Phase I/II study of irinotecan, 5-fluorouracil,and <Emphasis Type="Italic">l</Emphasis>-leucovorin combination therapy (modified Saltz regimen) in patients with metastatic colorectal cancer

Background A combination of irinotecan 125mg/m², 5-fluorouracil (5-FU) 500mg/m², and leucovorin (LV) 20mg/m² (Saltz regimen; treatment on days 1, 8, 15, and 22 every 6 weeks) is widely used for the treatment of metastatic colorectal cancer. A modified schedule with chemotherapy on days 1 and 8 of a 21-day cycle was recommended in 2001 because of early treatment-related mortality. We conducted a phase I/II study of this modified Saltz regimen as first-line therapy in Japanese patients with metastatic colorectal cancer to assess the maximum tolerated dose (MTD) and the recommended dose of 5-FU when given with fixed doses of l-LV and irinotecan, and to evaluate the efficacy and the feasibility of this regimen.Methods Irinotecan, 5-FU, and l-LV were administered on days 1 and 8 of a 21-day cycle. Irinotecan 100mg/m² was given intravenously over the course of 90min on day 1, followed by l-LV 10mg/m², and then 5-FU. The dose of 5-FU was escalated from 400mg/m² (level 1) to 500mg/m² (level 2). If neither level met the criteria for the MTD, the recommended dose was defined as level 2, and dose escalation was discontinued, because the maximum approved weekly dose of irinotecan alone in Japan is 100mg/m² and the dose of 5-FU in the original Saltz regimen was 500mg/m².Results One patient had grade 4 neutropenia with fever at level 1, and four patients had grade 3 neutropenia at level 2. There was no treatment-related death. Level 2 did not meet the criteria for the MTD. The relative dose intensities of the first five cycles were 91% for both 5-FU and irinotecan at level 1 and 86% for 5-FU and 93% for irinotecan at level 2. The response rates were 58% for all patients, and 69% for patients at level 2.Conclusion Our results confirm that the modified Saltz regimen is safe and efficacious for Japanese patients. The recommended doses for phase II studies are irinotecan 100mg/m², 5-FU 500mg/m², and l-LV 10mg/m².     

Induction of apoptosis by <Emphasis Type="Italic">p53</Emphasis>, <Emphasis Type="Italic">bax</Emphasis>, <Emphasis Type="Italic">bcl-2</Emphasis>, and <Emphasis Type="Italic">p21</Emphasis> expressed in colorectal cancer

Background We investigated the influence of genes on the apoptosis of colorectal tumor cells, based on DNA and mRNA kinetics.Methods In 30 colorectal cancer patients, we examined the mRNA expression of p53, bax, bcl-2, and p21 ^WAF1 , and we also investigated the development of tumor cell apoptosis, using a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) method.Results TUNEL-positive cells showed a positive correlation with bax (P = 0.010) and a negative correlation with p21 (P = 0.04). We also investigated the relationship between p53 point mutation, p21 immunostaining degree, and apoptosis, based on DNA ladder expression. A remarkable correlation (P = 0.0090) was found between p21 and apoptosis.Conclusions The present study findings suggest that tumor cell apoptosis is (1) strongly inhibited by p21, (2) induced by bax, and (3) influenced by bcl-2, which, presumably, inhibits tumor cell apoptosis.     

Association of the <Emphasis Type="Italic">TCF7L2</Emphasis> polymorphism with colorectal cancer and adenoma risk

We evaluated the association of a polymorphism in TCF7L2 (RS12255372) in the WNT signaling pathway, which previously has been strongly associated with risk of Type II Diabetes, with colorectal cancer (CRC) and adenoma in the prospective Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts. Hyperinsulinemia may be related to the risk of colon adenoma and cancer, therefore this variant associated with reduced insulin secretion would be predicted to be inversely associated with colorectal cancer. Overall, in the NHS and HPFS, there was suggestive evidence for an inverse association associated with homozygosity for the minor allele of RS12255372 (TCF7L2 TT) and CRC (conditional and covariate adjusted OR = 0.63, 95% CI: 0.37–1.08; P for heterogeneity 0.52 for the association in women and men). In summary, the marginal association of the TCF7L2 SNP with CRC might be due to chance, but warrants further laboratory and epidemiological investigation.     

Genetic variation in <Emphasis Type="Italic">IGF1</Emphasis>, <Emphasis Type="Italic">IGFBP3</Emphasis>, <Emphasis Type="Italic">IRS1</Emphasis>, <Emphasis Type="Italic">IRS2</Emphasis> and risk of breast cancer in women living in Southwestern United States

Background An insulin-related pathway to breast cancer has been hypothesized. Methods We examine the 19 CA repeat of the IGF1 gene, the -202 C > A IGFBP3, the G972R IRS, and the G1057D IRS2 polymorphisms among 1,175 non-Hispanic white (NHW) and 576 Hispanic newly diagnosed breast cancer cases and 1,330 NHW and 727 Hispanic controls living in Arizona, Colorado, New Mexico, and Utah. Results Among post-menopausal women not recently exposed to hormones, not having the 19 CA repeat of IGF1 gene was associated with breast cancer among NHW women [odds ratio (OR) 2.14, 95% confidence interval (CI) 1.21–3.79] and having an R allele of G972R IRS1 increased breast cancer risk among Hispanic women (OR 2.70, 95% CI 1.13–6.46). Among post-menopausal Hispanic women recently exposed to hormones the A allele of the -202 C > A IGFBP3 polymorphism increased risk of breast cancer (OR 1.57, 95% CI 1.06–2.33). The IGF1 19 CA repeat polymorphism interacted with hormone replacement therapy (HRT) among NHW post-menopausal women; women who had the 19/19 IGF1 genotype were at reduced risk of breast cancer (OR 0.64, 95% CI 0.47–0.88) if they did not use HRT. We also observed interaction between body mass index and IGF1 19 CA repeat (p=0.06) and between weight gain and the -202 C > A IGFBP3 polymorphism (p=0.05) in NHW post-menopausal women not recently exposed to hormones. Conclusions Our data suggest that associations between insulin-related genes and breast cancer risk among women living in the Southwestern United States may be dependent on estrogen exposure and may differ by ethnicity.     

<Emphasis Type="Italic">BRAF</Emphasis>/K-<Emphasis Type="Italic">ras</Emphasis> mutation,microsatellite instability,and promoter hypermethylation of <Emphasis Type="Italic">hMLH1</Emphasis>/<Emphasis Type="Italic">MGMT</Emphasis> in human gastric carcinomas

Background The BRAF and K-ras genes are the most frequently mutated oncogenes in various human malignancies. We examined BRAF and K-ras mutations in human gastric cancer, and investigated their relationship with microsatellite instability (MSI) and the hypermethylation of promoter regions in hMLH1 and O ⁶ -methylguanine DNA methyltransferase (MGMT).Methods Sixteen gastric cancer cell lines and 62 gastric cancer tissue samples were screened for BRAF and K-ras mutations by direct sequencing. We also performed a microsatellite assay and investigated methylation status in the promoter regions of hMLH1 and MGMT.Results mutation was not found in any of the cancer cell lines examined. One (1.6%) cancer tissue sample showed a point mutation in the BRAF gene (GT_G GA_G; V599E). K-ras mutation (GG_T GA_T, G12D) was detected in five (31%) gastric cancer cell lines and in 1 (1.6%) gastric cancer tissue sample. In the gastric cancer tissue samples examined, MSI was detected in 23 (37%) samples. Hypermethylated promoter regions in hMLH1 and MGMT, respectively, were detected in 6 (10%) and 13 (21%) gastric cancer tissue samples. Microsatellite stable (MSS) tumors showed frequent lymphatic invasion (P = 0.050).Conclusion Although BRAF mutation has been reported in a variety of other human cancers, it is a rare event in the carcinogenesis and progression/development of gastric cancer.     

The <Emphasis Type="Italic">CHEK2</Emphasis> 1100delC mutation is not present in Korean patients with breast cancer cases tested for <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutation

The germline CHEK2 1100delC mutation is a low penetrance breast cancer susceptibility allele, frequently observed in patient with family history of breast cancer and/or young age and the frequency varied according to race or ethnicity. In this study, we evaluated the significance of CHEK2 1100delC in predisposition to breast cancer by assessing its frequency in a material of 493 Korean breast cancer patients who had been screened for BRCA1 and BRCA2 mutations (42 patients had deleterious mutation of BRCA1/2). Mutation detection of CHEK2 1100delC was based upon analysis of primer extension products generated for previously amplified genomic DNA using a chip based MALDI-TOP mass spectrometry platform. After overall measurement automatically, assays which had bad peaks were checked again manually. None of the 493 Korean patients with breast cancer who were candidate for BRCA1 and BRCA2 test carried the 1100delC mutation observed in Caucasians with limited frequency. In the previous studies, we observed higher or comparable prevalence of BRCA1 and BRCA2 mutations in Korean patients with breast cancer compared to Caucasian breast cancer population. In the present study, we evaluated the role of a CHEK2 1100delC as a susceptibility mutation of breast cancer in the Korean population. However, our results suggest that this mutation is absent or may be very infrequent in Korean patients with breast cancer who have high risk of BRCA1 and BRCA2 mutation, making its screening irrelevant from the practical point view.     

Phase I study of irinotecan and S-1 combination therapy in patients with metastatic gastric cancer

Background Irinotecan plus intravenous 5-fluorouracil with leucovorin is effective against gastrointestinal cancer. S-1 is an oral fluoropyrimidine derivative combining tegafur with the modulators 5-chloro-2,4-dihydroxypyrimidine (a potent dihydropyrimidine dehydrogenase inhibitor), and potassium oxonate (an orotate phosphoribosyl transferase inhibitor), in a molar ratio of 1:0.4:1. S-1 has a high response rate, of about 40%, in advanced gastric cancer. A phase I study was conducted to assess the maximum tolerated dose and the recommended dose of the combination of irinotecan and S-1.Methods Irinotecan was given intravenously over the course of 90min on day 1 and S-1 was given orally from days 1 to 14 of a 21-day cycle. The dose of S-1 was 80mg/m² per day, given in two divided doses. The dose of irinotecan was escalated in a stepwise fashion from 100mg/m² (level 1; n = 3), to 125mg/m² (level 2; n = 3), and 150mg/m² (level 3; n = 6).Results Dose-limiting toxicity did not occur during cycle 1, and the recommended dose for phase II studies was determined to be level 3, which was associated with grade 3 diarrhea in one patient, and with refusal to continue treatment because of prolonged fatigue in two patients. Grade 3 neutropenia developed in one of three patients at level 1 and level 2, and in two of six during cycle 1 of level 3. The recommended dose was determined to be 150mg/m² of irinotecan on day 1 and 80mg/m² per day of S-1 on days 1 to 14 of a 21-day cycle. Five of seven patients with measurable lesions had a partial response.Conclusions A combination of irinotecan and S-1 can be recommended for further phase II studies in patients with gastric cancer.     

Prognostic significance of co-overexpression of the <Emphasis Type="Italic">EGFR</Emphasis>/<Emphasis Type="Italic">IGFBP-2</Emphasis>/<Emphasis Type="Italic">HIF-2A</Emphasis> genes in astrocytomas

Overexpression of the EGFR, IGFBP-2 and HIF-2A genes has been observed in high-grade astrocytomas and these genes seem to be functionally related to one another. This study aimed to define the profile of their expressions, interactions and correlation with clinical features and prognostic significance in microdissected tumor samples from 84 patients with astrocytomas of different grades and from 6 white matter non-neoplasic brain tissue sample. EGFR, IGFBP-2 and HIF-2A gene expression levels were analyzed by quantitative real-time PCR and differed significantly between grades I–IV astrocytic tumors (P < 0.0001, P < 0.0001 and P: 0.0013, respectively) when analyzed by the Kruskal–Wallis test. Grade I astrocytomas presented gene expression levels similar to those encountered in samples of microdissected white matter of non-neoplastic brain tissue Overexpression of the EGFR, IGFBP-2 and HIF-2A genes was significantly associated with lower 2-year survival (P: 0.009, P: 0.0002 and P: 0.008, respectively). Co-overexpression of these genes was strongly associated with high-grade gliomas and lower survival in univariate (P < 0.0001) and multivariate (P: 0.009) analysis, suggesting that the co-expression of the EGFR/IGFBP-2/HIF-2A pathway genes may have a more important clinical and biological impact than the expression of each individual gene alone. These data support the existence of a common pathway involving these genes that could contribute to the design of new target treatments.     

Use of the folinic acid/5-fluorouracil/irinotecan (FOLFIRI 1) regimen in elderly patients as a first-line treatment for metastatic colorectal cancer: a Phase II study

Background  The aim of this study was to evaluate the effects of a combination of folinic acid, 5-fluorouracil (5FU) and irinotecan (FOLFIRI 1) administered every 2 weeks in a population of elderly subjects with advanced colorectal cancer. Patients and methods  Patients with metastatic colorectal cancer included in this study were aged at least 70 years, with a performance status of 0/1, without geriatric syndrome and without previous palliative chemotherapy. They received irinotecan [180 mg/m² intravenous (iv) infusion over 90 min] followed by folinic acid (400 mg/m² iv over 2 h), then 5FU (400 mg/m² iv bolus) and 5FU (2,400 mg/m² continuous iv infusion for 46 h) every 2 weeks. Results  Forty eligible patients were included. The median age was 77.3 years (range 70–84.7). The objective response rate was 40% and the stabilisation rate was 45%. Median progression-free survival was 8 months, overall survival was 17.2 months and cancer-related specific survival was 20.2 months. In total, 300 cycles of chemotherapy were administered with a median number of eight cycles per patient (range 1–18). Tolerance was good; grade 3/4 toxicities included diarrhoea (15%), asthenia (15%), nausea/vomiting (7.5%) and neutropenia (7.5%). One toxic death was observed due to grade 4 diarrhoea. Conclusion  The FOLFIRI 1 regimen is a valid therapeutic option for elderly patients in good clinical condition. This study was partly sponsored by Pfizer, Paris, France.     

CPT-11联合5-FU/CF(FOLFIRI)化疗方案治疗晚期结直肠癌

背景与目的:CPT-11联合5-FU/CF(FOLFIRI)化疗方案是治疗晚期结直肠癌的有效方案.但是,该方案作为一线方案治疗中国晚期结直肠癌患者的资料缺乏,其疗效和安全性仍需进一步确定.本文旨在探讨FOLFIRI方案作为一线治疗方案对中国晚期结直肠癌患者的疗效和安全性.方法:自2002年1月至2005年9月期间,共54例晚期结直肠癌患者采用FOLFIRI方案作为一线方案进行治疗,回顾性分析其治疗有效率(response rate,BR)、疾病进展时间(time to progression,TTP)、总生存时间(overall survival,OS)和不良反应.结果:54例患者中52例可评价疗效.其中RR为42.6%,TTP为6个月,OS为15.2个月.最常见的不良反应为中性粒细胞减少(38.9%)、腹泻(37.1%)和恶心呕吐(50.0%),Ⅲ/Ⅳ级的发生率分别为5.6%、9.3%和9.3%,总体耐受性好.结论:FOLFIRI方案治疗中国晚期结直肠癌患者疗效肯定,作为一线化疗方案有较高的有效性,不良反应可以耐受.     

<Emphasis Type="Italic">NBS1</Emphasis> variant I171V and breast cancer risk

The NBS1/p95 protein has a pivotal role in the sensing and repair of chromosome breaks. A missense mutation in the NBS1 gene, I171V, has recently been associated with a ninefold increased risk of breast cancer in Polish patients. Positive associations have also been reported for leukaemia and larynx cancer suggesting that I171V could be a more general susceptibility factor for malignancies. We investigated the prevalence of this mutation in two large hospital-based case-control series from Germany and from the Republic of Belarus. The I171V substitution was detected in 20/1,636 Byelorussian breast cancer patients and in 18/1,014 Byelorussian controls (OR: 0.68; 95%CI: 0.36–1.30, P = 0.3). The I171V substitution was furthermore detected in 10/1,048 German breast cancer patients and in 7/1,017 German controls (OR: 1.39; 95%CI: 0.53–3.67, P = 0.7). There were no significant differences between I171V carriers and non-carriers among the cases with regard to age at diagnosis, family history or bilateral occurrence of disease. A meta-analysis of all hitherto available studies did not reveal a difference in the prevalence of I171V between breast cancer cases and controls (OR: 1.05; 95%CI: 0.64–1.74, P = 0.9). We conclude that the I171V substitution is unlikely to constitute a strong risk factor for breast cancer in our study populations. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Influence of germline polymorphisms of <Emphasis Type="Italic">GSTT1</Emphasis>, <Emphasis Type="Italic">GSTM1</Emphasis>, and <Emphasis Type="Italic">GSTP1</Emphasis> in familial versus sporadic breast cancer susceptibility and survival

Identifying genes associated with familial inheritance of breast cancer continues to be a major goal of current research as the known high penetrance genes could be attributable for only a small percentage of the risk. So, it is hypothesized that the low penetrance genes may also modify the risk for familial breast cancer. In the present case-control study, undertaken to examine the influence of polymorphisms of GSTs in familial and sporadic breast cancer susceptibility, 597 women including 222 sporadic breast cancer patients, 125 familial breast cancer patients and 250 females with no history of cancer as controls were genotyped by PCR based methods. Odds Ratios (ORs) and 95% Confidence Intervals (95%CIs) were calculated by unconditional logistic regression adjusted to age. Interestingly, GSTM1 deletion was found to be significantly associated only with familial breast cancer (OR = 2.0; 95%CI = 1.252-3.128) while GSTT1 was associated only with sporadic breast cancer (OR = 2.3; 95%CI = 1.336-3.970). GSTP1 Ile(105)Val polymorphism was associated neither with sporadic nor familial breast cancer susceptibility (P value > 0.05). The GST genotypes did not have any effect on the survival of both familial and sporadic breast cancer patients. However, familial breast cancer patients with GSTM1 null genotype had a relative risk of 0.42 (95%CI = 0.18-0.97) for an advanced disease stage. The results indicate that, in addition to the known high penetrance genes, certain low penetrance genes may also play a role, in the familial inheritance of breast cancer. It is also noticed that all the polymorphisms associated with sporadic breast cancer are not associated with familial breast cancer.     

<Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> germline mutation analysis in the Indonesian population

Specific mutations in BRCA1 and BRCA2 genes have been identified in specific populations and ethnic groups. However, little is known about the contribution of BRCA1 and BRCA2 mutations to breast cancers in the Indonesian population. One hundred-twenty moderate to high risk breast cancer patients were tested using PCR-DGGE, and any aberrant band was sequenced. Multiplex ligation-dependent probe amplification (MLPA) was performed on all samples to detect large deletions in the two genes. Twenty-three different mutations were detected in 30 individuals, ten were deleterious mutations and 20 were "unclassified variants" with uncertain clinical consequences. Three of seven (c.2784_2875insT, p.Leu1415X and del exon 13-15) and two of four (p.Glu2183X and p.Gln2894X) deleterious mutations that were found in BRCA1 and BRCA2 respectively, are novel. Several novel, pathogenic BRCA1 and BRCA2 germline mutations are found in early onset Indonesian breast cancer patients, these may therefore be specific for the Indonesian population.     

Active and passive smoking, <Emphasis Type="Italic">IL6</Emphasis>, <Emphasis Type="Italic">ESR1</Emphasis>, and breast cancer risk

We evaluated the association between smoking and risk of breast cancer in non-Hispanic white (NHW) and Hispanic or American Indian (HAI) women living in the Southwestern United States. Data on lifetime exposure to active and passive smoke data were available from 1527 NHW cases and 1601 NHW controls; 798 HAI cases and 924 HAI controls. Interleukin 6 (IL6) and Estrogen Receptor alpha (ESR1) polymorphisms were assessed in conjunction with smoking. Pack-years of smoking (≥15) were associated with increased risk of pre-menopausal breast cancer among NHW women (OR 1.6, 95% CI 1.1–2. 4). Passive smoke increased risk of pre-menopausal breast cancer for HAI women (OR 1.9, 95% CI 1.1–3.1 everyone; OR 2.3, 95% CI 1.2–4.5 nonsmokers). HAI pre-menopausal women who were exposed to 10+ h of passive smoke per week and had the rs2069832 IL6 GG genotype had over a fourfold increased risk of breast cancer (OR 4.4, 95% CI 1.5–12.8; P for interaction 0.01). Those with the ESR1 Xba1 AA genotype had a threefold increased risk of breast cancer if they smoked ≥15 pack-years relative to non-smokers (P interaction 0.01). These data suggest that breast cancer risk is associated with active and passive smoking.     

Polymorphisms of the <Emphasis Type="Italic">BRCA2</Emphasis> and <Emphasis Type="Italic">RAD51</Emphasis> Genes in Breast Cancer

Summary We performed a case-control study (150 cases and 150 controls) to test the association between three polymorphisms in BRCA2 and RAD51 genes and breast cancer risk. Genotypes were determined in DNA from blood cells by PCR–RFLP. Cancer occurrence was strongly associated with the BRCA2 Met/1915Thr homozygous polymorphic variants, whereas heterozygous variant was associated with significant reduction in breast cancer risk. Gene-gene interaction between the BRCA2-Met1915Thr Thr/Thr and BRCA2-Met784Val Met/Met homozygous variants increased the risk. Therefore, the Met1915Thr polymorphism in the BRCA2 gene may be considered as an independent marker of breast cancer.     

Absence of the common <Emphasis Type="Italic">IGF1</Emphasis> 19 CA-repeat allele is more common among <Emphasis Type="Italic">BRCA1</Emphasis> mutation carriers than among non-carriers from <Emphasis Type="Italic">BRCA1</Emphasis> families

BRCA1 mutations predispose to early-onset breast cancer. We previously reported an association between absence of the common IGF1 19 CA-repeat allele (IGF1-19/-19) and being a BRCA1 mutation carrier in young women from breast cancer high-risk families. Others have reported a four-fold risk of premenopausal breast cancer in women with a family history and the IGF1-19/-19 genotype. The aim of this study was to investigate whether the IGF1-19/-19 genotype was associated with being a BRCA1 mutation carrier among women from BRCA1 families. DNA was available from 268 women with known BRCA1 status from the South Swedish Health Care Region. IGF1 genotyping was successfully performed with fragment analysis in 211 women from 96 families. The IGF1-19/-19 genotype was significantly more common among BRCA1 mutation carriers (14.2%) than among non-carriers (4.8%), OR 3.3 (95%CI 1.11-9.78, P = 0.03) adjusted for family clustering. We confirmed our previous finding of an association between the IGF1-19/-19 genotype and BRCA1 mutation status. Since the IGF1-19/-19 genotype in combination with OC use or multiparity confers an increased risk for early onset breast cancer in high-risk women and in women from the general population, future studies are needed to elucidate the importance of the IGF1-19/-19 genotype concerning the variability in breast cancer risk among BRCA1 mutation carriers.     

<Emphasis Type="Italic">IL6</Emphasis> genotypes and colon and rectal cancer

Inflammation appears to play a key role in the development of colorectal cancer (CRC). In this study we examine factors involved in the regulation of inflammation and risk of CRC. Data from a multi-center case–control study of colon (N = 1579 cases and N = 1977 controls) and rectal (N = 794 cases and N = 1005 controls) cancer were used to evaluate the association between the rs1800795 and rs1800796 IL6 polymorphisms and CRC. We evaluated the joint effects of IL6 single nucleotide polymorphisms and regular use of aspirin/NSAIDs and vitamin D receptor (VDR) genotype. Having a C allele of the rs1800796 IL6 polymorphisms and the GG genotype of the rs1800795 IL6 polymorphisms was associated with a statistically significantly reduced the risk of colon (OR 0.76 95% CI 0.57, 1.00), but not rectal (OR 1.49 95% CI 1.02,2.16) cancer. Both IL6 polymorphisms were associated with significant interaction with current use of aspirin/NSAIDs to alter risk of colon cancer: individuals with a C allele in either polymorphism who were current users of aspirin/NSAIDs had the lowest colon cancer risk. CRC risk also was associated with an interaction between VDR and IL6 genotypes that was modified by current use of aspirin/NSAIDs. This study provides further support for inflammation-related factors in the etiology of CRC. Other studies are needed to explore other genes in this and other inflammation-related pathways.     

HER-2/<Emphasis Type="Italic">neu</Emphasis> expression in primary and metastatic breast cancer

Introduction Trastuzumab is a highly effective therapy for the treatment of HER-2/neu positive breast cancer. To maximize benefit and minimize unnecessary toxicity, patient selection is essential. Currently HER-2/neu analysis is routinely performed only for primary invasive breast cancers, and trastuzumab therapy is recommended based on primary analysis only. Methods Using immunohistochemistry, we performed a retrospective study comparing HER-2/neu expression in original primary to subsequent metastatic breast cancers. Results Tumors from 382 patients with metastatic breast cancer were studied. In 254 cases (66%) both primary and metastatic lesions were concordant. In 90 cases the primary lesion was HER-2/neu positive with the metastatic lesion negative; whereas, in 37 cases the primary lesion was HER-2/neu negative and the metastatic lesion positive. Primary HER-2/neu immunostaining was associated with a negative predictive value of 35.7%. Although all four groups were similar at diagnosis, survival differences were noted with the best survival experienced by patients with initial primary lesions HER-2/neu negative and subsequent metastatic lesions positive. Patients with hormone receptor and HER-2/neu positive primary lesions who received tamoxifen were more likely to have HER-2/neu positive metastasis. Conclusions The significant discordance between HER-2/neu expression in primary and metastatic tumors suggests that determination of HER-2/neu status in metastatic disease should be attempted.     

Mutation analysis of <Emphasis Type="Italic">PALB2</Emphasis> in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis>-negative breast and/or ovarian cancer families from Eastern Ontario,Canada

Background

PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient.

Methods

The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario.

Results

We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del – major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations.

Conclusions

PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families.     

I171V germline mutation in the <Emphasis Type="Italic">NBS1</Emphasis> gene significantly increases risk of breast cancer

Nijmegen Breakage Syndrome (NBS) is a rare autosomal, recessive disease caused by homozygous mutations in the NBS1 gene. The most common deletion of 5 bp (657del5) in exon 6, which affects mostly the population of Central Europe is observed. Among the typical features of this disorder is that NBS patients experience a high incidence of lymphoid malignancies as well. An increased risk of solid tumors development for 657del5 carriers was the reason to investigate the role of NBS1 gene as a susceptible one for the breast cancer. The purpose of this work is to identify mutations in all 16 exons of the NBS1 gene in the group of the patients with diagnosed breast cancer and the control group of healthy individuals. In the group of 270 women with breast cancer, seven cases of mutated NBS1 gene were revealed. In the subgroup presenting mutated NBS1 gene, the mutation I171V in 5th exon occurred in five cases. It is the first such a discovery concerning breast cancer patients because this mutation had been previously observed only in the course of lymphoid or hematological malignancies. The rate of I171V mutation in the group of breast cancer patients was significantly higher than in the controls (OR: 9.42; 95% CI: 1.09-81.05; P = 0.02). The conclusion is that heterozygous germline mutation I171V in NBS1 gene is a significant risk factor for breast cancer development. It concerns especially the women whose first degree relatives had a previously diagnosed breast cancer (OR: 6.00; 95% CI: 0.98-38.07; P = 0.04). The histopathological and clinical features of breast cancer with I171V mutation suggest accumulation of the negative prognostic factors. The treatment's results however were unexpectedly satisfactory, that is why further investigations are necessary to assess the role of I171V mutation in NBS1 gene as a prognostic and predictive factor for breast cancer.