Association of recurrent mutations in BRCA1, BRCA2, RAD51C, PALB2, and CHEK2 with the risk of borderline ovarian tumor.

BACKGROUND: There are several genes associated with ovarian cancer risk. Molecular changes in borderline ovarian tumor (BOT) indicate linkage of this disease to type I ovarian tumors (low-grade ovarian carcinomas). This study determined the prevalence and association of mutations in BRCA1, BRCA2, PALB2, RAD51C, and CHEK2 with the risk of BOTs. METHODS: The study group consisted of 102 patients with histologically confirmed BOT and 1743 healthy controls. In addition, 167 cases with ovarian cancer G1 were analyzed. The analyses included genotyping of 21 founder and recurrent mutations localized in 5 genes (BRCA1, BRCA2, PALB2, RAD51C, and CHEK2). The risk for developing BOT and low-grade ovarian cancer, as well as the association of tested mutations with survival, was estimated. RESULTS: The CHEK2 missense mutation (c.470T>C) was associated with 2-times increased risk of BOT (OR=2.05, p=0.03), at an earlier age at diagnosis and about 10% worse rate of a 10-year survival. Mutations in BRCA1 and PALB2 were associated with a high risk of ovarian cancer G1 (OR=8.53, p=0.005 and OR=7.03, p=0.03, respectively) and were related to worse all-cause survival for BRCA1 carriers (HR=4.73, 95%CI 1.45-15.43, p=0.01). CONCLUSIONS: Results suggest that CHEK2 (c.470T>C) may possibly play a role in the pathogenesis of BOT, but due to the low number of BOT patients, obtained results should be considered as preliminary. Larger more in-depth studies are required.

Neoadjuvant chemotherapy with dose dense MVAC is associated with improved survival after radical cystectomy compared to other cytotoxic regimens: A tertiary center experience.

INTRODUCTION: Neoadjuvant chemotherapy has become standard of care for cisplatin-eligible patients with muscle-invasive bladder cancer qualified to radical cystectomy, providing a modest increase in 5-year overall survival rate. Several regimens are being employed for neoadjuvant treatment, largely because of their efficacy in metastatic setting. There is however a scarcity of evidence on the optimal cytotoxic regimen for neoadjuvant chemotherapy. OBJECTIVES: We evaluated the efficacy of different protocols of neoadjuvant chemotherapy amongst patients who underwent radical cystectomy at our institution. METHODS: This is a single-center, retrospective, observational study including a cohort of 220 patients who underwent radical cystectomy between 2014 and 2020. The neoadjuvant chemotherapy cohort included 79 patients and was compared to the cohort of historical controls including 141 patients operated prior to routine administration of neoadjuvant chemotherapy and those who opted for upfront surgery. RESULTS: Administration of neoadjuvant chemotherapy decreased the risk of overall and cancer-specific mortality HR = 0.625 (95% CI 0.414-0.944), p = 0.025 and HR = 0.579 (95% CI 0.348-0.964), p = 0.036. Rates of downstaging, complete responses, lymph node metastasis, extravesical extension and positive surgical margins significantly favored neoadjuvant chemotherapy. Out of cytotoxic regimens, dose-dense MVAC and gemcitabine-cisplatin were similarly efficacious providing 46.9% and 50% of downstaging to

Recurrent Mutations in BRCA1, BRCA2, RAD51C, PALB2 and CHEK2 in Polish Patients with Ovarian Cancer.

The aim of the study was to analyze the frequency and magnitude of association of 21 recurrent founder germline mutations in BRCA1, BRCA2, PALB2, RAD51C, and CHEK2 genes with ovarian cancer risk among unselected patients in Poland. We genotyped 21 recurrent germline mutations in BRCA1 (9 mutations), BRCA2 (4 mutations), RAD51C (3 mutations), PALB2 (2 mutations), and CHEK2 (3 mutations) among 2270 Polish ovarian cancer patients and 1743 healthy controls, and assessed the odds ratios (OR) for developing ovarian cancer for each gene. Mutations were detected in 369 out of 2095 (17.6%) unselected ovarian cancer cases and 117 out of 1743 (6.7%) unaffected controls. The ovarian cancer risk was associated with mutations in BRCA1 (OR = 40.79, 95% CI: 18.67-114.78; p = 0.29 × 10-15), in BRCA2 (OR = 25.98; 95% CI: 1.55-434.8; p = 0.001), in RAD51C (OR = 6.28; 95% CI 1.77-39.9; p = 0.02), and in PALB2 (OR 3.34; 95% CI: 1.06-14.68; p = 0.06). There was no association found for CHEK2. We found that pathogenic mutations in BRCA1, BRCA2, RAD51C or PALB2 are responsible for 12.5% of unselected cases of ovarian cancer. We recommend that all women with ovarian cancer in Poland and first-degree female relatives should be tested for this panel of 18 mutations.

The diameter of metastasis in positive sentinel lymph node biopsy affects axillary tumor load in early breast cancer.

INTRODUCTION: Omission of axillary lymph node dissection (ALND) after positive sentinel lymph biopsy (SLNB) has become a standard procedure for breast cancer patients with one or two metastatic lymph nodes. Here the aim was model development for selection for ALND. MATERIAL AND METHODS: We analyzed 323 positive SLNB breast cancer patients, who afterwards underwent ALND. In 126 (39%), there were positive additional axillary lymph nodes. Specimens of resected lymph nodes were scanned and the volumes of tumors (expressed as diameter in mm) were calculated. The maximal diameter of metastasis in the sentinel lymph nodes (SLNDmax ) and axillary lymph nodes (ALNDsum ) indicated tumor load in the resected lymph nodes. ALNDsum higher or equal to 5 mm was defined as high and present in 62 patients (21%). RESULTS: Risk factors for high ALNDsum were primary tumor diameter (P = 0.0092), histopathological type (P = 0.0173), number of positive SLNs (P = 0.0012), type of metastasis (P = 0.0025), molecular type (P = 0.0037), SLNDmax (P = 0.0001), and Her-2 status (P = 0.0093). Independent variables for high ALNDsum were SLNDmax (P < 0.0001), number of positive SLNs (P = 0.0237) and primary tumor diameter (P = 0.0296). CONCLUSIONS: Twenty-one percent patients with positive SLNB are at risk of high ALNDsum . SLNDmax is the strong predictive factor for high ALNDsum after positive ALND.

INVESTIGATION OF SECONDARY MIXED RADIATION FIELD AROUND A MEDICAL LINEAR ACCELERATOR.

The aim of this study is to investigate secondary mixed radiation field around linac, as the first part of an overall assessment of out-of-field contribution of neutron dose for new advanced radiation dose delivery techniques. All measurements were performed around Varian Clinic 2300 C/D accelerator at Maria Sklodowska-Curie Memorial, Cancer Center and Institute of Oncology, Krakow Branch. Recombination chambers REM-2 and GW2 were used for recombination index of radiation quality Q4 determination (as an estimate of quality factor Q), measurement of total tissue dose Dt and calculation of gamma and neutron components to Dt. Estimation of Dt and Q4 allowed for the ambient dose equivalent H*(10) per monitor unit (MU) calculations. Measurements around linac were performed on the height of the middle of the linac's head (three positions) and on the height of the linac's isocentre (five positions). Estimation of secondary radiation level was carried out for seven different configurations of upper and lower jaws position and multileaf collimator set open or closed in each position. Study includes the use of two photon beam modes: 6 and 18 MV. Spatial distribution of ambient dose equivalent H*(10) per MU on the height of the linac's head and on the standard couch height for patients during the routine treatment, as well as relative contribution of gamma and neutron secondary radiation inside treatment room were evaluated.

Predictors of survival for breast cancer patients with a BRCA1 mutation.

PURPOSE: To evaluate in a contemporary cohort the impacts of chemotherapy and oophorectomy on survival for breast cancer patients with a BRCA1 mutation. EXPERIMENTAL DESIGN: We reviewed the pathology reports and medical records of 372 women with breast cancer and a BRCA1 mutation, diagnosed from 2005 to 2017, between the ages of 25 and 65 and followed them for death from all causes and death from breast cancer. Death was ascertained through the Poland vital statistics registry. We performed survival analysis to evaluate the impacts of chemotherapy (including neoadjuvant cisplatinum) and of oophorectomy on survival. RESULTS: After a mean follow-up of 5.6 years (median 5.2), 66 of the 372 women died; 56 of the deaths were from breast cancer and 6 were from ovarian cancer. 127 women received neoadjuvant cisplatinum and 245 women received other chemotherapies. Cisplatinum (versus all other therapies) was associated with a hazard ratio of 0.42 (95%CI 0.20-0.87) on breast cancer-specific survival. The 10-year actuarial all-cause survival for women who had both cisplatinum and an oophorectomy was 94.4%. The 10-year all-cause survival for women who had neither cisplatinum nor an oophorectomy was 65.4% (p < 0.01). CONCLUSIONS: Cisplatinum and oophorectomy are effective therapies for women with breast cancer and a BRCA1 mutation.

Higher antitumor activity of trabectedin in germline BRCA2 carriers with advanced breast cancer as compared to BRCA1 carriers: A subset analysis of a dedicated phase II trial.

Specific alkylators may allow synthetic lethality among patients with germline BRCA1/2-mutations related cancers. The tetrahydroisoquinolone trabectedin administered at 1.3 mg/m2 as a 3-h intravenous infusion every 3 weeks showed activity in patients with pretreated metastatic breast cancer (MBC) and BRCA germline mutations, but mainly in BRCA2 carriers. Data from a phase II study were retrospectively analyzed to compare the efficacy and safety of this trabectedin dose and schedule in pretreated MBC patients bearing germline BRCA1/2 mutations. The primary efficacy endpoint was the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST) by independent expert review. Duration of response (DR) and progression-free survival (PFS) were secondary efficacy endpoints. Safety was evaluated using the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Data from 26 BRCA1-mutated and 13 BRCA2-mutated patients were analyzed. 69% of BRCA1-mutated cancers were triple-negative vs. 31% of BRCA2-mutated ones. 77% of BRCA1 and 31% of BRCA2 carriers were platinum-pretreated. The ORR in BRCA2-mutated patients was higher than in BRCA1-mutated patients (33.3% vs. 9.1%). DR ranged for 1.4-6.8 months in BRCA2-mutated patients and for 1.5-1.7 months in BRCA1-mutated patients. More BRCA2-mutated patients had disease stabilization for ≥4 months (25.0% vs. 9.1%) and their median PFS was longer (4.7 vs. 2.5 months). Trabectedin was well tolerated in both patient subtypes. In conclusion, trabectedin showed higher antitumor activity in relapsed MBC patients with germline BRCA2 mutations than in those with BRCA1 mutations.

Pathological complete response after cisplatin neoadjuvant therapy is associated with the downregulation of DNA repair genes in BRCA1-associated triple-negative breast cancers.

Pathologic complete response (pCR) after neoadjuvant chemotherapy is considered a suitable surrogate marker of treatment efficacy in patients with triple-negative breast cancers (TNBCs). However, the molecular mechanisms underlying pCR as a result of such treatment remain obscure. Using real-time PCR arrays we compared the expression levels of 120 genes involved in the main mechanisms of DNA repair in 43 pretreatment biopsies of BRCA1-associated TNBCs exhibiting pCR and no pathological complete response (non-pCR) after neoadjuvant chemotherapy with cisplatin. Altogether, 25 genes were significantly differentially expressed between tumors exhibiting pCR and non-pCR, and these genes were downregulated in the pCR group compared to the non-pCR group. A difference in expression level greater than 1.5-fold was detected for nine genes: MGMT, ERCC4, FANCB, UBA1, XRCC5, XPA, XPC, PARP3, and RPA1. The non-homologous end joining and nucleotide excision repair pathways of DNA repair showed the most significant relevance. Expression profile of DNA repair genes associated with pCR was different in the node-positive (20 genes with fold change >1.5) and node-negative (only 3 genes) subgroups. Although BRCA1 germline mutations are the principal defects in BRCA1-associated TNBC, our results indicate that the additional downregulation of other genes engaged in major pathways of DNA repair may play a decisive role in the pathological response of these tumors to cisplatin neoadjuvant chemotherapy. The results suggest that patients with node-positive BRCA1-associated TNBCs that do not exhibit pCR after cisplatin neoadjuvant chemotherapy may be candidates for subsequent therapy with PARP inhibitors, whereas UBA1 may be a potential therapeutic target in node-negative subgroup.

Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?

Understanding of the etiology and risk of pancreatic cancer (PaCa) is still poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among PaCa patients and assessed their possible association with the risk of disease in Poland. In the study 383 PaCa patients and 4,000 control subjects were genotyped for founder mutations in: BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2 + 1G > A, del5395, I157T), NBS1 (657del5) and PALB2 (509_510delGA, 172_175delTTGT). A statistically significant association between the 657del5 mutation and an increased risk of pancreatic cancer was observed for NBS1 gene. The Slavic NBS1 gene mutation (657delACAAA) was detected in 8 of 383 (2.09%) unselected cases compared with 22 of 4,000 (0.55%) controls (OR: 3.80, p = 0.002). The PALB2 509_510delGA and 172_175delTTGT mutations combined were seen in 2 (0.52%) unselected cases of PaCa and in 8 (0.20%) of 4,000 controls (OR: 2.61, p = 0.49). For BRCA1, the three mutations combined were detected in 4 of 383 (1.04%) PaCa patients and in 17 of 4,000 (0.42%) controls (OR: 2.46, p = 0.20). CHEK2 mutations were not associated with the risk of pancreatic cancer (OR: 1.11, p = 0.72). The founder mutation in NBS1 (657del5) was associated with an increased risk of PaCa in heterozygous carriers, indicating that this mutation appears to predispose to cancer of the pancreas. By identifying pancreatic cancer risk groups, founder mutation testing in Poland should be considered for people at risk for PaCa.

The incidence of leukaemia in women with BRCA1 and BRCA2 mutations: an International Prospective Cohort Study.

BACKGROUND: Germline mutations in BRCA1 and BRCA2 increase the susceptibility to develop breast and ovarian cancers as well as increase the risk of some other cancers. Primary objective was to estimate the risk of leukaemia in BRCA1 and BRCA2 mutation carriers. METHODS: We followed 7243 women with a BRCA1 or a BRCA2 mutation for incident cases of leukaemia. We used the standardised incidence ratio (SIR) to estimate the relative risk of leukaemia, according to mutation and history of breast cancer. RESULTS: We identified five incident cases of leukaemia (two BRCA1, three BRCA2). All five women had a prior history of breast cancer and four had received chemotherapy. The mean time from breast cancer diagnosis to the development of leukaemia was 10.2 years (range 3-18 years). The SIR for BRCA1 carriers was 0.66 (95% CI: 0.11-2.19, P=0.61) and the SIR for BRCA2 carriers was 2.42 (95% CI: 0.61-6.58, P=0.17). The SIR was significantly higher than expected for women with a BRCA2 mutation and breast cancer (SIR=4.76, 95% CI:1.21-12.96, P=0.03), in particular for women who received chemotherapy (SIR=8.11, 2.06-22.07, P=0.007). CONCLUSIONS: We observed an increased risk of leukaemia in women with a BRCA2 mutation who receive chemotherapy for breast cancer.

Prognostic factors in Polish patients with BRCA1-dependent ovarian cancer.

BACKGROUND: Treatment outcomes appear to be better for ovarian cancer (OC) patients carrying the BRCA1/2 germline mutation than for patients with sporadic OC. However, most published data are for North American, British and Jewish populations. There have been very few studies on treatment outcomes in Central and Eastern European patients with OC. The aim of this study was to analyse prognostic factors in Polish patients with BRCA1-dependent OC (BRCA1-OC). METHODS: The records of patients with OC treated with surgery and chemotherapy at the Centre of Oncology in Kraków, Poland, between 2004 and 2009 were reviewed. Based on family history, a group of 249 consecutive patients fulfilling the criteria for risk of hereditary OC were selected and tested for the germline BRCA1 mutation. Response to combination therapy (surgery and chemotherapy) in the BRCA1-OC group was assessed based on clinical examination, imaging and serum CA125. RESULTS: Germline BRCA1 mutations were detected in 69 of the 249 patients, but three of these patients failed to complete the study. Finally, 66 patients with BRCA1-OC were included in the study group. The median age of the study patients was 49.5 years. All had undergone primary or interval cytoreductive surgery and chemotherapy. Progression occurred in 48 (72.7 %) of the 66 patients and median time to progression was 20 months. The 5-year overall survival rate in was 43.9 % and median survival time was 32.3 months. On multivariate analysis, the endometrial subtype of OC and serum CA125 < 12.5 U/ml at the end of treatment were independent, positive prognostic factors for 5-year overall survival. CONCLUSION: Prognostic factors for favourable treatment outcomes in Polish patients with BRCA1-OC do not appear to differ from those in patients with sporadic OC. The incidence of the endometrial subtype of OC was relatively high (34.9 %) among women in the study. This was unexpected and has not been reported previously. This subtype of OC was an independent prognostic factor for favourable treatment outcomes.

The Conductivity and pH Values of Dispersions of Nanospheres for Targeted Drug Delivery in the Course of Forced Equilibrium Dialysis.

BACKGROUND: In the available literature, the problem of pH and conductivity in FED is evaluated separately, and limited mainly to the final purity of the synthesized polymer. In this study data from conductivity and pH measurements were evaluated in the context of the structure of the macromolecule. OBJECTIVES: The aim of the study was to evaluate the conductivity and pH of dispersions of nanospheres synthesized with the use of N-isopropyl acrylamide (NIPA) as the main monomer, N,N'-methylenebisacrylamide (MBA) as the cross-linker and acrylic acid (AcA) as the anionic comonomer during the purification of dispersions via forced equilibrium dialysis (FED). MATERIAL AND METHODS: Six batches of nanospheres were obtained in the process of surfactant free precipitation polymerization (SFPP) under inert nitrogen. The conductivity and pH of the dispersions of nanospheres were measured at the beginning of FED and after finishing that process. The conductivity in the systems being studied decreased significantly in the process of FED. The initial values of conductivity ranged from 736.85±8.13 µS×cm(-1) to 1048.90±67.53 µS×cm(-1) After 10 days, when the systems being assessed gained stability in terms of conductivity level, the values of conductivity were between 4.29±0.01 µS×cm(-1) and 33.56±0.04 µS×cm(-1). The pH values inreased significantly after FED. The resulting pH was between 6.92±0.07 and 8.21±0.07, while the initial values were between 3.42±0.23 µS×cm(-1) and 4.30±0.22 µS×cm(-1). CONCLUSIONS: Conductivity and pH measurements performed during purification via FED provide important information on the composition of the resulting nanospheres, including the functional groups embedded in the structure of the polymer in the course of the synthesis, as well as the purity of the structures. The presence of a cross-linker and acidic comonomer in the poly-N-isopropyl acrylamide (polyNIPA) macromolecule may be confirmed by both the pH and the conductivity measurements.

Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis.

BACKGROUND: Mutations in PALB2 predispose to breast cancer, but the effect on prognosis of carrying a PALB2 mutation has not been ascertained. We aimed to estimate the odds ratio for breast cancer in women with an inherited mutation in PALB2 and 10-year survival after breast cancer in patients who carry a PALB2 mutation. METHODS: Between 1996 and 2012, patients with invasive breast cancer were recruited prospectively from 18 hospitals in Poland and genotyped for two deleterious mutations in PALB2 (509_510delGA and 172_175delTTGT). A control group of 4702 women without cancer was recruited for comparison. The primary endpoint was death from any cause, as determined by medical records from the Polish Ministry of the Interior and Administration. In patients with breast cancer, 10-year survival of carriers of a PALB2 mutation was calculated and compared with that of non-carriers. FINDINGS: 17 900 women with breast cancer were invited to participate, of whom 12 529 were genotyped successfully. A PALB2 mutation was present in 116 (0·93%, 95% CI 0·76-1·09) of 12 529 patients and in ten (0·21%, 0·08-0·34) of 4702 controls (odds ratio 4·39, 95% CI 2·30-8·37; p<0·0001). 10-year survival for women with breast cancer and a PALB2 mutation was 48·0% (95% CI 36·5-63·2), compared with 74·7% (73·5-75·8) for patients with breast cancer without a mutation (adjusted hazard ratio for death 2·27, 95% CI 1·64-3·15; p<0·0001). INTERPRETATION: Women with a PALB2 mutation face an increased risk of breast cancer and might be at a higher risk of death from breast cancer compared with non-carriers. Increased surveillance should be offered to unaffected women who carry a PALB2 mutation. FUNDING: Polish National Science Centre.

Germline RECQL mutations are associated with breast cancer susceptibility.

Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase (n = 195), followed by validation. We identified rare recurrent RECQL mutations in each population. In Quebec, 7 of 1,013 higher-risk breast cancer cases and 1 of 7,136 newborns carried the c.634C>T (p.Arg215*) variant (P = 0.00004). In Poland, 30 of 13,136 unselected breast cancer cases and 2 of 4,702 controls carried the c.1667_1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant (P = 0.008). RECQL is implicated in resolving stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks. This function is related to that of other known breast cancer susceptibility genes, many of which are involved in repairing dsDNA breaks. We conclude that RECQL is a breast cancer susceptibility gene.

Selenium as a marker of cancer risk and of selection for control examinations in surveillance.

Publication is summarization of existing data being results of literature review and our experience on usefulness of selenium as a diagnostic marker selection for control examinations in surveillance and as a marker of patients with high risk of cancers.

Management of ovarian and endometrial cancers in women belonging to HNPCC carrier families: review of the literature and results of cancer risk assessment in Polish HNPCC families.

BACKGROUND: Over half the cancer deaths in HNPCC families are due to extra-colonic malignancies that include endometrial and ovarian cancers. The benefits of surveillance for gynecological cancers are not yet proven and there is no consensus on the optimal surveillance recommendations for women with MMR mutations. METHODS: We performed a systematic review of the literature and evaluated gynecological cancer risk in a series of 631 Polish HNPCC families classified into either Lynch Syndrome (LS, MMR mutations detected) or HNPCC (fulfillment of the Amsterdam or modified Amsterdam criteria). RESULTS: Published data clearly indicates no benefit for ovarian cancer screening in contrast to risk reducing surgery. We confirmed a significantly increased risk of OC in Polish LS families (OR = 4,6, p < 0.001) and an especially high risk of OC was found for women under 50 years of age: OR = 32,6, p < 0.0001 (95% CI 12,96-81,87). The cumulative OC risk to 50 year of life was calculated to be 10%. Six out of 19 (32%) early-onset patients from LS families died from OC within 2 years of diagnosis. We confirmed a significantly increased risk of EC (OR = 26, 95% CI 11,36-58,8; p < 0,001). The cumulative risk for EC in Polish LS families was calculated to be 67%. CONCLUSIONS: Due to the increased risk of OC and absence of any benefit from gynecological screening reported in the literature it is recommended that prophylactic oophorectomy for female carriers of MMR mutations after 35 year of age should be considered as a risk reducing option. Annual transvaginal ultrasound supported by CA125 or HE4 marker testing should be performed after prophylactic surgery in these women. Due to the high risk of EC it is reasonable to offer, after the age of 35 years, annual clinical gynecologic examinations with transvaginal ultrasound supported by routine aspiration sampling of the endometrium for women from either LS or HNPCC families. An alternative option, which could be taken into consideration for women preferring surgical prevention, is risk reducing total hysterectomy (with bilateral salpingo-oophorectomy) for carriers after childbearing is complete.

The variant allele of the rs188140481 polymorphism confers a moderate increase in the risk of prostate cancer in Polish men.

A number of single nucleotide polymorphisms (SNPs) in the human genome have been associated with increased risk of prostate cancer. Recently, a single SNP in the region of chromosome 8q24 (rs188140481) has been associated with a three-fold increased risk of prostate cancer in Europe and North America. To establish whether rs188140481 is associated with the risk of prostate cancer in Poland, we genotyped 3467 men with prostate cancer and 1958 controls. The A allele of rs188140481 was detected in 44 of 3467 (1.3%) men with prostate cancer and in seven of 1958 (0.4%) controls (odds ratio=3.6; 95% confidence interval 1.6-7.9; P=0.0006). The allele was present in eight of 390 (2.1%) men with familial prostate cancer (odds ratio=5.8; 95% confidence interval 2.1-16.2; P=0.001). A positive family history of cancers at sites other than the prostate was observed in 27% of men who carried the rs188140481 risk allele and in 44% of noncarriers (P=0.04). No cancer at a site other than the prostate was more common in first-degree or second-degree relatives of carriers of the rs188140481 risk allele than relatives of noncarriers. The rs188140481 polymorphism in the 8q24 region confers a moderate increase in the risk of prostate cancer in Polish men. The SNP does not appear to be associated with susceptibility to cancers of other types.

The presence of prostate cancer at biopsy is predicted by a number of genetic variants.

Several single nucleotide polymorphisms (SNPs) have been associated with an elevated risk of prostate cancer risk. It is not established if they are useful in predicting the presence of prostate cancer at biopsy or if they can be used to define a low-risk group of men. In this study, 4,548 men underwent a prostate biopsy because of an elevated prostate specific antigen (PSA; ≥4 ng/mL) or an abnormal digital rectal examination (DRE). All men were genotyped for 11 selected SNPs. The effect of each SNP, alone and in combination, on prostate cancer prevalence was studied. Of 4,548 men: 1,834 (40.3%) were found to have cancer. A positive association with prostate cancer was seen for 5 of 11 SNPs studied (rs1800629, rs1859962, rs1447295, rs4430796, rs11228565). The cancer detection rate rose with the number of SNP risk alleles from 29% for men with no variant to 63% for men who carried seven or more risk alleles (OR = 4.2; p = 0.002). The SNP data did not improve the predictive power of clinical factors (age, PSA and DRE) for detecting prostate cancer (AUC: 0.726 vs. 0.735; p = 0.4). We were unable to define a group of men with a sufficiently low prevalence of prostate cancer that a biopsy might have been avoided. In conclusion, our data do not support the routine use of SNP polymorphisms as an adjunct test to be used on the context of prostate biopsy for Polish men with an abnormal screening test.

The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation.

Physicians are often approached by young women with a BRCA mutation and a recent history of breast cancer who wish to have a baby. They wish to know if pregnancy impacts upon their future risks of cancer recurrence and survival. To date, there is little information on the survival experience of women who carry a mutation in one of the BRCA genes and who become pregnant. From an international multi-center cohort study of 12,084 women with a BRCA1 or BRCA2 mutation, we identified 128 case subjects who were diagnosed with breast cancer while pregnant or who became pregnant after a diagnosis of breast cancer. These women were age-matched to 269 mutation carriers with breast cancer who did not become pregnant (controls). Subjects were followed from the date of breast cancer diagnosis until the date of last follow-up or death from breast cancer. The Kaplan-Meier method was used to estimate 15-year survival rates. The hazard ratio for survival associated with pregnancy was calculated using a left-truncated Cox proportional hazard model, adjusting for other prognostic factors. Among women who were diagnosed with breast cancer when pregnant or who became pregnant thereafter, the 15-year survival rate was 91.5 %, compared to a survival of 88.6 % for women who did not become pregnant (adjusted hazard ratio = 0.76; 95 % CI 0.31-1.91; p = 0.56). Pregnancy concurrent with or after a diagnosis of breast cancer does not appear to adversely affect survival among BRCA1/2 mutation carriers.