Three partially overlapping breast cancer polygenic risk scores (PRS) comprising 77, 179 and 313 SNPs have been proposed for European-ancestry women by the Breast Cancer Association Consortium (BCAC) ...for improving risk prediction in the general population. However, the effect of these SNPs may vary from one country to another and within a country because of other factors.
To assess their associated risk and predictive performance in French women from (1) the CECILE population-based case-control study, (2) BRCA1 or BRCA2 (BRCA1/2) pathogenic variant (PV) carriers from the GEMO study, and (3) familial breast cancer cases with no BRCA1/2 PV and unrelated controls from the GENESIS study.
All three PRS were associated with breast cancer in all studies, with odds ratios per standard deviation varying from 1.7 to 2.0 in CECILE and GENESIS, and hazard ratios varying from 1.1 to 1.4 in GEMO. The predictive performance of PRS313 in CECILE was similar to that reported in BCAC but lower than that in GENESIS (area under the receiver operating characteristic curve (AUC) = 0.67 and 0.75, respectively). PRS were less performant in BRCA2 and BRCA1 PV carriers (AUC = 0.58 and 0.54 respectively).
Our results are in line with previous validation studies in the general population and in BRCA1/2 PV carriers. Additionally, we showed that PRS may be of clinical utility for women with a strong family history of breast cancer and no BRCA1/2 PV, and for those carrying a predicted PV in a moderate-risk gene like ATM, CHEK2 or PALB2.
•Three polygenic risk scores for breast cancer assessed in 3 groups of French women.•All of them associated with breast cancer but effects varied depending on group.•Predictive ability is higher in women with no BRCA1 or BRCA2 pathogenic variant.•Opportunity to refine risk stratification in carriers of a moderate-risk variant.•Effects of SNPs in polygenic risk scores vary depending on country and population.
The genetic predisposition to familial hematological malignancies has been previously reported highlighting inherited gene mutations. Several genes have been reported but genetic basis remains not ...well defined. In this study, we extended our investigation to a potential candidate
GATA2
gene which was analyzed by direct sequencing in 119 cases including familial aggregations with a variety of hematological malignancies and sporadic acute leukemia belonging to Tunisian and French populations. We reported a deleterious
p.Arg396Gln GATA2
mutation in one patient diagnosed with both sporadic acute myeloid leukemia (AML) and breast cancer. We also reported several
GATA2
variations in familial cases. The absence of deleterious mutations in this large cohort of familial aggregations of hematological malignancies may strengthen the hypothesis that
GATA2
mutations are an important predisposing factor, although as a secondary genetic event, required for the development of overt malignant disease.
Assessment of age-dependent cancer risk for carriers of a predicted pathogenic variant (PPV) is often hampered by biases in data collection, with a frequent under-representation of cancer-free PPV ...carriers. TUMOSPEC was designed to estimate the cumulative risk of cancer for carriers of a PPV in a gene that is usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France. First- and second-degree relatives and cousins of PPV carriers are invited to participate whether they are affected by cancer or not, and genotyped for the familial PPV. Clinical, family and epidemiological data are collected, and all data including sequencing data are centralized at the coordinating centre. The three-year feasibility study included 4431 prospective index cases, with 19.1% of them carrying a PPV. When invited by the coordinating centre, 65.3% of the relatives of index cases (5.7 relatives per family, on average) accepted the invitation to participate. The study logistics were well adapted to clinical and laboratory constraints, and collaboration between partners (clinicians, biologists, coordinating centre and participants) was smooth. Hence, TUMOSPEC is being pursued, with the aim of optimizing clinical management guidelines specific to each gene.
Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, ...however, have examined whether the number and timing of pregnancies are associated with BC risk for
and
mutation carriers.
Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707
and 3525
mutation carriers) and a prospective cohort (2276
and 1610
mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.
For
mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio HR
= 0.99, 95% confidence interval CI = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HR
= 0.79, 95% CI = 0.69 to 0.91; HR
= 0.70, 95% CI = 0.59 to 0.82; HR
= 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively,
< .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort
= .0003). Relative to being nulliparous, uniparous
mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration HR
= 1.69, 95% CI = 1.09 to 2.62). For
mutation carriers, being parous was associated with a 30% increase in BC risk (HR
= 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HR
= 0.72, 95% CI = 0.54 to 0.98).
These findings suggest differential associations with parity between
and
mutation carriers with higher risk for uniparous
carriers and parous
carriers.
This study aimed to determine whether the expression of various tumor biomarkers of the mTOR pathway predicts tumor response to everolimus in metastatic recurrent endometrial cancer. Tumor blocks ...from 44 patients of a phase II clinical trial receiving everolimus until progression or toxicity were collected and evaluated at 3 and 6 months for response. Thirty-six blocks were available for analysis of ER, PR, HER2, LKB1, PI3K, PTEN, pAKT, 4E-BP1, p4E-BP1, and S6RP expression by immunohistochemistry, PTEN deletion by FISH, and mutational status of K-RAS, PIK3CA, PTEN, and AKT1 genes. Twelve of 34 evaluable patients had partial response or stable disease (PR, SD) and 22 had progressive disease (PD). Immunohistochemistry showed that no protein expression could predict response to everolimus. Neither could loss of PTEN expression or PTEN deletion or PTEN mutation predict patient outcome. Thirty-one samples were assessable for K-RAS mutations (ten for PR+SD and 21 for PD). There are only four patients with K-RAS mutations and none of them responded to treatment. Median progression-free survival (PFS) and overall survival (OS) were longer in patients without K-RAS mutations (PFS 3.12 ± 1.7 months versus 1.05 ± 0.4 months,
p
< 0.001; OS 9.28 ± 2.0 months versus 2.30 ± 1.4 months,
p
= 0.034). In conclusion, the level of expression of proteins of the PI3K/mTOR pathway tested in this study cannot predict response to everolimus. However, endometrial cancer patients with K-RAS mutations do not seem to derive benefit from everolimus treatment.
Abstract Background Information concerning management of anal canal cancer among the elderly is scarce and much less abundant than for younger subjects. Population and methods We retrospectively ...analysed 115 patients treated for anal epidermoid cancer between 2000 and 2010. The population was divided according to age (<70 years and ≥70 years). Results Of the 115 patients, 81 (70.4%) were <70 years old and 34 were ≥70 years (29.6%). Tumour characteristics were identical between the two groups and median follow-up was 62 months. Elderly patients had a less favourable performance status ( p = 0.001) and fewer had received radiochemotherapy (61.8% vs 82.5%, p = 0.004). Treatment-related grade 3 and 4 hematologic toxicity was observed more often among elderly subjects. The results at 5 years were less favourable for overall, disease-specific, and disease-free survival (respectively p = 0.002, p = 0.001, and p = 0.001). For patients treated with a curative intent, at 5 years there was no difference between the two groups in terms of overall survival ( p = 0.2). However, there was a statistically significant difference in favour of the younger group for disease-free survival and metastasis-free survival. Conclusion If radiochemotherapy can be delivered to elderly subjects with a good general status, the effects appear less favourable than in younger patients.
Depression is a sustainable state of deep sadness and abatement. It is frequently identified in patients with cancer and often undervalued by oncologists. The reduced PRIME-MD questionnaire is a ...questionnaire of 2 items validated in French. However, it has been neither translated nor validated in French. The objective of our study is to translate the PRIME-MD and validate it into French.
The PRIME-MD questionnaire was translated into French by using the recommendations of the EORTC and compared to the French gold standard questionnaire Mini-International Neuropsychiatric Interview (MINI).
Two hundred and ninety-nine patients were included in our study. With a 98% filling rate, the Q2i questionnaire has been well accepted. The prevalence of depression in our population was measured at 7.4%. With a sensitivity of 89.47%, a specificity of 58.85%, found percentages are equal to those of the questionnaire in English. The negative predictive value was measured at 98.52%.
This study demonstrates that the Q2i questionnaire is a quick and easy screening tool, requiring less than 2minutes to target patients likely to benefit from psychological support.
BRCA is a tumor suppressor gene implicated in the major mechanisms of cellular stability in every type of cell. Its mutations are described in numerous cancers, mainly breast and ovarian in women. It ...was also found an increase of lifetime risk of pancreas, colon, prostate cancer or lymphoma in men carriers. We report the cases of two female patients aged 40 and 58-years-old female patients and one 35-years-old male patient, with brain or medullar gliomas, carriers of a germline mutation of BRCA gene. Those gliomas were particularly aggressive and were not responding to the standard treatment, with chemo and radiotherapy. The very unusual characteristics in location and evolutive profile of these central nervous system tumors raise the question of a genetical underlying mechanism, maybe linked to the BRCA gene mutation that carry these patients. In addition, a non-fortuitous association between germline mutation of BRCA and occurrence of a glioma can be evoked according to the embryological, epidemiological and biomolecular findings noted in the literature. Other clinical and experimental studies are necessary to precise the physiopathological link existing between BRCA mutations and the occurrence of a glioma; this could have therapeutical and clinical implications in the future.
Malignant ascites are the cancer-associated accumulation of fluids in the peritoneal cavity. The neoplasms most frequently associated with ascites are ovarian, breast, colon, stomach and pancreas ...adenocarcinomas. Symptoms are abdominal distention, nausea, vomiting, anorexia, dyspnea and limbs oedemas. Several pathophysiological mechanisms might be implicated such as peritoneal carcinomatosis, lymphatic vessels' obstruction, portal hypertension or heart failure. Its diagnosis is most often performed in a context of already known neoplasia. Malignant ascites are associated with a pejorative evolution. Ascites which cannot be mobilized or show early recurrence and cannot be prevented by medical treatment are defined as refractory ascites. Therefore, management of refractory malignant ascites takes place in the context of palliative care and aims at improving the quality of life of these patients. This review lists the current data reported on the pathophysiology of malignant ascites and describes the present and future options for refractory malignant ascites management.
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