Prognostic Value of Stromal Tumor-Infiltrating Lymphocytes in Young, Node-Negative, Triple-Negative Breast Cancer Patients Who Did Not Receive (neo)Adjuvant Systemic Therapy

PURPOSE: Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative (N0), young (< 40 years), and chemotherapy-naïve, and thus can be used for chemotherapy de-escalation strategies, is unknown. METHODS: We selected all patients with N0 TNBC diagnosed between 1989 and 2000 from a Dutch population-based registry. Patients were age < 40 years at diagnosis and had not received (neo)adjuvant systemic therapy, as was standard practice at the time. Formalin-fixed paraffin-embedded blocks were retrieved (PALGA: Dutch Pathology Registry), and a pathology review including sTILs was performed. Patients were categorized according to sTILs (< 30%, 30%-75%, and ≥ 75%). Multivariable Cox regression was performed for overall survival, with or without sTILs as a covariate. Cumulative incidence of distant metastasis or death was analyzed in a competing risk model, with second primary tumors as competing risk. RESULTS: sTILs were scored for 441 patients. High sTILs (≥ 75%; 21%) translated into an excellent prognosis with a 15-year cumulative incidence of a distant metastasis or death of only 2.1% (95% CI, 0 to 5.0), whereas low sTILs (< 30%; 52%) had an unfavorable prognosis with a 15-year cumulative incidence of a distant metastasis or death of 38.4% (32.1 to 44.6). In addition, every 10% increment of sTILs decreased the risk of death by 19% (adjusted hazard ratio: 0.81; 95% CI, 0.76 to 0.87), which are an independent predictor adding prognostic information to standard clinicopathologic variables (χ2 = 46.7, P < .001). CONCLUSION: Chemotherapy-naïve, young patients with N0 TNBC with high sTILs (≥ 75%) have an excellent long-term prognosis. Therefore, sTILs should be considered for prospective clinical trials investigating (neo)adjuvant chemotherapy de-escalation strategies

Homologous recombination deficiency and cyclin E1 amplification are correlated with immune cell infiltration and survival in high-grade serous ovarian cancer

Background: How molecular profiles are associated with tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC) is incompletely understood. Therefore, we analyzed the TME and molecular profiles of HGSOC and assessed their associations with overall survival (OS). Methods: Patients with advanced-stage HGSOC treated in three Dutch hospitals between 2008–2015 were included. Patient data were collected from medical records. BRCA1/2 mutation, BRCA1 promotor methylation analyses, and copy number variations were used to define molecular profiles. Immune cells were assessed with immunohistochemical staining. Results: 348 patients were categorized as BRCA mutation (BRCAm) (BRCAm or promotor methylation) (30%), non-BRCA mutated HRD (19%), Cyclin E1 (CCNE1)-amplification (13%), non-BRCAmut HRD and CCNE1-amplification (double classifier) (20%), and no specific molecular profile (NSMP) (18%). BRCAm showed highest immune cell densities and CCNE1-amplification lowest. BRCAm showed the most favorable OS (52.5 months), compared to non-BRCAmut HRD (41.0 months), CCNE1-amplification (28.0 months), double classifier (27.8 months), and NSMP (35.4 months). Higher immune cell densities showed a favorable OS compared to lower, also within the profiles. CD8+, CD20+, and CD103+ cells remained associated with OS in multivariable analysis. Conclusions: Molecular profiles and TME are associated with OS. TME differs per profile, with higher immune cell densities showing a favorable OS, even within the profiles. HGSOC does not reflect one entity but comprises different entities based on molecular profiles and TME

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.Peer reviewe

A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants:Application to BRCA1 and BRCA2

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.</p

Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI therapy results in short-lived and heterogeneous responses

Purpose: Next to secondary epidermal growth factor receptor (EGFR) mutations, cMET amplification plays an important role in mediating acquired resistance to EGFR tyrosine kinase inhibitors (TKI) treatment. Crizotinib, a dual ALK and cMET inhibitor, can induce responses in patients with EGFR mutation positive non-small cell lung cancer (NSCLC) that acquire cMET amplification after EGFR TKI treatment. However, little is known about the duration of response and post-progression resistance mechanisms. Here, we report on the clinical outcome of a series of patients with cMET-driven resistance to EGFR TKIs, treated with crizotinib. Materials and methods: Eight patients with EGFR mutation positive NSCLC that acquired cMET amplification after EGFR TKI treatment were treated with crizotinib 250 mg twice daily, as monotherapy (n = 2) or in combination with an EGFR TKI (n = 6). Results: Four out of eight patients (50%) showed a partial response (PR) according to RECIST 1.1. Median progression-free survival (PFS) was 1.4 (95% CI 1.2–5.0) months. Responses were short-lasting with a median PFS of 3.5 (95% CI 1.4–5.2) months in patients with a PR. Median overall survival was 5.9 (95% CI 1.3–6.0) months and not statistically different between responders and non-responders (p = 0.37). All but one patient tolerated crizotinib treatment well. Heterogeneous responses were seen in patients with progressive disease as best response with a marked size decrease of the biopsied (cMET amplification positive) lesion and progression of other lesions. cMET amplification was not always mutually exclusive with other EGFR TKI resistance mechanisms. Post-progression biopsies were negative for cMET amplification. Conclusion: Crizotinib treatment for patients with EGFR mutation positive NSCLC that acquire cMET amplification after EGFR TKI treatment results in short-lived and often heterogeneous responses, possibly due to subclonality of cMET-driven resistance and co-occurrence of other EGFR TKI resistance mechanisms

Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment

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Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months

Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)-mutated ovarian cancer refractory or resistant (<3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies. Patients and Methods Patients were treated with carboplatin (area under the curve, 5 mg/mL?min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression. Results AZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff. Conclusion To our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (<3 months) to first-line therapy warrants further development