Rafał Wiśniowski

Ten-Year Survival in Patients With BRCA1-Negative and BRCA1-Positive Breast Cancer

PURPOSE To estimate 10-year overall survival (OS) rates for patients with early-onset breast cancer, with and without a BRCA1 mutation, and to identify prognostic factors among those with BRCA1-positive breast cancer. PATIENTS AND METHODS A total of 3,345 women with stage I to III breast cancer, age ≤ 50 years, were tested for three founder mutations in BRCA1. Information on tumor characteristics and treatments received was retrieved from medical records. Dates of death were obtained from the vital statistics registry. Survival curves for the mutation-positive and -negative subcohorts were compared. Predictors of OS were determined using the Cox proportional hazards model. RESULTS Of the 3,345 patients enrolled onto the study, 233 (7.0%) carried a BRCA1 mutation. The 10-year survival rate for mutation carriers was 80.9% (95% CI, 75.4% to 86.4%); for noncarriers, it was 82.2% (95% CI, 80.5% to 83.7%). The adjusted hazard ratio (HR) associated with carrying a BRCA1 mutation was 1.81 (95% CI, 1.26 to 2.61). Among BRCA1 carriers with a small (< 2 cm) node-negative tumor, the 10-year survival rate was 89.9%. Among BRCA1 mutation carriers, positive lymph node status was a strong predictor of mortality (adjusted HR, 4.1; 95% CI, 1.8 to 8.9). Oophorectomy was associated with improved survival in BRCA1 carriers (adjusted HR, 0.30; 95% CI, 0.12 to 0.75). CONCLUSION The 10-year survival rate among women with breast cancer and a BRCA1 mutation is similar to that of patients without a BRCA1 mutation. Among women with a BRCA1 mutation, survival was much improved after oophorectomy.

Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility

BackgroundCYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility.MethodsWe genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls.ResultsThe three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect.ConclusionGenetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations.

CHEK2 mutations and HNPCC-related colorectal cancer

Recently, the 1100delC variant of cell cycle checkpoint kinase 2 (CHEK2) has been reported to confer a colorectal cancer risk in hereditary non‐polyposis‐colorectal cancer (HNPCC) and HNPCC‐related families in the Netherlands. To investigate whether CHEK2 mutations confer increased cancer risk in HNPCC and HNPCC‐related families in Poland, we genotyped 463 probands from HNPCC and HNPCC‐related families, and 5,496 controls for 4 CHEK2 alleles (1100delC, IVS2+1G>A, del5395, I157T). All 463 probands were screened for mutations in the HNPCC‐related genes MSH2, MLH1 and MSH6. A positive association was observed for HNPCC‐related cancer and the I157T missense CHEK2 mutation (OR = 1.7; p = 0.007), but not for the truncating alleles (OR = 1.0; p = 1.0). The association with the I157T was seen both for the 117 cases who fulfill Amsterdam criteria (OR = 1.9; p = 0.1) and for the 346 cases who do not fulfill the criteria (OR = 1.6; p = 0.03). One hundred forty‐five of the 463 families had a mutation in MSH2, MLH1 or MSH6 (MMR‐positive families). A positive association between the CHEK2 I157T mutation and HNPCC‐related cancer was observed only for MMR‐negative cases (OR = 2.1; p = 0.0004), but not for MMR‐positive cases (OR = 0.8; p = 0.9). The association with I157T was particularly strong for MMR‐negative cases with familial colorectal cancer (2 or more first‐degree relatives affected) (OR = 2.5; p < 0.0001). We conclude that the I157T variant of CHEK2 increases the risk of colorectal cancer among MMR‐negative, HNPCC/HNPCC‐related families in Poland.

Neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients

502 Background: Neoadjuvant chemotherapy is administered to control disease, make surgical resection possible and increase the possibility of breast tissue conservation. A further advantage of neoadjuvant therapy is that it helps to assess chemo-sensitivity to a particular agent. Induction of a pathological complete response (pCR) is one of the primary goals of neoadjuvant therapy in order to achieve a better disease-free and overall survival. Experimental data suggest that BRCA1 related breast cancer may have increased sensitivity to platinum-based chemotherapy, but clinical data are limited. The aim of this study was to evaluate the frequency of complete pathologic response after neo-adjuvant treatment with cisplatin chemotherapy in women with breast cancer and a BRCA1 mutation. METHODS Twenty five women with breast cancer and a BRCA1 mutation with stage I, II, and III breast cancer between December 2006 and December 2008 were entered into this study. Patients were treated with cisplatin 75 mg/m2 intravenously every three weeks for four cycles. After chemotherapy, patients underwent surgery and were assessed for pathologic response in both the breast and axillary lymph nodes. Complete pathologic response was defined as no residual invasive disease in both the breast and axilla, however ductal carcinoma in situ was allowed. RESULTS Twenty five patients were enrolled in the study. Thirteen patients had tumors of greater than two centimeters (52%) and seven patients had positive lymph nodes at diagnosis (28%). Twenty two patients completed four cycles of cisplatin (88%) and three patients completed two cycles (12%). Clinical complete response was observed in eighteen patients (72%). Pathologic complete response was observed in eighteen patients (72%). CONCLUSIONS Platinum-based chemotherapy is effective in a high proportion of patients with BRCA1-associated breast cancers. Clinical trials are warranted to determine the optimum treatment for this subgroup of breast cancer patients. No significant financial relationships to disclose.

Neoadjuvant chemotherapy with Cisplatin in BRCA1 mutation carriers – results of treatment

Material and methods Between December 2006 and August 2011 seventy five women with BRCA1 mutation and diagnosed with breast cancer stage I to III were enrolled. Patients were treated with Cisplatin at dose 75 mg/m2 every three weeks for four cycles. After chemotherapy mastectomy was performed and followed with conventional chemotherapy. Seven patients had prior chemotherapy for a previous cancer diagnosis. Four patients received prior chemotherapy for their current cancer diagnosis and then received therapy according to our protocol. In the group of 67 patients treated with Cisplatin in first line of treatment 32 met the standard criteria for neoadjuvant chemotherapy, and in 35 cases the criteria were not met. Pathologic complete response was determined by review of surgical specimens. Complete pathologic response was defined as no residual invasive disease in both the breast and axilla. Information was collected on clinical stage, grade, hormone receptor status and HER2 status prior to treatment.

Lynch syndrome mutations shared by the Baltic States and Poland.

To the Editor : The definite diagnosis of Lynch syndrome (LS) is based on the identification of a mutation within one of the DNA mismatch repair (MMR) genes: MLH1 , MSH2 , MSH6 and PMS2 . To date, hundreds of pathogenic and suspected-pathogenic DNA variants in the MMR genes have been described worldwide (1). Large rearrangements account for about 10% of all MMR changes and can be easily detected by multiplex ligation-dependent probe amplification (MLPA), whereas substitutions, small deletions and insertions account for about 90% (2) and only full screening using either denaturing high-performance liquid chromatography (DHPLC), high resolution melting (HRM) or direct DNA sequencing seems to be the option for genetic analysis. Despite significant progress in the detection of gene mutations full screening remains expensive and time-consuming. According to the previous studies, majority of Polish families are affected by recurrent mutations found at least twice in our own series (2). That tendency provided an opportunity to design a common inexpensive assay for recurrent mutations, an approach that has been successfully applied as prescreening method (3). Founder mutations have been reported from a number of countries and geographical regions and are thought to be a result of population bottlenecks occurring throughout history. It is well recognized that populations from neighboring countries can share genetic changes and as such the probability of finding common mutation is greater. With respect to the regions bounded by Estonia, Latvia, Lithuania and Poland there are reports of common mutations occurring in these populations (4, 5).

The CHEK 2 GENE mutations and the risk of Gastric cancer

Background and aims CHEK2 gene is located on chromosome 22q12.1. and encodes the human analogue of the yeast checkpoint kinases Cds1 and Rad 53. Activation of CHEK2 in response to DNA damage prevents the cell from entering into mitosis. Three founder alleles are present in Poland. Two of these result in a truncated CHEK2 protein IVS2+1G>A in exon 3a nd 1100 del Ci n exon 10, the other, I157T is a missense substitution of an isoleucine for a threonine in exon 3. A single founder allele of the CHEK2 has been associated with predisposition to breast and prostate cancer in North America and Europe. CHK2 alterations are associated with an increased risk of thyroid, prostate, breast, colon and kidney cancer in Polish population. Recently, a large deletion of exons 9 and 10 of CHEK2 was identified in several unrelated patients with breast cancer of Czech or Slovak origin, the del 5395 also confers an increased risk of prostate cancer in Polish men. The CHEK2 is therefore a good candidate for a multisite cancer susceptibility gene. We reasoned, that CHEK2 alterations ought to be investigate in gastric cancer cases, too. Patients and methods We have examined the frequency of the CHEK2 gene mutations in a series of randomized individuals including 749 consecutively collected stomach cancer , 166 patients with familial gastric cancer, and 5496 control patients. The 1100 del C, IVS2+1G®A, I 157 T and del

Impact of BRCA1 mutation on survival after early onset breast cancer

Patients and methods 3354 women who were diagnosed with stage I to stage IV breast cancer, at or below 50 years of age, between January 1996 and December 2006 were contributed from 17 clinical centers in Poland. All patients were offered genetic testing for three founder mutations in BRCA1 (5382insC, C61G, 4184delA). Information on tumour characteristics at presentation and on treatments received was retrieved by reviewing the medical records. Mortality and dates of death were obtained by linkage to the vital statistics database of the Polish Ministry of Administration and Internal Affairs. Survival curves for the mutation-positive and mutation-negative sub-cohorts were constructed using Kaplan–Meier statistics and compared. Predictors of survival were determined using the Cox proportional hazards method.