Corrigendum: A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: a case report.

[This corrects the article DOI: 10.3389/fonc.2023.1102184.].

A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report.

The widespread adoption of gene panel testing for cancer predisposition is leading to the identification of an increasing number of individuals with clinically relevant allelic variants in two or more genes. The potential combined effect of these variants on cancer risks is mostly unknown, posing a serious problem for genetic counseling in these individuals and their relatives, in whom the variants may segregate singly or in combination. We report a female patient who developed triple-negative high grade carcinoma in the right breast at the age of 36 years. The patient underwent bilateral mastectomy followed by combined immunotherapy and chemotherapy (IMpassion030 clinical trial). Two years later she developed a skin recurrence on the right anterior chest wall. Despite intensive treatment, the patient died at 40-year-old due to disease progression. Gene panel testing of patient's DNA revealed the presence of a protein truncating variant in ATM [c.1672G>T; p.(Gly558Ter)] and of a not previously reported variant in the BRCA1 exon 22 donor splice site [c.5406+6T>C], whose clinical significance was unknown. The analysis of patient's RNA revealed the up-regulation of two alternative BRCA1 mRNA isoforms derived from skipping of exon 22 and of exons 22-23. The corresponding predicted protein products, p.(Asp1778GlyfsTer27) and p.(Asp1778_His1822del) are both expected to affect the BRCA1 C Terminus (BRCT) domain. The two variants were observed to co-occur also in the proband's brother who, in addition, was heterozygous for a common variant (c.4837A>G) mapped to BRCA1 exon 16. This allowed to ascertain, by transcript-specific amplification, the lack of functional mRNA isoforms expressed by the c.5406+6T>C allele and provided evidence to classify the BRCA1 variant as pathogenic, according to the guidelines of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium. To our knowledge, excluding two cases detected following the screening of population specific recurrent variants, only one ATM/BRCA1 double heterozygote has been reported in the literature, being the case here described the one with the youngest age at cancer onset. The systematic collection of cases with pathogenic variants in more than one cancer predisposition gene is needed to verify if they deserve ad hoc counseling and clinical management.

Prevalence and Spectrum of BRCA Germline Variants in Central Italian High Risk or Familial Breast/Ovarian Cancer Patients: A Monocentric Study.

Hereditary breast and ovarian cancers are mainly linked to variants in BRCA1/2 genes. Recently, data has shown that identification of BRCA variants has an immediate impact not only in cancer prevention but also in targeted therapeutic approaches. This prospective observational study characterized the overall germline BRCA variant and variant of uncertain significance (VUS) frequency and spectrum in individuals affected by breast (BC) or ovarian cancer (OC) and in healthy individuals at risk by sequencing the entire BRCA genes. Of the 363 probands analyzed, 50 (13.8%) were BRCA1/2 mutated, 28 (7.7%) at BRCA1 and 23 (6.3%) at BRCA2 gene. The variant c.5266dupC p.(Gln1756Profs) was the most frequent alteration, representing 21.4% of the BRCA1 variants and 12.0% of all variants identified. The variant c.6313delA p.(Ile2105Tyrfs) of BRCA2 was the most frequent alteration observed in 6 patients. Interestingly, two new variants were identified in BRCA2. In addition, 25 different VUS were identified; two were reported for the first time in BRCA1 and two in BRCA2. The number of triple-negative BCs was significantly higher in patients with the pathogenic BRCA1/2-variant (36.4%) than in BRCA1/2 VUS (16.0%) and BRCA1/2 wild-type patients (10.7%) (p < 0.001). Our study reveals that the overall frequency of BRCA germline variants in the selected high-risk Italian population is about 13.8%. We believe that our results could have significant implications for preventive strategies for unaffected BRCA-carriers and effective targeted treatments such as PARP inhibitors for patients with BC or OC.

Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVES: Brain metastases are common among patients with non-squamous non-small-cell lung cancer (NSCLC) and result in a poor prognosis. Consequently, such patients are often excluded from clinical trials. In Italy an expanded access program (EAP) was used to evaluate nivolumab efficacy and safety in this subpopulation outside a clinical trial. MATERIALS AND METHODS: In this EAP, nivolumab was available for patients with non-squamous NSCLC in progression after at least one systemic treatment for stage IIIB/IV disease. Nivolumab 3 mg/kg was administered intravenously every 2 weeks. Patients with brain metastases could be included if they were asymptomatic, neurologically stable and either off corticosteroids or on a stable or decreasing dose of ≤10 mg/day prednisone. RESULTS: 409 out of 1588 patients included had asymptomatic or controlled brain metastases. A median of 7 doses (range 1-45) were delivered. Median follow-up was 6.1 months (range 0.1-21.9). The disease control rate was 39%: 4 patients had a complete response, 64 a partial response and 96 showed stable disease. At baseline, 118 patients were on corticosteroids and 74 were undergoing concomitant radiotherapy. The median overall survival in this subpopulation was 8.6 months (95% CI: 6.4-10.8). 337 discontinued treatment for various reasons, 23 (7%) of whom due to adverse events, in line with that observed in the overall population and in previous studies. CONCLUSIONS: Our results confirm that nivolumab is active in non-squamous NSCLC patients with brain metastases, despite their poor prognosis. Its safety profile is also concordant with results in the EAP overall population and in patients with other malignancies.

Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.

BACKGROUND: Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase). METHODS: We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay. RESULTS: Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy. ical; CheckMate 227 ClinicalTrials.gov number, NCT02477826 .). CONCLUSIONS: Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceut

Influence of chemotherapeutic drug-related gene polymorphisms on toxicity and survival of early breast cancer patients receiving adjuvant chemotherapy.

BACKGROUND: We investigated whether GSTT1 ("null" allele), GSTM1 ("null"allele), GSTP1 (A313G), RFC1 (G80A), MTHFR (C677T), TS (2R/3R) polymorphisms were associated with toxicity and survival in patients with early breast cancer (EBC) treated with adjuvant chemotherapy (CT). METHODS: This prospective trial included patients with stage I-III BC subjected to CT with CMF or FEC regimens. PCR-RFLP was performed for MTHFR, RFC1 and GSTP1, while PCR for TS, GSTT1 and GSTM1 genes. RESULTS: Among the 244 patients consecutively enrolled, 48.7% were treated with FEC and 51.3% with CMF. Patients with TS2R/3R genotype showed less frequently severe neutropenia (G3/G4) than those with TS2R/2R and 3R/3R genotype (p = 0.038). Patients with MTHFRCT genotype had a higher probability of developing severe neutropenia than those with MTHFR CC genotype (p = 0.043). Patients with RFC1GG or GSTT1-null genotype or their combination (GSTT1-null/RFC1GG) were significantly associated with a shorter disease free survival (DFS) (p = 0.009, p = 0.053, p = 0.003, respectively) and overall survival (OS) (p = 0.036, p = 0.015, p = 0.005, respectively). Multivariate analysis confirmed the association of RFC1GG genotype with a shorter DFS (p = 0.018) and of GSTT1-null genotype of a worse OS (p = 0.003), as well as for the combined genotypes GSTT1-null/RFC1GG, (DFS: p = 0.004 and OS: p = 0.003). CONCLUSIONS: Our data suggest that TS2R/2R and 3R/3R or MTHFR CT genotypes have a potential role in identifying patients with greater risk of toxicity to CMF/FEC and that RFC1 GG and GSTT1-null genotypes alone or in combination could be important markers in predicting clinical outcome in EBC patients.

First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.

BACKGROUND: Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC. METHODS: We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more. RESULTS: Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. CONCLUSIONS: Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).

The safety of nivolumab for the treatment of advanced non-small cell lung cancer.

INTRODUCTION: Immune checkpoint blockaders (ICBs) act by unbalancing the immune system, thus favoring the development of an immune-mediated antitumor effect. ICBs targeting the programmed cell death receptor-1 (PD-1) have recently been investigated in a number of advanced tumors, including non-small cell lung cancer (NSCLC). Nivolumab, a fully human IgG4 kappa directed against PD-1, has been the first ICB to be approved for second-line treatment of advanced NSCLC. Areas covered: In this review we focus on the clinical development of nivolumab for the treatment of advanced NSCLC, with an emphasis on its safety profile. In addition, we summarize the most common types of immune-related adverse events (irAEs) associated with nivolumab, mainly due to organ inflammation secondary to autoimmunity. Expert opinion: Nivolumab is the preferred treatment option for platinum-pretreated advanced NSCLC, having convincingly shown higher efficacy compared with standard docetaxel chemotherapy in phase III trials. The same trials showed far less incidence of either any grade and severe treatment-related AEs with nivolumab compared with chemotherapy. IrAEs associated with nivolumab are rarely severe in intensity, and often resolve with prompt management. Future studies will explore nivolumab in combination strategies with either platinum-based chemotherapy or other ICBs in treatment-naïve advanced NSCLC patients.

Enteric-type adenocarcinoma of the lung harbouring a novel KRAS Q22K mutation with concomitant KRAS polysomy: a case report.

This case describes a novel KRAS Q22K mutation with simultaneous KRAS polysomy in a patient with advanced, enteric-type, adenocarcinoma of the lung. Despite the administration of systemic chemotherapy, the disease underwent rapid progression and led to the patient's death in a short period of time. Such an aggressive clinical course suggests that, in this specific case, KRAS dependency was the major genetic driver of poor prognosis. Direct deoxy ribonucleic acid (DNA) sequencing of the KRAS gene allows for the detection of novel KRAS mutations, and it might be advocated in patients with advanced non-small cell lung cancer in view of the emerging role of KRAS as a potential therapeutic target.

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.

BACKGROUND: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. INTERPRETATION: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. FUNDING: Bristol-Myers Squibb.