Distinct breast cancer phenotypes in BRCA 1/2 carriers based on ER status.

PURPOSE: BRCA1/2 genes are the two main genes associated with hereditary breast cancers (BC). In the present study, we explore clinical and molecular characteristics of BRCA-associated BC in relation to estrogen receptor (ER) status. METHODS: Three BC databases (DB) were evaluated: (i) Hadassah oncogenetics (n = 4826); (ii) METABRIC (n = 1980), and (iii) Nick-Zainal (n = 560). We evaluated age at diagnosis in BRCA positive (BP) and BRCA negative (BN) patients, and tested for mutational signature differences in cohort iii. mRNA differential expression analysis (DEA) and pathway analysis were performed in cohort ii. RESULTS: Age at diagnosis was lower in BP vs. BN tumors in all cohorts in the ER- group, and only in cohort i for the ER + group. Signature 3 was universal in BP BC, whereas several signatures were associated with ER status. Pathway analysis was performed between BP&BN, and was significant only in ER- tumors: the major activated pathways involved cancer-related processes and were highly significant. The most significant pathway was estrogen-mediated S-phase entry and the most activated upstream regulator was ERBB2. CONCLUSION: Signature 3 was universal for all BP BC, while other signatures were associated with ER status. ER + BP& BN show similar genomic characteristics, ER- BP differed markedly from BN. This suggests that the initial carcinogenic process is universal for all BRCA carriers, but further insults lead to the development of two genomically distinct subtypes ER- and ER + . This may shed light on possible mechanisms involved in BP and carry preventive and therapeutic implications.

Hospital readmission rates and risk factors for readmission following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal surface malignancies.

BACKGROUND: Cytoreductive surgery and Hyperthermic intra-peritoneal chemotherapy (CRS/HIPEC) for peritoneal surface malignancies is associated with high morbidity. The increased numbers of patients undergoing CRS/HIPEC in recent years mandates risk analysis and quality assurance. However, only scarce data exist regarding causative parameters for readmission. The aim of this study was to assess readmission rates and risk factors associated with readmission. METHODS: A retrospective-cohort study including patients from two high-volume centers who underwent CRS/HIPEC surgery between the years 2007-2016 was performed. Patients' demographics, peri-operative data and readmission rates were recorded. RESULTS: 223 patients were included in the study. The 7 and 30-day readmission rates were 3.5% (n = 8) and 11% (n = 25), respectively. Late readmission rates (up to 90 days) were 11% (n = 25). The most common causes of readmission were surgical related infections (35%), small bowel obstruction (17.5%) and dehydration (14%). Post-operative complications were associated with higher readmission rates (p = 0.0001). PCI score was not associated with higher rates of readmission. CONCLUSION: Readmissions following CRS/HIPEC occur mainly due to infectious complications and dehydrations. Patients following CRS/HIPEC should be discharged after careful investigation to a community based continuing care with access for IV fluid replacement or antibiotics administration when required.

Oncotype Dx recurrence score among BRCA1/2 germline mutation carriers with hormone receptors positive breast cancer.

Gene expression assays are widely used to predict risk of recurrence in early breast cancer (BC). We report the 21-gene expression assay (Oncotype Dx) recurrence score (RS) distribution of 27 BRCA carriers with estrogen receptor (ER) positive BCs, identified at Hadassah Medical Center, combined with 2 previous studies. Treatment decision and outcomes of the 27 BRCA carriers were compared with an Israeli cohort of 1594 patients published recently. We found Oncotype Dx RS low (<18), intermediate (18-30) and high (>30) among 12 (21.4%), 23 (41.1%) and 21 (37.5%) of 56 BRCA1 carriers compared with 15 (17.2%), 49 (56.3%) and 23 (26.4%) of 87 BRCA2 carriers (p = 0.2). The corresponding distribution in a population of 82,434 women published by Genomic Health was 53.4%, 36.3% and 10.3% for low, intermediate and high RS (p < 0.001 for BRCA1 and BRCA2). Treatment decision regarding chemotherapy according to RS was similar in BRCA1, BRCA2 and the control group. Two of 27 carriers had distant recurrence: a BRCA1 carrier with RS of 18 and a BRCA2 carrier with RS of 22; both have an excellent response to chemotherapy. We found an approximately ∼3 fold increased rate of high RS among BRCA1 and 2 carriers with ER positive BC compared with the general BC population. These data might indicate that hormone positive BC in BRCA carriers are molecularly unique. The surprisingly good response to chemotherapy in the metastatic setting in 2 patients may suggest that the predictive value of low-intermediate RS in carriers merits further studies.

Prospective validation of a surgical complications grading system in a cohort of 2114 patients.

BACKGROUND: We recently reported a grading system for surgical complications. This system proved to have a high sensitivity for recording minor but meaningful complications prolonging hospital stay in patients after colorectal surgery. We aimed to prospectively validate the complication grading system in a general surgery department over 1 year. METHODS: All surgical procedures and related complications were prospectively recorded between January 1st and December 31st, 2009. Surgical complications were graded on a severity scale of 1-5. The system classifies short-term outcome by grade emphasizing intensity of therapy required for treatment of the defined complication. RESULTS: During the study period, 2114 patients underwent surgery. Elective and oncological surgeries were performed in 1606 (76%) and 465 (22%) patients, respectively. There were 422 surgical complications in 304 (14%) patients (Grade 1/2: 203 [67%]; Grade 3/4: 90 [29%]; Grade 5: 11 [4%]). Median length of stay correlated significantly with complication severity: 2.3 d for no complication, 6.2 and 11.8 d for Grades 1/2 and 3/4, respectively (P < 0.001). Older age (OR 2.75, P < 0.001), comorbidities (OR 1.44, P = 0.02), American Society of Anesthesiology score >2 (OR 2.07, P < 0.001), contamination Grade (OR 1.85, P = 0.001), oncological (OR 2.82, P < 0.001), open (OR 1.22, P = 0.03), prolonged >120 min (OR 2.08, P < 0.001), and emergency surgery (OR 1.42, P = 0.02) independently predicted postoperative complications. CONCLUSIONS: This system of grading surgical complications permits standardized reporting of surgical morbidity according to the severity of impact. Prospective validation of this system supports its use in a general surgery setting as a tool for surgical outcome assessment and quality assurance.

Clinical and genetic characteristics of carriers of the TP53 c.541C > T, p.Arg181Cys pathogenic variant causing hereditary cancer in patients of Arab-Muslim descent.

TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 (TP53): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospectively examined our genetic databases to identify all carriers of TP53 p.Arg181Cys. We reached out to carriers and their relatives and collected clinical and demographic data, lifestyle factors, carcinogenic exposures as well as additional blood samples for genetic testing and whole exome sequencing. Between 2005 and 2022 a total of 2875 cancer patients underwent genetic testing using genetic panels, whole exome sequencing or targeted TP53 assays. A total of 30 cancer patients, all of Arab-Muslim descent, were found to be carriers of TP53 p.Arg181Cys, the majority from Jerusalem and Hebron, two of which were homozygous for the variant. Carriers were from 24 distinct families of them, 15 families (62.5%) met updated Chompret criteria for LFS. Median age of diagnosis was 35 years-old (range 1-69) with cancers characteristic of LFS (16 Breast cancer; 6 primary CNS tumors; 3 sarcomas) including 4 children with choroid plexus carcinoma, medulloblastoma, or glioblastoma. A total of 21 healthy carriers of TP53 p.Arg181Cys were identified at a median age of 39 years-old (range 2-54)-19 relatives and 2 additional pediatric non-cancer patients, in which the finding was incidental. We report a shared haplotype of 350kb among carriers, limited co-morbidities and low BMI in both cancer patients and healthy carriers. There were no demographic factors or carcinogenic exposures unique to carriers who developed malignancy. Upon exome analysis no other known pathogenic variants in cancer predisposing genes were identified. TP53 p.Arg181Cys is a founder pathogenic variant predominant to the Arab-Muslim population in Jerusalem and Hebron, causing attenuated-LFS. We suggest strict surveillance in established carriers and encourage referral to genetic testing for all cancer patients of Arab-Muslim descent in this region with LFS-associated malignancies as well as family members of established carriers.

Genetic predisposition to radiation induced sarcoma: possible role for BRCA and p53 mutations.

The estimated incidence of radiation-associated sarcoma (RAS) is 0.03-0.2 % in 5 years post treatment. Most cancer predisposing genes are involved in DNA repair; therefore, elevated RAS risk in these patients is plausible. Cases of angiosarcoma post breast cancer treatment were reported in BRCA1 and BRCA2 carriers. We report the genetic evaluation of seven cases with suspected RAS from patients counseled in our cancer-genetic clinic. Of 2,885 breast cancer patient, 470 were BRCA1 or two mutation carriers and three were p53 mutation carriers. Of them seven developed sarcoma in the field of irradiation; five in the chest wall and two in other sites. Genetic evaluation revealed BRCA1 mutation in two, BRCA2 mutation in additional patient and a carrier of p53 mutation. The estimation of risk for RAS in patients with genetic predisposition is limited due to the rarity of this event, and the bias in referral to the clinic toward younger age. With these limitations the rate of RAS is 0.43 % (2/470, 95 % CI -0.17 to 1.02, SE = 0.3) in this group in a median follow-up of 8.2 years (range 1 month to 51 years). If we assume irradiation for the breast in 80 % of the patients than rate of RAS in group is proximately 0.53 % (2/376, 95 % CI -0.21 to 1.26, SE = 0.37). A BRCA1 carrier which had sarcoma after irradiation to head and neck carcinoma was not included in these analyses. In conclusion, we found a high frequency of BRCA1/2 mutation among our patients diagnosed with RAS. However, we estimated approximately twofold increase in the risk of RAS in BRCA1/2 carriers which was not significant compared to reports in general population. Therefore, RAS is a rare event in BRCA carriers as in the general population, and should not be considered in the decision regarding irradiation treatment in this population.

Tumor STAT3 tyrosine phosphorylation status, as a predictor of benefit from adjuvant chemotherapy for breast cancer.

Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signaling pathways. In breast cancer cell lines and xenograft models activated STAT3 participates in breast tumorigenesis, while studies in humans have demonstrated that phosphorylated (tyrosine705)-STAT3 is a marker of good prognosis in breast cancer. In order to resolve this paradox we hypothesized that in clinic, phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy; therefore the goal of this study was to determine the usefulness of phospho-STAT3 status as a predictor of benefit from adjuvant chemotherapy in breast cancer patients. Immunohistochemical analysis of phospho-STAT3 was performed on a tissue microarray of breast cancer specimens. The expression pattern of phospho-STAT3 was retrospectively correlated with pathological parameters and overall survival in patients who were or were not treated with adjuvant chemotherapy. Of 375 tissue specimens interpretable for phospho-STAT3, 134 (36 %) exhibited positive phospho-STAT3 nuclear expression. Among 234 patients who received adjuvant therapy, those with tumors displaying positive phospho-STAT3 nuclear expression had a better ten-year rate of overall survival than patients with tumors displaying negative phospho-STAT3 nuclear expression (P = 0.001). Among patients who did not received adjuvant chemotherapy, positive phospho-STAT3 nuclear status was not correlated with increased overall survival (P = 0.54). Positive phospho-STAT3 was correlated with improved overall survival only among patients who received adjuvant chemotherapy in a multivariate analysis adjusted for stage, grade, hormonal status, Her2 status, and age, irrespective of the chemotherapy regimen received (hazard ratio for death, 0.35 [95 % CI 0.188-0.667]; P = 0.001). These findings support the role of phospho-STAT3 as a marker of favorable outcome in breast cancer patients treated with adjuvant chemotherapy. Whether phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy has to be validated on prospective, randomized, controlled studies.

Regulation of human protease-activated receptor 1 (hPar1) gene expression in breast cancer by estrogen.

A pivotal role is attributed to the estrogen-receptor (ER) pathway in mediating the effect of estrogen in breast cancer progression. Yet the precise mechanisms of cancer development by estrogen remain poorly understood. Advancing tumor categorization a step forward, and identifying cellular gene fingerprints to accompany histopathological assessment may provide targets for therapy as well as vehicles for evaluating the response to treatment. We report here that in breast carcinoma, estrogen may induce tumor development by eliciting protease-activated receptor-1 (PAR(1)) gene expression. Induction of PAR(1) was shown by electrophoretic mobility shift assay, luciferase reporter gene driven by the hPar(1) promoter, and chromatin-immunoprecipitation analyses. Functional estrogen regulation of hPar1 in breast cancer was demonstrated by an endothelial tube-forming network. Notably, tissue-microarray analyses from an established cohort of women diagnosed with invasive breast carcinoma exhibited a significantly shorter disease-free (P=0.006) and overall (P=0.02) survival of patients that were positive for ER and PAR(1), compared to ER-positive but PAR(1)-negative patients. We propose that estrogen transcriptionally regulates hPar(1), culminating in an aggressive gene imprint in breast cancer. While ER(+) patients are traditionally treated with hormone therapy, the presence of PAR(1) identifies a group of patients that requires additional treatment, such as anti-PAR(1) biological vehicles or chemotherapy.

Comparison of diagnostic and prognostic performance of two assays measuring thymidine kinase 1 activity in serum of breast cancer patients.

BACKGROUND: We compared two recently developed immunoassays for serum thymidine kinase 1 (TK1) activity: one manual assay (DiviTum, Biovica(®)) and one fully automated assay (Liaison, Diasorin(®)). METHODS: The study included 368 women: 149 healthy blood donors (control), 59 patients with benign breast disease (BBD) and 160 patients with primary breast cancer (BC). RESULTS: A regression analysis of the Liaison (y) and DiviTum (x) assays for all three groups yielded the equation y=3.93+0.03x (r=0.85, n=368). The r-value in BC was higher than in control and BBD (0.90 vs. 0.81 and 0.64). The correlation between the two assays for TK1 values above the cut-off was higher compared to that below (0.88 and 0.59). Breakdown of the BBD group into subgroups with proliferative and non-proliferative lesions was effective only with the measurement of TK1 with DiviTum assay (p=0.03). The TK1 activity determined preoperatively in BC patients with DiviTum and Liaison assays was significantly associated with T-stage (for both p=0.01), presence of vascular invasion (p=0.002 and p=0.02), lack of estrogen receptor (ER) (p=0.001 and p=0.01) and progesterone receptor (PR) (p=0.01 and p=0.03) expression. Only TK1 analyzed with the DiviTum assay was associated with tumor grade and molecular subtype of BC (p=0.02 and p=0.003). Multivariate Cox proportional hazards analyses demonstrated that T-stage, PR status and TK1 activity measured by both methods (DiviTum, RR=3.0, p=0.02 and Liaison, RR=3.1, p=0.01) were independent predictors of disease recurrence. CONCLUSIONS: In spite of differences observed between TK1 activity measured by the DiviTum and Liaison assays, both of them may be used for recurrence prediction in preoperative evaluation of BC patients.

Clinical Characteristics, Response to Platinum-Based Chemotherapy and Poly (Adenosine Phosphate-Ribose) Polymerase Inhibitors in Advanced Lung Cancer Patients Harboring BRCA Mutations.

The oncogenic role and clinical relevance of BRCA mutations in NSCLC remain unclear. We aim to evaluate the characteristics and clinical outcomes of patients with NSCLC harboring BRCA mutations treated at Hadassah Medical Center (HMC). We retrospectively assessed all patients with advanced NSCLC who underwent next-generation sequencing (NGS) and were found to have pathogenic somatic BRCA mutations (p-BRCA). We compared clinical outcomes in NSCLC patients with wild-type BRCA (wt-BRCA) matched by age, stage, gender, smoking, PDL-1 and driver mutations. Between 2015 and 2022, we evaluated 598 patients with advanced NSCLC using NGS and found 26 patients with p-BRCA, of whom 17 (65.4%) were carriers of germline BRCA variants and represented 1% of all BRCA carriers HMC. The median age of diagnosis was 67 years old (40-78), 13 patients (50%) had a history of smoking and 9 patients (34.6%) had additional driver mutations (EGFR, ALK, BRAF, MET or ERBB2). Objective response rate and median progression-free survival (PFS) for first-line platinum-based chemotherapy in the p-BRCA group compared to wt-BRCA controls were 72.2% and 16 months (CI 95%, 5-22), compared to 47.4% and 7 months (CI 95%, 5-9), respectively, and HR for PFS was 0.41 (CI 95%, 0.17-0.97). Six patients in the p-BRCA group were treated with advanced-line poly (adenosine-phosphate-ribose) polymerase inhibitors (PARPi), with a durable response observed in four patients (66%). In this cohort, patients with NSCLC harboring p-BRCA exhibit high-sensitivity PARPi and a prolonged response to platinum, suggesting some oncogenic role for BRCA mutations in NSCLC. The results support further prospective trials of the treatment of NSCLC harboring p-BRCA with PARPi.

Genetic anticipation of breast cancer among BRCA1/BRCA2 mutation carriers: A retrospective study.

OBJECTIVE: To study the anticipation phenomenon among hereditary breast cancer patients, by evaluating trends in age at diagnosis and phenotype of breast cancer across two successive generation pairs of BRCA1/2 mutation carriers/non-carriers with breast cancer after reports of an earlier age of diagnosis in successive generations among BRCA1/2 mutation carrier families. METHOD: A retrospective cohort study. Patient characteristics, pathologic data and survival were compared between mothers and daughters and between carriers and non-carriers. RESULTS: Overall, 126 patients were found, who formed 67 pairs of mothers and daughters diagnosed with breast cancer and genetically tested for BRCA mutations. Age at diagnosis was significantly younger in the daughter versus mother generation, in both groups of BRCA carriers/non-carriers. Tumor characteristics were not different between mothers and daughters. Survival analysis revealed a not significant better outcome for the daughter generation versus the mother generation. CONCLUSIONS: Breast cancer appeared to be diagnosed at an earlier age in successive generations among BRCA mutation carriers and non-carriers. The fact that we also observed a downshift at age of diagnosis in non-carrier pairs emphasizes that other factors (environmental, lifestyle, or social) may influence the age at diagnosis.

Breast Cancer with Low Recurrence Score on Oncotype DX©: Interplay Between Early Recurrence, Lobular Histology and BRCA Mutation.

INTRODUCTION: The 21-gene recurrence score assay Oncotype DX© (ODX) has clear prognostic and predictive value regarding adjuvant chemotherapy. However, recent studies have shown the clinical distinctiveness of both BRCA1/2-driven early breast cancer (EBC) and invasive lobular (ILC) breast cancers. We evaluated the association between BRCA1/2-driven EBC/ILC and Oncotype DX failure despite a recurrence score ≤ 20. METHODS: Here, we describe a small cohort of 16 patients from our center who, despite a low recurrence score (RS) ≤ 20, suffered from early disease recurrence. Clinical parameters of our cohort of patients were compared to a cohort from the general population of Clalit Health Service (CHS). RESULTS: Median age at diagnosis in our cohort was significantly younger. BRCA mutational status was available in 14 patients in our cohort. A high percentage of these patients had BRCA1/2 mutations (35.7%), either germline (in 3) or somatic (in 2). Half of our cohort was diagnosed with lobular carcinoma (ILC) relative to 10-15% in the general population of BC (p = 0.02). The median time to recurrence was 44 months. CONCLUSION: BRCA1/2 mutation and ILC are highly represented in this cohort. Although our cohort is small, these data may suggest that a RS ≤ 20 in these subgroups may not reflect a low risk of recurrence.

Potential Refinement of Recurrence Score by pSTAT3 Status.

The likelihood of recurrence in breast cancer patients with hormone receptor-positive (HR-positive) tumors is influenced by clinical, histopathological, and molecular features. Recent studies suggested that activated STAT3 (pSTAT3) might serve as a biomarker of outcome in breast cancer patients. In the present work, we have analyzed the added value of pSTAT3 to OncotypeDx Recurrence Score (RS) in patient prognostication. We have found that patients with low RS (<26) and low pSTAT3 might represent a population at a higher risk for cancer recurrence. Furthermore, we have observed that a positive pSTAT3 score alone can be a favorable marker for patients with HR-positive breast cancer under the age of 50. In an era of personalized medicine, these findings warrant further appraisal of chemotherapy benefit in this population.

"High-Risk Breast Cancer Screening in BRCA1/2 Carriers Leads to Early Detection and Improved Survival After a Breast Cancer Diagnosis".

BACKGROUND: Germline BRCA1/2 pathogenic variant (PV) carriers have high lifetime risk of developing breast cancer and therefore subjected to intense lifetime screening. However, solid data on the effectiveness of high-risk screening of the BRCA1/2 carrier population is limited. PATIENTS AND METHODS: Retrospectively, we analyzed 346 women diagnosed with breast tumors. Patients were divided according to the timing of BRCA1/2 PVrecognition, before (BRCA-preDx awareness, N = 62) or after (BRCA-postDx awareness group, N = 284) cancer diagnosis. RESULTS: Median follow-up times were 131.42 and 93.77 months in the BRCA-preDx awareness and BRCA-postDx awareness groups, respectively. In the BRCA-preDx awareness group, 78.7% of the patients had invasive tumors and 21.3% were diagnosed with pure ductal carcinoma in situ. In contrast, in the BRCA-postDx awareness group over 93% of women were diagnosed with invasive cancer and only 6.4% had in situ disease. The mode of tumor detection differed significantly between the groups: 71.9% in the BRCA-postDx awareness group and 26.2% in the BRCA-preDx awareness group were diagnosed after personally palpating a lump. Tumor size and nodal involvement were significantly more favorable in the BRCA-preDx awareness group. T stage was significantly lower in the BRCA-preDx awareness group: 54.84% at T1 and 20.96% at Tis. In the BRCA-postDx awareness group, only 37.54% were at T1 and 6.49% at Tis. The N stage was also significantly lower in the BRCA-preDx awareness group: 71% had no lymph node metastases, compared with 56.1% in the BRCA-postDx awareness group. Additionally, therapeutic procedures varied between the groups: BRCA-preDx awareness group patients underwent more breast conserving surgeries. Axillary lymph node dissection was done in 38% of women in the BRCA-postDx awareness group and in only 8.7% of the BRCA-preDx awareness group patients. Interestingly, improved survival was found among patients who underwent high-risk screening (hazard ratio=0.34). CONCLUSIONS: High-risk screening might facilitate downstaging of detected breast tumor among BRCA1/2 carrier population.

Clinical Characteristics and Prognosis of Gastric Cancer Patients with BRCA 1/2 Germline Mutations: Report of Ten Cases and a Literature Review.

BACKGROUND: The prognosis of gastric cancer (GC) is poor with a median overall survival (OS) of less than 12 months in advanced-stage disease. The search for distinct genetic subgroups of GC patients and predictive biomarkers is ongoing. While BRCA1 or BRCA2 germline mutations (gBRCAm) have potential therapeutic implications in ovarian, breast and pancreatic cancers, their significance in GC patients has not been established. PATIENTS AND METHODS: A retrospective multi-center data analysis of GC patients with gBRCAm was conducted, detailing the clinical characteristics and disease course in this unique subset of patients. RESULTS: Ten GC patients with gBRCAm were identified, six of them with metastatic disease. The median OS of all ten GC patients was 47.5 (13-192) months. Median OS for patients diagnosed with operable disease was 55.5 (13-192) months and of the patients with metastatic disease (calculated from metastatic disease diagnosis) 32 (15-52) months with an exceptional 1-, 2- and 3-year survival rate of 100%, 83.3% and 50%, respectively. CONCLUSION: These preliminary data suggest that gBRCAm in GC patients are associated with a favorable prognosis. Furthermore, gBRCAm might be a predictive biomarker to DNA-damaging agents response in GC patients, similarly to its established role in other malignancies. Further research is needed to confirm our findings.

Effects of the single nucleotide polymorphism at MDM2 309 on breast cancer patients with/without BRCA1/2 mutations.

BACKGROUND: A germ line single nucleotide polymorphism (SNP) in the first intron of the gene encoding MDM2 at position 309, an important modulator of p53, has been described. BRCA1/2 mutation have been associated with increased rates of breast cancers with mutated P53. It was shown that the presence of MDM2 309 SNP correlated with younger cancer onset age in individuals with a p53 mutations. The differential effects of this SNP were also linked to estrogen receptor activation. Here we report on our study of 453 Ashkenazi breast cancer patients of whom 180 were positive for the known Ashkenazi BRCA1/2 mutations METHODS: DNA from breast cancer patients was obtained for analysis of one of the three common BRCA1/2 mutations and MDM2 SNP309. Data regarding cancer onset and death ages was obtained from our database and Statistical analysis was performed using the SPSS statistical package (SPCC Inc., Chicago, IL), and JMP software (SAS Institute, Cary, NC). RESULTS: The percentage of MDM2 SNP309 in control and BRCA 1/2 population which is similar to that reported for other Jewish Ashkenazi populations at 52.2% for the heterozygotes and 25.0% for MDM2SNP309G/G and 22.8% for MDM2SNP309T/T.There was not a statistical significant difference in median age of disease onset in the different MDM2 SNP309 subgroups of the BRCA1/2 carriers. When we further divided the group into under and above 51 years old ( presumed menopause age) in the BRCA1 positive subset we found that there were less patients of the MDM2SNP309 G/G versus the MDM2SNP309 T/T in the over 51 patient group (p = 0.049). This result has been obtained in a relatively small subgroup and is of borderline statistical significance. Interestingly, in the BRCA1/2 mutation carriers, we found a survival advantage for patients harboring the SNP309 G/G genotype (p = 0.0086) but not for the 272 patients not harbouring this mutations. CONCLUSION: MDM2SNP309G/G main effect on BRCA1/2 positive mutation carriers is linked to its effect on patients survival. Further research is needed in order to understand the reason for this difference.

Mitomycin C and vinblastine: an active regimen in previously treated breast cancer patients.

BACKGROUND: Metastatic breast cancer has a substantial mortality burden on women worldwide. Presented herein is our experience with the combination of mitomycin-C and vinblastine in heavily pretreated breast cancer patients. METHODS: Candidates were women with measurable metastatic disease, previously exposed to two or more chemotherapy regimens. Mitomycin-C was given at the dose of 10 mg/m2 on day 1 and vinblastine at 6 mg/m2 on days 1 and 21 of each 42-day cycle. Analysis included patients exposed to one or more cycles of therapy. Kaplan-Meier curves were used to generate overall survival and time-to-treatment progression curves. RESULTS: Forty patients previously exposed to a median of three prior regimens were included. Partial response and stable disease were reported in 14 (35%) and 10 (25%), patients, respectively, for a clinical benefit of 60%. With a median follow-up of 11 months, the median time to progression and survival durations lasted 4 and 12 months, respectively. In a subgroup of 17 women with prior anthracycline and taxane exposure, partial response and stable disease were reported in 4 (23.5%) and 5 (29%), respectively. Treatment was generally well tolerated, with grade 3-4 hematologic and non-hematologic toxicity reported in 8 (20%) and 3 (7.5%) patients, respectively. Two cases of fatalities (5%) occurred with pulmonary toxicity in women heavily exposed to mitomycin-C (cumulative doses of > or = 40 mg/m2) and soon after red blood cell transfusion. CONCLUSIONS: Chemotherapy with mitomycin-C and vinblastine is active and well-tolerated in heavily pretreated breast cancer patients. Caution should be taken to avoid blood transfusion alone with mitomycin-C therapy.

Homologous recombination in lung cancer, germline and somatic mutations, clinical and phenotype characterization.

OBJECTIVES: Identifying new predictive biomarkers in lung cancer that will prolong survival for additional subgroups of patients is of utmost importance. We report response to treatment and survival among homologous recombination deficient (HRD) lung cancer patients mostly BRCA mutation carriers to better define the predictive value of HRD status among non-small cell lung cancer (NSCLC). METHODS: We retrospectively evaluated our genetic and pathology database and identified 14 carriers of germline mutation in BRCA1 (n = 5), BRCA2 (n = 8), or PALB2 (n = 1) and a patient with a somatic BRCA2 mutation. Platinum compounds were part of the initial or follow-on treatment protocols in 9/11 with metastatic disease. Overall survival (OS) and response to platinum were analyzed in these patients. RESULTS: Median OS for the 11 patients was 30 months. The 2- and 3-year survival rates in our cohort were 62.5% and 28.6%, respectively, and 7/10 patients with metastatic lung cancer survived for more than 1 year which compares favorably with the literature. Of eight patients who were treated with platinum compounds, seven responded; however, in two the response endured for <6 months. The Foundation Medicine LOH/HRD genomic score was calculated in three patients and the level was high in 2/3 (66%), including 1/2 tumors in germline BRCA mutation carriers and tumor in the patient with a somatic BRCA2 mutation. In both complete response to platinum was recorded. CONCLUSION: Response rate to platinum compounds and survival in these patients do suggest that platinum-based therapies should still be incorporated in our treatment regimen for the patients with HRD lung cancer, and that BRCA and other HRR associated gene testing may be important in lung cancer patients.

Mutation spectrum in HNPCC in the Israeli population.

Hereditary non-polyposis colon cancer is caused by mutations in DNA mismatch repair genes. The mutation spectrum in the Israeli population is poorly documented except for the c.1906G>C Ashkenazi founder mutation in the hMSH2 gene. To report our experience in HNPCC screening, the mutations detected and the clinical features among a cohort of Israeli patients. Diagnostic work-up was done in a multi-step process guided by clinical and ethnic information. Tumors of suspected patients were tested for microsatellite instability and immunohistochemistry. Based on tumor analyses, we proceeded to mutation screening by DHPLC followed by sequence analysis and multiplex ligase dependent probe amplification. Ashkenazi Jews were first tested for the c.1906G>C founder mutation. Of the 240 families, 24, including Arabs and Jews from different ethnic origins, were tested positive. All tumors that lost expression of mismatch repair proteins also showed microsatellite instability. There was evidence for involvement of hMSH2 (15) hMLH1 (6) and hMSH6 (3) genes. Mutations were identified in 17/24 (71%) patients: 6 Ashkenazi families harbored the c.1906G>C mutation. Eleven other mutations (2 nonsense, 3 splice site and 6 small deletions) were detected. Three of the mutations are novel. No gross deletions or insertions were detected. This is the first report that characterizes the profile of HNPCC in a cohort of patients in Israel. Tumor testing indicated that the 3 main MMR genes are involved, and that mutation spectrum is broad.

Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations.

BACKGROUND: The risks for cancers other than breast (BC) or ovarian (OC) cancer in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers were elevated in studies of carrier families. However, case-control studies did not confirm this observation. OBJECTIVE: To compare the risks for other cancers in BRCA1/2 mutation carriers and non-carriers, all affected with BC and/or OC. Both groups share risk modifiers of BC/OC, which enabled assessment of the role of BRCA1/2 mutations. METHODS: 1098 Ashkenazi Jewish women affected with BC and/or OC were ascertained during 1995-2003; molecular testing revealed 229 BRCA1 and 100 BRCA2 carriers and 769 non-carriers. COX proportional hazard models were used to evaluate the risk of other cancers. Analyses were conducted including all other cancers or only those diagnosed after BC/OC diagnosis. RESULTS: The HRs for any other cancer were 2.6 (95% CI 1.7 to 4.2, p<0.001) and 1.8 (95% CI 0.95 to 3.6, p = 0.07) in BRCA1 and BRCA2 carriers, respectively. The corresponding colon cancer HRs were 3.9 (95% CI 1.3 to 12.1, p = 0.02) and 2.3 (95% CI 0.5 to 11.3, p = 0.3) in BRCA1 and BRCA2 carriers. The HR for lymphoma was 11.9 (95% CI 3.1 to 46.2, p = 0.001) in BRCA2 carriers. Risk estimates for other cancers after the onset of BC/OC were similar. CONCLUSION: A 2.5-fold increase in any other cancer and a fourfold risk of colon cancer were found among BRCA1 carriers. The corresponding HRs in BRCA2 carriers were non-significant, except for the markedly elevated risk of lymphoma. These results suggest a role for BRCA1/2 mutations in colorectal cancer risk in a subgroup of BC/OC-affected carriers.