Detection of germline variants in Brazilian breast cancer patients using multigene panel testing.

Genetic diversity of germline variants in breast cancer (BC) predisposition genes is unexplored in miscegenated populations, such those living in Latin America. We evaluated 1663 Brazilian BC patients, who underwent hereditary multigene panel testing (20-38 cancer susceptibility genes), to determine the spectrum and prevalence of pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUS). Associations between P/LP variants and BC risk were estimated in a case-control analysis of BC patients and 18,919 Brazilian reference controls (RC). In total, 335 (20.1%) participants carried germline P/LP variants: 167 (10.0%) in BRCA1/2, 122 (7.3%) in BC actionable non-BRCA genes and 47 (2.8%) in candidate genes or other cancer predisposition genes. Overall, 354 distinctive P/LP variants were identified in 23 genes. The most commonly mutated genes were: BRCA1 (27.4%), BRCA2 (20.3%), TP53 (10.5%), monoallelic MUTYH (9.9%), ATM (8.8%), CHEK2 (6.2%) and PALB2 (5.1%). The Brazilian variant TP53 R337H (c.1010G>A, p.Arg337His), detected in 1.6% of BC patients and 0.1% of RC, was strongly associated with risk of BC, OR = 17.4 (95% CI: 9.4-32.1; p < 0.0001); monoallelic MUTYH variants c.1187G>A and c.536A>G, detected in 1.2% (0.9% RC) and 0.8% (0.4% RC) of the patients, respectively, were not associated with the odds of BC, the former with OR = 1.4 (95% CI: 0.8-2.4; p = 0.29) and the latter with OR = 1.9 (95% CI: 0.9-3.9; p = 0.09). The overall VUS rate was 46.1% for the entire patient population. Concluding, the use of multigene panel testing almost doubled the identification of germline P/LP variants in clinically actionable predisposition genes in BC patients. In Brazil, special attention should be given to TP53 P/LP variants.

Somatic Mutational Profile of High-Grade Serous Ovarian Carcinoma and Triple-Negative Breast Carcinoma in Young and Elderly Patients: Similarities and Divergences.

BACKGROUND: Triple-negative breast cancer (TNBC) and High-Grade Serous Ovarian Cancer (HGSOC) are aggressive malignancies that share similarities; however, different ages of onset may reflect distinct tumor behaviors. Thus, our aim was to compare somatic mutations in potential driver genes in 109 TNBC and 81 HGSOC from young (Y ≤ 40 years) and elderly (E ≥ 75 years) patients. METHODS: Open access mutational data (WGS or WES) were collected for TNBC and HGSOC patients. Potential driver genes were those that were present in the Cancer Gene Census-CGC, the Candidate Cancer Gene Database-CCGD, or OncoKB and those that were considered pathogenic in variant effect prediction tools. RESULTS: Mutational signature 3 (homologous repair defects) was the only gene that was represented in all four subgroups. The median number of mutated CGCs per sample was similar in HGSOC (Y:3 vs. E:4), but it was higher in elderly TNBC than it was in young TNBC (Y:3 vs. E:6). At least 90% of the samples from TNBC and HGSOC from Y and E patients presented at least one known affected TSG. Besides TP53, which was mutated in 67-83% of the samples, the affected TSG in TP53 wild-type samples were NF1 (yHGSOC and yTNBC), PHF6 (eHGSOC and yTNBC), PTEN, PIK3R1 and ZHFX3 (yTNBC), KMT2C, ARID1B, TBX3, and ATM (eTNBC). A few samples only presented one affected oncogene (but no TSG): KRAS and TSHR in eHGSOC and RAC1 and PREX2 (a regulator of RAC1) in yTNBC. At least ⅔ of the tumors presented mutated oncogenes associated with tumor suppressor genes; the Ras and/or PIK3CA signaling pathways were altered in 15% HGSOC and 20-35% TNBC (Y vs. E); DNA repair genes were mutated in 19-33% of the HGSOC tumors but were more frequently mutated in E-TNBC (56%). However, in HGSOC, 9.5% and 3.3% of the young and elderly patients, respectively, did not present any tumors with an affected CGC nor did 4.65% and none of the young and elderly TNBC patients. CONCLUSION: Most HGSOC and TNBC from young and elderly patients present an affected TSG, mainly TP53, as well as mutational signature 3; however, a few tumors only present an affected oncogene or no affected cancer-causing genes.

Survival analysis of young adults from a Brazilian cohort of non-small cell lung cancer patients.

BACKGROUND: The influence of age at diagnosis in non-small cell lung cancer (NSCLC) prognosis is unclear. OBJECTIVES: To compare in a Brazilian cohort of NSCLC patients of different age groups: 1) The overall survival; 2) Clinical features and treatment options. METHODS: This is a retrospective cohort study using a hospital-based registry, for NSCLC patients registered in years 2000-2009. Patients were grouped into three age groups: Young adults (YA: < 40 years), middle-aged (MA: 40-64 years) and elderly (E: ≥ 65 years). Kaplan-Meier was used to estimate overall survival and Cox regression for hazard ratios (HRs) and 95% confidence intervals. RESULTS: 17,422 NSCLC patients were included: 370 YA (2.1%), 8,697 MA (49.9%) and 8,355 E (48.0%). Compared with older age groups, the YA group had a higher proportion of females, patients diagnosed with adenocarcinoma and metastatic disease (63.2%). Overall survival was longer in YA in the entire cohort and in all clinical stages (CSs) (p < 0.001). For YA, higher education level was a good prognosis factor (compared with illiterate and incomplete elementary); advanced or metastatic disease (compared with early-stage disease) and treatment based in radiotherapy or chemotherapy (CT) (without surgery), compared with treatment combinations with surgery, were poor prognostic factors. Young men (but not women) had lower HR of death compared with older groups; YA had lower HR of death in all CSs compared with patients from older groups. A higher percentage of YA were treated with surgery or CT in early-stage disease compared with older groups. Besides that, YA and MA patients treated with surgery or CT had a better prognosis than elderlies. Conclusions: In this Brazilian cohort of NSCLC patients, most young individuals were diagnosed with metastatic disease. YA presented longer survival than older age groups in all CSs, but mainly in CS I/II and III, where some patients may achieve long remissions or cure.

Germline and Somatic mutations in postmenopausal breast cancer patients.

OBJECTIVES: In breast cancer (BC) patients, the frequency of germline BRCA mutations (gBRCA) may vary according to the ethnic background, age, and family history of cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the second most common somatic mutated gene in BC; however, the association of mutations in both genes with cancer has not been thoroughly investigated. Thus, our aims were to investigate gBRCA mutation frequency in a cohort of postmenopausal Brazilian BC patients and the association of gBRCA1/BRCA2 and PIK3CA somatic mutations. METHODS: Forty-nine postmenopausal (>55 years) and forty-one young (≤35 years) BC patients were included in this study. The postmenopausal group included patients who reported a positive family history of cancer. For these patients, gBRCA1/BRCA2 were sequenced using next-generation sequencing (NGS) or Sanger sequencing. Data for gBRCA in young patients were already available from a previous study. DNA from formalin-fixed, paraffin-embedded (FFPE) tumors was obtained from 27 postmenopausal and 41 young patients for analyzing exons 9 and 20 of PIK3CA. The association between gBRCA1/BRCA2 and somatic mutations in PIK3CA was investigated. RESULTS: The overall frequency of gBRCA1/BRCA2 among the 49 postmenopausal patients was 10.2%. The frequencies of somatic mutations in PIK3CA in the postmenopausal and young patients were 37% and 17%, respectively (ns). The most common PIK3CA mutation was found to be E454A. Nonsense and frameshift mutations, which may counteract the oncogenic potential of PIK3CA were also detected. Regardless of age, 25% of BRCA1/BRCA2 mutation carriers and non-carriers , each, had PIK3CA somatic mutations. CONCLUSIONS: Data obtained indicate that BRCA1/BRCA2 gene testing may be considered for postmenopausal patients with BC who have a family history of cancer. Although some of them are not considered pathogenic, somatic variants of PIK3CA are frequently observed in BC patients, especially in postmenopausal patients.

Analysis of RPL37A, MTSS1, and HTRA1 expression as potential markers for pathologic complete response and survival.

BACKGROUND: Non-metastatic locally advanced breast carcinoma (LABC) treatment involves neoadjuvant chemotherapy (NCT). We evaluated the association of clinical-pathological data and immunoexpression of hormone receptors, HER2 and Ki67, and new biomarkers, RPL37A, MTSS1 and HTRA1, with pathological complete response (PCR) or tumour resistance (stable disease or disease progression), disease-free survival (DFS) and cancer-specific survival (CSS). METHODS: This is a retrospective study of 333 patients with LABC who underwent NCT. Expression of MTSS1, RPL37A and HTRA1/PRSS11 was evaluated by immunohistochemistry in TMA slides. Cutoff values were established for low and high tumour expression. ROC plotter evaluated response to NCT. Chi-square test for factors related to PCR, and Kaplan-Meier test and Cox model for factors related to DFS and CSS were prformed. RESULTS: The mean follow-up was 70.0 months and PCR rate was 15.6%. At 120 months, DFS rate was 32.5% and CSS rate was 67.1%. In multivariate analysis, there was an association between: (1) necrosis presence, intense inflammatory infiltrate, ER absence, HER2 molecular subtype and high RPL3A expression with increased odds of PCR; (2) lymph node involvement (LNI), high Ki67, low RPL37A and high HTRA1 expression with increased risk for NCT non-response; (3) LNI, high proliferation, necrosis absence, low RPL37A and high HTRA1 expression with increased recurrence risk; (4) advanced LNI, ER negative tumours, high HTRA1, low RPL37A expression and desmoplasia presence with higher risk of cancer death. CONCLUSION: RPL37A is a potential biomarker for response to NCT and for prognosis. Additional studies evaluating HTRA1 and MTSS1 prognostic value are needed.

Germline and Somatic mutations in postmenopausal breast cancer patients

OBJECTIVES: In breast cancer (BC) patients, the frequency of germline BRCA mutations (gBRCA) may vary according to the ethnic background, age, and family history of cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the second most common somatic mutated gene in BC; however, the association of mutations in both genes with cancer has not been thoroughly investigated. Thus, our aims were to investigate gBRCA mutation frequency in a cohort of postmenopausal Brazilian BC patients and the association of gBRCA1/BRCA2 and PIK3CA somatic mutations. METHODS: Forty-nine postmenopausal (>55 years) and forty-one young (≤35 years) BC patients were included in this study. The postmenopausal group included patients who reported a positive family history of cancer. For these patients, gBRCA1/BRCA2 were sequenced using next-generation sequencing (NGS) or Sanger sequencing. Data for gBRCA in young patients were already available from a previous study. DNA from formalin-fixed, paraffin-embedded (FFPE) tumors was obtained from 27 postmenopausal and 41 young patients for analyzing exons 9 and 20 of PIK3CA. The association between gBRCA1/BRCA2 and somatic mutations in PIK3CA was investigated. RESULTS: The overall frequency of gBRCA1/BRCA2 among the 49 postmenopausal patients was 10.2%. The frequencies of somatic mutations in PIK3CA in the postmenopausal and young patients were 37% and 17%, respectively (ns). The most common PIK3CA mutation was found to be E454A. Nonsense and frameshift mutations, which may counteract the oncogenic potential of PIK3CA were also detected. Regardless of age, 25% of BRCA1/BRCA2 mutation carriers and non-carriers , each, had PIK3CA somatic mutations. CONCLUSIONS: Data obtained indicate that BRCA1/BRCA2 gene testing may be considered for postmenopausal patients with BC who have a family history of cancer. Although some of them are not considered pathogenic, somatic variants of PIK3CA are frequently observed in BC patients, especially in postmenopausal patients.

Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer.

Breast cancer stromal compartment, may influence responsiveness to chemotherapy. Our aim was to detect a stromal cell signature (using a direct approach of microdissected stromal cells) associated with response to neoadjuvant chemotherapy (neoCT) in locally advanced breast cancer (LABC). The tumor samples were collected from 44 patients with LABC (29 estrogen receptor (ER) positive and 15 ER negative) before the start of any treatment. Neoadjuvant chemotherapy consisted of doxorubicin and cyclophosphamide, followed by paclitaxel. Response was defined as downstaging to maximum ypT1a-b/ypN0. The stromal cells, mainly composed of fibroblast and immune cells, were microdissected from fresh frozen tumor samples and gene expression profile was determined using Agilent SurePrint G3 Human Gene Expression microarrays. Expression levels were compared using MeV (MultiExperiment Viewer) software, applying SAM (significance analysis of microarrays). To classify samples according to tumor response, the order of median based on confidence statements (MedOr) was used, and to identify gene sets correlated with the phenotype downstaging, gene set enrichment analysis (GSEA). Nine patients presented disease downstaging. Eleven sequences (FDR 17) were differentially expressed, all of which (except H2AFJ) more expressed in responsive tumors, including PTCHD1 and genes involved in abnormal cytotoxic T cell physiology, TOX, LY75, and SH2D1A. The following four pairs of markers could correctly classify all tumor samples according to response: PTCHD1/PDXDC2P, LOC100506731/NEURL4, SH2D1A/ENST00000478672, and TOX/H2AFJ. Gene sets correlated with tumor downstaging (FDR < 0.01) were mainly involved in immune response or lymphocyte activation, including CD47, LCK, NCK1, CD24, CD3E, ZAP70, FOXP3, and CD74, among others. In locally advanced breast cancer, stromal cells may present specific features of immune response that may be associated with chemotherapy response.

Frequency of CDH1 germline variants and contribution of dietary habits in early age onset gastric cancer patients in Brazil.

INTRODUCTION: The contribution of CDH1 germline variants to gastric cancer burden among young adults is unknown in Brazil. We aimed to evaluate the frequency of CDH1 germline variants and the diet/lifestyle habits in early age onset gastric cancer (EOGC, ≤ 55 years old) patients. METHODOLOGY: From 2013 to 2015, a total of 88 unrelated and consecutive patients diagnosed with EOGC were enrolled. All CDH1 exons and intronic boundaries were sequenced, and large genomic rearrangements were screened by MLPA. CDH1 transcription analysis was performed for variants that could potentially induce an effect on splicing. The diet and lifestyle habits of EOGC patients were compared to Brazilian population diet and lifestyle, obtained from governmental databases. RESULTS: Of 88 patients, the mean age at EOGC diagnosis was 39 years and 55% fulfilled the criteria for hereditary diffuse gastric cancer. The majority of the tumors were diffuse (74%) and poorly differentiated (80%). In total, 4 novel missense variants of uncertain significance (VUS) were identified: c.313T>A, c.387G>T, c.1676G>A, and c.1806C>A. The MLPA results revealed no rearrangements and CDH1 transcription analysis for variants of interest were inconclusive. EOGC patients had a higher red (OR:2.6, 95%CI:1.4-4.9) and processed (OR:3.1, 95%CI:1.6-6.0) meat intake and higher fruit consumption (OR:0.4, 95%IC:0.3-0.7) compared to eating habits of the Brazilian population. CONCLUSIONS: No unequivocal pathogenic germline CDH1 variants were identified in Brazilian EOGC patients. Dietary habits may be associated with the EOGC development.

Cost effectiveness of the cancer prevention program for carriers of the BRCA1/2 mutation.

OBJECTIVE: To analyze the cost effectiveness of the diagnostic program for the germline mutation in BRCA1/2 genes and of preventative strategies for the relatives of patients diagnosed with ovarian cancer associated with this mutation. METHODS: The study analyzed the cost effectiveness by developing an analysis of the Markov decision process from the perspective of the National Health System. The strategies compared reflect upon the adoption of genetic testing and preventative strategies for relatives or the usual care currently proposed. The incremental cost-effectiveness ratio was expressed in terms of cost per case avoided. The sensitivity analysis was performed in a univariate and deterministic manner. RESULTS: The study showed increments for effectiveness and for costs when performing genetic testing and adopting prophylactic measures for family members. The incremental cost-effectiveness ratio was estimated at R$908.58 per case of cancer avoided, a figure considered lower than the study's cost-effectiveness threshold (R$7,543.50). CONCLUSIONS: The program analyzed should be considered a cost-effective strategy for the national situation. Studies in various other countries have reached similar conclusions. One possible ramification of this research might the need to perform a budgetary-impact analysis of making the program one of the country's health policies.

Survival and prognosis of young adults with gastric cancer.

OBJECTIVES: Survival data for young adults (YA) with gastric cancer is conflicting and scarce in Brazil. The aim of this study was to compare the clinicopathological factors and survival rates of younger and older patients with gastric cancer. METHODS: Hospital registries for 294 gastric cancer patients from a reference cancer hospital in São Paulo, Brazil, were consulted for the retrieval of clinicopathological information and follow-up time. Patients were placed into the following groups: YA (≤40 years; N=71), older adult (OA: 41 to 65 years; N=129) and elderly (E: ≥66 years; N=94). Differences were assessed through Pearson's χ2 test, Kaplan-Meier analysis, Log rank test and Cox regression. RESULTS: More YA were diagnosed with advanced disease (clinical stage III/IV: 86.7% YA, 69.9% OA, and 67% E); however, fewer E patients underwent surgery (64.3% YA, 72.7% OA, and 52.4% E). The median overall survival among all patients was 16 months, and the overall survival rate was not significantly different among the age groups (p=0.129). There were no significant differences in the disease-free survival rate. Metastatic disease at diagnosis (HR=4.84; p<0.01) was associated with an increased hazard of death for YA. CONCLUSION: Overall survival was similar among age groups. Metastatic disease at diagnosis was the only factor associated with a poorer prognosis in YA. These results suggest that younger patients deserve special attention regarding the detection of early stage disease.

Clinical stage and histological type of the most common carcinomas diagnosed in young adults in a reference cancer hospital.

OBJECTIVES: Cancer in young adults represents a great challenge, both biologically and socially, and understanding the unique characteristics of neoplasms in this age group is important to improving care. We aimed to evaluate the most common carcinomas and their characteristics, such as histological type and clinical stage, in young adults in the largest cancer hospital in Latin America. METHODS: The hospital registry was consulted for the period between 2008 and 2014. Young adults were defined as individuals aged 18 to 39 years, and older adults were defined as individuals aged 40 years and older. Differences between age groups were assessed through chi-square tests. RESULTS: Of the 39,389 patients included, 3,821 (9.7%) were young adults. Among the young adults, the most frequent cancer types were the following: breast, lymph node, colorectal, thyroid, testicle, hematopoietic and reticuloendothelial, uterine cervix, brain, soft tissue and stomach; these sites accounted for 74.5% of the observed tumors. Breast, colorectal and stomach cancers were more frequently diagnosed at advanced stages in young adults than in older adults (p<0.001). The most common histological types were infiltrating ductal carcinoma (86.12%) for breast cancer, adenocarcinomas not otherwise specified (45.35%) for colorectal cancer, squamous cell carcinoma not otherwise specified (65.26%) for uterine cervix cancer, signet ring cell adenocarcinomas (49.32%) for stomach cancer and adenocarcinomas not otherwise specified (50.79%) for lung cancer. CONCLUSION: Young adults are diagnosed with cancer at more advanced stages, indicating that health professionals should be aware of cancer incidence in this age group. It is necessary to develop a better understanding of cancer in young adults and to implement dedicated health care strategies for these patients.

Survival and prognosis of young adults with gastric cancer

OBJECTIVES: Survival data for young adults (YA) with gastric cancer is conflicting and scarce in Brazil. The aim of this study was to compare the clinicopathological factors and survival rates of younger and older patients with gastric cancer. METHODS: Hospital registries for 294 gastric cancer patients from a reference cancer hospital in São Paulo, Brazil, were consulted for the retrieval of clinicopathological information and follow-up time. Patients were placed into the following groups: YA (≤40 years; N=71), older adult (OA: 41 to 65 years; N=129) and elderly (E: ≥66 years; N=94). Differences were assessed through Pearson's χ2 test, Kaplan-Meier analysis, Log rank test and Cox regression. RESULTS: More YA were diagnosed with advanced disease (clinical stage III/IV: 86.7% YA, 69.9% OA, and 67% E); however, fewer E patients underwent surgery (64.3% YA, 72.7% OA, and 52.4% E). The median overall survival among all patients was 16 months, and the overall survival rate was not significantly different among the age groups (p=0.129). There were no significant differences in the disease-free survival rate. Metastatic disease at diagnosis (HR=4.84; p<0.01) was associated with an increased hazard of death for YA. CONCLUSION: Overall survival was similar among age groups. Metastatic disease at diagnosis was the only factor associated with a poorer prognosis in YA. These results suggest that younger patients deserve special attention regarding the detection of early stage disease.

Clinical stage and histological type of the most common carcinomas diagnosed in young adults in a reference cancer hospital

OBJECTIVES: Cancer in young adults represents a great challenge, both biologically and socially, and understanding the unique characteristics of neoplasms in this age group is important to improving care. We aimed to evaluate the most common carcinomas and their characteristics, such as histological type and clinical stage, in young adults in the largest cancer hospital in Latin America. METHODS: The hospital registry was consulted for the period between 2008 and 2014. Young adults were defined as individuals aged 18 to 39 years, and older adults were defined as individuals aged 40 years and older. Differences between age groups were assessed through chi-square tests. RESULTS: Of the 39,389 patients included, 3,821 (9.7%) were young adults. Among the young adults, the most frequent cancer types were the following: breast, lymph node, colorectal, thyroid, testicle, hematopoietic and reticuloendothelial, uterine cervix, brain, soft tissue and stomach; these sites accounted for 74.5% of the observed tumors. Breast, colorectal and stomach cancers were more frequently diagnosed at advanced stages in young adults than in older adults (p<0.001). The most common histological types were infiltrating ductal carcinoma (86.12%) for breast cancer, adenocarcinomas not otherwise specified (45.35%) for colorectal cancer, squamous cell carcinoma not otherwise specified (65.26%) for uterine cervix cancer, signet ring cell adenocarcinomas (49.32%) for stomach cancer and adenocarcinomas not otherwise specified (50.79%) for lung cancer. CONCLUSION: Young adults are diagnosed with cancer at more advanced stages, indicating that health professionals should be aware of cancer incidence in this age group. It is necessary to develop a better understanding of cancer in young adults and to implement dedicated health care strategies for these patients.

Cost effectiveness of the cancer prevention program for carriers of the BRCA1/2 mutation

ABSTRACT OBJECTIVE: To analyze the cost effectiveness of the diagnostic program for the germline mutation in BRCA1/2 genes and of preventative strategies for the relatives of patients diagnosed with ovarian cancer associated with this mutation. METHODS: The study analyzed the cost effectiveness by developing an analysis of the Markov decision process from the perspective of the National Health System. The strategies compared reflect upon the adoption of genetic testing and preventative strategies for relatives or the usual care currently proposed. The incremental cost-effectiveness ratio was expressed in terms of cost per case avoided. The sensitivity analysis was performed in a univariate and deterministic manner. RESULTS: The study showed increments for effectiveness and for costs when performing genetic testing and adopting prophylactic measures for family members. The incremental cost-effectiveness ratio was estimated at R$908.58 per case of cancer avoided, a figure considered lower than the study's cost-effectiveness threshold (R$7,543.50). CONCLUSIONS: The program analyzed should be considered a cost-effective strategy for the national situation. Studies in various other countries have reached similar conclusions. One possible ramification of this research might the need to perform a budgetary-impact analysis of making the program one of the country's health policies.

Breast-conserving surgery in locally advanced breast cancer submitted to neoadjuvant chemotherapy. Safety and effectiveness based on ipsilateral breast tumor recurrence and long-term follow-up.

OBJECTIVE:: To evaluate ipsilateral breast tumor recurrence after breast-conserving surgery for locally advanced breast cancer. METHODS:: A retrospective observational cohort study was performed in patients with locally advanced breast cancer submitted to breast-conserving surgery after neoadjuvant chemotherapy based on an adriamycin-cyclophosphamide-paclitaxel regimen. We evaluated the clinical, pathologic, immunohistochemistry, and surgical factors that contribute to ipsilateral breast tumor recurrence and locoregional recurrence. A Kaplan-Meier analysis and Cox model were used to evaluate the main factors related to disease-free survival. RESULTS:: Of the 449 patients who received neoadjuvant chemotherapy, 98 underwent breast-conserving surgery. The average diameter of the tumors was 5.3 cm, and 87.2% reached a size of up to 3 cm. Moreover, 86.7% were classified as clinical stage III, 74.5% had T3-T4 tumors, 80.5% had N1-N2 axilla, and 89.8% had invasive ductal carcinoma. A pathologic complete response was observed in 27.6% of the tumors, and 100.0% of samples had free margins. The 5-year actuarial overall survival rate was 81.2%, and the mean follow-up was 72.8 months. The rates of ipsilateral breast tumor recurrence and locoregional recurrence were 11.2% and 15.3%, respectively. Multifocal morphology response was the only factor related to ipsilateral breast tumor recurrence disease-free survival (p=0.04). A multivariate analysis showed that the pathologic response evaluation criteria in solid tumors (RECIST)-breast cutoff was the only factor related to locoregional recurrence disease-free survival (p=0.01). CONCLUSIONS:: Breast-conserving surgery is a safe and effective therapy for selected locally advanced breast tumors.

Breast-conserving surgery in locally advanced breast cancer submitted to neoadjuvant chemotherapy. Safety and effectiveness based on ipsilateral breast tumor recurrence and long-term follow-up

OBJECTIVE: To evaluate ipsilateral breast tumor recurrence after breast-conserving surgery for locally advanced breast cancer. METHODS: A retrospective observational cohort study was performed in patients with locally advanced breast cancer submitted to breast-conserving surgery after neoadjuvant chemotherapy based on an adriamycin-cyclophosphamide-paclitaxel regimen. We evaluated the clinical, pathologic, immunohistochemistry, and surgical factors that contribute to ipsilateral breast tumor recurrence and locoregional recurrence. A Kaplan-Meier analysis and Cox model were used to evaluate the main factors related to disease-free survival. RESULTS: Of the 449 patients who received neoadjuvant chemotherapy, 98 underwent breast-conserving surgery. The average diameter of the tumors was 5.3 cm, and 87.2% reached a size of up to 3 cm. Moreover, 86.7% were classified as clinical stage III, 74.5% had T3-T4 tumors, 80.5% had N1-N2 axilla, and 89.8% had invasive ductal carcinoma. A pathologic complete response was observed in 27.6% of the tumors, and 100.0% of samples had free margins. The 5-year actuarial overall survival rate was 81.2%, and the mean follow-up was 72.8 months. The rates of ipsilateral breast tumor recurrence and locoregional recurrence were 11.2% and 15.3%, respectively. Multifocal morphology response was the only factor related to ipsilateral breast tumor recurrence disease-free survival (p=0.04). A multivariate analysis showed that the pathologic response evaluation criteria in solid tumors (RECIST)-breast cutoff was the only factor related to locoregional recurrence disease-free survival (p=0.01). CONCLUSIONS: Breast-conserving surgery is a safe and effective therapy for selected locally advanced breast tumors.

Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil.

BACKGROUND: Approximately 8-15% epithelial ovarian cancer patients are BRCA1 or BRCA2 germline mutation carriers. Brazilian inhabitants may have peculiar genetic characteristics associated with ethnic diversity, and studies focusing on the entire BRCA1/BRCA2 gene sequencing in Brazilian ovarian cancer patients are still lacking. The aim of this study was to evaluate BRCA1/2 mutations, through entire gene sequencing, in a Brazilian population of women with epithelial ovarian cancer. METHODS: In a cross sectional study performed in one reference centre for cancer treatment in São Paulo, Brazil, 100 patients diagnosed with epithelial ovarian cancer unselected for family history of breast and/or ovarian cancer were included. The complete coding sequence of BRCA1/2 genes was evaluated through Next-Generation or capillary sequencing. Large deletions were investigated through Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: Nineteen pathogenic mutations (BRCA1: n = 17 and BRCA2: n = 2) featuring 14 different mutations, including two large deletions in BRCA1 (exon 1-2 deleted and exon 5-7 deleted) were identified. Three mutations were detected more than once (c.3331_3334delCAAG, c.5266dupC and c.4484G > T). Two novel frameshift mutations were identified, one in BRCA1 (c.961_962delTG) and one in BRCA2 (c.1963_1963delC). BRCA1/2 mutations were seen in 35.5% of the patients with first and/or second-degree relatives with breast and/or ovarian cancer. Nineteen variants of uncertain significance (VUS) were detected (BRCA1: n = 2 and BRCA2: n = 17), including five distinct missense variants (BRCA1: c.5348 T > C; BRCA2: c.2350A > G, c.3515C > T, c.7534C > T, and c.8351G > A). CONCLUSIONS: Among epithelial ovarian cancer patients unselected for family history of cancer, 19% were BRCA1/2 germline mutation carriers. Almost ¾ of the BRCA mutations, including two large deletions, were detected only once. Our work emphasizes the need of entire gene sequencing and MLPA screening in Brazil.

The role of oncoplastic breast conserving treatment for locally advanced breast tumors. A matching case-control study.

BACKGROUND: Breast conserving surgery (BCS) after neoadjuvant chemotherapy (NC) in patients with locally advanced breast cancer (LABC) is an infrequent procedure. In these patients the association with BCS and oncoplastic surgery (OS) is reported as a possible procedure in case-series, but there are limited case-control studies. METHODS: A matched case-control study evaluated LABC submitted to NC and BCS. We evaluated 78 patients submitted to doxorubicin-cyclophosphamide regimen followed by paclitaxel regimen. The match case-control proportion was 2:1 and the patients were selected by tumor size, clinical T stage and year of diagnosis. RESULTS: 52 underwent classic BCS and 26 OS. The average size tumor was 5.25 cm and 88.5% of the tumors were larger than 3 cm. The clinical and pathological group characteristics were similar, except the weight of surgical specimens (p = 0.004), and surgical margins (p = 0.06), which were higher in OS group. The rate of complete pathologic response was 26.9%. 97.4% received postoperative radiotherapy. At 67.1 months of follow up, 10.2% had local recurrence (LR) and 12.8% locoregional recurrence (LRR) and 19.2% died because disease progression. The overall survival at 60 months was 81.7%. After surgery the disease free-survival at 60 months was 76.5%. The was no difference between groups related to pathologic response (p = 0.42), LR (p = 0.71), LRR (p = 1.00), overall survival (p = 0.99) and disease specific survival (p = 0.87). CONCLUSION: This study corroborates the fact that OS is a safety procedure for LABC, offering the similar oncologic results observed in patients submitted to classic BCS.

Somatic mutations in breast and serous ovarian cancer young patients: a systematic review and meta-analysis.

OBJECTIVE: our aim was to evaluate whether somatic mutations in five genes were associated with an early age at presentation of breast cancer (BC) or serous ovarian cancer (SOC). METHODS: COSMIC database was searched for the five most frequent somatic mutations in BC and SOC. A systematic review of PubMed was performed. Young age for BC and SOC patients was set at ≤ 35 and ≤ 40 years, respectively. Age groups were also classified in < 30 years and every 10 years thereafter. RESULTS: twenty six (1,980 patients, 111 younger) and 16 studies (598, 41 younger), were analyzed for BC and SOC, respectively. In BC, PIK3CA wild type tumor was associated with early onset, not confirmed in binary regression with estrogen receptor (ER) status. In HER2-negative tumors, there was increased frequency of PIK3CA somatic mutation in older age groups; in ER-positive tumors, there was a trend towards an increased frequency of PIK3CA somatic mutation in older age groups. TP53 somatic mutation was described in 20% of tumors from both younger and older patients; PTEN, CDH1 and GATA3 somatic mutation was investigated only in 16 patients and PTEN mutation was detected in one of them. In SOC, TP53 somatic mutation was rather common, detected in more than 50% of tumors, however, more frequently in older patients. CONCLUSION: frequency of somatic mutations in specific genes was not associated with early-onset breast cancer. Although very common in patients with serous ovarian cancer diagnosed at all ages, TP53 mutation was more frequently detected in older women.