Only 32.3% of Breast Cancer Families with Pathogenic Variants in Cancer Genes Utilized Cascade Genetic Testing.

BACKGROUND: Hereditary cancer predisposition syndromes are responsible for approximately 5-10% of all diagnosed cancer cases. In order to identify individuals at risk in a cost-efficient manner, family members of individuals carrying pathogenic alterations are tested only for the specific variant that was identified in their carrier relative. The purpose of this study was to investigate the clinical use and implementation of cascade family testing (CFT) in families of breast cancer patients with pathogenic/likely pathogenic variants (PVs/LPVs) in cancer-related predisposition genes. METHODS: Germline sequencing was carried out with NGS technology using a 52-gene panel, and cascade testing was performed by Sanger sequencing or MLPA. RESULTS: In a cohort of 1785 breast cancer patients (families), 20.3% were found to have PVs/LPVs. Specifically, 52.2%, 25.1%, and 22.7% of patients had positive findings in high-, intermediate-, and low-penetrance breast cancer susceptibility genes, respectively. Although CFT was recommended to all families, only 117 families (32.3%) agreed to proceed with genetic testing. Among the first-degree relatives who underwent CFT, 70.3% were female, and 108 of 121 (89.3%) were cancer free. Additionally, 42.7%, 36.7%, and 20.6% were offspring, siblings, and parents of the subject, respectively. Our data suggest that CFT was mostly undertaken (104/117, 88.8%) in families with positive findings in high-risk genes. CONCLUSIONS: Cascade family testing can be a powerful tool for primary cancer prevention by identifying at-risk family members. It is of utmost importance to implement genetic counseling approaches leading to increased awareness and communication of genetic testing results.

RediScore: Prospective validation of a pipeline for homologous recombination deficiency analysis.

Tumors harboring homologous recombination deficiency (HRD) are considered optimal candidates for poly(ADP-ribose) polymerase 1 (PARP) inhibitor treatment. Such deficiency can be detected by analyzing breast cancer type (BRCA)1/2 gene mutations, as well as mutations in other genes of the homologous recombination pathway. The algorithmic measurement of the HRD effect by identifying genomic instability (GI) has been used as biomarker. As compared with the direct measurement of somatic gene alterations, this approach increases the number of patients who could benefit from PARP inhibitor treatment. In the present study, the performance of the Oncoscan CNV assay, accompanied by appropriate bioinformatic algorithms, was evaluated for its performance in GI calculation and was compared with that of a validated next-generation sequencing (NGS) test (myChoice HRD test). In addition, the clinical utility of the GI score (GIS) and BRCA1/2 tumor analysis were investigated in a cohort of 444 patients with ovarian cancer. For that reason, single nucleotide polymorphism (SNP) arrays and appropriate bioinformatics algorithms were used to calculate GIS in 29 patients with ovarian cancer with known GIS status using a validated NGS test. Furthermore, BRCA1/2 analysis results were compared between the aforementioned assay and the amplicon-based Oncomine™ BRCA Research Assay. BRCA1/2 analysis was performed in 444 patients with ovarian cancer, while GIS was calculated in 175 BRCA1/2-negative cases. The bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis (RediScore), and the OncoscanR pipeline exhibited a high overall agreement with the validated test (93.1%). In addition, the Oncomine NGS assay had a 100% agreement with the validated test. The BRCA1/2 mutation frequency was 26.5% in the examined patients with ovarian cancer. GIS was positive in 40% of the BRCA1/2-negative cases. The RediScore bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis is a viable and effective approach for HRD calculation in patients with ovarian cancer, offering a positive prediction for PARP inhibitor responsiveness in 55% of the patients.

Copy Number Variations (CNVs) Account for 10.8% of Pathogenic Variants in Patients Referred for Hereditary Cancer Testing.

BACKGROUND/AIM: Germline copy number variation (CNV) is a type of genetic variant that predisposes significantly to inherited cancers. Today, next-generation sequencing (NGS) technologies have contributed to multi gene panel analysis in clinical practice. MATERIALS AND METHODS: A total of 2,163 patients were screened for cancer susceptibility, using a solution-based capture method. A panel of 52 genes was used for targeted NGS. The capture-based approach enables computational analysis of CNVs from NGS data. We studied the performance of the CNV module of the commercial software suite SeqPilot (JSI Medical Systems) and of the non-commercial tool panelcn.MOPS. Additionally, we tested the performance of digital multiplex ligation-dependent probe amplification (digitalMLPA). RESULTS: Pathogenic/likely pathogenic variants (P/LP) were identified in 464 samples (21.5%). CNV accounts for 10.8% (50/464) of pathogenic variants, referring to deletion/duplication of one or more exons of a gene. In patients with breast and ovarian cancer, CNVs accounted for 10.2% and 6.8% of pathogenic variants, respectively. In colorectal cancer patients, CNV accounted for 28.6% of pathogenic/likely pathogenic variants. CONCLUSION: In silico CNV detection tools provide a viable and cost-effective method to identify CNVs from NGS experiments. CNVs constitute a substantial percentage of P/LP variants, since they represent up to one of every ten P/LP findings identified by NGS multigene analysis; therefore, their evaluation is highly recommended to improve the diagnostic yield of hereditary cancer analysis.

Ribociclib and palbociclib-induced erythema multiforme: a case report.

Cyclin-dependent kinase 4/6 inhibitors (CKIs), ribociclib, palbocilb and abemaciclib, have been approved in combination with endocrine therapy for the treatment of hormone receptor-positive and human epidermal growth factor 2-negative advanced or metastatic breast cancer. Severe dermatological adverse events are rare with these agents; however, they require direct recognition and management in order not to become life-threatening. Erythema multiforme (EM) belongs to a dermatopathic spectrum that includes immune-mediated, widespread hypersensitivity reaction, which occurs with varying degrees of severity and affects the skin and/or the mucosa. We hereby present a case of ribociclib- and palbociclib-related EM. We sought to report this case given the implication of two agents from the same drug class in EM onset. We also aim to emphasize the breadth of mechanisms of actions of CKIs, with an impingement in the immune system as well, and the importance of promptly identifying and handling such skin toxicities.

Prognostic Significance of Low HER2 Expression in Patients With Metastatic Hormone Receptor-positive Breast Cancer Treated With First Line CDK4/6 Inhibitors: A Greek Multicenter Real-world Data Analysis.

BACKGROUND/AIM: Low expression of HER2 has defined a new "HER2-low" subgroup of breast cancer with distinct clinicopathological characteristics and both prognostic and predictive implications. The impact of low HER2 expression in metastatic hormone receptor-positive HER2-negative breast cancer treated with first-line CDK4/6 inhibitors has not been studied. Using real-world patient data, we aimed to identify prognostic differences in this patient population according to HER2 expression with immunohistochemistry. PATIENTS AND METHODS: We retrospectively analyzed 191 patients from 5 Oncology Department databases in Thessaloniki, Greece, with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK4/6 inhibitors in the first line, for whom detailed immunohistochemical HER2 data could be retrieved. RESULTS: Median progression-free survival was numerically different among the different HER2 subgroups (3.35 years for HER2 0 tumors, 2.18 years for HER2 +1 tumors, 1.74 years for HER2 +2/ISH-negative tumors), but this difference was not statistically significant (p=0.477). Median PFS was statistically significantly longer in patients without visceral metastases (5.45 years) compared to patients with visceral metastases (1.61 years) (p=0.017). Median PFS was also statistically significantly longer in patients taking an aromatase inhibitor (2.99 years) compared to patients taking fulvestrant (1.33 years) (p<0.0001). There were no statistically significant differences in the other subgroups examined. CONCLUSION: CDK4/6 inhibitors are equally effective as first-line treatment agents, regardless of the exact level of HER2 expression. Numerical differences, however, do exist among the different HER2 subgroups, and merit further evaluation in future studies to better study this phenomenon.

Treatment With Adjuvant Abemaciclib Plus Endocrine Therapy in Patients With High-risk Early Breast Cancer Who Received Neoadjuvant Chemotherapy: A Prespecified Analysis of the monarchE Randomized Clinical Trial.

Importance: Patients selected to receive neoadjuvant chemotherapy (NAC) are usually those at higher risk of relapse, and there is a need to find better therapeutic options for these patients. Objective: To determine the efficacy and safety outcomes for patients with hormone receptor (HR)-positive, ERBB2 (formerly HER2)-, high-risk early breast cancer enrolled in the randomized clinical trial monarchE who received NAC. Design, Setting, and Participants: The monarchE randomized clinical trial was a multicenter, phase 3, open-label study that evaluated adjuvant treatment with abemaciclib plus endocrine therapy (ET) compared with ET alone in patients with HR+, ERBB2-, and node-positive early breast cancer who were at high risk of recurrence. Patients were recruited between July 2017 and August 2019 from 603 sites in 38 countries. This subgroup analysis was performed with primary outcome data, with a cutoff date of July 8, 2020. Intervention: Enrolled patients were randomized (1:1) to receive standard of care ET for at least 5 years with or without treatment with abemaciclib (150 mg, twice daily) for 2 years (treatment period) or until criteria were met for discontinuation. Main Outcomes and Measures: Prior chemotherapy (NAC vs adjuvant vs none) was a stratification factor in monarchE, and and a prespecified exploratory analysis included outcomes in patients who received NAC. The data presented in this article are from the primary outcome analysis (395 invasive disease-free survival [IDFS] events; cutoff date, July 8, 2020; median follow-up 19 months [IQR, 15.6-23.9 months]). Invasive disease-free survival (the primary end point of monarchE) and distant relapse-free survival (DRFS) were evaluated using the Cox proportional hazard model and Kaplan-Meier method. Results: Of the 5637 patients (mean [SD] age, 49.9 [10.6] years; 2046 women [99.5%]; 462 Asian [22.8%], 54 Black [2.7%], and 1473 White participants [70.8%]) enrolled in monarchE, 2056 (37%) received treatment with NAC. In this subgroup, treatment with abemaciclib and ET demonstrated clinically meaningful benefit in IDFS (hazard ratio, 0.61; 95% CI, 0.47-0.80) and DRFS (hazard ratio, 0.61; 95% CI, 0.46-0.81), which corresponded with an absolute improvement of 6.6% in 2-year IDFS rates and 6.7% in 2-year DRFS rates. A consistent treatment benefit was observed across subgroups of pathological breast tumor size or number of positive lymph nodes at surgery. Conclusions and Relevance: In the randomized clinical trial monarchE, treatment with adjuvant abemaciclib combined with ET demonstrated a clinically meaningful improvement in IDFS and DRFS for patients with HR+, ERBB2-, node-positive, high-risk early breast cancer who received NAC before trial enrollment. Trial Registration: ClinicalTrials.gov Identifier: NCT03155997.

Prognostic Significance of Low HER2 Expression in Patients With Early Hormone Receptor Positive Breast Cancer.

BACKGROUND/AIM: A possible role of antibody-drug conjugates against tumors with low HER2-expression, leads to the emergence of a new "low-HER2" classification in breast cancer, encompassing tumors from the hormonal-receptor-positive and the triple-negative subgroups. There is a need for data (clinical trial data and real-world evidence) that will accurately describe this population, the risk of recurrence and the possible benefit of HER2 targeted therapies. PATIENTS AND METHODS: We retrospectively analyzed 949 patients from our Department databases, with hormonal receptor-positive and HER2-negative early breast cancer, for whom detailed data for immunohistochemical HER2-staining could be retrieved. RESULTS: HER2-low expression was detected in 66.6% of patients (472 IHC +1 and 160 IHC +2 and ISH-negative). Lobular, or mixed lobular and ductal cancers had a statistically significantly lower chance of being HER2-low when compared to pure infiltrative ductal carcinomas (53.1% vs. 69.3% respectively). HER2-low status was not prognostic for recurrence-free survival or response to neoadjuvant chemotherapy. There was a non-significant trend for increased risk of recurrence for HER2-low, compared to HER2-0, in patients with lobular or mixed lobular and ductal carcinomas (HR=2.192, 95% CI=0.819-5.912). CONCLUSION: Low expression of HER2 in hormonal receptor-positive early breast cancer does not affect prognosis but may lead to a shorter progression-free-survival in lobular and mixed ductal and lobular cancers. Despite optimal management, a large proportion of hormonal receptor-positive patients will relapse. Targeting HER2 in HER2-low cancers may offer a potential additional treatment strategy to improve survival of this group.

Ribociclib plus letrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer with no prior endocrine therapy: subgroup safety analysis from the phase 3b CompLEEment-1 trial.

BACKGROUND: The CDK4/6 inhibitor, ribociclib in combination with endocrine therapy significantly improved progression-free survival in the first line setting in post-menopausal patients with HR+/HER2- advanced breast cancer (ABC) in a pivotal phase 3, placebo-controlled trial (MONALEESA-2) and demonstrated superior overall survival in premenopausal patients with HR+/HER2- ABC (MONALEESA-7). The multinational, phase 3b, CompLEEment-1 trial, which assessed the safety and efficacy of ribociclib plus letrozole in a broader population of patients who have not received prior endocrine therapy for advanced disease, is the largest phase 3 clinical trial to date to evaluate the safety and efficacy of a CDK4/6 inhibitor. We report a subanalysis of data from patients (N = 339) enrolled in the central and south European countries of the SERCE (Southern Europe, RUC, Central Europe) cluster of CompLEEment-1. PATIENTS AND METHODS: Men and women of any menopausal status with HR+/HER2- ABC received once-daily oral ribociclib 600 mg (3-weeks on/1-week-off), plus letrozole 2.5 mg continuously. Men/premenopausal women also received a GnRH-agonist. The primary outcome was the number of patients with adverse events (AEs) over a timeframe of approximately 36 months. Time-to-progression, overall response rate, and clinical benefit rate were also measured. RESULTS: Safety results in the SERCE subgroup were consistent with those in the pivotal clinical trials of ribociclib in combination with endocrine therapy. Treatment-related AEs leading to dose adjustments/interruption occurred in 63.1% of patients but led to treatment discontinuation in only 10.6%. The most common treatment-related AEs of grade ≥ 3 were neutropenia and transaminase elevations. There were no fatal treatment-related events. CONCLUSIONS: These findings from the SERCE subgroup support the safety and manageable tolerability of ribociclib in a broad range of patients with HR+/HER2- ABC more representative of patients in real-world clinical practice.

Safety and Efficacy of RAD001 (Everolimus) Administered Upon Relapse During or After Adjuvant Treatment in Post-menopausal Women With Hormone Receptor Positive, HER2/neu Negative Locally Advanced or Metastatic Breast Cancer (CRAD001JGR08 "MELPOMENI" study).

BACKGROUND/AIM: This study aimed to provide real-world safety and effectiveness data of everolimus (EVE) plus exemestane (EXE) in estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced breast cancer (aBC). PATIENTS AND METHODS: This prospective observational study was conducted by 19 hospital-based oncologists in Greece. Eligible patients were treated with EVE+EXE in the first-line setting; EVE was initiated according to the approved label. RESULTS: Overall, 75 eligible patients (mean age: 66.9 years; visceral metastases: 49.3%; bone-only metastases: 37.3%) were included in the effectiveness analyses. Over a median (interquartile range) of 12.1 months (range=4.2-20.5 months) of EVE treatment, the median progression-free survival was 18.0 months and the overall response rate was 22.7%. Among patients that received ≥1 EVE dose (n=80), the incidence of EVE-related adverse events was 72.5% (serious: 55.0%); stomatitis (22.5%), fatigue (22.5%), pneumonitis (18.8%); and cough (18.8%) were the most common. CONCLUSION: In the routine care in Greece, EVE demonstrates clinical benefit and a predictable safety profile.

Revisiting the Implications of Positive Germline Testing Results Using Multi-gene Panels in Breast Cancer Patients.

BACKGROUND/AIM: The use of multi-gene panels for germline testing in breast cancer enables the estimation of cancer risk and guides risk-reducing management options. The aim of this study was to present data that demonstrate the different levels of actionability for multi-gene panels used in genetic testing of breast cancer patients and their family members. MATERIALS AND METHODS: We performed an analysis in our clinical database to identify breast cancer patients undergoing genetic testing. We reviewed positive results in respect of risk estimation and management, cascade family testing, secondary findings and information for treatment decision-making. RESULTS: A total of 415 positive test reports were identified with 57.1%, 18.1%, 10.8% and 13.5% of individuals having pathogenic/likely pathogenic variants in high, moderate, low and with insufficient evidence for breast cancer risk genes, respectively. Six point seven percent of individuals were double heterozygotes. CONCLUSION: Germline findings in 92% of individuals are linked to evidence-based treatment information and risk estimates for predisposition to breast and/or other cancer types. The use of germline findings for treatment decision making expands the indication of genetic testing to include individuals that could benefit from targeted treatments.

Cardiac safety of neoadjuvant chemotherapy with epirubicin and cyclophosphamide followed by docetaxel/pertuzumab/trastuzumab for HER2-positive breast cancer patients.

PURPOSE: Early-stage, HER2-positive breast cancer is increasingly treated with neoadjuvant chemotherapy (NAC). After the positive results of the Neosphere trial, the standard of care has been the combination of chemotherapy with two anti-HER2 agents, trastuzumab and pertuzumab. Many oncologists use the sequence of four cycles of anthracycline-containing regimen followed by four cycles of taxane with the two monoclonals. We report here the cardiac safety of four cycles of epirubicin with cyclophosphamide followed by four cycles of docetaxel with trastuzumab and pertuzumab, given at the neoadjuvant setting in early, HER2-positive breast cancer. METHODS: We retrospectively collected data from the medical records of patients treated at our clinic between 2014 and 2020. RESULTS: It total, 55 patients treated with the same regimen were identified. There were 20 estrogen receptor (ER)-negative and 35 ER-positive patients. Complete pathologic response was observed in 64.8% of the patients. After a median cardiac follow-up of 2.61 years, and a total of 283 echocardiograms, there was only one recorded asymptomatic Left Ventricular Ejection Fraction (LVEF) fall > 25% and no symptomatic left ventricular systolic dysfunction. LVEF consistently dropped during treatment, but the drop was not significant enough to necessitate treatment interruption, and improved during follow-up. CONCLUSION: Our data confirm the effectiveness and cardiac safety of the aforementioned neoadjuvant regimen.

Follow-up of tissue genomics in BRCA1/2 carriers who underwent prophylactic surgeries.

PURPOSE: The genomic status of non-malignant tissues from carriers of pathogenic germline BRCA1/2 (gBRCA1/2) variants may reveal information towards individualized prophylaxis. We performed spatiotemporal tissue genotype comparisons in a real-life cohort of gBRCA1/2 carriers of Greek origin, who underwent multiple risk-reducing/prophylactic surgeries at various time points. METHODS: Fifty-three women (median age 36 years) within cancer families were observed for up to 37.5 years; 43 were cancer carriers and 10 were healthy carriers. Histology review and genotyping were performed for 187 paraffin tissues (average: 3.5 per carrier) including 46 carcinomas (40 breast) and 141 non-malignant breast and gynecological samples. RESULTS: High allelic imbalance (AI) and somatic pathogenic TP53 variants were present in cancer carriers only (p values < 0.0001). High AI was associated with gBRCA1/2 indels (p < 0.0001) and gBRCA2 alterations (p = 0.0109). Somatic (pathogenic) variants were infrequently shared between non-malignant tissues and matched carcinomas. Aberrations of gBRCA1 variant heterozygosity were noticed in tissues from cancer carriers only (13/43, 30.2%). These pertained to classic LOH (neoplastic lesions in 9/43 carriers, 20.9%) and under-representation of the germline variants (5 samples, 4 non-malignant, all in the breast). Both aberrations coexisted in matched samples in one case. Over time, germline variant heterozygosity prevailed in non-malignant tissues; intra-carrier genomic alterations were aggravated (21.1%), ameliorated (26.3%) or remained stable. CONCLUSION: This real-life case study supports the need to address tissue genotypes from prophylactic surgeries in combination with polygenic scores towards personalized prophylaxis. To this end, knowing the traditionally classified pathogenic potential of a gBRCA1/2 variant may not be enough.

Clinical Utility of Functional RNA Analysis for the Reclassification of Splicing Gene Variants in Hereditary Cancer.

BACKGROUND: Classification of splicing variants (SVs) in genes associated with hereditary cancer is often challenging. The aim of this study was to investigate the occurrence of SVs in hereditary cancer genes and the clinical utility of RNA analysis. MATERIAL AND METHODS: 1518 individuals were tested for cancer predisposition, using a Next Generation Sequencing (NGS) panel of 36 genes. Splicing variant analysis was performed using RT-PCR and Sanger Sequencing. RESULTS: In total, 34 different SVs were identified, 53% of which were classified as pathogenic or likely pathogenic. The remaining 16 variants were initially classified as Variant of Uncertain Significance (VUS). RNA analysis was performed for 3 novel variants. CONCLUSION: The RNA analysis assisted in the reclassification of 20% of splicing variants from VUS to pathogenic. RNA analysis is essential in the case of uncharacterized splicing variants, for proper classification and personalized management of these patients.

Real-world experience of neoadjuvant chemotherapy for early breast cancer patients: an observational non-interventional study in Thessaloniki, Greece.

PURPOSE: Neoadjuvant chemotherapy has been increasingly used in early-stage breast cancer. The results of large randomized clinical trials suggest the need for the wider use of preoperative therapy as it can result in a more conservative surgery, and can guide physicians to a more individualized approach in the adjuvant setting. METHODS: We aimed to analyze the outcomes of 203 patients with early-stage breast cancer who had received neoadjuvant chemotherapy at our institutions. RESULTS AND CONCLUSION: Pathological complete responses (pCR) were obtained in 42.4% of all patients, with the highest percentage in hormonal receptor (HR)-negative and human epidermal growth factor receptor-2 (HER2)-positive cancers. Conversion of a clinically and/or cytologically node-positive to node-negative disease was achieved in 55.8% of patients. Patients who achieved a pCR had a significantly better outcome in terms of disease-free and distant disease-free survival. Patients with residual disease experienced a worse prognosis if they had HR-negative cancer compared to HR-positive patients for whom the use of adjuvant endocrine treatment likely led to better outcomes. These results are encouraging as they show that outcomes from large randomized clinical trials can be reproduced in the everyday clinical setting. Neoadjuvant chemotherapy may be the treatment of choice for HR-negative and/or HER2-positive early breast cancer patients. This may also be the case for the majority of HR-positive and HER2-negative patients with either locally advanced disease or disease extending to the axillary lymph nodes, as it may result in more conservative surgical interventions with fewer post-operative complications.

Highlighting the importance of multidisciplinary approach: A rare case of primary periurethral poorly differentiated carcinoma.

OBJECTIVE: Tumors in the periurethral area can be a rare clinical entity with many difficulties not only in the diagnosis, as well as in the treatment plan. Skene's gland adenocarcinoma accounts for less than 0.003% of all female urethral malignant neoplasms. CASE REPORT: This report describes an extremely rare case of woman with a poorly differentiated carcinoma arising from the periurethral glands. CONCLUSIONS: Reporting of such rare cases enhance the understanding of the biological behavior of such tumors and the best treatment plan as well. This case report highlights the need for multidisciplinary approach of such rare cases, the lack of experience for such cases and the fact that the optimal treatment plan is very critical for the best prognosis of these patients.

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

BACKGROUND: Hereditary cancer predisposition syndromes are responsible for approximately 5-10% of all diagnosed cancer cases. In the past, single-gene analysis of specific high risk genes was used for the determination of the genetic cause of cancer heritability in certain families. The application of Next Generation Sequencing (NGS) technology has facilitated multigene panel analysis and is widely used in clinical practice, for the identification of individuals with cancer predisposing gene variants. The purpose of this study was to investigate the extent and nature of variants in genes implicated in hereditary cancer predisposition in individuals referred for testing in our laboratory. METHODS: In total, 1197 individuals from Greece, Romania and Turkey were referred to our laboratory for genetic testing in the past 4 years. The majority of referrals included individuals with personal of family history of breast and/or ovarian cancer. The analysis of genes involved in hereditary cancer predisposition was performed using a NGS approach. Genomic DNA was enriched for targeted regions of 36 genes and sequencing was carried out using the Illumina NGS technology. The presence of large genomic rearrangements (LGRs) was investigated by computational analysis and Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: A pathogenic variant was identified in 264 of 1197 individuals (22.1%) analyzed while a variant of uncertain significance (VUS) was identified in 34.8% of cases. Clinically significant variants were identified in 29 of the 36 genes analyzed. Concerning the mutation distribution among individuals with positive findings, 43.6% were located in the BRCA1/2 genes whereas 21.6, 19.9, and 15.0% in other high, moderate and low risk genes respectively. Notably, 25 of the 264 positive individuals (9.5%) carried clinically significant variants in two different genes and 6.1% had a LGR. CONCLUSIONS: In our cohort, analysis of all the genes in the panel allowed the identification of 4.3 and 8.1% additional pathogenic variants in other high or moderate/low risk genes, respectively, enabling personalized management decisions for these individuals and supporting the clinical significance of multigene panel analysis in hereditary cancer predisposition.

Ιmpact of sunitinib-induced hypothyroidism on survival of patients with metastatic renal cancer.

BACKGROUND: Sunitinib plays an important role in managing the metastatic renal cell cancer (mRCC). Sunitinib-induced hypothyroidism is a common side-effect of the drug. There have been attempts to link hypothyroidism with a better clinical outcome in sunitinib-treated (mRCC) patients. Our aim was to relate the impact of hypothyroidism to the survival of these patients. METHODS: We have evaluated 70 patients with mRCC that received sunitinib as a first line treatment. Thyroid-stimulating hormone (TSH) was measured at baseline, after 15 days of treatment (day-15) and at the end of the second cycle (day-75). Biomarker data and correlations with response were analysed with Microsoft Excel. Comparison results from Student's t-test with a p less than 0.05 were considered statistically significant. Kaplan-Meyer and log-rank tests were performed using GraphPad Prism 5 for Windows. RESULTS: Regarding the response to treatment, a progression-free survival (PFS) of 9.47 months and an overall survival (OS) of 22.03 months were demonstrated. Our data are consistent with published data by other authors. On day-15 from the beginning of the treatment an important number of patients exhibited a TSH elevation. On day-15 42.86% had a TSH over the upper normal limit and 50.0% at the end of the second cycle (day-75). TSH increased earlier in patients that exhibited an objective response (× 3.33 times the baseline values on day-15) than patients that exhibited disease stabilisation (× 2.18) or disease progression (× 1.59). Early increases in TSH were associated with a longer PFS (11.92 vs. 8.82 months, p = 0.0476) and a longer OS (3.10 vs. 1.08 years, p = 0.0011). CONCLUSIONS: Early TSH-increase is associated with a clinical benefit. The patients that showed at least a twofold increase of their baseline TSH, responded to therapy by stabilisation or by regression of disease. This is the only study to our knowledge which shows that early increases - 2 weeks from starting the treatment - in TSH levels have a prognostic value. Both PFS and OS of the patients who demonstrated a higher than a twofold rise were significantly longer than the PFS and the OS of the patients that presented a lower or no TSH-increase.

Axillary Lymph Node Tattooing and Targeted Axillary Dissection in Breast Cancer Patients Who Presented as cN+ Before Neoadjuvant Chemotherapy and Became cN0 After Treatment.

INTRODUCTION: Targeted axillary dissection (TAD) is an alternative to axillary dissection for breast cancer patients who presented as cN+ before neoadjuvant chemotherapy (NAC) and became cN0 after treatment. TAD is defined as the removal of sentinel lymph nodes (SLNs) along with the pre-NAC marked positive nodes. Tattooing is an option to mark positive nodes. In this study we aimed to investigate the identification rate of tattooed nodes during surgery, correspondence between tattooed nodes and SLNs, and difficulties and pitfalls of the method. PATIENTS AND METHODS: In 75 patients who were cN+, with axillary lymph nodes known to have or suspected to have disease were tattooed pre-NAC with a sterile carbon suspension (Spot). After NAC completion all patients became cN0 and underwent TAD as an axillary staging procedure. RESULTS: SLNs were identified successfully in 70 of 75 patients (93.3%). All tattooed nodes were identified successfully intraoperatively in 71 of 75 patients (94.6%). Retrieval of all tattooed nodes in surgical specimens was achieved in 74 patients (98.6%). Correspondence between tattooed nodes and SLNs was observed in 53 of 70 patients (75.3%). In 34 patients (45.3%) the number of pigmented nodes in pathological examination was greater than the number of initially tattooed nodes, indicating the possibility of tattoo ink migration. CONCLUSION: Tattoo of axillary lymph nodes is a feasible, accurate, and low-cost method of positive node marking pre-NAC. Pathological confirmation of black pigment in the lymph nodes excised is not by itself warranty of retrieval of all marked node because of tattoo ink migration from one node to another. Intraoperative identification using visual inspection is essential.

Real-world experience of everolimus as second-line treatment in metastatic renal cell cancer after failure of pazopanib.

AIM: We aimed to provide real-life data on the outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus as second-line treatment after failure of first-line pazopanib. PATIENTS AND METHODS: Data from the medical charts of mRCC patients from 8 centers in Greece and Spain were reviewed. All patients had received or were continuing to receive second-line everolimus treatment after failure of first-line treatment with pazopanib. No other previous therapies were allowed. The primary end point was the determination of progression-free survival (PFS). RESULTS: In total, 31 patients were enrolled. Of these, 26% had performance status (PS) >0, 88% were of intermediate/poor Memorial Sloan-Kettering Cancer Center (MSKCC) risk group, and only 61% had undergone prior nephrectomy. Median PFS was 3.48 months (95% CI: 2.37-5.06 months). Median overall survival (OS) from everolimus initiation was 8.9 months (95% CI: 6.47-13.14 months). Median OS from pazopanib initiation was 14.78 months (95% CI: 10.54-19.08 months). Furthermore, 32% of patients temporarily discontinued everolimus due to adverse events (AEs), and 22% of patients discontinued everolimus permanently due to toxicity. Most common toxicities were anemia (29%), stomatitis (26%), pneumonitis (19%), and fatigue (10%). Moreover, 14 AEs (27%) were graded as 3 or 4 and were reported by 13 patients (42%). CONCLUSION: This study provides data exclusively on the sequence pazopanib-everolimus in mRCC. Everolimus has a favorable safety profile and is active. The short PFS and OS could be attributed to the fact that the pazopanib-everolimus sequence was mainly offered to patients with adverse prognostic features, resulting in a modest increase in the combined OS of our population.

Palliation With Endoscopic Metal Stents May Be Preferable to Surgical Intervention for Patients With Obstructive Pancreatic Head Adenocarcinoma.

The aim of this study was to evaluate the efficacy of endoscopically placed metal stents in comparison with operative procedures, in patients with obstructive pancreatic head cancer. Endoscopic stenting techniques and materials for gastrointestinal malignancies are constantly improving. Despite this evolution, many still consider operative procedures to be the gold standard for palliation in patients with unresectable obstructive pancreatic head cancer. This is a retrospective study of 52 patients who were diagnosed with obstructive (biliary, duodenal, or both) adenocarcinoma of the pancreatic head. Twenty-nine patients (endoscopy group) underwent endoscopic stenting. Eleven patients (bypass group) underwent biliodigestive bypass. Twelve patients (Whipple group) underwent Whipple operation with curative intent; however, histopathology revealed R1 resection (palliative Whipple). T4 disease was identified in 13 (44.8%), 7 (63.6%), and 3 (25%) patients in the endoscopy, bypass, and Whipple groups, respectively. Metastatic disease was present only in the endoscopy group (n = 12; 41.3%). There was no intervention-related mortality. Median survival was 280 days [95% confidence interval (95% CI), 103, 456 days], 157 days (95% CI, 0, 411 days), and 647 days (95% CI, 300, 993 days) for the endoscopy, bypass, and Whipple groups, respectively (P = 0.111). In patients with obstructive pancreatic head cancer, endoscopic stenting may offer equally good palliation compared with surgical double bypass. The numerically (not statistically) better survival after palliative Whipple might be explained by the smaller tumor burden in this subgroup of patients and not by the superior efficacy of this operation.