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Li-Fraumeni syndrome is caused by heterozygous germline pathogenic variants in the TP53 gene. It involves a high risk of a variety of malignant tumors in childhood and adulthood, the main ones being premenopausal breast cancer, soft tissue sarcomas and osteosarcomas, central nervous system tumors, and adrenocortical carcinomas. The variability of the associated clinical manifestations, which do not always fit the classic criteria of Li-Fraumeni syndrome, has led the concept of SLF to extend to a more overarching cancer predisposition syndrome, termed hereditable TP53-related cancer syndrome (hTP53rc). However, prospective studies are needed to assess genotype–phenotype characteristics, as well as to evaluate and validate risk-adjusted recommendations. This guideline aims to establish the basis for interpreting pathogenic variants in the TP53 gene and provide recommendations for effective screening and prevention of associated cancers in carrier individuals. [ABSTRACT FROM AUTHOR]

Introduction: Molecular-matched therapies have revolutionized cancer treatment. We evaluated the improvement in clinical outcomes of applying an in-house customized Next Generation Sequencing panel in a single institution.Methods: Patients with advanced solid tumors were molecularly selected to receive a molecular-matched treatment into early phase clinical trials versus best investigators choice, according to the evaluation of a multidisciplinary molecular tumor board. The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1).Results: Of a total of 231 molecularly screened patients, 87 were eligible for analysis. Patients who received matched therapy had a higher median PFS2 (6.47 months; 95% CI, 2.24-14.43) compared to those who received standard therapy (2.76 months; 95% CI, 2.14-3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008).Discussion: We demonstrate the pivotal role of the institutional molecular tumor board in evaluating the results of a customized NGS panel. This process optimizes the selection of available therapies, improving disease control. Prospective randomized trials are needed to confirm this approach and open the door to expanded drug access. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this multicenter study was to evaluate the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) who received sunitinib retreatment.Methods: Clinical data from patients treated with sunitinib rechallenge in nine Spanish centers were retrospectively analyzed. All patients received first-line sunitinib until progression or intolerance, followed by one or more successive drugs and rechallenge with sunitinib thereafter.Results: Thirty-seven patients were included. At first-line treatment, objective response rate (ORR) was 69.4% and median progression-free survival (PFS) was 19.4 months. At rechallenge, ORR was 27.2% and 39.4% of patients obtained stabilization of disease. Median PFS was 6.2 months. Clinical benefit was obtained by 21 patients (75%) with > 6-month interval between sunitinib treatments and by 1 patient (20%) among those with ≤ 6-month interval (P = 0.016). Hemoglobin levels ≥ lower level of normal were associated with clinical benefit (P = 0.019) and with PFS (P = 0.004). Median overall survival from start of first-line sunitinib was 52.7 months. No new adverse events were observed at rechallenge.Conclusions: Sunitinib rechallenge is a feasible treatment option for selected patients with mRCC. [ABSTRACT FROM AUTHOR]

Male breast cancer (MBC) is a rare disease that represents <1 % of all breast cancers (BCs). We analyze the results of a multicenter study performed in Spanish familial MBC including family history of hereditary breast and ovarian cancer syndrome (HBOCS) and clinicopathological features. We also study the relationship between BRCA1/ BRCA2 mutational status in male relatives affected with cancer (MAC) and, family history and tumor types. The study included 312 men index cases with family history of HBOCS and 61 MAC BRCA1/ 2 mutation-carriers. Family history, histological grade (HG), clinicopathological and immunohistochemistry data were collected. BRCA1/ 2 mutation analyses were performed by direct sequencing or screening methods and the large rearrangements by multiplex ligation dependent probe amplification. We found 49 mutation-carriers (15.7 %), 95.9 % with BRCA2 mutations. BRCA2 mutation-carriers were associated with families with at least one MBC and one BC in female (type II; p = 0.05). Strong association were found between the presence of pathogenic mutations in MBCs and the advanced HG ( p = 0.003). c.658_659delTG, c.2808_2811delACAA, c.6275_6276delTT and c.9026_9030delATCAT were the most prevalent mutations. In 61 MAC we found 20 mutations in BRCA1 and 41 in BRCA2. For MAC we show that mutational status was differentially associated with family history ( p = 0.018) and tumor type, being BRCA2 mutations linked with BC and prostatic cancer ( p = 0.018). MBC caused by BRCA1/ 2 mutations define two types of MBCs. The most frequent caused by BRCA2 mutation linked to type II families and the rarest one attributed to BRCA1 mutation. Tumor associated with MAC suggest that only BRCA2 mutations have to do with a specific type of cancer (BC and prostatic cancer); but the linkage to tumors is questionable for BRCA1 mutations . [ABSTRACT FROM AUTHOR]

Early-onset diagnosis is an eligibility criterion for BRCA1 and BRCA2 ( BRCA) testing in sporadic breast cancer patients. Limited family structure has been proposed as a predictor of BRCA mutation status in this group of patients. An overwhelming amount of data supports a strong association between BRCA1 mutations and triple-negative breast cancer (TNBC). Here, we analyze the feasibility of using limited family structure and TNBC as predictors of BRCA mutation status in early-onset breast cancer patients attending genetic counseling units. We have conducted the study in a cohort of sporadic early-onset (≤35 years) breast cancer patients ( N = 341) previously selected for BRCA genetic testing in Academic Hereditary Cancer Clinics from Spain. A retrospective review of medical records available at the time of risk assessment allowed us classifying patients according to family structure and TNBC. In addition, BRCAPRO score was calculated for all patients. Association between categorical variables was investigated using the Fisher's exact test. Binary Logistic Regression Analysis was used for multivariate analysis. Limited family structure (OR 3.61, p = 0.013) and TNBC (OR 3.14, p = 0.013) were independent predictors of BRCA mutation status. Mutation prevalence in the subgroup of patients with at least one positive predictor was 14 %, whereas it dropped to 3 % in non-TNBCs with adequate family history (OR 5.31, 95 % CI 1.38-23.89, p = 0.006). BRCAPRO correctly discerned between limited and adequate family structures. Limited family structure and TNBC are feasible predictors of BRCA mutation status in sporadic early-onset (≤35 years) breast cancer patients attending genetic counseling units. The low prevalence of mutations observed in non-TNBCs with adequate family structure suggests that this subgroup of patients might be excluded from genetic testing. [ABSTRACT FROM AUTHOR]

We recently described a novel g.8097_22733del14637 deletion encompassing exons 3-5 in BRCA1 gene. This rearrangement was detected in 3 of 15 (20 %) breast and/or ovarian cancer families of Eastern Spain. This finding made us suspect that the newly identified deletion could be a founder mutation. To confirm this hypothesis we studied 18 subjects belonging to the three families under study, 11 deletion carriers and 7 non-carriers. We performed a haplotype analysis using two BRCA1 intragenic microsatellite markers and two markers surrounding the BRCA1 locus. The segregation analysis showed one common particular haplotype established by D17S1325, D17S1323, D17S855 and D17S1320 markers detected in the deletion carriers but absent in the non-carriers. Our study sustain that the deletion of exons 3-5 of BRCA1, g.8097_22733del14637, identified in families of southeastern of the Valencian Community is the first founder rearrangement until now reported in Spanish population, confirming the hypothesis that this mutation could have Iberian ancestry. [ABSTRACT FROM AUTHOR]

The approval and use of molecular targeted agents for the first-line treatment of metastatic renal cell carcinoma (mRCC) has substantially improved the clinical outcome of patients. Although eventually all patients progress, hopes have been renewed with the approval of everolimus for patients who progress on or after treatment with tyrosine kinase inhibitors. In order to improve the prognosis for these patients, it is imperative to understand the reasons why patients with mRCC fail on first-line treatment. Currently, progression is assessed on the basis of the Response Evaluation Criteria in Solid Tumors, but it is known that targeted agents tend to cause disease stabilization rather than a significant decrease in tumor mass. Therefore, it may be time to evaluate the need to incorporate additional diagnostic methods in the assessment of disease response. Equally important is the study of the factors that determine the success or failure of second-line therapy in order to increase the chances of delivering the most effective and personalized therapy possible. In this article, we review the evidence related to the evaluation of patients with mRCC who fail on first-line treatment with targeted agents, including the systems to assess response and progression, the prognostic factors, the prognostic models that have been created based on these factors, and what is known about predictive biomarkers of disease outcome. [ABSTRACT FROM AUTHOR]

It has been demonstrated that monoallelic PALB2 (Partner and Localizer of BRCA2) gene mutations predispose to familial breast cancer. Some of the families reported with germline PALB2 mutations presented male breast cancer as a characteristic clinical feature. Therefore, we wanted to investigate the contribution of germline PALB2 mutations in a set of 131 Spanish BRCA1/BRCA2-negative breast/ovarian cancer families with at least one male breast cancer case. The analysis included direct sequencing of all coding exons and intron/exon boundaries as well as a Multiplex Ligation-dependent Probe Amplification-based analysis of genomic rearrangements. For the first time we have identified a genomic rearrangement of PALB2 gene involving a large deletion from exon 7 to 11 in a breast cancer family. We have also identified several PALB2 variants, but no other obvious deleterious PALB2 mutation has been found. Thus, our study does not support an enrichment of PALB2 germline mutations in the subset of breast cancer families with male breast cancer cases. The identification of intronic and exonic variants indicates the necessity of assessing the implications of variants that do not lead to PALB2 truncation in the pathoghenicity of the PALB2 gene. [ABSTRACT FROM AUTHOR]

Adjuvant chemotherapy prolongs survival in patients with breast cancer, but it also causes side effects such as ovarian-function suppression. The incidence of chemotherapy-induced amenorrhea (CIA) varies depending on the patients’ age, dose and the type of chemotherapy that they receive. CIA produced by anthracycline-based regimens has been widely studied, but less is known about the incidence of CIA caused by the combined use of taxanes and anthracyclines. It has been suggested that tamoxifen might influence the maintenance of amenorrhea. However, most studies of CIA have explored series of patients with hormone-sensitive and hormone-resistant tumors, so data about CIA could be strongly influenced by endocrine adjuvant therapy. The aims of our study were to assess the incidence of CIA with the addition of taxanes to anthracyclines regimens in pre- or perimenopausal patients diagnosed with hormone-sensitive breast cancer and to determine predictive factors for CIA. A retrospective non-randomized study was conducted in the Hospital Clinico Universitario of Valencia, Spain. Three hundred and five premenopausal and perimenopausal patients were recruited between January 1998 and May 2005, 212 of whom had been treated with anthracycline-based regimens and 93 with a combination of anthracyclines and taxanes. Amenorrhea was permanent in 222 patients (93.7%) and menses returned in 6.3%. CIA was present in 75.5% of patients treated with anthracyclines and in 82.7% of patients treated with anthracyclines and taxanes. This difference did not reach statistical significance ( p = 0.16). CIA appeared in 95% of patients older than 45 years, while the proportion of CIA decreased to 52% in patients younger than 40 years. This suggests age as an important predictive factor for CIA ( p < 0.001). Although a slightly superior incidence of CIA in patients with hormone-sensitive tumors treated with combination regimens was observed, no statistically significant difference in incidence was found. Age was found to be the main predictive factor for CIA in both groups. [ABSTRACT FROM AUTHOR]

Environmental or lifestyle factors are likely to explain part of the heterogeneity in breast and ovarian cancer risk among BRCA1 and BRCA2 mutation carriers. We assessed parity as a risk modifier in 515 and 503 Spanish female carriers of mutations in BRCA1 and BRCA2, respectively. Hazard ratios (HR) and their corresponding 95% confidence intervals (CI) were estimated using weighted Cox proportional hazards regression, adjusted for year of birth and study centre. The results for ever being parous and number of live-births were very similar for carriers of mutations in both genes. For all mutation carriers combined, the estimated HR associated with ever having had a live-birth was 0.74 (95% confidence interval [CI] = 0.55–1.01, P = 0.06), and that associated with each live-birth was 0.87 (95%CI = 0.77–0.98, P = 0.02). The latter association was observed only in women aged 40 and above (HR = 0.81, 95%CI = 0.70–0.94, P = 0.004 vs. HR = 0.99, 95%CI = 0.83–1.18, P = 0.9 for women under age 40), and this trend was highly consistently observed for carriers of mutations in each gene. There was no evidence of an association between breast cancer risk and age at first birth for parous BRCA1 or BRCA2 mutation carriers ( P-trend ≥ 0.3). The power to detect associations with ovarian cancer risk was much lower, especially for BRCA2 mutation carriers. Nevertheless, having a live-birth was associated with protection for BRCA1 mutation carriers (HR = 0.41, 95%CI = 0.18–0.94, P = 0.03), and a strong and consistent protective effect of age at first birth was observed for parous carriers of mutations in both genes (HR = 0.65, 95%CI = 0.52–0.83, P < 0.001). This is the third independent study to find that, as in the general population, parity appears to be associated with protection from breast cancer in women with mutations in BRCA1 and BRCA2. Parity appears to be protective for ovarian cancer in BRCA1 mutation carriers, but its role in BRCA2 mutation carriers remains unclear. Whether later age at first birth is also protective for ovarian cancer in mutation carriers requires further confirmation. [ABSTRACT FROM AUTHOR]

To evaluate the dose–response effect of an adjuvant anthracycline-based non-taxane chemotherapy in early breast cancer patients. This was a retrospective database analysis. Selection criteria included patients treated for early breast cancer from years 1980 to 2000 with an adjuvant anthracycline-based non-taxane chemotherapy. The delivery of chemotherapy was assessed through the number of delayed cycles, the number of delayed days and the relative dose intensity (RDI) administered (≥85%, <85%). Seven hundred and ninety-three breast cancer patients were included. The Kaplan–Meier disease-free survival (DFS) was affected by the number of delayed cycles ( P < 0.0001), the number of delayed days ( P < 0.0001) and the RDI ( P = 0.0029). The Kaplan–Meier overall survival (OS) was also affected by the number of delayed cycles ( P = 0.0008) and days ( P = 0.0115), as well as the RDI ( P = 0.0055). The Cox regression models showed that, when the number of nodes affected and the hormonal receptor status were controlled, all the study variables maintained their significance on DFS, but not on OS. The dose–response effect is a crucial factor in the administration of anthracycline-based non-taxane schedules for the adjuvant treatment of early breast cancer. Delays and/or reductions of chemotherapy should be avoided if possible to achieve the maximal benefit. [ABSTRACT FROM AUTHOR]

Randomised clinical trials with a control arm of non-screened patients are nowadays ethically impossible. The aim of this study was to establish the impact of mammography screening on a non-selected population. Between January 1993 and December 2002, 3662 patients were included, 2313 in the screened group and 1349 in the unscreened group. 55.3% of the screened patients were diagnosed in stage I vs. 26.1% in the non-screened group. The proportion of stage III–IV was 4.6% and 19.8% for the screened and unscreened groups respectively ( p<0.001). 48.8% in the screening group were submitted to mastectomy vs. 66.4% of the unscreened patients ( p<0.001). Overall survival was superior for the prevalent cases in the screening group, with a relative risk of 0.49, and was not significant for the incident cases. Diagnosis of breast cancer in the mammography screening programme of the Region of Valencia significantly increases conservative surgery rates and suggests an improvement in survival in prevalent cases. The increased rate of early stages in these patients could be the main reason of this benefit. [ABSTRACT FROM AUTHOR]