Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes.

BACKGROUND: Sarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases. METHODS: Germline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants. RESULTS: GPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (TP53, RB1, NF1, EXT1/2) but also in genes where that risk is still emerging/limited (ERCC2, TSC2 and BRCA2) or unknown (PALB2, RAD50, FANCM and others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%×6.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk. CONCLUSION: Our findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.

Characterization of Potential Melanoma Predisposition Genes in High-Risk Brazilian Patients.

Increased genetic risk for melanoma can occur in the context of germline pathogenic variants in high-penetrance genes, such as CDKN2A and CDK4, risk variants in low- to moderate-penetrance genes (MC1R and MITF), and possibly due to variants in emerging genes, such as ACD, TERF2IP, and TERT. We aimed to identify germline variants in high- and low- to moderate-penetrance melanoma risk genes in Brazilian patients with clinical criteria for familial melanoma syndrome. We selected patients with three or more melanomas or melanoma patients from families with three tumors (melanoma and pancreatic cancer) in first- or second-degree relatives. Genetic testing was performed with a nine-gene panel (ACD, BAP1, CDK4, CDKN2A, POT1, TERT, TERF2IP, MC1R, and MITF). In 36 patients, we identified 2 (5.6%) with germline pathogenic variants in CDKN2A and BAP1 and 4 (11.1%) with variants of uncertain significance in the high-penetrance genes. MC1R variants were found in 86.5%, and both red hair color variants and unknown risk variants were enriched in patients compared to a control group. The low frequency of germline pathogenic variants in the high-penetrance genes and the high prevalence of MC1R variants found in our cohort show the importance of the MC1R genotype in determining the risk of melanoma in the Brazilian melanoma-prone families.

Impact of BRCA1/2 Mutations on the Efficacy of Secondary Cytoreductive Surgery.

BACKGROUND: Phase III trials evaluating the role of secondary cytoreductive surgery (SCS) in recurrent ovarian cancer have pointed to the importance of patient selection. Two studies showed conflicting results regarding the benefit of SCS in BRCA1/2 mutation carriers. Our aim was to evaluate the impact of SCS on recurrent ovarian cancer according to BRCA1/2 status. METHODS: All patients with ovarian carcinoma with platinum-sensitive recurrent disease and tested for BRCA1/2 germline mutations were included. Cox regression and log rank test were used to evaluate the impact of SCS on progression-free survival (PFS) and the influence of BRCA1/2 mutations on the effect of SCS. RESULTS: 127 patients were included, 45.6% were treated with SCS and chemotherapy and 54.3% treated with chemotherapy only. Patients treated with SCS were younger, presented better performance status, had lower CA125, and had a longer platinum-free interval. In multivariate analysis SCS was associated with longer PFS (HR 0.42, 95% CI 0.25-0.72, p = 0.002). BRCA1/2 mutations were found in 35 patients (27.5%), and 11.8% of patients were treated with PARP inhibitors. Although not statistically significant, both BRCA1/2 wild type patients (PFS: 21.6 vs 18.4 months; p = 0.114) and BRCA1/2 mutation carriers (PFS: 23.1 vs 18.2 months, p = 0.193) appeared to derive benefit from SCS. DISCUSSION: The present study suggests a benefit of SCS irrespective of BRCA1/2 status among patients mostly not treated with PARP inhibitor. Further data on post hoc analysis from the phase III trials are warranted to confirm whether BRCA1/2 mutated patients should be selected for SCS.

Influence of treatment access on survival of metastatic renal cell carcinoma in brazilian cancer center.

BACKGROUND: Tyrosine kinase inhibitors (TKI) and immunotherapy improved survival in metastatic renal cell carcinoma (mRCC). Disparities in treatment access are present in healthcare systems globally. The aim of this study was to analyze survival outcomes of mRCC patients treated with first-line TKIs in the public (PHS) and private (PrS) health system in a Brazilian Cancer Center. MATERIALS AND METHODS: Records from all mRCC patients treated with first-line TKIs from 2007-2018 were reviewed retrospectively. Categorial variables were compared by Fisher's exact test. Survival was estimated by Kaplan-Maier method and survival curves were compared using the log-rank test. Prognostic factors were adjusted by Cox regression model. RESULTS: Of the 171 eligible patients, 37 (21.6%) were PHS patients and 134 (78.4%) were PrS patients. There were no difference in age, gender, or sites of metastasis. PHS patients had worse performance status (ECOG ≥2, 35.1% vs. 13.5%, p=0.007), poorer risk score (IMDC poor risk, 32.4% vs. 16.4%, p=0.09), and less nephrectomies (73% vs. 92.5%, p=0.003) than PrS patients. Median lines of therapy was one for PHS versus two for PrS patients (p=0.03). Median overall survival (OS) was 16.5 versus 26.5 months (p=0.002) and progression-free survival (PFS), 8.4 versus 11 months (p=0.01) for PHS and PrS patients, respectively. After adjusting for known prognostic factors on multivariate analysis, PHS patients still had a higher risk of death (HR: 1.61, 95% CI: 1.01-2.56, p=0.047). CONCLUSION: Patients with mRCC treated via the PHS had worse overall survival, possibly due to poorer prognosis at presentation and less drug access.

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America.

Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%-80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency.

Prevalence of BRCA1 and BRCA2 pathogenic and likely pathogenic variants in non-selected ovarian carcinoma patients in Brazil.

BACKGROUND: BRCA1/2 pathogenic (P) and likely pathogenic (LP) germline variants are frequent among patients with ovarian carcinoma. However, these variants have not been extensively characterized in patients with ovarian cancer in Brazil. METHODS: In this retrospective study we evaluated clinical characteristics and BRCA1/2 genetic test results from patients with ovarian carcinoma who underwent genetic counseling at A.C.Camargo Cancer Center (Brazil) between 2015 and 2017 and had performed germline genetic testing of BRCA1/2 genes. RESULTS: Among 158 patients, 33 P and LP variants and were found (20.8%), 27 in BRCA1 and six in BRCA2, and six variants of unknown clinical significance (VUS). Thirteen percent of the patients did not have Multiplex Ligation-dependent Probe Amplification (MLPA) results. Three P variants in BRCA1 were found in more than one patient: c.5266dupC (p.Gln1756Profs*74), c.3331_3334delCAAG (p.Gln1111Asnfs5*), and c.211A > G (p.Arg71Gly). One LP variant in BRCA1 had not been previously described, c.4153_4154delCT (p.Leu1385Ilefs*5). Patients with previous diagnosis of breast cancer were carriers of P or LP variant in 8 of 12 cases (66.7%), and patients with a family history of ovarian or breast cancer in first- or second-degree relatives were carriers of P or LP variant in 26.7% of cases compared to 16.9% for patients without family history (p = 0.166). CONCLUSION: Prevalence of BRCA1/2 germline P and LP variants is slightly higher than previously described by the largest occidental studies, with a high prevalence of variant c.5266dupC (p.Gln1756Profs*74) in BRCA1 observed. Moreover, we identified a new LP variant.

BRCA1 deficiency is a recurrent event in early-onset triple-negative breast cancer: a comprehensive analysis of germline mutations and somatic promoter methylation.

PURPOSE: BRCA1 germline mutation is closely associated with triple-negative breast cancer. BRCA deficiency leads to impaired DNA repair and tumor development, and understanding this deficiency, in both hereditary and sporadic scenarios, is of great clinical and biological interest. Here, we investigated germline or somatic events that might lead to BRCA1 impairment in triple-negative breast cancer. We also analyzed the clinical implications associated with BRCA deficiency. METHODS: Next-generation sequencing for the BRCA1/2 genes and multiplex ligation-dependent probe amplification (MLPA) for the BRCA1 gene were performed for mutation screening. A customized bisulfite next-generation sequencing approach was used for assessing BRCA1 promoter methylation status in tumor tissue. RESULTS: A total of 131 triple-negative cases were assessed, and germline pathogenic variants were detected in 13.0% of all cases and in 26% of cases diagnosed in young women. Most germline pathogenic variants (88.2%) occurred in the BRCA1 gene. BRCA1 promoter hypermethylation was detected in 20.6% of tumors; none of these tumors were in BRCA1/2 pathogenic variant carriers. BRCA1 impairment by either germline or somatic events was significantly more frequent in young women (55% in those ≤ 40 years; 33% in those 41-50 years; 22% in those > 50 years of age) and associated with better overall and disease-free survival rates in this group of patients. CONCLUSIONS: BRCA1 deficiency was recurrent in early-onset triple-negative breast cancer in Brazilian patients and associated with improved survival. With the new treatment modalities being investigated, including poly (ADP-ribose)-polymerase (PARP) inhibitor therapy, our results suggest that a significant proportion of young women with this subtype of tumor might benefit from PARP inhibitor treatment, which warrants further investigation.

Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09).

PURPOSE: Bempegaldesleukin (BEMPEG) is a pegylated interleukin (IL)-2 cytokine prodrug engineered to provide controlled and sustained activation of the clinically validated IL-2 pathway, with the goal of preferentially activating and expanding effector CD8+ T cells and natural killer cells over immunosuppressive regulator T cells in the tumor microenvironment. The open-label, phase III randomized controlled PIVOT-09 trial investigated the efficacy and safety of BEMPEG plus nivolumab (NIVO) as first-line treatment for advanced/metastatic clear cell renal cell carcinoma (ccRCC) with intermediate-/poor-risk disease. METHODS: Patients with previously untreated advanced/metastatic ccRCC were randomly assigned (1:1) to BEMPEG plus NIVO, or investigator's choice of tyrosine kinase inhibitor (TKI; sunitinib or cabozantinib). Coprimary end points were objective response rate (ORR) by blinded independent central review and overall survival (OS) in patients with International Metastatic RCC Database Consortium (IMDC) intermediate-/poor-risk disease. RESULTS: Overall, 623 patients were randomly assigned to BEMPEG plus NIVO (n = 311) or TKI (n = 312; sunitinib n = 225, cabozantinib n = 87), of whom 514 (82.5%) had IMDC intermediate-/poor-risk disease. In patients with IMDC intermediate-/poor-risk disease, ORR with BEMPEG plus NIVO versus TKI was 23.0% (95% CI, 18.0 to 28.7) versus 30.6% (95% CI, 25.1 to 36.6; difference, -7.7 [95% CI, -15.2 to -0.2]; P = .0489), and median OS was 29.0 months versus not estimable (hazard ratio, 0.82 [95% CI, 0.61 to 1.10]; P = .192), respectively. More frequent all-grade treatment-related adverse events (TRAEs) with BEMPEG plus NIVO versus TKI included pyrexia (32.6% v 2.0%) and pruritus (31.3% v 8.8%). Grade 3/4 TRAEs were less frequent with BEMPEG plus NIVO (25.8%) versus TKI (56.5%). CONCLUSION: First-line BEMPEG plus NIVO for advanced/metastatic ccRCC did not improve efficacy in patients with intermediate-/poor-risk disease but led to fewer grade 3/4 TRAEs versus TKI.

Functional pri-miR-34b/c rs4938723 and KRAS 3'UTR rs61764370 SNPs: Novel phenotype modifiers in Li-Fraumeni Syndrome?

PURPOSE: Li-Fraumeni Syndrome (LFS) is a rare cancer predisposing condition caused by germline pathogenic TP53 variants, in which core tumors comprise sarcomas, breast, brain and adrenocortical neoplasms. Clinical manifestations are highly variable in carriers of the Brazilian germline founder variant TP53 p.R337H, possibly due to the influence of modifier genes such as miRNA genes involved in the regulation of the p53 pathway. Herein, we investigated the potential phenotypic effects of two miRNA-related functional SNPs, pri-miR-34b/c rs4938723 and 3'UTR KRAS rs61764370, in a cohort of 273 LFS patients from Southern and Southeastern Brazil. METHODS: The genotyping of selected SNPs was performed by TaqMan® allelic discrimination and subsequently custom TaqMan® genotyping results were confirmed by Sanger sequencing in all SNP-positive LFS patients. RESULTS: Although the KRAS SNP showed no effect as a phenotype modulator, the rs4938723 CC genotype was significantly associated with development of LFS non-core tumors (first tumor diagnosis) in p.R337H carriers (p = 0.039). Non-core tumors were also more frequently diagnosed in carriers of germline TP53 DNA binding domain variants harboring the rs4938723 C variant allele. Previous studies described pri-miR-34b/c rs4938723 C as a risk allele for sporadic occurrence of thyroid and prostate cancers (non-core tumors of the LFS spectrum). CONCLUSION: With this study, we presented additional evidence about the importance of analyzing miRNA genes that could indirectly regulate p53 expression, and, therefore, may modulate the LFS phenotype, such as those of the miR-34 family.

Characterization of genetic predisposition to molecular subtypes of breast cancer in Brazilian patients.

Introduction: BRCA1 and BRCA2 germline pathogenic variants (GPVs) account for most of the 5-10% of breast cancer (BC) that is attributable to inherited genetic variants. BRCA1 GPVs are associated with the triple negative subtype, whereas BRCA2 GPVs are likely to result in higher grade, estrogen-receptor positive BCs. The contribution of other genes of high and moderate risk for BC has not been well defined and risk estimates to specific BC subtypes is lacking, especially for an admixed population like Brazilian. Objective: The aim of this study is to evaluate the value of a multigene panel in detecting germline mutations in cancer-predisposing genes for Brazilian BC patients and its relation with molecular subtypes and the predominant molecular ancestry. Patients and methods: A total of 321 unrelated BC patients who fulfilled NCCN criteria for BRCA1/2 testing between 2016-2018 were investigated with a 94-genes panel. Molecular subtypes were retrieved from medical records and ancestry-specific variants were obtained from off-target reads obtained from the sequencing data. Results: We detected 83 GPVs in 81 patients (positivity rate of 25.2%). Among GPVs, 47% (39/83) were identified in high-risk BC genes (BRCA1/2, PALB2 and TP53) and 18% (15/83) in moderate-penetrance genes (ATM, CHEK2 and RAD51C). The remainder of the GPVs (35% - 29/83), were identified in lower-risk genes. As for the molecular subtypes, triple negative BC had a mutation frequency of 31.6% (25/79), with predominance in BRCA1 (12.6%; 10/79). Among the luminal subtypes, except Luminal B HER2-positive, 18.7% (29/155) had GPV with BRCA1/2 genes contributing 7.1% (11/155) and non-BRCA1/2 genes, 12.9% (20/155). For Luminal B HER2-positive subtype, 40% (16/40) had GPVs, with a predominance of ATM gene (15% - 6/40) and BRCA2 with only 2.5% (1/40). Finally, HER2-enriched subtype presented a mutation rate of 30.8% (4/13) with contribution of BRCA2 of 7.5% (1/13) and non-BRCA1/2 of 23% (3/13). Variants of uncertain significance (VUS) were identified in 77.6% (249/321) of the patients and the number of VUS was increased in patients with Asian and Native American ancestry. Conclusion: The multigene panel contributed to identify GPVs in genes other than BRCA1/2, increasing the positivity of the genetic test from 9.6% (BRCA1/2) to 25.2% and, considering only the most clinically relevant BC predisposing genes, to 16.2%. These results indicate that women with clinical criteria for hereditary BC may benefit from a multigene panel testing, as it allows identifying GPVs in genes that directly impact the clinical management of these patients and family members.

Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy.

Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from the serosal surface of the abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within three years. The dismal survival makes DSRCT an orphan disease with an urgent need for new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors was evaluated by small trials. Recent studies using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.

Neoadjuvant hypofractionated radiotherapy and chemotherapy for extremity soft tissue sarcomas: Safety, feasibility, and early oncologic outcomes of a phase 2 trial.

BACKGROUND AND PURPOSE: Optimal treatment of extremity soft tissue sarcomas (ESTS) is controversial. The aim of this study was to evaluate neoadjuvant chemotherapy (ChT) plus concomitant hypofractionated RT (hypo-RT) in local and distant disease relapse. Here we report safety, feasibility and early outcomes. MATERIALS AND METHODS: This was a prospective, single arm study with a goal accrual of 70 patients. Between 2015 and 2018, 18 patients with histologically confirmed nonmetastatic ESTS were assigned to receive doxorubicin and ifosfamide for three neoadjuvant cycles, concomitant with hypo-RT (25 Gy in 5 fractions) followed by surgery. The primary endpoint was disease-free survival (DFS). Secondary outcomes were pathologic response, wound complications (WC), and morbidity rates. RESULTS: Median follow-up was 29 months. At last follow-up, 13/18 patients were alive without evidence of local or systemic disease (DFS 72%), 1 had died due to metastatic disease, and 3 were alive with distant metastasis. One patient presented with local relapse within the irradiated field. Mean DFS time was 48.6 months (95% CI: 37.3-59.9). Six patients (33%) had no residual viable tumor detected in pathologic specimens (3 of these myxoid liposarcomas). There was a significant difference in WC among patients with acute RT skin toxicity. Six patients (33%) developed major WC. No grade 3 or 4 ChT adverse events were reported. CONCLUSION: Despite the limited sample size, these early outcomes demonstrate that this treatment regimen is feasible and well tolerated with high rates of limb preservation, local control, and pathologic complete response, supporting further investigation in a multi-institutional setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02812654; https://clinicaltrials.gov/ct2/show/NCT02812654.

Inherited lung cancer: a review.

Lung cancer is the most common cancer worldwide and has high rates of mortality. The major risk factor associated with this disease is tobacco smoke, but approximately 10%-25% of all lung cancer cases occur in patients who have never smoked. Data suggest that lung cancer in never-smokers has a different molecular profile, tumour microenvironment and epidemiology than that in smokers. Several risk factors have been associated with its occurrence, and the possibility of inherited predisposition is becoming clearer. A better understanding of this disease is essential for the future development of personalised screening, diagnosis and treatment approaches, with consequent reduction of mortality. In this review, we discuss historical studies of lung cancer in never-smokers and the currently available evidence of inherited predisposition to this disease.

Clinical Characteristics, Management, and Outcomes of 19 Nonpediatric Patients with Desmoplastic Small Round Cell Tumor: A Cohort of Brazilian Patients.

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive mesenchymal malignancy, usually affecting young males. There is no consensus on the best therapeutic approach. We seek to characterize a cohort of nonpediatric patients with DSRCT treated at a large Brazilian cancer center. We performed a retrospective analysis of patients with histologically confirmed DSRCT referred to our institution (2007-2020). Clinical and imaging data were extracted and summarized with descriptive statistics. Survival analyses were conducted by the Kaplan-Meier method and compared with the log-rank test. We included 19 patients with DSRCT, the median age at diagnosis was 26 years (range: 15-41 years), and 68% were male. Ninety percent presented with abdominopelvic masses, and 32% had extra-abdominal metastasis at diagnosis. Eleven patients (58%) underwent surgery, four patients (21%) received whole abdominal adjuvant radiotherapy, and five patients (26%) had hyperthermic intraperitoneal chemotherapy. Median OS was 27 months (interquartile range: 18-51 m). The five-year OS rate was 12%. Our data confirm the aggressiveness of DSRCT despite intense multimodality treatment. Outcomes of patients treated in a reference cancer center in a developing country are similar to cancer centers in developed nations. Multicenter cooperation is urgent to the development of clinical trials and to improve diagnosis and treatment efficacy.

Clinical and Molecular Assessment of Patients with Lynch Syndrome and Sarcomas Underpinning the Association with MSH2 Germline Pathogenic Variants.

Lynch syndrome (LS) is a hereditary cancer-predisposing syndrome associated most frequently with epithelial tumors, particularly colorectal (CRC) and endometrial carcinomas (EC). The aim of this study was to investigate the relationship between sarcomas and LS by performing clinical and molecular characterization of patients presenting co-occurrence of sarcomas and tumors from the LS spectrum. We identified 27 patients diagnosed with CRC, EC, and other LS-associated tumors who had sarcomas in the same individuals or families. Germline genetic testing, mismatch repair (MMR) protein immunohistochemistry, microsatellite instability (MSI), and other molecular analyses were performed. Five LS patients presenting personal or family history of sarcomas were identified (3 MSH2 carriers and 2 MLH1), with 2 having Muir-Torre phenotypes. For two MSH2 carriers we confirmed the etiology of the sarcomas (one liposarcoma and two osteosarcomas) as LS-related, since the tumors were MSH2/MSH6-deficient, MSI-high, or presented a truncated MSH2 transcript. Additionally, we reviewed 43 previous reports of sarcomas in patients with LS, which revealed a high frequency (58%) of MSH2 alterations. In summary, sarcomas represent a rare clinical manifestation in patients with LS, especially in MSH2 carriers, and the analysis of tumor biological characteristics can be useful for definition of tumor etiology and novel therapeutic options.

XAF1 as a modifier of p53 function and cancer susceptibility.

Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.

Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance.

OBJECTIVE: Paraganglioma (PGL) and pheochromocytoma (PCC) are rare neuroendocrine tumors that were considered to be predominantly sporadic. However, with the identification of novel susceptibility genes over the last decade, it is currently estimated that up to 40% of cases can occur in the context of a hereditary syndrome. We aimed to characterize PGL/PCC families to exemplify the different scenarios in which hereditary syndromes can be suspected and to emphasize the importance for patients and their families of making an opportune genetic diagnosis. MATERIALS AND METHODS: Retrospective analysis of patients diagnosed with PGL/PCC. Germline mutations were studied using next-generation sequencing panels including SDHA, SDHB, SDHC and SDHD. Clinical data were collected from clinical records, and all patients received genetic counseling. RESULTS: We describe 4 families with PGL/PCC and germline mutations in SDH complex genes. 2 families have SDHB mutations and 2 SDHD mutations. The clinical presentation of the patients and their families was heterogeneous, with some being atypical according to the literature. CONCLUSIONS: PGL/PCC are more commonly associated with a germline mutation than any other cancer type, therefore, all individuals with these types of tumors should undergo genetic risk evaluation. NGS multigene panel testing is a cost-effective approach given the overlapping phenotypes. Individuals with germline mutations associated with PGL/PCC should undergo lifelong clinical, biochemical and imaging surveillance and their families should undergo genetic counseling. For all these reasons, it is critical that all medical staff can suspect and diagnose these inherited cancer predisposition syndromes.

The efficacy of everolimus and sunitinib in patients with sporadic or germline mutated metastatic pancreatic neuroendocrine tumors.

BACKGROUND: Hyperactivation of mTOR pathway and angiogenesis have been implicated in the pathogenesis of neuroendocrine tumors (NETs). Everolimus, an oral inhibitor of mTOR, and sunitinib, an antiangiogenic drug, are effective targeted therapies approved to treat locally advanced/metastatic pancreatic neuroendocrine tumors (pNETs). Most pNETs are sporadic and mutations in genes involved directly or indirectly in mTOR pathway regulation have been implicated, including somatic mutation in MEN1 in 44% of cases. About 10% of pNETs can be part of hereditary syndromes, e.g., multiple endocrine neoplasia type 1 (MEN1) and Von-Hippel Lindau (VHL), and these patients are underrepresented in pivotal phase III trials. We hypothesized that everolimus would be particularly effective in patients with MEN1-associated pNETs. Likewise, we inferred that sunitinib would also be beneficial to patients with VHL-associated pNETs. METHODS: We conducted a multicenter retrospective and comparative study to assess the efficacy of everolimus and/or sunitinib in a cohort of patients with advanced pNETs with or without known MEN1 or VHL syndrome. The evaluation of the germline mutational status of VHL and MEN1 genes was retrospectively collected from the medical records. The primary endpoints were progression free survival (PFS) and time to treatment failure (TTF) of patients who received at least one month of sunitinib or everolimus in monotherapy. RESULTS: Thirty-three patients were identified from September 2009 to April 2018. Most were male 60.6%. Median Ki67 was 9%, liver metastases were present in 97%. The majority of tumors were non-functioning. Thirty-one patients received everolimus, of them 8 patients had germline mutations (6 in MEN1 and 2 in VHL genes). Nine patients received sunitinib, of them 3 had germline mutation (2 in MEN1 and 1 in VHL genes). In a median follow up of 26 months, among everolimus-treated patients, mTTF and mPFS were numerically superior in patients with germline mutations compared with those with sporadic pNETs (mTTF: 16.1 vs. 9.9 months, P=0.888; mPFS: 33.1 vs. 12.3 months, P=0.383). The disease control rate with everolimus was numerically higher in favor of germline mutated tumors compared to sporadic ones (87.5% vs. 68.4%). Sunitinib was used by 1 patient with VHL syndrome, achieving a PFS of 17.6 months. In the subgroup of sporadic pNETs, sunitinib was used by 6 patients reaching a mPFS of 18 months (range, 5-25 months), predominantly in second line. CONCLUSIONS: Our study suggests that everolimus may offer a prolonged tumor control in pNETS with germline mutations (MEN1 or VHL) compared to sporadic ones. The small number of patients and the retrospective nature of this study precludes any definitive conclusions.

Complete metastasectomy in renal cell carcinoma: a propensity-score matched by the International Metastatic RCC Database Consortium prognostic model.

INTRODUCTION: We evaluated overall survival (OS) benefit of complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) using a propensity score-matched (PSM) analysis to balance groups by age, gender and by the International Metastatic RCC Database Consortium prognostic model (IMDC). METHODS: We included patients (pts) treated at the AC Camargo Cancer Center between 2007 and 2016. Pairs were matched by age, gender and IMDC. Kaplan-Meier survival estimates and Cox proportional hazard models were used to evaluate OS on CM and no-CM group. RESULTS: We found 116 pts with clear cell mRCC. After PSM, the number was reduced to 74 (37 CM, 37 no-CM). The median OS for CM and no-CM was 98.3 months and 40.5 months, respectively (hazard ratio 0.24 95%CI 0.11-0.53 p < 0.001). The OS benefit of CM was confirmed on favourable and intermediate IMDC but was absent on poor IMDC. The CM group received less systemic therapy than the no-CM group. Ten pts in the CM group still have no evidence of disease (NED). CONCLUSION: After matching for age, gender and IMDC, we found CM impacts on OS and also diminishes the need for systemic treatment. Survival benefit was confirmed for favourable/intermediate IMDC but not for the poor IMDC prognostic model. Further studies correlating IMDC and metastasectomy are needed to guide clinical decision-making.

Expanding morphological and clinical aspects of hereditary leiomyomatosis and renal cell carcinoma (HLRCC): a case report in a patient with unusual morphology and clinical presentation.

Renal cell carcinoma (RCC) accounts for 2-3% of all malignant disease in adults. Hereditary RCC represents 5 to 8% of kidney tumors. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) represents an autosomal dominant syndrome that results from a germline mutation in fumarate hydratase gene (FH). HLRCC patients typically present with skin or uterine leiomyomas and renal neoplasms. HLRCC was recently recognized as a distinct renal tumor subtype by the WHO 2016 classification. Many morphological patterns such as papillary, solid, tubular, and cystic had been described as part of morphological aspects of HLRCC. In this study, we describe a case of a patient that had a history of persistence of ductus arteriosus (PDA) and cryptorchidism. In addition, the renal tumor showed a very unusual hystiocytoid morphological aspect. We confirmed the presence of a FH germline mutation both in the patient and his mother.