, without palpable axillary lymph node or known distant metastasis. AD was realized for any patient whose invasive tumor was larger than 3 cm on pathologic examination, who had at least one positive lymph node, immediately if diagnosed intraoperatively, delayed if only diagnosed on final pathologic examination. Women were asked to fill a home-mailed questionnaire, which contained socio-demographic data, the dominant hand side and measure of morbidity [European organization for research and treatment of cancer (EORTC) QLQ-BR 23 arm and breast symptoms scales, item 47 to 53 (2); visual analogic scale (VAS); Questionnaire de la Douleur de Saint Antoine (QDSA) de Boureau (3,4)], quality of life (items 29 and 30 of the EORTC QLQ-C30 (5)], depression level [center for epidemiologic studies depression scale of Fuhrer (6)]. During the study period 441 questionnaires were sent. The response rate was 77.7%. Finally, 343 patients were included. The groups did not differ significantly for dominant hand side, existence of a partner, time between surgery and answer to the questionnaire or consultation, cancer evolution, but patients were younger in AD group (p = 0.014), without differences between immediate or delayed AD. As expected, tumors were significantly smaller in SLB group than in AD group (p < 0.001), and number of removed lymph nodes and positive lymph nodes were significantly higher (p < 0.001) in AD group. Table 1 resumes type of surgery (lumpectomy, mastectomy or other surgery in the 2 years, such as reconstruction) an different adjuvant treatments in each group (Table 1). Table 2 summarizes the frequencies of the different symptoms reported by patients. Sentinel lymph node biopsy group had a better quality of life score (EORTC QLQ-C30) than AD group (p = 0.034), and a depression score significantly lower (p = 0.014) (Table 3). We did not find any significant difference between group immediate or delayed AD. After multivariate linear regression, it appears that hormonotherapy significantly diminishes quality of life score, and that this score is higher for patients with secondary education. Sequelae scores are significantly correlated to the global quality of life and depression scores. Arm scores (EORTC BR23 arm problems scale) were higher in AD group than in SLB group (p < 0.001), without difference between the two AD groups (p = 0.789) (Table 3) with no other element significantly linked with arm score in a multivariate linear regression model. Sensitivity disorders were more frequently reported in AD group than in SLB group (p < 0.001). Among patients who reported sensitivity disorder (n = 191), patients from AD group report a heavier disturbance (p = 0.007). Lymphoedema was significantly more frequent in AD group. In a logistic regression model, only axillary surgical procedure seemed associated with lymphoedema. Breast score (EORTC BR23 breast scale) was comparable for the three groups (non significant) Address correspondence and reprint requests to: Dr. Maryam Al Nakib, Hôpital Nord, 83 chemin des Bourrelys, 13015 Marseille, France, or e-mail: maryam.alnakib@ap-hm.fr.